Emma Page

HCV reinfection incidence and treatment outcome among HIV-positive MSM in London

Objective:Liver disease secondary to hepatitis C virus (HCV) infection in the context of HIV infection is one of the leading non-AIDS causes of death. Sexual transmission of HCV infection among HIV-positive MSM appears to be leading to increased reports of acute HCV infection. Reinfection after successful treatment or spontaneous clearance is reported among HIV-positive MSM but the scale of reinfection is unknown. We calculate and compare HCV reinfection rates among HIV-positive MSM after spontaneous clearance and successful medical treatment of infection. Design:Retrospective analysis of HIV-positive MSM with sexually acquired HCV who subsequently spontaneously cleared or underwent successful HCV treatment between 2004 and 2012. Results:Among 191 individuals infected with HCV, 44 were reinfected over 562 person-years (py) of follow-up with an overall reinfection rate of 7.8/100 py [95% confidence interval (CI) 5.8–10.5]. Eight individuals were subsequently reinfected a second time at a rate of 15.5/100 py (95% CI 7.7–31.0). Combining all reinfections, 20% resulted in spontaneous clearance and treatment sustained viral response rates were 73% (16/22) for genotypes one and four and 100% (2/2) for genotypes two and three. Among 145 individuals with a documented primary infection, the reinfection rate was 8.0 per 100 py (95% CI 5.7–11.3) overall, 9.6/100 py (95% CI 6.6–14.1) among those successfully treated and 4.2/100 py (95% CI 1.7–10.0) among those who spontaneously cleared. The secondary reinfection rate was 23.2/100 py (95% CI 11.6–46.4). Conclusion:Despite efforts at reducing risk behaviour, HIV-positive MSM who clear HCV infection remain at high risk of reinfection. This emphasizes the need for increased sexual education, surveillance and preventive intervention work.

Treatment of acute HCV infection in HIV-positive patients: experience from a multicentre European cohort.

BACKGROUND Early treatment of acute HCV infection has been shown to improve virological response rates in HIV-positive patients; however, details on when and how to best treat acute HCV infection remain unclear at present. METHODS In this European multicentre cohort study, HIV-positive patients with acute HCV infection were offered immediate or delayed anti-HCV therapy, pegylated interferon or pegylated interferon plus ribavirin combination therapy for 24 or 48 weeks, depending on the local protocol. The main outcome measure was the rate of sustained virological response (SVR). RESULTS A total of 150 HIV-infected men with acute HCV were enrolled between 2001 and 2006, 111 of whom received anti-HCV therapy. The predominant HCV genotype was type 1 and was present in 71 (64%) patients. Patients were treated with pegylated interferon (n=14) or pegylated interferon plus ribavirin (n=97), with a median duration of treatment of 25 weeks. SVR was obtained in 62% (95% confidence interval 52-71) of patients. There was no difference in SVR by genotype, CD4(+) T-cell count, HIV RNA, HCV RNA, alanine aminotransferase levels or use of ribavirin. Negative HCV RNA at weeks 4 and 12 were strong predictors of SVR. CONCLUSIONS High rates of SVR (62%) were obtained in HIV-coinfected patients with acute HCV infection undergoing early anti-HCV treatment using pegylated interferon alone or in combination with ribavirin. Treatment response at weeks 4 and 12 might be of help to further guide treatment duration. Urgent prospective studies are needed to further determine the optimal treatment regimen and the duration of therapy.

HIV and hepatitis C coinfection: pathogenesis and microbial translocation.

PURPOSE OF REVIEW Human immune deficiency virus (HIV)-1 and hepatitis C virus (HCV) coinfected individuals progress more rapidly to fibrosis than their HCV mono-infected counterparts. Increased microbial translocation in HIV-1/HCV coinfection may play an important role. RECENT FINDINGS The mechanisms of accelerated liver fibrosis in HIV-1/HCV coinfection are complex. Products of microbial translocation may promote liver fibrosis either by direct interaction with Kupffer cells and hepatic stellate cells (HSCs) or indirectly via induction of systemic immune activation and activation-induced apoptotic cell death. HIV-1 enteropathy is associated with increased microbial translocation and systemic immune activation. Mechanisms that underlie increased microbial translocation include direct effects of HIV-1 infection on epithelial barrier function and alteration in intestinal permeability secondary to inflammatory cytokines and CD4 T-cell depletion. Risk of liver fibrosis is increased in HIV-1/HCV coinfection and associated with reduced CD4 T-cell counts and raised lipopolysaccharide levels and/or depletion of hepatic Kupffer cells. SUMMARY Large-scale longitudinal clinical studies are needed to confirm the importance of microbial translocation in promotion of hepatic fibrosis. If microbial translocation is a significant contributory factor to hepatic fibrosis, targeted interventions against microbial products may improve clinical outcomes.

Liver Fibrosis Progression After Acute Hepatitis C Virus Infection in HIV-Positive Individuals

Fibrosis progression after acute hepatitis C virus (HCV) infection in human immunodeficiency virus (HIV)-infected patients with follow-up >9 months became similar to reported rates from studies in chronic HIV/HCV coinfection, as measured with transient elastometry. The duration of follow-up and serum alanine transaminase correlated with liver stiffness, and short follow-up resulted in high fibrosis progression rates.

