More than 5 million people worldwide, with the vast majority in resource-limited countries, are receiving HIV treatment with life-saving antiretroviral drug combinations. The WHO treatment guidelines are significant, as most developing nations rely on them to devise their own treatment guidelines. The WHO last revised its treatment guidelines in 2010, replacing some older, more toxic regimens with four new regimens: these all include the drug tenofovir and either of the medications lamivudine or emtricitabine, as well as one of another pair, nevirapine or efavirenz.
As part of a systematic review of the four WHO-recommended regimens for initial treatment, the researchers culled through nearly 1,800 publications and conference abstracts, identifying 33 studies that contained data on efficacy of the four newly recommended drug combinations. Only three published studies were found for the least expensive of these combinations: tenofovir/lamivudine/nevirapine. Two of the studies involved clinical trials of this combination that had to be stopped early because of high failure rates within the first three to four months.
A third study looked retrospectively at more than 9,000 patients who received antiretroviral therapy in Nigeria; again, the tenofovir/lamivudine/nevirapine regimen was found to have the highest failure rate.
“We pursued multiple lines of evidence that strongly suggested that this particular regimen poses a risk to successful therapy,” said Robert Shafer, MD, a professor of medicine and the principal investigator in the research. “It’s not just that it appeared inferior [to other alternatives] but among patients with treatment failure, drug resistance developed quickly.”
Shafer said that the drug regimen is increasingly being used in sub-Saharan Africa, where limited monitoring makes it difficult to spot fallacies in any given regimen. “In regions where there is less-frequent monitoring — where virus load testing is not done very often and resistance testing is not done at all — it could take several years to pick up problems,” he said. “So unless there is a prospective study, it will take a lot of retrospective data to confirm our concerns that this regimen may pose an unacceptable risk of failure compared with the other WHO-recommended regimens.”
The analysis was published online Feb. 22 in the journal Clinical Infectious Diseases and will appear in print March 15. In an accompanying editorial, researchers from Harvard Medical School, the University of Zimbabwe and the University of Witwatersrand in South Africa echoed the researchers’ concerns about the drug combination and urged that international bodies, with the support of drug manufacturers, conduct a randomized clinical trial to verify whether it should remain on the WHO list.
Shafer’s colleagues in the study are Michele Tang, MD, a postdoctoral scholar in infectious disease at Stanford who was the lead author, and Phyllis Kanki, PhD, professor of immunology and infectious disease at Harvard School of Public Health who directs one of the U.S. President’s Emergency Fund for AIDS Relief Programs in sub-Saharan Africa.