D. Scott Bowden

Chronic hepatitis C: Effect of alcohol on hepatic activity and viral titre

BACKGROUND/AIMS Alcohol and the hepatitis C virus have been postulated to interact to adversely affect the natural history of patients with chronic liver disease. The aim of this study was to examine the effect of alcohol on hepatitic activity and serum HCV RNA levels in patients with chronic hepatitis C. METHODS Forty-five consecutive patients with chronic hepatitis C were classified according to alcohol intake over the 3-month period preceding study entry: group 1 (n = 23), > 10 g alcohol/day; group 2 (n = 22), < or = 10 g alcohol/day. Hepatitic activity and alcohol intake were assessed at study entry and, following moderation of alcohol intake, after a mean follow-up period of 4.4 +/- 0.2 months. RESULTS Hepatitic activity was significantly greater in the patients who consumed > 10 g of alcohol/day. Moderation of alcohol consumption in patients consuming > 10 g/day resulted in a significant decrease in both disease activity (p = 0.0002) and viral RNA titre (p = 0.018); there was no change over the study period in patients with a consistently low alcohol intake. CONCLUSION The results support the hypotheses that, in patients with chronic hepatitis C, alcohol aggravates hepatic injury, increases viral load and adversely affects the natural history of the associated liver disease.

Effects of Silybum marianum on serum hepatitis C virus RNA, alanine aminotransferase levels and well-being in patients with chronic hepatitis C

Background/Aims:  Silybum marianum is a herbal preparation commonly used by subjects with chronic hepatitis C (CHC). The aims of this pilot study were to assess the efficacy and safety of S. marianum on serum hepatitis C virus (HCV) RNA, alanine aminotransferase levels and well‐being in patients with CHC.

A Multistate Outbreak of Hepatitis A Associated With Semidried Tomatoes in Australia, 2009

BACKGROUND A large outbreak of hepatitis A affected individuals in several Australian states in 2009, resulting in a 2-fold increase in cases reported to state health departments compared with 2008. Two peaks of infection occurred (April-May and September-November), with surveillance data suggesting locally acquired infections from a widely distributed food product. METHODS Two case-control studies were completed. Intensive product trace-back and food sampling was undertaken. Genotyping was conducted on virus isolates from patient serum and food samples. Control measures included prophylaxis for close contacts, public health warnings, an order by the chief health officer under the Victorian Food Act 1984, and trade-level recalls on implicated batches of semidried tomatoes. RESULTS A multijurisdictional case-control study in April-May found an association between illness and consumption of semidried tomatoes (odds ratio [OR], 3.0; 95% CI 1.4-6.7). A second case-control study conducted in Victoria in October-November also implicated semidried tomatoes as being associated with illness (OR, 10.3; 95% CI, 4.7-22.7). Hepatitis A RNA was detected in 22 samples of semidried tomatoes. Hepatitis A virus genotype IB was identified in 144 of 153 (94%) patients tested from 2009, and partial sequence analysis showed complete identity with an isolate found in a sample of semidried tomatoes. CONCLUSIONS The results of both case-control studies and food testing implicated the novel vehicle of semidried tomatoes as the cause of this hepatitis A outbreak. The outbreak was extensive and sustained despite public health interventions, the design and implementation of which were complicated by limitations in food testing capability and complex supply chains.

Blood-borne virus infections among Australian injecting drug users: Implications for spread of HIV

