Search

Summary On-treatment hepatitis C virus (HCV) RNA has been used to predict response to interferon (IFN)-based therapy. The concept of response-guided treatment (RGT) was established to determine optimal treatment duration and to early identify patients not responding to futile therapies. RGT helped to improve sustained virologic response (SVR) rates and lower the rates of adverse effects. RGT was of particular importance for telaprevir- and boceprevir-based triple therapies. RGT strategies are dependent on highly sensitive and reproducible HCV RNA quantification. However, different HCV RNA assays are used in routine clinical practice and these differ significantly in their performance characteristics. The development of IFN-free therapies has fundamentally changed the role of on-treatment HCV RNA for SVR prediction. Given the high efficacy and excellent tolerability of IFN-free regimens, the interest in treatment individualization has decreased. However, shorter treatment durations may still be desirable, particularly with respect to the high costs of current IFN-free direct-acting antiviral agents (DAAs). Moreover, some difficult-to-treat patients remain, e.g., those infected with HCV genotype 3 in whom the current standard of care may not always be sufficient to achieve SVR, especially in treatment-experienced patients with cirrhosis. Here, a RGT extension may be feasible. However, current data on the predictive value of on-treatment HCV RNA are limited and have shown conflicting results. As more potent DAAs become available, the role of response prediction may diminish further. Currently, shorter treatment duration is only based on baseline HCV RNA whereas no RGT strategy is recommended for any of the approved DAA regimens available. [ABSTRACT FROM AUTHOR]

Background & Aims: The combination of a hepatitis C virus (HCV) protease inhibitor, peginterferon, and ribavirin is the standard of care for patients with HCV genotype 1 infection. We report the efficacy and safety of response-guided therapy with danoprevir (a potent second-generation protease inhibitor), peginterferon alfa-2a (40 KD), and ribavirin in these patients. Methods: Treatment-naïve patients (N = 237) were randomly assigned to groups given 12 weeks of danoprevir (300 mg every 8 hours; 600 mg every 12 hours, and 900 mg every 12 hours) or placebo plus peginterferon alfa-2a and ribavirin, followed by peginterferon alfa-2a and ribavirin. Patients given danoprevir who had an extended rapid virologic response (eRVR4−20: HCV RNA <15 IU/mL during weeks 4−20) stopped therapy at week 24; those without an eRVR4−20 continued therapy to 48 weeks. Patients who were given placebo received 48 weeks of peginterferon alfa-2a and ribavirin. The primary efficacy end point was sustained virologic response (SVR: HCV RNA <15 IU/mL after 24 weeks without treatment). Results: Rates of SVR were higher among patients given danoprevir 300 mg (68%), 600 mg (85%), and 900 mg (76%) than placebo (42%) (95% confidence interval: 26%−59%). Seventy-nine percent of patients given danoprevir 600 mg had an eRVR4−20; among these, 96% had an SVR. Serious adverse events were reported in 7% to 8% of patients given danoprevir and 19% given placebo. Four patients given danoprevir (1 patient in the 600-mg group and 3 in the 900-mg group) had reversible, grade 4 increases in alanine aminotransferase, which led to early discontinuation of the 900-mg arm of the study. Conclusions: The combination of danoprevir, peginterferon alfa-2a, and ribavirin leads to high rates of SVR in patients with HCV genotype 1 infection, but high doses of danoprevir can lead to grade 4 increases in alanine aminotransferase. Studies of lower doses of danoprevir with ritonavir, to reduce overall danoprevir exposure while maintaining potent antiviral activity, are underway; Clinicaltrials.gov number, NCT00963885. [Copyright &y& Elsevier]

