Mutagenic effects of ribavirin and response to interferon/ribavirin combination therapy in chronic hepatitis C

BACKGROUND/AIMS: To elucidate whether ribavirin acts as a mutagen in the clinical setting and to clarify the relationship between ribavirin-induced mutations and virological response to combined therapy. METHODS: Thirty-four patients with hepatitis C virus (HCV) genotype 1b received ribavirin monotherapy for 4 weeks, followed by a 24-week course of IFN/ribavirin therapy. HCV mutations during a non-treatment observation period and during subsequent ribavirin monotherapy were determined, and the relationship between mutations and response to subsequent IFN/ribavirin therapy was evaluated. RESULTS: Serum HCV significantly decreased from 6.90 to 6.56 log10copy/ml in response to ribavirin monotherapy (P < 0.0001). Nucleotide mutations in the NS5A and NS5B regions occurred during ribavirin monotherapy at a rate of 2.9 x 10(-2)/site/year and 1.3 x 10(-2)/site/year, respectively, a significantly higher rate than the mutation rates during the prior non-treatment observation period (0.60 x 10(-2)/site/year and 0.24 x 10(-2)/site/year, P = 0.02, respectively). Mutation rates in the NS5A region were significantly higher in sustained viral responders (SVRs, n = 10) than in non-responders (8.8 x 10(-2)/site/year vs. 0.38 x 10(-2)/site/year, P = 0.0005, respectively). In the NS5A region, non-synonymous mutations only occurred in SVRs. CONCLUSIONS: Ribavirin may act as a mutagen, and mutations occurring during ribavirin therapy correlate with the virological response to subsequent IFN/ribavirin combination therapy.     

Mutagenic effect of ribavirin on hepatitis C nonstructural 5B quasispecies in vitro and during antiviral therapy

BACKGROUND AND AIMS: Addition of ribavirin to interferon alfa treatment has substantially increased sustained virologic response rates in patients with chronic hepatitis C (CHC). Ribavirin acts as an RNA virus mutagen in vitro, thereby leading to error catastrophe. However, data in CHC are controversial. METHODS: The nonstructural (NS) 5B quasi-species heterogeneity was analyzed in Huh7 cells harboring a subgenomic hepatitis C virus (HCV) replicon system treated with ribavirin or levovirin. Accordingly, NS5B quasi-species were studied in 14 patients with CHC who received ribavirin alone or combined with pegylated interferon alfa both at baseline and during the first weeks of therapy. Analysis of NS3 quasi-species served as control. RESULTS: Cultivation of HCV replicon cells with ribavirin led to higher NS5B mutational frequencies compared with levovirin-treated or untreated cells (P < .05). Patients receiving ribavirin monotherapy showed higher overall mutational frequencies within NS3 and NS5B during therapy as compared with baseline (P < .01). Proportions of ribavirin-specific G-to-A and C-to-T transitions increased (P < .01). Paired analysis confirmed significant mean increases of mutational frequencies of approximately 5%. Ribavirin serum concentrations were positively correlated with mutational frequency changes (P < .05). In patients receiving combination therapy, a decrease of NS5B mutational frequencies ( approximately 10%) and lower proportions of G-to-A and T-to-C mutations (P < .01) were detectable. CONCLUSIONS: Ribavirin, but not its L-enantiomer levovirin, is a mutagen in HCV replicon cells. In patients with CHC, ribavirin monotherapy exhibits a moderate mutagenic effect early during therapy that is not detectable in combination with pegylated interferon alfa.     

扶正解毒方联合标准方案治疗基因1型慢性丙型肝炎的前瞻性研究

目的探索我国基因1型慢性丙型肝炎(chronic hepatitis C,CHC)中西医结合治疗方案的临床疗效。方法给予我国汉族初治基因1型CHC患者中西医结合治疗,进行多中心、大样本、随机、双盲、安慰剂对照的前瞻性研究。研究分为治疗组[聚乙二醇干扰素(pegylated interferon,Peg-IFN)α-2a┼利巴韦林(ribavirin,RBV)┼扶正解毒方]和对照组(Peg-IFNα-2a┼RBV┼中药安慰剂),治疗48周,本文分析治疗至第24周时的数据。结果研究共纳入我国汉族基因1型初治CHC患者352例(治疗组178例,对照组174例)。治疗组和对照组分别有88.0%和81.1%的患者获得完全早期病毒学应答。治疗第24周时,治疗组和对照组HCV RNA阴转率分别为88.2%和83.0%。2组比较,差异均无统计学意义。最多见的不良反应为流感样症状、白细胞或血小板减少。无患者因不良反应而脱失,无严重不良反应发生。结论中西医结合治疗方案一定程度上可提高基因1型CHC患者的HCV RNA阴转率。     

Early hepatitis C virus changes and sustained response in patients with chronic hepatitis C treated with peginterferon alpha-2b and ribavirin.