To describe the epidemiology of infection with hepatitis C virus (HCV), hepatitis B virus (HBV) and human immunodeficiency virus (HIV) among injecting drug users (IDUs) in Australia, in relation to the potential for further spread of HIV in IDUs, a cross-sectional analysis was performed on data from a sample of injecting drug users, correlating markers of exposure to blood-borne viruses with sex, age, sexual orientation, primary current drug injected and duration of injecting in rural and metropolitan Victoria, Australia. The subjects were currently active IDUs from a wide spectrum of age, sex, sexual orientation, geographical location and social background, contacted and recruited through their social networks and from community agencies and prisons by trained peer workers who interviewed and collected blood from them in the field. Sera were tested for antibody to HIV, HCV and hepatitis B core antigen (HBcAg), for hepatitis B surface antigen (HBsAg), and for HCV RNA using reverse transcription and polymerase chain reaction (RT-PCR). At entry to the study, 4.5% (14/311) had antibody to HIV, 47% (146/308) to HBcAg and 68% (206/303) to HCV. Prevalence of HBsAg was 1.8% overall (5/282), and 50% (84/168) were positive for HCV RNA. By multivariate analysis, HIV seropositivity was strongly associated with a history of homosexual contact in males and with exposure to HBV but not to HCV. Those who reported their current primary injected drug to be amphetamines were at greater and continuing risk of HIV infection than were current heroin injectors, while the reverse applied for HCV. The different patterns of exposure to different blood-borne viruses in this particular population of IDUs probably reflects different interactions among different social networks. HCV exposure provides a good surrogate marker for risk behaviour among these IDUs, but HBV exposure provides a better marker for risk of HIV infection. More detailed surveillance strategies for HIV infection, and more targeted HIV prevention programs are necessary to detect and to prevent further spread of HIV in these populations.

Molecular Epidemiology of Hepatitis C Virus in a Social Network of Injection Drug Users

BACKGROUND We aimed to measure the overlap between the social networks of injection drug users (IDUs) and the patterns of related hepatitis C virus (HCV) infections among IDUs. METHODS A cohort of 199 IDUs (138 of whom were HCV RNA positive) was recruited from a local drug scene in Melbourne, Australia, and was studied using social network analysis and molecular phylogenetic analysis of 2 regions of the HCV genome. RESULTS Eighteen clusters of related infections involving 51 IDUs (37.0% of HCV RNA-positive IDUs) were detected; these clusters could be separated into 66 discrete pairs. Twelve (18.2%) of the 66 IDU pairs with related infections reported having previously injected drugs together; conversely, only 12 (3.8%) of the 313 pairs of HCV RNA-positive IDUs who were injection partners had strong molecular evidence of related infections. The social and genetic distances that separated IDUs with identical genotypes were weakly associated. Significant clusters of phylogenetically related sequences identified from core region analysis persisted in the analysis of the nonstructural 5a protein region. Genotyping and sequence analysis revealed 2 mixed-genotype infections. CONCLUSIONS Static social network methods are likely to gather information about a minority of patterns of HCV transmission, because of the difficulty of determining historical infection pathways in an established social network of IDUs. Nevertheless, molecular epidemiological methods identified clusters of IDUs with related viruses and provided information about mixed-genotype infection status.

IL28B genotype is not useful for predicting treatment outcome in Asian chronic hepatitis B patients treated with pegylated interferon-α.

IL28B genotype predicts response to pegylated interferon (peg‐IFN)‐based therapy in chronic hepatitis C. However, the utility of IL28B genotyping in chronic hepatitis B (CHB) cohorts treated with peg‐IFN is unclear. It was investigated whether IL28B genotype is associated with peg‐IFN treatment outcomes in a predominantly Asian CHB cohort.

Hepatic iron overload does not prevent a sustained virological response to interferon-α therapy: A long term follow-up study in hepatitis C-infected patients with β thalassemia major

