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/μL 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.

Funding: Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III PI16/00837-PI16/00678.

Figure 1

Trial participant flow chart. Intention-to-treat exposed population includes every participant receiving at least one dose of dolutegravir+lamivudine. Per protocol population excludes participants who received the therapy with protocol deviations.

Figure 2

Proportion of patients with virological suppression at W48 in Intention-to-treat-exposed (ITT-e) and Per-protocol analysis. ITT-e population is defined as all participants who received at least one dose of study treatment; PP population is defined as all participants who received at least one dose of study treatment and had no deviation to the eligibility criteria. Virological suppression was defined as an HIV RNA viral load of less than 50 copies per mL. Abbreviations: 3TC: lamivudine.

Figure 3

Viral load evolution of the patient presenting over 1000 copies/mL at W36. Abbreviations: 3TC: lamivudine. DRV/c: darunavir/cobicistat. DTG: dolutegravir. EFV: efavirenz. NGS: Next-generation sequencing. RT: Retrotranscriptase. TDF: tenofovir disoproxil fumarate.