Cost‐effectiveness analyses of anti‐hepatitis C virus treatments using quality of life scoring among patients with chronic liver disease in Hiroshima prefecture,Japan

Aim

We estimated the cost‐effectiveness of direct‐acting antiviral treatment (DAA) compared to triple therapy (simeprevir, pegylated interferon‐α [Peg‐IFN], and ribavirin [RBV]) (scenario 1), Peg‐IFN + RBV (scenario 2), and non‐antiviral therapy (scenario 3).

Methods

Cost‐effectiveness was evaluated as incremental cost‐effectiveness ratios (ICERs) using direct costs and indirect costs, which included loss of wages during the patient's lifetime due to early death caused by viral hepatitis infection. Quality of life (QOL) scores were determined by EQ‐5D‐3L questionnaire survey on 200 HCV patients in Hiroshima.

Results

The QOL scores for chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma were estimated as 0.871, 0.774, and 0.780, respectively. The follow‐up period that the ICER of scenario 1 becomes shortest (cost <¥6 million) was 25 years after treatment in men and women who started treatment at the age of 20–60. In contrast, those of scenarios 2 and 3 was 10 years after treatment in patients who started treatment at age <80 years. Based on the sensitivity analysis in scenario 1, the most significant factor affecting the value of ICER is the QOL score after sustained virologic response (SVR), followed by the SVR rate of DAA or follow‐up period.

Conclusions

Direct‐acting antiviral treatment was estimated to be cost‐effective from 10 to 25 years after treatment, depending on the SVR rate of the drugs and the age of onset of treatment. In order to increase the cost‐effectiveness of DAA treatment, measures or effort to improve the QOL score of patients after SVR are necessary.     

Add‐on effects of fluvastatin in simeprevir/pegylated‐interferon/ribavirin combination therapy for patients with genotype 1 hepatitis C virus infection: A randomized controlled study

Background

The Japan Society of Hepatology guidelines indicate that hepatitis C virus (HCV) protease inhibitor combination therapy with simeprevir (SMV), pegylated‐interferon (Peg‐IFN), and ribavirin (RBV) is a therapeutic option for patients who fail to respond to a direct direct‐acting antiviral‐containing regimen. However, treatment outcomes have room for improvement. Fluvastatin (FLV) add‐on treatment in Peg‐IFN and RBV combination therapy for HCV‐infected patients significantly improved the sustained virologic response (SVR), but the add‐on effect of FLV on SMV combination therapy is not well understood.

Methods

This was a prospective, randomized, multicenter study in which a total of 61 HCV genotype 1b‐infected patients were recruited and 60 eligible patients were randomly allocated to two groups that received 12 weeks of SMV/Peg‐IFN/RBV followed by 12 weeks of Peg‐IFN/RBV with or without 24 weeks of FLV. The SVR rate and adverse events were compared between the two groups.

Results

Thirty‐one patients were allocated to the FLV add‐on group and 29 patients were allocated to the control group. Baseline clinical factors, including median age, baseline platelet count, alanine aminotransferase level, HCV RNA titer, Fibrosis‐4 index, and rate of IL28B minor genotype, were all similar between the two groups. The rapid virologic response, end‐of‐treatment response rates, SVR rates at 24 weeks after treatment, and safety profiles were also similar between the two groups.

Conclusions

This prospective, randomized, multicenter study indicated that FLV had no add‐on effect when given with SMV/Peg‐IFN/RBV combination therapy for genotype 1b HCV‐infected patients.     

Thrombocytopenia in pegylated interferon and ribavirin combination therapy for chronic hepatitis C

Background

This study aimed to examine the therapeutic effect and prognostic indicators of pegylated interferon (PEG-IFN) and ribavirin (RBV) combination therapy in thrombocytopenic patients with chronic hepatitis C, hepatitis C virus (HCV)-related cirrhosis, and those who underwent splenectomy or partial splenic embolization (PSE).

Methods

Of 326 patients with HCV-related chronic liver disease (252 with genotype 1b and 74 with genotype 2a/2b) treated with PEG-IFN/RBV, 90 were diagnosed with cirrhosis.

