Dolutegravir a Promising Treatment Option for HIV

The integrase inhibitor dolutegravir, used in combination with the nucleoside reverse transcriptase inhibitors abacavir and lamivudine, showed more efficacy and a better safety profile in the treatment of HIV-1 infection compared with a regimen consisting of efavirenz-tenofovir disoproxil fumarate emtricitabine (EFV-TDF-FTC), according to results of a study [N Engl J Med. 2013;369:1807-1818.]

“Dolutegravir belongs to a new class of antiretroviral agents called integrase inhibitors, which prevent the virus from integrating into the genetic material of the CD4 lymphocytes,” said Sharon L. Walmsley, MD, University Health Network, Toronto, Canada, during an interview with First Report Managed Care.

Approved in August 2013 by the FDA, dolutegravir was developed for use in combination with abacavir-lamivudine as a single-tablet regimen to treat HIV infection. Dr. Walmsley and her colleagues designed the phase 3, randomized, double-blind trial known as SINGLE to evaluate the safety and efficacy of dolutegravir in combination with abacavir-lamivudine compared with EFV-TDF-FTC. At the time of the trial, EFV-TDF-FTC was the only single-tablet regimen preferred in US HIV treatment guidelines.

There were 833 participants included in the analysis (n=414, dolutegravir group; n=419, EFV-TDF-FTC group). Study participants had to be ≥18 years of age with no prior history of antiretroviral therapy (ART), a plasma HIV-1 ribonucleic acid (RNA) level of 1000 copies/mL, and negative status for the HLA-B*5701 allele. Patients were randomized according to their plasma HIV-1 RNA level (≤100,000 copies/mL vs >100,000 copies/mL) and CD4+ T-cell count (≤200 per cubic millimeter vs >200 per cubic millimeter) at the time of screening (Figure - Below).

Dolutegravir was given at a dose of 50 mg and abacavir-lamivudine at 600 mg and 300 mg, respectively. The other treatment group received EFV-TDF-FTC at fixed doses of 600 mg, 300 mg, and 200 mg, respectively. Both groups received the same number of tablets each day.

The primary efficacy end point was the proportion of patients with a plasma HIV-1 RNA level of <50 copies/mL at week 48. Secondary efficacy end points included the time to viral suppression and the change from baseline in the CD4+ T-cell count. The median HIV-1 RNA level at baseline was 4.68 log₁₀ copies/mL; median CD4+ T-cell count was 338 cells/mm³.

Results showed 88% of the dolutegravir group met the primary end point compared with 81% of the EFV-TDF-FTC group, with the dolutegravir regimen shown to be statistically superior (P=.003). The median time to reach the primary end point was 28 days for the dolutegravir group and 84 days for the EFV-TDF-FTC group (P<.001). The researchers also found the adjusted mean change from baseline by week 48 in the CD4+ T-cell count was greater for participants in the dolutegravir group than the EFV-TDF-FTC group (267 cells/mm³ vs 208 cells/mm³; P<.001).

By week 48, drug-related adverse events had occurred more frequently in patients taking EFV-TDF-FTC compared with patients taking the dolutegravir regimen (66% vs 43%, respectively), and the percentage of patients who discontinued therapy due to adverse events was 2% in the dolutegravir group versus 10% in the EFV-TDF-FTC group.

Diarrhea, nasopharyngitis, nausea, headache, and fatigue were the most common adverse events observed during the 48 weeks. Overall, adverse events of grade 3 or 4 were seen in 10% of patients in the dolutegravir group and 16% of patients taking the EFV-TDF-FTC regimen.

Women comprised only 16% of the study population, which was acknowledged by the authors as a limitation of the study. The proportion of patients with relatively low CD4+ T-cell count of <200 per cells/mm³ is another, although according to the researchers, reflective of evolving guidelines for beginning therapy.

“This study provides evidence for a new option for antiretroviral combination therapy, which was found to be superior to EFV-TDF-FTC, [which is] the current standard of care,” said Dr. Walmsley. “The improved outcome with dolutegravir in combination with abacavir and lamivudine largely relates to better tolerability and fewer side effects. Its advantage over other agents in the class is its long half-life, enabling it to be given as 1 tablet once per day.”