Variants in STAT4 Associated With Cure of Chronic HBV Infection in HBeAg-positive Patients Treated With Pegylated Interferon-alpha.

BACKGROUND & AIMS: Variants in STAT4 (rs7574865) have been associated with seroconversion to hepatitis B e antigen (HBeAg) and reduction in levels of hepatitis B virus (HBV) DNA in patients with chronic infection treated with interferon alpha (IFNA). We evaluated the associations among rs7574865, loss of HB surface antigen (HBsAg, a marker of functional cure of HBV infection), and response to treatment with pegylated IFNA (PegIFN) or nucleos(t)ide analogues (NUCs) in HBeAg-positive patients with chronic HBV infection. METHODS: We performed a retrospective analysis of 1823 HBeAg-positive patients with chronic HBV infection (954 patients treated with PegIFN and 869 patients treated with NUCs) included in 4 phase-4 multicenter randomized controlled trials. The Cochran-Armitage trend test was used to evaluate the association of rs7574865 genotype with combined response (CR, defined as HBeAg seroconversion and HBV DNA level <2000 IU/mL) and loss of HBsAg at week 72, for patients given PegIFN, or week 104, for patients given NUCs. RESULTS: We found a significant association between rs7574865 genotype and CR (P = .004) and loss of HBsAg (P = .037) in patients treated with PegIFN. In patients with HBV genotype B infection, 43.6% of those with rs7574865 TT achieved a CR, compared to patients with rs7574865 GG (20.5%), and 7.7% had loss of HBsAg, compared to 1.9% of patients with rs7574865 GG. However, in patients treated with NUCs, we found no association of rs7574865 genotype with CR (P = .811) or loss of HBsAg (P=.439). CONCLUSIONS: In a retrospective analysis of data from 4 clinical trials, we found rs7574865 in STAT4 to be associated with functional cure of chronic HBV infection by PegIFN treatment, but not NUCs treatment, in HBeAg-positive patients with HBV genotype B infection.

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.

Baseline quantitative hepatitis B core antibody titre alone strongly predicts HBeAg seroconversion across chronic hepatitis B patients treated with peginterferon or nucleos(t)ide analogues.

OBJECTIVE: The investigation regarding the clinical significance of quantitative hepatitis B core antibody (anti-HBc) during chronic hepatitis B (CHB) treatment is limited. The aim of this study was to determine the performance of anti-HBc as a predictor for hepatitis B e antigen (HBeAg) seroconversion in HBeAg-positive CHB patients treated with peginterferon (Peg-IFN) or nucleos(t)ide analogues (NUCs), respectively. DESIGN: This was a retrospective cohort study consisting of 231 and 560 patients enrolled in two phase IV, multicentre, randomised, controlled trials treated with Peg-IFN or NUC-based therapy for up to 2 years, respectively. Quantitative anti-HBc evaluation was conducted for all the available samples in the two trials by using a newly developed double-sandwich anti-HBc immunoassay. RESULTS: At the end of trials, 99 (42.9%) and 137 (24.5%) patients achieved HBeAg seroconversion in the Peg-IFN and NUC cohorts, respectively. We defined 4.4 log10 IU/mL, with a maximum sum of sensitivity and specificity, as the optimal cut-off value of baseline anti-HBc level to predict HBeAg seroconversion for both Peg-IFN and NUC. Patients with baseline anti-HBc ≥4.4 log10 IU/mL and baseline HBV DNA <9 log10 copies/mL had 65.8% (50/76) and 37.1% (52/140) rates of HBeAg seroconversion in the Peg-IFN and NUC cohorts, respectively. In pooled analysis, other than treatment strategy, the baseline anti-HBc level was the best independent predictor for HBeAg seroconversion (OR 2.178; 95% CI 1.577 to 3.009; p<0.001). CONCLUSIONS: Baseline anti-HBc titre is a useful predictor of Peg-IFN and NUC therapy efficacy in HBeAg-positive CHB patients, which could be used for optimising the antiviral therapy of CHB.

Response-guided peginterferon therapy in patients with HBeAg-positive chronic hepatitis B: A randomized controlled study.

