Treatment of chronic hepatitis C in patients with HIV/HCV coinfection

Hepatitis C virus (HCV) infection is one of the most frequent causes of comorbidity and mortality in the human immunodeficiency virus (HIV) population, and liver-related mortality is now the second highest cause of death in HIV-positive patients, so HCV infection should be countered with adequate antiviral therapy. In 2011 began the era of directly acting antivirals (DAAs) and the HCV NS3/4A protease inhibitors telaprevir and boceprevir were approved to treat HCV-genotype-1 infection, each one in combination with pegylated interferon alfa (Peg-IFN) + ribavirin (RBV). The addition of the first generation DAAs, strongly improved the efficacy of antiviral therapy in patients with HCV-genotype 1, both for the HCV-monoinfected and HIV/HCV coinfected, and the poor response to Peg-IFN + RBV in HCV/HIV coinfection was enhanced. These treatments showed higher rates of sustained virological response than Peg-IFN + RBV but reduced tolerability and adherence due to the high pill burden and the several pharmacokinetic interactions between HCV NS3/4A protease inhibitors and antiretroviral drugs. Then in 2013 a new wave of DAAs arrived, characterized by high efficacy, good tolerability, a low pill burden and shortened treatment duration. The second and third generation DAAs also comprised IFN-free regimens, which in small recent trials on HIV-positive patients have shown comforting preliminary results in terms of efficacy, tolerability and adherence.     

Functional polymorphisms of TLR8 are associated with hepatitis C virus infection

Chronic hepatitis C virus (HCV) infection is a worldwide threat to public health. Toll‐like receptor 8 (TLR8) is critical for eliminating RNA viruses, and variation within the TLR8 gene may alter the function of TLR8 in response to HCV infection. Our previous study demonstrated that the TLR8‐129G>C (rs3764879) and TLR8+1G>A (rs3764880) variants were in complete linkage disequilibrium, and that the frequency of TLR8‐129C/+1A was significantly higher in male patients with HCV infection compared with the healthy controls. In the present study, we found that the promoter activity of TLR8‐129G was higher than that of TLR8‐129C in THP‐1 cells. Moreover, TLR8‐129G mRNA stability and competitive DNA‐binding ability were significantly lower than that of TLR8‐129C. To investigate the functional effects of TLR8 polymorphisms, we compared the nuclear factor‐κB (NF‐κB)‐driven luciferase activity in HEK293 cells transfected with the TLR8 variants. TLR8+1A plasmids induced less NF‐κB signalling than did those transfected with TLR8+1G after 20 μm CL075 (P = 0·011) stimulation. We also analysed the mRNA expression and cytokine production in whole blood and monocytes from people of various genotypes stimulated ex vivo by the interferon‐γ and TLR7/8 agonist CL075, R848. TLR8 expression in CD14⁺ cells derived from volunteers with TLR8‐129G/+1G was significantly higher than that derived from TLR8‐129C/+1A, and interleukin‐12p40 production was higher in volunteers with TLR8‐129G/+1G after stimulation. The data indicate that variations in TLR8 genes may modulate immune responses during HCV infection.     

Isolation and functional analysis of circulating dendritic cells from hepatitis C virus (HCV) RNA-positive and HCV RNA-negative patients with chronic hepatitis C: role of antiviral therapy

Hepatitis C virus (HCV) RNA has been localized in antigen-presenting dendritic cells (DCs) from patients with chronic hepatitis C (CHC). DCs from patients with CHC also exhibit impaired functional capacities. However, HCV RNA in DCs and functional impairment of DCs in CHC might be independent or interrelated events. Moreover, the impact of antiviral therapy on the functions of DCs in CHC is not well documented. In order to address these issues, we took advantage of antiviral therapy in these patients. Ten patients with CHC, expressing HCV RNA in circulating DCs, became negative for HCV RNA in circulating DCs after therapy with interferon-alpha and ribavirin for 4 weeks. The functions of DCs from HCV RNA+ patients (isolated before antiviral therapy) and HCV RNA- patients (isolated 4 weeks after antiviral therapy) were compared in allogenic mixed leucocyte reactions. In comparison to circulating DCs from normal control subjects, DCs from HCV RNA+ patients had a significantly decreased capacity to stimulate allogenic T lymphocytes (P < 0.01) and produce interleukin-12 (P < 0.05). However, the allostimulatory capacity of circulating DCs from HCV RNA- patients was several-fold higher compared to that of HCV RNA+ DCs from the same patient. DC from HCV RNA- patients also produced significantly higher levels of interleukin-12 compared to HCV RNA+ DCs from the same patient (P < 0.01). Taken together, this study is the first to provide experimental evidence regarding the impact of HCV RNA and antiviral therapy on the function of DCs in patients with CHC.     

