HAART Mitigates Liver Disease Progression in HIV- Viral Hepatitis Co-infected Men Jennifer Price 1, Eric Seaberg 2, Sheila Badri 3, Mallory Witt 4, Kristin DAcunto 5, Chloe Thio 1 1 Johns Hopkins University School of Medicine, Baltimore, MD 2 Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 3 Rush University Medical Center, Chicago, IL 4 David Geffen School of Medicine at UCLA, Torrance, CA 5 University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA

HIV and Liver Disease Since HAART, substantial reduction in AIDS deaths Relative increase in liver-related morbidity & mortality o Common non-AIDS causes of death among HIV+ HCV or HBV co-infection: o Accelerated liver fibrosis, risk of cirrhosis, risk of liver decompensation and death Studies on impact of HAART on liver disease in HIV-viral hepatitis co-infection conflicting J Acquir Immune Defic Syndr 2006;43: Arch Intern Med 2006;166: Clin Infect Dis 2001;32: AIDS Res Hum Retroviruses 2001;17:

AST-to-Platelet Ratio Index (APRI) 100x (AST/ULN)/platelet count Validated as surrogate marker of significant fibrosis (Ishak 3) in HCV +/- HIV co- infection o Cut-off APRI>1.5: 40% sensitive, 95% specific Highly predictive of liver-related mortality in cohort with HCV +/- HIV co-infection Hepatology 2003;38: Am J Gastroenterol 2010;105:

Hypothesis Liver disease progression, as measured by APRI, will improve with HAART use in a cohort of men at-risk for HIV and viral hepatitis infections

Methods Multicenter AIDS Cohort Study (MACS) o Ongoing prospective cohort study of HIV+/- MSM o Enrollment began 1984 (HAART availability ~1996) Men categorized by disease status: o No infection (neither HIV, HCV, HBV) o HIV monoinfection o Hepatitis monoinfection (HCV, HBV or both) o HIV-Hepatitis co-infection (HCV, HBV or both)

Study Design Baseline (N=1839) Follow-up (N=1799) HIV-Hep co- infected HIV monoinfected Hepatitis monoinfected (n=72) Uninfected (n=1152) 1 year 2 years APRI HAART Initiation HAART naïve (n=18) HAART initiated (n=43) HAART naïve (n=136) HAART initiated (n=367) Baseline= pre-HAART visit or calendar- matched time point Study time

Analysis APRI slope calculated (Δ APRI points/yr) Linear regression APRI slope among men without significant liver disease (APRI 1.5) at baseline o Performed in entire cohort & limited to hepatitis + o Sensitivity analysis including men with APRI >1.5

*p-values for comparison across all groups use Kruskall-Wallis rank test or chi- squared test + comparison limited to hepatitis-infected ¥ comparison limited to HIV-infected Baseline (pre-HAART) Characteristics

Baseline APRI No InfectionHIV MonoinfectedHep MonoinfectedCoinfected Baseline APRI APRI <0.5 (none/mild) APRI (intermediate ) APRI >1.5 (significant) Percent

APRI Change Over Time No Infection HIV Monoinfected Hep Monoinfected Coinfected Mean APRI Baseline (Year 0) HAART Initiation (cases) Follow-up (Year 3) Change in APRI over Time

Factors Associated with APRI Slope: Multivariate Analysis *Baseline APRI, age, race, and alcohol use also included in model Difference in APRI Slope 95% CIp-value Disease Category (ref=HIV, Hep uninfected) HIV mono <0.001 Hepatitis mono HIV-Hep co-infection <0.001 HAART use (ref= no HAART) APRI slope for models reference group: pt/yr (95% CI , 0.015)*

Multivariate Analysis Limited to Hepatitis-Positive *Baseline APRI, age, race, alcohol use also included in model; n=110 Difference in APRI Slope 95% CIp-value HIV-Hep Co-infected (ref= Hep mono) HAART use (ref= no HAART) APRI slope for models reference group: pt/yr (95% CI , 0.113)* HAART reduced HIV-associated APRI increase by 73% (0.114/0.156)

Summary Baseline APRI values: o Co-infected> HIV mono Hep Mono >Uninfected o AST drives APRI differences more than platelets APRI slope over follow-up: o Co-infected> HIV mono Hep Mono >Uninfected HAART is associated with lower APRI slope Compared to hepatitis monoinfected men o HAART naïve co-infected men have significantly higher APRI slope o HAART reduces this by 73%

Conclusion Observations of change in APRI suggest HIV-Hep co-infection is associated with faster liver fibrosis progression than either infection alone HAART mitigates but does not fully overcome this accelerated progression

Acknowledgements Chloe Thio, MD Eric Seaberg, PhD Melissa Saulynas MACS participants and staff This work was funded by the NCRR 1KL2RR and the NIDA 5R03DA

APRI Change Among HIV+ HIV Mono HI HIV Mono HN Co-infected HI ¥ Co-infected HN* Mean APRI Baseline (Year 0) HAART Initiation (cases) Follow-up (Year 3) Change in APRI over Time Among HIV+ Co-infected HN Co-infected HI HIV Mono HI/HN *HN=HAART Naïve ¥ HI=HAART Initiator

HAART Naïve (HN) vs HAART Initiators (HI)

Factors Associated with Baseline APRI Entire Cohort* *Model also includes BMI, alcohol, race, calendar year Fold-difference APRI (95%CI) p-value Hepatitis+ vs Hep (1.97, 2.79) <0.001 HIV VL 100, (1.05, 1.45) CD (1.04, 1.44) Model also includes age, calendar year, BMI, alcohol, race, ART Limited to HIV-positive +