HIV: Non-Efavirenz Regimens Effective in Initial Treatment

Veronica Hackethal, MD

October 10, 2014

Several regimens that exclude efavirenz have similar efficacy in the initial treatment of HIV, according to results from a phase 3 AIDS Clinical Trials Group randomized controlled trial published online October 6 in the Annals of Internal Medicine. The results expand the treatment options for people who cannot take the drug.

The study is the first head-to-head comparison of three different non-efavirenz-based therapies recommended by the US Department of Health and Human Services for treatment-naive patients with HIV.

"All 3 regimens achieved equivalent and high rates of virologic suppression, whereas raltegravir had a more favorable tolerability profile and caused less elevation in lipid levels," write Jeffrey Lennox, MD, from Emory University School of Medicine in Atlanta, Georgia, and colleagues. "Among [protease inhibitor (PI)]-containing regimens, ritonavir-boosted darunavir was better tolerated than ritonavir-boosted atazanavir, primarily because of differences in hyperbilirubinemia."

Guidelines from both the World Health Organization and the US Department of Health and Human Services recommend efavirenz-based combination therapy for the initial treatment of HIV-1 in adults and adolescents, according to background information in the article. However, efavirenz-based therapies may not be suitable for women who are thinking about becoming or could be pregnant or for people with serious mental illness because of increased risk for birth defects and suicidal thoughts.

The current trial took place from May 2009 to June 2011 in 57 sites in the United States and Puerto Rico. Researchers used an open-label design and randomly assigned participants to one of three different non-efavirenz-based treatment groups: 300 mg/day atazanavir with 100 mg/day ritonavir, 800 mg/day darunavir with 100 mg/day ritonavir, or 400 mg/twice daily of raltegravir. All regimens included a backbone of emtricitabine 200 mg/day (Truvada, Gilead Sciences) and tenofovir disoproxil fumarate 300 mg/day. Patients were followed for at least 96 weeks.

A total of 1809 treatment-naive patients enrolled in the trial, of whom 24.0% were women and 34.0% were non-Hispanic white.

At 96 weeks, all three groups had similar rates of virologic failure when stratified by baseline viral load, race/ethnicity, and sex. The ritonavir-boosted atazanavir group had a 12.6% cumulative probability of virologic failure compared with 9.0% in the raltegravir group and 14.9% in the ritonavir-boosted darunavir group. The authors found no significant differences in efficacy in pairwise comparisons of the regimens.

However, ritonavir-boosted atazanavir was significantly less well tolerated than either raltegravir or ritonavir-boosted darunavir. Specifically, pairwise comparisons showed a 12.7% higher dropout rate in the ritonavir-boosted atazanavir group compared with raltegravir and a 9.2% higher rate compared with ritonavir-boosted darunavir. Hyperbilirubinemia was particularly common in the ritonavir-boosted atazanavir group.

Women seemed to tolerate raltegravir better than ritonavir-boosted darunavir (P = .047).

For combined virologic efficacy and tolerability, ritonavir-boosted darunavir was better than ritonavir-boosted atazanavir. Raltegravir proved better than both PIs on this variable.

Although rare, antiviral resistance with virologic failure was more frequent with raltegravir. Three percent of patients receiving raltegravir experienced virologic failure with resistance compared with 1.5% of those in either of the two ritonavir-boosted PI groups.

The researchers found that low-density lipoprotein cholesterol and triglycerides did not increase as greatly in the raltegravir group compared with in the ritonavir-boosted PI-containing groups (P ≤ .001 for all).

Effect on Practice Unclear

Despite these findings, this study is "not likely" to change clinical practice, according to Michael Kolber, MD, PhD, professor of medicine, director of the Comprehensive AIDS Program, and director of Adult HIV Services at the University of Miami Miller School of Medicine in Florida. Dr Kolber was not involved in this study.

"The results of the study confirm much of the preexisting data in terms of toxicity and resistance expectations. In that regard, it is important," Dr Kolber commented. "In the vast majority of patients, all regimens [in this study] were tolerated well."

He added, "As always, the most important aspect of choosing a therapy is between a patient and physician. Notable in a physician's choice is whether they feel a patient will take the medications. It has been known that PI-boosted regimens, especially atazanavir, have more liver toxicity.

"An interesting point not addressed [in this study] is that in 2010, ritonavir changed from gel capsules, which are known to have higher [gastrointestinal] side effects, to tablet form. This may have an impact on tolerability, especially the [gastrointestinal] aspects," Dr Kolber added.

"One should note that the field continues to change. As medication combinations are coformulated, the guidelines will continue to change to address preferred agents," Dr Kolber emphasized. "As such, it is always difficult to stay ahead when doing a clinical trial."

The study was primarily funded by the National Institute of Allergy and Infectious Disease, with additional support from the National Institute of Mental Health, National Institute of Dental and Craniofacial Research, and AIDS Clinical Trials Group. The study medications were provided by Bristol-Myers Squibb, Merck, Janssen Therapeutics, and Gilead Sciences. Ritonavir was not provided, but copayments were reimbursed when allowed by law. One coauthor is an employee of Janssen Pharmaceuticals. Another coauthor reports being an employee and stock holder of Gilead Sciences. Another coauthor is an employee of Merck. One or more coauthors reports grants, personal fees, or other support from one or more of the following: , Pfizer, Gilead Sciences, Janssen, Enterahealth, Merck, Gilead Sciences, GlaxoSmithKline, MBio Diagnostics Inc, Bristol-Myers Squibb, AbbVie, ViiV Healthcare, Theratechnologies, EMD Serono, GlaxoSmithKline, Brigham and Women's Hospital, Celera, and Bristol-Myers Squibb. One coauthor reports that his spouse serves on scientific advisory boards or as clinical PI for Gilead, CytoDyn, Merck, MBio Diagnostics, Bristol-Myers Squibb, Santarus, Monogram Biosciences, GlobeImmune, and Boehringer Ingelheim. Funds for this work were submitted to University of California, San Diego. Dr Kolber has disclosed no relevant financial relationships.

Ann Intern Med. 2014;161:461-467. Abstract

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