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 mu g pegylated interferon (PEG-IFN)-alpha-2a (weekly) and ribavirin 1000-1200mg (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 (= 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-alpha-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-alpha-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. Eur J Gastroenterol Hepatol 22:1443-1448 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins

Immunogenicity of two different dosages (10 and 5 μg) of recombinant DNA hepatitis B vaccine in healthy neonates

The immunogenicity of a half (5 μg) and a full (10 μg) dosage of recombinant DNA yeast-derived hepatitis B vaccine (HB-Vax-DNA) in healthy neonates was assessed in order to compare two candidate dosages of vaccine. After randomization 174 newborns of HBsAg-negative mothers entered the study. Neonates received four doses of either 10 or 5 μg hepatitis B vaccine, according to the DTP polio immunization schedule at months 3, 4, 5 and 11. No serious adverse reactions were observed; 15.5% of vaccinated newborns suffered mild transient local symptoms. The vaccine was highly immunogenic irrespective of dosage of vaccine; all infants developed anti-HBs levels ⩾ 10 IUl−1, 99% ⩾ 100 IUl−1. A dosage of 10 μg hepatitis B vaccine produced higher antibody levels than 5 μg hepatitis B vaccine after primary vaccination (first three doses) but not after booster vaccination (fourth dose) (p = 0.06 and 0.75, respectively). Either vaccine dosage can be recommended for incorporation in the Expanded Programme on Immunization in the Netherlands

Interferon (IFN)-γ-Inducible Protein-10: Association with Histological Results, Viral Kinetics, and Outcome during Treatment with Pegylated IFN-α2a and Ribavirin for Chronic Hepatitis C Virus Infection

BackgroundWe investigated associations between interferon (IFN)-γ-inducible protein (IP)-10 and liver histological results, viral kinetic response, and treatment outcome in patients infected with hepatitis C virus (HCV) genotypes 1-4 MethodsPlasma IP-10 was monitored before, during, and after treatment with pegylated IFN-α2a and ribavirin in 265 HCV-infected patients ResultsIn univariate analyses, a low baseline IP-10 level was significantly associated with low baseline viral load, rapid viral response (RVR), a sustained viral response (SVR), body mass index <25 kg/m2, and less-pronounced fibrosis, inflammation, and steatosis (for HCV genotypes other than 3). When the results of the univariate analyses were included in multivariate analyses, a low plasma IP-10 level, low baseline viral load, and genotype 2 or 3 infection were independent predictors of an RVR and SVR. IP-10 levels decreased 6 weeks into treatment and remained low in patients with an SVR. By contrast, plasma levels of IP-10 rebounded in patients who had detectable HCV RNA after the completion of treatment. Using cutoff IP-10 levels of 150 and 600 pg/mL for predicting an SVR in patients infected with HCV genotype 1 yielded a specificity and sensitivity of 81% and 95%, respectively ConclusionBaseline IP-10 levels are predictive of the response to HCV treatmen

Patient profiled data for treatment decision-making:valuable as an add-on to hepatitis C clinical guidelines?

Background and Aims: Systematic reviews and medical guidelines are widely used in clinical practice. However, these are often not up-to-date and focussed on the average patient. We therefore aimed to evaluate a guideline add-on, TherapySelector (TS), which is based on monthly updated data of all available high-quality studies, classified in specific patient profiles. Methods: We evaluated the TS for the treatment of hepatitis C (HCV) in an international cohort of patients treated with direct-acting antivirals between 2015 and 2020. The primary outcome was the number of patients receiving one of the two preferred treatment options of the HCV TS, based on the highest level of evidence, cure rate, absence of ribavirin-associated adverse effects, and treatment duration. Results: We enrolled 567 patients. The number of patients treated with one of the two preferred treatment options according to the HCV TS ranged between 27% (2015) and 60% (2020; p &lt; 0.001). Most of the patients received a regimen with a longer treatment-duration (up to 34%) and/or addition of ribavirin (up to 14%). The effect on the expected cure-rate was minimal (1–6% higher) when the first preferred TherapySelector option was given compared to the actual treatment.Conclusions: Medical decision-making can be optimised by a guideline add-on; in HCV its use appears to minimise adverse effects and cost. The use of such an add-on might have a greater impact in diseases with suboptimal cure-rates, high costs or adverse effects, for which treatment options rely on specific patient characteristics.</p

IP-10 predicts viral response and therapeutic outcome in difficult-to-treat patients with HCV genotype 1 infection

Plasma from 173 patients with HCV genotype 1 infection was analyzed for IP-10 levels prior to treatment with pegylated interferon-α-2a and ribavirin. Significantly lower IP-10 levels were observed in patients achieving a rapid viral response (RVR) (P &lt; .0001), even in those with body mass index (BMI) ≥ 25 kg/m2 (P = .004) and with baseline viral load ≥ 2 million IU/mL (P = .001). Similarly, significantly lower IP-10 levels were observed in patients obtaining a sustained viral response (SVR) (P = .0002), including those having higher BMI (P &lt; .05), higher viral load (P = .0005), and both higher BMI and viral load (P &lt; .03). In multivariate logistic regression analyses, a low IP-10 value was independently predictive of both RVR and SVR. A baseline cutoff IP-10 value of 600 pg/mL yielded a negative predictive value (NPV) of 79% (19/24) for all genotype 1-infected patients, which was comparable with that observed using a reduction in HCY-RNA by at least 2 logs after 12 weeks of therapy (NPV 86%; 19/22); by combining the two, 30 of 38 patients (NPV 79%) potentially could have been spared unnecessary therapy. In patients having both higher BMI and viral load, cut-off levels of 150 and 600 pg/mL yielded a positive predictive value (PPV) of 71% and NPV of 100%, respectively. In conclusion, pretreatment IP-10 levels predict RVR and SVR in patients infected with HCV genotype 1, even in those with higher BMI and viral load. A substantial proportion of the latter patients may achieve SVR in spite of unfavorable baseline characteristics if their pretreatment IP-10 level is low. Thus, pretreatment IP-10 analysis may prove helpful in decision-making regarding pharmaceutical intervention.</p