BACKGROUND & AIMS: Response-guided therapy has been confirmed to be an effective strategy for the treatment of chronic hepatitis C in the pegylated interferon (PegIFN) era, but no randomized trial utilizing this strategy has been conducted in chronic hepatitis B. METHODS: In this open-label, multicenter, randomized trial, HBeAg positive patients were treated with PegIFN (180µg/week) for 24weeks. Early responders (HBsAg <1500IU/ml and HBV DNA <10(5)copies/ml at week 24) received PegIFN for a further 24weeks (arm A), while non-early responders were randomized to PegIFN for another 24weeks (arm B), another 72weeks (arm C) or PegIFN for another 72weeks plus adefovir for 36weeks (arm D). The primary endpoint was the change of quantitative HBsAg from baseline to the end of follow-up (EOF). RESULTS: For non-early responders, 96-week PegIFN monotherapy did not lead to a greater reduction of HBsAg from baseline to EOF, compared with 48-week PegIFN (-0.71 vs. -0.67log10IU/ml, P=0.407). The rate of HBeAg seroconversion with HBV DNA <2000IU/ml at EOF were similar for arms B, C and D (17.9%, 23.9% and 25.0% respectively). For patients with HBsAg <1500IU/ml or HBV DNA <10(5)copies/ml at week 24, 38.4% and 37.0% achieved HBeAg seroconversion with HBV DNA <2000IU/ml at EOF respectively. CONCLUSIONS: Patients with HBsAg <1500IU/ml or HBV DNA <10(5)copies/ml at week 24 would benefit from continued PegIFN treatment. Extending the duration of PegIFN with or without adding adefovir did not show superiority over 48weeks PegIFN monotherapy. LAY SUMMARY: Extending the duration of pegylated interferon (PegIFN) alfa-2a is not recommended in HBeAg positive patients as treatment extension beyond 48weeks did not show convincing benefit. Patients who achieved HBsAg <1500IU/ml or HBV DNA <10(5)copies/ml after 24-week PegIFNα-2a showed satisfactory outcome after the withdrawal of finite PegIFNα-2a treatment. CLINICAL TRIAL NUMBER: NCT01086085.

Serum hepatitis B virus RNA is encapsidated pregenome RNA that may be associated with persistence of viral infection and rebound.

BACKGROUND & AIMS: Hepatitis B virus (HBV) RNA in serum has recently been linked to efficacy and prognosis of chronic hepatitis B (CHB) treatment. This study explored the nature, origin, underlying mechanisms, and potential clinical significance of serum HBV RNA. METHODS: The levels of HBV DNA and RNA were determined in the supernatant of induced HepAD38, HBV-expressing HepG2.2.15 cells and primary human hepatocytes (PHH), and in the serum of transgenic mice and CHB patients. NP-40 and proteinase K treatment, sucrose density gradient centrifugation, electron microscopy, northern blot, multiple identification PCRs and 5' rapid-amplification of cDNA ends were performed to identify the nature of serum HBV RNA. RESULTS: Although significantly lower than HBV DNA levels, abundant HBV RNA was present in the serum of CHB patients. A series of experiments demonstrated that serum HBV RNA was pregenome RNA (pgRNA) and present in virus-like particles. HBV pgRNA virion levels increased after blocking the reverse transcription activity of HBV DNA polymerase, and decreased after blocking the encapsidation of pgRNA. Furthermore, the presence of HBV pgRNA virion was associated with risk of viral rebound after discontinuation of nucleot(s)ide analogues (NAs) therapy in CHB patients. CONCLUSIONS: Serum HBV RNA was confirmed to be pgRNA present in virus-like particles. HBV pgRNA virions were produced from encapsidated particles in which the pgRNA was non- or partially reverse transcribed. Clinically, HBV pgRNA virion might be a potential biomarker for monitoring safe discontinuation of NA-therapy. LAY SUMMARY: HBV may have another virion form in which the nucleic acid is composed of RNA, not DNA. The level of HBV RNA virion in serum may be associated with risk of HBV viral rebound after withdrawal of treatment, and therefore, a potential predictive biomarker to monitor the safe discontinuation of nucleot(s)ide analogues-therapy.

Nationwide survey of specialist knowledge on current standard of care (Peg-IFN/RBV) and barriers of care in chronic hepatitis C patients in China.

