First-line HIV treatment outcomes following the introduction of integrase inhibitors in UK guidelines

Abstract

on behalf of the UK CHIC StudyObjective: To investigate the characteristics and outcomes of people who initiated different antiretroviral therapy (ART) regimens during the era of integrase strand transfer inhibitors (INSTIs).Design: UK-based observational cohort study.Methods: UK Collaborative HIV Cohort study participants were included if they had started ART between 1 January 2012 and 30 June 2017. Virological failure was defined as the first of two consecutive plasma HIV RNA more than 50 copies/ml, at least 6 months after starting ART. Follow-up was censored at ART discontinuation, class switch or death. The risk of virological failure among those on INSTI, protease inhibitor or nonnucleoside reverse transcriptase inhibitor (NNRTI) regimens was compared using Kaplan-Meier and Cox regression methods.Results: Of 12 585 participants, 45.6% started a NNRTI, 29.0% a protease inhibitor and 25.4% an INSTI regimen. Over a median follow-up of 20.3 months (interquartile range 7.9-38.9), 7.5% of participants experienced virological failure. Compared with those starting an NNRTI regimen, people receiving INSTIs or protease inhibitors were more likely to experience virological failure: INSTI group adjusted hazard ratio 1.52, 95% confidence interval 1.19-1.95, P ¼ 0.0009; protease inhibitor group adjusted hazard ratio 2.70, 95% confidence interval 2.27-3.21, P less than 0.0001, likelihood ratio test P less than 0.0001. Conclusion:First-line INSTI regimens were associated with a lower risk of virological failure than protease inhibitor regimens but both groups were more likely to experience virological failure than those initiating treatment with a NNRTI. There is likely to be residual channelling bias resulting from selected use of INSTIs and protease inhibitors in specific clinical contexts, including in those with a perceived risk of poor adherence.

Non-nucleoside reverse transcriptase inhibitor-based combination antiretroviral therapy is associated with lower cell-associated HIV RNA and DNA levels as compared with therapy based on protease inhibitors

“…In fact, also in this study low-level plasma HIV RNA was more frequently detectable in PI-treated than in NNRTI-treated participants, despite no difference in therapy adherence by regimen. Notably, a recent large study of more than 12,000 participants starting ART revealed that PI-treated participants were on average 2.7 times more likely to experience virological failure compared with NNRTI-treated participants [47]. Moreover, three independent clinical trials of triple ART intensification with raltegravir have previously demonstrated much stronger increases in episomal HIV DNA in PI- compared to NNRTI-treated participants, suggesting that at “baseline”, PI-treated individuals had higher levels of residual replication [21, 22, 25].…”

“…We previously proposed CA RNA as a sensitive marker of the active HIV reservoir and residual replication [6], a role that is further reinforced by the results of this study. Monitoring of CA RNA levels to detect residual HIV activity despite ART is warranted in order to prevent possible ART complications such as persistent immune activation or therapy failure [47, 64, 65], especially in individuals treated with PI-based regimens.…”

No overall impact on rate of weight gain with integrase inhibitor‐containing regimens in antiretroviral‐naïve adults

“…Integrase strand transfer inhibitors (INSTIs) are one of the recommended third agents for initial antiretroviral therapy (ART) regimens [1]. Raltegravir (RAL) and dolutegravir (DTG) remain the most widely used INSTIs in the UK [2]. 'Excessive' weight gain with INSTI-based regimens has been reported in a variety of settings, although the magnitude of the weight gain impact attributable to INSTIs, and what level of change should be considered significant remains unclear.…”

Non-nucleoside reverse transcriptase inhibitor-based combination antiretroviral therapy is associated with lower cell-associated HIV RNA and DNA levels compared to protease inhibitor-based therapy

“…In fact, also in this study low-level plasma HIV RNA was more frequently detectable in PItreated than in NNRTI-treated participants, despite no difference in therapy adherence by regimen. Notably, a recent large study of more than 12,000 participants starting ART revealed that PI-treated participants were on average 2.7 times more likely to experience virological failure compared with NNRTI-treated participants [53]. Moreover, three independent clinical trials of triple ART intensification with raltegravir have previously demonstrated much stronger increases in episomal HIV DNA in PI-compared to NNRTI-treated participants, suggesting that at "baseline", PI-treated individuals had higher levels of residual replication [21,22,25].…”

“…We previously proposed CA RNA as a sensitive marker of the active HIV reservoir and residual replication [6], a role that is further reinforced by the results of this study. Monitoring of CA RNA levels to detect residual HIV activity despite ART is warranted in order to prevent possible ART complications such as persistent immune activation or therapy failure [39,53,75], especially in individuals treated with PI-based regimens. i Mann-Whitney tests were used for continuous variables and Fisher's exact tests or Chi-square tests were used for categorical variables.…”