ITPA gene polymorphisms significantly affect hemoglobin decline and treatment outcomes in patients coinfected with HIV and HCV

Published studies have described a strong association with a single‐nucleotide polymorphism (SNP) in the inosine triphosphate pyrophosphatase (ITPA) gene and ribavirin (RBV)‐induced hemolytic anemia in HCV‐infected patients receiving pegylated interferon (pegIFN) and RBV. This study sought to evaluate the effect of these polymorphisms on anemia, hemoglobin reduction, HCV kinetics, and treatment outcomes. Sixty‐three patients coinfected with HIV and HCV and 58 patients infected with HCV only were treated with pegIFN/RBV were genotyped using the ABI TaqMan allelic discrimination kit for the 2 ITPA SNP variants rs1127354 and rs7270101. A composite variable of ITPA deficiency using both SNPs was created as previously reported. Statistical analysis was performed using Mann‐Whitney test or Chi square/Fishers exact test for categorical data and mixed model analysis for multiple variables. Thirty‐five patients (30%) were predicted to have reduced ITPA activity. ITPA deficiency was found to be protective against the development of hemoglobin reduction >3 g/dl over the course of treatment. The rates of hemoglobin reduction >3 g/dl decreased in correlation with the severity of ITPA deficiency. ITPA deficiency was associated with slower hemoglobin decline early in treatment (week 4, P = 0.020) and rapid virologic response (RVR) at week 4 (P = 0.017) in patients coinfected with HIV and HCV. ITPA polymorphisms are associated with hemoglobin decline and in patients coinfected with HIV and HCV it is also associated with early virologic outcomes. Determination of ITPA polymorphisms may allow prediction of RBV‐induced anemia and earlier initiation of supportive care to ensure optimal therapeutic outcomes. J. Med. Virol. 84: 1106–1114, 2012. Published 2012. This is a US Government work and as such is in the public domain in the United States of America.     

Virus-specific T-cell responses associated with hepatitis C virus (HCV) persistence in the liver after apparent recovery from HCV infection

Hepatitis C virus (HCV) RNA persistence in the liver has been described even after apparent resolution of HCV infection. Because T-cell reactivity plays a role in recovery from HCV infection, virus-specific T-cell responses were investigated in apparently recovered individuals in whom hepatic HCV RNA persistence was documented: 15 sustained virological responders to interferon (IFN)-treatment and 9 asymptomatic aviremic anti-HCV carriers. HCV-specific CD4(+) T-cell proliferative responses were detected significantly more often in apparently recovered individuals (sustained virological responders: 60%; asymptomatic anti-HCV carriers: 66%) compared with 50 chronic hepatitis C patients (28%; P < 0.05). However, T-cell frequencies and numbers tended to decline over time and the number of HCV proteins targeted by CD4(+) T-cell proliferative responses was limited. Interestingly, liver viral load correlated inversely with virus-specific immune responses. Thus, CD4(+) T-cell responders showed significantly lower hepatic HCV RNA levels (P < 0.05). HCV-specific IFN-gamma-secreting CD4(+) T-cells were not detected in all the apparently recovered patients although they were found significantly more often compared with chronic hepatitis C patients (P < 0.05). Also, HCV NS3-specific CD8(+) T-cells were detected in 11 HLA-A2-positive apparently recovered individuals (8 sustained virological responders and 3 asymptomatic anti-HCV carriers); T-cell frequencies tended to be greater in those patients who had lower hepatic viral levels. In conclusion, HCV-specific T-cells are detectable in apparently recovered individuals in whom HCV RNA can persist in the liver indicating that HCV replication may be prolonged in the face of an insufficient or inadequate virus-specific CD4(+) and CD8(+) T-cell response.     

