Treatment outcomes differ between women taking first-line antiretroviral therapy based on ritonavir-boosted atazanavir and efavirenz, investigators from the United States report in the online edition of Clinical Infectious Diseases. Women taking the boosted protease inhibitor had a higher risk of virological failure than women treated with efavirenz. There was also some evidence that outcomes differed between women and men treated with atazanavir/ritonavir.
These findings were “unexpected”, but the investigators believe they are of clinical significance. Currently, US guidelines recommend atazanavir/ritonavir as the preferred treatment during pregnancy because of the theoretical risk of birth abnormalities associated with efavirenz.
Little is known about the association between sex and antiretroviral treatment outcomes. This is an import question to address as an increasing proportion of HIV infections involve women.
Investigators therefore designed the ACTG A5202 study. A total of 1857 participants, 322 of whom were women, were recruited to the study at sites across the US and Puerto Rico between 2005 and 2007. All the participants were aged 16 years and over and were taking HIV treatment for the first time.
The study was open-label and the participants were randomised to receive therapy based on ritonavir (Norvir)-boosted atazanavir (Reyataz) or efavirenz (Sustiva or Stocrin), in combination with a nucleoside/nucleotide backbone of either 3TC/abacavir (Kivexa) or FTC/tenofovir (Truvada).
The study’s endpoints were: virological failure (viral load above 1000 copies/ml between weeks 16 and 24 of therapy, or a viral load above 200 copies/ml after 24 weeks of treatment), and also safety and tolerability.
Overall, atazanavir/ritonavir and efavirenz had similar virological efficacy among participants taking the Kivexa backbone. However, outcomes differed significantly according to sex. The risk of virological failure was higher for women randomised to atanzanavir/ritonavir than efavirenz, with incidence rates of 12.52 per 100 person-years versus 4.86 per 100 person-years (HR = 2.55; 95% CI, 1.20-5.41). Women taking atazanavir/ritonavir also had a higher risk of virological failure then men taking this drug (HR = 1.72; 95% CI, 0.99-2.99).
Outcomes also differed by sex in the Truvada arms. The risk of treatment failure was higher among women randomised to atazanavir/ritonavir than among women taking efavirenz (incidence = 10.90 vs. 5.06 per 100 person years. HR = 2.16; 95% CI, 0.97-4.80). Women taking atazanavir/ritonavir also had a higher risk of treatment failure than men randomised to this drug (HR = 2.36; 95% CI, 1.30-4.26).
Adherence did not differ by sex and did not affect the investigators' findings.
“This is the first randomized clinical trial to identify a higher risk of VF [virological failure] in women assigned to an ATV/r [atazanavir/ritonavir]-containing regimen compared to a regimen with EFV [efavirenz],” comment the authors.
There were also some differences in safety and tolerability outcomes between men and women.
There was also some evidence that safety outcomes differed according to sex and nucleoside/nucleotide backbone.
Among the participants randomised to take Kivexa, women were more likely to experience side-effects than men (HR = 1.32; 95% CI, 1.03-1.70). Women taking atazanavir/ritonavir also had a slightly increased risk of gastrointestinal side-effects compared to men taking this protease inhibitor (13 vs 7%) and also compared to women treated with efavirenz (13 vs 6%).
There was no evidence that safety outcomes differed between men and women taking Truvada as their nucleoside/nucleotide backbone.
Pharmacokinetic analysis showed that atazanavir oral clearance and trough concentrations differed according to sex, with women having higher concentrations than men (p = 0.004 and p = 0.003, respectively).
The investigators hypothesise that “higher ATZ levels may lead to higher rates of low level (unmeasured) toxicity that could affect outcomes”.
They conclude that this could have important clinical implications, “given that RTV [ritonavir]-boosted PIs are often favored over EFV for women of childbearing potential…the findings of the current study should warrant additional investigation of antiretroviral regimens in randomized clinical trials and cohorts with large enrollment of women.”
Smith KY et al. Outcomes by sex following treatment initiation with atazanavir plus ritonavir or efavirenz with abacavir/lamivudine or tenofovir/emtricitabine. Clin Infect Dis, online edition, 2013.