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Interferon stimulates the expression of a number of genes encoding enzymes with antiviral activities, including myxovirus resistance-1 (MxA), 2-5-oligoadenylate synthetase 1 (OAS-1) and double-stranded RNA-dependent protein kinase (PKR). We examined whether polymorphisms in these genes influenced the outcome of hepatitis C virus (HCV) infection. We observed a lower frequency of the GG genotype at position -88 in the MxA gene promoter in self-limiting HCV infection (OR=0.56; 95% CI: 0.35-0.8; P=0.010) and in nonresponders to therapy (OR=0.49; 95% CI: 0.25-0.95; P=0.020). This genotype predominantly influenced the outcome of treatment in patients with viral genotype 1 (OR=0.22 95% CI: 0.07-0.67; P=0.002). A polymorphism in the 3'-untranslated region of the OAS-1 gene was associated with outcome of infection (GG genotype less frequent in self-limiting infection: OR=0.43; 95% CI: 0.21-0.86; P=0.010). A polymorphism at position -168 in the promoter region of the PKR gene was associated with self-limiting infection (CT genotype: OR=2.75; 95% CI: 1.45-5.24; P=0.002). Further associations were found with a CGG trinucleotide repeat in the 5'UTR region of the PKR gene. Polymorphisms in the interferon-induced genes, MxA, OAS-1 and PKR appear thus associated with HCV outcome.

Cytotoxic T lymphocyte antigen-4 (CTLA4) suppresses cytotoxic T lymphocyte activity. We examined the associations of CTLA4 single-nucleotide polymorphisms (SNPs) at promoter site -318 and exon-1 site 49 with clearance of hepatitis C virus (HCV) after treatment with combination interferon-alpha plus ribavirin (IFN-alpha+R) therapy in 79 white sustained responders (SRs) and 79 nonresponders (NRs). SRs had higher frequencies of 49G, alone (odds ratio [OR], 2.3; P=.042) and tightly linked with -318C in a haplotype (OR, 2.4; P=.030). Homozygosity for the -318C-49G haplotype was even more frequent among SRs (OR, 5.2; P=.049). Comparably strong associations persisted after multivariable analysis. Relationships were not seen with non-1 genotype viruses (OR, 0.93-1.25; P>.25). Virus load also declined more rapidly in carriers of both 49G (P=.0095) and the -318C-49G haplotype. CTLA4 49G in exon 1 alone and in a haplotype with -318C promoter is associated with sustained IFNalpha+R response in white patients with HCV genotype 1 infection.

Background Transmission of hepatitis C vims (HCV) is strongly associated with use of contaminated blood products and injection drugs. Other "non-parental" modes of transmission including sexual activity have been increasingly recognized. We examined risk factors for acquiring HCV in patients who were referred to two tertiary care centers and enrolled in an antiviral therapy protocol. Methods Interviews of 148 patients were conducted apart from their physician evaluation using a structured questionnaire covering demographics and risk factors for HCV acquisition. Results Risk factors (blood products, injection/intranasal drugs, razor blades/ toothbrushes, body/ear piercing, occupational exposure, sexual activity) were identified in 141 (95.3%) of participants; 23 (15.5%) had one (most frequently blood or drug exposure), 41 (27.7%) had two, and 84 (53.4%) had more than two risk factors. No patient reported sexual activity as a sole risk factor. Body piercing accounted for a high number of exposures in women. Men were more likely to have exposure to street drugs but less exposure to blood products than women. Blood product exposure was less common in younger than older HCV patients. Conclusion One and often multiple risk factors could be identified in nearly all HCV-infected patients seen in a referral practice. None named sexual transmission as the sole risk factor. The development of a more complete profile of factors contributing to transmission of HCV infection may assist in clinical and preventive efforts. The recognition of the potential presence of multiple risk factors may have important implications in the approach to HCV surveillance, and particularly the use of hierarchical algorithms in the study of risk factors.