BACKGROUND: Interferon-based therapy induces changes in viral dynamics in chronic hepatitis C (CHC) patients. AIMS: The aim of this study was to assess early hepatitis C virus (HCV)-RNA changes and evaluate its predictive value to achieve sustained viral response (SVR) in patients with CHC treated with peginterferon alpha-2b weekly plus ribavirin daily for 48 weeks. METHODS: HCV-RNA was measured at baseline, 48 h, 4, 12, 24 and 48 weeks of treatment and 24 weeks after treatment. RESULTS: Eighteen HCV genotype 1 patients were included (13 male, five female) with a mean age of 44.4+/-11.9 years. Nine patients achieved SVR (50%). Viral decline occurred as early as 48 h; the magnitude of decline was statistically different between both groups (P<0.01). Responders had a > or =1 log(10) drop in HCV-RNA at 48 h (positive predictive value (PPV) of 89% to achieve SVR) that persisted at week 4. By week 12, serum HCV-RNA was undetectable (PPV 100%). CONCLUSIONS: Our data indicate that peginterferon alpha-2b plus ribavirin treatment produces significant changes in HCV dynamics that can be detected as early as 48 h after the first dose of peginterferon alpha-2b and that these changes are useful in predicting response to therapy in CHC patients.     

抗病毒治疗对慢性丙型肝炎患者HCV NS特异性T细胞应答的影响

目的探讨HCV特异性T细胞应答与慢性丙型肝炎(chronic hepatitis C,CHC)患者抗病毒治疗疗效之间的关系.方法聚乙二醇干扰素α联合利巴韦林治疗CHC患者48例,在治疗前及治疗第4周、第12周时收集患者血清和外周血单个核细胞,通过酶联免疫斑点法检测对HCV非结构蛋白(non-structural protein,NS)区合成肽的特异性T细胞应答,进行纵向比较分析.结果基线时,52%的患者可检测出HCV NS3、NS4和NS5A特异性T细胞应答,其中NS3诱导的免疫反应最强.持续病毒学应答(sustained virological response,SVR)组患者较非SVR组患者对多肽刺激的应答率高.SVR组患者在治疗第12周时仍维持较高水平的HCV特异性T细胞应答,而非SVR组患者在治疗第4周时HCV特异性T细胞应答明显下降,第12周时仅维持低水平.结论在接受抗病毒治疗的CHC患者中,HCV特异性T细胞应答与SVR相关.     

冷球蛋白血症对丙型肝炎患者病毒学应答的影响

目的 探讨在应用聚乙二醇干扰素α-2a联合利巴韦林抗病毒治疗的慢性丙型肝炎(CHC)患者中,冷球蛋白血症对抗病毒治疗效果的影响. 方法 40例接受聚乙二醇干扰素α-2a联合利巴韦林抗病毒治疗的CHC患者进入研究,检测HCV基因型与基线、用药后4周、12周及治疗结束后24周患者血清HCV RNA水平,并检测基线患者血清中的冷球蛋白.连续型变量用独立样本t检验或秩和检验,分类资料用x2检验或Fisher' s精确概率法,对抗病毒治疗效果相关影响因素的分析用多元logistic回归分析.结果 治疗4周后快速病毒学应答发生率在冷球蛋白阳性患者(6/18,33.3％)低于阴性患者(15/22,68.2％,P=0.028).冷球蛋白阳性患者的持续病毒学应答发生率也低于阴性患者(0对比6/6,P=0.012).结论 冷球蛋白阳性的CHC患者快速病毒学及持续病毒学应答疗效低于冷球蛋白阴性的CHC患者.     

Efficacy of interferon alpha-2b induction therapy before retreatment for chronic hepatitis C.

