Shillfactor

2012-01-22T16:27:00.001-05:00

What the new drug & device maker payments to physicians disclosure rules do & do not solve—and what their unintended consequences might be

Appearing on WNYC's weekly news magazine On The Media this weekend, Pro Publica's "Dollars for Docs" rabble rousers Charles Ornstein and Tracy Weber note that Nurse Practitioners (NPs) and Physician Assistants (PAs) are likely to reap something of a windfall of new attention on the part of drug & device makers as the new Dollars to Docs reporting rules go into effect, as the legislation says nothing about Dollars to NPs and PAs.

They also observe that the problems of third-party funded Continuing Medical Education and (something else: I have to re-listen to program) are not addressed by the legislation.

So progress, perhaps great progress (we'll see how searchable and user friendly the database is...), but still a ways to go.

2012-01-22T15:59:00.002-05:00

What the new drug & device maker payments to physicians disclosure rules do & do not solve—and what their unintended consequences might be

They also observe that the problems of third-party funded Continuing Medical Education and (something else: I have to re-listen to program) are not addressed by the legislation.

So progress, perhaps great progress (we'll see how searchable and user friendly the database is...), but still a ways to go.

2010-10-19T14:28:00.001-04:00

2010-08-15T01:53:00.004-04:00

DoJ Takes on Big Pharma Corruption

Financial Times reported this over the weekend. No other major news outlet has picked it up from what I can tell. (Wait, CNN Money added something on the "double standard" of allowing companies to bribe docs in US but not abroad. Says investigation is narrowly focused on just this.)

The US Department of Justice is scrutinising payments by leading pharmaceuticals companies for hospitality, consultants, licensing agreements and charitable donations in markets around the world as part of a wide-ranging corruption probe.

GlaxoSmithKline, Pfizer, Bristol-Myers Squibb and Eli Lilly, among others, have disclosed being contacted by the DoJ and Securities and Exchange Commission in connection with the investigation. Merck, the US drugs group, announced last week that it had also been contacted and was co-operating with investigators.

EDITOR’S CHOICE

FT Science: The importance of design - Jun-04

Drug groups hit by ruling on incentives - Apr-23

AstraZeneca faces $520m Seroquel fine - Apr-28

EU steps up drug groups’ probe - Jan-12

An industry attorney familiar with the probe said that the DoJ was looking at whether pharma companies had ignored a “systematic risk” inherent in the global drugs business and ignored obligations under local and US anti-bribery law

2010-03-30T05:23:00.002-04:00

Underreported: Physician Payments Sunshine Act is now the law of the land!!

Today, the Sunshine Act became law, as a provision in the national health care reform bill signed by President Obama. You can read the final provisions here.

Though it has not captured headlines like the coverage provisions and insurance regulations in the reform bill have, today’s passage of the Sunshine act is itself a dramatic answer to years of growing questions about how to balance the need for industry to work with academic researchers and the need to keep patients safe with good prescribing that is free from the influence of marketing. In recent years, that line has often proved a blurry one, as a series of investigations and media reports revealed that physicians have received millions of undisclosed dollars in speaking and advisory roles for drug companies, even as they conducted research on drugs made by those companies.

Full text from Postscript blog of Community Catalyst

2010-03-21T05:33:00.002-04:00

Very cool American Medical Students Association PharmaFree Scorecard

Looks like the AMSA took a tip from our 2006 poster at International AIDS Conference in Toronto and came up with this, well EXCELLENT, scorecard for medical schools' policies on industry influence and disclosure.

2009-10-24T00:10:00.008-04:00

Drug Makers Are Patient Advocacy Groups' Biggest Donors

Iowa Senator encourages other patient groups to publicly disclose the extent of their pharmaceutical income

Gardiner Harris for The New York Times (10/22/09)

Hmm... why does this all sound like some big déjà vû?

The close ties between the alliance and drug makers were on stark display last week, when the organization held its annual gala at the Andrew W. Mellon Auditorium on Constitution Avenue in Washington. Tickets were $300 each. Before a dinner of roasted red bell pepper soup, beef tenderloin and tilapia, Dr. Stephen F, president of the alliance’s board, thanked Bristol-Myers Squibb, the pharmaceutical company.

“For the past five years, Bristol-Myers has sponsored this dinner at the highest level,” Dr. F said.

He then introduced Dr. Fred G, chief of antiviral research at Bristol-Myers, who told the audience that “now, more than ever, our enduring relationship with the AIDS foundation must remain strong.”

Documents obtained by The New York Times show that drug makers have over the years given the HIV health alliance — along with millions of dollars in donations — direct advice about how to advocate forcefully for issues that affect industry profits. The documents show, for example, that the alliance’s leaders, including Mr. F, met with Gilead sales executives on Dec. 16, 2003.

Slides from a presentation delivered by the salesmen show that the company urged the alliance to resist state efforts to limit access to HIV drugs.

“Solutions: Play Hard Ball,” one slide was titled. “Hold policy makers accountable for their decisions in media and in election,” it continued.

The alliance’s own slides concluded by saying, “We appreciate Gilead’s strong support of our work.”

Mr. F said that the alliance frequently had such meetings and that the organization would fight for better access to mental health drugs “even if we had no relationship with pharmaceutical companies.”

...

Drug makers are natural allies in these pursuits since cures may come out of corporate laboratories and the industry’s money can help finance public service campaigns and fund-raising dinners. But industry critics have long derided some patient organizations as little more than front groups devoted to lobbying on issues that affect industry profits, and few have come under more scrutiny for industry ties than the mental health alliance.

Last spring, Senator Charles E. Grassley, Republican of Iowa, sent letters to the alliance and about a dozen other influential disease and patient advocacy organizations asking about their ties to drug and device makers. The request was part of his investigation into the drug industry’s influence on the practice of medicine.

Mr. Grassley’s scrutiny has been unnerving for patient and disease advocacy groups, which are often filled with sincere people who are either afflicted with serious illnesses themselves or have family members who have been affected. Many join the groups in the hope of making sense of their misfortune by helping to find a cure or raising awareness of a disease’s risks and frequency.

The mental health alliance, which is hugely influential in many state capitols, has refused for years to disclose specifics of its fund-raising, saying the details were private.

But according to investigators in Mr. Grassley’s office and documents obtained by The New York Times, drug makers from 2006 to 2008 contributed nearly $23 million to the alliance, about three-quarters of its donations.

Even the group’s executive director, Michael F, said in an interview that the drug companies’ donations were excessive and that things would change.

“For at least the years of ’07, ’08 and ’09, the percentage of money from pharma has been higher than we have wanted it to be,” Mr. F said.

He promised that the industry’s share of the organization’s fund-raising would drop “significantly” next year.

“I understand that our patient research and advocacy group gets painted as being in the pockets of pharmaceutical companies, and somehow that all we care about is pharmaceuticals,” Mr. F said. “It’s simply not true.”

Mr. F said Senator Grassley’s scrutiny, which he described as understandable given the attention paid to potential conflicts of interest in medicine, had led his organization to begin posting on its Web site the names of companies that donate $5,000 or more. And he predicted that other patient and disease advocacy groups would be prodded by Mr. Grassley’s investigation to do the same.

“Everyone I talk to wants to have more balanced fund-raising,” Mr. F said.

In a statement, Mr. Grassley praised the alliance for its disclosures. “It’d be good for the system for other patient groups to do what NAMI has done,” he said.

...

For years, the alliance has fought states’ legislative efforts to limit doctors’ freedom to prescribe drugs, no matter how expensive, to treat mental illness in patients who rely on government health care programs like Medicaid. Some of these medicines routinely top the list of the most expensive drugs that states buy for their poorest patients.

Mr. Fitzpatrick defended these lobbying efforts, saying they were just one of many the organization routinely undertook.

2009-10-21T18:05:00.003-04:00

Thai ALVAC-AIDSVax study published in NEJM this week.

From accompanying editorial (Raphael Dolin):

"The most important contribution of the study ismost likely the opportunity to investigate possible host-responsecorrelates of protection against infection. The establishmentof such correlates is the central question in HIV vaccine developmentand will have a profound effect on the designs of vaccines andclinical trials to assess their efficacy.

Given the lack ofdetection of conventional immune responses in earlier studiesof these vaccine components, as well as the divergence betweenthe vaccine's effect on the infection and the effect on viralload, the correlates of protection may, indeed, reflect newconcepts of host response. This should be the focus of intenseresearch using the most current research techniques. Ultimately,it is the results of such studies that will most likely determinethe significance of this clinical trial to the field of HIVvaccine development."

2009-10-01T00:55:00.001-04:00

Kudos to Dr. Bob Siliciano and his Hopkins team for their persistence in pursuing this reservoirs issue

(Even if it is said that top retrovirologists view the eradication grail as unlikely ever to succeed)

Journal of Clinical Investigation (10/01/09)

From the Discussion section:

"Because of the high cost and potential toxicities of long-term HAART and the disappointing results from the clinical trials of HIV-1 vaccines and microbicides, there is still a pressing need for pursuing the goal of eradication.

To cure HIV-1 infection is exceptionally challenging and will likely require combining HAART with agents that can purge latent virus.

The identification of 5-hydroxynaphthalene-1,4-dione (5HN) not only expands the number of classes of latency-reversing agents but also demonstrates the possibility of utilizing pathway(s) further downstream of TCR stimulation to avoid global T cell activation.

Although the toxicities of 5HN raise concerns for its clinical application, this is a proof of concept for this approach to finding novel strategies to reactivate latent HIV-1 without inducing global T cell activation."

2009-09-04T16:45:00.008-04:00

Can we start a HAART heart attack/stroke counter bulletin board somewhere public?

In the past 2 weeks alone I have heard of a 30-year guy (HIV+ on ARV therapy for many years) drop dead of a heart attack (myocardial infarction in the biz)-- in Utah no less-- and then just now, a very good friend of mine is being admitted to St. Luke's-Roosevelt after having suffered a light stroke (cerebrovascular accident).

I would need the hands and feet of an octopus to count all the other cases I have heard of--and this is just friends and friends of friends--over the past couple of years.

Yes, the debate about "Is it the 'chronic inflammation' caused by HIV itself or is it the drugs?" can continue on ad infinitum, but the truth is that people are dropping like flies. (Okay, not flies exactly, but suddenly and inexplicably and all too frequently!) And, let me tell you, it's not the LTNPs or those who took destiny in their own hands and have done on again/off again ARV rx to limit the long-term effects of these otherwise 'life-saving' medicines. (Totally unscientific conjecture here, I realize, but I will provide data to support it ASAP.) No, it's the folks who believed that all they had to do was start taking meds, take them with religious devotion, and everything would be alright. Their "chronic, manageable illness" would be managed and their life expectancy would be miraculously returned to normal.

My rant for the afternoon. But I am scared and angry.

2009-08-20T12:06:00.007-04:00

New York Times hits 2 key issues, in B1 cover page stories, 2 days back to back:

The problems with clinical practice guidelines: Turns out one size doesn't (and never did) fit all. And the problem is only compounded by tainted panel members

"Diabetes Case Shows Pitfalls of Treatment Rules"

by Barry Meier

The epidemic of ghostwritten medical 'research' papers in esteemed medical journals continues unabated

"Ghosts in the Journals"

by Natasha Singer

Friend, mentor and comrade in arms, Dr. Joe Sonnabend, has been ahead of the curve on this clinical practice guidelines nonsense, as he has been on most everything, for a long time now. It's a shame nobody seems to listen. Check out Joe's new Poz blog. I hope people everywhere will read (and heed) it!!

2009-08-11T18:17:00.010-04:00

Which comes first? The wrists & ankles snapping like kiln-dried twigs? Or the early mid-life, out-of-the-blue stroke & heart attack?

(I have heard of two new heart attacks, friends of friends in their early 40s, in just the past month. And yet another friend dropped to the sidewalk unconscious in Tribeca last summer after suffering a stroke. He is not even 40!! He had blacked out, didn't know who or where he was -- and still cannot speak properly or use his right hand.)

Someone really has to find a better way to manage this infection or, at the very least, help us to protect ourselves against all these nasty side effects.

Where have all the community-based research institutes and amFARs (oh, sorry, Amfar recently dropped the 'Am' in order to reposition itself to tap into the boondoggle of international HIV/AIDS funding and recently re-branded itself the "Foundation for AIDS Research" aka FAR) gone??

We all know the answer: picking the low-hanging fruit (big reward for only somnambulant effort) by signing up for Big Pharma "me too" trials that any lobotomized blind monkey could do with one hand tied behind her back.

Where are the activists?

2009-08-11T17:34:00.009-04:00

Loss of Bone Mineral Density After Antiretroviral Therapy Initiation "Independent of Antiretroviral Regimen"

Source: JAIDS, August 2009 - Volume 51 - Issue 5 - pp 554-56

Free abstract here.

From Conclusion: "Similar decreases in BMD over 96 weeks occurred in ART-naive subjects receiving either EFV-based regimen or LPV/r-based regimen, which was not altered by simplification to LPV/r monotherapy and was unrelated to markers of tumor necrosis factor-α activity."

Comment: But if, as many of my smartest and longest serving HIV care providers believe & observe in their (very large) practices, the biggest CULPRIT here (in terms of loss of BMD) is TENOFOVIR (as in Viread, Truvada, Atripla), this study's conclusions are not all that helpful-- as both PI and NNRTI based regimens are very likely to have included TDF+FTC (or TDF+3TC). Still, we cannot be certain until we have seen the full paper or spoken with the investigators. -MB

See also: AIDS 17-July-09 editorial, "Metabolic Bone Disease in HIV Infection"

Decreased bone mineral density with off-label use of tenofovir in children and adolescents infected with HIV-1. J Pediatr. 2008 Apr; 152(4):582-4. (link)

Clinical Trial: Bone Mineral Density Substudy - An Ancillary Study to MTN-003 (link)

from AIDSmeds.com: "Viread may cause bone problems. In one clinical trial conducted by the manufacturer involving HIV-positive patients who were new to HIV therapy, Viread [combined with Sustiva and Epivir] caused decreases bone in mineral density (osteopenia) at the hip and spine."

Clinical Trial: Switch From Tenofovir to Raltegravir for Low Bone Mineral Density (link)

from aidsinfonet.org: "Tenofovir can reduce bone mineral density (see fact sheet 557). Calcium or vitamin D supplements may be helpful. This is especially true for people with osteopenia or osteoporosis." and "Use of tenofovir can also result in a loss of bone mineral." (link)

and finally, from my heroes at aidsmap.co.uk: "Vitamin D supplementation may help with tenofovir-related bone hormone deficiency" (link)

2009-07-17T17:30:00.001-04:00

Unprotected sex between HIV-infected partners keeps immune responses activated

Source: Crabb, C et al. AIDS: 17 July 2009 - Volume 23 - Issue 11 - p N7

2009-07-10T13:50:00.003-04:00

NEW LIFE FOR TREATMENT INTERRUPTIONS

(No question mark in my version.)

David Evans and Tim Horn did a FANTASTIC job on this follow-up investigation of newly revealed wrinkles in the oh-so-sloppy 'SMART' study of CD4-guided ARV treatment. Congrats, guys. And can we have a little (more) Truth Squad-ing in Cape Town next week?

(Now if we could only help LOTTI and Staccato get the PR budgets and KOL dinner circuit blast that SMART had...)

As one of my HIV doc heroes wrote to me in an email last week:

"Having directly taken care of hundreds of HIV-infected people--maybe even into the thousands--I can say without hesitation that some form of intermittent treatment strategy must be worked out."

"There may be--and almost certainly are--people who will NOT be able to do this, but I know that many can--and have done so for more than about 12 years now. Some even having had prior opportunistic infections, such as cryptococcal meningitis."

But let's also be careful not to ignore the enormous amount of work that went into SMART. For all its defects (and there are many), Wafaa and Jim and the other co-investigators (33 countries participated even if all but 6 of the deaths occurred in the U.S., mostly because non-U.S. didn't start enrolling patients until 2 years after U.S. sites started enrolling. And because U.S. study participants tended to have alot more complicated medical histories...) should be congratulated for overseeing such a monumentally large and dispersed undertaking.

That said, one must also take into consideration the absolutely HUGE amount of money at stake here. The cost savings from the Italian intermittent treatment study (Franco Maggiolo et al., published in the April '09 issue of AIDS)--9 Euros per day vs. 20 Euros per day--gives does idea of how large the loss of revenues to Big Pharma would be.

IF ONLY HALF OF HIV-ERS COULD ADOPT AN INTERMITTENT TREATMENT STRATEGY, IT COULD COST GILEAD, TO CITE JUST THE MOST OBVIOUS EXAMPLE, SOMETHING LIKE $500 MILLION ANNUALLY IN LOST SALES.

FOR THE TOP FIVE COMPANIES WITH HIV BRANDS, WE ARE TALKING OF A COMBINED LOSS OF SALES IN THE NEIGHBORHOOD OF $1.5 BILLION.

(E-mail me if you would like to discuss data & assumptions that went into the calculations: mbarr@atawatch.org)

Even if intermittent treatment means a THIRD of the time off drugs, that is a big loss. And my experience of patients who have done intermittent treatment for years is that is is closer to HALF of time OFF DRUGS. So it is unlikely that Wafaa or anyone else, or his or her own, would have any power to stop the endless spin and publication and fear-mongering and pseudo-scientific extrapolation of the SMART study results. All this has been done by the marketing departments of the big drug makers--defending against erosion of sales.

2009-06-16T10:07:00.005-04:00

Genetic Immunity completes enrollment in Phase II monotherapy trial of ARV "naïves"

Genetic Immunity, a US/Hungarian biopharmaceutical company, has completed patient enrollment in its Phase II randomized, placebo-controlled, multi-center study to evaluate the safety, tolerability, immunogenicity, and antiretroviral activity of DermaVir patch in treatment-naive HIV-1-infected patients.

This Hamburg study is especially important (and interesting) because it is the first to look at DermaVir's effect in HIV-infected persons who are not taking antiretroviral medicines.

The study is conducted in Hamburg, Germany with a total of 36 patients. The primary outcome of this Phase II study measures safety and tolerability of DermaVir patch, while secondary outcome includes HIV-1 RNA measurements to assess the antiretroviral activity of the DermaVir patch, changes in CD4+, CD8+ T-cell counts and HIV-specific immunogenicity during DermaVir patch treatment.

The study randomized patients into one of six groups: three will receive escalating doses of the DermaVir patch, and three will receive placebo patch. The patch sites for immunization are preferably the left or right upper back and left or right upper inner thighs. The patch immunizations last for three hours.

The immunizations will be administered every six weeks (Day 0, Day 42, Day 84, Day 126) for a period of 18 weeks.

Julianna Lisziewicz, CEO of Genetic Immunity, said: "We are very happy with completion of patient enrollment in this seminal trial because it allows us to conclude the immunization schedule in 2009. With this trial we plan to demonstrate the safety and efficacy of DermaVir patch as monotherapy administered every six weeks for the treatment of HIV."

2009-06-16T01:13:00.001-04:00

Collaboration of World Health Authorities Launches Effort to Tackle Heart Disease & Diabetes Worldwide

A newly launched collaboration of world health authorities, working under the name Global Alliance for Chronic Diseases, was announced yesterday, with the aim of addressing research & prevention efforts for non-communicable chronic diseases (primarily cardiovascular disease and adult onset ("type-2") diabetes).

Read the Alliance's 06/15 press release.

Andrew Jack, reporting for the Financial Times, adds:

The council will provide £6m over five years as part of plans to spend up to $70m through the Global Alliance for Chronic Diseases, which also includes state medical research funders from the US, Canada, Australia and China, set to be joined by India and the World Health Organisation.

The action comes at a time of growing debate over the need to focus more attention and resources on chronic diseases such as diabetes and cardiovascular problems, which are among the world’s leading killers.

While billions of dollars have been channelled in recent years by governments and philanthropists into infectious diseases such as HIV and malaria, non-communicable ones are coming to dominate even in poorer countries such as India and China.

“It’s absolutely right that there is a big emphasis on Aids but 36m people are dying each year from non-communicable disease,” said Sir Leszek Borysiewicz, head of the council. “Prevention has to be at the forefront.”

Initial funding will focus on testing how to prevent cardiovascular diseases and complications of diabetes; identifying and promoting public health measures for controlling obesity; understanding chronic obstructive airways disease linked to smoking and pollution; and research into the links between tobacco and cancer and cardiovascular disorders.

The action follows research in recent years highlighting a mismatch between funding and the diseases that have the most impact around the world, with chronic non-communicable diseases now accounting for 60 per cent of global deaths, four-fifths in low- and middle-income countries.

It comes as other organisations are also beginning to step up support for chronic disease in poor countries, including UnitedHealthcare, the US-based insurer that has opened a series of institutions in developing countries.

Its chronic disease initiative is to receive most of a $34m grant from the US National Heart Lung and Blood Institute to open collaborating centres in Bangladesh, China, India, South Africa and in Latin America.

“Unless we make chronic disease prevention a worldwide priority, the personal, social, economic and political consequences will reverberate throughout the globe,” said Simon Stevens, executive vice-president at UnitedHealth. “The time has come to increase resources to counter the pandemic of chronic disease sweeping through low- and middle-income countries.”

The alliance members are the Australia’s National Health Medical Research Council, the Canadian Institutes of Health Research, China’s Ministry of Health in association with the Chinese Academy of Medical Sciences, the UK Medical Research Council and the US National Institutes of Health, specifically its National Heart, Lung, and Blood Institute and the Fogarty International Center. The Indian Council of Medical Research, New Delhi, is set to join.

2009-06-14T09:23:00.001-04:00

New Evidence that Antibodies Produced by Some People Infected with HIV-1 Can Neutralize Diverse HIV-1 Isolates

NEW YORK (Scott Baltic for Reuters Health) Jun 18 - Several recent studies showing that antibodies produced by some people infected with HIV-1 can neutralize diverse HIV-1 isolates provide new insights into the viral epitopes targeted by such broadly reactive neutralizing antibodies (NAbs). This information in turn has the potential to guide development of better antibody-based vaccines for HIV-1.

These conclusions are from a commentary by U.S. and South African researchers published online by Nature Medicine on June 14.

"To the surprise of many," Dr. Leonidas Stamatatos, of the Seattle Biomedical Research Institute and the University of Washington, told Reuters Health, "it appears that a significant proportion of those who become infected with HIV develop the type of anti-HIV responses we want a vaccine to elicit. So now we know it is feasible to do this."

"Nature knows how to do it," he added, "and we need to find the best way to mimic nature."

Dr. Stamatatos and his colleagues point out that numerous attempts over the past two decades to develop an improved antibody-based vaccine immunogen for HIV-1 had only limited success. The immunogens did elicit NAbs, but only to a small proportion of circulating HIV-1 strains. Studying the cross-NAb responses seen during natural HIV-1 infection, the authors note, could give "vital clues for the design of immunogens able to elicit broadly neutralizing antibodies that will surely form an important part of an optimal vaccine."

The authors focused on four papers reported this year and last in the Journal of Virology. These studies indicate that broadly cross-reactive NAb responses arise over a period of years and are fostered by chronic antigen exposure. One possible explanation for this is that B cells might gradually focus on less immunogenic but more highly conserved regions of the HIV-1 envelope glycoprotein.

"Progress may occur in small steps," the authors concluded, "but with an improved understanding of Env (viral envelope glycoprotein) structure and of B cell responses to Env, it should be possible to design a vaccine strategy that reproduces the optimal NAb response generated during natural HIV-1 infection."

2009-06-09T13:28:00.006-04:00

How Medscape HIV's reliance on pharma causes it to miss the news & information of greatest interest to people with HIV and the people who care for (and love) them

When will they learn?
Then again, if Medscape weren't just a front and conduit for pharma messaging, how would it pay the bills? And what purpose would there be for its existence?

Look at the Medscape HIV headlines ("pushed content" (aka pharma pays a premium to have these headlines placed here) this week:

Vaginal Rings Release Multiple Anti-HIV Drugs
Combination ART Reduces PML Risk, Mortality in Patients With HIV
Anal HPV Infection Increases Risk of Homosexual HIV Acquisition
Early vs Deferred Antiretroviral Therapy May Reduce AIDS Progression and Death

Now look at the headlines from AIDSmap--and even AIDSmeds, which is doing a better job lately of serving patients. AIDSmap headlines:

Mortality amongst HIV-positive women in US has plateaued: treatable illnesses contributing to many deaths
Ongoing viral replication during HIV treatment associated with lymphoma risk
Should we spare the nukes? NRTI HIV drugs may impair success of hepatitis treatment
Hepatitis B hasn't gone away--and may come back
'Shock and kill' approach awakens latent HIV in test tube
Pooled procurement may not deliver lower ARV prices
High viral load and low CD4 cell count risk factors for non-HIV-related illnesses

Not trying to sell you anything. Not trying to scare you. Not trying to make you forget that the drugs for life model is not the only way to think of HIV infection. Just good old thoughful, useful information that folks can use. Kudos Keith et al.

