Dolutegravir plus lamivudine for maintenance of HIV viral suppression in adults with and without historical resistance to lamivudine: 48-week results of a non-randomized, pilot clinical trial (ART-PRO)

Abstract

Background: We investigated the efficacy of a switch to dolutegravir plus lamivudine in aviremic individuals without evidence of persistent lamivudine resistance-associated mutations in baseline proviral DNA population sequencing. Methods: Open-label, single-arm, 48-week pilot trial. HIV-1 infected adults, naïve to integrase inhibitors, with CD4+ above 350 cell/mL and fewer than 50 HIV-1 RNA copies per mL the year prior to study entry switched to dolutegravir plus lamivudine. Participants were excluded if baseline proviral DNA population genotyping detected lamivudine resistance-associated mutations. To detect resistance minority variants, proviral DNA next-generation sequencing was retrospectively performed from baseline samples. Primary efficacy endpoint was proportion of participants with fewer than 50 HIV-1 RNA copies per mL at week 48. Safety and tolerability outcomes were incidence of adverse events and treatment discontinuations. ART-PRO is registered with ClinicalTrials.gov, NCT03539224. Findings: 41 participants switched to dolutegravir plus lamivudine, 21 with lamivudine resistance mutations in historical plasma genotypes. Baseline next-generation sequencing detected lamivudine resistance mutations (M184V/I and/or K65R/E/N) over a 5% threshold in 15/21 (71¢4%) and 3/20 (15%) of participants with and without history of lamivudine resistance, respectively. At week 48, 92¢7% of participants (38/41) had fewer than 50 HIV-1 RNA copies per mL. There were no cases of virologic failure. Three participants with historical lamivudine resistance were prematurely discontinued from the study (2 protocol violations, one adverse event). Ten participants (4 in the group with historical lamivudine resistance) had a transient viral rebound, all resuppressed on dolutegravir plus lamivudine. There were 28 drug-related adverse events, only one leading to discontinuation. Interpretation: In this pilot trial, dolutegravir plus lamivudine was effective in maintaining virologic control despite past historical lamivudine resistance and presence of archived lamivudine resistance-associated mutations detected by next generation sequencing. Further studies are needed to confirm our results.

Dolutegravir Plus Lamivudine Two-Drug Regimen: Safety, Efficacy and Diagnostic Considerations for Its Use in Real-Life Clinical Practice—A Refined Approach in the COVID-19 Era

“…In one of these studies, the risk was limited to patients with a shorter virological suppression time before the switch (<96 months), albeit at the limit of statistical significance [ 75 ]. All other real-life data available today, however, agree in terms of the exclusion of an association between the M184V mutations in historical GRTs and VF to DTG/3TC, at least up to 48- or 96-weeks after switch [ 23 , 74 , 75 , 77 , 80 , 92 , 94 , 95 , 96 ], and regardless of the duration of the time-lapse between the detection of RAMs and the start of 2DR [ 23 ].…”

“…A recent meta-analysis reported random-effects pooled estimates for a viral suppression of 98.6% and 97.5% at 48-weeks and 96-weeks of DTG/3TC, respectively, by combining the results of 11 real-world studies [ 72 ]. In fact, all the real-life studies available today, including the most recent, report on the excellent and sustained efficacy of this 2DR when used as a switch regimen ( Table 5 ) [ 15 , 23 , 62 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 ]. These results are consistently maintained in both patients with a previous history of VF and resistance [ 23 , 62 , 74 , 75 , 76 , 80 , 82 ], and over longer observation periods [ 75 , 76 , 84 ].…”

“…DTG in dual-formulations has a high genetic barrier to resistance development, as evidenced by the extreme rarity of CVW from long-term RCTs [ 64 ], as well as VFs in real-life studies ( Table 5 ) [ 15 , 23 , 62 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 ].…”

“…Some real-life studies have agreed with the RCTs in excluding patients who presented InSTI or NRTI RAMs at BL, or who had previously experienced a VF. A small number of studies, however, used less stringent enrollment criteria, and allowed us to analyze the behavior of DTG/3TC in the presence of RAMs, and/or in patients with an history of failures [ 23 , 62 , 74 , 75 , 77 , 80 , 82 , 92 , 93 , 94 , 95 , 96 ] ( Table 5 ).…”

Antiretroviral Drug Treatment of Individuals that Used Preexposure Prophylaxis (PrEP) Before Diagnosis

“…Simplifying initial three drug antiretroviral drug regimens to two drug regimens has been documented to maintain viral suppression in individuals without prior virological failure or evidence of drug resistance [35•, 47]. Recent studies have reported that patients who had the M184I/V viral mutation before viral suppression can be successfully switched to a two drug regimen including lamivudine [48,49]. It should be noted that all these studies are on maintenance therapy; i.e., patients who were already virologically suppressed with combination antiretroviral drug therapy consisting of at least three different antiretroviral drugs were switched to dual therapy.…”