1. Link4Health Study: A combination strategy for linkage to and retention in HIV care in Swaziland Margaret L. McNairy, Matthew R. Lamb, Averie B. Gachuhi, Harriet Nuwagaba-Biribonwoha, Sean Burke, Sikhathele Mazibuko, Velephi Okello, Peter Ehrenkranz, Ruben Sahabo, and Wafaa M. El-Sadr July 20, 2016 1

2. Background All steps in the HIV care cascade must be achieved to optimize health outcomes and decrease HIV transmission. 2 *Bicego et al, Plos One 2013; Swaziland MOH 2012 Swaziland has a severe generalized HIV epidemic. – Adult HIV prevalence 31% * – HIV incidence 2.4% * Barriers to engagement across the cascade include structural, behavioral and biomedical factors.

3. Link4Health: Purpose To evaluate the effectiveness of a combination strategy of multiple interventions targeting barriers at various cascade steps on linkage and retention 3

4. Assessed for ART eligibility Retained in care Link4Health: Intervention Combination Intervention Strategy (CIS) 4 Cascade S tep Linked to Care Assessed for ART Eligibility Initiated ART Retained in Care CIS Components 1. Point-of-care CD4 at HIV testing XXX 2. Accelerated ART for CD4 < 350 XX 3. SMS appointment reminders XX 4. Basic care and prevention package XX 5. Non-cash financial incentive XX

5. Link4Health: Study Design Implementation science design Cluster-randomized controlled trial – 10 study units randomized to CIS versus Standard of Care – Study unit included 1 secondary and 1 affiliated primary-level health clinic – Stratified by location (rural/urban) and implementing partner Study population: – > 18 years identified as HIV+ – Willing to receive HIV care at study unit – No prior ART in past 6 months – Not currently pregnant – Not planning to leave catchment area Study follow-up: 12 months 5

6. Link4Health: Study Outcomes Primary outcome: Linkage: HIV clinic visit within 1 month after HIV testing at assigned study unit and Retention: HIV clinic visit within 12 months (+/- 3 months) after HIV testing at assigned study unit Secondary outcomes: – Linkage at 1 month – Retention at 12 months – Assessment for ART eligibility (i.e. CD4 cell count/WHO Stage) – ART initiation – Mortality 6

7. Link4Health: Data Collection & Analysis Data abstracted from routine health records including clinic registers and patient files and patient tracking Intent-to-treat analysis – Comparison of Relative Risk (RR) for achieving primary outcome among all participants in CIS versus SOC Per-protocol analysis – Comparison of RR for achieving primary outcome among participants who received full package of CIS versus SOC for duration of study participation Interaction analysis – Assessment of RR for achieving primary outcome by key sub- group using Interaction Contrast Ratios 7

8. CIS (5 Study Units) SOC (5 Study Units) Link4Health: Study Population Screened for study eligibility (N = 1,234) Refused (N = 23) Refused (N = 114) Ineligible (N = 111)Ineligible (N = 101) Enrolled in study (N = 1,100) Reasons ineligible: CIS arm: < 18 yrs (N = 4), not HIV-positive (N = 3), refuse referral to SU (N = 26), refuse to provide contact information (N = 4), plans to move in next year (N = 22), recent history of HIV care or ART (N = 12), other (N = 40) SOC arm: < 18 yrs (N = 2), not HIV-positive (N = 1), refuse referral to SU (N = 28), plans to move in next year (N = 21), recent history of HIV care or ART (N = 13), other (N = 34) Screened for study eligibility (N = 1,316) Enrolled in study (N = 1,101) Primary Outcome Assessment (N = 1,036) Primary Outcome Assessment (N = 932) 8 10 Study Units

9. Link4Health: Site and Participant Characteristics Site Characteristics 60% urban, 100% supported by MOH All 4 regions of Swaziland Participant Characteristics 2,201 HIV+ adults enrolled August 2013-November 2014 59% female Median age 32 years (IQR 26-40), 20% <25 years 37% married 53% unemployed; median income $9 (IQR 0-32)/week HIV testing site: 80% VCT, 20% PICT 9

