Innovative Strategies to Promote Biomedical HIV Prevention Uptake and Retention Among High-risk Adults at Drinking Venues in Kenya and Uganda
Phase: NA
Conditions: HIV/AIDS
Sponsor: University of California, San Francisco

Protocol Version: January 6, 2025 
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Innovative strategies to promote biomedical HIV prevention uptake and 
retention among high-risk adults at drinking venues in Kenya and Uganda 
The Outreach and Prevention at ALcohol venues in East Africa study 
(OPAL-East Africa study) 
 
Funded by: National Institute on Alcohol Abuse and Alcoholism 
 
 
Protocol Version Number: 2.6 
 
Protocol Version Date: January 6, 2025 
 
 
 
 
 
 
 
 
Principal Investigator:  
Gabriel Chamie, MD, MPH 
 
 
 
 
University of California, San Francisco 
 
 
 

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Table of Contents 
Study Investigators ................................................................................................................................................. 4 
Glossary of Terms ................................................................................................................................................... 6 
1. Study Synopsis .................................................................................................................................................... 7 
1.1. Introduction ................................................................................................................................................. 7 
2. Study Objectives ................................................................................................................................................. 8 
3. Background and Rationale .................................................................................................................................. 8 
3.1 Preliminary Studies ..................................................................................................................................... 12 
4. Study Setting & Population ............................................................................................................................... 14 
5. Study Design ...................................................................................................................................................... 14 
5.1. Study Overview .......................................................................................................................................... 14 
6. Drinking Venue Mobilization Strategies (Aim 1) Trial ....................................................................................... 15 
6.1 Aim 1 Study Design ..................................................................................................................................... 15 
6.2 Eligibility Criteria ......................................................................................................................................... 15 
6.3 Consent Process .......................................................................................................................................... 15 
6.4 Community Engagement Plan .................................................................................................................... 15 
6.5 Enrollment & Randomization...................................................................................................................... 16 
6.6 Study Groups ............................................................................................................................................... 16 
6.7 Procedures .................................................................................................................................................. 17 
6.8 Measurements ............................................................................................................................................ 18 
6.9 Data collection & management .................................................................................................................. 19 
6.10 Analysis ..................................................................................................................................................... 19 
6.10.1 Primary Analysis ................................................................................................................................. 19 
6.10.2 Analysis of qualitative data ................................................................................................................ 20 
6.10.3 Power Calculations............................................................................................................................. 20 
7. Healthy Living Intervention for HIV prevention (Aim 2) Trial ........................................................................... 20 
7.1 Study Design................................................................................................................................................ 20 
7.2 Study Population & Eligibility Criteria ......................................................................................................... 21 
7.3 Recruitment & Screening Process ............................................................................................................... 21 
7.4 Enrollment & Randomization...................................................................................................................... 21 
7.5 Study Groups ............................................................................................................................................... 21 
7.6 Procedures .................................................................................................................................................. 22 
7.7 Measurements ............................................................................................................................................ 23 
7.8 Data Collection & Management ................................................................................................................. 24 
7.9 Analysis ....................................................................................................................................................... 24 
8. Costing (Aim 3) .................................................................................................................................................. 24 

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8.1 Study Population ......................................................................................................................................... 24 
8.2 Measurements for Aim 3 ............................................................................................................................ 25 
8.3 Analytic approach for Aim 3 ....................................................................................................................... 25 
9. Human Subjects ................................................................................................................................................ 25 
9.1 Risks to Human Subjects ............................................................................................................................. 26 
PrEP/PEP Use ................................................................................................................................................ 26 
Hair Collection ............................................................................................................................................... 26 
Phlebotomy ................................................................................................................................................... 26 
Psychological stress ...................................................................................................................................... 26 
Potential risk of exposure to SARS-CoV-2 during clinic visits ....................................................................... 26 
9.2 Adequacy of protection against risks .......................................................................................................... 26 
Informed Consent ......................................................................................................................................... 26 
Maintaining privacy and avoiding stigmatization ......................................................................................... 27 
Minimizing coercion to participate in research ............................................................................................ 27 
Data Security ................................................................................................................................................. 27 
SARS-CoV-2 Biosafety ................................................................................................................................... 27 
Biosafety – Universal precautions ................................................................................................................ 27 
Institutional Review Board Approval ............................................................................................................ 28 
9.3 Potential benefits ........................................................................................................................................ 28 
9.4 Importance of the knowledge to be gained ............................................................................................... 28 
10. Publication of Research Findings .................................................................................................................... 28 
11. References ...................................................................................................................................................... 29 
 
 
 

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Study Investigators 
Principal Investigator 
 
Gabriel Chamie, MD, MPH 
Associate Professor of Medicine 
Division of HIV, Infectious Diseases & Global Medicine 
San Francisco General Hospital 
University of California, San Francisco 
UCSF Box 0874, 995 Potrero Avenue 
San Francisco, CA  94110, USA 
Phone: 415-476-4082, ext. 445 
Email: gabriel.chamie@ucsf.edu 
 
Protocol Statistician 
 
Laura B. Balzer, PhD, MPhil 
Associate Professor of Biostatistics  
University of California, Berkeley 
2121 Berkeley Way #5317 
Berkeley, CA 94720, USA 
Phone: 203-558-3804 
Email: laura.balzer@berkeley.edu 
 
Co-Investigators 
 
James Ayieko, MBChB, MPH, PhD 
Researcher, Kenya Medical Research Institute 
Address: P.O. Box 517-20107, Njoro, Kenya 
Phone: +254-720-925262 
Email: jimayieko@gmail.com  
 
Carol S. Camlin, PhD, MPH 
Professor 
Department of Obstetrics, Gynecology and Reproductive Sciences 
University of California, San Francisco 
1330 Broadway St 
Oakland CA 94612, USA 
Phone: 510-986-8981 
Email: carol.camlin@ucsf.edu 
 
Judith A. Hahn, PhD, MA 
Professor of Medicine 
Division of HIV, Infectious Diseases & Global Medicine 
University of California, San Francisco 
550 16th Street 
San Francisco, CA 94158, USA 
Phone: 415-476-5815 

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Email: judy.hahn@ucsf.edu  
 
Diane V. Havlir, MD 
Professor of Medicine, Chief 
Division of HIV, Infectious Diseases & Global Medicine 
University of California, San Francisco 
San Francisco General Hospital 
995 Potrero Avenue 
San Francisco, CA 94110, USA 
Phone: 415-476-4082, ext. 424 
Email: dhavlir@php.ucsf.edu 
 
Moses R. Kamya, MBChB, MMed, MPH, PhD 
Professor of Medicine 
Department of Medicine, Makerere University College of Health Sciences 
Executive Director, Infectious Diseases Research Collaboration (IDRC) 
Plot 4B, Kololo Hill Drive 
P.O. Box 7972, Kampala, Uganda   
Phone: +256-414-533200 
Email: mkamya@infocom.co.ug 
 
Maya L. Petersen, MD, PhD 
Professor of Biostatistics, Epidemiology and Computational Precision Health 
University of California, Berkeley 
2121 Berkeley Way #5315 
Berkeley, CA 94720, USA 
Phone: (510) 642-0563 
Email: mayaliv@berkeley.edu 
 
Starley B. Shade, PhD, MPH 
Professor 
Department of Epidemiology & Biostatistics 
University of California, San Francisco 
550 16th Street 
San Francisco CA 94158, USA 
Phone: 415-476-5798 
Email: Starley.Shade@ucsf.edu  
 
Sarah Woolf-King 
Associate Professor 
Department of Psychology 
Syracuse University 
510 Huntington Hall 
Syracuse, New York 12344 
Phone: 315-443-9917 
Email: sewoolf@syr.edu 
 

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Glossary of Terms 
ART 
 
 
Antiretroviral therapy 
AUDIT-C 
 
Alcohol Use Disorders Identification Test-Concise 
DM 
 
 
Diabetes mellitus 
HLI 
 
 
Healthy Living Intervention 
HTN 
 
 
Hypertension 
MoH  
 
Ministry of Health 
PrEP 
 
 
Pre-exposure prophylaxis 
PEP 
 
 
Post-exposure prophylaxis 
PEth   
 
Phosphatidylethanol 
 
 
 

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1. Study Synopsis  
The project will rigorously test innovative interventions in Kenya and Uganda to increase uptake and use of 
biomedical HIV prevention, and assess facilitators, barriers, and cost-effectiveness of these approaches. 
The project will have the following aims: Aim 1: Compare the effectiveness of two mobilization strategies to 
increase uptake of biomedical HIV prevention among adults at drinking venues. Aim 2: Determine the efficacy 
of the Healthy Living Intervention (HLI) to reduce heavy alcohol use vs. standard care (control) on retention in 
biomedical HIV prevention in a randomized trial among adults with heavy alcohol use. Aim 3: Determine the 
cost-effectiveness of interventions that increase biomedical HIV prevention uptake (Aim 1) and retention (Aim 
2) among adults at high-risk for HIV who attend drinking venues. 
The proposed research will address the critical intersection of alcohol use and HIV risk in SSA, by promoting 
reach, uptake and retention in biomedical HIV prevention and exploring associated facilitators and barriers. 
1.1. Introduction 
HIV incidence remains unacceptably high in sub-Saharan Africa (SSA) due in part to inadequate access, uptake, 
and retention in biomedical HIV prevention services, including pre- and post-exposure prophylaxis (PrEP/PEP), 
among persons at increased HIV risk. Alcohol use is a common risk factor for both HIV acquisition and poor 
HIV prevention uptake and retention in SSA. Interventions that promote biomedical HIV prevention among 
persons with heavy alcohol use and their sexual partners are urgently needed. 
Alcohol-serving drinking venues play an important role as sites of HIV transmission in SSA and are ideal sites to 
engage women and men at increased risk of HIV in biomedical prevention services. However, despite long-
standing awareness of drinking venues as transmission “hot spots”, few interventions exist to reach and 
engage persons in PrEP and PEP from drinking venues in SSA. Major barriers to reaching and engaging persons 
at high risk of HIV from community settings such as drinking venues in HIV testing – a critical first step to 
accessing biomedical HIV prevention – include HIV-associated stigma and poor perceptions of risk. To address 
these barriers, we have developed a mobilization strategy of integrating HIV testing within multi-disease 
screening that recruited >2,000 people from drinking venues in Kenya and Uganda, reaching >75% of adults 
recruited for HIV testing. We now need to determine whether multi-disease mobilization can promote uptake 
of HIV prevention for adults at drinking venues in the context of new biomedical prevention options. 
Following uptake of biomedical HIV prevention, persons with heavy alcohol use face challenges with retention 
in care and adherence to PrEP/PEP. We have adapted a brief alcohol counseling intervention (Health Living) to 
reduce alcohol use and promote antiretroviral therapy (ART) adherence and HIV viral suppression among 
persons with HIV in Kenya and Uganda. We now need to determine whether this intervention can promote 
retention in biomedical prevention and PrEP/PEP adherence among adults with heavy alcohol use.  
Problem Statement: HIV incidence remains above global targets for epidemic control in sub-Saharan Africa 
(SSA), and suboptimal retention in biomedical HIV preventive care undermines the promise of PrEP for HIV 
prevention. Alcohol use is a common risk factor for both HIV acquisition and poor HIV prevention uptake and 
retention in SSA. Interventions that promote biomedical HIV prevention among persons with heavy alcohol 
use and their sexual partners – persons at greatly increased risk of HIV – are urgently needed. 
Justification of the study: This study will test innovative interventions to increase uptake and use of biomedical 
HIV prevention options by engaging women and men at drinking venues in rural Kenya and Uganda in care and 
evaluating a brief alcohol counseling intervention among adults with heavy alcohol use at high risk for HIV, 
while gaining insights into the facilitators, barriers, and cost-effectiveness of these approaches. The findings of 
this study will provide valuable information to policymakers and HIV prevention programs on the effectiveness 
of approaches – including strategies to mobilize and support prevention initiation and retention in prevention 
service care – to promote biomedical HIV prevention engagement among adults at drinking venues. Despite 
clear evidence that persons at drinking venues are at increased risk of HIV infection, there are very few 

