Impact of ribavirin exposure on early virological response to hepatitis C therapy in HIV-infected patients with chronic hepatitis C

BACKGROUND: The use of pegylated interferon (PEG-IFN) plus ribavirin (RBV) is currently the recommended treatment for chronic hepatitis C virus (HCV) infection. Coinfection with HIV is a negative predictor of response, for reasons not well understood. METHODS: We examined the virological response at weeks 4 and 12 in 198 HCV/HIV-coinfected patients enrolled in a prospective trial in which PEG-IFN alpha 2a (180 microg per week) and RBV (1000-1200 mg daily) were provided. RESULTS: In an on-treatment analysis, 52.8% of patients achieved undetectable HCV-RNA (<600 IU/ml) at week 4, while 63% and 77.2% of patients had a decline of at least 2 and 1 log10, respectively. At week 12, 73.1% of patients reached undetectable HCV-RNA, and 83.5% and 89% achieved at least a 2- and 1-log10 drop, respectively. More than 85% of HCV genotypes 2/3 cleared HCV-RNA at week 4, a proportion significantly higher when compared with genotypes 1 (33.8%) and 4 (28.6%). Multivariate logistic regression analysis identified genotype 3 and RBV exposure (mg/kg of body weight) as independent predictors of virological response at week 12 of therapy. CONCLUSION: Early virological response rates to PEG-IFN plus RBV in HCV/HIV-coinfected patients seem to be similar to those reported for HCV-monoinfected subjects. The use of suboptimal doses of RBV in most earlier trials might account for the low response rates seen in coinfected patients. To our knowledge, this is the first report demonstrating that RBV exerts a significant independent effect on early virological response. Therefore, strategies aimed at optimizing doses and adherence to RBV might help to improve responses to HCV therapy in coinfected patients.     

High prevalence of glucose abnormalities in patients with hepatitis C virus infection: a multivariate analysis considering the liver injury

OBJECTIVE: The aim of this study was to compare the prevalence of both impaired fasting glucose (IFG) and diabetes between hepatitis C virus (HCV)-infected patients and patients with other liver diseases but anti-HCV-, taking into account the degree of liver damage. RESEARCH DESIGN AND METHODS: A total of 642 consecutive patients attending the outpatient liver unit of a university hospital (498 anti-HCV+ and 144 anti-HCV-) were prospectively recruited. Patients were classified as having chronic hepatitis (n = 472) or cirrhosis (n = 170) by means of the result of either a liver biopsy or by typical clinical features. A logistic regression model was used to determine independent associations of covariates (age, sex, BMI, HCV antibody status, and triglycerides) with the presence of glucose abnormalities. RESULTS: A threefold increase in the prevalence of glucose abnormalities was observed in HCV+ patients with chronic hepatitis in comparison with HCV- subjects (32 vs. 12%; P = 0.0003). In contrast, among patients with cirrhosis, although both diabetes and IFG were more prevalent in anti-HCV+ patients (40%) than in anti-HCV- patients (36%), the differences were not statistically significant. Finally, the logistic regression analysis showed that HCV infection was independently related to glucose abnormalities in those patients with chronic hepatitis (odds ratio 4.26 [95% CI 2.03-8.93]). In contrast, HCV was not an independent predictor of glucose abnormalities in cirrhotic patients. CONCLUSIONS: The high prevalence of IFG and diabetes found in HCV-infected patients observed in our study suggests that screening for glucose abnormalities should be indicated in these patients. In addition, we provide evidence that the genuine connection between HCV infection and diabetes is initiated at early stages of hepatic disease.     

