The impact of insulin resistance, serum adipocytokines and visceral obesity on steatosis and fibrosis in patients with chronic hepatitis C

Aims To assess whether host metabolic factors influence the degree of hepatic steatosis and fibrosis in patients infected with hepatitis C virus, and to evaluate the impact of anti‐viral therapy on insulin resistance and serum levels of adipocytokines. Methods Clinical and biochemical features, anthropometrical characteristics, and levels of fasting insulin, leptin, adiponectin and resistin were measured in ‘naïve’ patients with chronic hepatitis C, before, during and after therapy with Peg‐Interferon‐alpha 2a plus Ribavirin. Results Forty‐eight patients were included (M/F 28/20; mean age 50.0 ± 12.6 years; 62.5% genotype‐1). Body mass index was 26.4 ± 4.0 kg/m², and visceral obesity was present in 24 patients. At multivariate analysis (RR; 95% CI), steatosis was associated to older age (1.08; 1–1.18), necroinflammatory activity (17.67; 1.6–194.46), and raised insulin levels (1.39; 1.1–1.77). Fibrosis was related to necroinflammatory activity (25.73; 2.54–261.11), and steatosis (6.47; 1.09–38.29). Sustained viral response was achieved by 62.5% of patients and was associated with younger age (0.92; 0.85–0.99), genotype non‐1 (10.61; 1.52–73.76) and absence of visceral obesity (13.78; 2.36–80.29). At the end of follow‐up, insulin and the homeostasis model assesment for insulin resistance were reduced and adiponectin increased when compared with baseline, all unrelated to the outcome of treatment. Conclusions Visceral obesity correlates with the degree of steatosis and fibrosis, and it negatively affects treatment response. Significant changes of insulin resistance and adipocytokines occur under treatment, irrespective of virological outcome.     

Human immunodeficiency virus (HIV) protease inhibitors have no effect on hepatitis C virus (HCV) serum levels of HIV-HCV co-infected patients

Ten severely immunocompromised HIV-HCV co-infected patients were enrolled in a quantifiable HCV-RNA assay. Serum alanine aminotransferase, HCV-RNA levels and HIV viral loads were determined at baseline, at month three and at month six after initiation of a highly active antiretroviral therapy including an HIV protease inhibitor. HCV genotypes were determined using a line probe assay kit. Our results suggested that this therapy did not result in lower HCV viraemia, whatever the HCV genotypes, and probably had no effect on the outcome of chronic viral hepatitis C. As our patients were severely immunocompromised and their mean increase of CD4 cell counts was less than 50/mm(3), we cannot reach any conclusions about the impact of the improvement of immune status on the HCV-RNA load.     

广东地区丙型肝炎患者HCV基因亚型分析

目的 了解广东地区丙型肝炎患者HCV的基因亚型分布特征,为丙型肝炎的治疗与预防提供依据.方法 采用巢式逆转录-聚合酶链反应扩增广东省194例丙型肝炎患者HCVNS5B基因区域,特异性PCR产物测序后通过美国洛斯拉莫斯国家实验室HCV数据库的Blast程序进行HCV基因亚型分析.结果 194例丙型肝炎患者中有99例为单纯HCV感染者、95例为HIV/HCV共感染者.丙型肝炎患者HCV共有8种基因亚型,其中1b亚型占42.3％(82/194)、6a亚型占35.0％(68/194)、3a亚型占11.9％(23/194)、3b亚型占6.7％(13/194)、2a亚型占2.6％(5/194)、1a亚型占0.5％(1/194)、4a亚型与0.5％(1/194)、5a亚型占0.5％(1/194).丙型肝炎患者中的单纯HCV感染者HCV有7种基因亚型,以1b亚型为主,占67.7％(67/99);丙型肝炎患者中的HIV/HCV共感染者HCV有5种基因亚型,以6a亚型为主,占53.7％(51/95).结论 广东地区丙型肝炎患者HCV基因亚型呈现多样性,主要基因亚型为1b亚型和6a亚型;丙型肝炎患者中的单纯HCV感染者与HIV/HCV共感染者HCV主要基因亚型不同.     

