Long-term effects of treatment and response in patients with chronic hepatitis C on quality of life. An international, multicenter, randomized, controlled study.

BACKGROUND: Hepatitis C decreases health related quality of life (HRQL) which is further diminished by antiviral therapy. HRQL improves after successful treatment. This trial explores the course of and factors associated with HRQL in patients given individualized or standard treatment based on early treatment response (Ditto-study). METHODS: The Short Form (SF)-36 Health Survey was administered at baseline (n = 192) and 24 weeks after the end of therapy (n = 128). RESULTS: At baseline HRQL was influenced by age, participating center, severity of liver disease and income. Exploring the course of HRQL (scores at follow up minus baseline), only the dimension general health increased. In this dimension patients with a relapse or sustained response differed from non-responders. Men and women differed in the dimension bodily pain. Treatment schedule did not influence the course of HRQL. CONCLUSIONS: Main determinants of HRQL were severity of liver disease, age, gender, participating center and response to treatment. Our results do not exclude a more profound negative impact of individualized treatment compared to standard, possibly caused by higher doses and extended treatment duration in the individualized group. Antiviral therapy might have a more intense and more prolonged negative impact on females.

Age- and region-specific hepatitis B prevalence in Turkey estimated using generalized linear mixed models: a systematic review.

BACKGROUND: To provide a clear picture of the current hepatitis B situation, the authors performed a systematic review to estimate the age- and region-specific prevalence of chronic hepatitis B (CHB) in Turkey. METHODS: A total of 339 studies with original data on the prevalence of hepatitis B surface antigen (HBsAg) in Turkey and published between 1999 and 2009 were identified through a search of electronic databases, by reviewing citations, and by writing to authors. After a critical assessment, the authors included 129 studies, divided into categories: 'age-specific'; 'region-specific'; and 'specific population group'. To account for the differences among the studies, a generalized linear mixed model was used to estimate the overall prevalence across all age groups and regions. For specific population groups, the authors calculated the weighted mean prevalence. RESULTS: The estimated overall population prevalence was 4.57, 95% confidence interval (CI): 3.58, 5.76, and the estimated total number of CHB cases was about 3.3 million. The outcomes of the age-specific groups varied from 2.84, (95% CI: 2.60, 3.10) for the 0-14-year olds to 6.36 (95% CI: 5.83, 6.90) in the 25-34-year-old group. CONCLUSION: There are large age-group and regional differences in CHB prevalence in Turkey, where CHB remains a serious health problem.

Systemic and intrahepatic interferon-gamma-inducible protein 10 kDa predicts the first-phase decline in hepatitis C virus RNA and overall viral response to therapy in chronic hepatitis C.

UNLABELLED: High systemic levels of interferon-gamma-inducible protein 10 kDa (IP-10) at onset of combination therapy for chronic hepatitis C virus (HCV) infection predict poor outcome, but details regarding the impact of IP-10 on the reduction of HCV RNA during therapy remain unclear. In the present study, we correlated pretreatment levels of IP-10 in liver biopsies (n = 73) and plasma (n = 265) with HCV RNA throughout therapy within a phase III treatment trial (DITTO-HCV). Low levels of plasma or intrahepatic IP-10 were strongly associated with a pronounced reduction of HCV RNA during the first 24 hours of treatment in all patients (P < 0.0001 and P = 0.002, respectively) as well as when patients were grouped as genotype 1 or 4 (P = 0.0008 and P = 0.01) and 2 or 3 (P = 0.002, and P = 0.02). Low plasma levels of IP-10 also were predictive of the absolute reduction of HCV RNA (P < 0.0001) and the maximum reduction of HCV RNA in the first 4 days of treatment (P < 0.0001) as well as sustained virological response (genotype 1/4; P < 0.0001). To corroborate the relationship between early viral decline and IP-10, pretreatment plasma samples from an independent phase IV trial for HCV genotypes 2/3 (NORDynamIC trial; n = 382) were analyzed. The results confirmed an association between IP-10 and the immediate reduction of HCV RNA in response to therapy (P = 0.006). In contrast, pretreatment levels of IP-10 in liver or in plasma did not affect the decline of HCV RNA between days 8 and 29, i.e., the second-phase decline, or later time points in any of these cohorts. CONCLUSION: In patients with chronic hepatitis C, low levels of intrahepatic and systemic IP-10 predict a favorable first-phase decline of HCV RNA during therapy with pegylated interferon and ribavirin for genotypes of HCV.

