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

CD4 > 500

CD4 350-500

CD4 200-350

CD4 < 200

Minimal symptoms

Bacterial pneumonia Skin infections

Elevated TB risk

Cotrimoxazole

Multiple concomitant

therapies

Opportunistic Infections Early Mortality

Antibiotics

Anti-TB therapy

Current ART strategy allow deterioration, then rebuilds… Early universal ART may keep patients in the “green zone”

SEARCH Consortium Sustainable East Africa Research for Community Health

SEARCH: Cluster randomized trial of universal vs. standard ART

16 villages; n = 10,000 each

ART at all CD4 •  Annual and

targeted testing •  Enhanced linkage,

retention Country-guided ART

Community Health • HIV incidence • HIV population viral metrics • AIDS • Maternal and child health • TB •  NCD (HT, DM)

Outcome Year 3 and 5  

Community Productivity/Costs • Workforce participation • Child labor prevalence • Agricultural output • Household income • Educational attainment • Healthcare utilization

SEARCH Partners

PEPFAR NIH

WHO World Bank

UNAIDS Gilead

Sciences Uganda MOH

Kenya MOH  

UGANDA KENYA

Mbarara

Tororo

Nyanza

Standard of Care Communities:

Intervention Communities:

HIV Screening/Diagnosis Malaria testing & care HTN and Diabetes testing Maternal/child health

Community Health Campaign

16 villages; n = 10,000 each

32 communities; 3 geographic regions; 320,000 persons

•  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 Campaigns

Community Health Campaign- HIV + other diseases

0% 20% 40% 60% 80%

0-200 201-350 >350 CD4+ Count

HIV adults with HIV 8% Hypertension 12% Diabetes 3.5%

(1) Chamie, PLOS Med, 2012

Rain Or shine!

Pilot study in western Uganda (1)

EARLI PILOT: ART for HIV+ adults in rural Uganda With High CD4+ Cell Counts: Week 48 Results

CD4≥350 (n=200)

Age, median (IQR) 35 years (29-41)

Sex, % 65.1% F / 34.9% M

CD4, median (IQR) 564/uL (448-712)

HIV RNA, median (IQR)

22,400 c/mL (4,137-87,759)

Total Retention: 193/197= 98%

CD4>350  n=200  enrolled  

Withdrawn,  n=3  HIV  nega9ve  at  baseline  tes9ng  

Deaths,  n=2  

Lost  to  follow-­‐up,  n=2  

 Visit CD4>350 (n=197) Week 4 94.4% (186/197) Week 8 97.8% (182/186) Week 12 99.4% (183/184) Week 24 98.9% (188/190) Week 36 98.3% (176/179) Week 48 98.9% (178/180) Total 97.9% (1093/1116)

Week 24 Week 48 95.4%

(188/197) 96.9%

(186/192)

4: Viral Suppression

3: Retention 2: Adherence 1: Demographics

6: Rapid Transit through Clinic

5: Medical Officer Usage

• Low overall usage, mostly for urgent care complaints. • Largely clustered within first 3 months on ART

• 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

CROI, 2014

•  Compared to CD4<200, CD4≥500 associated with –  5.8 more days worked/month –  2.2 more hours worked/day

(40% more than ref. mean of 5.5)

•  Linear regression model with age, age-squared, and sex included as controls

•  ** p<0.05, * p<0.10 •  Reference group has CD4<200

Regression  model  coefficients(1) (2)

Outcome:Days  worked  in  the  

past  monthHours  worked  on  usual  day  in  past  

CD4<200 Reference ReferenceCD4  200-­‐349 2.7 1.8CD4  350-­‐499 4.8 0.9CD4  ≥500 5.8** 2.2*Observations 107 107

Those with CD4≥500 worked nearly 1 week/month more than those with CD4<200, and as much as HIV-uninfected adults

Thurminathy, AIDS, 2013

Pilot study: Employment Measure

Levels of Engagement and Partnership

SEA

RC

H T

eam

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 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 and Kenya •  Over 250,000

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

•  Study Type: Community Randomized

•  Population: SubSaharan Africa

•  Intervention: HIV testing and treatment

•  Outcomes –  HIV incidence –  AIDS/mortality –  Mother/child health –  TB –  Cost/Cost effectiveness

COMMON FEATURES to other combination prevention studies SEARCH UNIQUE FEATURES

•  Community health campaign HIV testing strategy inclusive of multiple infectious and non-communicable diseases

•  Household economic impact/education outcomes

•  Chronic disease management platform

•  Real time data feedback for cascade optimization for HIV, NCDs (diabetes/hypertension)

•  Extensive study integration into in- country community and health systems