Search

Background: Direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection is highly curative and tolerable. Among patients with hepatocellular carcinoma (HCC), optimal timing of DAA therapy remains unclear. Data on efficacy of DAA therapy in patients with HCC would inform this decision-making., Aim: To evaluate response to DAA therapy among patients diagnosed with HCV infection and HCC., Methods: Bibliographic databases and conference abstracts were searched. Meta-analysis was conducted to pool sustained virologic response (SVR) estimates., Results: Fifty-six studies with 5522 patients with HCV and HCC were included. Overall SVR was 88.3% (95% CI 86.1-90.4). Twenty-seven studies included patients with prior or present HCC (n = 3126) and patients without HCC (n = 49 138), in which SVR was 88.2% (95% CI 85.0-91.4) and 92.4% (95% CI 91.1-93.7) among patients with and without HCC, respectively (odds ratio: 0.54, 95% CI 0.43-0.68, P < .001). In the subgroup analyses, higher SVR was seen in patients who received curative HCC management (SVR 90.4%, 95% CI 88.3-92.4), or treated with sofosbuvir + NS5A inhibitor DAAs (SVR 96.9%, 95% CI 94.3-99.4), or in patients with HCV genotype 1 infection (SVR 92.0%, 95% CI 88.1-95.6)., Conclusion: Response to DAA therapy was lower in patients with HCC compared to those without HCC, regardless of cirrhosis status. Among HCC patients, there was an impact of proportion with curative HCC management on DAA therapy response., (© 2019 John Wiley & Sons Ltd.)

Nambu's dynamics formulation has been extended to electromagnetic optics by making use of intrinsic geometrical structures (dual vector bases) linked to equations of evolution of the wavefront. Two conserved quantities (electric and magnetic energy densities) are put in correspondence with Cauchy's quadrics associated with material tensors. A general expression of an eikonal equation for linear inhomogeneous anisotropic media has been derived, and illustrative graphic constructions to outline ray behavior are proposed. The methodology is particularized for several kinds of natural and artificial media.

While Australia now has well-established national screening programs for breast, bowel and cervical cancers, research continues into the feasibility of developing systematic screening programs for a number of other cancers. In this paper, experts in their fields provide perspectives on the current state of play and future directions for screening and surveillance for melanoma, Lynch syndrome, and liver, lung and prostate cancers in Australia. Although the evidence does not support population screening, there may be opportunities to prevent thousands of deaths through systematic approaches to the early detection of lung cancer and melanoma, testing for Lynch syndrome, and organised surveillance for hepatocellular carcinoma among individuals at high risk - guided by targeted research. The paper also looks at what impact new prostate specific antigen testing guidelines are having on screening for prostate cancer., Competing Interests: FM has done paid consultancy work for Rhythm Biosciences and received payment for providing medicolegal opinions. BA’s then-employer, the Sax Institute, was reimbursed by the Prostate Cancer Foundation of Australia (PCFA) for remunerated time spent advising the systematic evidence review team for the PSA testing guideline and on writing parts of the guideline document. BA is a member of the PCFA’s Board and Chair of their Research Advisory Committee. He receives no remuneration for either of these positions, but all expenses for attending meetings are paid for by the PCFA.

