Item #19: 4 of 22 Infants Died in HIVNET 006. Is this a Problem?

A small Phase I trial preceded HIVNET 012 that studied the safety, primarily, of nevirapine in pregnant women but also looked at efficacy. It was called HIVNET 006, and it enrolled twenty-one pregnant women for initial study. Of twenty-two infants born, four died. There were twelve “serious adverse events” reported. The study also showed that there was no lowering of viral load in the mothers who took the study drug (the industry's agreed-upon standard for interrupting maternal transmission).

Footnote 6 states in relation to HIVNET 006 “Of twenty-two infants born, four died. There were twelve 'serious adverse events' reported. “ Farber's implication is that the adverse events and deaths were due to nevirapine.

The investigators of this Ugandan study studied drug toxicity in detail. They report “There were no serious adverse events or grade 3 or 4 clinical or laboratory toxicities thought by investigators to be related to nevirapine among the mothers of either cohort. There were five serious adverse events including two deaths in the infants in cohort 1. Only one of the five serious adverse events was thought by the investigators to be possibly, but not likely, study drug related. This infant developed respiratory distress at birth and seizures after a difficult and prolonged labor requiring the use of forceps. In cohort 2 there were seven serious adverse events, including two infant deaths, although none were related to the study drug.”40

HIVNET 006 did not have a placebo, so there was no yardstick to measure the occurrence of adverse events against. As the Gallo documents quotes the researchers: “Only one of the five serious adverse events was thought by the investigators to be possibly, but not likely, study drug related.” [1] The researchers, in the absence of verifiable evidence, got to decide what adverse events were caused by the drugs and what were not.
The concept of the randomized, placebo-controlled, double-blind (neither patient nor investigator knows who is receiving placebo versus active treatment) clinical trial was created to eliminate the inevitable bias of researchers. Consciously or unconsciously, researchers will almost always want the active treatment to prove safe and effective. The only safe approach, in absence of a placebo, is to assume that all observed adverse events are due to the study drug.
Farber is right to be shocked that out of 22 infants there were 12 serious adverse events and four deaths. Taking a conservative approach one can only conclude that maternal/infant use of nevirapine is terribly dangerous and should never be used again in a clinical trial without a placebo, and even then only in desperate situations when a greater than 50% rate of adverse events and an 18% death rate can be expected. Few, if any, such situations exist.

1. Musoke P et al. A phase I/II study of the safety and pharmacokinetics of nevirapine in HIV-1-infected pregnant Ugandan women and their neonates (HIVNET 006). AIDS. 1999 Mar 11; 13(4): 479-86.