Item #24: Farber’s Description of HIVNET 012

Since Boehringer had not originally intended to use this study for licensing purposes, it decided to perform its own inspection before the FDA arrived. Boehringer’s team arrived in Kampala and did a sample audit. They were the first to discover what a shambles the study was. According to Boehringer’s preinspection report, “serious non-compliance with FDA Regulations was found” in the specific requirements of reporting serious adverse events. Problems also were found in the management of the trial drug and in informed-consent procedures. DAIDS then hired a private contractor, a company named Westat, to go to Uganda and do another preinspection. This time the findings were even more alarming. One of the main problems was a “loss of critical records.” One of two master logs that included follow-up data on adverse events, including deaths, was said to be missing as the result of a flood. The records failed to make clear which mothers had gotten which drug, when they’d gotten it, or even whether they were still alive at various followup points after the study. Drugs were given to the wrong babies, documents were altered, and there was infrequent follow-up, even though one third of the mothers were marked “abnormal” in their charts at discharge. The infants that did receive follow-up care were in many cases small and underweight for their age. “It was thought to be likely that some, perhaps many, of these infants had serious health problems.” The Westat auditors looked at a sample of forty-three such infants, and all forty-three had “adverse events” at twelve months. Of these, only eleven were said to be HIV positive. The HIVNET team had essentially downgraded all serious adverse events several notches on a scale it had created to adapt to “local” standards. That downgrade meant, among other things, that even seemingly “life-threatening” events were logged as not serious. Deaths, unless they occurred within a certain time frame at the beginning of the study, were not reported or were listed as “serious adverse events” rather than deaths. In one case, “a still birth was reported as a Grade 3 adverse event for the mother.”
As a defense, the HIVNET team often cited ignorance. They told the Westat monitors that they were unaware of safety-reporting regulations, that they’d had no training in Good Clinical Practice, and that they had “never attempted a Phase III trial.” The principal investigators and sub-investigators “all acknowledged the fin dings [of the audit] as generally correct,” the Westat report said. “Dr. Guay and Dr. Jackson noted that many (‘thousands’) of unreported AE’s and SAE’s occurred. . . . They acknowledged their use of their own interpretation of ‘serious’ and of severity.” “All agreed” that the principal and subinvestigators “had generally not seen the trial patients,” and “all agreed” that in evaluating adverse and serious adverse events “they had relied almost entirely on second or third hand summaries . . . without attempting to verify accuracy.” Westat also discovered that half the HIVpositive infants were also enrolled in a vitamin A trial, which ef fectively invalidates any data associated with them.

This page contains a highly biased account of the analysis of HIVNET 012. So as not to labour each of Farber's misrepresentations and omissions, the following should be noted:

In all the innuendo and accusations made by Farber and other AIDS denialists, as well as by Fishbein, no evidence has been put forward about the conduct of HIVNET 012 that calls into question its scientific findings.

HIVNET 012 was imperfect. The NIH has been honest about this. They state:

“NIAID and NIH initiated several reviews and re-reviews of HIVNET 012. These reviews identified procedural flaws in the study that led NIAID to implement improvements in the conduct of clinical research it supports both in the United States and abroad. We understand that certain previously recognized criticisms of the conduct of HIVNET 012 have re-emerged, but stress strongly that throughout multiple reviews, the overall conclusions regarding the safety and efficacy of single-dose nevirapine in this setting have remained intact.” (our emphasis)

They further state:

“The statement in the Associated Press article of December 13, 2004, that there may have been thousands of underreported serious adverse events in the HIVNET 012 study implies that those were due to the drug nevirapine. This implication is absolutely false. Remonitoring reports of HIVNET 012 found no additional serious adverse reactions related to nevirapine. The original published study and the multiple subsequent reviews of the HIVNET 012 trial that have carefully scrutinized its data have found only a very small number of serious adverse reactions that potentially might be due to nevirapine.”44

See also NIAID (2004)45 .

The Institute of Medicine is part of the National Academy of Sciences. One of the purposes of the academy is to act as an independent reviewer of scientific issues. One could view it as the arbiter of scientific disputes of this nature, analogous to the way in which the US Supreme Court rules on matters of jurisprudence. In contrast to Farber or any of the AIDS denialists as well as the Associated Press journalist Farber refers to, the IOM extensively examined the documentation of HIVNET 012, including patient records. It concluded:

“Based on its review, the committee finds no reason to retract the publications or alter the conclusions of the HIVNET 012 study. The committee concludes that data and findings reported in Guay et al. (1999) and Jackson et al. (2003) are sound, presented in a balanced manner, and can be relied upon for scientific and policy-making purposes.”46

Short-course nevirapine has been tested in the South African Intrapartum Nevirapine Trial, a much bigger trial than HIVNET 012. Not a single life-threatening event due to nevirapine was found. The trial used double the dose of HIVNET 012 on mothers. It confirmed short-course nevirapine's efficacy too. 47 Short-course nevirapine has been added to an AZT regimen in a Thai trial and found to further reduce MTCT. The authors of this study state “No serious adverse effects were associated with nevirapine therapy.”48

Short-course nevirapine has been used extensively in operational settings, e.g. Ayouba et al. (2003) 49 .

From a safety perspective, not a single life-threatening event has been recorded due to short-course nevirapine. From an efficacy perspective, results have been mixed; some cohorts have done well, others less well than expected. There is no cohort however that has reported worse results than would be expected with placebo including the Ghent study referred to by Farber. In the absence of any intervention, The rate of MTCT varies but is seldom less than 25% after a few months in a breast-feeding population50 , or even predominantly non breast-feeding populations51 .

In many cases in the developing world the benefit of ARVs for reducing MTCT at the time of delivery is undone by the later transmission of HIV through breast-milk. Resolving this additional mode of transmission is a complex scientific, operational and social undertaking. However, in wealthy countries, paediatric epidemics have been virtually eliminated through a combination of long-course ARV treatments, caesarian sections and formula-feeding. There are also success stories in the developing world, including the Cameroon study cited above, an MSF site in Cape Town, South Africa, a hospital in Johannesburg, South Africa (which found a 9% transmission rate in an operational setting, much lower than would be achieved with placebo) and the Ugandan site where HIVNET 012 was conducted.

The Gallo document admits that there were many adverse events in the nevirapine trial HIVNET 012, but claims that none were due to Nevirapine. Without a placebo this is impossible to determine. Instead of a placebo the trial researchers who have a vested interest in its success, get to decide whether an adverse event is drug related or not. Not surprisingly they determine that the vast majority or all adverse events are not due to the study drug.