INTRODUCTION
Resistance to antiretrovirals (ARV), particularly protease inhibitors (PI), threatens to roll back progress towards expanding access to effective antiretroviral therapy in sub-Saharan Africa. Using routinely collected data from a MSF supported project in rural Malawi, we report ARV resistance and third-line treatment outcomes among patients failing second-line therapy.

METHODS
We analysed data from a retrospective cohort comprising patients failing second-line therapy, involving a PI-containing antiretroviral therapy (ART) regimen, who received genotyping between 2014-2018. Treatment failure was defined as two consecutive high viral loads (VL; >1,000 copies/mL). Third-line was defined as an ART regimen that changed at least two ARVs, and included one integrase inhibitor. Resistance was defined as scores of >=30 using the Stanford University HIV Drug Resistance Database. We used multivariable logistic models to assess the association between PI resistance and key risk factors.

ETHICS
This research fulfilled the exemption criteria set by the MSF Ethics Review Board (ERB) for a posteriori analyses of routinely collected clinical data and thus did not require MSF ERB review. It was conducted with permission from Clair Mills, Operational Centre Paris, MSF.

RESULTS
Among 50,979 patients that were on ART from 2014-2018, 3,579 (7.0%) patients were started on second line. Among 177 patients failing second-line ART that received genotyping, 86 were receiving lopinavir/ritonavir and 91 atazanavir/ritonavir based regimens. Median age was 16.8 years (interquartile range (IQR) 11.8-40.4); 85 (48.0%) were female. Median time on second-line ART was 32.4 months (IQR 15.5-48.6), and 53 patients (29.9%) were resistant to at least one PI. 134 patients (75.7%) were resistant to at least one nucleoside reverse transcriptase inhibitor (NRTI), 29 (16.4%) were resistant to all available NRTIs, and 151 (85.3%) were resistant to at least one non-nucleoside reverse transcriptase inhibitor. PI resistance was more common amongst patients on second-line ART for more than two years (aOR 2.85; 95%CI 1.34-6.06). We did not observe an association between age or gender, and likelihood of PI resistance (age >= 20yr versus <20yr, aOR 1.07, 95%CI 0.55-2.11; male versus female, aOR 1.36, 95%CI 0.69-2.68). For 76 patients (42.9%) switched to third-line ART, retention in care at 12 months after third-line initiation was 97.2% (95%CI 89.4-99.3). VL suppression six and 12 months following third-line initiation was 87.0% (47/54) and 87.9% (29/33), respectively. Amongst 101 patients (57.1%) remaining on second-line ART, retention in care 12 months following genotyping was 89.0% (95%CI 78.9-94.4). VL suppression at six and 12 months following genotyping was 40.0% (24/60) and 45.0% (18/40), respectively.

CONCLUSION
Over 40% of patients failing second-line ART required third-line initiation, highlighting the need for genotyping to identify patients that require third-line therapies and the need for wider access to third-line drugs. We found that patients switched to third-line regimens can achieve good outcomes in a resource-limited setting. Those remaining on second-line treatment experienced poor outcomes, suggesting the need for simpler and better tolerated second-line regimens, and tailored adherence interventions.

CONFLICTS OF INTEREST: None declared.

David Maman started to work for MSF in 2007, and has been medical coordinator in Malawi since February 2018, where MSF France has supported an HIV project since 1996. David is a medical doctor, also holding a Master’s, as well as a PhD, in epidemiology, which he started with Epicentre where he was based for 7 years, both in Paris and in Cape Town. In addition to his MSF work, David is also honorary senior lecturer at the University of Cape Town and co-supervises the PhD’s of two MSF staff.

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Antiretroviral drug resistance and third-line treatment outcomes amongst HIV patients failing second-line therapy in Malawi