Risk of serious disease and death in people with HIV viral suppression on ART: an epidemiologic perspective The Lancet and Cell Meeting What Will it Take to Achieve an AIDS-free World? Session 4: Long term consequences of living with HIV: comorbidities & ageing San Francisco, 3-5 November 2013

Trend in median CD4 count in clinic populations CD4 count (/mm 3 ) Smith C, Lampe F, Johnson M, et al

Prevalence of viral load > 50c/mL in people on ART* Smith C, Lampe F, Johnson M, et al Proportion *Of those receiving ART>24 weeks

Trends in death rate in people with HIV: UK Source: Public Health England Number of deaths in year Number seen for care in year Year Rate per 100 people

Trend in cause-specific death rate in people with HIV: D:A:D AIDS Other - known Liver CVD Unknown Non-AIDS cancer D:A:D unpublished

Projected life expectancy of UK man infected age 30 Nakagawa et al, AIDS 2012

What are the residual excess disease risks due to HIV in people with viral suppression ?

Cause-specific death rate in SMART/ESPRIT control arms: baseline viral load < 500 cps/mL Rate per 100 person- yrs Liver CVDAIDS Other/ unknown Cancer All causes

What are the residual excess disease risks due to HIV in people with viral suppression ? Insufficient CD4 count recovery Inflammation Adverse effects of antiretroviral drugs Note: looking at risks due to HIV and not correlates of HIV such as lifestyle factors (smoking, alcohol, recreational drug use) and mental health and hepatitis.

What are the residual excess disease risks due to HIV in people with viral suppression ? Insufficient CD4 count recovery Inflammation Adverse effects of antiretroviral drugs

CD4 count recovery on ART if fully virally suppressed UK CHIC Study; Hughes et al, HIV Medicine 2010; see also Mocroft et al Lancet 2007

Attainment of CD4 count above key thresholds in people starting ART with CD4 count < 100/mm 3 with sustained virologic suppression n=400 median CD4 count at start of ART 38 /mm 3 O’Connor et al; in revision

CD4 count and risk of death in people on ART with viral suppression: COHERE COHERE PLoS Med 2012; also Weber et al D:A:D Arch Intern Med 2006 Most recent CD4Death rate (/1000 person years) cell count (/mm 3 ) Death fromDeath from causes any causeunrelated to HIV < >

CD4 count and risk of non-AIDS disease events in people on ART with viral suppression: D:A:D Source: D:A:D (unpublished) 500 CD4 count Rate ratio Liver MI Stroke Renal Non-AIDS Cancer Trend highly statistically significant in all cases except for MI

Lodi et al; JID 2011 Natural history of HIV: CD4 count distribution according to time from infection

What are the residual excess disease risks due to HIV in people with viral suppression ? Insufficient CD4 count recovery Inflammation Adverse effects of antiretroviral drugs

Biomarker levels in SMART participants with viral load < 400 cps/mL compared with HIV negative people in CARDIA and MESA studies Neuhaus et al, JID 2010 People age 33-44People age nfold-difference IL (p < 0.001) (p < 0.001) D-dimer (p < 0.001) adjusted for age, race, sex, body mass index, smoking, ratio of total cholesterol:high-density lipoprotein cholesterol, diabetes, lipid-lowering therapy, and blood pressure–lowering therapy

Odds ratio for elevated* IL-6 and D-dimer levels in HIV positive people on ART with viral load < 500 cps/mL compared with HIV negative people: VACS study Armah et al, CID 2012 Odds Ratio (95% confidence interval) IL ( ) D-dimer0.71 ( ) n ~ 1800; *elevated level is > 75th percentile adjusted for age, race/ethnicity, prevalent CVD, hypertension, diabetes, smoking, BMI, cholesterol lowering medication use, HDL, LDL, triglycerides, cocaine use in the past year, alcohol use, HCV infection, and renal disease.

INSIGHT, unpublished Grund et al, CROI 2013 n=3766 adjusted for age and sex Baseline IL-6 / D-dimer levels and risk of serious non- AIDS and mortality in people in SMART, ESPRIT and SILCAAT control arms with viral load < 500 cps/mL

IL-6 and D-dimer and risk of serious non-AIDS events and death adjusted for age and sex Grund et al, CROI 2013 n=3766

What are the residual excess disease risks due to HIV in people with viral suppression ? Insufficient CD4 count recovery Inflammation Adverse effects of antiretroviral drugs

D:A:D N Engl J Med 2003 Antiretroviral drugs and risk of myocardial infarction

D:A:D Lancet 2008 Unanticipated association between abacavir use and raised risk of myocardial infarction

Antiretroviral drugs and renal impairment Ryom L et al; D:A:D CID 2013 People with initial eGFR > 90 mL/min Rate ratio (95% CI) per extra year of exposure Rate ratio (95% CI) per extra year of exposure Progression to eGFR < 60 Progression to eGFR < 70 adjusted for baseline eGFR, age, sex, ethnicity, risk group, sex, nadir CD4 count, cohort, prior AIDS, baseline date, HBV, HCV, smoking, hypertension, diabetes, CVD, CD4 count, viral load, cumulative exposure to specific drugs.

