Predictive value of on‐treatment response during full‐dose antiviral therapy of patients with hepatitis C virus cirrhosis and portal hypertension

Objective. Therapy with full‐dose pegylated interferon (PEG‐IFN) and weight‐based ribavirin has been evaluated in limited series of patients with hepatitis C virus (HCV) and advanced disease. In this study, we evaluated the efficacy and tolerability of full‐dose antiviral therapy in patients with compensated, fully developed cirrhosis, and assessed the predictive value of on‐treatment virological response. Design and subjects. We studied 85 HCV‐positive cirrhotic patients (82 Child‐Pugh class A; 41 treatment‐naïve) who were treated with PEG‐IFN α‐2_a (1.5 μg kg^?1week^?1) or α‐2_b (180 μg week^?1) and weight‐based ribavirin for 24 (genotype 2–3) or 48 (genotype 1–4) weeks. Forty‐three patients were genotype 1 (51%), and HCV‐RNA was >600 000 IU mL^?1 in 53 patients (62%). Prevalence of portal hypertension and diabetes was 81% and 18% respectively. Results. Sustained virological response (SVR) was obtained in 22 patients (26%). Positive serum HCV‐RNA at week 4 and week 12 of therapy predicted nonresponse (NR) in 85% (52/61) and 100% (38/38) of patients, respectively. Treatment was discontinued due to adverse events in 14 patients (16%). Genotype 1–4 (P = 0.02) and HCV‐RNA >600 000 IU mL^?1 (P = 0.02) were the baseline parameters significantly associated with lack of SVR, whilst positive serum HCV‐RNA at week 12 was the only parameter independently associated with NR (100% negative predictive value). Conclusion. Full‐dose antiviral therapy with PEG‐IFN and ribavirin can be safely carried out even in patients with compensated, fully established cirrhosis and portal hypertension. Selecting patients on the basis of HCV genotype and viral load, and application of on‐treatment stopping rule may help rationalize treatment in patients who are unlikely to obtain SVR.     

Impact of ribavirin priming on viral kinetics and treatment response in chronic hepatitis C genotype 1 infection

Ribavirin amplifies the interferon‐alpha (IFN) signalling cascade. As ribavirin needs 4 weeks to reach steady state, ribavirin priming may optimize hepatic IFN sensitivity before starting a pegylated (PEG)‐IFN/ribavirin combination therapy. This study investigated potential benefits of ribavirin priming prior to PEG‐IFN2a/ribavirin combination therapy on viral kinetics, on‐treatment and sustained virological response (SVR) in chronic hepatitis C virus (HCV) genotype 1 infection. Sixty‐eight treatment naive patients were randomized 2:2:1 to ribavirin (ribavirin arm) or placebo (placebo arm) or PEG‐IFN2a (PEG‐IFN2a arm) for 6 weeks prior to 12 weeks of PEG‐IFN2a/ribavirin combination therapy within a double‐blind, placebo‐controlled trial. Then, standard PEG‐IFN2a/ribavirin combination therapy according to the German guidelines was continued under the responsibility of the investigators. Ribavirin was given according to body weight and PEG‐IFN2a at a dose of 180 μg subcutaneously once/week. During ribavirin priming, HCV RNA showed a decline of −0.58 log₁₀ IU/mL (P < 0.001) that was unrelated to the IL28B rs12979860 genotype (CC vs CT/TT, P = 0.244). Ribavirin priming did neither increase the PEG‐IFN2a‐induced first‐ or second‐phase viral decline (P values >0.100) nor on‐treatment response or SVR (HCV RNA undetectable at week 12 of combination therapy: ribavirin arm 56%, placebo arm 38%, PEG‐IFN2a arm 50%; SVR: ribavirin arm 41%, placebo arm 54%, PEG‐IFN2a arm 50%; P values >0.300). In conclusion, ribavirin monotherapy showed a significant antiviral activity that was not influenced by the IL28B genotype. Ribavirin priming prior to PEG‐IFN2a/ribavirin combination therapy did neither increase the first‐ or second‐phase viral decline nor on‐treatment response or SVR.     