Results

Regardless of the degree of thrombocytopenia, the administration rate was significantly higher in the splenectomy/PSE group compared to the cirrhosis group. However, in patients with genotype 1b, the sustained virological response (SVR) rate was significantly lower in the cirrhosis and the splenectomy/PSE groups compared to the chronic hepatitis group. No cirrhotic patients with platelets less than 80,000 achieved an SVR. Patients with genotype 2a/2b were more likely to achieve an SVR than genotype 1b. Prognostic factors for SVR in patients with genotype 1b included the absence of esophageal and gastric varices, high serum ALT, low AST/ALT ratio, and the major homo type of the IL28B gene. Splenectomy- or PSE-facilitated induction of IFN in patients with genotype 2a/2b was more likely to achieve an SVR by an IFN dose maintenance regimen. Patients with genotype 1b have a low SVR regardless of splenectomy/PSE. In particular, patients with a hetero/minor type of IL28B did not have an SVR.

Conclusions

Splenectomy/PSE for IFN therapy should be performed in patients expected to achieve a treatment response, considering their genotype and IL28B.     

IFNL4 polymorphism effects on outcome of simeprevir,peginterferon, and ribavirin therapy for older patients with genotype 1 chronic hepatitis C

Aim

Older patients with chronic hepatitis C have a lower virological response to interferon (IFN)‐based treatments compared to younger patients. A single nucleotide polymorphism in the IFN‐λ‐4 (IFNL4) gene has a potent predictive effect on treatment response to IFN‐based treatments. The efficacy of simeprevir (SMV) plus pegylated‐IFN (PEG‐IFN) and ribavirin therapy and the predictive value of IFNL4 on the outcome of therapy for older patients have not been addressed.

Methods

This retrospective multicenter study included 234 consecutive Japanese patients with genotype 1 chronic hepatitis C. We assessed the predictive factors for sustained virological response (SVR) to SMV, PEG‐IFN, and ribavirin triple therapy in 170 younger (<70 years) and 64 older (≥70 years) patients. IFNL4 polymorphism ss469415590 was analyzed by Invader assay.

Results

The SVR rate for older patients was similar to that for younger patients (63.9% and 72.0%, respectively). The SVR rate for the IFNL4 TT/TT group was significantly higher than the IFNL4 TT/ΔG or ΔG/ΔG group both in younger (93.6% and 46.1%, respectively, P < 0.01) and older patients (84.4% and 33.3%, respectively, P < 0.001). In multivariate regression analysis, IFNL4 TT/TT genotype, response to previous treatment and IFNL4 TT/TT genotype were identified as independent predictive factors for SVR in older and younger patients, respectively. Decrease in hemoglobin level was similar between the two groups.

Conclusion

The virological response to SMV triple therapy in older patients was similar to that of younger patients. Analysis of IFNL4 polymorphisms is a valuable predictor in both younger and older patients.

     

Hepatitis C Virus Clearance in Older Adults

Objectives

To determine whether older adults with the hepatitis C virus (HCV) achieve a sustained viral response (SVR) after treatment with direct‐acting antiviral therapy.

Participants

Individuals aged 80 and older with chronic HCV infection (N = 253; n = 213 with cirrhosis, n = 40 with advanced fibrosis).

Measurements

We investigated the efficacy, safety, and global clinical effect of treatment with different combinations of direct antiviral agents (DAAs). Participants with cirrhosis were staged according to Child‐Pugh‐Turcotte class, Model for End‐Stage Liver Disease score, and the D'Amico staging system. The type and number of comorbidities at baseline and hepatic and nonhepatic events during follow‐up were registered.

Results

Ninety‐five percent of participants with cirrhosis and 95% of those with advanced fibrosis attained SVR. The rate was independent of sex, HCV genotype, and treatment schedule. During a mean follow‐up of 14 ± 4 months (range 5–23 months), 34 events occurred in 27 participants: 10 hepatocellular carcinomas, 12 hepatic decompensations, 9 nonhepatic events, 3 deaths. Multivariate analysis of risk factors for experiencing adverse events during follow up showed that participants in D'Amico Stages 4 and 5, with a baseline serum albumin level of 3.5 mg/dL or less, and 3 or more comorbidities were the most at risk.

Conclusion

In a real‐world setting, DAAs are safe and effective in older adults with HCV‐related advanced fibrosis or cirrhosis. Individuals with preserved albumin synthesis and fewer than 3 comorbidities at baseline have the most to gain from long‐term DAA therapy.     