Adjusted rate ratios for associations between ART exposure and AIDS- and non-AIDS-defining cancer Adjusted for age, sex, cohort, HIV mode of acquisition, ethnic group, calendar year, body mass index, any prior cancer, prior AIDS diagnosis, prior AIDS cancer, smoking status, HCV and HBV status AIDS-defining cancer (n = 1,151)Non-AIDS-defining cancer (n = 1,091) aRR and 95% CI Any cARTPINNRTI 0.8 ART exposure (/year) Any cARTPINNRTI 0.8 aRR and 95% CI ART exposure (/ year ) Bruyand et al D:A:D CROI 2013 Also Chao et al, AIDS 2012, Piketty et al J Clin Oncol 2012

Comparisons of people with high CD4 count with HIV negative populations What are the residual excess disease risks due to HIV in people with viral suppression ?

Confounding due to differences between HIV positive and HIV negative or general population comparator; e.g. smoking, drug use, socio-economic status, mental health, access to regular health care Differential ascertainment of events Selection bias within the HIV positive people; e.g. achieved viral suppression, diagnosed earlier at higher CD4 count, better health seeking behaviour, entry into a clinical trial Small relative risks correspond to large absolute risk differences at older ages Comparisons of people with high CD4 count with HIV negative populations - issues with interpretation

Myocardial Infarction rates compared with general population: Kaiser-Permanante database Klein et al; CROI 2011 HIV +ve: 90,961 HIV –ve: 1,133,444 Relative rate95% CIp-value (compared with HIV negative) MI overall <0.001 CHD overall <0.001 CD4 > 500, on ART CD4 > 500, not on ART matched on age, sex, medical center, year of start of follow-up. Adjusted for smoking, alcohol/drug use, obesity, diabetes, lipid lowering drugs, antihypertensive drugs.

Comparison of MI risk with HIV uninfected: VACS study Freiberg et al; JAMA Intern Med 2013 Hazard ratio* (95% CI) Uninfected1.00 Infected viral load > ( ) Infected viral load < ( ) *adjusted for age, sex, race/ethnicity, hypertension, lipids, smoking, HMG-CoA reductase-inhibitor use, hepatitis C virus infection, renal disease, body mass index, and cocaine and alcohol abuse and dependence.

Lewden et al, IJE 2012 See also Zwahlen et at IJE, 2009 Death rate in ART-experienced MSM with CD4 count > 500, compared with the general population: COHERE n ~ 28,000 MSM Previous AIDS No previous AIDS >60 Age 5 yrs 4 yrs 3 yrs 2 yrs 1 yr SMR Time with CD4 > 500 Current

Survival in people on ART without risk factors compared with the general population in Denmark Obel et al, PLoS One 2011 Estimated probability of survival from age 25 to 65 years (95% CI) General population0.88( ) HIV infected without0.86( ) HIV risk factors, comorbidities or substance abuse

SMR in non-IDU in SMART and ESPRIT control groups compared with the general population - Viral load 350 in past 6 months CD CD4 > 500 SMR (95% CI) ( )( ) Rodger et al, AIDS 2013

Summary and Conclusions - 1 The main causes or potential causes of excess risk of serious disease due to HIV in people with viral suppression are on- going CD4 cell immunodeficency, inflammation and related factors, and adverse effects of ART. CD4 cell immunodefiency is markedly improved with virally suppressive ART but full re-normalisation can take several years and may not always be achieveable. Some excess inflammation appears to persist in people with viral suppression. Potential therapeutic approaches to enhance the rate of CD4 count restoration and/or reduce inflammation should be investigated.

Summary and Conclusions - 2 We should remain vigilant over potential adverse effects of antiretroviral drugs. Comparisons of people with high CD4 count with HIV negative people show some evidence, albeit inconsistent, for modest residual raised risk of serious clinical events and death. Interpretation is difficult and significant biases in either direction are highly possible. Nonetheless, there is sufficient evidence for excess risks, and concern that these will become more significant with ageing, that this group must remain the focus of study.

Acknowledgements Helpful comments, advice and extra analyses from: Jim Neaton Colette Smith Jason Baker Fiona Lampe Alison Rodger Caroline Sabin, Steve Deeks Amanda Mocroft David Kamara Jemma O’Connor Jacquie Neuhaus Debby Wentworth Alessandro Cozzi Lepri Jens Lundgren