José M. Sánchez-Tapias

PREVALENCE OF ANTIBODIES TO HEPATITIS C VIRUS IN SPANISH PATIENTS WITH HEPATOCELLULAR CARCINOMA AND HEPATIC CIRRHOSIS

The prevalence of antibodies against hepatitis C virus (HCV) was investigated in 96 patients with hepatocellular carcinoma, 106 patients with liver cirrhosis without evidence of cancer, and 177 controls without liver disease. 75% of patients with hepatocellular carcinoma had HCV antibodies (anti-HCV), a significantly higher proportion than that observed in patients with cirrhosis (55.6%), or controls (7.3%). The prevalence of anti-HCV was significantly higher in patients with alcoholic cirrhosis and hepatocellular carcinoma (76%) than in patients with alcoholic cirrhosis alone (38.7%) whereas in patients with cryptogenic cirrhosis there was no significant difference between those with and without primary liver cell cancer (81.4% and 77.5%, respectively). These results indicate that HCV infection may have a role in the pathogenesis of hepatocellular carcinoma, even in patients with chronic liver disease apparently related to other agents such as alcohol, and that this recently identified hepatitis virus may be found in a large proportion of patients with cryptogenic cirrhosis.

Survival and prognostic factors in 366 patients with compensated cirrhosis type B: a multicenter study

A multicenter longitudinal study was performed to assess the survival of hepatitis B surface antigen positive compensated cirrhosis, primarily in relation to hepatitis B virus replication and hepatitis delta virus infection, and to construct a prognostic index based on entry characteristics. This cohort study involved nine university medical centers in Europe. Three hundred and sixty-six Caucasian HBsAg positive patients with cirrhosis who had never had clinical manifestations of hepatic decompensation were enrolled and followed for a mean period of 72 months (6 to 202 months). Inclusion criteria were biopsy-proven cirrhosis, information on serum hepatitis B e antigen and antibody to hepatitis D virus at the time of diagnosis and absence of complications of cirrhosis. At entry 35% of the patients were HBeAg positive, 48% of the patients tested were HBV-DNA positive and 20% anti-HDV positive. Death occurred in 84 (23%) patients, mainly due to liver failure (45 cases) or hepatocellular carcinoma (23 cases). The cumulative probability of survival was 84% and 68% at 5 and 10 years, respectively. Coxs regression analysis identified six variables that independently correlated with survival: age, albumin, platelets, splenomegaly, bilirubin and HBeAg positivity at time of diagnosis. According to the contribution of each of these factors to the final model, a prognostic index was constructed that allows calculation of the estimated survival probability. No difference in survival of hepatitis D virus infected and uninfected patients was observed. Termination of hepatitis B virus replication and/or biochemical remission during follow up correlated with a highly significant better survival. These data show that in compensated cirrhosis B, hepatitis B virus replication, age and indirect indicators of poor hepatic reserve and established portal hypertension significantly worsen the clinical course of the disease, whereas hepatitis D virus infection does not influence the prognosis. The highly significant improvement in life expectancy following cessation of hepatitis B virus replication and biochemical remission favors antiviral therapy in those patients with a guarded prognosis, as estimated by a prognostic index.

Impact of the recurrence of hepatitis C virus infection after liver transplantation on the long-term viability of the graft.

BACKGROUND The impact of hepatitis C virus (HCV) infection recurrence after orthotopic liver transplantation (OLT) on graft viability is still not accurately defined. Our study aims to evaluate the magnitude and rate of progression of HCV-induced liver damage after OLT in a single institution cohort of 122 HCV-infected recipients. METHODS All patients transplanted at our institution between 1988 and 1996 with positive serum HCV antibodies before OLT, minimum postoperative survival of 6 months, and without hepatitis B virus coinfection or severe non-HCV-related graft complications were retrospectively included in the study. RESULTS HCV infection recurrence was almost universal, and genotype 1b was observed in 87% of the cases. After a median histological follow-up of 43 months (range: 7-96), evidences of HCV-induced histological damage were found in 94% of the cases. The actuarial rates of severe graft damage (including cirrhosis, fibrosing cholestatic hepatitis, and submassive liver necrosis) were 15%, 33%, and 44% at 3, 5, and 7 years, respectively, and among these patients, 52% developed decompensated liver disease during the follow-up and 36% lost their grafts. The biochemical severity at the onset of the recurrent hepatitis and the development of cholestasis or cytomegalovirus disease were independent predictors of severe HCV-related graft damage. No differences were found in graft and patient survival when positive-HCV OLT recipients were compared with a coetaneous cohort of 215 non-HCV OLT recipients. CONCLUSIONS HCV infection recurrence leads to severe liver damage and subsequently to clinical decompensation in a significant proportion of OLT recipients. Some clinical and biochemical characteristics can predict the severity of HCV-induced graft damage.