Interferon Alpha-2b Therapy in Chronic Hepatitis Delta

Background:

Approximately 5% of hepatitis B virus (HBV) carriers are coinfected with hepatitis D virus (HDV). HBV/HDV coinfection is a major cause of cirrhosis and end stage liver disease in chronic HBsAg carriers. The only approved therapy for chronic hepatitis delta is interferon alpha (IFN α) in either pegylated or conventional forms. Although higher doses and longer durations of IFN α therapy in HBV/HDV coinfected patients are currently applied, yet treatment response is low.

Objectives:

We aimed to determine the efficacy of IFN α-2b therapy in patients with HBV/HDV coinfection.

Patients and Methods:

In this cross sectional study, 20 HBsAg carriers with positive Anti-HDVAb and RT-PCR for HDV RNA were recruited and treated for three year duration with 5 million units (MU) of IFN α-2b, three times weekly or one year with 5 MU of IFN α-2b daily. Sustained virological response (SVR) was defined as a negative qualitative HDV RT-PCR, 6 months after treatment cessation.

Results:

Overall, 3 (15%) subjects achieved SVR, 10 cases (50%) relapsed after treatment cessation and 7 (35%) patients did not clear HDV during the treatment.

Conclusions:

HDV coinfection with HBV had very low response rate to high doses and long durations of IFN α-2b therapy.     

Excellent superiority and specificity of COBAS TaqMan HCV assay in an early viral kinetic change during pegylated interferon alpha-2b plus ribavirin treatment

Background  

An early virological response (EVR) after the start of interferon (IFN) treatment for chronic hepatitis C leads to a successful virological outcome. To analyze an association between sustained virological response (SVR) and EVR by comparing TaqMan with Amplicor assays in HCV genotype 1-infected patients treated with pegylated (PEG)-IFN alpha-2b plus ribavirin (RBV).     

Impact of hepatitis C virus recombinant form RF1_2k/1b on treatment outcomes within the Georgian national hepatitis C elimination program

Aim

Hepatitis C virus (HCV) recombinant form RF1_2k/1b is common in ethnic Georgians. This chimera virus contains genomic fragments of genotype 2 and genotype 1 and is misclassified as genotype 2 by standard genotyping. We aimed to identify RF1_2k/1b strains among genotype 2 patients and assess its impact on treatment outcomes.

Methods

The study included 148 patients with HCV genotype 2 as determined by 5‐untranslated region/core genotyping assay. RF1_2k/1b was identified by sequencing the non‐structural protein 5B region. Patients were treated within the national hepatitis C elimination program with sofosbuvir/ribavirin (SOF/RBV), interferon (IFN)/SOF/RBV, or ledipasvir (LDV)/SOF/RBV.

Results

Of 148 patients, 103 (69.5%) had RF1_ 2k/1b. Sustained virologic response (SVR) data was available for 136 patients (RF1_ 2k/1b, n = 103; genotype 2, n = 33). Sustained virologic response was achieved in more genotype 2 patient than in RF1_2k/1b patients (97.0% vs. 76.7%, P = 0.009). Twelve weeks of LDV/SOF/RBV treatment was highly effective (100% SVR) in both genotypes. Among RF1_2k/1b patients, LDV/SOF/RBV for 12 weeks was superior (100% SVR) to SOF/RBV for 12 weeks (56.4%, P < 0.0001) or 20 weeks (79.2%, P = 0.05). Twelve weeks of IFN/SOF/RBV also showed better response than SOF/RBV for 12 weeks (88.9% vs. 56.4%, P = 0.02) in these patients.

Conclusions

High prevalence of the RF1_2k/1b strain can significantly affect treatment outcomes. Treatment with IFN/SOF/RBV and especially LDV/SOF/RBV ensured significantly higher SVR in patients infected with RF1_2k/1b strain compared to standard HCV genotype 2 treatment with SOF/RBV. There is a need to reassess existing methods for the management of HCV genotype 2 infections, especially in areas with high prevalence of the RF1_2k/1b strain.     

Long‐term follow‐up of clinical trial patients treated for chronic HCV infection with daclatasvir‐based regimens

Background & Aims

Daclatasvir has achieved high sustained virologic response (SVR) rates in diverse hepatitis C virus (HCV) populations. This study evaluated the long‐term efficacy and safety of daclatasvir‐based regimens administered during clinical studies.