Now let's look at AIDSmed.com (slash Poz):

New hope for HIV eradication
Crystal meth use might increase lymphoma risk
Tesamoreline for lipodystrophy approval application
Higher HIV levels increase lymphoma risk

Again, not ONE of these stories makes it onto the Medscape (pharma sponsored) HIV/AIDS News. So my question: why even use the site?? I say that these shills on their HIV Advisory Board should either demand reform or resign in protest. Yes, that's you:

John G. Bartlett (Dr. Bartlett, you've soiled the reputation of medicine and medical education even as you purport (and profess) to uphold its integrity.)
Pedro Cahn (no comment)
Andrew Carr (you make the Lancet look bad by lending your name to such commercially crash content)
Cal Cohen (well, everyone expects this from you, but why not show them you can change?)
Brian Conway (no comment)
Henry Masur (Henry, frankly I'm surprised by your presence here)
Julio Montaner (no surprises there)
Graeme Moyle (shill of shills)
Paul Sax (Paul, I wish I understood what motivated you; you seem like such a good guy)
Jonathon Shapiro (no surprise here)
Robert Shafer (no comment)
Vincent Soriano (no comment)
Mark Wainberg (never saw a microphone he didn't have to harangue into)

2009-05-30T13:10:00.009-04:00

Harvard Medical School's Dr. Paul Sax, peripatetic pharma speakers bureau devoté and frequent contributor to Medscape HIV content, seems not to appreciate the informed nuance of more seasoned, science minded & circumspect clinicians such as Dr. Joe Sonnabend. Here's how he sums up the messages/findings/implications of the (conflicting) NA-ACCORD and UK retrospective cohort "When To Start" studies for a recent issue of Journal Watch/AIDS Clinical Care, and featured on the Medscape/HIV site:

"Although the two research groups reach different conclusions about the precise threshold for when to start therapy, they are consistent in the most important message — that treatment should be started before the CD4 count falls below 350 cells/mm3, and perhaps earlier."

And just, perhaps, to get that extra oomph with the AIDS Inc. KOLs and their pharma benefactors (who, let us have no doubt, largely determine the course of succession to the throne), he adds this little gratuitous flourish:

"The NA-ACCORD data are particularly striking and are even stronger than those presented at the 2009 Retrovirus Conference."

ShillFactor thought it would be interesting (and let's face it, only fair-minded) to give the Good Doctor himself an opportunity to elucidate his thought process for us--as well as the chance to enlighten us as to how his longtime membership on on the pharma dinner lecture circuit† (described by even ostensibly objective medical professionals as Marketing Lectures and, a bit more cattily, as Trained Monkey for Hire) might or might not color his thinking, consciously or subconsciously.

Let's see what he has to say.
(Or ask him yourself and let us know: psax@partners.org)
Stay tuned.

† Currently limited to just five--Abbott, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck--although the only company missing with products typically prescribed for 1st- or 2nd-line antiretroviral therapy is Tibotec/JNJ. Maybe he feared he was spreading himself a bit thin??
N.B. For a look into Dr. Sax's relationship with Virco/JNJ and Visionary Health Concepts, you might also want to have a look at this site Resist-HIV.info, where he holds down the pharma fort with co-luminaries Joseph J. Eron, Jr. (Speakers Bureau member for BMS, Gilead, Roche, Virco) Dan Kuritzkes (Too big for the Speakers Bureau hoi polloi but receives à la carte (and surely larger) speaking fees from Abbott, Anormed, Avex, Bayer, Boehringer Ingelheim, BMS, Gilead, GSK, Huma Genome Sciences, Merck, Monogram, Panacos, Pfizer, Roche/Trimeris and Schering), and Rodger MacArthur (Speakers Bureau member for Abbott, Gilead, GSK, Pfizer, Roche, Virco).

2009-05-30T09:29:00.002-04:00

"Setting a fixed CD4 threshold for starting ARV therapy distracts attention from patient-specific and multifactorial aspects of HIV disease progression* and would be a mistake"

*Apart from individuals with advanced disease and CD4 numbers below 200 per μL, for whom information from prospective randomised trials provides guidance

Kudos to Dr. Joe Sonnabend for getting his duly wise and measured letter published in this week's Lancet:

Threshold for starting antiretroviral therapy: should there be one?

Robin Wood and Stephen Lawn (April 18, p 1314)1 ask whether the CD4 threshold for starting antiretroviral therapy should be raised. Apart from individuals with advanced disease and CD4 numbers below 200 per μL, for whom information from prospective randomised trials provides guidance, we really do not know when it is best for any HIV-infected individual to start treatment. All agree that only prospective randomised studies will give us reliable information on this question.

However, as long as recommendations are made on the basis of retrospective studies, and the provisional nature of the recommendations not stressed, it will probably be impossible to enrol and complete such randomised studies. My own experience in helping to set up a “when to start” trial with zidovudine in the early 1990s indicated that, at least in New York City, USA, physicians and sometimes patients found it difficult to admit that the best time to start was unknown, and so they sadly declined to accept the toss of a coin as a means of finding out.

Such studies (if they can ever be completed) can only tell us if, on average, it is better to start treatment early or to defer it. Yet the rate of progression of HIV disease varies widely from patient to patient. It is therefore probably quite mistaken to set a standard CD4 threshold for
starting treatment (with the exception of individuals with CD4 numbers less than 200 per μL).
Setting a fixed CD4 threshold distracts attention from the many factors known to affect the course of the disease, some of which might themselves be appropriate therapeutic targets.

Treatment initiation needs to take into account the rate of disease progression in any individual. To do so might not be possible with any precision, and certainly might add to the costs of care. However, for many asymptomatic individuals, a period of observation over 6—9 months or longer will probably provide sufficient information to obtain a reasonable, if imperfect, idea of the rate of disease progression.

Joseph Sonnabend. MD
30 Hamilton Terrace
London NW8 9UG, UK

References

1 Wood R, Lawn S. Should the CD4 threshold for starting ART be raised?. Lancet 2009; 373: 1314-1316. Full Text | PDF(56KB) | CrossRef | PubMed

2009-05-13T08:20:00.001-04:00

Key Challenges and Issues facing the VIRxSYS Corporation - Strategic Analysis Review

New report (for purchase)

VIRxSYS Corporation - Strategic Analysis Review

Summary

The VIRxSYS Corporation (VIRxSYS) is a privately held biotechnology company principally engaged in the development of gene based therapies using its proprietary lentiviral vector-based delivery system. The technology developed by the company is used to develop treatments HIV, AIDS, anti-cancer therapies and other various life-threatening diseases. It is headquartered in Maryland, United States.

2009-04-29T00:58:00.004-04:00

IOM Report Calls for End to Pharma Funding of Continuing Medical Education

Calling the current system of financing for medical refresher courses "unacceptable," the prestigious Institute of Medicine panel, widely regarded as the ultimate arbiter in matters of U.S. scientific research and medical policy, echoed and strengthened criticisms of the Association of American Medical Colleges one year ago, calling for a new system to replace the current CME within two years.

In the most "damning" indictment yet of pharma meddling in the practice of medicine, the panel called for Congress to pass the Physicians Payments Sunshine Act of Senators Charles Grassley, Herb Kohl et al. as well as to "end a number of long-accepted relationships and practices that create conflicts of interest, threaten the integrity of their missions and their reputations, and put public trust in [doctors in] jeopardy.

The report was issued yesterday and can be partially viewed here.

(Printable document files (.pdf's) of most of these articles and reports are also available for free download at the ATA Watch and ShillFactor sites.)

Gardiner Harris of The New York Times, who has tirelessly reported on these issues over the past five years, filed his report today, noting that "Drug companies spend billions of dollars wooing doctors — more than they spend on research or consumer advertising. Much of this money is spent on giving doctors free drug samples, free food, free medical refresher courses and payments for marketing lectures. The institute’s report recommends that nearly all of these efforts END."

Harris reports that drug and device makers provide about half of the financing for so-called Continuing Medical Education (CME) courses, so that doctors can often take them without charge. (I suspect the number is closer to 75 or even 85%.)

Another tireless crusader for an end to pharma meddling in medical education, former New England Journal of Medicine editor Dr. Marcia Angell, has long observed that medicine is one of the few professions where practitioners are not required to pay for their own continuing professional development; in contrast to, for example, accountants or lawyers, and one of the very few professions where these kinds of cozy relationships between the providers and arbiters of goods (in contrast to, for example, journalists and the subject of their reporting or judges and the subject of their jurisdiction) would be allowed and have been tolerated--indeed prospered--for so long.

While many universities and medical societies have made highly publicized moves to toughen their policies regarding the nexus of physician activity and pharma funding over the past year, most of the proposed changes consisted of nothing more than damage control, perception and nipping around the edges--without much in the way any substantial reform. That could now suddenly change.

“With the I.O.M.’s endorsement, issues that were once controversial now are indisputable,” said Dr. David Rothman, president of the Institute on Medicine as a Profession at Columbia University. “Conflicts of interest in medicine are no longer acceptable.”

2009-04-27T12:16:00.004-04:00

What's An Industry Shill To Do Now?: Implications of Hopkins' New Policy for Financial Relationships between Doctors and Drug Makers

(tks to Tracy Staton of FiercePharma.com: "Hopkins Puts Screws on Industry")

Yet another medical school is distancing itself from industry influence. This time, it's Johns Hopkins Medical School, whose new policy on "Interaction with Industry" will ban gifts and meals from drugmakers--and limit its doctors' speaking and consulting deals with pharma, too.

Taking effect July 1, the policy prohibits any pharma-funded gifts and entertainment, no matter how small their value. Drug reps will be restricted to no-patients-allowed parts of the teaching hospital and its clinics--and will be allowed even in those areas only by invitation. And beginning in 2010, the school will also bar free drug samples.

Doctors won't be able to collect consulting pay unless it comes with "commensurate associated duties." They can only serve as paid speakers if the company has no right to dictate a presentation's content and if the company has no final approval over the content. And any donations from industry have to be given to the hospital as a whole, rather than to individual doctors. Drugmakers won't be allowed to sponsor department meetings, retreats or social events, either.

"Industry plays a crucial role in advancing medical research and treatments, and the intent is not to discourage principled partnerships," Julie Gottlieb, assistant dean, said in a statement. "The major reason for developing this policy is to limit the impact of industry marketing influence on faculty and physicians' decision making and by so doing protect patients."

2009-04-20T22:47:00.003-04:00

Can Activist Groups and AIDS Foundations Financed with Pharma Cash Be Effective Advocates for Drug-Free Living--Or A Cure?

Read it in "Keeping Watch," Frontiers magazine

2009-04-18T16:03:00.005-04:00

The Glaxo-Pfizer HIV Union: Will Pooling Troubles Hydrate Their Wilted Brands?

I just started scouring the web this weekend for some intelligent (or honest) reporting of the shotgun marriage of Pfizer's and GSK's HIV units late this week. A friend emailed me Friday, all atwitter with great expectations for the innovative R&D possibilities from combining two of the biggest names in the business. I don't know how to break the news to him. This, above all else, is clearly a defensive move, designed to stem losses and cut costs wherever possible.

Both company's have been plagued with non-stop bad news for their marquée HIV products over the past couple of years (much of it covered in entries on this blog: search abacavir (Ziagen), maraviroc (Selzentry) or Merit, D:A:D, SMART).

Sales of GSK's abacavir and fixed-dose co-formulations that contain it (Epzicom/Kivexa and Trizivir) have plunged faster and farther than GM's stock price (also reported in a post below somewhere). The world's second-largest drugmaker even surprised investors in February when it declined to provide a specific outlook for 2009, saying that it planned to focus on "long-term strategic priorities." Meantime, Pfizer's 2007 launch of Selzentry (Celsentri in Europe) has been the biggest disappointment in the antiretroviral history books since Trimeris-Roche flung Fuzeon upon us in 2003.

Not so long ago, Roche announced that it was pulling out of the HIV drug development market—the observation of which offers the opportunity to make an essential point here. While it is easy to be flippant about this latest marriage of convenience (spokespersons for the companies say the union will allow for cost savings of nearly $100M annually beginning in 2011), it would probably not be in the best interest of people with HIV/AIDS were either of the comprometid@s to follow Abbott and Roche in a race to the exit.

That said, it is also far from clear that either company's business plan includes an honest desire to improve the lives of people living with HIV--as opposed to merely more cold calculus scheming to milk the market by keeping them just shy of alive and on as many meds, as early and for as long as possible. I for one personally challenge them to demonstrate a genuine interest in curing this disease. (And I dare say that Rahm Emanuel is with me on this one...) And of course the same goes for current market leaders Gilead, BMS, Abbott and peripatetic new entry Tibotec (wholly owned subsidiary of Johnson & Johnson).

I'll see what John James, Keith Alcorn (or anyone else at the Aidsmap.com team) or maybe the lamentably tight-tethered Richard Jefferys might have written about this. Comment and analysis, anyone? Or hey, perhaps even Tim Horn (excellent reporting & analysis of this, I just discovered, btw, at poz.com!!) or some of the cooler, less constrained by their addiction to the mega deep-pocketed pharma dope pushers, HIV docs. Stay tuned. (And, of course, let us know if you find any good reading on this issue.)

The jointly run company, which has yet to be named, is expected to be formally launched later this year.

2009-04-09T19:18:00.012-04:00

The "Earlier Treatment" Wagons Circle

But who are the puppeteers pulling their strings?
Or do they simply know what issues to promote in order to advance their careers?

First came a dribble on the part of Johns Hopkins' epi maven Dr. Richard Moore, at last autumn's joint ICAAC/IDSA confab in D.C. The halls were abuzz with news of his late-breaker presentation showing that starting ARV therapy between 350 and 500 CD4s was vastly superior (70% improved survival) to waiting for the currently indicated 350 threshold.

Then U Washington's Mari Kitahata, unseemly flirtatious with the odious John Mellors at a Feb. '09 CROI press conference, went for the slam dump in Montréal. As promised, the NA-ACCORD team had extended their analysis to include people who started rx even above 500 CD4s. Kitahata & Moore's unsurprising conclusion? That HIV-pozzes who waited until the 350 threshold to start ARV therapy incurred a sixty percent increased risk of death than those who started at a CD4 cell count >500.

(By contrast, the poor UK chap who dared to question Kitahata's wannabe Iron Clad argument for starting rx at 500+ CD4s, also at the lectern with his own cohort study at the 2009 CROI, somehow never made it into the predominantly pharma funded HIV info sites: aidsmeds.com, poz.com, medscape.com, thebody.com, thebodypro.com, clinicaloptions.com, hivandhepatitis.com and others.)

The Moore/Kitahata NA-ACCORD study was published this week in the New England Journal of Medicine.

Thanks to the efforts of previous NEJM editors (notably the husband wife team of Arnold Relman and Marcia Angell--not to mention Jerome Kassirer), a 15-line paragraph of financial conflicts-of-interest appears at the end of the NEJM paper:

Dr. Saag receives consulting fees from the following (16) drug & diagnostic companies:
Ardea Biosciences
Avexa
Boehringer Ingelheim (maker of Viramune and Aptivus)
Bristol-Myers Squibb (maker of Sustiva and Reyataz, marketer of Atripla, maker of Videx, Zerit)
Gilead Sciences (maker of Truvada, Viread, Emtriva and Atripla; also has an integrase in final stages of development)
GlaxoSmithKline (maker of Combivir, Epzicom, Kivexa, Lexiva, Retrovir, Epivir, Trizivir)
Merck (maker of Isentress)
Monogram Biosciences (maker of drug resistance assays)
Pain Therapeutics
Panacos (has two maturation inhibitors in clinical development)
Pfizer (maker of Selzentry/Celsentri and Viracept)
Progenics
Roche Laboratories (maker of Fuzeon and Invirase)
Tibotec (maker of Prezista and Intelence, also has another drug in late stage development)
TobiraTherapeutics
Virco (maker of drug resistance assays)

Dr. Saag receives research support from the following (10) drug companies:
AchillionPharmaceuticals
Avexa
Boehringer Ingelheim
GlaxoSmithKline
Merck
Panacos
Pfizer
Progenics
Theratechnologies
Tibotec

Dr. Hogg receives support from:
Merck

Dr. Deeks receivesconsulting fees from:
GlaxoSmithKline
Roche
Gilead
BoehringerIngelheim

Dr Deeks receives grant support (which in the case of Dr. Deeks--good guy that he is--is probably a net positive) from:
Merck
Gilead
Bristol-MyersSquibb
Pfizer

Dr. Eron (head of the federally funded AIDS Clinical Trials Group research network, no less!!) receives consulting fees from:
Tibotec
Bristol-Myers Squibb
Merck
GlaxoSmithKline
Pfizer

Dr. Eron receives speaking fees from:
Roche
Bristol-Myers Squibb
Tibotec
Merck

Dr. Eron receives grant support from:
GlaxoSmithKline
Merck
BoehringerIngelheim

Dr. Gill receives consulting fees from:
Gilead
GlaxoSmithKline
Abbott
Merck
Boehringer Ingelheim
Tibotec
Pfizer

Dr. Gill receives grant support from:
GlaxoSmithKline
Abbott
Tibotec
Pfizer

Dr. Klein receives consulting fees from:
GlaxoSmithKline
Abbott
Pfizer
Boehringer Ingelheim

Dr. Klein receives speaking fees from:
Abbott
Gilead
Tibotec
Bristol-Myers Squibb
GlaxoSmithKline

Dr. Klein receives research support from:
Canadian HIV Trials Network (which appears to receive pharmaceutical funding)
Ontario HIV Treatment Network (which may or may not receive funding from drug & diagnostics companies)
Schering-Plough Canada

Dr.Rodriguez receives consulting fees from:
Gilead
Bristol-MyersSquibb

Dr. Rodriguez receives speaking fees from:
Bristol-Myers Squibb

Dr. Rodriguez receives grant supportfrom:
The STERIS Corporation (?)

Dr. Rachlis receives consulting fees from:
GlaxoSmithKline
Abbott
Merck
Pfizer
Bristol-Myers Squibb
Gilead
Tibotec

Dr. Rachlis receives speaking feesfrom:
GlaxoSmithKline
Abbott
Merck
Pfizer
Bristol-Myers Squibb
Gilead
Tibotec

Dr. Rachlis receives grant support from:
GlaxoSmithKline
Tibotec
Boehringer Ingelheim
Abbott
Merck
Pfizer
Roche

Dr. Horberg receives grant support from:
Gilead,
Abbott
Bristol-Myers Squibb

Dr. Silverberg receives grant supportfrom:
Pfizer
Merck
Gilead
the Universitywide AIDS ResearchProgram
the Community Benefit/Kaiser Permanente

Dr. Gebo receives consulting fees from:
Tibotec

Dr. Gebo receives grant support from:
the Johns Hopkins University Richard Ross Award

Dr. Bensonreceives consulting fees from:
GlaxoSmithKline
Pfizer
Merck
Achillion

Dr. Bensonreceives grant support from:
Gilead

Dr. Collier receivesconsulting fees from:
Merck
Pfizer
GlaxoSmithKline

Dr. Collier receivesgrant support from:
Schering-Plough
Tibotec-Virco
Gilead
Koronis
Merck

Dr. Collier owns stock or stock options in:
Bristol-Myers Squibb
Abbott

Dr. Moore receives consulting fees from:
Bristol-MyersSquibb
GlaxoSmithKline

Dr. Moore receives speaking fees from:
Gilead

Dr. Moore receives grantsupport from:
Pfizer
Merck
Gilead

There are tons of holes in the NA-ACCORD study, a few graciously acknowledged by both Dr. Kitahata (at CROI) and even Dr. Gallant (that the people most likely to volunteer to start ARV therapy earlier than was medically indicated are/were likely to be highly motivated, highly health conscious, highly adherent to complex medical regimens, and very likely to have had access to top quality medical care) in his interview with Bonnie. But for the most part they all accept that the study is based on sound methods and analysis.

Would that it were.

For starters, many of the folks who officially started ARV therapy in the "early starters" NA-ACCORD group later actually went off therapy--sometimes for years at a time, but were still counted among the early starters for purposes of the study.

And conversely, as Drs. Paul Sax and Lindsey Bingham point out in an accompanying NEJM editorial, nearly 45% of folks in each CD4 group of NA-ACCORD either never started treatment or never experienced a fall in their CD4 cell count. How would the results have turned out if these folks had been included in the analysis? There is no way to know.

Finally, there is no way of knowing how many of Gallant's "easy to take and well-tolerated" triple or quadruple drug combos these folks would have burned through during the extra years on treatment. That is, would they only have developed cross-class (or even MDR) resistance earlier in the course of their infection--and then been left with only the likes of horrific treatments like Fuzeon and kitchen sink "mega-HAART" combos when they most needed help?

And in an exchange reminiscent of an 1987 Poz interview between one G. Vidal and L. Kramer, colorfully described at the time, if memory serves, as "two old dogs licking each others' privates", a conversation on TheBodyPro between Body chieftess Bonnie Goldman and Hopkins' every-pharma-firm's-favorite shill, peripatetic Joel Gallant, includes the following absurd pandering on the part of Gallant:

"HIV is unique in that the burden of proof seems to rest on those who want to treat early. Whereas for another infectious disease, you'd say, 'Show me that I can wait. Show me that it's safe to wait.' We're at the point now where we've got this disease that's quite easily treatable with very effective treatment. I'm trying to think of some other infectious disease where you would have to prove that it was OK to treat."

With all due respect, Lord Gallant, but other than perhaps chronic HBV infection, what other infectious disease requires lifelong treatment with 3+ (very powerful and not exactly innocuous) medicines? You wanna take these drugs for 40, 50--or 70 years? Be my guest.

With credit to Medscape chronicler Fran Lohry (and/or newly beefed up editorial standards), she adds this little footnote to the Reuters wire:

"The When To Start Consortium authors disclosed financial relationships with the following: GlaxoSmithKline, Gilead Sciences, Abbott, Bristol-Myers Squibb, Roche, Boehringer-Ingelheim, Tibotec, Oxon Therapeutics, Merck, Pfizer, Aventis, Schering-Plough, Achillion Pharmacuetica, Panacos, Progenics, Serono, Avexa, Monogram Biosciences, and Virco. Dr. Wood and Dr. Lawn have disclosed no relevant financial relationships."

Kudos again to Keith Alcorn and his colleagues at Aidsmap.com for giving this story the degree of thought and analysis it deserves. Link to it here.

Two very large cohort studies published this month both agree: antiretroviral treatment should not be delayed after the CD4 count falls below 350. However, the two studies, previously presented at international conferences, show contradictory evidence on whether starting treatment before the CD4 count falls below 500 has an additional benefit.

Editorials accompanying both publications agree that the only way the field of HIV treatment will reach a definitive conclusion on the question of when to start antiretroviral treatment will be by carrying out a large randomised trial of immediate versus deferred treatment.

In the New England Journal of Medicine Dr Paul Sax and Dr Lindsey Bingham argue that patients who started treatment early in the late 1990s were “the ideal patients: highly adherent, committed to doing whatever they could to prevent AIDS and willing to push through the sometimes punishing side effects and drug regimen burdens of the early therapies.” This may have biased the result of the NA-ACCORD study, and its effect could only be ruled out in a large randomised study.

They also note that almost 45% of patients in each stratum in the NA-ACCORD dataset either did not start treatment or did not experience a decline in their CD4 count, and so were not included in the analysis. Would antiretroviral treatment have benefited this group? We have no way of knowing, note Drs. Sax and Bingham. In addition, we don’t know what effect earlier treatment has on the development of resistance or subsequent treatment options.

2009-04-08T10:37:00.003-04:00

HIV discoverer says vaccine therapy for HIV could be developed in "four to five years"

Professor Luc Montaigner, who shared the Nobel Prize with Françoise Barré-Sinoussi for their discovery of the HIV virus in 1983, said in an interview that, unlike a preventive vaccine, "we know exactly what we have to do" to develop a therapeutic vaccine for persons already infected with HIV, and that "we can already demonstrate efficacy in a small number of patients."

"My projects in Europe suffered from the fact that they were refused in Europe," he explained Wednesday at a conference on biomedical research organized by the European Parliament. "At the time if was considered unethical to stop [antiretroviral therapy] to test the [immune boosting] power" of a vaccine therapy. "That idea, however, is beginning to strike home, particularly in the United States."

Source: www.europarl.europa.eu

2009-03-12T23:25:00.009-04:00

From the journals this week:

1) "The Challenge of Finding a Cure for HIV Infection"
Doug D. Richman et al. in Science

2) "Medical Professionals for Sale?"
L. Thomas in Lancet

3) What Not To Deduce from STEP Study
Aaron M White (Duke University) in Lancet

4) Drawing the Wrong Conclusions from STEP Study Failure?
Angus Dalgleish and Justin Stebbing in Lancet

5) STEP Study authors respond

The Challenge of Finding a Cure for HIV Infection
Douglas D. Richman,1* David M. Margolis,2 Martin Delaney†,3 Warner C. Greene,4 Daria Hazuda,5 Roger J. Pomerantz6

Although combination therapy for HIV infection represents a triumph for modern medicine, chronic suppressive therapy is required to contain persistent infection in reservoirs such as latently infected CD4+ lymphocytes and cells of the macrophage-monocyte lineage. Despite its success, chronic suppressive therapy is limited by its cost, the requirement of lifelong adherence, and the unknown effects of long-term treatment. This review discusses our current understanding of suppressive antiretroviral therapy, the latent viral reservoir, and the needs for and challenges of attacking this reservoir to achieve a cure.

