慢性丙型肝炎治疗:更多的机遇,更多的挑战

自从聚乙二醇干扰素(PEG-IFN)α联合利巴韦林(RBV)应用于慢性丙型肝炎的治疗,并且基因2型或基因3型感染者可获得50%的持续病毒学应答(SVR)以来,PEG-IFN α联合RBV已经成为慢性丙型肝炎的标准治疗方案[1-2].     

难治性丙型肝炎治疗现状及发展趋势

慢性丙型肝炎当前惟一有效的治疗方法是干扰素联合利巴韦林(RBV)的治疗,聚乙二醇干扰素(PEG-IFN)的开发进一步提高了治疗的应答率,Ⅲ期临床试验结果显示其持久病毒学应答(SVR)高达66%.     

以索非布韦为基础的慢性丙型肝炎治疗中利巴韦林相关不良事件:一个社区实践经验

正【据《J Dig Dis》2016年1月报道】题:以索非布韦为基础的慢性丙型肝炎治疗中利巴韦林相关不良事件:一个社区实践经验(作者Tong MJ等)由于索非布韦的持续病毒学应答率高,目前以索非布韦为基础的疗法是治疗丙型肝炎的主要方法。索非布韦联合聚乙二醇干扰素和利巴韦林会影响患者治疗期间的生活质量。美国亨廷顿医学研究所的Tong等比较了一个社区诊疗机构中联合疗法治     

难治性慢性丙型肝炎——我们面临的新挑战

慢性丙型肝炎是可以治愈的疾病,经过标准治疗:聚乙二醇干扰素(PEG-IFN)联合利巴韦林(RBV)治疗达到持久病毒学应答(SVR)的患者,在5年内约有95%以上仍然维持完全应答,即认为是临床治愈[1].     

抗HCV小分子化合物的研究

目前抗HCV治疗的标准疗法是聚乙二醇干扰素(PEG-IFN)联合利巴韦林(RBV),但仍有部分患者不能达到治愈。近年来,靶向针对HCV生活周期中病毒蛋白的小分子化合物的研究得到了迅速发展,小分子化合物联合PEG-IFN、RBV三联治疗可以提高持续病毒学应答率。而对于不能应用/耐受干扰素治疗的慢性丙型肝炎患者,各类小分子化合物之间的联合抗病毒治疗也可取得较好的疗效。因此,认为小分子化合物给今后慢性丙型肝炎治疗带来新的希望。     

基因1型慢性丙型肝炎初治患者获得持续病毒学应答的相关因素研究

目的研究接受长效干扰素和利巴韦林治疗的基因1型慢性丙型肝炎患者获得持续病毒学应答的预测因素。方法 73例基因1型慢性丙型肝炎患者接受干扰素α-2a联合利巴韦林治疗24周或48周,随访6个月。结果 47.9%患者获得早期病毒学应答,38.4%患者获得持续病毒学应答;分析表明治疗前低病毒载量（小于8×105IU/ml）、体重指数低于25kg/m2和出现早期病毒学应答者更容易获得持续病毒学应答。结论病毒载量、体重指数和是否出现早期病毒学应答与基因1型慢性丙型肝炎初治患者获得持续病毒学应答相关。     

聚乙二醇干扰素α-2b联合利巴韦林治疗慢性丙型肝炎的随机对照临床研究

目的评价小剂量聚乙二醇干扰素α-2b联合利巴韦林治疗慢性丙型病毒性肝炎的疗效和安全性.方法192例慢性丙型肝炎患者随机分为两组：聚乙二醇干扰素α-2b 0.5μg/kg每周一次联合利巴韦林750～1050 mg/d,或普通干扰素α-2b 3 MIU每周3次联合利巴韦林750～1050 mg/d.疗程48周,治疗结束后随访24周.结果聚乙二醇干扰素α-2b联合利巴韦林治疗的持续病毒学应答率为53.8%,而普通干扰素α-2b联合利巴韦林治疗的持续病毒学应答率为58.1%,两组持续病毒学应答率相当（P=0.966）.聚乙二醇干扰素α-2b治疗组的药物相关性不良反应发生率为100%,而普通干扰素α-2b治疗组的不良反应发生率为95.2%,两组间差异有统计学意义（P=0.033）.但是没有与干扰素α-2b聚乙二醇化相关的特有的新的不良反应发生.结论小剂量聚乙二醇干扰素α-2b联合利巴韦林治疗慢性丙型肝炎的疗效和安全性与普通干扰素α-2b联合利巴韦林治疗的疗效和安全性相当.     

