Intersection of HIV & NCD’s: Clinical Implications

Mosepele Mosepele MD, MSc

University of Botswana Faculty of Medicine

Botswana-Harvard AIDS Institute Partnership & Harvard School T.H. Chan School of Public Health

OVERVIEW: HIV Patients will Face Increased Rates of NCDs as they Age

• Predicted burden of non-communicable diseases (NCDs) in HIV patients modeled for 2010-2030

• NCDs include• Cardiovascular disease

(hypertension, hypercholesterolemia, myocardial infarction, stroke)

• Diabetes• Chronic kidney disease• Osteoporosis• Non-AIDS malignancies

Smit Lancet ID 2015.

Hospitalization Rates by Diagnosis

• CVD admissions surpassed AIDS-defining illnesses in 4 U.S. clinics

• In military cohort, higher nadir/recent CD4 count associated with decreased risk all-cause hospitalization

Berry IAC 2010. Abstract TUPE0221; Crum-Cianflone JAIDS 2010;54:2478-257

CVD Mortality in HIV –French National Study

Morlat AIDS 2014.

Outline: End Organ Dysfunction

• HIV and cognitive function

• HIV and the liver

• HIV and bone

• HIV and muscle

• HIV and Cardiovascular Disease/Inflammation

Neurocognitive Impairment

• Spectrum of neurologic deficits

• HANDS-Mild, and common (~30%), associated with Inflammation, CM in some studies

• HAD-Severe and rare (~3%), declined with widespread use of ART

• High rates of depression 20-40%, 2 fold higher than general population

• Economic impact unknown

Management of MDD, HANDS

• SSRIs preferred, but should be avoided in there is diarrhea

• Fluoxetine effective in a placebo-controlled RCT1

• Open label trial of Fluoxetine, Sertraline & Paroxetine: 70-90% response rates2,3

• Fluoxetine and group therapy can be effective

• TCA effective, but may worsen symptoms of oral thrush

• No known effective therapy for HANDS

1.Rabkin JG, et al Am J Psychiatry. 1999;156(1):101–107.2.Ferrando SJ, et al Int Rev Psychiatry. 2008;20(1):61–71

3.Rabkin JG, et al J Clin Psychiatry. 1994;55(3):92–97.

Integrase and Maraviroc Intensification in Neurocognitive Dysfunction (InMIND)-A5324

To assess if addition of maraviroc (MVC) and dolutegravir (DTG) to existing suppressive ART regimen will improve neurocognitive performance at 48 weeks (3 arms)

Enrollment will complete in 2018

Look out for more data on this!

https://clinicaltrials.gov/ct2/show/record/NCT02519777

Non-Alcoholic Fatty Liver Disease (NAFLD)

• Up to 1/3 of HIV-infected patients

• In HIC, liver disease is a leading cause of illness and dearth among PLWHIV

• Metabolic factors are the main risk factors

• However, there is limited information on NAFLD (?14% in general population) among mono-infected HIV-infected patients in Africa

1.Maurice et al. AIDS 2017; Morse et al. AIDS 2017

nutrientology.com

Management of NAFLD

• No known effective therapies

• Inflammation thought to play a significant role

• Treat underlying metabolic disorders (NAFLD is associated with excess CVD risk)

• There are no registered drugs for NAFLD. Telmisartan did not lead to improvement. Cinicriviroc (CCR2/CCR5 inhibitor) is currently being evaluated – including for arterial inflammation too. What about statin therapy?

