Clinical features and outcomes of hepatocellular carcinoma in Caucasian cirrhotic patients on long-term analogue therapy for hepatitis B.

BACKGROUND: Long-term oral nucleos(t)ide analogue (NUC) therapy in hepatitis B virus (HBV)-related compensated cirrhotics prevents clinical decompensation but not hepatocellular carcinoma (HCC) development. AIMS: To define the clinical features and outcomes of HCC in long-term NUC-treated HBV patients. METHODS: All HCCs developing between 2005 and 2016 in NUC-treated HBV patients under surveillance were studied, excluding those that occurred within the first 6 months of therapy. Clinical features of HCC, alpha faetoprotein (AFP) patterns and patients' outcome were studied. RESULTS: Seventy-six HCC patients were included. Median age was 67 (40-83) years, 84% males, 96% Caucasian, 95% HBeAg-negative, 96% with undetectable HBV DNA, 83% with normal ALT levels, and 92% with compensated cirrhosis. Median serum AFP levels were 4 (1-3615) ng/mL (>7 ng/mL in 36%). HCC was monofocal in 78%, had a median diameter of 20 (6-57) mm and was in its early stage in 92% which allowed potentially curative treatments in 78% (39% ablation, 28% surgical resection, 11% liver transplantation). Overall, a complete response was obtained in 61 (80%) patients: in 40 after a first-line treatment, in 3 after the second-line treatment, in 2 after the third-line treatment, while 16 underwent liver transplantation (8 as second line). During 45 (7-144) months after HCC diagnosis, 19 patients died, 84% from HCC progression. The median time to recurrence was 20.2 (3-53) months, and the cumulative 5-year liver-related survival was 74%. CONCLUSIONS: HCCs developing in patients under long-term NUC treatment were single, small tumours, amenable to curative therapies able to confer excellent 5-year survival rates.

Hepatitis C virus/human immunodeficiency virus coinfection in hemophiliacs: high rates of sustained virologic response to pegylated interferon and ribavirin therapy.

BACKGROUND: Progression of chronic hepatitis C virus (HCV) infection to end-stage liver disease is accelerated in patients coinfected with human immunodeficiency virus (HIV). HCV/HIV-coinfected hemophiliacs are no exception. Although eradication of HCV with pegylated interferon (Peg-IFN) plus ribavirin (Rbv) is the only approach to halt the progression of liver disease, the rates of sustained virologic response (SVR) in coinfected patients are attenuated as compared with those in HCV-monoinfected patients. Nonetheless, in HCV-infected hemophiliacs, who are considered to constitute a difficult-to-treat population, current treatment strategies yielded rates of SVR similar to those obtained in non-hemophiliacs. OBJECTIVES AND PATIENTS: In this open-label, prospective, multicenter study, the efficacy and safety of therapy with Peg-IFNalpha2a plus Rbv was evaluated in 34 HCV/HIV-coinfected adult hemophiliacs naive to previous antiviral therapy. METHODS: Peg-IFNalpha2a was administered at a dose of 180 mug subcutaneously once-weekly plus oral Rbv 1000-1200 mg day(-1) for 48 weeks, irrespective of HCV genotype. RESULTS: All but one patient (3%) completed the study, 15 (44%) achieved an SVR, and 13 (38%) required dose reduction of either drug. A rapid virologic response (HCV-RNA clearance at week 4; P = 0.01), a complete early virologic response (HCV RNA clearance at week 12; P = 0.005) and absence of cirrhosis (P = 0.04) were independent predictors of SVR. During a median post-treatment follow-up of 3 years, a steady increase in CD4+ cell count and CD4+/CD8+ cell ratio was observed in SVR patients. CONCLUSIONS: These results strongly support the use of anti-HCV therapy in HCV/HIV-coinfected hemophiliacs.

Hepatitis C reactivation in patients with chronic infection with genotypes 1b and 2c: a retrospective cohort study of 206 untreated patients.