聚乙二醇干扰素联合利巴韦林治疗血清丙氨酸转氨酶异常慢性丙型肝炎的临床疗效

目的：观察慢性丙型肝炎患者体内血清丙氨酸转氨酶（ALT）水平对聚乙二醇干扰素（PegIFNα-2a）联合利巴韦林（RBV）治疗丙型肝炎疗效的影响。方法68例慢性丙型肝炎患者按照血清 ALT 水平分为2组,ALT 异常组（A 组）36例,ALT 正常组（B 组）32例,均按体质量给予 PegIFNα-2a 联合 RBV 治疗,疗程为48周,比较2组治疗后丙型肝炎病毒转阴率及干扰素应答率。结果 A 组患者治疗后丙型肝炎病毒转阴率为93．8％,持久病毒学应答率为86．7％;B 组患者治疗后丙型肝炎病毒转阴率为94．4％,持久病毒学应答率为88．2％。两组患者 HCV RNA 应答率差异无统计学意义（P ＞0．05）。结论PegIFNα-2a 联合 RBV 对 ALT 正常及异常的慢性丙型肝炎患者均有较好疗效,血清 ALT 水平不影响干扰素治疗慢性丙型肝炎的疗效。     

小剂量干扰素α-1b联合利巴韦林、胸腺肽α1治疗慢性丙型肝炎的疗效

<正>基因1型是目前慢性丙型肝炎(CHC)难以获得完全病毒学应答的重要因素之一[1]。聚乙二醇干扰素(PEG-IFN)联合利巴韦林(RBV)仍然是目前国内治疗基因1型CHC的标准方案[2]。但PEG-IFN价格昂贵,对于我国广大不发达地区患者难以承受。本研究应用小剂量干扰素(IFN)α-1b联合RBV、胸腺肽(thymosin,T)α1治疗基因1型CHC取得了与标准治疗     

聚乙二醇干扰素-α-2b联合利巴韦林治疗慢性丙型肝炎患者的长期病毒学应答北大核心CSCD

聚乙二醇干扰素α（peg—IFN—α）联合利巴韦林（RBV）治疗慢性丙型肝炎（chronic hepatitis virus C,CHC）结束后随访24周,患者血HCVRNA阴性可认为获得了持续病毒学应答（sustained virologic response,SVR）。     

粒细胞集落刺激因子联合聚乙二醇干扰素α-2a及利巴韦林治疗丙型肝炎肝硬化的疗效观察

目的观察粒细胞集落刺激因子（G-CSF）联合聚乙二醇干扰素（PEG-IFNα）及利巴韦林的标准化方案与PEG-IFNα减量治疗对代偿期丙肝肝硬化抗病毒的疗效比较。方法选择代偿期丙肝肝硬化患者48例,随机分为G-CSF联合PEG-IFNα及利巴韦林标准治疗组和PEG-IFNα减量组;以慢性丙肝接受标准化抗病毒治疗方案患者28例为对照组。观察快速病毒学应答（RVR）、早期病毒学应答（EVR）、治疗结束时病毒学应答（ETVR）、持续病毒学应答（SVR）、停药后复发,并随访48周,同时观察肝功能复常和其他不良反应。组间比较采用方差分析或卡方检验分析。结果 G-CSF治疗组的ETVR率、SVR率等指标与CHC的标准化抗病毒治疗组比较,差异无统计学意义（P〉0.05）;但是PEG-IFN减量组在ETVR率、SVR率方面均低于CHC的标准化抗病毒治疗组,且差异有统计学意义（χ2=8.266、4.467,P均〈0.05）。另外,G-CSF治疗组的ETVR率明显高于PEG-IFN减量组,且差异有统计学意义（χ2=4.009,P〈0.05）。结论用GM-CSF陪伴标准化治疗方案抗病毒治疗对丙肝肝硬化患者疗效明显优于PEG-IFNα减量组。     