Introduction: Over the last two decades, the incidence of hepatitis C virus (HCV) co-infection among men who have sex with men (MSM) living with HIV began increasing in post-industrialized countries. Little is known about transmission of acute or recent HCV, in particular among MSM living with HIV co-infection, which creates uncertainty about potential for reinfection after HCV treatment. Using phylogenetic methods, clinical, epidemiological and molecular data can be combined to better understand transmission patterns. These insights may help identify strategies to reduce reinfection risk, enhancing effectiveness of HCV treatment as prevention strategies. The aim of this study was to identify multi-risk profiles and factors associated with phylogenetic pairs and clusters among people with recent HCV infection., Methods: Data and specimens from five studies of recent HCV in Australia and New Zealand (2004 to 2015) were used. HCV Core-E2 sequences were used to infer maximum likelihood trees. Clusters were identified using 90% bootstrap and 5% genetic distance threshold. Multivariate logistic regression and latent class analyses were performed., Results: Among 237 participants with Core-E2 sequences, 47% were in a pair/cluster. Among HIV/HCV co-infected participants, 60% (74/123) were in a pair/cluster, compared to 30% (34/114) with HCV mono-infection (p < 0.001). HIV/HCV co-infection (vs. HCV mono-infection; adjusted odds ratio (AOR), 2.37, 95% confidence interval (CI), 1.45, 5.15) was independently associated with phylogenetic clustering. Latent class analysis identified three distinct risk profiles: (1) people who inject drugs, (2) HIV-positive gay and bisexual men (GBM) with low probability of injecting drug use (IDU) and (3) GBM with IDU & sexual risk behaviour. Class 2 (vs. Class 1, AOR 3.40; 95% CI, 1.52, 7.60), was independently associated with phylogenetic clustering. Many clusters displayed homogeneous characteristics, such as containing individuals exclusively from one city, individuals all with HIV/HCV co-infection or individuals sharing the same route of acquisition of HCV., Conclusions: Clusters containing individuals with specific characteristics suggest that HCV transmission occurs through discrete networks, particularly among HIV/HCV co-infected individuals. The greater proportion of clustering found among HIV/HCV co-infected participants highlights the need to provide broad direct-acting antiviral access encouraging rapid uptake in this population and ongoing monitoring of the phylogeny., (© 2019 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Purpose of Review: The scale-up of direct-acting antiviral (DAA) therapy and introduction of preexposure prophylaxis (PrEP) has changed the epidemiology of sexually acquired hepatitis C virus (HCV) amongst HIV-positive and HIV-negative MSM., Recent Findings: Sexually acquired HCV continues to occur predominantly amongst HIV-positive MSM. Despite an increased uptake of DAA therapy the incidence of acute HCV has not declined consistently amongst HIV-positive MSM, likely a result of high infection and reinfection rates. Increasing cases of sexually acquired HCV have been reported amongst HIV-negative MSM accessing PrEP. Despite a lower prevalence of HCV at baseline, HIV-negative MSM accessing PrEP have an equally high overall incidence of HCV compared with HIV-positive MSM during follow-up. Behavioural factors (high-risk sexual behaviours and sexualized drug use) appear to be driving this HCV epidemic amongst MSM and effective behavioural interventions and early identification of reinfections are essential to control the HCV epidemic amongst MSM., Summary: An improved understanding of the epidemiology of sexually acquired HCV will allow implementation of more effective public health interventions to control the transmission of HCV amongst HIV-positive and HIV-negative MSM.

CD4 + T helper (Th) cells that express the gut homing chemokine receptor CCR9 are increased in the peripheral blood of patients with inflammatory bowel disease and Sjögren's syndrome and in the inflamed lesions of autoimmune diseases that affect the accessory organs of the digestive system. However, despite the important role of the GIT in both immunity and autoimmunity, the nature of CCR9-expressing cells in GIT lymphoid organs and their role in chronic inflammatory diseases remains unknown. In this study, we analyzed the characteristics of CCR9 + Th and T follicular helper (Tfh) cells in GIT associated lymphoid tissues in health, chronic inflammation and autoimmunity. Our findings reveal an association between the transcriptome and phenotype of CCR9 + Th in the pancreas and CCR9 + Tfh cells from GIT-associated lymphoid tissues. GIT CCR9 + Tfh cells exhibited characteristics, including a Th17-like transcriptome and production of effector cytokines, which indicated a microenvironment-specific signature. Both CCR9 + Tfh cells and CCR9 + Th cells from GIT-associated lymphoid tissues migrated to the pancreas. The expression of CCR9 was important for migration of both subsets to the pancreas, but Tfh cells that accumulated in the pancreas had downmodulated expression of CXCR5. Taken together, the findings provide evidence that CCR9 + Tfh cells and Th cells from the GIT exhibit plasticity and can accumulate in distal accessory organs of the digestive system where they may participate in autoimmunity.

Opto-mechanical analogies have been derived by casting electromagnetic field conservation laws for linear anisotropic media as balance equations of continuous mechanics, starting only and exclusively from Maxwell equations. Focusing on the asymmetry of Maxwell stress tensor T¯¯, electromagnetic couple density C is obtained in terms of the antisymmetric part of T¯¯, by using an equivalent system of forces. By considering a wavefront as a discontinuity surface, analogies with impulsive dynamics and the double-layer model for anisotropic media have been suggested. The procedure is applied to impedance-matched metamaterials and the eikonal equation for these media is reobtained.

