Determinants of hepatitis C virus clinical outcomes

Hepatitis C virus (HCV) infection is characterized by a broad spectrum of clinical outcomes. An estimated 14%-46% of individuals exposed to HCV are able to clear the virus, while the other portion develops chronic (persistent) infections. Among the individuals with chronic HCV who are treated with interferon-based therapies, only a portion are able to experience sustained virological suppression. Similarly, a number of chronically infected individuals have autoimmune extrahepatic manifestations such as the presence of autoantibodies. The pathological mechanisms behind these phenomena are not known, but it is believed that host genetic factors may play a role. This thesis examines the hypothesis that host genetic factors may contribute to the diverse spectrum of HCV clinical outcomes. In addition, it examines the pathogenesis of antinuclear antibodies (ANA) in chronic HCV, and the effect of ANA positivity on the natural history of HCV. Correlations were observed between female gender and geographic location and ANA positivity. No relationships were observed for an effect of ANA positivity on response rates to interferon therapy. We observed a trend of ANA positivity with faster progression of HCV-related fibrosis, although this failed to achieve statistical significance. ANA-positive individuals tended to have more plasma cells in their liver than ANA-negative individuals. This study also observed a number of correlations between genotypes of the interferon induced genes encoding the myxovirus resistance 1 protein (MxA), 2'-5'oligo-adenylate synthase 1 (OAS-1), and protein kinase (PKR), as well as genes encoding cytotoxic T-lymphocyte antigen-4 (CTLA4), and inducible nitric oxide synthase (iNOS) (encoded by the NOS2A gene) with several outcomes including self-limiting versus chronic HCV infection, along with the response to interferon therapy. This study identified several factors to be correlated with ANA positivity in HCV. These factors may serve as future points for investigation by basic scientists understanding the mechanisms of HCV-mediated autoimmunity. Importantly, this study suggests that low titre ANA positivity should not be a contraindication to therapy. This study also highlighted the importance of several genetic pathways in HCV infection. These may serve as targets for future pharmacologic interventions or genetic tests designed to screen for those who will not benefit from interferon therapies.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Risk among men who have sex with men in the United States: a comparison of an Internet sample and a conventional outreach sample.

This study compared the demographics and risk behaviors of two samples of men who have sex with men (MSM), using cross-sectional data that were collected via the Internet and through conventional bar-based outreach. The Internet sample was significantly older, more likely to identify as "bisexual," and less educated than the bar sample. After controlling for age and education, few differences were observed between the samples. However, three variables that markedly differentiated the samples were history of sexually transmitted disease infection, HIV serostatus, and sources utilized to obtain health information. No difference in Internet use was found. Based on the possible decreased social desirability promoted by the use of electronic data collection methodologies, these findings provide preliminary evidence that Internet and bar respondents are similar and that the Internet may serve as an expedient as well as reliable methodology to increase understanding of risk among MSM

Hepatitis B e antigen status and hepatitis B DNA levels in women of childbearing age with chronic hepatitis B infection screening for clinical trials

BACKGROUND: Perinatal or mother-to-child transmission of hepatitis B virus (HBV) results in a high frequency of chronic infection. Risk of mother-to-child transmission is associated with maternal viral factors including hepatitis B e antigen (HBeAg) positivity and viral load. AIM: To investigate associations between age, HBeAg status, HBV DNA levels and genotype in female patients screened for inclusion into two contemporary, randomized HBV trials. METHODS: Retrospective analyses focused on differences between women of childbearing age (≤44 years) and older women. Female patients (N = 355; 18-69 years) were included in the analysis: 41.7% of patients were Asian. In total, 44.4% were HBeAg-positive. RESULTS: Significantly more women aged ≤44 years were HBeAg-positive compared to women ≥45 years (57.2% versus 27.5%, respectively, p108 copies mL: ≤44 years 46.0% vs ≥45 years 25.5%, respectively; p CONCLUSIONS: Women of childbearing age with CHB are more likely to have high HBV viral load and HBeAg positivity than older women; this likelihood decreases with age. Maternal serological and virological status should therefore be established early in pregnancy, taking into account age and genotype, and a risk-reducing strategy implemented in any patient who is HBeAg positive and has a high viral load

Risk factors for acquisition of hepatitis C virus infection: a case series and potential implications for disease surveillance

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

Long-term clinical outcomes in cirrhotic chronic hepatitis B patients treated with tenofovir disoproxil fumarate for up to 5 years