IP-10 predicts viral response and therapeutic outcome in difficult-to-treat patients with HCV genotype 1 infection

Plasma from 173 patients with HCV genotype 1 infection was analyzed for IP-10 levels prior to treatment with pegylated interferon-α-2a and ribavirin. Significantly lower IP-10 levels were observed in patients achieving a rapid viral response (RVR) (P &lt; .0001), even in those with body mass index (BMI) ≥ 25 kg/m2 (P = .004) and with baseline viral load ≥ 2 million IU/mL (P = .001). Similarly, significantly lower IP-10 levels were observed in patients obtaining a sustained viral response (SVR) (P = .0002), including those having higher BMI (P &lt; .05), higher viral load (P = .0005), and both higher BMI and viral load (P &lt; .03). In multivariate logistic regression analyses, a low IP-10 value was independently predictive of both RVR and SVR. A baseline cutoff IP-10 value of 600 pg/mL yielded a negative predictive value (NPV) of 79% (19/24) for all genotype 1-infected patients, which was comparable with that observed using a reduction in HCY-RNA by at least 2 logs after 12 weeks of therapy (NPV 86%; 19/22); by combining the two, 30 of 38 patients (NPV 79%) potentially could have been spared unnecessary therapy. In patients having both higher BMI and viral load, cut-off levels of 150 and 600 pg/mL yielded a positive predictive value (PPV) of 71% and NPV of 100%, respectively. In conclusion, pretreatment IP-10 levels predict RVR and SVR in patients infected with HCV genotype 1, even in those with higher BMI and viral load. A substantial proportion of the latter patients may achieve SVR in spite of unfavorable baseline characteristics if their pretreatment IP-10 level is low. Thus, pretreatment IP-10 analysis may prove helpful in decision-making regarding pharmaceutical intervention.</p

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

Changes in anti-viral effectiveness of interferon after dose reduction in chronic hepatitis c patients: a case control study

BACKGROUND: High dose interferon induction treatment of hepatitis C viral infection blocks viral production over 95%. Since dose reduction is often performed due to clinical considerations, the effect of dose reduction on hepatitis C virus kinetics was studied. METHODS: A new model that allowed longitudinal changes in the parameters of viral dynamics was used in a group of genotype-1 patients (N = 15) with dose reduction from 10 to 3 million units of interferon daily in combination with ribavirin, in comparison to a control group (N = 9) with no dose reduction. RESULTS: Dose reduction gave rise to a complex viral kinetic pattern, which could be only explained by a decrease in interferon effectiveness in blocking virion production. The benefit of the rapid initial viral decline following the high induction dose is lost after dose reduction. In addition, in some patients also the second phase viral decline slope, which is highly predictive of success of treatment, was impaired by the dose reduction resulting in smaller percentage of viral clearance in the dose reduction group. CONCLUSIONS: These findings, while explaining the failure of many induction schedules, suggest that for genotype-1 patients induction therapy should be continued till HCVRNA negativity in serum in order to increase the sustained response rate for chronic hepatitis C

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

Toy M, Önder FO, Wörmann T, et al. Age- and region-specific hepatitis B prevalence in Turkey estimated using generalized linear mixed models: a systematic review. BMC infectious diseases. 2011;11(1): 337.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

Interferon-Ribavirin for Chronic Hepatitis C with and without Cirrhosis: Analysis of Individual Patient Data of Six Controlled Trials

Background & Aims: The aim of this study was to compare interferon (IFN)- ribavirin combination therapy with IFN monotherapy in chronic hepatitis C with particular focus on its efficacy in cirrhosis. Methods: A multivariate analysis of individual patient data of all randomized controlled trials using an IFN-ribavirin arm, reported between 1991 and March 1998, was performed. Centers included 1 Asian and 5 European university-based referral centers for liver disease . A total of 197 patients with chronic hepatitis C received IFN-alpha (3 MU three times weekly) and ribavirin (1-1.2 g daily) for 6 months, and 147 patients received IFN-alpha (3 MU three times weekly) for 6 months. Patients were characterized according to previous IFN therapy, presence of cirrhosis, and genotype 1. Efficacy of therapy was evaluated by assessing the sustained response rate by logistic regression analysis. Results: Patients without cirrhosis treated with IFN-ribavirin had a significantly higher sustained response rate than those treated with IFN, approximately 3-fold for previously untreated patients (IFN- ribavirin: genotype 1, 33%; genotype 2/3, 65%; IFN: genotype 1, 8%; genotype 2/3, 24%). In cirrhosis, sustained response rates with IFN-ribavirin (previously untreated: genotype 1, 7%; genotype 2/3, 24%) were also significantly higher than those with IFN (previously untreated: genotype 1, 1%; genotype 2/3, 5%). Clinical relevant superiority of combination therapy over IFN monotherapy was also observed for relapse; the same trend was observed for nonresponders. Tolerance for IFN-ribavirin was similar for patients with or without cirrhosis. Conclusions: Combination with ribavirin significantly enhances the sustained response rate of IFN therapy in major patient types (cirrhosis, genotype 1) with chronic hepatitis C. Thus, IFN -ribavirin combination is likely to become the antiviral therapy of choice for cirrhosis caused by hepatitis C