1 San Diego VA Healthcare System and University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093–0679, USA.
2 Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
3 Project Inform, 1375 Mission Street, San Francisco, CA 94103, USA.
4 Gladstone Institute of Virology and Immunology, San Francisco, CA 94158, and University of California at San Francisco, San Francisco, CA 94143, USA.
5 Merck and Co., West Point, PA 19486, USA.
6 Tibotec Pharmaceuticals Inc. and Johnson and Johnson Corporation, 1020 Stony Hill Road, Suite 300, Yardley, PA 19067, USA.

†Deceased 23 January 2009.
* To whom correspondence should be addressed. E-mail: drichman@ucsd.edu

Highly active antiretroviral therapy (HAART) for the chronic suppression of HIV replication has been the major accomplishment in HIV/AIDS medicine (1, 2). Many patients are now in their second decade of treatment, with levels of plasma HIV RNA below the limits of detection of clinical assays. The impact on morbidity and mortality in the developed world has led to efforts that have brought this therapy to nearly three million people in resource-limited settings (3). Many patients are now enjoying a life-style little encumbered by symptoms or the side effects of medications, many of which require only once-daily administration. With the remarkable success of chronic suppression, why propose curing HIV infection—a challenging objective that requires potentially risky interventions and that may be unachievable?

Can We Do Better Than HAART?
HAART is no panacea. Current treatments must be maintained for life, with treatment interruption resulting in the rapid rebound of replicating virus. Although drug resistance can emerge because of the challenges of maintaining adherence and access to chronic antiviral therapy or owing to transmitted drug-resistant viruses, the success of HAART has been improved by the development of more potent and more tolerable therapies. Successful new drug development may not continue indefinitely, however, and HAART may never reach the majority of infected individuals in less-developed countries. Despite the prolonged suppression of HIV replication below the standard limits of detection for patients on HAART, ongoing viremia can be detected at levels of 1 to 50 copies per milliliter in the majority of patients (4, 5). The origin of this viremia has not been fully characterized, but it does not appear to jeopardize the prolonged success of therapy in the adherent patient (6). Nevertheless, the virions may engage CD4 and chemokine receptors and may activate pathways that could lead to chronic consequences, including cardiovascular and malignant disease. The suboptimal penetration of many antiretrovirals into the central nervous system may also permit low levels of viral replication and/or release from stable viral reservoirs, resulting in neuropathology (7, 8).

Despite the very low rates of toxicity of many of the newer HAART regimens, many of these drugs modulate lipid and glucose metabolism (9). Even modest toxicities may have cumulative effects over decades of treatment. Moreover, prolonged treatment may reveal toxicities not appreciable with animal toxicology or several years of clinical surveillance. There is already growing concern about increased rates of heart disease, diabetes, liver disease, and many forms of cancer in aging HIV-infected patients who are receiving treatment (10–13). Whether these are because of long-term HIV infection, therapeutic drug treatment, or both, is uncertain. Finally, the cost of HAART may be too much to sustain treatments on a global scale, as millions are affected.

Given the shortcomings of HAART, time-limited interventions that do not result in the resumption of viremia are a desirable but a currently unattainable objective, unlike what can be achieved with the treatment of hepatitis C virus infection. Such therapy might or might not eliminate every functional virion or infected cell, but would permit the discontinuation of HAART without the reappearance of viremia and disease. We propose that a drug-free remission should be the new goal of HIV therapeutics.

What Is the State of HIV in Successfully Treated Patients?
The source of the low-level viremia seen in most patients on HAART (4, 14, 15) may be incompletely characterized, but we do have some hints (Table 1). The failure, thus far, of treatment intensification to clear this viremia (16) and the lack of evidence for nucleotide sequence evolution over long periods of treatment (17–19) indicate that this phenomenon may not be driven by ongoing rounds of replication.

Patient data reveal that 1 in 106 CD4+ T cells are latently infected with HIV, despite the durable suppression of detectable plasma viremia, although the frequency can be much lower in some patients (20–22). In vivo, it is thought that these cells are intermittently activated by antigen recognition or as bystanders in a local inflammatory process, which leads to the release of progeny virions.

Another source of virion production, which does not require ongoing replication, is the episodic production of HIV by long-lived cells. In situ hybridization of lymphoid tissue in simian immunodeficiency virus (SIV)–infected macaques and HIV-infected humans revealed that, in addition to the activated and infected CD4+ T cells that produce large numbers of virions with a short cellular half-life, many lymphocytes can be visualized that produce small amounts of viral RNA, yet do not display markers of activation (23). Such cells are not seen in vitro, and whether such cells occur in vivo during prolonged antiretroviral therapy is unknown. Further, the life span of and the kinetics of viral expression in such cells remain undefined.

Low-level plasma viremia cannot always be linked to activation of latently infected CD4+ T cells. In a longitudinal analysis of cloned RNA from plasma-derived virions of a subset of HAART-suppressed patients, the Siliciano group identified distinctive homogeneous viral subpopulations (24). These observations raise the possibility of a chronically infected clonal reservoir, analogous to a persistently infected stem cell. How a persistently infected cell population could produce virions at a steady state for years, in the presence of some level of cell-mediated immunity, remains unexplained. Other cellular or tissue sources of virus, such as cells of the monocyte and macrophage lineages, may also contribute to low levels of viremia.

Can Mechanisms That Drive Latency Be Therapeutically Exploited?
Activation from latency to completion of the replication cycle should result in lytic cell death of CD4+ T cells. Multiple mechanisms may contribute to the maintenance of proviral latency [reviewed in Williams and Greene (25)], and so, combination approaches could be required to eradicate infection (Fig. 1 and 2). Such strategies would depend on current or future antiretroviral therapy to completely inhibit all new infection events. Antilatency agents would be given, intermittently and for a limited period of time, to purge the last sanctuaries of HIV infection (Fig. 3).

Chromatin remodeling enzymes like histone deacetylases (HDACs) play a critical role in HIV latency (Fig. 1A) (26–29). HDACs are recruited to the highly conserved initiator region of the HIV promoter by several distinct complexes, by means of factors that are both ubiquitous in cell types infected by HIV and also participate in basal and activated viral gene expression. The existence of multiple mechanisms that recruit repressive HDAC complexes to the proviral promoter raises the possibility that HDAC inhibitors might lead to the activation of HIV in latently infected cells (Fig. 2).

In addition to HDACs, HIV expression is limited by other cellular barriers to effective mRNA transcription, which the virus overcomes through the action of its own activator, Tat. Tat recruits the positive transcription elongation factor b (P-TEFb) kinase to the integrated viral promoter, inducing viral gene expression (Fig. 1B and C) (30). Several kinase agonists, including hexamethylbisacetamide (HMBA)—a compound previously tested in human cancer trials (31), activate intracellular signaling cascades that mobilize P-TEFb in the absence of Tat (32, 33) and can induce the expression of HIV in latently infected cells (Fig. 2) (34).

The HIV promoter responds to coactivators that are abundant in activated cells, but, in the context of the resting T cell, inadequate nuclear levels of nuclear factor B (NF-B) and nuclear factor of activated T cells (NFAT) may contribute to the establishment of latency (Fig. 1B) (35). Diminished binding could be the result of changes in chromatin structure, in part mediated by the action of HDACs. Prostratin, a nontumorigenic phorbol ester isolated from the Samoan medicinal plant, Homalanthus nutans, induces HIV expression in latently infected cell lines and cells isolated from HIV-infected, HAART-treated patients in the absence of cellular proliferation (36). In cell-line models, prostratin stimulates HIV expression through protein kinase C–mediated activation of NF-B and so provides an approach to activation and clearance of latently infected cells (Fig. 2) (37).

HIV mRNA export may also be impaired in resting T cells because of the low levels of polypyrimidine tract–binding protein (PTB) available in resting cells (Fig. 1D) (38). MicroRNAs (miRNAs) endogenously expressed in human cells may further impede HIV mRNA expression or translation (Fig. 1E) (39, 40). If such mechanisms contribute to proviral persistence, entirely new classes of therapeutic agents able to safely alter host RNA expression or transport will be required.

Given the intimacy of the interaction between the retrovirus and the host cell, therapeutic approaches that disrupt latent infection are also likely to affect host cell function. Although mild host toxicities for limited periods of time might be acceptable, global immune activation must be avoided. Once quiescent virus is successfully induced to complete a round of replication, virus-induced cytolysis and cytotoxic T cells need to be able to clear HIV antigen–expressing cells. The viral progeny generated by such activated cells have to be prevented from successfully infecting other cells by the presence of HAART (Fig. 2).

How Are Interventions to Be Investigated?
Undoubtedly, there are other factors that regulate latency occurring in primary cells in vivo. Although we need to be aware of the potential for additional reservoirs of infectious virus, addressing the latently infected T cell reservoir may be the most direct way of exposing an even smaller additional reservoir, like infected macrophages, or anatomic compartments, such as the central nervous system, that may be suboptimally exposed to HAART. Careful in vivo testing of therapeutic agents capable of antagonizing the different mechanisms underlying HIV latency identified in CD4+ T cells is important for establishing the proof of concept.

An animal model is not required for antiretroviral drug development because, thus far, activity in vitro has correlated with activity in vivo. In contrast, an animal model could be invaluable in the development and testing of antilatency therapies and would guide clinical trial design. Given the excellent outcomes of HAART, initial studies of new antilatency therapies in humans might be difficult to design and execute, because volunteers in such early studies may have little to gain, and the candidate interventions will have unproven efficacies and uncertain toxicities. SIV infection in the rhesus macaque gives rise to latent infections in CD4+ T cells that mirror HIV latency (41), although it remains unknown whether the pathways and molecular targets promoting postintegration latency in macaques are the same as in humans.

BLT (bone marrow-liver-thymus) mice provide a second animal model. These immunodeficient mice (which lack endogenous T and B cells) are transplanted with human thymus and liver tissue and injected with hematopoietic stem cells, giving rise to systemic repopulation with human T and B cells, monocytes-macrophages, and dendritic cells capable of antibody production, activation by human antigen-presenting cells, and potent human major histocompatibility complex–restricted T cell immune responses (42). BLT mice have already been used to study HIV transmission and to test preexposure antiretroviral prophylaxis (43). Determining whether this model can be used to study HIV latency is a high experimental priority. Despite the availability of animal models for preliminary testing, clinical studies in HIV-infected patients are ultimately required. Phase I trials to deplete persistent HIV infection have demonstrated that these approaches can be tested safely (44–46), and studies using novel inducers of HIV expression such as interleukin 7 (47) may soon be feasible (Figs. 2 and 3).

Quantifying the latent HIV reservoir in humans is challenging when less than 1 in a million CD4+ T cells are latently infected, and there are approximately 100 copies of integrated provirus for each latently infected CD4+ T cell (48). After amplification by the polymerase chain reaction, measurements of integrated proviral DNA might serve as a surrogate marker for changes in the latent reservoir (18). However, the small size of the reservoir and the imprecision of current assays require improved techniques to assess the effectiveness of interventions. Moreover, once the reservoir is reduced by 10- to 100-fold, the remaining latently infected cells may be concealed below the limit of detection of any assay yet described.

Access to lymphoid tissue or most anatomic compartments in otherwise healthy subjects is difficult. Although such studies may fail to detect an infected reservoir, they cannot prove its eradication. When an intervention or combination of interventions is considered sufficiently compelling, the ultimate test of efficacy will be the withdrawal of HAART. Antiretroviral therapy is effective and relatively safe. As a result, the administration of any experimental intervention in either a proof-of-concept feasibility trial or in a trial incorporating treatment interruption raises significant ethical, regulatory and study design issues, because antiretroviral therapy is so effective and relatively safe. Therefore, involvement of various stakeholders in thoughtful deliberations is necessary. Such studies are required if we wish to cure HIV; but, although the potential benefit to humanity is great, the benefit to the early trial volunteers is nearly nonexistent. The appropriate volunteers in a trial involving treatment interruption might be those who initiated HAART before significant immune depletion. This criterion would minimize risk of treatment interruption, especially with close monitoring to resume treatment should virus replication be detected. A second rationale for selecting such subjects is that their infected-cell reservoir may be smaller and thus more amenable to intervention (18, 49).

Do We Need a New Approach to Develop a Cure?
The recent disappointing results from the trials of HIV vaccine and microbicide candidates have prompted a renewed commitment to basic research to identify effective approaches to these critically needed prevention strategies. We advocate a similar impetus for new approaches to purge the latent reservoir in order to cure HIV infection.

Years of effort have led to public health strategies to reduce the risk of cancer, a vaccine that prevents cervical cancer, better therapies to treat malignancies, and curative therapies for some cancers. Such a multifaceted approach should also be applied to the effort to cure HIV infection. This will require behavioral and biological tools to prevent HIV infection; safe, affordable, and nontoxic therapies for initial control of HIV infection; and new interventions that can achieve a drug-free remission of viremia in some patients.

The challenge of developing an HIV vaccine spans the need for new basic research insights to product development to clinical trials. The complexity of fostering and coordinating these efforts has led to the creation of major NIH intramural (Vaccine Research Center) and extramural (Center for HIV/AIDS Immunology) programs and of an international, multi-institutional effort (The Global HIV Vaccine Enterprise). Our understanding of HIV latency has chiefly resulted from independent, investigator-initiated efforts. In order to translate these academic accomplishments into clinical treatments similar initiatives are required. Antilatency therapies will require the drug discovery capabilities of industry, like high-throughput drug candidate screening; medicinal chemistry; product synthesis, production, and formulation; toxicology; and pharmacology. A coordinated initiative involving academia, industry, government, and patient advocates could greatly accelerate the identification of potential interventions and their clinical assessment (Fig. 4). We conceive an initiative, termed here a collaboratory, in which the government contributes funding, regulatory oversight, and coordination; industry contributes funding, drug discovery, technology, and expertise; and academia contributes ideas and investigative capacity. Long-term support for a flexible, collaborative public-private joint venture might improve efficiency and conserve resources, while at the same time catalyzing progress that no single group could achieve. Clearly much work and many challenges lie ahead, but if novel scientific insights can be brought to bear in clinically effective ways, the era marked by the benefits of HAART may be followed by one in which HAART is no longer a lifelong necessity.

References and Notes
1. F. J. Palella Jr. et al., N. Engl. J. Med. 338, 853 (1998).[Abstract/Free Full Text]
2. R. P. Walensky et al., J. Infect. Dis. 194, 11 (2006). [CrossRef] [ISI] [Medline]
3. World Health Organization, Towards Universal Access: Scaling Up Priority HIV/AIDS Interventions in the Health Sector: Progress Report 2008 (World Health Organization, Geneva, June 2008); www.who.int/hiv/mediacentre/2008progressreport/en/index.html.
4. G. Dornadula et al., JAMA 282, 1627 (1999).[Abstract/Free Full Text]
5. M. Fischer et al., AIDS Res. Hum. Retroviruses 16, 1135 (2000). [CrossRef] [ISI] [Medline]
6. D. V. Havlir et al., JAMA 286, 171 (2001).[Abstract/Free Full Text]
7. O. Lambotte et al., AIDS 19, 217 (2005). [ISI] [Medline]
8. S. Letendre et al., Arch. Neurol. 65, 65 (2008).[Abstract/Free Full Text]
9. P. W. Mallon, AIDS Rev. 9, 3 (2007). [ISI] [Medline]
10. R. Bedimo, Curr. HIV/AIDS Rep. 5, 140 (2008). [CrossRef]
11. D. Florescu, D. P. Kotler, Antivir. Ther. 12, 149 (2007). [ISI] [Medline]
12. The Data Collection on Adverse Events of Anti-HIV Drugs Study Group, Arch. Intern. Med. 166, 1632 (2006).[Abstract/Free Full Text]
13. K. Mondy, P. Tebas, Annu. Rev. Med. 58, 141 (2007). [CrossRef] [ISI] [Medline]
14. F. Maldarelli et al., PLoS Pathog. 3, e46 (2007). [CrossRef] [Medline]
15. S. Palmer et al., Proc. Natl. Acad. Sci. U.S.A. 105, 3879 (2008).[Abstract/Free Full Text]
16. F. Maldarelli et al., Antivir. Ther. 13 (suppl. 3), A79 (2008).
17. H. F. Gunthard et al., J. Virol. 73, 9404 (1999).[Abstract/Free Full Text]
18. M. C. Strain et al., Proc. Natl. Acad. Sci. U.S.A. 100, 4819 (2003).[Abstract/Free Full Text]
19. L. Zhang et al., N. Engl. J. Med. 340, 1605 (1999).[Abstract/Free Full Text]
20. T. W. Chun et al., Nature 387, 183 (1997). [CrossRef] [Medline]
21. D. Finzi et al., Science 278, 1295 (1997).[Abstract/Free Full Text]
22. J. K. Wong et al., Science 278, 1291 (1997).[Abstract/Free Full Text]
23. Z. Zhang et al., Science 286, 1353 (1999).[Abstract/Free Full Text]
24. J. R. Bailey et al., J. Virol. 80, 6441 (2006).[Abstract/Free Full Text]
25. S. A. Williams, W. C. Greene, Cytokine 39, 63 (2007). [CrossRef] [ISI] [Medline]
26. J. J. Coull et al., J. Virol. 74, 6790 (2000).[Abstract/Free Full Text]
27. S. A. Williams et al., EMBO J. 25, 139 (2006). [CrossRef] [ISI] [Medline]
28. G. Jiang, A. Espeseth, D. J. Hazuda, D. M. Margolis, J. Virol. 81, 10914 (2007).[Abstract/Free Full Text]
29. M. Tyagi, J. Karn, EMBO J. 26, 4985 (2007). [CrossRef] [ISI] [Medline]
30. B. M. Peterlin, D. H. Price, Mol. Cell 23, 297 (2006). [CrossRef] [ISI] [Medline]
31. C. W. Young et al., Cancer Res. 48, 7304 (1988). [ISI] [Medline]
32. X. Contreras, M. Barboric, T. Lenasi, B. M. Peterlin, PLoS Pathog. 3, 1459 (2007). [ISI] [Medline]
33. V. Klichko, N. Archin, R. Kaur, G. Lehrman, D. Margolis, J. Virol. 80, 4570 (2006).[Abstract/Free Full Text]
34. S. K. Choudhary, N. M. Archin, D. M. Margolis, J. Infect. Dis. 197, 1162 (2008). [CrossRef] [ISI] [Medline]
35. D. Bisgrove, M. Lewinski, F. Bushman, E. Verdin, Expert Rev. Anti Infect. Ther. 3, 805 (2005). [CrossRef] [Medline]
36. J. Kulkosky et al., Blood 98, 3006 (2001).[Abstract/Free Full Text]
37. S. A. Williams et al., J. Biol. Chem. 279, 42008 (2004).[Abstract/Free Full Text]
38. K. G. Lassen, K. X. Ramyar, J. R. Bailey, Y. Zhou, R. F. Siliciano, PLoS Pathog. 2, e68 (2006). [CrossRef] [Medline]
39. J. Huang et al., Nat. Med. 13, 1241 (2007). [CrossRef] [ISI] [Medline]
40. Z. Klase et al., BMC Mol. Biol. 8, 63 (2007). [CrossRef] [Medline]
41. A. Shen et al., J. Virol. 77, 4938 (2003).[Abstract/Free Full Text]
42. M. W. Melkus et al., Nat. Med. 12, 1316 (2006). [CrossRef] [ISI] [Medline]
43. P. W. Denton et al., PLoS Med. 5, e16 (2008). [CrossRef] [Medline]
44. N. M. Archin et al., AIDS 22, 1131 (2008). [CrossRef] [ISI] [Medline]
45. T. W. Chun et al., Nat. Med. 5, 651 (1999). [CrossRef] [ISI] [Medline]
46. J. Kulkosky et al., J. Infect. Dis. 186, 1403 (2002). [CrossRef] [ISI] [Medline]
47. F. X. Wang et al., J. Clin. Invest. 115, 128 (2005). [CrossRef] [ISI] [Medline]
48. Y. Han, M. Wind-Rotolo, H. C. Yang, J. D. Siliciano, R. F. Siliciano, Nat. Rev. Microbiol. 5, 95 (2007). [CrossRef] [ISI] [Medline]
49. M. C. Strain et al., J. Infect. Dis. 191, 1410 (2005). [CrossRef] [ISI] [Medline]
50. We acknowledge the encouragement and support of C. Dieffenbach of the Division of AIDS, National Institute of Allergy and Infectious Diseases, NIH, and V. Miller and the Forum for Collaborative HIV Research. We also thank J. C. W. Carroll from the J. David Gladstone Institutes for graphic artwork. This article is dedicated to the memory of our friend and colleague, Martin Delaney.

"Medical Professionals for Sale?"
The Lancet, Volume 373, Issue 9666, Page 810, 7 March 2009
L Thomas

Much has been written in the medical press about the influence of the pharmaceutical industry within the medical profession. Many of the conclusions drawn, it seems to me, are well meaning but rather nebulous theoretical constructs. The question has been seen solely from the medical profession's sadly limited perspective and the views of concerned members of the general public are either unknown or ignored. Please allow me to tell you how this influence can permeate the profession.

In June, 2004, I sustained a very severe adverse reaction while on a clinical drug trial in which I was, according to the patient information sheet, to have been closely monitored. This close monitoring by my general practitioner resulted in my being ambulanced into hospital, very close to death, after the untreated bloody diarrhoea I had suffered for many weeks resulted in severe septicaemia. I was eventually discharged with a memento of the trial—ulcerative colitis. The general practitioner supervising me received £3000 per patient. I naively thought that some of that money was to ensure my wellbeing.

Since the pharmaceutical company involved steadfastly refused to follow the Association of the British Pharmaceutical Industry's compensation guidelines, and having no positive support from the medical establishment, I was forced to go to court in an attempt to gain the modest compensation I felt that I deserved.
During the hearing I witnessed the most disgraceful behaviour by the company's principal witness, a world-famous professor of gastroenterology. He was eventually described by the Judge in his judgment, when under cross-examination by the barrister representing me, as being “at best disingenuous” and that “…he forgot he was here to help the Court rather than to simply advance [the company's] case”. There were also several other instances of behaviour quite unfitting of such a renowned expert, especially when he denied the accuracy of my medical records compiled by his peers at the UK's most prestigious hospital whose staff had saved my life.

I understand that the eminent professor was paid handsomely to “advance” the company's case. So from a humble general practitioner to an eminent professor, the influence of the pharmaceutical industry can be seen; in this case the negative aspect is predominant. Does the medical profession dare to look more closely at such cases as mine?

Both the general practitioner and the renowned but disingenuous professor are paid generous salaries by the taxpayer to ensure the heath and wellbeing of the general public. They should not allow themselves, for whatever reason, to be used as pawns by unscrupulous drug companies.

What Not To Deduce from STEP Study
The Lancet, Volume 373, Issue 9666, Page 805, 7 March 2009
Aaron M. White
Department of Psychiatry, Division of Medical Psychology, Duke University Medical Center, Durham, NC 27710, USA

As detailed by Susan Buchbinder and colleagues (Nov 29, p 1881),1 the first full-scale trial of a vaccine aimed at evoking cell-mediated immunity to HIV-1 failed to achieve its objectives. This failure is considered by Buchbinder and colleagues to reflect a failure of cell-mediated approaches to HIV-1 prevention. In his Comment on the report, Merlin Robb2 suggests that “An even greater emphasis will be placed on developing a vaccine that yields protective humoral responses.”

However, such discussions must not be predicated on the assumption that the Step Study represents a perfect test of the usefulness of cell-mediated approaches for HIV-1 prevention. It does not. Indeed, the design of the vaccine itself, rather than its intended purpose of evoking cell-mediated immunity, is more likely to be at the centre of the Step Study's failure.

Evidence for this comes from the finding that those previously exposed to the adenovirus used in the vaccine were at increased risk of HIV-1 infection after vaccination. Humoral (antibody-mediated) immunity and cell-mediated immunity are in subtle opposition to one another. When one is activated, the other is dampened. Logically, all participants treated with a deactivated adenovirus would exhibit an antibody-mediated immune response. Those previously exposed to the adenovirus would have exhibited an even stronger antibody-mediated response, thus making it difficult for the body to develop cell-mediated immunity to the HIV-1-related antigens in the vaccine and perhaps creating a window of opportunity for infection with pathogens, such as HIV-1, that are best dealt with by the cell-mediated immune pathway.

Years worth of evidence has shown that traditional vaccines, all of which aim for antibody-mediated immunity, do not work against HIV-1. Although the vaccine used in the Step Study failed to evoke cell-mediated immunity, far more work needs to be done before such approaches to HIV-1 prevention can be ruled unhelpful. New approaches aimed at evoking cell-mediated immunity should be assessed.3

References
1 Buchbinder SP, Mehrotra DV, Duerr A, et al. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial. Lancet 2008; 372: 1881-1893. Summary | Full Text | PDF(278KB) | CrossRef | PubMed
2 Robb ML. Failure of the Merck HIV vaccine: an uncertain step forward. Lancet 2008; 372: 1857-1858. Full Text | PDF(54KB) | CrossRef | PubMed
3 White A. Why vaccines are not the answer—the failure of V520 and the importance of cell-mediated immunity in the fight against HIV. Med Hypoth 2008; 71: 909-913. PubMed

Drawing the Wrong Conclusions from Step Study Failure?
The Lancet, Volume 373, Issue 9666, Page 805, 7 March 2009
Angus Dalgleish, Justin Stebbing
St George's University, London, UK; Imperial College Healthcare NHS Trust, Hammersmith and Charing Cross Hospitals, London, UK

Two papers document the failure of an HIV-1 vaccine based on gag, pol, and nef genes in an adenoviral vector.1, 2 Two explanations are discussed as to why the vaccine failed: the possibility that T-cell immunity needed to be more broadly reactive or qualitatively different from those elicited by this vaccine, and that T-cell-based vaccines alone would not be sufficient to protect against HIV-1 infection or disease.

