Integrated Care Delivery for HIV Prevention and Treatment in Adolescent Girls and Young Women in Zambia: Protocol for a Cluster-Randomized Controlled Trial

Background Among countries in sub-Saharan Africa, Zambia has one of the highest incidences of HIV. Adolescent girls and young women (AGYW) are a particularly affected group because of their social and economic vulnerability. Objective The goal of this study is to test a multilevel package of interventions at the community and health system levels in Zambia in order to connect AGYW with a source of regular care, which will in turn allow for sustainable, successful implementation of regular HIV testing and adherence to antiretroviral treatment. Methods We will adapt prior tools to create the SHIELD (Support for HIV Integrated Education, Linkages to Care, and Destigmatization) intervention to educate and empower Zambian AGYW of 10-24 years of age and their families and to create community-based youth clubs to foster peer support. We will also develop integrated wellness care clinics to offer a youth-friendly environment that provides tailored clinical services. We will perform formative research, including focus groups and in-depth interviews, among AGYW, caregivers, and stakeholders to help inform the development and tailoring of the interventions. A cluster-randomized controlled trial will be implemented in Lusaka, with six clinic catchment areas randomized into three groups: zones with integrated wellness care clinics and SHIELD intervention, zones with only SHIELD intervention, and control zones with no intervention. We will assess HIV testing among the HIV-negative or unknown (HIV-/u) cohort, and retention in care along with viral load suppression will be evaluated in the HIV-positive (HIV+) cohort. We will use in-depth interviews and surveys to collect staff and stakeholder feedback after the trial. Cost-effectiveness of the interventions and return-on-investment impacts will be quantified using a microsimulation model. Results Interim results are expected in 2021, and the final results are expected in 2022. If this multilevel intervention is successful in establishing a comprehensive care continuum for HIV-affected AGYW, the Zambian Ministry of Health may advocate for expansion to additional settings to support national scale-up. Conclusions This integrated service delivery model can also be a platform to implement additional preventive services, so HIV-/u and HIV+ AGYW can receive comprehensive, integrated services. Trial Registration ClinicalTrials.gov NCT03995953; https://clinicaltrials.gov/ct2/show/NCT03995953 International Registered Report Identifier (IRRID) PRR1-10.2196/15314

1 UG3 HD096908-01 3 ZHD1 DSR-N (52) SUBRAMANIAN, S analysis to evaluate and describe impact along the HIV care continuum and disseminate findings to national partners and the international community. This integrated service delivery model, if successful, can also serve as a platform to implement additional preventive services, including pre-exposure prophylaxis (PrEP) for high-risk AGYW, which is currently under consideration by the government.

PUBLIC HEALTH RELEVANCE:
Zambia has one of the highest incidences of HIV in the world, and adolescent girls and young women (AGYW) are a particularly affected group because of their social and economic vulnerability. The overall goal of this study is to test a multilevel package of interventions at the community and health system levels to connect AGYW with a source of regular care to provide a sustainable platform for successful implementation of regular HIV testing and adherence to antiviral treatment. This approach will avoid siloes and provide a comprehensive HIV care continuum with a holistic and integrated health care delivery approach that is recommended by the Zambian HIV guidelines.

CRITIQUE 1
Significance: 3 Investigator(s): 1 Innovation: 2 Approach: 3 Environment: 1 Overall Impact: This high impact application addresses low testing and poor adherence to ART therapy among AGYW in Zambia by seeking to adapt a successful cervical cancer screening program to integrate services such as providing the HPV vaccine and HIV testing to young women, and linking seroconverters to care. If successful, this could serve as an important approach to identify HIV-infected and at-risk AGYW for additional services. Using the IWC clinics as an entry point to testing and care, and the DCE are innovative approaches. The team is led by a highly accomplished and well-trained investigator, Dr. Subramanian, and she will be assisted by an excellent team of collaborators with welldefined roles. A key weakness that raised concerns is the SHEILD intervention and the potential for its sustainability beyond the study period. Another concern is with the discrete choice experiments which will use the same sample that participates in the randomized trial. Will this introduce bias in the findings?
An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance:
Strengths  The scientific premise for this study is strong because while HIV prevalence is high among adolescent girls and young women (AGYW) aged 15-24 in Zambia, they are also less likely to test and adhere to ART therapy than older women.
 This application seeks to adapt a successful cervical cancer screening program to integrate services such as providing the HPV vaccine and HIV testing to young women. If successful, this could serve as an important approach to identify HIV-infected and at-risk AGYW for additional services.
Weaknesses 1 UG3 HD096908-01 4 ZHD1 DSR-N (52) SUBRAMANIAN, S  The potential for the sustainability of the SHIELD intervention is unclear. Previous studies have found that programs that include youth clubs are not sustainable beyond the study period or when donor funding ends. How will this be addressed in the study?

