Historical epidemiology of hepatitis C virus (HCV) in selected countries.

Chronic infection with hepatitis C virus (HCV) is a leading indicator for liver disease. New treatment options are becoming available, and there is a need to characterize the epidemiology and disease burden of HCV. Data for prevalence, viremia, genotype, diagnosis and treatment were obtained through literature searches and expert consensus for 16 countries. For some countries, data from centralized registries were used to estimate diagnosis and treatment rates. Data for the number of liver transplants and the proportion attributable to HCV were obtained from centralized databases. Viremic prevalence estimates varied widely between countries, ranging from 0.3% in Austria, England and Germany to 8.5% in Egypt. The largest viremic populations were in Egypt, with 6,358,000 cases in 2008 and Brazil with 2,106,000 cases in 2007. The age distribution of cases differed between countries. In most countries, prevalence rates were higher among males, reflecting higher rates of injection drug use. Diagnosis, treatment and transplant levels also differed considerably between countries. Reliable estimates characterizing HCV-infected populations are critical for addressing HCV-related morbidity and mortality. There is a need to quantify the burden of chronic HCV infection at the national level.

Strategies to manage hepatitis C virus (HCV) disease burden.

The number of hepatitis C virus (HCV) infections is projected to decline while those with advanced liver disease will increase. A modeling approach was used to forecast two treatment scenarios: (i) the impact of increased treatment efficacy while keeping the number of treated patients constant and (ii) increasing efficacy and treatment rate. This analysis suggests that successful diagnosis and treatment of a small proportion of patients can contribute significantly to the reduction of disease burden in the countries studied. The largest reduction in HCV-related morbidity and mortality occurs when increased treatment is combined with higher efficacy therapies, generally in combination with increased diagnosis. With a treatment rate of approximately 10%, this analysis suggests it is possible to achieve elimination of HCV (defined as a >90% decline in total infections by 2030). However, for most countries presented, this will require a 3-5 fold increase in diagnosis and/or treatment. Thus, building the public health and clinical provider capacity for improved diagnosis and treatment will be critical.

The present and future disease burden of hepatitis C virus (HCV) infection with today's treatment paradigm.

The disease burden of hepatitis C virus (HCV) is expected to increase as the infected population ages. A modelling approach was used to estimate the total number of viremic infections, diagnosed, treated and new infections in 2013. In addition, the model was used to estimate the change in the total number of HCV infections, the disease progression and mortality in 2013-2030. Finally, expert panel consensus was used to capture current treatment practices in each country. Using today's treatment paradigm, the total number of HCV infections is projected to decline or remain flat in all countries studied. However, in the same time period, the number of individuals with late-stage liver disease is projected to increase. This study concluded that the current treatment rate and efficacy are not sufficient to manage the disease burden of HCV. Thus, alternative strategies are required to keep the number of HCV individuals with advanced liver disease and liver-related deaths from increasing.

Impact of age on viral kinetics of peginterferon alfa-2a/ribavirin in chronic hepatitis C: final analysis from the PROPHESYS cohort.

The population of patients with chronic hepatitis C viral infection is ageing; however, elderly, hepatitis C-infected patients are understudied and less frequently treated. This subanalysis of data from the multinational PROPHESYS study examined associations between age (≤65 vs >65 years), on-treatment virological response and sustained virological response (SVR) in patients treated with peginterferon alfa-2a (40KD)/ribavirin in accordance with local licences. PROPHESYS comprised three cohorts studied in 19 countries according to country-specific legal and regulatory requirements. This subanalysis includes treatment-naive HCV mono-infected patients assigned to receive peginterferon alfa-2a (40KD)/ribavirin, with 6276 individuals aged ≤65 years and 349 aged >65 years. Rapid virological response (RVR) rates by Week 4 were consistently lower in older genotype (G) 1 (21.6% vs 27.2% in younger patients), G2 (80.7% vs 85.1%) and G3 (60.0% vs 74.2%) patients. SVR rates were significantly lower (29.8% vs 43.0%) and relapse rates significantly higher (43.1% vs 26.7%) in older G1 patients (P = 0.0002 vs ≤65 years). In contrast, SVR and relapse rates were similar in G2 and G3 patients regardless of age. The positive predictive value of RVR for SVR was comparable in older and younger G1 patients (66.7% vs 68.6%, respectively) and higher in older G2 (80.7% vs 75.6%) and G3 (77.8% vs 66.8%) patients. Virological response rates are generally lower in elderly CHC patients, and RVR is a reliable positive predictor of SVR in patients >65 years.