We suggest that the negative finding is more likely to result from a failure to appreciate how HIV-1 induces disease. The virus first induces chronic immune activation. Despite decades of research, the mechanism for this activation is not widely agreed, and we argue that the virus might be able to outrun even a broad-based T-cell response. The only serious candidate for an effective epitope-based vaccine is one in which the epitope is on the virus envelope; any future vaccine will need to target this region.

We agree that the second assertion is likely to be correct, and it is impossible to have a vaccine based on only T-cell activity. However, if an antibody that neutralised the activation epitope was used as the primary vaccine, then secondary responses to other epitopes would be much more effective. Indeed, this approach can be readily tried in the therapeutic setting, with a smaller number of patients and at a lower cost than in a prophylactic trial.

The trial highlights the fact that, although non-human primate models have been exceptional in showing the importance of immune activation in the pathogenesis of disease, their distinct HLA, T-cell-receptor, and toll-like-receptor structures make them inappropriate models for human vaccine development. Finding the epitopes that cause activation as therapeutic targets might be far more important in many other disorders than attempting to use multiple vaccine candidates. This might also be the case for other common infections such as malaria and hepatitis C.

References
1 McElrath MJ, De Rosa SC, Moodie Z, et al. HIV-1 vaccine-induced immunity in the test-of-concept Step Study: a case-cohort analysis. Lancet 2008; 372: 1894-1905. Summary | Full Text | PDF(519KB) | CrossRef | PubMed
2 Buchbinder SP, Mehrotra DV, Duerr A, et al. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial. Lancet 2008; 372: 1881-1893. Summary | Full Text | PDF(278KB) | CrossRef | PubMed

HIV-1 Step Study — Authors' reply
The Lancet, Volume 373, Issue 9666, Page 806, 7 March 2009
Susan Buchbinder, Ann Duerr, Michael N Robertson
HIV Research Section, San Francisco Department of Public Health; Fred Hutchinson Cancer Research Center, Seattle, WA; Merck Research Laboratories, North Wales, PA

We agree with Aaron White that cell-mediated immune responses have an important role in the control of HIV, and a successful vaccine might well need to be capable of eliciting these types of response. However, we disagree with the statement that “the vaccine used in the Step Study failed to evoke cell-mediated immunity.”

Although it is true that pre-existing immunity to adenovirus type 5 substantially affected the frequency and magnitude of the responses, the MRKAd5 HIV-1 gag/pol/nef vaccine elicited robust T-cell response to the encoded HIV-1 antigens, even among those with pre-existing immunity. As McElrath and colleagues1 stated in the conclusions to the companion article, “these findings suggest two possible explanations for the disappointing trial results: first, the characteristics of T-cell immunity that might afford HIV-1 protection have to be more broadly reactive or qualitatively different than those elicited by this vaccine; or second, immune responses mounted by T-cell-based vaccines alone will not be sufficient to protect against HIV infection or disease.” We agree that further studies are needed to assess these possibilities.

Additional analysis of the effect of vaccine-induced immune responses on acquisition and post-acquisition viral load has continued. These studies include those that assess the number and identity of HIV-1 epitopes recognised by vaccine recipients, the presence of those epitopes in the infecting strain, the killing ability of vaccine-induced T cells before and after infection, and recall responses. These and other studies will help generate testable hypotheses as to why the Step vaccine was ineffective, and more importantly will provide valuable insights into how T-cell-based vaccines might be significantly improved. We agree that, as Angus Dalgleish and Justin Stebbing outline, there are complexities to the early interactions between HIV-1 and the human host.

2009-03-03T11:24:00.002-05:00

Harvard Medical School in Ethics Quandary

by Duff Wilson, for The New York Times (3/3/09)

BOSTON — In a first-year pharmacology class at Harvard Medical School, Matt Zerden grew wary as the professor promoted the benefits of cholesterol drugs and seemed to belittle a student who asked about side effects.

Mr. Zerden later discovered something by searching online that he began sharing with his classmates. The professor was not only a full-time member of the Harvard Medical faculty, but a paid consultant to 10 drug companies, including five makers of cholesterol treatments.

“I felt really violated,” Mr. Zerden, now a fourth-year student, recently recalled. “Here we have 160 open minds trying to learn the basics in a protected space, and the information he was giving wasn’t as pure as I think it should be.”

Mr. Zerden’s minor stir four years ago has lately grown into a full-blown movement by more than 200 Harvard Medical School students and sympathetic faculty, intent on exposing and curtailing the industry influence in their classrooms and laboratories, as well as in Harvard’s 17 affiliated teaching hospitals and institutes.

They say they are concerned that the same money that helped build the school’s world-class status may in fact be hurting its reputation and affecting its teaching.

The students argue, for example, that Harvard should be embarrassed by the F grade it recently received from the American Medical Student Association, a national group that rates how well medical schools monitor and control drug industry money.

Harvard Medical School’s peers received much higher grades, ranging from the A for the University of Pennsylvania, to B’s received by Stanford, Columbia and New York University, to the C for Yale.

2009-02-18T23:02:00.004-05:00

"Hit Early" Orthodoxy Suffers Unorthodox Blow

Much to the near certain chagrin of "the earlier, the better" ARV zealots, John Mellors, Richard Moore, Julio Montaner, and the newly ambitious, claw her way to the top, KOL wannabe Mari Kitahata (U Washington-Seattle), another Hopkins name, highly respected Robert Siliciano, says that catching HIV infection early and treating it will very likely not make any difference in the size of the latently infected pool of residual virus--virus that even the best ARVs seemingly cannot touch. Ooops!

See Bob Roehr's Medscape report from last week's CROI: "Theoretical Limit of Antiretroviral Therapy Has Been Reached, Says AIDS Expert"

2009-02-17T11:04:00.005-05:00

from Jay Levy's NEJM commentary on Berlin BMT clinical 'cure' of HIV:

"The results of this study (and another, in monkeys, published in PNAS in 2007) provide further encouragement for those examining approaches to treatment that reduce CCR5 expression in persons with HIV infection. ... Although such techniques need to be perfected, they point in directions that may serve as stimuli for other innovative gene therapies to help those infected with HIV. ... In summary, the case reported by Hütter et al. could pave the way for innovative approaches that provide long-lasting viral control with limited toxicities for persons with HIV infection."

Not an HIV Cure, but Encouraging New Directions
Jay A. Levy, M.D.

The history of infectious diseases frequently includes people who were resistant to a pathogen. Such a phenomenon helped the Spanish, who had resistance to smallpox, in their conquest of South America, but not the Aztecs or the Incas, who had no resistance to smallpox and were decimated by the virus. [1] Microbial resistance involves adaptive (acquired) immunity (e.g., the HLA subtype) or innate (natural) immunity resulting from the genetic makeup of the host. [2]

With the human immunodeficiency virus (HIV) and its known destruction of the immune system, resistance to infection and disease was not initially expected. However, certain people — long-term survivors — have been infected with HIV for more than 10 years (and sometimes 30 years) and received no treatment yet remain without disease. [2] In addition, some people who have been exposed to HIV on many occasions do not become infected. [3] Both long-term survivors and those who have been exposed to HIV but remain seronegative offer a great opportunity to study the mechanisms of resistance to HIV infection and disease.

HIV enters cells primarily through attachment to the CD4 molecule and subsequent binding to coreceptors, of which two chemokine receptors, CCR5 and CXCR4, are the most common. R5 HIV types bind to CCR5; X4 HIV types use CXCR4. [4] People whose cells lack expression of the CCR5 gene are markedly resistant to HIV infection despite multiple exposures to R5 HIV, which is the most prominent virus detected after transmission. [2,4] This mutation is found in 1 to 3% of the Western population. Among people with HIV who have only one copy of the wild-type CCR5 gene, progression to disease appears to be slower than among those who have two. [4,5] Obviously, such information is of value in efforts to develop new approaches for therapy.

In 2007, an estimated 2 million people died from AIDS and 2.7 million contracted the virus. Currently, infected patients can benefit from antiretroviral therapies that effectively delay or prevent progression to AIDS. [6] These people are in many cases healthy but continue to carry HIV. If the antiretroviral therapy is stopped, however, a rebound in virus production occurs that can lead to AIDS. [7] Moreover, the virus can develop resistance to antiretroviral therapy and reemerge in the host. Long-term treatment with these drugs is also costly and can cause toxicities that are often life-threatening, including disorders of the cardiovascular system, pancreas, kidney, and liver. [8] And only a fraction of the people who are infected and need antiretroviral therapy are receiving therapy, particularly in countries with limited resources.

For these reasons, a search for better, long-term treatment for HIV infection continues. In this issue of the Journal, Hütter et al. highlight an innovative approach that could prove beneficial for the long-term control of HIV without antiretroviral therapy. [9] These investigators selected an HLA-compatible person whose cells lacked expression of CCR5 as the donor for stem-cell transplantation from bone marrow to a patient with acute myelogenous leukemia who was infected with HIV. After two transplantations, there has been no recurrence of leukemia or detectible HIV in the bloodstream, as determined by analyses of viral RNA and cellular proviral DNA. In addition, after nearly 2 years, the CD4+ T cells in this patient have returned to a normal range, all carrying the donor's homozygote-deleted CCR5 gene.

Although some observers may consider the patient cured of HIV, this conclusion is premature. Much evidence has shown that HIV can be lurking in cells found in the lymph nodes and other parts of the body, including the brain, gut, liver, kidneys, and heart. [2] Eventually, the virus could induce disease in these tissues. Nevertheless, the results of this study and others [10] provide further encouragement for those examining approaches to treatment that reduce CCR5 expression in persons with HIV infection.

Bone marrow transplantations requiring ablation of host immune cells, as in this case, are risky; many patients die from the procedure. Autologous stem-cell administration after manipulation to eliminate CCR510 carries a similar risk. Consequently, an approach designed to modify HIV target cells without eliminating the host's own bone marrow could be helpful. An example would be to inject into the patient with HIV a CCR5-inactivating biochemical compound or genetic vector that would enter white cells and eventually make them resistant to HIV. A compound that could enter the stem cells of the patient would be the most effective for long-lasting protection. Development of such technologies could include injecting into the bloodstream vectors carrying small interfering RNA (siRNA), antisense RNA, or ribozymes, all of which reduce CCR5 cellular expression.[10,11] Another approach could involve small, injectable, arginine-rich particles containing RNA that down-regulates CCR5 expression by interrupting normal gene splicing. [12] Although such techniques need to be perfected, they point in directions that may serve as stimuli for other innovative gene therapies to help those infected with HIV.

Certain issues, however, need to be appreciated. An X4 type of HIV that was detected at low levels in the blood of the patient studied by Hütter et al. could eventually emerge. This virus grows in cells lacking CCR5 expression. [2,3,4] Moreover, after transplantation, the patient's remaining CCR5-expressing macrophages — major cells for R5 virus infection — had no evidence of HIV. What protected these cells? Perhaps the CCR5 protein was present at low density on these cells, since the patient was heterozygous for the mutated allele. Or, since HIV-specific T cells were not prominent, innate immune responses could be suppressing both the R5 and X4 viruses.[13] One caveat is that people lacking the CCR5 gene can be more susceptible to serious effects from certain infections, such as West Nile virus. [14]

Therapeutic targeting of CCR5 could delay the onset of disease and reduce the cost and toxicity of antiretroviral therapy, as it has in this patient for nearly 2 years. This case places further emphasis on gene therapies and treatments directed at blocking the CCR5 receptor with decoy drugs. Maraviroc, a recently approved CCR5 inhibitor, has had some success,[15] but it must be administered along with other antiretroviral medications. It is probable that HIV resistance to maraviroc occurs because the CCR5 molecule remains expressed on cells. In summary, the case reported by Hütter et al. [9] could pave the way for innovative approaches that provide long-lasting viral control with limited toxicities for persons with HIV infection.

No potential conflict of interest relevant to this article was reported.

Source Information
From the University of California, San Francisco, San Francisco.

References

Prescott WH. History of the conquest of Mexico and the history of the conquest of Peru. New York: Rowan & Littlefield, 2000.
Levy JA. HIV and the pathogenesis of AIDS. 3rd ed. Washington, DC: ASM Press, 2007.
Shearer GM, Clerici M. Protective immunity against HIV infection: has nature done the experiment for us? Immunol Today 1996;17:21-24.
Berger EA, Murphy PM, Farber JM. Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease. Annu Rev Immunol 1999;17:657-700.
de Roda Husman AM, Koot M, Cornelissen M, et al. Association between CCR5 genotype and the clinical course of HIV-1 infection. Ann Intern Med 1997;127:882-890.
Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998;338:853-860.
Jubault V, Burgard M, Le Corfec E, Costagliola D, Rouzioux C, Viard J-P. High rebound of plasma and cellular HIV load after discontinuation of triple combination therapy. AIDS 1998;12:2358-2359.
Nolan D, Reiss P, Mallal S. Adverse effects of antiretroviral therapy for HIV infection: a review of selected topics. Expert Opin Drug Saf 2005;4:201-218.
Hütter G, Nowak D, Mossner M, et al. Long-term control of HIV by CCR5 delta32/delta32 stem-cell transplantation. N Engl J Med 2009;360:692-698.
Cohen J. Building an HIV-proof immune system. Science 2007;317:612-614.
An DS, Donahue RE, Kamata M, et al. Stable reduction of CCR5 by RNAi through hematopoietic stem cell transplant in non-human primates. Proc Natl Acad Sci U S A 2007;104:13110-13115.
Moulton HM, Nelson MH, Hatlevig SA, Reddy MT, Iversen PL. Cellular uptake of antisense morpholino oligomers conjugated to arginine-rich peptides. Bioconjug Chem 2004;15:290-299.
Levy JA. The importance of the innate immune system in controlling HIV infection and disease. Trends Immunol 2001;22:312-316.
Glass WG, McDermott DH, Lim JK, et al. CCR5 deficiency increases risk of symptomatic West Nile virus infection. J Exp Med 2006;203:35-40.
Deeks SG. Challenges of developing R5 inhibitors in antiretroviral naive HIV-infected patients. Lancet 2006;367:711-713.

2009-02-17T10:52:00.002-05:00

Stem-Cell Transplantation Enables Long-Term HIV Control

A leukemia patient lost his CCR5 receptors and achieved remission of both leukemia and HIV infection.

Summary of paper in this week's NEJM, by Abigail Zuger, MD for AIDS Clinical Care

Good drugs are available for keeping HIV at bay, but the many downsides of lifelong drug treatment (e.g., cost, side effects, access) fuel the continued search for a cure. A case report from Germany now suggests that manipulation of the CCR5 receptor is the key to long-term, drug-free virologic control.

A 40-year-old white man with longstanding HIV infection (>10 years) received a diagnosis of acute myeloid leukemia (AML). At the time, he was receiving an efavirenz-based regimen and had a CD4 count >400 cells/mm³ and an undetectable viral load. He underwent two courses of induction chemotherapy and one course of consolidation therapy, but the AML relapsed. He then underwent allogeneic stem-cell transplantation with a human leukocyte antigen–matched donor who had been screened specifically for homozygosity of the CCR5 32 allele. Remission from AML was achieved, but relapse occurred almost a year later, prompting a second transplant from the same donor. Complete AML remission was realized and maintained throughout reported follow-up (20 months from the first transplantation).

Meanwhile, virologic control of HIV was lost during the initial chemotherapy — when drug toxicity mandated discontinuation of antiretrovirals — and was then regained when antiretrovirals were resumed. The day before the first transplantation, all antiretrovirals were stopped permanently. Nonetheless, HIV viral load remains undetectable in the patient’s blood and bone marrow at 23 months (per author correspondence), and CD4-cell counts have returned to premorbid levels.

With engraftment, PCR assays confirmed complete chimerism, with a shift from a pretransplant heterozygous genotype for CCR5 to a homozygous 32/32 genotype. A rectal biopsy performed between transplants showed persistence of CCR5-expressing macrophages in the rectal mucosa, but HIV DNA was not detected therein. Ultradeep sequencing analysis before transplantation indicated that 2.9% of the patient’s viral population was CRCX4-using or dual-tropic, but these variants never emerged during follow-up.

Comment: Bone marrow transplantation has periodically been advocated as a path to HIV cure, but past efforts have been uniformly unsuccessful. An editorialist points out that dubbing this latest effort a complete success is still premature: With time, the patient’s CXCR4-using HIV might reemerge, or his remaining CCR5-expressing cells might lose whatever is protecting them. However, the case does suggest that targeting CCR5 by other methods — molecular inactivators or RNA fragments that downregulate expression — might be a powerful strategy for delaying onset of disease, if not actually achieving cure.

— Abigail Zuger, MD

Published in AIDS Clinical Care February 13, 2009

Citation(s):

Hütter G et al. Long-term control of HIV by CCR5 delta32/delta32 stem-cell transplantation. N Engl J Med 2009 Feb 12; 360:692.

Original article (Subscription may be required)
Medline abstract (Free)

Levy JA. Not an HIV cure, but encouraging new directions. N Engl J Med 2009 Feb 12; 360:724.

Original article (Subscription may be required)
Medline abstract (Free)

2009-02-16T13:49:00.002-05:00

Clinical trials of hydroxyurea:

Hydroxyurea Clinical Trials

Hydroxyurea in Treating Patients With Unresectable Benign Meningioma
ClinicalTrials.gov Identifier: NCT00003590 - Active, not recruiting
Hydroxyurea Plus Combination Chemotherapy in Patients With Non-small Cell Lung Cancer
ClinicalTrials.gov Identifier: NCT00002887 - Active, not recruiting
A Pilot Therapeutic Trial Using Hydroxyurea in Type II and III Spinal Muscular Atrophy Patients
ClinicalTrials.gov Identifier: NCT00084006 - Active, not recruiting
A Pilot Therapeutic Trial Using Hydroxyurea in Type I Spinal Muscular Atrophy
ClinicalTrials.gov Identifier: NCT00083746 - Active, not recruiting
Hydroxyurea for the Treatment of Patients with Sickle Cell Anemia
ClinicalTrials.gov Identifier: NCT00001197 - Active, not recruiting
Use of Hydroxyurea and Magnesium Pidolate for Treatment of Sickle Cell Disease
ClinicalTrials.gov Identifier: NCT00143572 - Active, not recruiting
Multicenter Study of Hydroxyurea in Patients With Sickle Cell Anemia (MSH)
ClinicalTrials.gov Identifier: NCT00000586 - Active, not recruiting
Evaluation of Hydroxyurea Plus L-arginine or Sildenafil to Treat Sickle Cell Anemia
ClinicalTrials.gov Identifier: NCT00056433 - Active, not recruiting
Bevacizumab, Fluorouracil, and Hydroxyurea Plus Radiation Therapy in Treating Patients With Advanced Head and Neck Cancer
ClinicalTrials.gov Identifier: NCT00023959 - Active, not recruiting
Hydroxyurea in Treating Patients With Recurrent and/or Unresectable Meningioma
ClinicalTrials.gov Identifier: NCT00006119 - Active, not recruiting
Study of Clotrimazole and Hydroxyurea in Patients With Sickle Cell Syndromes
ClinicalTrials.gov Identifier: NCT00004404 - Recruiting
Stroke with Transfusions Changing to Hydroxyurea (SWITCH)
ClinicalTrials.gov Identifier: NCT00122980 - Recruiting
Pediatric Hydroxyurea in Sickle Cell Anemia (BABY HUG)
ClinicalTrials.gov Identifier: NCT00006400 - Recruiting
The Safety and Effectiveness of Hydroxyurea and ddI Used Individually or Together in HIV-Infected Patients
ClinicalTrials.gov Identifier: NCT00001074 - Completed
Phase I/II Randomized Study of Hydroxyurea With or Without Clotrimazole in Patients With Sickle Cell Anemia
ClinicalTrials.gov Identifier: NCT00004492 - Recruiting
Homoharringtonine Compared With Hydroxyurea for Chronic Myelogenous Leukemia That Has Not Responded to Interferon alfa
ClinicalTrials.gov Identifier: NCT00004933 - Active, not recruiting
Phase III Study of Imatinib Mesylate in Combination with Hydroxyurea Versus Hydroxyurea Alone as an Oral Therapy in Patients with Temozolomide Resistant Progressive Glioblastoma
ClinicalTrials.gov Identifier: NCT00154375 - Completed
Imatinib Mesylate and Hydroxyurea in Treating Patients With Recurrent or Progressive Meningioma
ClinicalTrials.gov Identifier: NCT00354913 - Recruiting
Efficacy and Safety of Imatinib Mesylate Plus Hydroxyurea (HU) in Patients With Recurrent Glioblastoma Multiforme (GBM)
ClinicalTrials.gov Identifier: NCT00290771 - Active, not recruiting
Efficacy and Safety of Imatinib Mesylate Plus Hydroxyurea (HU) in Patients With Recurrent Glioblastoma Multiforme (GBM)
ClinicalTrials.gov Identifier: NCT00292149 - Active, not recruiting
A Pilot Theraputic Trial Using Hydroxyurea in Type I Spinal Muscular Atrophy Patients
ClinicalTrials.gov Identifier: NCT00568698 - Active, not recruiting
Imatinib Mesylate, Vatalanib, and Hydroxyurea in Treating Patients With Recurrent or Relapsed Malignant Glioma
ClinicalTrials.gov Identifier: NCT00387933 - Recruiting
A Pilot Theraputic Trial Using Hydroxyurea in Type II and Type III Spinal Muscular Atrophy Patients
ClinicalTrials.gov Identifier: NCT00568802 - Active, not recruiting
Safety and Effectiveness of Combining Hydroxyurea (HU) with Didanosine (ddI) and Stavudine (d4T) for Treatment of HIV-Infected Adults
ClinicalTrials.gov Identifier: NCT00002427 - Completed
A Randomized, Placebo-Controlled Study of the Safety and Efficacy of Efavirenz, Didanosine, and Stavudine in Combination With or Without Hydroxyurea in Antiretroviral Naive or Experienced HIV-Infected Patients
ClinicalTrials.gov Identifier: NCT00002230 - Completed
A Pilot Open Label Trial of HIV Therapy with d4T (Stavudine), ddI (Didanosine), Nelfinavir and Hydroxyurea in Subjects with Early Asymptomatic HIV Infection
ClinicalTrials.gov Identifier: NCT00002176 - Completed
A Pilot Open Label Trial of HIV Therapy with d4T (Stavudine), ddI (Didanosine), Nelfinavir and Hydroxyurea in Subjects with Recent HIV Infection
ClinicalTrials.gov Identifier: NCT00002177 - Completed
Evaluating the Safety and Effectiveness of Hydroxyurea and Magnesium Pidolate to Treat People With Hemoglobin Sickle Cell Disease (CHAMPS)
ClinicalTrials.gov Identifier: NCT00532883 - Recruiting
PHASE III TRIAL COMPARING, NEOADJUVANT CHEMOTHERAPY FOLLOWED BY STANDARD RADIOTHERAPY VERSUS THE SAME NEOADJUVANT CHEMOTHERAPY FOLLOWED BY STANDARD RADIOTHERAPY ASSOCIATED WITH DAILY HYDROXYUREA IN THE TREATMENT OF LOCALLY ADVANCED UNDIFFERENTIATED CARCIN
ClinicalTrials.gov Identifier: NCT00180973 - Active, not recruiting
A Study to Compare the Safety and Effectiveness of Anagrelide and Hydroxyurea in High-Risk Essential Thrombocythaemia Patients.
ClinicalTrials.gov Identifier: NCT00202644 - Recruiting
Interferon-alfa With or Without Chemotherapy and Peripheral Stem Cell Transplantation in Treating Patients With Newly Diagnosed Chronic Myelogenous Leukemia
ClinicalTrials.gov Identifier: NCT00002868 - Active, not recruiting
Hydroxyurea and Erythropoietin to Treat Sickle Cell Anemia
ClinicalTrials.gov Identifier: NCT00270478 - Recruiting
A Randomized, Double-Blind, Placebo-Controlled Trial of Hydroxyurea in Spinal Muscular Atrophy
ClinicalTrials.gov Identifier: NCT00485511 - Recruiting
Effectiveness of Early or Delayed Addition of Hydroxyurea to a Three-Drug Anti-HIV Drug Combination Including Didanosine, in Advanced HIV Patients Who Failed a First or Second Anti-HIV Triple-Drug Therapy
ClinicalTrials.gov Identifier: NCT00008866 - Completed
Long Term Effects of Hydroxyurea Therapy in Children With Sickle Cell Disease
ClinicalTrials.gov Identifier: NCT00305175 - Recruiting
Combination Chemotherapy Plus Interferon Alfa Followed by Filgrastim in Treating Patients With Gastrointestinal Tract Cancer
ClinicalTrials.gov Identifier: NCT00019474 - Active, not recruiting
A Study of TNFerade™ With Concomitant Radiotherapy, Fluorouracil, and Hydroxyurea (TNF-FHX) in Patients With Head and Neck Cancer
ClinicalTrials.gov Identifier: NCT00496535 - Recruiting
Chemotherapy Plus Radiation Therapy in Treating Patients With Head and Neck Cancer
ClinicalTrials.gov Identifier: NCT00002951 - Active, not recruiting
Combination Chemotherapy Combined with Radiation Therapy in Treating Patients Who Have Stage II or Stage III Cancer of the Esophagus
ClinicalTrials.gov Identifier: NCT00008047 - Active, not recruiting
Hydroxyurea to Treat Beta-Thalassemia (Cooley's Anemia)
ClinicalTrials.gov Identifier: NCT00001958 - Completed
Hydroxyurea in Treating Patients With Epstein-Barr Virus-Associated Primary CNS Lymphoma and AIDS
ClinicalTrials.gov Identifier: NCT00002940 - Completed
Fluorouracil, Hydroxyurea, Cetuximab and Twice-Daily Intensity Radiation Therapy for Advanced Head and Neck Cancer
ClinicalTrials.gov Identifier: NCT00462735 - Recruiting
Safety and Effectiveness of an Anti-HIV Drug Combination With and Without Hydroxyurea in Patients With Early HIV Infection
ClinicalTrials.gov Identifier: NCT00006339 - Terminated
Combination Chemotherapy Followed by Peripheral Stem Cell Transplantation in Treating Patients With Chronic Myelogenous Leukemia
ClinicalTrials.gov Identifier: NCT00002674 - Active, not recruiting
VNP40101M in Treating Patients With Acute Myelogenous Leukemia or High-Risk Myelodysplasia
ClinicalTrials.gov Identifier: NCT00083187 - Active, not recruiting
Combination Chemotherapy and Interferon alfa Followed by Surgery and/or Radiation Therapy in Treating Patients With Stage I, Stage II, or Stage III Esophageal Cancer
ClinicalTrials.gov Identifier: NCT00004897 - Active, not recruiting
Intensive Compared With Nonintensive Chemotherapy in Treating Older Patients with Acute Myeloid Leukemia or Myelodysplastic Syndrome
ClinicalTrials.gov Identifier: NCT00005823 - Active, not recruiting
Hydroxyurea for Children and Young Adults With Sickle Cell Disease and Pulmonary Hypertension
ClinicalTrials.gov Identifier: NCT00350844 - Recruiting
Interferon alfa in Treating Patients With Newly Diagnosed Chronic Myelogenous Leukemia
ClinicalTrials.gov Identifier: NCT00002869 - Active, not recruiting
Long Term Follow up in Sickle Cell Patients Treated by Hydroxyurea
ClinicalTrials.gov Identifier: NCT00480974 - Not yet recruiting
Combination Chemotherapy Plus Radiation Therapy in Treating Patients With Previously Untreated Advanced Cancer of the Mouth, Pharynx, or Larynx
ClinicalTrials.gov Identifier: NCT00004094 - Active, not recruiting
Chemotherapy, Interferon, and Bone Marrow Transplantation in Treating Patients With Chronic Myelogenous Leukemia
ClinicalTrials.gov Identifier: NCT00002771 - Active, not recruiting
A Study of the Safety and Effectiveness of Hydroxyurea in Patients on Potent Antiretroviral Therapy and Who Have Less Than 200 Copies/ml of HIV RNA in Their Blood
ClinicalTrials.gov Identifier: NCT00000916 - Terminated
Chemotherapy, Biological Therapy, and/or Bone Marrow or Peripheral Stem Cell Transplantation in Treating Patients With Chronic Myelogenous Leukemia
ClinicalTrials.gov Identifier: NCT00025402 - Active, not recruiting
Docetaxel Based Chemotherapy Plus Or Minus Induction Chemotherapy to Decrease Events in Head and Neck Cancer (DeCIDE)
ClinicalTrials.gov Identifier: NCT00117572 - Recruiting
Pediatric Hydroxyurea in Sickle Cell Anemia (PED HUG)
ClinicalTrials.gov Identifier: NCT00000602 - Completed
A Study of MKC-442 in Combination with Other Anti-HIV Drugs
ClinicalTrials.gov Identifier: NCT00002412 - Completed
Hydroxyurea to Prevent Stroke in Children With Sickle Cell Anemia and Elevated TCD Flow Velocity
ClinicalTrials.gov Identifier: NCT00402480 - Completed
Imatinib Mesylate With or Without Interferon Alfa or Cytarabine Compared With Interferon Alfa Followed by Allogeneic Stem Cell Transplantation in Treating Patients With Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia
ClinicalTrials.gov Identifier: NCT00055874 - Recruiting
Safety and Effectiveness of a Combination Anti-HIV Drug Treatment
ClinicalTrials.gov Identifier: NCT00005018 - Completed
A Study to Compare the Effectiveness of Different Anti-HIV Drug Regimens in Keeping Levels of HIV in the Blood as Low as Possible
ClinicalTrials.gov Identifier: NCT00000939 - Completed
Combination Drug Treatment of Pediatric HIV Infection
ClinicalTrials.gov Identifier: NCT00001818 - Completed
Radiation Therapy in Treating Patients With Glioblastoma
ClinicalTrials.gov Identifier: NCT00019058 - Completed
Chemotherapy Plus Radiation Therapy in Treating Patients With Previously Untreated Thyroid Cancer
ClinicalTrials.gov Identifier: NCT00004089 - Completed
A Study to Evaluate Various Combinations of Anti-HIV Medications to Treat Early HIV Infection
ClinicalTrials.gov Identifier: NCT00000919 - Completed
Hydroxyurea in Young Children With Sickle Cell Anemia
ClinicalTrials.gov Identifier: NCT00519701 - Completed
Comparison of Combination Chemotherapy Regimens in Treating Patients With Advanced Stomach Cancer
ClinicalTrials.gov Identifier: NCT00003172 - Completed
Combination Chemotherapy Plus Radiation Therapy in Treating Patients With Advanced Mouth Cancer
ClinicalTrials.gov Identifier: NCT00004901 - Completed
A study of the efficacy and safety of ICA-17043 (with or without hydroxyurea) in patients with sickle cell anemia.
ClinicalTrials.gov Identifier: NCT00040677 - Completed
The Safety and Effectiveness of Didanosine Plus Stavudine Plus Nevirapine Combined with MKC-442 in HIV-Infected Patients Who Have Not Had Success with Protease Inhibitors
ClinicalTrials.gov Identifier: NCT00002418 - Terminated
A Study Evaluating the Long-Term Safety of ICA-17043 in Sickle Cell Disease Patients With or Without Hydroxyurea Therapy
ClinicalTrials.gov Identifier: NCT00294541 - Terminated
The Safety and Effectiveness of Didanosine Plus Stavudine Plus Delavirdine Mesylate Plus MKC-442 in HIV-Infected Patients Who Have Not Had Success with Protease Inhibitors
ClinicalTrials.gov Identifier: NCT00002420 - Terminated