Patients co-infected with hepatitis C virus (HCV) and human immunodeficiency virus recover genotype cross-reactive neutralising antibodies to HCV during antiretroviral therapy

When severely immunodeficient HIV/HCV co-infected patients are treated with antiretroviral therapy, it is important to know whether HCV-specific antibody responses recover and whether antibody profiles predict the occurrence of HCV-associated immune restoration disease (IRD). In 50 HIV/HCV co-infected patients, we found that antibody reactivity and titres of neutralising antibodies (nAb) to JFH-1 (HCV genotype 2a virus) increased over 48 weeks of therapy. Development of HCV IRD was associated with elevated reactivity to JFH-1 before and during the first 12 weeks of therapy. Individual analyses of HCV IRD and non-HCV IRD patients revealed a lack of an association between nAb responses and HCV viral loads. These results showed that increased HCV-specific antibody levels during therapy were associated with CD4⁺ T-cell recovery. Whilst genotype cross-reactive antibody responses may identify co-infected patients at risk of developing HCV IRD, neutralising antibodies to JFH-1 were not involved in suppression of HCV replication during therapy.     

Quasispecies nature of hepatitis C virus (HCV) in patients with chronic hepatitis C with mixed HCV subtypes

The quasispecies nature of hepatitis C virus (HCV) in patients with mixed HCV subtype infection was compared with that in patients with single HCV subtype infection. The number of HCV quasispecies was compared between 35 patients with mixed HCV subtype infection and 83 patients with single subtype infection. Subtype was determined by primers deduced from the core region and by line probe assay respectively. The number of quasispecies was evaluated by polymerase chain reaction amplification of hypervariable region 1 and by fluorescence single-strand conformation polymorphism analysis. There was no difference in clinical background between patients with mixed subtype infection and patients with single subtype infection. The number of quasispecies in patients with multiple subtype HCV infection was larger than in patients with single subtype HCV infection. The immunologic environments which allow the coexistence of more HCV quasispecies in patients with multiple HCV subtype infection differs from that in patients with single HCV subtype infection. J. Med. Virol. 54:80–85, 1998. © 1998 Wiley-Liss,Inc.     

Loss of serum HCV RNA at week 4 of interferon-α therapy is associated with more favorable long-term response in patients with chronic hepatitis C

To determine the virological factors associated with a favorable long-term response to interferon-α (IFN) therapy in chronic hepatitis C virus (HCV) infection, 61 Japanese patients with chronic HCV infection were treated with IFN for 24 weeks (780 million units in total) and followed for 8 to 16 months after cessation of therapy. Ten patients dropped out because of severe side effects. Of the 51 patients who completed IFN therapy, 23 showed complete and sustained response (CR→SR), 13 complete response with early relapse (CR→Rel), and 15 no response to IFN (NR). For the pretreatment serum HCV RNA level, 20/23 who had CR→SR had <l0⁶ eq/ml compared to 3/13 CR→Rel and 1/15 NR (P< 0.01). Serologically defined HCV type 2 infection was also associated with a better opportunity to develop CR→SR compared to CR→Rel of NR (P<0.01). Loss of serum HCV RNA at week 4 of IFN therapy was also associated with a more favorable long-term response [17/19 CR→SR were HCV RNA negative compared to 3/11 CR→Rel (P<0.01)and2/13NR(P<0.01)]. n contrast, normalization of serum alanine ami-notransferase (ALT) levels at week 4 was found in 9/19 CR→SR compared to 8/11 CR→Re1 (P= NS), and 0/13 in NR (P<0.01). Six months after cessation of IFN therapy, 3/25 CR→SR patients were HCV RNA positive despite normalization of serum ALT levels. These data indicated that in addition to pretreatment serum HCV RNA levels and HCV type, the kinetics of response to IFN (at week 4) were also predictive of subsequent long-term response to IFN in patients with chronic HCV infection. © 1995 Wiley-Liss, Inc. © 1995 Wiley-Liss, Inc.     