Baclofen promotes alcohol abstinence in alcohol dependent cirrhotic patients with hepatitis C virus (HCV) infection

Hepatitis C virus (HCV) and alcoholic liver disease (ALD), either alone or in combination, count for more than two thirds of all liver diseases in the Western world. There is no safe level of drinking in HCV-infected patients and the most effective goal for these patients is total abstinence. Baclofen, a GABA(B) receptor agonist, represents a promising pharmacotherapy for alcohol dependence (AD). Previously, we performed a randomized clinical trial (RCT), which demonstrated the safety and efficacy of baclofen in patients affected by AD and cirrhosis. The goal of this post-hoc analysis was to explore baclofen's effect in a subgroup of alcohol-dependent HCV-infected cirrhotic patients. Any patient with HCV infection was selected for this analysis. Among the 84 subjects randomized in the main trial, 24 alcohol-dependent cirrhotic patients had a HCV infection; 12 received baclofen 10mg t.i.d. and 12 received placebo for 12-weeks. With respect to the placebo group (3/12, 25.0%), a significantly higher number of patients who achieved and maintained total alcohol abstinence was found in the baclofen group (10/12, 83.3%; p=0.0123). Furthermore, in the baclofen group, compared to placebo, there was a significantly higher increase in albumin values from baseline (p=0.0132) and a trend toward a significant reduction in INR levels from baseline (p=0.0716). In conclusion, baclofen was safe and significantly more effective than placebo in promoting alcohol abstinence, and improving some Liver Function Tests (LFTs) (i.e. albumin, INR) in alcohol-dependent HCV-infected cirrhotic patients. Baclofen may represent a clinically relevant alcohol pharmacotherapy for these patients.     

Serum HCV RNA levels and HCV genotype do not affect insulin resistance in nondiabetic patients with chronic hepatitis C: a multicentre study

Background  Chronic hepatitis C (CHC) induces insulin resistance (IR) and subsequently diabetes.
Aim  To examine viral, metabolic and histological predictors of IR in 275 CHC patients to test the hypothesis that IR differs among HCV genotypes and that viral replication directly affects IR.
Methods  We studied 275 nondiabetic treatment-naïve CHC patients. Histological lesions were evaluated according to Ishak. IR was assessed using homeostasis model assessment for insulin resistance (HOMA-IR).
Results  HOMA > 3.0 was found in 37% of patients, independently associated with higher BMI and GGT. In genotype non-3 patients, HOMA > 3.0 was associated with higher BMI and GGT values, while no significant association was noted in genotype 3 patients. In non-obese patients with minimal fibrosis, HOMA > 3.0 was found in 20% of cases without significant differences among genotypes. No association between HOMA > 3.0 and HCV-RNA levels was found. Severe fibrosis (stage 5–6) related to older age (OR:1.048), HOMA-IR (OR:1.177), necroinflammation (OR: 2.990) and higher ALT (OR: 1.009) and GGT (OR:1.006).
Conclusions  IR develops at early stages of CHC without significant differences among genotypes. It is more frequent in obese patients with steatosis and contributes to fibrosis progression. However, IR does not seem to be associated with viraemia and therefore its exact pathogenetic mechanism in CHC remains elusive.     

Hepatic steatosis and insulin resistance are associated with serum imbalance of adiponectin/tumour necrosis factor-alpha in chronic hepatitis C patients

