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The HIVNET 012 Study

Background

In November 1997, investigators from Johns Hopkins University and Makerere University in Uganda began the HIVNET 012 clinical trial to evaluate the efficacy and safety of single-dose nevirapine (NVP) and [very] shortcourse zidovudine (ZDV) regimens for preventing mother-to-child transmission of HIV infection. The trial was initially designed as a randomized, double-blind, placebo-controlled trial, but the placebo arm was dropped after results from a study in Thailand found short-course zidovudine to be effective in reducing mother-to-child transmission of HIV. Enrollment in the trial was concluded in April 1999. The trial was sponsored by the Division of AIDS (DAIDS) at the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH). Preliminary trial results were published in the journal Lancet in 1999 (Guay et al.). [note: preliminary analysis led to publication of the results and termination of the trial. The analysis was a planned interim analysis but results were definitive and the trial stopped, so there aren't separate final results]. Given the encouraging evidence that single-dose nevirapine reduced the risk of mother-to-child transmission of HIV, Boehringer Ingelheim (BI), the manufacturer of nevirapine, decided to pursue a U.S. Food and Drug Administration (FDA) labeling change for the drug using HIVNET 012 as a registrational trial for its application in the United States. The decision to use the HIVNET 012 study as support for the labeling change made the trial subject to reviews that were conducted in a manner that was far more in-depth than would ordinarily occur for a clinical trial that, like HIVNET 012, was not originally intended to generate data to support a submission to FDA for approval of a new drug or new indication for an old drug. (ref: Review of the HIVNET 012 Perinatal HIV Prevention Study, 2005)

IOM Analysis

Because of some problems in record-keeping, including loss of records due to a flood, and because of questions about serious adverse events (brought forth as a result of Boehringer Ingelheim's application to the FDA for a labeling change which required in-depth audits of the trial's records), HIVNET 012 was subject to several reviews. The Institute of Medicine of the National Academies performed the final review and determined that policy-makers and other scientists could rely on the resulting data and conclusions, despite some flaws in record keeping and procedural issues.

The data from the HIVNET 012 study, which showed that nevirapine effectively prevents many infants from contracting HIV from their infected mothers, are sound and reliable," said James Ware, chair of the committee that wrote the report, and professor of biostatistics, Harvard School of Public Health, Boston. "None of the shortcomings that we discovered upon reviewing the data and conducting our own original analysis of source documents indicates a need to retract or discount the study's findings. Our confidence in the trial's data and findings is based on several factors, including evidence that the study's design was both scientifically sound and ethically implemented, that participants adhered well to the treatment regimens, and that a high percentage of participants remained in the study so that the effectiveness and safety of the drug could be thoroughly assessed."

See the full press release.

The Placebo Arm

AIDS denialists have claimed the results of HIVNET 012 are invalid because the trial's placebo arm was dropped. For example, Valendar Turner (a denialist and member of the Perth Group in Australia who hold the discredited view that HIV does not exist) in a letter to Nature claims that "Without supporting evidence from a placebo-controlled randomized trial, such statements [that the study's results are valid] seem unwarranted." There were several problems with Turner's letter, including a dishonest misrepresentation about mother-to-child transmission without antiretrovirals. This misrepresentation is explained here. Denialist Celia Farber, in her Out of Control article in Harper's Magazine, repeats the Valendar Turner letter in framing the issue of HIVNET 012's results beginning with "A short letter published in the March 10, 2005, issue of Nature quietly unpegged the core claim of NIAID and its satellite organizations in the AIDS industry regarding nevirapine’s “effectiveness.” While all of Valendar Turner's charges were repeated in the article, Farber did not include the rebuttal letter (also published in Nature) by the study's Principal Investigator, Brooks Jackson, and Thomas Fleming. The key statement of that letter - "when an experimental drug is found to be superior to a control that itself is not harmful (thus replacing a placebo), the effectiveness of the experimental drug is thereby established." If the Farber article were a fair and truthful one it would have included the key points of both letters, not just one side while completely ignoring the other. And if Harper's Magazine had done thorough fact checking (as they claim), they would have discovered the letter by Jackson and Fleming. By omitting the Jackson/Fleming rebuttal, Farber is free to assert "there was no placebo group, so HIVNET’s results are a statistical trick, a shadow play..." Farber continues bashing the lack of a placebo arm with "The failure of the HIVNET researchers to properly control their study with a placebo group..." and later continues the drum beat "This pattern of jettisoning standard experimental controls has continued up to the present, as the HIVNET affair amply demonstrates..." The study was originally designed with a placebo arm which was dropped shortly after the study began. Here's the story behind the dropping of the placebo arm: In July 1, 1998 the public interest group Public Citizen, who's mission is "Protecting Health, Safety, and Democracy," issued a press release with the title "HEALTH GROUP ATTACKS SECOND GENERATION OF UNETHICAL PERINATAL TRIALS IN AFRICA", subtitle "Researchers to Deny HIV-positive Pregnant Women Effective, Less Expensive Drug Regimens." In the body of the press release we find:

