Long-term follow-up of HIV-infected patients with chronic hepatitis C virus infection treated with interferon-based therapies

BACKGROUND: Chronic hepatitis C virus (HCV) infection is frequent among HIV-infected patients. Clearance of serum HCV RNA 6 months after discontinuing HCV therapy is generally interpreted as a cure of HCV infection in HIV-negative subjects. However, the occurrence of liver complications (including hepatocellular carcinoma) and/or HCV relapses in coinfected patients when followed for long periods of time after HCV therapy is not well known. METHODS: All HIV-infected patients who had been treated for chronic hepatitis C at our institution and had a minimum follow-up of 6 months after discontinuing therapy were retrospectively analysed. They had received one of three HCV treatment modalities: IFN monotherapy, IFN plus ribavirin (RBV) or pegylated interferon (PEG-IFN) plus RBV. RESULTS: A total of 351 patients were retrospectively analysed. Sustained virological response (SVR) to HCV therapy had been reached by 77 (22%) of them: 22/119 (18.5%) with IFN monotherapy, 17/106 (16%) with IFN plus RBV and 38/126 (30.2%) with PEG-IFN plus RBV. Considering the HCV genotypes, SVR had been reached by 19/184 (10.3%) of patients with genotype 1, 54/138 (39.1%) with genotypes 2 or 3, and 4/29 (13.8%) of those with genotype 4. Within a total of 4466 patient-months follow-up (mean of 58 months), none of the 77 patients with SVR showed HCV-RNA rebounds, elevations in liver enzymes potentially linked to HCV, development of hepatocellular carcinoma or episodes of decompensated cirrhosis. In contrast, all 274 patients who did not reach SVR with HCV therapy showed evidence of persistent serum HCV RNA and 90% of them showed liver enzyme elevations during a total of 15344 patient-months follow-up (mean of 56 months). Moreover, 11 (4%) developed clinical complications of liver cirrhosis and two of them died of end-stage liver disease. CONCLUSIONS: HCV replication and HCV-related liver disease seem to be permanently halted in HIV/HCV-coinfected patients showing HCV-RNA clearance 6 months after completing any kind of IFN-based therapy. In contrast, complications of liver disease due to persistent HCV infection continue to occur in non-responders. The role of maintenance HCV therapy should be explored in HIV/HCV-coinfected patients.     

Low response to pegylated interferon plus ribavirin in HIV-infected patients with chronic hepatitis C treated with abacavir

BACKGROUND: There is little information about the influence of antiretroviral drugs on the antiviral activity of pegylated interferon (PEG-IFN) plus ribavirin (RBV) against hepatitis C virus (HCV). METHODS: All HIV-infected patients with chronic hepatitis C who received first-line PEG-IFN plus RBV were retrospectively analyzed. Only patients in whom virological stopping rules were applied and who did not change their antiretrovirals were chosen. Plasma RBV concentrations were measured at week 4. RESULTS: A total of 493 patients (78% males, mean age 41 years, 78% on antiretroviral therapy, mean CD4+ T-cell count 561 cells/microl) fit the study inclusion criteria. Mean baseline serum HCV RNA was 5.89 log10 IU/ml, 65% were infected by genotypes 1 or 4 and 40% had advanced liver fibrosis (Metavir F3F4). The overall rate of sustained virological response (SVR) was 38%. Factors associated with lack of SVR in the multivariate analyses (odds ratio [95% confidence interval], P-value) were higher baseline serum HCV RNA (2.42 per log10 IU/ml [1.31-4.46], 0.005), HCV genotypes 1 or 4 (5.95 [2.50-14.29], < 0.001) and lower RBV plasma trough concentrations (1.74 per microg/ml [1.15-2.63], 0.009). Interestingly, a trend was noticed for abacavir use (2.22 [0.91-5.40], 0.08), which become significant when only considering the subset of patients with RBV plasma levels < 2.3 microg/ml (7.63 [1.39-41.67], 0.02). CONCLUSIONS: The use of abacavir might interfere with the anti-HCV activity of PEG-IFN plus RBV. As both antivirals are guanosine analogues, an inhibitory competition between abacavir and RBV might explain this observation, which is more prominent in patients with lower RBV exposure.     