Methods

Patients enrolled within 6 months of parent study completion or protocol availability at the study sites. The primary objective was durability of SVR at follow‐up Week 12 (SVR12). Secondary objectives included analysing HCV sequences in non‐responders or responders who relapsed, and characterization of liver disease progression.

Results

Between 24 February 2012 and 17 July 2015, this study enrolled and began following 1503 recipients of daclatasvir‐based regimens (follow‐up cut‐off, 13 October 2015); 60% were male, 18% aged ≥65 years, 87% had genotype‐1a (42%) or ‐1b (45%) infection, and 18% had cirrhosis. Median follow‐up from parent study follow‐up Week 12 was 111 (range, 11‐246) weeks. 1329/1489 evaluable patients were SVR12 responders; 1316/1329 maintained SVR until their latest visit. Twelve responders relapsed by (n = 9) or after (n = 3) parent study follow‐up Week 24; one was reinfected. Relapse occurred in 3/842 (0.4%) and 9/487 (2%) responders treated with interferon‐free or interferon‐containing regimens, respectively. Hepatic disease progression and new hepatocellular carcinoma were diagnosed in 15 and 23 patients, respectively. Among non‐responders, emergent non‐structural protein‐5A (NS5A) and ‐3 (NS3) substitutions were replaced by wild‐type sequences in 27/157 (17%) and 35/47 (74%) patients, respectively.

Conclusions

SVR12 was durable in 99% of recipients of daclatasvir‐based regimens. Hepatic disease progression and new hepatocellular carcinoma were infrequent. Emergent NS5A substitutions persisted longer than NS3 substitutions among non‐responders.     

Sofosbuvir plus ribavirin with or without peginterferon for the treatment of hepatitis C virus: Results from a phase 3b study in China

Background and Aim

Sofosbuvir is a nucleotide analog inhibitor of the hepatitis C virus (HCV) NS5B RNA polymerase with pangenotypic potency. This phase 3b study evaluated the safety and efficacy of sofosbuvir + ribavirin ± peginterferon in Chinese patients infected with HCV genotype 1, 2, 3, or 6.

Methods

Patients with genotype 1 or 6 received sofosbuvir + peginterferon/ribavirin for 12 weeks or sofosbuvir + ribavirin for 24 weeks, depending on prior treatment and interferon eligibility. Patients with genotype 2 or 3 received sofosbuvir + ribavirin for 12 or 24 weeks, respectively. The primary endpoint was sustained virologic response at 12 weeks after the end of treatment (SVR12).

Results

Of 389 patients, 42% had genotype 1, 16% genotype 2, 32% genotype 3, and 9% genotype 6. Half were male, 58% were treatment‐naïve, and 15% had cirrhosis. SVR12 rates for patients receiving 12 weeks of sofosbuvir + peginterferon/ribavirin were 94% (95% confidence interval [CI], 87–98%) for HCV genotype 1 and 97% (95% CI, 84–100%) for genotype 6. SVR12 rates for those receiving sofosbuvir + ribavirin for 24 weeks were 95% (95% CI, 87–99%) for genotype 1, 100% (95% CI, 40–100%) for genotype 6, and 95% (95% CI, 90–98%) for genotype 3. For genotype 2 patients receiving sofosbuvir + ribavirin for 12 weeks, the SVR12 rate was 92% (95% CI, 83–97%). Twenty patients (5%) relapsed. Ten (3%) experienced serious adverse events. Three (< 1%) discontinued treatment because of adverse events, of whom one died because of treatment‐unrelated adverse events.

Conclusions

Sofosbuvir‐based regimens were highly effective and safe in Chinese patients with HCV genotype 1, 2, 3, or 6, suggesting sofosbuvir could serve as the backbone for HCV treatment in China irrespective of genotype.     

Delivery of biannual ultrasound surveillance for individuals with cirrhosis and cured hepatitis C in the UK

Background

Previous studies show the uptake of biannual ultrasound (US) surveillance in patients with cirrhosis is suboptimal. Here, our goal was to understand in broader terms how surveillance is being delivered to cirrhosis patients with cured hepatitis C in the UK.

