Dolutegravir-based regimen superior to efavirenz-based regimen in treatment-naive patients

Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection.

Walmsley SL, Antela A, Clumeck N, Duiculescu D, Eberhard A, Gutiérrez F, Hocqueloux L, Maggiolo F, Sandkovsky U, Granier C, Pappa K, Wynne B, Min S, Nichols G; SINGLE Investigators.  N Engl J Med. 2013 Nov 7;369(19):1807-18. doi: 10.1056/NEJMoa1215541.

Background: Dolutegravir (S/GSK1349572), a once-daily, unboosted integrase inhibitor, was recently approved in the United States for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in combination with other antiretroviral agents. Dolutegravir, in combination with abacavir-lamivudine, may provide a simplified regimen.

Methods: We conducted a randomized, double-blind, phase 3 study involving adult participants who had not received previous therapy for HIV-1 infection and who had an HIV-1 RNA level of 1 000 copies per milliliter or more. Participants were randomly assigned to dolutegravir at a dose of 50 mg plus abacavir-lamivudine once daily (DTG-ABC-3TC group) or combination therapy with efavirenz-tenofovir disoproxil fumarate (DF)-emtricitabine once daily (EFV-TDF-FTC group). The primary end point was the proportion of participants with an HIV-1 RNA level of less than 50 copies per milliliter at week 48. Secondary end points included the time to viral suppression, the change from baseline in CD4+ T-cell count, safety, and viral resistance.

Results: A total of 833 participants received at least one dose of study drug. At week 48, the proportion of participants with an HIV-1 RNA level of less than 50 copies per milliliter was significantly higher in the DTG-ABC-3TC group than in the EFV-TDF-FTC group (88% vs. 81%, P=0.003), thus meeting the criterion for superiority. The DTG-ABC-3TC group had a shorter median time to viral suppression than did the EFV-TDF-FTC group (28 vs. 84 days, P<0.001), as well as greater increases in CD4+ T-cell count (267 vs. 208 per cubic millimeter, P<0.001). The proportion of participants who discontinued therapy owing to adverse events was lower in the DTG-ABC-3TC group than in the EFV-TDF-FTC group (2% vs. 10%); rash and neuropsychiatric events (including abnormal dreams, anxiety, dizziness, and somnolence) were significantly more common in the EFV-TDF-FTC group, whereas insomnia was reported more frequently in the DTG-ABC-3TC group. No participants in the DTG-ABC-3TC group had detectable antiviral resistance; one tenofovir DF-associated mutation and four efavirenz-associated mutations were detected in participants with virologic failure in the EFV-TDF-FTC group.

Conclusions: Dolutegravir plus abacavir-lamivudine had a better safety profile and was more effective through 48 weeks than the regimen with efavirenz-tenofovir DF-emtricitabine.

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Editor’s notes: In this 48- week double-blind randomized controlled trial in treatment-naive patients, dolutegravir plus abacavir / lamivudine outperformed efavirenz plus tenofovir / emtricitabine in terms of efficacy (viral suppression at 48 weeks and time to viral suppression), immunological recovery and discontinuation of therapy for adverse events. The difference in virologic response was largely due to higher levels of regimen discontinuation for adverse events in the efavirenz arm. The superior virologic response in the dolutegravir arm was consistent regardless of baseline viral load (above or below 100 000 copies/ml). 4% of patients in both arms developed virologic failure (two consecutive viral load measures >50 copies/ml). As expected, non-nucleoside reverse transcriptase inhibitors (NNRTI) mutations and K65R mutations emerged in patients failing the efavirenz-based regimen; however no mutations emerged amongst patients failing the dolutegravir-based regimen.

 Dolutegravir is clearly an attractive future treatment option: its long half-life supports once a day dosing; there are few relevant drug interactions; trials performed to date show that it is well tolerated; and a fixed drug combination tablet of dolutegravir, abacavir and lamivudine is currently being developed. However, until the cost is lowered we are unlikely to see widespread use of this drug.

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