Re-treatment of chronic hepatitis C patients after relapse: efficacy of peginterferon-alpha-2a (40 kDa) and ribavirin

SUMMARY. We conducted a randomized multinational study to determine whether 48 weeks of re-treatment with peginterferon- alpha-2a (40 kDa) plus ribavirin would induce a sustained virological response (SVR) in relapsed chronic hepatitis C patients. Patients who had previously relapsed during 24 weeks of untreated follow-up, after having achieved an end-of-treatment virological response with 24 weeks of peginterferon-alpha-2a (40 kDa)/ribavirin combination therapy, within a phase III trial, were studied. Although the recommended dosage was the same as that used at the end of the initial trial, adjustments were permitted. Data on serious adverse events, or adverse events that resulted in dose reductions or discontinuations, were collected. Following re-treatment, the overall SVR rate in the 64 patients was 55%. The SVR rates in patients infected with hepatitis C virus (HCV) genotype 1 and non-1 genotypes were 51% and 63%, respectively. Early (week 12) virological responses were seen in 39 patients (61%) and were predictive of an SVR. Re-treatment was well tolerated. The most frequent adverse events recorded were fatigue (5%) and abdominal pain (3%). Dosages of peginterferon-alpha-2a (40 kDa) and/or ribavirin were modified because of adverse events in 3% and 13% of patients, and because of laboratory abnormalities in 23% and 5% of patients, respectively. Thus, a 48-week course of peginterferon-alpha-2a (40 kDa) plus ribavirin induces an SVR in 55% of patients who relapsed during follow-up after 24 weeks of combination therapy. Physicians should not hesitate to offer re-treatment to patients who relapse after an initial, 24-week course of combination therapy, or who have prematurely stopped treatment because, for example, of laboratory abnormalities.

Transcriptome analysis of a cnidarian-dinoflagellate mutualism reveals complex modulation of host gene expression

Background: Cnidarian - dinoflagellate intracellular symbioses are one of the most important mutualisms in the marine environment. They form the trophic and structural foundation of coral reef ecosystems, and have played a key role in the evolutionary radiation and biodiversity of cnidarian species. Despite the prevalence of these symbioses, we still know very little about the molecular modulators that initiate, regulate, and maintain the interaction between these two different biological entities. In this study, we conducted a comparative host anemone transcriptome analysis using a cDNA microarray platform to identify genes involved in cnidarian - algal symbiosis. Results: We detected statistically significant differences in host gene expression profiles between sea anemones ( Anthopleura elegantissima) in a symbiotic and non-symbiotic state. The group of genes, whose expression is altered, is diverse, suggesting that the molecular regulation of the symbiosis is governed by changes in multiple cellular processes. In the context of cnidarian dinoflagellate symbioses, we discuss pivotal host gene expression changes involved in lipid metabolism, cell adhesion, cell proliferation, apoptosis, and oxidative stress. Conclusion: Our data do not support the existence of symbiosis- specific genes involved in controlling and regulating the symbiosis. Instead, it appears that the symbiosis is maintained by altering expression of existing genes involved in vital cellular processes. Specifically, the finding of key genes involved in cell cycle progression and apoptosis have led us to hypothesize that a suppression of apoptosis, together with a deregulation of the host cell cycle, create a platform that might be necessary for symbiont and/or symbiont-containing host cell survival. This first comprehensive molecular examination of the cnidarian - dinoflagellate associations provides critical insights into the maintenance and regulation of the symbiosis.

Using cohort studies to estimate mortality among injecting drug users that is not attributable to AIDS

Background: Injecting drug use (IDU) and associated mortality appear to be increasing in many parts of the world. IDU is an important factor in HIV transmission. In estimating AIDS mortality attributable to IDU, it is important to take account of premature mortality rates from other causes to ensure that AIDS related mortality among injecting drug users (IDUs) is not overestimated. The current review provides estimates of the excess non-AIDS mortality among IDUs. Method: Searches were conducted with Medline, PsycINFO, and the Web of Science. The authors also searched reference lists of identified papers and an earlier literature review by English et al (1995). Crude. mortality rates (CMRs) were derived from data on the number of deaths, period of follow UP, and number of participants. In estimating the all-cause mortality, two rates were calculated: one that included all cohort studies identified in the search, and one that only included studies that reported on AIDS deaths in their cohort. This provided lower and upper mortality rates, respectively. Results: The current paper derived weighted mortality rates based upon cohort studies that included 179 885 participants, 1 219 422 person-years of observation, and 16 593 deaths. The weighted crude AIDS mortality rate from studies that reported AIDS deaths was approximately 0.78% per annum. The median estimated non-AIDS mortality rate was 1.08% per annum. Conclusions: Illicit drug users have a greatly increased risk of premature death and mortality due to AIDS forms a significant part of that increased risk; it is, however, only part of that risk. Future work needs to examine mortality rates among IDUs in developing countries, and collect data on the relation between HIV and increased mortality due to all causes among this group.