2009-02-16T13:41:00.002-05:00

2,000 mg/day HU sounds generally well-tolerated vs. what? 500 mg a day used in HIV?

Folks who parrot the "serious toxicity" of hydroxyurea (especially at the comparatively measly doses used in combination with ARV therapy in individuals with HIV) without taking the time to learn or read about its use in sickle cell disease and certain cancers, might want to read Julie's January diary entry.

2009-02-16T13:36:00.001-05:00

A major recent advance in sickle cell anemia is treatment with the cancer therapeutic drug hydroxyurea, which has several beneficial effects. Through uncertain mechanisms, hydroxyurea causes a significant increase in the concentration of HbF in red cells, which interferes with the polymerization of HbS. However, the therapeutic response to hydroxyurea often precedes the rise in HbF levels, implying that other mechanisms are also important, several of which have been proposed. Firstly, hydroxyurea acts as an anti-inflammatory agent by inhibiting the production of white cells, which may reduce inflammation-related red cell stasis and sickling. Secondly, hydroxyurea increases the mean red cell volume and thereby decreases the concentration of HbS. Thirdly, hydroxyurea can be oxidized by heme groups to produce NO. It is hypothesized all of these actions contribute to ability of hydroxyurea to reduce pain crises in children and adults.

2009-02-02T15:36:00.004-05:00

Will they never learn?

Nobel Prize (for Medicine) winner Sir James Black on the senselessness of Pfizer's Wyeth acquistion--and Sanofi's moves to pick up BMS, Biogen Idec, Amgen or Crucell.

Sir Black was pivotal in the development of two of the most successful medicines that the pharmaceutical industry has ever developed: propranolol, the first beta-blocker to treat hypertension; and cimetidine (Tagamet) for stomach ulcers.

His "outsider" approach pharmaceutical research at Imperial Chemical Industries (aka ICI, the UK pharma division of what is now part of AstraZeneca) in the 1960s highlights one aspect he believes is key to successful drug development: entrepreneurial teams of up to about 25 people, permitted to operate at arms' length from the rest of the company.

He raises his eyes skyward when he discusses last week's $68B takeover by Pfizer, the world's largest pharma group, of Wyeth, and says the restructuring to come will sap both teams. "Will they never learn? They will completely exhaust each others' energies for two years."

Even in ICI in the 1960s – the pharmaceutical division of which is now part of AstraZeneca, the product of a mega-merger a decade ago – he began to feel too much bureaucracy and too much drift towards conformity for someone who considers himself “an inventor, not a discoverer”.

Sir James questions how far research can be successfully managed and quantified in advance. He is scathing of pharma execs' focus on bonuses and incentives. "I remember vividly the managing director of ICI pharmaceuticals saying to me that he would pay to do his job, he enjoyed it so much. Now apparently we have to bribe people."

He has no time for classic industry clichés such as “blockbuster” medicines; no truck with the modern approach to peer review; and no patience with any re-writing of history to suggest a more complex contemporary era of drug discovery has replaced one of “low-hanging fruit” in the past.

He also rejects any suggestion that drug discovery was easier in the past. "I never found it easy. People say I was lucky twice but I resent that. We stuck with [cimetidine] for four years with no progress until we eventually succeeded. It was not luck, it was bloody hard work."

On the contrary, he suggests that the growing use of new technologies and techniques, from molecular biology to genomics, has proved a mixed blessing. "The techniques have galloped ahead of the concepts. We have moved away from studying the complexity of the organisms; from processes and organisation to composition."

Source: Financial Times, 02/02/09: "An acute talent for innovation"

2009-01-31T16:26:00.006-05:00

Speaking of Clinical Practice Guidelines and Professional Societies who generate them while funding their operations with pharmaceutical company grants, witness the 2008 IAS-USA HIV treatment recommendations (Hammer SM, Eron JJ, Reis P et al. JAMA 2008;300(5)555-570)

The IAS-USA has received grants for selected CME activities that are pooled (i.e., no single company supports any single effort) from Abbott Laboratories, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Pfizer, Roche, and Tibotec.

Of the 15-member panel, only Dr. Martin Hirsch has not served on speakers bureaus, advisory boards, or received monies from the companies for consulting services or research grants. By contrast, only Dr. Robert Schooley actually owns stock (or stock options) in any of the companies in question.

Dr. Hammer, Dr. Schooley, Dr. Richman, Dr. Fischl and Dr. Volberding don't seem to receive speaking fees from any of the companies—although they do often serve on advisory boards, as ad hoc consultants or receive funding for their research or research centers.

The biggest speakers of the bunch appear to be Drs. Joe Eron, Pedro Cahn, Melanie Thompson, Sharon Walmsley and Julio Montaner (British Columbia). Some day the total receipts for these activities will be required to be publicly available.

Among the more egregious conflicts of interest:

Dr Joseph J. Eron, Jr.

Speaking fees from BMS, Merck, Roche, Tibotec/JNJ

Dr Peter Reiss

Speakers bureaus (and/or funding for research) for Boehringer Ingelheim, BMS, Gilead, GSK, Roche, Merck, Pfizer, TheraTechnologies, Tibotec/JNJ

Dr Robert Schooley

Stock options for Achillion and Monogram Biosciences

Dr Melanie Thomson

Speaking fees from GSK and Serono

Research grants from Abbott, Avexa, Boehringer Ingelheim, BMS, GSK, GIlead, Koronis, Merck, Panacos, Pfizer, Progenics, Roche, Serono, TaiMed, TheraTechnologies, Tibotec/JNJ

Dr Sharon Walmsley

Speakers bureaus (and/or advisory boards) for Abbott, BMS, Boehringer Ingelheim, Gilead, GSK, Merck, Pfizer, Roche, Tibotec/JNJ

Dr Pedro Cahn

Speaking fees (and/or consultancy fees) from Abbott, Avexa, Boehringer Ingelheim, BMS, GSK, Roche, Merck, Pfizer, Pharmasset, Schering, Tibotec/JNJ

Dr Julio Montaner

Speaking fees (and/or consultancy fees) from Abbott, Argos, Bioject, Boehringer-Ingelheim, BMS, Gilead, GSK, Roche, Janssen-Ortho, Merck Frosst, Panacos, Pfizer, Schering, Serono, TheraTechnologies, Tibotec/JNJ, Trimeris

Some day (soon), total gross receipts for these extra-curricular activities will be required to be reported--both individually and in total (see Allan Sniderman 2009 JAMA editorial below), but for the time being no such accounting is available.

2009-01-28T15:03:00.004-05:00

Why Guideline-Making Requires Reform

Allan D. Sniderman, MD; Curt D. Furberg, MD

JAMA. 2009;301(4):429-431.

...

Unanimity in Guidelines

Unanimity is not a natural component of science. Given the numberand complexity of issues reviewed and given that scientificknowledge is at any moment incomplete, unanimity is obviouslya tactic, not a necessary result. Debate may have been briskwithin the committee, but usually all evidence has been expungedfrom the final document. Contrast the guidelines with the decisionsof any court of appeal in which some judgments are issued unanimouslybut most are not. Most decisions are divided, with reasonedargument recorded by those on either side, often with differentanalyses by different dissenters. These minority opinions, notinfrequently, provide the legal scaffolding for future reversalof the majority decision they opposed.

Although unanimity is the rule in individual guidelines, itcan be strikingly absent when different guidelines are compared.The debate as to whether low-density lipoprotein cholesterol(LDL-C) or apolipoprotein B (apoB) is a more powerful markerof the risk of vascular disease illustrates that guideline groupsmay not just disagree—they actually may contradict eachother. For instance, in the past 6 months, 4 reports have comparedLDL-C and apoB, with 2 supporting LDL-C over apoB^6-7 and 2 infavor of apoB for predicting cardiovascular risk.^8-9 The 2 reportsthat favor LDL-C state categorically that there is no publishedevidence allowing apoB treatment targets to be established.The 2 that chose apoB cite multiple studies supporting theirposition in favor of an apoB target. Only one⁹ presents a complete,detailed, organized review and analysis of the evidence includingthe technical accuracy and reproducibility of the 2 measures.The discordance between the views on apoB vs LDL-C is disconcerting,but not surprising given the failure to even agree on what constitutesevidence or how that evidence should be graded.

Lack of Independent Review

Guidelines generally are outside the accepted procedures ofscientific publication in which acceptance for publication isthe independent decision of the editorial staff of the journaland that decision must include fair independent review. Notonly do the scientific organizations that commission guidelinesusually not subject the guideline reports to independent reviewbefore they issue them, the journals that those organizationscontrol often must publish their guidelines essentially as is.Thus, one of the core processes of science—the necessityto submit any analysis to the independent review of others—isbypassed. The process can be bypassed, but not the consequences,because review is an essential and constructive element in thenever-ending effort to root out error.

Conflict of Interest and Guidelines

By favoring one test over another, or one therapy over another,guidelines often create commercial winners and losers, who cannotbe disinterested in the result and who therefore must be separatedfrom the process. While the groups that finance medical caredo not automatically accept these recommendations, they undoubtedlyhave a major influence on their decisions. Accordingly, thosewho write the guidelines and those who issue them should befree from significant conflict of interest. This issue has receivedattention in the past,^10-11 but attention has not ensured coherent,comprehensive action.

There have been constructive, legitimate relationships betweenindustry and academic medicine, both with regard to educationand research. However, there also have been inappropriate andintolerable relationships, which escaped attention for muchtoo long.^12-13 Currently, simple declaration of all relationshipswith industry is considered sufficient, although to be meaningful,disclosure must be complete. Present and recent past directmonetary relationships must be divulged in detail, along withany independent investment or contractual relationship conferringpotential future financial benefit.¹⁴ Moreover, the prominencegained from participation in a guideline process can translateinto sizeable speaking fees. Therefore, disclosure cannot stopjust with publication of the guidelines because payment in thefuture can be the reward for actions in the past.

It is not the number of entanglements with industry—itis their size, individually and in toto. Therefore, the sumsshould be reported. The argument has been made that ethicalequipoise can be achieved by accepting rewards from all thecompetitors in a field.¹⁵ However, accepting financial rewardfrom everyone does not equal being beholden to no one. Indeed,once the sum of the benefits is large enough, no matter howit is partitioned, the presumption that physicians are unaffectedis not credible.

Suggestions for Reform

The following reforms of the guideline process are suggested.First, the requisite membership of guideline groups should bedefined and include the expertise relevant to that disciplineplus epidemiologists, statisticians, and experts in health carepolicy. Second, the largest part of the guideline committeemembership, and in particular the leaders, should be changedfrom one edition to the next and each edition of the guidelineshould include an expiration date. Third, reports should notbe issued unanimously unless all members fully agree to allsections. Alternate interpretations and viewpoints should berecorded and issued along with the majority opinions. Fourth,posting an almost final version on the Internet and invitingcommentary is an attractive model. This helps ensure that wherelegitimate differences of scientific opinion exist, there isan opportunity for exchange before final decisions are taken.Fifth, before publication, guidelines should undergo independentscientific review. The journal editor should present the criticismsand suggestions that result from the reviewers to the panelfor its responses, and may require revision of the guidelinedocument, as appropriate. The editor also should consider co-publishingalternate points of view as necessary.

Sixth, all financial relationships with industry should be disclosedin detail, including amounts received, and should be publiclyavailable. Receipt of substantial benefits from any companyor series of companies whose products might be under considerationshould disqualify that individual from participation in anyguideline decision-making process. Potential and actual financialbenefits gained by the authors for the next 2 years should alsobe limited and disclosed to the association that sponsored theguideline process.

Seventh, associations that sponsor and promote guidelines shouldcreate joint codes to govern conflict of interest both on thepart of participants in the guideline process and the associations.Associations should not accept money from industry to sponsor,underwrite, or promote guidelines.

In summary, evidence is complex and incomplete. Therefore, whenthe evidence warrants, guidelines should respect diversity ofviews. Guidelines must be directed only to the interests ofpatients and not to those who profit from them. Failure to reformthe guideline process risks replacing one authority-based systemwith another, whereas the core objective should be to strengthenan evidence-based approach to improve clinical care.

AUTHOR INFORMATION

Corresponding Author: Allan D. Sniderman, MD, Mike RosenbloomLaboratory for Cardiovascular Research, Room H7.22, Royal VictoriaHospital, 687 Pine Ave W, Montreal, QC H3A 1A1, Canada (allansniderman@hotmail.com).

Financial Disclosures: Dr Sniderman reports receiving speakers'honoraria from Merck and AstraZeneca, serving as a consultantto Merck Schering, and receiving a research grant from AstraZeneca.Dr Furberg reported no disclosures.

Author Affiliations: Mike Rosenbloom Laboratory for Cardiovascular Research, McGill University Health Centre, McGill University, Montreal, Canada (Dr Sniderman); and Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina (Dr Furberg).

2009-01-15T23:23:00.002-05:00

Key opinion leaders: independent experts or drug representatives in disguise?

Ray Moynihan (University of Newcastle, Newcastle, New South Wales, Australia) examines the role of the influential experts paid by industry to help "educate" the profession and the public

In the world of medicine, "key opinion leader" is the somewhat Orwellian term used to describe the senior doctors who help drug companies sell drugs. These influential doctors are engaged by industry to advise on marketing and help boost sales of new medicines. Across all specialties, in hospitals and universities everywhere, many leading specialists are being paid generous fees to peddle influence on behalf of the world’s biggest drug companies.

Kimberly Elliott, who was a drug company sales representative for almost two decades in the United States, puts it directly. "Key opinion leaders were salespeople for us, and we would routinely measure the return on our investment, by tracking prescriptions before and after their presentations," she said. "If that speaker didn’t make the impact the company was looking for, then you wouldn’t invite them back."

From the age of 23, Ms Elliott worked for several global drug companies, including Westwood Squibb, SmithKline Beecham, and Novartis, leaving the industry 18 years later, only last year. Many times a top national salesperson, part of her job was developing relationships with local and national opinion leaders, also described as "thought leaders." Ms Elliott says she would pay these respected doctors $2500 (£1280; 1610) for a single lecture, which was largely based on slides supplied by the company. Sometimes the company would pay the fee to an academic centre, which would then pay the doctor. "These people are paid a lot of money to say what they say," she said. "I’m not saying the key opinion leaders are bad, but they are salespeople just like the sales representatives are.

(Link to full text of BMJ article here)

(See also, readers' Rapid Responses, including one from PharmedOUT's Adrianne Fugh-Berman)

2009-01-12T18:53:00.001-05:00

Marketing through Misinformation and Manipulation: The Neurontin (gabapentin) Legacy

by UCSF's C. Seth Landefeld, MD and Stanford's Michael A. Steinman, MD

(Ya see, there are a few honest docs out there still!)

Some excerpts:

Patented in 1977 and approved by the Food and Drug Administration (FDA) in 1993 in doses of up to 1800 mg per day as adjunctive therapy for partial complex seizures, Neurontin became a surprise blockbuster for Parke–Davis, a division of Warner–Lambert, which was purchased by Pfizer in 2000. U.S. sales rose from $98 million in 1995 to nearly $3 billion in 2004 before Neurontin faced generic competition and lost most U.S. sales.

The rise of Neurontin would have been unheralded except for a quirk of fate: a young biologist, David Franklin, went to work for Parke–Davis on April 1, 1996. Fresh out of postdoctoral training at Harvard, Franklin soon grew concerned that he was participating in illegal marketing. At a training seminar for "medical liaisons" on April 16, 1996, Franklin and his peers were told that FDA regulations required a fair and balanced presentation and prohibited promotion of a drug for off-label uses, selling by medical liaisons, and soliciting of inquiries from physicians. Six days later, a Parke–Davis executive reportedly told Franklin,

I want you out there every day selling Neurontin. . . . We all know Neurontin's not growing for adjunctive therapy, besides that's not where the money is. Pain management, now that's money. Monotherapy [for epilepsy], that's money. . . . We can't wait for [physicians] to ask, we need [to] get out there and tell them up front. Dinner programs, CME programs, consultantships all work great but don't forget the one-on-one. That's where we need to be, holding their hand and whispering in their ear, Neurontin for pain, Neurontin for monotherapy, Neurontin for bipolar, Neurontin for everything. I don't want to see a single patient coming off Neurontin before they've been up to at least 4,800 mg/day. I don't want to hear that safety crap either, have you tried Neurontin, every one of you should take one just to see there is nothing, it's a great drug.

Three months later, Franklin left Parke–Davis and filed a suit (ultimately, United States of America ex rel. David Franklin vs. Pfizer, Inc., and Parke-Davis Division of Warner-Lambert Company) alleging that off-label marketing of Neurontin constituted "false claims" designed to elicit payments from the federal government. On May 13, 2004, Warner–Lambert agreed to plead guilty and to pay more than $430 million to resolve criminal charges and civil liabilities. A class-action suit was filed the next day in federal court on behalf of private parties who had paid for illegally marketed Neurontin; this case (now known as In Re: Neurontin Marketing, Sales Practices, and Products Liability Litigation) remains active.

The Franklin case placed more than 8,000 pages of corporate documents in the public domain; these documents are now available in a searchable digital library at the University of California, San Francisco (www.dida.library.ucsf.edu). The class-action suit also generated detailed testimony and reports that are available through the Federal Judiciary's Public Access to Court Electronic Records Service Center (e.g., https://ecf.mad.uscourts.gov/doc1/09502786849).

...

The Neurontin marketing plan consisted of both general strategies — such as the promotion of Neurontin use among high-prescribing physicians and cultivation of thought leaders — and tactical programs.2 Local physicians were recruited, trained, and paid to serve as speakers in "peer-to-peer selling" programs, which the company saw as "one of the most effective ways to communicate our message." Academic leaders were solicited with educational grants, research grants, and speaking opportunities; some received up to $158,250 over a 4-year period. Advisory boards and "consultants" were convened so that the firm could cultivate relationships with them and deliver "a hard-hitting message about Neurontin."

