Increased Risk of Hepatic Decompensation in HIV/HCV-Coinfected Versus
HCV-Monoinfected Patients Despite ART
Vincent Lo Re, MD, MSCEJ 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 DiseasesCenter 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 pts
• ART slows progression of HCV fibrosis
• Few 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 study• Setting: VACS Virtual Cohort (1997 – 2010)
– Electronic medical record data from:• HIV-infected veterans across U.S.• 1:2 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 pts• Inclusion criteria:
• Excluded if during initial 12 months:– Hepatic decompensation, hepatocellular ca– Received interferon-based HCV therapy
HIV/HCV-coinfected on ART HCV-Monoinfected• Detectable HCV RNA • Detectable HCV RNA
• 12 months of follow-up • 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:– Ascites– Spontaneous bacterial peritonitis– Esophageal variceal bleed
• HD date: hospital admission, 1st outpatient visit• 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)
• Severe liver event: HD, HCC, or liver-related death*
• Death from any cause
*Liver-related death = death from HD, alcoholic liver disease, viral hepatitis, liver cancer, or non-alcoholic liver disease
Demographic Diagnoses Laboratory Pharmacy
Age Alcohol abuse ALT / AST AntiretroviralsSex Cirrhosis HCV genotype
Race Drug abuse HCV RNABody mass index Diabetes mellitus CD4 countSize of VA center Decompensation Creatinine
Year of ART HCC FIB-4Death (NDI) Liver transplant Platelets
HBsAgHemoglobin
HIV RNA
Data Collection
Data Analysis: Follow-up
Study Endpoint
Death
HCV Therapy
Last Visit Before Sept. 30, 2010
HIV/HCVon ART
HCV
12 moIn VA
Baseline
12 moin VA
Baseline
Follow-up
Follow-up
Start ofFollow-up
Start ofFollow-up
Data Analysis: Evaluation of Outcomes
• Compared 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 HD
*Fine J, Gray RJ. J Am Stat Assoc 1999;94:496-509.
HIV/HCV Patient Selection9,086
HIV/HCV Patients Prescribed ART in VACS Virtual Cohort (1997-2010)
4,280HIV/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 Selection11,237
HCV Patientsin VACS Virtual Cohort (1997-2010)
6,079HCV 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 CharacteristicsCharacteristic HIV/HCV
(n=4,280)HCV
(n=6,079)
Mean age (yrs) 48.3 47.1
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/mm3 (%) 44.9%
Median follow-up (yrs) 6.8 9.9
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% 0.004Median age at decompensation (yrs) 52 53 0.44
Perc
ent w
ith D
ecom
pens
atio
n Ev
ent
Ascites Spontaneous Bact. Peritonitis
Variceal Bleed0
10
20
30
40
50
60
70
80
90
HIV/HCV
HCV
83%
77%
18%22%
p=0.226%
55%
p<0.001
p=0.1Frequency 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 carcinoma 1.69 (1.13 - 2.52)
Severe liver events 1.77 (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.
Standardized Cumulative Incidence of Hepatic Decompensation*
ART-TreatedHIV/HCV-Coinfected
HCV-MonoinfectedLog-rank p<0.001
* Based on competing risk regression analysis.
Risk Factors for Decompensation in HIV/HCV Patients on ART
Risk Factor Hazard Ratio (95% CI)
Pre-ART CD4 (cells/mm3) 500 350-499 200-349 <200
Ref0.94 (0.56 - 1.58)0.93 (0.58 - 1.49)1.14 (0.72 - 1.79)
HCV RNA (IU/mL) <400,000 400,000
Ref0.78 (0.52 – 1.18)
Similar results observed with competing risk regression analyses.
• May have missed outcomes– Incidence rates of HD similar to published rates
– Identified liver-related deaths outside VA• Unmeasured confounders: duration, stage of HCV• Generalizability
Potential Limitations
Current Study Prior AnalysesHIV/HCV-coinfected 9.54/1,000 11.6/1,0001
HCV-monoinfected 5.69/1,000 3.4/1,0002
1Pineda JA et al. Hepatology 2007;46:622-30.2Thomas DL et al. JAMA 2000;284:450-6.
• Despite ART, HIV/HCV pts had higher risk of HD than HCV-monoinfected pts
• Future directions: evaluate risk factors, develop predictive index
Conclusions
Acknowledgements• 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:– A. Russell Localio– Michael J. Kallan– K. Rajender Reddy– Jay R. Kostman– Brian L. Strom
• Funding source:– K01 AI 07001 (NIAID)
• VACS patients