Open, randomized, multicentre italian trial on PEG-IFN plus ribavirin versus PEG-IFN monotherapy for chronic hepatitis C in HIV-coinfected patients on HAART

BACKGROUND: Chronic hepatitis C is common and aggressive in HIV-positive patients, so the development of a well-tolerated HCV therapy is a priority. We evaluated the efficacy and safety of pegylated interferon alpha2b (PEG-IFN) plus ribavirin (RBV) versus PEG-IFN monotherapy in HIV/HCV-coinfected patients undergoing highly active antiretroviral therapy (HAART), and analysed the predictive factors of response. METHODS: An Italian, multicentre, open-label trial including 135 coinfected patients, randomized to PEG-IFN 1.5 microg/kg/week plus RBV 400 mg twice daily (n=69, arm A) or PEG-IFN 1.5 microg/kg/week (n=66, arm B) for 48 weeks. We assessed the predictive values of early virological response (EVR) at week 8 (HCV-RNA drop >2 log10 compared with baseline or undetectable levels) on sustained virological response (SVR). RESULTS: Fifty-five patients (28 from arm A and 27 from arm B) completed 48 weeks of therapy. At the end of treatment, 20/28 patients in arm A and 11/27 in arm B had HCV-RNA <50 IU/ml. In a per-protocol analysis, SVR was reached by 54% of patients in arm A (genotype 2-3, 11/16; genotype 1-4, 4/12) and 22% in arm B (genotype 2-3, 3/15; genotype 1-4, 3/12). In an intention-to-treat analysis, the SVR was 22% in arm A (genotype 2-3, 11/32; genotype 1-4, 4/37) versus 9% in arm B (genotype 2-3, 3/32; genotype 1-4, 3/34). The best predictors of SVR were the use of combination therapy, infection with HCV genotype 3 versus genotype 1, and EVR at week 8. Thirty patients (15 from arm A and 15 from arm B) dropped out of the trial prematurely due to side effects. The positive predictive value of EVR at week 8 was 65%, the negative predictive value was 86%. CONCLUSIONS: PEG-IFN plus RBV can be considered a solid option for the treatment of HIV/HCV-coinfected patients. The key to successfully improving efficacy is strong compliance through strict overall patient monitoring, in order to best manage drug toxicity. EVR assessment at week 8 may become a useful stategy in the management of therapy.     

Impact of ribavirin exposure on early virological response to hepatitis C therapy in HIV-infected patients with chronic hepatitis C

BACKGROUND: The use of pegylated interferon (PEG-IFN) plus ribavirin (RBV) is currently the recommended treatment for chronic hepatitis C virus (HCV) infection. Coinfection with HIV is a negative predictor of response, for reasons not well understood. METHODS: We examined the virological response at weeks 4 and 12 in 198 HCV/HIV-coinfected patients enrolled in a prospective trial in which PEG-IFN alpha 2a (180 microg per week) and RBV (1000-1200 mg daily) were provided. RESULTS: In an on-treatment analysis, 52.8% of patients achieved undetectable HCV-RNA (<600 IU/ml) at week 4, while 63% and 77.2% of patients had a decline of at least 2 and 1 log10, respectively. At week 12, 73.1% of patients reached undetectable HCV-RNA, and 83.5% and 89% achieved at least a 2- and 1-log10 drop, respectively. More than 85% of HCV genotypes 2/3 cleared HCV-RNA at week 4, a proportion significantly higher when compared with genotypes 1 (33.8%) and 4 (28.6%). Multivariate logistic regression analysis identified genotype 3 and RBV exposure (mg/kg of body weight) as independent predictors of virological response at week 12 of therapy. CONCLUSION: Early virological response rates to PEG-IFN plus RBV in HCV/HIV-coinfected patients seem to be similar to those reported for HCV-monoinfected subjects. The use of suboptimal doses of RBV in most earlier trials might account for the low response rates seen in coinfected patients. To our knowledge, this is the first report demonstrating that RBV exerts a significant independent effect on early virological response. Therefore, strategies aimed at optimizing doses and adherence to RBV might help to improve responses to HCV therapy in coinfected patients.     

