Impact of scaling up dolutegravir on antiretroviral resistance in South Africa: A modeling study.

Anthony Hauser,Matthias Egger,Huldrych F Günthard,Julien Riou,Katharina Kusejko,Roger D Kouyos,Gilles Wandeler,Leigh F Johnson,Amitabh Bipin Suthar

doi:10.1371/journal.pmed.1003397

Abstract

Rising resistance of HIV-1 to non-nucleoside reverse transcriptase inhibitors (NNRTIs) threatens the success of the global scale-up of antiretroviral therapy (ART). The switch to WHO-recommended dolutegravir (DTG)-based regimens could reduce this threat due to DTG's high genetic barrier to resistance. We used mathematical modeling to predict the impact of the scale-up of DTG-based ART on NNRTI pretreatment drug resistance (PDR) in South Africa, 2020 to 2040. We adapted the Modeling Antiretroviral drug Resistance In South Africa (MARISA) model, an epidemiological model of the transmission of NNRTI resistance in South Africa. We modeled the introduction of DTG in 2020 under 2 scenarios: DTG as first-line regimen for ART initiators, or DTG for all patients, including patients on suppressive NNRTI-based ART. Given the safety concerns related to DTG during pregnancy, we assessed the impact of prescribing DTG to all men and in addition to (1) women beyond reproductive age; (2) women beyond reproductive age or using contraception; and (3) all women. The model projections show that, compared to the continuation of NNRTI-based ART, introducing DTG would lead to a reduction in NNRTI PDR in all scenarios if ART initiators are started on a DTG-based regimen, and those on NNRTI-based regimens are rapidly switched to DTG. NNRTI PDR would continue to increase if DTG-based ART was restricted to men. When given to all men and women, DTG-based ART could reduce the level of NNRTI PDR from 52.4% (without DTG) to 10.4% (with universal DTG) in 2040. If only men and women beyond reproductive age or on contraception are started on or switched to DTG-based ART, NNRTI PDR would reach 25.9% in 2040. Limitations include substantial uncertainty due to the long-term predictions and the current scarcity of knowledge about DTG efficacy in South Africa. Our model shows the potential benefit of scaling up DTG-based regimens for halting the rise of NNRTI resistance. Starting or switching all men and women to DTG would lead to a sustained decline in resistance levels, whereas using DTG-based ART in all men, or in men and women beyond childbearing age, would only slow down the increase in levels of NNRTI PDR.

Highlights

The rollout of antiretroviral therapy (ART) in South Africa is estimated to have prevented 0.73 million HIV infections between 2004 and 2013 as well as 1.72 million deaths between 2000 and 2014 [1,2]
The model projections show that, compared to the continuation of nucleoside reverse transcriptase inhibitor (NNRTI)-based ART, introducing DTG would lead to a reduction in NNRTI pretreatment drug resistance (PDR) in all scenarios if ART initiators are started on a DTG-based regimen, and those on NNRTI-based regimens are rapidly switched to DTG
Our model shows the potential benefit of scaling up DTG-based regimens for halting the rise of NNRTI resistance

Summary

Introduction

The rollout of antiretroviral therapy (ART) in South Africa is estimated to have prevented 0.73 million HIV infections between 2004 and 2013 as well as 1.72 million deaths between 2000 and 2014 [1,2]. The spread of non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant viruses is threatening this success [3]. Mathematical models explored the effectiveness and cost-effectiveness of prescribing DTG to all ART initiators [10]. Rising resistance of HIV-1 to non-nucleoside reverse transcriptase inhibitors (NNRTIs) threatens the success of the global scale-up of antiretroviral therapy (ART). We used mathematical modeling to predict the impact of the scale-up of DTG-based ART on NNRTI pretreatment drug resistance (PDR) in South Africa, 2020 to 2040

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Results

Conclusion