Acute polymyositis during treatment of acute hepatitis C with pegylated interferon alpha-2b

Hepatitis C virus is not cleared after primary infection in 50-85% of subjects exposed to hepatitis C virus. Anti-viral treatment during the early phase of infection significantly enhances the likelihood of a sustained clearance of hepatitis C virus. Although, a variety of autoimmune-related side effects have been observed during interferon therapy for chronic hepatitis, immuno-mediated adverse reactions have not been reported during treatment of acute hepatitis C. We describe the case of a patient who developed acute hepatitis C virus infection and, while receiving pegylated interferon alpha-2b monotherapy, developed a severe polymyositis. This case illustrates the potential risk of autoimmunity by interferon, also for acute hepatitis, and underlines the importance of a prompt diagnosis and a rapid discontinuation of interferon treatment for an improvement of clinical outcomes.     

化学发光法检测丙型肝炎核心抗原滴度与丙型肝炎RNA含量的相关性研究

目的分析化学发光法检测的丙型肝炎病毒核心抗原(HCV-cAg)与HCV RNA的相关性。方法运用化学发光免疫分析法(CMIA)对84例HCV RNA阳性标本进行HCV-cAg检测。结果在84例HCV RNA阳性标本中,HCV-cAg阳性标本79例,检出率为94.04%,两者相关性为0.822。结论 HCV-cAg阳性检出率与HCV RNA检测有明显相关性,化学发光法检测HCV-cAg有较高的敏感性和特异性,操作简便快速,费用低廉,缩短了窗口期,相对于ELISA检测法提高了阳性率,利于丙型肝炎患者的早期发现、治疗及监测。还可以用于献血员HCV筛查,以及在一些无条件开展PCR的实验室作为HCV RNA的替代方法。     

Predicting interferon therapy efficacy from hepatitis C virus genotype and RNA titer

We classified 53 Japanese patients with chronic hepatitis C who were treated with natural interferon- into genotypes and also tested the amounts of hepatitis C virus (HCV) RNA. The rate of the long-term complete response group, whose alanine aminotransferase levels remained within the normal range during the six months after therapy, was significantly higher (P<0.01) in the type-III patients (4/5, 80.0%) than in type-II patients (4/43, 9.3%). For these long-term complete responders, the amounts of HCV RNA was less than 10⁷ copies/ml serum in type-II patients, whereas two type-III patients with relatively high amounts of HCV RNA responded completely. These results confirm that the genotype of HCV is an important factor for predicting the response to interferon therapy. The amounts of HCV RNA can also predict its efficacy in type-II patients.This work was supported by a Grant-in-Aid from the Ministry of Education, Science and Culture, Japan, and the Research Group of Intractable Hepatitis sponsored by the Ministry of Health and Welfare of Japan.     

慢性丙型肝炎患者HCV基因型分析

目的研究慢性丙型肝炎患者HCV基因型概况。方法采用基因芯片法检测HCV基因分型;采用PCR法测定HCV RNA定量。结果在570例患者中,HCV RNA阳性552例（95%）,其中1b型400例（72.4%）,2a型63例（11.4%）,3a型20例（3.6%）,3b型20例（3.6%）,1b＋2a型12例（2.1%）,1a型2例（0.4%）,6型7例（1.26%）,1b＋3a型1例（0.18%）,2a＋1b型3例（0.5%）,未定型24例（4.3%）;不同HCV基因型感染者血清HCVRNA水平无统计学差异（P〉0.05）。结论本组患者HCV基因型以1b型为主,2a型次之,多种混合型的出现提示HCV基因型呈现多样化趋势。     

Changes in serum hepatitis C virus RNA titer and response to interferon therapy in patients with chronic hepatitis C

