Mark Danta

Recent epidemic of acute hepatitis C Virus in HIV-positive men who have sex with men linked to high-risk sexual behaviours.

Objective:To characterize the mode of hepatitis C virus (HCV) transmission in a recent epidemic of acute HCV in HIV-infected individuals using linked molecular and clinical epidemiological studies. Design:Individuals diagnosed with acute HCV between 1999 and 2005 at three urban HIV units in the UK were enrolled into a phylogenetic and case–control study. Phylogenetic trees were constructed from the amplified sequences of the E1/E2 region of the HCV genome and were used to compare cases with unrelated sequences. A questionnaire-based, case–control study using matched controls recruited from each HIV unit identified putative transmission factors. Results:One hundred and eleven HIV-positive men who have sex with men with acute HCV (genotype 1: 84%) were enrolled. Phylogenetic analysis of 93 E1/E2 sequences revealed seven monophyletic clusters signifying multiple independent HCV lineages co-circulating in the HIV-positive population. Permucosal rather than percutaneous transmission factors were associated with case/control status. Cases (n = 60) had more sexual partners, increased levels of high-risk sexual behaviour and were more likely to have shared drugs via a nasal or anal route in the preceding year in comparison with controls (n = 130). Sex in a group of more than two people was the strongest predictor of case/control status; odds ratios associated with participation in two or at least three types of high-risk sexual behaviour in a group were 9.16 (95% confidence interval, 3.51–23.90) and 23.50 (95% confidence interval, 9.47–58.33), respectively. Conclusion:The identified co-circulating HCV lineages belong to different subtypes and genotypes, implying that rather than viral change, the epidemic is due to permucosal transmission factors that should be the focus of public health interventions.

Acute hepatitis C in HIV-infected men who have sex with men: an emerging sexually transmitted infection.

Since 2000 outbreaks of acute hepatitis C virus (HCV) among HIV-positive men who have sex with men (MSM) who denied injecting drug use have been reported from Europe, the United States, Canada and Australia. Given the burden of liver disease, in particular HCV, on the morbidity and mortality in HIV patients in the era of combination antiretroviral therapy, the rapid and significant rise in the incidence of HCV in the HIV-infected MSM population in high-income countries is alarming. This relates to a significant change in the epidemiology of HCV that has occurred, with HCV emerging as a sexually transmitted infection within this population. Work to date suggests that this permucosal HCV transmission results from high-risk sexual and noninjecting drug use behaviours, reopening the discussion on the importance of sexual transmission. Given this occurs almost exclusively in HIV-infected MSM, HIV probably has a critical role mediated either through behavioural and/or biological factors. Finally, the management of acute HCV in HIV infection is complicated by concomitant HIV infection and combination antiretroviral therapy. This review will synthesize the most recent epidemiological, immunological and management issues that have emerged as a result of the epidemic of acute HCV among HIV-infected MSM.

Impact of HIV on Host-Virus Interactions during Early Hepatitis C Virus Infection

BACKGROUND Human immunodeficiency virus (HIV) may influence the outcome and natural history of hepatitis C virus (HCV) infection through an impact on acute HCV-specific T cell responses. METHODS Fifty-five HIV-positive males with acute HCV infection were identified; monoinfected individuals (n = 8) were used for peripheral blood mononuclear cell comparison. In 14 coinfected and 8 HCV-monoinfected patients, HCV-specific T cell responses against a range of HCV antigens were assessed using interferon (IFN)-gamma enzyme-linked immunospot (ELISpot) and proliferation assays. E1/E2 region genetic diversity and the selection pressure on the virus were measured in 8 coinfected patients by use of cloned sequences over time. RESULTS HCV persisted in 52 (95%) coinfected individuals. HCV/HIV coinfection significantly reduced IFN-gamma ELISpot responses versus those in HCV-monoinfected individuals, especially against nonstructural proteins (1/10 vs. 5/8; P = .008). In coinfected patients, increased HCV genetic diversity was observed between the first and subsequent time points, with no evidence for positive selection in the E1/E2 region sequenced. CONCLUSION HIV coinfection is associated with increased rates of HCV persistence and a lack of critical CD4 T cell responses, with no evidence of immune selection pressure during early HCV infection. Loss of key cellular immune responses against HCV during acute disease may contribute to the failure of early host control of HCV in HCV/HIV-coinfected patients.

Sexually transmitted hepatitis C infection: the new epidemic in Msm?

Purpose of review Increasing evidence has emerged for permucosal transmission of hepatitis C amongst HIV-infected MSM. Recent findings A rising incidence of acute hepatitis C virus (HCV) in HIV-infected MSM has been observed since 2000 in Europe, Australia, USA and Asia. Transmission appears to occur through the permucosal rather than the more usual parenteral route. Although often multifactorial, permucosal risk factors can be classified as behavioural (sexual practices and mucosally administered drugs) and biological (HIV and sexually transmitted infections). This review will describe the epidemiology of HCV infection in this cohort. Current and future treatment strategies will also be outlined in the context of novel, orally bioavailable, directly acting antiviral therapies. Summary An improved understanding of HCV epidemiology will allow implementation of more effective public health interventions to limit onward transmission of HCV.

