Item #2: “Outer limits of bearable toxicity”

The objective of the trial, PACTG 1022, was to compare the “treatment-limiting toxicities” of two anti-HIV drug regimens…PACTG 1022 was a “safety” trial as well as an efficacy trial, which means that pregnant women were being used as research subjects to investigate “safety” and yet the trial was probing the outer limits of bearable toxicity.

Farber states that PACTG 1022 probed the “outer limits of bearable toxicity”.

PACTG 1022 compared ARVs, that had already been found to be safe and effective for treatment in the absence of pregnancy, in pregnant women. All drugs used in the trial had been shown in previous trials to benefit people with HIV. This is why the FDA has registered them. The PACTG 1022 trial happened to find higher than expected toxicity of nevirapine in very specific circumstances. Even here, toxicity was sufficiently rare as to be outweighed by the likely benefits of nevirapine use. The FDA revised its nevirapine recommendations on the basis of this trial. Nevirapine remains an important antiretroviral medicine whose risks outweigh its benefits. Nevirapine (or a drug, efavirenz, used instead of it) has been shown in an analysis of clinical trials to slow disease progression, particularly in patients with low CD4 counts. 5 Safety trials are obviously associated with a calculated risk, but they are permitted when the expected benefits are considered to outweigh this risk. Would Farber suggest that no clinical trials be conducted whatsoever?

We know that the text in blue is a typographical error in the Gallo document, which was corrected in a later version, but we definitely agree with the latter part of the statement.

This is patently false, and egregiously distortive. The FDA and equivalent regulatory agencies all across the industrialized world, in the late 1990s, rejected approval of nevirapine for the treatment of pregnant HIV positive women because of early reports of toxicities, maternal, and fetal deaths, including in pilot studies in South Africa. The FDA instructed Boehringer Ingelheim to withdraw its application to have NVP approved for maternal use after it reviewed the catastrophic HIVNET 012 study. To date, NVP is not approved by any industrialized nation for use in pregnancy. Canadian authorities rejected NVP not once but twice—in 1996 and again in 1998, finding it had no effect on surrogate markers and was “alarmingly toxic.”

If Farber is incorrect and the study did not probe the “outer limits of bearable toxicity,” then why did the NIH specifically cite the study as one that tested the “treatment limiting toxicities,” of HIV drugs in pregnant women? [1] [2]

In addition to the toxicities, deaths, and numerous warnings about NVP and “life threatening liver toxicity” in Farber’s Harpers article, beginning as early as 2000, additional data has emerged. These include but are not limited to one case of “Fatal Liver Failure with NVP” in a pregnant woman, whose baby’s fate was not cited. [3]

In the “discussion” section of a paper in JAIDS titled “Maternal Toxicity With Continuous Nevirapine in Pregnancy: Results From PACTG 1022,” a total of six maternal deaths are cited from NVP use in pregnancy, with the first case reported in 2000. [4]

1. Maternal Toxicity with Continuous Nevirapine in Pregnancy: Final Results From PACTG 1022 hivandhepatitis.com/recent/women/061804_c.html.
2. http://clinicaltrials.gov/ct/show/NCT00017719?order=1. Note that the phrase “treatment limiting toxicities” was removed from this page some time in April or May, 2006.
3. Langlet P, Guillaume MP, Devriendt J, et al. Fatal liver failure associated with Nevirapine in a pregnant HIV patient: the first reported case. Gastroenterology. 2000; 118: A1461.
4. Hitti J et al. Maternal toxicity with continuous nevirapine in pregnancy: results from PACTG 1022. JAIDS. 2004 Jul 1. 36(3): 772-6.