BACKGROUND/AIMS: Chronic hepatitis C (HCV) patients who have failed previous treatment have low sustained viral response (SVR) rates with repeat treatment. We evaluated whether interferon (IFN) induction during retreatment improves response rates. METHODS: Two randomized, controlled trials were conducted in chronic HCV patients who failed IFN. In Study 1, patients received IFN 3 MU daily plus ribavirin (RBV) 1000 mg/day for 4 weeks, followed by IFN 3 MU TIW plus RBV 1000 mg/day for 44 weeks (induction; n=232), or IFN 3 MU TIW plus RBV 1000 mg/day for 48 weeks (non-induction; n=237). In Study 2, patients received IFN 5 MU B.I.D. plus RBV 1000-1200 mg/day for 2 weeks, followed by pegylated IFN (PEG-IFN) 75-150 mug weekly plus RBV 1000-1200 mg/day for 46 weeks (induction; n=201), or PEG-IFN 75-150 mug weekly plus RBV 1000-1200 mg/day for 48 weeks (non-induction; n=206). The primary end point for both trials was SVR. RESULTS: Induction did not increase SVR compared with non-induction, but did increase the on-treatment response among genotype non-1 patients in Study 2. By intention-to-treat (ITT) analysis, SVR in Study 1 was 13% for induction vs. 9% for non-induction (P=NS). In Study 2 (ITT), SVR was 20% for induction vs. 24% for non-induction (P=NS). However, by non-ITT analysis of Study 2, genotype non-1-previous non-responders showed significantly higher response rates with induction than non-induction. CONCLUSION: For chronic HCV patients who have failed IFN, induction with retreatment does not improve SVR, but may be beneficial for patients with genotype non-1 HCV.     

Association of IL28B gene variations with mathematical modeling of viral kinetics in chronic hepatitis C patients with IFN plus ribavirin therapy

Asian patients with chronic hepatitis C (CHC) are known to have better virological responses to pegylated (Peg) IFN-based therapy than Western patients. Although IL28B gene polymorphisms may contribute to this difference, whether favorable hepatitis C virus (HCV) kinetics during treatment plays a role remains unclear. We enrolled 145 consecutive Taiwanese patients with CHC receiving Peg-IFN α-2a plus ribavirin for the study. Blood samples were taken more frequently at defined intervals in the first 3 d. Peg-IFN was administered at week 1. It was then administered weekly in combination with daily ribavirin for 24 or 48 wk. A mathematical model fitted to the observed HCV kinetics was constructed, which could interpret the transient HCV titer elevation after Peg-IFN treatment. The results demonstrated a comparable viral clearance rate (c = 3.45 ± 3.73) (day(-1), mean ± SD) but lower daily viral production rate (P = 10(6)-10(12)) in our patients than those reported previously in Western patients. Of 110 patients with a sustained virological response (SVR), 47 (43%) had a transient elevation of viral titer within 12 h (proportion of 12 h/3 d: 44% in non-SVR vs. 70% in SVR; P = 0.029). Among 91 patients with available rs8099917 data, patients with the TT genotype had an early surge of viral titer after therapy and a higher SVR and viral clearance rate than those with the GT genotype. In conclusion, Taiwanese patients with CHC receiving Peg-IFN plus ribavirin therapy have a lower daily viral production rate than Western patients, and the rs8099917 TT genotype may contribute to the increased viral clearance rate and better virological responses in these patients.     

A health economic model to assess the long term effects and cost-effectiveness of PEG IFN alpha-2a in hepatitis C virus infected patients

OBJECTIVES: Chronic Hepatitis C (CHC) is associated with long-term complications. Treating CHC with Pegylated interferon alpha-2a (PEG IFN alpha-2a) improves response rates and may contribute to less morbidity and mortality compared to standard interferon therapy. The objectives of this study were to estimate the long-term clinical consequences of such treatment as well as the resulting cost-effectiveness. RESEARCH DESIGN AND METHODS: A Markov model was developed in order to predict the clinical and economic outcomes over a 25 year period. Three analyses were conducted: 1. for all Hepatitis C Virus (HCV) genotypes where PEG IFN alpha-2a was compared to interferon alpha-2a (IFN alpha-2a) in monotherapy for 48 weeks; 2. for the HCV genotypes 1-4-5-6 comparing PEG IFN alpha-2a with interferon alpha-2b (IFN alpha-2b) both combined with ribavirin 1000/1200 mg for 48 weeks; and 3, where PEG IFN alpha-2a with 800 mg ribavirin was compared to IFN alpha-2b with ribavirin 1000/1200 mg for 24 weeks in genotypes 2 and 3. RESULTS: In analysis one the cost-effectiveness of PEG IFN alpha-2a is 4,569/quality adjusted life year (QALY) gained. In the second analysis, the result was 14,763 euros/QALY, while for the 24 weeks therapy (analysis 3) the result was 903 per QALY gained. In an extensive sensitivity analysis cost-effectiveness was confirmed within reasonable assumptions. CONCLUSIONS: These results suggest that PEG IFN alpha-2a is cost-effective in the management of all CHC patients. Real life evidence about longer term benefits of PEG IFN alpha-2a will be of importance for future decision making.     

