icon-folder.gif   Conference Reports for NATAP  
  AASLD (American Association for the Study of Liver Diseases)
Nov 2-5, 2002, Boston, MA
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HCV in HIV Coinfection and in IVDUs
Reported by Jules Levin
  Accelerated Fibrosis Observed in HCV/HIV Coinfected Patients
Mohsen (King's College Hospital, London, UK) reported on a study comparing the rate of fibrosis progression in HCV/HIV coinfected and HCV monoinfected patients. 50 HCV/HIV coinfected and 125 HCV mono-infected persons with known duration of HCV infection were analyzed. The liver biopsies were scored by a single observer (modified Ishak). The majority of co-infected persons were male (73%) and had received HAART (66%). Risk factors for HCV acquisition included intravenous drug use in 81% and blood products/transfusion in 19%.
The average progression rate in coinfected patients was faster than in monoinfected patients: 0.2 fibrosis unit/year compared to 0.125 in HCV mono-infected patients (p=0.001).
The estimated time from infection to established cirrhosis in coinfected patients was 20 years compared to 32 years in HCV mono-infected persons. The rate of HCV progression in 6 patients who had paired liver biopsies was 0.29 fibrosis unit/year, with an estimated time to cirrhosis of 13.8 years. In addition, co-infected patients had significantly higher inflammatory grade (p=0.006) despite lower alcohol consumption.
There were no significant differences in sex distribution, age at infection and estimated duration of HCV, source of infection, and genotype distribution between the two groups.
Multivariable analysis confirmed the association between severe disease (fibrosis stage 3 and 4) with HIV (OR=4, p=0.0001], ALT greater than 80 IU/l (OR=2.82, p=0.007), and duration of HCV infection [OR=1.1, p=0.0001). CD4 less than 200 was the only HIV factor associated with severe disease [OR=5.33, p=0.05}.
The authors concluded that HCV/HIV co-infected patients have a more rapid rate of fibrosis progression and higher inflammatory grades compared to HCV mono-infected patients. ALT > 80 is an independent marker for more aggressive disease in this patient cohort.
Possible Reasons Why HIV Accelerates HCV Progression
Lapoile and French research group (abstract 741) reported at AASLD on a study that looks at potential mechanisms to explain how HIV accelerates progression of HCV in HCV/HIV coinfected patients. This is a retrospective case-controls study comparing 179 HIV/HCV co-infected patients and 179 matched HCV-infected patients. Pathological analysis included the Metavir score, evaluation of neutrophiles infiltrates, Mallory bodies, steatosis, and an immunohistochemical detection of HCV antigens by a polyclonal antibody on cryostat liver sections in 23 patients (14 coinfected and 9 monoinfected).
Co-infected patients had a higher HCV viremia (p<0.03) and more severe biochemical (p=0.001) or pathological liver damage (p=0.0001), corresponding to a faster fibrosis progression rate (0 .15 + or - 0.13 vs. 0.10 + or - 0.09 fibrosis unit/year, p< 0.001).
Histopathological lesions corresponding to alcoholic hepatitis despite similar alcohol consumption (7.8 vs 2.8%, p < 0.04) or with drug-induced hepatitis (2.2 vs. 0%, p = 0.06), steatosis (67.2 vs. 49.2%, p = 0.0001), Mallory bodies (6.7 vs. 1.7%, p = 0.02) and neutrophiles infiltrates (16.6 vs. 5.0%, p = 0.0001) were more frequent in co-infected patients, suggesting a higher sensitivity to toxic lesions in HIV-infected patients.
There was a correlation between the immunohistochemical detection of HCV antigens and the level of intrahepatic HCV RNA (p = 0.0001). Positive immunochemistry was observed in all co-infected patients but only in 6 monoinfected patients (p=0.04) and the quantitation of HCV RNA by PCR was higher in coinfected patients (p=0.04) suggesting a potential direct cytotoxicity (producing a toxic effect on cells) of HCV in co-infected patients.
The authors concluded that the more severe liver disease in HIV/HCV co-infected patients includes a higher sensitivity to toxic (alcoholic and drug-related) lesions and to a direct cytotoxicity of HCV enhanced by immune deficiency.
Effect of Alcohol and HIV on HCV Progression
Ikeda (University of Pennsylvania & Philadelphia VA Medical Center, Philadelphia PA) also reported at AASLD on a study examining the influence of chronic heavy alcohol intake and HIV coinfection on HCV-specific CD4 T cell response and HCV viremia.
