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.

Daily ciprofloxacin treatment for patients with advanced liver disease awaiting liver transplantation reduces hospitalizations.

BACKGROUND: Progressive deterioration in liver function is a common cause of hepatic decompensation and indication for liver transplantation in patients with advanced liver disease. Previous studies in animal models of acute and chronic liver disease revealed that daily ciprofloxacin improves biochemical parameters of hepatic function. AIMS: The primary objective of this study was to determine whether hepatic function improves in patients with advanced liver disease after 1 month of daily ciprofloxacin therapy. A secondary objective was to determine whether ciprofloxacin treatment for 1 or 3 months results in fewer hospitalizations for decompensated liver disease. METHODS: Forty-four patients with advanced liver disease awaiting liver transplantation received oral ciprofloxacin (250 or 500 mg twice daily) or placebo for 1 (n=22/group) or 3 (n=10 ciprofloxacin, 14 placebo) months. RESULTS: Compared to placebo recipients, ciprofloxacin-treated patients had mild improvements in serum albumin levels (+1.5 versus -3.4%, p=0.026) while bilirubin and international normalized ratios (INR) of prothrombin times remained unchanged. Overall, fewer hospitalizations occurred in ciprofloxacin-treated patients (1/22, 5% versus 7/22, 32%, respectively, p=0.02) during the study period. Treatment was well tolerated and no resistant infections occurred in either cohort. CONCLUSIONS: The results of this study suggest that daily ciprofloxacin may result in fewer hospitalizations for patients with advanced liver diseases awaiting liver transplantation but not by enhancing hepatic function.

A mathematical model to study the effect of hepatitis B virus vaccine and antivirus treatment among the Canadian Inuit population.

The prevalence of hepatitis B among the Canadian Inuit population is 4%. This study will use a mathematical model to compare the roles of vaccination and therapy to predict future prevalence and incidence among the Canadian Inuit population for the next 50 years. We applied a mathematical model developed by Medley et al. (Nat Med 7(5):619-624, 2001), combined with data on hepatitis B incidence, prevalence, and vaccination coverage, to predict trends of hepatitis B virus (HBV) among the Inuit population over the next 50 years. The current estimated prevalence of HBV is 6.04% and the incidence is 3.4/100,000 persons among Canadian Inuit. If HBV vaccination coverage levels of 47.2% remain unchanged, the prevalence of HBV will decrease to 1.91% and the incidence will decrease to 0.81/100,000 persons by 2058. If vaccination coverage levels are increased to 57.2%, the prevalence and incidence of HBV will decrease to 1.74% and 0.63/100,000 persons, respectively. If we increase both immunization and therapy by 10%, this will produce the greatest reduction in prevalence and incidence, to 1.56% and 0.54/100,000 persons, respectively. The combination of immunization and treatment programs seems to have the best result in decreasing the prevalence and incidence of HBV among the Inuit population.

Does SEN-V and other non-A-E hepatotropic viruses contribute to the development and progression of non-alcoholic fatty liver disease?

Approximately 10-20% of patients with non-alcoholic fatty liver disease (NAFLD) are at risk of progressing to cirrhosis. The cause of such progression is unclear. SEN-V is a hepatotropic virus that has been associated with more severe and advanced liver disease in patients with chronic hepatitis C virus infections. In this study we tested 32 NAFLD patients for evidence of SEN-V infection and correlated the results with histologic findings. The results of the study revealed similar disease severity and stage of progression in SEN-V positive and negative patients. Although not supportive of our hypothesis, the possibility that SEN-V and/or other non-A-E hepatotropic viruses contribute to the development and course of NAFLD is discussed.

An independent and prospective comparison of two commercial fibrosis marker panels (HCV FibroSURE and FIBROSpect II) during albinterferon alfa-2b combination therapy for chronic hepatitis C.

