干扰素在慢性丙型肝炎抗病毒治疗中的应用

自干扰素（IFN）进入临床以来，慢性丙型肝炎的治疗经过几次飞跃式的发展。2000年以前是普通IFN的时代。慢性丙型肝炎的治疗以IFN单药治疗为主，但24周的有效率只有约12％，48周的有效率为15％～22％。从1992年开始，IFN与利巴韦林的联合应用，将治疗48周的持续病毒学应答率（SVR）提高到了41％。但普通IFN血清浓度波动大，可能导致较重的不良反应或病毒重新复制和反跳，从而限制了其应用。2000年，聚乙二醇化干扰素（PEG-IFN）用于治疗慢性丙型肝炎，为慢性丙型肝炎患者的治疗提供了新的选择。[第一段]     

直接抗病毒药物治疗慢性丙型肝炎的作用机制

近年来随着直接抗病毒药物(DAAs)在全球的研发上市,慢性丙型肝炎的治疗方案不断演化,DAAs在我国也即将上市。DAAs主要作用于HCV的非结构蛋白,抑制HCV RNA的复制。介绍了各类DAAs的作用靶位、作用机制、耐药特性以及在中国的研发现状和临床Ⅲ期试验结果,旨在为慢性丙型肝炎DAAs联合其他抗病毒治疗方案提供临床参考。     

慢性丙型肝炎抗病毒治疗进展

抗病毒是治疗慢性丙型肝炎最重要的手段。叙述了近年来抗病毒治疗包括聚乙二醇干扰素和利巴韦林联合治疗、特异性靶点治疗、基因治疗等的进展情况。认为未来抗HCV治疗还需要更有效的药物联用治疗方式、更短的用药疗程、更低的毒副作用以及更高的耐药阈值等。     

重视利巴韦林在慢性丙型肝炎抗病毒治疗中的应用

当前干扰素是对慢性丙型肝炎治疗有确切抗丙型肝炎病毒（HCV）作用的药物，但单独使用普通干扰素治疗，仅有16％～20％的患者取得持续病毒应答（sustained virologic response，SVR），虽然开发的聚乙二醇化干扰素克服了普通干扰素存在的皮下注射后快速吸收、血清浓度波动大、系统分布广、肾脏清除率高和血清半衰期短，使得抗病毒程度不充分等缺陷，但也只能将SVR提高到30％～42％，即使增加聚乙二醇化干扰素的剂量也难以显著提高应答率。     

慢性丙型肝炎抗病毒治疗后复发的治疗

最近10年来慢性丙型肝炎治疗有较大进展，从单用α干扰素（interferon-α，IFN-α）治疗发展到以IFN与利巴韦林（RBV）联合治疗。新近几年，由于pegyloated聚乙二醇干扰素（PEG）的应用，提倡PEGIFN／RBV联合治疗，提高了SVR率。     

辨证论治联合抗病毒药物治疗丙型肝炎临床观察

目的:探讨中药辨证论治联合西医抗病毒药物治疗慢性丙型肝炎(CHC)的临床疗效。方法:将62例CHC患者随机分成治疗组(32例)和对照组(30例),对照组采用聚乙二醇干扰素α-2a(派罗欣)180μg皮下注射,1次/周,利巴韦林1 000 mg/d口服,疗程48周;治疗组在对照组用药基础上加用中药辨证治疗24周,1剂/d,分2次口服,然后停用中药,总疗程为48周。观察两组患者治疗24周后不良反应、肝纤维化指标、临床表现、HCV RNA的改变情况。结果:治疗24周后,治疗组患者不良反应、肝纤维化指标、临床表现与对照组相比,差异有统计学意义(P<0.05);HCV RNA转阴率较对照组高,但差异无统计学意义(P>0.05)。结论:采用中药辨证论治联合西药抗病毒治疗CHC可减少抗病毒药物的不良反应,有利于疗程的顺利进行,并可延缓患者肝脏纤维化进展、显著改善临床症状,值得临床推广应用。     

