Searching for chronic hepatitis B patients in a low prevalence area – role of racial origin

Abstract Background Clinical studies for testing new drugs against hepatitis B ought to be carried out in low prevalence areas despite difficulties on patient recruitment. In such areas, relatives of chronic hepatitis B patients are considered to be at risk of acquiring the hepatitis B virus (HBV). The aim of this study was to evaluate the prevalence of HBV markers (anti-HBc, HBsAg and anti-HBs) in familial members of chronic hepatitis B (CHB) patients according to their origin (Asian or Western) in a low prevalence area, the city of São Paulo, Brazil. Methods Twenty three Asian CHB probands and their 313 relatives plus 31 CHB probands of Western origin and their 211 relatives were screened for HBV serological markers; the study was carried out in the outpatient clinic of the University of São Paulo School of Medicine. Results Mother to child transmission was greater in the Asian group whereas sexual transmission was more frequent in the Western group (p < 0.0001). Anti-HBc was positive in 90% and 57% of the Asian and Western parents (p = 0.0432) and in 97% and 33% of the Asian and Western brothers (p = 0.0001), respectively. HBsAg was more frequent among the Asian (66%) than the Western (15%) mothers (p = 0.0260) as well as among the Asian (81%) than the Western (19%) brothers (p = 0.0001). We could detect 110 new HBsAg-positive subjects related to the 54 index patients, being the majority (81%) of Asian origin. Conclusion In low prevalence area of hepatitis B, family members and household contacts of chronic HBV carriers are at high risk for acquiring hepatitis B.

Therapeutic vaccination for chronic hepatitis B in the Trimera mouse model

Therapeutic vaccination for chronic hepatitis B in the Trimera mouse modelrnRaja Vuyyuru and Wulf O. BöcherrnHepatitis B is a liver disease caused by Hepatitis B virus (HBV). It ranges in severity from a mild illness, lasting a few weeks (acute), to a serious long-term (chronic) illness that can lead either to liver disease or liver cancer. Acute infection is self limiting in most adults, resulting in clearance of virus from blood and liver and the development of lasting immunity. However 5% of acutely infected patients do not resolve primary HBV infection, leading to chronic infection with persistent viral replication in the liver. The strength of the initial antiviral immune response elicited to Hepatitis B determines the subsequent clinical outcome. A strong and broad T cell response leads to spontaneous resolution. Conversely, a weak T cell response favours viral persistence and establishment of chronic disease. While treatments using interferon-alpha or nucleos(t)ide analogues can reduce disease progression, they rarely lead to complete recovery. The lack of a suitable small animal model hampered efforts to understand the mechanisms responsible for immune failure in these chronic patients.rnIn current study we used Trimera mice to study the efficacy of potential vaccine candidates using HBV loaded dendritic cells in HBV chronic infection in vivo. The Trimera mouse model is based on Balb/c mice implanted with SCID mouse bone marrow and human peripheral blood mononuclear cells (PBMC) from HBV patients, and thus contains the immune system of the donor including their HBV associated T cell defect.rnIn our present study, strong HBV specific CD4+ and CD8+ T cell responses were enhanced by therapeutic vaccination in chronic HBV patients. These T cell responses occurred independently of either the course of the disease or the strength of their underlying HBV specific T cell failure. These findings indicate that the Trimera mouse model represents a novel experimental tool for evaluating potential anti-HBV immunotherapeutic agents. This in vivo data indicated that both the HBV specific CD4+ cell and CD8+ responses were elicited in the periphery. These HBV specific T cells proliferated and secreted cytokines upon restimulation in Trimera mice. The observation that these HBV specific T cells are not detectable directly ex vivo indicates that they must be immune tolerant or present at a very low frequency in situ. HBV specific T cell responses were suppressed in Trimera mice under viremic conditions, suggesting that viral factors might be directly involved in tolerizing or silencing antiviral T cell responses. Thus, combination of an effective vaccine with antiviral treatment to reduce viremia might be a more effective therapeutic strategy for the future. Such approaches should be tested in Trimera mice generated in HBV or HBs expressing transgenic mice before conducting clinical trials.rn