Baseline anti-NS4a antibodies in combination with on-treatment quantitative HCV-RNA reliably identifies nonresponders to pegylated interferon-ribavirin combination therapy after 4 weeks of treatment.

BACKGROUND: Early detection of nonresponders to hepatitis C therapy limits unnecessary exposure to treatment and its side-effects. A recent algorithm combining baseline anti-NS4a antibodies and on-treatment quantitative PCR identified nonresponders to a combination of interferon and ribavirin after 1 week of treatment. AIM: To validate a stopping rule based on baseline anti-NS4a antibody levels and early on-treatment virological response in treatment-naive genotype 1 chronic hepatitis C patients treated with the current standard pegylated interferon and ribavirin combination therapy. METHODS: Eighty-nine genotype 1 patients from the Dynamically Individualized Treatment of hepatitis C Infection and Correlates of Viral/Host dynamics Study treated for 48 weeks with standard 180 µg pegylated interferon (PEG-IFN)-α-2a (weekly) and ribavirin 1000-1200 mg (daily) were analysed. Baseline anti-NS4a antibody enzyme-linked immunosorbent assay (NS4a AA 1687-1718) was performed on pretreatment serum. Hepatitis C virus-RNA was assessed at days 0, 1, 4, 7, 8, 15, 22, 29, weeks 6, 7, 8, 10, 12 and 6 weekly thereafter until end of treatment. Multiple regression logistic analysis was performed. RESULTS: Overall 54 of 89 (61%) patients achieved sustained virological response. A baseline anti-NS4a antibody titre less than 1/1250 correlated with absence of favourable initial viral decline according to variable response types (P = 0.015). The optimal algorithm was developed using the combination of the absence of anti-NS4a Ab (<1/1250) at baseline and the presence of a viral load ≥ 100.000 IU/ml at week 4. This algorithm has a specificity of 43% and negative predictive value of 100% to detect nonresponse to standard PEG-IFN-α-2a and ribavirin therapy at fourth week of therapy (intention-to-treat analysis). CONCLUSION: The decision to stop the therapy in genotype 1 chronic hepatitis C patients treated with PEG-IFN-α-2a and ribavirin can be confidently made after 4 weeks of treatment based on the absence of baseline anti-NS4a Ab and a week-4 hepatitis C virus-RNA above 100.000 IU/ml.

Screening and early treatment of migrants for chronic hepatitis B virus infection is cost-effective.

BACKGROUND & AIMS: Persons with chronic hepatitis B virus (HBV) infection are at risk of developing cirrhosis and hepatocellular carcinoma. Early detection of chronic HBV infection through screening and treatment of eligible patients has the potential to prevent these sequelae. We assessed the cost-effectiveness in The Netherlands of systematically screening migrants from countries that have high and intermediate HBV infection levels. METHODS: Epidemiologic data of the expected numbers of patients with active chronic HBV infection in the target population and information about the costs of a screening program were used in a Markov model and used to determine costs and quality-adjusted life years (QALY) for patients who were and were not treated. RESULTS: Compared with the status quo, a 1-time screen for HBV infection can reduce mortality of liver-related diseases by 10%. Using base case estimates, the incremental cost-effectiveness ratio (ICER) of screening, compared with not screening, is euros (euro) 8966 per QALY gained. The ICER ranged from euro7936 to euro11,705 based on univariate sensitivity analysis, varying parameter values of HBV prevalence, participation rate, success in referral, and treatment compliance. Using multivariate sensitivity analysis for treatment effectiveness, the ICER ranged from euro7222 to euro15,694; for disease progression, it ranged from euro5568 to euro60,418. CONCLUSIONS: Early detection and treatment of people with HBV infection can have a large impact on liver-related health outcomes. Systematic screening for chronic HBV infection among migrants is likely to be cost-effective, even using low estimates for HBV prevalence, participation, referral, and treatment compliance.