BACKGROUND AND AIM: Chronic hepatitis C virus (HCV) infection is the leading cause of liver diseases including cirrhosis and hepatocellular carcinoma. In China, it is a major national health problem that demands nationwide coordinated emphasis on prevention and treatment. To inform these initiatives, a nationwide survey was conducted from January to April 2015 to evaluate the knowledge, awareness, and perceived obstacles to HCV care. METHODS: A sample of 1000 HCV specialists across mainland China were recruited. Respondents were asked a series of 30 open-ended single or multiple response and Likert-scale questions about their HCV treatment knowledge, experience, assessment of HCV care status in China, and perceptions about treatment barriers. RESULTS: Sixty percent of the respondents answered incorrectly to more than half of the questions on basic HCV treatment principles. Over half of them incorrectly believed that maintenance therapy should be prescribed for non-responders (72%) and longer treatment duration improved sustained viral response rates (62%), regardless of HCV RNA level changes. Sixty-six percent of them believed that HCV treatment would still be interferon-based therapy in the next 5 years in China. Patient-related barriers, in particular lack of disease awareness, were considered to be the most significant barriers to HCV care. Payer and medical-provider barriers included affordability issues, lack of reimbursement coverage for testing and treatments, and lack of referral to HCV specialists. CONCLUSIONS: Focused and intense patient and provider education should be carried out to increase awareness. More effective direct-acting antivirals should be made available and affordable in China.

Response-guided peginterferon therapy in hepatitis B e antigen-positive chronic hepatitis B using serum hepatitis B surface antigen levels.

UNLABELLED: On-treatment levels of hepatitis B surface antigen (HBsAg) may predict response to peginterferon (PEG-IFN) therapy in chronic hepatitis B (CHB), but previously proposed prediction rules have shown limited external validity. We analyzed 803 HBeAg-positive patients treated with PEG-IFN in three global studies with available HBsAg measurements. A stopping-rule based on absence of a decline from baseline was compared to a prediction-rule that uses HBsAg levels of <1,500 IU/mL and >20,000 IU/mL to identify patients with high and low probabilities of response. Patients with an HBsAg level <1,500 IU/mL at week 12 achieved response (HBeAg loss with HBV DNA <2,000 IU/mL at 6 months posttreatment) in 45%. At week 12, patients without a decline in HBsAg achieved a response in 14%, compared to only 6% of patients with HBsAg >20,000 IU/mL, but performance varied across HBV genotype. In patients treated with PEG-IFN monotherapy (n = 465), response rates were low in patients with genotypes A or D if there was no decline of HBsAg by week 12 (negative predictive value [NPV]: 97%-100%), and in patients with genotypes B or C if HBsAg at week 12 was >20,000 IU/mL (NPV: 92%-98%). At week 24, nearly all patients with HBsAg >20,000 IU/mL failed to achieve a response, irrespective of HBV genotype (NPV for response and HBsAg loss 99% and 100%). CONCLUSION: HBsAg is a strong predictor of response to PEG-IFN in HBeAg-positive CHB. HBV genotype-specific stopping-rules may be considered at week 12, but treatment discontinuation is indicated in all patients with HBsAg >20,000 IU/mL at week 24, irrespective of HBV genotype.

Hepatitis B surface antigen quantification: why and how to use it in 2011 - a core group report.

Quantitative HBsAg had been suggested to be helpful in management of HBV, but assays were cumbersome. The recent availability of commercial quantitative assays has restarted the interest in quantitative serum hepatitis B surface antigen (HBsAg) as a biomarker for prognosis and treatment response in chronic hepatitis B. HBsAg level reflects the transcriptional activity of cccDNA rather than the absolute amount of cccDNA copies. Serum HBsAg level tends to be higher in hepatitis B e antigen (HBeAg)-positive than HBeAg-negative patients. Among patients with a low HBV DNA (<2000IU/ml), HBsAg <1000IU/ml in genotype D HBV infection and HBsAg <100IU/ml in genotype B/C HBV infection is associated with inactive carrier state in HBeAg-negative patients. The HBsAg reduction by nucleos(t)ide analogues (NA) is not as pronounced as by interferon treatment. On peginterferon treatment, sustained responders tend to show greater HBsAg decline than the non-responders. The optimal on-treatment HBsAg cutoff to predict response needs further evaluation in HBeAg-positive patients, but an absence of HBsAg decline together with a <2 log reduction in HBV DNA at week 12 can serve as stopping rule in HBeAg-negative patients with genotype D HBV infection. A rapid serum HBsAg decline during NA therapy may identify patients who will clear HBsAg in the long-term. There are early reports among Asian patients that an HBsAg level of <100IU/ml might predict lower risk of relapse after stopping NA treatment. In clinical practice, serum HBsAg level should be used together with, but not as a substitute for, HBV DNA.

