In the fall of 2004, the NIH ( National Institute of Health ) requested that the Institute of Medicine ( IOM ) of the National Academies of Sciences review the HIVNET 012 perinatal HIV prevention trial and provide an assessment of the validity of the study results.
Previous evaluations of HIVNET 012 left lingering uncertainties about the trial's results, suggesting the need for a definitive, objective review.
The IOM focused on the scientific validity of the study's conclusions based on a close examination of how researchers from Johns Hopkins University and Uganda's Makerere University conducted the trial.
The Committee did not examine the impact of other recent studies of potential toxicity or resistance buildup associated with the use of Nevirapine either in short- or long-term treatment of HIV-infected individuals.
A trial ( HIVNET 012 ) found that the AIDS medication Nevirapine ( Viramune ) is effective and safe in preventing HIV transmission from mother to unborn child during birth.
The IOM's analysis of the design and methodology of the 1997 drug study in Uganda, called HIVNET 012, determined that policy-makers and other scientists can rely on the resulting data and conclusions, despite some flaws in record keeping and procedural issues.
The Hopkins and Makerere researchers' conclusion that Nevirapine is effective is supported by data on rates of survival and HIV infection among newborns in the study, the Committee determined, noting that the trial researchers accurately recorded that information in the database created for the study.
No evidence was found that the trial researchers either failed to report or mistakenly reported the deaths of any of the infants.
Regarding the trial researchers' findings on Nevirapine's safety, the Committee's review of source documents for the subset of 49 infants found that deaths, hospitalizations, and serious adverse events observed during clinic visits also were recorded accurately in the trial database.
In some instances, however, not all serious adverse events that occurred simultaneously were reported, and some less-serious adverse events were underreported.
However, there was no evidence of a difference in the level of underreporting of adverse events among patients receiving Nevirapine versus those receiving Zidovudine, a second AIDS drug that also was studied in HIVNET 012. The trial investigators' comparative findings on safety are valid, the Committee said.
A concern about HIVNET 012 focused on whether cases of jaundice -- or hyperbilirubinemia -- among infants in the study were underreported.
While the study investigators reported only one infant with abnormal levels of bilirubin, a subsequent safety report issued by DAIDS ( NIAID Division of AIDS ) initially stated that there were 63 cases of elevated bilirubin.
DAIDS later retracted the safety report as incorrect.
The IOM Committee, based on its own analysis, determined that the DAIDS safety report initially used an incorrect upper limit of the normal range for bilirubin levels in newborns. When the correct upper limit is applied, the trial data confirm the original HIVNET 012 investigators' findings and the subsequent DAIDS retraction.
Overall, the Hopkins and Makerere researchers conducted the trial ethically and in accordance with U.S. and international standards for research and management of patient care, the IOM report says.
Although there were some problems with full documentation of compliance with all the requirements for the trial, the Committee determined that the HIVNET 012 study was designed and implemented with approval from the boards that oversaw the trial's design and protocols; that the researchers enrolled women only after they gave free and informed consent; and that fathers were involved in the consent process when they were reasonably available.
Blood tests that detected the presence of Nevirapine in mothers and infants and other data showed that trial participants received the right drug and there was a high level of adherence to the treatment regimens, the committee found. It also noted that trial investigators achieved high rates of retention and follow-up among participants.
The Committee found no reason that medical journals should revise or retract articles that reported on the efficacy and safety of Nevirapine for reducing mother-to-child transmission of HIV based on the HIVNET 012 trial.
Source: Institute of Medicine ( IOM ), 2005