Usefulness of a new immunoradiometric assay of HCV core antigen to predict virological response during PEG-IFN/RBV combination therapy for chronic hepatitis with high viral load of serum HCV RNA genotype 1b

We investigated the clinical usefulness of a new immunoradiometric (IRM) assay of hepatitis C virus (HCV) core antigen in predicting virological response during pegylated interferon plus ribavirin (PEG-IFN/RBV) combination therapy for chronic hepatitis with high viral loads of serum HCV RNA genotype 1b. Thirty-nine patients received a regimen of PEG-IFNalpha-2b (1.5 microg/kg/week s.c.) in combination with RBV (600-1,000 mg/day). Of the 39 patients, 18 (46.2%) achieved sustained virological response (SVR), 11 (28.2%) attained partial response (PR) and 10 (25.6%) showed no response (NR). Four weeks after the start of therapy, 1- and 2-log reductions in the amount of HCV core antigen were observed in 20 (2/10) and 0% (0/10) showing NR, 91 (10/11) and 63.6% (7/11) with PRs, and 88.9 (16/18) and 55.6% (10/18) of patients with SVR, respectively. The 1- and 2-log reductions 4 weeks after the start of therapy were not a defining condition for PR and SVR. The amount of HCV core antigen was significantly different between SVR and PR patients on days 1 and 7, and between patients with NR and SVR at all points of time. In conclusion, this new IRM assay is useful in predicting virological response during PEG-IFN/RBV therapy.     

Impaired response to interferon-alpha2b plus ribavirin in cirrhotic patients with genotype 3a hepatitis C virus infection

Patients with chronic infection with the 3a genotype of hepatitis C virus (HCV) are considered as 'easy-to-treat' with interferon/ribavirin (IFN/RBV), independent of liver disease severity. However, patients with extensive fibrosis or cirrhosis were under-represented in all the registration Phase III trials performed so far. To assess the influence of liver fibrosis on the outcome of anti-HCV therapy, all patients with genotype 3a hepatitis C who were naive to IFN-based therapies, and received RBV combined with standard IFN or pegylated IFN-(alpha2b (peg-IFN-alpha2b) as standard of care for their disease, were investigated at our centre. A sustained virological response (SVR) was achieved in 68 of 91 patients (75%) independent of IFN type, pretreatment viraemia, clearance of HCV RNA at week 4 and relevant co-morbidities. A SVR was less common in cirrhotics (6 of 17) than in non-cirrhotics (62 of 74; 35% vs 84%; P<0.0005). Compared to non-cirrhotics, the age and sex adjusted odds ratio (OR) of treatment failure for cirrhotics was 10.1 (95% confidence interval: 2.4-41.7). By multivariate analysis, cirrhosis was the only predictor of non-SVR. In conclusion, cirrhosis is an independent predictor of IFN/RBV treatment failure in patients chronically infected with HCV 3a and is associated with an increased risk of post-treatment hepatitis relapse. Evaluation of liver fibrosis is important in the management of patients with genotype 3a hepatitis C, since it helps to predict response to IFN/RBV therapy.     

HCV genotype as a predictor of response to interferon therapy in patients with chronic hepatitis C

Hepatitis C virus(HCV) genotype is one of the most important predicting factors of response to interferon(IFN) therapy in patients with chronic hepatitis C. According to the molecular evolutionary analysis, HCV is classified into six major genotypes. The patients infected with genotype 1 show high HCV RNA levels and poor response to IFN therapy compared to those with genotype 2 or 3. No sufficient data are observed on response to IFN in patients with genotype 4 to 6. When PEG-IFN plus ribavirin therapy is introduced, high proportion of patients without genotype 1 must show complete response. In the near future, to predict good response to IFN therapy, it will be necessary to know whether patients have HCV genotype 1 or not.     