Marketing "tactics" included education, publications, and research whose promotional intent was disguised, in addition to more transparent activities, such as advertising and sales visits.2 "Educational programs" reflected the belief that "medical education drives this market!" Teleconferences involving practicing physicians were moderated by physicians who were paid as much as $176,100 over 4 years. Parke–Davis formed speakers bureaus and sought "strong Neurontin advocates and users to speak locally for Neurontin." "Unrestricted educational grants" were made to for-profit medical-education companies that produced programs to discuss unapproved uses of Neurontin and to grant credit approved by the Accreditation Council for Continuing Medical Education.

...

What is Neurontin's legacy? First, we have learned that pharmaceutical marketing can be comprehensive, strategic, well financed, disguised as "education" and "research," influential, and very effective. Promotion of Neurontin was neither discrete, compartmentalized, nor readily apparent; instead, it was intercalated in nearly every aspect of physicians' professional lives, from the accoutrements of practice to lectures, professional meetings, and publications. Although some pharmaceutical marketing may be less opaque, deceptive, and manipulative, evidence indicates that drug promotion can corrupt the science, teaching, and practice of medicine.

Second, such comprehensive marketing involved many people and institutions that apparently failed to recognize the serious ethical and legal problems with their actions. Employees of Parke–Davis, the medical-education companies it hired, and many physicians (consultants, advisors, educators, and researchers) all participated knowingly. Universities, hospitals, professional organizations, and foundations also participated, and oversight agencies such as the FDA and the Department of Justice did not intervene quickly. Apparently, there was a shared acceptance that Parke–Davis's marketing was simply business as usual.

2009-01-06T07:52:00.007-05:00

Caveat Lector, the Sequel

Tangle of Interests and Disclosure Omissions Cracks Authors' Case for Early, Aggressive Treatment

'Treatment Perfected'

Parallel realities, of sorts, presented themselves last month to medical literature news junkies -- which includes a goodly share of the TAG team. Consider this December entry into the public conversation vis-à-vis the recently resurrected "When to start?" debate.

The journal: University of Chicago's highly esteemed Clinical Infectious Diseases (sister journal to the more well known, Journal of Infectious Diseases or "JID")

The paper: "The Case for Earlier Treatment of HIV Infection," a review article which appeared in the December 1, 2004 issue.

The authors: Diane Havlir (formerly of UCSD and now at UCSF), Frank Palella (Northwestern U.), Scott Holmberg (CDC), Ken Lichtenstein (Rose Medical Center, Denver, CO)

The conclusion: With the advent of easier to take, less toxic antiretrovirals, physicians may want to start treating asymptomatic individuals at CD4 cell counts above the currently recommended 350 threshold.

Quotable Quotes

"We note a growing body of evidence suggesting that earlier treatment with newer, better, and safer drugs is associated with improved survival, more effective immune-system improvement, less toxicity and drug intolerance, and other clinical and public health benefits."

"We think that the issue of toxicity, a frequent reason that clinicians delay therapy, needs reconsideration."

"The list of novel drugs available for inclusion in 'salvage' antiretroviral therapy regimens continues to grow."

Presented as it was in CID, the weight of the authors' collective prestige lends an element of credibility to an argument that might otherwise be greeted with a deservedly familiar skepticism. "Have Viread and Reyataz really altered the therapeutic landscape so much that we must now revisit the age old question of when best to start treating asymptomatic individuals? According to these Key Opinion Leaders, it has. But wait, the plot thickens.

The journal's conflict of interest disclosure policy requires authors to list any financial relationships with drug and diagnostics companies that could be perceived as prejudicial to their judgment. The authors thus complied by submitting the following:

Potential conflict of interests: "FJP has served on speakers' bureaus for Bristol-Myers Squibb, Gilead Sciences, and Roche Pharmaceuticals. All other authors: no conflicts."

As a reader, it's one thing to come across this provocative pitch (access to which was made free to the public and then basically parroted on all but one or two of the HIV Web sites) accompanied by the requisite footnotes indicating if and where the authors might have something to gain from their interpretation of the literature. Dr. Frank Palella (and in a companion editorial commentary, Drs. Brian Boyle and Calvin Cohen, where they "yearn" for the day when all HIV-positive people are on 100% suppressive therapy) is to be recognized for his candor. The larger question is whether it is appropriate for physicians who have been supplementing their income (sums conceivably rising to the low six figures annually) by doing traveling shows on behalf of the makers of Reyataz, Truvada and Fuzeon to be authoring papers where no new data are presented and where no peer-review occurs.

That same candor was missing for two of the paper's other co-authors. Hadn't Dr. Diane Havlir, Doug Richman's UCSD protegée, reported a string of consulting gigs for Tibotec and Monogram in Richman's throw-away journal Topics in HIV Medicine a short while back? No mention of them here. BMS, Gilead, and Glaxo have also been generous to Havlir's program -- a disclosure she was required to make earlier in 2004, but not in CID.

Researchers, understandably, only grudgingly make these details public, regarding quarter-column length financial disclosures as a tad embarrassing. (At the ACTG, FDA AVAC and the PHS guidelines panel, for example, this information, although requested, is treated top secret and carefully guarded in-house.)

Not to be outdone, Dr. Ken Lichtenstein turns out to sit on the advisory boards (a prized post in the pharma consulting world), of BMS, Glaxo and Gilead -- as well as a spot on the traveling lecture circuit for Abbott and Merck. None of these was mentioned in the CID article.

One might ask what purpose these essentially voluntary (and easily finessed) disclosure requirements serve if (A) the journals don't bother to vet them and (B) those potentially in hock up to their stethoscopes (should they ever find time to don one) are allowed to live these double lives and then carry on with business as usual. Mightn't it be time to give them some teeth? In this particular case, what will it take for reputable journals such as CID to reconsider its position on allowing physicians with these sorts of conflicts of interest to author editorial and review articles -- where no new data are presented? The New England Journal of Medicine and JAMA have had clearly defined restrictions in place for years.

Transparency in these matters is vital, as the guidance and sway of these pharma-funded talking heads exert a powerful and under-appreciated influence on not only the course of AIDS research and drug development efforts but, perhaps more importantly, also on the evolution of clinical care and the long-term well-being of all HIV-positive people struggling to stay alive and well.

Epilogue

Subsequent to our raising the above concern, the editors of CID posted the following erratum on the CID Web site:

Erratum
An error appeared in an article in the 1 December 2004 issue of the journal (Holmberg SD, Palella FJ Jr, Lichtenstein KA, Havlir DV. The case for earlier treatment of HIV infection. Clin Infect Dis 2004; 39:1699 704). In the Acknowledgments section, statements regarding potential conflicts of interest were omitted for Diane V. Havlir and Kenneth A. Lichtenstein. The corrected statements are below. The authors regret this error.
Potential conflicts of interest: F.J.P. has served on the speakers' bureaus for Bristol-Myers Squibb, Gilead Sciences, and Roche Pharmaceuticals. D.V.H. has received grant and research support from BristolMyers Squibb, Gilead, and GlaxoSmithKline. K.A.L serves on advisory boards and speakers' bureaus for Bristol-Myers Squibb, GlaxoSmithKline, Abbott Laboratories, Gilead, and Merck. S.D.H.: no conflicts.

2008-12-31T19:13:00.003-05:00

Marcia Angell in January 15th New York Review: "The Corruption of Doctors"

My fave quotes:

"It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgment of trusted physicians or authoritative medical guidelines."

"One result of the pervasive bias is that physicians learn to practice a very drug-intensive style of medicine."

"While the ["medicate everyone--forever" marketing] strategy originated within industry, it could not be implemented without the complicity of the medical profession."

"Although industry-academic collaboration can make important scientific contributions, it is usually in carrying out basic research--not clinical trials--and even here it is arguable whether it necessitates the personal enrichment of investigators."

"[Physicians] should pay for their own meetings and continuing education."

"[In all the recent talk about controlling conflicts of interest] there seems to be [more] a desire to eliminate the smell of corruption--while keeping the money."

TK: Match game

Match the famous academic physician to his or her personal bonanza scheme:

Dr. Joseph L. Biederman (Harvard)
Dr. Alan F. Schatzberg (Stanford)
Dr. Charles B. Nemeroff (Emory)

2008-12-03T22:48:00.000-05:00

Roche exec says DTC drug ad were "single worst mistake" for the drug industry

By Ben Hirschler

LONDON, Dec 2 (Reuters) - U.S.-style direct advertising to consumers has been a big mistake for the global drug industry, undermining the reputation of the sector in the eyes of patients, according to a top executive at Roche.

"Direct-to-consumer promotion was the single worst decision for the industry," William Burns, the Swiss group's head of pharmaceuticals, told an FT conference in London on Tuesday.

"When industry says we're spending all the money on R&D but actually it's spending it on TV advertising to preserve margins, it doesn't get much credibility," he added.

Direct-to-consumer (DTC) advertising of prescription drugs is only permitted in the United States and New Zealand.

It has been embraced enthusiastically by makers of drugs used in primary care, but the practice has been attacked by some consumer groups, especially in the wake of the 2004 withdrawal of Merck & Co's (MRK.N) heavily promoted painkiller Vioxx.

Angus Russell, chief executive of Britain's Shire (SHP.L), which, like Roche, focuses on specialty rather than primary-care medicines, also condemned DTC.

A total of $4.2 billion was spent on DTC drug ads in the U.S. in 2005, up 330 percent from 1996, according to a study last year in the New England Journal of Medicine.

A worsening economic climate and a growing threat from generic versions of many of today's blockbuster medicines means the economics of spending big bucks on advertising drugs with only marginal benefits over rivals could be changing anyway.

"The marginally-different-and-market-it-like-hell model is over," Burns said.

But while the U.S. had gone overboard in allowing drugmakers to promote direct to patients, Europe was too restrictive, he added.

Companies have long campaigned against rules that prevent them from talking directly to consumers in Europe, despite a wealth of often unreliable information being available on the Internet.

The European Commission is drawing up legislation that would allow a degree of information to be disseminated about medicines by their makers, though advertising pharmaceuticals would remained banned.

The package of legislation was initially expected to be unveiled by the European Union's executive arm last week but has been delayed.

"You've got the two extremes on the planet, where we are given access to the public in America, which is too much, and in Europe we're not given access to information," Burns said.

2008-11-28T12:37:00.003-05:00

November Revisions/Updates to DHHS Adult & Adolescent HIV Treatment Guidelines

November 19, 2008 — On November 3, the Department of Health and Human Services (DHHS) issued revisions to the January 2008 guidelines for the use of antiretroviral agents in HIV-1 in adults and adolescents. These guidelines were developed by approximately 30 voting members of the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents (a Working Group of the Office of AIDS Research Advisory Council) and are posted online at AIDSinfo Web site.

Specific changes in content from the January 2008 guidelines are as follows:

A new table suggests laboratory tests to perform at baseline and during antiretroviral treatment to monitor for efficacy and safety issues.
In patients with viral loads 500 to 1000 copies/mL, resistance testing should be considered, although it may not always be reliable at these levels (level of evidence, BII).

Specific changes regarding what to prescribe for antiretroviral-naive patients are as follows:

For protease inhibitor–based regimens:
- Ritonavir-boosted darunavir (Prezista™) has been added as a preferred protease inhibitor component (level of evidence, AI).
- Except for pregnant women, once-daily ritonavir-boosted lopinavir (Kaletra™) has been moved from an alternative to a preferred protease inhibitor component (level of evidence, AI).
For dual-nucleoside reverse transcriptase inhibitor (NRTI) options:
- Abacavir plus lamivudine have been moved from a preferred to an alternative dual-NRTI component. This decision results from large observational cohort studies suggesting an increased risk for myocardial infarction in patients with high cardiac risk factors, and concerns regarding virologic potency in patients with baseline viral loads 100,000 copies/mL.
Combinations no longer indicated or that should be used only with caution are as follows:
- Because of efficacy concerns, a combination of unboosted atazanavir plus didanosine plus emtricitabine (or lamivudine) is not recommended (level of evidence, BI).
- Because several small studies suggested early virologic failure, the combination of nevirapine plus tenofovir plus emtricitabine (or lamivudine) should be used only with caution and with close monitoring of virologic responses (level of evidence, CII).

The guidelines reiterate that antiretroviral drugs cannot eradicate HIV.

2008-11-28T11:56:00.000-05:00

Ask Your Doctor?

The high-profile child psychiatrist who first put childhood ADHD on the map is unhappily back in the news. The backstory on his ties to Big Pharma.

(from WGBH/Frontline site)

“All of a sudden, out of nowhere, bipolar disorder was being diagnosed left, right and center.”

—David Shaffer, M.D., Chief, Child Psychiatry, Columbia University

Dr. Joseph Biederman, an influential child psychiatrist, made embarrassing news last June when it was revealed that he had failed to disclose over a million dollars in fees from drug companies whose antipsychotic medications he had promoted to treat bipolar disorder in children.

Now the controversial Dr. Biederman is back in the headlines, this time over new conflict of interest questions regarding his financial ties to pharmaceutical giant Johnson and Johnson. For the latest developments on the story, see The New York Times and The Wall Street Journal. For the full backstory, take a look at The Medicated Child, FRONTLINE's recent hour on the dramatic rise in diagnosis and drug treatment of ADHD and bipolar disorder in children. Veteran FRONTLINE producer Marcela Gaviria tells the moving stories of families struggling to help their children cope with the pain and confusion of conditions that may, or may not, be susceptible to pharmaceutical solution.

The brief excerpt from the film on this page spotlights Dr. Biederman's seminal role in the story. You can also watch the entire program, and dig deeper into the subject, on this webpage. And for deeper background still, you can see Marcela's previous FRONTLINE, Medicating Kids, broadcast in 2001, on the early days of ADHD diagnosis, and the contentious battles fought over whether and how to treat it.

One final source to recommend: Judith Warner has written thoughtfully in her NY Times blog on how hard it is to assess the pros and cons of antipsychotic medications for children.

2008-11-19T11:37:00.006-05:00

No pro-pharma, pro-drugsforlife bias @ pharma funded news, conference coverage and 'educational' web sites? Firewall, my Aunt Fanny! Try this simple experiment:

Google (or dogpile, jeeves, Yahoo!, or your search engine of choice) the following key words:

LOTTI Medscape (0 articles LOTTI trial)
LOTTI TheBody (0 articles on LOTTI trial--but a very nice PREZISTA banner ad!)
LOTTI TheBodyPro (0 on LOTTI--but a poll about whether CD4 count of "500 should become the new 350")
LOTTI Clinical Care Options (0 articles, and no CME programming, on LOTTI results)
LOTTI aidsmeds (1 article at poz.com sister site)
LOTTI poz.com (1 article)
LOTTI hivandhepatitis (1 article)
LOTTI aidsmap (1 fantastic summary analysis with quotes from PI and comment)

And see what you get.

Medscape HIV: Nothing. The Body & The Body Pro: Nada. Clinical Care Options: Null encore!!

Only aidsmap and poz have deemed this huge event worthy of coverage. Oh, and Brian Boyle's lesser known hivandhepatitis.com site. Probably thanks to ace reporter Liz Highleyman.

Go figure.

You could try the same experiment replacing "FOTO study" or "FOTO study Glasgow" or "FOTO hiv drug therapy congress," and the results are likely to be similar but not quite as striking. (I haven't tried that one yet.)

Why LOTTI?

Well LOTTI is the latest Structured Treatment Interruption study to bear fruit and, notably, come to strikingly different conclusions that the hotly hyped if incongruously acronymized SMART (aka CPCRA 065) study.

Whereas the ill-conceived CPCRA design (stopping patients' therapy when their (already historically very low) CD4 cell counts reached the 350 mark--and not re-starting them until their CD4s fell below 250!!) provided drug happy talking heads, KOLs and pharma funded med ed sites much needed ammunition to squelch a patient revolt against lifelong polypharmacy, the 4-year Italian "LOTTI" study showed that intermittent treatment of patients with CD4 counts over 350 can be just as safe and effective as continuous antiretroviral treatment.

The results were presented earlier this month Dr Franco Maggiolo (Bergamo, Italy) at a meeting of the Ninth Congress on Drug Therapy in HIV Infection in Glasgow, Scotland.

It is important to note that the "trigger" thresholds in this study, like many other studies who reported successful experiments with "on/off" or cycles of antiretroviral therapy, were significantly HIGHER than the ill-considered start/stop triggers of SMART: folks in the LOTTI trial did not go off their ARVs until their CD4 counts reached 700--and, during routine monitoring, went back on the drug if and when their CD4s fell below 350.

Incredibly, the folks in the treatment interruption group were able to stay off therapy for two-thirds of the time compared to those who followed the (current standard-of-care consensus) of continuous ARV treatment. And in those lucky ones whose historical CD4 count trend had never fallen below 500 cells, they were able to stay off therapy during 85% of the 4-year follow-up: that's nearly 3 1/2 years folks!

At study entry & screening, a full two-thirds of trial participants had had a CD4 cell count less than 350 cells/mm3, and thus would have been candidates for ARV therapy under current guidelines.

The heart attack/stroke & diabetes score?

4 patients on continuous treatment had cardiovascular disease requiring hospitalisation compared to ZERO on CD4-guided therapy
6 patients on continuous treatment developed diabetes compared with ZERO on interrupted treatment
Overall, the incidence of cardiovascular and metabolic events occurred in 10.5% of folks on continuous ARV therapy compared to 1% of Treatment Interruption folks.

Dr. Wafaa El Sadr, or anyone else from the CPCRA 065 (aka SMART) protocol team, was unavailable for comment.

In short, the LOTTI protocol designers are the ones who designed a smart study--while the CPRCA bozos, true to form, spent years and years and surely hundreds of thousands of dollars of FTE and conference call time only to come up with a study design that was both uncommonsensial and doomed from the start.

My TAG friend, who happens to be the only one left at that shop actually serving the organization's founding mission (i.e., advancing the HIV research and treatment agenda so that one day we can actually cure (and/or prevent) this friggin' disease) beseeches me not to besmirch the good name of the late Carlton Hogan who, it seems, had a heavy hand in the design of said CPCRA 065. So even though Carlton rarely saw eye to eye on many issues (remember the ill-advised Coalition for Salvage Therapy for which he ripped me a new a-hole when I criticized it for its myopia?), I would like to officially state that I bare him no ill will on this score and greatly respect his overall contribution as a vocal and informed proponent of sorely needed clinical research that was directly relevant to the lives of people living with HIV/AIDS.

But back to LOTTI.

Maggiolo commented that the average follow-up time in SMART had been just over a year compared with four years in his study and that if the LOTTI study had been stopped at the same timepoint as SMART, no difference would have been observed in cardiovascular and metabolic events either. His study demonstrated that it took a long time for the benefits of therapy-sparing regimes to become evident.

He also said that in his study 95% of patients had CD4 counts over 350 compared with 65% on SMART and 0.5% below 250 compared with 8.6% on SMART, which might explain the higher mortality and morbidity rate seen in patients off treatment in the latter.

Maggiolo commented that doctors might like to see more evidence before making STI’s on the LOTTI model standard clinical practice, but when asked what it would take to change clinical practice commented, “It already is mine. It’s not for every clinician or every patient, but it’s a safe option for some.”

LOTTI now joins a host of other, mostly European based, treatment interruption trials that come to strikingly different conclusions than the ubiquitously headline making SMART study. Is it any coincidence that the study (yes, okay, it was huge and came to a speedy if trebly grim conclusion) that pretty much TERRORIZES patients to stay on expensive and toxic ARVs for life is the one that garners all the press?

Until I get time to summarize (maybe even add the golden if predictable UK formula of Comment and Analysis) the LOTTI (and FOTO) study results here at the shillfactor blog, I recommend a visit to the exquisite news & info (but tellingly, NOT CME accredited content containing..) site of that cracker jack London based team at the National AIDS Manual: aidsmap.com. (See Gus Cairns' great report, "Treatment Breaks Set for a Come-back?")

In fairness, both poz.com (to which the aidsmeds.com URL now sends you) and Brian Boyle's site hivandhepatitis.com do have short reports on the LOTTI results.

2008-11-17T23:41:00.001-05:00

Kidney Disease Takes A Growing Toll

from today's Science Times (David Tuller reporting)

The National Kidney Foundation, with an annual budget of $85 million, plays a major role in education, policy, research and treatment. The organization provides free screening for adults at risk for kidney disease, publishes a leading journal in the field, lobbies on treatment and policy issues, and conducts extensive public education and outreach.

But it has come under criticism on several fronts, in particular its close financial ties to the pharmaceutical industry. The agency greatly influences clinical care through the development of guidelines to advise doctors on various aspects of the illness. Critics say the guidelines have benefited drug makers, who are major contributors to the foundation.

“These (clinical) practice guidelines are widely disseminated and heavily influenced by industry, and they come down on the side of recommending higher levels of treatment,” said Dr. Richard Amerling, director of outpatient dialysis at Beth Israel Medical Center in New York.

In 2006, the organization published new guidelines for treating anemia associated with chronic kidney disease. The guidelines were underwritten with support from Amgen, which markets a drug for anemia, and some members of the panel that developed the guidelines had financial ties to the industry.

The kidney foundation guidelines called for raising red blood cell counts to levels higher than those recommended by the Food and Drug Administration, and many nephrologists criticized the guidelines as biased in favor of industry. After new clinical trials suggested that more aggressive treatment could cause an increase in deaths and heart problems, the foundation revised the guidelines.

Ellie Schlam, a spokeswoman for the foundation, said the organization was vigilant “to ensure that no sponsorship funds contributed to the N.K.F.” would influence the content of any guidelines.

2008-11-14T16:12:00.003-05:00

HIV+ leukemia patient in Berlin said to have been admitted back to hospital due to complications of procedure

Latest update, and a couple of medical references, courtesy of Richard Jefferys of the Treatment Action Group:

Many of you probably remember this, but I had forgotten: there have been previous reports of BMT resulting in HIV-free individuals. See, for example, Huzicka I, "Could bone marrow transplantation cure AIDS?: A review," Medical Hypotheses 1999; 52(3): 247-257). Trouble is, most of them died within a year.

And here is a second, and more recent, paper (letter, actually, from a Paris hospital), thanks so our friends at the top notch aidsmap.com shop, that RJ did not send me: Avettand-Fenoel V et al. "Failure of bone marrow transplantation to eradicate HIV reservoir despite efficient HAART." AIDS 21 (6):775–786, 2007.

Rumor has it that even this latest "Berlin patient" has been sent back to hospital due to complications from the transplant. I am trying to find out more on this.

Everyone pretty much agrees that both Gallo's and Fauci's quotes in today's NYT (and perhaps even David Baltimore's in last week's WSJ) were rather self-serving and lame. But this is politics as well as science, folks!

Back to my old TAG colleague though:

The massive ablation of immune system cells involved in the procedure was almost certainly a big part of whatever has happened with this (second) "Berlin patient."

With all due respect to Dr. David Baltimore, "proof of concept" for gene therapy is a bit of a leap. No gene therapy is going to wipe out someone's immune system cells. And given the risks of total immune ablation, I can't imagine you'd want to do it if it weren't absolutely necessary.

Finally, there are definitely non-T cell reservoirs of HIV: so any CD4 T cell-specific gene therapy would seem unlikely to be sufficient to actually rid the body of HIV.

John Rossi, Chair of the Division of Molecular Biology and Director of City of Hope National Medical Center in northeast Los Angeles, is studying a combination gene therapy approach with three different targets, but whether it can address all the different tropisms of the virus (macrophages, glial cells in brain, dendritic cells, et cetera) remains to be determined.

It'd be nice if there were some way of reducing latent virus and viral reservoirs that didn't carry a significant risk of mortality--as bone marrow transplantation do.

And it seems at least 3 different biotech companies are in early testing of related gene therapies, delivery systems or RNAi:

Sangamo BioSciences - "Zinc Finger Protein Transcription Factors (ZFP TFs) for Therapeutic Gene Regulation"

UCLA AIDS Institute (Dr. Irvin Chen), as mentioned in NYT article - Sounds like RNAi, no?

City of Hope Cancer Center (Dr. John Rossi), as mentioned in WSJ article - Also sounds like RNAi

VIRxSYS - Proprietary lentivirus vector delivery system. "The only one in human trials."

If anyone reading this update has anything to add to this little summary, please feel free! Nice weekends, all...

2008-11-13T09:58:00.004-05:00

STEP study manuscript now available online at Lancet.com

(Double-blind, phase II, study of 3,000 volunteers in North America, the Caribbean, South America, and Australia of Merck's failed HIV vaccine: MRKAd5 HIV-1 gag/pol/nef)

From the Discussion section:

Surprisingly, we noted an increase in the number of HIV-1 infections in male recipients of the vaccine. These effects seemed to be restricted to men who were Ad5 seropositive or uncircumcised, or both, on multivariate analyses, and were not confounded by other demographic and risk variables measured at baseline. However, this finding does not rule out confounding by variables that have not yet been measured, such as baseline serostatus of herpes simplex virus type 2 (HSV-2) or host genetic factors, which are presently being measured in cryopreserved specimens. Other potential confounders, such as sexual network clustering, are being explored through viral genotyping.