Sarcoidosis in patients with chronic hepatitis C virus infection: analysis of 68 cases.

Abstract: We describe the clinical characteristics, the patterns of association, and the role of antiviral therapies in patients with sarcoidosis associated with chronic hepatitis C virus (HCV) infection. Sixty-eight patients were included in the current study, 56 cases identified in the literature search plus 12 unpublished cases from our department. In 50 HCV patients, sarcoidosis appeared after starting antiviral therapy. Antiviral therapy associated with triggered sarcoidosis consisted of α-interferon monotherapy in 20 cases and combined therapy with α-interferon and ribavirin in 30. Sarcoidosis appeared during the first 6 months after starting therapy in 66% of patients. The clinical picture of sarcoidosis included predominantly pulmonary disease in 38 (76%) patients and cutaneous sarcoidosis in 30 (60%). Antiviral therapy was discontinued in 60% of patients and continued or adjusted in 14%, while sarcoidosis appeared after completed therapy in the remaining cases. Specific therapy for sarcoidosis was started in only 21 patients, mainly with oral corticosteroids. The outcome of patients was detailed in 46 cases: remission or improvement was observed in 38/46 (83%) patients, stabilization of sarcoidosis in 5/46 (11%), and reactivation of sarcoidosis after an initial improvement in 3/46 (6%). Finally, 18 treatment-naive HCV patients presented sarcoidosis, with 14/18 (87%) patients presenting with pulmonary involvement and 8/18 (44%) with cutaneous involvement. In summary, sarcoidosis may be observed in HCV patients in 2 different situations: triggered by antiviral therapy (in 75% of cases) and unrelated to treatment. Sarcoidosis during antiviral therapy may present mainly as cutaneous or pulmonary disease, with a benign, uncomplicated evolution in more than 85% of cases. However, more complicated cases are observed, especially in HCV patients with preexisting sarcoidosis and/or with previous antiviral treatment. Clinicians should be aware of the possibility that sarcoidosis may initially manifest or be reactivated during or shortly after treatment with antiviral therapy in patients with chronic HCV infection. Abbreviations: HCV = hepatitis C virus, IFNα = α-interferon.

Randomized trial comparing pegylated interferon α‐2b versus pegylated interferon α‐2a, both plus ribavirin, to treat chronic hepatitis C in human immunodeficiency virus patients

Although two pegylated interferons (Peg‐IFN) are available to treat chronic hepatitis C virus (HCV) infection, no head‐to‐head comparative studies have been published. We aim to compare the efficacy and safety of PEG IFN alfa‐2b (PEG 2b) versus PEG IFN alfa‐2a (PEG 2a), plus ribavirin (RBV). A prospective, randomized, multi‐center, open‐label clinical trial including 182 human immunodeficiency virus (HIV)–hepatitis C virus (HCV) patients naïve for HCV therapy was performed. Patients were assigned to PEG 2b (80‐150 μg/week; n = 96) or PEG 2a (180 μg/week; n = 86), plus RBV (800‐1200 mg/day) for 48 weeks. The primary endpoint was sustained virological response (SVR: negative HCV‐RNA 24 weeks after completion of treatment). At baseline, both groups were well balanced: 73% male; 63% HCV genotype 1 through 4; 29% had fibrosis index of 3 or greater. The overall SVR was 44% (42% PEG 2b versus 46% PEG 2a, P = 0.65). Among genotypes 1 through 4, SVRs were 28% versus 32% (P = 0.67) and 62% versus 71% (P = 0.6) in genotypes 2 through 3 for PEG 2b and PEG 2a, respectively. Early virological response (EVR; ≥2 log reduction from baseline or negative HCV‐RNA at week 12) was 70% in the PEG 2b group and 80% in the PEG 2a group (P = 0.13), reaching a positive predictive value of SVR of 64% and a negative predictive value of 100% in both arms. Side effects were present in 96% of patients but led to treatment discontinuation in 10% of patients (8% on PEG 2b and 13% on PEG 2a, P = 0.47). Conclusion: In patients with HIV, HCV therapy with PEG 2b or PEG 2a plus RBV had no significant differences in efficacy and safety. (HEPATOLOGY 2009;49:22‐31.)