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rigorous studies of strategies for engaging persons at risk of HIV from drinking venues. Similarly, despite 
increasing evidence that heavy alcohol use is a barrier to adherence to and retention in HIV biomedical 
preventive services, the effectiveness of brief alcohol counseling interventions to support retention and 
adherence to biomedical prevention remains unknown. Specifically, the first trial (Aim 1) will evaluate the 
relative effectiveness of offering multi-disease services vs. HIV-focused prevention services to promote 
biomedical HIV prevention uptake among persons from drinking venues, and the second trial (Aim 2) will 
evaluate whether a brief alcohol counseling intervention can improve retention in HIV preventive care. 
2. Study Objectives 
We will rigorously test innovative interventions in Kenya and Uganda to increase uptake and use of biomedical 
HIV prevention by engaging adults at drinking venues, evaluating the Healthy Living Intervention (HLI: brief 
alcohol counseling intervention) on PrEP/PEP retention and adherence in adults with heavy alcohol use at high 
HIV risk, and assessing facilitators, barriers, and cost-effectiveness of these approaches. We propose the 
following aims:  
Aim 1: Compare the effectiveness of two mobilization strategies to increase uptake of biomedical HIV 
prevention among adults at drinking venues. We will compare HIV-focused vs. multi-disease mobilization to 
recruit adults at drinking venues for health center-based HIV or multi-disease testing, respectively. 
Participants in both arms (up to 5,000/arm) will be offered oral PrEP, the Dapivirine vaginal ring (women only) 
or PEP if HIV-uninfected, or ART if HIV-infected. The primary outcome will be PrEP/PEP initiation. Our 
hypothesis is that multi-disease mobilization will result in greater PrEP/PEP uptake. Secondary outcomes 
include HIV testing uptake, yield of persons with heavy drinking and with untreated HIV, and ART uptake. 
Qualitative research, including in-depth interviews among a stratified random sample of participants and 
observations at venues will be conducted to evaluate facilitators and barriers to prevention uptake and 
perceptions of the strategies. Aim 1 will address the research question: will mobilization of high-risk persons at 
drinking venues via a multi-disease approach be more effective than an HIV-focused approach in promoting 
biomedical prevention initiation?  
Aim 2: Determine the efficacy of the Healthy Living Intervention (HLI) to reduce heavy alcohol use vs. 
standard care (control) on retention in biomedical HIV prevention in a randomized trial among adults with 
heavy alcohol use. We will compare a brief alcohol counseling intervention (already adapted to a Ugandan 
and Kenyan context) vs. control among 400 adults with heavy alcohol use initiating PrEP/PEP. The primary 
outcome will be HIV prevention coverage (proportion of time that a person is protected from HIV with 
PrEP/PEP) over 24 weeks. Our hypothesis is that the HLI will promote greater HIV prevention coverage. 
Secondary outcomes will include reductions in alcohol use (by AUDIT-C and phosphatidylethanol [PEth]) and 
HIV seroconversion. In-depth interviews in a stratified random sample of participants will evaluate facilitators 
and barriers to retention and adherence to HIV prevention. Aim 2 will address the research question: will a 
brief alcohol counseling intervention (the Healthy Living Intervention) promote greater retention in biomedical 
HIV prevention services - by reducing alcohol use and increasing healthy behavior – than standard care among 
adults at high risk for HIV with heavy alcohol use? 
Aim 3: Determine the cost-effectiveness of interventions that increase biomedical HIV prevention uptake 
(Aim 1) and retention (Aim 2) among adults at high-risk for HIV who attend drinking venues. We will 
estimate the costs and cost-effectiveness of the interventions based on trial effectiveness measures.  
3. Background and Rationale 

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HIV incidence is high and well above global targets for epidemic control in sub-Saharan Africa (SSA), 
particularly among key populations at increased HIV risk, despite universal antiretroviral therapy (ART) 
eligibility for persons with HIV (PWH) and increasing availability of highly effective options for biomedical 
prevention.1 In SSA, which accounts for 59% of new infections globally,2 reducing HIV incidence requires 
strategies to optimize the effectiveness of biomedical HIV prevention, including pre-exposure prophylaxis 
(PrEP), in oral and injectable forms,3-6 and post-exposure prophylaxis (PEP) among persons at risk for HIV.  
Realizing the full potential of biomedical HIV prevention in SSA requires reaching and engaging persons at 
high risk of HIV. Despite increasing availability of biomedical prevention, several barriers exist to PrEP and PEP 
uptake among high-risk populations in SSA, including poverty, costs associated with accessing care, stigma, 
and inadequate knowledge about prevention (or how to access it) and about one’s risk of HIV acquisition.7-11 
In implementation studies that have overcome access challenges and identified eligible adults at increased risk 
of HIV, PrEP uptake has been low to moderate, with <50% of eligible persons initiating PrEP. For example, in 
our large-scale Sustainable East Africa Research in Community Health (SEARCH) study of PrEP uptake, 
retention and adherence in Kenya and Uganda, we found that only 27% of PrEP-eligible adults initiated PrEP 
following population-wide HIV testing and risk assessment.12 Notably, the likelihood of PrEP uptake among 
women was significantly lower for those working in bars or reporting alcohol consumption in this setting. 
Similarly, in a pilot study of PrEP uptake among adults with heavy alcohol use in South Africa, only 27% of 
eligible adults reached at drinking venues who were offered PrEP agreed to initiate it,13 and in a cluster 
randomized trial in Zimbabwe that included community mobilization for female sex workers, 38% of sex 
workers who were screened and offered oral PrEP initiated it.14 Though some studies have found high 
acceptance and initiation of PrEP offered in clinical settings15-17, how to effectively reach and engage adults at 
high HIV risk from community settings, such as drinking venues, to promote PrEP/PEP uptake is unclear.  
Suboptimal adherence to PrEP and retention in 
biomedical HIV preventive care also undermine the 
promise of PrEP for HIV prevention. Despite the high 
efficacy of PrEP, its effectiveness is dependent on 
adequate adherence and retention in care. In two oral 
PrEP trials among women in SSA, adherence was low 
(≤30%) and PrEP was not effective in reducing HIV risk.18,19 
In the majority of PrEP implementation studies (apart from 
those among mutually-disclosed discordant couples20,21), 
including the SEARCH study (Figure 1), adherence has 
dropped rapidly with <50% of PrEP initiators adhering by 
six months.22 In one study in Kenya, PrEP uptake was 86% 
among eligible young women and 66% among female sex 
workers; however, only half continued at one month and 20% at six months.23 Although PrEP use is ideally 
aligned with periods of HIV risk (i.e. “prevention-effective adherence”24), adherence has been found to be low 
even during periods of high risk.25-27 As PrEP is now being brought to scale in SSA,22 effective strategies to 
support retention in biomedical HIV prevention programs are critical.  
Alcohol use is a common risk factor for both HIV acquisition and poor HIV prevention uptake, adherence, 
and retention in SSA. Multiple studies have found that alcohol use contributes to risk of HIV acquisition across 
SSA, including in Kenya and Uganda.28-30 In prior meta-analyses, persons who consume alcohol are nearly two 
times more likely to be infected with HIV compared to those who abstain.31,32 Several behaviors that increase 
HIV risk and have been associated with alcohol use include sex without a condom,33 casual partnering and 
having multiple partners,34 transactional sex35, as well as impaired risk assessment, sexual negotiation and 
sexual decision-making.34,36 In addition, a growing body of evidence suggests that alcohol use is associated 
with lower uptake and adherence to PrEP. As noted above, in our large-scale PrEP demonstration project 
Figure 1. PrEP program engagement and adherence in 
3,466 adults who initiated PrEP in the SEARCH study. 

