Macrophage inhibitory cytokine-1/growth differentiation factor-15 as a predictor of colonic neoplasia.

BACKGROUND: Serum macrophage inhibitory cytokine-1 (MIC-1/GDF15) concentration has been associated with colonic adenomas and carcinoma. AIMS: To determine whether circulating MIC-1/GDF15 serum concentrations are higher in the presence of adenomas and whether the level decreases after excision. METHODS: Patients were recruited prospectively from a single centre and stratified into five groups: no polyps (NP); hyperplastic polyps (HP); sessile serrated ademona (SSA); adenomas (AP); and colorectal carcinoma (CRC). Blood samples were collected immediately before and 4 weeks after colonoscopy. MIC-1/GDF15 serum levels were quantified using ELISA. RESULTS: Participants (n=301) were stratified as: NP; n=116 (52%), HP; n=37 (12%), SSA; n=19 (7%), AP; n=68 (23%); and CRC; n=3 (1%). Patients were excluded from the study due to nondiagnostic pathology (n=9, 3%) and exclusion criteria (n=20, 6%). In the 272 remaining subjects (M=149; F=123), age (P=.005), history of colonic polyps (P=.003) and family history of colonic polyps (P=.002) were associated with presence of adenomas. Baseline median MIC-1/GDF15 serum levels increased significantly from NP 609 (460-797) pg/mL, HP 582 (466-852) pg/mL, SSA 561 (446-837) pg/mL to AP 723 (602-1122) pg/mL and CRC 1107 (897-1107) pg/mL; (P<.001). In the pre- and postpolypectomy paired adenoma samples median MIC-1/GDF15 reduced significantly from 722 (603-1164) pg/mL to 685 (561-944) pg/mL (P=.002). A ROC analysis for serum MIC-1/GDF15 to identify adenomatous polyps indicated an area under the curve of 0.71. CONCLUSIONS: Our data suggest that serum MIC-1/GDF15 has the diagnostic characteristics to increase the detection of colonic neoplasia and improve screening.

The complex legal and ethical issues related to generic medications. Viral hepatitis: a case study.

The economic impact of medications is significant, with many countries unable to afford the essential medicines listed by the WHO. Generic medications are one strategy to address this issue. Generic medications are similar to but not the same as originator medications. They have a significant cost advantage because they do not require the background research and development studies to support registration. Consequently, they are gaining increased market share in both the developed and developing world. Many new medications are now licensed to generic manufacturers in the developing world. As a result, it is possible for patients to bypass regulatory and cost barriers by importing medications directly from generic producers. Importation of the novel hepatitis C direct-acting antiviral therapy into Australia before it was registered in the country is an illustrative case study. This review will characterise generic medications and some of the legal and ethical issues around their utilisation, focusing on the relevant players, including pharma, government, patients and doctors.

Evidence of a large, international network of HCV transmission in HIV-positive men who have sex with men.

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.

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.

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.

Adefovir dipivoxil: review of a novel acyclic nucleoside analogue.

Adefovir dipivoxil (ADF) is a novel acyclic nucleoside analogue that has recently been approved for the treatment of chronic hepatitis B virus (HBV). Adefovir was initially assessed at higher doses for the treatment of human immunodeficiency virus (HIV) infection. However, in these studies, nephrotoxicity proved a dose-limiting side effect. Large randomised controlled studies have recently shown that ADF results in histological, virological and biochemical improvement in both hepatitis B e antigen (HBeAg)-positive and HBeAg-negative chronic HBV. While the rate of HBeAg seroconversion at 1 year (12%) was lower than both lamivudine and interferon, this increases with prolonged treatment. The clinical improvements occurred without serious side effects or the development of resistance at the dose of 10 mg daily, in treatment trials of up to 2 years, although resistance has now been observed. In addition, the drug is efficacious in HBV/HIV co-infection and hepatitis B-infected liver transplant recipients, particularly in those who have developed lamivudine resistance. ADF can be added as a treatment option to existing treatment options (interferon-alpha and lamivudine) and assumes a role in the ongoing management of chronic HBV. The optimal use of ADF as either a monotherapy or as part of combination therapy requires further assessment.