Hepatitis C Virus Infection in Patients with Nonalcoholic Chronic Liver Disease

STUDY OBJECTIVE To determine the prevalence and meaning of antibodies to the hepatitis C virus (HCV) in patients with nonalcoholic chronic liver diseases. DESIGN Cross-sectional study. SETTING The liver unit of a referral-based university hospital. PATIENTS Three hundred and forty-six consecutive patients, including 137 with cryptogenic chronic liver disease, 156 with chronic hepatitis B, 47 with primary biliary cirrhosis, and 8 with persistently abnormal aminotransferase serum levels and normal liver histology. Among patients with cryptogenic liver disease, 41 received blood transfusions before discovery of liver disease and 18 had circulating nonorgan-specific autoantibodies. For comparison, 1495 apparently healthy volunteer blood donors were included in the study. LABORATORY INVESTIGATIONS: The presence of anti-HCV antibodies (anti-HCV) was determined by a recently developed enzyme-linked immunoassay. MEASUREMENTS AND MAIN RESULTS In patients with cryptogenic liver disease, the prevalence of anti-HCV was 82% (95% CI, 76% to 89%), being higher (P = 0.02) in patients with histories of blood transfusion than in those with unknown sources of exposure. Antibodies to HCV were not detected in patients with antinuclear antibodies at high titer. Among patients with chronic hepatitis B, anti-HCV were found in 11% (CI, 5% to 18%) of those with hepatitis B virus (HBV)-associated DNA in serum and in 29% (CI, 17% to 43%) of those with undetectable HBV replication (P less than 0.05). The prevalence of anti-HCV in blood donors was 1.2% (CI, 1.1% to 1.3%). CONCLUSIONS Our results indicate that HCV infection probably plays an important etiologic role in cryptogenic liver disease and, in some patients, in chronic hepatitis B. Determining whether anti-HCV are present appears to be useful for differentiating viral from autoimmune chronic liver diseases.

Prevalence and mother‐to‐infant transmission of hepatitis viruses B, C, and E in Southern Tanzania

Hepatitis B and C markers were tested in 980 pregnant women, in the infants born to infected mothers, and in a random sample of 42 and 50, respectively, children born to uninfected mothers in Tanzania. Sixty‐two women (6.3%) were positive for HBsAg and 15 (24%) were HBeAg‐seropositive. Anti‐HCV was detected in 49 women (5%), 15 (31%) of whom had detectable viremia. HCV RNA serum levels were low and only genotype 4 was identified. Sixty‐six women (6.7%) were positive for anti‐HIV, six of whom were coinfected with HBV and one with HCV. Anti‐HEV was negative in the 180 women tested. At 8 months of age, HBsAg was detected in 8% and 2% of children born to HBV‐infected and noninfected mothers, respectively (P = 0.2). Corresponding figures at 18 months of age were 31% and 21% (P = 0.3). When tested at 2 months of age, HCV RNA was not detected in any of the 43 children born to anti‐HCV–positive mothers nor in any of 50 children born to anti‐HCV–negative mothers. At 18 months, only one child, born to an anti‐HCV–positive mother, had detectable HCV RNA. None of the infants born to women with HIV coinfection were infected with hepatitis viruses. This study suggests that exposure to HEV does not occur in southern Tanzania. The prevalence of current HBV infection in pregnant women from rural Tanzania is lower than in other sub‐Saharan areas. In early childhood, HBV infection appears to occur by horizontal rather than maternofilial mechanisms of transmission. The prevalence of HCV infection is similar to that in other African countries. The results of this study show for the first time in Africa that mother‐to‐infant transmission does not play a significant role in the acquisition of HCV infection. J. Med. Virol. 58:215–220, 1999.

Prevalence of hepatitis C virus infection in patients with antiphospholipid syndrome

BACKGROUND/AIMS The aim of this study was to determine the prevalence and clinical significance of hepatitis C virus (HCV) infection in patients with the antiphospholipid syndrome (APS). METHODS A series of 88 consecutive patients (78 female and 10 male), with a mean age of 39 years (range 15-79), was prospectively studied. All patients had been diagnosed with APS: 54 (61%) primary APS and 34 (39%) APS associated with systemic lupus erythematosus. A group of 200 apparently healthly blood donors was included in the study. Anti-HCV antibodies were investigated in the serum of all patients using a third-generation ELISA and confirmed by recombinant immunoblot assay. RNA-HCV was investigated in anti-HCV positive samples by polymerase chain reaction. Anticardiolipin, anti-beta2-glycoprotein I and antiprothrombin antibodies were evaluated by ELISA. Lupus anticoagulant was studied by coagulometric assays. RESULTS Only 2 (2.2%) patients showed positivity for anti-HCV antibodies, but none of them had clinical or biochemical signs of liver disease. Furthermore, RNA-HCV was not detected in serum of any of these patients. Lupus anticoagulant was positive in 57% of patients. Anticardiolipin antibodies were positive in 60% of patients, anti-beta2-glycoprotein I antibodies in 43% of patients, and antiprothrombin antibodies in 56% of patients. The prevalence of anti-HCV in blood donors was 1%. CONCLUSIONS The prevalence of anti-HCV in patients with APS is low and similar to that in healthy people in our area. HCV infection does not seem to be involved in the etiopathogenesis of this syndrome.

