The broad range of HIV co-morbidities: the next health challenge for PLHIV in LMICs

1. The broad range of HIV co-morbidities: the next health challenge for PLHIV in LMICs Research Priorities Paolo G. Miotti NIH Office of AIDS Research 23 July 2014

2. What Contributes to the Risk of Co-morbidities in HIV? HOST Genetics Lifestyle VIRUS Antiretroviral Therapy Relative contributions of each of these factors to the pathogenesis of specific co-morbidities: key to develop strategies for prevention and treatment From J. Currier (2013)

4. What type of research studies can provide the answers? • Epidemiology and basic science • Clinical science • Implementation science

5. Epidemiology - Resources for research on HIV and NCDs in LMICs • Community-based longitudinal studies • Routine clinical databases and cohorts • Cross-sectional demographics and health surveys (DHS) • WHO STEP surveys • SEARCH (Sustainable East Africa Research on Community Health)

6. Epidemiology - Problems with existing data sources • Lack of population-based cohorts • Absence of HIV-negative comparison groups • Incomplete NCD-specific outcome ascertainment • Incomplete measurement of key factors affecting clinical decision-making (e.g. about treatment)

7. International Epidemiological Database to Evaluate AIDS (IeDEA)

8. Basic science – The questions • Do common pathways exist affecting different end-organ systems? • How do we differentiate co-morbidities from cumulative treatment toxicity (ARV and other drugs)?

9. What’s the role of inflammation?

10. HIV-associated fat Metabolic syndrome CMV Excess pathogens HIV production HIV replication Inflammation ↑ Monocyte activation ↑ T cell activation Dyslipidemia Hypercoagulation Microbial translocation Loss of regulatory cells Co-morbidities Aging S. Deeks, 2013

11. Inflammation predicts disease in treated HIV infection, as it does in the general population • Mortality (Kuller, PLoS Med, 2008, Sandler JID 2011, Tien JAIDS 2011) • Cardiovascular Disease (Baker, CROI 2013) • Lymphoma (Breen, Cancer Epi Bio Prev, 2010) • Venous Thromboembolism (Musselwhite, AIDS, 2011) • Type II Diabetes (Brown, Diabetes Care, 2010) • Cognitive Dysfunction(Burdo AIDS 2012) • Frailty (Erlandson, JID 2013) S. Deeks, 2013

12. A single measurement of IL-6 or D-dimers predicts morbidity or mortality over several years

13. Specific NCDs in PLHIV – Some clinical questions • Coronary arterial disease • Neurologic diseases • Kidney and liver • Cancer • Bone/muscle • Metabolism

14. Coronary Arterial Disease (CAD) • Are there HIV-specific factors driving excess CAD risk in treated disease? • Monocyte activation/inflammation, hyper-coagulation, treatment toxicity • Which interventions should be advanced to clinical endpoint studies? • Statins (REPRIEVE), ASA, ACE-inhibitors, anti-inflammatory drugs • Which biomarkers define those individuals at risk for disease and who might benefit from emerging interventions?

15. Neurologic Diseases • How much harm is associated with acute HIV infection? Does early ART prevent any residual harm to CNS/PNS? • Which neurologic conditions persist during ART? Which conditions (if any) continue to progress during ART? • Does HIV replication in CNS persist during ART? • Why does inflammation persist in CNS during ART and does it matter?

16. Kidney and Liver What is role of HIV replication, HIV-associated inflammation and treatment toxicity in causing renal/hepatic dysfunction? Will subtle changes in renal/hepatic function - which is common - have long-term clinical implications? Are there strategies to prevent end-organ toxicity (e.g., ACE inhibitor and renal disease)? Can we develop biomarkers to detect kidney and liver damage before function is lost?

17. Cancer • Which cancers are increased in HIV disease? • Why are some cancers elevated while others such as prostate/breast may be lower? • What role does treatment toxicity, inflammation and immune deficiency have in causing cancer? • Why are virus-associated cancers so prevalent and why are they difficult to manage? • KS IRIS: cause, how to prevent? • HPV-associated anal dysplasia/cancer: how to screen/manage? • HPV-associated cervical disease in HIV-infected women: how to screen/manage in resource limit settings?

18. Metabolism Why is insulin resistance, diabetes mellitus and the metabolic syndrome common in HIV disease? Is inflammation contributing to these syndromes? What role do inflammatory lipids and visceral adiposity have in causing co-morbidities? Will some or all statins worsen some of these metabolic conditions (e.g., insulin resistance)?

19. Bone/Muscle • What is role of inflammation on osteopenia/osteoporosis? • Why does ART cause immediate depletion in BMD? • Are children particularly vulnerable? • What is role of co-infections (HCV), low testosterone, insulin resistance and metabolic syndrome in causing bone disease? • Who should get vitamin D and bisphosphonates? Will statins be protective? • Should adults/children be screened for bone disease?

20. Research Discovery Scale-Up Implementation W. El-Sadr, 2014

21. Implementation Science (I.S.) • Addresses factors beyond clinical efficacy • I.S. questions are about “how” (traditional scientific inquiry focuses on quantifying mean effects across samples) • I.S. includes economic analyses, cost-effectiveness research, systems dynamics and simulation modeling, and continuous quality improvement (QI) strategies.