Potential impact of long-term nucleoside therapy on the mortality and morbidity of active chronic hepatitis B.

UNLABELLED: The potential impact of long-term antiviral therapy on the burden of chronic hepatitis B has hardly been documented. The aim of this study was to estimate the effects of prolonged antiviral therapy and antiviral resistance on the mortality and morbidity of active chronic hepatitis B patients. A population cohort of chronic hepatitis B patients in the Netherlands was constructed and stratified according to 10-year age groups, prevalence of hepatitis B surface antigen, hepatitis B virus DNA level, alanine aminotransferase level, hepatitis B e antigen status, and presence of cirrhosis. A Markov model was created to mathematically simulate the cohort's progression through a finite series of health states. The analysis was performed on the basis of four scenarios: natural history, long-term therapy with a high-resistance profile drug without or with salvage, and therapy with a low-resistance profile drug. It has been estimated that there were 64,000 people (0.4%) suffering from chronic hepatitis B infection in the Netherlands in 2005, with 6521 (10%) of them having high viremia and elevated alanine aminotransferase levels. Within a 20-year period, 1725 (26%) of the 6521 patients in the active chronic hepatitis B cohort will die because of liver-related causes. Of the 5685 without cirrhosis at entry, 1671 (29%) will develop cirrhosis. Of those 836 with cirrhosis at entry, 619 (74%) will die within a 20-year period. If this active chronic hepatitis B cohort is fully detected and treated, mortality related to liver disease can be reduced by 80% if a low-resistance profile drug is chosen from the start. The effect is due to both the reduction in complications of cirrhosis and the prevention of the development of cirrhosis. CONCLUSION: Long-term antiviral therapy with a strategy that minimizes or controls resistance will have a major preventive effect on liver-related mortality and morbidity.

A non-invasive fibrosis score predicts treatment outcome in chronic hepatitis C virus infection.

OBJECTIVE: The results of a previous study suggest that an index calculated according to the formula (normalized ASAT x PK-INR) x 100/thrombocyte count (x 10(9)/L; GUCI) may reflect liver fibrosis in patients with chronic hepatitis C virus (HCV) infection. The aims of the present study were (i) to validate the association between the Göteborg University Cirrhosis Index (GUCI) score and liver fibrosis and (ii) to evaluate the utility of this index in predicting the outcome of antiviral treatment. MATERIAL AND METHODS: A total of 269 patients with chronic HCV infection, stratified according to HCV genotype (1/4 versus 2/3) participated in a phase III trial using pegylated interferon alpha-2a and ribavirin (DITTO study). Retrospective analyses of the baseline GUCI scores and assessments of pretreatment liver biopsies using the Ishak protocol were performed. Cut-off GUCI scores were calculated to distinguish patients with a high or low probability of sustained viral response (SVR). RESULTS: Striking associations between GUCI and Ishak fibrosis stages (stages 0-2 versus stages 3-4, p = 0.0002, stages 3-4 versus stages 5-6, p = 0.002) were observed. In patients with genotype 1 or 4, a GUCI score below 0.33 was associated with a rapid viral response to antiviral treatment and an SVR rate of 80%. Ninety-two percent of patients (92/101) with a SVR had a pretreatment GUCI score below 1.11. CONCLUSIONS: Our results suggest that the GUCI score appropriately reflects the stage of liver fibrosis in HCV-infected patients, and predicts initial viral kinetics as well as treatment outcome in patients infected with HCV genotype 1 or 4.