Efficacy and safety of pegylated interferon alpha‐2a therapy for chronic hepatitis C in HIV‐infected patients with haemophilia

Summary. The objective of this study was to evaluate the efficacy and safety of pegylated interferon (PEG‐IFN) alpha‐2a monotherapy in a cohort of Chinese haemophilic patients co‐infected with human immunodeficiency virus (HIV)/hepatitis C virus (HCV) and undergoing highly active antiretroviral drugs therapy. Twenty‐two (n = 22) patients with CD4 lymphocyte counts over 200 cells μL^?1 were treated with 180 μg of PEG‐IFN alpha‐2a subcutaneously once in a week for 48 weeks. HCV load (HCV RNA), HIV load (HIV RNA) and CD4 lymphocyte counts were measured at baseline and 4, 12, 24, 48 and 72 weeks after initiation of anti‐HCV therapy. Efficacy and safety were analysed according to baseline CD4 status (≥350 cells μL^?1). Significant HCV‐RNA decreases (>1 log₁₀ copies mL^?1) were observed through week 72 after PEG‐INF alpha‐2a monotherapy across both CD4 strata. CD4 status was not associated with treatment outcomes as evaluated using rapid viral response rate (P = 0.655), early viral response rate (P = 0.387), end‐of‐treatment viral response rate (P = 1.000) or sustained viral response rate (SVR, P = 0.674). A sustained virological response was achieved in nine patients (41%), five with genotype 2a (83%) and four with genotype 1b (25%, P = 0.023). SVR was HCV genotype dependent. Eleven patients required a dose reduction in PEG‐IFN alpha‐2a. PEG‐IFN alpha‐2a monotherapy could be considered as a safe and effective option for the treatment of HCV infection in HIV patients with haemophilia, particularly in resource‐limited settings. While higher CD4 lymphocyte counts resulted in greater HCV‐RNA reduction, HCV genotype was a predictor for sustained virological response.     

Polymorphisms in the IFNL3/IL28B gene and hepatitis C: From adults to children

The purpose of the present review is to summarise the current knowledge on the association between single nucleotide polymorphisms (SNPs) in the interferon L3 (IFNL3) gene and hepatitis C virus (HCV) infection in children. Many studies in adults have demonstrated that genetic variation in IFNL3 is a strong predictor of the virological response in treatment-naive patients with HCV genotype 1 who were treated with Pegylated-IFN-α and ribavirin. Genetic variation in IFNL3 is also associated with the spontaneous clearance of HCV. Thus far, few paediatric studies have explored the association between variations in the IFNL3 gene and either spontaneous or treatment-induced clearance of HCV. The CC genotype of the rs12979860 SNP is associated with the spontaneous clearance of HCV in children independently of HCV genotype. Four paediatric studies have shown that both the CC genotype of the rs12979860 SNP and the TT genotype of the rs8099917 SNP are associated with the treatment-induced (IFN monotherapy and Pegylated-IFN-α and ribavirin association) clearance of HCV, while the rs12980275 SNP did not affect the virological response. The possible role of IFNL3 gene variation as a pre-treatment and on-treatment predictor of virological response in children is highly attractive but still undetermined. Further paediatric studies are needed to evaluate if testing for SNPs in IFNL3, either alone or together with other predictors of response to treatment, could be used to direct treatment strategies, including an avoidance of unnecessary protease inhibitor therapy and the duration of treatment.     

Interferon‐lambda4 genetic polymorphism is associated with the therapy response for hepatitis C virus recurrence after a living donor liver transplant

The standard therapy against hepatitis C virus (HCV) recurrence postliver transplantation includes interferon (IFN)α and ribavirin. IFNL4 ss469415590 polymorphism has been reported as a novel predictor of the response to IFN therapy for chronic HCV infection. We examined the impact of IFNL4 polymorphism on the responsiveness to IFN therapy after liver transplantation. Tissue specimens were collected from 80 HCV‐infected recipients and 78 liver donors, and their IFNL4 ss469415590 genotype, hepatic IFNL4 and interferon‐stimulated genes' mRNA expression levels were examined. The association of the polymorphism and expression levels in terms of the IFN therapy response to HCV recurrence was analysed. Most individuals who had rs8099917 risk alleles also had ss469415590 risk alleles (R² = 0.9). Sustained virological response (SVR) rates were higher in both liver graft recipients and transplants with ss469415590 TT/TT alleles than in those with the risk ΔG allele (P = 0.003 and P = 0.005, respectively). In recipients with ss469415590 TT/TT, IFNL4 TT mRNA levels showed no significant differences between livers of patients who responded to therapy and those who did not (P = 0.4). In recipients with the risk ΔG allele, IFNL4 ΔG mRNA expression levels were significantly lower in SVR patients than in non‐SVR patients (P = 0.02). Hepatic interferon stimulable genes and IFNL4 mRNA expression were correlated. Our findings suggest that analysing the ss469415590 genotype and IFNL4 ΔG expression provides a novel prediction strategy for the possible response to IFN therapy after liver transplantation.     

