HIV: New Single-Pill Treatment Effective, Safe

Jenni Laidman

June 28, 2012

June 28, 2012 — A new once-a-day treatment for HIV appears to be as effective and as safe as 2 other recommended HIV drug regimens among treatment-naive adults, according to reports on 2 large double-blind, randomized phase 3 trials, published in the June 30 issue of the Lancet.

The so-called Quad pill, which combines 3 antiretrovirals and a booster molecule in a single daily dose, suppressed patient viral load to undetectable levels (<50 HIV RNA copies/mL of blood) faster than the treatments it was tested against. By 48 weeks, however, all 3 treatments were equally effective, produced roughly the same low number of adverse effects, and led to the same modest level of drug resistance.

Rik Schrijvers and Zeger Debyser, MD, PhD, professor of medicine, Division of Molecular Medicine, Katholieke Universiteit Leuven, Flanders, Belgium, write in an accompanying editorial that the 2 phase 3 studies "show that Quad has high efficacy and a good tolerability profile, with the limitations of potential drug interactions and a need to be taken with food."

However, the editorial writers caution, "The underrepresentation of women in these studies, and absence of long-term safety data (especially for renal toxic effects) and resistance data, warrant further research."

A US Food and Drug Administration (FDA) advisory committee announced support for Quad in May and the agency is expected to make a final decision by August.

Quad, if approved, would be the only single-pill integrase-inhibitor-based treatment on the market. It combines the investigational HIV integrase inhibitor elvitegravir with the investigational booster molecule CYP3A4 inhibitor cobicistat and 2 reverse transcriptase inhibitors, emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF).

In a randomized, blinded study comparing Quad performance with the only approved single-pill treatment of efavirenz (EFV), FTC, and TDF, 348 patients from across North America received the Quad pill and 352 received EFV/FTC/TDF. To ensure neither patients nor investigators could tell which treatment a patient received, all participants were given a placebo pill of the alternate treatment.

Paul E. Sax, MD, clinical director of the HIV Program and Division of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts, and colleagues found that 87.6% (305/348) of the patients receiving Quad and 84.1% of the patients receiving EFV/FTC/TDF (296/352) had undetectable viral load at 48 weeks (difference, 3.6%; 95% confidence interval [CI], −1.6% to 8.8%).

A similar number of patients in both treatment groups discontinued treatment because of adverse effects: 13 of 348 patients (4%) in the Quad group and 18 of 352 patients (5%) in the EFV/FTC/TDF group. In the Quad group, diarrhea was the most frequent adverse effect (23% of patients receiving Quad vs 19% of patients receiving EFV/FTC/TDF), followed by nausea (21% vs 14%, respectively) and abnormal dreams (15% vs 27%, respectively). The most common adverse effect for EFV/FTC/TDF was abnormal dreams, followed by dizziness (24% vs 7% for the patients receiving Quad), diarrhea, insomnia (14% vs 9% for the patients receiving Quad), and nausea.

Edwin DeJesus, MD, medical director, Orlando Immunology Center in Florida, and colleagues tested Quad against a ritonavir-boosted (RTV) protease inhibitor regimen of atazanavir (ATV) accompanied by a combination tablet of FTC and TDF. This combination is an alternative for patients resistant to nonnucleoside reverse transcriptase inhibitors, those unlikely to adhere to therapy, and women of childbearing age or for avoiding neuropsychiatric disorders associated with EFV.

The double-blind, randomized trial assigned 353 previously untreated patients recruited in Australia, Europe, North America, and Thailand to receive Quad and 355 to receive the ATV/RTV+FTC/TDF combination. To blind patients and caregivers to treatment assignment, all trial participants received 4 pills daily comprising both their treatment and placebos that resembled the alternative treatment.

Both treatments reduced viral load to undectable levels in 48 weeks in a substantial number of patients, with 89.5% (316/353) of the patients receiving Quad reaching nondetect status and 86.8% (308/355) of the patients receiving ATV/RTV+FTC/TDF with undetectable viral load at 48 weeks (adjusted treatment difference, 3.0%; 95% CI, −1.9% to 7.8%). CD4 counts increased in both groups, with a mean count of 207 cells/μL in the Quad group and 211 cells/μL in the ATV/RTV+FTC/TDF group.

Few patients withdrew from the trial because of the adverse effects of either treatment: 13 (3.7%) withdrew from Quad treatment and 18 (5.1%) from the ATV/RTV+FTC/TDF group. Most adverse events were mild or moderate in severity (grade 1 or grade 2). The most common adverse events for Quad were diarrhea (22% vs 27% for ATV/RTV+FTC/TDF; P = .097), followed by nausea (20% vs 19%, respectively; P = .92). These were also the most common adverse effects for ATV/RTV+FTC/TDF.

Fewer patients receiving Quad had abnormal liver function results than those in the ATV/RTV+FTC/TDF group. Increases in fasting triglyceride concentration were also smaller in the Quad group (90 μmol/L vs 260 μmol/L; P = .006). Participants in both groups saw small median increases in serum creatinin concentration with decreases in estimated glomerular filtration rate by week 2. These rates stabilized by week 8 and remained stable (median change, 11 μmol/L for Quad vs 7 μmol/L for ATV/RTV+FTC/TDF).

The development of a once-a-day, single-pill treatment is considered an important step in avoiding drug resistance in HIV patients, Dr. Sax said in a news release.

"Patient adherence to medication is vital, especially for patients with HIV, where missed doses can quickly lead to the virus becoming resistant to medication. Older HIV treatment regimens involve taking several pills multiple times a day," Dr. Sax said in the release. "Our results provide an additional highly potent, well-tolerated treatment option, and highlight the simplicity of treatment resulting from combining several antiretrovirals in a single pill. Studies have shown that single pill treatments improve both adherence and patient satisfaction, and help prevent prescription errors, thereby reducing the likelihood of treatment failure and drug resistance."

In a news release, Brian Kearney, a study author from Gilead Sciences, which developed Quad, said: "If approved by regulatory agencies, the Quad would be the first once-daily single-tablet regimen containing an HIV integrase inhibitor."

Gilead Sciences sponsored the trials, designed them, collected and analyzed the data, interpreted the results, and helped write the report. All authors had access to data used in the analysis and could ask for additional information. On the Quad vs ATV/RTV+FTC/TDF paper, Dr. DeJesus received research grant support from Gilead Sciences and several others, as well as consulting fees as a member of an advisory board for Gilead Sciences and others. Other authors received lecture fees and advisory board honoraria, acted as a consultant, participated in advisory boards, received speaker fees, and have been an investigator for clinical trials from Gilead Sciences and others. Several authors are employees of Gilead Sciences. On the Quad vs EFV/FTC/TDF paper, Dr. Sax has received research support and consulting fees for speakers bureau and advisory boards from Gilead Sciences and others. Several authors are employees of Gilead Sciences. Rik Schrijvers and Dr. Debyser have disclosed no relevant financial relationships.

Lancet. 2012;379:2429-2448. DeJesus article abstract, Sax article abstract, Editorial extract