聚乙二醇干扰素联合利巴韦林治疗慢性丙型肝炎患者疗效及其影响因素分析

目的：观察聚乙二醇干扰素（PEG IFNα-2a）联合利巴韦林（RBV）治疗慢性丙型肝炎（CHC）患者的疗效及其影响因素。方法对331例慢性丙型肝炎患者予 PEG IFNα-2a（180μg/w 或135μg/w）联合利巴韦林（RBV）900~1200 mg/d 抗病毒治疗,疗程48～72 w,随访24 w;治疗前检测丙型肝炎病毒基因型,采用 PCR 法检测丙型肝炎病毒（HCV）RNA 水平及肝功能,以病毒学应答和生化学应答作为疗效的主要评价指标。结果在331例CHC 患者中,获得快速病毒学应答率（RVR）、早期病毒学应答率（EVR）和持续病毒学应答率（SVR）分别为65%（215/331）、94.9%（314/331）和84.9%（281/331）;对176例行基因分型,结果108例基因1型与68例非1型感染者SVR 分别为88.0%和79.4%,两组比较无明显差异;75例血清 HCV RNA 水平小于4×105 IU/ml 的患者 SVR 为93.3%,高于256例 HCV RNA 水平大于4×105 IU/ml 患者的82.4%（P〈0.05）;215例获得 RVR 的 CHC 患者的SVR 明显高于116例未获得 RVR 患者（92.6%对70.7%,x2=28.099,P=0.000）,314例获得 EVR 患者的 SVR 也明显高于17例未获得 EVR 组（88.5%对17.6%,x2=63.194,P=0.000）;50例未获得 SVR 的 CHC 患者年龄和感染丙型肝炎病毒的时间分别为（46±15）岁和（14.8±8.0）年,显著大或长于281例获得 SVR 患者[（38±13）岁和（11.5±7.7）年,P 均〈0.05]。结论聚乙二醇干扰素联合利巴韦林治疗慢性丙型肝炎疗效较好,预测临床疗效的关键因素是患者年龄、感染丙型肝炎的病程、治疗前 HCV RNA 水平及在治疗过程中能否及时获得 RVR 和 EVR。     

Hepatitis C virus genotype 3: Meta-analysis on sustained virologic response rates with currently available treatment options

AIM: To address the therapeutic efficacy of various treatment regimens in genotype 3 selecting randomized clinical trials and prospective National Cohort Studies.METHODS:(1) PEG-INF-based therapy including sofosbuvir(SOF) + RBV for 12 wk vs SOF + RBV 24 wk;(2) SOF + RBV therapy 12 wk/16 wk vs 24 wk; and(3) the role of RBV in SOF + daclatasvir(DCV) and SOF + ledipasvir(LDV) combinations. This metaanalysis provides robust information with the intention of addressing treatment strategy for hepatitis C virus genotype 3.RESULTS: A combination treatment including SOF + RBV + PEG-IFN for 12 wk notes better SVR than with only SOF + RBV for 12 wk, although its association with more frequent adverse effects may be a limiting factor. Longer duration therapy with SOF + RBV(24 wk) has achieved higher SVR rates than shorter durations(12 or 16 wk). SOF + LDV are not an ideal treatment for genotype 3. CONCLUSION: Lastly, SOF + DCV combination is probably the best oral therapy option and the addition of RBV does not appear to be needed to increase SVR rates substantially.     

Effectiveness and safety of sofosbuvir‐based regimens plus an NS5A inhibitor for patients with HCV genotype 3 infection and cirrhosis. Results of a multicenter real‐life cohort

Patients with HCV genotype 3 (GT3) infection and cirrhosis are currently the most difficult to cure. We report our experience with sofosbuvir+daclatasvir (SOF+DCV) or sofosbuvir/ledipasvir (SOF/LDV), with or without ribavirin (RBV) in clinical practice in this population. This was a multicenter observational study including cirrhotic patients infected by HCV GT3, treated with sofosbuvir plus an NS5A inhibitor (May 2014‐October 2015). In total, 208 patients were included: 98 (47%) treatment‐experienced, 42 (20%) decompensated and 55 (27%) MELD score >10. In 131 (63%), treatment was SOF+DCV and in 77 (37%), SOF/LDV. Overall, 86% received RBV. RBV addition and extension to 24 weeks was higher in the SOF/LDV group (95% vs 80%, P=.002 and 83% vs 72%, P=.044, respectively). A higher percentage of decompensated patients were treated with DCV than LDV (25% vs 12%, P=.013). Overall, SVR12 was 93.8% (195/208): 94% with SOF+DCV and 93.5% with SOF/LDV. SVR12 was achieved in 90.5% of decompensated patients. Eleven treatment failures: 10 relapses and one breakthrough. RBV addition did not improve SVR (RR: 1.08; P=.919). The single factor associated with failure to achieve SVR was platelet count <75×10E9/mL (RR: 3.50, P=.019). In patients with MELD <10, type of NS5A inhibitor did not impact on SVR12 (94% vs 97%; adjusted RR: 0.49). Thirteen patients (6.3%) had serious adverse events, including three deaths (1.4%) and one therapy discontinuation (0.5%), higher in decompensated patients (16.7% vs 3.6%, P<.006). In patients with GT3 infection and cirrhosis, SVR12 rates were high with both SOF+DCV and SOF/LDV, with few serious adverse events.     