慢性丙型肝炎患者第一高变区抗体的交叉反应性与抗病毒治疗早期病毒应答的关系

目的 探讨慢性丙型肝炎患者血清第一高变区( HVR1)抗体的交叉反应性与抗病毒治疗早期病毒应答(EVR)的关系.方法 用ELISA丙型肝炎病毒(HCV)HVR1抗体交叉反应性矩阵试剂检测抗HCV高变区抗体差异性,16条高变区抗原与患者血清交叉反应性比较采用Fisher精确概率检验.同时对2009年1月至12月首都医科大学附属北京佑安医院46例慢性丙型肝炎患者抗病毒治疗前基线血清标本进行分析.用荧光定量逆转录(RT)-PCR检测46例患者在治疗前、聚乙二醇干扰素联合利巴韦林治疗12周、48周的血清HCV RNA水平,并进行基因分型.结果 46例慢性丙型肝炎患者中,HCV2a型16例,1b型30例;治疗12周及结束时分别检测HCV RNA,其中,EVR组33例,非EVR组13例;2a型EVR发生率[93.8％ (15/16)]高于1b型[60.0％( 18/30),x2=4.316,P＜0.05].HCV 1b型慢性丙型肝炎患者中,EVR组平均多靶点HVR1抗原阳性反应数目为(12±4)个,明显高于非EVR组[(7±5)个,t=2.797,P＜0.01].经Fisher精确概率法检验,HVR1抗原编号分别为001、003、009、013、016的5条抗原在EVR组患者基线血清的反应阳性率明显高于非EVR组(P均＜0.05).结论 HVR1抗体的交叉反应性可能是一项抗病毒治疗疗效的预测指标.     

Quantitative analysis of the peripheral blood cytotoxic T lymphocyte response in patients with chronic hepatitis C virus infection.

Hepatitis C virus (HCV)-specific cytotoxic T lymphocytes (CTL) are present in the peripheral blood and liver of chronically infected patients. The current study was performed to study the relationship between the strength of the CTL response, liver disease severity, and viral load. The results may be summarized as follows: first, using CTL precursor frequency (CTLpf) analysis to quantitate the peripheral blood CTL response, chronically infected patients were less strongly sensitized to a panel of well-defined HCV epitopes than they were to an epitope within the influenza matrix protein. Second, HCV-specific CTLpf did not correlate with disease activity or viral load in the majority of patients on a cross-sectional basis, although it did increase in three patients concomitant with sharp increases in liver disease. Finally, interferon therapy did not enhance the CTLpf against the HCV epitopes studied in these patients, indicating that its antiviral effect is independent of the CTL response. Since the HCV-specific CTLpf in the blood is actually quite low, the CTL may contribute to ongoing liver disease in these patients while being quantitatively inadequate to destroy all of the infected hepatocytes, thereby facilitating HCV persistence and contributing to chronic liver disease.     

Danoprevir monotherapy decreases inflammatory markers in patients with chronic hepatitis C virus infection

Danoprevir is a potent and selective direct-acting antiviral agent that targets the protease activity of hepatitis C virus (HCV) NS3/4A. This agent results in a significant rapid decline in HCV RNA levels when it is used in monotherapy. The present study evaluated whether plasma concentrations of the inflammatory markers gamma interferon-inducible protein 10 (IP-10) and neopterin or the interferon-stimulated gene product 2'-5'-oligoadenylate synthetase (OAS-1) were correlated with the plasma HCV RNA concentration before or during 14-day danoprevir monotherapy. In contrast to pegylated interferon and ribavirin treatment, a higher baseline IP-10 concentration was positively correlated with a greater first-phase HCV RNA decline upon danoprevir administration. Changes in the IP-10 plasma concentration during danoprevir administration were also associated with categorical changes in HCV RNA concentration at days 7 and 14. The neopterin concentration appeared to be moderately decreased during danoprevir administration, although these changes were not statistically significant. However, changes in neopterin concentration showed a statistically significant correlation with changes in IP-10 concentration. Considerable variation in the OAS-1 concentration was observed before and during treatment, including in patients treated with placebo and/or patients with minimal virologic response. Overall, these results suggest that effective treatment with a direct-acting antiviral agent may reduce hepatic inflammation and that first-phase HCV RNA decline during treatment with an NS3/4A protease inhibitor is more robust in patients with high baseline IP-10 concentrations.     

Phylogenetic analysis of hepatitis GB virus type C/hepatitis G virus in Spanish patients with chronic hepatitis B or C virus infection.