Hepatocellular carcinoma risk following direct-acting antiviral HCV therapy: A systematic review, meta-analyses, and meta-regression

BACKGROUND & AIMS The risk of hepatocellular carcinoma (HCC) occurrence or recurrence following direct-acting antiviral (DAA) hepatitis C virus (HCV) therapy remains unclear. The aims of this study were to compare the rate of HCC occurrence in patients with HCV-related cirrhosis, following DAA vs. interferon (IFN)-based cure, and to compare the rate of HCC recurrence in patients who received curative HCC treatment, following DAA vs. IFN-based cure. METHODS A search was conducted for reports published between January 2000 and February 2017. Studies were included if they assessed HCC outcomes by type and response to HCV therapy. Random-effects meta-analyses were undertaken to determine a combined estimate of HCC incidence rate per 100/person-years (py) among patients with a sustained virological response (SVR). RESULTS A total of 41 studies (n=13,875 patients), including 26 on HCC occurrence (IFN=17, DAA=9; prospective=19, retrospective=5, retrospective-prospective=2), and 17 on HCC recurrence (IFN=7, DAA=10; prospective=11, retrospective=5 and retrospective-prospective=1) were included. In studies assessing HCC occurrence, average follow-up was shorter (1.0 vs. 5.5years), and average age older (60 vs. 52years) in DAA studies. In studies assessing HCC recurrence, average follow-up was shorter (1.3 vs. 5.0years), but average age similar (64 vs. 66years) in DAA studies. HCC occurrence was 1.14/100 py (95% CI 0.86-1.52) and 2.96/100 py (95% CI 1.76-4.96) in IFN and DAA studies respectively. HCC recurrence was 9.21/100 py (95% CI 7.18-11.81) and 12.16/100 py (95% CI 5.00-29.58) in IFN and DAA studies respectively. In meta-regression adjusting for study follow-up and age, DAA therapy was not associated with higher HCC occurrence (RR 0.68; 95% CI 0.18-2.55; p=0.55) or recurrence (RR 0.62, 95% CI 0.11-3.45, p=0.56). CONCLUSION There is no evidence for differential HCC occurrence or recurrence risk following SVR from DAA and IFN-based therapy. LAY SUMMARY The risk of hepatocellular carcinoma (HCC) occurrence or recurrence following direct-acting antiviral (DAA) hepatitis C virus (HCV) therapy remains unclear. We conducted a meta-analysis to compare occurrence and recurrence of HCC in patients receiving either DAA or interferon (IFN) therapy. There is no evidence that HCC occurrence or recurrence is different between patients receiving DAA or IFN therapy.

Genetic variation in IL28B and treatment-induced clearance of hepatitis C virus in HIV-positive patients with acute and chronic hepatitis C.

Recently, a IL28B (rs 12979860) gene polymorphism was identified as a predictor for response to hepatitis C virus-specific treatment in human immunodeficiency virus (HIV)-uninfected and -infected patients with chronic hepatitis C. In an analysis of HIV-infected patients with acute hepatitis C, we found that the IL28B genotype was associated with serum levels of hepatitis C virus RNA, g-GT, and CD4 cell count. In contrast to HIV-infected patients with chronic hepatitis C, the IL28B genotype was not significantly associated with treatment response rates in patients with acute hepatitis C. Thus, effects of the IL28B single-nucleotide polymorphism may differ in HIV-infected patients with chronic and acute hepatitis C.

Serum Macrophage Inhibitory Cytokine-1 (MIC-1/GDF15): A Potential Screening Tool for the Prevention of Colon Cancer?

Background: Macrophage inhibitory cytokine-1 (MIC-1/GDF15) mediates nonsteroidal anti-inflammatory drug (NSAID) protection from colonic polyps in mice and is linked to the development of colorectal carcinoma in humans. Therefore, changes in serum MIC-1/GDF15 levels could predict the presence of premalignant colonic polyposis and assist in population screening strategies. Methods: Serum MIC-1/GDF15 levels were measured in subjects in the Polyp Prevention Trial, in which NSAID use and colon cancer risk factors were defined. Subjects had an initial adenoma removed, a repeat colonoscopy removing previously unidentified polyps, and serum MIC-1/GDF15 estimation. Three years later recurrent adenomas were identified and serum MIC-1/GDF15 levels reestimated. The relationship between serum MIC-1/GDF15 levels and adenoma presence or recurrence was examined. Results: Serum MIC-1/GDF15 levels differed by adenoma status and were significantly related to colon cancer risk factors. In addition, mean serum MIC-1/GDF15 levels rose with increasing numbers of adenomas present and high-risk adenoma recurrence. NSAID users had higher serum MIC-1/GDF15 concentrations, which were related to protection from adenoma recurrence. Furthermore, adjusted serum MIC-1/GDF15 levels at final follow-up were related to adenoma recurrence (highest quartile MIC-1/GDF15; OR = 14.7, 95% CI: 3.0–73). Conclusions: These data suggest that MIC-1/GDF15 mediates at least some of the protection afforded by NSAIDs against human colonic polyposis. Furthermore, serum MIC-1/GDF15 levels vary with the development of adnenomatous colonic polyps. Impact: Serum MIC-1/GDF15 determination may hold promise as the first serum screening test to assist the detection of premalignant adenomatous colonic polyposis. Cancer Epidemiol Biomarkers Prev; 21(2); 337–46. ©2011 AACR.