SUMMARY: Noninvasive markers that accurately follow changes in fibrosis may provide alternatives to liver biopsy for assessment of histological endpoints of antiviral therapy in chronic hepatitis C (CHC). This study compared two commercially available serum marker panels (HCV FibroSURE and FIBROSpect II) during interferon-based therapy. Ninety-five interferon-naïve patients with genotype 1 CHC were enrolled in a phase 2b, active-controlled study of albinterferon alfa-2b/ribavirin for 48 weeks. Proprietary and simple biochemical marker panels were independently evaluated in serum before and during the study. Baseline liver biopsies were evaluated for METAVIR fibrosis by a single pathologist. Index scores were obtained for HCV FibroSURE (n = 84) and FIBROSpect II (n = 95); mean biopsy length: 17.8 +/- 8.0 mm. For detecting fibrosis stages 2-4 (prevalence 23% [22/95] and 21% [18/84]), HCV FibroSURE and FIBROSpect II indicated high sensitivity (1.00 and 0.95, respectively), lower but comparable specificity (0.61 and 0.66, respectively), and a good area under the receiver operating characteristic curve (0.89 and 0.90, respectively). Simple indices had high indeterminate rates (31-40%) at baseline. Patients with a sustained virological response had lower baseline scores than nonresponders, and reduced median percent changes in index scores for HCV FibroSURE (-20.0%vs 2.9%; P = 0.14) and FIBROS Spect II (-6.8%vs 18.4%; P = 0.05). The panels demonstrated comparable performance characteristics for differentiating mild from moderate-severe stage disease in CHC. Lower index scores at baseline that continue to decline likely reflect reduced fibrogenesis activity in patients with successful antiviral responses to therapy.

Autoimmune hepatitis in a North American Aboriginal/First Nations population.

North American Aboriginal populations are at increased risk for developing immune-mediated disorders, including autoimmune hepatitis. In the present study, the demographic, clinical, biochemical, serological, radiological and histological features of autoimmune hepatitis were compared in 33 First Nations (FN) and 150 predominantly Caucasian, non-FN patients referred to an urban tertiary care centre. FN patients were more often female (91% versus 71%; P=0.04), and more likely to have low serum albumin (69% versus 36%; P=0.0006) and elevated bilirubin (57% versus 35%; P=0.01) levels on presentation compared with non-FN patients. They also had lower hemoglobin, and complement levels, more cholestasis and higher serum immunoglobulin A levels than non-FN patients (P=0.05 respectively). Higher histological grades of inflammation and stages of fibrosis, and more clinical and radiological evidence of advanced liver disease were observed in FN patients, but the differences failed to reach statistical significance. The results of the present study suggest that in addition to being more common, autoimmune hepatitis may be more severe in FN populations, compared with predominantly Caucasian, non-FN populations.

Hepatitis C infection and survivals of liver transplant patients in Canada, 1997-2003.

INTRODUCTION: Liver transplantation is an important health and health care issue for Canadians. Very few studies have estimated the survival results among liver transplant patients infected with hepatitis C virus (HCV) in Canada. METHODS: We carried out a retrospective cohort study to analyze 1- to 5-year survival rates among liver transplant patients, using Canadian Organ Replacement Registry data (1997-2003). Patients less than 19 years old were excluded from the study. The patients were categorized according to previous HCV infection status. The HCV-positive and HCV-negative groups were compared in the following characteristics: age group, gender, ethnicity, blood groups, donor type, pretransplantation medical status. Survival curves were plotted by Kaplan-Meier method. Stepwise regression model was applied to control the confounding impact related to gender, age, and HCV infection status. RESULTS: A total of 1842 liver transplant patients were included in the analysis. One-year survival rate for all patients was 85.4%. There were 319 HCV-positive recipients in the exposed group and 813 in the HCV-negative group. The HCV-positive and HCV-negative groups were comparable in age groups, ethnicity, ABO blood group, pretransplantation medical status, and donor organ type. The HCV-positive group had the higher male:female ratio (2.32:1) than the HCV-negative recipients (1.49:1) (Mantel Haenszel (MH) chi2 = 10.0311, P = .0015). There was no significant difference in 1-year survival rate between HCV-positive and HCV-negative groups, but the differences in the 2-year and 5-year survival rates were significant even after adjusting gender factor by stepwise regression analysis (MH chi2 = 4.4203, P = .0355). CONCLUSION: In Canada, the first-year survival rate is about 85.4%, which is comparable with other industrialized countries. The exaggerated survival disadvantage for HCV-positive recipients seems to be middle and long term, not short term.

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.