The nucleotide sequence of hepatitis GB virus type C (HGBV-C)/hepatitis G virus (HGV) NS3/helicase and 5'-untranslated regions from 23 Spanish patients were analyzed to assign the HGV isolates one of the proposed HGBV-C/HGV genotypes. The analysis of the evolutionary distance frequency showed that the distances among all sequences in NS3/helicase region were distributed around a single peak of 0.20, suggesting that all included sequences belonged to the same HGBV-C/HGV genotype. By contrast, in the 5'-untranslated region, all the distances corresponding to our sequences and those of the HGBV-C/HGV types 2 and 3 were distributed around a major peak of 0.03. The remaining distances corresponding to the HGBV-C/HGV type 1 sequences were distributed around a minor peak of 0.11. The phylogenetic tree and pairwise comparison of evolutionary distances among the 5'-untranslated region of the infected patients and each HGBV-C/HGV genotype demonstrated that our HGBV-C/HGV isolates belonged to subtype 2a (17/23; 78%) and 2b (5/23; 22%). No relation was found between HGBV-C/HGV subtype and hepatitis B or C virus infection.     

Treatment of chronic hepatitis C virus infection

OBJECTIVE: To review the literature on the treatment of chronic hepatitis C virus (HCV) infection. DATA SOURCES: MEDLINE search (1986-December 1999) using key words such as HCV, hepatitis, non-A and non-B hepatitis, as well as terms regarding treatment during that time period. DATA SYNTHESIS: HCV infection was initially treated with interferon monotherapy, but only a minority of patients responded to long-term therapy. A higher rate of response in both interferon-na?ve patients and interferon-relapsers has been achieved by using the combination of interferon and ribavarin. Other treatment regimens including high-dose interferon protocols, ursodeoxycholic acid, amantadine, and nonsteroidal antiinflammatory drugs have been less promising. Many alternative therapies are being investigated. CONCLUSIONS: HCV infection is a major public health problem. It is now possible to achieve a cure in nearly 50% of the patients with this infection. Many additional therapies are being evaluated in order to achieve a higher cure rate.     

In situ analysis of intrahepatic virological events in chronic hepatitis B virus infection

Persistent hepatitis B virus (HBV) infection is established by the formation of an intranuclear pool of covalently closed circular DNA (cccDNA) in the liver. Very little is known about the intrahepatic distribution of HBV cccDNA in infected patients, particularly at the single-cell level. Here, we established a highly sensitive and specific ISH assay for the detection of HBV RNA, DNA, and cccDNA. The specificity of our cccDNA probe set was confirmed by its strict intranuclear signal and by a series of Southern blot analyses. Use of our in situ assay in conjunction with IHC or immunofluorescence uncovered a surprisingly mosaic distribution of viral antigens and nucleic acids. Most strikingly, a mutually exclusive pattern was found between HBV surface antigen–positive (HBsA-positive) and HBV DNA– and cccDNA-positive cells. A longitudinal observation of patients over a 1-year period of adeforvir therapy confirmed the persistence of a nuclear reservoir of viral DNA, although cytoplasmic DNA was effectively depleted in these individuals. In conclusion, our method for detecting viral nucleic acids, including cccDNA, with single-cell resolution provides a means for monitoring intrahepatic virological events in chronic HBV infection. More important, our observations unravel the complexity of the HBV life cycle in vivo.     

Chemokine antagonism in chronic hepatitis C virus infection

Immune responses to hepatitis C virus (HCV) fail to clear the virus in most individuals. Why patients who are less likely to clear HCV infection have high plasma levels of CXCL10 (also known as IP-10), a chemokine that directs T cells to sites of infection, has long been unclear. In this issue of the JCI, Casrouge and colleagues shed light on this paradox by showing that CXCL10 in the plasma of many HCV patients is enzymatically processed to produce a CXCL10 receptor antagonist. These findings introduce a role for chemokine antagonism during HCV infection and unveil new avenues for improved HCV diagnosis and therapy.     

高病毒载量慢性丙型肝炎快速病毒学应答的预测因素分析

目的探讨高病毒载量慢性丙型肝炎抗病毒治疗的快速病毒学应答(RVR)预测因素。方法对55例高病毒载量(HCVRNA>1×105拷贝/ml)慢性丙型肝炎使用聚乙二醇干扰素α-2a联合利巴韦林进行抗病毒治疗者进行前瞻性研究,聚乙二醇干扰素α-2a135μg或180μg/次,皮下注射,每周1次,利巴韦林900～1200mg/d口服,于治疗前及治疗第4周检测HCVRNA定量,4周血清HCVRNA检测不到为获得RVR。采用Logistic多元回归分析RVR的影响因素,并比较治疗前不同病毒载量患者RVR的比例。结果 RVR与基线病毒载量呈负相关(B=-1.292)。基线HCVRNA≥1×105拷贝/ml且<1×107拷贝/ml者快速应答率为86.49%(32/37),基线HCVRNA≥1×107拷贝/ml者快速应答率为61.11%(11/18),两组比较有统计学差异(χ2=4.571,P=0.043)。结论基线HCVRNA水平可作为高病毒载量慢性丙型肝炎患者聚乙二醇干扰素联合利巴韦林治疗过程中RVR的预测因素,治疗前HCVRNA<1×107拷贝/ml者疗效较好。     

Graves' disease in interferon-alpha-treated and untreated patients with chronic hepatitis C virus infection.

