Dolutegravir (formerly known as S/GSK 572) is an investigational integrase inhibitor that is in the late stages of development. It is administered once daily and does not require pharmacokinetic boosting. Two recently presented Phase 3 studies evaluated dolutegravir in combination with nucleoside/nucleotide analogues in treatment-naive subjects.
The first of these, presented at the IAS conference in July, randomized more than 800 subjects to dolutegravir (50 mg once daily) or raltegravir (400 mg BID), given with either tenofovir/emtricitabine or abacavir/lamivudine as determined by investigators. At 48 weeks, HIV suppression to <50 copies/mL was seen in 88% of the dolutegravir group and 85% of the raltegravir group, indicating noninferiority of dolutegravir according to study criteria. In subjects with HIV RNA levels of >100,000 copies/mL at baseline, 82% of the dolutegravir group and 75% of the raltegravir group had HIV RNA of <50 copies/mL. There were no differences in outcomes between the two NRTI backbones. Increases in median CD4 counts were the same in the treatment groups, as were adverse events.
A second randomized controlled study, presented at the 52nd ICAAC, compared dolutegravir (50 mg once daily) + abacavir/lamivudine with the fixed-dose combination of efavirenz/tenofovir/emtricitabine (Atripla) in more than 800 subjects. At 48 weeks, by snapshot analysis, HIV suppression to <50 copies/mL was seen in 88% of the dolutegravir group and 81% of the efavirenz group, a statistically significant difference (p = .003). In subjects with baseline HIV RNA of >100,000 copies/mL, the rates of virologic suppression were 83% and 76%, respectively. The differences in overall treatment success appeared to be driven mostly by higher rates of treatment discontinuation (owing to adverse effects) in the efavirenz group; rates of virologic failure appeared to be similar in the two groups. Median CD4 increases were 267cells/µL in dolutegravir recipients and 208 cells/µL in efavirenz recipients (p = .001).
In both studies, no ARV resistance was identified in subjects who developed virologic failure while taking dolutegravir + abacavir/lamivudine. By comparison, resistance mutations involving integrase and/or reverse transcriptase emerged in 4 of 20 subjects with virologic failure in the raltegravir + NRTIs group; mutations affecting NNRTIs emerged in 4 and of 9 subjects with virologic failure in the efavirenz/tenofovir/emtricitabine group and NRTI mutations in 1 of 9.
Dolutegravir generally was very well tolerated. Small elevations in serum creatinine and decreases in estimated GFR were noted in the dolutegravir groups in both studies; these were attributed to inhibition of tubular secretion of creatinine by dolutegravir (rather than to a decrease in true GFR).
Clinical Bottom Line
Based on the data from these two studies, dolutegravir looks to be a promising integrase inhibitor for initial therapy: It is potent, is taken once daily (unlike raltegravir), does not require PK boosting (unlike elvitegravir, and has few significant side effects or drug interactions. Additionally, (though further study will be required to determine this) virologic failure on dolutegravir may result in less-consequential resistance issues than failure of other integrase inhibitors or an NNRTI. Other studies have shown that dolutegravir is effective against some viruses that are resistant to raltegravir, so dolutegravir also is likely have a role in advanced lines of therapy.