PURPOSE: We sought to identify factors associated with hepatitis B virus vaccination, including knowledge and attitudes about hepatitis vaccination, and sexual and nonsexual risk behaviors among at-risk homosexual and bisexual men. SUBJECTS AND METHODS: Internet electronic communications were used to collect data from homosexual and bisexual men from the United States, using a 31-item online questionnaire accessible for 1 month. RESULTS: The mean (± SD) age of the 336 respondents was 38 ± 11 years. Nearly 42% (142) reported at least one dose of vaccine; the remainder were completely unvaccinated. About 21% (n = 71) reported having no information about hepatitis. Approximately 72% (242) of respondents reported never using condoms during oral intercourse, and 26% (n = 87) reported using condoms during less than half of their episodes of anal intercourse. In multivariate analysis, variables associated with vaccination were younger age (odds ratio [OR] 0.7 per 10-year increase in age; 95% confidence interval [CI] 0.59 to 0.84, P = 0.002), high level of knowledge about the vaccine (OR 1.4; 95% CI: 1.03 to 1.83, P = 0.007), communication with a health-care provider about hepatitis (OR 1.98; 95% CI 1.31 to 2.98, P = 0.006), and professional training that included hepatitis education (OR 2.77; 95% CI 1.7 to 4.5, P = 0.001). CONCLUSIONS: Our findings underscore the need for health care providers to emphasize vaccine efficacy and safety, and to encourage high-risk patients to receive vaccination, particularly among men at high risk based on sexual and drug use behaviors.

Pro-inflammatory cytokines including tumour necrosis factor (TNF) mediate the pathogenesis of hepatitis C virus (HCV) infection. The distribution of TNF gene polymorphisms was examined among cirrhotic and non-cirrhotic patients infected with HCV. Thirty Caucasians with cirrhosis due to chronic HCV infection and 114 HCV-infected patients histopathologically free of cirrhosis were genotyped for genetic variants in TNF, lymphotoxin alpha and TNF-receptor type I using PCR-based techniques. Variability in the progression of HCV-related cirrhosis was assessed in a multivariate model including genetic and non-genetic factors such as gender, estimated duration of infection, alcohol consumption, and viral genotype. Viral genotype and non-genetic host features were not independently related to the occurrence or rate of development of cirrhosis in the patient population. In contrast, the TNF promoter variants TNF2 (-238A) and TNF3 (-308A) conferred a 3.2-fold and 5.1-fold risk of cirrhosis respectively (P = 0.03 for both). Reciprocal effects were observed with several TNF alleles and haplotypes defined by the -238G/A and -308G/A dimorphic sequences. Polymorphisms in the TNF alpha promoter appear to be associated with variability in the histological severity of chronic hepatitis C infection.

Erythrocyte tropomodulin (E-Tmod), a globular protein of 359 residues, is highly expressed in the erythrocyte, heart and skeletal muscle. By binding to the N-terminus of tropomyosin (TM) and actin, E-Tmod blocks the elongation and depolymerization of the actin filaments at the pointed end. In erythrocytes, the E-Tmod/TM complex contributes to the formation of the short actin protofilament, which in turn defines the geometry of the membrane skeleton. In juvenile mice, over-expression of E-Tmod is associated with dilated cardiomyopathy. We have previously cloned the human E-Tmod cDNA, identified its TM-binding region, and mapped its gene to chromosome 9q22. Through genomic library screening and PCR-based genomic walking we have now cloned the mouse E-Tmod gene, whose coding region spans approximately 60kb containing nine exons and eight introns. The human E-Tmod gene obtained by PCR has an identical exon-intron organization. In sanpodo, a Tmod homologue in Drosophila, the exon boundaries are also conserved except that exons 2-5 and 6-7 are 'fused' and alternative splicing of two additional 5' exons and the 3' exons may give rise to several sanpodo isoforms. In a Tmod-like gene of C. elegans, exons 2-3 are 'fused', boundaries of exons 1, 7, 8, and 9 are conserved and exon/intron junctions of exons 4, 5 and 6 are shifted by a few residues. Analyses of 15 Tmod members from six species show no insertions or deletions of residues in the region of exons 6 and 7. A 5' rapid amplification of cDNA ends reveals that mouse E-Tmod transcripts obtained from embryonic stem cells, skeletal muscle and heart, but not smooth muscle, contain an additional 86bp untranslated cDNA sequence further upstream from exon 1. Thus, alternative promoters may provide a possible mechanism for tissue-specific expression and regulation of E-Tmod. This study is the first to report the exon organization of E-Tmod genes, which allows their regulation, manipulation, and disease relevance to be further investigated.