Response to interferon (IFN) therapy for chronic hepatitis C has been determined by the alteration of serum alanine aminotransferase (ALT) values. However, eradication of hepatitis C virus (HCV) could be another aim of the therapy. Thus, we serially measured serum HCV RNA levels during therapy and for at least 12 months after cessation of therapy in 65 patients with chronic hepatitis C who received IFN- (49 cases) or - (16 cases). The presence of HCV and its amount were measured by the combination of nested and competitive PCR. Twenty-seven patients, who were categorized as complete responders, showed sustained normalization of ALT values for more than six months posttreatment. The viral RNA titers at pretreatment were significantly lower in complete responders (logarithmic copy numbers/ml: 5.4±1.3,P<0.001) than in partial and nonresponders. Complete response rate was significantly higher in patients with HCV genotype III (68.4%,P<0.01) than those with type II (23.6%). Among 27 complete responders, HCV RNA became undetectable in only 13 patients six months after completion of therapy, and 11 still had low levels of viremia; however, none experienced relapse of the disease during follow-up of 12–24 months. Three complete responders showed lasting high-titered viremia, and their ALT values rose again during follow-up. Our data suggest that IFN treatment of chronic hepatitis C is often ineffective in eradicating HCV infection even in responders, and long-term follow-up study is necessary to determine the sustained beneficial effect of IFN.     

Effectiveness of glycyrrhizin for oral lichen planus in patients with chronic HCV infection

Oral lichen planus (OLP), an intractable inflammatory disease characterized by a band-like lymphocytic invasion under the oral mucosa, is frequently associated with hepatitis C virus (HCV) infection. We investigated the effects of glycyrrhizin, which is used to treat chronic liver dysfunction, in nine patients with OLP who were positive for HCV antibody and HCV RNA. A control group, eight patients with OLP who were also positive for HCV antibody and HCV RNA, was given only dental cleaning. Glycyrrhizin (GL) was given intravenously, at a dose of 40ml (0.2% solution) daily, for 4 consecutive weeks. Six (66.7%) of the nine patients given GL improved clinically (P=0.0141 vs non-GL group), suggesting that GL is useful in treating OLP.     

Challenge of managing hepatitis B virus and hepatitis C virus infections in resource-limited settings

The global burden of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections and coinfection represents a major public health concern, particularly in resource-limited settings. Elimination of HCV by 2030 has become foreseeable, with effective direct-acting antiviral oral therapies and the availability of affordable generics in low-and-middle-income countries (LMICs). However, access to oral nucleos(t)ide therapy for HBV remains critical and is limited outside the existing global HIV program platforms despite affordable prices. Prevention of mother-to-child transmission of HBV through scaling up of birth dose implementation in LMICs is essential to achieve the 2030 elimination goal. Most individuals living with HBV and/or HCV in resource-limited settings are unaware of their infection, and with improved access to medications, the most significant barrier remains access to affordable diagnostics and preventive strategies. The coronavirus disease 2019 pandemic interrupted hepatitis elimination programs, albeit offered opportunities for improved diagnostic capacities and raised political awareness of the critical need for strengthening health care services and universal health coverage. This review underpins the HBV and HCV management challenges in resource-limited settings, highlighting the current status and suggested future elimination strategies in some of these countries. Global efforts should continue to improve awareness and political commitment. Financial resources should be secured to access and implement comprehensive strategies for diagnosis and linkage to care in resource-constrained settings to fulfill the 2030 elimination goal.     

Correlation of serum HCV RNA and alanine aminotransferase levels in chronic hepatitis C patients during treatment with ribavirin

