Presentation on theme: "Increased Risk of Hepatic Decompensation in HIV/HCV-Coinfected Versus HCV-Monoinfected Patients Despite ART Vincent Lo Re, MD, MSCE J Tate, MJ Kallan,"— Presentation transcript:
Increased Risk of Hepatic Decompensation in HIV/HCV-Coinfected Versus HCV-Monoinfected Patients Despite ART Vincent Lo Re, MD, MSCE J Tate, MJ Kallan, JK Lim, MB Goetz, D Rimland, MB Klein, MC Rodriguez-Barradas, AA Butt, CL Gibert, ST Brown, JR Kostman, BL Strom, KR Reddy, AC Justice, R Localio for the Veterans Aging Cohort Study (VACS) Team Division of Infectious Diseases Center for Clinical Epidemiology and Biostatistics University of Pennsylvania
HCV-Related Liver Complications in HIV/HCV Patients on ART Hepatic decompensation (HD), hepatocellular ca (HCC) contribute to morbidity in HIV/HCV ptsHepatic decompensation (HD), hepatocellular ca (HCC) contribute to morbidity in HIV/HCV pts ART slows progression of HCV fibrosisART slows progression of HCV fibrosis Few data compare liver complications between ART-treated HIV/HCV and HCV only ptsFew data compare liver complications between ART-treated HIV/HCV and HCV only pts –Unclear if rates of HD in HIV/HCV pts on ART similar to those with HCV alone Qurishi N et al. Lancet. 2003;362:1708-13. Brau N et al. J Hepatol 2006;44:47-55.
Specific Aim Aim: To compare the incidence of HD between ART-treated HIV/HCV-coinfected and HCV-monoinfected pts Hypothesis: Rates of HD would remain higher in HIV/HCV pts despite ART
Study Design / Setting Design: Retrospective cohort studyDesign: Retrospective cohort study Setting: VACS Virtual Cohort (1997 – 2010)Setting: VACS Virtual Cohort (1997 – 2010) –Electronic medical record data from: HIV-infected veterans across U.S.HIV-infected veterans across U.S. 1:2 age-, race/ethnicity-, and site-matched sample of HIV-uninfected veterans1:2 age-, race/ethnicity-, and site-matched sample of HIV-uninfected veterans –Diagnoses, lab, pharmacy fill data –Death date recorded –Cause of death (National Death Index)
Study Subjects: Inclusion / Exclusion Criteria From HIV+, HIV- groups chronic HCV ptsFrom HIV+, HIV- groups chronic HCV pts Inclusion criteria:Inclusion criteria: Excluded if during initial 12 months:Excluded if during initial 12 months: –Hepatic decompensation, hepatocellular ca –Received interferon-based HCV therapy HIV/HCV-coinfected on ARTHCV-Monoinfected Detectable HCV RNA 12 months of follow-up Received ART + had HIV RNA >500 c/mL within 6 months prior to ART No HIV diagnosis or ARV fills
Primary Outcome: Hepatic Decompensation (HD) Defined by: 1 hospital ICD-9 diagnosis or 2 outpatient diagnoses for:Defined by: 1 hospital ICD-9 diagnosis or 2 outpatient diagnoses for: –Ascites –Spontaneous bacterial peritonitis –Esophageal variceal bleed HD date: hospital admission, 1 st outpatient visitHD date: hospital admission, 1 st outpatient visit 91% had HD by case arbitration *91% had HD by case arbitration * –Hepatic encephalopathy, non-obstructive jaundice evaluated, but had low positive predictive value *Lo Re V et al. Pharmacoepidemiol Drug Saf 2011;20:689-99.
Secondary Outcomes Hepatocellular ca (HCC): VA Cancer Registry (pathology, cytology, consistent CT / MRI)Hepatocellular ca (HCC): VA Cancer Registry (pathology, cytology, consistent CT / MRI) Severe liver event: HD, HCC, or liver-related death *Severe liver event: HD, HCC, or liver-related death * Death from any causeDeath from any cause * Liver-related death = death from HD, alcoholic liver disease, viral hepatitis, liver cancer, or non-alcoholic liver disease
DemographicDiagnosesLaboratoryPharmacy Age Alcohol abuseALT / ASTAntiretrovirals SexCirrhosisHCV genotype RaceDrug abuseHCV RNA Body mass indexDiabetes mellitusCD4 count Size of VA centerDecompensationCreatinine Year of ARTHCCFIB-4 Death (NDI)Liver transplantPlatelets HBsAg Hemoglobin HIV RNA Data Collection
Data Analysis: Follow-up Study Endpoint Death HCV Therapy Last Visit Before Sept. 30, 2010 HIV/HCV on ART HCV 12 mo In VA Baseline 12 mo in VA Baseline Follow-up Start of Follow-up Start of Follow-up
Data Analysis: Evaluation of Outcomes Compared incidence, rates of outcomes: HIV/HCV vs. HCV cohortsCompared incidence, rates of outcomes: HIV/HCV vs. HCV cohorts –Cox regression (hazard ratios [HRs]) –Competing risk regression (HRs) * –Standardized cumulative incidence of HD Exploratory (HIV/HCV pts): evaluated pre-ART CD4 and HCV RNA level as risk factors for HDExploratory (HIV/HCV pts): evaluated pre-ART CD4 and HCV RNA level as risk factors for HD * Fine J, Gray RJ. J Am Stat Assoc 1999;94:496-509.