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(SEARCH) in Kenya and Uganda, self-reported alcohol use of ≥1 day per month was associated with 
significantly lower odds of PrEP uptake among eligible women.12 Alcohol use has been associated with 
decreased adherence to PrEP among sex workers in Uganda37 and Zimbabwe38, and HIV sero-discordant 
couples in Kenya and Uganda,39 and non-retention in PrEP clinic among men who have sex with men in 
Kenya40 and in PEP programs.41 Given the convergence of increased HIV risk and suboptimal PrEP uptake and 
retention, interventions to improve HIV prevention uptake and retention are urgently needed for persons with 
heavy alcohol use in SSA. 
Alcohol-serving drinking venues play an important role as sites of HIV transmission in SSA and are ideal sites 
to engage persons at increased risk of HIV in biomedical prevention services. In multiple studies and settings, 
attendance at drinking venues has been associated with increased HIV risk.42 Increased risk of HIV has been 
found both among patrons and employees of drinking venues.43-45 Even after controlling for alcohol use, 
attending drinking venues has been associated with high-risk sex.46 However, despite these strong 
associations, there have been few HIV prevention interventions that have included drinking venues.47  In 
addition, given the recency of PrEP availability in SSA, approaches to reach and engage persons in PrEP and 
PEP from drinking venues remain largely unexplored. Furthermore, there are no studies evaluating 
implementation of flexible choice of prevention for engaging this high-risk population. In a recent feasibility 
study of community-delivered PrEP in South Africa, study staff offered HIV testing and AUDIT screening 
outside of shebeens (drinking venues) 27 times over six months. Over this time, 162 shebeen patrons were 
screened of whom 136 (84%) were eligible for PrEP. Notably, only 37 patrons (27%) initiated PrEP, and the 
vast majority of shebeen patrons who participated in screening were men (92%).13  
Common barriers to reaching and engaging persons at high HIV risk in biomedical HIV prevention from 
community settings in SSA are HIV-associated stigma and poor perceptions of HIV risk. HIV stigma is a well-
established factor negatively impacting engagement in HIV-related services globally.48-50 Mechanisms by which 
stigma results in lower HIV-related health engagement include enacted stigma from community members and 
health care providers, anticipated stigma (an expectation of stigma), and internalized stigma.51 Fear of being 
perceived as HIV infected when accessing PrEP (as TDF/FTC are antiretroviral medications used in HIV 
treatment), or at high risk for HIV due to stigmatized behaviors when accessing HIV testing or other services, 
repeatedly emerge as barriers to care.52,53  In drinking venues, HIV stigma may intersect with stigma 
associated with alcohol use54 and commercial sex work, creating further challenges to reaching and engaging 
persons at risk for HIV. Poor perceptions of HIV risk and competing demands also contribute to low 
engagement,55,56 and strategies to increase demand for HIV services among persons at risk are needed. 
Offering multi-disease (non-HIV-focused) 
health services can be a compelling 
demand generating strategy that allows 
persons at risk for HIV to cope with 
stigma when engaging in HIV services. In 
Kenya and Uganda, we have shown that 
offering multi-disease services – such as 
screening for TB, malaria, diabetes and 
hypertension in addition to HIV – results 
in high uptake of testing in both men and 
women (Table 1).57-60 In both the SEARCH universal HIV “test and treat” trial57 and our trial engaging high-risk 
adults in Uganda61, multi-disease services led to very high rates of HIV testing uptake, with >95% population 
HIV testing coverage in SEARCH with this approach.62  Multi-disease screening may also alleviate stigma 
associated with accessing HIV testing and prevention services in isolation and engage persons with low 
perceptions of HIV risk. Qualitative data showed SEARCH community residents were drawn by non-HIV 
services and attracted those who reported prior reluctance to test for HIV.63 While our prior studies are highly 
Table 1. Multi-disease community-based testing uptake among census-
enumerated residents in SEARCH trial communities in Kenya & Uganda 

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suggestive that offering multi-disease services can boost HIV testing and prevention service uptake compared 
to offering HIV-focused services alone,64 no randomized trials have evaluated this question. In the proposed 
trial, we will directly test whether mobilization of high-risk persons at drinking venues via a multi-disease 
approach is more effective than an HIV-focused approach, in promoting biomedical prevention initiation.  
In SSA, interventions to improve retention in biomedical HIV preventive care among persons with heavy 
alcohol use are limited. However, multi-session brief counseling for alcohol use interventions have been 
shown to be effective in reducing heavy alcohol use in multiple settings,65 including studies in low- and middle-
income countries.66-68 Among PWH, such interventions can increase viral suppression via increased medication 
adherence,68,69 suggesting that brief alcohol counseling interventions offer a potential, relatively low-cost 
intervention strategy for promoting retention in HIV preventive services and adherence to PrEP/PEP among 
persons with heavy alcohol use. The “Healthy Women Healthy Living” (HWHL) brief alcohol intervention 
demonstrated efficacy in reducing heavy drinking and unprotected vaginal sex among women living with HIV 
in the US.70 It is based on an efficacious physician-delivered brief intervention in primary care.71 Given its 
efficacy in reducing alcohol use and increasing HIV viral suppression,68 our research group has adapted the 
HWHL intervention to a Ugandan context72 and implemented this “Healthy Living” intervention (HLI) among 
PWH with heavy alcohol use in Uganda in a randomized trial of HLI vs. standard counseling to reduce heavy 
alcohol use (EXTEND study: NCT03928418). Our group has since further adapted it for Western Kenya, to 
evaluate the impact of HLI on viral suppression among PWH with heavy alcohol use in Kenya and Uganda in 
the SAPPHIRE trial (NCT04810650). Whether this intervention could promote retention in biomedical HIV 
prevention services, including oral and injectable PrEP and PEP – by reducing alcohol use and increasing 
healthy behavior – among adults at high risk for HIV with heavy alcohol use remains unknown.  
Patient-centered care in which the needs and desired health outcomes of patients are central to care 
provision can improve multiple HIV-related outcomes, including medication adherence among persons with 
hazardous alcohol use. In the SEARCH HIV “test and treat” trial, providing patient-centered care – which 
included flexible clinic hours, phone access to a health care worker and a welcoming environment – resulted in 
improved retention in care and higher HIV viral suppression than 
standard care.62,73-75 Furthermore, following population-wide HIV 
testing, patient-centered care significantly reduced disparities in viral 
suppression among PWH with heavy alcohol used compared to those 
who abstain from alcohol in the SEARCH trial (Figure 2).76 Building on 
these findings, in the ongoing SAPPHIRE trial in Kenya and Uganda, 
we are evaluating a patient-centered approach to prevention – 
“Dynamic Choice Prevention” – that provides flexible access to 
biomedical HIV prevention options, including oral PrEP, the 
dapivirine vaginal ring and event-based PEP. The Dynamic Choice 
Prevention approach incorporates flexibility in choice to optimize 
uptake, adherence, and retention. Dynamic Choice Prevention 
provides an ideal context to evaluate interventions to engage and 
retain persons with hazardous alcohol use in biomedical HIV 
prevention.  
In summary, interventions are urgently needed to ensure persons at high risk for HIV due to alcohol 
consumption are reached and engaged with effective biomedical HIV prevention tools. We are at a point in 
the HIV pandemic where, all too often, persons at greatest risk for HIV acquisition are not reached for or 
engaging with highly effective biomedical HIV prevention options. The relationship between alcohol use, 
drinking venues and HIV infection risk in SSA is clear and must be addressed. This study will test innovative 
interventions to increase uptake and use of biomedical HIV prevention by engaging persons at drinking venues 
Figure 2. HIV viral suppression at year 3, by 
SEARCH trial arm and baseline hazardous 
drinking among PWH. 

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in care, evaluating the HLI intervention among adults with heavy alcohol use at high risk for HIV, and gaining 
insights into the facilitators, barriers, and cost-effectiveness of these approaches.   
 
3.1 Preliminary Studies 
We have developed and effectively 
implemented a recruitment card approach to 
mobilize adults from drinking venues in rural 
Kenya and Uganda for HIV testing followed by 
linkage to care for PWH. Using recruitment 
cards as proposed for the Aim 1 trial, we have 
implemented drinking venue mobilization in 
several studies.61,77 We identified 61 drinking 
venues and distributed 960 cards with multi-disease messaging in a randomized trial to promote HIV retesting 
among adults at increased HIV risk in peri-urban Uganda. Of 960 persons who received cards at drinking 
venues, 773 (81%) adults presented to clinic within a week of card distribution, of whom 261 (34%) were 
adults with HIV.45,61 Of the remaining 512 adults without HIV infection from drinking venues, 351 (69%) self-
reported a significant risk for HIV in the prior 12 months, including multiple concurrent partners, sexual 
partners with HIV, diagnosis of ≥1 sexually transmitted infection and transactional sex. Using this same 
approach in Kenya in the ongoing SAPPHIRE trial (NCT04810650), we have distributed 1,131 recruitment cards 
with multi-disease messaging to formal and informal drinking venues in Western Kenya, and 863 adults (76%) 
have linked to our study clinics to date for screening and HIV testing. Of the 863 adults who linked to care, 270 
(31%) were PWH, and 60 (7%) were identified with untreated HIV (Table 3).  
We have evaluated multi-disease strategies for community-based mobilization to promote HIV testing, 
prevention, and treatment for over 10 years. Such approaches have included large-scale community health 
fairs,58,59,78,79 home-based testing57 and community-based outreach and testing among key populations at 
increased risk of HIV.61,80 Qualitative data from such strategies suggest that offering HIV testing and services 
within the broader context of maintaining health impacts community-level stigma associated with accessing 
HIV services.81 However, whether multi-disease screening can lead to improved uptake of HIV testing and 
prevention compared to standard, HIV-focused outreach,47 by providing a means to cope with stigma and 
leveraging broader demand for services, particularly among adults at increased risk of HIV, has not been 
rigorously tested or adopted by programs to reach key populations such as adults at drinking venues. 
We have led one of the largest PrEP implementation 
studies to date and will leverage existing research 
infrastructure to implement and evaluate “Dynamic 
Choice” HIV prevention and measure prevention 
coverage, including use of oral PrEP, the dapivirine 
vaginal ring and PEP, for the proposed trial. In the 
SEARCH trial (NCT01864603), our team offered PrEP to 
>12,000 persons at elevated HIV risk during population-
wide HIV testing in 16 rural communities in Kenya and 
Uganda.12,82,83 Notably, the likelihood of PrEP uptake 
among women was significantly lower for those reporting 
alcohol consumption than those who abstain from 
alcohol (Table 4).12 Among 3,466 people who initiated 
PrEP, there were substantial declines in PrEP program retention and adherence over time. Only 54% of PrEP 
initiators were engaged in care and 25% were adherent at 48 weeks. Even among a sub-group who reported 
Table 4. Factors associated with PrEP uptake among 
women at elevated HIV risk in 16 communities in rural 
Kenya and Uganda in the SEARCH trial. 
Table 3. Yield of recruitment card approach to mobilize adults from 
drinking venues in Kenya and Uganda for HIV testing. 