OBJECTIVES:Transfusion-acquired chronic hepatitis C infection and systemic iron overload are common in patients with β thalassemia major. The magnitude of hepatic iron overload has been associated with a poor response to interferon-based antiviral therapy for hepatitis C. The aim of this study was to evaluate the effect of hepatic iron concentration (HIC) on response to interferon monotherapy in patients with massive hepatic iron overload.METHODS:Twenty-eight patients with β thalassemia major, transfusion-acquired iron overload, and chronic hepatitis C infection were prospectively treated with interferon for 6 months. HIC was measured by atomic absorption spectroscopy before treatment. Serum iron, ferritin, hepatitis C virus genotype, viral load, and liver histology were analyzed.RESULTS:Eight patients (28%) achieved a sustained virological response that has been durable after a mean of 66 months of follow-up. The median HIC was 2583 μg/g dry weight. There was no difference in HIC between responders and nonresponders to therapy. Serum hepatitis C virus RNA was lower in responders than in nonresponders. Genotype 1 was more frequent in nonresponders, and non-1 genotypes were more frequent in responders, although this did not reach statistical significance because of patient numbers.CONCLUSIONS:A long term response to interferon is unrelated to HIC in this patient group, and a durable response can occur despite massive iron overload. HIC may be a factor in liver cell injury, but it does not reliably predict a response to interferon therapy.

Molecular analysis of human immunodeficiency virus strains associated with a case of criminal transmission of the virus.

An investigation was done of the evidence for transmission of human immunodeficiency virus (HIV) from an HIV-positive man to several male and female sex contacts. Phylogenetic analysis of sequences from the gag and env genes showed a close relationship between the predominant virus strains from the source and 2 contacts. However, the likelihood that a female contact was infected by the source could not be determined, despite contact tracing indicating that this may have occurred. One male, shown by contact tracing and molecular evidence to have been infected by the source, subsequently transmitted HIV to his female sex partner. HIV sequence from a plasma sample used as a control in the phylogenetic analysis contained env and gag sequences that were closely related to those from the source. An epidemiologic link between these 2 individuals was subsequently confirmed by contact tracing.

Lamivudine resistance in patients with chronic hepatitis B: Role of clinical and virological factors

Background:  Lamivudine resistance is associated with long‐term monotherapy for chronic hepatitis B and can lead to potentially serious clinical consequences. Scant information exists regarding the influence of hepatitis B virus variants in the development of resistance. The present study was designed to identify factors predictive of lamivudine resistance, with a particular focus on the role of precore and basal core promoter variants in the setting of hepatitis B e antigen‐negative disease.

ITPA genotype protects against anemia during peginterferon and ribavirin therapy but does not influence virological response

On‐treatment anemia is associated with higher sustained virological response (SVR) rates during peginterferon plus ribavirin (RBV) therapy. Inosine triphosphatase (ITPA) variants causing ITPase deficiency have been shown to protect against RBV‐induced anemia. However, ITPase activity has not been associated with SVR. To study this discrepancy, we examined the relationships between ITPase activity, on‐treatment anemia, SVR, and RBV levels in hepatitis C virus genotype 1 (HCV‐1) patients from the CHARIOT study. ITPA genotype (rs7270101, rs1127354) was used to define ITPase activity in 546 patients. Plasma RBV levels were measured using high‐performance liquid chromatography (HPLC). Relationships between ITPase activity, on‐treatment hemoglobin (Hb) levels, RBV levels, and SVR were tested using regression modeling, survival analysis, and locally weighted scatterplot smoothing (LOWESS) plot analysis. Hb decline was independently associated with SVR (P < 0.0001). ITPase deficiency was present in 35%. ITPase deficiency strongly protected against Hb decline (P < 0.0001), but was not associated with SVR (P = 0.28). The probability of SVR increased with lower nadir Hb for both wild‐type and deficient ITPase activity, but the association curve shifted to describe a parallel relationship at higher Hb levels in patients with ITPase deficiency. In a subset (n = 203), we tested the hypothesis that the association between Hb decline and SVR reflected RBV levels rather than actual Hb level. RBV levels were associated with on‐treatment Hb decline and SVR, but not ITPase activity. In regression models, adjustment for RBV levels attenuated the association between Hb decline and SVR. Conclusion: ITPase deficiency protects against RBV‐induced anemia, but is not associated with SVR. Our data suggest that the relationship between Hb decline and SVR is not mechanistic, but is linked to RBV levels. (Hepatology 2014;59:2152–2160)