Survival analysis of liver transplant patients in Canada 1997-2002.

UNLABELLED: Liver transplantation is an important health care issue for Canadians. Very few studies have assessed survival and determinants of survival in liver transplant patients in Canada. METHODS: We carried out an epidemiological analysis of 1 year survival and determinants of 1 year survival in liver transplant patients, using Canadian Organ Replacement Registry data (1997-2002). Survival curves were plotted by the Kaplan-Meier method. Cox proportional hazards analysis was applied to evaluate hazard ratios with different age groups, gender, ethnicity, blood groups, donor type, pretransplantation medical status, and HBV infection status. RESULTS: A total of 1164 liver transplant patients were included in the analysis. One-year survival rate was 84.7%. Male recipients had a 21% higher risk of developing organ failure than females. Recipients over 60 years of age had a 5% lower survival probability in comparison with recipients below 20 years of age. Pacific Islanders and Aboriginals had 32% and 9% lower survival probabilities, respectively, in comparison with Caucasians. Type B blood recipients had a 12% higher survival probability, whereas type AB blood recipients had a 7% lower survival probability compared with type O blood recipients. Twenty-six live organ recipients had 40% higher survival probabilities than 1138 cadaveric organ recipients. Patients with fulminant hepatitis (status 3F) had the highest survival, while patients with fulminant failure in ICU with intubation/ventilation (status 4F) had the lowest survival. One hundred sixty-seven recipients with positive HBsAg antigen showed 10% lower survival probability than 997 cases with negative HBsAg antigen. CONCLUSION: In Canada, the first year survival rate is about 85%, which is comparable with other industrialized countries. Type of donor organs and recipient gender, ethnicity, ABO blood group, pretransplantation medical status, and HBV infection status had significant affects on the recipient survival.

Are community health interventions evaluated appropriately? A review of six journals.

OBJECTIVES: To determine if Randomized Controlled Trial (RCT) methodology was used appropriately in community health, we: (1) determined the proportion of non-randomized studies that should have been RCTs, and (2) assessed the quality of the RCTs. METHODS: The 1992 issues of six community health journals were manually searched. Intervention studies were analyzed. Studies that did not use randomization were analyzed for feasibility and practicality of RCT methods; RCTs were analyzed for quality using a checklist. RCTs were compared with community health RCTs from The New England Journal of Medicine. The proportion of studies meeting each criterion was determined. RESULTS: Fourteen percent of 603 studies were interventions and 4% were RCTs. Of those not using randomization, 42% should have. Mean RCT scores were significantly lower for the community health journals than for The New England Journal of Medicine. Many criteria important to quality scored poorly. CONCLUSIONS: RCTs are underused and lack methodologic rigor in community health. Conclusions regarding the effectiveness of interventions are therefore suspect.

Fasciitis complicating subcutaneous injection of interferon beta.

Data pertaining to 65 patients treated at the Health Sciences Center Hepatology Research Unit in Winnipeg, Manitoba describing local complications related to subcutaneous interferon (IFN) injection administered to treat hepatitis C virus infection are presented. Nine patients experienced local erythematous reactions at the injection region. No life-threatening complications were identified. One case of fasciitis complicating IFN beta injection - a complication not previously reported - was successfully managed with surgical debridement and antibiotic therapy. This case is a dramatic example of why sterile technique during infections must be adhered to.

Outcomes following liver transplantation for patients with alcohol- versus nonalcohol-induced liver disease.