Methods

Hepatitis C cirrhosis patients achieving a sustained viral response (SVR) to antiviral therapies were identified from the national Hepatitis-C-Research-UK resource. Data on (i) liver/abdominal US examinations, (ii) HCC diagnoses, and (iii) HCC curative treatment were obtained through record-linkage to national health registries. The rate of US uptake was calculated by dividing the number of US episodes by follow-up time.

Results

A total of 1908 cirrhosis patients from 31 liver centres were followed for 3.8 (IQR: 3.4–4.9) years. Overall, 10 396 liver/abdominal USs were identified. The proportion with biannual US was 19% in the first 3 years after SVR and 9% for all follow-up years. Higher uptake of biannual US was associated with attending a liver transplant centre; older age and cirrhosis decompensation. Funnel plot analysis indicated significant inter-centre variability in biannual US uptake, with 6/29 centres outside control limits. Incident HCC occurred in 133 patients, of which 49/133 (37%) were treated with curative intent. The number of US episodes in the two years prior to HCC diagnosis was significantly associated with higher odds of curative-intent treatment (aOR: 1.53; 95% CI: 1.12–2,09; p = .007).

Conclusions

This study provides novel data on the cascade of care for HCC in the UK. Our findings suggest biannual US is poorly targeted, inefficient and is not being delivered equitably to all patients.     

Effectiveness and safety of daclatasvir plus asunaprevir for patients with hepatitis C virus genotype 1b aged 75 years and over with or without cirrhosis

Aim

The aim of this study was to evaluate the efficacy and safety of 24‐week daclatasvir (NS5A inhibitor) plus asunaprevir (NS3/4 A protease inhibitor) treatment for elderly patients with hepatitis C virus (HCV) genotype 1b infection.

Methods

This prospective, multicenter study consisted of 321 Japanese HCV genotype 1b patients who were interferon‐ineligible/intolerant or non‐responders to interferon‐based regimens, including 103 (32.1%) aged ≥75 years and 127 (39.6%) with cirrhosis. Sustained virological response (SVR) at 24 weeks after the end of treatment and adverse effects were analyzed according to age.

Results

The overall SVR rate was 90.3%. In terms of by age, 94.5% (69/73), 88.3% (128/145), and 90.3% (93/103) of the patients aged <65, 65–74, and ≥75 years, respectively, achieved SVR. For the entire cohort, pre‐existent NS5A resistance‐associated variants and prior simeprevir failure were independently associated with treatment failure. According to the analysis of patients without these unfavorable pretreatment factors, 90.8% (89/98) aged ≥75 years achieved SVR, although this was significantly lower than for those aged <65 years (98.5%, 66/67) (P < 0.05). The frequency of adverse effects was comparable for the <75 and ≥75 age groups, the most common being an elevated alanine aminotransferase level (>150 U/L, 8.7%), however, no decompensating events were seen.

Conclusions

Daclatasvir plus asunaprevir for HCV genotype 1b was well tolerated and effective for patients without pre‐existent NS5A resistance‐associated variants or simeprevir failure, irrespective of fibrosis status. However, it was less effective for very old patients aged ≥75 years compared to those aged <65.

     

Long-Term Viral Negativity After Interferon for Chronic Hepatitis C Virus Infection in Hemodialysis

Summary

Background and objectives

Interferon (IFN) and pegylated-IFN treatment of hepatitis C virus (HCV) infection in hemodialysis patients result in sustained virological response (SVR) rates of 45% and 37%, respectively. Although most nonhemodialysis patients who achieve SVR remain persistently viral negative, the durability of SVR in hemodialysis patients is unknown. We analyzed the rate of long-term virological negativity in hemodialysis patients who achieved SVR after IFN or pegylated-IFN through analysis of patient-level data.

Design, setting, participants, & measurements

After performing a systematic literature review for IFN-based treatment of hemodialysis patients with chronic HCV infection, we extracted patient-level data on patients who achieved SVR. We performed life table analysis to estimate long-term virological negativity rates after SVR in patients who continued on hemodialysis or subsequently underwent kidney transplantation.

Results

Long-term HCV RNA outcomes following SVR were available for 121 hemodialysis patients (20 studies) and 45 patients who subsequently underwent transplantation (11 studies). The probability of remaining HCV RNA negative was 86% (95% confidence interval, 77% to 96%) for patients followed on hemodialysis 48 months after SVR and 95% (95% confidence interval, 89% to 100%) for kidney recipients followed 48 months after transplant.