Dose-dependent and genotype-independent sustained virological response of a 12 week pegylated interferon alpha-2b treatment for acute hepatitis C

OBJECTIVES: The optimal regimen for acute hepatitis C (AHC) is considered to be a 24 week treatment with interferon (IFN) alpha-2b. A 24 week treatment with pegylated IFN (PEG-IFN) alpha-2b is also effective. This study was designed to assess response rates to a 12 week regimen of PEG-IFN alpha-2b. PATIENTS AND METHODS: Patients with AHC were treated with PEG-IFN alpha-2b for 12 weeks in an open, non-randomized, prospective cohort study. Diagnosis of AHC was made with positive serum HCV RNA and elevated alanine aminotransferase (ALT) levels with a documented seroconversion or a known risk factor in the preceding 6 months. Treatment was administered within a median of 31 days (range 0-116) of the ALT level peak at a dosage varying from 1.06 to 1.66 microg/kg/week. The primary end-point was a sustained virological response (SVR). RESULTS: Nineteen patients were treated, of whom 11 patients (57.9%) had HCV genotype 1. Fourteen patients were asymptomatic. An SVR was achieved in 74% of patients and the SVR rate was 100 and 83.3%, respectively, in genotype 1 and non-1 infected patients treated with a dosage>or=1.33 microg/kg, compared with 40 and 50%, respectively, in those who received a lower dosage. An SVR was significantly associated by multivariate analysis only with PEG-IFN dosage>or=1.33 microg/kg/week. No significant association was found with any viral genotype. CONCLUSIONS: The rate of SVR was independent of the HCV genotype and was significantly associated by multivariate analysis only with the higher PEG-IFN dosage. Early identification and treatment of AHC is likely to decrease the burden of chronic hepatitis, especially when caused by HCV genotype 1.     

Hepatic interferon receptor mRNA expression: clinical relevance and its relationship with effectiveness of interferon plus ribavirin therapy in patients with genotype 1b hepatitis C virus infection

BACKGROUND/AIMS: Hepatic expression of interferon (IFN) receptor mRNA has been shown to correlate with the effectiveness of IFN monotherapy in patients with chronic hepatitis C virus (HCV) infection. We investigated the expression of hepatic IFN receptor alpha/beta (IFNAR2c) mRNA and its association with the effectiveness of IFN plus ribavirin (RBV) therapy and with the clinical features in patients with HCV genotype 1b (HCV-1b) infection. METHODS: A total of 42 naive patients who had chronic HCV-1b infection were treated with IFN alpha-2b 3 MU or 5 MU three times weekly plus RBV for 24 weeks. Hepatic IFNAR2c mRNA was quantified by real-time RT-PCR. RESULTS: There was no significant difference in the mean expression level of IFNAR2c mRNA between patients with sustained virological response (SVR) and non-SVR (0.069 +/-0.042 versus 0.053 +/-0.033, P=0.182). Multiple linear regression analysis showed that lower fibrosis scores (P=0.006) and younger age (P=0.03) were associated with hepatic IFNAR2c mRNA expression with r2=0.34. CONCLUSIONS: Hepatic IFNAR2c mRNA expression may not be useful for predicting the response to IFN plus RBV therapy in patients with HCV-1b infection, but appeared to correlate inversely with the fibrosis stage and age.     

Estimation of two real-time RT-PCR assays for quantitation of hepatitis C virus RNA during PEG-IFN plus ribavirin therapy by HCV genotypes and IL28B genotype

Hepatitis C virus (HCV) RNA values measured with two real-time PCR methods (Cobas Ampliprep/Cobas TaqMan, CAP/CTM, and the Abbott real-time PCR test, ART) vary among patients with genotype 1. We investigated HCV RNA values measured by two real-time PCR assays during pegylated interferon plus ribavirin (PEG-IFN/RBV) therapy. We evaluated 185 cases of chronic hepatitis C patients, among which 97 patients received the PEG-IFN/RBV therapy. HCV RNA values of CAP/CTM for genotype 1 were significantly higher than those of ART (p < 0.05) The difference in HCV RNA values (CAP/CTM minus ART) of genotype 1 was significantly higher than those in genotype 2 (p < 0.0001). The positive rate (>0) of the difference of HCV RNA values in genotype 1 was 100 % (55/55), which was significantly higher than the 78.6 % (33/42) of genotype 2 (p < 0.001). There was no difference between TT and TG/GG genotype groups in terms of difference of HCV RNA values (CAP/CTM minus ART). After PEG-IFN/RBV therapy was administered, reduction of HCV measurements was observed from day 1 for both assays regardless of genotype. The HCV value of CAP/CTM during PEG-IFN/RBV therapy was consistently higher than the value of ART, although the difference in these two values gradually became smaller during the course of therapy, and eventually no significant difference was observed near the detection level. No correlation was observed between the sustained virological response (SVR) rate and the difference between the CAP/CTM HCV values and the ART HCV value before treatment.     