to evaluate the effect of ribavirin on serum hepatitis C virus (HCV) RNA and alanine aminotransferase (ALT) levels, 22 patients with chronic HCV infection were treated with oral ribavirin 1200 mg daily in three divided doses for 4 weeks. At the end of 4 weeks treatment, the serum ALT decreased in all but one patient and became normal in three individuals. The mean pretreatment serum ALT was reduced significantly from 193 ± 45 i.u./L to 95 ± 16 i.u./L after 4 weeks therapy (P= 0.009). However, 8 weeks after cessation of treatment, the serum ALT rose to a mean value of 154 ± 21 i.u./L. The mean pretreatment serum HCV RNA was not significantly decreased at the end of 4 weeks treatment (7.0 × 10⁵vs 4.1 × 10⁵ copies/mL, P > 0.05). However, serum HCV RNA levels were decreased in 12 and increased in 10 patients at the end of 4 weeks therapy. Eight weeks after cessation of therapy, the serum HCV RNA of 22 patients rose to a mean value of 4.9 ± 10⁵ copies/mL. Six patients who continued to have elevated serum ALT and positive HCV RNA after the initial 4 weeks treatment received oral ribavirin at the same dosage for an additional 24 weeks. The serum ALT again decreased in all six patients during therapy, but rose to pretreatment values by 8 weeks after cessation of the treatment. In addition, no significant changes were noted in the mean serum HCV RNA levels during and after 24 weeks of ribavirin therapy. Our results indicate that oral ribavirin only transiently lowered serum ALT values and did not efficiently suppress HCV synthesis in patients with chronic hepatitits C infection.     

HCV-marker-positive autoimmune-type chronic active hepatitis: a possible relation between HCV infection and liver autoreaction

This study focused on 32 patients who were diagnosed as having autoimmune hepatitis based upon clinical and histological factors. Fifteen of these patients were positive for HCV-RNA and for one of the HCV-related markers tested, including anti-C100, ELISA II, and RIBA 2 (Group 2). The remaining 17 patients were negative for all HCV-related markers (Group 1). Clinical factors in the two groups, including the frequency of autoantibodies, serum levels of aminotransferase and gammaglobulin, HLA phenotypes, and the response to corticosteroid treatments, were compared. The titer of serum anti-nuclear antibodies and the level of serum aminotransferase at initial diagnosis were significantly higher in Group 1 than in Group 2. Furthermore, the genetic background of the two groups, as indicated by HLA phenotypes, differed. All cases in Group 1 were HLA-DR4-positive, whereas only 60% of those in Group 2 cases had HLA-DR4. Also, all cases in Group 1 but only 66.7% of the cases in Group 2 showed good clinical responses to corticosteroid treatment. Finally, no cases of HCV-related-marker-positive autoimmune hepatitis (Group 2) had antibodies for LKM, suggesting that these cases were clinically different from type II autoimmune hepatitis. These data indicated that immunosuppressive treatment might be the preferred initial treatment in patients who either satisfy the criteria for AIH or who are sero-positive for an HCV-marker.     

Understanding the interaction of hepatitis C virus with host DEAD-box RNA helicases

The current therapeutic regimen to combat chronic hepatitis C is not optimal due to substantial side effects and the failure of a significant proportion of patients to achieve a sustained virological response.Recently developed direct-acting antivirals targeting hepatitis C virus(HCV)enzymes reportedly increase the virologic response to therapy but may lead to a selection of drug-resistant variants.Besides directacting antivirals,another promising class of HCV drugs in development include host targeting agents that are responsible for interfering with the host factors crucia for the viral life cycle.A family of host proteins known as DEAD-box RNA helicases,characterized by nine conserved motifs,is known to play an important role in RNA metabolism.Several members of this family such as DDX3,DDX5 and DDX6 have been shown to play a role in HCV replication and this review will summarize our current knowledge on their interaction with HCV.As chronic hepatitis C is one of the leading causes of hepatocellular carcinoma,the involvement of DEADbox RNA helicases in the development of HCC will also be highlighted.Continuing research on the interaction of host DEAD-box proteins with HCV and the contribution to viral replication and pathogenesis could be the panacea for the development of novel therapeutics against HCV.     