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ongoing high HIV risk and self-reported PrEP adherence, pill-taking was a challenge with 33% having hair levels 
consistent with taking <4 doses of PrEP/week. Our group has also studied PEP implementation in Kenya and 
Uganda and demonstrated high PEP retention (97%) and adherence (85%) at 4 weeks in adults following high-
risk sexual exposures.84 In the ongoing SAPPHIRE trial, we are evaluating a patient-centered “Dynamic Choice 
Prevention” approach to promote PrEP/PEP uptake and retention among adults at-risk for HIV that we will 
leverage for the proposed trial. This Dynamic Choice approach includes choice of oral PrEP (with access to the 
dapivirine vaginal ring in all SAPPHIRE intervention communities to begin in 2023) or event-driven PEP, and 
flexibility to go back and forth between current and emerging options when available (e.g., dapivirine vaginal 
ring). The well-developed, existing research infrastructure in the SAPPHIRE trial thus provides an opportunity 
to rigorously measure prevention uptake by adults at drinking venues and retention in biomedical HIV 
prevention among adults with heavy alcohol use. 
We have adapted and implemented an intervention (Healthy Living Intervention [HLI]) to reduce heavy 
alcohol use and promote ART adherence and HIV viral 
suppression among PWH in Kenya and Uganda. Given the 
relative lack of interventions to reduce hazardous drinking in SSA, 
our group (led by Hahn and Camlin) has adapted a brief alcohol 
counseling intervention previously shown to be effective in 
reducing alcohol use in resource-limited settings,66 to a Ugandan 
context (Figure 3).72 The adapted HLI has now been effectively 
implemented in the EXTEND study (NCT03928418) among PWH, 
and adapted to a Kenyan context for PWH with heavy alcohol use 
in the SAPPHIRE trial. While the results of these trials are still 
pending, similar versions of this intervention have been shown to 
be effective to decrease alcohol use in PWH in low/middle income settings (Baltimore, Vietnam, India) and 
reduce viral suppression in one.66,68,70 In addition, our team has extensive experience measuring alcohol use 
outcomes in SSA, including using biomarkers such as phosphatidylethanol (PEth). PEth is a phospholipid which 
is formed only in the presence of alcohol and thus is highly specific.85 PEth is the most sensitive medium-term 
biomarker,86 and PEth levels have been well correlated (Spearman’s r= 0.6-0.8) with level of consumption in 
controlled studies.87-90 We found that PEth was 95% sensitive and 73% specific for detecting prior 21-day 
heavy drinking, and highly correlated with the number of drinking days in PWH in Uganda.90 It is tested from 
whole blood or dried blood spots which are easy to store and transport. We have subsequently used PEth to 
confirm suspected under-reporting in Uganda.91,92 Our team is therefore well-positioned to rigorously test the 
HLI as an intervention to promote retention in HIV prevention services and adherence to PrEP and PEP among 
adults with heavy alcohol use at greatly increased HIV risk, and will include objective measures of the prime 
mediator, unhealthy alcohol use.  
We have integrated qualitative and costing measures and gained valuable insights into participant and 
provider facilitators and barriers to trial outcomes, cost-effectiveness and scalability. Qualitative and mixed 
method studies (led by Camlin) have provided rich understanding of local contexts, barriers and facilitators to 
engaging in HIV services, and perceptions of study interventions, including alcohol interventions. For example, 
in the SEARCH universal “test and treat” trial, focus group discussions and in-depth interviews among young 
adults who initiated vs declined PrEP revealed barriers such as HIV and ART-associated stigma, desire for 
“proof” of PrEP efficacy and misinformation/rumors,93 that have informed interventions developed for the 
subsequent SAPPHIRE trial. Similarly, in SEARCH, costing studies (led by Shade) have provided valuable data 
for stakeholders and policymakers regarding the low added costs of adding multi-disease screening to HIV 
testing,94 and of delivery of integrated hypertension/HIV care.95  
Figure 3. Example of images added to the HLI 
intervention workbook during cultural adaptation 

Protocol Version: January 6, 2025 
14 
4. Study Setting & Population 
The study will take place in rural Kenya and Uganda (i.e., not defined as an urban municipality in either 
Uganda or Kenya) in eight geographically dispersed communities (each served by an ART/PrEP/PEP-providing 
health center) that are participating in the ongoing SAPPHIRE trial (NCT04810650). The study communities are 
in southwestern Uganda (4 communities) and western Kenya (4 communities) where adult HIV prevalence is 
7% and 18%, respectively.57 Uganda has one of the highest rates of alcohol use in SSA, and in both settings, 
heavy alcohol use is common, with an estimated 21% and 11% of the adult (≥15 years) population reporting 
heavy episodic drinking (i.e., >60 grams of pure alcohol on at least one occasion at least once a month),96 and 
likely further unreported unhealthy alcohol use.97,98 We have been at the forefront of implementing 
innovative HIV prevention and treatment approaches12,74,84,99 and alcohol intervention72,100 and 
measurement97,101 studies in these regions. Access to Dynamic Choice Prevention (offered within the 
SAPPHIRE trial) and support from Ministries of Health (MoH) provide an optimal setting for the proposed 
study. 
5. Study Design 
5.1. Study Overview 
We will determine the effectiveness of novel interventions to reach and engage adults who attend drinking 
venues in biomedical HIV prevention services, and then promote retention in preventive services, including 
adherence to oral PrEP and event-based PEP, among adults with heavy alcohol use in rural Kenya and Uganda. 
In Aim 1, we will compare two strategies – HIV-focused vs. multi-disease mobilization, testing and counseling – 
on initiation of PrEP or PEP among adults recruited from drinking venues. In Aim 2, we will determine the 
efficacy of a brief, multi-session alcohol counseling intervention on HIV prevention coverage (retention and 
adherence in PrEP/PEP), as well as reductions in heavy alcohol use, over 48 weeks. We will conduct in-depth 
qualitative interviews with a subset of participants from Aims 1 and 2, with stratified, random sampling based 
on key outcome measures, including perceptions of mobilization messaging, and barriers and facilitators to 
PrEP/PEP uptake and adherence among adults with heavy alcohol use. In Aim 3 we will determine the costs 
and cost-effectiveness of interventions that promote HIV prevention uptake and retention among adults at 
high-risk for HIV who attend drinking venues (Table 2). 
Table 2. Overview of proposed study aims, with study population, design, and outcome measures. 
Aim 
Study Population 
Study Design 
Outcomes 
Aim 1 
Adults (≥18 yrs) at drinking 
venues (patrons or workers) 
in study communities 
(N=up to 10,000 
participants, from ~120 
drinking venues) 
Cluster randomized trial comparing 
drinking venue mobilization via HIV-
focused (Arm 1) vs. Multi-disease 
(Arm 2) mobilization, testing, and 
counseling, on biomedical HIV 
prevention uptake 
Primary: Initiation of PrEP or PEP at time of 
HIV testing among HIV-uninfected adults 
Secondary: a) HIV testing uptake; b) yield of 
adults with heavy EtOH use; c) yield of 
untreated HIV; d) ART uptake if HIV+ 
Qualitative: a) Perceptions of drinking venue 
mobilization strategies; b) 
barriers/facilitators of biomedical HIV 
prevention uptake 
Aim 2 
HIV-uninfected adults with 
heavy alcohol use (N=400) 
 
Eligible individuals who 
decline Aim 2 RCT 
participation but consent to 
Randomized trial comparing the 
Healthy Living intervention to reduce 
hazardous alcohol use vs. standard 
care (control) on PrEP/PEP retention 
among heavy drinkers offered 
Dynamic Choice prevention 
Primary: HIV Prevention coverage (retention 
in PrEP or PEP) over 24 weeks 
Secondary: a) Heavy alcohol use (AUDIT-C, 
PEth), b) HIV Prevention coverage (retention 
in PrEP or PEP) over 48 weeks, c)HIV 
seroconversion 

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qualitative interview only 
(N=20) 
Qualitative: a) Perceptions of intervention, 
alcohol use, and dynamic choice; b) barriers 
and facilitators to retention and adherence 
Aim 3 
Aim 1 and 2 study 
populations & care 
providers 
Costing and Cost-Effectiveness 
Analyses (CEA)  
CEA: Cost per HIV infection averted and cost 
per DALY averted 
6. Drinking Venue Mobilization Strategies (Aim 1) Trial  
Restatement of Aim 1: Compare the effectiveness of two mobilization strategies to increase uptake of 
biomedical HIV prevention among adults at drinking venues. 
6.1 Aim 1 Study Design 
We will conduct a two-arm, cluster randomized controlled trial of multi-disease vs. HIV-focused mobilization 
strategies to promote biomedical HIV prevention uptake among adults at drinking venues (Figure 4: 
Schematic). 
6.2 Eligibility Criteria  
Inclusion criteria: Drinking venue 
eligibility: venue within the study 
community at which alcohol is sold 
and consumed; Participant 
inclusion: a) adult (≥18 years); b) 
patron or worker at a drinking 
venue within the study community. 
Participant exclusion criteria: a) age 
<18 years; b) inability to provide 
informed consent (e.g., if heavily 
intoxicated from alcohol use at time 
of health center-based screening). 
6.3 Consent Process 
a) Recruitment card distribution at drinking venues: When initiating interaction with persons at drinking 
venues within the study communities, study staff will identify themselves as members of the research team 
and, after verbally confirming a person is ≥18 years of age (in both Kenya and Uganda, persons <18 years old 
are not legally allowed to attend drinking venues), they will briefly describe the purpose of the study and 
proceed with recruitment card distribution.  
b) Health screening at local health centers (written consent): Study staff working with each local health 
center’s triage/check-in office will receive adults presenting with recruitment cards and obtain written 
consent for participation in additional health screening. Persons with gross inebriation or inability to provide 
informed consent at the time of health center screening will be ineligible to provide written consent and told 
they may return later (when no longer grossly inebriated) to undergo screening. 
 
6.4 Community Engagement Plan 
Study staff will engage community leaders, healthcare leaders, community members, and other key 
stakeholders in meetings to introduce and discuss the study, with approaches we have used in prior 
community-based studies in Kenya and Uganda. 
Figure 4: Aim 1 Drinking Venue Mobilization Trial Schematic 

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Meetings with key leaders and stakeholders will be held in each region to introduce the study, answer 
questions, and engage leaders/stakeholders. In preparation for drinking venue mobilization activities (Aim 1), 
study staff will also meet with drinking venue owners, drinking venue managers, and key community 
representatives, to seek input on the following: 
• Identification of potential challenges and solutions to implementation 
• Communities and subgroups that may require special consideration 
• Other issues tailored to individual regions 
Dissemination: At the end of the study period, we will invite key community stakeholders to a dissemination 
meeting to share results of the study and discuss how the results of the study could be incorporated into 
routine clinical practice to improve care for persons at risk of HIV at drinking venues. 
 
6.5 Enrollment & Randomization 
a) Enrollment: Study recruitment will occur at the time of recruitment card distribution at drinking venues, 
following a brief verbal introduction. Staff will enroll participants and obtain written consent for study 
participation (including HIV testing and/or multi-disease screening) at the time that participants come to the 
clinic with recruitment cards. Study staff will continue to recruit participants and distribute recruitment cards 
until they have distributed recruitment cards to up to 10,000 drinking venue attendees/study participants.  
b) Randomization: We will randomize drinking venue clusters, with specification of clusters based on 
neighborhood, parish/sublocation or geographic co-location to be determined upon completion of drinking 
venue mapping (see Section 6.6.1. Procedures: Drinking venue mapping, below). We anticipate a minimum of 
16 clusters, and a maximum of 120 clusters (i.e., the anticipated number of drinking venues total in all 8 
communities). Randomization will be conducted within strata defined by country, community, venue size 
(average number of persons at drinking venues within the cluster), and potentially other characteristics 
determined upon completion of the mapping, but prior to randomization. We will randomize clusters 1:1, 
using a random number generator, to either multi-disease mobilization messaging (intervention) or HIV-
focused messaging (control) prior to initiation of participant recruitment and enrollment. Recruitment cards 
will be the same size, shape, and color, but messaging on one side of the cards will vary by mobilization 
strategy (randomization arm). Staff distributing the cards will aim to provide one card per adult encountered 
at the drinking venue. 
 