A sustained virological response to interferon or interferon/ribavirin reduces hepatocellular carcinoma and improves survival in chronic hepatitis C: a nationwide, multicentre study in Taiwan

BACKGROUND: The long-term benefit for chronic hepatitis C (CHC) patients treated with interferon (IFN)/ribavirin (RBV) combination therapy remains unclear. We aimed to evaluate the long-term effects of IFN monotherapy and IFN/RBV combination therapy on reducing hepatocellular carcinoma (HCC) and mortality in patients with chronic hepatitis C virus (HCV) infection, adjusting for risk factors. METHODS: A total of 1,619 patients with biopsy-proven CHC, including 1,057 receiving IFN-based therapy (760 on IFN/RBV combination therapy) and 562 untreated controls from three medical centres and one regional core hospital in Taiwan were enrolled in this retrospective-prospective cohort study. RESULTS: The incidence of HCC and survival during a follow-up period of 1.0-15.3 (mean 5.18) and 1-16 (mean 5.15) years in treated and untreated patients, respectively, was analysed using Cox proportional hazards regression. The cumulative incidence of HCC was 35.2% and 12.2% for untreated and treated groups, respectively (P=0.0013). The cumulative survival rate was 93.1% and 96.2% for untreated and treated groups, respectively (P=0.3928). Significantly lower incidences of HCC and mortality were observed in sustained virological responders (both for IFN monotherapy and IFN/RBV combination) but not in nonresponders when compared with untreated patients. HCV genotype 1 patients had significantly higher incidences of HCC than genotype non-1 patients. In multivariate analysis, pre-existing cirrhosis, non-response, HCV genotype-1 and age were associated with HCC; pre-existing cirrhosis and non-response correlated to mortality. CONCLUSION: A sustained virological response secondary to IFN monotherapy or IFN/RBV combination therapy could reduce the risk for HCC and improve survival of CHC patients.     

Hepatitis C virus-RNA clearance in HIV-coinfected patients with chronic hepatitis C treated with pegylated interferon plus ribavirin

Hepatitis C virus (HCV)-RNA clearance seems to occur more slowly in HIV/HCV-coinfected patients than in HCV-monoinfected subjects treated with pegylated interferon alpha (peg-IFN) plus ribavirin (RBV). As a consequence, concern has arisen over the feasibility of following the treatment rules applied to HIV-negative patients with chronic hepatitis C. A total of 89 HIV/HCV-coinfected patients who had fully completed a course of peg-IFN plus RBV were analysed. Of these, 29 (32.6%) reached sustained virological response (SVR). Reductions >2 logs in plasma HCV-RNA occurred in 52 (58%) patients at week 12 of treatment (early virological response; EVR). None of patients who showed HCV-RNA drops <2 logs at week 12 reached SVR (negative predictive value: 100%). The positive predictive value of EVR was 56%. On the other hand, relapses occurred in 19 (39.6%) out of the 48 patients who had negative HCV-RNA at the end of treatment, and there were no differences noted when comparing patients with HCV genotypes 2/3 and 1/4. In summary, the quantitative assessment of plasma HCV-RNA at week 12 predicts the chance of SVR using peg-IFN plus RBV in HIV-positive patients with chronic hepatitis C, as it does in HIV-negative individuals. Thus, discontinuation of anti-HCV therapy, which is associated with frequent side effects, might be warranted in HIV/HCV-coinfected patients showing HCV-RNA reductions <2 logs at week 12 of treatment. On the other hand, relapses in virological responders were unexpectedly high in HIV/HCV-coinfected patients when treatment was provided following the rules applied to HIV-negative subjects. This is particularly relevant for HCV genotypes 2/3, which only rarely relapse in HIV-negative patients. Therefore, extending therapy (for 12 months in HCV genotypes 2/3 and perhaps for 18 months in HCV genotypes 1/4) might be warranted in HIV/HCV-coinfected patients showing EVR.     

