Intersection of HIV & NCD s: Clinical Implications

Transcription

1 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

2 OVERVIEW: HIV Patients will Face Increased Rates of NCDs as they Age Predicted burden of non-communicable diseases (NCDs) in HIV patients modeled for NCDs include Cardiovascular disease (hypertension, hypercholesterolemia, myocardial infarction, stroke) Diabetes Chronic kidney disease Osteoporosis Non-AIDS malignancies Smit Lancet ID 2015.

3 Hospitalization Rates by Diagnosis CVD admissions surpassed AIDSdefining illnesses in 4 U.S. clinics In military cohort, higher nadir/recent CD4 count associated with decreased risk all-cause hospitalization Berry IAC Abstract TUPE0221; Crum-Cianflone JAIDS 2010;54:

4 CVD Mortality in HIV French National Study Morlat AIDS 2014.

5 Outline: End Organ Dysfunction HIV and cognitive function HIV and the liver HIV and bone HIV and muscle HIV and Cardiovascular Disease/Inflammation

6 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

7 Management of MDD, HANDS SSRIs preferred, but should be avoided in there is diarrhea Fluoxetine effective in a placebo-controlled RCT 1 Open label trial of Fluoxetine, Sertraline & Paroxetine: 70-90% response rates 2,3 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): Ferrando SJ, et al Int Rev Psychiatry. 2008;20(1): Rabkin JG, et al J Clin Psychiatry. 1994;55(3):92 97.

8 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!

9 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

10 nutrientology.com

11 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?

12 HIV & Cardiovascular Disease

13 Traditional CVD risk factors among HIVinfected 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

14 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 CHD in HIV (age 18-33) vs. control Triant 2007 Partners 3851 MI in HIV vs. control Obel 2007 Danish cohort 3953 CHD in HIV (on ART) vs. control Lang 2010 FHDH MI in HIV vs. 3 population registries Durand 2011 Quebec 7053 MI in HIV vs. 4:1 matched control Freiberg 2013 VA MI in HIV vs. 2:1 matched control Silverberg 2014 Kaiser MI and CHD in HIV vs. 10:1 matched control 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.

15 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.

16 Malawi case-control study on Stroke, Benjamin et al Neurology 2016;86:

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

18 New Cardiovascular Risk Guidelines Goff Circulation 2014.

19 CLINICAL INDICATION OF STATINS individuals most likely to benefit from cholesterollowering therapy 4 statin benefit groups; Clinical ASCVD LDL-C 5.1mmol/L, Age 21 years Primary prevention Diabetes: Age years, LDL-C mmol/L (LDL in the normal range) Primary prevention -No Diabetes: 7.5%, 10-year ASCVD risk, Age years, LDL-C mg/dl

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21 Challenges in Applying New Cholesterol Guidelines to HIV Stone Circulation Dose-adjustment in HIV (with PIs) Contraindicated in HIV (with PIs) Awaiting further study in HIV

22 5 Year Event Rate (%) 5 Year Event Rate (%) FRS and ACC/AHA Underestimate CVD Risk in HIV 25 FRS 25 ACC/AHA <2.5% % % 5 Year Predicted Risk % 0 <2.5% % % 5 Year Predicted Risk % Predicted Observed Predicted Observed 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

23 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.

24 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

25 From: Immunologic Basis of Cardiovascular Disease in HIV-Infected Adults J Infect Dis. 2012;205(suppl_3):S375-S382. doi: /infdis/jis200 J Infect Dis The Author Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please journals.permissions@oup.com

26 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 NCT

27 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

28 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?

29 Antiinflammatory Therapy with Canakinumab for 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

30 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

31 Effect of IL-1β Inhibition on Inflammation and Cardiovascular Risk (clinicaltrials.gov, Hsue P et al CROI 2017 Abstract 126) Background & Methods To evaluate the effects of IL-1β inhibition on safety, measures of systemic and vascular inflammation and endothelial function among 10 virally suppressed HIVinfected patients Study drug: 150mg Canakinumab Evaluations: pre- and 8 weeks post exposure included FDG-PET imaging, hscrp/il-6 measurements

32 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

33 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

34 CLINICAL INDICATION OF STATINS individuals most likely to benefit from cholesterollowering therapy 4 statin benefit groups; Clinical ASCVD LDL-C 5.1mmol/L, Age 21 years Primary prevention Diabetes: Age years, LDL-C mmol/L (LDL in the normal range) Primary prevention -No Diabetes: 7.5%, 10-year ASCVD risk, Age years, LDL-C mg/dl REPRIVE primary prevention strategy: no Diabetes, ASCVD <7.5% eligible if LDL <5.0

35 REPRIEVE (A5332) Design Only selected sites are participating in the substudy. Time 6 year F/u Screening Asymptomatic HIV+ patients with no history of CVD And Consent R (n=6500) Placebo Pitavastatin 4mg/day Intervention Mechanistic Study (n=800) Randomization Coronary plaque, vascular Mechanistic inflammation, immune activation Primary Endpoint CV Death CV Death MI MI Unstable Unstable Angina Angina Stroke Stroke Arterial Arterial Revasc RevascPAD Clinical Primary Endpoint Individual components of primary endpoint All cause death Incidence/Progression of noncalcified plaque; High-risk plaque Inflammatory, immunological, metabolic biomarkers Secondary Endpoints Predictors All Cause of statin Death effects Statin safety and non AIDS comorbidities: DM, Infections, Cancer 35 -TO

36 Effects of the Probiotic Visbiome Extra Strength on Gut Microbiome & Immune Activation Markers ( Assess if probiotics will reduce inflammation among virally suppressed adults Main outcome measure is scd14 Results expected in 2018

37 Safety, Tolerability, Immunogenicity, and Virologic Efficacy of an anti-cmv Vaccine (Triplex ) ( Protocol in development *With almost 100% CMV sero-prevalence in Africa, this study will be highly relevant for HIV-infected patients in Africa

38 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