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)
Tobira Therapeutics
Virco (maker of drug resistance assays)
Dr. Saag receives research support from the following (10) drug companies:
Achillion Pharmaceuticals
Avexa
Boehringer Ingelheim
GlaxoSmithKline
Merck
Panacos
Pfizer
Progenics
Theratechnologies
Tibotec
Dr. Hogg receives support from:
Merck
Dr. Deeks receives consulting fees from:
GlaxoSmithKline
Roche
Gilead
Boehringer Ingelheim
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-Myers Squibb
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
Boehringer Ingelheim
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-Myers Squibb
Dr. Rodriguez receives speaking fees from:
Bristol-Myers Squibb
Dr. Rodriguez receives grant support from:
The STERIS Corporation (?)
Dr. Rachlis receives consulting fees from:
GlaxoSmithKline
Abbott
Merck
Pfizer
Bristol-Myers Squibb
Gilead
Tibotec
Dr. Rachlis receives speaking fees from:
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 support from:
Pfizer
Merck
Gilead
the Universitywide AIDS Research Program
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. Benson receives consulting fees from:
GlaxoSmithKline
Pfizer
Merck
Achillion
Dr. Benson receives grant support from:
Gilead
Dr. Collier receives consulting fees from:
Merck
Pfizer
GlaxoSmithKline
Dr. Collier receives grant 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-Myers Squibb
GlaxoSmithKline
Dr. Moore receives speaking fees from:
Gilead
Dr. Moore receives grant support 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.
