Adolescent transition to adult care for HIV-infected adolescents in Kenya (ATTACH): Study protocol for a hybrid effectiveness-implementation cluster randomised trial

Introduction Successfully transitioning adolescents to adult HIV care is critical for optimising outcomes. Disclosure of HIV status, a prerequisite to transition, remains suboptimal in sub-Saharan Africa. Few interventions have addressed both disclosure and transition. An adolescent transition package (ATP) that combines disclosure and transition tools could support transition and improve outcomes. Methods and analysis In this hybrid type 1 effectiveness-implementation cluster randomised controlled trial, 10 HIV clinics with an estimated ≥100 adolescents and young adults age 10-24 living with HIV (ALWHIV) in Kenya will be randomised to implement the ATP and compared with 10 clinics receiving standard of care. The ATP includes provider tools to assist disclosure and transition. Healthcare providers at intervention clinics will receive training on ATP use and support to adapt it through continuous quality improvement cycles over the initial 6 months of the study, with continued implementation for 1 year. The primary outcome is transition readiness among ALWHIV ages 15-24 years, assessed 6 monthly using a 22-item readiness score. Secondary outcomes including retention and viral suppression among ALWHIV at the end of the intervention period (month 18), implementation outcomes (acceptability, feasibility, fidelity, coverage and penetration) and programme costs complement effectiveness outcomes. The primary analysis will be intent to treat, using mixed-effects linear regression models to compare transition readiness scores (overall and by domain (HIV literacy, self-management, communication, support)) over time in control and intervention sites with adjustment for multiple testing, accounting for clustering by clinic and repeated assessments. We will estimate the coefficients and 95% CIs with a two-sided α=0.05. Ethics and dissemination The study was approved by the University of Washington Institutional Review Board and the Kenyatta National Hospital Ethics and Research Committee. Study results will be shared with participating facilities, county and national policy-makers. Trials registration number NCT03574129; Pre-results. The adolescent transition to adult care for HIV infected adolescents (ATTACH) study aims to determine the effectiveness of an ATP using a hybrid type 1 effectiveness-implementation cluster randomised controlled trial (RCT) design in 20 HIV clinics in Kenya. A hybrid type 1 approach allows testing an intervention’s effects on clinical outcomes while simultaneously understanding factors that influence effective implementation36 (figure 1). A cluster RCT design was chosen as the intervention will be implemented at the clinic level. The ATP will be administered in 10 randomly selected intervention sites. Standard-of-care practices for disclosure and transition, consistent with Kenyan national guidelines and clinical care policies, will continue in the 10 control sites.34 37 Standard of care practices include age-based disclosure and transition assessments, including job aids to remind clinicians to explore disclosure and transition topics at clinic visits. Study time line and time point for assessment of effectiveness and implementation outcomes. Prior to trial implementation, data on organisation climate, patient satisfaction and baseline effectiveness outcomes are collected. In the first 6 months of the trial implementation outcomes are continuously evaluated. Effectiveness outcomes are measured 1 year after ATP implementation. Implementation outcomes are measured at 1 year (microcosting) and at the end of ATP implementation. ATP, adolescent transition package; Prior to the RCT, 102 clinics in 26 counties in Kenya participated in a clinic survey and electronic medical records (EMR) abstraction to evaluate disclosure and transition services available, correlates of successful transition and inform ATP tool development. The survey results have been reported previously and were incorporated in ATP development meetings.34 Clinics were randomly selected from ~300 HIV clinics in Kenya that used EMR systems in 2016 and had ≥300 total (including adults, adolescents and children) active patients (estimated at least 30 adolescents) enrolled in HIV care. Twenty RCT sites were selected from 32 HIV clinics that had an estimated ≥100 adolescents and young adults (AYA) age 10–24 years and were in the four counties participating in the pretrial surveys with the highest number of ALWHIV (Homa Bay, Nairobi, Kajiado and Nakuru counties) (figure 2). Specific clinic adolescent volumes were obtained from national viral load registers and data abstractions from EMR records in individual clinics. Where clinics had fewer than 100 ALWHIV, they were replaced with other clinics in the county that did not participate in the pre-trial surveys. For Homa Bay County, of the initial 15 clinics that met selection criteria; one clinic was excluded because the clinic size (1700 enrolled