In April 1997, Public Citizen’s Health Research Group criticized 15 studies, most funded by the U.S. government, in which thousands of HIV-positive pregnant women were denied access to AZT, a drug shown in a study in the U.S. and France to dramatically reduce perinatal HIV transmission. The studies were designed to identify more affordable versions of the successful U.S./French regimen that could be utilized in developing countries where the vast majority of the 500,000 annual perinatal HIV transmission occur. Public Citizen criticized the failure to provide AZT to some of the women in these studies; in some studies women received placebos instead of the known effective medication. In September 1997, Public Citizen renewed its attack in the New England Journal of Medicine; the Journal’s Executive Editor, Marcia Angell, supported Public Citizen’s criticism. Despite this, most of the studies continued. In February 1998 a CDC-sponsored placebo-controlled study in Thailand confirmed what Public Citizen had predicted all along: short courses of AZT reduced the rate of HIV transmission from mother to infant, by 51%. "It is simply unbelievable that any researcher would design a study in which no intervention whatsoever is offered to the women, particularly after the Thai/CDC results," said Dr. Lurie. "What was the purpose of the previous round of studies if not to identify drug regimens that could actually be offered to HIV-positive pregnant women?" Dr. Lurie will also discuss two U.S. government-funded studies: HIVNET 012 (Principal Investigator: Brooks Jackson, Johns Hopkins University) in which the HIV-positive pregnant women will not receive any AZT prior to delivery (this was an important part of the Thai/CDC regimen) and another HIVNET study involving chlorhexidine vaginal washings (Principal Investigator: Sten Vermund, University of Alabama) in which no women receive any AZT.

Here's the full text of the press release. With ongoing pressure by Public Citizen, and in the wake of the Thailand study which showed that a short-term regimen of AZT reduced mother-to-child transmission by 51%, the CDC, the NIH, the French National Agency for AIDS Research, and the Joint United Nations Programme on HIV/AIDS made a joint recommendation to drop the placebo arms from all ongoing perinatal HIV trials. Note that the decision to drop the placebo arms applied to ALL ongoing perinatal HIV trials, including HIVNET 012.

Results

The HIV transmission rate, from mother-to-child at 6-8 weeks of age, was 20% for the very short-course AZT group, and 11.8% for the (single-dose) nevirapine group. As Brooks Jackson and Thomas Fleming stated in their letter to Nature, "when an experimental drug is found to be superior to a control that itself is not harmful (thus replacing a placebo), the effectiveness of the experimental drug is thereby established." Jackson and Fleming concluded the letter with "Most people would conclude that zidovudine does not increase the risk of transmission. Hence, our finding that single-dose nevirapine was significantly more effective in preventing HIV transmission than a very short course of zidovudine justifies the conclusion that the HIVNET 012 nevirapine regimen is more effective than nothing in preventing mother-to-infant HIV transmission." Note that the 20% transmission rate for the very short-course AZT group, which Jackson and Fleming refer to as "a control that itself is not harmful (thus replacing a placebo)" is close to the transmission rate observed in the placebo groups of two previous perinatal transmission studies. In ACTG 076 (1994) the mother-to-child transmission rate was 22.6% and in 1998 Thailand Study the mother-to-child transmission rate was 18.6%.

WHO Recommendations

The World Health Organization (WHO) continues to support the use of nevirapine in MTCT-prevention programmes. Read the full WHO statement here. The WHO agrees with the findings of the National Institutes of Health report that the HIVNET 012 trial's scientific findings remain valid.

It should be noted that under-resourced health facilities should where possible be migrating to more effective regimens than single-dose nevirapine alone. Another reasonably affordable regimen is to combine short-course AZT with single-dose nevirapine. This regimen was shown to be effective in a 2004 Thai study.