输血后丙型肝炎病毒感染的血清病毒定量研究

目的 研究血清丙型肝炎病毒（ＨＣＶ）含量与ＨＣＶ致病的关系及ＨＣＶ含量与抗－ＨＣＶ和丙氨酸转氨酶（ＡＬＴ）的相关性。方法 以逆转录－聚合酶链反应（ＲＴ－ＰＣＲ）法对ＨＣＶ感染的受血及相关供血系列血清进行ＨＣＶ ＲＮＡ定量分析,同时检测ＡＬＴ与抗－ＨＣＶ。结果 致输血后ＨＣＶ感染的供血中,ＨＣＶ ＲＮＡ平均含量为１０＾８．６拷贝／Ｌ,抗－ＨＣＶ及ＡＬＴ的异常检出率随ＨＣＶ ＲＮＡ滴度升高而增加。结论     

HCV基因型对慢性丙型肝炎干扰素疗效的影响

目的 探讨HCV基因型对慢性丙型肝炎的干扰素（IFN）治疗效果的影响。方法 采用随机、开放和对照的多中心临床试验设计。208例受试者按1：1随机分到聚乙二醇干扰素α—2a(Peg-IFN）组和IFN-α-2a组。在治疗之前，用Simmonds基因分型法酶切分型，在治疗24周结束和完成24周的随访后检测患者的ALT和HCV RNA，以HCV RNA的阴转率作为主要评价指标，经ITT人群的统计学分析。结果 202例患者确定了HCV基因型，基因1型158例（78.2%），非基因1型44例（21.8%），治疗结束病毒应答率（ETVR）和持续病毒应答率（SVR）基因1型患者分别为53.8%和25.3%，非基因1型患者分别为61.4%和43.2%，SVR两组患者差异有显著性，x^2=5.313,P=0.021。Peg IFN组基因1型和非1型患者的ETVR分别为76.8%和81.0%，SVR分别为35.4%和66.7%，SVR两组患者差异有显著性，x^2=6.735,P=0.01。病毒复发率基因1型和非基因1型患者分别为55.6%和23.5%，差异有显著性，x^2=5.496,P=0.02.IFN-α-2a组，ETVR和SVR基因1型患者分别为29.0%和14.5%，非基因1型患者分别43.5%和21.7%，差异无显著性。病毒复发率基因1型患者为72.7%，非基因1型患者为50.0%，差异无显著性。结论 IFN对基因1型丙型肝炎患者的疗效低于非基因1型，HCV基因型主要影响IFN对慢性丙型肝炎的持续应答，也与药物和IFN的疗程相关。     

Hepatitis C virus genotypes and hepatic fibrosis regulate 24-h decline of serum hepatitis C virus RNA during interferon therapy in patients with chronic hepatitis C

BACKGROUND AND AIMS: Recently, hepatitis C virus (HCV) dynamics during interferon (IFN) therapy have been studied in detail. We examined factors that regulate the viral kinetics and the relationship between the viral kinetics and clinical effect of IFN therapy. METHODS: Eighty-eight patients with chronic hepatitis C entered this study. All patients had been treated with 3 MU of IFN-beta twice a day for the first 2-4 weeks, then IFN-alpha for the next 20-22 weeks (three injections per week). The levels of serum HCV RNA were determined by Amplicor HCV Monitor version 1.0, before and 24 h after the first injection of IFN; then the decline of HCV was calculated. Liver inflammation and fibrosis were scored as 0 (none), 1 (mild), 2 (moderate) or 3 (severe) using biopsy specimens. RESULTS: The decline of serum HCV RNA was 1.42 +/- 0.65 log copies/mL in genotype 1b and 1.83 +/- 0.72 in genotype 2a or 2b (P < 0.01). By a logistic regression model, genotype (1b, 2a or 2b) and hepatic fibrosis (0 or 1, 2 or 3) associated with 24-h decline of serum HCV RNA, independently. As the predictor of IFN therapy, the decline of serum HCV RNA and serum HCV RNA levels before IFN therapy were the independent significant factors (P < 0.001). CONCLUSIONS: The decline of serum HCV RNA during the first 24 h of IFN therapy was regulated by genotypes and hepatic fibrosis. The decline of serum HCV RNA and initial HCV load were independent factors that can be the predictor of the subsequent sustained viral response to IFN therapy.     