Background: Phase 3 clinical studies have shown that long-term treatment with tenofovir disoproxil fumarate (TDF) can suppress hepatitis B viral load and promote significant fibrosis regression and cirrhosis reversal in a majority of treated chronic hepatitis B (CHB) patients. This retrospective analysis investigated the impact of baseline cirrhosis status on virologic, serologic, and histologic outcomes in patients treated with TDF. Methods: Patients enrolled in studies GS-US-174-0102 and GS-US-174-0103 who had baseline liver biopsy–diagnosed cirrhosis and entered the open-label phase of the studies were included in the virologic and serologic analyses. Patients (both HBeAg positive and negative) with paired liver biopsies at baseline and 5 years (N = 348) were included in a histologic analysis. Results: After 5 years on study, comparing patients with and without baseline cirrhosis, respectively: 99.2 and 98.0 % achieved virologic response (hepatitis B viral load < 69 IU/ml) (p = 0.686); 79.7 and 81.9 % had normal serum levels of alanine aminotransferase (p = 0.586); 4.0 and 1.2 % developed hepatocellular carcinoma (p = 0.044). In HBeAg-positive patients with and without baseline cirrhosis, HBsAg loss occurred in 14.4 and 8.3 % of patients, respectively (p = 0.188). One HBeAg-negative patient had HBsAg loss. Conclusions: This represents the largest analyses to date of CHB patients with sequential liver biopsies demonstrating that treatment with TDF for up to 5 years is associated with favorable virologic, serologic, and histologic outcomes, regardless of baseline cirrhosis status. Notably, histologic improvement was observed in the majority of cirrhotic and noncirrhotic patients

Determinants of hepatitis C virus clinical outcomes

Hepatitis C VIruS (HCY) infection is characterized by a broad spectrum of clinical outcomes. An estimated 14%-46% of individuals exposed to HCY are able to clear the virus, while the other portion develops chronic (persistent) infections. Among the individuals with chronic HCY who are treated with interferon-based therapies, only a portion are able experience sustained virological suppression. Similarly, a number of chronically infected individuals have autoimmune extrahepatic manifestations such as the presence of autoantibodies. The pathological mechanisms behind these phenomena are not known, but it is believed that host genetic factors may playa role. This thesis examines the hypothesis that host genetic factors may contribute to the diverse spectrum of HCY clinical outcomes. In addition, it examines the pathogenesis of antinuclear antibodies (ANA) in chronic HCY, and the effect of ANA positivity on the natural history of HCY. Correlations were observed between female gender and geographic location and ANA positivity. No relationships were observed for an effect of ANA positivity on response rates to interferon therapy. We observed a trend of ANA positivity with faster progression of HCY-related fibrosis, although t his failed to achieve statistical significance. ANA-positive individuals tended to have more plasma cells in their liver than ANA-negative individuals. This study also observed a number of correlations between genotypes of the interferon induced genes encoding the myxovirus resistance 1 protein (MxA), 2'-5'0Iigo-adenylate synthase 1 (OAS- I), and protein kinase (PKR), as well as genes encoding cytotoxic T -lymphocyte antigen-s (CTLA4), and inducible nitric oxide synthase (iNOS) (encoded by the NOS2A gene) with several outcomes including self-limiting versus chronic HCY infection, along with the response to interferon therapy. This study identified several factors to be correlated with ANA positivity in HCY. These factors may serve as future points for investigation by basic scientists understanding the mechanisms ofHCY-mediated autoimmunity. Importantly, this study suggests that low titre ANA positivity should not be a contraindication to therapy. This study also highlighted the importance of several genetic pathways in HCY infection. These may serve as targets for future pharmacologic interventions or genetic tests designed to screen for those who will not benefit from interferon therapies

Increasing hepatitis B vaccination among young African-American men who have sex with men: simple answers and difficult solutions.

Using a bar-based sample, we identified factors associated with hepatitis B virus (HBV) vaccination among young African American men who have sex with men (MSM). The mean (+/- standard deviation [SD]) age of the 170 participants was 26 +/- 6.5 years. Nearly 40% reported at least one dose of vaccine; the remainder were completely unvaccinated. Approximately 22% (37) reported having never heard of HBV. Less than 7% of participants reported using condoms the majority of the time during oral intercourse within the past 3 months, and approximately 50% reported using condoms the majority of the time during anal intercourse within the past 3 months. In multivariable analysis, variables associated with vaccination were younger age (odds ratio [OR], 0.44 per 10-year increase in age; 95% confidence interval [CI]: 0.21-0.93, p = 0.032), higher educational attainment (OR, 4.6; 95% CI: 1.17-12.59, p = 0.003), homosexual as opposed to bisexual behavior (OR, 0.15; 95% CI: 0.06-0.41, p = 0.0001), and recent visits to a health care provider (OR, 4.31; 95% CI: 2.08-8.94, p = 0.0001). Our findings underscore the need to reach MSM for HBV vaccination. Innovative approaches are necessary to ensure the prevention of infection, transmission and disease among individuals with limited education, bisexual MSM, and men who have limited access to health care