There has been a traditional view that divided epidemiology into infectious and chronic diseases. Since we now know that at least 15% of cancers worldwide are caused by infections, 1 that infections frequently have a natural history lasting decades and that the same epidemiological methods can be applied to both infectious and non-infectious diseases, this view can be considered purely historical. However, the nature of infectious diseases has implications for the application of epidemiological approaches including the specific example of life course epidemiology. Whilst the definition of this is still debated, it clearly refers to the way in which influences at different stages of life affect and modify risks of disease. Life course epidemiology particularly focuses on disease in adult life and so that is what we discuss here. We are not going to consider childhood or adolescent diseases. In addition it recognizes two types of influence on risk: (1) a simple accumulation of risks and (2) ‘programming’. 2 The latter is the way in which an influence modifies a biological system so that it responds differently to subsequent exposures. The epidemiological paradigm for this has been David Barker’s hypothesis that intra-uterine nutrition determines physiological responses in the cardiovascular system. 3 When we come to talk about infections we have to deal with a few semantics. Susceptibility means that the subject is vulnerable to infection if they are exposed. Infants may not be susceptible because of transferred immunity from their mother. Many, but not all, infections result in a loss of susceptibility due to immune memory. Exposure is traditionally used to define exposure to the infectious agent. We will use it in that context here and use the term ‘influence’ for non-agent exposures. There is a critical difference between infection and disease. The proportion of individuals infected who develop disease varies from 0% (as with infection with the hepatitis G virus) to virtually 100% (with measles and the human immunodeficiency virus [HIV]) depending on the infection. However, for many infections the relationship is strongly dependent on the age at which infection occurs—an obvious entree for life course epidemiology. Thus Epstein-Barr virus infection in childhood hardly causes any symptoms whereas in adolescence it results in glandular fever. Severity and rate of disease progression are also influenced by age at infection. Hepatitis A becomes an increasingly severe disease the older the subject. We return to this point below. Finally, we use the term ‘reactivation’ for persistent infections that produce disease after a prolonged period of latency following a first disease episode. Varicella zoster virus remains latent for years following chickenpox until around a fifth of infected people develop shingles. The simple model in Figure 1 shows how influences may affect various stages of the process. This emphasises proximate biological factors. Clearly there are more distal factors that may be more easily measured. For example, exposure to the infectious agent is highly dependent on behaviour—mixing patterns with other young children may determine exposure to childhood infections and sexual activity modulates risk of sexually transmitted infections. The timing from susceptibility to disability, death or recovery is incredibly variable. With many infections that do not persist, symptoms of disease occur, if they are going to, within days—at most months—after initial infection. Agents, such as hepatitis B and C viruses, that persist and replicate within the body may not lead to disease (in this case primary liver cancer) until 50 years after infection. Once infectious disease is recognized the natural history is as variable as that of non-communicable diseases. The reasons for all this variation are the influences at each stage.

24 weeks of interferon-ribavirin therapy should not routinely be given to all hepatitis C patients

Editor,—Estimates of the prevalence of hepatitis B virus (HBV) markers among men who have sex with men (MSM) range from 5% to 81%, and the prevalence of HBV surface antigen varies from 1% to 11%.1,2 Despite a safe and effective vaccine against HBV, sexually active MSM are not vaccinated adequately.2–5 Few empirical data describe the factors associated with HBV vaccination among MSM. We conducted a study to identify correlates of HBV vaccination among MSM that could inform future interventions designed to enhance HBV …

Background & AimsLong-term treatment with tenofovir disoproxil fumarate (TDF) alone, or in combination with emtricitabine (FTC) is associated with sustained viral suppression in patients with lamivudine resistant (LAM-R) chronic hepatitis B (CHB).MethodsLAM-R CHB patients were randomised 1:1 to receive TDF 300mg or FTC 200mg and TDF 300mg once daily in a prospective, double blind, study. The proportion of patients with plasma hepatitis B virus (HBV) DNA