Selection of an entecavir-resistant mutant despite prolonged hepatitis B virus DNA suppression, in a chronic hepatitis B patient with preexistent lamivudine resistance: successful rescue therapy with tenofovir.

BACKGROUND AND OBJECTIVE: Entecavir has potent activity against hepatitis B virus. Drug resistance has not been reported in nucleoside-naïve patients and is low in lamivudine-refractory patients. METHODS AND RESULTS: A 43-year-old man was treated with lamivudine for hepatitis B e antigen-positive chronic hepatitis B. A viral breakthrough owing to a drug-resistant mutant was observed and entecavir 1 mg daily was added. After the viral load had been near the lower detection range of the PCR assay for 30 weeks, lamivudine was discontinued. The serum hepatitis B virus DNA remained low until a second viral breakthrough was observed after 45 weeks of entecavir monotherapy. Treatment was switched from entecavir to tenofovir disoproxil 245 mg daily, which resulted in a decline below 1000 copies/ml. Sequence analysis revealed the presence of rtL180M and rtM204V lamivudine-resistant-associated mutations at the start of entecavir treatment. During entecavir treatment, the rtS202G mutation was selected. Retrospective analysis revealed that during lamivudine treatment three other mutations had been selected as well, namely rtE1D, rtV207L, and rtI220L. CONCLUSION: We describe the first case of entecavir resistance in a lamivudine-resistant patient with good initial suppression of viral replication for 70 weeks. On the basis of the data from cross-resistance and sensitivity testing in vitro and treatment outcomes, tenofovir proves to be a good treatment option for entecavir-resistant patients.

Increased risk of hepatocellular carcinoma among patients with hepatitis C cirrhosis and diabetes mellitus.

UNLABELLED: Recent studies suggest that diabetes mellitus increases the risk of developing hepatocellular carcinoma (HCC). The aim of this study is to quantify the risk of HCC among patients with both diabetes mellitus and hepatitis C in a large cohort of patients with chronic hepatitis C and advanced fibrosis. We included 541 patients of whom 85 (16%) had diabetes mellitus. The median age at inclusion was 50 years. The prevalence of diabetes mellitus was 10.5% for patients with Ishak fibrosis score 4, 12.5% for Ishak score 5, and 19.1% for Ishak score 6. Multiple logistic regression analysis showed an increased risk of diabetes mellitus for patients with an elevated body mass index (BMI) (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.00-1.11; P = 0.060) and a decreased risk of diabetes mellitus for patients with higher serum albumin levels (OR, 0.81; 95% CI, 0.63-1.04; P = 0.095). During a median follow-up of 4.0 years (interquartile range, 2.0-6.7), 11 patients (13%) with diabetes mellitus versus 27 patients (5.9%) without diabetes mellitus developed HCC, the 5-year occurrence of HCC being 11.4% (95% CI, 3.0-19.8) and 5.0% (95% CI, 2.2-7.8), respectively (P = 0.013). Multivariate Cox regression analysis of patients with Ishak 6 cirrhosis showed that diabetes mellitus was independently associated with the development of HCC (hazard ratio, 3.28; 95% CI, 1.35-7.97; P = 0.009). CONCLUSION: For patients with chronic hepatitis C and advanced cirrhosis, diabetes mellitus increases the risk of developing HCC.

Hepatitis C viral kinetics in plasma and peripheral blood mononuclear cells during pegylated interferon-alpha2a/ribavirin therapy.