Prevalence of hepatitis C virus infection in patients with COPD.

Some studies have suggested that chronic hepatitis C virus (HCV) infection may induce an accelerated decline of forced expiratory volume in 1 second (FEV(1)). We performed a cross-sectional study to determine the prevalence of HCV infection in a sample of chronic obstructive pulmonary disease (COPD) patients and in a control group of blood donors. The clinical characteristics of HCV-positive and HCV-negative patients were compared. Anti-HCV antibody was determined and confirmed by HCV-RNA. The prevalence of HCV infection in COPD patients was 7.5% (95% CI 6.52-8.48) and in blood donors was 0.41% (95% CI 0.40-0.42). The HCV-positive patients had a lower FEV(1) (34.7 +/- 8.6%) and a higher BODE index (median = 6) than HCV-negative patients (42.7 +/- 16.5%, median = 4, respectively) (P = 0.011 and 0.027, respectively). Our results suggest a high prevalence of chronic HCV infection in patients with COPD in comparison with the blood donors. HCV-positive patients have a more severe disease.

Results of up to 2 years of entecavir vs lamivudine therapy in nucleoside-naïve HBeAg-positive patients with chronic hepatitis B.

Entecavir is a potent inhibitor of hepatitis B virus (HBV) polymerase. The efficacy and safety of entecavir in nucleoside-naïve patients with hepatitis B virus e antigen (HBeAg)-positive chronic hepatitis B was established in a large, international, double-dummy study (ETV-022) where patients were randomized to entecavir 0.5 mg/day (n = 354) or lamivudine 100 mg/day (n = 355) once daily. ETV-022 had a 52-week blinded treatment phase, followed by an extended blinded treatment phase for up to 44 additional weeks (96 weeks total). Treatment was discontinued for patients achieving a protocol-defined response as determined by patient management criteria that intended to test the possibility of finite therapy, which has not previously been studied for entecavir or other anti-HBV agents in a large trial. Early results from this study have been previously presented/published separately. This paper compiles the results of up to 2 years of treatment for protocol-defined responders, virologic responders and nonresponders. For responders who discontinued therapy (per protocol), 24-week off-treatment evaluation is presented to provide a more 'complete picture' of what clinicians can expect when treating nucleoside-naïve HBeAg-positive patients with chronic hepatitis B. For patients who discontinued therapy because of nonresponse (nonresponders) and subsequently entered the rollover study ETV-901, follow-up results, including resistance profile, are provided.

Peginterferon alfa-2a (40KD) (PEGASYS) plus ribavirin (COPEGUS) in retreatment of chronic hepatitis C patients, nonresponders and relapsers to previous conventional interferon plus ribavirin therapy.

Peginterferon alfa plus ribavirin is currently the treatment of choice for chronic hepatitis C. Peginterferon alfa-2a (40KD) plus ribavirin has given an overall sustained virological response of 18% in F3/F4 previous nonresponder US patients. We evaluated the effectiveness of peginterferon alfa-2a (40KD) plus ribavirin in Brazilian patients who were relapsers or nonresponders to previous interferon-based therapy. One-hundred-thirty-four patients with biopsy-proven chronic hepatitis C, HCV RNA positive, elevated ALT and who were either relapsers (n=37) or nonresponders (n=97) to at least 24 weeks of conventional interferon/ribavirin therapy were retreated with peginterferon alfa-2a (40KD) 180mg/qw and ribavirin 800 mg bid for 48 weeks. Efficacy was assessed as virological response (defined as undetectable HCV RNA) at the end of treatment (EoT) and at the end of follow-up (SVR - Sustained Virological Response). Safety assessments consisted of clinical and laboratory evaluations. In the patient sample, 72% were genotype 1 and 34% were cirrhotic. In an intention-to-treat analysis, relapser patients showed 78% EoT response and 51% SVR. Nonresponders showed 57% EoT response and 26% SVR. Positive predictive factors of SVR were non-1 genotype and relapser state. Six percent of the patients interrupted treatment because of adverse events and 45% had dose reduction (mainly associated with leucopenia and anemia). Brazilian patient relapsers and nonresponders to conventional interferon and ribavirin treatment can achieve a sustained virological response when retreated with peginterferon alfa-2a (40KD) and ribavirin. The safety profile is similar to that of naive patients.

Peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS®) in retreatment of chronic hepatitis C patients, nonresponders and relapsers to previous conventional interferon plus ribavirin therapy

Peginterferon alfa plus ribavirin is currently the treatment of choice for chronic hepatitis C. Peginterferon alfa-2a (40KD) plus ribavirin has given an overall sustained virological response of 18 percent in F3/F4 previous nonresponder US patients. We evaluated the effectiveness of peginterferon alfa-2a (40KD) plus ribavirin in Brazilian patients who were relapsers or nonresponders to previous interferon-based therapy. One-hundred-thirty-four patients with biopsy-proven chronic hepatitis C, HCV RNA positive, elevated ALT and who were either relapsers (n=37) or nonresponders (n=97) to at least 24 weeks of conventional interferon/ribavirin therapy were retreated with peginterferon alfa-2a (40KD) 180mg/qw and ribavirin 800mg bid for 48 weeks. Efficacy was assessed as virological response (defined as undetectable HCV RNA) at the end of treatment (EoT) and at the end of follow-up (SVR - Sustained Virological Response). Safety assessments consisted of clinical and laboratory evaluations. In the patient sample, 72 percent were genotype 1 and 34 percent were cirrhotic. In an intention-to-treat analysis, relapser patients showed 78 percent EoT response and 51 percent SVR. Nonresponders showed 57 percent EoT response and 26 percent SVR. Positive predictive factors of SVR were non-1 genotype and relapser state. Six percent of the patients interrupted treatment because of adverse events and 45 percent had dose reduction (mainly associated with leucopenia and anemia). Brazilian patient relapsers and nonresponders to conventional interferon and ribavirin treatment can achieve a sustained virological response when retreated with peginterferon alfa-2a (40KD) and ribavirin. The safety profile is similar to that of naive patients.

Cost-effectiveness of combination peginterferon alpha-2a and ribavirin compared with interferon alpha-2b and ribavirin in patients with chronic hepatitis C.

BACKGROUND: Sustained virological response (SVR) is the primary objective in the treatment of chronic hepatitis C (CHC). Results from a recent clinical trial of patients with previously untreated CHC demonstrate that the combination of peginterferon alpha-2a and ribavirin produces a greater SVR than interferon alpha-2b and ribavirin combination therapy. However, the cost-effectiveness of peginterferon alpha-2a plus ribavirin in the U.S. setting has not been investigated. METHODS: A Markov model was developed to investigate cost-effectiveness in patients with CHC using genotype to guide treatment duration. SVR and disease progression parameters were derived from the clinical trials and epidemiologic studies. The impact of treatment on life expectancy and costs were projected for a lifetime. Patients who had an SVR were assumed to remain virus-free for the rest of their lives. In genotype 1 patients, the SVRs were 46% for peginterferon alpha-2a plus ribavirin and 36% for interferon alpha-2b plus ribavirin. In genotype 2/3 patients, the SVRs were 76% for peginterferon alpha-2a plus ribavirin and 61% for interferon alpha-2b plus ribavirin. Quality of life and costs were based on estimates from the literature. All costs were based on published U.S. medical care costs and were adjusted to 2003 U.S. dollars. Costs and benefits beyond the first year were discounted at 3%. RESULTS: In genotype 1, peginterferon alpha-2a plus ribavirin increases quality-adjusted life expectancy (QALY) by 0.70 yr compared to interferon alpha-2b plus ribavirin, producing a cost-effectiveness ratio of $2,600 per QALY gained. In genotype 2/3 patients, peginterferon alpha-2a plus ribavirin increases QALY by 1.05 yr in comparison to interferon alpha-2b plus ribavirin. Peginterferon alpha-2a combination therapy in patients with HCV genotype 2 or 3 is dominant (more effective and cost saving) compared to interferon alpha-2b plus ribavirin. Results weighted by genotype prevalence (75% genotype 1; 25% genotype 2 or 3) also show that peginterferon alpha-2a plus ribavirin is dominant. Peginterferon alpha-2a and ribavirin remained cost-effective (below $16,500 per QALY gained) under sensitivity analyses on key clinical and cost parameters. CONCLUSION: Peginterferon alpha-2a in combination with ribavirin with duration of therapy based on genotype, is cost-effective compared with conventional interferon alpha-2b in combination with ribavirin when given to treatment-naïve adults with CHC.

Hepatitis C virus genotypes in Southern Brazil.