Analyse von Pathomechanismen im Rahmen der Hepatitis-C-Infektion

Das Hepatitis C Virus stellt mit weltweit 170 Millionen infizierten Menschen ein großes gesundheitliches Problem dar. Zwar sind in den letzten Jahren deutliche Fortschritte in der Behandlung der Hepatitis C gemacht worden, gleichwohl ist die Hepatitis C durch das Fehlen eines potenten Impfstoffes weiterhin ein relevantes gesundheitliches Risiko, da sich Infektionsraten auf diesem Wege nicht eindämmen lassen. Der Ansatz dieser Dissertation bestand in der Konstruktion adenoviraler Vektoren, die Anteile des HCV-Genoms beinhalten. Mit Hilfe dieser Vektoren sollten verschiedene Zelltypen transduziert werden, eine Überexpression viraler Proteine initiert werden und Effekte der HCV Proteine HCV-Core und HCV-NS5a ermittelt werden. Diese Dissertationsschrift beschreibt die Konstruktion der adenoviralen Vektoren, die die Hepatitis Gene Core bzw. NS5a tragen. Die Klonierungsschritte werden umfassend aufgezeigt. Darauf aufbauend werden Versuche gezeigt, die die erfolgreiche adenovirale Transduktion in Zielzellen bestätigen. Es werden phänotypische Veränderungen der verschiedenen Zielzellen anhand mikroskopischer Aufnahmen demonstriert. Zusätzlich wird die erfolgreiche Konstruktion der Vektoren durch Detektion der viralen Proteine im Western Blot bestätigt. Es konnte gezeigt werden, dass sich verschiedene Zielzellen mit den Vektoren transduzieren lassen und die Proteinexpression der HCV-Proteine einer dosisabhänigen Expressionskinetik folgt. In weiteren Untersuchungen konnten Veränderungen der Viabilität der Zellen durch die Expression der viralen Proteine HCV-Core und HCV-NS5a gezeigt werden. Durch eine dosisabhängige Herunterregulation des anti-apoptoischen Proteins MCL-1 ist das Gesamtüberleben der Zellen vermindert. Die Wachstumskinetik der transduzierten Zellen ist signifikant herabgesetzt.

Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study

Hepatitis C virus (HCV) induces chronic infection in 50% to 80% of infected persons; approximately 50% of these do not respond to therapy. We performed a genome-wide association study to screen for host genetic determinants of HCV persistence and response to therapy.

The recent breakthroughs in the understanding of host genomics in hepatitis C

Hepatitis C Virus (HCV) infection is spontaneously resolved in about 30% of acutely infected individuals. In those who progress to chronic hepatitis C, HCV therapy permanently eradicates infection in about 40% of cases. It has long been suspected that host genetic factors are key determinants for the control of HCV infection.

Molecular epidemiology of a large community-based outbreak of hepatitis B in Bristol, U.K.

A large outbreak of hepatitis B virus (HBV) infection in the U.K. occurred between 2001 and 2005 in Bristol, U.K.

Investigation of a large community-based outbreak of hepatitis B infection in the United Kingdom

We describe the largest outbreak of hepatitis B virus infection reported to date in the UK. Between July 2001 and December 2005, 237 cases were identified in Avon, South West England. The likely route of transmission was injecting drug use in 44% (104/237) and heterosexual intercourse in 30% (71/237) of cases. A case-control study in injectors showed that injecting crack cocaine [adjusted odds ratio (aOR) 23·8, 95% confidence interval (CI) 3·04-186, P<0·001] and sharing injecting paraphernalia in the year before diagnosis (aOR 16·67, 95% CI 1·78-100, P=0·010) were strongly associated with acute hepatitis B. In non-IDUs number of sexual partners and lack of consistent condom use were high compared to a national sample. We describe the control measures implemented in response to the outbreak. This outbreak has highlighted the problems associated with the low uptake from the national hepatitis B vaccination policy which targets high-risk groups, the difficulties of identifying those at risk of acquiring hepatitis B infection through heterosexual sex, and injecting crack cocaine as a risk factor for hepatitis B.

Impact of a nurse vaccination program on hepatitis B immunity in a Swiss HIV clinic

We evaluated the impact of a nurse program for hepatitis B virus vaccination in a center from the Swiss HIV Cohort Study. Immunity (anti-HBs >10 IU/mL) increased from 32% to 76% in the intervention center (n = 238) where vaccine management was endorsed by nurses, but only from 33% to 39% in control centers (n = 2712, P < 0.001) where management remained in charge of physicians. Immunity against HBV in the HIV population is insufficient in Switzerland. Specific nurse vaccination program may efficiently improve health care.

Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis

Chronic hepatitis C virus (HCV) infection outcomes include liver failure, hepatocellular carcinoma (HCC), and liver-related death.

Characteristics of patients with chronic hepatitis C who develop hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most frequent form of primary liver cancer and chronic infection with hepatitis C virus is one of the main risk factors for HCC. This study analyses the characteristics of the patients with chronic hepatitis C participating in the Swiss Hepatitis C Cohort Study who developed HCC.

Serum ferritin levels are associated with a distinct phenotype of chronic hepatitis C poorly responding to pegylated interferon-alpha and ribavirin therapy

Elevated serum ferritin levels may reflect a systemic inflammatory state as well as increased iron storage, both of which may contribute to an unfavorable outcome of chronic hepatitis C (CHC). We therefore performed a comprehensive analysis of the role of serum ferritin and its genetic determinants in the pathogenesis and treatment of CHC. To this end, serum ferritin levels at baseline of therapy with pegylated interferon-alpha and ribavirin or before biopsy were correlated with clinical and histological features of chronic hepatitis C virus (HCV) infection, including necroinflammatory activity (N = 970), fibrosis (N = 980), steatosis (N = 886), and response to treatment (N = 876). The association between high serum ferritin levels (> median) and the endpoints was assessed by logistic regression. Moreover, a candidate gene as well as a genome-wide association study of serum ferritin were performed. We found that serum ferritin ≥ the sex-specific median was one of the strongest pretreatment predictors of treatment failure (univariate P < 0.0001, odds ratio [OR] = 0.45, 95% confidence interval [CI] = 0.34-0.60). This association remained highly significant in a multivariate analysis (P = 0.0002, OR = 0.35, 95% CI = 0.20-0.61), with an OR comparable to that of interleukin (IL)28B genotype. When patients with the unfavorable IL28B genotypes were stratified according to high versus low ferritin levels, SVR rates differed by > 30% in both HCV genotype 1- and genotype 3-infected patients (P < 0.001). Serum ferritin levels were also independently associated with severe liver fibrosis (P < 0.0001, OR = 2.67, 95% CI = 1.68-4.25) and steatosis (P = 0.002, OR = 2.29, 95% CI = 1.35-3.91), but not with necroinflammatory activity (P = 0.3). Genetic variations had only a limited impact on serum ferritin levels. Conclusion: In patients with CHC, elevated serum ferritin levels are independently associated with advanced liver fibrosis, hepatic steatosis, and poor response to interferon-alpha-based therapy.

Impact of Lifetime Alcohol Use on Liver Fibrosis in a Population of HIV-Infected Patients With and Without Hepatitis C Coinfection

BACKGROUND: The effect of alcohol on liver disease in HIV infection has not been well characterized. METHODS: We performed a cross-sectional multivariable analysis of the association between lifetime alcohol use and liver fibrosis in a longitudinal cohort of HIV-infected patients with alcohol problems. Liver fibrosis was estimated with 2 noninvasive indices, "FIB-4," which includes platelets, liver enzymes, and age; and aspartate aminotransferase/platelet ratio index ("APRI"), which includes platelets and liver enzymes. FIB-4 <1.45 and APRI <0.5 defined the absence of liver fibrosis. FIB-4 >3.25 and APRI >1.5 defined advanced liver fibrosis. The main independent variable was lifetime alcohol consumption (<150 kg, 150 to 600 kg, >600 kg). RESULTS: Subjects (n = 308) were 73% men, mean age 43 years, 49% with hepatitis C virus (HCV) infection, 60% on antiretroviral therapy, 49% with an HIV RNA load <1,000 copies/ml, and 18.7% with a CD4 count <200 cells/mm(3) . Forty-five percent had lifetime alcohol consumption >600 kg, 32.7% 150 to 600 kg, and 22.3% <150 kg; 33% had current heavy alcohol use, and 69% had >9 years of heavy episodic drinking. Sixty-one percent had absence of liver fibrosis and 10% had advanced liver fibrosis based on FIB-4. In logistic regression analyses, controlling for age, gender, HCV infection, and CD4 count, no association was detected between lifetime alcohol consumption and the absence of liver fibrosis (FIB-4 <1.45) (adjusted odds ratio [AOR] = 1.12 [95% CI: 0.25 to 2.52] for 150 to 600 kg vs. <150 kg; AOR = 1.11 [95% CI: 0.52 to 2.36] for >600 kg vs. <150 kg; global p = 0.95). Additionally, no association was detected between lifetime alcohol use and advanced liver fibrosis (FIB-4 >3.25). Results were similar using APRI, and among those with and without HCV infection. CONCLUSIONS: In this cohort of HIV-infected patients with alcohol problems, we found no significant association between lifetime alcohol consumption and the absence of liver fibrosis or the presence of advanced liver fibrosis, suggesting that alcohol may be less important than other known factors that promote liver fibrosis in this population.