HIV/HCV Patient Selection 9,086 HIV/HCV Patients Prescribed ART in VACS Virtual Cohort (1997-2010) 4,280 HIV/HCV Patients on ART 4,806 Did not meet inclusion criteria: 122 Decompensation at baseline 62 Interferon prior to start of follow-up 1,466 HIV RNA <500 within 6 months prior to ART 1,089 Missing HIV RNA within 6 months prior to ART 851 Negative HCV RNA 1,216 Missing HCV RNA
HCV Patient Selection 11,237 HCV Patients in VACS Virtual Cohort (1997-2010) 6,079 HCV Patients 5,158 Did not meet inclusion criteria: 214 Without 12 months of follow-up 216 Decompensation at baseline 91 Interferon prior to start of follow-up 730 Negative HCV RNA 3,906 Missing HCV RNA 1 Cause of death listed as HIV/AIDS
Baseline Characteristics CharacteristicHIV/HCV (n=4,280) HCV (n=6,079) Mean age (yrs)48.347.1 Male sex (%)98.5%99.1% Black race (%)65.1%61.4% Alcohol dependence/abuse (%) 26.4%30.7% HCV ≥400,000 IU/mL (%)65.2%55.0% Mean pre-ART HIV (log c/mL)5.1 Pre-ART CD4 ≤200/mm 3 (%)44.9% Median follow-up (yrs)6.89.9
Hepatic Decompensation Events * * Initial hepatic decompensation may have presented with >1 event. Outcome HIV/HCV (n=4,280) HCV (n=6,079) P-Value Hepatic decompensation (%)6.3%5.0%0.004 Median age at decompensation (yrs)52530.44 Percent with Decompensation Event p=0.1 Frequency of Decompensation Events At Incident Decompensation
Frequency of Secondary Outcomes Outcome HIV/HCV (n=4,280) HCV (n=6,079) P- Value Hepatocellular ca (n, %)1.2%0.9%0.25 Severe liver event (n, %)7.7%6.0%0.001 Death (n, %)32.9%15.4%<0.001 Liver deaths (of all deaths; %)7.8%20.1%<0.001
Risk of Outcomes in ART-Treated HIV/HCV vs. HCV Outcome Adjusted Hazard Ratio * (95% CI) Hepatic decompensation All patients HIV/HCV patients with: HIV RNA<1,000 during follow-up (n=966) HIV RNA<400 during follow-up (n=386) 1.83 (1.54 - 2.18) 1.71 (1.23 - 1.36) 1.73 (1.00 - 3.01) Hepatocellular carcinoma1.69 (1.13 - 2.52) Severe liver events1.77 (1.52 - 2.06) * Adjusted for age, race, BMI, history of alcohol / drug abuse, and size of VA center. Similar results observed with competing risk regression analyses. Similar results observed with competing risk regression analyses.
Standardized Cumulative Incidence of Hepatic Decompensation * ART-Treated HIV/HCV-Coinfected HCV-Monoinfected Log-rank p<0.001 * Based on competing risk regression analysis.
Risk Factors for Decompensation in HIV/HCV Patients on ART Risk FactorHazard Ratio (95% CI) Pre-ART CD4 (cells/mm 3 ) 500 350-499 200-349 <200 Ref 0.94 (0.56 - 1.58) 0.93 (0.58 - 1.49) 1.14 (0.72 - 1.79) HCV RNA (IU/mL) <400,000 400,000 Ref 0.78 (0.52 – 1.18) Similar results observed with competing risk regression analyses.
May have missed outcomesMay have missed outcomes –Incidence rates of HD similar to published rates –Identified liver-related deaths outside VA Unmeasured confounders: duration, stage of HCVUnmeasured confounders: duration, stage of HCV GeneralizabilityGeneralizability Potential Limitations Current StudyPrior Analyses HIV/HCV-coinfected9.54/1,00011.6/1,000 1 HCV-monoinfected5.69/1,0003.4/1,000 2 1 Pineda JA et al. Hepatology 2007;46:622-30. 2 Thomas DL et al. JAMA 2000;284:450-6.
Despite ART, HIV/HCV pts had higher risk of HD than HCV-monoinfected ptsDespite ART, HIV/HCV pts had higher risk of HD than HCV-monoinfected pts Future directions: evaluate risk factors, develop predictive indexFuture directions: evaluate risk factors, develop predictive index Conclusions
Acknowledgements VACS Liver Core:VACS Liver Core: –Joseph K. Lim (Co-Chair) –Janet Tate –Matthew B. Goetz –Adeel A. Butt –David Rimland –Maria Rodriguez-Barradas –Cynthia L. Gibert –Sheldon T. Brown –Marina B. Klein –Lesley Park –Robert Dubrow –Amy C. Justice Penn:Penn: –A. Russell Localio –Michael J. Kallan –K. Rajender Reddy –Jay R. Kostman –Brian L. Strom Funding source:Funding source: –K01 AI 07001 (NIAID) VACS patientsVACS patients