Transmission of HCV in HIV-positive populations

PURPOSE OF REVIEW The epidemiology of hepatitis C virus (HCV) in HIV has changed significantly over the past decade. This review will outline the current epidemiology of HCV in HIV infection, focusing on the recent changes and factors which have been related to the increase in HCV transmission in HIV-infected men who have sex with men (MSM). RECENT FINDINGS Since 2000 there has been recognition in the postindustrialized world that there has been a dramatic rise in the incidence of HCV in HIV-infected MSM. Whereas sexual transmission of HCV remains controversial in the general population, there is increasing evidence that permucosal (sexual and mucosally administered drugs) rather than parenteral risks have become key factors in HCV transmission in HIV-infected MSM. At the most basic level, transmission depends on disruption of a barrier and exposure to infected fluids, usually blood. Whereas transmission factors are often closely entwined, they can be characterized as behavioural and biological factors. SUMMARY With an improved understanding of the epidemiology of HCV in this population, interventions by relevant health authorities could be better focused.

Acute HCV in HIV-Positive Individuals : A Review

HCV/HIV co-infection is a major public health problem with between 10-25% of HIV-positive individuals infected with HCV. Following the introduction of effective HIV therapies, HCV has become a leading cause of morbidity and mortality in the HIV population. Since the early 2000s, there has been a marked rise in the diagnosis of acute HCV in HIV-positive populations. Cohorts have been reported in Europe, USA and Australia. Molecular studies have revealed multiple HCV variants circulating within the HIV-positive men who have sex with men (MSM) population. There is also evidence of a large international transmission network, particularly in Europe. Significantly, permucosal rather than percutaneous risk factors related to high-risk traumatic sexual and drug factors have been associated with transmission. This has important implications for public health interventions aimed at mitigating the spread of HCV. HIV also impacts the early cell-mediated immunological responses to HCV, leading to higher rates of persistence. Data now exists supporting early treatment of these individuals with combination pegylated interferon and ribavirin. This epidemic has come about as a result of significant change in patient behavioural risk factors and these factors need to be the focus of a concerted effort on the part of public health specialist, clinicians and HIV-positive individuals themselves at a national and international level. Acute HCV in HIV-positive individuals differs significantly from acute HCV mono-infection in its epidemiology, natural history, immunology and virology and is becoming an increasingly significant problem in the HIV community. This will be the focus of this review article.

Effect of the interleukin‐6 C174G gene polymorphism on treatment of acute and chronic hepatitis C in human immunodeficiency virus coinfected patients

Hepatitis C virus (HCV)/human immunodeficirency virus (HIV) coinfection poses a difficult therapeutic problem. Response to HCV‐specific therapy is variable but might be influenced by host genetic factors, including polymorphisms of cytokine genes. Here, we studied whether interleukin‐6 (IL‐6) C174G gene polymorphism affects the response to antiviral treatment in HCV‐infected HIV‐positive subjects. We determined IL‐6 genotypes in HIV‐positive patients with acute (n = 52) and chronic (n = 60) hepatitis C treated with pegylated interferon‐α. Two hundred ten HCV monoinfected, 197 HIV monoinfected, and 100 healthy individuals were studied as controls. Patients were classified into high and low producers according to IL‐6 genotypes. Rates of sustained virological responses (SVRs) were compared between the IL‐6 genotypes. Signal transducer and activator of transcription three phosphorylation was analyzed by Western blot in HCV core‐transfected human hepatoma cell line (HUH7) cells. Distribution of IL‐6 genotypes did not differ significantly between the study groups. SVR was achieved in 63% of HIV/HCV coinfected patients. Carriers of the IL‐6 high producer (HP) genotype had significantly higher SVR rates than patients with an IL‐6 low producer genotype (70.1% versus 52%; P < 0.002). This effect was seen in both HIV‐positive patients with acute (74% versus 33%; P < 0.05) and chronic (66% versus 33%; P < 0.05) hepatitis C. Multivariate analysis confirmed IL‐6 HP carriage as an independent positive predictor for SVR (Odd′s ratio 6.1; P = 0.004). This effect corresponds to the in vitro observation that in HCV core‐transfected HUH7 cells, IL‐6 overcomes the HCV core‐mediated inhibition of STAT3 activation. Conclusion: Response rates to HCV‐specific treatment are higher in HCV/HIV‐positive patients carrying the IL‐6 HP genotype, which might be because of IL‐6 mediated STAT3 activation. (HEPATOLOGY 2007.)