Can simplified antiretroviral drug combination therapies resist resistance?

The efficacy of triple-drug antiretroviral regimens in the treatment of patients infected with HIV was established in several randomized clinical trials conducted in the 1990s, in terms of achieving and maintaining full virologic suppression and leading to immune reconstitution [1,2]. In a landmark article from 1998, 1255 patients receiving care in nine American clinics in whom a nadir CD4+ cell count less than 100 cells/μl had been documented, a reduction in mortality from 29.4 to 8.8 per 100 person-years was documented between the first quarter of 1995 and the second quarter of 1997 [3]. Combination antiretroviral therapy was found to be the most significant driver of this benefit. The era of the ‘three drug cocktail’ as the standard of care in HIV therapeutics had arrived. For patients who were naive to antiretroviral therapy, this offered great hope. If they were adherent to the new combinations of the day, long-term virologic suppression was the expected outcome. Some of the earlier versions of the three drug combinations were unduly complex or toxic. Over time, new agents and combinations became available that were simpler and better tolerated. Many studies showed that individuals with long-term virologic suppression and no history of virologic failure could switch from one regimen to another without compromising (and perhaps even enhancing) the long-term benefits of the intervention [4,5]. For patients who had received prior nonsuppressive therapies, virologic suppression was less predictable, because of the prior emergence of drug resistance. Of particular concern was the frequent development of the M184 V/I mutation that confers high-level resistance to lamivudine (3TC) or emtricitabine (FTC), included in the backbone of all early triple-therapy regimens and the majority of recommended regimens to this day. A strategy to address this clinical dilemma was to create multidrug rescue regimens, often with a preceding therapeutic treatment interruption to promote the re-emergence of more susceptible viral isolates in the circulation [6,7]. In many cases, virologic suppression was subsequently achieved but at the price of great complexity and, quite often, significant side effects. Many patients have since benefited from some attempt at therapeutic simplification. However, it remains unclear whether they can safely be prescribed the most potent contemporary regimens based on integrase inhibitors as a third agent, often as a convenient and flexible single tablet regimen, without risking therapeutic failure because of archived drug resistance. The article by Andreatta et al.[8] in this issue of AIDS provides us with important information in this regard. In their analysis of six clinical trials, 2386 participants with virologic suppression (HIV-1 RNA <50 copies/ml for 3 or 6 months) on a three-drug regimen were switched to a combination of bictegravir with emtricitabine and tenofovir alafenamide (B/F/TAF) and monitored for maintenance of virologic suppression over time. A total of 182 study participants were identified with preexisting M184 V/I mutations (including archived resistance detected by proviral DNA testing) and received B/F/TAF for a median duration of 69 weeks. At the last on treatment visit, 179 of 182 (98%) had HIV-1 RNA measures less than 50 copies/ml (as compared with 99% of the overall study population), with only one individual with a value greater than 100 copies/ml, this being associated with significant nonadherence to prescribed medications. Additional preexisting resistance mutations were detected in almost half of the cases, including eight instances of tenofovir resistance (K65R) and four cases of integrase inhibitor resistance. None of these genetic changes were associated with loss of virologic suppression on B/F/TAF. To our minds, these findings help inform clinical practice. For patients who have developed resistance to 3TC or FTC with mutations at codon 184 (an extremely common occurrence among those who have experienced virologic breakthrough, because of prior receipt of nonsuppressive regimens, nonadherence and/or treatment interruptions), the combination of B/F/TAF appears to be extremely resilient and forgiving, leading to sustained virologic suppression once initiated in this context. In some cases, the M184 V/I mutations are not detected in the circulation, may still be present in viral reservoirs, and may emerge if a patient is placed on a potentially nonsuppressive combination. The data generated in this analysis suggest that this phenomenon is not of concern in patients switched to B/F/TAF for simplification. We must be cautious in extrapolating these results to other single tablet regimens, we may consider for simplification. In particular, two drug regimens, such as dolutegravir with lamivudine should probably be avoided, as the preexistence of lamivudine resistance may transform this into a single drug regimen. It is also premature to extrapolate these data to other baseline resistance patterns (such as K65R) even though B/F/TAF appeared to still retain efficacy in a small number of patients that carried this mutation in the current analysis. Finally, going forward, we must be mindful of the risk of emergence of integrase inhibitor resistance in the longer term. This remains quite rare in clinical practice but has been described in patients receiving second generation integrase inhibitors, such as cabotegravir, albeit in the context of two-drug combinations [9]. Over 25 years, after the heady days of the advent of the initial three drug regimens to treat HIV infection, antiretroviral therapy has become simpler, more effective, and better tolerated. The data of Andreotti et al.[8] suggest that the combination of B/F/TAF, as a single tablet administered once a day, can resist resistance and can be safely and effectively administered to patients with preexisting mutations at codon 184. Whether this benefit can be extended to those carrying isolates with different or more complex resistance patterns is worthy of further study, so that we can extend the benefits of regimens such as B/F/TAF as broadly as possible. Acknowledgements Conflicts of interest B.C. has received grant support, honoraria and acted as a remunerated advisor for AbbVie Corporation, Gilead Sciences Inc., Indivior Canada Ltd., Merck & Co., Moderna, Sanofi Pasteur, and ViiV Healthcare. B.G.B. has received research funding and honoraria from Gilead Sciences and Merck.