Long-term follow-up of hepatitis B virus and hepatitis C virus replicative levels in chronic hepatitis patients coinfected with both viruses

Dual infection with hepatitis B and C viruses is often encountered in endemic areas of both viruses. However, understanding of the clinical and virological implications is limited. The aim of this study was to investigate the role of each virus in liver injury and the interaction between the two viruses in dual infection with hepatitis B and C viruses. Three patients who had chronic infection with both hepatitis B and C viruses were examined, and a longitudinal study of both serum hepatitis B virus DNA and hepatitis C virus RNA levels over 4 years was undertaken. The results were correlated with serum alanine aminotransferase levels. Serum alanine aminotransferase values showed a relationship with hepatitis B virus replicative levels, but not with hepatitis C virus replicative levels in all 3 patients. Serial changes of replicative levels of both viruses were studied, and it was found that hepatitis C virus replicative levels were enhanced after the decline of hepatitis B virus replication in 1 of the 3 patients. In the remaining 2 patients, a transient rise of hepatitis C virus replicative levels in association with a decrease of hepatitis B virus replication was also observed during part of the follow-up period. These findings indicate that hepatitis B virus may play a dominant etiological role in liver injury, and that a suppressive action between hepatitis B and C viruses may occur in dual infection with both viruses. © 1995 Wiley-Liss, Inc.     

Viral (hepatitis C virus,hepatitis B virus,HIV) persistence and immune homeostasis

Immune homeostasis is a host characteristic that maintains biological balance within a host. Humans have evolved many host defence mechanisms that ensure the survival of individuals upon encountering a pathogenic infection, with recovery or persistence from a viral infection being determined by both viral factors and host immunity. Chronic viral infections, such as hepatitis B virus, hepatitis C virus and HIV, often result in chronic fluctuating viraemia in the face of host cellular and humoral immune responses, which are dysregulated by multi‐faceted mechanisms that are incompletely understood. This review attempts to illuminate the mechanisms involved in this process, focusing on immune homeostasis in the setting of persistent viral infection from the aspects of host defence mechanism, including interferon‐stimulated genes, apolipoprotein B mRNA editing enzyme catalytic polypeptide 3 (APOBEC3), autophagy and interactions of various immune cells, cytokines and regulatory molecules.     

Prospective study of mother-to-infant transmission of hepatitis C virus (HCV) infection

Seventy-five women with anti-hepatitis C virus (HCV) antibody were enrolled prospectively during pregnancy or at delivery for study of mother-to-child transmission of HCV. Twenty-three women were coinfected with the human immunodeficiency virus (HIV). Seventy babies were monitored for at least 6 months. HCV infection was diagnosed in six infants (8.6%), four of whom were born to anti-HIV–positive mothers. HCV RNA was first detected between 2 and 6 months, and the genotypes of infected babies matched those of their mothers (type 1: n = 4; type 3: n = 2). Identical master sequences of the hypervariable region (HVR1) were detected in a mother–infant pair. In three babies coinfected with HCV and HIV, anti-HCV disappeared between 2 and 7 months, being persistently negative in two cases monitored for 11 and 26 months. Transmitting mothers did not differ significantly from those who did not transmit the infection with anti-HIV, HCV genotypes, and viral load at delivery, but had lower rate of reactivity to C100 by the recombinant immunoblot assay (RIBA) (P < .01). This prospective study confirms transmission of HCV from anti-HIV–negative mothers (4.4% in this series). Absence of anti-C100 antibodies at delivery is apparently related to increased risk of vertical transmission. Seronegative HCV infection can be observed in children coinfected with HIV. J. Med. Virol. 54:12–19, 1998. © 1998 Wiley-Liss, Inc.     