BACKGROUND/AIMS: Analysis of hepatitis C virus (HCV) RNA kinetics in compartments other than plasma may help in understanding HCV replication and identifying clinically significant patterns of treatment response. METHODS: After 6 weeks of pegylated interferon-alpha2a/ribavirin therapy, 74 chronic hepatitis C patients were randomized to individualized or standard treatments for another 42 weeks. HCV RNA was quantified in peripheral blood mononuclear cells (PBMCs) by TaqMan-based real-time PCR and compared to plasma HCV RNA. RESULTS: HCV RNA declines in PBMCs and plasma were comparable during the initial 12 weeks of therapy (Spearman's rank correlation range over different time points, 0.73-0.97). However, a delay of HCV RNA decay in PBMCs, expected if kinetics in PBMCs only reflected kinetics in plasma, was rarely observed. For many patients, HCV RNA decline in PBMCs started as early as in plasma and for some of them the kinetics strongly differed in the two compartments, hinting at a compartment-specific HCV replication and treatment effect. Fast viral decay in PBMCs was associated with sustained virological response, but viral kinetics in PBMCs added only minor predictive information compared with kinetics in plasma. CONCLUSIONS: Future kinetics studies of HCV RNA during therapy with new antivirals should take into account their compartment-specific effect.

Estimating the future health burden of chronic hepatitis B and the impact of therapy in Spain.

BACKGROUND: Chronic hepatitis B virus (HBV) infection can lead to fatal complications and death. Only a relatively small proportion of patients actually receive medication, and the majority requires long-term antiviral therapy that can result in the emergence of resistant strains of HBV. The study aimed to estimate the future burden of chronic hepatitis B in Spain over the next 20 years, the impact of current lamivudine treatment and the emergence of drug-resistant HBV. METHODS: We constructed a hypothetical cohort of people with active chronic HBV infection in Spain in 2005, and 'followed' the cohort for 20 years. The cohort was stratified with respect to factors that affect prognosis (i.e. hepatitis B e-antigen and histology-defined status). To estimate the burden, Markov mathematical simulation was performed based on three scenarios: natural history, treatment with antiviral drug (lamivudine) and treatment with a hypothetical drug with identical profiles to lamivudine but to which there is no resistance. RESULTS: We estimated that in 2005 there were around 111,000 individuals suffering from active chronic HBV infection. If the cohort is not treated, by the year 2025 there will be about 60,000 events of morbidity and 40,000 cases of liver-related deaths, with 1.84 billion euro expected to be consumed in providing care for the cohort. Treating 35% of the cohort with lamivudine will reduce the morbidity and mortality by 19 and 15%, respectively; whereas the hypothetical drug will reduce the morbidity and mortality by 27 and 24%. The cumulative cost savings resulting from the use of lamivudine and the hypothetical drug, respectively, are 160 and 300 million euro. Antiviral resistance accounts for a reduction of about one-third in the potential benefit of treatment, and almost a half of the potential cost saving. CONCLUSION: Chronic hepatitis B will pose a great burden in the future if the individuals with active disease are left untreated. Effective antiviral therapy and treatment coverage have substantial impact in reducing the future burden; however, antiviral resistance decreases treatment benefit considerably.

Peginterferon for the treatment of chronic hepatitis B in the era of nucleos(t)ide analogues.

The practising clinician is currently faced with a number of effective treatment options for chronic hepatitis B, including two formulations of interferon (standard IFN and pegylated IFN) and five nucleos(t)ide analogues (lamivudine, adefovir, entecavir, telbivudine and tenofovir). Treatment strategies can be divided into those aiming for sustained response after discontinuation of therapy and those that need to be maintained by prolonged antiviral therapy. Sustained response is particularly achieved with interferon-based therapy, while treatment-maintained response can be achieved with long-term nucleos(t)ide analogue therapy in the majority of patients. Of currently available drugs for the treatment of chronic hepatitis B, PEG-IFN seems to result in the highest rate of off-treatment sustained response after a 1-year course of therapy. Sustained transition to the immune-control phase (inactive HBsAg carrier state) can be achieved in 30-35% of HBeAg-positive patients and 20-25% of HBeAg-negative patients. Loss of HBsAg has been observed in 11% of both HBeAg-positive and HBeAg-negative patients after 3-4 years. Since hepatitis B virus (HBV) genotype is an important predictor of response to PEG-IFN, determination of HBV genotype is essential in patients in whom sustained off-treatment response is pursued. Aiming for sustained response is of particular interest because many HBV-infected patients are in need of antiviral therapy at a young age and may otherwise require indefinite antiviral therapy.