The prevalence of hepatitis C virus (HCV) genotypes in Southern Brazil was studied in the plasma of 100 HCV-RNA-positive patients attended in Porto Alegre, South of Brazil. Reverse transcription-polymerase chain reaction (RT-PCR) products from the 5' noncoding region were double digested with RsaI-HaeIII and BstNI-HinfI and analyzed by restriction fragment length polymorphism (RFLP). Three genotypes (1, 2 and 3) were demonstrable, the most prevalent being HCV type 1 (55 of 100 patients, 55%), followed by HCV type 3 (37 of 100 patients, 37%) and HCV type 2 (8 of 100 patients, 8%). There was an unusual high prevalence of genotype 3, in contrast to the majority of published data from the Southeast region.

Hepatitis C virus genotypes in Southern Brazil

The prevalence of hepatitis C virus (HCV) genotypes in Southern Brazil was studied in the plasma of 100 HCV-RNA-positive patients attended in Porto Alegre, South of Brazil. Reverse transcriptionpolymerase chain reaction (RT-PCR) products from the 5' noncoding region were double digested with RsaI-HaeIII and BstNI-HinfI and analyzed by restriction fragment length polymorphism (RFLP). Three genotypes (1, 2 and 3) were demonstrable, the most prevalent being HCV type 1 (55 of 100 patients, 55 per cent), followed by HCV type 3 (37 of 100 patients, 37 per cent) and HCV type 2 (8 of 100 patients, 8 per cent). There was an unusual high prevalence of genotype 3, in contrast to the majority of published data from the Southeast region.

Procollagen-III peptide and chronic viral C hepatitis.

UNLABELLED: Chronic hepatitis develops in at least half of persons acutely infected with hepatitis C virus (HCV). Ten to 25% of these patients will develop cirrhosis. Serum procollagen-III peptide (PIIIP) may be of value in predicting the development of chronic active fibrogenic liver disease. It has been reported that in chronic viral C hepatitis, the levels of hepatitis C virus-RNA (HCV-RNA) correlate directly with the severity of hepatic histology and inversely with response to interferon therapy. OBJECTIVES: The aims of this study were to correlate the level of PIIIP with HCV-RNA concentrations, ALT values, and histological severity in patients with chronic viral C hepatitis. METHODS: Eighty-six patients with chronic C hepatitis were divided into three groups: group I (n = 34), mild chronic active hepatitis, group II (n = 25), moderate to severe chronic active hepatitis, and group III (n = 27), cirrhosis. HCV-RNA was measured by Quantiplex, and PIIIP was measured by radioimmunoassay-gnostic assay. RESULTS: Mean +/- SD level of ALT in group I was 114 +/- 48 U/L, group II was 169 +/- 115 U/L, and group III was 160 +/- 94 U/L. The mean +/- SD level of HCV-RNA in group I was 110 +/- 130 x 10(5) Eq/ml, in group II was 140 +/- 140 x 10(5) Eq/ml, and in group III was 70 +/- 80 x 105 Eq/ml. The mean +/- SD level of PIIIP in group I was 0.6 +/- 0.2 U/ml, in group II was 0.9 +/- 0.4 U/ml, and in group III was 1.2 +/- 0.6. There was a significant difference in the levels of PIIIP among the three groups (p = 0.0001). There was no correlation among ALT, HCV-RNA, and PIIIP in any of the three groups. CONCLUSIONS: PIIIP peptide determinations in patients with chronic viral C hepatitis are reflective of histological severity and may provide relatively noninvasive means of following disease progression.

Laparoscopic and histologic findings in patients with the human immunodeficiency virus.

Hepatic dysfunction frequently develops in patients infected with the human immunodeficiency virus (HIV). This retrospective study was undertaken to determine the laparoscopic and histologic findings in a group of HIV-seropositive patients with or without the acquired immune deficiency syndrome (AIDS). Fifty-four patients, 44 with AIDS and 10 HIV-positive, underwent laparoscopic examination and visually guided biopsies for the assessment of clinical or biochemical evidence of liver injury. Significant abnormalities were detected in 31/44 (70%) AIDS patients and 3/10 (30%) HIV-positive patients. Overall, specific laparoscopic findings were described in 25/54 (46%). The most common findings were peritoneal involvement, massive intra-abdominal adhesions, focal lesions of the liver or spleen, and diffuse nodularity of the liver; these were usually related to opportunistic infections or neoplasms such as non-Hodgkin's lymphomas and Kaposi's sarcoma. No procedure-related deaths occurred. Laparoscopy is a safe and accurate method to detect underlying disease in a selected population of HIV-seropositive patients.

Viral pathogenesis of hepatocellular carcinoma in the United States.

