Time to rethink endpoints for new clinical trials of antiretrovirals? Long-term re-suppression of HIV RNA with integrase inhibitors

Abstract

In the ADVANCE study of first-line treatment, there were 48 participants with HIV RNA at least 50 copies/ml in the week 48 window who had subsequent follow-up data available with no change in randomized treatment. More participants achieved virological re-suppression in the TAF/FTC+DTG and TDF/FTC+DTG arms (26/34, 76%) than on TDF/FTC/EFV (6/14 = 43%; P = 0.0421). It is unclear whether participants with HIV RNA at least 50 copies/ml at week 48 should be termed ‘virological failures’ on integrase inhibitor-based treatment.

Virologic efficacy of tenofovir, lamivudine and dolutegravir as second-line antiretroviral therapy in adults failing a tenofovir-based first-line regimen

“…the era of second generation integrase inhibitors, which are more robust to the development of resistance [30].…”

“…All of our participants who were not suppressed at week 24 had low-level viraemia (most of them <100 copies/ml). None of those who did have a viral load greater than 50 copies/ml at any visit after week 12 developed virological failure and most re-suppressed with enhanced adherence counselling, which has repeatedly been shown to result in high rates of resuppression [28][29][30]. This is important to consider in interpreting whether unsuppressed viral loads represent the risk of failure because of resistance or rather poor adherence without development of resistance.…”

“…Although sustained low-level viraemia can lead to accumulation of resistance mutations [31], virological failure is less likely to develop when the unsuppressed viral load is less than 200 copies/ml than at higher viral loads [32]. In the ADVANCE study, low-level viraemia at the primary endpoint visit did not predict later virological failure in the dolutegravir arms, leading the authors to suggest that the endpoints for ART trials may need to be rethought in the era of second generation integrase inhibitors, which are more robust to the development of resistance [30].…”

Recycling Tenofovir in Second-line Antiretroviral Treatment With Dolutegravir: Outcomes and Viral Load Trajectories to 72 weeks

“…23 Low-level viremia at the primary end point did not predict later virologic failure in participants on first-line TLD in the ADVANCE study, resulting in a recommendation that the goal of treatment on dolutegravir regimens could be shifted to less stringent targets than a VL ,50 copies/mL. 24 The low proportion of participants meeting criteria for virologic failure on TLD despite ongoing low-level viremia in our study seems to support this recommendation.…”

Need assessment for HIV drug resistance testing and landscape of current and future technologies in low- and middle-income countries

“…Very few data have been published in this regard. One post-hoc analysis of patients receiving DTG with VL > 1000 copies/mL after 48 weeks of treatment reported PLOS GLOBAL PUBLIC HEALTH that 12 of 15 (80%) had VL < 1000 copies/mL after adherence counselling [19]. This parameter is likely to change with further research and monitoring, and so the calculations below are subject to revision when additional information is available.…”