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Dolutegravir in Treatment-Naive Patients

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Dolutegravir in Treatment-Naive Patients

The 48-week results of the SPRING-1 study of dolutegravir (S/GSK 572), an investigational integrase inhibitor, were presented at the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention. This Phase 2b partially blinded dose-ranging study randomized 205 treatment-naive subjects to 1 of 3 dosages of dolutegravir (10, 25, or 50 mg QD) or to efavirenz, coadministered with either tenofovir/emtricitabine (67%) or abacavir/lamivudine (33%). The mean baseline HIV RNA level was 4.46 log10 copies/mL (roughly 20% had HIV RNA levels of >100,000 copies/mL) and the mean baseline CD4 count was 324 cells/µL.

At week 48, 88-91% of subjects in the dolutegravir groups had HIV RNA levels of <50 copies/mL, compared with 82% of the efavirenz group. The rate of virologic nonresponse or rebound was the same in the 3 dolutegravir groups and the efavirenz group. Virologic failure (HIV RNA levels of >400 copies/mL) was seen in 3 subjects who received dolutegravir; no integrase inhibitor resistance mutations or phenotypic changes were detected in the 2 subjects that have been evaluated to date. Dolutegravir in general was associated with fewer adverse effects than efavirenz, and fewer ART discontinuations. Rash and neuropsychiatric adverse effects were not seen in dolutegravir recipients, and adverse lipid changes were minimal. However, small increases in serum creatinine (0.1-0.15 mg/dL) were observed in dolutegravir recipients; these declined toward baseline over time and were not associated with decreases in glomerular filtration rate (GFR) as measured by iohexol clearance (the purported mechanism is inhibition of tubular secretion of creatinine by dolutegravir). Increases in CD4 counts were not statistically different in the 4 treatment groups.

Clinical bottom line

These and earlier efficacy and safety data are very encouraging, and they offer the possibility of another once-daily option for initial treatment of HIV. Phase 3 study of dolutegravir is under way, using the dolutegravir 50 mg QD dosage. In addition, a pharmacokinetic study of fixed-dose combination tablets comprising dolutegravir/abacavir/lamivudine is in progress.

References

  1. Min S, Carrod A, Curtis L, et al. Safety profile of dolutegravir (DTG, S/GSK1349572), in combination with other antiretrovirals in antiretroviral (ART)-na´ve and ART-experienced adults from two phase IIb studies. In: Program and abstracts of the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 17-20, 2011; Rome. Abstract TUPE238.
  2. Van Lunzen J, Maggiolo F, Phung B, et al. Rapid, robust and sustained antiviral response with once-daily (QD) dolutegravir (DTG, S/GSK1349572), a next generation integrase inhibitor (INI) in combination therapy in antiretroviral-na´ve adults: 48 week results from SPRING-1 (ING112276). In: Program and abstracts of the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 17-20, 2011; Rome. Abstract TUAB0102.