6.6 Study Groups 
a) HIV-focused messaging: Recruitment cards distributed at drinking venues will offer free HIV testing with 
access to biomedical HIV prevention. The cards will include the health center name, location, and hours. 
Participants who present to the health center with the HIV-focused recruitment cards will receive HIV-
counseling and testing alone, emphasizing the risk of HIV infection and benefits of biomedical HIV prevention 
for adults who attend or work at drinking venues.  
b) Multi-disease messaging: Recruitment cards distributed at drinking venues will offer a free health screening 
for multiple conditions, that may include: hypertension (HTN), diabetes mellitus (DM), HIV, tuberculosis (if 
symptomatic with cough, fever, weight loss or night sweats) and malaria (if febrile), with access to biomedical 
HIV prevention and multi-disease treatment services. Participants who present to the health center with the 
multi-disease recruitment cards will receive multi-disease (HTN, DM, HIV, TB and malaria) testing and 
counseling, with an emphasis on staying healthy and prevention and treatment of non-communicable and 
communicable diseases, including discussion of the risk of HIV infection and benefits of biomedical HIV 
prevention for adults who attend or work at drinking venues. 
In both groups, participants who link to the health center for HIV or multi-disease screening with a 
recruitment card will receive a one-time travel voucher of up to US$5 for reimbursement of travel expenses. 

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All participants (both groups) who test HIV negative will be offered Dynamic Choice Prevention (see 
Procedures, below). Adults with untreated HIV who link to clinic will receive counseling emphasizing the 
benefits of antiretroviral therapy (ART) in preventing morbidity and HIV transmission with immediate referral 
to on-site HIV care and ART. 
 
6.7 Procedures 
1. Drinking venue mapping: Study staff will map all drinking venues, including bars, night clubs, hotels, and 
informal drinking dens (e.g., where commercial beer and local brews and spirits – changaa in Kenya, and 
malwa/waragi – are sold) in the study communities while recording global positioning system (GPS) location 
of each venue visited.102,103 At each venue, staff will meet with venue owners prior to recruitment card 
distribution to describe the study and determine optimal times of the week and day for staff visits, based on 
attendance at drinking venues. 
2. Recruitment card distribution: Staff will then visit each venue periodically throughout the Aim 1 trial to 
distribute recruitment cards to persons at drinking venues (based on randomization group assignment of the 
cluster), including patrons and employees, until all drinking venues have been visited at least once (with up to 
10,000 cards distributed: up to 5,000 with HIV-focused messaging; up to 5,000 with multi-disease messaging. 
As noted above, recruitment cards will be the same size, shape, and color, but messaging on one side of the 
cards will vary by mobilization strategy. Staff will distribute cards and provide a brief, focused script that varies 
based on drinking venue randomization assignment, encouraging each adult to come to the local health center 
for screening (either HIV or multi-disease) with the recruitment card. The script, in both arms, may include 
brief messaging on availability of PrEP for HIV prevention at local clinics and the importance of ART for those 
with untreated HIV. All cards will indicate that travel costs (up to US$5) will be reimbursed for persons who 
come for screening and present a recruitment card. Prior to distribution, staff will record unique identifiers 
(recruitment card serial numbers) noting to which drinking venue each card was to be distributed and the date 
of mobilization (using procedures we have previously developed and implemented45,61). For each card 
distributed, staff will record the sex and age of the person to whom the card was given.  
3. Clinic-based screening: Study staff working with each local health center’s triage/check-in office will receive 
adults presenting with recruitment cards and obtain written consent for participation in additional health 
screening and a baseline survey to assess demographics, socio-economic status, HIV risk, HIV-related stigma 
and alcohol use. We will use digital fingerprint biometric metrics (with procedures used in prior studies57,99) or 
other personal identifiers (such as full name, age and household identification number) at time of screening to 
ensure participants enroll only once in the trial. Staff will provide clinic-based counseling and testing according 
to the approach indicated on the recruitment card, as follows: 
a) HIV testing and counseling: Study staff will provide HIV testing performed according to national (Kenya or 
Uganda) MoH guideline rapid HIV antibody testing algorithms,104,105 as well pre- and post-test counseling. Staff 
will focus on HIV risk and HIV counseling alone. 
b) Multi-disease testing and counseling: Study staff will provide counseling emphasizing general health and 
wellbeing, and options for prevention and treatment of common communicable and non-communicable 
diseases. Staff may provide the following screening services: i) HIV testing performed according to national 
(Kenya or Uganda) MoH guideline rapid HIV antibody testing algorithms,104,105 as well pre- and post-test 
counseling; ii) hypertension screening by automated sphygmomanometer; iii) diabetes mellitus screening by 
random blood glucose measure; iv) malaria screening by rapid diagnostic test, if febrile; v) option of TB 
screening (by sputum specimen collection for sputum microscopy or Xpert MTB/RIF assay, if symptomatic with 
fever, cough, night sweats or weight loss; and/or chest x-ray, depending on clinic availability); vi) option of 
urine pregnancy testing for pre-menopausal women; and vii) referral for sexually transmitted infection (STI) 

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testing for symptomatic men and women. We have offered similar multi-disease screening in prior 
studies.57,59,61  
In both arms, study staff will offer eligible participants who test HIV negative initiation of oral PrEP or PEP if 
indicated, within the Dynamic Choice prevention service delivery model of the SAPPHIRE trial.  
Study staff will also emphasize the importance of adherence to PrEP and PEP in preventing HIV infection, and 
the potential consequences associated with non-adherence (including HIV seroconversion). 
4. Dynamic Choice Prevention is a patient-centered approach implemented in the intervention arm of the 
ongoing SAPPHIRE trial (NCT04810650) designed to address barriers to biomedical HIV prevention with PrEP 
and PEP that we identified when offering PrEP to >12,000 persons with risk factors for HIV acquisition in the 
study regions.12 Components are delivered by study nurses and may include: a) choice of oral or injectable 
PrEP, the dapivirine vaginal ring (when available; women only) or event-driven PEP by country guidelines, and 
flexibility to go back and forth between current and emerging options once available (e.g., the dapivirine 
vaginal ring); b) client-centered care in which PrEP/PEP is offered in a supportive environment; c) flexibility in 
location of PrEP/PEP delivery over time; d) longer refills (up to 3 months) of oral PrEP; and e) HIV testing 
options of either rapid clinic-based testing or self-testing. 
5. HIV treatment: Staff will refer all adults with untreated HIV to on-site HIV care for immediate offer of ART.  
6. Qualitative interviews and observation at venues: Following clinic-based screening, study staff will recruit a 
subset of participants stratified by sex and uptake of PrEP/PEP from each study group for in-depth interviews 
to better understand motivations and stigma among adults at drinking venues for participating in screening 
and initiating PrEP/PEP. Study team members will also conduct qualitative observations during study activities 
at venues to gain insights into public reactions and interactions related to implementation. 
 
6.8 Measurements 
Outcome variables 
1. Primary Outcome: The Aim 1 primary outcome will be biomedical HIV prevention uptake, defined as the 
proportion of HIV- adults, receiving a randomization card, who initiate PrEP or PEP after mobilization. The 
primary analysis will focus on a 4-week PrEP/PEP initiation period after recruitment card distribution; 
secondary analyses will consider initiation periods of 8 and 12 weeks.  
2. Secondary Outcomes: By study arm, we will compare: a) HIV testing uptake: defined as presentation for 
clinic-based HIV testing with a recruitment card; b) yield of adults with untreated HIV: defined as the 
proportion of persons testing who are identified with newly diagnosed HIV or self-reported, known HIV 
infection but out of care and off of ART; c) yield of adults with heavy alcohol use, defined as AUDIT-C score of 
≥4 for men and ≥3 for women; and d) proportion of adults with untreated HIV that initiate ART within one 
week of presenting for clinic-based screening with a recruitment card.  
3. Qualitative inquiry. A.) In-depth semi-structured interviews: In accordance with principles of Grounded 
Theory106, we will iteratively collect and rapidly analyze interview transcript data, continuing to randomly 
select participants within theoretically-informed categories (e.g. not only categories such as study group, age 
group and sex, but characteristics found to be salient for further sampling) until the data attain theoretical 
saturation. Based on our prior qualitative research in the setting, we anticipate adequate thematic saturation 
with N=10-20 participants with PrEP/PEP uptake and N=10-20 who declined PrEP/PEP initiation per study arm 
(N=80 total), with a ‘ceiling’ number of participants set based on practical study schedule requirements. The 
interview guide will be designed to elicit responses in two thematic areas: i) perceptions, attitudes, and 
preferences related to the mobilization strategy received, including perceptions of HIV-related stigma; and ii) 
motivations and barriers related to biomedical HIV prevention uptake among adults who attend or work at 
drinking venues, including qualitative exploration of risk preferences, effects of alcohol use, other psychosocial 

Protocol Version: January 6, 2025 
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factors (e.g. fatalism, coping style, stigma, and perceived gender norms) and other contextual factors. Trained 
interviewers will pursue lines of questioning following the domains of inquiry outlined above, while allowing 
participants to discuss salient subjects. Interviews will be audio-recorded, transcribed, and translated into 
English. B.) Participant observation at drinking venues: Following community entry and after obtaining local 
permissions, study team members will visit selected drinking venues (composed of a balanced number of 
venues across randomization groupings) during the recruitment card distribution activities described above. 
Team members will observe reactions of and interactions between individuals within venues during 
implementation in order to gain a deeper understanding of contextual factors that may influence study 
implementation and outcomes. Observations will be recorded in field notes following each exercise. 
 