HIV & Cardiovascular Disease

Traditional CVD risk factors among HIV-infected patients in Africa• Undiagnosed traditional CVD risk

factors are common (estimated at about 50%)

• Hypertension(20-30%), dyslipidemia (30%), smoking (23-48%), pre-diabetes (16-24%), diabetes mellitus (1-18%)

• In one study (Cameroon), 18% of participants had 2 or more CVD risk factors

HIV and Risk of Acute Myocardial Infarction

Study Year Population N (HIV) Primary Result Effect Size

Klein 2002 Kaiser 4159 ↑ MI and CHD in HIV vs. control 1.5 (MI) 1.7 (CHD)

Currier 2003 CA Medicaid 28513 ↑ CHD in HIV (age 18-33) vs.

control

2.06

Triant 2007 Partners 3851 ↑ MI in HIV vs. control 1.75

Obel 2007 Danish cohort 3953 ↑ CHD in HIV (on ART) vs.

control

2.12

Lang 2010 FHDH 74958 ↑ MI in HIV vs. 3 population

registries

1.5

Durand 2011 Quebec 7053 ↑ MI in HIV vs. 4:1 matched

control

2.11

Freiberg 2013 VA 27350 ↑ MI in HIV vs. 2:1 matched

control

1.48

Silverberg 2014 Kaiser 22081 ↑ MI and CHD in HIV vs. 10:1

matched control

1.4

Klein JAIDS 2002; Currier JAIDS 2003; Triant JCEM 2007; Obel HIV Med 2010; Lang AIDS 2010; Durand JAIDS 2011; Freiberg JAMA Intern Med 2013; Silverberg JAIDS 2014.

CVD Incidence by Gender and Age

• Increased relative risk in patients traditionally considered low risk

• May reflect the different distribution of CVD risk factors in HIV

Triant CROI 2014, abstract 738.

Malawi case-control study on Stroke, Benjamin et al Neurology® 2016;86:324–333

Managing CVD among HIV-infected patients: using general population guidelines

New Cardiovascular Risk Guidelines

Goff Circulation 2014.

CLINICAL INDICATION OF STATINS➢individuals most likely to benefit from cholesterol-

lowering therapy

➢4 statin benefit groups;

• Clinical ASCVD

• LDL-C ≥5.1mmol/L, Age ≥21 years

• Primary prevention –Diabetes: Age 40-75 years, LDL-C 1.84-5.0mmol/L (LDL in the normal range)

• Primary prevention -No Diabetes: ≥7.5%, 10-year ASCVD risk, Age 40-75 years, LDL-C 1.84-5.0 mg/dL

Challenges in Applying New Cholesterol Guidelines to HIV

Stone Circulation 2014.

Dose-adjustment in HIV (with PIs)

Contraindicated in HIV (with PIs)

Awaiting further study in HIV

FRS and ACC/AHA Underestimate CVD Risk in HIV

• Partners HIV longitudinal cohort, 2239 patients

• ACC/AHA risk score and FRS underestimate CVD risk in HIV

• 14.1% versus 9.4% recommended statin in Gaborone by ACC/AHA versus FRS*

Regan CROI 2015, abstract 751.; Mosepele et al IAS, Durban 2016

FRS

0

5

10

15

20

25

5 Y

ear

Eve

nt R

ate

(%

)

<2.5%

2.5-4.9%

5.0-7.4%

7.5-9.9%

5 Year Predicted Risk

Predicted Observed

ACC/AHA

0

5

10

15

20

25

5 Y

ear

Eve

nt R

ate

(%

)

<2.5%

2.5-4.9%

5.0-7.4%

7.5-9.9%

5 Year Predicted Risk

Predicted Observed

CVD Risk Prediction in HIV: Strategies• Unknown accuracy of FRS and new ACC/AHA calculator in HIV

• New ACC/AHA risk score overestimates risk in general population but may underestimate risk in HIV

• In HIV, risk scores discordant in approximately 19%• FRS assigns low risk and ACC/AHA high risk in 99% of discordant cases

Clinical strategy

• Consider calculating both Framingham Risk Score and ACC/AHA risk score

• Patients in high-risk category by at least one score (>10% for FRS and >7.5% for ACC/AHA) merit:• Suppressive ART if not already treated• Strong consideration of statin• Aggressive CVD risk factor reduction

Preliminary data, Partners HIV cohort.