22. Research Priorities • Estimate burden of NCDs in PLHA in diverse environments • Incidence, prevalence, today and in 10, 20, … years? • Ascertain the most important risk factors for NCDs in PLHA • Prevalence, strengths of association, prediction models • Do basic science and clinical studies in LMICs • Difference between HIV-infected vs uninfected • Do implementation science studies to compare treatment and care at individual and health systems level • Integration of care, health worker education, task shifting • Do cost-effectiveness analysis of interventions at individual and population level • Point-of-care diagnosis and treatment, community health promotion

23. NCD echoing the lessons of HIV? Scientific American, June 2014

24. Acknowledgments • Steven Deeks, UCSF • Sten Vermund, Vanderbilt U. • Judith Currier, UCLA • Wafaa El Sadr, Columbia U. • Meg Doherty, WHO • Alan Landay, Rush U.

26. Incorporating recommendations for NCD prevention in general population • Consistency across programs within a region • Where might the recommendations differ? • Use NCD guidance as the foundation • Prioritize the issues of greatest impact for those living HIV • Application to younger patient populations • Consider drug interactions with locally available ART

28. Type of studies needed • Common pathogenesis • Research priorities

29. NCD/Priority Areas for Guidelines Development (WHO Scoping Consultation on NCDs, July 2014)

30. Research Priorities • Public health surveillance and clinical epidemiology • NCD incidence in PLHIV in diverse environments, NCD risk factors • Mortality rates and morbidity outcomes in PLHIV • Basic and clinical research • Inflammation, coagulation, and immune mechanisms: role on NCD expression • Interaction between HIV and NCD pathogenic processes • Response to NCD management in different subgroups • NCD biomarkersscreening tools • Impact of ART regimens • Implementation science and health systems • Cost-effectiveness of POC screening tests • Models of integrated NCD and HIV care • Telemedicine and mobile technologies

31. Recommendations for observational studies of NCDs in PLHIV • Use existing data sources, secondary data analysis • Do record linkage between HIV clinical databases and registries • For high prevalence NCD, add NCD to other large prospective studies • Recruit behaviorally and demographically similar HIV pos and neg • Address methodological challenges (selection bias, confounding, loss to F/U, competing risks) • Facilitate collaborative research • Build local research capacity

32. Implementation Science

33. Research and clinical priorities in the era of “complete “ viral suppression: Test and treat, reduce inflammation, insure healthy aging, and provide chronic care (until there is a cure) HIV Infection Testing, linkage to care, retention Antiretroviral Treatment Anti-inflammatory drugs Treatment Toxicity Immune Dysfunction/Inflammation Preventive medicine NCD Co-Morbidities Co-occurring chronic diseases Overburdened Health Care Delivery Systems Operational research S. Deeks, Lancet (2013)

34. Early ART is associated with less inflammation during ARTWill this result in benefit? • ART-naïve with CD4+ count > 500 cells/mm3 • Deferred ART Group • Defer ART until the CD4+ count declines to < 350 cells/mm3 • N=2,300 • Early ART Group • Initiate ART immediately • N=2,300

35. HIV is now a chronic disease requiring treatment for many decades Persistent inflammation/immune dysfunction Subtle but cumulative ART toxicity Additional co-morbidities (non-AIDS events) Clinical aging modified from S. Deeks, 2013

36. Chronic Infectious Diseases • How does TB, malaria, hepatitis and other highly prevalent infectious disease impact HIV and overall health? • How should TB and LTBI be diagnosed and treated? • True point of care diagnostics with improved sensitivity • Shorter drug sensitive regimens & more effective MDR regimens that are compatible with ART • How does HCV drive comorbidity with HIV? • Synergistically increased inflammation or acting via independent pathways? • Will there be residual issues in era of direct acting antiviral drugs?

38. HIV and NCD co-morbidities

39. Stepped wedge study design

40. Implementation science (I.S.) The scientific study of methods and strategies to promote the systematic uptake of clinical research findings and other evidence-based practices into routine practices and, hence, to improve quality (effectiveness, safety appropriateness, equity, cost-efficiency) of health care

41. Low-resource countries – Medium/long term scenario • People taking ART will take them for decades • The larger number of people taking ART may overburden the health systems of many LMICs • Effects of new WHO Guidelines (2013)

42. HIV co-morbidities - What organ systems are affected? • Cardiovascular disease • Cancer • Neurologic and cognitive • Metabolic and bone • Kidney • Liver, gastrointestinal, and nutritional • Lung • Co-infections

43. HIV and NCD co-morbidities The broad scientific question: Are there differences between these HIV co-morbidities in high-income vs. low and middle income countries (LMICs)?

44. HIV and NCD co-morbidities – Key points • Type of studies needed • Common pathogenesis • Research priorities

45. WHO Package of Essential NCD (PEN) tools in low-resource settings

46. WHO- Package of Essential NCD (PEN) Interventions (2010) (partial list)

47. HIV and NCD co-morbidities To impact population health: How should these HIV co-morbidities be diagnosed and managed in LMICs?

48. The epidemiology and the data • Specific HIV co-morbidities and regional HIV epidemics • Identify biomarkers and other indicators to screen for co-morbidities and predict outcomes • Use above data to devise training algorithms for health workers to effectively address co-morbidities in LMICs

49. The epidemiology and the data • Scanty data make it difficult to answer main question: “do HIV populations in LMIC have excess risk of NCD?” • To devise sustainable interventions, use evidence from multiple sources, e.g. clinical care cohorts, interval cohorts (prospective studies), demographic & health surveys, WHO STEP surveillance

50. How important are studies of NCD in PLWHA in LMIC? • The main unmet goal is getting ART to all in need and be able to do so for many years • But studies of NCD co-morbidities in PLHA are important because too little is known about their prevalence, characteristics and management in LMIC