慢性丙型肝炎病毒感染者外周血淋巴细胞增殖反应

目的　观察慢性丙型肝炎患者外周血淋巴细胞对丙型肝炎病毒（ＨＣＶ） 抗原刺激的增殖反应．方法　外周血单个核细胞（ＰＢＭＣ） 与ＨＣＶ 抗原ｃ２２ 、ｃ３３ 、ｃ１００ － ３ 、ＮＳ５ 和植物血凝素（ＰＨＡ） 分别共同孵育,加入胸腺嘧啶核苷（３ ＨＴｄＲ） ,然后收集细胞于液闪仪测定每分钟脉冲数（ｃｐｍ） ．结果　根据对不同ＨＣＶ 抗原的淋巴细胞增殖反应发现,以ｃ２２免疫原性最强,ｃ１００ － ３ 次之：淋巴细胞激活与ＨＣＶ 基因型关系不大;健康对照和慢性乙型肝炎患者对各ＨＣＶ 抗原未能显示有效的淋巴细胞增殖反应;与健康对照比较,慢性丙型肝炎和乙型肝炎患者对ＰＨＡ 刺激的淋巴细胞增殖反应降低．结论　ＨＣＶ 抗原ｃ２２ 免疫原性最强,丙型肝炎患者对ＨＣＶ 抗原的淋巴细胞增殖反应系特异性;慢性丙型肝炎和乙型肝炎患者存在抑制的细胞免疫应答．     

Sero-epidemiologic study of hepatitis C virus infection in Fukuoka, Japan

We conducted an epidemiological study of 509 residents of H town, Fukuoka, Japan, to investigate the high mortality rate from liver disease. Antibodies to hepatitis C virus (HCV) (anti-HCV) were detected in 120 residents (23.6%); HCV RNA in 91 (17.9%), and hepatitis B surface antigen (HBsAg) in 13 (2.6%). Multivariate logistic regression analyses showed that presence of anti-HCV, male gender, and history of liver disease were associated with the presence of liver dysfunction, and that age of more than 40 years and a particular district were associated with the presence of anti-HCV. HCV RNA was more frequently detected in anti-HCV-positive men than women (41, or 85.4% versus 50, or 69.4%) (P < 0.05). The incidence of liver dysfunction was significantly higher in HCV RNA-positive men than women (32, or 66.7% versus 22, or 30.6%) (P < 0.05). These findings suggest that: (1) HCV was correlated with the high mortality rate from liver diseases, (2) there were district-related differences in the incidence of HCV, and (3) the lower frequency of elimination of HCV from men may explain why they showed a high mortality from liver disease. (Received Mar. 4, 1997; accepted Aug. 22, 1997)     

Occult persistence and lymphotropism of hepatitis C virus infection

Recent discovery of occult hepatitis C virus （HCV） infection persisting after spontaneous or antiviral therapy-induced resolution of hepatitis C was made possible by the introduction of nucleic acid amplification assays capable of detecting HCV RNA at sensitivities superseding those offered by clinical tests. Although individuals with this seemingly silent HCV infection are usually anti-HCV antibody reactive and have normal liver function tests, occult HCV infection has also been reported in anti-HCV-negative individuals with persistently elevated liver enzymes of unknown etiology. Studies have shown that HCV RNA can persist for years in serum, lymphomononuclear cells and liver in the absence of clinical symptoms, although histological evidence of a mild inflammatory liver injury can be occasionally encountered. Furthermore, while HCV RNA can be detected in circulating lymphoid cells in approximately 30% of cases, a short-term culture under stimulatory conditions augments HCV replication in these cells allowing detection of virus in otherwise HCV-negative cases. HCV infects different immune cell subsets, including CD4^＋ and CD8^＋ T lymphocytes, B cells and monocytes. Studies employing clonal sequencing and single-stranded conformational polymorphism analyses have revealed unique HCV variants residing in immune cells, further strengthening the notion of HCV lymphotropism. Overall, the data accumulated suggest that occult HCV infection is a common consequence of resolution of symptomatic hepatitis C and that examination of the cells of the immune system is an effective approach to diagnosis of HCV infection and its long-term persistence. Further work is required to fully realize pathogenic and epidemiological consequences of occult HCV persistence.     

