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

Author summary Why was this study done? The scale-up of antiretroviral therapy (ART) in resource-limited settings has achieved an unprecedented reduction in HIV-related morbidity and mortality. The success of ART is however threatened by increasing levels of resistance to antiretroviral drugs of the non-nucleoside reverse transcriptase inhibitors (NNRTI) class. Replacing NNRTIs by dolutegravir (DTG) may curb the spread of resistance, but it is unclear how effective this switch will be and which patient groups should be switched from NNRTI to DTG. It has been debated whether DTG should be given to women, because of a potential risk of birth defects, and to patients already on an NNRTI-based therapy. What did the researchers do and find? Using a mathematical model simulating the HIV epidemic in South Africa, we find that scaling up DTG-based ART can halt the increase of NNRTI resistance. This predicted effect of DTG depends crucially on including both women and people already on NNRTI-based ART among patients to whom DTG will be prescribed. Restricting DTG to men or to patients initiating ART would substantially reduce its potential to curb resistance at the population level, as in this case it could merely slow down but not halt the spread of NNRTI resistance. Patients still relying on NNRTI-based therapy would in this case face increased risk of resistance and therapy failure. What do these findings mean? Our model highlights the potential of DTG scale up to curb NNRTI resistance. In order to halt the increase in NNRTI resistance, DTG should become accessible to both women and people currently on NNRTI-based therapy. Background 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. Methods and findings 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. Conclusions 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.