NIH Office of AIDS Research 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

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)

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

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)

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)

International Epidemiological Database to Evaluate AIDS (IeDEA)

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)?

What’s the role of inflammation?

Microbial translocation Loss of regulatory cells 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

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

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

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

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?

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?

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?

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?

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)?

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?

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

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.

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

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

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

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

Type of studies needed Common pathogenesis Research priorities

NCD/Priority Areas for Guidelines Development (WHO Scoping Consultation on NCDs, July 2014) HIGH PRIORITY NEW INFO TO BE ASSESSED IN PLHIV CVD risk assessment and interventions Mental health screening and interventions Modification of ARV regimens Growth/puberty delay in children & adolescents MEDIUM PRIORTIY/ MORE INFO NEEDED BEFORE ASSESSMENT DECISION IN PLHIV Screening for Hep B&C Screening for renal dysfunction Bone health in children and older patients Behavioural changes for obesity reduction (diet and physical counselling) Smoking cessation Management of alcohol and substance abuse LOW PRIORITY INFO ALREADY INCLUDED OR MINOR ADJUSTMENTS CAN BE NEEDED Screening for cervical cancer Harm reduction package for Hep B&C in IDU HPV vaccine HBV vaccine

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

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

Implementation Science

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 Immune Dysfunction/Inflammation Treatment Toxicity Preventive medicine NCD Co-Morbidities Co-occurring chronic diseases Overburdened Health Care Delivery Systems Operational research S. Deeks, Lancet (2013)

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

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

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?

HIV and NCD co-morbidities

Stepped wedge study design

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

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)

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

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)?

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

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

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

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

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

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

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

Things to do Identify data gaps Identify questions of interest to investigators to implementing agencies (e.g. PEPFAR) Provide evidence base for Guidelines (e.g. WHO Guidelines) Test research findings in cost-effectiveness models Synergies & Partnerships

HIV and NCD co-morbidity in LMIC– A Systematic Review Systematic review of studies from Medline and Embase (2000-2012) Magnitude and determinants of NCDs in PLHA 37 studies (25 from Africa), 20 countries, 31344 PLHA CVD: in >1/3 clinic attenders (myocardial and conduction disorders more common than vascular) Cancer: relatively low prevalence of AIDS def. and non-AIDS def. cancers, but high pre-cancerous lesions (cervical SIL) Diabetes: < 5% (young patients?). DM-TB relationship? Metabolic abnormalities (incl. dyslipidemia):13-28%

HIV as a chronic disease (cont’d) Studies of co-morbidities in PLWHA require investigating: Different (additional) risk factors Different level of disease expression More and different drug toxicities (ARV and other drugs)

What are the most pressing questions regarding the pathogenesis and management of organ system dysfunction/disease?

Potential Clinical Consequences of Microbial Translocation Deeks, Immunity 2013

Therapeutic Options in Development Anti-inflammatory drugs Chloroquine, hydroxychloroquine Minocycline NSAIDs (COX-2 inhibitors), aspirin Statins Methotrexate (low-dose; CIRT) Talidomide, lenalidomide, pentoxyfylin Biologics (e.g., TNF inibitors, IL-6 inhibitors, anti-INF-alpha) Anti-coagulants: low dose warfarin, dabigatran, aspirin, clopidogrel Chemokine receptor inhibitors: maraviroc, TB-652 Anti-infective therapy: CMV, EBV, HSV, HCV/HBV Microbial translocation: sevelamer, colostrum, rifaximin, pre-biotics, probiotics, isotrentinoin Enhance T cell renewal: growth hormone, IL-7 Anti-fibrotic drugs: perfenidone, ACE inhibitors, ARBs Anti-aging: caloric restriction, sirtuin activators, vitamin D, omega-3 fatty acids, sirolimus, diet, exercise Deeks IAS 2013