Splenectomy and antiviral treatment for thrombocytopenic patients with chronic hepatitis C virus infection

Summary. Thrombocytopenic patients with chronic hepatitis C virus (HCV) infection are poor candidates for antiviral treatment with interferon (IFN), but no standard treatment for thrombocytopenia has yet been established. We evaluated the safety of splenectomy and its efficacy for the initiation and continuation of antiviral therapy. From March 2003 to April 2006, 10 patients (mean age 62.5 years) with HCV‐related cirrhosis, low platelet count (≦106 000/mm³) and splenomegaly (spleen size ≧10 cm) underwent splenectomy. Platelet counts significantly increased at 4–8 weeks after splenectomy [pre: 64 200 ± 6900/mm³vs post 209 000 ± 40 600/mm³ (P = 0.004)]. No severe operative complications were observed. All patients subsequently received antiviral therapy. Of the eight patients who were infected with HCV genotype 1 and had a high viral load (≧100 KIU/mL), four received combination therapy with pegylated IFNα‐2b plus ribavirin, and the other four received standard IFNα‐2b plus ribavirin. One patient infected with HCV genotype 2 and another with HCV genotype 1 and a low viral load (<100 KIU/mL) were treated with pegylated IFNα‐2a. Six patients achieved sustained virologic response (SVR). Among four patients who failed to achieve SVR, one was given retreatment with pegylated IFN plus ribavirin, and the other three received low‐dose long‐term IFN therapy. Although this study was small, the treatment results were similar to those for patients without thrombocytopenia and suggested that splenectomy would not reduce the antiviral efficacy of IFNα‐based treatment.     

Changes in von Willebrand factor level and von Willebrand activity with age in type 1 von Willebrand disease

In a normal population, VWF plasma levels (VWF:Ag) and VWF activity (VWF:RCo) increase by approximately 0.17 and 0.15 IU mL^?1 per decade, but the influence of age is unknown in patients with type 1 von Willebrand disease (VWD). In a retrospective cohort study, the medical records of 31 type 1 VWD patients over the age of 30, who had been followed for ≥5 years, were reviewed for baseline clinical data and previously performed VWF:Ag, VWF:RCo and factor VIII levels (FVIII:C). VWF multimer analysis was normal in 28/31 cases performed. Mean age at diagnosis was 33 (range 16–60 years), and duration of follow‐up ranged from 5 to 26 years (mean 11 years). Patients had 2–10 time points of VWD testing (mean of 5.2). The mean VWF:Ag, VWF:RCo and FVIII:C at time of diagnosis were 0.44 IU mL^?1 0.34 IU mL^?1 and 0.75 IU mL^?1. At last follow‐up, the mean VWF:Ag, VWF:RCo and FVIII:C were significantly increased to 0.71 IU L^?1, 0.56 IU mL^?1 and 0.90 IU mL^?1 (P ≤ 0.001, <0.001, and 0.0081 respectively). Here 18/31 patients had VWF:Ag, VWF:RCo and FVIII: C levels that increased into the normal range. The rate of change in VWF:Ag, VWF:RCo and FVIII was 0.30 IU mL^?1 (0.21–0.39, CI 95%, P < 0.0001), 0.20 IU mL^?1 per decade (0.13–0.27, CI 95%, P = 0.0001) and 0.20 IU mL^?1 (0.11–0.29, CI 95%, P = 0.0011). Patients with type 1 VWD experience age‐related increases to VWF:Ag and VWF:RCo which can result in normalization of VWF levels. Further studies are required to determine if the bleeding phenotype resolves with the increases in VWF:Ag and VWF:RCo levels.     