Comparison of fibrosis regression of entecavir alone or combined with pegylated interferon alpha2a in patients with chronic hepatitis B.

BACKGROUND AND AIMS: Antiviral treatment with necleos(t)ide analogues contributes to histological improvement and virologic response in chronic hepatitis B (CHB) patients. However, whether adding pegylated interferon alpha2a (Peg-IFN-α-2a) can help additional clinical benefit, particularly on fibrosis regression was still unknown. METHODS: Chronic hepatitis B patients with pre-treatment biopsy-proven Ishak fibrosis score 2, 3 or 4 were randomly assigned to entecavir (ETV) alone or ETV plus Peg-IFN-α-2a (Peg-IFN-α-2a add-on) group (1:2 ratio). Post-treatment liver biopsy was performed at week 78. Fibrosis regression was defined as decrease in Ishak fibrosis score by ≥ 1 stage or predominantly regressive categorized by P-I-R score. Serum HBV DNA levels were assessed at baseline and every 26 weeks, while HBsAg and HBeAg were evaluated at baseline and every 52 weeks. RESULTS: A total of 218 treatment-naive CHB patients were randomly assigned to ETV alone or Peg-IFN-α-2a add-on group. Totals of 155 patients (ETV alone: Peg-IFN-α-2a add-on, 47:108) were included in statistical analysis. Fibrosis regression rates were 68% (32/47) in the ETV alone and 56% (60/108) in Peg-IFN-α-2a add-on group (p = 0.144). Both groups showed a similar trend of virological suppression during the process of 104-week antiviral therapy (p = 0.132). HBeAg or HBsAg loss or seroconversion rates in the ETV alone group were lower than Peg-IFN-α-2a add-on group though without statistical significance. CONCLUSIONS: Peg-IFN-α-2a add-on therapy did not yield additional fibrosis regression and virologic response than ETV alone therapy.

A missense variant in complement factor B (CFB) is a potential predictor of 24-week off-treatment response to PegIFNα therapy in Chinese HBeAg-positive chronic hepatitis B patients.

BACKGROUND: To date, 14 single-nucleotide polymorphisms (SNPs) have been identified as susceptibility loci for chronic hepatitis B (CHB). AIM: To investigate if these SNPs are associated with treatment response of hepatitis B e antigen (HBeAg)-positive CHB patients. METHODS: We performed a retrospective analysis of 1623 Han Chinese HBeAg-positive CHB patients (782 patients treated with pegylated interferon alpha [PegIFNα] for 48 weeks plus 24 weeks follow-up, and 841 patients treated with nucleos(t)ide analogues [NUCs] for 104 weeks) included in four phase-IV multicentre randomised controlled trials. All 14 SNPs were genotyped for each CHB patient. A polygenic score (PGS) was used to evaluate the cumulative effect of multiple SNPs. The associations of SNPs or PGS with combined response (CR) and hepatitis B s antigen (HBsAg) loss were assessed. RESULTS: We found that rs12614, a missense variant of complement factor B (CFB), was significantly associated with CR in PegIFNα-treated patients, and the CR rate in patients with the rs12614 TT/CT genotype was less than one-third of that in patients with the CC genotype (7.4% vs 22.6%, P = 0.009). Moreover, a PGS integrating CFB rs12614 and STAT4 rs7574865 (previously reported to be associated with response to PegIFNα) was significantly associated with both CR (P-trend = 4.000 × 10-4 ) and HBsAg loss (P-trend = 0.010) in PegIFNα-treated patients. However, none of the SNPs were associated with treatment response in NUCs-treated patients. CONCLUSIONS: CFB rs12614 is an independent predictor of response to PegIFNα therapy in Chinese HBeAg-positive CHB patients. A PGS integrating CFB rs12614 with STAT4 rs7574865 can effectively discriminate responders to PegIFNα from nonresponders.

Comparing the safety, tolerability and quality of life in patients with chronic hepatitis B vs chronic hepatitis C treated with peginterferon alpha-2a.