Non-response to antiviral therapy is associated with obesity and increased hepatic expression of suppressor of cytokine signalling 3 (SOCS-3) in patients with chronic hepatitis C, viral genotype 1

Background: Interferon alpha (IFN-alpha) activated cellular signalling is negatively regulated by inhibitory factors, including the suppressor of cytokine signalling (SOCS) family. The effects of host factors such as obesity on hepatic expression of these inhibitory factors in subjects with chronic hepatitis C virus (HCV) are unknown. Objectives: To assess the independent effects of obesity, insulin resistance, and steatosis on response to IFN-alpha therapy and to determine hepatic expression of factors inhibiting IFN-alpha signalling in obese and nonobese subjects with chronic HCV. Methods: A total of 145 subjects were analysed to determine host factors associated with non-response to antiviral therapy. Treatment comprised IFN-alpha or peginterferon alpha, either alone or in combination with ribavirin. In a separate cohort of 73 patients, real time-polymerase chain reaction was performed to analyse hepatic mRNA expression. Immunohistochemistry for SOCS-3 was performed on liver biopsy samples from 38 patients with viral genotype 1 who had received antiviral treatment. Results: Non-response (NR) to treatment occurred in 55% of patients with HCV genotypes 1 or 4 and 22% with genotypes 2 or 3. Factors independently associated with NR were viral genotype 1/4 (p < 0.001), cirrhosis on pretreatment biopsy (p = 0.025), and body mass index >= 30 kg/m(2) (p = 0.010). Obese subjects with viral genotype 1 had increased hepatic mRNA expression of phosphoenolpyruvate carboxy kinase (p = 0.01) and SOCS-3 (p = 0.047), in comparison with lean subjects. Following multivariate analysis, SOCS-3 mRNA expression remained independently associated with obesity (p = 0.023). SOCS-3 immunoreactivity was significantly increased in obesity (p = 0.013) and in non-responders compared with responders (p = 0.014). Conclusions: In patients with chronic HCV viral genotype 1, increased expression of factors that inhibit interferon signalling may be one mechanism by which obesity reduces the biological response to IFN-alpha.

Symptom prevalence and clustering of symptoms in people living with chronic hepatitis C infection

Quality of life has been shown to be poor among people living with chronic hepatitis C However, it is not clear how this relates to the presence of symptoms and their severity. The aim of this study was to describe the typology of a broad array of symptoms that were attributed to hepatitis C virus (HCV) infection. Phase I used qualitative methods to identify symptoms. In Phase 2, 188 treatment-naive people living with HCV participated in a quantitative survey. The most prevalent symptom was physical tiredness (86%) followed by irritability (75%), depression (70%), mental tiredness (70%), and abdominal pain (68%). Temporal clustering of symptoms was reported in 62% of participants. Principal components analysis identified four symptom clusters: neuropsychiatric (mental tiredness, poor concentration, forgetfulness, depression, irritability, physical tiredness, and sleep problems); gastrointestinal (day sweats, nausea, food intolerance, night sweats, abdominal pain, poor appetite, and diarrhea); algesic (joint pain, muscle pain, and general body pain); and dysesthetic (noise sensitivity, light sensitivity, skin. problems, and headaches). These data demonstrate that symptoms are prevalent in treatment-naive people with HCV and support the hypothesis that symptom clustering occurs.

RNA Virus Evolution: a Cross-scale, Disease Dynamic Perspective

RNA viruses are an important cause of global morbidity and mortality. The rapid evolutionary rates of RNA virus pathogens, caused by high replication rates and error-prone polymerases, can make the pathogens difficult to control. RNA viruses can undergo immune escape within their hosts and develop resistance to the treatment and vaccines we design to fight them. Understanding the spread and evolution of RNA pathogens is essential for reducing human suffering. In this dissertation, I make use of the rapid evolutionary rate of viral pathogens to answer several questions about how RNA viruses spread and evolve. To address each of the questions, I link mathematical techniques for modeling viral population dynamics with phylogenetic and coalescent techniques for analyzing and modeling viral genetic sequences and evolution. The first project uses multi-scale mechanistic modeling to show that decreases in viral substitution rates over the course of an acute infection, combined with the timing of infectious hosts transmitting new infections to susceptible individuals, can account for discrepancies in viral substitution rates in different host populations. The second project combines coalescent models with within-host mathematical models to identify driving evolutionary forces in chronic hepatitis C virus infection. The third project compares the effects of intrinsic and extrinsic viral transmission rate variation on viral phylogenies.