Peginterferon alpha-2a (40 KD) plus ribavirin for the treatment of chronic hepatitis C in Japanese patients

Background: The efficacy and safety of peginterferon alpha‐2a (40 KD) (peg‐IFNα‐2a) plus ribavirin has not been reported for Japanese patients with chronic hepatitis C. The aim of this study was to evaluate this combination in treatment‐naïve patients and in non‐responders or relapsers to interferon monotherapy. Methods: Overall, 201 treatment‐naïve patients with hepatitis C virus (HCV) genotype‐1b were randomly assigned to 180 µg peg‐IFNα‐2a once‐weekly plus ribavirin 600–1000 mg/day or peg‐IFNα‐2a plus placebo for 48 weeks. Additionally, peg‐IFNα‐2a plus ribavirin was administered for 48 weeks to 100 non‐responders or relapsers (85% genotype‐1) to previous interferon monotherapy. Results: A sustained virological response (SVR) was attained among significantly more treatment‐naïve patients receiving combination therapy than monotherapy (61% vs 26%, P < 0.001). For patients with high baseline HCV RNA, the SVR rate was 59% with peg‐IFNα‐2a plus ribavirin versus 24% with peg‐IFNα‐2a monotherapy. Among non‐responders or relapsers to previous interferon monotherapy, 54% attained an SVR. Adverse events were generally mild, and discontinuations rates due to adverse events or laboratory abnormalities were low. Conclusion: In Japanese patients, peg‐IFNα‐2a plus ribavirin provided significant improvement in SVR rates compared with peg‐IFNα‐2a alone in treatment‐naïve patients, and was effective as re‐treatment for non‐responders or relapsers to previous treatment with interferon monotherapy.     

Epigenetic analysis of the IFNλ3 gene identifies a novel marker for response to therapy in HCV‐infected subjects

Chronic hepatitis C virus (HCV) infection is characterized by high interindividual variability in response to pegylated interferon and ribavirin. A genetic polymorphism on chromosome 19 (rs12979860) upstream of interferon‐λ3 (IFNλ3) is associated with a twofold change in sustained virologic response rate after 48 weeks of treatment with pegylated interferon/ribavirin in HCV genotype 1 (GT1) treatment‐naïve patients. We conducted epigenetic analysis on the IFNλ3 promoter to investigate whether DNA methylation is associated with response to HCV therapy. DNA samples from HCV GT1‐infected subjects receiving an interferon‐free paritaprevir‐containing combination regimen (N=540) and from HCV‐uninfected, healthy controls (N=124) were analysed for IFNλ3 methylation levels. Methylation was strongly associated with rs12979860 allele status whether adjusting for HCV status (r=65.0%, 95% CI: [60.2%, 69.5%]), or not (r=64.4%), both with P<2.2×10^?16. In HCV GT1‐infected subjects, C/C genotypes had significantly lower methylation levels relative to C/T or T/T genotypes (P<1×10^?14), with each T allele resulting in a nine‐unit increase in mean methylation level. Methylation levels did not correlate with response in subjects treated for 12 or 24 weeks. However, non‐C/C subjects with higher methylation levels were more likely to relapse when treatment duration was 8 weeks. This analysis suggests that methylation status of the IFNλ3 promoter region may be a useful parameter that identifies patients more likely to relapse following HCV therapy; however, continuing therapy for a sufficient duration can overcome this difference. These findings may provide mechanistic insight into the role of IFNλ3 genetic variants in HCV treatment response.     

A randomized controlled trial adding fluvastatin to peginterferon and ribavirin for naïve genotype 1 hepatitis C patients

Fluvastatin or simvastatin has demonstrable antiviral activity against hepatitis C virus (HCV) as monotherapy. The safety and efficacy of adding fluvastatin or simvastatin to peginterferon/ribavirin for 48 weeks was tested in HCV genotype 1 naïve‐to‐treatment veterans. Thirty‐seven naïve‐to‐treatment genotype 1 HCV patients were randomized to either a control group (n = 20) to receive peginterferon alfa plus ribavirin or an experimental group (n = 18) to similarly receive peginterferon alfa plus ribavirin as well as fluvastatin 20 mg/day. In addition, seven patients who presented for HCV treatment already were on simvastatin and could not be withdrawn. These simvastatin users were not randomized but were entered into a concurrent prospective pilot arm. There were no unique safety issues with fluvastatin or simvastatin when these drugs were given with peginterferon/ribavirin for 48 weeks. Thirteen of 25 statin patients achieved sustained viral response (SVR), while 5 of 20 control patients achieved SVR. Analysis of SVR by intention‐to‐treat showed P = 0.078. In this phase 2 study, there were no safety issues with the addition of fluvastatin or simvastatin to peginterferon and ribavirin for 48 weeks. There was a trend towards improvement in SVR when fluvastatin or simvastatin was administered with peginterferon/ribavirin. The size of the groups did not reach the prestudy size thought needed to show significant difference (type II error). These results support the significant results of two other larger randomized controlled trials reported using the same dose of fluvastatin in naïve‐to‐treatment genotype 1 HCV patients.     