BACKGROUND: We previously described hepatitis reactivation in two carriers of the hepatitis C virus (HCV) genotype 2c. AIM: To assess the relationship between HCV genotypes and risk of hepatitis reactivation, we studied the course of aminotransferases in patients infected with the two relevant genotypes in Italy. PATIENTS: A cohort of 100 patients with genotype 2c chronic hepatitis and 106 with genotype 1b were subjected to surveillance. METHODS: Hepatitis reactivation was defined as an alanine aminotransferase (ALT) value > or =400 IU/l or a maximum/minimum ALT ratio value of > or =8. RESULTS: Over a period of 71 (24-144) months, one or more flares of ALT (201-2200 IU/l, 6-90 months' duration) occurred in 31 patients with genotype 2c and in eight patients with genotype 1b (rates of flares: 55.6 per 1000 person years for genotype 2c v 15.0 for genotype 1b; p=0.001). On repeat biopsy, hepatic fibrosis increased by more than 2 points in 10/16 patients examined either during or after an ALT flare compared with 7/36 flare free patients (63% v 19%; p=0.003). Hepatitis flares were significantly associated with genotype 2c (odds ratio 6.48 (95% confidence interval 2.57-16.35)) but not with sex, age, modality or duration of infection, baseline ALT values or histological severity of hepatitis, hepatitis other than HCV, or reinfection. CONCLUSIONS: Genotype 2c carriers are at high risk of hepatitis reactivation, suggesting that virus genetic heterogeneity is important in the natural history of HCV, questioning the linearity of hepatic fibrosis progression during hepatitis C.

Hepatitis C in haemophilia: lights and shadows.

Hepatitis C is a major cause of morbidity and mortality in haemophiliacs who received clotting factor concentrates before the availability of virus-inactivated factors in the mid-1980s. Early studies gave conflicting indications as to the severity of hepatitis C (originally termed non-A non-B hepatitis), as mild, slowly progressive hepatitis was documented in several infants and young adults with haemophilia who were examined with repeat liver biopsies, whereas more progressive hepatitis and cirrhosis was documented in others. One major point of dispute was whether these discrepancies could in part be accounted for by epidemiological differences among studies, as hepatitis C acquired early in life may initially run a benign course and later worsen owing to spontaneous recrudescence of hepatitis or interference with such comorbidity factors as alcohol abuse or infection with the human immunodeficiency virus (HIV). In the mid 1990s, the latter infection overshadowed hepatitis C as a cause of death in this patient population. Because hepatocellular carcinoma is emerging as an important complication in haemophiliacs with long-standing hepatitis C virus (HCV) infection who survived HIV infection, and because of recent advances in treating HIV, morbidity and mortality associated with chronic hepatitis C have regained emphasis amongst haemophiliacs. The development of newer interferon-based therapies provides an opportunity for modifying the natural history of HCV infection in a substantial number of haemophilic patients.

Progressive hepatic fibrosis in healthy carriers of hepatitis C virus with a transaminase breakthrough.

In short-term studies, patients with chronic hepatitis C virus (HCV) infection, consistently normal serum aminotransferase (ALT) levels, and minimal or mild necro-inflammatory changes in the liver, did not progress to histologically severe hepatitis. There are no data on longer term outcome of liver disease in these patients. We describe two patients with HCV infection (genotype 2c) with a rise in serum ALT values greater than 10 times the upper normal value that occurred after an 8- and 15-year period of persistently normal or minimally elevated ALT levels. In both patients, the rise in ALT values lasted more than 16 weeks and was not associated with any symptom or risk factor for acute hepatitis. A liver biopsy performed 4 and 18 months after the ALT flare showed clear-cut progression from chronic hepatitis with mild activity to chronic hepatitis with severe activity and central to portal septal fibrosis (Ishak score: grading 14 and 6; staging: 4 and 5, respectively). Hence, extended surveillance of HCV carriers with consistently normal or minimally elevated ALT values is warranted as these patients are at risk of ALT flares and may develop progressive liver disease.

A prospective multicenter study of hepatocellular carcinoma in italian hemophiliacs with chronic hepatitis C. The Study Group of the Association of Italian Hemophilia Centers.

To assess the risk factors, natural history, and eligibility for curative treatment of early-detected hepatocellular carcinoma (HCC), 385 hemophiliacs who were treated with blood or plasma derivates for at least 10 years and had persistently elevated aminotransferase values underwent an annual screening with an abdominal ultrasound examination and measurement of the serum alpha-fetoprotein (AFP) level. Of these, 355 had serum antibody to hepatitis C virus (anti-HCV), 29 had anti-HCV and hepatitis B surface antigen (HBsAg), and one had HBsAg alone; 141 had serum antibody to human immunodeficiency virus (anti-HIV). During 48 months of follow-up study, six patients developed HCC. All HCC patients had a HCV-related cirrhosis and had been exposed to HCV risk at a median age of 40 years. All patients had a multicentric tumor, which was not eligible for curative treatment. Univariate analysis showed age, cirrhosis, and baseline AFP levels to be significantly associated with an increased risk of HCC. By multivariate analysis, the risk of HCC was infinite in patients with cirrhosis, 31.0 for those with baseline AFP higher than 11 ng/mL, and 17.9 for those more than 45 years of age. In conclusion, the risk of cancer was greater for patients infected later in life, particularly those with cirrhosis and high AFP. Annual screening of hemophiliacs with ultrasound and AFP fails to identify potentially curable tumors because the diagnosis is made at a late stage of the disease.