6.9 Data collection & management 
Baseline survey data: Staff will collect questionnaire data using hand-held computers (tablets) or paper 
questionnaires (as back up, if tablets are not functioning, with subsequent data entry into computers or 
tablets). Data will be transferred via secure electronic transfer to our data center facilities in Kenya and/or 
Uganda and stored on a secure server.   
Drinking venue GPS: Each drinking venue location will be mapped using a hand-held GPS receiver. Readings 
will be taken from the main entry door of the drinking venue, if possible, or from a point that is most 
representative of the venue. The GPS coordinates for each drinking venue will be recorded by the time of 
distribution of recruitment cards. GPS data will be synchronized from the GPS device to an electronic database 
and then transferred via a secure electronic transfer to the data center facilities in Kenya and/or Uganda and 
stored on a secure server. 
Digital fingerprint biometric: A digital biometric identifier based on an electronic fingerprint of each 
participant at time of clinic-based screening will be captured in an electronic database and linked to the study 
participant’s name. The biometric identifier will be saved into the study electronic database. The database will 
be transferred via a secure electronic transfer to the data center facilities in Kenya and/or Uganda and stored 
on a secure server. Alternatively, staff may obtain other personal identifiers (such as full name, age and 
household identification number) at time of screening. 
HIV Test Results: Staff working at the study community clinics will record all lab test results, including HIV 
antibody test results, and HIV diagnosis status information, under each participant’s study identification 
number (ID) in either paper lab logs or computers.  Staff will also record non-HIV (multi-disease) 
screening/test results under each participant’s study ID in either paper lab logs or computers. Data from these 
logs or devices will be transferred via a secure electronic transfer to our data center facilities in Kenya and/or 
Uganda and stored on a secure server. Staff will record PrEP/PEP initiation and ART start (when applicable) 
from clinical records, following HIV screening and referral to clinical services. 
Qualitative Data: Staff will record interviews on audio devices using study IDs (not participant names), and 
transcribed interviews and translations, along with field notes, will be data entered into appropriate software 
on password-protected study computers. Data from interviews will be transferred via a secure electronic 
transfer to our data center facility and stored on a secure server. 
6.10 Analysis 
6.10.1 Primary Analysis  
We will compare the primary outcome of biomedical HIV prevention (PrEP/PEP) uptake between the two 
study groups, accounting for clustering. We will evaluate the interventions using targeted maximum likelihood 
estimation (TMLE), a pre-specified approach to data-adaptively adjust for stratification factors used in 
randomization (country) as well as chance imbalances between randomized arms in additional baseline 
predictors of the outcome.107,108 This approach provides precision and power gains over standard approaches 

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that only adjust for stratification factors. We will test the null hypothesis of no difference in HIV prevention 
uptake by mobilization strategy. 
6.10.2 Analysis of qualitative data 
Translated interview data and textual field note data will be imported into a qualitative analysis software 
program, for thematic analysis109 guided by grounded theoretical approaches106, in which research team 
members iteratively analyze transcripts and field notes and develop a common set of inductive codes 
describing patterns observed in the data. New codes proposed by research team members will be vetted and 
defined in relation to existing codes. As new data are collected and reviewed, and data reach analytic 
saturation, the research team members will independently code the interviews and field notes and discuss 
data segments that are particularly rich or difficult to code. Team members will discuss and resolve divergent 
coding and interpretations of findings to ensure that codes are applied consistently. Analytical memos will 
extract and summarize findings following the domains of inquiry outlined above, in order to extract themes 
and central ideas that explain the meaning of the data. 
6.10.3 Power Calculations 
We have powered our trial to identify enough eligible adults for enrollment in the Aim 2 trial and to detect a 
difference of ≥10% in HIV prevention uptake between the two arms. We plan to mobilize a minimum of 5,000 
adults from a minimum of 16 drinking venue clusters (8 clusters, 60 venues, and 2,500 adults per trial arm). If 
we assume that ~20% of those mobilized are PWH or currently on PrEP/PEP, we expect ~4,000 adults 
mobilized to be eligible to initiate PrEP/PEP (~250 adults/cluster). Based on prior work61,77, we anticipate that 
up to 80% of those mobilized will present for screening in the 
HIV-focused arm. Also based on prior studies,12-14 we 
estimate that ~25% of adults offered prevention will initiate 
PrEP/PEP in the HIV-focused arm. Altogether, we anticipate 
20% prevention uptake in the HIV-focused arm. With a 
coefficient of variation (k=0.175), we will estimate having 
80% power to detect a ≥7.5% increase in prevention uptake 
in the multi-disease arm (2-sided, α=0.05). As shown in the 
Figure, these calculations are fairly robust to the uptake in 
the HIV-focused arm and the average number of participants 
per cluster. If, after drinking venue mapping, 32 drinking 
venue clusters (each with ~125 eligible participants) are 
selected as the unit of randomization, then we estimate 
having 80% power to detect a ≥5.6% increase. We expect 
these calculations to be conservative, because of the 
precision gained through stratified randomization and 
through covariate adjustment during the analysis. 
7. Healthy Living Intervention for HIV prevention (Aim 2) Trial 
Restatement of Aim 2: Determine the efficacy of the Healthy Living Intervention (HLI) to reduce heavy alcohol 
use vs. standard care (control) on retention in biomedical HIV prevention in a randomized trial among adults 
with heavy alcohol use. 
7.1 Study Design 
We will conduct a two-arm, individually randomized controlled trial of a brief alcohol counseling intervention 
adapted to a Ugandan and Kenyan context (the Healthy Living Intervention72) vs. control (standard alcohol 

Protocol Version: January 6, 2025 
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counseling per national MoH guidelines) on retention in biomedical HIV preventive care over 48 weeks among 
HIV-uninfected adults with heavy alcohol use initiating PrEP or PEP (Figure 5). 
7.2 Study Population & Eligibility Criteria 
We will recruit HIV-uninfected adults with heavy alcohol use at the time of initiation of PrEP or PEP within 
Dynamic Choice Prevention (delivered by the SAPPHIRE trial) and screen for trial eligibility, as follows: 
Inclusion: a) adult (≥18 years); b) HIV-uninfected (by rapid HIV antibody test); c) AUDIT-C score of ≥4 for men 
and ≥3 for women; d) attending a clinical visit for initiation of biomedical HIV prevention with oral PrEP, oral 
PEP, or the dapivirine vaginal ring; and e) has access to a mobile phone. 
Exclusion: a) ineligible for PrEP based on MoH guidelines104,105 (e.g., signs or symptoms concerning for acute 
HIV); b) intention to move away from the study community in the coming year; c) gross inebriation or inability 
to provide informed consent. 
7.3 Recruitment & Screening 
Process 
Study staff will recruit 
participants from the Aim 1 trial, 
from distribution of Aim 2 
recruitment cards, or from the 
ongoing SAPPHIRE trial, who 
initiate PrEP, the dapivirine ring 
or PEP and administer the 
standardized 3-question AUDIT-C 
tool to assess alcohol use.110 
Those with an AUDIT-C score of 
≥4 for men and ≥3 for women 
will be considered positive for 
heavy alcohol use and eligible for 
enrollment in the Aim 2 trial. 
Participants with AUDIT-C scores 
≥8 will be invited to participate and will also be referred to their physician for a higher level of care for 
potential alcohol use disorder, regardless of their Aim 2 trial randomization.  
 
7.4 Enrollment & Randomization 
Study staff will obtain written informed consent and administer a questionnaire to collect baseline data on 
socio-economic and demographic information, HIV risk behavior and alcohol use, and obtain a baseline blood 
draw. Staff will then randomize participants 1:1, stratified by country, study community and sex, to either the 
alcohol counseling intervention (HLI) or standard care. 
 
7.5 Study Groups 
a) Healthy Living Intervention (HLI): In this arm, participants will receive brief alcohol counseling based on the 
Healthy Women Healthy Living (HWHL) study,70 developed for women with HIV in the US, and adapted for use 
in a Ugandan (EXTEND)72 and Kenyan context (SAPPHIRE) as the HLI.   
The Healthy Living brief alcohol counseling intervention was developed using the Information, Motivation, and 
Behavioral skills (IMB) model, a framework in which information, motivation, and behavioral skills are key 
determinants of health behavior. In brief, in the intervention, information is provided about the harmful 
effects of alcohol use overall and on HIV risk, at baseline and during follow-up visits. Motivation is addressed 
Figure 5: Aim 2 Healthy Living Intervention for HIV Prevention Trial Schematic 

Protocol Version: January 6, 2025 
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via an interactive discussion of reasons to cut down on drinking (e.g., money saved when not spent on alcohol) 
and the selection of specific drinking goals, to increase the likelihood that intervention participants will be 
inclined to act on the information they have received. Behavioral skills are developed with discussions of 
specific strategies to overcome drinking triggers (e.g., resisting peer pressure to drink, identifying non-drinking 
activities to reduce boredom, and engaging a support person). The motivation and behavioral skills 
components are reinforced during booster calls and in-person follow-up sessions. 
b) Standard care (control): In this arm, participants will receive standard, brief unstructured advice regarding 
the health risks associated with heavy alcohol use, including risk of HIV acquisition.  
In both groups, participants will have flexible access to oral PrEP, the dapivirine vaginal ring (once available) 
and PEP via Dynamic Choice Prevention (DCP) service delivery. 
7.6 Procedures 
Following randomization, study staff will perform the following study procedures: 
1. Counseling: 
In the HLI group, trained counselors will deliver the baseline and 3-month in-person counseling using the HLI 
workbook, as well as mobile phone-delivered booster sessions at 3-, 6- and 9-weeks post-baseline. Counselors 
will also deliver in-person or phone booster sessions at 24, 36 and 48-weeks post-baseline. The counselors will 
be trained by a licensed clinical psychologist in techniques to conduct the alcohol counseling sessions; training 
will include mock counseling sessions, with procedures used in the EXTEND and SAPPHIRE trials. The in-person 
sessions will be audio-recorded and 15% will be reviewed for fidelity, using a checklist of intervention 
components as in previous alcohol intervention trials.111,112  
In the control group, study staff provide brief, standard of care advice regarding health risks associated with 
heavy alcohol use at baseline. In both groups, participants will receive PrEP/PEP adherence and HIV risk 
reduction counseling, provided through the SAPPHIRE trial (see Figure 5, above). 
2. Monitoring: All participants will be monitored at 4- and 12-weeks, and then every 12 weeks thereafter for 
48 weeks, with brief surveys regarding alcohol use (including AUDIT-C surveys). The week 4 monitoring visit 
will be conducted through SAPPHIRE DCP for the purpose of providing PrEP/PEP adherence and HIV risk 
reduction counseling; there will be no OPAL-specific surveys or activities at week 4. PrEP and PEP will be 
administered via enrollment in the SAPPHIRE trial. During the proposed study, the SAPPHIRE trial will be 
implementing the SAPPHIRE Dynamic Choice Prevention (DCP) intervention at each community’s health 
center, whereas the present Aim 2 trial will be evaluating the Healthy Living brief alcohol intervention on 
PrEP/PEP adherence among persons with heavy alcohol use at increased risk for HIV. Table 5 delineates the 
present (OPAL-East Africa) trial’s activities from the SAPPHIRE trial activities. 
 