Investigator(s):
Strengths  Dr. Subramanian is an accomplished investigator who is very well suited to lead the study.
 An excellent team of seasoned collaborators with commendable achievements, expertise, and skills.
Weaknesses  None noted.

Innovation:
Strengths  The approach to use integrated wellness clinics (IWCs)to provide HIV testing, HIV treatment (in coordination with the HIV clinic and dispensary in the same facility), HPV vaccination, and other SRH services to AGYW is innovative.
 Discrete Choice Experiments is an innovative method to understand how AGYW value services and attributes.

Weaknesses
 Justification is not provided for testing the combination of the SHIELD and IWC interventions.

Approach:
Strengths  The timeline for the UG3 and UH3 and the Transition Milestones phases are well-reasoned, feasible, and appropriate.
 The strategy for UG3-1 is well developed and reasonable.
 Focus on AGYW for the proposed study is appropriate and justified.
 Establishing a sampling frame will lead to enrollment of adequate numbers of AGYW.
 Assigning peer navigators to specific zones will help insure recruitment of discrete, nonduplicated subjects.

Weaknesses
 The same sample that participates in the DCE will also participate in the randomized trial. Will this introduce bias in the findings?
 It is not clear from the application the goal of the SHIELD intervention separate from that of the IWC.
 Rigor of the analytical design is in question because the application does not adequately describe how the separate effects of the SHIELD intervention on AGYW will be assessed i.e. direct effect of the intervention on AGYW and indirect effect on AGYW through the intervention effects on caregivers and other family members.
1 UG3 HD096908-01 5 ZHD1 DSR-N (52) SUBRAMANIAN, S  Scalability and sustainability, particularly of the SHIELD intervention is doubtful. The likelihood of scalability and sustainability is greater for the IWC approach.

Environment:
Strengths  RTI, Population Council, and UNC-Zambia offer exceptional environments that will ensure success.
Weaknesses  None noted.  Adequate plans are in place to enroll minors and for referral of seroconverters and highrisk participants.
 Adequate plans to protect participant information.

Protections for Human Subjects:
Data and Safety Monitoring Plan (Applicable for Clinical Trials Only):

Inclusion of Women, Minorities and Children:
 Sex/Gender: An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance:
Strengths  Directly addresses the PATCH3 targets, in particular, challenges with engaging and providing supportive care to young women.
 The AIMS are ambitious and potentially transformative.
 The SHIELD, community-based intervention appears particularly appealing.

Weaknesses
 The investigators first acknowledge the problems with "HIV clinics' and stigma, but then propose nesting the work in existing HIV clinics. In their defense, they will compare with communitybased interventions.

Investigator(s):
Strengths  Very strong investigators, led by Dr. Subramanaian. They emanate from strong programs at RTI, Population Council, UNC, and Zambian MOH. -A wisely chosen set of collaborators.
 Key experience and accomplishments in critical, central areas of the project.

Innovation:
Strengths  The SHIELD community-based tool appears innovative and well thought out.

Weaknesses
 This is both a strength and weakness: all elements of the project have essentially been created and are in the field to some extent. While there will be some tool building, this is essentially implementation of existing tools.

Approach:
Strengths  Partnership between strong NGOs and the Zambian MOH -bodes well for future implementation if successful.
 Experts in clinical implementation, social-behavioral concepts, and stigma.
 Rigorous UH stage testing of tools and concepts.
 Interesting linkage of core implementation science (PEPFAR/USAID) and behavioral implementation research (NIH/CDC).
 Nice study of cost and cost effectiveness at the UH3 level -worry that this won't be scalable.