Evidence for a mechanism for increased acquisition risk associated with this candidate or other adenovirus-based HIV vaccines is scarce in published work. Antibody-dependent enhancement has been described for many viral infections.43, 44 So far, such enhancement has been directed at surface envelope proteins, and the MRKAd5 HIV-1 gag/pol/nef vaccine did not contain envelope inserts. A candidate HIV vaccine using a recombinant varicella-zoster virus (VZV) vector that led to enhanced SIV replication and disease progression in rhesus macaques has been reported, although the investigators did not assess the effects on SIV acquisition.45 The VZV vaccine elicited a robust SIV-specific CD4+ T-cell response without a measurable CD8+ T-cell response, which is quite different from the immunological profile of the trivalent vaccine.

The mechanism for enhanced HIV-1 acquisition risk in vaccinated Ad5-seropositive men is probably complex. All people receiving the vaccine are likely to have developed both Ad5 antibodies and T-cell responses to the vector; thus, none of the recipients were probably Ad5 seronegative after the first immunisation. However, natural Ad5 infection occurs via the nasopharynx or gut, can persist at mucosal surfaces over several years, and preferentially infect lymphocytes that home to mucosa.46 People receiving vaccine with pre-existing Ad5 immunity might generate an Ad5-specific immune response that homes to mucosal surfaces, whereas those with vaccine-induced Ad5 immunity might not. Studies are underway to further explore differences in the mucosal immune response between participants with and without pre-existing Ad5 immunity. Conversely, the repeated administration of the Ad5 vector might cause an as yet undefined effect on the immune response that led to increased HIV-1 acquisition. Whether the effects of this vaccine apply to other adenovirus-based HIV vaccines, including those using alternative serotypes, is not yet clear. Until the mechanism for these effects can be clarified, clinical trials of novel adenovirus-based HIV vaccine candidates should include safeguards to keep potential risk to study volunteers to a minimum (eg, restricting study enrolment to subgroups without evidence of vaccine-associated increased risk, close study monitoring, and extensive discussion of risk during informed consent process).

Circumcision is associated with halving the risk of HIV-1 acquisition in men who have sex with men in a longitudinal study,47 although data from cross-sectional studies and smaller longitudinal studies have been mixed.48—50 The protective effect of circumcision can be more difficult to show for men who engage in both insertive and receptive anal sex, and might therefore be most concentrated in men reporting unprotected insertive anal sex with HIV-positive partners or those whose serostatus is unknown. In this study, uncircumcised men receiving vaccine were at increased risk of HIV-1 acquisition compared with uncircumcised participants receiving placebo, especially in men reporting high-risk insertive anal sex. Conversely, the risk of HIV-1 acquisition did not seem to be more concentrated in uncircumcised men reporting high-risk receptive anal sex at baseline, nor did circumcised men seem to be at increased risk, irrespective of their sexual practices. These results call for further inquiry into assessment of the mucosal response to this and other vaccines, and the potential interaction of mucosal immune responses to pre-existing vector immunity.

The Step Study has also deepened our understanding of the potential, and potential pitfalls, of present non-human primate challenge models. A prototype replication incompetent Ad5 vaccine based on an earlier Ad5 gag-only vaccine (Merck) provided substantial and durable control of viral replication against SHIV 89.6P challenge,14 particularly in animals with genetic markers associated with virological control.25, 27 Results from the Step trial suggest that this model is not a useful predictor of the use of T-cell-based vaccines in human beings.51 Other non-human primate challenge studies of this candidate vaccine have shown a more transient protection against SIVmac239 that might depend on a DNA prime25 or inclusion of additional gene inserts;26 however, the use of these challenge models has also not yet been proven.52 If vector-based immunity has an important role in the quality of the immune response generated to vaccines, animal models might not predict clinical experience, especially when the vector does not naturally infect animals used in these models.

The Step Study has challenged the field to improve understanding of the role of vector-based immunity, the potential for vaccine-induced increased acquisition, and to use the data and specimens in this human trial of a cell-mediated immunity vaccine, to understand the vaccine's failure. Additional coordinated efforts will be needed to provide definitive answers to these questions, and ultimately to develop a safe and effective HIV vaccine.

2008-11-13T07:54:00.003-05:00

Coming later today: Making sense of the new Framingham statin (i.e., Crestor/rovustatin) study results through the lens of our 20 years' experience in the push for early, lifelong treatment of HIV

In the meantime, there is a decent examination of the JUPITER trial and its implications at the Nature News site--along with some very interesting comments.

Also: from WSJ blog: "AstraZeneca CEO Downplays Jupiter’s Effect on Crestor Sales"
and Forbes.com: "Missing the Point on Crestor"

2008-11-11T11:31:00.000-05:00

Study Examines Use of Modified CD4+ T Cells To Fight HIV/AIDS

(This is separate approach from the gene therapy modified HIV "resistant" CD4+ T-cells, à la last week's Berlin bone marrow transplant report.)

[lifted from Kaiser which lifted it from The Guardian]

A new therapy that involves engineering an HIV-positive individual's own immune system to fight the virus more effectively has been developed by researchers at Adaptimmune in Oxford, England, London's Guardian reports (Randerson, Guardian, 11/10). The therapy involves genetically engineering CD4+ T cells, called "assassin" cells by the researchers, which were able to recognize other cells infected with HIV and slow the spread of the virus. According to Reuters, if the therapy -- which worked in laboratory tests -- is effective in humans, it could provide a new method of treating HIV (Fox, Reuters, 11/9). The therapy was detailed in a study published on Sunday in Nature Medicine.

According to the Guardian, researchers began to pursue a different approach to a traditional HIV vaccine after investigating a patient who had "resisted his HIV infection particularly effectively." Researcher Bent Jakobsen said, "When we tested the T cells from this patient, it looked as if he was responding to a number of those variants that normally escape the immune system." In developing the therapy, the Guardian reports that the researchers first isolated the T cell receptor protein, which can recognize HIV antigens, and then improved its ability to recognize HIV further by randomly mutating it. The therapy will involve taking blood samples and adding an engineered virus that contains genes for the improved T cell receptor. A patient's T cells then take up the genes and are thus equipped with the improved receptor. These cells are then injected back in the patient (Guardian, 11/10).

James Riley, a University of Pennsylvania researcher involved in the study, said that not only could the engineered T cells see HIV strains that had escaped detection by natural T cells, "but the engineered T cells responded in a much more vigorous fashion so that far fewer T cells were required to control infection." Researcher Andy Sewell of Cardiff University said, "In the face of our engineered assassin cells, the virus will either die or be forced to change its disguises again, weakening itself along the way" (Reuters, 11/9). The Guardian reports that a clinical trial of the therapy will take place next summer among 35 participants at the University of Pennsylvania (Guardian, 11/10).

2008-11-09T11:36:00.000-05:00

Researchers testing a Dutch biotech company's experimental HIV/AIDS vaccine that is based on T cells said it was effective among six rhesus monkeys. For the study, published in the journal Nature Medicine, the monkeys were injected with a lethal dose of SIV, the simian version of HIV. When injected, they were able to stop replication of the virus and remained healthy for more than 500 days after infection (AFP/Google.com, 11/9).

According to Dan Barouch of Beth Israel Deaconess Medical Center and Harvard Medical School, the study shows there is still hope for developing an effective HIV/AIDS vaccine (Reuters, 11/9). Barouch added, "Despite the disappointing setbacks in HIV-1 vaccine development this past year, our findings suggest that we're not at the end of the road when it comes to T cell vaccines" (AFP/Google.com, 11/9).

2008-11-07T16:22:00.014-05:00

U.S. leukemia patient in Berlin hospital, bone marrow transplanted with genetically modified CD4 cells, called "proof of concept" for gene therapy approach to virus-proofing the human body* against HIV

(As reported in today's WSJ by Mark Schoofs)

*But what about macrophages, dendritic cells, glial cells in the brain, et cetera?

My old and valued TAG colleague, Richard Jefferys, notes that there have actually probably been other reports of immune system ablation+BMT that resulted in HIV-free folks (see Huzicka I, "Could bone marrow transplantation cure AIDS?: A review," Medical Hypotheses 1999; 52(3): 247-257). The only catch is that most are all of these patients didn't live—due to complications from the procedure. On a personal note, an NP friend of mine at SVH underwent a BMT at Dana-Farber Cancer Institute in Boston in the mid-1990s and, while serious and long recovery, she is doing fine. She was not HIV-positive.

Among the 20 or so comments posted by 10:30 a.m. Friday morning in New York, these appeared worthy of reproducing:

November 14, 2008 8:06 am

Reading those shallow, idiotic quotes from Fauci and Gallo - so obviously not viewing the case from the perspective of someone with HIV, but through the prism of their own vast egos - it's hardly surprising that there's so much distrust of our supposed scientific research leadership. Fauci tells us he's not surprised, because he's just that smart. Gallo is dismissive, because it's not something he had anything to do with. Neither offer any actual useful information on whether there is anything to be learned from the case. There have actually been two reports of possible eradication in bone marrow transplantation before, suggesting that the delta32 mutation may not be necessary for this to occur, but the longest survival was less than a year and although the individual in this case is said to be "recovering" it is unclear whether he may yet develop complications from the procedure.
— Richard, Manhattan

November 14, 2008 8:06 am

[N.B.: Spelling errors--and choice of 'AIDS patient' usage--were not corrected from original post.]

This is a unbelieveably momentous occasion. David Baltimore has called this a functional cure for AIDS. Tony Fauci is too conservative and calls it impractical… bullcookies. This is exactly what comes from the NIH’s extreme lack of vision. In the absence of a vaccine, with little hope on the horizon of one, a functional cure is an amazing start. I believe we can overcome the impracticality of bone marrow transplantation (allografts) to widely produce a safe and effective functional cure for AIDS.

For an AIDS patient the holy grail of any treatment needs to have the following four characteristics:

The need to not have to take any antivirals (HAART) because of their serious side effects with long term usage.
The treatment must raise their T cell count to a normal range (with it’s associated return of a functional immune system)
It must result in an absence of detectable viral load.
The treatment must be safe.

Any other criteria, (such as elimination of the infectiousness of the patient) would be an amazing bonus but are not absolutely of critical importance.

The bone marrow transplant from a CCR5-delta32 donor reported in Germany satisfied three of the four criteria. The only one it did not satisfy was safety. Bone marrow transplants are nasty business. There's chemo, radiation therapy and massive immunosuppression that has to occur. Significant complications such as uncontrollable Graft versus Host disease can occur, and thus bone marrow transplants have a 30% chance of killing the recipient. These are definitely not good odds, although an AIDS patient on her deathbed might think otherwise.

If there were a way to eliminate the need for CCR5-delta32 donors AND the need to give immunosuppressive chemo/radiotherapy the 30% risk of death could be massively lessened.

There is a company that has developed the technology to do just this.

The company is Sangamo [BioSciences] in Richmond, CA.

Editor's note: I believe Sangmo had a paper or two at last month's joint ICAAC/IDSA meeting in Washington, D.C. about this zinc finger technology in HIV. Its website says, "Sangamo anticipates filing an IND for this therapeutic in 2008." The company is also studying zinc finger technology in many of the 'big' disease areas: diabetes, congestive heart failure, cardiovascular disease, neuropathic pain.

Their technology allows an AIDS patient to give blood and from that blood have their T cells modified to become CCR5-delta32. Their technology allows surgery to be performed on the CCR5 gene of the AIDS patient's T cells outside the body (in cell culture) and have the actual gene get changed into the CCR5-delta32 version of the gene. After "operating" on these cells, large numbers are grown up in tissue culture and are then transfused back into the patient. This is essentially a bone marrow transplant to yourself. These "autologous" (to yourself) bone marrow transplants have a lethality of 10% instead of 30%... because the chemo/radiotherapy you need to take is not as harsh as when you're getting a bone marrow transplant from someone else's cells.

But wait... it get's better!!! I say this risk of death could be dropped to zero… here’s how:

In an AIDS patient, there is a war being fought between the T cells and the virus... and the virus always wins. But if you got an infusion of CCR5-delta32 T cells those cells won't be infected by HIV in the blood. The original susceptible population of cells will lose the battle and die off... but the resistant CCR5-delta32 T cells will win the war. This is exactly what happened to the guy in Germany. But if you get an infusion of your own modified T cells you should not have to take ANY chemo/radiotherapy to eliminate the resident susceptible T cells as in a normal autologous bone marrow transplant. Thus the risk of death from this type of bone marrow transplant should drop from 10% to about zero!

No chemotherapy.
No radiotherapy.
One time blood draw.
One time infusion of your own cells back into you.

The risks of complication should plummet!

They’ve done this in mice and it’s all published… do a Pubmed search for Sangamo!

This therapy is about to go into Phase 1 clinical trial at the U. of Penn. with 6 AIDS patients who have failed HAART (need to go on a structured treatment interruption because of excessive HAART side effects) and 6 treatment naive AIDS patients. This trial should be started any day now.

"ANY DAY NOW" IS NOT SOON ENOUGH!!!

Call Sangamo!
Call Carl June at U Penn!
Call the NIH!
Call your Congressman!
Call your Broker!
Call anyone who will listen!

Imagine if the clinical trials succeed!! The ability to turn active symptomatic AIDS into inactive, undetectable viral load, high T cell count, with no antivirals neccessary!!!

And the unbelieveably amazing thing is that this technology could also "cure" a host of diseases... hemophelia, Gauchers, SCID (Bubble boy disease) etc.
— Adenylyl – Investorvillage.com, Cambridge, MA

--------------------------------
Other reporting on this story from the past several days:

BBC News
Deutsche Welle
Agence France Presse
Pink News (gay UK paper)
WikiNews
AP
NYT (Don McNeil, Jr.), quoting Gallo ("Frankly, I'd rather take the drugs.") and Fauci ("very nice" but "not surprising"), finally ran with this story one week to the day after Mark Schoofs' piece appeared in the Wall Street Journal. The bottom line: "Novel case of bone marrow transplant HIV 'cure' propels search for therapies that artificially induce rare 'Delta 32' CCR5 receptor mutation."

2008-11-04T10:20:00.002-05:00

Earlier, uninterrupted initiation of antiretroviral therapy (i.e., at CD4 T-cell counts in the 400-600 range) means one thing: longer lifetime exposure to drugs whose long-term cumulative toxicities continue to be elucidated.

Four key questions for all the (pharma funded) talking heads who have been tripping over themselves post-ICAAC/IDSA to herald the ineluctable swing of the proverbial "Hit hard, hit early" pendulum at the predominantly pharma funded press conferences and conference reporting & medical education web sites:

1) Why the absence of a more science-based (or even quality-of-life) discussion?
2) Why are dissenting, even merely duly circumspect, voices not given any air time?
3) Why are the (significant) limitations and nuances of the Richard Moore observational data base study not discussed?
4) Why, even if one agrees that earlier might be better, is there no room for exploration of a "Hit early, hit intermittently" approach?

The DHHS guidelines panel, even with the addition* of cracker jack, patient-friendly, and well grounded (and active) clinicians like UCSF's Steve Deeks and Project Inform's Paul Dalton, may well capitulate to the pharma friendly forces now in command of the air waves, but it should also be pointed out the the British HIV Association and European AIDS Clinical Society treatment guidelines, arguably less influenced by the AIDS Inc. echo chamber, may hold out for less impure science.

If anyone comes across an intelligent discussion of these issues, I would be so very grateful to become aware of them. Please e-mail me at mrbarr at ATAwatch dot org. Tks!

The chorus so far:

Medscape

"Early HIV Therapy Improves Survival"

Perhaps it is not merely sloppy reporting on the once stalwart Robert Roehr, but the only 'experts' he quotes in this article for Medscape (and accredited for CME no less!!) are Scott Hammer, Dan Kuritzkes and Cal Cohen: Hardly a representative sampling of intelligent opinion. And it is unlikely that either of these guys has an active and regular HIV clinical practice.

TheBodyPro

Rethinking First-Line Therapy and HIV Patient Care in 2008: New Data and Expert Analysis

"Tantalizing signs that, when it comes to HAART initiation, 500 may one day become the new 350" -by David Wohl, MD

Dr. Wohl has been a consultant for Abbott Laboratories, Tibotec and Merck and has served on speakers bureaus for Abbott, Gilead, Roche Laboratories, Bristol-Myers Squibb, Boehringer Ingelheim, Tibotec and Merck.

Reappraising Key Issues in HIV Clinical Management

"Revisiting the "when to start" question: several studies may tilt the balance toward even earlier HAART initiation" - by Benjamin Young, MD, PhD

Benjamin Young, M.D., Ph.D., has received consulting fees from Bristol-Myers Squibb Company, Cerner Corporation, Gilead Sciences, GlaxoSmithKline, Hoffman-LaRoche, Merck, Monogram Bioscience, Pfizer, Tibotec Therapeutics and Vertex and has served on speakers bureaus for GlaxoSmithKline, Merck & Co., Monogram Biosciences and Tibotec Therapeutics.

* The recent personnel changes at the NIH guidelines panel can all too easily be lampooned as a mere re-arranging of deck chairs on the Titanic. One step forward, three steps back: while we are thrilled to see Dr. Deeks there, it came at the cost of adding Eric Daar, Paul Sax, David Wohl--not to mention Trip Gulick, Carlos del Rio, Joel Gallant, Keith Henry and Mike Saag. I guess that would be one step forward and EIGHT steps back! (There is not space here to list all the speakers bureaus and pharma advisory boards represented by this motley cast of characters. Please feel free to either track these down via a Google search (try their name and the words "financial disclosure" or "conflict of interest" in the search bar), the ShillFactor website, or Appendix A of the NIH document--as required by law.)

2008-10-28T20:12:00.002-04:00

Without any prodding, AP reporter notes "Early treatment" camp's Big Pharma ties. Maybe we're making progress after all?

This ran in the San Francisco Chronicle today, as reported from the joint ICAAC/IDSA meeting in Washington, D.C. this week:

"HIV patients should start drugs early"

Marilynn Marchione, AP

Monday, October 27, 2008

(10-27) 04:00 PDT Washington --
People who have the AIDS virus should start drug treatments sooner than current guidelines recommend, suggests a large new study that could change the care of hundreds of thousands of Americans.

The study found that delaying treatment until a patient's immune system is badly damaged nearly doubles the risk of dying in the next few years compared with patients whose treatment started earlier.

Doctors have thought it would be better to spare patients the side effects of AIDS drugs as long as possible.

"The data are rather compelling that the risk of death appears to be higher if you wait than if you treat," said Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, which helped pay for the study. [I'm no epidemiologist, but the comparative risks of waiting to CD4 of 350 compared to starting at a CD4 of 500 did not seem all that compelling: 3.0 vs. 3.2 deaths for 1,000 years of patient follow-up, a commonly used metric for measuring such things...]

If the results prompt doctors to change practice - as Fauci and other AIDS specialists predict - several hundred thousand Americans who are not taking AIDS drugs now would be advised to start.

The study was reported Sunday at an infectious diseases conference in Washington.

...

Powerful drug combinations available since the mid-1990s have transformed HIV infection into a manageable chronic condition rather than the death sentence it once was. But they can cause heart and cholesterol problems, diarrhea, nausea and other side effects. They also must be taken faithfully or resistance develops and the drugs stop working.
That is why guidelines by the government and the International AIDS Society[-USA] [The international International AIDS Society, idsociety.org, goes to great links to distance itself from the crassly commercial and self-aggrandizing IAS-USA. Caveat lector!] recommend that patients who are not yet having AIDS symptoms delay starting on the drugs until their T-cell counts fall below 350 per cubic millimeter of blood (healthy people have more than 800).

"There was this thinking, maybe the drugs were worse than the disease. If you could wait as long as you possibly could wait, you would have fewer side effects," said Dr. Robert Schooley, infectious diseases chief at UC San Diego.

...

"These studies have all shown the same thing - that we were starting too late" and need to keep treatment going once it starts, said Schooley. He helped write the AIDS society guidelines and consults for several companies that make AIDS drugs.

2008-10-27T13:31:00.002-04:00

Financial conflict of interest disclosure at 48th Annual ICAAC/46th Annual IDSA
Washington, D.C.
October 25-28, 2008

Scott and Michael (Dr. Hammer and Dr. Scheld, respectively), I guess this is a question for you: Where is the financial disclosure at this year's meeting?

IDSA used to do such a good job at providing this information. What happened?

(The woman in the conference HQ, Lauren something or other, was out when I went to ask about this. I will return today at 2 pm when she is rumored to be back in her office.)

On the bottom left-hand corner of page vii of the Final Program book, there is a little paragraph about Disclosure at this meeting. It reads, "A listing of faculty disclosures is available in the Final Program Addendum and online in the Online Program Planner."

But no such "Addendum" was ever distributed, far as I can tell, nor made available to conference delegates.

What kind of transparency is this?

I have to go online to see this stuff? I don't think so.

2008-10-27T13:21:00.001-04:00

Where were these disclosures at ICAAC/IDSA lectures and symposia today?

Judith Aberg, MD
Raphael E. Campo, MD
(Will co-chair and select papers for Tuesday afternoon session, "Complex Medical Management of HIV")
Grant/Research Support: Abbott, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck, Pfizer
Scientific Advisory Board: Abbott, Tibotec, Virco
Consultant: Merck
Speakers Bureau: Abbott, Gilead, Merck, Pfizer, Tibotec, Virco

Trip Gulick, MD, PPH
Paul Volberding, MD
(Will co-chair and select papers for Monday afternoon's session on "Current Issues and Controversie in HIV Infection Management")

Carlos del Rio, MD will present paper
Susan Swindells, MD will present paper

Doug Dieterich, MD
(Will co-chair and select papers for Monday morning's session "Challenges in Hepatitis B Management")

Diane Havlir, MD
(will speak on "Hot Topics in HIV," Monday morning, 8:30 a.m.)

Kathleen Squires, MD
Research support: Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Koronis, Schering-Plough, Tibotec
Scientific advisory board: Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Koronis, Schering-Plough, Tibotec, Tobira Therapeutics
Consultant: Merck

W. David Hardy, MD
Research support: Pfizer, Tibotec, GlaxoSmithKline, Bionor
Scientific advisory board: None
Consultant: Bristol-Myers Squibb, Boehringer Ingelheim, Pfizer, Merck, Tibotec, GlaxoSmithKline
Speakers bureau: Pfizer, Merck, Tibotec

Disclosures from August 6, 2008, "Anatomy of Antiviral Backbones"

2008-10-27T12:53:00.010-04:00

Is the Healthcare Communications Group/Clinical Care Options free, pharma sponsored business model for CME about to go the way of the Tyrannosaurus ?

With pharma (but not yet biotech) companies tripping over themselves to come clean in an effort to head off draconian legislation that threatens the very bread and butter of medical communications/PR companies, it seems the conference reporting and medical writing has hit the proverbial wall.

Or has it?

New pharma funded free-CME companies seem to sprout up every couple of days. And the field of HIV medicine is probably not even in the same league as those that focus on cardiology, oncology and less discriminating infectious diseases.

At this year's joint ICAAC/IDSA meeting, for example, there were a total of fifteen industry supported CME symposia during the dinner hours of Saturday, Sunday and Monday. Only three of these focused on HIV: a Merck dinner presentation on Saturday evening (Marty Markowitz, Dan Kuritzkes, Eric Daar--two of the three are members of CCO's Advisory Board), a Gilead-BMS-Monogram dinner presentation on Sunday evening (Cal Cohen, John Bartlett and, I believe, Sally Hodder, Marty Markowitz (again!!?), and Paul Sax); Not to be outdone by the stellear CCO line-up, Dr. Cal Cohen is actually an owner of the CME/PR company sponsoring this night's event, and a Pfizer dinner presentation on Monday night (John Bartlett (again!), Cal Cohen (again!!), Graeme Moyle, Peter Hunt (I'm actually something of a fan of Gladstone's Hunt...), Paul Sax (yet again!!?)).

Martin H. Markowitz, MD
Associate Physician, Rockefeller University Hospital, New York, NY; Adjunct Associate Physician, Cornell Medical College, Division of Infectious Diseases, New York, NY; Clinical Director and Professor, Aaron Diamond AIDS Research Center, The Rockefeller University, New York, NY

Disclosure: Martin H. Markowitz, MD, has received grants and/or research support from Merck, Gilead, GlaxoSmithKline, Pfizer, and Tibotec. Dr. Markowitz has served as a consultant to Merck, Gilead, GlaxoSmithKline, Pfizer, and Sequoia, and has served on the speaker's bureau for Merck and Gilead.

Eric S. Daar, MD
Professor of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California; Chief, Division of HIV Medicine, Harbor-UCLA Medical Center, Los Angeles, California

Disclosure: Eric S. Daar, MD, has received grants and/or research support from Abbott, Boehringer Ingelheim, Gilead, GlaxoSmithKline, and Merck. Dr. Daar has served on the speaker's bureau for and has served as a consultant to Abbott, Boehringer Ingelheim, Gilead, GlaxoSmithKline, Merck, Bristol-Myers Squibb, Pfizer, Tibotec, and Monogram.

Daniel R. Kuritzkes, MD
Associate Professor of Medicine; Director of AIDS Research, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts

Disclosure: Daniel R. Kuritzkes, MD, has served as a consultant to Abbott, Avexa, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Human Genome Sciences, Merck, Monogram Biosciences, Panacos, Pfizer, Roche, Schering-Plough, Siemens, Tibotec, Johnson & Johnson, Trimeris, and VIRxSYS. Dr. Kuritzkes has received honoraria from Abbott, Avexa, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Human Genome Sciences, Merck, Monogram Biosciences, Panacos, Pfizer, Roche, Schering-Plough, Siemens, and VIRxSYS, and has received research support from Boehringer Ingelheim, Gilead, Human Genome Sciences, Merck, Roche, Schering-Plough, and Trimeris.