Table 5: Delineation of OPAL trial study activities and SAPPHIRE trial activities 
 Key Study Activities 
OPAL Aim 2  
HLI Trial 
SAPPHIRE 
Trial 
Dynamic Choice Prevention: including initiation and maintenance of PrEP/PEP, 
adherence counseling and HIV-risk reduction counseling at 4 and 12 weeks, follow-up 
HIV testing during PrEP/PEP, pregnancy testing (for women), symptom screening for 
acute HIV, STI screening and follow-up creatinine testing 
 
X 
Health Living Intervention (brief alcohol counseling) 
X 
 
Brief alcohol use survey (AUDIT-C) at baseline, 12, 24, 36 and 48-weeks 
X 
 
PEth measurement (baseline and 48-weeks) 
X 
 
Hair testing for tenofovir 
X 
 
Aim 2 Qualitative Interviews 
X 
 
PrEP/PEP Adherence Counseling 
X 
X 
 

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Study staff will work closely with SAPPHIRE trial and health facility staff and document follow-up visits, PrEP 
discontinuations (and reasons for discontinuation), and oral PrEP refills/administration and PEP use. All Aim 2 
trial participants will also be provided a mobile number to call for PEP starts (7/days week, including holidays, 
provided by the SAPPHIRE trial). Any participants that test positive for HIV during follow-up will be referred for 
immediate initiation of ART at the local health center.  
3. Qualitative interviews: After completion of trial participation, study staff will recruit a subset of participants 
stratified by sex and prevention modality (oral PrEP, dapivirine ring PrEP, and PEP) from each arm, as well as a 
sample of persons who are eligible for the Aim 2 trial but decline enrollment, for in-depth semi-structured 
interviews to better understand barriers and facilitators to retention in biomedical HIV preventive services, 
including perceived effects of heavy alcohol use, the HLI (intervention) and Dynamic Choice Prevention. We 
will also explore preferences, barriers, and facilitators regarding provision of PrEP/PEP on-site at drinking 
venues in the community compared to clinic, following qualitative data collection as described in Aim 1. 
 
7.7 Measurements 
1. Biomedical HIV Prevention coverage: The primary outcome will be PrEP/PEP “prevention coverage” defined 
as the proportion of time at risk during 24 weeks of follow up or until study end that an individual is protected 
from HIV infection with either PrEP or PEP, as assessed by prescription refills (with secondary analyses 
integrating drug levels from hair samples113 for persons on oral PrEP). Prescription refill data will be collected 
from MoH medical and pharmacy records, augmented by OPAL trial case report forms, using procedures from 
the SAPPHIRE trial. Hair samples will be collected at 48 weeks among participants using oral PrEP. Each 
participant will be followed for 48 weeks; follow-up time will be censored at HIV seroconversion, death, or 
withdrawal from the trial. 
2. Secondary Outcomes: a) Alcohol use: Study staff will assess AUDIT-C scores (modified to refer to the prior 3 
months) with a standard drink guide adapted to local context at baseline and every 12-weeks post-baseline. 
Blood will also be collected, and dried blood spots prepared for phosphatidylethanol (PEth) testing at baseline 
and 48-weeks for confirmation of self-reported alcohol use. We will assess AUDIT-C,114 and PEth as continuous 
variables, and explore social desirability115 if AUDIT-C and PEth conclusions differ; b) PrEP/PEP “prevention 
coverage” (as defined above: see primary outcome) during 48 weeks of follow-up or until study end, as 
assessed by prescription refills and augmented by integrating drug levels from hair samples for persons on oral 
PrEP (as noted above); c) HIV seroconversion will be measured as documented rapid HIV antibody test 
positivity with Geenius confirmation116 or documented detectable HIV viral load, with rapid HIV testing at PrEP 
refill and injection visits, or completion of a course of PEP. 
3. In-depth semi-structured interviews: Using a similar approach to Aim 1, we will iteratively collect and 
rapidly analyze interview transcript data, continuing to randomly select participants within theoretically 
informed categories (e.g., not only study group but categories such as age group and level of alcohol use) until 
the data attain theoretical saturation. We anticipate that data in each study group will attain saturation with 
N=40 participants who chose oral PrEP/PEP or the dapivirine ring per study arm (N=80 total), plus an 
additional 20 adults who met eligibility criteria but declined trial enrollment (N=20 Aim 2 IDI-participants 
only).  An overview of qualitative studies for Aims 1 and 2 are shown in Table 6. 
Table 6. Overview of OPAL trial qualitative studies. 
Aim 
Behavior 
Study 
population 
Stratified random sampling strategy for in-
depth interviews 
Timing of in-depth 
interview 
Aim 1  
PrEP/PEP 
uptake 
Adults recruited 
from drinking 
venues who are 
eligible for 
PrEP/PEP 
(N=80) 
1. Sex: male/female 
2. Uptake: initiated or declined PrEP/PEP 
3. Aim 1 trial arm: multi-disease or HIV-focused 
recruitment 
Following clinic-
based screening for 
HIV and offer of 
PrEP/PEP 

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Aim 2 
PrEP/PEP 
adherence 
Adults with 
heavy alcohol 
use at 
increased risk 
of HIV (N=100) 
1. Sex: male/female 
2. Prevention modality: oral PrEP, dapivirine ring, 
or PEP 
3. Aim 2 trial participation: HLI [intervention] arm, 
control arm, or eligible but declined to participate 
in trial 
48-weeks after 
PrEP/PEP initiation 
 
7.8 Data Collection & Management 
Baseline survey data: Staff will collect questionnaire data using hand-held computers (tablets) or paper 
questionnaires (as back up, if tablets are not functioning, with subsequent data entry into computers or 
tablets). Data will be transferred via secure electronic transfer to our data center facilities in Kenya and/or 
Uganda and stored on a secure server.   
HIV Test Results: Staff working at the study community clinics will record all lab test results, including HIV 
antibody test results, and HIV diagnosis status information, under each participant’s study identification 
number (ID) in either paper lab logs or computers.  Data from these logs or devices will be transferred via a 
secure electronic transfer to our data center facilities in Kenya and/or Uganda and stored on a secure server. 
Qualitative Data: Staff will record interviews on audio devices using study IDs (not participant names), and 
transcribed interviews and translations will be data entered into appropriate software on password-protected 
study computers. Data from interviews will be transferred via a secure electronic transfer to our data center 
facility and stored on a secure server. 
7.9 Analysis 
1. Primary and secondary analyses: As in Aim 1, we will evaluate the intervention effects using TMLE, which 
provides precision and power gains over simple stratified approaches by adjusting not only for stratification 
factors but also for chance imbalance between randomized arms in additional baseline predictors of the 
outcome.107 We may also use longitudinal causal mediation analysis to explore reductions in alcohol use as a 
potential mediator of the HLI intervention on increased HIV prevention coverage.117,118 We will test the null 
hypothesis of no change in biomedical HIV prevention coverage due to the HLI with a two-sided test at the 5% 
significance level. 
 
2. Analysis of qualitative data: We will conduct analyses using the same analytic approach described in Aim 1. 
 
3. Power Calculations: We anticipate having 80% power to detect at least a 9.8% absolute increase in 
prevention coverage with a standard deviation of 0.35 and 200 participants/arm. Even with 25% attrition 
(from 200 down to 150 participants/arm) and higher than expected variability (e.g., standard deviation=0.40), 
these calculations suggest we would be well-powered to detect at least a 13% absolute increase in prevention 
coverage based on enrolling 400 participants in Aim 2 for measurement of the primary endpoint. 
8. Costing (Aim 3) 
Restatement of Aim 3. Determine the cost-effectiveness of interventions that increase biomedical HIV 
prevention uptake (Aim 1) and retention (Aim 2) among adults at high-risk for HIV who attend drinking 
venues. 
8.1 Study Population 
In Aim 3, we will evaluate the costs of delivering interventions to participants in Aims 1 and 2. No additional 
participants will be enrolled. 
 

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8.2 Measurements for Aim 3 
Costs: We will employ rigorous, time-driven, activity-based methods119 to determine intervention costs from 
the health system perspective. We will undertake micro-costing and time and motion (T&M) studies, using a 
uniform cost data collection protocol to quantify the resources needed to implement each intervention.120,121 
We will conduct two-week site visits in each community at three different times to assess the costs associated 
with each intervention component (e.g., training, implementation of bar-based recruitment, clinic-based 
screening, dynamic choice prevention, and HLI implementation). Cost will be organized in standard 
expenditure categories—personnel (e.g. wages, benefits and stipends), recurring goods (e.g. office supplies, 
testing supplies; PEP/PrEP medications, fuel), services (e.g. hiring advertisement, laboratory testing, utilities), 
equipment (e.g. vehicles, office equipment, computers, medical equipment) and facility costs (e.g. space 
rental).  Information will be obtained through examination of expenditure records, discussion with program 
managers and staff and observation of service delivery for a sample of interactions for each intervention 
activity. “Economic” costs (the true value of resources consumed or “opportunity cost”) will be assessed by 
identifying the value of subsidized resources using databases (e.g., wage rates) and, as needed, 3 price quotes 
from appropriate market sources. We will conduct T&M studies, using continuous self-reporting by providers, 
to allocate personnel effort toward each intervention component as well as to activities outside of 
intervention components. Personnel costs will be estimated as the sum of the product of resources (e.g., staff 
minutes) times unit costs. Costs for fixed costs (e.g., equipment) will be amortized on a straight-line basis over 
expected useful life and assume no salvage value.  
 