Nosocomial transmission of HCV in the liver unit of a tertiary care center.

Despite its medical and legal implications, there are no prospective studies analyzing the incidence and mechanisms involved in the nosocomial transmission of hepatitis C virus (HCV) in liver units. This study prospectively investigates the nosocomial transmission of HCV in the liver unit of a tertiary care center from August 2000 to October 2002. The median prevalence of HCV infection among hospitalized patients was 50%. Anti‐HCV–negative patients admitted to the liver unit during the study period were prospectively followed, and serum markers of HCV infection were repeated 6 months after discharge. All known risk factors for HCV transmission (including the physical allocation of HCV‐infected and noninfected patients during hospitalization) were recorded. Complete follow‐up data were available in 1,301 (84.5%) of 1,540 patients. Six patients (0.46%) acquired HCV infection (annual incidence: 0.27/100 admissions). Phylogenetic analyses of recovered HCV sequences identified the source of infection as an HCV‐infected roommate (3 cases) and a patient receiving care by the same nurse team (1 case). The most relevant risk factors associated with HCV acquisition were duration of hospitalization (>10 days; OR, 35; 95% CI, 1.96‐622) and hospitalization with an HCV‐infected roommate (>5 days; OR, 12; 95% CI, 1.39‐103). In fact, HCV infection occurred in 1.7% of the 357 patients hospitalized longer than 10 days. In conclusion, HCV nosocomial infection appears to occur via patient‐to‐patient transmission in liver units, particularly in individuals who require long hospitalizations. Continuous reinforcement of universal prevention measures and, when possible, isolation of patients at higher risk might further reduce nosocomial HCV transmission. (HEPATOLOGY 2005;41:115–122.)

Response-guided peg-interferon plus ribavirin treatment duration in chronic hepatitis C: Meta-analyses of randomized, controlled trials and implications for the future†‡

Response‐guided pegylated interferon (peg‐IFN) plus ribavirin (P/R) therapy trials on genotype (G)1 and G2/G3 hepatitis C virus–infected patients provide contradictory results. We conducted meta‐analyses of randomized, controlled trials to address (1) the benefit of a 72‐week extended‐duration therapy in G1‐slow responders and (2) adequate shortened duration therapy in G1 and G2/G3‐rapid responders. Seventeen trials were selected, including 624 G1 rapid responders, 570 G1 slow responders, and 2,062 G2/G3 rapid responders. Virologic outcomes and treatment discontinuation data were collected from published articles and by asking investigators. Pooled estimates of sustained virologic response (SVR), relapse, and dropouts were calculated using the random effects model, considering the variability of shortened duration, ribavirin dose, genotype, and baseline viral load. In G1 slow responders, a 72‐week extended duration increased SVR (+10.7%; 95% CI [confidence interval]: +4.4% to + 17.1%), decreased relapse (−12.3%; 95% CI: −25.4% to 0%), and did not significantly increase drop‐out rates (+4.5%; 95% CI: −0.6% to + 9.6%). The benefit of extended duration was lower when using a weight‐based ribavirin regimen (+8.7%; 95% CI: +1.7% to + 15.8%). In G1 rapid responders, a 24‐week shortened duration decreased SVR (−12.5%; 95% CI: −19.2% to −5.8%) and increased relapse rates (+8.8%; 95% CI: +2.9% to + 14.8%). Such differences were not significant in patients with baseline viral load <400,000 UL/mL (−4.4%; 95% CI: −9.8% to + 1%). In G2/G3 rapid responders, SVR was more common for standard 24‐week duration than for shortened durations (+4.1%; 95% CI: +0.1% to + 8.5), but this benefit was not significant when ribavirin was weight‐adjusted and the short duration was 16 weeks (−1.7%; 95% CI: −6.1% to + 2.7%) and for G2 patients (+1.6%; 95% CI: −0.2% to + 5.5%). Conclusion: Long durations of P/R therapy improve SVR, regardless of genotype. This effect is nonetheless negligible in rapid responders, with the most favorable conditions for SVR (G2, G1 with low viral load, and G3 with weight‐adjusted ribavirin regimen). (HEPATOLOGY 2011;)