Pegylated interferon plus optimized weight-based ribavirin dosing negate the influence of weight and body mass index on early viral kinetics and sustained virological response in chronic hepatitis C.

AIM: Elevated body mass index (BMI) in chronic hepatitis C (CHC) has been associated with reduced rates of sustained virological response (SVR). The aims of this study were to determine whether early viral kinetics (and subsequently SVR) are influenced by weight or BMI by measuring HCV RNA at week 4 using two PCR assays with differing sensitivities. METHODS: Patients with CHC treated with peginterferon plus weight-based ribavirin were included in this retrospective study. Body mass index, pretreatment viral load, genotype and liver histology were abstracted from the clinical database. HCV RNA PCR (lower limit of detection (LLD) <50 IU/mL) at treatment week 4 and 6 months after completion of therapy were recorded to determine the presence of rapid virological response (RVR-50) and SVR, respectively. In those who achieved RVR-50, stored week 4 serum was retested using Taqman (LLD < 15 IU/mL, RVR-15). RESULTS: Of 134 patients included (genotype 1 57%, BMI 26.7 ± 4.5 kg/m², ribavirin dose 13.9 ± 2.6 mg/kg/day), 59% achieved SVR. RVR-50 was observed in 39.6% and RVR-15 in 27.6%. Neither body weight nor BMI influenced RVR-50, RVR-15 or SVR. The positive predictive values (PPVs) of RVR-50 and RVR-15 for SVR were 88.7% and 97.3% (P = 0.23). RVR-50 and RVR-15 superceded genotype and viral load as the strongest independent predictors of SVR (OR 9.25 (1.9-45.11) and OR 30.74 (3.08-317.96), respectively). CONCLUSIONS: RVR is the strongest predictor of SVR. Early viral kinetics is not influenced by body weight or BMI when weight-based ribavirin is prescribed.

Prognosis of hepatitis C virus-infected Canadian post-transfusion compensation claimant cohort.

Accurate prognostic estimates were required to ensure the sufficiency of the $1.1 billion compensation fund established in 1998 to compensate Canadians who acquired hepatitis C virus (HCV) infection through blood transfusion between 1986 and 1990. This article reports the application of Markov modelling and epidemiological methods to estimate the prognosis of individuals who have claimed compensation. Clinical characteristics of the claimant cohort (n = 5004) were used to define the starting distribution. Annual stage-specific transition probabilities (F0-->F1, . . ., F3-->F4) were derived from the claimants, using the Markov maximum likelihood estimation method. HCV treatment efficacy was derived from the literature and practice patterns were estimated from a national survey. The estimated stage-specific transition probabilities of the cohort between F0-->F1, F1-->F2, F2-->F3 and F3-->F4 were 0.032, 0.137, 0.150 and 0.097 respectively. At 20 years after the index transfusion, approximately 10% of all living claimants (n = 3773) had cirrhosis and 0.5% developed hepatocellular carcinoma (HCC). For nonhaemophilic patients, the predicted 20-year (2030) risk of HCV-related cirrhosis was 23%, and the risk of HCC and liver-related death was 7% and 11% respectively. Haemophilic patients who are younger and are frequently co-infected with human immunodeficiency virus would have higher 20-year risks of cirrhosis (37%), HCC (12%) and liver-related death (19%). Our results indicate that rates of progression to advanced liver disease in post-transfusion cohorts may be lower than previously reported. The Canadian post-transfusion cohort offers new and relevant prognostic information for post-transfusion HCV patients in Canada and is an invaluable resource to study the natural history and resource utilization of HCV-infected individuals in future studies.

When to treat and the benefits of treating hepatitis C in patients with haemophilia.

