SEARCH- Uganda and Kenya

Diane Havlir, MD, University of California, San Francisco Principal Investigator, SEARCH Moses Kamya, MD, PhD, Makerere University Co-Principal Investigator SEARCH

http://www.searchendaids.com/

Statistician: Maya Petersen Vice-Chair: Edwin Charlebois KEMRI:Elizabeth Bukusi KEMRI:/UCSF: Craig Cohen SEARCH – Sustainable East Africa Research for Community Health

• Ongoing HIV test and treat study of 320,000 persons in rural East Africa • Sponsored by : Multinational, multidisciplinary research consortium established in 2010 to test bold community health interventions to inform policy makers • Directors: Diane Havlir (UCSF); Moses Kamya (Makerere University) • Stakeholders: PEPFAR /OGAC, NIH, WHO, UNAIDS, World Bank, Gilead, MOH Uganda, MOH Kenya, Implementing partners • Institutions: UCSF, Makerere University, IDRC, KEMRI, UC Berkeley SEARCH Study Hypothesis

The implementation of population based universal HIV treatment* in rural communities in East Africa will result in • Reduced HIV, TB and infectious disease burden • Lower maternal and infant mortality rates • Improved economic and educational productivity compared to standard treatment

*treatment includes enhanced HIV testing, linkage, and retention in the context of ongoing prevention activities Aims of the study

• Evaluate the effect of ART at any CD4 cell count, delivered with enhanced testing, linkage, and streamlined care, on – 5 year HIV cumulative incidence – Community health • Mortality, AIDS, TB, Maternal mortality • Vertical transmission, infant and child mortality • Transmitted drug resistance, CD4 counts, HIV RNA levels – Economic and educational outcomes • Workforce participation, education, agricultural output – Health Care utilization • Linkage, retention and time to ART initiation – Costs – Attitudes of community, patients, and providers • Build and evaluate chronic disease model of care (hypertension, diabetes) Key study design features

• Type of Study: Pair matched community cluster randomized trial

• Study Context: Rural communities in Uganda and Kenya

• Key study elements: – Baseline community household census – HIV serostatus (inclusive HIV RNA and CD4) on all community members at baseline, year 3 and year 5 – Integration of all activities into government health system – HIV diagnosis and treatment imbedded in a larger chronic disease model • Intervention : – Annual community wide testing, with additional testing for targeted populations – Immediate ART at all CD4 counts – Enhanced linkage and retention – Streamlined HIV care

• Sample size: 32 Communities, population ~10,000 each (320,000 total)

• Outcomes: – 5 year HIV incidence among stable residents >=15 years (interim analysis at year 3) • Measured directly with longitudinal data – Maternal/Child Health, AIDS, population HIV RNA metrics, TB, Economic/Education/Productivity, Health Care Utilization, ART Cascade, NCD Cascade, Costs and Cost effectiveness

MORE DETAILS AT clinicaltrial.gov : NCT 01864603 SEARCH Consortium Sustainable East Africa Research for Community Health

Current ART strategy allow deterioration, then rebuilds… Early universal ART may keep patients in the “green zone” 32 communities; 3 geographic regions;

Cotrimoxazole 320,000 persons CD4 > 500 Minimal SEARCH symptoms UGANDA To ro ro Partners KENYA PEPFAR NIH Bacterial pneumonia Mbarara Nyanza CD4 350-500 Skin infections Antibiotics WHO World Bank CD4 200-350 Elevated TB risk Anti-TB therapy UNAIDS Gilead Multiple Opportunistic Infections Sciences concomitant CD4 < 200 Early Mortality Uganda MOH therapies Kenya MOH SEARCH: Cluster randomized trial of universal vs. standard ART

Intervention Communities:

ART at all CD4 Community • Annual and Community targeted testing Community Health Productivity/Costs Health Campaign • HIV incidence • Enhanced linkage, 16 villages; n = 10,000 each • Workforce participation Outcome • HIV population viral metrics retention HIV Screening/Diagnosis • Child labor prevalence Year 3 and 5 • AIDS • Agricultural output Malaria testing & care HTN and Diabetes testing • Maternal and child health • Household income

Standard of Care Maternal/child health • TB • Educational attainment Communities: • NCD (HT, DM) • Healthcare utilization Country-guided ART 16 villages; n = 10,000 each Community Health Campaigns

• Multidisease health campaign – remove AIDS exceptionalism • Reflects community health priorities • High throughput, rapid transit, on site treatment • Staffed by community workers, laptop, rapid data entry • Information sharing with ART programs and Ministry of Health • Linkage for HIV and NCDs to government health centers Community Health Campaign- HIV + other diseases