A randomized, controlled trial of a 24-month course of interferon alfa 2b in patients with chronic hepatitis B who had hepatitis B virus DNA without hepatitis B e antigen in serum.

Short-term interferon treatment of serum hepatitis B e antigen (HBeAg)-negative carriers with serum hepatitis B virus (HBV) DNA and histological features of chronic hepatitis B has been largely unsuccessful. In a pilot study of long-term treatment, 42 such patients were randomly assigned to 6 million units of interferon alfa 2b (IFN-alpha2b) three times per week for 24 consecutive months (n = 21, 4 with cirrhosis) or to no therapy (n = 21, 3 with cirrhosis). Five patients (24%) discontinued therapy because of treatment-related adverse reactions. Serum levels of alanine transaminase (ALT) became persistently normal and HBV DNA undetectable by dot-blot assay in 8 patients receiving interferon and in 2 untreated controls (38% vs. 10%; P = .03). Hepatitis flare-ups disappeared in 17 patients during therapy compared with 6 controls (81% vs. 29%; P < .001). During a median period of 22 months after interferon was stopped, 2 treated patients (10%) lost serum hepatitis B surface antigen (HBsAg) and seroconverted to antibodies to hepatitis B surface antigen (anti-HBs). Serum ALT remained persistently normal and HBV DNA undetectable by dot-blot assay in 6 initial responders and 1 initial nonresponder, compared with none of the 21 untreated controls (sustained response: 33% vs. 0; P < .001). Comparative analysis of pre- and posttreatment liver biopsies showed that mean Knodell scores dropped in the treated group (10.3 to 5.3; P = .01), but not in the untreated group (9.3 to 9.8; not significant). In conclusion, a 24-month course of treatment with 6 MU IFN-alpha2b was well tolerated by most patients, led to sustained suppression of HBV in one third, and attenuated hepatitis in 81% of patients.

High rates of hepatitis G virus infection in multitransfused patients with hemophilia.

The parallel measurement of serum antibodies to the hepatitis G virus (anti-HGV) and of viremia (HGV-RNA) should improve our understanding of HGV transmission by coagulation factor concentrates. The aim of this study was to assess the relationship between HGV, the type of concentrate infused, and liver disease in multitransfused hemophiliacs. To this end, anti-HGV and HGV-RNA were evaluated by an enzyme-linked immunosorbent assay and a nested-polymerase chain reaction assay in patients treated lifelong with nonvirus-inactivated plasma-derived concentrates (n = 128), virus-inactivated concentrates (n = 33), or recombinant factors (n = 7), and in 200 regular blood donors. The prevalence of serum HGV-RNA and anti-HGV was higher in the recipients of nonvirus-inactivated factors than in blood donors (HGV-RNA: 9% v 1.5%, P = .002; anti-HGV: 32% v 5%, P < .0001). In the recipients of virus-inactivated concentrates the prevalences of these markers were similar to those in blood donors (HGV-RNA: 3% v 1.5%; anti-HGV: 15% v 5%). The prevalence of either marker in the recipients of nonvirus-inactivated concentrates was higher than in the recipients of virus-inactivated factors (39% v 18%, P = .04). The former group had serum hepatitis C virus (HCV) RNA or anti-HCV more frequently than the latter group (HCV-RNA: 86% v 15%, P < .0001; anti-HCV: 96% v 18%, P < .0001). Serum alanine aminotransferase was persistently high in 83 (81%) patients with HCV-RNA alone, in 8 (89%) with HCV/HGV coinfection, and in none of the three patients with HGV-RNA only. Thus, HGV infection in hemophiliacs is more common than previous studies of HGV-RNA prevalence have suggested, but it resolved in most cases and caused chronic viremia only in a small number of patients, without biochemical evidence of persistent liver damage.

Long-term titrated recombinant interferon-alpha 2a in chronic hepatitis C: a randomized controlled trial.