Loss of Th22 cells is associated with increased immune activation and IDO-1 activity in HIV-1 infection.

Background:Immune activation plays a key role in the immunopathogenesis of HIV-1 infection. Microbial translocation, secondary to loss of epithelial integrity and mucosal immune deficiency, is believed to contribute to systemic immune activation. Interleukin 22 maintains intestinal epithelial barrier integrity and stimulates the secretion of antimicrobial peptides that limit bacterial dissemination and intestinal inflammation. Interleukin 22 is secreted by CD4 T-helper (Th)22 cells independently of interleukin 17A and interferon &ggr;. Th22 cells are characterized by the expression of chemokine receptors (CCR)4, CCR6, and CCR10. Methods:We analyzed the frequency of Th22, Th17, Th1, and CD4 T regulatory (Treg) cells, markers of immune activation (expression of CD38 on CD8 T cells, neopterin, soluble CD14), microbial translocation (lipopolysaccharide-binding protein and 16s ribosomal DNA), and indoleamine 2,3-dioxygenase 1 activity in peripheral blood of antiretroviral therapy (ART)-experienced and ART-naive HIV-1–infected patients and healthy controls. Results:We showed a significant reduction in the frequency of Th22 cells in HIV ART-naive patients compared with the healthy controls and HIV ART-experienced patients. We observed a shift away from Th22 and Th17 to Treg cells, which was partially reversed by effective ART. Markers of immune activation negatively correlated with Th22 and Th17 proportions, and with Th22:Treg and Th17:Treg ratios in ART-naive patients. Increased indoleamine 2,3-dioxygenase 1 activity negatively correlated with Th22:Treg and Th17:Treg ratios in the ART-naive group. Conclusions:Loss of Th22 cells and disruption in the balance of Th22 and Treg cells may contribute toward systemic immune activation and mucosal immune deficiency during HIV-1 infection.

Clearance of hepatitis C virus RNA from serum in HIV/hepatitis C virus coinfection indicates eradication from peripheral blood mononuclear cells.

Objectives:The objectives of this study are to determine the frequency of hepatitis C virus (HCV) RNA persistence in peripheral blood mononuclear cells (PBMCs) of HIV-positive patients with clearance of the virus from serum and to identify the presence of any ongoing replication. Design:This is a prospective cross-sectional study. Methods:HIV antibody-positive individuals with previous exposure to HCV, but not current infection with HCV, were recruited. Blood was taken to allow identification of HCV RNA in both serum and PBMCs. Intracellular HCV was extracted using the QIAamp RNA Blood MiniKit. Reverse transcriptase-PCR was performed using a modification of the COBAS TaqMan HCV Test for use with the high pure system. Results:Twenty-six HIV-positive individuals were recruited to the study. All had previously been infected with HCV. Six individuals had spontaneously cleared HCV, 10 had achieved sustained virological response following 24 weeks of pegylated interferon and ribavirin for acute HCV, and 10 had achieved sustained virological response following standard pegylated interferon and ribavirin therapy for chronic HCV. None demonstrated HCV RNA persistence in either serum or PBMCs. Conclusion:Our findings lend support to the view that clearance of HCV RNA from serum in HIV/HCV coinfection indicates eradication from PBMCs. Thus, absence of serum HCV RNA 6 months after the end of therapy can be used as a marker of treatment success for interferon-based therapies. However, the advent of small molecule HCV inhibitors may require us to rethink our definitions of response and cure.

Hepatitis C and sex

An outbreak of acute hepatitis C among HIV-positive men who have sex with men (MSM) in the last decade has been shown to be sexually transmitted. Initially recreational drug use, in particular drug injection, was not prevalent among those becoming infected with hepatitis C. However more recently chemsex (the use of drugs to enhance sexual experience) and its associated drugs, which are not uncommonly injected, have become more frequently reported among those diagnosed with hepatitis C. It is hoped that the widespread -introduction of direct-acting antivirals and upscaling of numbers treated may have a positive impact on this epidemic. However their introduction may negatively impact on the perceived risk of acquiring hepatitis C and in conjunction with the introduction of HIV transmission prevention strategies may result in increased transmissions and spread to the HIV-negative MSM population.

Direct-acting antiviral-based therapy for acute hepatitis C coinfection.

Purpose of reviewModern interferon (IFN)-free, and potentially also ribavirin-free, combinations consisting of two or three direct-acting antivirals (DAAs) are highly efficacious in treating chronic hepatitis C virus (HCV) infection with treatment durations being much shorter and with much more favorable toxicity profiles. With the acute HCV (AHC) epidemic among men who have sex with men (MSM) still ongoing, the question remains should we be using DAAs in the acute phase of the infection? Recent findingsTo date, none of the currently available DAAs has been licensed for use in the setting of AHC infection. Thus, the current gold standard of treatment still is a combination of pegylated interferon (pegIFN) and weight-adapted ribavirin (RBV). However, with less patients being treated in the acute phase, the current epidemic of AHC in HIV-positive MSM will continue. SummaryA decision to treat AHC with pegIFN and RBV can currently only be made on an individual basis in an open discussion between patient and physician which will need to weigh up the risk and benefits of a rather toxic and lengthy treatment now versus the likely available options in the chronic phase. Therefore, studies with IFN-free DAA combinations remain of great urgency to further evaluate the role of DAAs in the treatment of AHC.