Achieving sustained virologic response after interferon‐free hepatitis C virus treatment correlates with hepatic interferon gene expression changes independent of cirrhosis

Chronic hepatitis C virus (HCV) infection can now be treated with oral directly acting antiviral agents, either with or without ribavirin (RBV). Virologic relapse after treatment can occur, and in some studies was more common in cirrhotic subjects. We previously observed changes in hepatic immunity during interferon (IFN)‐free therapy that correlated with favourable outcome in subjects with early liver disease. Here, we compared changes in endogenous IFN pathways during IFN‐free, RBV‐free therapy between cirrhotic and noncirrhotic subjects. mRNA and microRNA (miRNA) expression analyses were performed on paired pre‐ and post‐treatment liver biopsies from genotype‐1 HCV subjects treated with sofosbuvir/ledipasvir (SOF/LDV) for 12 weeks (n = 4, 3 cirrhotics) or SOF/LDV combined with GS‐9669 or GS‐9451 for 6 weeks (n = 6, 0 cirrhotics). Nine of ten subjects achieved a sustained virologic response (SVR), while one noncirrhotic subject relapsed. Hepatic IFN‐stimulated gene expression decreased with treatment in the liver of all subjects, with no observable impact of cirrhosis. Hepatic gene expression of type III IFNs (IFNL1, IFNL3, IFNL4‐ΔG) similarly decreased with treatment, while IFNA2 expression, undetectable in all subjects pretreatment, was detected post‐treatment in three subjects who achieved a SVR. Only the subject who relapsed had detectable IFNL4‐ΔG expression in post‐treatment liver. Other IFNs had no change in gene expression (IFNG, IFNB1, IFNA5) or could not be detected. Although expression of multiple hepatic miRNAs changed with treatment, many miRNAs previously implicated in HCV replication and IFN signalling had unchanged expression. In conclusion, favourable treatment outcome during IFN‐free HCV therapy is associated with changes in the host IFN response regardless of cirrhosis.     

The impact of antihyperlipidemic drugs on the viral load of patients with chronic hepatitis C infection: a meta‐analysis

Several studies investigating the role of statins and fibrates in chronic hepatitis C virus (HCV) infection offered so far conflicting evidence regarding the antiviral potency of these medications, whereas combination of these drugs with pegylated interferon and ribavirin improved in some trials therapeutic outcome. We conducted a literature search to identify trials that included monoinfected HCV patients, treated with statins or fibrates as monotherapy with the primary end point of our meta‐analysis being the quantitative change of HCV‐RNA induced by these medications. Logarithmic changes of the viral load (ΔlogVL) and confidence intervals (CIs) were calculated according to the DerSimonian‐Laird estimate. Statistical heterogeneity was assessed with the I² statistic. We identified eight observational studies that evaluated the potency of bezafibrate and different statins as monotherapy to induce a significant reduction of HCV‐RNA in HCV‐monoinfected patients (n = 281). Overall, a significant reduction of viral load with mean 0.19 [log₁₀ IU/mL] (95%‐confidence interval, (CI) 0.11–0.28) could be observed when antihyperlipidemic medications were administered. Bezafibrate featured the highest antiviral efficacy (0.45 log₁₀ reduction, 95%‐CI, 0.17–0.72) among all medications and fluvastatin (0.20 log₁₀ reduction, 95%‐CI, 0.09–0.31) among all statins tested. Based on meta‐analysis, fibrates and statins induce a reduction of HCV viral load. We suggest that the addition of statins and fibrates to antiviral regimes, especially in HCV patients with concomitant dyslipidemia, could beside the established reduction of cardiovascular risk increase the potency of antiviral therapy.     

Effect of ribavirin on the frequency of RNase L cleavage sites within the hepatitis C viral genome