慢性丙型肝炎直接抗病毒药物应用现状及存在问题

慢性丙型肝炎可导致肝硬化、肝细胞癌等终末期肝病的发生,及时抗病毒治疗是改善预后的关键。直接抗病毒药物(DAAs)的诞生及发展使慢性丙型肝炎治疗发生了划时代的改变。当下世界各国正逐渐或已经步入DAAs时代,我国DAAs获批上市较晚,药物应用于临床时间短,临床数据有限。主要从国外相关研究出发,对适合我国患者的DAAs代表药物、治疗方案及存在的问题进行综述。     

慢性丙型肝炎抗病毒治疗患者甲状腺功能异常及其影响因素

目的 探讨慢性丙型肝炎(CHC)抗病毒治疗患者甲状腺功能异常情况并分析其影响因素. 方法 对194例CHC患者应用聚乙二醇干扰素(Peg-IFN) α-2a联合利巴韦林(RBV)治疗,疗程48周,停药后随访24周.按治疗结束时甲状腺功能分为正常组和异常组.采用病例对照方法,回顾性分析患者治疗前后甲状腺功能异常情况及其影响因素.计数资料采用x2检验,计量资料采用t检验;对有统计学意义的性别、甲状腺自身抗体进行logistic回归分析. 结果 治疗结束时甲状腺功能异常52例,占26.80％,正常142例,占73.20％;其中甲状腺功能亢进症(甲亢)1例,占0.52％,甲状腺功能减退症(甲减)10例,占5.15％);亚临床甲亢4例,占2.06％),亚临床甲减37例,占19.07％;抗病毒治疗前后甲状腺功能异常率差异有统计学意义(12.37％对比26.80％,x2=12.829,P＜ 0.05).影响甲状腺功能的因素主要有性别(x2=4.038,P＜0.05,95％ CI:1.016 ～ 3.040)和甲状腺自身抗体(P＜0.05,95％ CI:1.681 ～ 36.183);但抗病毒疗效差异无统计学意义;细胞因子中,正常和异常组白细胞介素6 (IL-6)差异有统计学意义[(27.08±14.90) ng/L对比(11.65±5:46)ng/L,t=3.127,P＜0.05,95％ CI:5.28 ～ 25.58],治疗24周末:2组IL-6差异无统计学意义[(6.30±2.47) ng/L对比(6.81±2.80) ng/L,t=0.352,P＞0.05].甲状腺功能异常组治疗前后IL-6差异无统计学意义[ (11.65±5.46) ng/L对比(6.81±2.80) ng/L,t=1.997,P＞0.05].甲状腺功能正常组治疗前后IL-6差异有统计学意义[(27.08±14.90) ng/L对比(6.30±2.47)ng/L,t=3.632,P＜0.05). 结论 Peg-IFNα-2a联合RBV治疗CHC患者可引起甲状腺功能异常,其中引起甲状腺功能减退症常见.女性,甲状腺自身抗体阳性患者Peg-IFNα-2a联合RBV治疗后容易发生甲状腺功能异常.IL-6可作为预测Peg-IFN α-2a联合RBV治疗引起甲状腺功能异常的辅助诊断参考指标.     

慢性丙型肝炎的抗病毒治疗及早期疗效预测

目前,在全世界范围内丙型肝炎病毒(HCV)感染者已达1.7亿,其中约70%～80%的受感染者可发展成为慢性丙型肝炎(chronic hepatitis C).慢性丙型肝炎患者经过10～30年,其中20%可发展为肝硬化及出现相关并发症,这其中又有约1%～4%发展为肝细胞癌.自1989年Houghton等发现HCV以来,对HCV的认识及慢性丙型肝炎的诊断与治疗研究都有了很大的进展. 慢性丙型肝炎的抗病毒治疗经历了由单一干扰素治疗到干扰素联合利巴韦林再到目前长效干扰素以及长效干扰素联合利巴韦林治疗的发展过程.抗病毒治疗的疗效也不断提高,仅仅在10年前抗病毒治疗的持久病毒应答率仅达5%～10%.随着治疗的不断改进,目前抗病毒治疗的疗效几乎提高了近10倍.抗病毒治疗不仅可抑制HCV病毒复制,改善肝脏炎症活动,防止肝纤维化及肝硬化的进展,也可防止和减少肝细胞癌的发生.本文对慢性丙型肝炎的抗病毒治疗、HCV对治疗应答的病毒动力学以及早期疗效预测等3个方面作一综述.     