Intermittent detection of hepatitis C virus (HCV) in semen from men with human immunodeficiency virus type 1 (HIV-1) and HCV

HCV is usually transmitted via the blood, but HCV RNA has been detected recently in seminal fluid. This study was done to study HCV seminal shedding and factors that could influence the presence of HCV in the seminal fluid of men coinfected with HCV and HIV-1. HCV and HIV-1 genomes were assayed in multiple paired blood and semen samples obtained from 35 men enrolled in an assisted medical procreation protocol. HCV RNA was found intermittently in semen samples from 9 patients (25.7%). Samples from 9 men with HCV RNA in their semen and 26 men without were compared to further analyze these parameters. No correlation was found between HCV RNA in the seminal fluid and age, HCV virus load, the duration of HIV-1 infection, HIV treatment, the CD4(+) cell count, HIV-1 virus load or HIV-1 detection in the semen. The intermittent detection of HCV RNA in semen samples support the systematic search for HCV RNA in semen and the use of processed spermatozoa in assisted medical procreation of infertile HCV serodiscordant couples.     

Lack of monomeric IgM anti-hepatitis C virus (HCV) core antibodies in patients with chronic HCV infection

Antibodies of the IgM class against the hepatitis C virus core antigen are found in up to 70% of patients with either acute or chronic hepatitis C. The sedimentation rate of such IgM was analyzed by rate-zonal centrifugation of nine sera taken from seven patients, two acutely and five persistently infected with hepatitis C virus. All patients had circulating high-molecular weight (i.e. pentameric) IgM, indicating that the production of low molecular weight IgM, commonly observed in other persistent viral infections, does not apply to hepatitis C virus and cannot be used to distinguish acute from chronic hepatitis C virus infection.     

HIV/HCV共感染患者病毒特异性CTL细胞定量研究

目的探讨病毒特异性CTL对HIVHCV共感染患者病情进展的影响机制。方法观察对象为HIVHCV共感染患者、单纯HIV感染者、单纯HCV感染者。采用四聚体技术,运用流式细胞仪检测病毒特异性CTL。前瞻性比较HIV、HCV特异性CTL在三组中的异同,并对HIVHCV共感染患者的HIV、HCV特异性CTL进行相关性分析。结果HIVHCV共感染组与单纯HIV感染组比较HIV特异性CTL,差异无显著性(P=0.586)。HIVHCV共感染组中HCV特异性CTL的百分数及绝对计数(0.37±0.29,3.52±3.79)均高于单纯HCV感染组(0.15±0.05,0.86±0.33),差异有统计学意义(P=0.001,P=0.002)。HIVHCV共感染组中的HIV特异性CTL与HCV特异性CTL存在正性线性相关(P<0.001),方程成立。并且各系数均有统计学意义,方程似然比(r2)0.761。结论HCV特异性CTL可能是HIVHCV共感染组中肝脏功能损伤加重的原因之一;HIV与HCV在同一患者存在相互影响。     

Immune complexed (IC) hepatitis C virus (HCV) in chronically and acutely HCV-infected patients

In infected individuals, hepatitis C virus (HCV) exists in various forms of circulating particles which role in virus persistence and in HCV resistance to IFN therapy is still debated. Here, the proportion of HCV bound to immunoglobulin was determined in plasma of 107 chronically infected patients harbouring different HCV genotypes and, for comparison, of six patients with acute HCV infection. The results showed that, in spite of wide individual variability, chronically HCV-infected patients exhibited an extremely high proportion of immune complexed (IC) virus regardless of plasma HCV load and infecting genotype. Moreover, no significant association was found between baseline proportion of IC HCV and response to IFN treatment. Plasma samples collected within 2 weeks of treatment from 20 patients revealed a significant decline of mean IC HCV values relative to baseline that clearly paralleled the decay of total HCV load. In acutely infected patients, circulating HCV was not IC or IC at very low levels only in patients developing chronic HCV infection. Collectively, these findings strengthen the possibility that IC virus could play a critical role in the pathogenesis of HCV infection.     