The efficacy and tolerability of 12-month treatment with titrated doses of recombinant interferon-alpha 2a (IFN-alpha 2a) in chronic hepatitis C were studied in 67 consecutively recruited patients randomly assigned either to a starting dose of IFN-alpha 2a 6 MU, subsequently adjusted to the serum alanine aminotransferase (ALT) response (n = 35), or to no therapy (n = 32; controls). End-of-treatment ALT levels were normal and hepatitis C virus (HCV) RNA was negative by nested polymerase chain reaction (PCR) in 17 (49%) treated patients compared to none of the controls (P < 0.001). During the 12 months after stopping treatment the number of patients who remained in remission was eight (23%) and one respectively (4%) (P = 0.031). Follow-up liver biopsy showed reduced hepatic inflammation in 80% of treated patients and in 29% of controls (P < 0.001). The eight sustained responders and 27 non-responders or relapsers received similar mean total doses of IFN (565 MU vs 545 MU) and had a similar incidence of anti-IFN neutralizing antibodys (13% vs 19%). Absence of cirrhosis was the only independent pretreatment parameter that predicted a sustained response. In conclusion, a mean cumulative dose of IFN 549 MU, titrated over 12 months, was well tolerated, and resulted in the long-term clearance of HCV RNA and normal ALT levels in 23% of patients.

Persistence of "wild-type" and "e-minus" hepatitis B virus infection in chronic healthy HBsAg/anti-HBe positive carriers.

We examined nine chronic healthy hepatitis B surface antigen/antibody to hepatitis Be carriers with consistently normal liver chemistries and negative serum hepatitis B virus-DNA. Liver biopsy, performed twice, 10-11 years apart in all patients, showed normal histology and negative hepatitis B core antigen. DNA extracted from the second liver biopsy specimen, from 1 ml of serum from each patient and from an additional serum sample of 6 ml from two patients, was tested for pre-C/C and pre-S regions of hepatitis B virus-DNA by polymerase chain reaction amplification. Viral sequences were found in six of nine liver DNA extracts. In four cases both pre-C/C and pre-S regions were amplified, while the pre-C/C alone and the pre-S alone were detected in one case each. Direct sequencing of the amplified DNAs revealed no significant genomic changes in the pre-S and Core regions, while analysis of the pre-Core demonstrated the presence of a double viral population (wild-type and "e-defective") in four cases, and only "e-defective" hepatitis B virus in one case. No hepatitis B virus genomes were revealed in the serum sample when DNA was extracted from 1 ml of serum, while viral sequences were detected in both extracts of 6 ml of serum, indicating the presence of very low levels of viremia. These data suggest that episomal hepatitis B virus-DNA may persist for years in the liver of chronic healthy carriers in a latent state which may involve both wild-type and HBeAg-defective hepatitis B virus.

The natural history of asymptomatic hepatitis B surface antigen carriers.

OBJECTIVE: To assess the long-term outcome in hepatitis B surface antigen (HBsAg) carriers who have normal liver function tests, focusing on survival and the development of severe liver disease and hepatocellular carcinoma. DESIGN: Cohort study with a mean follow-up of 130 months. SETTING: Liver clinic of a referral center. PATIENTS: Ninety-two HBsAg-positive blood donors with normal liver function tests. MEASUREMENTS: Histologic evaluation of liver specimens at baseline; clinical, biochemical, and serologic follow-up; and repeat liver biopsy if clinically indicated or after 10 years of follow-up. RESULTS: At baseline, 69 subjects had normal histologic findings or only minor abnormalities, 18 had chronic persistent hepatitis, and 5 had mild chronic active hepatitis. Serum enzyme levels remained normal in 58 of 68 patients who had regular follow-up. Three patients had biochemical changes consistent with hepatitis B virus (HBV) infection; in one of these patients, a later histologic evaluation showed progression to chronic active hepatitis. One patient developed alcoholic cirrhosis. Six other patients had mild or transient transaminase elevations, with no evidence of HBV replication, hepatitis D virus infection, hepatitis C virus (HCV) infection, or histologic deterioration. Liver histologic findings also remained unchanged in 21 patients who showed no biochemical changes during 10 years of follow-up and consented to have repeated liver biopsy. Ten patients showed loss of HBsAg; 2 of these patients acquired antibody to hepatitis B surface antigen (anti-HBs). All patients who did not have regular follow-up, except 1, were interviewed by telephone during 1990: All denied having liver disease. No patients developed hepatocellular carcinoma. CONCLUSIONS: Italian HBsAg carriers with initially normal liver function tests have an excellent prognosis: Delta superinfection is infrequent and the risk for developing hepatocellular carcinoma is low.

Development of antibody to hepatitis C virus (HCV) in acute and chronic non-A, non-B post-transfusion hepatitis.