PEG-IFNα联合利巴韦林治疗慢性丙型肝炎37例临床观察

目的 观察聚乙二醇-IFNα干扰素（PEG-IFNα）联合利巴韦林（RBV）治疗慢性丙型肝炎（CHC）的疗效和安全性.方法 将73例CHC患者随机分为观察组37例和对照组36例,均予RBV口服,并分别予PEG-IFNα及IFNα皮下注射,疗程均为48周.用药12周、疗程结束及停药后6个月时观察两组HCV-RNA阴转率、ALT复常率及不良反应.结果 观察组在治疗结束和停药后6个月ALT复常率显著高于对照组,且治疗12周、治疗结束和停药后6个月HCV-RNA阴转率均显著高于对照组（P均〈0.05）;两组均未发生严重不良反应,均完成治疗.结论 PEG-IFNα联合RBV治疗CHC具有良好的疗效和安全性.     

Re-treatment of interferon-resistant patients with chronic hepatitis C with interferon-α

Summary. Non-responders to 6-months treatment with recombinant interferon (rIFN)-α, 3 MU thrice weekly (primary non-responders) were treated for 6 further months with the same therapy or with a double dose of rIFN-α or with a different type of IFN (L-IFN). 112 primary non-responders were randomly enrolled into four groups of 28 patients each over a period of 4 years and were followed up for 6 months: group A continued the same dose of rIFN-α, group B was treated with the same rIFN-α but received a double dose (6 MU thrice weekly), group C received L-IFN, 3 MU thrice weekly, and group D stopped IFN therapy and did not receive any treatment. Patients were examined at monthly intervals and response was defined as a complete normalization of alanine amino transferase (ALT). The four groups were homogeneous as to age, sex, duration of the disease, probable source of infection, histological diagnosis, ALT and γ glutamyl transferase (γGT) levels. No patient discontinued therapy for side-effects. Further treatment with rIFN-α 3MU thrice weekly (group A) induced normalization of ALT levels in four patients (14%); treatment with double-dosed rIFN-α (group B) induced normalization of liver enzymes in six cases (21%); a different type of interferon (L-IFN) (group C) achieved normalization of serum ALT in five patients (18%). None of 28 primary non-responders who did not receive any treatment (group D) showed normalization of ALT levels. None of the patients was anti-HCV negative at the end of the study and no statistically significant difference was noted between responders and non-responders to the second course of IFN therapy as to age, sex, duration of the disease, ALT and γGT levels at the end of the trial. Overall at the end of the study the primary non-responders with normal levels of ALT were 15/112 (13%), with a therapeutic advantage of 7%. No statistically significant difference in the response rate was found among patients who continued IFN therapy, but prolongation of rIFN-α treatment at double dosage seems to be the best therapeutic regimen.     

Human leucocyte interferon-alpha in the treatment of chronic hepatitis C

AIM: To assess the efficacy of different schedules of human leucocyte interferon alpha in chronic hepatitis C. PATIENTS AND METHODS: A total of 213 naive patients with chronic hepatitis C were treated with 4 different schedules of human leucocyte interferon alpha. Sustained response was defined as persistently normal alanine amino transferase values with negative serum hepatitis C virus-RNA up to 12 months after therapy withdrawal. RESULTS: Rates of sustained response were 16% with 3 MU tiw for 6 months, 33% with 6 MU tiw for 5 months after a priming dose of 9 MU tiw for a month, 32% with 3 MU tiw for 12 months and 20% with 3 MU daily for 6 months. The major factors affecting the response rate were age and the hepatitis C virus genotype, as a sustained response was significantly higher in patients under 45 years and infected by hepatitis C virus types other than hepatitis C virus-1. Treatment was well tolerated and side-effects and drop-out events were similar to those described with other types of alpha-interferons. CONCLUSIONS: Human leucocyte interferon alpha appears to be equivalent to recombinant interferon-alpha in the treatment of chronic hepatitis C.     

