October 21, 2013
A head-to-head comparison of two single-pill, once-daily HIV treatment regimens appears to favor the long-term use of elvitegravir/cobicistat/emtricitabine/tenofovir (Stribild) over efavirenz/tenofovir/emtricitabine (Atripla) in African Americans, but the difference may be largely due to adverse effects and not drug efficacy, according to research presented at IDWeek 2013.
The data presented at IDWeek were from an ad hoc analysis of Study 102, one of the key clinical trials that ultimately led to the U.S. Food and Drug Administration approval of elvitegravir/cobicistat/emtricitabine/tenofovir (also commonly called the "quad") in August 2012. That study showed comparable efficacy for the quad when stacked up against efavirenz/tenofovir/emtricitabine -- but recent research has also raised concerns that African Americans generally appear to fare worse on first-line antiretroviral regimens than patients who are not black, for reasons that have thus far been unclear.
A group of researchers -- led by David Hardy, M.D., of the David Geffen School of Medicine at the University of California-Los Angeles, and supported by Gilead Sciences, Inc., which markets both the quad and efavirenz/tenofovir/emtricitabine in the U.S. -- sought to explore the racial question by closely examining 96-week results from Study 102. A total of 700 treatment-naive volunteers took part in that study, all of whom began treatment with an HIV viral load of at least 5,000 copies/mL (there were no CD4+ cell count restrictions). This was a racially diverse study population, with roughly 28% of volunteers identifying as African American (and similar proportions across study arms). Non-black volunteers and black volunteers had similar baseline HIV viral loads, CD4+ cell counts and injection drug use histories; black volunteers showed a trend toward higher rates of hepatitis C virus infection. A greater proportion of the black volunteers were female (21%) compared to non-black volunteers (7%).
The by-race analysis found that, when considering the study's primary endpoint -- achieving an HIV viral load below 50 copies/mL -- black patients tended to be more likely to succeed on the quad (81%) than on efavirenz/tenofovir/emtricitabine (73%) through 96 weeks, although this was not a statistically significant difference. (No such trend was discernible for non-black patients.) However, virologic failure rates among black patients were nearly identical at week 96 (12% in both study arms), and emergent resistance at failure was similar (and uncommon). Black patients also experienced nearly identical -- and substantial -- CD4+ cell count gains regardless of regimen (319 cells/mm3 on the quad; 315 on efavirenz/tenofovir/emtricitabine).
The real difference between the study arms appeared to lay in the subset of patients with "no data" at 96 weeks -- which seemed, for the most part, to be due to patients discontinuing the study drug because of adverse events. Ten of 197 black patients quit the study drug for this reason; nine of them were on the efavirenz/tenofovir/emtricitabine arm. By comparison, 31 of 503 non-black patients quit the study drug due to adverse events, split almost evenly between patients receiving the quad and patients receiving efavirenz/tenofovir/emtricitabine.
Reasons for discontinuation varied widely across racial groups, with no single side effect more likely than another to be the trigger for discontinuation among black patients. The bulk of these events were those commonly associated with efavirenz (Sustiva, Stocrin), including rash and central nervous system events such as depression, nightmare, sluggishness and suicidality. Renal events -- which had been closely scrutinized earlier in the quad's development timeline due to cobicistat's tendency to initially inhibit renal tubular secretion -- were not a factor in study discontinuations at 96 weeks (though they had been at 48 weeks for seven non-black patients on the quad), and in fact had stabilized in the study population long before the 96-week point.
Although ad hoc study results lack the statistical gravitas of, say, prospective study findings, these data are nonetheless "reassuring," said Kathleen Squires, M.D., a professor of medicine and the director of the Division of Infectious Diseases at Thomas Jefferson University, who was not involved in the study. "In a lot of studies where they have done these analyses, it's been shown that if you're black, your chances of virologic success are actually less" on first-line therapy. "In this study, they did not show this."
These findings by no means conclusively solve the mystery regarding why African-American patients sometimes seem to fare more poorly on first-line antiretroviral therapy than their non-black counterparts -- a mystery that seems to extend beyond traditionally assumed risk factors for virologic non-success, such as poor adherence.
That said, these data do suggest some dovetailing with previous studies that have found higher drug levels of efavirenz in African-American patients, which may account for the greater occurrence of adverse events leading to study discontinuation among them. And the findings also suggest that, in general, African-American patients do quite well whether they're on the quad or efavirenz/tenofovir/emtricitabine. But there clearly is much more room for study on the broader question.
Myles Helfand is the editorial director of TheBody.com and TheBodyPRO.com.
Follow Myles on Twitter: @MylesatTheBody.