Implementation Science Elaine Abrams, MD Senior Research Director

1. Implementation Science Elaine Abrams, MDSenior Research Director

2. Objectives • Provide overview of Implementation Science Research approach and methods • Overview of PEPFAR Implementation Science initiative • Introduce ICAP’s new Implementation Science studies • Describe, in greater depth, a subset of these studies

3. What is Implementation Research? • ‘Research to promote the uptake & successful implementation of evidence-based interventions and policies’ (Sanders) • ‘Evidence that informs effective, sustained & embedded adoption of interventions by health systems & communities’ (Allottey) • ‘All aspects of research relevant to the scientific study of methods to promote the uptake of research findings into routine settings in clinical, community and policy contexts’ • ‘Research to significantly improve access to efficacious interventions by developing practical solutions to common implementation problems’ (WHO) • ‘Scientific study of methods to promote the systematic uptake of research findings & evidence-based practices into routine practice, to improve the quality and effectiveness of health’ Sanders et al, PLOS Med, 3:e186; Allottey et al, BMC Pub Health 8:343, WHO; Remme et al, PLOS Med Nov 2010

4. Implementation Research • ‘Implementation research aims to develop new strategies for available or new health interventions in order to improve access to, and the use of, these interventions by the populations in need’ (Remme) • Seeks to address the “know-do gap’ – why and how best to successfully implement evidenced based interventions Remme et al, PLOS Med Nov 2010

5. Implementation Research • IR tests practical solutions to service delivery and challenges in order to • Address problems specific to a health system or environment or those that are common to a particular region • Identify how evidence-based interventions, tools, and services should be modified to achieve sustained health impacts in real-world settings • Determine the best way to introduce practical solutions into health systems and facilitate full-scale implementation, evaluation, modification

6. Implementation Research • IR uses contextual knowledge to study processes to improve practice • IR applies research findings and methods to real-world contexts and settings • IR places particular emphasis on access to efficacious interventions, service delivery models, feasibility of interventions in different settings • The outcome of a successful IR project is integration of findings into practice or policy

7. Characteristics of Implementation Research • Systematic • Adheres to norms of scientific inquiry • Specific intervention, specific setting • Balances relevance with rigor • Multidisciplinary • Considers biological, social, economic, political, system and environmental factors that impact implementation • Collaborations between behavioral and social scientists, clinicians, epidemiologists, statisticians, policy makers, stakeholders

8. Characteristics of Implementation Research (continued) • Contextual • Relevant to local circumstances and need • Generates generalizable knowledge that can be applied across contexts • Complex • Dynamic and adaptive • Occurs at multiple levels of health care system, community • Analyzes multi-component programs

9. Defining research to improve systems Remme et al, PLOS Med Nov 2010

10. Remme et al, PLOS Med Nov 2010

11. PEPFAR Implementation Science Model • PEPFAR implements scientific advances on a large scale through its programs • PEPFAR has shifted towards an Implementation Science model as the scientific framework to guide program implementation and scale-up that focuses on effectiveness and efficiency to build the evidence base necessary to inform the best approaches to achieve sustainable prevention, care and treatment programs

12. PEPFAR Implementation Science Model & Initiative • Current Implementation Science efforts include a range of funded evaluation activities including: • Implementation Science (IS) Awards • Basic Program Evaluations (BPE) • Impact Evaluations (IE) • PEPFAR created a $60 million dollar initiative to support Implementation Science Research to evaluate PEPFAR programs. • The Initiative was funded through collaborations with the CDC, NIH and USAID

13. ICAP’s ‘won’ 7 Implementation Science Awards • USAID funded • Engage4Health (Ligaçõespelasaúde), Mozambique • Safe Generations (SitukulwaneLesiphephile), Swaziland • START (Start TB patients on ART and Retain on Treatment), Lesotho • NIH funded • LINK4HEALTH, Swaziland • MCH-ART, South Africa • MIR4Health (Mother-Infant Retention for Health), Kenya • ENRICH (Enhance Initiation and Retention in IPT Care for HIV), Ethiopia

14. ICAP’s Implementation Science Studies • 7 different countries in Sub Saharan Africa • Represent productive collaborations between PI, NY teams, and country teams • Address several key clinical domains: adult ART linkage and retention, TB treatment and prevention IPT, and PMTCT including maternal and infant health • Encompass a variety of scientific approaches, methodologies, patient populations, outcomes • All grow out of the programmatic work leading to critical implementation questions around how best to successfully implement evidenced based interventions

15. SitukulwaneLesiphephileSafe Generations

16. Safe GenerationsSitukulwaneLesiphephile • Partnership in the Kingdom of Swaziland between: • MOH(Sexual and Reproductive Health Unit (SRHU) and Swaziland National AIDS Program (SNAP) • ICAP • University of Cape Town • Elizabeth Glazer Pediatric AIDS Foundation • NERCHA