Summary. The mechanisms of synergy in antiviral activity of interferon‐α and ribavirin in treating chronic hepatitis C virus (HCV) infection are still unknown. Interferon‐α indirectly induces cleavage of viral RNA by RNase L at UU/UA dinucleotides. There is evidence that HCV genomes with a higher number of UU/UA dinucleotides are more sensitive to interferon‐α. As a guanosine analogue, ribavirin exerts a mutagenic effect promoting G‐to‐A and C‐to‐U transitions. This study investigates whether ribavirin‐induced mutagenesis causes a higher frequency of UU/UA dinucleotides in the viral progeny sequences. Increased mutational frequencies in favour of G‐to‐A and C‐to‐U transitions during ribavirin treatment was reported by Hofmann et al. (Gastroenterology 2007;132:921–930). Overall, 937 nucleotide sequences from that publication were reanalysed for RNase L cleavage sites. These included HCV NS3 quasispecies from three patients with ribavirin monotherapy and NS5B quasispecies from patients who received ribavirin alone (n = 7) or in combination with interferon‐α (n = 7) at baseline and during treatment; NS5B quasispecies from a subgenomic HCV replicon system after 24, 48 and 72 h of cultivation with or without ribavirin or with levovirin. For NS3 quasispecies during ribavirin monotherapy and NS5B quasispecies from patients who received ribavirin alone or in combination with interferon‐α, analysis of RNase L cleavage sites did not reveal changes during treatment or differences between treatment regimes. Similarly, RNaseL cleavage sites from NS5B quasispecies of the HCV replicon did not differ significantly between time points or treatments. In conclusion, Ribavirin‐induced mutagenesis did not increase RNase L cleavage sites (UU/UA dinucleotides) within the HCV NS3 or NS5B encoding regions.     

Management issues in chronic viral hepatitis: hepatitis C

The natural history of chronic hepatitis C virus (HCV) infection and intervention with antiviral therapy are closely linked issues that cause the greatest controversy and concern for the person infected with HCV, as well as for the clinician involved in the assessment and treatment of people with chronic HCV infection. The outstanding challenge of natural history is to identify the person who is likely to develop serious liver disease, and to make that determination early in the course of chronic HCV infection when treatment is likely to be of the greatest benefit. Significant advances in the therapy of chronic HCV infection have occurred over the past decade. A sustained virological response (SVR), defined as undetectable HCV-RNA in blood 6 months after completing antiviral treatment, is the best indicator of a beneficial treatment effect. Relapse, breakthrough or non-response should all be regarded as unsuccessful outcomes of therapy. Interferons are still the mainstay of antiviral therapy for chronic HCV infection. The combination of interferon and ribavirin has improved SVR by decreasing the relapse rate. Treatment responses vary according to host factors such as age and gender, fibrotic severity and to viral factors like genotype and viral load. Patients with genotype 1 HCV and a high viral load require 12 months of treatment to achieve a SVR in approximately 30%, compared to those with genotypes 2 or 3 who achieve a SVR in approximately 65% after 6 months. Patients who relapse after an end-of-treatment response to interferon monotherapy have a good chance of responding to combination interferon and ribavirin given for 6 months, but a longer treatment course should be considered in less optimal cases. At present, the treatment of those with non-response is less clear, but there is interest in more intense forms of interferon therapy, such as induction dosing or pegylated interferon in combination with ribavirin. Clinicians need to be aware of the common side-effects of interferon and ribavirin so that appropriate counseling and testing can be instituted before and during therapy. The combination of pegylated interferon and ribavirin will be the new standard of therapy for hepatitis C and pegylated interferon monotherapy provides quite acceptable efficacy for those patients intolerant of ribavirin. Current data strongly support the concept that SVR in HCV infection (or treatment-induced latency) provides a cure in terms of its beneficial effects on quality of life and sustained amelioration of liver injury.     

Response to treatment following recently acquired hepatitis C virus infection in a multicentre collaborative cohort

Pegylated interferon therapy is highly effective in recently acquired HCV. The optimal timing of treatment, regimen and influence of host factors remains unclear. We aimed to measure sustained virological response (SVR) during recent HCV infection and identify predictors of response. Data were from five prospective cohorts of high‐risk individuals in Australia, Canada, Germany and the United States. Individuals with acute or early chronic HCV who commenced pegylated interferon therapy were included. The main outcome was SVR, and predictors were assessed using logistic regression. Among 516 with documented recent HCV infection, 237 were treated (pegylated interferon n = 161; pegylated interferon/ribavirin n = 76) (30% female, median age 35 years, 56% ever injected drugs, median duration of infection 6.2 months). Sixteen per cent (n = 38) were HIV/HCV co‐infected. SVR among those with HCV mono‐infection was 64% by intention to treat; SVR was 68% among HCV/HIV co‐infection. Independent predictors of SVR in HCV mono‐infection were duration of HCV infection (the odds of SVR declined by 8% per month of infection, aOR 0.92, 95% CI 0.85–0.99, P = 0.033), IFNL4 genotype (adjusted OR 2.27, 95% CI 1.13–4.56, P = 0.021), baseline HCV RNA <400 000 IU/mL (aOR 2.06, 95% CI 1.03–4.12, P = 0.041) and age ≥40 years (vs <30: aOR 2.92, 95% CI 1.31–6.49, P = 0.009), with no difference by drug regimen, HCV genotype, symptomatic infection or gender. The effect of infection duration on odds of SVR was greater among genotype‐1 infection. Interferon‐based HCV treatment is highly effective in recent HCV infection. Duration of infection, IFNL4 genotype and baseline HCV RNA levels can predict virological response and may inform clinical decision‐making.     