Escalating cost of medicines is rapidly becoming a serious threat to patients and health systems. This trend has been documented to impact patient outcomes adversely. As clinicians and tax payers, it is our responsibility to be aware of the potential detrimental effects spiralling costs have on our patients, our community and our health system and to mitigate these effects by exposing this issue to our respective professional societies, representatives of the pharmaceutical companies that we interact with, government regulatory bodies and to patients who we are caring for. Only through understanding and constructive actions will we be able to provide the best quality of care to our patients and continue to enjoy universal healthcare in our country., (© 2017 Royal Australasian College of Physicians.)

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., (Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Current guidelines recommend hepatitis C virus (HCV) testing for HIV-infected men who have sex with men (MSM) with ongoing risk behaviour, without specifying the type of risk behaviour. We developed and validated the HCV-MOSAIC risk score to assist HCV testing in HIV-infected MSM. The risk score consisted of six self-reported risk factors identified using multivariable logistic regression using data from the Dutch MOSAIC study (n = 213, 2009-2013). Area under the ROC curve (AUC), sensitivity, specificity, post-test-probability-of-disease and diagnostic gain were calculated. The risk score was validated in case-control studies from Belgium (n = 142, 2010-2013) and the United Kingdom (n = 190, 2003-2005) and in cross-sectional surveys at a Dutch sexually transmitted infections clinic (n = 284, 2007-2009). The AUC was 0.82; sensitivity 78.0% and specificity 78.6%. In the validation studies sensitivity ranged from 73.1% to 100% and specificity from 56.2% to 65.6%. The post-test-probability-of-disease ranged from 5.9% to 20.0% given acute HCV prevalence of 1.7% to 6.4%, yielding a diagnostic gain of 4.2% to 13.6%. The HCV-MOSAIC risk score can successfully identify HIV-infected MSM at risk for acute HCV infection. It could be a promising tool to improve HCV testing strategies in various settings., (This article is copyright of The Authors, 2017.)

Background: Disruption of gastrointestinal tract epithelial and immune barriers contribute to microbial translocation, systemic inflammation, and progression of HIV-1 infection. Antiretroviral therapy (ART) may lead to reconstitution of CD4 + T cells in gut-associated lymphoid tissue (GALT), but its impact on humoral immunity within GALT is unclear. Therefore, we studied CD4 + subsets, including T follicular helper cells (Tfh), as well as resident B cells that have switched to IgA production, in gut biopsies, from HIV + subjects on suppressive ART compared to HIV-negative controls (HNC)., Methods: Twenty-three HIV + subjects on ART and 22 HNC undergoing colonoscopy were recruited to the study. Single-cell suspensions were prepared from biopsies from left colon (LC), right colon (RC), and terminal ileum (TI). T and B lymphocyte subsets, as well as EpCAM + epithelial cells, were accurately enumerated by flow cytometry, using counting beads., Results: No significant differences in the number of recovered epithelial cells were observed between the two subject groups. However, the median TI CD4 + T cell count/10 6 epithelial cells was 2.4-fold lower in HIV + subjects versus HNC (19,679 versus 47,504 cells; p  = 0.02). Similarly, median LC CD4 + T cell counts were reduced in HIV + subjects (8,358 versus 18,577; p  = 0.03) but were not reduced in RC. Importantly, we found no significant differences in Tfh or IgA + B cell counts at either site between HIV + subjects and HNC. Further analysis showed no difference in CD4 + , Tfh, or IgA + B cell counts between subjects who commenced ART in primary compared to chronic HIV-1 infection. Despite the decrease in total CD4 T cells, we could not identify a selective decrease of other key subsets of CD4 + T cells, including CCR5 + cells, CD127 + long-term memory cells, CD103 + tissue-resident cells, or CD161 + cells (surrogate marker for Th17), but there was a slight increase in the proportion of T regulatory cells., Conclusion: While there were lower absolute CD4 + counts in the TI and LC in HIV + subjects on ART, they were not associated with significantly reduced Tfh cell counts or IgA + B cells, suggesting that this important vanguard of adaptive immune defense against luminal microbial products is normalized following ART.