Aim: To use existing hepatitis C virus (HCV) antiviral therapies as access to new treatments is limited., Methods: A PubMed search for randomised control trials or meta-analysis related to response-guided therapy of HCV genotype 1 patients was undertaken using pegylated interferon and ribavirin (PR), boceprevir (B) and telaprevir (T) and lead-in where response-guided therapy at TW4(TW4), 8(TW8), 10(TW10), or 12(TW12) based on HCVRNA(+) or HCVRNA(-). Studies presented at major conferences were also used. Where necessary, a post-hoc analysis was performed. A response-guided management roadmap was created based on sustained virological response (SVR)., Results: Starting with PR, those with HCVRNA(-) at TW4 have > 86% SVR, while those are HCVRNA(+) have 34%-41.7% SVR. HCVRNA(-) TW4 patients can have 24 wk PR if HCVRNA < 400000 IU/mL. Alternatively, 28 wk BPR has similar SVR. If HCVRNA(+) at TW4, 72 wk PR leads to 53% SVR, hence BPR is a better option, and if HCVRNA(-) by TW8, 28 wk therapy is sufficient. If HCVRNA(+) at TW8, then HCVRNA should be checked at TW10 and TW12. By TW12, HCVRNA ≥ 100 IU/mL activates the stopping rule. This roadmap is applicable for treatment-naïve, treatment failures and cirrhotic patients. Validation from an Asia Pacific early access boceprevir program confirmed the findings that HCVRNA(-) at TW4, or TW8 conferred > 80% SVR, leading to the "80-80" rule., Conclusion: Using a roadmap based on HCVRNA(-) at TW4 or TW8 (the "80-80" rule), high SVR can be achieved, and guide the best choices for treatment, and also reduces drug exposure in poor responders.

Aim: To observe the effect of response-guided add-on therapy with adefovir (ADV) and lamivudine (LAM) in cirrhotic hepatitis B (CHB) patients., Methods: A total of 100 patients with CHB and cirrhosis were divided into three arms according to hepatitis B virus (HBV) DNA level after 24 wk LAM monotherapy: Arm A (complete response, HBV DNA ≤ 60 IU/mL, n = 49), Arm B (partial response, HBV DNA: 60-2000 IU/mL, n = 31) and Arm C (inadequate response, HBV DNA > 2000 IU/mL, n = 20). ADV was added to LAM at week 48 in Arms A and B, but at week 24 in Arm C. Virological response, YMDD mutations, biochemical response, and liver function were evaluated., Results: Comparison of the three arms demonstrated that early complete virologic response at week 24 was associated with maintained viral suppression (undetectable rate of HBV DNA at week 144 was 95.96%, 66.67% and 35.29%, respectively, P = 0.000) and reduced YMDD mutations (mutation rate at week 144 was 0%, 3.23% and 15%, respectively, P = 0.015) after 144 wk treatment. For patients who failed to achieve complete virological response at week 24, switching to combination therapy further decreased HBV DNA level by 1 log10 IU/mL. All three arms obtained biochemical benefits including decline of alanine aminotransferase and elevation of albumin. In patients who developed HBV DNA breakthrough for YMDD mutations, ADV add-on therapy did not induce further multiple drug resistance to LAM or ADV., Conclusion: Optimized response-guided add-on therapy of ADV and LAM maintains long-term suppression of HBV DNA and improves liver function in CHB patients with compensated liver cirrhosis.

Second wave direct acting antivirals such as sofosbuvir, simeprevir and daclatasvir can be combined with pegylated interferon alpha and ribavirin (PEG-IFN/RBV) as triple therapy in patients with hepatitis C virus (HCV) infection. In patients with HCV genotype 1 (HCV-1), a PEG-IFN/RBV-based regimen with sofosbuvir is highly effective but the presence of cirrhosis and the non-CC IFNL3 genotype have been associated with a poorer response. A PEG-IFN/RBV-based regimen with simeprevir or daclatasvir is based on response-guided therapy and its efficacy depends on predictors of response to IFN. HCV-1 subtype is also a major predictor of response. In HCV-1a infected patients, the K80Q mutation in NS3 or the presence of NS5A variants at baseline are associated with poor response with simeprevir- or daclatasvir-containing regimens respectively. Thus, these regimens should be only used in HCV-1b patients with good predictors of response to IFN., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