17. Background • There is sound scientific evidence on the efficacy of ARV interventions during pregnancy, delivery and breastfeeding and enormous PMTCT success in high resource settings with MTCT rates ~ 1-2% • However, despite major advances in PMTCT interventions in 2011, there were ~ 330,000 new pediatric infections worldwide, 90% of them attributable to MTCT.1,3 • Swaziland is currently implementing WHO ‘Option A’* • Lifelong treatment for ART-eligible women • Prophylaxis for non-eligible women: AZT from 14 weeks’ gestation with sd-NVP at delivery plus a 7-day tail of twice daily AZT and 3TC postpartum, and daily NVP to the infant during breastfeeding • Substantial implementation challenges have been encountered *WHO Option B: lifelong ART for eligible women and triple ARV prophylaxis during pregnancy and breast feeding

18. Maternal PMTCT Cascade, Swaziland, 2011

19. Infant PMTCT Cascade Swaziland, 2011

20. Testing a New Strategy for PMTCT • The country of Malawi adopted a new strategy for PMTCT – Option B+ : lifelong ART for all pregnant and breast feeding women • Recognizing the complexity of Option A and considerable implementation challenges encountered in the field, WHO recently endorsed Options B+ and outlined considerable programmatic and implementation advantages of this approach • However, there are limited data on Option B+ implementation and/or comparisons with other approaches • The Swaziland MOH reluctant to adopt new approach without strong evidence of benefit

21. Situkulwane LesiphephileSafe Generations: Objectives • Primary Objective: To compare the impact of implementing Option A and Option B+ on the composite endpoints of infant HIV positive DNA PCR OR maternal loss to follow-up (LTFU) 6 months postpartum • Secondary Objectives: To compare Option A and Option B+: • Cost effectiveness • Patient and provider acceptability • Proportion of pregnant women CD4+<350 cells/mm3 who start ART • Proportion of women retained in HIV care at 12, and 18 months postpartum

22. Situkulwane LesiphephileSafe Generations: Study Hypothesis Option B+: integration of prevention and treatment into a uniform and streamlined treatment and retention approach modified for the continuum of perinatal maternal-child care will: • Result in higher proportion of mother-child pairs completing the PMTCT cascade • Fewer paediatric infections • Lead to higher proportion of women with CD4+<350 initiating ART earlier in pregnancy • Be more acceptable to staff and clients • Be more feasible and more cost-effective

23. Situkulwane LesiphephileSafe Generations: Study Components • This study is comprised of three study components: • Option B+ evaluation • Acceptability evaluations with PMTCT clients and health care workers • Cost-effectiveness analysis

24. Study Design: Option B+ Intervention Evaluation • Stepped wedge design: One facility per month will transition from Option A to Option B+ (total 10 facilities) • Estimated 2,700 women enrolling into care during study period

25. Outcome Measurements: Option B+ Evaluation (1) • PMTCT (A and B+) will be provided as standard of care at study sites. Women will be consented to allow chart review and abstraction of health records (for mom and baby) • Primary outcome: Combined maternal-child endpoint at 6 months post partum of: • Infant HIV PCR positive OR • Mother Lost To Follow-Up

26. Outcome Measurements: Option B+ Evaluation (2) • Secondary outcomes: • Proportion of pregnant women with CD4+<350 initiating ART during pregnancy • Duration of ART received prior to delivery for ART-eligible pregnant women • Proportion of women and children retained in HIV care at 12, and 18 months postpartum • Birth outcomes (birth weight, SGA, gestation age) • Infant feeding practices • Maternal health outcomes

27. Outcome Measurements: Option B+ Acceptability • Interviews with PMTCT clients will focus on: • PMTCT and ART knowledge and beliefs • Barriers to PMTCT services • Perception of women’s uptake of services • Quality of care that the receive • Interviews with HCWs will focus on: • Barriers to PMTCT implementation • Understanding and attitude towards B+ intervention • Perceptions of PMTCT client uptake

28. Outcome Measurements: Option B+ Cost Effectiveness Assessment • Cost-effectiveness assessment will be lead by UCT collaborators • Data on unit costs including human resources costs will be abstracted from the following sources: • Routine facility and MOH accounts • Facility utilization data and staffing plans, and pharmacy accounts maintained by the MOH • Data on service utilization by participants will come directly from the evaluation • Program costs will be based on local standards for training and materials development • Outcome data will be used to calculate the incremental cost required to improve patient outcomes of infant HIV PCR positivity, maternal retention, and their combination, all assessed at 6 months postpartum.

