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Introduction:The burden of HIV in sub-Saharan Africa (SSA) remains unacceptably high, and disproportionately affects girls and women. While the introduction of oral HIV pre-exposure prophylaxis (PrEP) in 2012 revolutionized HIV prevention, its effectiveness is dependent on user adherence and its implementation in SSA has faced numerous challenges. Patient-level, interpersonal and structural barriers, including, for example, daily pill burden, side effects, lack of partner support, testing and disclosure, and costs have been found to reduce adherence to oral PrEP. Discussion: Long-acting extended delivery (LAED) formulations for PrEP, such as injectable long-acting cabotegravir (CAB-LA) and dapivirine vaginal ring (DPV-VR) are critical additions to the HIV prevention toolkit and are especially important for populations such as adolescent girls and young women (AGYW) and other key populations who remain at significant risk of HIV acquisition while facing substantial barriers to preventive services. These LAED formulations have been shown to result in better adherence and fewer side effects, with CAB-LA being superior to oral PrEP in reducing the risk of HIV acquisition. They can be used to overcome user burden and adherence challenges. However, the successful rollout of the DPV-VR and CAB-LA may be hampered by issues such as a shortage of healthcare providers (HCPs), inadequate parenteral medication infrastructure, increased workload for HCPs, patient concerns, the price of the medications and the possibility of drug resistance. Conclusions: SSA must develop laboratory capabilities for monitoring patients on LAED formulations and enhance research on developing more non-injectable LAED formulations. There is a need to train and retain more HCPs, implement task shifting, invest in healthcare infrastructure and integrate healthcare services. To reduce costs and improve availability, the region must advocate for patent license waivers for LAED formulations and procure drugs collectively as a region.

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