Treatment of chronic hepatitis C in Europe

The lifetime cumulative risk of developing cirrhosis and hepatocellular carcinoma is the rationale for treating patients with chronic hepatitis C with antivirals. The standard treatment is combination therapy with interferon-alfa and ribavirin. In patients with high transaminases and histologic signs of chronic hepatitis, 6- to 12-month therapy with 3 mega units (MU) interferon-alfa thrice weekly, combined with ribavirin, yielded up to 30% sustained responders, and this was increased to 50% with pegylated interferon combined with ribavirin. Favorable predictors of response to the former treatment were genotype 2 or 3, less than 2 million copies of hepatitis C virus (HCV), no portal fibrosis at biopsy, age less than 40 years, and female sex. The same was true for the latter treatment; however, with body weight less than 82?kg replacing female sex. A 98% cure of community-acquired acute hepatitis C was achieved with early treatment with daily doses of 5?MU interferon, compared with a calculated 30% HCV-RNA clearance in untreated patients. More cost-effective strategies for ceasing treatment, based upon early clearance of HCV, are under investigation, with cutoff equal to or more than a 2?log decrease in serum HCV-RNA at week 12. This approach has 100% negative predictive value and 80% positive predictive value. Treatment can also be optimized by combination retreatment of relapsers and nonresponders to monotherapy, which yielded sustained responses of 50% and 25%, respectively. There are difficult-to-treat patients who have high viremia, genotype 1 and 4, or coinfection with HIV or HBV, or carry an organ graft, and those who did not respond to combination therapy. Extended treatment of the latter patients with pegylated interferon might slow down the progression of fibrosis.     

Liver stiffness decrease after effective antiviral therapy in patients with chronic hepatitis C: Longitudinal study using FibroScan

Aim: The aim of the present study was to assess the changes of liver stiffness (LS) and its associated factors in patients with chronic hepatitis C virus infection (HCV) after interferon (IFN)‐based therapy. Methods: Patients with chronic HCV who had previously undergone at least 20 weeks of IFN‐based therapy were enrolled. The patients’ initial LS measurement was taken at the time of enrollment, and a second LS measurement was made after an interval of at least 38 weeks. LS measurement was carried out with FibroScan®, and changes of LS and its associated factors were analyzed. Results: One hundred and forty‐four patients, including 95 sustained virological response (SVR) patients and 49 non‐sustained virological response (NSVR) patients, were enrolled. There was a significant decrease of LS among SVR patients (median, 0.6; P < 0.001). NSVR patients showed an increase of LS (median, 0.8; P = 0.557). For SVR patients, a high initial LS was the predictive factor of a rapid reduction of LS values. However, advanced fibrosis stage before therapy, higher body mass index (BMI) and longer time remission were predictive factors for slow reduction of LS values. Conclusions: LS decreases in sustained responders following IFN‐based therapy in patients with chronic HCV. Advanced fibrosis, higher BMI, longer time for remission and lower initial LS value are predictive factors for a slow improvement of LS in sustained responders.     

重组α-1b干扰素治疗慢性乙型肝炎110例临床观察

目的观察不同状况的慢性乙型肝炎与干扰素联合应答之间的关系。方法将110例接受重组α-1b干扰素治疗的慢性乙型肝炎患者,分别按性别、是否母婴传播、ΑLT水平、HBVDNA定量、是否联合用药、药物的剂量和疗程进行分组,观察其联合应答率。结果非母婴传播者、治疗前ΑLT2～5×ULN、HBVDNA<107copies/ml、疗程1年以上者联合应答率较高;未见性别对干扰素疗效的影响;干扰素3MU与5MU剂量之间,以及联合用药与非联合用药之间,疗效无明显差异。结论非母婴传播者、治疗前ALT为2～5 ×ULN、HBVDNA<107copies/ml、疗程1年以上者应用干扰素治疗疗效较好,可作为干扰素疗效的预测因子。     

Efficacy of interferon-alpha treatment in Japanese children with chronic hepatitis C