adolescents) was much higher than the other clinics and would likely have undue influence on the results, and another 8 with the lowest number of ALWHIV were excluded. In Nairobi and Kajiado, three new clinics were included due to low numbers of ALWHIV or logistical concerns due to the presence of other transition related studies (figure 2). The final list of sites is available in online supplemental material appendix 1. Site selection criteria and reasons for inclusion and exclusion. From 300 clinics using EMR systems and that had >300 enrolled clients in 2016, we randomly selected 102 clinics, then 32 clinics in 4 counties with the highest HIV burden. Clinics found to have few AYA, logistically difficult to conduct the study due to ongoing studies were replaced to a final list of twenty clinics, ten intervention and 10 control sites across four counties. AYA, adolescents and young adults; EMR, electronic medical records. bmjopen-2020-039972supp001.pdf Clinics were randomised using computer generated random numbers to either intervention or control status, using restricted randomisation. Restriction was performed to balance clinics by county and estimated number of ALWHIV (<200, 201–400, 401–500 and >500). Randomisation was performed at the University of Washington by a biostatistician with access only to the clinic characteristics of interest. After randomisation, the list of clinics with their allocation arm was sent to the study team. The intervention is administered at the clinic-level, therefore, it is not possible to blind participating clinics or study team members. The ATP will include two evidence-based interventions. The validated Namibia HIV Disclosure Intervention38 consists of a disclosure intervention comic book ‘Why I take my medicine’, HCW training material, a disclosure readiness assessment, and a disclosure tracking tool (to be used with ALWHIV over 10 years of age) (cover page and select pages presented in online supplemental material appendix 2 (full material available on request: email [email protected])). The disclosure intervention progresses from incomplete to complete disclosure using a narrative about soldiers fighting the battle of infection as the rationale for taking medicine. The transition intervention is an adapted transition toolkit consisting of a systematic transition guide ‘Taking Charge’, tracking tool to monitor individual progress and a readiness assessment tool (transition guide cover page and select pages presented in online supplemental material appendix 3 (full material available on request: email [email protected])). The transition intervention will be administered to all ALWHIV ages ≥15 years who know their HIV status. The transition toolkit was informed by existing tools, including the US-based ‘Got Transition’ tool, USAID tools and qualitative work with HCWs, policy-makers, adolescents and caregivers31–33 and supported by evidence that structured transition programmes improve transition outcomes.30 For this study, core elements of transition were contextually and culturally adapted to develop the ‘Taking Charge’ transition intervention at an adolescent stakeholder’s workshop in Kenya.3 The ATP will be implemented during regularly scheduled clinic visits with periodic assessments as described in table 1 (adapted Standard Protocol Items Recommendations for Interventional Trials checklist) and has been translated to two local languages (Swahili and Luo). HCWs working in the HIV clinic including doctors, clinical officers, nurses, counsellors, social workers and peer leaders who are involved in adolescent care will participate in intervention delivery. Adapted Standard Protocol Items Recommendations for Interventional Trials *Time points for assessing primary outcome. †Bimonthly for the first 6 months. EMR, electronic medical records; HCWs, healthcare workers. We have previously described varying transition and disclosure practices by clinic, with majority of clinics adopting specific adolescent clinic days and varying ages of transition to adult care,34 and no differentiation of adolescents with perinatally or behaviourally acquired HIV. Typically for disclosure, caregivers give permission for disclosure processes to begin. For transition, national guidelines recommend an age-based transition approach focusing on HIV disclosure and basic HIV literacy among adolescents age 10–12, and importance of medication adherence and participation in support groups (age 13–19).37 All ALWHIV aged 10–24 years attending the selected clinics will be eligible to participate in the study. The intervention will be offered based on disclosure status and age. ALWHIV who have not attained full disclosure will be offered the disclosure intervention, while those age 15 years and above will be offered the transition intervention. This is because the intervention period (12–18 months) is not long enough to observe adolescents passing from disclosure (early adolescence: 10–13 years) to transition preparation (middle adolescence: 13–17 years) to effective transition (late adolescence/young adulthood: 18–24 years). Permission