A Systematic Review of Race and Ethnicity in Hepatitis C Clinical Trial Enrollment.

The African American/Black population in the United States (US) is disproportionately affected by hepatitis C virus (HCV) and has lower response rates to current treatments. This analysis evaluates the participation of African American/Blacks in North American and European HCV clinical trials. The data source for this analysis was the PubMed database. Randomized controlled clinical trials (RCT) on HCV treatment with interferon 2a or 2b between January 2000 and December 2011 were reviewed. Inclusion criteria included English language and participants 18 years or older with chronic HCV. Exclusion criteria included non-randomized trials, case reports, cohort studies, ethnic specific studies, or studies not using interferon-alfa or PEG-interferon. Of the 588 trials identified, 314 (53.4%) fit inclusion criteria. The main outcome was the rate of African American/ Black participation in North American HCV clinical trials. A meta-analysis comparing the expected and observed rates was performed. Of the RCT's that met search criteria, 123 (39.2%) reported race. Clinical trials in North America were more likely to report racial data than European trials. Racial reporting increased over time. There was a statistically significant difference among the expected and observed participation of African Americans in HCV clinical trials in North America based on the prevalence of this disease within the population. The burden of HCV among African Americans in North America is not reflected in those clinical trials designed to treat HCV. Research on minority participation in clinical trials and how to increase minority participation in clinical trials is needed.

The Affordable Care Act and the Transformation of US Health Care

The neoliberal period was accompanied by a momentous transformation within the US health care system.  As the result of a number of political and historical dynamics, the healthcare law signed by President Barack Obama in 2010 ‑the Affordable Care Act (ACA)‑ drew less on universal models from abroad than it did on earlier conservative healthcare reform proposals. This was in part the result of the influence of powerful corporate healthcare interests. While the ACA expands healthcare coverage, it does so incompletely and unevenly, with persistent uninsurance and disparities in access based on insurance status. Additionally, the law accommodates an overall shift towards a consumerist model of care characterized by high cost sharing at time of use. Finally, the law encourages the further consolidation of the healthcare sector, for instance into units named “Accountable Care Organizations” that closely resemble the health maintenance organizations favored by managed care advocates. The overall effect has been to maintain a fragmented system that is neither equitable nor efficient. A single payer universal system would, in contrast, help transform healthcare into a social right.

The Iowa Viral Hepatitis Strategic Plan 2012-2016, August 26, 2014

Since the creation of the first viral hepatitis plan in 2004 several documents and advancements have been released that help Iowa plan and prioritize this revision of our hepatitis plan. The Institute of Medicine report identified that current approach to the prevention and control of chronic hepatitis B and hepatitis C is not working. As a remedy, the IOM recommends increased knowledge and awareness about chronic viral hepatitis among health care providers, social service providers, and the public; improved surveillance for hepatitis B and hepatitis C; and better integration of viral hepatitis services.

Infecciones de transmisión sexual en hombres internos en prisión: riesgo de desarrollo de nuevas infecciones

Objetivo: Medir la incidencia y determinar los factores de riesgo de las infecciones de transmisión sexual (ITS) en la población del Centro Penitenciario de Daroca (Zaragoza). Método: Estudio de cohortes retrospectivo (2005-2013) para medir la incidencia de ITS y estudio transversal para estudiar los factores de riesgo. Resultados: De los 203 internos, 79 desarrollaron una ITS, 37 tenían ITS previas, el 55,2% conocimientos y el 28,9% comportamientos no favorables a la prevención de ITS. La incidencia fue de 6,5 ITS por cada 1000 internos-año. Las de mayor incidencia fueron la hepatitis B (39,7%), la infección por Ureaplasma urealyticum (19,1%), el herpes simple (16,2%) y la infección por el virus de la inmunodeficiencia humana (8,8%). El riesgo (hazard ratio [HR]) de adquirir una nueva ITS fue significativamente mayor en los internos con antecedentes de ITS previa (HR = 2,61; intervalo de confianza del 95% [IC95%]: 1,01-6,69), y en el límite de la significación para los comportamientos no preventivos (HR = 2,10; IC95%: 0,98-4,53), pero no en los conocimientos frente a ITS (HR = 1,33; IC95%: 0,58-3,07). Conclusión: Los factores de riesgo más relevantes en prisión son los comportamientos y los antecedentes de ITS. Otros factores son ser reincidente, el consumo de drogas inyectadas o estar en un programa de metadona. Los/las profesionales sanitarios y la educación por pares pueden facilitar la prevención y el control.