Background: This study aimed to investigate the potential influence of venue-based networks on HCV transmission in HIV-positive gay and bisexual men (GBM)., Methods: This was a prospectively recruited cohort of HIV-infected GBM with recently-acquired HCV infection resident in Melbourne and Sydney. Clinical and demographic data were collected together with blood samples for HCV sequencing. Phylogenies were inferred and clusters of individuals infected with HCV with genetic sequence homology were identified. Venues used for sourcing sexual partners were identified; sourcing partners from the same venue was considered a potential social link. Using the Jaccard similarity coefficient, associations were identified between the network of sites where men sourced sex partners and transmission relationships as defined by phylogenetic clustering., Results: Forty individuals were recruited, of whom 62.5% were considered to have sexually- and 37.5% IDU-acquired HCV. Venue use was consistent with men being members of a more sexually adventurous gay community subculture. Six phylogenetically-determined pairs or clusters were identified, comprising fifteen (15/28, 53.6%) individuals. Participants belonging to phylogenetic clusters were observed within the same networks. There was a significant correlation between the network and phylogenetic clustering when both cities were considered simultaneously (p = 0.005), raising the possibility that social connections may be important for HCV transmissions., Conclusions: Venue-based network elicitation is a promising approach for elucidating HCV transmissions amongst HIV-infected GBM. Public health approaches targeting individuals and venues prominent within networks may reduce onward HCV transmission., Competing Interests: The authors have declared that no competing interests exist.

Unnoticed and hidden optomechanical analogies between kinematics of planar motion of a rigid solid and catacaustics generated by mirror reflection on smooth profiles in geometrical optics are discussed. A concise and self-consistent theory is developed, which intends to explain and clarify many partial aspects covered by the literature.

Background: We aimed to characterize seminal hepatitis C virus (HCV) RNA dynamics in human immunodeficiency virus (HIV)-positive men with acute HCV infection given its potential role in sexual transmission of HCV., Methods: Men with acute HCV infection (duration, ≤12 months) or chronic HCV infection (duration, >12 months) were prospectively recruited. Paired semen and blood samples were assayed for HCV RNA levels. Results were analyzed using χ(2), Fisher exact, Mann-Whitney U, and Kruskal-Wallis tests., Results: Eighteen men (27.3%) had acute HCV and HIV coinfection, 22 (33.3%) had chronic HCV infection and HIV coinfection, and 26 (39.4%) had chronic HCV monoinfection. HCV RNA was detected in semen specimens from 29 of 66 men (43.9%). The median HCV RNA level in blood was 4.0 log IU/mL higher than that in semen. HCV RNA levels were correlated in semen and blood (r(2) = 0.142). Neither HIV positivity nor acute HCV infection was associated with an increased frequency of seminal HCV RNA detection. Among men with acute HCV and HIV coinfection, the median HCV RNA level in blood specimens from those with seminal HCV RNA was higher than that in blood specimens from those without seminal HCV RNA (P = .001). Seminal HCV RNA was detected in ≥1 sample for 26 of 35 men (74.3%) attending follow up., Conclusions: HCV RNA was detected in semen during both acute and chronic HCV infection. This was unaffected by HIV positivity or the phase of HCV infection. Elevated seminal HCV RNA levels could contribute to sexual transmission of HCV, but other factors, including high-risk behaviors, may be the main drivers for HCV transmission in HIV-infected individuals., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Introduction: There is controversy regarding the role of yttrium-90 (90Y) radioembolization in the management of advanced, unresectable hepatocellular carcinoma (HCC)., Methods: Forty-five consecutive patients underwent resin-based 90Y radioembolization for unresectable, HCC between 2006 and 2013 in Sydney, Australia. All patients were followed up with imaging studies at regular intervals until death. Radiologic response was evaluated with the Response Criteria in Solid Tumors (RECIST) criteria. Clinical toxicities were prospectively recorded. Survival was calculated by the Kaplan-Meier method and potential prognostic variables were identified on univariate and multivariate analysis., Results: Follow-up in the complete cohort was 7.8 (range, 0.1-41.8) months. The median survival after 90Y radioembolization was 27.7 months with a 36-month survival of 26%. By RECIST criteria of the 40 patients followed-up beyond 2 months, a complete response (CR) to treatment was observed in 1 patients (3%), partial response (PR) in 18 (45%), stable disease (SD) in 11 (22%) and progressive disease (PD) in 10 (25%). On multivariate analysis only radiological response to treatment was independently associated with improved survival: CR/PR to treatment vs. SD vs. PD; p < 0.001. Thirteen patients (29%) developed clinical toxicity after treatment; all complications were minor (grade I/II) and resolved without active intervention., Conclusion: Radioembolization with 90Y is a safe and effective treatment for unresectable HCC., (Copyright © 2014. Published by Elsevier Ltd.)