Analysis of genotype 2 and 3 hepatitis C virus variants in patients treated with telaprevir demonstrates a consistent resistance profile across genotypes

Study C209 evaluated the activity of telaprevir in treatment‐naïve patients with genotypes 2 or 3 (G2, G3) hepatitis C virus (HCV) infection. Telaprevir monotherapy showed potent activity against HCV G2, but limited activity against G3. This analysis was performed to characterize HCV viral variants emerging during telaprevir‐based treatment of G2/G3 HCV‐infected patients. Patients were randomized to receive 2 weeks of treatment with telaprevir (telaprevir monotherapy), telaprevir plus peginterferon alfa‐2a and ribavirin (triple therapy), or placebo plus peginterferon alfa‐2a and ribavirin (control), followed by 22–24 weeks of peginterferon/ribavirin alone. Viral breakthrough was defined as an increase >1 log₁₀ in HCV RNA from nadir, or HCV RNA >100 IU/mL in patients previously reaching <25 IU/mL. Twenty‐three patients (47%) had G2 and 26 (53%) had G3 HCV. Viral breakthrough occurred during the initial 2‐week treatment phase in six G2 patients (66.7%; subtypes 2, 2a and 2b) and three G3 patients (37.5%; all subtype 3a), all in the telaprevir monotherapy arm. Four breakthrough patients (three G2, one G3) subsequently achieved sustained virologic response (SVR). In all patients with breakthrough and available sequence data, mutations associated with reduced susceptibility to telaprevir in genotype 1 (G1) HCV were observed. No novel G2/G3‐specific mutations were associated with telaprevir resistance. The telaprevir resistance profile appeared consistent across HCV genotypes 1, 2 and 3. Although viral breakthrough with resistance occurred in patients receiving telaprevir monotherapy, half of these patients achieved an SVR upon addition of peginterferon/ribavirin highlighting the importance of combination therapy.     

Low glomerular filtration rate is a risk factor for ribavirin‐associated anaemia in old patients with chronic hepatitis C

Elderly patients with chronic hepatitis C have a reduced responsiveness to antiviral therapy with Peg‐interferon and ribavirin. The dose reduction or the discontinuation of ribavirin due to the occurrence of anaemia is one of the most important causes for the low sustained viral response observed in older patients. We aimed to evaluate the relationship between baseline renal function and the early onset of ribavirin‐associated anaemia in older (≥60 years) patients. Using data from 348 patients with chronic hepatitis C consecutively treated with peg‐interferon plus ribavirin, we investigated which factors were associated with the occurrence of anaemia in elderly patients (≥60 years). Ribavirin‐induced anaemia occurred in 40.5% of patients. Older patients showed a rate of anaemia significantly higher than younger patients (51.5% vs 36.3%; P = 0.009). Consequently, the rate of ribavirin dose reduction or discontinuation due to anaemia was 35.1% in older patients and 23.5% in younger patients (P = 0.029). A significantly higher proportion of older patients had a low baseline glomerular filtration rate (GFR) compared with younger patients (56.7% vs 27.1%; P < 0.001). At the multivariate regression analysis, low baseline GFR (<70 mL/min) was associated with an increased risk of ribavirin‐associated anaemia only in the older patients (OR: 3.526; 95% CI: 1.385–8.979; P = 0.008). In this subset, baseline GFR was significantly correlated with both absolute (r = ?0.320; P < 0.001) and relative (r = ?0.324; P < 0.001) haemoglobin decrease within the first 8 weeks of treatment. In patients aged >60 years, a low pre‐treatment GFR was strongly associated with the risk to develop ribavirin‐related anaemia with consequent reduction in ribavirin doses.     