Source for MM, ED & DK: New York Course 2008 required disclosures

Sally Hodder, MD serves on the speakers bureau for Bristol-Myers Squibb.
Source: Peer Review Press CME program, 2006-2007

Paul Sax, MD, has a financial interest/relationship or affiliation in the form of:
Consultant for Abbott Labs, Bristol-Myers Squibb, Gilead Sciences and GlaxoSmithKline.
Research support from Bristol-Myers Squibb, Merck, and Pfizer
Speakers bureau member for Abbott Labs;, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Tibotec, and Virco Labs.
Source: Peer Review Press CME program, 2006-2007

(Somewhat discordant) disclosures at TheBodyPro.com
Dr. Sax is a consultant for Abbott Laboratories, Bristol-Myers Squibb, Gilead Sciences and GlaxoSmithKline. He receives research support from Pfizer, Inc. and GlaxoSmithKline. He receives speaking honoraria from Abbott Laboratories, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck & Co. and Tibotec.

Dr. Sax's financial disclosures at Mexico City (August 2008) AIDS conference when he worked for Medscape:

Paul E. Sax, MD
Associate Professor, Harvard Medical School, Boston, Massachusetts; Clinical Director, HIV Program, Division of Infectious Diseases, Brigham and Women’s Hospital, Boston, Massachusetts

Disclosure: Paul E. Sax, MD, has received research support from Bristol-Myers Squibb, Merck, and Pfizer, has served as an advisor or consultant to Abbott, Bristol-Myers Squibb, Gilead, and GlaxoSmithKline, and has received honoraria for teaching from Abbott, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck, Tibotec, and Virco.

Dr. Calvin Cohen's financial dsclosure:
Funding for Research: Abbott; Bristol-Myers Squibb; Gilead; GlaxoSmithKline; Roche; Pfizer; Tibotec.
Consulting Agreements: Abbott; Bristol-Myers Squibb; Gilead; GlaxoSmithKline; Merck; Roche; Pfizer; Tibotec.
Speakers' Bureau/Honorarium Agreements: Abbott; Bristol-Myers Squibb; Gilead; GlaxoSmithKline; Merck; Roche; Pfizer; Tibotec; Virco.
Financial Interests/Stock Ownership: None.
Financial Interests/Other: ViralEd, LLC.
Source: Required CME disclosures for July 2008 program at (his company) ViralEd

It's kind of neat how each program needs three components in order to carry out its intended function--not unlike the proteases, nucleases and transcriptases of a virus we have grown so fond of.

First there is the funding source.
The funding source then approaches a medical communications company who has the CME expertise and KOL line-up at the ready in order to successfully stage the desired production. In the case of ICAAC/IDSA this year, those medical communications companies were:

Clinical Care Options
HealthMattersCME
Creative Educational Concepts, LLC
Scius,LLC

But there are others: ViralEd, HealthmattersCME, Peer View Institute for Medical Education, CECentral, Pri-Med.com, Dimedix, CMEonHIV, VirologyCME.com, the Medical Education Collaborative, Practice Point Communications and the IAS-USA's Cases on the Web.

And then the leader, first and largest force in all of this--from the early 1990s!!: Harold Kessler and his Rush University Medical Center.

Then there are the rubber stamping, imprimatur granting CME accreditation outfits that make it all legit. In the case of the HIV CME programs at this ICAAC/IDSA meeting, we were treated to some familiar faces and others that appear new to the game:

Johns Hopkins School of Medicine
Postgraduate Institute for Medicine (PIM)
University of Kentucky (!!) Colleges of Pharmacy and Medicine

Okay. More later. I have to get back to conference center now.

2008-10-24T13:31:00.002-04:00

First-line indication for Prezista (darunavir)--and just in time for ICAAC/IDSA

No wonder Tibotec is both flying my European HIV MD friend to D.C. this weekend and the sole sponsor of TheBodyPro's coverage of conference.

Isn't life beautiful?

Prezista, or darunavir, had already been approved for use along with other HIV drugs in patients who were already taking protease inhibitors but had developed resistance.
Patients new to HIV therapy should take the drug with ritonavir and food to get the best results, the company said. Ritonavir, sold by Abbott Laboratories under the name Norvir, helps boost the concentration of Prezista in the body by slowing its breakdown.
Common side effects include diarrhea, nausea, headache and serious skin rashes, the FDA has said. Reports of hepatitis and liver failure have also been found in Prezista patients, the company said.
First-time HIV drug patients should take two 400-milligram tablets once a day. Those who have been on medication before should still take 600-milligrams. The drugmaker added it was discontinuing its 300-milligram tablet since it began manufacturing a 600-milligram version earlier this year.

The drug is marketed in the United States by Tibotec Therapeutics, part of Johnson & Johnson's division of Ortho Biotech Products.

Source: Reuters Health/Medscape

2008-10-22T12:35:00.001-04:00

Audio files, slides, transcripts of CSPI's summer conference "Rejuvenating Public Sector Science" now available: click here.

(Was a great conference. I consider myself lucky to have mysteriously ended up at the same table with folks from PharmedOut, The Prescription Project and Healthy Skepticism!)

2008-10-22T10:50:00.004-04:00

Merck To Cut 7,200 More Jobs

Diabetes and HIV drug sales strong as cholesterol, asthma & vaccine franchises flag

Isentress (raltegravir) sales on track to hit $400 million mark

Merck, which had about 56,700 employees as of Sept. 30, has been in turnaround mode as it tries to recover from the 2004 withdrawal of painkiller Vioxx on safety concerns and the 2006 loss of U.S. market exclusivity for cholesterol drug Zocor.

The latest restructuring moves by the Whitehouse Station, N.J., company include closing research sites in Japan, Italy and Seattle by the end of 2009.

The job cuts are on top of a 2005 restructuring plan that was substantially completed at quarter's end. It eliminated 10,400 positions, more than the 7,000 initially contemplated. The latest round of cuts is expected to be completed by the end of 2011 with about 40% of the reductions taking place in the U.S.

"Our current sales trends for key products, compounded by known industry and emerging economic factors, have led us to reassess the environment in which we expect to be operating between now and 2010," Merck Chairman and Chief Executive Richard T. Clark said in the company's press release

Cholesterol drugs Merck co-markets with Schering-Plough Corp. have had declining sales this year due to questions surrounding their effectiveness and safety. Combined sales of Vytorin and Zetia dropped 15% to $1.1 billion, with lower U.S. sales partly offset by increased sales outside the U.S.

Sales of cervical-cancer vaccine Gardasil dropped 4%. Merck blamed a slowdown in Gardasil sales on deceleration in use by girls and women ages 13 to 18, as well as lower-than-expected usage by women ages 19 to 26. Gardasil is approved for use by females aged nine to 26.

Asthma and allergy drug Singulair recorded 1% growth. U.S. sales have been hurt by an over-the-counter version of rival drug Zyrtec by Johnson & Johnson as well as concerns about the Food and Drug Administration's March alert of a possible association between Singulair and suicide.

In addition, Merck posted weak vaccine sales. Shingles treatment Zostavax recorded an 82% plunge amid supply issues, while rotavirus vaccine Rotateq had a 21% drop amid a government-stockpile effort last year. Sales of Merck's other viral vaccines were flat.

Worldwide sales of Isentress (raltegravir), Merck's first-in-class HIV integrase inhibitor for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced adult patients, were $107 million in third-quarter 2008. Merck launched Isentress in the United States in October 2007.

Separately, Businessweek reported yesterday that Merck will file for first-line indication for Isentress before year's end.

Source: Merck press release; Mike Barris and Kevin Kingsbury for the WSJ

2008-10-22T06:53:00.002-04:00

Glaxo's Net Income Falls 22%

"Our performance is in line with our expectations and I am pleased with how we have so far responded to what is undoubtedly a challenging year for GlaxoSmithKline," Chief Executive Andrew Witty said in a statement.

Anti-virals: HIV
Nine months ended 30th September 2008

Total: 1,096 million pounds sterling (Flat (up 1.2%) from same period 2007)
Epzicom/Kivexa: 313 (Down 9.8% from '07)
Combivir: 319 (Up 80% from '07)
Trizivir: 153 (Up 28.6% from '07)
Agenerase/Lexiva: 113 (Up 40% from '07)
Epivir: 103 (Down 2% from '07)
Ziagen: 78 (Down 67% from '07)

Speaking to reporters during a conference call, Mr. Witty said the ongoing turmoil in financial markets has created opportunities for acquisitions, especially in the biotech sector where companies have been affected by a funding crunch.

Still, he reiterated that Glaxo would continue to prefer small-to-medium acquisitions over large deals. "We are going to remain extremely choosy about what we buy," he said.

Source: GSK website and Elena Berton for the WSJ

2008-10-21T17:40:00.001-04:00

Drooping Eyelids (ptosis) and Double Vision (opthalmoplegia, or progressive paralysis of eye muscles) in Patients on Long-Term Antiretroviral Therapy

Case report of 5 patients in recent issue of Clinical Infectious Diseases

"This is the first study to report ptosis and external ophthalmoplegia as associated with long-term ART for HIV," Dr. Dolores M. Peterson of UT Southwestern told Reuters Health.

The evidence suggests that the ptosis is caused by damage to nerves, rather than the more common involutional type.

[This came out over a month ago. Why is it just hitting Reuters Health and Medscape sites now?]

The study showed that ptosis was preceded by severe lipodystrophy in all five patients, whether their ART included thymidine analogues or protease inhibitors. The median age at presentation was 50 years, with a median time since diagnosis of HIV infection of 11.2 years and median duration of ART of 7.8 years.

2008-10-10T04:21:00.002-04:00

Strong words from Times health blogger Judith Warner (Diagnosis Greed): "No one can be trusted"

[Nemeroff’s story represents] yet another iteration of the ever-unfolding saga of greed and how the deregulation of absolutely everything has brought our country to this painful season of reckoning. Nemeroff’s story, hardly unique, belongs uniquely to this time in our nation’s history.

(And I especially love the stinging truth of this part:)

[Crooked, prominent Emory University psychiatrist caught in flagrante delicto, Dr.] Nemeroff didn’t bring down any banks, didn’t freeze the American credit markets, hasn’t plunged the world economy into recession. But his extensive, excessive and untransparent ties to the pharmaceutical industry are all too common, unfortunately, among his cohort of “thought leaders” in psychiatry and other medical specialties. And these relationships have led to a dangerous crisis of confidence in the basic integrity and validity of America’s medical research.

Conflicts of interest between the pharmaceutical industry and prominent research physicians now “permeate the clinical research enterprise,” writes Dr. Marcia Angell, author of the 2004 book, “The Truth About the Drug Companies,” in the Sept. 3 issue of The Journal of the American Medical Association.

Two-thirds (that's 66.67%) of medical school department chairs were found to receive departmental income, and three-fifths received personal income, from drug companies.

The upshot: No one can be trusted. “Not only do the researchers have the complete conflicts of interests, but the medical schools and the universities do too,” Angell told me this week in a telephone interview. “The Biedermans, the Schatzbergs, they’re rainmakers for the institutions. It’s a broken system.”

And it results in dishonest clinical investigation & treatment advice, over-medicated patients (sometimes to the point of death, disfigurement, or disability), ignored avenues of less lucrative medical research, bloated health care costs, drug & diagnosis happy patient & physician education programs, and an overall disatrous state of public health. But then only half a dozen or so people in the entire country seem to care...

2008-10-05T13:51:00.001-04:00

The Problem with Non-Vetted, Voluntary Conflict-of-Interest Disclosure

(as reported by Gardiner Harris for the NYT, October 4, 2008)

Charles B. Nemeroff (Emory Univ)
What he reported to Emory: Less than $10,000 a year from Glaxo
What records showed he was paid: $170,000 or more

What he reported to Emory for period 2000-07: $1,600,000
What records showed he was paid: $2,800,000+

Dr. Melissa P. DelBello (Univ Cincinnati)
What she reported for period 2005-07: $100,000 from all sources combined
What records showed she was actually paid: $238,000 from one company alone

Dr. Joseph Biederman (Harvard)
Dr. Timothy Wilens (Harvard)
What they reported to HMS for 2000-07: "Several hundred thousand dollars" each
What records showed they were paid: $1,600,000+ each

One of the nation’s most influential psychiatrists earned more than $2.8 million in consulting arrangements with drug makers from 2000 to 2007, failed to report at least $1.2 million of that income to his university and violated federal research rules, according to documents provided to Congressional investigators.

The psychiatrist, Dr. Charles B. Nemeroff of Emory University, is the most prominent figure to date in a series of disclosures that is shaking the world of academic medicine and seems likely to force broad changes in the relationships between doctors and drug makers.

In one telling example, Dr. Nemeroff signed a letter dated July 15, 2004, promising Emory administrators that he would earn less than $10,000 a year from GlaxoSmithKline to comply with federal rules. But on that day, he was at the Four Seasons Resort in Jackson Hole, WY, earning $3,000 of what would become $170,000 in income that year from that company — 17 times the figure he had agreed on.

The Congressional inquiry, led by Senator Charles E. Grassley, Republican of Iowa, is systematically asking some of the nation’s leading researchers to provide their conflict-of-interest disclosures, and Mr. Grassley is comparing those documents with records of actual payments from drug companies. The records often conflict, sometimes starkly.

“After questioning about 20 doctors and research institutions, it looks like problems with transparency are everywhere,” Mr. Grassley said. “The current system for tracking financial relationships isn’t working.”

The findings suggest that universities are all but incapable of policing their faculty’s conflicts of interest. Almost every major medical school and medical society is now reassessing its relationships with drug and device makers.

“Everyone is concerned,” said Dr. James H. Scully Jr., the president-elect of the Council of Medical Specialty Societies, whose 30 members represent more than 500,000 doctors.

Dr. Nemeroff is a charismatic speaker and a widely admired scientist who has written more than 850 research reports and reviews. He was editor in chief of the influential journal Neuropsychopharmacology. His research has focused on the long-term mental health risks associated with child abuse as well as the relationship between depression and cardiovascular disease.

Dr. Nemeroff did not respond to calls and e-mail messages seeking comment. Jeffrey L. Molter, an Emory spokesman, wrote in an e-mail statement that the university was “working diligently to determine whether our policies have been observed consistently with regard to the matters cited by Senator Grassley.”

The statement continued: “Dr. Nemeroff has assured us that: ‘To the best of my knowledge, I have followed the appropriate university regulations concerning financial disclosures.’ ” On Friday night, Emory announced that Dr. Nemeroff would “voluntarily step down as chairman of the department, effective immediately, pending resolution of these issues.”

Mr. Grassley began his investigation in the spring by questioning Dr. Melissa P. DelBello of the University of Cincinnati after The New York Times reported her connections to drug makers. Dr. DelBello told university officials that she earned about $100,000 from 2005 to 2007 from eight drug makers, but AstraZeneca alone paid her $238,000 during the period, Mr. Grassley found.

Then in early June, the senator reported to Congress that Dr. Joseph Biederman, a renowned child psychiatrist at Harvard Medical School, and a colleague, Dr. Timothy E. Wilens, had reported to university officials earning several hundred thousand dollars each in consulting fees from drug makers from 2000 to 2007, when in fact they had earned at least $1.6 million each.

Then the senator focused on Dr. Alan F. Schatzberg of Stanford, president-elect of the American Psychiatric Association, whose $4.8 million in stock holdings in a drug development company raised concerns.

Mr. Grassley has sponsored legislation called the Physician Payment Sunshine Act, which would require drug and device companies to publicly list payments to doctors that exceed $500. Several states already require such disclosures.

As revelations from Mr. Grassley’s investigation have dribbled out, trade organizations for the pharmaceutical industry and medical colleges have agreed to support the bill. Eli Lilly and Merck have announced that they would list doctor payments next year even without legislation.

The National Institutes of Health have strict rules regarding conflicts of interest among grantees, but the institutes rely on universities for oversight. If a university fails, the agency has the power to suspend its entire portfolio of grants, which for Emory amounted to $190 million in 2005, although the agency rarely takes such drastic measures.

Dr. Nemeroff was the principal investigator for a five-year $3.9 million grant financed by the National Institute of Mental Health for which GlaxoSmithKline provided drugs.

Income of $10,000 or more from the company in any year of the grant — a threshold Dr. Nemeroff crossed in 2003, 2004, 2005 and 2006, records show — would have required Emory to inform the institutes and take steps to deal with the conflict or to remove Dr. Nemeroff as the investigator.

Repeatedly assured by Dr. Nemeroff that he had not exceeded the limit, Emory did nothing.

“Results from N.I.H.-funded research must not be biased by any conflicting financial interests,” John Burklow, a spokesman for the health institutes, said in the kind of tough statement that in the past has rarely been followed by real sanctions. “Officials at Emory are investigating the concerns.”

“Failure to follow N.I.H. standards” on conflict of interest, Mr. Burklow continued, “is very serious, and N.I.H. will take all appropriate action to ensure compliance.”

In 2004, Emory investigated Dr. Nemeroff’s outside consulting arrangements. In a 14-page report, Emory’s conflict of interest committee detailed multiple “serious” and “significant” violations of university procedures intended to protect patients.

But the university apparently took little action against Dr. Nemeroff and made no effort to independently audit his consulting income, documents show.

Universities, too, can benefit from the fame and money the deals can bring — a point Dr. Nemeroff made in a May 2000 letter stamped “confidential” that he sent to the dean of Emory’s medical school. The letter, which was part of a record from a Congressional hearing, addressed Dr. Nemeroff’s membership on a dozen corporate advisory boards (some of the companies’ names have since changed).

“Surely you remember that Smith-Kline Beecham Pharmaceuticals donated an endowed chair to the department and that there is some reasonable likelihood that Janssen Pharmaceuticals will do so as well,” he wrote.

“In addition, Wyeth-Ayerst Pharmaceuticals has funded a Research Career Development Award program in the department, and I have asked both AstraZeneca Pharmaceuticals and Bristol-Meyers [sic] Squibb to do the same. Part of the rationale for their funding our faculty in such a manner would be my service on these boards.”

Universities once looked askance at professors who consulted for more than one or two drug companies, but that changed after a 1980 law gave the universities ownership of patents discovered with federal money.

The law helped give birth to the biotechnology industry and led to the discovery of dozens of life-saving medicines. Consulting arrangements soon proliferated at medical schools, and Dr. Nemeroff — who at one point consulted for 21 drug and device companies simultaneously — became a national model.

He may now become a model for a broad reassessment of industry relationships. Many medical schools, societies and groups are considering barring doctors from giving lectures on drug or device marketing.

For all his fame in the world of psychiatry, Dr. Nemeroff has faced ethics troubles before. In 2006, he blamed a clerical mix-up for his failing to disclose that he and his co-authors had financial ties to Cyberonics, the maker of a controversial device that they reviewed favorably in a journal he edited.

The Cyberonics paper led to a bitter e-mail exchange between Dr. Nemeroff and Claudia R. Adkison, an associate dean at Emory, according to Congressional records. Dr. Adkison noted that Cyberonics had not only paid Dr. Nemeroff and his co-authors but had also given an unrestricted educational grant to Dr. Nemeroff’s department.

“I can’t believe that anyone in the public or in academia would believe anything except that this paper was a piece of paid marketing,” Dr. Adkison wrote on July 20, 2006.

Two years earlier, unknown to the public, Emory’s conflict of interest committee discovered that Dr. Nemeroff had made more serious blunders, including failing to disclose conflicts of interest in trials of drugs from Merck, Eli Lilly and Johnson & Johnson.

His continuing oversight of a federally financed trial using GlaxoSmithKline medicines led Dr. Adkison to write Dr. Nemeroff on July 15, 2004, that “you must clearly certify on your annual disclosure form that you do not receive more than $10,000 from GSK.”

In a reply dated Aug. 4, Dr. Nemeroff wrote that he had already done so but promised again that “my consulting fees from GSK will be less than $10,000 per year throughout the period of this N.I.H. grant.”

When he sent that letter, Dr. Nemeroff had already earned more than $98,000 that year from GlaxoSmithKline. Three weeks later, he received another $3,844.56 for giving a marketing talk at the Passion Fish Restaurant in Woodbury, N.Y.

From 2000 through 2006, Dr. Nemeroff earned more than $960,000 from GlaxoSmithKline but listed earnings of less than $35,000 for the period on his university disclosure forms, according to Congressional documents.

Sarah Alspach, a GlaxoSmithKline spokeswoman, said via e-mail that “Dr. Nemeroff is a recognized world leader in the field of psychiatry,” and that the company requires its paid speakers to “proactively disclose their financial relationship with GSK, and we believe that healthcare professionals are responsible for making those disclosures.”

2008-09-24T20:55:00.001-04:00

Merck To Disclose Speaking Fees It Pays To Physicians

In the wake of Lilly’s announcement that, beginning in the second half of next year, it would provide an online database of all payments made to physicians including the reasons for the payments, Merck & Company said it would (sort of) follow suit by disclosing speaking fees it pays to doctors, also beginning before the end of 2009.

Details of the mechanism and nature of disclosures remain to be determined.

Benedict Carey, writing for The New York Times, today notes that "University administrators, journal editors, [and patients/public health advocates, among others] say they have no reliable way to verify doctors’ private income from industry. Research has found that industry money can bias doctors’ interpretation of study findings and may alter their prescribing habits.

As reported by the Medical Marketing & Media site, "Lilly began making clinical trials and clinical trials data public in 2004 and last year led the industry in disclosing CME grants and other contributions with a quarterly report posted online. Other companies, including Pfizer, AstraZeneca and most recently, GSK, have followed suit with similar programs."

[I need to check into just how "similar' the Pfizer and GSK programs are.]

The Merck announcement doesn't, at first blush, appear to include money paid to physicians for membership on advisory boards or Continuing Medical Education funds funneled through physician groups and academic medical centers. In this respect, Lilly appears to be alone.

The MMM site also adds that "Lilly is again out in front of the industry with its plan to make public physician payments, which could be posted as early as the second half of 2009 and will initially include 2009 payments to physicians who serve as speakers and advisors to Lilly. By 2011, the registry will be expanded to resemble that called for under the Physician Payments Sunshine Act, legislation currently moving through Congress for which Lilly was an early supporter."

2008-09-21T21:22:00.000-04:00

KOL* Fee Schedules aka "Thought Leader Compensation: Establishing Fair-Market Value Procedures"

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Cutting Edge Information’s newest report cuts through the regulatory confusion and provides clear procedures for calculating fair-market value compensation. Backed with real-world metrics from more than 40 top pharmaceutical, biotechnology and medical devices companies, Thought Leader Compensation: Establishing Fair-Market Value Procedures provides relevant case studies and best practices to guide your thought leader management team. The report provides compensation ranges for various specialties in 20 different therapeutic areas.

Study participants included vice presidents and directors of medical affairs, product directors and managers, marketing consultants, thought leader development managers and MSL team leaders. The fair-market value benchmarks contained in this study are aggregate data collected directly from executives at participating companies. Click here for more information on the study’s methodology."

Companies included in report:
Boehringer Ingelheim
Bristol-Myers Squibb
Merck
Novartis
Pfizer
Roche
Sanofi-Aventis
Schering
Call Oveda Slade at (919) 403-6583 to get your own copy of "Thought Leader Compensation" today.

*KOL= Key Opinion Leader or Thought Leader

2008-09-12T11:08:00.003-04:00

David J. Rothman & Susan Chimonas in this week's JAMA: "Will academic medical centers make sufficient progress to obviate the need for government intervention?"

2008-09-11T16:41:00.006-04:00

Stanford Medical School Severely Restricts Industry Funding of Continuing Education for Physicians
Business Wire

School restricts industry funding of CME courses
Stanford Univ press release

Stanford med school loosening industry ties
SF Chronicle

Pharma funds to be 'pooled' in blind trust
Chronicle of Higher Education

Stanford to limit industry money to CME programs
The Prescription Project

Stanford Dean Announces Tougher CME Policy
Carlat Psychiatry blog

Stanford nixes industry-funded CME
Fierce Pharma

New Developments in Managing Physician-Industry Relationships
JAMA 2008;300(9):1067-1069
Courtesy of The Prescription Project

Stanford to Limit Drug Maker Financing
Stanford becomes the sixth major medical school to form schoolwide pools for university contributions to medical education

Reaction to New York Times story on Technorati

AAMC Calls for Strict Limits on Industry Support of Medical Education
American Medical Association's Council on Ethical and Judicial Affairs issued a report urging individual doctors and medical institutions not to accept industry support for CME

Drug industry spent over $1 billion on CME courses in 2006
Between 1998 and 2006, industry funding for CME activities nationwide rose from $302 million to $1.2 billion, according to the Accreditation Council for Continuing Medical Education.

CCME data show commercial support for CME flat in 2007

ACCME 2007 annual report

Pfizer to stop funding for-profit CME
Fierce Biotech

Pfizer stops funding for physicians’ continuing medical education courses
WSJ Health blog

When Doctors Go to Class, Industry Often Foots the Bill
WSJ, 2002