Background: This study aimed to collect and analyze data on patient knowledge of colonoscopy and their preferences regarding the provision of information about the procedure. Specifically, how much detail patients know about different aspects of the procedure and through which methods they best understand risk are evaluated and demographic correlations identified., Materials and Methods: The study sample consisted of colonoscopy patients from 2 colorectal surgeons and a gastroenterologist at St Vincent's Public Hospital, Sydney for the period August 1 to November 1, 2010. A voluntary questionnaire was performed in the waiting room before colonoscopy. The questionnaire collected data on patient demographics; patient-perceived knowledge of the procedure; and understanding and preferences of various communication formats., Results: Measures of patient-perceived knowledge about colonoscopy were significantly lower than those that would be preferred by patients (P=0.002). Those with higher levels of education preferred communication of colonoscopy-related information via a leaflet form, whereas those with lower levels preferred verbal information from a doctor or nurse (P=0.049). The most preferred format for explaining the risk of perforation was the pie graph, followed by both the 1000-person pictograph and absolute risk ratios., Conclusions: Patients received suboptimal levels of information about colonoscopy compared with their preferences. Key areas for improvement include providing more understandable information about the risks of colonoscopy. A combination of written information, diagrams and graphs, and then a discussion of this information to check the understanding is likely to be most effective. Further research into the communication of risk, with larger groups of patients, is likely to help clinicians in gaining fully informed consent in all patients.

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.

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., (©2011 AACR.)

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.

Objective: Cytotoxic lymphocyte antigen 4 (CTLA4), a co-receptor expressed on T lymphocytes, is involved in the regulation of T-cell functions. Here, we analyzed the potential impact of the CTLA4 polymorphisms on response to hepatitis C virus (HCV)-specific treatment in HIV(+) patients co-infected with HCV., Patients and Methods: A total of 184 HIV/HCV co-infected Caucasian patients were enrolled into this study, including 109 patients with chronic and 75 patients with acute hepatitis C. CTLA4 genotypes were determined by LightCycler PCR., Results: We found the CTLA4 -318 C/C genotype to be associated with sustained virological response in HCV/HIV co-infection (P = 0.035). Moreover, response rates were significantly higher in patients with a +49G/G genotype [23/29 (79.3%)] than in carriers of other +49 genotypes [59/155 (38.1%); OR 6.2; P = 0.00005]. Of note, the CTLA4 +49G/G genotype was confirmed as an independent predictor for treatment response in both patients with acute and chronic hepatitis C., Conclusion: CTLA4 polymorphisms are associated with treatment-induced resolution of HCV infection in HIV co-infected patients. These findings underline the impact of genetic host factors for successful treatment.

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.

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.

Unlabelled: Hepatitis C virus (HCV)/human immunodeficiency 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-alpha. 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.

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.

Alterations in normal intestinointestinal reflexes may be important contributors to the pathophysiology of irritable bowel syndrome (IBS). Our aims were to compare the rectal tonic responses to colonic distension in female IBS patients with predominant constipation (IBS-C) and with predominant diarrhea (IBS-D) to those in healthy females, both fasting and postprandially. Using a dual barostat assembly, 2-min colonic phasic distensions were performed during fasting and postprandially. Rectal tone was recorded before, during, and after the phasic distension. Colonic compliance and colonic sensitivity in response to the distension were also evaluated fasting and postprandially. Eight IBS-C patients, 8 IBS-D patients, and 8 age- and sex-matched healthy subjects (group N) participated. The fasting increments in rectal tone in response to colonic distension in both IBS-C (rectal balloon volume change -4.6 +/- 6.1 ml) and IBS-D (-7.9 +/- 4.9 ml) were significantly reduced compared with group N (-34 +/- 9.7 ml, P = 0.01). Similar findings were observed postprandially (P = 0.02). When adjusted for the colonic compliance of individual subjects, the degree of attenuation in the rectal tonic response in IBS compared with group N was maintained (fasting P = 0.007; postprandial P = 0.03). When adjusted for colonic sensitivity there was a trend for the attenuation in the rectal tonic response in IBS patients compared with group N to be maintained (fasting P = 0.07, postprandial P = 0.08). IBS patients display a definite attenuation of the normal increase in rectal tone in response to colonic distension (colorectal reflex), fasting and postprandially. Alterations in colonic compliance and sensitivity in IBS are not likely to contribute to such attenuation.