Patients were recruited from the Addiction Recovery Unit and Outpatient Clinics at the Philadelphia VA Medical Center (PVAMC) and University of Pennsylvania. Inclusion criteria included presence of chronic HCV infection (HCV antibody and HCV-RNA positive) with HCV genotype 1 virus with or without HIV coinfection (HIV antibody or DNA positive). Among HIV/HCV coinfected patients, only patients with CD4 counts >450 with compensated immune status were included. Patients were assessed for history of alcohol consumption using a Lifetime Drinking History questionnaire. Heavy drinking was defined as chronic alcohol use > 40gm/day consecutively for more than 10 years during life time, and was further considered "active" based on chronic alcohol intake >40gm/day within 1 year period prior to our analysis. Light drinking was defined as alcohol use no greater 20gm/day for more than 1 year period over life time. HCV-specific CD4 T cell response was assessed using 3 recombinant proteins coding for HCV core, NS3, NS4, NS5 and control SOD protein in standard proliferation and IFN gamma (Th1) elispot assay. HCV viral load was determined using real time PCR based on the conserved 5'noncoding region.
A total of 49 HCV monoinfected patients (29 heavy drinkers and 20 light drinkers) and 15 HIV/HCV coinfected patients were examined. Among 29 heavy drinkers, 8 were actively drinking more than 40gm of ETOH/day within 1 year of this study. Interestingly, HCV-specific CD4 proliferative T cell response did not differ significantly between the heavy drinkers and light drinkers (31% vs 40%, p=NS). Similarly, HCV-specific Th1 response was also observed in similar frequency in both groups (76% vs 65%, p=NS), suggesting that alcohol does not suppress HCV specific CD4 T cell memory response during chronic HCV infection. In fact, HCV-specific Th1 response was detectable in 8/8 active drinkers relative to only 13/20 light drinkers.
The combined frequency of circulating Th1 cells specific for HCV core, NS3, NS4 and NS5 antigens averaged at 97+166 /million PBL in the HCV monoinfected patients, consisting of significant (albeit low) responses for both HCV core (66+127/million PBL) and nonstructural antigens (31+64/million PBL). Interestingly, the analysis of HIV/HCV coinfected patients revealed a comparable Th1 response to HCV core (46+64/million PBL), but not the nonstructural antigens (7+7/million), suggesting a preferential loss of T cell response against HCV nonstructural antigens among the HIV/HCV coinfected patients.
The researchers found that chronic heavy alcohol use does not result in suppressed HCV-specific CD4 T cell proliferation or IFN gamma production during established chronic HCV infection. In contrast, there was a preferential loss of Th1 response against HCV nonstructural antigens but not core antigen in HIV coinfected patients, suggesting a differential susceptibility to HIV-associated suppression of HCV-specific T cells based on antigen specificity. Thus, the accelerated HCV-associated liver disease progression in the setting of chronic alcoholism and HIV coinfection differ and is not due to a similar mechanism or global suppression of HCV-specific CD4 T cell response.
Can HCV Be Eradicated in Coinfected Patients as in Monoinfected
Trimoulet (abstract 767) reported on a study evaluating serum (blood) and intrahepatic HCV RNA loads in co-infected patients before and after anti-HCV therapy. Twenty HIV-HCV co-infected and IFN-naive patients with chronic hepatitis C (14 males; mean age: 35.6) were enrolled in a clinical trial evaluating IFN alfa-2a and ribavirin. Sera and liver biopsies were obtained on the same day, before and 6 months after therapy. Sustained responders (SR) were defined by undetectable serum HCV RNA 6 months after completion of the treatment.
All patients were positive for serum and liver HCV RNA before treatment, both levels did not correlate. Pre-treatment intrahepatic HCV RNA amounts did not correlate with the degree of histological activity (P=0.99) nor the degree of fibrosis (p=0.77). After treatment, 17 patients were found to be non-responders (NR) and 3 were SR. No correlation was found between serum and liver HCV RNA levels after therapy (p=0.42). In the 3 SRs, HCV RNA was also negative in post-treatment liver biopsy samples. In NR patients, although serum HCV RNA load was significantly higher before than after treatment (p<0.0001), pre- and post-therapy intrahepatic viral loads were not different.
The authors concluded that as previously described in immunocompetent patients, intrahepatic HCV RNA is not detectable in HIV-HCV co-infected SR, suggesting viral eradication. In addition, intrahepaticHCV RNA level does not correlate with the degree of liver lesions.