The antibody to hepatitis C virus (anti-HCV) was measured by an immunoassay in 507 serum samples from 94 patients with acute and chronic post-transfusion non-A, non-B hepatitis (NANB) and in 436 healthy blood donors. Anti-HCV was found in 70.8 of patients with acute hepatitis, in 78.2 with chronic hepatitis, and in 1.4 of healthy blood donors. In acute hepatitis, anti-HCV appeared in the serum from 4 to 34 weeks after transfusion and from 1 to 30 weeks after the onset of the overt disease. Three patients with resolving hepatitis (21%) and 2 who developed chronic hepatitis (10%) lost anti-HCV during a mean follow-up period of 28 months. Among the 36 patients with chronic hepatitis, 2 (6%) lost anti-HCV after 12 months and 8 years respectively. These data indicate that in recent years HCV has been the major etiologic agent of acute and chronic transfusion-associated hepatitis (TAH) in our geographical area. The late appearance of anti-HCV from the onset of clinical and biochemical signs of acute hepatitis in more than 70% of patients limits the diagnostic utility of this assay for an earlier serological diagnosis of acute NANB hepatitis. Additional studies are required to determine the diagnostic significance of this antibody in chronic NANB hepatitis.

Hepatitis C virus and hepatocellular carcinoma.

Epidemiological, clinical and laboratory data point to a role of hepatitis C virus infection in hepatocellular carcinoma. The connection appears to be indirect and to be mediated by cirrhosis. Thus, geographical differences can be observed, based on the locally prevalent etiological factors for cirrhosis. In the end, prospective studies of hepatitis C virus infected persons will be needed to elucidate the role of this agent in liver cancer.

Hepatitis C antibody in patients with chronic liver disease and hepatocellular carcinoma.

Hepatitis C virus (HCV) is the major etiologic agent of parenterally transmitted non-A, non-B hepatitis. To determine whether there is a relationship between this virus agent and hepatocellular carcinoma (HCC), the sera of patients with HCC and chronic hepatitis were assessed using a sensitive immunoassay for HCV antibody. Anti-HCV was detected in 65% of 132 patients with HCC, without any relationship with the presence of the hepatitis B surface antigen (HBsAg). The prevalence (74%) of anti-HCV was high, as expected in patients with putative non-A, non-B cirrhosis also. The prevalence of anti-HCV was less in patients with HBsAg-positive cirrhosis (28%) and in patients with disease not related to viral hepatitis and healthy controls (8%). These data suggest, but do not prove, that HCV is an important factor associated with HCC.

Hepatocellular carcinoma in Italy: report of a clinical trial with intravenous doxorubicin.

Sixty-six patients with hepatocellular carcinoma (HCC) in various stages of hepatic involvement were studied prospectively. Of these, 50 (75%) had associated cirrhosis and 19 (28%) had serum hepatitis B surface antigen (HBsAg). Six (9%) patients were eligible for tumor resection, 34 were selected for doxorubicin chemotherapy (60 mg/m2, i.v., given every 3 weeks, up to a maximum dose of 550 mg/m2), and 26 were followed up without treatment. Untreated patients survived 1-18 months (median 1) after diagnosis. Surgically treated patients survived 1-14 months (median 4.5). In the doxorubicin group, six patients died soon after the first course of treatment, leaving 28 patients to be evaluated. Seven (24.5%) responded to therapy, surviving 2-26 months (median 8.0). Twenty-one (75.5%) did not respond to chemotherapy and had a median survival of 3.5 months (range: 2-12). Initial performance status and the degree of hepatic impairment were found to be covariates of prognostic significance. The type and severity of drug-related side-effects appeared to be comparable to those reported by others. In accordance with previous reports, our patients with HCC often had non-resectable tumors or responded poorly to chemotherapy. The association between this tumor and cirrhosis might partially account for treatment failure.

Anti-LAV/HTLV-III antibodies in groups of individuals at high risk for infection in Italy.

We have studied anti-LAV/HTLV-III antibody prevalence in individuals at high risk for infection, such as intravenous drug addicts, hemophiliacs and homosexual men. Among intravenous drug addicts, LAV/HTLV-III infection was first recognized in 1981 and positive serum reactions for anti-LAV/HTLV-III antibody rose in successive years to 53%. Anti-LAV/HTLV-III antibody prevalence was 13.5% in the group of homosexual men, while in hemophiliacs treated with commercial concentrates it was 37% in 1984 and had increased to 45% in 1985. There was a significant correlation between antibody status and concentrate consumption in these patients. Results of studies of anti-LAV/HTLV-III antibody patterns with the Western blot technique suggest that antibodies against core proteins (mainly p25 and p18) and the envelope protein gp40 are always present in asymptomatic individuals and in patients with the lymphadenopathy syndrome, but usually not in patients with full-blown AIDS. These last patients have typical positive reactions only against the envelope proteins gp110 and gp40.