BACKGROUND: Steatosis and insulin resistance (IR) have a pathogenic role in chronic hepatitis C (HCV). Adipocytokines balance modulates hepatic lipid content and IR. AIM: To evaluate serum adipocytokines and relationship with virological, histological and metabolic parameters in chronic HCV. METHODS: Adiponectin and tumour necrosis factor-alpha (TNF-alpha) levels, HCV genotypes, HCV-RNA, IR (HOMA-IR), body mass index and liver steatosis and fibrosis were assessed in 161 non-diabetic chronic HCV patients. RESULTS: Chronic HCV patients with steatosis showed lower serum adiponectin levels and higher levels of TNF-alpha, HOMA, alanine aminotransferase, gamma-glutamiltransferase and Histological Activity Index (HAI) and fibrosis scores. Low adiponectin levels were independently associated with grades of steatosis and HOMA-IR. Higher tumour necrosis factor-alpha levels were observed in patients with low adiponectin levels. The extension of steatosis was inversely correlated with adiponectin levels. A correlation between grade of steatosis with HOMA-IR and fibrosis was observed. HCV genotype 3-infected patients showed lower adiponectin levels than those with other genotypes. An independent predictor of low adiponectin levels in genotype 3 infection was the extension of steatosis. Liver fibrosis score was associated with steatosis, HAI and age. CONCLUSIONS: Chronic HCV patients with steatosis showed a serum adiponectin/TNF-alpha imbalance that is associated with IR. Reduced adiponectin levels may be involved in the pathogenesis of steatosis, which in turn accelerates progression of fibrosis in chronic HCV.     

妊娠合并慢性丙型病毒性肝炎患者胰岛素抵抗状况分析

目的 分析妊娠合并慢性丙型病毒性肝炎患者的胰岛素抵抗状况.方法 选择87例妊娠合并慢性丙型病毒性肝炎患者为观察组,80例未合并丙型肝炎孕妇为对照组.检测并比较两组空腹血糖(FPG)、空腹胰岛素(FINS)水平和胰岛素抵抗指数(IRS).结果 观察组FPG、FINS、IRS分别为(5.40±1.01)mmol/L、( 69.43±38.05) mU/L和(16.65±12.29),对照组分别为(4.53±0.56) mmol/L、( 50.54±20.07) mU/L和(10.17±4.66),两组差异均有统计学意义(=3.26、3.87、4.01,均P＜0.05).结论 妊娠合并慢性丙型病毒性肝炎患者存在明显的胰岛素抵抗.     

Lopinavir/ritonavir pharmacokinetics in HIV and hepatitis C virus co-infected patients without liver function impairment: influence of liver fibrosis

BACKGROUND AND OBJECTIVE: To assess the influence of hepatitis C virus (HCV) co-infection and the extent of liver fibrosis on lopinavir/ritonavir pharmacokinetics in HIV-infected patients without liver function impairment. METHODS: Cross-sectional, comparative study enrolling HIV-infected adults receiving lopinavir/ritonavir (400 mg/100 mg twice daily). HIV/HCV co-infected patients were grouped as having advanced fibrosis (HCV+/FIB+, n=7) or not (HCV+/FIB-, n=8) based on the FIB-4 index. A full concentration-time profile was obtained for each patient, and blood samples were collected before (0), and 1, 2, 4, 6, 8, 10 and 12 hours after a lopinavir/ritonavir dose. Lopinavir and ritonavir concentrations in plasma were determined by high-performance liquid chromatography. Maximum and minimum plasma concentrations (Cmax and Cmin), area under the plasma concentration-time curve from 0 to 12 hours (AUC12), apparent oral clearance at steady state (CLss/F), and apparent volume of distribution after oral administration (Vd/F) were calculated for each individual using a non-compartmental approach. RESULTS: Twenty-six HCV- and 22 HCV+patients were enrolled. Lopinavir and ritonavir pharmacokinetics were comparable between HCV- and HCV+patients. However, the Vd/F of lopinavir was 125% higher in HCV+/FIB+patients than in HCV-patients (p=0.015) and 107% higher than in HCV+/FIB-(p=0.040) patients. The CLss/F of ritonavir was 40% lower in HCV+/FIB+patients than in HCV-patients (p=0.005) and 44% lower than in HCV+/FIB-patients (p=0.040). Thus, for ritonavir AUC12, Cmax and Cmin in HCV+/FIB+patients were 63%, 86% and 100% higher, respectively, when compared with those parameters in HCV-patients (p=0.005, p=0.012 and p=0.015, respectively), and 80%, 86% and 100% higher, respectively, when compared with levels in HCV+/FIB- patients (p=0.040, p=0.040 and p=0.029, respectively). CONCLUSION: Lopinavir exposure is similar in HIV-infected patients with or without HCV co-infection and without liver function impairment. However, ritonavir exposure may be higher in this setting, particularly in individuals with advanced liver fibrosis.     