Pilot study in western Uganda (1) 80% HIV adults with HIV 8% 60% Hypertension 12% 40% Diabetes 3.5% 20% 0% 0-200 201-350 >350 CD4+ Count

Rain Or shine! (1) Chamie, PLOS Med, 2012 EARLI PILOT: ART for HIV+ adults in rural Uganda With High CD4+ Cell Counts: Week 48 Results

CROI, 2014 1: Demographics 2: Adherence 3: Retention

CD4≥350 (n=200) Withdrawn, n=3 HIV Age, median (IQR) 35 years (29-41) Visit CD4>350 (n=197) negave at Week 4 94.4% (186/197) CD4>350 baseline tesng Total Retention: Sex, % 65.1% F / 34.9% M n=200 Week 8 97.8% (182/186) 193/197= 98% enrolled Deaths, Lost to 564/uL Week 12 99.4% (183/184) n=2 follow-up, CD4, median (IQR) n=2 (448-712) Week 24 98.9% (188/190) Week 36 98.3% (176/179) HIV RNA, median 22,400 c/mL Week 48 98.9% (178/180) (IQR) (4,137-87,759) Total 97.9% (1093/1116)

4: Viral Suppression 5: Medical Officer Usage • Low overall usage, mostly for urgent care complaints. • Largely clustered within first 3 months on ART Week 24 Week 48 95.4% 96.9% (188/197) (186/192) 6: Rapid Transit through Clinic • Average transit time 30-40 minutes. • Favorably compares to 200-300 m in SW region clinics.

High CD4+ patients have shown excellent viral suppression, low toxicity Pilot study has been adapted for ART delivery in SEARCH Pilot study: Employment Measure

• Compared to CD4<200, Regression model coefficients (1) (2) CD4≥500 associated with Days worked in the Hours worked on – 5.8 more days worked/month Outcome: past month usual day in past CD4<200 Reference Reference – 2.2 more hours worked/day CD4 200-349 2.7 1.8 (40% more than ref. mean of CD4 350-499 4.8 0.9 5.5) CD4 ≥500 5.8** 2.2* Observations 107 107 • Linear regression model with age, age-squared, Those with CD4≥500 and sex included as controls • ** p<0.05, * p<0.10 worked nearly 1 week/ • Reference group has CD4<200 month more than those with CD4<200, and as much as HIV- uninfected adults Thurminathy, AIDS, 2013 Levels of Engagement and Partnership

Sponsors: PEPFAR , NIH/NIAID, World Bank & Gilead

Country Partnerships: USG Partners (CDC & USAID), Uganda MoH, Kenya MoH, UNAIDS, WHO, UCSF & Makerere Univ.

PEPFAR HIV Implementing Partner (IPs) & District Health Office: STAR E, STAR EC, MJAP, TASO, District Health teams & health facility in-charges

Community level: Local councils, CABs, Parish SEARCH Team Team SEARCH chiefs, religious & opinion leaders, PLWHIV 11 Community is the foundation for the population based approach What will SEARCH tell us?

• Can a population -based ART strategy “shut down” new HIV infections? * – What are the additional gains? (maternal child health, TB, education, household earning power?) – What is the best way to do it? – What would it cost? • Can efficient HIV chronic care models be adapted to establish care for other chronic diseases (hypertension and diabetes)?

*In the context of a combination prevention approach SEARCH progress

Sites in Uganda • Over 250,000 and Kenya persons enrolled in SEARCH • Ascertainment HIV status > 80% all adults • Study on track to complete enrollment of 320,000 persons by July, 1, 2014 Teamwork Intervention: Population based universal ART • Enhanced HIV testing – Annual testing at CHC/home based – Targeted testing for high risk groups • Enhanced Linkage – Linkage appointment made at the time of diagnosis* – Travel voucher for linkage to clinic (first visit only)* – Cell phone number for clinic medical officer provided – Outreach visit for “no-shows” • Enhanced retention and re-engagement – “Same” day ART start – Streamlined visits – Enhanced outreach/ART delivery for “no shows” * both study arms REAL TIME DATA FEEDBACK SEARCH Unique Features

COMMON FEATURES to other combination prevention studies SEARCH UNIQUE FEATURES

• Community health campaign • Study Type: Community HIV testing strategy inclusive of Randomized multiple infectious and non- • Population: SubSaharan communicable diseases Africa • Household economic impact/ • Intervention: HIV testing education outcomes and treatment • Chronic disease management • Outcomes platform – HIV incidence • Real time data feedback for – AIDS/mortality cascade optimization for HIV, – Mother/child health NCDs (diabetes/hypertension) – TB • Extensive study integration – Cost/Cost effectiveness into in- country community and health systems