Current antiviral combination therapy for chronic hepatitis C patients who failed to interferon alfa-based treatment

What is known and Objective: Interferon‐alfa‐based therapy is effective in the treatment of Hepatitis C. However, some patients fail to respond and others relapse, after initially responding. Our objective was to assess the efficacy, safety and predictive factors for sustained virological response (SVR) to peginterferon plus ribavirin in chronic hepatitis C patients who failed to interferon‐alfa (IFNα)‐based therapy. Methods: Seventy‐five consecutive patients who failed to IFNα‐based therapy were retreated with peginterferon plus ribavirin. Of these patients, 85% were infected by genotype 1. The primary endpoint was SVR. Results and Discussion: Of 75 non‐responder (n = 54) or relapser patients (n = 21), 50 were previously treated with IFNα‐monotherapy and 25 with IFNα plus ribavirin. Global SVR rate was 41·3%: for patients re‐treated with IFNα the response was 48% whilst for those retreated with IFNα plus ribavirin, it was 28%. For previous non‐responders the SVR rate was 37% and for relapsers it was 52·4%. What is new and Conclusion: Retreatment with peginterferon plus ribavirin is an effective option for some chronic hepatitis C non‐responder or relapser patients. Higher SVR rate was achieved in relapsers and in those patients who received IFNα monotherapy previously.     

Predicting the therapeutic response in patients with chronic hepatitis C: the role of viral kinetic studies

A substantial proportion of patients infected with hepatitis C virus (HCV) genotype 1 still does not respond to pegylated interferon-alfa/ribavirin (IFN/RBV) therapy. Factors which identify potential non-responders are needed to limit exposure to drugs in patients unlikely to benefit from treatment and to save health care resources. Host predictive factors have a low negative predictive value. In contrast, viral factors have a high precision in predicting outcome of therapy. Viral kinetics are the basis for the study of response of therapy. The decrease in viral load within 24 h after administration of a single test dose of conventional IFN reflects the IFN-sensitivity of the virus strain and predicts the outcome of conventional IFN/RBV therapy even before treatment with a specificity of 100% and a sensitivity of 83%. In contrast to conventional IFN, the two available PEG-IFN preparations differ considerably in how they suppress viral replication, and cut-off values have to be prospectively established separately for each drug. Patients without an early virological response (HCV-RNA either undetectable or decrease by >or=2 log10 after 12 weeks) (EVR), do not achieve a sustained virological response (SVR; negative predictive value: 97-98%). Thus, in the absence of an EVR, treatment should be stopped. The outcome of PEG-IFN alfa-2a/RBV combination therapy is dependent on the rapidity of the virological response. Patients who become HCV-RNA negative after 4 weeks have the best chance of achieving an SVR. The rapidity of viral elimination may be a useful guide to tailoring the length of treatment in patients with an EVR.     

Role of viral kinetics under HCV therapy in HIV/HCV-coinfected patients

Patients coinfected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) are less responsive to anti-HCV therapies and are at a higher risk of toxicity than HCV monoinfected patients. HCV viral kinetics is the basis for the study of response to interferon-based therapy and for predicting sustained virological response (SVR). A lack of early virological response (EVR; undetectable HCV RNA or a decrease of >/=2 log(10) from baseline) after 12 weeks of pegylated interferon (peg-IFN) plus ribavirin (RBV) is an equally reliable predictor of lack of SVR in HIV/HCV-coinfected patients and in the monoinfected HCV population. Early stopping rules are particularly important in coinfected HIV/HCV patients, considering their low chances of response in the more difficult-to-treat HCV genotypes 1 and 4 (<30%). Several factors have been involved in this low efficacy, including higher baseline HCV viraemia, slower viral kinetics decay under interferon pressure and a defective immune substratum. A better understanding of HCV viral kinetics under HCV therapy may be the basis for assaying different peg-IFN plus RBV schedules, such as induction or extending strategies, and may help physicians to make tailored decisions for the management of their patients.     

Therapy for treatment-refractory chronic hepatitis C virus genotype 1b infection: A retrospective analysis

Background:

The most effective current therapy for hepatitis C virus (HCV) infection is the combination of pegylated interferon (peg-IFN) plus ribavirin (RBV).

