Deep sequencing analysis of M184V/I mutation at the switch and at the time of virological failure of boosted protease inhibitor plus lamivudine or boosted protease inhibitor maintenance strategy (substudy of the ANRS-MOBIDIP trial)

Abstract

Background The ANRS12286/MOBIDIP trial showed that boosted protease inhibitor (bPI) plus lamivudine dual therapy was superior to bPI monotherapy as maintenance treatment in subjects with a history of M184V mutation. Objectives We aimed to deep analyse the detection of M184V/I variants at time of switch and at the time of virological failure (VF). Methods Ultra-deep sequencing (UDS) was performed on proviral HIV-DNA at inclusion among 265 patients enrolled in the ANRS 12026/MOBIDIP trial, and on plasma from 31 patients experiencing VF. The proportion of M184V/I variants was described and the association between the M184V/I mutation at 1% of threshold and VF was explored with logistic regression models. Results M184V and I mutations were detected in HIV-DNA for 173/252 (69%) and 31/252 (12%) of participants, respectively. Longer duration of first-line treatment, higher plasma viral load at first-line treatment failure and higher baseline HIV-DNA load were associated with the archived M184V. M184I mutation was always associated with a STOP codon, suggesting defective virus. The 48 week estimated probability of remaining free from VF was comparable with or without the M184V/I mutation for dual therapy. At failure, M184V and major PI mutations were detected in 1/17 and 5/15 patients in the bPI arm and in 2/2 and 0/3 in the bPI+lamivudine arm, respectively. Conclusions Using UDS evidenced that archiving of M184V in HIV-DNA is heterogeneous despite past historical M184V in 96% of cases. The antiviral efficacy of lamivudine-based dual therapy regimens is mainly due to the residual lamivudine activity.

Two-drug antiretroviral regimens for HIV

“…Baseline resistance testing is not recommended or performed before initiating ART in low and middle income countries, and, although transmitted resistance to integrase inhibitors is rare, surveillance is needed if dolutegravir is to be rolled out as first line treatment. In addition, there may be baseline HIV drug resistance to the other agents in two-drug regimens, namely lamivudine or emtricitabine, although existing data suggest that the presence of the most common resistance mutation to these drugs, M184V/I, does not seem to affect virological outcomes in those taking oral two-drug regimens 6566676869…”

“…However, most studies on two-drug regimens come from high-income settings.Baseline resistance testing is not recommended or performed before initiating ART in LMIC, and while transmitted resistance to INSTI is rare, surveillance is needed if dolutegravir is to be rolled out as first-line in LMIC. In addition, there may be baseline HIV drug resistance to the other agents in INSTI-based two-drug regimen, namely lamivudine or emtricitabine, although existing data suggest that the presence of the most common resistance mutation to these drug, M184V/I, does not appear to impact virological outcomes in those on oral twodrug regimens(60)(61)(62)(63)(64).Standard three-drug regimens contain tenofovir which has activity against Hepatitis B, preventing Hepatitis B viral replication and reactivation. Hepatitis B is not systematically screened for in low-income settings, and use of two-drug regimens may leave individuals with Hepatitis B coinfection sub-optimally treated for Hepatitis B, which may lead to compromise future treatment with entecavir.…”

Kinetics of Archived M184V Mutation in Treatment-Experienced Virally Suppressed HIV-Infected Patients

“…This question is crucial for dual therapies including 3TC, to accompany boosted darunavir or dolutegravir. The MOBIDIP study and its associated in-depth virological analysis suggested that an archived M184V mutation may not affect the viral efficacy of the darunavir/ritonavir/lamivudine two-drug therapy [6,41]. However, data are much less robust for the dolutegravir/lamivudine two-drug therapy, with a very limited number of patients included [8,9,42].…”