Comparison of peg-interferon,ribavirin plus telaprevir vs simeprevir by propensity score matching

AIM: To compare efficacy of telaprevir(TVR) and simeprevir(SMV) combined with pegylated interferon(PEG-IFN) and ribavirin(RBV) while treating chronic hepatitis C(CHC). METHODS: In all, 306 CHC patients were included in this study. There were 159 patients in the TVR combination therapy group and 147 patients in the SMV combination therapy group. To evaluate pretreatment factors contributing to sustained virological response at 12 wk(SVR12), univariate and multivariate analyses were performed in TVR and SMV groups. To adjust for patient background between TVR and SMV groups, propensity score matching was performed. Virological response during treatment and SVR12 were evaluated.RESULTS: Overall rates of SVR12 [undetectable serum hepatitis C virus(HCV) RNA levels] were 79.2% and 69.4% in TVR and SMV groups, respectively. Patients in the SMV group were older, had higher serum HCV RNA levels, lower hemoglobin, higher prevalence of unfavorable interleukin-28B(IL28B) genotype(rs8099917), and poorer response to previous PEG-IFN and RBV treatment. Propensity score matching was performed to adjust for backgrounds(n = 104) and demonstrated SVR12 rates of 74.0% and 73.1% in the TVR and SMV groups, respectively. In the TVR group, discontinuation rates were higher because of adverse events; however, breakthrough and nonresponse was more frequent in the in SMV group. Multivariate analysis revealed IL28 B genotype(rs8099917) as the only independent predictive factor of SVR12 in both groups.CONCLUSION: SVR12 rates were almost identical following propensity score matching.     

利巴韦林联合不同剂量普通干扰素α-2b治疗基因2、3型慢性丙型肝炎的疗效观察

目的观察利巴韦林（RBV）联合不同剂量干扰素（IFN）OL-2b治疗基因2、3型慢性丙型肝炎的临床疗效。方法将2009年4月至2012年1月收治的46例基因2、3型慢性丙型肝炎患者分为治疗组24例和对照组22例,两组均在第1个月每日肌肉注射IFNα-2b6MU1次;治疗组在第2个月隔日肌肉注射IFNα-2b6MU1次,在第3个月及以后隔日肌肉注射IFNα-2b3MU1次;对照组在第2个月及以后隔日肌肉注射IFNα-2b6MU1次;两组均每日分3次口服RBV900～1200mg,疗程均为6个月;两组获得治疗结束时病毒学应答（ETVR）的患者在疗程结束后6个月时随访;无应答（NR）的患者延长疗程3个月。比较两组治疗后快速病毒学应答（RVR）、早期病毒学应答（EVR）、治疗结束时病毒学应答（ETVR）、无应答（NR）和持久病毒学应答（SVR）情况;比较两组治疗费用和不良反应。计数资料组间比较采用,检验。结果治疗组24例和对照组22例获得RVR、EVR、EVR均较高,分别为15例（62．50％）和13例（59．09％）（X^2=0．056,P〉0．05）、17例（70．83％）和15例（68．18％）（X^2=0．038,P〉0．05）、20例（83．33％）和19例（86．36％）（X^2=0．082,P〉0．05）;治疗组和对照组NR均较低,分别为4例（16．67％）和3例（13．64％）（X^2=0．082,P〉0．05）;治疗组和对照组获得SVR也较高,分别为18例（75．00％）和17例（77．27％）（X^2=0．033,P〉0．05）,差异均无统计学意义。治疗组使用IFNα-2b的总量及治疗费用比对照组少近30％,药物不良反应也较轻。结论RBV联合IFNα-2b“诱导疗法”治疗基因2、3型慢性丙型肝炎可获得较高的RVR、EVR,减少IFN剂量的维持治疗也能获得较高的ETVR和SVR,能减轻患者经济负担和药物不良反应。     

A real-world impact of cost-effectiveness of pegylated interferon/ribavarin regimens on treatment-naïve chronic hepatitis C patients in Taiwan

