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Drivers of HIV-1 Drug Resistance to Non-Nucleoside Reverse-Transcriptase Inhibitors (NNRTIs) in Nine African Countries: A Modelling Study

Background: The rise of HIV-1 drug resistance to non-nucleoside reverse-transcriptase inhibitors (NNRTI) threatens antiretroviral therapy (ART) programmes' long-term success. NNRTIs will likely remain an essential drug for the management of HIV-1 due to the adverse effects and safety concerns associated with integrase inhibitors. Mathematical models can contribute to a better understanding of the mechanisms that shape the HIV-1 epidemic and the rise of NNRTI pretreatment resistance in a country. We fitted a dynamic transmission model to data 2000-2018 from nine countries of southern Africa. 
 
Methods: We included data on HIV-1 prevalence, ART coverage, HIV-related mortality, and survey data on NNRTI pretreatment drug resistance from Botswana, Eswatini, Lesotho, Malawi, Mozambique, Namibia, South Africa, Zambia, and Zimbabwe, from a systematic review, UNAIDS and the World Bank. Using a Bayesian hierarchical framework, we developed a dynamic transmission model linking the country-specific data on the HIV-1 epidemic to survey data on NNRTI drug resistance in each country. We estimated the proportion of resistance attributable to unregulated, off-programme use of ART. We examined the vulnerability of national ART programmes to NNRTI resistance by defining a fragility index: the ratio of the rate of NNRTI resistance emergence during first-line ART over the rate of switching to second-line ART. We explored associations between national ART programme's fragility and the characteristics of health systems and countries. 
 
Findings: The model reliably described the dynamics of the HIV-1 epidemic and NNRTI resistance in each country. Predicted levels of resistance in 2018 ranged between 3.3% (95% credible interval [CrI] 1.9 to 7.1%) in Mozambique and 25.3% (17.9 to 33.8%) in Eswatini. The proportion of NNRTI pretreatment drug resistance attributable to unregulated antiretroviral use ranged from 6% (95%CrI 2-14) in Eswatini to 64% (95%CrI 26-85) in Mozambique. The fragility index was low in Botswana (0.01; 95%CrI 0.0-0.11) but high in Namibia (0.48; 95% CrI 0.16-10.17), Eswatini (0.64; 95%CrI 0.23-11.8) and South Africa to 1.21 (95%CrI 0.83-9.84). The combination of high fragility of ART programmes and high levels of ART coverage was associated with a sharp increase in NNRTI pretreatment drug resistance. 
 
Interpretation: This comparison of nine countries shows that NNRTI pretreatment drug resistance can be controlled despite high ART coverage levels, as in Botswana, Mozambique, or Zambia, most likely because of better HIV care delivery, including rapid switching to second-line ART of patients failing first-line ART.  
 
Funding Statement: National Institute of Allergy and Infectious Diseases (grant 5U01-AI069924-05) and Swiss National Science Foundation (grant 174281). 
 
Declaration of Interests: We declare no conflict of interest.