will be sought from county and clinic administrators for clinic participation. Separate study training will be conducted for intervention and control sites. HCWs from intervention clinics will be trained on the intervention procedures and supported to implement the ATP by the study team. During the first 6 months of the trial, clinics will participate in twice-monthly continuous quality improvement (CQI) meetings that use modified plan-do-study-act cycles for ATP adaptation at each clinic. CQI meetings are used to review key performance indicators at a clinic level (eg, number of trained HCWs providing the intervention, number of adolescents exposed to the intervention) to identify opportunities to optimise intervention delivery. Attendees of CQI meetings will complete surveys to assess implementation challenges, successes and outcomes. Control sites will be trained on study related data collection. All ALWHIV age 10–19 will be assessed by clinic staff to determine disclosure status. Caregivers and adolescents in intervention sites who have not reached full disclosure will be offered the disclosure intervention and will be followed up until they reach full disclosure or end of study period. Those in control sites will be offered standard of care disclosure procedures and similarly followed up. All disclosure tools and outcomes will be administered and assessed by clinic staff. The study team will support retention by phone calls in all sites to remind ALWHIV to attend clinic visits if not already part of regular care. Caregivers of ALWHIV will review disclosure material and will give consent to allow disclosure procedures with the adolescent. Disclosure status will be assessed at every visit and caregiver disclosure readiness information reviewed every 6 months. ALWHIV age 15–24 who have reached full disclosure will be recruited to participate in the transition intervention by clinic staff during their scheduled clinic visits. Prior to exposure to the transition intervention, informed consent will be obtained by study staff from individual ALWHIV for study staff administered transition readiness assessments conducted at baseline, 6 and 12 months. Since ALWHIV age 15 and above frequently come to clinic alone, the study has obtained approval for waiver of parental consent for those under 18 years (the legal age of consent in Kenya). All other intervention materials (the systematic transition guide ‘Taking Charge’ and transition guide tracking tool) will be implemented by clinic staff. Enrolled ALWHIV in intervention sites will be individually monitored for progress through the chapters in the transition guide. Retention and viral suppression will be determined through medical record abstraction. Data quality checks will be routinely conducted to ensure EMR records match viral load data. Study staff will collect data on transfers to adult clinic or clinic days (specific day of the week dedicated to adolescent care) and monitor post-transfer retention. HCWs will participate in quantitative and qualitative data collection. At baseline, HCWs will complete an organisational readiness for implementation change39 40 assessment before intervention implementation to quantify attitudes and beliefs that may impact later-stage implementation outcomes. At 6 and 18 months after beginning of ATP implementation, HCWs will be invited to participate in focus group discussions (FGDs) and complete quantitative surveys to identify factors influencing effective implementation. We will evaluate determinants of later-stage implementation outcomes including intervention coverage, penetration, and fidelity. HCW FGDs and survey questions will be guided by the Consolidated Framework for Implementation Research (CFIR).41 At the end of the intervention period, a subset of adolescents, caregivers and HCWs from clinics will participate in anonymous post-trial surveys, and post-trial in-depth interviews (IDIs) and FGDs to measure satisfaction and implementation outcomes. Adolescents and caregivers participating in surveys will be randomly selected, while HCW surveys will include all available HCWs from study clinics. IDIs will use stratified purposive sampling to recruit adolescents with varied modes of HIV transmission (perinatal or behavioural), age, and transition status (transitioned or not). FGDs will be conducted with HCWs from intervention sites, and additional IDIs will be conducted with a subset of HCWs from low and high performing intervention sites. For costing and cost-effectiveness analyses, HCWs will be interviewed and observed to assess the average time needed to complete the ATP intervention. Time in motion observations will be conducted and variability in clinic flow assessed to inform efficiency assumptions. Up to 200 HCW (20 per intervention clinic) working in ALWHIV clinics and who are willing to participate will complete implementation surveys. The primary outcome will be assessed using a 22-item scale that measures adolescent readiness to transition to adult care. The scale has questions measuring attainment of knowledge and skills to