Rate of Progression to Cirrhosis and Related Risk Factors in 754 IVDUs with Chronic HCV: is HIV involved in increased rate of progression
Minola and Italian researchers (abstract 750) reported on a study evaluating IVDUs with chronic HCV and their rate of HCV progression and factors related. This retrospective study included all the 754 anti HCV positive viremic IVDUs consecutively recruited from January 1990 to December 2000. Medical records included: demographic characteristics, medical history, daily ethanol intake (g/day), body mass index (kg/m 2), liver tests, iron-related indexes and serum levels of cryoglobulins. HCV genotype, HBsAg and anti HBc (IgG) were also tested. US guided liver biopsy was offered to all patients. Histological findings were classified according to Ishak et al.(J Hepatol 1995; 22:696-9) and a staging score of 5 or 6 was considered consistent with cirrhosis. A logistic regression model was used to identify those variables independently associated with the development of cirrhosis.
A total of 648 IVDUs (529 males and 119 females) i.e the 86% of the initial cohort, underwent liver biopsy. Patient mean age at liver biopsy was 31.8 years (range 18-49) and the mean duration of HCV infection, as counted from the first year of intravenous drug use, was 14.8 years (range 3-30). During a mean follow up of 112 months (range 36-252), a total of 53 patients (i.e. the 8.2% of the entire cohort) progressed to cirrhosis.
The proportion of patients with HIV infection, HBsAg positivity and alcohol abuse (> 100 g/day) was significantly higher in cirrhotics than in non-cirrhotics (20.7 vs 7.2%, p .001; 13.2 vs 4.4 %, p .014 and 22.6 vs 2.0%, respectively, p .0001). Moreover, the HIV-infected group of patients had a significantly higher mean age at biopsy (36 vs 31 yrs, p .001), longer duration of drug addiction (10.1 vs 6.8 , p .0001), and higher BMI ( 24.4 vs 23.4 kg/m2 , p .009), GGT (166 vs 69 UI/L, p .001), ferritin levels (353 vs 171 ng/mL, p .0001) and histologic grading (7.7 vs , p .0001).
At multivariate analysis alcohol consumption, duration of intravenous drug use, concomitant HIV infection and age at biopsy were independently associated with the development of cirrhosis. The authors reported that the present findings indicate that in anti-HCV positive viremic IVDUs, the concomitant presence of chronic alcohol abuse and HIV infection and the duration of drug addiction negatively influence the progression of liver disease.
Lorna Dove, Teresa Wright, Brian Edlin and others reported (abstract 747) on the risk for fibrosis in IVDUs. Injection drug users represent the largest population of patients infected with hepatitis C (HCV) in the United States. Most of the published natural history data chronicles the disease course in patients that acquired HCV from transfusion. Natural history may differ in patients with multiple and continued exposures to different viral populations. We propose that there is greater risk for advanced fibrosis and end-stage liver disease in active injection drug users. This study aims to (I) characterize the clinical spectrum of HCV-related liver disease, (ii) to characterize the histologic spectrum of liver disease, (iii) to determine cofactors associated with advanced fibrosis or cirrhosis.
The Urban Health Study (UHS) is a HIV seroepidemiological study conducted in selected neighborhoods in a large metropolitan area. Study participants are recruited from street settings by out-reach workers. All anti-HCV positive participants were invited to participate in a clinical evaluation of hepatitis C, including a medical history, physical examination, laboratory testing and liver biopsy (if there were no contraindications). Patients were felt to have definite clinical cirrhosis if they had any of the following: history of cirrhosis or a complication (ascites, hepatic encephalopathy, variceal bleeding); or evidence on physical and laboratory exam (ascites, asterixis, hepatic encephalopathy, PT>13.2 without alternative explanation).
In patients that underwent biopsy, fibrosis was scored from 0 to 4 and fibrosis progression rates were calculated using the year of first injection as the presumed year of infection. Ordinal logistic regression was used to model fibrosis stage and linear regression to model fibrosis progression rate.
248 clients participated in the clinical evaluation. 70% were male and 62% African-American. 23% consumed >50g/d of alcohol. The median duration of injection drug use was 27 years (1-50). 78% were HCV-RNA+ and 48% had abnormal ALT. 13 (5%) had definite clinical cirrhosis and were excluded from biopsy.
Of the 185 with chronic HCV, 56 (30%) agreed to biopsy, the demographic characteristics did not differ significantly from those who refused biopsy. 67% had stage 0 or 1 fibrosis; 96% had stage 2 disease or less. Only two patients (4%) had evidence of cirrhosis on biopsy. The total estimated prevalence of cirrhosis was 9%. The median fibrosis progression rate was 0.04 stages/year, slow. Predictors of increased fibrosis rate were age at infection, female sex and elevated ALT.
The authors concluded that despite ongoing injection drug use, repeated exposure to HCV and concurrent alcohol use in some, many injectors have minimal progression of hepatic fibrosis after decades of infection. These data refute our hypothesis and differ from those in the published literature. Fibrosis progression in injection drug users may be slower than previously reported.