Chronic hepatitis C (CHC), a curable infection, remains endemic worldwide. More than 90% of individuals with haemophilia have been infected with hepatitis C virus (HCV) mostly caused by transfusion with non-virucidally treated clotting factor concentrates. Relevant to haemophilics, the risk of cirrhosis with CHC infection is greatest in males, those who have been infected for a long time, consume alcohol regularly, and/or are co-infected with HIV. The cure rate, using the current standard therapy for CHC with pegylated-interferon-alpha given weekly and ribavirin daily, ranges from 43% to 65% in those infected with genotype 1 and 50-90% with genotype 2 and 3 infections. Eradication of hepatitis C in those co-infected with HIV is less in part because full dose therapy is poorly tolerated. Achieving a sustained virological response (SVR) prevents progression to cirrhosis and in those with established cirrhosis prevents liver failure, and reduces the risk if hepatocellular carcinoma, and the need for liver transplant. Novel treatment options now in development are predominantly focused on inhibitors of HCV-specific enzymes. The treatment paradigm for haemophilics infected with hepatitis C is that all should be assessed for treatment once a diagnosis of chronic hepatitis C is made in order to achieve the highest chance of an SVR, i.e. cure.

Antimitochondrial antibody-negative primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is considered a classic autoimmune disease insofar as 95% of patients are seropositive for specific antimitochondrial antibodies (AMA). Yet it is still the case that the remaining 5% of patients have equivalent disease but test persistently AMA negative. Although variations exist in the immunologic profile of these patients, clinically there are no discernable differences, and although the diagnostic threshold is higher, the treatment and prognosis mirror that of classic disease. Previous terminology, therefore, has been abandoned in favor of the description, AMA-negative PBC.

Primary biliary cirrhosis: the future.

Primary biliary cirrhosis is a progressive cholestatic liver disease of presumed autoimmune etiology. Patterns of disease are changing with earlier recognition and better access to investigation and treatment. With the convergence of animal, genetic, and clinical studies over the coming years, it is hoped that a greater understanding in the pathophysiology of the disease will translate into improved clinical endpoints for patients.

Histological benefits of virological response to peginterferon alfa-2a monotherapy in patients with hepatitis C and advanced fibrosis or compensated cirrhosis.

BACKGROUND: Patients with chronic hepatitis C virus and advanced fibrosis or cirrhosis are at risk for disease progression and hepatic decompensation. AIM: To determine the effects on hepatic histology of treatment with peginterferon alfa-2a (90 or 180 mug/week) or interferon alfa-2a (3 million units three times weekly) for 48 weeks in patients with paired biopsies. METHODS: Liver biopsies were obtained at baseline and 6 months after end of treatment. Histological and virological responses were compared. RESULTS: Patients attaining sustained virological response (n = 40) demonstrated the greatest improvements in fibrosis (-1.0, P < 0.0001) and inflammation (-0.65, P < 0.0001). Patients who cleared hepatitis C virus during treatment, but later relapsed (n = 59), experienced less improvement in fibrosis (-0.04, P < 0.0001) and inflammation (-0.14, P = 0.0768). Nonresponders (n = 85) showed no significant improvement in inflammation or fibrosis. Multiple regression analysis showed that the only factors contributing to improvement in fibrosis were sustained virological response (vs. nonresponder, P = 0.0005; vs. relapse, P = 0.7525) and body mass index < or =30 kg/m2 (P = 0.0995). CONCLUSIONS: These findings indicate that virological response to peginterferon alfa-2a improves inflammation and fibrosis in hepatitis C virus patients with advanced fibrosis or cirrhosis. Improving virological response and maintaining ideal body weight are critical for achieving optimal histological outcomes in hepatitis C virus patients.

Induction versus noninduction antiviral therapy for chronic hepatitis C virus in patients with congenital coagulation disorders: a Canadian multicentre trial.

