Impact of pre-existing drug resistance on risk of virological failure in South Africa

Abstract

Objectives There is conflicting evidence on the impact of pre-existing HIV drug resistance mutations (DRMs) in patients infected with non-B subtype virus. Methods We performed a case–cohort substudy of the AIDS Drug Resistance Surveillance Study, which enrolled South African patients initiating first-line efavirenz/emtricitabine/tenofovir. Pre-ART DRMs were detected by Illumina sequencing of HIV pol and DRMs present at <20% of the viral population were labelled as minority variants (MVs). Weighted Cox proportional hazards models estimated the association between pre-ART DRMs and risk of virological failure (VF), defined as confirmed HIV-1 RNA ≥1000 copies/mL after ≥5 months of ART. Results The evaluable population included 178 participants from a randomly selected subcohort (16 with VF, 162 without VF) and 83 additional participants with VF. In the subcohort, 16% of participants harboured ≥1 majority DRM. The presence of any majority DRM was associated with a 3-fold greater risk of VF (P = 0.002), which increased to 9.2-fold (P < 0.001) in those with <2 active drugs. Thirteen percent of participants harboured MV DRMs in the absence of majority DRMs. Presence of MVs alone had no significant impact on the risk of VF. Inclusion of pre-ART MVs with majority DRMs improved the sensitivity but reduced the specificity of predicting VF. Conclusions In a South African cohort, the presence of majority DRMs increased the risk of VF, especially for participants receiving <2 active drugs. The detection of drug-resistant MVs alone did not predict an increased risk of VF, but their inclusion with majority DRMs affected the sensitivity/specificity of predicting VF.

Clinical Impact of Pretreatment Human Immunodeficiency Virus Drug Resistance in People Initiating Nonnucleoside Reverse Transcriptase Inhibitor–Containing Antiretroviral Therapy: A Systematic Review and Meta-analysis

“…An increased likelihood of VF among people with PDR on EFV/XTC/TDF was also observed in 2 recent large studies: a the phase 3, randomized clinical trial comparing TAF/FTC/DTG, TDF/FTC/DTG or TDF/FTC/EFV for first-line treatment of HIV-1 infection (ADVANCE) [ 44 ], in which VS among those with and without PDR was 65% and 85%, respectively ( P < .001), and a case-cohort substudy of the HIV/AIDS Drug Resistance Surveillance Study (ADReSS), enrolling 1000 patients initiating first-line efavirenz/emtricitabine/tenofovir in KwaZulu-Natal, South Africa [ 45 ], in which PDR was associated with a 3-fold greater risk of VF ( P = .002).…”

Low-frequency HIV-1 drug resistance mutations in antiretroviral naïve individuals in Botswana

“…It has also been reported that individuals with preexisting low-frequency DRMs at baseline have the same DRMs at the time of VF. [40,41] However, other studies have found no association between baseline low-frequency DRMs and VF on cART. [40,42,43] Conflicting results on the clinical importance of low-frequency DRMs indicate the need for further investigations on the clinical impact of low-frequency DRMs in different settings.…”

Pre‐existing singleton E138A mutations in the reverse transcriptase gene do not affect the efficacy of first‐line antiretroviral therapy regimens using rilpivirine in human immunodeficiency virus‐infected patients

“…In a study of patients entering the SENSE trial for first‐line ART in Europe, Russia, and Israel, 13.9% of patients presented with at least one polymorphic mutation in their baseline plasma (V90I, V106I, or E138A), without any impact on the virological outcomes of an etravirine‐based ART program 26 . In a South African cohort, the detection of drug‐resistant mutations alone, including E138A, did not predict an increased risk of virological failure 27 . Additionally, there was one patient in the Eviplera clinical trial, who presented with an E138A mutation at baseline and was shown to maintain virological suppression throughout Week 48 28…”

“… 26 In a South African cohort, the detection of drug‐resistant mutations alone, including E138A, did not predict an increased risk of virological failure. 27 Additionally, there was one patient in the Eviplera clinical trial, who presented with an E138A mutation at baseline and was shown to maintain virological suppression throughout Week 48. 28…”