Objective:

The aim of this retrospective analysis was to determine the rateof response to this therapy, and the factors affecting outcome, in patients with treatment-refractory chronic HCV genotype l b.

Methods:

The records of patients with chronic HCV infection and HCV geno-type1b who failed (nonresponse or relapse) previous treatment with standard interferon (IFN) + RSV were retrospectively analyzed for demographic data, virologic load, liver histology, biochemistry, treatment-related adverse effects (AEs), and the effects of dose reduction during treatment with peg-IFN + RBV for 48 weeks. Early virologic response (EVR) was defined as ≥2-log (copies/mL) decrease from baseline in serum HCV RNA concentration or the absence of detectable serum HCV RNA at treatment week 12. End-of-treatment response (ETR) was defined as the absence of detectable serum HCV RNA at treatment week 48. Sustained virologic response (SVR) was defined as the absence of detectable serum HCV RNA 24 weeks after treatment was discontinued. Factors affecting treatment outcome were determined using correlation analyses.

Results:

Data from the files of 17 patients (12 men, 5 women; mean [SD] age, 48 [2] years) were analyzed. EVR was achieved in 7 patients; however, viral breakthrough occurred in 2 of these patients during the treatment period, and 5 of these patients discontinued treatment because of severe treatment-related AEs (depression [1 patient] and neutropenia [4]). Seven patients achieved ETR, but HCV infection relapsed during the follow-up period. Three (18%) patients achieved SVR. Data concerning previous patterns of response to IFN + RBV therapy were available in 10 patients. Of these, 3 of 6 patients who had experienced relapse with the previous treatment achieved SVR with peg-IFN + RBV; neither of the 2 patients with nonresponse to the previous treatment achieved SVR. Major determinants of failure to reach SVR in these patients included previous nonresponder pattern, noncompliance with the therapy, and advanced-stage liver fibrosis. Tolerability was similar to that with the previous treatment.

Conclusions:

In this study in patients with chronic HCV genotype lb infectionand a history of relapse or nonresponse to standard IFN + RSV treatment, treatment with peg-IFN + RBV achieved an SVR rate of 18%. Further research is needed to determine the role of peg-IFN + RBV in the re-treatment of HCV infection.     

Anti HCV drugs--ribavirin, telaprevir

The goal of treatment of chronic hepatitis C is the elimination of HCV. Ribavirin and telaprevir are currently used with interferon. In patients with genotype 2 HCV, PEG-IFN+ RBV combination therapy is very effective, but in patients with genotype 1, only SVR can be achieved in only approximately 50%. Furthermore in genotype 1, viral factors i.e. ISDR, IRRDR and/or core amino acid mutations and host factors i.e. IL28B are reported as SVR-related factors. Although the triple therapy with telaprevir resulted in more adverse event it is able to achieve higher SVR by carefully monitoring adverse event and predict to therapeutic effect by previous therapy.     

ISDR pattern and evolution in patients with chronic hepatitis C treated with standard or PEG-IFN plus ribavirin

The aim of the study was to characterize the interferon sensitivity determining region (ISDR) mutation pattern and its changes at 4 weeks of treatment in a population of patients infected with hepatitis C virus (HCV) genotype 1b receiving standard or PEG-IFN plus ribavirin (RBV), to find possible early correlates of therapy outcome. Forty-five patients with chronic hepatitis due to HCV 1b were treated by PEG-IFN-alpha2b (n=23) or IFN-alpha2b (n=22) plus RBV 1000-1200 mg/day. They were classified 24 weeks after stopping therapy as sustained responders (SR), relapsers (REL) or non-responders (NR). Sixteen patients were SR, 12 REL and 17 NR. ISDR mutations were evaluated by direct sequencing at baseline in all and after 4 weeks in patients with detectable viraemia (n=30). The frequency of the three ISDR types was 26.7% wild-type, 64.4% intermediate-type and 8.9% mutant-type, without significant difference in their frequency in SR, REL and NR, independent of IFN formulation. Average numbers of mutations in SR, REL and NR were 1.88 +/- 0.54, 1.33 +/- 0.33 and 0.94 +/- 0.25, respectively, P>0.05. The baseline number of ISDR mutations was not related to the extent of viral load decline in the first month of therapy. Sequence analysis of ISDR region performed 4 weeks after starting therapy revealed qualitative or quantitative changes of ISDR sequence in only seven patients, without correlation with response. Thus, in our patients the baseline pattern of ISDR was unrelated to treatment outcome. Selection towards a dominant IFN-resistant strain did not occur under standard or PEG-IFN plus RBV.     