Y型聚乙二醇干扰素α-2b注射液治疗HCV基因2/3型慢性丙型肝炎患者疗效和安全性的多中心随机对照试验研究*

目的 以标准剂量的聚乙二醇干扰素（PegIFN）α-2a联合利巴韦林作为阳性对照,评价新型试验药物Y型PegIFNα-2b注射液联合利巴韦林治疗2型/3型慢性丙型肝炎（CHC）患者的疗效和安全性。方法 采用多中心、随机开放、阳性药对照的Ⅲ期临床试验,筛选符合要求的2型/3型CHC患者,按照2:1的比例随机分配到Y型PegIFNα-2b组和PegIFNα-2a组,同时口服利巴韦林,疗程24 w,停药随访24 w。采用Abbott RealTime HCV Genotype II检测HCV基因型,采用Cobas TaqMan实时定量PCR法检测血清HCV RNA水平。详细记录不良事件。主要疗效指标为持续病毒学应答（SVR）,并进行非劣效检验。结果 本试验实际入组2型/3型CHC患者255例,实际治疗241例。全分析集（FAS）数据显示,158例试验组和83例对照组患者SVR分别为85.4%（95% CI 79.94%~90.94%）和79.5%（95% CI 70.84%~88.20%,P=0.2402）;对符合方案分析集（PPS）人群分析显示,试验组和对照组患者SVR分别为87.9%（95% CI 82.45%~93.27%）和85.9%（95% CI 77.82%~94.01%,P=0.7060）,率差的95%可置信区间均符合非劣效标准;对PPS人群分析显示,85.8%受试者获得了早期病毒学应答（RVR）,RVR的阳性预测值为90.1%;试验组和对照组不良事件发生率相似,分别为95.6%和95.2%,严重不良事件发生率分别为3.8%和3.6%。结论 应用PegIFNα联合利巴韦林治疗2型/3型CHC患者,新型试验药物Y型PegIFNα-2b具有与对照药物PegIFNα-2a相似的疗效和安全性。     

聚乙二醇干扰素α-2a联合利巴韦林个体化治疗慢性丙型肝炎的疗效

目的 探讨据聚乙二醇干扰素α-2a联合利巴韦林应答情况指导治疗的个体化策略在基因1型HCV感染慢性丙型肝炎患者中的应用效果. 方法 140例基因1型HCV感染慢性丙型肝炎患者注射聚乙二醇干扰素α-2a 180 μg,每周一次;联合利巴韦林800～1200 mg/d.治疗4周达到快速病毒学应答(RVR)患者(定为A组)随机分为两组,分别接受24周治疗(A1组)、48周治疗(A2组);未达到RVR者在12周达到完全早期病毒学应答(cEVR)的患者(B组)再随机分为两组,分别接受48周治疗(B1组)、72周治疗(B2组); 24周延迟病毒学应答(PVR)的患者接受72周治疗(C1组),24周无PVR的患者终止治疗(C2组).治疗停止后随访24周.用荧光定量PCR法检测不同时间点的HCV RNA水平,比较不同疗程组的疗效.计量资料两组间比较采用t检验,计数资料采用x2检验.结果 治疗24周患者的治疗结束时病毒学应答(ETR)率为100%,持续病毒学应答(SVR)率为65.9%,复发率为34.1%;治疗48周患者的ETR率为95.3%,SVR率为82.8%,复发率为12.5%;治疗72周患者的ETR率为82.1%,SVR率为67.9%,复发率为14.3%.A1组、A2组患者的SVR率分别是65.9%和84.4%,差异有统计学意义(P<0.00).A组中HCV RNA<1×106拷贝/ml的患者接受24周和48周疗程的SVR率分别为72.7%和100%,差异无统计学意义(P>0.05); HCV RNA≥1 × 106拷贝/ml的患者接受24周和48周疗程的SVR率分别是63.6%和85.3%,差异有统计学意义(P<0.05).B1组、B2组患者的SVR率分别是78.9%和73.7%,差异无统计学意义(P>0.05).C1组患者的SVR率是55.6%.在治疗期间均无特殊不良事件发生.结论 RVR、cEVR是慢性丙型肝炎应答指导的预测因子.获得RVR者,治疗48周比24周的SVR率高;但获得RVR且基线HCV RNA<2×106拷贝/ml患者,可缩短疗程,接受24周的治疗.未获得RVR而达到cEVR的患者,延长治疗至72周并未提高SVR率.24周延迟应答者,延长疗程至72周可以提高SVR率.     