BACKGROUND/AIMS: Hepatitis B and C viruses (HBV and HCV) are two clinically distinct but related diseases. Pooled data from five studies of peginterferon alpha-2a in patients with chronic HCV infection (CHC) were compared with two studies of the drug in patients with chronic HBV infection (CHB). METHOD: The HBV studies included both hepatitis B e antigen (HBeAg)-positive (n=271) and HBeAg-negative (n=177) patients; 791 patients took part in the HCV trials. In all studies, patients were treated with 180 microg peginterferon alpha-2a monotherapy once weekly for 48 weeks. The number of adverse events (AEs), discontinuations and dose modifications were documented. Health-related quality of life (HRQL) was assessed using the Short-Form 36 questionnaire. Safety was assessed throughout the treatment period. A 24-week treatment-free follow-up period was also included. RESULTS: Differences (HBV vs HCV) were observed in the incidence of AEs (88-89 vs 96-100%), serious AEs (4-5 vs 7-16%) and treatment withdrawals (6-8 vs 17-33%). The frequency of depression-related events was lower in CHB patients (4 vs 22%, P<0.001), as was the impact of treatment on HRQL. CONCLUSIONS: The safety and tolerability of peginterferon alpha-2a in patients with CHB compares favourably with that observed in CHC patients, with a lower incidence of common interferon-related AEs and a significantly lower incidence of depression.

No association between IFNL3 (IL28B) genotype and response to peginterferon alfa-2a in HBeAg-positive or -negative chronic hepatitis B.

BACKGROUND & AIMS: It has yet to be firmly established whether host IFNL3 (IL28B) genotype influences interferon responsiveness in patients with chronic hepatitis B. We investigated associations between single-nucleotide polymorphisms (SNPs) in the IFNL3 region and response to peginterferon alfa-2a in 701 patients enrolled in three large, randomized, international studies. METHODS: Responses were defined as hepatitis B surface antigen (HBsAg) loss and/or hepatitis B e antigen (HBeAg) seroconversion plus hepatitis B virus (HBV) DNA <2000 IU/ml in HBeAg-positive patients, and HBsAg loss and/or HBV DNA <2000 IU/ml in HBeAg-negative patients (24 weeks after end of treatment). Associations between treatment response and the number of copies of the poor-response allele at three SNPs (rs8099917, rs12980275, rs12979860) were explored with logistic regression models in Asian and white patients. RESULTS: The HBeAg-positive and -negative populations comprised 465 (92% Asian, 50% HBV genotype C) and 236 (79% Asian, 41% HBV genotype C) patients, respectively, and had respective response rates of 26% and 47%. The IFNL3 genotype was strongly associated with ethnicity. There was no association between IFNL3 genotype and treatment response in HBeAg-positive or -negative patients. Independent predictors of treatment response were: sex, HBV DNA level and alanine aminotransferase level in HBeAg-positive Asian patients; age in HBeAg-negative Asian patients; and HBV DNA in HBeAg-negative white patients. CONCLUSIONS: This is the largest analysis to date of associations between IFNL3 genotype and peginterferon response in patients with chronic hepatitis B. The data suggest that IFNL3 polymorphism is not a major determinant of the response to peginterferon alfa-2a in either HBeAg-positive or HBeAg-negative patients.

[Factors associated with HBeAg seroconversion in chronic hepatitis B patients treated with interferon alfa-2a].

OBJECTIVE: The aim of this paper was to investigate the factors associated with viral response and HBeAg seroconversion and the relationship between them at different stages of interferon treatment in HBeAg-positive chronic hepatitis B patients. METHODS: PEG-IFN alfa-2a was injected subcutaneously in doses of 180 microg once a week for 48 weeks to HBeAg-positive chronic hepatitis B patients, and the patients were followed for another 24 weeks after the treatment. The serum HBV DNA load was measured by real-time quantitative PCR assay. Microparticle enzyme immunoassay analysis (MEIA) was then carried out by an automatic enzyme immunoassay analysis instrument to measure HBeAg and anti-HBe. Virological response and HBeAg seroconversion rates, and the factors associated with them were analyzed. RESULTS: The differences in ALT baselines between viral responding and non-responding groups were significant at treatment time and at the end of the follow-up period. These differences were also significant in patients with HBeAg seroconversion at 12 weeks and at the end of the follow-up period compared with the non-conversion group. No significant difference of HBV DNA baseline was observed between the HBeAg seroconversion and non-conversion group. At 12, 24 and 48 weeks, in patients with viral response during the treatment, their HBeAg seroconversion rates were 43.8%, 21.4% and 18.9% respectively; their respective HBeAg seroconversion rates remaining at 72 weeks were 42.9%, 33.3% and 27.6%. HBeAg seroconversion was related to HBV DNA negativity at 48 weeks treatment in the multivariate analysis (OR=2.15, 95.0% CI=1.744-2.664, P less than 0.01). CONCLUSIONS: Viral response and early and sustained HBeAg seroconversion were associated with pretreatment ALT levels. HBeAg seroconversion was related to viral response during IFN treatment, but not to the baseline HBV DNA load.