Targets of emerging therapies for viral hepatitis B and C

Viral hepatitis B and C, structurally two completely different viruses, commonly infect human hepatocytes and cause similar clinical manifestations. Since their discovery, IFN has been a pillar in the treatment. However, because of the different natures of the viruses, therapeutic approaches diverge and new treatment targets are tailored specifically for each virus. Herein, the authors analyse therapeutic approaches for hepatitis B virus (HBV) and hepatitis C virus (HCV) and focus on emerging concepts that are under clinical evaluation. In particular, promising viral inhibitors for HBV and HCV are reviewed and the current status of research for gene therapy for HCV is described. Immune therapy is a fast-moving field with fascinating results which include therapeutic vaccines and toll-like receptor agonists that could improve tomorrow's treatment approaches.

Hepatitis A vaccines and the elderly

Hepatitis A virus (HAV) exposure in unprotected adults may cause severe and serious symptoms, with risk of both morbidity and mortality increasing with age. As seroprevalence of HAV is low in industrialised countries, and an increasing number of people, with an increasing median age, travel from areas of low HAV endemicity to high endemicity, pre-travel vaccination is warranted. Vaccination of the elderly against HAV, however, may be associated with reduced seroprotection, since the immune response decreases with age. Studies with monovalent hepatitis A vaccine or combined hepatitis A and B vaccine show good efficacy in adults in general. Few studies have assessed the immune response in older adults. The only prospective study with monovalent hepatitis A vaccine in the elderly showed a reduced seroprotection of approximately 65% after a single primary dose in subjects over the age of 50 years, while seroprotection was 98% in this age group after receiving a booster dose. The only prospective study with combined hepatitis A and B vaccine in younger subjects or older than 40 years showed similar seroprotection (99-100%) against HAV compared to a monovalent vaccine after receiving three doses. As data on seroprotection for HAV in the elderly are limited, further studies are needed to elucidate how optimal protection in the elderly can be achieved. In the mean time, based on the available data, the suggestion is made to screen elderly travellers to areas endemic for HAV for the presence of naturally acquired immunity, and, if found susceptible, be immunised well in advance of their trip, to allow time for post-vaccination antibody testing and/or administration of a second dose of the vaccine.

Eligibility for and outcome of hepatitis C treatment of HIV-coinfected individuals in clinical practice: the Swiss HIV cohort study

BACKGROUND: Morbidity and mortality of individuals co-infected with HIV and hepatitis C virus (HCV) is often determined by the course of their HCV infection. Only a selected proportion of those in need of HCV treatment are studied in randomized controlled trials (RCTs). We analysed the prevalence of HCV infection in a large cohort, the number of individuals requiring treatment, the eligibility for HCV treatment, and the outcome of the combination therapy with pegylated interferon-a and ribavirin in routine practice. METHODS: We analysed prescription patterns of HCV treatment and treatment outcomes among participants from the Swiss HIV Cohort Study with detectable hepatitis C viraemia (between January 2001 and October 2004). Efficacy was measured by the number of patients with undetectable HCV RNA at the end of therapy (EOTR) and at 6 months after treatment termination (SVR). Intention-to-continue-treatment principles were used. RESULTS: A total of 2150 of 7048 (30.5%) participants were coinfected with HCV; HCV RNA was detected in 60%, and not assessed in 26% of HCV-antibody-positive individuals. One hundred and sixty (12.5%) of HCV-RNA-positive patients started treatment. In patients infected with HCV genotypes 1/4 or 2/3, EOTR was achieved in 43.3% and 81.2% of patients, respectively, and SVR rates were 28.4% and 51.8%, respectively. More than 50% of the HCV-treated patients would have been excluded from two large published RCTs due to demographic, clinical and laboratory criteria. CONCLUSIONS: Despite clinical and psychosocial obstacles encountered in clinical practice, HCV treatment in HIV-coinfected individuals is feasible with results similar to those obtained in RCTs.