Ribavirin rather than PEG-interferon pharmacodynamics predict nonresponse to antiviral therapy in naive chronic hepatitis C patients

Twenty to fifty per cent of patients with chronic hepatitis C (CHC) experience nonresponse to current antiviral therapy, which may relate in part to ribavirin or PEG-interferon pharmacodynamics. We evaluated potential relevance of various factors for nonresponse. Two hundred forty-two naive CHC patients who received in a previous trial at least 24 weeks of antiviral therapy, including PEG-interferon alfa-2b and ribavirin, were analysed. Of them, 53% were infected with hepatitis C virus (HCV) genotype 1-4, 71% exhibited high viral load and 32% had severe fibrosis/cirrhosis. After 24 weeks of treatment, 39 patients (16%) were nonresponders. In multivariate analysis, lower serum ribavirin concentrations, HCV genotype 1-4 and higher baseline γ-GT predicted nonresponse. Week-24 ribavirin concentrations (2.2 vs 2.8 mg/L, P < 0.001), average ribavirin doses (14.5 vs 15.2 mg/kg per day, P = 0.03) and week-24 haemoglobin decreases (1.7 vs 2.0 mm, P = 0.02) were lower in nonresponders. Nonresponse rates increased progressively at decreasing ribavirin concentrations: 4%, 11%, 13% and 36% in case of serum ribavirin concentrations ≥4, 3-4, 2-3 and ≤2 mg/L, respectively (P = 0.001). Ribavirin concentrations correlated with both week-24 haemoglobin decreases (r = 0.42, P < 0.001) and ribavirin doses (r = 0.17, P = 0.01). Subgroup analysis in HCV genotype 1-4 patients revealed essentially the same results. Nonresponse was exceptional in HCV genotype 2-3 patients and associated with ribavirin concentrations <2 mg/L. Presumed interferon-related factors (average PEG-interferon doses and decreases in leucocytes, granulocytes, platelets and body weight) did not differ between nonresponders and responders. In conclusion, ribavirin- rather than PEG-interferon-related factors are independent and potentially modifiable predictors of nonresponse in treatment-naive CHC patients.     

Virological response and safety outcomes in therapy-nai ve patients treated for chronic hepatitis C with taribavirin or ribavirin in combination with pegylated interferon alfa-2a: a randomized, phase 2 study

BACKGROUND/AIMS: Pegylated interferon plus ribavirin can cause dose-limiting anemia. Taribavirin, a ribavirin prodrug, has shown a lower incidence of anemia. We sought to determine the efficacy and safety of taribavirin vs. ribavirin combined with pegylated interferon in patients with chronic hepatitis C (CHC). METHODS: This phase 2 open-label study randomized 180 patients with CHC to receive pegylated interferon alfa-2a 180 microg/week plus taribavirin 800, 1200 or 1600 mg QD or ribavirin 1000 or 1200 mg QD. Efficacy variables included proportions of patients with undetectable serum HCV RNA levels at end of treatment and after a 24-week follow-up. RESULTS: The proportions of patients with undetectable HCV RNA at 12 weeks did not differ significantly between taribavirin (38%, 42%, and 49% for the 800, 1200, and 1600 mg groups) and ribavirin (49%). The highest proportion of patients with undetectable HCV RNA at end of treatment and at follow-up occurred in both the taribavirin 1200mg QD (63% and 37%) and ribavirin groups (62% and 44%). SVR rates were 23%, 37% and 29% for taribavirin and 44% for ribavirin. Fewer patients on any dose of taribavirin had severe anemia (hemoglobin <10 g/dL) than on ribavirin (6/135 [4%] vs. 12/45 [27%]). CONCLUSIONS: Given with interferon, taribavirin produced SVR rates comparable to those of ribavirin, with a lower occurrence of anemia.     