Traditional Risk Factors Do Not Explain CVD Risk in HIV• Increased AMI risk persists despite accounting for established CVD

risk factors and ART use• Traditional risk factors only account for 10-25% of risk in large cohorts

• Persistent 40-80% increased risk in HIV-infected patients

• Persistently increased risk thought to be driven by HIV-specific inflammation and immune activation, supported by extensive data• SMART study

• Biomarkers of inflammation linked to surrogate markers of CVD

• Vulnerable plaque and arterial inflammation linked to monocyte activation

• Low CD4 and high viral load linked to CVD events

From: Immunologic Basis of Cardiovascular Disease in HIV-Infected AdultsJ Infect Dis. 2012;205(suppl_3):S375-S382. doi:10.1093/infdis/jis200

J Infect Dis | © The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.

All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

ART and CVD Risk: Strategies

• Treat HIV to reduce CVD risk

• CVD-related benefit from virologic suppression and immune reconstitution achieved by treating HIV thought to outweigh possible proatherogenic effects of individual medications

• START trial was first RCT to assess rates of comorbidities including CVD by early versus deferred ART initiation

Clinical strategy

• Treat HIV to reduce inflammation, immune activation, and associated cardiovascular risk

• Consider underlying CVD risk when selecting specific drugs, as individual ART medications may have varying risk

Thompson JAMA 2010; clinicaltrials.gov NCT00867048.

Surrogate biomarkers of Atherosclerotic CVD in Africa (RSA, Rwanda, Uganda, Botswana, Zambia, Cameroon, Eithopia)

• More data on surrogate markers than hard end-points

• Dynamic vascular imaging suggest increased stiffness, increased pulse wave velocity

• Non-dynamic vascular imaging suggests excess common carotid intima thickness while others do not

• Almost all show elevated plasma biomarkers of endothelial dysfunction pre-ART and many years after attaining viral suppression

• Others biomarkers associated with excess CVD are elevated: sCD163, sCD14, IL-6, CRP

What is in the pipeline?

• Anti-inflammatory agents

• Statins for patients considered low CVD risk by standard CVD risk prediction equations

• Alteration of the gut microbiome?

• Anti-CMV vaccines?

Antiinflammatory Therapy with Canakinumabfor Atherosclerotic Disease P.M. Ridker, B.M. Everett, T. Thuren, J.G. MacFadyen, W.H. Chang, C. Ballantyne, F. Fonseca, J. Nicolau, W. Koenig, S.D. Anker, J.J.P. Kastelein, J.H. Cornel, P. Pais, D. Pella, J. Genest, R. Cifkova, A. Lorenzatti, T. Forster, Z. Kobalava, L. VidaSimiti, M. Flather, H. Shimokawa, H. Ogawa, M. Dellborg, P.R.F. Rossi, R.P.T. Troquay, P. Libby,and R.J. Glynn, for the CANTOS Trial Group* NEJM

IL-1 & HIV-associated atherosclerotic disease

• IL-1 pathway is an upstream mediator of inflammation and innate immune system

• IL-1B induces HIV progression, atherosclerosis by binding to IL-1 receptor

Subramanian S. JAMA. 2012

Effect of IL-1β Inhibition on Inflammation and Cardiovascular Risk (clinicaltrials.gov, Hsue P et al CROI 2017 Abstract 126)

Background & MethodsTo evaluate the effects of IL-1β inhibition on safety, measures of systemic and vascular inflammation and endothelial function among 10 virally suppressed HIV-infected patients

Study drug: 150mg Canakinumab

Evaluations: pre- and 8 weeks post exposure included FDG-PET imaging, hsCRP/IL-6 measurements

Effect of IL-1β Inhibition on Inflammation and Cardiovascular Risk (clinicaltrials.gov, Hsue P et al CROI 2017 Abstract 126)

Results:Among 10 virally suppressed male HIV-infected patients, median 59 years old, 80% on statin therapy,