Therapy of chronic hepatitis C virus infection in HIV co-infected people

The introduction of highly active anti-retroviral therapy (HAART) for Human Immunodeficiency Virus (HIV) infection has significantly improved the life expectancy of HIV positive patients. Hepatitis C virus (HCV) co-infection is common in HIV infected patients and is now a significant cause of morbidity and mortality. Optimal management and treatment of HCV in HIV infected patients is therefore essential. Interferon-alpha (IFN-alpha) and ribavirin is the mainstay of treatment for HCV infection in HIV infected people. The sustained virological response rate (SVR) with combination therapy is lower than that commonly observed in HCV mono-infected patients. This is, at least in part, due to the very high treatment drop out rates. Ribavirin in combination with HAART is associated with particular side effects such as mitochondrial toxicity. Therefore, vigilant monitoring of patients during therapy, in specialist centers is essential. Pegylated interferon (PEG-IFN) plus ribavirin is particularly promising as it is easier to administer and will probably become the treatment of choice for co-infected patients. A SVR is associated with genotype 2 and 3, in addition to a high CD4+ cell count and a low HCV load prior to therapy. The progression of HCV related liver disease in HIV positive patients is faster than in subjects with HCV infection alone. As a result, there is an increasing incidence of cirrhosis and end-stage liver disease in co-infected patients. Liver transplantation is being evaluated in many centers. To date the experiences are very limited but encouraging in term of survival rate.     

Antiretroviral drugs do not facilitate hepatitis C virus (HCV) infection in vitro

An estimated 4 to 5 million people are co-infected with HIV/HCV worldwide. Recently observed outbreaks of acute HCV infection among HIV-positive men who have sex with men (MSM) have been linked to behavioral factors such as high risk sexual practices and recreational drug use. However, at the molecular level, many drugs such as glucocorticoids or cyclosporine A have been found to modulate viral replication. Thus, it is conceivable that drugs used in highly active antiretroviral therapy (HAART) may heighten susceptibility to HCV infection and contribute to the recent outbreaks. We therefore performed a comprehensive screen of antiretroviral drugs covering all available drug classes both individually and in typical combinations used during HAART to probe for direct effects on HCV cell entry, replication, new particle assembly and release. Importantly, no significant enhancement or inhibition of HCV cell entry, replication or new particle production was detected. While raltegravir and ritonavir boosted atazanavir reduce HCV replication, a tenfold reduction of HCVcc entry by the CCR5 antagonist maraviroc was observed. In conclusion, commonly used HAART agents do not specifically enhance HCV replication. Thus recent epidemic outbreaks of acute HCV in HIV-infected MSM are unlikely to be related to enhancing effects of HAART drugs.     

Neurocognition in individuals co-infected with HIV and hepatitis C

Due to similar routes of viral transmission, many individuals infected with the human immunodeficiency virus (HIV) are also infected with the hepatitis C virus (HCV). Each virus can cause cognitive compromise among mono-infected individuals; evidence is accumulating that HIV/HCV co-infection may have a particularly deleterious impact on cognition. We present neuropsychological data obtained from 118 HIV+ adults with advanced HIV disease, 35 of whom were co-infected with HCV, who completed a comprehensive neurocognitive evaluation. Rates of global cognitive impairment were higher among co-infected patients than among those with HIV alone (63% vs. 43%). Within the specific domains of learning and memory, co-infected individuals were significantly more likely to be impaired than were the HIV mono-infected participants. Finally, we discuss implications of these findings and potential future directions for research in this area.     