Pioglitazone improves virological response to peginterferon α‐2b/ribavirin combination therapy in hepatitis C genotype 4 patients with insulin resistance

Background & aim: Insulin resistance (IR) affects sustained virological response (SVR). The use of insulin‐sensitizing agents has been proposed to improve therapy outcome. The safety and efficacy of pioglitazone on insulin sensitivity and SVR in treatment‐naïve patients with chronic hepatitis C (CHC) genotype 4 with IR receiving standard antiviral therapy were evaluated in a randomized‐controlled study. Methods: Ninety‐seven previously untreated patients with CHC and IR [homeostasis model assessment (HOMA>2)] were randomly assigned into two arms; (arm A; n=48) were given pioglitazone 30 mg/day combined with peginterferon (Peg‐IFN)‐α‐2b/ribavirin (RBV) for 48 weeks, and (arm B; n=49) were given standard of care (Peg‐IFN‐α‐2b/RBV for 48 weeks); HOMA index and hepatitis C virus RNA (HCV RNA) levels were measured at baseline, during therapy and follow‐up. Treatment was stopped in patients without an early virological response or those who were HCV RNA positive at 24 weeks. Results: Baseline data of both groups were comparable, with no significant statistical differences. The percentages of rapid virological response (RVR) and SVR were significantly higher in patients given triple therapy compared with standard of care (27.08 vs. 6.1%; P=0.006 and 60.4 vs. 38.7%; P=0.04 respectively); patients in arm A showed a greater decrease in the HOMA index than those in arm B (?1.8 ± 0.3, ?2.1 ± 0.3 vs. ?1.1 ± 0.6, ?1.3 ± 0.7) at week 24 and at the end of follow‐up (P=0.001 at both time points). The triple therapy was well tolerated. Conclusions: A combination of pioglitazone, Peg‐IFN‐α‐2b and ribavirin increased RVR, SVR and decreased IR, compared with patients given Peg‐IFN plus ribavirin without an increase in adverse events.     

Randomized placebo-controlled trial of interferon alpha-2b plus ribavirin with and without lactoferrin for chronic hepatitis C.

Lactoferrin (LF), an iron-binding glycoprotein, exhibits several biological activities, including anti-viral activity and immunomodulatory functions. LF has been reported to inhibit hepatitis C virus (HCV) infection in cultured human hepatocytes and HCV viremia in low pretreatment HCV RNA titers of patients with chronic hepatitis C (CHC). However, the combination of interferon (IFN) alpha-2b plus ribavirin with LF for CHC has not been previously investigated. Thirty-six CHC patients, who were positive for HCV RNA with high serum levels of HCV RNA or who did not respond to or relapsed after interferon monotherapy, were randomly assigned to two groups: IFN alpha-2b and ribavirin plus LF for 24 weeks (18 patients), and IFN alpha-2b and ribavirin plus placebo (18 patients). Treatment was discontinued in three patients (17%) in the LF group and eight patients (44%) in the placebo group. For the 25 patients who finished the 24 weeks of treatment, virological sustained response was seen in 6 (40%) patients in the LF group and in 5 (50%) patients in the placebo group and there was no statistically significant difference between the two groups (p=0.7). Serum alanine aminotransferase concentrations remained normal throughout the follow-up period in nine patients (60%) in the LF group as compared with five patients (50%) in the placebo group (p=0.7). The proportion of patients with a virological or biochemical response at the end of the treatment period did not differ between the two groups. Furthermore, there were no statistically significant differences between the two groups in hemoglobin concentration, serum iron, ferritin, Th1/Th2 ratio or ribavirin concentration throughout the treatment and follow-up periods. In conclusion, we could not demonstrate that LF in combination with IFN alpha-2b and ribavirin increases the virological and biochemical response rate for CHC patients with high serum levels of HCV RNA or for CHC patients who do not response to or relapse after IFN monotherapy.     

