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Background: The burden of HIV is especially concerning for Eastern and Southern Africa (ESA), as despite expansion of test-and-treat programmes, this region continues to experience significant challenges resulting from high rates of morbidity, mortality and new infections. Hard-won lessons from programmes on the ground in ESA should be shared. Objectives: This report summarises relevant evidence and regional experts’ recommendations regarding challenges specific to ESA. Method: This commentary includes an in-depth review of relevant literature, progress against global goals and consensus opinion from experts. Results: Recommendations include priorities for essential research (surveillance data collection, key and vulnerable population education and testing, in-country testing trials and evidence-based support services to improve retention in care) as well as research that can accelerate progress towards the prevention of new infections and achieving ambitious global goals in ESA. Conclusion: The elimination of HIV in ESA will require continued investment, commitment to evidence-based programmes and persistence. Local research is critical to ensuring that responses in ESA are targeted, efficient and evaluated.