Virological Failure and Acquired Genotypic Resistance Associated With Contemporary Antiretroviral Treatment Regimens

Abstract

Background: There are few descriptions of virologic failure (VF) and acquired drug resistance (HIVDR) in large cohorts initiating contemporary antiretroviral therapy (ART).

Methods: We studied all persons with HIV (PWH) in a California clinic population initiating ART between 2010 and 2017. VF was defined as not attaining virologic suppression, discontinuing ART, or virologic rebound prompting change in ART.

Results: During the study, 2315 PWH began ART. Six companion drugs were used in 93.3% of regimens: efavirenz, elvitegravir/c, dolutegravir, b-darunavir, rilpivirine, and raltegravir. During a median follow-up of 36 months, 214 (9.2%) PWH experienced VF (2.8 per 100 person-years) and 62 (2.7%) experienced HIVDR (0.8 per 100 person-years). In multivariable analyses, younger age, lower CD4 count, higher virus load, and b-atazanavir were associated with increased VF risk; lower CD4 count, higher virus load, and nevirapine were associated with increased HIVDR risk. Compared with efavirenz, dolutegravir, raltegravir, and b-darunavir were associated with reduced HIVDR risk. Risks of VF and HIVDR were not significantly associated with ART initiation year. Of the 62 PWH with HIVDR, 42 received an non-nucleoside RT inhibitor (NNRTI), 15 an integrase-strand transfer inhibitor (INSTI), and 5 a protease inhibitor (PI). Among those with HIVDR on an NNRTI or first-generation INSTI, 59% acquired dual class resistance and 29% developed tenofovir resistance; those receiving a PI or dolutegravir developed just M184V.

Conclusions: Despite the frequent use of contemporary ART regimens, VF and HIVDR continue to occur. Further efforts are required to improve long-term ART virological responses to prevent the consequences of ongoing HIV-1 replication including virus transmission and HIVDR.

Keywords: HIV-1; antiretroviral therapy; drug resistance; virological outcome.

Figure 1.

Yearly distribution of the 6 most common ART companion drugs used as part of the initial ART (n = 2315). Abbreviations: ART, antiretroviral therapy; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; EVG, elvitegravir; IQR, interquartile range; PWH, people with HIV; RAL, raltegravir; RPV, rilpivirine.

Figure 2.

Disposition of virological outcomes, genotypic resistance testing, and acquired drug resistance in the overall cohort of PWH starting ART between January 2010 and December 2017. Forty PWH who left KPNC within 6 months of starting therapy without having attained virologic suppression were censored in the primary analysis. Abbreviations: ART, antiretroviral therapy; GART, genotypic antiretroviral resistance test; KPNC, Kaiser Permanente Northern California; New DRMs, drug-resistance mutations that emerged on therapy; PWH, people with HIV; VF, virological failure; VS, virologic suppression.

Figure 3.

Cumulative incidence of VF and VF plus acquired HIVDR for the 2315 PWH over a period of 60 months. PWH were censored if they died, discontinued KPNC care, switched to a third ART regimen, or reached December 31, 2018 without experiencing VF. Abbreviations: ART, antiretroviral therapy; HIVDR, HIV drug resistance; KPNC, Kaiser Permanente Northern California; HIVDR, drug-resistance mutations that emerged on therapy; PWH, people with HIV; VF, virological failure.