A new treatment paradigm for hepatitis C is that the treatment must include an existing direct-acting antiviral agent, namely, a protease inhibitor (PI) combined with PEGylated interferon-α and ribavirin. The currently marketed PIs and PIs in clinical trials have different mechanisms of action. The development of new PIs aims for an improved safety profile and higher effectiveness. This article reviews NS3/4A protease inhibitors, focusing on major criteria such as their effectiveness and safety. Specific attention is paid to dosing regimens and adverse event profiles of PIs administered in clinical settings.

Hepatitis C genotype 6 is endemic in Southeast Asia [prevalence varies between 10%-60% among all hepatitis C virus (HCV) infection], as well as also sporadically reported outside the area among immigrations. The diagnosis of HCV genotype can be inaccurate with earlier methods of genotyping due to identical 5'-UTR between genotype 6 and 1b, hence the newer genotyping methods with core sequencing are preferred. Risk factors and clinical course of HCV genotype 6 do not differ considerably from other genotypes. Treatment outcome of HCV genotype 6 with a combination of pegylated interferon and ribavirin is superior to genotype 1, and nearly comparable to genotype 3, with expected sustained virological response (SVR) rates of 60%-90%. Emerging data suggests that a shorter course 24-wk treatment is equally effective as a standard 48-wk treatment, particularly for those patients who attained undetectable HCV RNA at week 4 (RVR). In addition, baseline and on-treatment predictors of response used for other HCV genotypes appear effective with genotype 6. Although some pan-genotypic direct-acting antivirals have completed phase II/III studies (sofosbuvir and simeprevir) with clinical benefit demonstrated in small number of patients with genotype 6, broad availability of these agents in Southeast Asia may not be expected in the near future. While awaiting the newer therapy, response-guided therapy seems appropriate for patients with HCV genotype 6. Patients with RVR (representing > 70% of patients) are suitable for 24-wk treatment with expected SVR rates > 80%. Patients without RVR and/or those with poor response predictors may benefit from 48 wk of therapy, and a detectable HCV RNA at week 12 (with no early virological response) serves as a stopping rule. This treatment scheme is likely to have a major economic impact on HCV therapy, particularly in Southeast Asia, wherein treatment can be truncated securely in the majority of patients with HCV genotype 6.

Pegylated interferon and ribavirin combination therapy is accepted as the standard antiviral treatment for chronic hepatitis C regardless of HCV genotype. This combination therapy achieves higher response rates than previous therapy, but, nevertheless, a large proportion of patients suffer from treatment failure or adverse events. Recent clinical studies of viral kinetics during antiviral treatment have led to the introduction of response-guided therapy, the concept of 'customized therapy depending on viral response', which focuses on modulation of the treatment period depending on the viral response to create a sustained viral response without unnecessary medication and costs. New upcoming direct-acting antivirals (DAAs) maximize response rate, and triple therapy including DAAs along with pegylated interferon and ribavirin combination therapy could soon be the standard therapy. In this article, we reviewed the factors affecting treatment, response guided treatment, retreatment after failure of standard treatment, management of adverse events during treatment, and new treatment options.

Pegylated interferon α (IFNα) in combination with ribavirin is currently recommended as a standard-of-care treatment for chronic hepatitis C virus (HCV) infection. This combination therapy has drastically improved the rate of sustained virological response, specifically in difficult-to-treat patients. Recently, individualized treatment, such as response-guided therapy, is being developed based on host-, HCV- and treatment-related factors. Furthermore, modified regimens with currently available medications, novel modified IFNα and ribavirin or combinations with specifically targeted antiviral therapy for HCV agents, are currently being investigated. The purpose of this review is to address some issues and epoch-making topics in the treatment of chronic HCV infection, and to discuss more optimal and highly individualized therapeutic strategies for HCV-infected patients.