Aktueller Stand der Hepatitis-C-Therapie

The approval of two NS3/4A protease inhibitors, boceprevir and telaprevir, as the first directly acting antiviral substances in combination with pegylated (PEG) interferon alfa and ribavirin, markedly changed the treatment of chronic hepatitis C genotype 1 infections. The pivotal studies showed significantly improved rates of sustained virologic response (SVR) of triple therapy combining a protease inhibitor with PEG interferon alfa and ribavirin in the range of 63–75 % in treatment-naïve patients and 59–65 % in treatment-experienced patients compared to 38–44 % and 17–21 %, respectively in the control groups without the protease inhibitor. The standard of care for all other HCV genotypes is still dual combination therapy with PEG interferon and ribavirin. Besides this considerable progress, HCV genotype 1 infected patients with previous null response and with liver cirrhosis showed limited response rates. In addition management of triple therapy is complicated by complex treatment schedules, drug-drug interactions and supplemental side effects, such as aggravation of anemia or a rash. The second generation of direct acting antiviral substances is currently in advanced stages of clinical development and will lead to a shortening and simplification of HCV therapy in addition to further improvement of efficiency including all HCV genotypes and interferon-free therapy.     

Safety, pharmacokinetics and resistant variants of telaprevir alone for 12 weeks in hepatitis C virus genotype 1b infection

Summary. Background: Telaprevir in combination with peginterferon and ribavirin is a promising advancement in chronic hepatitis C treatment. However, the safety, tolerability, pharmacokinetics and antiviral profiles of telaprevir alone beyond 2 weeks have not been studied. Methods: In a phase 1b study in Japan, 10 treatment‐naïve patients infected with hepatitis C virus genotype 1b with high viral load (>5 log₁₀ IU/mL) received telaprevir 750 mg every 8 h (q8h) for 12 weeks. We examined the safety, tolerability, pharmacokinetics, hepatitis C virus (HCV) RNA levels and resistant variants of telaprevir. Results: Neither serious adverse events nor discontinuations of study drug owing to an adverse event occurred. The most common adverse drug reactions were rash (80%) and anaemia (70%). Telaprevir concentration reached its steady state within 2 days after the first administration without abnormal accumulation. Telaprevir alone provided potent antiviral activity: a median log₁₀ decrease of 2.325 at 16 h and 5.175 on Day 14. During the treatment, HCV RNA levels at the nadir were below the limit of the quantification in seven patients and undetectable in three of 10 patients. Viral breakthrough associated with mainly Ala¹⁵⁶‐substituted variants occurred in eight patients, and only one patient showed end‐of‐treatment response. The selected variants reverted to the wild‐type during the 24‐week follow‐up period. Conclusion: Telaprevir alone was well tolerated at 750 mg q8h for up to 12 weeks. The safety profile and emergence of resistant variants of genotype 1b under telaprevir monotherapy for 12 weeks will become increasingly important in evaluating an oral combination of telaprevir with other direct‐acting antiviral agents.     

Ribavirin plasma concentration is a predictor of sustained virological response in patients treated for chronic hepatitis C virus genotype 2/3 infection

Summary. In hepatitis C virus (HCV) genotype 1 infection, the likelihood of obtaining sustained virological response (SVR) is associated with higher ribavirin exposure. Such an association has not been demonstrated for HCV genotype 2/3 infection, where a fixed 800 mg daily dosing of ribavirin is generally recommended. The primary aim of this study was to investigate the correlation between ribavirin concentration at day 29 and therapeutic response in patients with HCV genotype 2/3 infection. A total of 382 patients were randomized to 12 or 24 weeks of treatment with pegylated interferon‐alfa 2a 180 μg weekly and 800 mg ribavirin daily. Trough plasma concentration of ribavirin was measured at day 29 and week 12 and the primary outcome was SVR (HCV‐RNA undetectable 24 weeks after treatment). Of the 382 patients, 355 had a ribavirin concentration available at day 29. SVR was 84% among patients with a ribavirin concentration ≥2 mg/L at day 29 compared to 66% in those with concentrations <2 mg/L (P = 0.002). The corresponding figures in the 12‐week treatment group were 74% and 57% (P = 0.12), and in the 24‐week treatment group 91% and 75% (P = 0.02), respectively. In a multivariate analysis, ribavirin concentration at day 29 was an independent predictor of SVR (P = 0.002). In conclusion, a higher plasma ribavirin concentration is associated with an increased likelihood of achieving SVR in HCV genotype 2/3 infection. Individualization of ribavirin dosing may be helpful in improving outcome, especially in the presence of unfavourable baseline characteristics. This, however, requires evaluation in a prospective trial.