BACKGROUND: Patients with congenital coagulation disorders and chronic hepatitis C virus (HCV) infection have multiple risk factors (ie, infection predominantly with genotype-1 HCV, long duration of the disease, HIV coinfection and male sex) for poor response to antiviral therapy. The present study compared induction therapy with interferon-alpha (IFN-alpha)-2b with standard IFN-alpha2b therapy. Pegylated IFN was not available at the time that the study was initiated. PATIENTS AND METHODS: A randomized study was performed comparing the efficacy of traditional IFN-alpha2b therapy (group A -- three million units, three times weekly for 24 to 48 weeks) and daily ribavirin (1.0 g to 1.2 g according to weight for 24 to 48 weeks), with induction IFN-alpha2b therapy (group B -- three million units, daily for eight weeks followed by the same dose administered three times a week for a further 16 to 40 weeks) and daily ribavirin (same dose as above) in IFN-naive patients with congenital coagulation disorders and chronic HCV infection. RESULTS: Between 2000 and 2003, 54 HIV-negative patients were recruited and randomly assigned to group A or B (n=27 each). Both groups were comparable in terms of age, sex, ethnicity, body mass index, baseline HCV RNA titre, viral genotype, liver fibrosis stage and type of coagulation disorder. Induction therapy did not significantly alter sustained virological response rates (group A 50%, group B 50%; P=1.0). Multiple logistic regression analysis indicated that induction therapy did not benefit individuals with difficult-to-treat infection (ie, those infected with genotypes 1 and 4, or those with high baseline viral loads). CONCLUSIONS: There was no benefit with induction antiviral therapy for HCV infection in individuals with congenital coagulation disorders.

Distinguishing nonalcoholic steatohepatitis from fatty liver: serum-free fatty acids, insulin resistance, and serum lipoproteins.

OBJECTIVES: The prognosis of nonalcoholic fatty liver disease is determined by liver biopsy; steatohepatitis can be progressive whereas fatty liver is benign. Insulin resistance and increased hepatic-free fatty acids are central to the pathophysiology of this disorder. Our objective was to assess whether serum-free fatty acids, lipoproteins, and insulin resistance are increased in steatohepatitis compared with fatty liver and healthy controls, and thus may be potential noninvasive markers for liver disease severity. METHODS: Fifteen subjects with biopsy proven nonalcoholic steatohepatitis, 15 with histological fatty liver, and 15 healthy controls were enrolled. Fasting serum glucose and insulin levels, serum-free fatty acids, HDL, LDL, and cholesterol were collected from each subject. Insulin resistance was calculated using the homeostasis assessment model. RESULTS: Insulin resistance, LDL, and cholesterol-to-HDL ratio values were significantly higher in steatohepatitis, whereas HDL was significantly lower compared with both fatty liver and controls. Free fatty acids were similar in all groups. CONCLUSIONS: Along with insulin resistance, serum LDL, and cholesterol-to-HDL ratio values increase with worsening severity of liver histology, and serum HDL values decline. Free fatty acids, however, do not vary between groups.

The PTPN22 1858T variant is not associated with primary biliary cirrhosis.

The minor allele of a single nucleotide polymorphism (SNP) in the PTPN22 gene (1858T) encoding the Lyp-tyrosine phosphatase has been recently associated with multiple autoimmune disorders, raising the possibility that this variant may also represent a risk allele for primary biliary cirrhosis (PBC). We therefore investigated the possible association of the PTPN22(1858T) variant with PBC in a Canadian population. We studied 160 Caucasian patients with biopsy and antimitochondrial antibodies (AMA)-proven PBC who were genotyped for the PTPN22(C1858T) SNP using a single-base primer extension assay and mass spectrometry. The frequency of the PTPN22(1858T) allele was then compared between the patients and 290 healthy controls. No association was detected between the PTPN22(1858T) allele and PBC, the frequency of this variant being similar in patients with PBC (7.5%) and controls (8.4%). Restricting the analysis to patients with PBC with any second autoimmune condition or specifically with sicca syndrome or autoimmune thyroid disease also revealed no association with this variant. Thus the PTPN22(1858T) variant is not associated with PBC or with the combination of PBC and a second autoimmune disease. These data suggest that this variant does not confer risk for PBC and does not account for the frequent presence of other autoimmune diseases in patients with PBC.

Response to long-term lamivudine treatment (up to 5 years) in patients with severe chronic hepatitis B, role of genotype and drug resistance.

