Previous antiretroviral drug use compromises standard first-line HIV therapy and is mediated through drug-resistance

Seth C Inzaule,Wendy Stevens,T Sonia Boender,Pascale Ondoa,Raph L Hamers,Alani Sulaimon Akanmu,Tobias F Rinke De Wit,Denise Naniche,Margaret Siwale,Maureen Wellington,Kim C E Sigaloff,Marleen De Jager,Prudence Ive,Cissy M Kityo,Kishor Mandaliya

doi:10.1038/s41598-018-33538-0

Abstract

In ART programs in sub-Saharan Africa, a growing proportion of HIV-infected persons initiating first-line antiretroviral therapy (ART) have a history of prior antiretroviral drug use (PAU). We assessed the effect of PAU on the risk of pre-treatment drug resistance (PDR) and virological failure (VF) in a multicountry cohort of HIV-infected adults initiated on a standard non-nucleoside reverse transcriptase inhibitor (NNRTI)-based first-line ART. Multivariate logistic regression was used to assess the associations between PAU, PDR and VF (defined as viral load ≥400 cps/mL). Causal mediation analysis was used to assess the proportion of the effect of PAU on VF that could be eliminated by intervening on PDR. Of 2737 participants, 122 (4.5%) had a history of PAU. Participants with PAU had a 7.2-fold (95% CI 4.4–11.7) risk of carrying PDR and a 3.1-fold (95% CI 1.6–6.1) increased risk of VF, compared to antiretroviral-naïve participants. Controlling for PDR would eliminate nearly half the effect of PAU on the risk of VF. Patients with a history of PAU are at increased risk of ART failure, which is to a large extent attributable to PDR. These findings support the recent WHO recommendations for use of differentiated, non-NNRTI-based empiric first-line therapy in patients with PAU.

Highlights

In low and middle-income countries (LMICs), antiretroviral treatment (ART) regimens to treat HIV-1 infections are standardized under the WHO-defined public health approach[1]
This study aimed to investigate the effects of prior antiretroviral drug use (PAU) on pre-treatment drug resistance (PDR) and virological failure (VF) in a multi-country cohort in sub-Saharan Africa, and the extent of which this effect could be eliminated by intervening on PDR
This prospective study among HIV-infected adults in sub-Saharan Africa starting first-line nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy (ART) found that persons who had a history of PAU, i.e. ART or single-dose nevirapine (sdNVP) for prevention of mother-to-child transmission (PMTCT), were seven times more likely to have PDR, and three times more likely to experience VF within the first year of NNRTI-based ART, compared to those who were antiretroviral-naïve at ART initiation

Summary

Introduction

In low and middle-income countries (LMICs), antiretroviral treatment (ART) regimens to treat HIV-1 infections are standardized under the WHO-defined public health approach[1]. Reliable data are limited, ART programs in sub-Saharan Africa have reported that between 10 and 25% of first-line ART initiators have previously used antiretroviral drugs, either because they re-started ART after disengaging from care, or they used short-course antiretrovirals through prevention of mother-to-child transmission (PMTCT) programs, or pre- or post-exposure prophylaxis[2]. People with previous antiretroviral drug use (denoted PAU) are at an increased risk of having drug-resistant HIV before starting ART (denoted pre-treatment drug resistance, PDR)[2,3], which impairs response to standard non-nucleoside reverse transcriptase inhibitor (NNRTI)-based first-line ART4–6. This study aimed to investigate the effects of PAU on PDR and virological failure (VF) in a multi-country cohort in sub-Saharan Africa, and the extent of which this effect could be eliminated by intervening on PDR

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Conclusion