OBJECTIVE: To document and compare the outcomes of adult patients who received liver transplants for alcohol- and nonalcohol-induced liver diseases who attended a liver transplantation follow-up clinic in an urban, nontransplantation centre at a time when no formal alcohol abuse program for transplant candidates and/or recipients was offered. PATIENTS AND METHODS: The study population comprised 10 alcoholic patients and 48 nonalcoholic patients followed for an average of 41 months (range five to 79 months) and 46 months (range two to 116 months), respectively. Primary outcome variables included rates of recidivism, duration of abstinence after transplantation and compliance with post-transplant medical follow-up visits. Time to discharge after transplantation, episodes of graft rejection, liver and renal biochemical abnormalities, diabetes, hypertension, sepsis, strictures, complications unrelated to transplantation and changes in psychosocial status were secondary outcome variables. RESULTS: Significant differences were found with respect to a higher incidence of recidivism (50% for alcoholic patients compared with 2% for nonalcoholic patients, P<0.0001), a shorter period of abstinence after transplantation (14.7+/-17.2 months for alcoholic patients compared with 26.3+/-23.0 months for nonalcoholic patients, P<0.05) and more missed office visits (2.7+/-3.5 for alcoholic patients compared with 1.0+/-1.9 for nonalcoholic patients, P=0.05) in the alcoholic group. The alcoholic group also had a lower incidence of rejection episodes (10% for alcoholic patients compared with 44% for nonalcoholic patients, P<0.05) but higher rates of post-transplantation diabetes (40% for alcoholic patients compared with 2% for nonalcoholic patients, P<0.05), more nontransplantation-related complications (20% for alcoholic patients compared with 0% for nonalcoholic patients, P<0.05), and higher serum creatinine but lower bilirubin and cyclosporine A levels (P<0.05, respectively). Marital separations were also more common in the alcoholic group (20% for alcoholic patients compared with 0% for nonalcoholic patients, P<0.05). CONCLUSIONS: In the absence of formal alcohol abuse programs, the post-transplantation outcome in alcoholic patients generally does not compare well with that of patients who undergo transplantation for nonalcohol-related liver diseases.

Early changes in hepatitis C virus (HCV) RNA levels predict response to interferon treatment in noncirrhotic HCV patients.

UNLABELLED: The role of hepatitis C virus (HCV) RNA quantification in determining ideal interferon (IFN) treatment of noncirrhotic HCV liver disease is uncertain. The specific aim of this study was to determine whether measurement of baseline HCV RNA or changes in HCV RNA levels (DHCV RNA) early during therapy predict response to IFN alpha in noncirrhotic HCV patients. PATIENTS AND METHODS: Twenty-one noncirrhotic patients with chronic HCV were treated with 3 MU IFN alpha-2a three times per week. HCV RNA levels were determined at baseline and after two, four, six, eight and 12 weeks of treatment. Baseline HCV RNA and DHCV RNA during therapy were compared with treatment response results at six months. Data were expressed as mean +/- SE, and differences were assessed using Student's t test. RESULTS: Twenty-one patients initiated IFN alpha therapy. Two patients were noncompliant and lost to follow-up. One patient discontinued IFN alpha due to side effects. Apart from age, where responders tended to be younger than nonresponders, the baseline clinical characteristics and alanine aminotransferase (ALT), aspartate aminotransferase, bilirubin and HCV RNA levels did not differ between IFN alpha responders and nonresponders. Levels of HCV RNA were significantly lower after both two and four weeks of therapy in IFN alpha responders compared with nonresponders (P<0.001). Changes in log HCV RNA levels after both two and four weeks of therapy were significantly greater in IFN alpha responders compared with nonresponders (P<0.001). Changes in log HCV RNA of more than 1.0 after two weeks of IFN alpha therapy identified all six-month responders, with a sensitivity of 100% and a specificity of 89%. Potential financial impact of these findings on patients' management was also calculated. Decisions regarding discontinuation of therapy based on early changes in HCV RNA levels would result in a 40% to 50% reduction in IFN alpha cost. CONCLUSIONS: In noncirrhotic HCV patients, the change in quantitative HCV RNA after the first two weeks of IFN alpha therapy identifies responders. This finding would result in a 40% to 50% cost savings if decisions about continuing IFN alpha were based on early changes in HCV RNA levels rather than ALT or HCV RNA assessment after the completion of three months of IFN alpha treatment.

Profile of a liver transplant follow-up clinic in a nontransplant Canadian urban centre.