MASP2 gene polymorphism is associated with susceptibility to hepatitis C virus infection

Hepatitis C virus (HCV) has become a major public health issue and is prevalent in most countries. We examined several MASP2 functional polymorphisms in 104 Brazilian patients with moderate and severe chronic hepatitis C using the primers set to amplify the region encoding the first domain (CUB1), a critical region for the formation of functional mannan-binding lectin (MBL)/MBL-associated serine proteases (MASP)-2 complexes, and the fifth domain (CCP2), which is essential for C4 cleavage of the MASP2 gene. We identified five single nucleotide polymorphisms in patients and controls: p. R99Q, p. D120G, p.P126L, p.D371Y, and p.V377A. Our results show that the p.D371Y variant (c.1111 G > T) is associated with susceptibility to HCV infection (p = 0.003, odds ratio = 6.33, 95% confidence interval = 1.85-21.70). Considered as a dominant function for the T allele, this variant is associated with high plasma levels of the MASP-2 in hepatitis C patients (p < 0.001). However, further functional investigations are necessary to understand the degree of involvement between MASP2 and the HCV susceptibility.     

Autoimmune forms of chronic hepatitis associated with hepatitis C virus (HCV) infection with and without HCV-RNA: histological differences from pure autoimmune hepatitis and chronic hepatitis C

Liver biopsy specimens of pure autoimmune hepatitis (pAIH), autoimmune forms of chronic hepatitis with positivity for anti-hepatitis C virus (anti-HCV) and negativity for HCV-RNA (cAIH-RNA(-)), autoimmune forms of chronic hepatitis with positivity for anti-HCV and HCV-RNA (cAIH-RNA(+)), and chronic hepatitis C (CHC) were compared histologically and statistically to clarify the histological character of the autoimmune form of chronic hepatitis with HCV infection. The following representative histological features were used to investigate: inflammation, fibrosis, plasma cell infiltration, lymphoid aggregates/follicles, non-suppurative destructive cholangitis, and the shape of the enlarged portal tracts. While a considerable overlap in histological features between the pAIH and cAIH-RNA(-) groups and between the CHC and cAIH-RNA(+) groups was recognized, the overlap between the pAIH and CHC groups was small. Significant differences were found between cAIH-RNA(-) and cAIH-RAN(+) groups, especially in necroinflammatory findings. In conclusion, most cases of cAIH-RNA(-) with histological features similar to those of pAIH were shown to be AIH. The remaining cases might be CHC with subsidence of viral duplication. Conversely, many cases of cAIH-RNA(+) with histological findings similar to those of CHC were shown to be CHC clinically mimicking pAIH. The remaining cases might represent coexistence of pAIH and HCV infection.     

Benefit of direct-acting antiviral therapy for hepatitis C virus (HCV) in monoinfected and HIV-HCV-coinfected patients with mixed cryoglobulinaemia

ObjectivesMixed cryoglobulinaemia (MC) is found in 40–60% of patients with chronic hepatitis C virus (HCV) infection. Direct-acting antiviral (DAA) regimens considerably improve clinical outcome of HCV infection with sustained virological response rates (SVR) above 90%. We aimed to evaluate the impact of DAA therapy on cryoglobulin clearance and on MC-related symptoms in patients with HCV-associated MC.MethodsThirty-five HCV-monoinfected and 12 HIV-HCV-coinfected patients with symptomatic or asymptomatic MC treated with DAA regimen were analysed. Cryoglobulin levels were assessed at DAA initiation, at different time points during treatment and after treatment and until cryoglobulin clearance if any.ResultsMedian age was 61 years and 51% (24/47) were males. HIV patients had all undetectable HIV RNA with combined antiretroviral therapy. MC was symptomatic in 77% (27/35) of HCV-monoinfected patients and in 8% (1/12) of HIV-HCV-coinfected patients (p < 0.001). Fifty-one per cent (24/47) of patients were previous non-responders to pegylated-interferon/ribavirin (PEG-IFN/RBV) therapy and 32% (15/47) were cirrhotics. One patient received DAA + PEG-IFN/RBV and all others received an IFN-free DAA regimen. The overall SVR12 rate was 100%. Cryoglobulinaemia persisted in 34% (n = 16/47) of patients at the end of follow-up: 17% (2/12) of HIV-HCV-coinfected and 40% (14/35) of HCV-monoinfected patients. Among these patients, median cryoglobulin level decreased from 101.4 mg/L at DAA treatment initiation to 51.7 mg/L at the end of follow-up.ConclusionsDAA-induced SVR allows cryoglobulin clearance in two-thirds of patients.