Conclusions

Viral negativity from IFN-based HCV treatment in hemodialysis patient appears durable during extended follow-up, including after kidney transplantation. The certainty of the viral negativity estimate is limited by the small number with follow-up beyond 48 months or longer. Transplantation does not confer an increased risk of relapse. Future research should investigate whether IFN-based treatment improves clinical outcomes for hemodialysis patients.     

Clinico‐immunological outcomes of HCV‐cured cryoglobulinemia: Lower relapse rate with interferon‐based than interferon‐free therapy

Sustained virological response (SVR) obtained with interferon (IFN) or with direct‐acting antivirals (DAAs) is commonly followed by response of hepatitis C virus (HCV)‐associated mixed cryoglobulinemia vasculitis (MCV), but relapse of MCV despite SVR has been reported in several patients after DAAs and rarely after IFN. Since relapses could have been overlooked in studies with IFN, we retrospectively compared the outcomes of MCV in SVR patients treated with DAAs (n = 70) or IFN (n = 39) followed‐up, respectively, for 30.5 (range 11‐51) or 48 months. Groups were comparable for demographics and clinics and response rates of MCV were similar (92% and 86%); however, DAA‐treated patients less efficiently reduced cryoglobulins (P = .006) and circulating B‐cell clones (P = .004), and had more frequently relapses of MCV (18% vs 3%, P = .028) and need for rituximab therapy (P = .01). Although largely inferior on an intention‐to‐treat basis, IFN may be superior to DAAs on clinico‐immunological outcomes possibly owing to its antiproliferative activity.     

Durability of Sustained Virologic Response in Chronic Hepatitis C

Background/Aims

The aim of this study is to investigate the rate of sustained virologic response (SVR) in chronic hepatitis C patients receiving antiviral treatment.

Methods

The files of patients with chronic hepatitis C treated with interferon±ribavirin between 1995 and 2009 were reviewed retrospectively. Six months after the end of treatment, patients with negative hepatitis C virus (HCV)-RNA (<50 IU/mL, as determined by the polymerase chain reaction method) were enrolled in the study.

Results

The mean age of 196 patients (89 males) was 46.13±11.10 years (range, 17 to 73 years). In biopsies, the mean stage was 1.50±0.94; histological activity index was 7.18±2.43. In total, 139 patients received pegylated interferon (IFN)+ribavirin, 21 patients received classical IFN+ribavirin, and 36 patients received IFN alone. The HCV genotypes of 138 patients were checked: 77.5% were genotype 1b, and 22.5% were other genotypes. After achievement of SVR, the median follow-up period was 33.5 months (range, 6 to 112 months), and in this period relapse was only detected in two patients (1.02%) at 18 and 48 months after treatment.

Conclusions

In total, 98.9% of patients with SVR in chronic hepatitis C demonstrated truly durable responses over the long-term follow-up period of 3 years; relapsed patients had intermittent or low-grade viremia.     

Efficacy and anticarcinogenic activity of interferon for hepatitis C virus-related compensated cirrhosis in patients with genotype 1b low viral load or genotype 2

Background: We assessed the efficacy and anticarcinogenic effects of interferon (IFN) therapy in patients with hepatitis C virus (HCV)-related cirrhosis. Methods: The study subjects were 123 Japanese patients with HCV-related cirrhosis with genotype 1b low viral load or genotype 2 who received IFN from 1989 to 2005 (18 patients continue to receive IFN therapy). They included 81 men and 42 women aged 29-74 years (median, 56 years). Results: Univariate analysis identified four parameters that significantly influenced SVR; viral load (low HCV concentration, P < 0.001), duration of IFN therapy (>/= 52 weeks, P = 0.029), daily dose of IFN (>/= 6 million units, P = 0.018), induction therapy (presence, P = 0.010) and choline esterase (> 1.0 DeltapH, P = 0.037). Multivariate analysis identified viral load (risk ratio = 6.329, P < 0.001) and daily dose of IFN (risk ratio = 2.62, P = 0.042) as two independent parameters thatinfluenced SVR. During the observation period, newly developed hepatocellular carcinoma (HCC) was detected in 22 patients. The rates of development of HCC in patients with SVR were 5.8% at the fifth year and 10.3% at the 10th year, compared with 25.8% at the fifth year and 42.5% at the 10th year in non-SVR patients. Multivariate analysis showed that IFN efficacy (SVR) was the only independent factor of hepatocarcinogenesis (hazard ratio: 0.185, 95% confidence interval: 0.042-0.810, P = 0.025) Conclusion: Among patients with HCV-related cirrhosis, the rate of development of HCC is significantly less in patients with SVR.     