10. CIS N = 1100 SOC N = 1101 RR (95 % CI)P value Intent-to-Treat705 (64%)477 (43%)1.48 (1.36-1.60)<0.001 Accounting for Clustering* 1.52 (1.18-1.95)0.003 Per-protocol* # 672 (72%)477 (43%)1.68 (1.53-1.79)<0.001 * Accounting for within study unit clustering using a random-intercept log-poisson regression model with robust standard error # Adjusted participants who received CIS against those in SOC according to study protocol ^ Considered achievement of outcome if participant reported linkage and retention in their study unit or in follow-up questionnaire to a different clinic Link4Health: Primary Outcome Linkage within 1 month & Retention at 12 months after HIV Testing 10

11. CIS Arm: N = 705 (64%) SOC Arm: N = 477 (43%) Intent-to-treat: Relative Risk 1.48 (95% CI 1.36-1.60 p< 0.0001) Accounting for Clustering: Relative Risk 1.52 (95% CI 1.18-1.95 p= 0.0026) Link4Health: Primary Outcome Linkage within 1 month & Retention at 12 months after HIV Testing 11

12. CIS (N =1100) SOC (N= 1101) RR^ (95 % CI)P value Linkage1 month1010 (92%)918 (83%)1.12 (0.96-1.30)0.15 Mean time (std) 2.5 days (19.5)7.4 days (46.6)0.003 Retention12 months720 (65%)498 (45%)1.47 (1.17-1.85)0.002 ART Eligibility Assessment Ever1100 (100%)920 (84%)1.20 (1.07-1.34)0.004 ART InitiationTotal710 (65%)*635 (58%)**1.16 (0.96-1.40)0.13 Median time (IQR) 8 days (3-37)17 days (7-57)<0.001 DeathBefore ART Initiation 10 (1%)23 (2%)0.44 (0.19-1.00)0.05 After ART Initiation 25 (2%)20 (2%)1.18 (0.57-2.46)0.64 Link4Health: Secondary Outcomes ^Accounting for clustering using random-intercept model with robust error estimates * (85% among eligible)**(88% among eligible) 12

13. Link4Health: HIV Care Cascade 53% on ART 12% Pre- ART 39% on ART 6% Pre-ART P = 0.15 P 0.04 P = 0.13 P = 0.002 13 Retention 12 months after HIV testing HIV + Test (Study Enrollment) Linked within 1 month

14. Subgroup Analysis of Primary Outcome Age (yrs) Sex Daily Income (USD) EmploymentMarital Status Away from home in last year Travel Time First HIV+ Test Household member with HIV Facility Type Relative Risk for Primary Outcome

15. Strengths and Limitations Strengths Pragmatic study design integrated in clinical care Multiple interventions along the HIV care cascade evaluated Majority of clinics in Swaziland included Limitations Primary outcome from routinely collected data in medical records Inability to evaluate effectiveness of individual components of CIS intervention 15

16. Conclusions The Link4Health combination strategy of evidenced- based interventions, aimed at gaps in the HIV care cascade, was associated with a 50% increase in prompt linkage to care and 12-month retention. The combination strategy improved ART eligibility assessment, reduced median time to ART initiation, and reduced mortality among participants prior to ART initiation. This effective and pragmatic strategy can be adapted to other settings and to specific patient populations to enhance the trajectory of patients across the HIV care cascade. 16

17. Many thanks to all of the collaborators, health workers, and patients who made this study possible. Investigators Wafaa El-Sadr Peter Ehrenkranz Matthew Lamb Margaret McNairy Sikhathele Mazibuko Harriet Nuwagaba-Biribonwoha Velephi Okello Ruben Sahabo ICAP NY Study Staff Averie Gachuhi Neena Philip This study is funded by NIH R01AI100059 and conducted in collaboration with CDC and PEPFAR ICAP Swaziland Study Staff Pido Bongomin Sean Burke Cebsile Dlamini Thabiso Fakudze Henry Ginindza Altaye Kidane Veli Madau Yvonne Mavengere Nozipho Ndlovu Fortune Ndhlovu Rita Nunu Zweli Simelane Nkosikhona Dlamini Ministry of Health Nomthandazo Lukhele Simangele Mthethwa Rejoice Nkambule Simon Zwane Health facility staff 17