navigate adult care systems. The scale is divided into four domains: HIV literacy (maximum score 5), self-management (maximum score 9), communication (maximum score 5) and support (maximum score 3). Scores across all domains will be summed to get a total readiness score (maximum score 22, minimum 0). A higher score indicates the more prepared an ALWHIV is to transition to adult care. Individual scores for each domain will also be assessed as separate primary outcomes (table 2). Summary of primary and secondary outcomes ALWHIV, adolescents living with HIV; EMR, electronic medical records; FGDs, focus group discussions; FRAME, Framework for Reporting Adaptations and Modifications-Enhanced; HCWs, healthcare workers; IDIs, in-depth interviews. Secondary outcomes will be retention and viral suppression in 10–24 year olds (defined as proportion of 10–24 year olds completing one or more visits within 6 months of their last visit and viral load of less than 1000 copies per ml after at least 6 months of antiretroviral therapy (ART), respectively) at the end of the intervention period (month 18). Exploratory outcomes will be proportion of adolescents in intervention and control sites with full disclosure by age 10–12, 13–15 and 16–19 years, time to full disclosure and post-transition retention (defined as completing an adult clinic visit day after transfer to adult services and at least one other visit within 6 months of the first adult visit (total of 2 visits)) (table 2). Implementation outcomes include intervention acceptability, feasibility, appropriateness, penetration, coverage, intervention fidelity, programme costs and cost-effectiveness (outcome definitions and measurement approach in table 2). HCWs will complete surveys during clinic CQI meetings to determine the association between intervention adaptations and implementation outcomes. These surveys use validated measures of perceived appropriateness, acceptability, feasibility and fidelity of the ATP adaptations.42 43 We anticipate that adaptations made during quality improvement cycles will be associated with improved acceptability, coverage and appropriateness of the intervention, and improved feasibility and fidelity of intervention implementation. Adaptations will be evaluated over time at each clinic and summarised over the 6-month adaptation period to determine the number and types of changes tested. Adaptations will be described using a standardised classification system based on the Framework for Reporting Adaptations and Modifications-Enhanced (FRAME) framework to determine the content and nature of the modification, as well as who will be making the modifications and the level of delivery impacted by the modification.44 45 We will estimate the economic cost of providing the ATP intervention per ALWHIV. We will conduct a microcosting study in intervention and control clinics from a payer perspective.46 Costs (2019 US dollars) will be collected from expense reports, staff and expert interviews, and divided into: personnel, equipment, supplies, buildings and overhead, and start-up. In-country time and motion observations will be conducted by a trained research assistant using cost menus in Excel. Research time (eg, administering informed consent) and other research costs will be removed from programmatic costs. We will conduct semistructured interviews with staff to assess daily responsibilities associated with the ATP intervention. Time and motion surveys and staff interviews will be used to inform productivity assumptions (average number of ALWHIV provided the intervention per day). Capital costs and start-up costs (eg, staff hiring/training) will be annualised assuming 5-year useful life and discounted annually at 3%. We will assume 5% supply wastage. We will conduct sensitivity analyses to assess the impact of uncertain parameters on the cost of providing the intervention. We will parameterise a model with cost and effectiveness data from the ATTACH trial and project HIV infections, HIV-related deaths and disability-adjusted life-years averted associated with scaling up the ATP. Trial outcomes to be used in the model include proportion of ALWHIV are retained and virally suppressed after 6 months in adult care by gender and mode of transmission. We will use a previously published compartmental mathematical model of HIV transmission and progression parameterised to epidemiological data from Kenya and focusing on the AYA population.47 Individuals in the model are stratified by sex, 5-year age group (0–59 years), sexual activity (low, medium and high), circumcision status, and ART status. HIV natural history is modelled through six stages of viral load and six stages of CD4 count. Susceptible individuals can acquire HIV and transition to acute infection, characterised by short duration and high probability of HIV transmission. Individuals then progress through CD4 and viral load stages and can initiate and drop out of ART. The model tracks costs and health outcomes over time allowing for the estimation of the incremental cost effectiveness ratio of implementing the ATP intervention