Treatments with pegylated interferon/ribavirin (PEG-IFN/RBV) has been standard-of-care in patients with chronic hepatitis C virus (HCV) (CHC) infection and reimbursed in Taiwan. However, the actual cost-effectiveness remains unclear. We aimed to evaluate a real-world cost-effectiveness for CHC patients treated with PEG-IFN/RBV by using a clinical cohort with linkage to the National Health Insurance Research Database of Taiwan. The total and itemized medical-care expenses of outpatient visits of 117 treatment-naïve CHC patients with linkage to the two million sampling of the National Health Insurance Research Database were collected. Four components of costs were assessed, including antiviral agents, nonantiviral agents, laboratory testing and consultation costs. The cost per sustained virological response (SVR) achieved was calculated to evaluate the cost-effectiveness. The average cost per treatment in 117 naïve Taiwanese CHC patients was $4620. With an overall SVR rate of 78.6%, the average cost per SVR was $5878. The average medical-care cost per treatment for 52 Genotype 1 (G1) patients was $5133, including $4420 for antivirals, $380 for nonantivirals, $302 for laboratory, and $78 for consultation, compared to $4209, $3635, $317, $233, and $56 for 65 Genotype 2 (G2) patients. With an SVR rate at 67.3% for G1 and 87.7% for G2 patients, the cost per SVR achieved was significantly higher in G1 patients than those in G2 patients ($7627 vs. $4799, p = 0.001). In the current study, we provided the real-world cost-effectiveness of PEG-IFN/RBV for treatment-naïve CHC patients. The genotype-specific cost-effectiveness could enhance decision-making for policy-makers in the coming era of directly acting antiviral therapy.     

Impact of ribavirin dose on retreatment of chronic hepatitis C patients

AIM: To study the efficacy and factors associated with a sustained virological response (SVR) in chronic hepatitis C (CHC) relapsing patients.METHODS: Out of 1228 CHC patients treated with pegylated interferon (PEG-IFN) and ribavirin (RBV), 165 (13%) had a relapse. Among these, 62 patients were retreated with PEG-IFN-α2a or -α2b and RBV. Clinical, biological, virological and histological data were collected. Initial doses and treatment modifications were recorded. The efficacy of retreatment and predictive factors for SVR were analyzed.RESULTS: An SVR was achieved in 42% of patients. SVR was higher in young (< 50 years) (61%) than old patients (27%) (P = 0.007), and in genotype 2 or 3 (57%) than in genotype 1 or 4 (28%) patients (P = 0.023). Prolonging therapy for at least 24 wk more than the previous course was associated with higher SVR rates (53% vs 28%, P = 0.04). Also, a better SVR rate was observed with RBV dose/body weight > 15.2 mg/kg per day (70% vs 35%, P = 0.04). In logistic regression, predictors of a response were age (P = 0.018), genotype (P = 0.048) and initial RBV dose/body weight (P = 0.022). None of the patients without a complete early virological response achieved an SVR (negative predictive value = 100%).CONCLUSION: Retreatment with PEG-IFN/RBV is eff-ective in genotype 2 or 3 relapsers, especially in young patients. A high dose of RBV seems to be important for the retreatment response.     

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.     

Triple therapy for HCV genotype 1 infection: telaprevir or boceprevir?

Boceprevir and telaprevir are the first two protease inhibitors available for the treatment of patients infected with hepatitis C virus (HCV) genotype 1. A sustained virological response (SVR) of 70-80% is observed when either of these protease inhibitors is utilized with pegylated interferon (PEG-IFN) and ribavirin (RBV) in treatment na?ve patients. Both agents are also highly effective in patients who failed to achieve a SVR during previous treatment with PEG-IFN/RBV. A rapid virological response (RVR) is observed in 56-60% of treatment na?ve patients. Patients who achieve a RVR can be treated with a shorter course of therapy (24-28 weeks) and still achieve a SVR rate of 90% or higher. Patients who do not achieve a RVR, those with cirrhosis and certain prior non-responders should be treated for 48 weeks. Although the SVR rates observed with boceprevir and telaprevir are quite similar both globally and within sub-populations, the treatment algorithms for the two agents are unique. The decision of which protease inhibitor to use should assess several factors including the treatment scheme, duration of therapy, adverse event profile, cost and the likelihood of achieving a RVR. The latter is highly dependent upon IFN sensitivity and the IL28B genotype.