Risk factors, HIV patho-physiology Prolonged HIV infection Immune activation Aging ART effects Oncogenic infections Other co-infections Substance use Inflammation and immune activation Immune suppression

Lancet, series on NCDs The Lancet

Some limitation of studies of NCDs in HIV+ patients Independant markers of NCD causality Need for predictive markers Use of surrogate outcomes Age adjustement needed to assess accentuated vs accelerated risk Confounding factors Independant markers (risk factors, biomarkers) => tell us about association between factor and outcome but do not imply a causal link to actual clinical events. Sometimes they are In many studies, risk factors are used as surrogate outcomes instead of actual clinical events. Talk by a cardiologist that was pointing out that there are many factors that are independantly associated with CVD but What we need are markers that can discriminate those will/wont develop a certain outcome.

Co-morbidity – Cardiovascular / pulmonary Hypertension Cardiomyopathy Pericarditis/pericardial effusion Pulmonary arterial hypertension Ischemic heart disease, coronary disease, large vessel disease: role in LMIC?

Co-morbidity – Malignancies AIDS-defining cancers Kaposi sarcoma Non-Hodgkin lymphoma Cervical (invasive, mostly squamous cell) Non AIDS-defining cancers Hodgkin lymphoma Anal and colorectal Liver (HCC) Lung

Co-morbidity – Mental, neurological and substance use Depression Alcohol abuse 3. HIV-associated neurocognitive disorders (HAND) 1+2+3: WHO Mental Health GAP Action Programme

Co-morbidity – Metabolic and bone Diabetes Dysglycemias Dyslipidemias Body composition changes lipodystrophy obesity Bone mineral density abnormalities

Co-morbidity – renal and genito-urinary HIV-associated nephropathy (HIVAN): genetic predisposition (MYH9 and APOL1 genes on chromosome 22) Hypertension and kidney disease Genetic overlap between risk of hypertension, focal segmental glomerulosclerosis (FSGS) and HIVAN Genito-urinary: kidney stones related to ART, prostatitis

Co-morbidity – GI, hepatic and nutritional Liver disease: major mortality in high resource countries HBV, HCV, HDV associated hepatotoxicity Medication-related hepatotoxicity Non-alcoholic fatty liver disease (NAFLD) Hepatocellular carcinoma (HCC) Malnutrition and ART

Co-morbidity – Obstructive lung disease- Difference in population risk factors Environmental exposures Diagnostic limitations Clinical and implementation issues

Low income & middle income countries (LMIC) World Bank definition using annual Gross National Income (GNI) per capita (2013): Low $ 1,035 or less Low-middle $ 1,036-4,085 Upper-middle $ 4,086-12,615 High $ 12,616 or more

Essential interventions for NCDs in low resource settings

What Contributes to the Risk of Co-morbidities in HIV? HOST Genetics Lifestyle Virus/Immune System Antiretroviral Therapy (ART) Relative contributions of each of these factors to the pathogenesis of specific co-morbidities: key to develop strategies for prevention and treatment

More than 50% of HIV-infected adults age 55-60 had >2 co-morbidities, a number higher than HIV-uninfected adults who are a decade older Peter Reiss et al, U. of Amsterdam

Recommendations for observational studies of NCDs in PLHIV Use existing data sources, secondary data analysis Do record linkage between HIV clinical databases and registries (hospital, pharmacy, lab and mortality registries) For high prevalence NCD, add NCD to other large prospective studies Recruit behaviorally and demographically similar HIV pos and neg individuals Assess core risk factors for NCD and variables influencing clinical decision making Disentangle effects of HIV on NCD from HIV-NCD associations due to confounding

Recommendations for observational studies of NCDs in PLHIV (cont’d) Address methodological challenges (selection bias, confounding, informative missingness and loss to F/U, competing risks) Facilitate collaborative research Do meta-analyses of individual participant data (IPD) to overcome limited power of single studies Compare predictions from different mathematical models Build local research capacity

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