An association between Graves' disease (GD) and chronic hepatitis C (C-HC) has been observed both in the presence and the absence of recombinant interferon-alpha (rIFN-alpha) treatment. rIFN-alpha-induced GD is characterized by suppressed thyroid-stimulating hormone levels; normal or elevated free triiodothyronine (FT3) and free thyroxine (FT4) values; the presence of thyroid peroxidase antibodies, antithyroglobulin antibodies, and thyroid receptor antibodies; and high iodine thyroid uptake. In contrast, GD developed during C-HC without rIFN-alpha is less clearly defined. In this study, we examined two groups of patients: group A, 28 patients with C-HC treated with rIFN-alpha who developed GD after 1 to 9 months, and group B, 10 patients with C-HC who developed GD without a previous rIFN-alpha treatment. At the time of GD, both groups started methimazole therapy; thyroid function was reevaluated after 3, 6, 9, and 12 months. Group A patients continued IFN. After 12 months, all patients of group A were euthyroid, and 21 of them (75%) had already stopped methimazole treatment, whereas all patients of group B were euthyroid and only 2 (20%) had stopped methimazole. In conclusion, the data show a better course of GD, with a more precocious and significantly higher number of recoveries in patients with rIFN-alpha-induced GD than in rIFN-alpha-unrelated disease. Further studies are needed to establish whether the two types of GD differ not only from a clinical point of view but also because of different underlying pathogenetic mechanisms.     

福建省慢性丙型肝炎患者丙型肝炎病毒基因分型的分析

目的观察福建省慢性丙型肝炎患者基因型分布特点以及与患者性别、年龄、丙型肝炎病毒（HCV） RNA 之间的关系。方法应用反转录聚合酶链反应（RT-PCR）和 SANGER 测序法对155例慢性丙型肝炎患者的HCV 进行基因分型。结果在155例标本中,HCV 基因1型占55．48％,基因2型占18．71％,基因3型13．51％,基因6型12．26％,未见基因4、5型;男女慢性 HCV 感染均以1型为主要基因型,在其他基因型中,男性3型、6型多于2型,女性则以2型为主,差异有统计学意义（P ＜0．05）;基因2型平均年龄为（49岁）,3型平均年龄为（35岁）,差异有统计学意义（P＜0．05）。结论福建地区 HCV 基因型以1b 型为主,其次是2a 型,未见基因4、5型;基因2型的感染者平均年龄较基因3型大。     

Long-term follow-up of HIV-infected patients with chronic hepatitis C virus infection treated with interferon-based therapies

BACKGROUND: Chronic hepatitis C virus (HCV) infection is frequent among HIV-infected patients. Clearance of serum HCV RNA 6 months after discontinuing HCV therapy is generally interpreted as a cure of HCV infection in HIV-negative subjects. However, the occurrence of liver complications (including hepatocellular carcinoma) and/or HCV relapses in coinfected patients when followed for long periods of time after HCV therapy is not well known. METHODS: All HIV-infected patients who had been treated for chronic hepatitis C at our institution and had a minimum follow-up of 6 months after discontinuing therapy were retrospectively analysed. They had received one of three HCV treatment modalities: IFN monotherapy, IFN plus ribavirin (RBV) or pegylated interferon (PEG-IFN) plus RBV. RESULTS: A total of 351 patients were retrospectively analysed. Sustained virological response (SVR) to HCV therapy had been reached by 77 (22%) of them: 22/119 (18.5%) with IFN monotherapy, 17/106 (16%) with IFN plus RBV and 38/126 (30.2%) with PEG-IFN plus RBV. Considering the HCV genotypes, SVR had been reached by 19/184 (10.3%) of patients with genotype 1, 54/138 (39.1%) with genotypes 2 or 3, and 4/29 (13.8%) of those with genotype 4. Within a total of 4466 patient-months follow-up (mean of 58 months), none of the 77 patients with SVR showed HCV-RNA rebounds, elevations in liver enzymes potentially linked to HCV, development of hepatocellular carcinoma or episodes of decompensated cirrhosis. In contrast, all 274 patients who did not reach SVR with HCV therapy showed evidence of persistent serum HCV RNA and 90% of them showed liver enzyme elevations during a total of 15344 patient-months follow-up (mean of 56 months). Moreover, 11 (4%) developed clinical complications of liver cirrhosis and two of them died of end-stage liver disease. CONCLUSIONS: HCV replication and HCV-related liver disease seem to be permanently halted in HIV/HCV-coinfected patients showing HCV-RNA clearance 6 months after completing any kind of IFN-based therapy. In contrast, complications of liver disease due to persistent HCV infection continue to occur in non-responders. The role of maintenance HCV therapy should be explored in HIV/HCV-coinfected patients.     