Care of the growing number of liver transplant recipients will increasingly fall on the referring centres. Thus, there is a need to define more clearly the demographic, clinical and laboratory profiles of liver transplant recipients, particularly in the setting of a centre where a liver transplantation program does not exist. The present study documented these features in 37 patients attending an adult ambulatory care clinic in an urban, nonliver transplant centre. Mean +/- SD age of the study population was 44 +/- 11.9 years. Twenty-one patients (57%) were male. Annual enrolment in the clinic increased from three patients at the completion of the clinic's first year (1988) to 16 patients in the final year of the study (1993). Time between the transplantation procedure and the patient's return to the referring centre decreased from a mean of 12 weeks in 1988 to four weeks in 1993. During those seven years no patient required an unscheduled return to the transplant centre for surgical complications or problems associated with immuno-suppressive therapy. In conclusion, these data provide a profile of liver transplant patients attending a nonliver transplant centre for follow-up and support the concept that nontransplant centres are capable of providing safe and, in terms of travel, less expensive care for liver transplant recipients.

A comparative trial of recombinant interferon alpha 2A versus alpha 2 beta on myelosuppression in healthy adult volunteers.

BACKGROUND/AIMS: Recombinant interferon (r-IFN) is an antiviral agent used to treat patients with chronic viral hepatitis patients. Unfortunately, the use is often limited due to its myelosuppressive properties. Currently, there are two forms of r-IFN commercially available: r-IFN alpha-2a and rIFN alpha-2b. Although both are thought to be equally effective, a comparative study of their myelosuppressive properties has not been undertaken. MATERIALS AND METHODS: In the present study, three groups of healthy adult volunteers (n = 6/group) were randomized to receive a two week course of either r-IFN alpha-2a or r-IFN alpha-2b (5 million units, subcutaneously, thrice weekly) or no treatment. All subjects were then followed for an additional two week post treatment; observation period. RESULTS: The results of the study revealed that both forms of r-IFN alpha caused a significant and similar decrease in white blood cell counts (maximum declines of 37.9 +/- 6.8% for alpha-2a and 39.5 +/- 6.0% for alpha-2b at day 4) and platelet counts (maximum declines of 19.5 +/- 8.6% for alpha-2a and 20.2 +/- 8.4% for alpha-2b at day 2) from baseline values. Following discontinuation of therapy, white blood cell and platelet counts returned to pretreatment levels. Hemoglobin levels remained unchanged throughout the study period. CONCLUSION: The results of this study indicate that r-IFN alpha causes a prompt and significant decrease in white blood cell and platelet counts. However, no differences exist between r-IFN alpha-2a and r-IFN alpha-2b in terms of their myelosuppressive properties in humans.

The prevalence of intrinsic host risk factors associated with progressive disease in patients with chronic hepatitis C viral infections.

The prevalences of three risk factors that have been identified as important predictors of more progressive forms of chronic hepatitis C viral (HCV) infections (male gender, transfusion recipients and age greater than 50 years at the onset of infection) were documented by a retrospective chart review of 337 HCV-infected patients attending an urban, hospital-based, viral hepatitis clinic. One hundred and ninety-five patients (58%) were male. One hundred and eighteen (35%) had received blood or blood product transfusions in the past, 33% of whom also gave a history of intravenous drug use. Approximately 5% of patients were over the age of 50 years at the estimated time of infection. Twenty percent of patients had two and 4% had all three risk factors. In conclusion, intrinsic host risk factors associated with progressive HCV infection were common in this patient population. If confirmed in other centres, these results suggest that the medical and financial demand on the health care system is likely to be appreciable unless effective and safe therapies for HCV are identified and implemented in the near future.

Viral hepatitis in a Canadian street-involved population.

BACKGROUND: Data on the prevalence and compliance with management of viral hepatitis in the street-involved population are limited. METHOD: Hepatitis A (HAV), B (HBV) and C (HCV) serology and compliance with HBV vaccination were documented in 533 street-involved individuals. RESULTS: The mean age of the study population was 25.7 years (range: 11-65) and 53% were female. Serologic evidence of HAV infection was present in 53%; HBV, 12% (3% ongoing infection); and HCV, 17%. HAV infections were associated with Aboriginal/Metis ethnicity and age over 25 years; HBV with injection drug use (IDU); and HCV with IDU, sex trade work and age over 25 years. Compliance with three-step HBV vaccination was 98%, 77% and 63%. CONCLUSIONS: HAV, HBV and HCV are common infections in urban street-involved persons. Successful HBV (and presumably HAV) vaccination can be achieved in the majority of this population, but concerns exist regarding compliance with more long-term, parenterally-based antiviral therapies.