Incidence of extrahepatic cancers among individuals with chronic hepatitis B or C virus infection: A nationwide cohort study

This study examined the association between chronic HBV or HCV infection and the risk of extrahepatic cancers. A total of 537 103 adults aged ≥20 years without history of cancer were identified from the Korean National Health Insurance Service‐National Sample Cohort between 2003 and 2013. The difference in cancer incidence was compared between those with and without chronic HBV or HCV infection. During 3 854 130 person‐years of follow‐up (median follow‐up: 8.0 years), 19 089 participants developed cancer. After adjusting for sex, body mass index, smoking, drinking, income percentile, residential area and comorbidities, hazard ratios (HRs) for incident extrahepatic cancer were significantly higher in participants with chronic HBV infection (HR: 1.27, 95% confidence interval [CI]: 1.20‐1.35), HCV infection (HR: 1.31, 95% CI: 1.16‐1.48) or HBV/HCV dual infection (HR: 1.41, 95% CI: 1.31‐1.72) compared to participants without HBV or HCV infection. In chronic HBV infection, the cancer risk was higher for haematologic malignancy [HR (95% CI) = 2.46 (1.92‐3.15)], gallbladder [1.55 (1.05‐2.29)], pancreas [1.52 (1.07‐2.15)], stomach [1.39 (1.22‐1.58)], lung [1.27 (1.04‐1.55)], colorectum [1.21 (1.03‐1.42)] and thyroid cancer [1.20 (1.05‐1.36)]. In chronic HCV infection, the cancer risk was higher for testis [10.34 (1.35‐79.78)], gallbladder [2.90 (1.62‐5.18)], prostate [2.51 (1.65‐3.82)] and thyroid cancer [1.46 (1.10‐1.93)]. In conclusion, chronic HBV or HCV infection was not only associated with an increased risk of liver cancer, but also associated with an increased risk of multiple extrahepatic cancers.     

Hepatitis C virus (HCV) genotypes in Spanish patients with HCV infection: relationship between HCV genotype 1b, cirrhosis and hepatocellular carcinoma

Background/Aims: The influence of the infecting virus genotype on the progression of the underlying liver disease in patients with chronic hepatitis C virus (HCV) infection remains controversial. The aim of this study was to investigate the prevalence of HCV genotypes in Spanish patients with chronic HCV infection and to elucidate the relationship between the infecting genotype and severity of the disease.Methods: A cross-sectional, retrospective analysis of frequency distribution of HCV genotypes was carried out in 414 Spanish patients with chronic HCV infection, including 243 patients with asymptomatic or minimally symptomatic chronic hepatitis, 112 patients with cirrhosis and hepatocellular carcinoma and 59 patients with decompensated cirrhosis. HCV genotype was determined by restriction fragment length polymorphisms of the 5′ non-coding region.Results: Infection with HCV genotype 1b was found in 72% of patients with chronic hepatitis and in more than 90% of patients with cirrhosis, with or without hepatocellular carcinoma. Older age, infection with genotype 1b and absence of overt parenteral exposure as a possible source of infection were associated with cirrhosis and hepatocellular carcinoma by univariate analysis and this association was confirmed by regression analysis.Conclusions: HCV genotype 1b is associated with advanced liver disease in our geographical area. However, this may be related to a cohort-effect caused by over-representation of genotype 1b in older patients with more advanced disease, because, in our country, this HCV genotype appeared earlier in time and is therefore associated with more prolonged periods of infection.