compared with standard of care.48 Data for outcomes will be collected from study tools introduced to the clinics as part of the ATP intervention. Disclosure and transition tracking tools will be completed by HCWs in intervention and control sites, manually abstracted and entered into Research Electronic Data Capture (REDCap). REDCap is a secure, web-based electronic data capture tool, hosted at the University of Washington, that supports research data collection, provides an intuitive interface for validated data entry, audit trails for tracking data manipulation, and automated export procedures for seamless data downloads to common statistical packages.49 A 10% data check for consistency between REDCap and paper forms will be conducted for all forms in each site. Retention and viral suppression data will be obtained from clinic EMR systems and the Kenya National Viral load database respectively. Study staff have been trained in data protection; link logs linking participant to study data will be accessible only to study staff. With 20 clinics, 10 intervention and 10 control, and an average cluster size of 50 ALWHIV, we will have >80% power to detect mean transition readiness score differences of >1.0, assuming a two-sided test, alpha=0.05 and an SD of 3 (table 3). Power and sample size calculations for the primary outcome Alpha=0.05, two-sided test, 80% power, average cluster size 50. The primary analysis will be intent to treat, assuming ALWHIV in the intervention arm will be exposed to the ATP intervention. Baseline clinic and adolescent characteristics will be summarised by arm and presented using descriptive statistics. Primary outcomes will be estimated using mixed effects linear regression models to compare transition readiness scores (overall and by domain (HIV literacy self-management, communication and support)) over time in control and intervention sites with adjustment for multiple testing (Benjamini-Hochberg method). These models will account for clustering at the clinic level and repeated transition assessments. We will estimate the coefficients and 95% CIs with a two-sided α=0.05. For secondary outcomes, retention/suppression in intervention and control sites will be compared using generalised estimating equations with a log link (adjusting for baseline retention/viral suppression). Proportions of adolescents with full disclosure by age 10–12, 13–15 and 16–19 in the study arms at 12 months post enrolment will be compared using generalised linear models) with a log link and random effect for site. Survey data on implementation determinants and adaptations will be summarised as Likert data and evaluated using basic descriptive statistics including frequencies (variability), median values (central tendency), Kendall τ (associations) and χ2 tests. Interrupted time series analysis will be used to evaluate whether the adaptation process improved implementation outcomes. Adaptations made to the intervention over time will be compared with planned implementation procedures to evaluate fidelity and categorised using the FRAME framework. Determinants of implementation will be evaluated using FGDs and IDIs with HCWS that are guided by the CFIR. Qualitative analysis will focus on identifying and understanding key factors facilitating or impeding ATP coverage, penetration and implementation fidelity in intervention clinics. Qualitative analysis of IDIs with adolescents and caregivers will focus on understanding personal experiences with transition and satisfaction with intervention materials. IDIs and FGDs will be analysed using a combination of directed and conventional content analysis,50 and thematic network analysis.51 Analysis will employ a modified version of the constant comparison approach and will use within and between case analysis methods52 to compare experiences between clinics and individuals. All data will be coded in ATLAS.ti by at least two members of the research team, using codebooks that are developed inductively using open and in vivo coding strategies and deductively based on literature reviews, IDI/FGD guides and the team’s previous research experience. All data will be summarised to align with the Consolidated Criteria for Reporting Qualitative Research.53 We will use mathematical modelling to estimate the incremental cost-effectiveness of adding the ATP intervention to adolescent HIV care. We will calculate ICER as the ratio of the difference in costs divided by the difference in effects for the intervention compared with standard-of-care scenario over a 20-year horizon. Consistent with guidelines, we will discount costs and health benefits at 3% annually, and consider ICERs below Kenya’s per capita GDP to be cost-effective. We will perform extensive sensitivity analyses to identify influential assumptions. Exploratory stratified analysis by mode of HIV infection (perinatally or behaviourally acquired HIV defined by maternal HIV status and or age at ART initiation (age 10 and 12))4 13 will be conducted for primary, secondary and cost outcomes. All coauthors will have access to the final study dataset.