Weaknesses
 A convincing argument has not been provided that the IWC clinics are sufficiently different from ART clinics.
 Will the program primarily recruits those open to care and interventions and not be fully representative of the community at large? No analysis of those who refuse participation which may be very important for future planning and programmatic design. Consider dressing this more formally in the UG3-2 sampling frame establishment.
 The proposed DCE selections seem obvious -won't there be a groundswell towards no wait time, high level privacy, flexible hours, and very low to no cost of care?
 Differing PN support for the zone clusters may affect outcomes.
 Addresses women only -very important, but misses half of the critical population.

Strengths
 Very strong environment with established programmatic infrastructure.
 Linkage to local governing and oversight bodies. This is an interesting study targeting adolescent girls and young women in Zambia to increase HIV testing, linkage to care, retention in care, and viral suppression by developing Integrated Wellness Clinics based on previous cervical cancer screening programs. This is a collaborative effort by the Zambian Ministry of Health, RTI International, The Population Council, and the University of North Carolina. The main goals are to increase HIV testing by HIV negative and unknown youth and for those living with HIV to keep them engaged in care and support adherence/viral suppression. This study will take advantage of a HPV vaccine role out. This is a strong proposal from a talented and experienced group of investigators that will expand on existing infrastructure and collaborations within the Zambian Ministry of Health. It would be strengthened if the proposal contained preliminary date or information on the initial cervical cancer screening study to evaluate potential enrollment and feasibility of enrolling 1800 individuals in 1 year.

Weaknesses
An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance:
Strengths  Targeting high risk population of adolescent girls and young women in Zambia.

 Targeting populations living with and without HIV
 Expanding on existing infrastructure and working with the national department of health.
 Analysis of efficacy as well as sustainability and cost effectiveness Weaknesses  The intervention is only targeting females; therefore, does not address the male population or structural processes involved in new infections although this still fits within the RFA.
 No mention of prevention services for those who are HIV negative other than uptake of HIV testing. This seems like a missed opportunity to offer expanded prevention services or PrEP, or guage PrEP interest if not yet available in Zambia. Weaknesses  The research team is large and quite diverse. The proposal does not indicate how the investigators will interact and how frequent they will meet.

Investigator(s):
 Since this is within the Zambian infrastructure it may not have generalizability outside of this setting.

Innovation:
Strengths  Using existing infrastructure and collaborations that were used for cervical cancer screening intervention.
 The use of discrete choice experiments is an innovative method of intervention design for youthfriendly services.
 Development of age based developmental interventions for 5 different age groups Weaknesses 4. Approach:

Strengths
 The SHIELD intervention is theory based and will be developed with the use of community and youth advisory boards based on existing evidence based interventions Stepping Stones and Families Matter!  Weekly meeting with peer navigators to monitor fidelity of the intervention.
 The use of voice-enabled components and tablets with headphones to reduce stigma and assist with younger adolescents who may not be as literate.
 Given the complexity of the interventions a cluster randomized trial is appropriate.
 The use of propensity scoring to adjust for baseline differences in the cluster sample is a strength.
 The primary endpoints of retention in care and viral suppression are a strength.
 The investigators will be conducting a cost-effective analysis using previously validated models.

Weaknesses
 It is not clear how the discrete choice experiment attributes and levels were chosen. Although the attributes seem important the levels are less clear. When tailoring youth-friendly services there are potential other factors that may influence adolescent engagement.
 Enrolling 1800 individuals in 12 months while completing Aims UG3 -2 and UG3 -3 to meet the UG3 milestone seems overly ambitious. It would be strengthened if the investigators documented prior success in such enrollment. ZHD1 DSR-N (52) SUBRAMANIAN, S  There is no preliminary data presented making it difficult to determine the feasibility of such a large and rapid enrollment.

Environment:
Strengths  Zambian Ministry of Health, RTI International, The Population Council, and the University of North Carolina have sufficient resources to conduct this proposal and have collaborated together previously and provide strong letters of support.
 The research team has more than a decade of experience working in Zambia with the target population.