Lamivudine is effective in suppressing viral replication, normalizing alanine aminotransferase (ALT), and improving histological appearance in HBe positive and negative hepatitis. It is unclear whether hepatitis B virus (HBV) genotype influences the response to lamivudine. We report the long-term response of patients with chronic hepatitis B with and without cirrhosis at baseline treated with lamivudine according to HBV genotype. Retrospective review of charts of all patients treated with lamivudine monotherapy between 1993 and 2002. Response to therapy defined as ALT in the normal range, undetectable HBV DNA, and in the HBeAg positive group loss of HBeAg and/or the development of anti-HBe. HBV DNA measured by the Digene Hybrid capture assay (sensitivity 1.4 x 10(6) copies/mL). YMDD mutation at rtL180M and rtM204V/I measured by restriction digest of amplified products. Genotyping performed by sequencing and phylogenetic tree analysis of the preS region of the virus genome. Seventy-one patients treated with lamivudine for 6 months or more, 53 (75%) were male, average age 47 years, 38 (54%) were HBeAg+ and 33 (46%) HBeAg-. Mean baseline HBV DNA viral titre was 1280.2 copies/mL and 518 copies/mL respectively. Cirrhosis was present in 30 (42%). Sera were examined for YMDD mutations at last patient visit in 61 (86%), and were detected in 45 (74%), there being no association with a particular genotype. Data from up to 5 years on lamivudine indicated no difference in biochemical or virological response between genotypes. Cirrhosis was more prevalent with specific genotypes. We found no influence of HBV genotype on the development of resistance to lamivudine, however liver disease severity was influenced by genotype.

Which patients with primary biliary cirrhosis or primary sclerosing cholangitis should undergo endoscopic screening for oesophageal varices detection?

BACKGROUND: Recent guidelines from an AASLD Single Topic Symposium suggest that patients with cirrhosis, including those with primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC), should be screened for oesophageal varices when the platelet count is <140,000/mm3. AIM: To determine the validity of these guidelines in clinical practice in patients with PBC or PSC. METHODS: Retrospective review of individuals undergoing screening upper endoscopy for oesophageal varices at a single centre. Oesophageal varices were reported as being present or absent. RESULTS: A total of 235 patients with chronic liver disease, including 86 patients with PBC (n=79) or PSC (n=7), 104 patients with chronic viral hepatitis, and 45 with non-alcoholic cirrhosis of differing aetiologies, underwent a single screening endoscopy between 1996 and 2001. Oesophageal varices were detected in 26 (30%) of the PBC/PSC group, 38 (37%) of the viral hepatitis group, and 21 (47%) of the "other" group. Applying multiple logistic regression analysis to the data in the group with PBC/PSC, platelets <200,000/mm3 (odds ratio (OR) 5.85 (95% confidence interval (CI) 1.79-19.23)), albumin <40 g/l (OR 6.02 (95% CI 1.78-20.41)), and serum bilirubin >20 micromol/l (OR 3.66 (95% CI 1.07-12.47)) were shown to be independent risk factors for oesophageal varices. Prothrombin time was unhelpful. The values at these cut offs were not useful in predicting oesophageal varices in the other groups. CONCLUSION: We conclude that current guidelines recommended by the AASLD Single Topic symposium are invalid in our cohort of patients with PBC and PSC. Patients with a platelet count <200,000/mm3, an albumin level <40 g/l, and a bilirubin level >20 micromol/l should be screened for oesophageal varices.

Fatigue in chronic cholestasis.

Fatigue is probably the most intriguing symptom affecting patients with chronic cholestatic disorders, in particular those with primary biliary cirrhosis. It is postulated that fatigue in patients with primary biliary cirrhosis may be associated with morphological abnormalities of the central nervous system secondary to accumulation of manganese. However, we are still far from understanding this complex issue.

Epidemiology of autoimmune liver disease.