8.3 Analytic approach for Aim 3 
Costs: We will estimate the total incremental cost and the incremental cost per participant associated with 
each intervention. Costs will be organized in standard expenditure categories.  
Efficiency: For each intervention, we will estimate the incremental cost per additional person: a) initiated on 
biomedical prevention b) identified with untreated HIV; c) linked to ART; and d) retained in PrEP/PEP services.  
Health Effects: We will develop a decision model to explicitly define the paths and estimate the health effects 
associated with the health states defined in Aims 1 and 2 (i.e., heavy alcohol use, prevention uptake and 
adherence, HIV status, and ART use). We will use information from this study, our previous studies and the 
scientific literature to estimate the community prevalence of HIV, the risk of acquisition of HIV among 
individuals in our study, reduction in risk associated with PrEP/PEP uptake and adherence, reduction in risk 
associated with reduction in heavy alcohol use, morbidity and mortality associated with heavy alcohol use 
and/or HIV, and the reduction in morbidity and mortality associated with reduction in heavy alcohol use 
and/or treatment for HIV. We will translate each health state into a standard metric of burden of disease, 
Disability-Adjusted Life Years (DALYs),122 which combines morbidity (and associated disability) with premature 
mortality (lost “life years”), as well as HIV transmissions averted in our study and if each intervention were 
scaled up to a population of 100,000 over 5, 10 and 20 years.   
Cost-Effectiveness Analysis (CEA): We will compute the incremental cost per DALY averted (our incremental 
cost-effectiveness ratio, ICER) and per HIV transmission averted for each intervention in our study sample and 
if the intervention were scaled up in a population of 100,000. We will compute these estimates during the 
short (during the trial) and long term (5, 10 and 20 years). Costs will reflect net cost per participant by 
adjusting for added or averted health care costs over each period. Future costs and DALYs will be discounted 
at 3% per year. We will conduct extensive sensitivity analysis to estimate the variability of each of our 
estimates. 
9. Human Subjects 

Protocol Version: January 6, 2025 
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9.1 Risks to Human Subjects 
Potential risks: There are relatively few risks to study participants. The primary risks involved in study 
participation are inadvertent HIV status disclosure or HIV risk factor or heavy alcohol use disclosure with 
associated stigma. Given the sensitive and private nature of the HIV test results to be collected during 
implementation of the research aims, extra cautions will be put in place to ensure maintenance of privacy, 
confidentiality, and security of the data obtained. Data collection and storage procedures will include the use 
of encrypted, password-protected devices and servers.  
PrEP/PEP Use. There are no “experimental” drugs in this study. We will be measuring the uptake of standard 
and approved drugs – TDF/3TC or TDF/FTC, the dapivirine vaginal ring for PrEP, and 3-drug antiretroviral 
regimens for 28-day PEP – that will be provided through the Kenya and Uganda health systems. The risk level 
associated with the offer and implementation of country guideline PrEP and PEP services to participants is 
classified as “Minimal”, consisting of: blood sampling, hair collection for PrEP drug concentration 
measurement, and low risk behavioral questions.  
Hair Collection: The risk of a cut to the skin from scissors during hair collection is extremely low. Our 
colleagues at UCSF have been collecting small hair samples from HIV-positive participants on antiretroviral 
therapy in the NIH- funded Women’s Interagency HIV Study (WIHS), a large multicenter prospective study of 
HIV-infected and at-risk HIV-uninfected women, every six months since 2002. They have collected over 20,000 
hair specimens in the WIHS via the collection procedure outlined in the research plan above and have never 
had an injury or any other adverse event reported from the collection process. The risk of cosmetic effects 
from hair collection is also extremely low. The human scalp loses an average of 100 strands of hair per day, so 
the amount of hair we propose to collect for this project is less than what a participant’s scalp would typically 
lose on an average day. Moreover, the size of the hair sample collected for the tenofovir assays is extremely 
small and collection is usually easily accomplished from participants with short or limited amounts of hair. 
Over the past 12 years of collecting hair from participants in the WIHS cohort, our colleagues have never 
registered any complaints that the process has been disruptive to hair styles, and there are high rates of 
acceptability of hair collection in the overall study (ranging from 88-97%, depending on the site). We have also 
been collecting hair from HIV-infected women and their infants in Uganda,123 HIV-infected pregnant women in 
South Africa, persons with HIV and heavy alcohol use in Uganda (in the DIPT trial)100 and participants in PrEP 
trials.12 We have experienced high rates of acceptability of hair collection in each of these studies (~95%), have 
not registered any reports of adverse events, including accidental skin cuts or disruption of hair styles, in any 
of these studies. 
Phlebotomy associated risks include bruising, bleeding, infection, phlebitis, and pain. Bruising is common, 
minor pain with needle stick is universal, the other risks are rare. 
Psychological stress could be caused by the interview in which participants will be asked sensitive questions 
regarding HIV, alcohol use, sexual behavior, and socio-economic status. Distress caused by the length of the 
interview is also possible. Study staff will be trained to address these issues with a calm, non-judgmental 
attitude. These minimal risks are not likely and will be minimized further by only selecting patients who 
understand the study and are willing to participate. 
Potential risk of exposure to SARS-CoV-2 during clinic visits: SARS-CoV-2 virus is easily transmitted from person-
to-person through infected respiratory droplets/airborne droplet nuclei via sneezing, coughing, talking, singing 
or through handling fomites recently contaminated by infected droplets. We will ensure that participants are 
well-informed regarding the potential risk of SARS-CoV-2 exposure when leaving their homes and visiting 
health centers and ensure a safe clinical environment for participants and study staff members. 
9.2 Adequacy of protection against risks 
Informed Consent: Written informed consent (Aims 1 and 2) will be obtained from all participants by trained 
research assistants. In Aim 2, the research assistants will find a private place; carefully explain the nature and 

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purpose of the study to each potential participant, potential risks and benefits, and will describe the study 
groups to which participants will be randomized. The consent process will be offered in English or local 
dialects (as per the participant’s preferences). Our study team has prior experience in obtaining informed 
consent for research and clinical trials within the cultural contexts of Kenya and Uganda. The informed 
consent procedure has been designed to maximize understanding of potential risks. Participants will be told 
that they may decline to participate at any point. 
Maintaining privacy and avoiding stigmatization: Recruitment at drinking venues (Aim 1 only) will occur within 
the eight study communities (4 in Kenya and 4 in Uganda), and study staff will be trained on community-based 
mobilization and engaging with adults at drinking venues safely and in a professional, non-judgmental manner 
to reduce stigmatizing patrons and workers at drinking venues, based on our prior experience conducting 
mobilization activities at these sites in >2000 adults in Kenya and Uganda to date. Aims 1 and 2 study visits 
with participants to screen, consent, enroll and follow-up participants will occur at the eight health centers 
participating in the SAPPHIRE (Phase B) trial, four in Kenya and four in Uganda, in order to reduce the unlikely 
possibility of stigmatizing study participants. Every effort will be made to ensure privacy is maintained during 
administration of questionnaires. Participants will be given a unique study identification number (their study 
ID number). Participants’ names and study number, and thus their HIV status and name, will never appear in a 
dataset together.  
Minimizing coercion to participate in research: To minimize the likelihood of persons feeling pressured to 
participate in research we will emphasize the concepts of individual voluntary choice to participate in research 
and the need for individuals to respect the voluntary choice of others during the process of obtaining 
informed consent. Study participants will also be informed that study enrollment can be stopped at any point 
during the study at their request.  
Data Security: All information will be recorded using study identification numbers, rather than participant 
names, and stored securely in locked offices at the study data centers. All study computers are password 
encrypted and kept in locked offices.  
SARS-CoV-2 Biosafety: We will follow MOH requirements and current local guidelines for infection control in 
clinical settings. To minimize any risk to participants or study staff, we will take the following precautions:  
a) Participants: Interviews will take place in well-ventilated (by natural ventilation) clinical rooms.  Face masks 
will be provided on-site for all participant interactions, in accordance local Kenyan and Ugandan guidelines for 
clinical care. Individuals may choose to wear a face mask to reduce droplet exposure during study visits.  
b) Study staff: To minimize risk to study staff from potentially SARS-CoV-2 virus infected participants, masks 
will be made available to all participants (regardless of symptoms). Study staff will be offered SARS-CoV-2 
vaccination (according to national guidelines in Kenya and Uganda), if not already vaccinated, and provided 
access to isolation masks to wear during participant interactions if they choose. All study staff will perform 
handwashing or alcohol-based hand disinfectant use between each participant encounter. Any face shield or 
mask that is contaminated by visible droplets (e.g. participant sneezes or coughs on the face mask/shield) will 
be disposed of and replaced or disinfected after that participant’s encounter. Study staff will use disinfectant 
solution and paper towels or wipes to clean any electronic tablets or other equipment that is touched by study 
participants after each participant encounter. 
Biosafety – Universal precautions: All study staff will be trained on universal precautions according to WHO 
guidelines to help prevent the spread of infectious diseases. Staff will perform handwashing or use an alcohol-
based hand sanitizer before and after participant encounters, and after removing gloves. Staff will wear 
personal protective equipment like gloves, masks, and face shields as applicable during sample collection and 
processing to avoid exposure to blood and other bodily fluids. All sharps will be properly disposed of in sharp 
boxes which will be provided. Surfaces used for testing of participant specimens on-site will be cleaned daily. 
Medical waste will be conducted according to the health facility’s medical waste disposal procedures. 

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Institutional Review Board Approval: Approval from the UCSF institutional review board, the Kenyan 
institutional review boards (the Scientific Ethics Review Unit [SERU] at KEMRI), and the Ugandan institutional 
review boards (the School of Medicine Research and Ethics Committee [SOMREC], and the Uganda National 
Council for Science and Technology [UNCST]) will be obtained prior to initiation of study activities. All study 
staff are required to undergo training in human subjects’ research, and good clinical practice (GCP).  
 
9.3 Potential benefits 
The primary benefits of the proposed research to Aim 1 participants are support in engaging with HIV testing 
and biomedical HIV prevention in adults at increased risk of infection, along with post-test counseling and 
referral to HIV care if HIV-infected or prevention services if HIV-uninfected. For Aim 2 participants, the primary 
benefits are support in adherence to PrEP/PEP and retention in biomedical HIV prevention services, as well as 
counseling regarding heavy alcohol use.  The benefits for the community may include increased engagement 
in HIV testing and biomedical prevention by adults at high risk of infection, decreases in heavy alcohol use 
among Aim 2 participants, and early diagnosis and prompt linkage to antiretroviral therapy for those who HIV-
positive.  
 
9.4 Importance of the knowledge to be gained 
The minimal risk in this study is far outweighed by the importance of knowledge to be gained. Given the public 
health importance of improving uptake and use of biomedical HIV prevention among adults at drinking venues 
who are at high risk of infection, and reducing heavy alcohol use, it is vital to have effective, low-cost 
interventions that can be used to achieve these objectives. 
 
9.5 Study Scientific Advisory Committee 
The findings of this will be shared with the SAPPHIRE trial (NCT04810650) advisory scientific committee, as the 
OPAL trial is being implemented within the larger SAPPHIRE community cluster randomized trial. The 
SAPPHIRE trial scientific advisory committee meets annually and includes experts in HIV prevention and 
treatment; experts in PrEP and youth in Uganda and Kenya; and experts in economics/development in East 
Africa. 
10. Publication of Research Findings 
The findings from this study may be published in a medical journal. No individual identities will be used in any 
reports or publications resulting from the study. The researchers will publish results of the study in accordance 
with NIAAA, UCSF, Makerere University, UNCST and SERU/KEMRI guidelines. 
 
 

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