Ready for HIV Dual Therapy? – New Data from IAS 2017

The introduction of combination antiretroviral therapy (ART) in the 1990s has fundamentally transformed the landscape of HIV clinical practice, greatly improved disease morbidity and mortality, and reduced transmission rates across all demographic groups. Central to this success is the idea that in order to achieve best outcomes and prevent the emergence of drug resistance, at least three antiretroviral agents be used in HIV treatment. This therapeutic strategy is a core tenetof HIV medicine, backed by incontrovertible scientific evidence and made easy to deploy by the high adherencelevels with once-daily coformulations, which have generally been well tolerated.
However, there has been increasing support in favor of a paradigm shift towards dual therapy in recent years, particularly in the maintenance phase of treatment. This concept advocates that once virologic suppression has been achieved with three or more antiretroviraldrugs during the treatment initiation phase, switching to a two-drug regimen for maintenance therapy should be possible. Notably, the results of the LAMIDOL (Joly et al., Abstract 458) and phase III SWORD 1&2 (Llibre et al., Abstract 44LB) trials presented at the 2017 Conference on Retroviruses and Opportunistic Infections (CROI 2017) earlier this year seemed to lend support this hypothesis.
More new data was recently presented at the 9th IAS Conference on HIV Science (IAS 2017) that adds to the growing body of evidence in support of a two-drug regimen approach in maintenance therapy. TheLATTE-2 study (Eron et al., Abstract 5628) was of major interest because of the exciting new therapeutic options that long-acting injectable antiretroviral agents may offer in the near future. But more than that, the findings of comparable response between a traditional three-drug oral regimen and a novel injectable twodrug regimen at 96 weeks were quite noteworthy. In this phase II multicenter open-label study of 286 HIVinfected ART-naïve patients, once daily oral cabotegravir/abacavir/lamivudine achieved virologic suppression in 84% of study subjects. In comparison, 87% in theinjectable cabotegravir/rilpivirine once four-weekly group and 94% in injectable cabotegravir/rilpivirine once eight-weekly group remained suppressed at 96 weeks. Crucially, no drug resistance mutations were seen in study participants who remained adherent to their treatment regimen.
While the two-drug regimen strategy has been entertainedin maintenance therapy, there has been little willingness to consider this approach in the initiation of ART in treatment-naïve HIV-infected patients because of the justifiable concerns that exist around the emergence of drug resistance. Despite this, new data presented at the IAS 2017 meeting suggests that the idea is not without merit. In a proof of concept single-arm pilot study (ACTG A5353) which looked at 120 treatment naïve HIV-infected subjects with high study entry viral load (VL ≥ 1,000 and < 500,000 copies/mL), it was shown that once daily dolutegravir/lamivudine had virologic efficacy of 90% at 24 weeks, with 96% of the as-treated study population achieving VL < 50 copies/mL (Taiwo et al., Abstract MOAB0107LB).The regimen was well tolerated, with no reported drug resistance mutations while study participants remained on treatment.
There may be many real-world advantages to the two-drug regimen approach, among them lower costs(crucial in resource-poor settings where affordability may be a limiting factor), fewer adverse effects or drug toxicities, improved tolerability, and possibly better adherence to treatment regimen. These are all increasingly important considerations in clinical decision-making, given that improved mortality means patients are now expected to remain on ART for longer than has been previously seen. But how the two-drug regimen approach will stack up against tradition and firmly established norms is far from clear, and it is almost certain that the uneasiness that understandably surroundsthis idea is likely to persist. Until the case for the twodrug regimen approach is made more convincingly in ongoing and future trials, the “three or moreâ€? rule will reign in HIV medicine, not merely as orthodoxy, but in fact as the cornerstone of good practice.