1. 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

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. 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

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
Implementation
Scale-Up
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)
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

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
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)

34. 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

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

51. 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

52. HIV and NCD co-morbidity in LMIC– A Systematic Review
Systematic review of studies from Medline and Embase ( )
Magnitude and determinants of NCDs in PLHA
37 studies (25 from Africa), 20 countries, 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%

53. 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)

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

55. Potential Clinical Consequences of Microbial Translocation
Deeks, Immunity 2013

56. 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

57. 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

59. Lancet, series on NCDs
The Lancet

60. 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.

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

62. 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

63. 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

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

65. 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

66. 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

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

68. 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

69. Essential interventions for NCDs in low resource settings

70. 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

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

72. 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

73. 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

74. 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?