29. the start study StartTB patients onART andRetain onTreatment Andrea Howard Yael Hirsch-Moverman Suzue Saito Wafaa El-Sadr Yingfeng Wu Amrita Daftary Tal Gross Koen Frederix Maama-MaimeLlang Bridget Mabatloung

30. Background and Rationale • TB is a leading cause of death, accounts for nearly a quarter of HIV-related deaths worldwide • Early initiation of ART during TB treatment significantly increases AIDS-free survival by 34-68%1-3 • In the African Region only 42% of TB patients were on ART in 2010 • In Lesotho it was as low as 27% in 2010 1Karim 2011; 2Havlir 2011; 3Blanc 2011

31. Background & Rationale (2) • Barriers to early ART initiation and retention include: • Health Care Workers • Lack knowledge about benefits of early ART, guidelines for TB/HIV co-management (adverse events, IRIS)1,2 • Patients • Unaware of importance of early ART during TB treatment3 • Fear of toxicity, side effects, death, concerns about pill burden3,4 • Lack funds for transportation to clinic1,3,5,6 • Lack social and family support4,5 • Urgent need to identify programmatic interventions that address these barriers to implementation 1Okot-Chono 2009; 2Dong 2007; 3Kumwenda 2011; 4Harris 2008; 5Chileshe 2010; 6Zachariah 2006

32. Study Aims Specific Aim 1: • To evaluate the effectiveness of integrating a combination intervention package (CIP) for ART provision during TB treatment

33. Study Aims (2) Specific Aim 2: • To assess the cost-effectiveness (incremental cost per health adjusted life-year gained) of CIP Specific Aim 3: • To assess provider and patient acceptability of CIP for ART provision during TB treatment Specific Aim 4: • To describe the safety and tolerability of ART during TB treatment under programmatic conditions

34. Study Design • Two-arm cluster randomized trial, randomized at the TB/HIV clinic level • Twelve TB/HIV clinics at health facilities in Berea district, Lesotho • Clinics randomized to deliver CIP or standard of care (SOC) • Stratification by facility type (hospital or health center)

35. Study Interventions: SOC vs. CIP

36. Study Participants • All newly registered TB/HIV patients (~1200) • Measurement cohort of ART initiators (with 6-9 months follow up) • CIP (n=192) • SOC (n=192) • Key informant interviews at CIP sites • ART non-initiators (n=30) • ART initiators (n=30) • Health care workers (n=30)

37. Study Outcomes

38. Study Measures

39. Innovation • Combination approach: A combination of practical, feasible, scalable interventions targeting multiple barriers to timely ART initiation and retention among TB patients • Rigorous study design: Two-arm site-randomized trial to rigorously assess whether CIP improves early ART initiation and retention compared to SOC • Lesotho: Focus on a country with one of the highest burdens of TB and HIV • Research capacity: A key study component is building partner research capacity • Collaboration: Strong collaboration with public, private, and non-profit sector partners in Lesotho

40. ENRICHstudy ENhanceInitiation andRetention inIPTCare for HIV Andrea Howard Yael Hirsch-Moverman Suzue Saito Wafaa El-Sadr Yingfeng Wu ZenebeMelaku TsigeredaGadisa

41. Background and Rationale • IPT reduces TB risk by 33% overall, by 64% if TST+, in absence of ART1 • IPT reduces risk of death during early ART2 • IPT + ART results in greater reduction in TB risk than either alone3,4 • ~180,000 PLWH received IPT in 2010 (12% of 1.5 million PLWH newly enrolled in HIV care)5 • ProTEST project: IPT completion 24%-59%6 1Akolo 2010; 2Charalambous 2010; 3Golub 2007; 4Golub 2009; 5WHO 2011; 6WHO2004

42. Background & Rationale (2) • Barriers to IPT implementation include: • Health Care Workers • Lack of knowledge/clarity on IPT benefits, guidelines1,2 • Concern about toxicity, resistance, inadequate adherence1,2,3 • Programs • Lack SOPs to assess IPT eligibility, monitoring for AEs, adherence1,3 • Patients • Lack funds for transportation to clinic2,4 • Lack social and family support4,5 • Beliefs about IPT efficacy, side effects5 • Urgent need to identify programmatic interventions that address these barriers to implementation 1Getahun 2010; 2Lester 2010; 3Date 2010, 4Rowe 2005; 5WHO 2004

43. Study Aims Specific Aim 1: • Characterize and compare the effectiveness of CIP with SOC for IPT provision in Ethiopia • IPT initiation • IPT adherence • IPT completion Specific Aim 2: • Assess the impact of CIP compared with SOC on HIV-related outcomes • Retention in care • ART adherence • CD4+ count

44. Study Aims (2) Specific Aim 3: • Assess safety and tolerability of IPT among HIV-infected individuals under routine program conditions Specific Aim 4: • Identify patient and program characteristics associated with IPT adherence and completion at SOC sites

45. Study Design • Two-arm cluster randomized trial, randomized at the HIV clinic level • Ten HIV clinics at health centers in Dire Dawa and Harari, Ethiopia • Clinics randomized to deliver CIP or SOC • Stratification by clinic size

46. Study Interventions: SOC vs. CIP

47. Interactive Voice Response Messaging • Prepaid mobile phones for patients starting IPT • Low mobile phone penetration • Interactive Voice Response calls in local languages • Low literacy rate • PIN to protect confidentiality • Medication and appointment adherence reminders • Call schedule tailored to patient’s preferences • Monitoring messages to assess adherence, side effects • Peer educators follow-up with patients with difficulties

48. Study Participants • All new HIV patients eligible for IPT (~1120) • Measurement cohort of IPT initiators (with 6-9 months follow up) • CIP (n=250) • SOC (n=250)

49. Study Outcomes

50. Study Measures