Pegylated interferon alfa-2a (40 kD) and ribavirin in haemodialysis patients with chronic hepatitis C.

BACKGROUND: Chronic hepatitis C virus (HCV) infection is associated with liver dysfunction and hepatocellular carcinoma. In patients with normal kidney function, treatment with pegylated interferon (PEG-IFN) and ribavirin (RBV) frequently leads to eradication of HCV. Treatment in dialysis patients has long been controversial and until recently, the use of RBV was considered to be contra-indicated. We used plasma trough levels of RBV to promote tolerance, safety and efficacy. PEG-IFN alfa-2a (40 kD) was chosen because it is cleared predominantly via hepatic metabolism. METHODS: Seven haemodialysis patients with chronic HCV infection were eligible and started with 135 microg PEG-IFN alfa-2a (40 kD) weekly and 200 mg RBV every other day. Dose adaptations were allowed following study guidelines. Genotypes 1 and 4 (five patients) were treated for 48 weeks and genotypes 2 and 3 (two patients) for 24 weeks. HCV-RNA was determined after 12, 24 and 48 weeks (and at 72 weeks for genotypes 1 and 4). RBV trough plasma levels were monitored regularly by HPLC-technique. RESULTS: All patients completed the treatment. In two patients, the PEG-IFN dose had to be reduced to 90 microg/week because of adverse events. To achieve the target range (1.5-2.5 microg/ml) of the plasma trough level, the mean RBV dose was increased to a dose between 133 and 200 mg each day in five patients. Despite an increase of the weekly erythropoietin (Epo) dose, two to a max of four red cell transfusions were given to four patients. A sustained viral response (SVR) was reached in five patients (3/5 with genotype 1/4 and 2/2 with genotype 2/3). CONCLUSION: In our series of seven patients, we were able to use RBV monitoring drug levels in combination with PEG-IFN alfa-2a (40 kD) and achieve high sustained response rates. However, Epo and transfusion requirements may increase. In two patients adverse events were observed, but manageable with dose reduction of PEG-IFN.

Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis.

BACKGROUND: Clinical outcomes of chronic hepatitis C infection in patients with advanced fibrosis include liver failure, hepatocellular carcinoma, and death. OBJECTIVE: To investigate whether sustained virologic response to treatment for hepatitis C is associated with improved clinical outcomes. DESIGN: Retrospective cohort study. SETTING: 5 hepatology units of tertiary care centers in Europe and Canada caring for patients with chronic hepatitis C treated between 1990 and 2003. PATIENTS: Consecutively treated patients with chronic hepatitis C who had biopsy-proven advanced fibrosis or cirrhosis (Ishak score, 4 to 6). MEASUREMENTS: Sustained virologic response, defined as absence of detectable hepatitis C virus RNA at 24 weeks after the end of treatment, and clinical outcomes, defined as death (liver-related or non-liver-related), liver failure, and hepatocellular carcinoma. RESULTS: Of 479 patients, 29.6% had sustained virologic response and 70.3% did not. Median follow-up was 2.1 years (interquartile range, 0.8 to 4.9 years). Four patients with and 83 without sustained virologic response had at least 1 outcome event. Sustained virologic response was associated with a statistically significant reduction in the hazard of events (adjusted hazard ratio, 0.21 [95% CI, 0.07 to 0.58]; P = 0.003). The effect was largely attributable to a reduction in liver failure, which developed in no patients with and 42 patients without sustained virologic response (5-year occurrence, 0% vs. 13.3% [CI, 8.4% to 18.2%]; unadjusted hazard ratio, 0.03 [CI, 0.00 to 0.91]). LIMITATIONS: Because few events occurred in the sustained virologic response group, the study had limited ability to detect differences between groups in individual outcomes. In addition, the study was retrospective; selection and survival biases may therefore influence estimates of effect. CONCLUSION: Sustained virologic response to treatment is associated with improved clinical outcomes, mainly prevention of liver failure, in patients with chronic hepatitis C and advanced fibrosis.