An inadequate dose of ribavirin is related to virological relapse by chronic hepatitis C patients treated with pegylated interferon alpha-2b and ribavirin

The aim of this large-scale analysis was to assess the effect of 48-week pegylated interferon (PEG-IFN) α-2b and ribavirin (RBV) therapy on virological relapse by patients infected with hepatitis C virus (HCV) genotype 1. The relationship between virological relapse and the dose of PEG-IFNα-2b and RBV was investigated in 619 patients who had once cleared HCV RNA during PEG-IFNα-2b and RBV treatment for 48 weeks. The overall virological relapse rate was 34.1% (211 of 619). The relapse rate was 59.5% (22 of 37) for patients who received <6 mg/kg/day of RBV, even if a sufficient dose of PEG-IFNα-2b (≥1.5 μg/kg/day) was received. In contrast, the relapse rate was 28.1% (16 of 57) for patients who received ≥12 mg/kg/day of RBV, irrespective of the PEG-IFNα-2b dose. The relapse rates were significantly increased with the reduction of the RBV dose for both PEG-IFNα-2b doses of ≥1.2 and <1.2 μg/kg/week (P < 0.0001 and P = 0.0006, respectively). Moreover, the relapse rate was 41.2% (35 of 85) for patients with an early virological response (EVR) who received <6 mg/kg/day of RBV. The relapse rates were significantly increased with the reduction of the RBV dose in both those patients with an EVR and those with a late virological response (P = 0.0006 and P = 0.0088, respectively). To summarize, for HCV genotype 1 patients treated with PEG-IFNα-2b and RBV, the virological relapse of HCV was RBV dose-dependent, irrespective of the dose of PEG-IFNα or the effect of early viral kinetics.     

Ultradeep Sequencing Study of Chronic Hepatitis C Virus Genotype 1 Infection in Patients Treated with Daclatasvir,Peginterferon, and Ribavirin

Direct-acting antivirals (DAAs) are either part of the current standard of care or are in advanced clinical development for the treatment of patients chronically infected with hepatitis C virus (HCV) genotype 1, but concern exists with respect to the patients who fail these regimens with emergent drug-resistant variants. In the present study, ultradeep sequencing was performed to analyze resistance to daclatasvir (DCV), which is a highly selective nonstructural protein 5A (NS5A) inhibitor. Eight patients with HCV genotype 1b, who were either treatment naive or prior nonresponders to pegylated interferon plus ribavirin (Rebetol; Schering-Plough) (PEG-IFN/RBV) therapy, were treated with DCV combined with PEG-IFN alpha-2b (Pegintron; Schering-Plough, Kenilworth, NJ) and RBV. To identify the cause of viral breakthrough, the preexistence and emergence of DCV-resistant variants at NS5A amino acids were analyzed by ultradeep sequencing. Sustained virological response (SVR) was achieved in 6 of 8 patients (75%), with viral breakthrough occurring in the other 2 patients (25%). DCV-resistant variant Y93H preexisted as a minor population at higher frequencies (0.1% to 0.5%) in patients who achieved SVR. In patients with viral breakthrough, DCV-resistant variant mixtures emerged at NS5A-31 over time that persisted posttreatment with Y93H. Although enrichment of DCV-resistant variants was detected, the preexistence of a minor population of the variant did not appear to be associated with virologic response in patients treated with DCV/PEG-IFN/RBV. Ultradeep sequencing results shed light on the complexity of DCV-resistant quasispecies emerging over time, suggesting that multiple resistance pathways are possible within a patient who does not rapidly respond to a DCV-containing regimen. (This study has been registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT01016912","term_id":"NCT01016912"}}NCT01016912.)