1 INTRODUCTION 1.1 Background Adolescent girls and young women (AGYW) aged 15-24 years in Sub-Saharan Africa (SSA) are at substantial risk for HIV infection and in 2020, AGYW accounted for 32% of new HIV infections in East and Southern Africa \[1\]. In the general population in Uganda, the HIV prevalence among AGYW is estimated at 1.8% among 15-19 year-olds and 5.1% among 20-24 year-olds \[2\]. The prevalence among AGYW living in fishing communities in Uganda, and young female sex workers (FSWs) is even higher estimated at 15.4% and 22.5% respectively \[3, 4\]. During recent years, biomedical interventions for HIV prevention have been developed and are currently at different stages of the pipeline with some already approved for use. For example, anti-retroviral (ARV) implants for pre-exposure prophylaxis (PrEP) to protect HIV negative girls from becoming HIV infected, have recently been assessed in pre-clinical studies \[5, 6\]. Other biomedical interventions for HIV prevention among vulnerable HIV negative sub-groups, including AGYW in SSA, have further been assessed in clinical trials for example: the Dapivirine vaginal ring (DVR) \[7, 8\], long acting injectable PrEP \[9, 10\], HIV vaccines \[11\] and oral PrEP \[12, 13\]. Oral PrEP is a single pill taken once daily during periods of risk to HIV infection, and is highly efficacious when adherence is good (\>90%) \[12\]. Tenofovir is one of the most common HIV drugs and tenofovir-based oral PrEP is also one of the World Health Organization (WHO) approved biomedical HIV prevention interventions \[14, 15\]. In 2016, the Uganda government approved use of oral PrEP for HIV prevention among individuals at substantial risk of HIV infection \[16\], and increased access to targeted key populations including AGYW. The HIV prevention landscape is promising as other novel biomedical HIV prevention interventions are in various stages of development, including long acting injectable PrEP, anti-retroviral (ARV) implants and HIV vaccines. The Dapivirine vaginal ring is approved by WHO as an additional HIV prevention choice for women \[17\], has been approved for use in South Africa \[18\] and, has been added to the drug register of the National Drug Authority in Uganda \[19\]. Injectable cabotegravir may also be available soon having shown efficacy in the HIV Prevention Trials Network (HPTN084) study \[10\]. End-user preferences for HIV prevention products may predict method uptake \[20\] and there is a need to increase researchers' knowledge about current preferences for HIV prophylaxis among AGYW in SSA who continue to be at substantial risk of HIV.

1.2 Oral PrEP Uptake and Adherence among Adolescent Girls and Young Women Oral PrEP is still currently the only available biomedical HIV prevention method in most parts of SSA. PrEP implementation projects have been facilitated through the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) funding. Despite the potential benefits in HIV prevention, uptake and adherence to oral PrEP remain low among AGYW in Uganda and other parts of SSA \[21, 22\]. A recent study among AGYW in Kampala, Uganda, with high reported prevalence of being engaged in sex for compensation, also found a low oral PrEP uptake (31%) in this population \[23\]. The study also found that the uptake was higher in respondents with more sexual partners and among those who showed higher preference for oral PrEP over other biomedical HIV prevention methods when asked at enrolment. Importantly, tests for Tenofovir levels in blood showed very low adherence. Conversely, the Prevention Options for Women Evaluation Research (POWER) project which also enrolled 16-25-year-old AGYW in Kenya and South Africa reported high PrEP uptake (90%) associated with higher risk behavior, intimate partner violence (IPV), depression and chlamydia/ gonorrhea diagnosis \[24\]. Despite high PrEP uptake, the POWER project reported early discontinuation of PrEP use due to side effects, challenges with accessing services and product characteristics such as need for daily dosing \[24, 25\]. Other studies have identified pill burden, side effects \[21, 22\], low risk perception \[26, 27\] and limited awareness of oral PrEP \[28\] as barriers to PrEP uptake among AGYW in SSA. Interviews with potential PrEP users in multiple settings in central Uganda also showed that stigma, transport costs to get PrEP refills, accessibility, busy schedules, and forgetfulness were barriers to PrEP uptake while closeness of PrEP providers to one's home was a facilitator \[29\]. Thus, there is a need for interventions that may promote PrEP use among AGYW populations in SSA who are at increased risk of HIV infection.

1.3 Rationale Peer-to-peer support is one of the strategies proposed for improving HIV prevention and promotion of safer sexual behaviors in the Uganda National HIV research agenda \[30\], but there is limited evidence of its effectiveness in PrEP programs. Studies show that young people easily take on behaviors when in groups than as individuals, easily adopt behaviors and norms of their peers \[31, 32\], and are more easily affected by peer influence compared to children and older adults \[33\]. Among young people living with HIV in Zimbabwe, peer-led psycho-social support services among HIV positive individuals led to a 13% decrease in detectable viremia at 6 months compared with counselling delivered by health care workers (HCWs) \[34\]. A recent study among refugee adolescents in Northern Uganda showed same day acceptance of contraception was 9% higher among those who received peer counselling compared to counselling provided by HCWs \[35\]. In addition, trained peers have led to improvements in the HIV care and treatment cascade and contraceptive use through peer counselling, peer support for example delivery of interventions, peer referral etc. \[36, 37\]. Previous evidence suggests that peer counselling and support interventions have improved HIV testing, utilization of health care services, anti-retroviral therapy (ART) initiation, adherence to treatment, adherence to HIV viral load testing at 6 months and HIV viral suppression among young people living with HIV in Zimbabwe \[37, 38\]. Peer support interventions may therefore also improve oral PrEP uptake and adherence, and also reduce sexual behavior risk among AGYW, but this has not been widely studied.

2. STUDY AIMS AND RESEARCH QUESTIONS 2.1 The main aims of this project are: i) To determine oral PrEP preference and predictors of preference for oral PrEP among 14-24-year-old AGYW at risk of HIV infection in Kampala, Uganda. ii) To evaluate the effect of a peer support intervention on oral PrEP uptake and adherence, sexual behavioral and reproductive health outcomes of 14-24-year-old AGYW who are at high risk of HIV infection.

2.2 Research Questions i. What proportion of AGYW aged 14-24 years in Uganda prefer oral PrEP for HIV prevention and what predicts method preference for Oral PrEP the currently available method? (Sub-study 1) ii. What is the effect of a peer support intervention on uptake of and adherence to oral PrEP among AGYW aged 14-24 years at high risk of HIV infection in Uganda? (Sub- study 2) iii. What are the effects of a peer support intervention for oral PrEP uptake and adherence on sexual behavior and reproductive health outcomes of AGYW aged 14- 24 years at high risk of HIV infection in Uganda? (Sub-study 3) iv. What are AGYW´s perceptions and experiences of a peer support intervention aimed at improving oral PrEP uptake and adherence? (Sub-study 4)

The investigators hypothesize that the peer support intervention will: (i) improve oral PrEP uptake and adherence among AGYW; (ii) reduce sexual behavioral risk, pregnancy and sexually transmitted infection (STI) rates and (iii) be supportive of AGYW perceptions and attitudes towards peer-led support.