The LATTE study: a provocative brew.

The history of the development of combination antiretroviral therapy (ART) has shaped our understanding of the principles governing ART’s construction and use. It was at the 11th International AIDS Conference held 19 years ago in Vancouver, BC, Canada, that the results of the fi rst ART studies assessing combination therapy using two nucleoside analogue reverse transcriptase inhibitors (NRTIs) plus a protease inhibitor were reported. This was followed shortly after by reports of successful combination therapy using a non-NRTI plus two NRTIs. This sequence of events founded the principle that triple therapy was the minimum requirement for control and main tenance of long-term virological suppression. This principle was reinforced by the early unsuccessful attempts to use an induction–maintenance strategy (using two drugs from either one or two ART classes) as a means to streamline long-term HIV management. Despite that general understanding, some investigators have continued to pursue alternative strategies that challenge the dominant triple-therapy framework, particularly combination ART that does not include nucleoside/nucleotide reverse transcriptase inhibitors (N[t]RTIs). This approach was rationalised on the basis that the major adverse events and toxic eff ects associated with combination ART have been most closely linked to the N(t)RTI drug class, and that ART is a lifelong commitment that requires the parsimonious use of agents in a way that should preserve future eff ective combination therapy for decades. The DMP-006 study was the fi rst to show the improved effi cacy of an efavirenz-anchored strategy over a proteaseinhibitor-anchored strategy. Less well remembered is that the results of DMP-006 also showed that a strategy of dual ART using indinavir three times daily (unboosted) plus efavirenz once daily was superior to indinavir three times daily plus zidovudine and lamivudine. 10 years later the ACTG 5142 study, with a similar design to DMP-006 but with boosted lopinavir instead of unboosted indinavir, showed that a regimen with a boosted protease inhibitor plus two N(t)RTIs was inferior to the efavirenz plus two N(t)RTI regimen; the result for the boosted lamivudine plus efavirenz regimen was consistent with non-inferiority compared with the efavirenz plus two N(t)RTI regimen. With the approval over the past 8 years of drugs in new and existing classes, opportunities have arisen for trials of alternative dual therapy regimens and induction–maintenance strategies. The most recent of these have suggested that dual therapy might be noninferior to conventional triple therapy in either fi rst-line or second-line therapy. Results of two studies of triple induction, dual maintenance ART suggest a role for this strategy to avoid toxic eff ects associated with abacavir and tenofovir. However, at least in patients naive to ART, fi ndings of no study have been convincing enough to recommend N(t)RTI-sparing ART as either initial or maintenance therapy alongside standard ART. In The Lancet Infectious Diseases, David Margolis and colleagues present the results of the phase 2, doseranging LATTE trial in which they studied cabotegravir (a longacting analogue of dolutegravir) combined with rilpivirine as a maintenance strategy for patients with successful virological suppression after 24 weeks of induction with conventional triple therapy. At baseline, participants were randomly assigned to receive one of three separate doses of cabotegravir (10 mg, 30 mg, or 60 mg) plus abacavir-lamivudine or tenofoviremtricitabine, or to efavirenz 600 mg plus abacavirlamivudine or tenofovir-emtricitabine. Participants with a viral load of fewer than 50 copies per mL at week 24 in the cabotegravir groups ceased background N(t)RTIs and continued with dual maintenance therapy of cabotegravir plus rilpivirine 25 mg. The overall result was impressive. Of 243 patients in the primary analysis, 149 (82%) of 181 patients who received cabotegravir plus rilpivirine during maintenance had a viral load of fewer than 50 copies per mL after 24 weeks of maintenance therapy, compared with 44 (71%) of 62 participants who received 48 weeks of efavirenz plus two N(t)RTIs. At week 96 (after 72 weeks of maintenance therapy) this diff erence was sustained: 137 patients (76%) receiving dual maintenance therapy had a viral load of fewer than 50 copies per mL compared with 39 (63%) of those receiving conventional efavirenz plus two N(t)RTI triple therapy. Although this study is a typical phase 2 study—ie, it is not powered for defi nitive conclusions about the relative performance of the experimental strategy and regimen— its results are nonetheless radical and provocative. They challenge the notion that dual therapy is not a realistic option compared with triple therapy. They also challenge Published Online July 20, 2015 http://dx.doi.org/10.1016/ S1473-3099(15)00224-8