[Retreatment with interferon of relapsed chronic hepatitis C patients].

OBJECTIVE: To evaluate the efficacy and investigate the influencing factors of the interferon (IFN) retreatment for patients with chronic hepatitis C relapsed after a previous IFN treatment. METHODS: A retrospective study was designed to analyze the retreatment with IFN of 60 relapsed chronic hepatitis C patients. All patients were from a randomized, opened and multi-center clinical trial about the efficacy and security of PEG-IFNalpha-2a compared to CIFNalpha-2a in the treatment of chronic hepatitis C in China. There were 35 patients treated with PEG-IFNalpha-2a and 25 with CIFNalpha-2a. The main parameter to evaluate the efficacy was sustained viral response (SVR) rate. The influence of viral concentration in serum, genotype and drug categories on the responses to IFN were analyzed. RESULTS: For all the patients, the end of treatment virus response (ETVR) and SVR rates were 55.00% and 35.00% respectively. ETVR rate of PEG-IFNalpha-2a was significantly higher than that of CIFNalpha-2a (74.29% and 28.00% respectively, P < 0.01). SVR rate of PEG-IFNalpha-2a was also markedly higher than that of CIFNalpha-2a (45.71% and 20.00% respectively, P < 0.05). However, there was no significant difference between the high and low viral load groups. Among the patients with genotype 1, ETVR and SVR rates of PEG-IFNalpha-2a (75.00%, 45.83%) were significantly higher than those of CIFNalpha-2a (22.22%, 11.11%), (P < 0.01, P < 0.05 respectively), but in patients with genotype non-1, there were no such differences between the two groups. CONCLUSION: Some relapsed patients were not responsive to the IFN retreatment. The efficacy of PEG-IFNalpha-2a was superior to CIFNalpha-2a. The conventional IFN was not suggested to be used in the relapsed cases with genotype 1. The viral load was not associated with the efficacy of IFN retreatment.

Predictive factors for sustained response to interferon treatment in patients with chronic hepatitis C: a randomized, open, and multi-center controlled trial.

BACKGROUND: This study was undertaken to investigate the predictive factors of sustained viral response in roferon-A or pegasys treated chronic hepatitis C patients after logistic regression analysis of the factors that might be associated with the therapeutic effects of interferon (IFN). METHODS: All patients enrolled into this randomized, open and multi-center controlled trial were divided into two groups randomly and treated with pegasys and roferon-A for 24 weeks, then followed up for another 24 weeks. Before treatment, hepatitis C virus (HCV) genotype was determined, and HCV-RNA in serum was detected before and at the end of treatment and follow-up. HCV-RNA turning negative was considered the major index for evaluating the therapeutic effect. The clinical characteristics including gender, age, infection route of HCV, treatment with IFN, platelet count, AST/ALT ratio and treatment drugs were analyzed by logistic regression. RESULTS: Intention to treat (ITT) and per-protocol (PP) population groups have 208 and 197 patients respectively. In the PP group, after treatment for 24 weeks, the response rates of female patients aged less than 50 years, infected through non-transfusion, relapsed after IFN treatment, and presented with a AST/ALT ratio/=1, virus load equal or more than 8 x 10(5) IU/ml, and genotype 1 infection, and treated finally with roferon-A. But, at the end of follow-up, the patients with a AST/ALT ratio>/=1 and virus load more than 8 x 10(5) IU/ml had a higher rate of sustained response than did those with a AST/ALT ratio

Impact of virus genotype on interferon treatment of patients with chronic hepatitis C: a multicenter controlled study.