慢性乙型肝炎合并脂肪肝对替比夫定疗效的影响

目的了解慢性乙型肝炎合并脂肪肝病人对替比夫定抗乙型肝炎病毒疗效的影响。方法回顾分析128例使用替比夫定抗乙型肝炎病毒治疗慢性乙型肝炎病人的肝组织病理检查,分为慢性乙型肝炎合并脂肪肝组43例,男性32例,女性11例,年龄(36±s 16)岁;单纯慢性乙肝组85例,男性62例,女性23例,年龄(37±11)岁。结果替比夫定抗病毒治疗1年丙氨酸转移酶(ALT)复常率2组分别为60%和84%(χ~2=5.892,P<0.01),乙肝病毒脱氧核糖核酸(HBV DNA)转阴率分别为70%和86%(χ~2=5.135,P<0.01)。肝穿病理结果存在肝细胞脂肪变性的慢性乙型肝炎病人对于替比夫定抗乙型肝炎病毒的ALT复常率和HBV DNA转阴率下降。结论肝细胞脂肪变性是影响替比夫定抗病毒疗效的重要因素之一。     

Management of chronic hepatitis C in patients co-infected with HIV: focus on safety considerations.

Hepatitis C virus (HCV) infection is a significant public health problem and one of the most important causes of chronic liver disease worldwide. Co-infection with HCV and HIV occurs frequently, mainly because both viruses share the same transmission routes. In recent years, the life expectancy of patients with HIV disease has been increased due to the introduction of highly active antiretroviral therapy (HAART). Furthermore, several studies have established that HIV infection is associated with a major progression of the HCV-related liver disease. Thus, end-stage liver disease has become a leading cause of morbidity and mortality in this population, emphasising the importance of treatment of chronic hepatitis C in HIV-infected persons.The biological and histological benefit of interferon-alpha (IFNalpha) therapy in patients co-infected with HCV/HIV is not significantly different from that noted in similar patients without HIV when the HIV infection is adequately controlled. However, patients with low CD4+ cell counts tend to respond poorly to anti-HCV therapy.Given the relatively low sustained virological response rate to IFN alone, the use of IFNalpha monotherapy has been largely abandoned in favour of combination therapy with ribavirin. In the last 2 years, IFN plus ribavirin combination therapy has been the standard care for the treatment of chronic hepatitis C. Although information on the safety and efficacy of this dual therapy in HCV/HIV co-infected patients is scarce, recent trials have reported that the combination of IFN plus ribavirin is well tolerated and feasible in patients co-infected with HCV/HIV. However, the rates of sustained virological response seem to be worse than those observed in patients without HIV infection. New IFN formulations (e.g. pegylated interferon) plus ribavirin appear to be way of the future for the treatment of chronic hepatitis C in patients both with and without HIV co-infection.     

Tetrahydrocurcumin ameliorates free fatty acid-induced hepatic steatosis and improves insulin resistance in HepG2 cells

Elevated levels of free fatty acids (FFAs) in the liver, resulting from either increased lipolysis or imbalanced FFAs flux, is a key pathogenic factor of hepatic steatosis. This study was conducted to examine the therapeutic effect of tetrahydrocurcumin (THC), a naturally occurring curcuminoid and a metabolite of curcumin, on oleic acid (OA)-induced steatosis in human hepatocellular carcinoma cells and to elucidate the underlying mechanism. HepG2 cells were incubated with OA to induce steatosis, and then treated with various concentrations of THC. The results showed that THC treatment significantly decreased lipid accumulation in OA-treated HepG2 cells, possibly, by inhibiting the expression of the lipogenic proteins, sterol regulatory element-binding protein 1 (SREBP-1c), peroxisome proliferator-activated receptor gamma (PPARγ), fatty acid synthase (FAS), and fatty acid-binding protein 4 (FABP4). Moreover, THC attenuated OA-induced hepatic lipogenesis in an adenosine monophosphate–activated protein kinase (AMPK)-dependent manner, which was reversed by pretreatment with an AMPK inhibitor. THC promoted lipolysis and upregulated the expression of genes involved in β-oxidation. Glucose uptake and insulin signaling impaired in HepG2 cells incubated with OA were abated by THC treatment, including phosphorylation of the insulin receptor substrate 1 (IRS-1)/phosphoinositide 3-kinase (PI3K)/Akt and downstream signaling pathways, forkhead box protein O1 (FOXO1) and glycogen synthase kinase 3 β (GSK3β), which are involved in gluconeogenesis and glycogen synthesis, respectively. Altogether, these results demonstrated the novel therapeutic benefit of THC against hepatic steatosis and, consequently, a potential treatment for non-alcoholic fatty liver disease (NAFLD).