Gamma-glutamyltransferase and rapid virological response as predictors of successful treatment with experimental or standard peginterferon-alpha-2b in chronic hepatitis C non-responders.

BACKGROUND: High-dose peginterferon-alpha (PegIFN-alpha) induction and prolongation of therapy may be an option to improve sustained virological response (SVR) rates among hepatitis C virus (HCV) non-responders, although a higher and a longer dosing of PegIFN-alpha may intensify side effects. METHODS: We randomized 53 patients, who previously failed with standard IFN-alpha+/-ribavirin, to a high-dose induction and an extended regimen with PegIFN-alpha-2b [3.0 microg/kg once weekly (q.w.) 12 weeks-->2.0 microg/kg q.w. 12 weeks-->1.5 microg/kg q.w. 48 weeks] or a standard regimen (1.5 microg/kg q.w. 48 weeks). All patients received daily weight-based ribavirin (800-1200 mg/day). The short-form 36 health survey was used to evaluate health-related quality of life (HRQL). RESULTS: Intention-to-treat analysis showed no significant difference in SVR rate (44% vs. 37%, P=0.62) and relapse rate (9% vs. 31%, P=0.17) between experimental and standard treatment. Overall, 80% of the [positive predictive value (PPV)] patients with rapid virological response (RVR, HCV-RNA negativity at week 4) achieved SVR. No significant dose-related differences in HRQL were seen between both groups. At baseline, genotype 2 or 3 [odds ratio (OR): 7.4, 95% confidence interval (CI): 1.4-33.3, P=0.01] and gamma-glutamyltransferase (GGT) levels <2 x ULN (upper limit of normal) (OR: 6.76, 95% CI: 1.5-31.3, P=0.009) were significantly associated with SVR. Multivariate logistic regression at week 4 showed that only baseline GGT <2 x ULN (OR: 7.3, 95% CI: 1.4-38.5, P=0.01) and RVR (OR: 15.6, 95% CI: 3.2-76.9, P<0.001) were independently predictive for SVR. CONCLUSION: Retreatment with PegIFN-alpha-2b and ribavirin for a minimum of 48 weeks should be considered in all patients unresponsive to previous IFN-based therapies. Baseline GGT values and RVR are highly predictive for retreatment outcome.

HCV-specific T-cell response in relation to viral kinetics and treatment outcome (DITTO-HCV project).

BACKGROUND & AIMS: The second slope of viral decline induced by interferon treatment has been suggested to be influenced mainly by the hepatitis C virus (HCV)-specific T-cell response; however, this hypothesis needs to be validated by results derived from experimental studies. METHODS: To address this issue, the HCV-specific T-cell response of 32 genotype-1-infected patients of the 270 patients enrolled in the dynamically individualized treatment of hepatitis C infection and correlates of viral/host dynamics phase III, open-label, randomized, multicenter trial was studied in relation to viral kinetics and treatment outcome. RESULTS: Greater proliferative responses by HCV-specific CD8 cells were found before treatment in patients with a fast viral decline and with a sustained viral response. However, no significant improvement of HCV-specific CD8 responses was observed in the first weeks of therapy in both rapid viral responder and non-rapid viral responder patients. A mild enhancement of proliferative T-cell responses and a partial restoration of the cytotoxic T-cell potential was expressed only late during treatment, likely favored by HCV clearance. CONCLUSIONS: Early restoration of an efficient T-cell response does not seem to be an essential requirement for a rapid viral decline in the first weeks of treatment. However, patients presenting a better HCV-specific CD8 cell proliferative potential at baseline are more likely to present a rapid and sustained viral response. Therefore, future treatment protocols should consider the development of strategies aimed at improving HCV-specific T-cell responses.

