BACKGROUND: Macrophage inhibitory cytokine-1 (MIC-1/GDF15) mediates 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 pre-malignant colonic polyposis and assist in population screening strategies.METHODS: Serum MIC-1/GDF15 levels were measured in subjects in the Polyp Prevention Trial, where 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 re-estimated. 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. Additionally, 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. Further, 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. Further, 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 pre-malignant adenomatous colonic polyposis.

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.

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.

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.

HASH(0x286c7390)

BACKGROUND & AIMS: Since 2000, there has been a marked rise in acute hepatitis C virus (HCV) in human immunodeficiency virus (HIV)-positive men who have sex with men (MSM). We conducted an international phylogenetic study to investigate the existence of an HCV transmission network among MSM. METHODS: HIV-positive MSM diagnosed with recent HCV (n = 226) in England (107), The Netherlands (58), France (12), Germany (25), and Australia (24) between 2000 and 2006 were enrolled into a molecular phylogenetic study. Using real-time polymerase chain reaction (PCR), the NS5B region of the HCV genome (436 base pair) was amplified, sequenced, and compared with unrelated NS5B sequences. RESULTS: NS5B sequences were obtained from 200 (89%) cases. Circulating HCV genotypes were 1a (59%), 4d (23%), 3a (11%), 1b (5%), and 2b/c (3%). Phylogenetic analysis revealed 156 (78%) sequences that formed 11 clusters (bootstrap value > 70%) containing between 4 and 37 individual sequences. Country mixing was associated with larger cluster size (17 vs 4.5 sequences; P =.03)."Molecular clock" analysis indicated that the majority (85%) of transmissions occurred since 1996. CONCLUSIONS: Phylogenetic analysis revealed a large international network of HCV transmission among HIV-positive MSM. The rapid spread of HCV among neighboring countries is supported by the large proportion (74%) of European MSM infected with an HCV strain co-circulating in multiple European countries, the low evolutionary distances among HCV isolates from different countries, and the trend toward increased country mixing with increasing cluster size. Temporally, this epidemic coincides with the introduction of highly active antiretroviral therapy and associated increases in sexual risk behaviors. International collaborative public health efforts are needed to mitigate HCV transmission among this population.

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.

BACKGROUND: Coinfection with the hepatitis C virus (HCV) in HIV-positive patients is an emerging health problem. The factors affecting response to HCV-specific therapy are poorly understood but may involve host genetic factors. HCV NS5A-induced inhibition of transforming growth factor-beta signaling has been suggested as a potential mechanism involved in HCV pathogenesis. Transforming growth factor-beta, a multifunctional cytokine, displays gene polymorphisms (transforming growth factor-beta codon 10T/C and codon 25G/C) associated with differential cytokine secretion. Here, we studied whether transforming growth factor-beta gene polymorphisms affect treatment response in HCV/HIV coinfection. METHODS: Transforming growth factor-beta genotypes were determined in 60 HIV-positive patients with acute hepatitis C treated with pegylated interferon-alpha. Patients were classified into those with a high-producer genotype and others with non-high-producer genotypes. Rates of sustained virological responses were compared between high-producer and non-high-producer patients. As a control, 100 healthy, 201 HIV(+)/HCV(-), and 148 HCV(+)/HIV(-) subjects were studied. RESULTS: Transforming growth factor-beta genotype distribution did not differ significantly between the groups. In HIV/HCV coinfection carriers of the transforming growth factor-beta high-producer genotype had significantly higher sustained virological response rates than patients with a transforming growth factor-beta non-high-producer genotype (75 vs. 41.7%; P = 0.039). In a forward-conditional stepwise regression model, transforming growth factor-beta high-producer genotype was confirmed as an independent positive predictor for sustained virological response in interferon-alpha therapy (odds ratio, 4.4; 95% confidence interval, 1.5-13.4; P = 0.009). CONCLUSION: Response rates to interferon-alpha therapy are enhanced in acute HCV-infected HIV-positive patients carrying the transforming growth factor-beta 'high-producer' genotype. This finding may indicate that a transforming growth factor-beta 'high-producer' state can partially compensate HCV NS5A-induced inhibition of transforming growth factor-beta signaling.