Shillfactor

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."

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

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."

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

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.

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

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

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

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)

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

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?

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

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!!

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

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.

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

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."

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

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.

2008-06-21T12:50:00.000-04:00

Pathophilia blog entry on ACCME's June 2008 annual policy announcement

Excerpt:

The most controversial aspect of the ACCME's Policy Announcements is in a "For Comment" section, which proposes that the commercial support of CME should only be allowed to continue after several considerable changes. These changes are likely to make the production of timely CME difficult and probably more trouble than it's worth for many providers. (The ultimate and ironic consequence [described below] of the ACCME's proposed conditions should be evident to anyone who has played chess.)

1. When educational needs are identified and verified by organizations that do not receive commercial support and are free of financial relationships with industry.

The ACCME cites government agencies as a example; although, it does not stipulate which government agencies engage in or would engage in the identification of CME needs, or how current CME providers would access or use this information to obtain grant support from industry. Also, what defines freedom from financial relationships?

2. If the CME addresses a professional practice gap of a particular group of learners that is corroborated by bona fide performance measurements (eg, National Quality Form[sic]) of the learners' own practice.

Another ill-considered hoop. Other than citing the National Quality Forum, a nonprofit "performance-improvement" organization, it's not clear what would qualify as valid corroboration. At its website, the NQF notes that it endorses a number of "clinician-level performance measures" and is currently asking for measures related to cancer, infectious disease, and surgical care. But how this information may be obtained or used by CME providers is not described by the ACCME or the NQF.

3. When the CME content is from a continuing education curriculum specified by a bona fide organization, or entity (eg, AMA, AHRQ, ABMS, FSMB).

Again, how CME providers may obtain and use another organization's curriculum for content is not clear (and perhaps not yet known).

4. When the CME is verified as free of commercial bias.

And who or what determines commercial bias?

Now the big irony of the ACCME's proposed crackdown on commercially supported CME is that it conceivably leads to the organization's undoing through the following process.

Industry will provide less commercial support for CME (as has been the case during the last year or so).
There will be considerably fewer organizations producing certified CME and, therefore, fewer organizations will need accreditation to provide CME.
Fewer accredited CME providers will reduce the ACCME's fee revenue.

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

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

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."

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

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.

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

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.