Peginterferon alpha-2b is safe and effective in HBeAg-positive chronic hepatitis B patients with advanced fibrosis.

UNLABELLED: Chronic hepatitis B (CHB) patients with advanced fibrosis are often not considered for treatment with peginterferon (PEG-IFN) because IFN therapy may precipitate immunological flares, potentially inducing hepatic decompensation. We investigated the efficacy and safety of treating hepatitis B e antigen (HBeAg)-positive CHB patients with 52 weeks of PEG-IFN-alpha-2b (100 microg weekly) alone or in combination with lamivudine (100 mg daily). Seventy patients with advanced fibrosis (Ishak fibrosis score 4-6) and 169 patients without advanced fibrosis, all with compensated liver disease, participated in the study. Virologic response, defined as HBeAg seroconversion and hepatitis B virus (HBV) DNA < 10,000 copies/ml at week 78, occurred significantly more often in patients with advanced fibrosis than in those without (25% versus 12%, respectively; P = 0.02). Also patients with cirrhosis (n = 24) exhibited a virologic response more frequently than did patients without cirrhosis (30% versus 14%, respectively; P = 0.02). Improvement in liver fibrosis occurred more frequently in patients with advanced fibrosis (66% versus 26%, P < 0.001). HBV genotype A was more prevalent among patients with advanced fibrosis than among those without (57% versus 24%, P < 0.001). Most adverse events, including serious adverse events, were observed equally as frequently in patients with advanced fibrosis and those without. Fatigue, anorexia, and thrombocytopenia occurred more often in patients with advanced fibrosis than in those without (P < 0.01). Necessary dose reduction or discontinuation of therapy was comparable for both patient groups (P = 0.92 and P = 0.47, respectively). CONCLUSION: PEG-IFN is effective and safe for HBeAg-positive patients with advanced fibrosis. Because PEG-IFN therapy results in a high rate of sustained off-therapy response, patients with advanced fibrosis or cirrhosis but compensated liver disease should not be excluded from PEG-IFN treatment.

Genetic characteristics of hepatitis B virus genotypes as a factor for interferon-induced HBeAg clearance.

The factors determining the responsiveness of different hepatitis B virus (HBV) genotypes to interferon treatment are not fully understood. We investigated the relationship between HBV genetic characteristics and the outcome of short (16 weeks) or prolonged (32 weeks) treatment with standard interferon-alpha in a prospectively followed cohort of 103 patients across Europe with HBeAg positive chronic hepatitis B. INNO-LiPA assays and HBV DNA sequencing were used to determine HBV genotypes, mutations in the core promoter and precore/core regions. After 16-weeks interferon-alpha treatment, the rate of HBeAg clearance was higher in genotype A versus all other genotypes (P = 0.014), or genotype D alone (P = 0.05). The HBV genome analysis revealed that: (i) after 16-weeks treatment, an HBV subpopulation with core promoter mutations emerged or increased (P < 0.001) only in genotype A; (ii) the core gene of genotype A has the lowest number of amino acid variations in comparison with genotypes B, C, or D. Logistic regression analysis identified genotype A as a positive predictor of short (16 weeks) treatment response (P = 0.001; odds ratio 6.19, 95 confidence interval 1.94-19.8), having a greater impact than baseline HBV DNA or alanine aminotransferase (ALT) levels. In contrast, the response to prolonged interferon-alpha treatment was not different between HBV genotypes. These results suggest that HBV genotype A responds earlier to interferon treatment than other genotypes, which is associated with its molecular characteristics. The optimal duration of interferon-based therapies in chronic hepatitis B may vary between different HBV genotypes.