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CROI 2017: Dolutegravir in 2-Drug Simplification Studies
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In recent years, a number of studies have evaluated 2-drug or even 1-drug ARV regimens, either in initial therapy or in switch regimens for patients with virologic suppression on 3-drug therapy. In general, these have not been as successful in achieving or maintaining virologic suppression as standard ARV therapy. However, a couple of 2-ARV combinations have appeared promising for patients switching from suppressive standard regimens--eg, the integrase inhibitor cabotegravir + the NNRTI rilpivirine or the boosted protease inhibitors darunavir + ritonavir and lopinavir/ritonavir with the NRTI lamivudine (3TC). At CROI, two studies of dual therapy involving the integrase inhibitor (INSTI) dolutegravir were presented, both done in patients with suppressed HIV viremia on standard therapies.

The SWORD-1 and SWORD-2 studies are large (n = 1,024) identical open-label Phase 3 studies of patients on stable ARV regimens who were randomized to switch to dolutegravir + rilpivirine or to continue their current ART. At baseline, patients were on their first or second ART regimen with no history of virologic failure; the median duration of ART was 52 months. At week 48, in snapshot analysis of pooled data from the two studies, 95% of patients in both groups maintained HIV RNA <50 copies/mL; this result indicates noninferiority of the dual-therapy regimen. Two patients in the dolutegravir + rilpivirine arm had virologic failure; neither developed INSTI resistance, one developed an NNRTI mutation. Adverse effects were more common in the group that switched to dual therapy but they were consistent with known effects of the two ARVs.

LAMIDOL, a much smaller (n = 110) single-arm open-label study, evaluated a switch from suppressive first-line ART to dolutegravir + 3TC. At baseline, patients had wild-type HIV and had been on their standard 3-drug ART regimen for 4 years. Patients initially switched the third agent in their regimen to dolutegravir (50 mg once daily) for 8 weeks, then (if HIV RNA remained <50 copies/mL) switched from 2 NRTIs to 3TC. 97% of patients who switched to dual therapy maintained viral suppression after 40 weeks. Three patients had HIV RNA >50 copies/mL; none of these had INSTI mutations, one had an NRTI mutation. Five patients had serious adverse effects, including one with depression and one with suicidal ideation.

Clinical Bottom Line

The large randomized SWORD-1 and SWORD-2 studies showed that dolutegravir + rilpivirine dual therapy can be as effective as standard therapy in appropriate, carefully selected patients with virologic suppression. The LAMIDOL study of dolutegravir + 3TC was tiny in comparison, one tenth the size of the SWORD studies, and had no comparator arm. While its results are encouraging, we will need data from larger randomized studies to know whether dolutegravir + 3TC is a viable switch option for patients on standard ART. Several additional trials of both these 2-drug regimens are under way, as are trials of fixed-dose combinations of both. For now, though, it is important to remember that simplification to dual therapy has not been well studied; it should be considered only for carefully selected patients for whom standard triple therapy is not appropriate or not optimal and who have stable viral suppression and HIV that has no known resistance to the new ARV agents.

Llibre JM, Hung CC, Brinson C, et al. Phase III SWORD 1&2: switch to DTG+RPV maintains virologic suppression through 48 wks. In: Program and abstracts of the 2017 Conference on Retroviruses and Opportunistic Infections; February 13-16, 2017; Seattle. Abstract 44LB.
Joly V, Burdet C, Landman R, et al. Promising results of dolutegravir + lamivudine maintenance in ANRS 167 LAMIDOL trial. In: Program and abstracts of the 2017 Conference on Retroviruses and Opportunistic Infections; February 13-16, 2017; Seattle. Abstract 458.