BACKGROUND: Some factors have been reported to be associated with a greater likelihood of sustained viral response (SVR) in the interferon (IFN) treatment of chronic hepatitis C. The factors include HCV genotype, HCV RNA level in serum, state of liver disease, baseline body weight, age, sex, and race. The aim of this trial was to investigate the influence of HCV genotype on the IFN treatment of patients with chronic hepatitis C. METHODS: The genotypes of HCV virus were determined in the patients with chronic hepatitis C from several hospitals of China enrolled into the randomized, opened and controlled trial of Peg-IFN alpha-2a (pegasys) treatment, controlled with IFN-alpha-2a (roferon-A). The serum ALT levels and HCV RNA concentrations of the patients were detected before and at the end of treatment and during the follow-up. The influence of HCV genotype on the IFN treatment of patients with chronic hepatitis C was analyzed in intention-to-treat (ITT) population. RESULTS: The HCV genotypes of 202 patients were determined. Of these patients, 158(78.22%) were infected with genotype 1 HCV and 44(21.78%) with genotype non-1. The viral response at the end of treatment (ETVR) and sustained viral response (SVR) rates were 53.80% and 25.32% respectively in patients with genotype 1 HCV, but they were 61.36% and 43.18% in patients with genotype non-1. The difference of SVR between patients with genotype 1 HCV and those with genotype non-1 was significant (P=0.021). After being grouped by the used drugs, the ETVR rates of patients infected with genotype 1 and non-1 HCV were 76.83% and 80.95% in the patients treated with pegasys (P=0.686); but their SVR rates were 35.37% and 66.67% (P=0.01). The viral relapse rate of genotype 1 HCV (55.56%) was significantly higher than that of genotype non-1 HCV (23.53%) (P=0.02). In roferon-A group, the ETVR and SVR rates of patients with genotype 1 HCV were 28.95% and 14.47% respectively, which were lower but not more significant than those of patients with genotype non-1 HCV (43.48% and 21.74%). Moreover, the viral relapse rate of genotype 1 HCV (72.73%) was higher but not more significant than that of genotype non-1 HCV (50.00%) (P=0.21). CONCLUSION: HCV genotype could affect the efficacies, mainly sustained responses, of IFN treatment in patients with chronic hepatitis C, and the effects of IFN are related to drugs and therapeutic course.

[The pegasys using and HCV genotype were the independent predictors of the response to antiviral therapy in chronic hepatitis C].

OBJECTIVE: To investigate the predictors of IFN therapy in patients with chronic hepatitis C through making the multivariate logistic regression analysis. METHODS: The patients in the opened, randomized and controlled trial were enrolled into two group, pegasys and Roferon-A group, and were given 24 weeks of pegasys (injection of 180 microg a week), and Roferon-A (injection three times of Roferon-A 3 MU a week) therapy, and followed 24 weeks. The HCV RNA content was determined at the time before, end of treatment and at the followed-up. The association of the response to the treatment with the clinical characteristics including age, gender, way of HCV infection, history of IFN treatment, planet count, AST/ALT ratio, HCV RNA level, HCV genotype and treatment drugs was made trough multivariate logistic regression analysis. RESULTS: The PP population containing 197 cases was analyzed. After controlling for age, gender, way of HCV infection, history of IFN treatment, planet count, AST/ALT ratio, HCV RNA level and treatment, the HCV genotype was not predictor of the end of treatment viral response (ETVR) to IFN therapy (OR 0.604, 95% CI 0.271-1.349, P = 0.219), but was the independent predictor of sustained viral response (SVR) (OR 0.408, 95% CI 0.189-0.881, P = 0.023). After controlling for other characteristics, the treatment drug was the predictors of ETVR (OR 0.105, 95% CI 0.052-0.212, P < 0.001) and SVR (OR 0.255, 95% CI 0.123-0.529, P < 0.001). CONCLUSION: The pegasys using and HCV genotype were the independent predictors of the response to antiviral therapy in chronic hepatitis C.

[The influence of HCV genotype on the IFN treatment of patients with chronic hepatitis C].