Interferon and ribavirin therapy does not select for resistance mutations in hepatitis C virus polymerase

Summary.  Ribavirin has a minor and transient effect on hepatitis C virus (HCV) replication and has been suggested to select a novel mutation, F415Y, in the RNA-dependent RNA polymerase of subtype 1a viruses. Twenty-nine patients with chronic hepatitis C (subtyped by INNO LiPA as 1a, 17; 1b, 11; 1a/1b, 1) who were nonresponders to interferon-based therapies were identified retrospectively and screened at Baseline, week 24 of treatment, and 24 weeks post-treatment. Selection of resistance mutations, including at amino acid position 415 of the polymerase, was investigated. Using clonal sequencing and pyrosequencing of the NS5B gene, we screened for the F415Y resistance mutation among patients who received combination therapy with ribavirin and interferon α. Of the 15 subtype 1a patients treated with interferon plus ribavirin, only one had the F415Y change at week 24, and an F/Y mixture was still present 24 weeks after therapy. Four additional patients in this group had the F415Y change 24 weeks post-therapy. The NS5B genes were sequenced in order to identify amino acid changes associated with ribavirin therapy, but no evidence was found that ribavirin selects for particular amino acids in the RNA-dependent RNA polymerase. Ribavirin, a weak inhibitor of HCV replication, does not select for resistance mutations in the sequence of the HCV RNA polymerase.     

Hepatic iron accumulation is associated with disease progression and resistance to interferon/ribavirin combination therapy in chronic hepatitis C

BACKGROUND AND AIMS: Liver iron accumulation in patients with chronic hepatitis C (CHC) has received increasing attention in recent years. The aim of this study was to determine the prevalence and severity of liver iron deposition in CHC, to assess its relationship with clinical, biochemical and histological characteristics, and to study its influence on the response to interferon (IFN) plus ribavirin combination therapy. METHODS: We studied liver biopsy specimens from 103 hepatitis C virus (HCV) and 34 hepatitis B virus (HBV) infected patients and total iron score (TIS) was measured. Seventy patients infected with HCV genotype 1b were treated with IFN/ribavirin for 24 weeks. RESULTS: CHC patients had a significantly higher TIS than chronic hepatitis B (CHB) patients (7.03 +/- 5.34 vs 4.41 +/- 4.49, P = 0.0056). TIS was significantly correlated with alcohol intake (P = 0.0213, r = 0.290), transaminase level (P = 0.0126, r = 0.247), platelet count (P = 0.0002, r = -0.369), histological grading (P = 0.0121, r = 0.248) and staging (P = 0.0003, r = 0.356) in CHC patients. Pretreatment TIS was significantly higher in non-sustained virological responders (SVR) than in SVR to IFN/ribavirin treatment (TIS = 7.69 +/- 5.76 vs 4.39 +/- 3.27, P = 0.0310). Multiple regression analysis showed that TIS was the only independent variable associated with resistance to IFN/ribavirin (P = 0.0277). CONCLUSIONS: Liver iron deposition was common in CHC compared to CHB and was associated with liver disease progression. Increased hepatic iron stores in CHC were related to resistance to IFN/ribavirin treatment.     

Peginterferon-alfa2a plus ribavirin for 48 versus 72 weeks in patients with detectable hepatitis C virus RNA at week 4 of treatment

BACKGROUND & AIMS: Patients with chronic hepatitis C who do not respond rapidly to therapy have a low chance of developing a sustained virologic response (SVR) when treated for 48 weeks. This study investigated whether treatment for 72 weeks increases the rate of SVR in patients with detectable hepatitis C virus (HCV)-RNA levels at week 4 of treatment. METHODS: A total of 510 treatment-naive patients were treated with peginterferon-alfa2a (180 microg/wk) plus ribavirin (800 mg/day). Patients with detectable HCV-RNA levels at week 4 (n = 326) were randomized to complete 48 (group A, n = 165) or 72 weeks (group B, n = 161) of treatment. Patients with undetectable HCV-RNA levels at week 4 (n = 184) were allocated into group C (n = 148) or group D (n = 36), according to HCV genotype and baseline viremia, and treated for 24 or 48 weeks, respectively. All patients were followed-up for 24 weeks after the end of treatment. RESULTS: The end-of-treatment response rate (61%) was similar in groups A and B, but the SVR rate was higher in group B (45% vs 32% in A; P = .01). In genotype 1-infected patients randomized to group A (n = 149) or B (n = 142), SVR rates were 28% and 44%, respectively (P = .003). The incidence of adverse events was similar in all groups. Treatment discontinuation was more frequent in group B (36%) than in group A (18%) (P = .0004). SVR rates in groups C and D were 79% and 64%, respectively. CONCLUSIONS: Extension of treatment with peginterferon-alfa2a plus ribavirin from 48 to 72 weeks significantly increases the rate of SVR in patients with detectable viremia at week 4 of treatment.