Chronic hepatitis B virus infection is closely associated with the development of hepatocellular carcinoma, which is a major cause of cancer death worldwide. Recent studies have implicated hepatitis C virus infection as a major pathogenic agent of HBsAg-negative hepatocellular carcinoma. The significance of hepatitis C virus and hepatitis B virus infections in the occurrence of HBsAg-negative hepatocellular carcinoma has not been well established in the United States. We studied 91 HBsAg-negative American patients with hepatocellular carcinoma for evidence of hepatitis C virus or hepatitis B virus infection. These patients had no other predisposing factors to hepatocellular carcinoma. A sensitive polymerase chain reaction was employed to detect hepatitis C virus RNA and hepatitis B virus DNA in serum and liver. Three sets of hepatitis C virus and hepatitis B virus primers were used to optimize the detection of viral genomes. Hepatitis C virus antibodies were measured with second-generation immunoassays. Twenty-six (29%) of these patients carried low levels of hepatitis B virus DNA in either serum, liver/tumor tissue or both. On the basis of the results from serological and polymerase chain reaction analyses of serum and liver, we found that 53 of 91 patients (58%) exhibited evidence of hepatitis C virus infection. When data were combined, 14 patients (15%) had evidence of hepatitis B virus/hepatitis C virus coinfection, whereas 12 (13%) were infected with hepatitis B virus alone and 39 (43%) had hepatitis C virus only. Twenty-six (29%) had no markers of hepatitis B virus or hepatitis C virus infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Detection of hepatitis C virus antibody by first and second generation assays and polymerase chain reaction in patients with autoimmune chronic active hepatitis types I, II, and III.

In this study we have attempted to classify a group of North American patients with autoimmune chronic hepatitis into types I, II, and III according to the class of autoantibody present in serum, and determine the prevalence and significance of antibody to hepatitis C virus (anti-HCV). A total of 62 patients (type I, 51; type II, 3; type III, 8) were tested with first-generation enzyme-linked immunosorbent assay (ELISA)-1. Seropositive patients were assessed by second-generation recombinant immunoblot assay (RIBA)-2 and polymerase chain reaction (PCR). Our results demonstrate that 12 (19%) of the 62 patients with autoimmune hepatitis were anti-HCV ELISA-1 positive (type I, 9; type II, 1; type III, 2). Only one patient with type II autoimmune hepatitis was reactive by RIBA-2 and PCR. Eight of the 12 seropositive patients entered remission after corticosteroid therapy and seven of them became seronegative by ELISA-1. The RIBA-2 and PCR reactive patient did not respond to immunosuppressive therapy and remained seropositive. We conclude that there is a low prevalence of anti-HCV antibody in autoimmune hepatitis. Results based only on ELISA-1 anti-HCV testing can be misleading, and second-generation testing is necessary to recognize the presence of HCV infection. The fact that the only RIBA-2 reactive patient had type II autoimmune hepatitis may suggest a role for HCV infection in the pathogenesis of this condition. Nevertheless, corticosteroid therapy remains effective in those patients who are ELISA-1 seropositive, but RIBA-2 and PCR nonreactive.

Fulminant or subfulminant non-A, non-B viral hepatitis: the role of hepatitis C and E viruses.

BACKGROUND: Although non-A, non-B (NANB) viral hepatitis has been implicated as an etiology of fulminant hepatitis, hepatitis C virus (HCV) has not been shown to result in acute hepatic failure and hepatitis E virus (HEV) has predominantly been associated with fulminant hepatitis among pregnant women. METHODS: Using polymerase chain reaction to detect HCV and HEV genomes, four-antigen radioimmunoblot assay (4-RIBA) to measure anti-HCV antibodies, and enzyme-linked immunosorbent assay (ELISA) to detect anti-HEV immunoglobulin M (IgM) antibodies, 17 patients with sporadic fulminant or subfulminant hepatitis of presumed NANB viral etiology were studied. RESULTS: The diagnosis of acute NANB viral hepatitis was made based on clinical information, serological tests, biochemical profiles, and pathological features. All 17 patients were negative for anti-HEV IgM antibodies and HEV RNA in either serum and/or liver. HCV RNAs were detected in 2 patients although anti-HCV antibodies were negative in all of them. CONCLUSIONS: It is shown that HCV is infrequently associated with and HEV is not an identifiable cause of presumed NANB fulminant or subfulminant hepatitis in this patient population. Although further studies will be required for identification of the causative agent, it is possible that another agent is responsible for the occurrence of sporadic NANB fulminant or subfulminant hepatitis.