The increasing incidence of hepatocellular carcinoma (HCC) is becoming a considerable problem in Europe. While no national surveillance programme exists, there is increasing evidence that surveillance programmes are efficacious and may be cost-effective. The prognosis of large, symptomatic HCC is poor and only palliative treatment is available. In contrast small tumours are now amenable to several modes of treatment including liver transplantation, surgical resection and loco-regional ablation with acceptable 5 year survival rates. Therefore, the identification of small lesions through screening should prolong survival. Consequently, the European Association for the Study of the Liver (EASL) has recommended surveillance with ultrasound scans and tests for alpha fetoprotein every 6 months. Screening is now routine clinical practice in many parts of the developed world.

Tonic reflexes in the colon and rectum are likely to be important in health and in disorders of gastrointestinal function. The aim of this study was to evaluate the fasting and postprandial "colorectal" and "rectocolic" reflexes in response to 2-min isobaric distensions of the colon and rectum, accounting for enteric sensation, compliance, and distending balloon volume. In 14 healthy fasting subjects, a dual barostat assembly was positioned (descending colon and rectum). A 2-min phasic distension was performed in the colon and rectum in random order while the opposing balloon volume was recorded. Sensation (phasic distension) and compliance (ramp distension) were also determined. The experiment was repeated postprandially. Colonic distension resulted in significant rectal tonic contraction in the fasting (rectal volume change: -35.4 +/- 8.4 ml, P < 0.01) and postprandial (-22.2 +/- 8.4 ml, P < 0.01) states. After adjustment for colonic sensitivity, for compliance, and for distending balloon volume, the rectal volume change remained significant; the extent of the tonic response, however, correlated significantly with increasing pain score (P < 0.01). In contrast, rectal distension did not produce a significant tonic response in the colon (fasting: -6.5 +/- 7.3 ml; postprandial: 2.7 +/- 7.3 ml), either unadjusted or adjusted for rectal sensitivity, compliance, and distending balloon volume. In conclusion, the colorectal reflex, but not the rectocolic reflex, can be readily demonstrated both before and after a meal in response to a 2-min isobaric distension in the colon and rectum, respectively. Although the presence of the colorectal reflex does not depend on colonic sensitivity or the volume of the distending colonic balloon, these factors modulate the reflex, especially in the fasting state.

Objective: To determine factors associated with hepatic fibrosis development in people with chronic hepatitis C virus (HCV) infection., Methods: As a requirement for access to interferon therapy through the S100 scheme in Australia, individual pretreatment demographic and clinical information was collected on 2986 patients from 61 hospital-based liver clinics from 1 October 1994 through 31 December 1996. Patients with both a hepatic fibrosis score and an estimated duration of HCV infection (910) were divided into 540 with no or minimal hepatic fibrosis (stage 0-1) and 370 with moderate to severe hepatic fibrosis (stage 2-3). Seven factors were examined: age at HCV infection, sex, ethnicity, source of infection, duration of infection, alcohol intake, and mean ALT level. A further analysis was performed for all 1135 patients with a hepatic fibrosis score disregarding age at and duration of HCV infection., Results: In multivariate analysis, four factors were significantly associated with moderate to severe hepatic fibrosis: age at infection (OR, 2.33 for age 31-40 years, 5.27 for age > 40 years, and 0.20 for age < 15 years, compared with 15-20 years); duration of infection (OR, 1.44 for 11-20 years, 2.74 for 21-30 years, and 8.71 for > 30 years, compared with < 11 years); alcohol intake in previous six months (OR, 1.51 for any intake, compared with none); and mean ALT level (OR, 1.81 for 2-3 times, 2.27 for > 3 times, compared with 1.5-2 times the upper limit of normal). In the analysis disregarding age at HCV infection and duration of HCV infection, older age was strongly associated with moderate to severe hepatic fibrosis (OR, 2.32 for age 36-40 years, 2.46 for age 41-50 years, 7.87 for age 51-60 years, and 7.15 for age > 60 years, compared with 16-30 years). There was no association in either analysis with sex or source of HCV infection., Conclusion: These factors may assist in targeting patients for both liver biopsy-based investigation and therapeutic intervention.