Quasispecies dynamics and treatment outcome during early hepatitis C infection in a cohort of HIV-infected men

Hepatitis C virus (HCV) is emerging as one of the leading causes of morbidity and mortality in individuals infected with HIV and has overtaken AIDS-defining illnesses as a cause of death in HIV patient populations who have access to highly active antiretroviral therapy. For many years, the clonal analysis was the reference method for investigating viral diversity. In this thesis, a next generation sequencing (NGS) approach was developed using 454 pyrosequencing and Illumina-based technology. A sequencing pipeline was developed using two different NGS approaches, nested PCR, and metagenomics. The pipeline was used to study the viral populations in the sera of HCV-infected patients from a unique cohort of 160 HIV-positive patients with early HCV infection. These pipelines resulted in an improved understanding of HCV quasispecies dynamics, especially regarding studying response to treatment. Low viral diversity at baseline correlated with sustained virological response (SVR) while high viral diversity at baseline was associated with treatment failure. The emergence of new viral strains following treatment failure was most commonly associated with emerging dominance of pre-existing minority variants rather than re-infection. In the new era of direct-acting antivirals, next generation sequencing technologies are the most promising tool for identifying minority variants present in the HCV quasispecies populations at baseline. In this cohort, several mutations conferring resistance were detected in genotype 1a treatment-naïve patients. Further research into the impact of baseline HCV variants on SVR rates should be carried out in this population. A clearer understanding of the properties of viral quasispecies would enable clinicians to make improved treatment choices for their patients.

Qualidade de vida em portadores crónicos do vírus da hepatite B

Dissertação de Mestrado realizada apresentada no Instituto Superior de Psicologia Aplicada para obtenção de grau de Mestre na especialidade de Psicologia Clínica em Clínica

Does Epoetin Beta Still Have a Place in Peginterferon Alpha-2a Plus Ribavirin Treatment Strategies for Chronic Hepatitis C?

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Correlation between TH1 response standard cytokines as biomarkers in patients with the delta virus in the western Brazilian Amazon

Hepatitis D virus (HDV) is endemic in the Amazon Region and its pathophysiology is the most severe among viral hepatitis. Treatment is performed with pegylated interferon and the immune response appears to be important for infection control. HDV patients were studied: untreated and polymerase chain reaction (PCR) positive (n = 9), anti- HDV positive and PCR negative (n = 8), and responders to treatment (n = 12). The cytokines, interleukin (IL)-2 (p = 0.0008) and IL-12 (p = 0.02) were differentially expressed among the groups and were also correlated (p = 0.0143). Future studies will be conducted with patients at different stages of treatment, associating the viral load with serum cytokines produced, thereby attempting to establish a prognostic indicator of the infection.

The Role of Epstein-Barr Virus LMP-1 Immunohistochemical Staining in Childhood Hodgkin Lymphoma

Background: There are a few published studies about prognostic markers of Epstein-B virus (EBV) related to outcomes in pediatric Hodgkin Lymphoma (HL). Objectives: We aimed to investigate the prognostic value and effect of EBV on survival by using biopsy materials in children and adolescents diagnosed with HL. Patients and Methods: EBV LMP-1 expression was examined using immunohistochemical methods in 58 tumor samples. Clinical features, overall survival (OS) and failure free survival time (FFS) were compared between EBV LMP-1 positive and negative patients. Results: In 20 (35%) patients tumors were LMP-1 positive. When compared with patients above 10 years old, EBV LMP-1 was often positive in patients under 10 years old (30% vs. 70%, P = 0.02). In our most cases having B symptoms and advanced stage, EBV positiveness in Hodgkin Reed-Stenberg cells (H-RS) was not a significant determinant for survival (P = 0.78). Half of the past clinical trials in childhood HL reported longer survival rates in EBV LMP-1 positive patients. In some trials similar to our results there was no significant relationship between EBV and prognosis. Conclusions: The reason of diminished EBV positiviness may be related to technical methods such as not using immunohistochemical and in situ hybridization for EBER antigen but in laboratory conditions painting of control tissues with EBV impair this probability. In addition, cases enrolled to our study were living in Istanbul where social and economical factors are improved rather than generally.