BACKGROUND: We investigated the efficacy of natural interferon (IFN)-alpha treatment in 34 Japanese children with chronic hepatitis C. METHODS: Thirty-four children completed 6 months of therapy with natural IFN-alpha and were followed for 12 months or longer. We examined the serum hepatitis C virus (HCV) RNA titer and liver histology before, during, and after IFN treatment. RESULTS: At 6 months after the cessation of IFN-alpha treatment, 16 patients (47%) had normal serum alanine aminotransferase concentration and no detectable serum HCV RNA. There were no major side-effects, excluding some influenza-like symptoms during the IFN-alpha treatment. Most genotype 2a patients had a complete response (80%). Moreover, patients who had a low HCV RNA titer (<102 copies/mL) after 1 month of IFN-alpha treatment became complete responders at 6 months after the cessation of treatment. Histological improvement was observed in almost all patients after IFN-alpha treatment. CONCLUSION: Interferon-alpha treatment is safe and effective for children with chronic hepatitis C and has no serious side-effects. A HCV RNA concentration of <102 copies/mL after 1 month of IFN-alpha treatment and genotype 2a may be useful predictors of long-term IFN efficacy.     

Clinical predictors of response to recombinant interferon-α treatment in patients with chronic non-A, non-B hepatitis (hepatitis C)

SUMMARY. Chronic non-A, non-B hepatitis (NANBH) is a common and often progressive liver disease. Based on current serological tests, hepatitis C virus (HCV) infection is responsible for most cases. Interferon-α (IFN) treatment at a dose of 3 × 10⁶ units given three times per week for 24 weeks has been shown to be effective in normalizing serum alanine aminotransferase (ALT) levels and reducing hepatic inflammation in approximately 40% of these patients. The purpose of this study was to identify pretreatment characteristics in patients with chronic hepatitis C(CH-C) which would best predict a favourable response to IFN treatment (normalization of serum ALT). One hundred and sixty-three adult patients who had participated in a large multi-centre treatment trial were included in the study group: 84 had been treated with 3 × 10⁶ units of recombinant IFN-α-2b (rIFN) subcutaneously three times per week for 24 weeks and 79 patients had been treated with 1 × 10⁶ units rIFN in the same dosage schedule. Forty-one pretreatment historical, clinical, laboratory and histological variables were evaluated. In addition, early biochemical improvement during treatment was evaluated as a predictor of ultimate response. Univariate analysis identified six variables (dose, dose m^-2, weight, body surface area, ongoing ethanol use, white blood cell count and the presence of symptoms) as potential predictors of response (two-tailed, P < 0.15). By multivariate analysis, however, only the 3 × 10⁶ dose of rIFN was independently predictive of response (P < 0.01). When the analysis of response was confined to those patients who received treatment with 3 × 10⁶ units of rIFN, seven variables [body weight, surface area, dose m^-2, current ethanol use, serum albumin and the presence of chronic persistent hepatitis (CPH) on entry liver biopsy] were more frequent in patients who responded to therapy. In a multivariate model, only CPH and body weight predicted an increased likelihood of response (P < 0.01). However, the model was not a sensitive predictor of response as only 18% of the study group had CPH on liver biopsy. A decrease in serum ALT levels within the first 12–16 weeks of rIFN treatment was found to be the strongest indicator of an ultimate response to treatment. Thus, assessment of early response to IFN treatment is the only practical means of predicting complete response and avoiding prolonged and unnecessary therapy in those with little chance of response.     

直接抗病毒药物对儿童慢性丙型肝炎的治疗进展

聚乙二醇干扰素α-2a或α-2b联合利巴韦林是目前治疗儿童慢性丙型肝炎的标准方案。该方案最早应用于成人,对HCV的有效率仅约50%,并且对于儿童HCV的治疗有效率最高也只达70%。近年来,直接作用于HCV基因靶点的抗病毒药物(direct-acting antiviral agents,DAAs)不断被研发出来,对HCV的治疗起到质的飞跃,但该类药物在儿童HCV治疗中的应用大多处在临床试验阶段。本文通过对目前DAAs在儿童慢性丙型肝炎中的研究进展作一综述,以期为HCV患儿的临床治疗提供参考依据。