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 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 Antiretrovirals

Sex Cirrhosis HCV genotype

Race Drug abuse HCV RNA

Body mass index Diabetes mellitus CD4 count

Size of VA center Decompensation Creatinine

Year of ART HCC FIB-4

Death (NDI) Liver transplant Platelets

HBsAg

Hemoglobin

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 Selection

9,086 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 Selection

11,237 HCV Patients

in 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.

OutcomeHIV/HCV(n=4,280)

HCV(n=6,079)

P-Value

Hepatic decompensation (%) 6.3% 5.0% 0.004

Median age at decompensation (yrs) 52 53 0.44

Pe

rce

nt

wit

h D

ec

om

pe

ns

ati

on

Ev

en

t

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

OutcomeHIV/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 Analyses

HIV/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