Shifting to tenofovir use in first-line antiretroviral therapy for HIV-positive adults in public sector treatment programs in sub-Saharan Africa
Brennan, Alana Teresa
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The success of scale up of antiretroviral therapy (ART) in low- and middle-income countries (LMICs) is in large part due to the introduction of a “public health approach” to access advocated by the World Health Organization (WHO) which emphasized standardized treatment regimens that could be purchased in large quantities and delivered at scale. In 2010 the WHO updated their global HIV treatment guidelines recommending the substitution of stavudine with tenofovir (both of which are members of the non-nucleoside reverse transcriptase inhibitor (NRTI) class of drugs) in first-line antiretroviral therapy (ART). Given the size of treatment programs in sub-Saharan Africa, changing the NRTI used in first-line therapy for HIV could have a substantial impact on treatment outcomes. We conducted three prospective cohort studies using clinical datasets from several sub-Saharan African countries to answer questions surrounding the impacts of exposure to tenofovir in first-line therapy. The first study examines the frequency of stavudine use and single-drug substitutions (substituting the NRTI in first-line ART) in three regions in sub-Saharan Africa by calendar year, 2004–2014. We found a total of 33,441 (8.9%; 95% CI: 8.7–8.9%) single-drug substitutions occurred among 377,656 patients in the first 24 months on ART, close to 40% of which were amongst patients on stavudine. The decrease in single-drug substitutions corresponded with the phasing out of stavudine. We saw an 80% reduction in the risk of single-drug substitutions when comparing tenofovir to stavudine and close to a 70% reduction in the risk when comparing zidovudine to stavudine. The second study uses a regression discontinuity design to evaluate the impact of national HIV treatment guideline changes in South Africa and Zambia recommending tenofovir in first-line ART on treatment outcomes. We found that updated WHO guidelines increased the proportion of patients initiating tenofovir (risk difference (RD) (South Africa): 81%; 95% CI: 73%, 89%; RD (Zambia): 42%; 95% CI: 38%, 45%). Intent to treat estimates showed a decrease in single-drug substitutions in South Africa (RD: -15%; 95% CI: -18%, -12%) and Zambia (RD: -2.0%; 95% CI: -3.6%, -0.3%). In both countries, there was no effect on mortality, attrition or viral load failure (South Africa only). The third study investigates the effect of the 2012 tenofovir stock shortage in South Africa on provider and patient level outcomes, using data from four public-sector Right to Care clinics, two of which experienced a tenofovir stock shortage and two that did not. While imprecise, our results suggest a potential shift in how providers managed patients during the period of the shortage, mainly, a noticeable decrease in the average number of days between visits during the shortage compare to before or after at all four clinics and a significant difference in the proportion of patients missing visits. Difference-in-difference regression results showed a small, but significant, increase in the risk of missed visits during the shortage compared to after (RD: 1.2%; 95% CI: 0.5%, 2.0%), mainly driven by ACTs clinic. No significant difference was seen in other outcomes. Great strides have been made to extend access to ART as well as increase the quality of the services provided to patients in sub-Saharan Africa. Continued access to and a consistent supply of tenofovir in this setting is necessary for patients to receive drugs that are comparable to those used for HIV treatment in high-income countries, as we show that phasing out of stavudine and for either zidovudine or tenofovir potentially reduced toxicities and potentially improved quality of life in multiple regions throughout sub-Saharan Africa. While we show little effect on treatment outcomes when comparing patients accessing care and treatment during the shortage of tenofovir compared to those that did not, this most likely reflects the clinics’ ability to offset the crisis by continuing to initiate newly diagnosed and eligible patients on treatment and keep treatment experienced patients on their current regimen.