Impact of the M184V/I Mutation on the Efficacy of Abacavir/Lamivudine/Dolutegravir Therapy in HIV Treatment-Experienced Patients

Abstract

Background The impact of the M184V/I mutation on the virological failure (VF) rate in HIV-positive patients with suppressed viremia switching to an abacavir/lamivudine/dolutegravir regimen has been poorly evaluated. Methods Observational study from five European HIV cohorts among treatment-experienced adults with ≤50 copies/mL of HIV-1 RNA who switched to abacavir/lamivudine/dolutegravir. Primary outcome was the time to first VF (two consecutive HIV-1 RNA >50 copies/mL or single HIV-1 RNA >50 copies/mL accompanied by change in ART). We also analyzed a composite outcome considering the presence of VF and/or virological blips. We report also the results of an inverse probability weighting (IPW) analysis on a restricted population with a prior history of VF on any ART regimen to calculate statistics standardized to the disparate sampling population. Results We included 1626 patients (median follow-up, 288.5 days [IQR, 154-441]). Patients with a genotypically documented M184V/I mutation (n=137) had a lower CD4 nadir and a longer history of antiviral treatment. The incidence of VF was 29.8 (11.2-79.4) per 1000 person-years in those with a previously documented M184V/I, and 13.6 (8.4-21.8) in patients without documented M184V/I. Propensity score weighting in a restricted population (n=580) showed that M184V/I was not associated with VF or the composite endpoint (HR 1.27 [95% CI 0.35-4.59]; HR 1.66 [95% CI 0.81–3.43], respectively). Conclusions In ART-experienced patients switching to an abacavir/lamivudine/dolutegravir treatment, we observed few VFs and found no evidence for an impact of previously-acquired M184V/I mutation on this outcome. Additional analyses are required to demonstrate whether these findings will remain robust during a longer follow-up.

No impact of previous NRTIs resistance in HIV positive patients switched to DTG+2NRTIs under virological control: Time of viral suppression makes the difference.

“…Our study highlights the virological efficacy of DTG+2NRTIs combination therapy with only 3.2% of patients who discontinued the regimen due to VF during the time of observation. This finding is in line with the virological efficacy of DTG based regimens reported in observational studies with a mixed population of patients harbouring or not resistance to NRTIs [15,16,19].…”

“…Second, the high discontinuation rate and the median time of observation of only 12 months did not allow to assess the long term impact of NRTIs mutations. Third, a very few VFs were observed despite our conservative definition of VF, although in line with the rate reported in previous works[15,16]. Finally, when considering the K65R mutation, a type 2 error cannot be excluded due to the low number of cases and consequently our findings should not be generalized to such patients.According to our findings, the risk of VF after switching to DTG+2NRTIs appears to be low.Previous NRTIs mutations seem to have no impact on the risk of VF in patients under virological control on ART regimens based on DTG+2NRTIs.…”

“…On the contrary, in the SPIRAL study demonstrating the non inferiority of RAL, patients had a longer median time of viral suppression before the switch [67 months (IQR 59-73)] [12]. Moreover, in the study by Olearo et al, in which patients had a longer viral suppression than in our study before switching to ABC/3TC/DTG (134 months and 83.5 months in those with and without M184V/I vs 31 months, respectively), no impact of the time of viral suppression on VF was observed [15].…”

“…This finding is interesting because no information is available from randomized clinical trial due to the exclusion of patients with previous NRTIs mutations [6,7]. Nevertheless, a recent large observational study conducted in several European countries confirmed the absence of the impact of M184V/I on the virological efficacy of ABC/3TC/DTG regimen in switch strategy [15]. Furthermore, the DAWNING study showed that, in patients failing their first antiretroviral regimen, DTG was superior to boosted lopinavir in obtaining virological suppression at 48 weeks [20].…”

Virologic suppression in patients with a documented M184V/I mutation based on the number of active agents in the antiretroviral regimen

“…16 Of note, the patients in this trial had only the M184V/I mutation, unlike the population in our study which often had multiple resistance-conferring mutations present. Olearo et al 17 retrospectively examined switching to a regimen containing ABC, 3TC, and DTG in treatment-experienced patients and found that the M184V mutation, present in 137 patients (8.4% of study population), was not associated with increased risk of virologic failure. Finally, Sahloff and colleagues retrospectively evaluated the use of boosted DRV plus TDF/FTC in 32 treatment-experienced patients with at least an M184V/I mutation.…”