Initial treatment with efavirenz-free regimens appears effective in treatment-naive HIV patients

Three treatment regimens for HIV infection that did not include efavirenz appeared to achieve high, equivalent virologic control, according to a new study.

The U.S. Department of Health and Human Services recommends that initial treatment of HIV infection include a combination of 2 reverse transcriptase inhibitors plus a nonnucleoside reverse transcriptase inhibitor (NNRTI), a ritonavir-boosted protease inhibitor (PI), or an integrase inhibitor. Efavirenz is the recommended NNRTI, but it is not preferred for women considering pregnancy, patients with NNRTI resistance, and patients with severe psychiatric disorders. To examine the safety and efficacy of the available alternatives, researchers performed a phase 3, open-label randomized trial comparing the following therapies: atazanavir, 300 mg/d, plus ritonavir, 100 mg/d; raltegravir, 400 mg twice daily; or darunavir, 800 mg/d, plus ritonavir, 100 mg/d, and combination emtricitabine, 200 mg/d, and tenofovir disoproxil fumarate, 300 mg/d.

The study measured virologic failure, defined as confirmed HIV-1 RNA level above 1,000 copies/mL between 16 and 24 weeks, or confirmed HIV-1 RNA level above 200 copies/mL at or after 24 weeks. It also measured tolerability failure, defined as discontinuation of atazanavir, raltegravir, or darunavir because of toxicity. Virologic efficacy and tolerability was a combined secondary end point. The study took place at 57 sites in the U.S. and Puerto Rico and was funded by the Division of AIDS of the National Institute of Allergy and Infectious Diseases; Bristol-Myers Squibb, Merck, Janssen Therapeutics, and Gilead Sciences provided the study drugs and also contributed to the protocol development and to manuscript review. The AIDS Clinical Trials Group was solely responsible for final manuscript review and approval. The study results appear in the Oct. 7 Annals of Internal Medicine.

Overall, 1,814 volunteers enrolled in the study between May 22, 2009, and June 9, 2011; 1,809 were included in the final analysis. Six hundred five patients were assigned to the atazanavir/ritonavir group, 603 were assigned to the raltegravir group, and 601 were assigned to the darunavir/ritonavir group. Twenty-four percent of the study population was women, and 34% were non-Hispanic whites. Two hundred sixty-two patients (14.5%) discontinued follow-up before June 2013, the end of the study.

Two hundred ninety-five participants (16.3%) had confirmed virologic failure, 54 (18.3%) before 24 weeks, 67 (22.7%) between weeks 24 and 48, and 174 (59.0%) after week 48. Cumulative probability of virologic failure by 96 weeks was 12.6% in the atazanavir/ritonavir group, 9.0% in the raltegravir group, and 14.9% in the darunavir/ritonavir group. Over 96 weeks, incidence of virologic failure in pairwise comparisons were considered equivalent (margin of equivalence, −10% to 10%). Tolerability was equivalent in the raltegravir and darunavir/ritonavir groups, while the atazanavir/ritonavir group had a 12.7% and 9.2% higher incidence of tolerability-related discontinuation, respectively, due mainly to hyperbilirubinemia. For the combined end point of virologic efficacy and tolerability, darunavir/ritonavir outperformed atazanavir/ritonavir; raltegravir, meanwhile, was superior to both of the other PI regimens. Although antiretroviral resistance was rare at virologic failure, it was more common in those taking raltegravir.

The authors noted that their trial was open-label and that they did not directly provide ritonavir to participants, although copayments for the drug were reimbursed. However, they concluded that the 3 studied regimens yielded equivalent rates of virologic suppression and that raltegravir was more easily tolerated, with less effect on lipid levels. Further, they said, of the PI regimens, darunavir/ritonavir had better tolerability than atazanavir/ritonavir. “When tolerability and virologic response are considered together, raltegravir-based therapy was superior overall to both PI-based therapies and ritonavir-boosted darunavir was superior to ritonavir-boosted atazanavir,” the authors wrote. “An advantage of the ritonavir-boosted PIs over the raltegravir-based regimen is the reduced likelihood of drug resistance if virologic failure occurs.”