Impact of disease severity on outcome of antiviral therapy for chronic hepatitis C: Lessons from the HALT-C trial

In patients with chronic hepatitis C, advanced fibrosis and cirrhosis are associated with lower rates of sustained virologic response (SVR) to interferon (IFN)-based therapy. In this study, we assessed virologic response to retreatment with peginterferon alfa-2a and ribavirin (RBV), as a function of the baseline fibrosis score (Ishak staging) and platelet count, in 1,046 patients enrolled in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial. All patients had failed prior treatment with IFN or peginterferon +/- RBV and had Ishak fibrosis scores > or = 3. Four groups of patients with increasingly severe liver disease were compared: (A) bridging fibrosis (Ishak 3 and 4) with platelet counts >125,000/mm3 (n = 559); (B) bridging fibrosis with platelet counts < or =125,000/mm3 (n = 96); (C) cirrhosis (Ishak 5 and 6) with platelet counts >125,000/mm3 (n = 198); and (D) cirrhosis with platelet counts < or =125,000/mm3 (n = 193). SVR rates were 23%, 17%, 10%, and 9% in groups A, B, C, and D, respectively (P < .0001 for trend). Reduction in SVR as a function of increasingly severe disease was independent of age, percent African American, HCV genotype, HCV level, and type of prior therapy. Dose reduction lowered SVR frequencies, but to a lesser extent than disease severity. By logistic regression, cirrhosis (P < .0001) was the major determinant that impaired virologic response, independent of dose reduction or platelet count. In conclusion, disease severity is a major independent determinant of rate of SVR in patients with advanced chronic hepatitis C. New strategies are needed to optimize antiviral therapy in these "difficult-to-cure" patients.     

Occurrence of late relapse of hepatitis C virus confirmed by molecular analysis after sustained virologic response to interferon–ribavirin‐based therapy

Aim

The optimal duration of follow‐up for patients who achieve sustained virologic responses (SVR) has become an important issue. Reports on long‐term follow‐up of SVR have indicated that 99% of patients maintained SVR. However, the limitations of a majority of studies include small patient numbers, short study periods, and lack of molecular analysis of hepatitis C virus (HCV) genome. The present study sought to evaluate the late relapse rate in long‐term follow‐up of patients who achieved SVR, with molecular analysis of HCV.

Methods

A total of 224 patients with chronic hepatitis C who were treated by interferon and ribavirin‐based therapy and achieved SVR were enrolled. All patients were recommended for follow‐up every 6 or 12 months.

Results

The mean follow‐up period was 6.0 years (range, 1.0–13.6 years). Cumulative 5‐ and 10‐year follow‐up rates of the patients after SVR were 87.8% and 78.8%, respectively. Cumulative 5‐ and 10‐year follow‐up rates of serum HCV RNA after SVR were 85.5% and 52.6%, respectively. Two patients had detectable serum HCV RNA at 20 and 30 months, respectively, after SVR. Phylogenetic analyses of core, non‐structural protein 3, and 5A regions of HCV strains from late relapse patients confirmed the same strain was present at baseline and late relapse.

Conclusions

Two of 224 patients developed late relapse of HCV by the original strain, which was confirmed by direct sequencing analysis. Although few patients may develop late relapse, SVR achieved with interferon and ribavirin‐based therapy is durable for prolonged periods.     

Effect of Previous Interferon Treatment on Outcome After Curative Treatment for Hepatitis C Virus-Related Hepatocellular Carcinoma

Background and Aims  

Treatment of chronic hepatitis C virus (HCV) infection with interferon (IFN) prevents the development of hepatocellular carcinoma (HCC). The purpose of this study was to clarify the effect of previous IFN treatment before the development of HCC on recurrence and survival in HCV-related HCC patients.