Canakinumab associated with 10% decrease in arterial inflammation

Canakinumab was associated with statistically significant decline in hsCRP, IL-6

Canakinumab associated with 11% decrease in bone marrow metabolic activity

REPRIEVE

• The REPRIEVE trial is the first large-scale randomized clinical trial to test a strategy for preventing heart-related disease among people living with HIV

• Hypothesis: Statins will prevent cardiovascular disease in HIV-infected patients, particularly among the large group with minimal traditional risk and not meeting current guidelines for clinical use of statins but at risk for CVD based on unique pathophysiology of vulnerable plaque morphology and inflammation

CLINICAL INDICATION OF STATINS➢individuals most likely to benefit from cholesterol-

lowering therapy

➢4 statin benefit groups;

• Clinical ASCVD

• LDL-C ≥5.1mmol/L, Age ≥21 years

• Primary prevention –Diabetes: Age 40-75 years, LDL-C 1.84-5.0mmol/L (LDL in the normal range)

• Primary prevention -No Diabetes: ≥7.5%, 10-year ASCVD risk, Age 40-75 years, LDL-C 1.84-5.0 mg/dL

• REPRIVE primary prevention strategy: no Diabetes, ASCVD <7.5% eligible if LDL <5.0

6 year F/u

(n=6500)

(n=800)

Intervention

Clinical

Primary Endpoint

TimeScreening

And

Consent

Asymptomatic HIV+ patients with no history of CVD

Pitavastatin 4mg/dayPlacebo

MICV Death Unstable Angina Arterial Revasc

Secondary

Endpoints

Individual components of primary endpoint

All Cause Death

RandomizationR

Incidence/Progression of noncalcified plaque; High-risk plaque

Mechanistic

Study

Inflammatory, immunological, metabolic biomarkers

Mechanistic

Primary Endpoint

Coronary plaque, vascular inflammation, immune activation

Stroke

Predictors of statin effects

Statin safety and non AIDS comorbidities: DM, Infections, Cancer

All cause death

Intervention

Clinical

Primary Endpoint

TimeScreening

And

Consent

Asymptomatic HIV+ patients with no history of CVD

Pitavastatin 4mg/dayPlacebo

MICV Death Unstable Angina Arterial Revasc

Secondary

Endpoints

Individual components of primary endpoint

All Cause Death

RandomizationR

Incidence/Progression of noncalcified plaque; High-risk plaque

Mechanistic

Study

Inflammatory, immunological, metabolic biomarkers

Mechanistic

Primary Endpoint

Coronary plaque, vascular inflammation, immune activation

Stroke

Predictors of statin effects

Statin safety and non AIDS comorbidities: DM, Infections, Cancer

All cause death

PAD

Only selected sites are participating in the substudy.

REPRIEVE (A5332) Design

35 -TO

Effects of the Probiotic Visbiome Extra Strength on Gut Microbiome & Immune Activation Markers (www.actgnetwork.org)

• Assess if probiotics will reduce inflammation among virally suppressed adults

• Main outcome measure is sCD14

• Results expected in 2018

Safety, Tolerability, Immunogenicity, and VirologicEfficacy of an anti-CMV Vaccine (Triplex®) (www.actgnetwork.org)

Protocol in development

*With almost 100% CMV sero-prevalence in Africa, this study will be highly relevant for HIV-infected patients in Africa

Management of NCDs in HIV: Key Principles• Significant impact of Depression, Neurocognitive disorders, Chronic liver disease,

CVD in HIV populations anticipated

• Pathophysiology driven in large part by HIV-related immunologic and inflammatory changes (not a feature of recommended interventions)

• Recommended strategies• Build Depression screening, TOTAL CVD risk assessment into ROUTINE clinical practice

• Manage traditional risk factors aggressively (e.g. alcohol, smoking), helps with NAFLD

• COMMONEST indication for statin therapy in different populations is primary prevention, so, if you don’t calculate predicted CVD risk, you may never initiate statin therapy for primary prevention!

• Treat HIV to reduce CVD risk