Increased risk of type 2 diabetes in noncirrhotic patients with chronic hepatitis C virus infection

OBJECTIVES: To investigate whether patients with chronic hepatitis C virus (HCV) infection without evidence of cirrhosis have an increased risk of diabetes mellitus (DM) and to evaluate possible risk factors for diabetes in this group. PATIENTS AND METHODS: We conducted a case-control study of 45 consecutive eligible patients with HCV infection and no clinical, scintigraphic, or histological evidence of cirrhosis, and a control group of 90 subjects without liver disease matched by age, sex, and body mass index and similar in their origin distribution. Eighty-eight patients with chronic hepatitis B virus (HBV) infection with no evidence of cirrhosis were also evaluated. The diagnosis of diabetes was based on the 1997 American Diabetes Association criteria. RESULTS: Fifteen patients (33%) with HCV infection were found to have type 2 diabetes compared with 5.6% in the control group without liver disease (P < .001) and 12% in the group with HBV infection (P = .004). Comparison of the patients with and without diabetes revealed that positive family history of diabetes, HCV 1b genotype, and a more severe liver histology were significantly associated with DM. CONCLUSIONS: Patients with chronic HCV infection have an increased prevalence of type 2 diabetes, and this prevalence is independent of cirrhosis. The pathogenesis is intriguing, appears to be unique to HCV, and requires further study.     

Prevalence of mixed infection by different hepatitis C virus genotypes in patients with hepatitis C virus-related chronic liver disease.

Multiple infection by different hepatitis C virus (HCV) genotypes may be of great clinico-pathologic interest. In this study we determined the effective prevalence of coinfections by two or more HCV genotypes in 213 subjects with HCV-positive chronic hepatitis by using genotype-specific polymerase chain reaction (PCR), genotype-specific probe hybridization, and direct sequencing. The most prevalent genotype was HCV-1b (54%). HCV-2 (a/c) was also prevalent (27%), and types 1a and 3a were found in 5% and 3% of patients, respectively. A mixed infection was detected in 23 patients (10.8%): 4 out of 23 were coinfected by types 1a + 1b, while the remaining 19 patients had a b + 2 (a/c) mixed infection. Further analysis based on restriction fragment length polymorphism (RFLP) on type-specific PCR products was used to verify genotyping results. Only four coinfections (1a + 1b in 2 patients and 1b + 2 (a/c) in the remaining 2 patients, respectively) were confirmed by enzyme cleavage. All patients with true coinfection had long-lasting infection and liver cirrhosis. Both true and false mixed infections resulting from RFLP analysis were confirmed by direct sequencing of type-specific amplification products. We also determined a recurrent C/T transversion at position 618 in all sequenced samples. In 4 cases another point mutation (G/A at position 626) was found, reducing the number of mismatches between HCV-2 and HCV-1b from 4 to 3 (or 2). Interestingly, all HCV-2 isolates sequenced showed the highest degree of nucleotide homology with HCV-2 subtype c, confirming the relatively high prevalence of this subtype in Italy. In conclusion, we showed the possibility of multiple infection by different HCV types in the general population of chronically infected patients without particular risk factors, even if in a low percentage of cases. Further studies are needed to assess the clinical relevance of chronic HCV infection with multiple genotypes.