Primary biliary cirrhosis (PBC), autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC) are chronic liver diseases that likely have an autoimmune basis to their pathogenesis. Although significant strides have been made in the clinical management of these conditions, their pathogenesis remains obscure. Understanding of various epidemiological factors may shed light on predisposing or causative factors for these diseases. Most is known about the epidemiology of PBC, with only minimal information on that of PSC and AIH. In this review, the current data on the epidemiology of PBC, AIH and PSC are summarized and suggestions are made for future work in this important area.

Transcription-mediated amplification is more sensitive than conventional PCR-based assays for detecting residual serum HCV RNA at end of treatment.

OBJECTIVE: In patients chronically infected with hepatitis C virus (HCV) undergoing antiviral therapy, sustained virologic response is suggested by viral clearance by end of treatment (EOT). Viral clearance is defined by nondetection of serum HCV RNA, usually by qualitative PCR-based assays with limits of detection ranging from 100 to 1000 copies/ml. However, some individuals relapse after achieving apparent viral clearance by EOT. These individuals may have low levels of viremia not detected by current PCR methods. The aim of this retrospective study was to determine whether the Bayer HCV RNA Qualitative Assay, which employs Transcription Mediated Amplification (TMA) and detects 50 HCV RNA copies/ml, could detect residual serum HCV RNA in patients who achieved apparent viral clearance by EOT and subsequently relapsed. METHODS: Samples were obtained at EOT (wk 24 or 48) and follow-up (wk 24-26 posttreatment) from 97 patients treated for HCV (78 relapsing patients, 19 sustained responders). All samples in which HCV RNA was not detected by PCR were tested in a blinded manner for HCV RNA by the TMA-based assay. RESULTS: HCV RNA was detected by the TMA-based assay in 27 (34.6%) EOT and 76 (97.4%) follow-up samples from relapsing patients, but not in any of the EOT or follow-up samples from sustained responders. CONCLUSION: Residual serum HCV RNA was detected by the TMA-based assay in EOT samples from 34.6% of patients that had achieved apparent viral clearance by PCR. The detection of HCV RNA by the TMA-based assay could help redefine EOT response and assist in the antiviral management of HCV infection.

Peginterferon alfa-2a in patients with chronic hepatitis C.

BACKGROUND: Covalent attachment of a 40-kd branched-chain polyethylene glycol moiety to interferon alfa-2a results in a compound (peginterferon alfa-2a) that has sustained absorption, a slower rate of clearance, and a longer half-life than unmodified interferon alfa-2a. We compared the clinical effects of a regimen of peginterferon alfa-2a with those of a regimen of interferon alfa-2a in the initial treatment of patients with chronic hepatitis C. METHODS: We randomly assigned 531 patients with chronic hepatitis C to receive either 180 microg of peginterferon alfa-2a subcutaneously once per week for 48 weeks (267 patients) or 6 million units of interferon alfa-2a subcutaneously three times per week for 12 weeks, followed by 3 million units three times per week for 36 weeks (264 patients). All the patients were assessed at week 72 for a sustained virologic response, defined as an undetectable level of hepatitis C virus RNA (<100 copies per milliliter). RESULTS: In the peginterferon group, 223 of the 267 patients completed treatment and 206 completed follow-up. In the interferon group, 161 of the 264 patients completed treatment and 154 completed follow-up. In an intention-to-treat analysis in which patients who missed the examination at the end of treatment or follow-up were considered not to have had a response at that point, peginterferon alfa-2a was associated with a higher rate of virologic response than was interferon alfa-2a at week 48 (69 percent vs. 28 percent, P=0.001) and at week 72 (39 percent vs. 19 percent, P=0.001). Sustained normalization of serum alanine aminotransferase concentrations at week 72 was also more common in the peginterferon group than in the interferon group (45 percent vs. 25 percent, P=0.001). The two groups were similar with respect to the frequency and severity of adverse events, which were typical of those associated with interferon alfa. CONCLUSIONS: In patients with chronic hepatitis C, a regimen of peginterferon alfa-2a given once weekly is more effective than a regimen of interferon alfa-2a given three times weekly.