OBJECTIVE: To investigate the influence of HCV genotype on the IFN treatment of patients with chronic hepatitis C. METHODS: The genotypes of HCV virus were determined in the patients enrolled into the Randomized, opened and controlled trial of Peg-IFN alpha-2a (Pegasys) treatment, controlled with IFN-alpha-2a (Roferon-A), on chronic hepatitis C patients in China. The serum ALT levels and HCV RNA concentration of the patients were detected in the time of before treatment, the end of therapy and follow-up. The influence of HCV genotype on the IFN treatment of patients with chronic hepatitis C was analyzed in intention to treat (ITT) population. RESULTS: The HCV genotypes of 202 cases were determined. 158 (78.2%) cases infected with genotype 1 HCV and 44 (21.8%) cases with genotype non-1. For overall patients, the viral response at the end of treatment (ETVR) and sustained viral response (SVR) rates were 53.8% and 25.3% respectively in patients with genotype 1 HCV, but in genotype non-1 patients those was 61.4% and 43.2%, and the difference of SVR between genotype 1 and non-1 was significant (P=0.021). After grouped by the used drugs, in the patients given Pegasys treatment, the ETVR rates of patients with genotype 1 and non-1 HCV infection were 76.8% and 81.0%, the difference was not significant (P=0.686), but the difference of SVR rates, which were 35.4% and 66.7%, of the patients was significant (P=0.01). The viral relapse rate of genotype 1 was 55.6%; it was significant higher than that of genotype non-1 (23.5%) (P=0.02). In Roferon-A group, the ETVR and SVR rates of patients with genotype 1 HCV were 29.0% and 14.5%, which were lower, but not significant, than those of patients with genotype non-1 (43.5% and 21.7%). The viral relapse rate of genotype 1 was 72.7% and higher, but not significant, than that of genotype non-1 also (50.0%) (P=0.21). CONCLUSION: HCV genotype could affects the efficacies, mainly the sustained responses, of IFN treatment of patients with chronic hepatitis C, and the effects of IFN were related to the kinds of drugs and therapeutic course.

Increasing newly diagnosed rate and changing risk factors of HCV in Yanbian Prefecture, a high endemic area in China.

BACKGROUND: The newly diagnosed rate of HCV infection is increasing in China. However, the risk factors have not been fully identified. Here, a survey was performed in Yanbian Prefecture, a high-endemic area in China. METHODS: We identified newly diagnosed HCV infection in 2007-2011, using the local National Disease Supervision Information Management System from the Chinese Center for Disease Control and Prevention. We determined the risk factors using a case-control survey by questionnaire. RESULTS: Yanbian Prefecture had a rapid increase in the yearly newly diagnosed rate of HCV infection from 32.6 to 72.1/100.000 from the year 2007 to 2011. People aged 50-64 years had a high HCV infection of 43.4%, but only 0.3% of cases were reported in those aged less than 20 years. Cosmetic treatment, family history, blood transfusion, and dental treatment were independent risk factors for HCV infection. Unexpectedly, cosmetic treatments [odd ratio (OR) = 5.15, 95% confidence interval (CI) = 2.31-11.48, P = 0.00] and family history (OR = 4.68, 95% CI = 2.67-8.75, P = 0.00) showed a higher risk than the conventional risk factors of blood transfusion (OR = 4.49, 95% CI = 1.95-10.37, P = 0.001) and dental treatment (OR = 2.98, 95% CI = 1.42-6.25, P = 0.00). To further analyze the intrafamilial transmission, we found that spouses of HCV patients had an increased risk for acquiring HCV (OR = 5.75, 95% CI: 1.94-17.07), without significant association between either HCV RNA viral load (P = 0.29) or genotype (P = 0.43). CONCLUSIONS: HCV infection was increased in Yanbian Prefecture. Cosmetic treatment was a higher risk factor than medical procedure. HCV infection had a clear family clustering phenomenon, especially between spouses.

Management of adverse effects of Peg-IFN and ribavirin therapy for hepatitis C.

HCV infects approximately 2-3% of the global population and is a leading cause of end-stage liver disease and hepatocellular carcinoma. Treatment of HCV infection with Peg-IFN in combination with ribavirin can eradicate HCV infection in 40-90% of patients; however, a major barrier to treatment uptake and delivery is the association of this therapy with frequent and, at times, serious adverse effects. Recognition and effective management of these adverse effects are critical components of the successful treatment of chronic HCV infection. In clinical trials, approximately 10-15% of patients discontinue Peg-IFN and ribavirin therapy due to adverse effects; however, in clinical practice, the rate of treatment discontinuation has been reported to be substantially higher. The off-target effect of Peg-IFN and ribavirin impacts most, if not all, organ systems; the most common adverse effects are hematologic, dermatologic, neurologic, immunologic, gastrointestinal, pulmonary, cardiovascular, and ocular. Regional and global variability exists in the nature of these adverse effects and the strategies employed to ameliorate their impact. This article provides a comprehensive literature review that systematically describes the adverse effects of Peg-IFN-α and ribavirin on various organ systems and, more importantly, recommends consensus approaches to managing those effects.