Pegylated Interferon and Ribavirin Dosing Strategies to Enhance Sustained Virologic Response

Hepatitis C virus (HCV) affects about 170 million people worldwide and is the most common chronic blood borne infection in the United States. Since the advent of blood screening protocols in the early 1990s, injection drug use has become the leading cause of infection. Hepatitis C can have both hepatic and nonhepatic manifestations of infection. Hepatic manifestations include hepatic fibrosis, cirrhosis, liver cancer, and liver failure. The standard treatment for chronic HCV is combination therapy with pegylated interferon-α and ribavirin. Although pegylated interferon and ribavirin has been used against HCV for close to a decade, advances in therapy have centered on doses and treatment durations. There has been increasing interest in applying on-treatment response or viral kinetics to predict antiviral response rates and shape therapeutic intervention. Protease inhibitors are a promising adjuvant to combination therapy, but their efficacy and safety are still under investigation

The Evolution of the Major Hepatitis C Genotypes Correlates with Clinical Response to Interferon Therapy

Patients chronically infected with hepatitis C virus (HCV) require significantly different durations of therapy and achieve substantially different sustained virologic response rates to interferon-based therapies, depending on the HCV genotype with which they are infected. There currently exists no systematic framework that explains these genotype-specific response rates. Since humans are the only known natural hosts for HCV-a virus that is at least hundreds of years old-one possibility is that over the time frame of this relationship, HCV accumulated adaptive mutations that confer increasing resistance to the human immune system. Given that interferon therapy functions by triggering an immune response, we hypothesized that clinical response rates are a reflection of viral evolutionary adaptations to the immune system.We have performed the first phylogenetic analysis to include all available full-length HCV genomic sequences (n = 345). This resulted in a new cladogram of HCV. This tree establishes for the first time the relative evolutionary ages of the major HCV genotypes. The outcome data from prospective clinical trials that studied interferon and ribavirin therapy was then mapped onto this new tree. This mapping revealed a correlation between genotype-specific responses to therapy and respective genotype age. This correlation allows us to predict that genotypes 5 and 6, for which there currently are no published prospective trials, will likely have intermediate response rates, similar to genotype 3. Ancestral protein sequence reconstruction was also performed, which identified the HCV proteins E2 and NS5A as potential determinants of genotype-specific clinical outcome. Biochemical studies have independently identified these same two proteins as having genotype-specific abilities to inhibit the innate immune factor double-stranded RNA-dependent protein kinase (PKR).An evolutionary analysis of all available HCV genomes supports the hypothesis that immune selection was a significant driving force in the divergence of the major HCV genotypes and that viral factors that acquired the ability to inhibit the immune response may play a role in determining genotype-specific response rates to interferon therapy

A systematic review of frameworks for the interrelationships of mental health evidence and policy in low- and middle-income countries

Background: The interrelationships between research evidence and policy-making are complex. Different theoretical frameworks exist to explain general evidence–policy interactions. One largely unexplored element of these interrelationships is how evidence interrelates with, and influences, policy/political agenda-setting. This review aims to identify the elements and processes of theories, frameworks and models on interrelationships of research evidence and health policy-making, with a focus on actionability and agenda-setting in the context of mental health in low- and middle-income countries (LMICs). Methods: A systematic review of theories was conducted based on the BeHeMOTh search method, using a tested and refined search strategy. Nine electronic databases and other relevant sources were searched for peer-reviewed and grey literature. Two reviewers screened the abstracts, reviewed full-text articles, extracted data and performed quality assessments. Analysis was based on a thematic analysis. The included papers had to present an actionable theoretical framework/model on evidence and policy interrelationships, such as knowledge translation or evidence-based policy, specifically target the agenda-setting process, focus on mental health, be from LMICs and published in English. Results: From 236 publications included in the full text analysis, no studies fully complied with our inclusion criteria. Widening the focus by leaving out ‘agenda-setting’, we included ten studies, four of which had unique conceptual frameworks focusing on mental health and LMICs but not agenda-setting. The four analysed frameworks confirmed research gaps from LMICs and mental health, and a lack of focus on agenda-setting. Frameworks and models from other health and policy areas provide interesting conceptual approaches and lessons with regards to agenda-setting. Conclusion: Our systematic review identified frameworks on evidence and policy interrelations that differ in their elements and processes. No framework fulfilled all inclusion criteria. Four actionable frameworks are applicable to mental health and LMICs, but none specifically target agenda-setting. We have identified agenda-setting as a research theory gap in the context of mental health knowledge translation in LMICs. Frameworks from other health/policy areas could offer lessons on agenda-setting and new approaches for creating policy impact for mental health and to tackle the translational gap in LMICs

Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress

In human addicts, drug relapse and craving are often provoked by stress. Since 1995, this clinical scenario has been studied using a rat model of stress-induced reinstatement of drug seeking. Here, we first discuss the generality of stress-induced reinstatement to different drugs of abuse, different stressors, and different behavioral procedures. We also discuss neuropharmacological mechanisms, and brain areas and circuits controlling stress-induced reinstatement of drug seeking. We conclude by discussing results from translational human laboratory studies and clinical trials that were inspired by results from rat studies on stress-induced reinstatement. Our main conclusions are (1) The phenomenon of stress-induced reinstatement, first shown with an intermittent footshock stressor in rats trained to self-administer heroin, generalizes to other abused drugs, including cocaine, methamphetamine, nicotine, and alcohol, and is also observed in the conditioned place preference model in rats and mice. This phenomenon, however, is stressor specific and not all stressors induce reinstatement of drug seeking. (2) Neuropharmacological studies indicate the involvement of corticotropin-releasing factor (CRF), noradrenaline, dopamine, glutamate, kappa/dynorphin, and several other peptide and neurotransmitter systems in stress-induced reinstatement. Neuropharmacology and circuitry studies indicate the involvement of CRF and noradrenaline transmission in bed nucleus of stria terminalis and central amygdala, and dopamine, CRF, kappa/dynorphin, and glutamate transmission in other components of the mesocorticolimbic dopamine system (ventral tegmental area, medial prefrontal cortex, orbitofrontal cortex, and nucleus accumbens). (3) Translational human laboratory studies and a recent clinical trial study show the efficacy of alpha-2 adrenoceptor agonists in decreasing stress-induced drug craving and stress-induced initial heroin lapse

Effectiveness of treatment with pegylated interferon and ribavirin in an unselected population of patients with chronic hepatitis C: A Danish nationwide cohort study

<p>Abstract</p> <p>Background</p> <p>The effect of peginterferon and ribavirin treatment on chronic hepatitis C virus (HCV) infection has been established in several controlled clinical studies. However, the effectiveness of treatment and predictors of treatment success in routine clinical practice remains to be established. Our aim was to estimate the effectiveness of peginterferon and ribavirin treatment in unselected HCV patients handled in routine clinical practice. The endpoint was sustained virological response (SVR), determined by the absence of HCV RNA 24 weeks after the end of treatment.</p> <p>Methods</p> <p>We determined the proportion of SVR in a nationwide, population-based cohort of 432 patients with chronic HCV infection who were starting treatment, and analyzed the impact of known covariates on SVR by using a logistic regression analysis.</p> <p>Results</p> <p>The majority of treated patients had genotype 1 (133 patients) and genotype 2/3 (285 patients) infections, with 44% and 72%, respectively, obtaining SVR. Other than genotype, the predictors of SVR were age ≤ 45 years at the start of treatment, completion of unmodified treatment, the absence of cirrhosis and non-European origin.</p> <p>Conclusions</p> <p>The effectiveness of peginterferon and ribavirin treatment for chronic hepatitis C in a routine clinical practice is comparable to that observed in controlled clinical trials, with a higher SVR rate in genotype 2 and 3 patients compared to genotype 1 patients. Our data further indicate that age at start of treatment is a strong predictor of SVR irrespective of HCV genotype, with patients 45 years or younger having a higher SVR rate.</p

The Association Between Pre-pregnancy BMI and Preterm Delivery in a Diverse Southern California Population of Working Women

Whereas preterm birth has consistently been associated with low maternal pre-pregnancy weight, the relationship with high pre-pregnancy weight has been inconsistent. We quantified the pre-pregnancy BMI—preterm delivery (PTD) relationship using traditional BMI categories (underweight, normal weight, overweight and obese) as well as continuous BMI. Eligible women participated in California’s statewide prenatal screening program, worked during pregnancy, and delivered a live singleton birth in Southern California in 2002–2003. The final analytic sample included 354 cases delivering at <37 weeks, as identified by clinical estimate of gestational age from screening records, and 710 term normal-birthweight controls. Multivariable logistic regression models using categorical BMI levels and continuous BMI were compared. In categorical analyses, PTD was significantly associated with pre-pregnancy underweight only. Nonparametric local regression revealed a V-shaped relationship between continuous BMI and PTD, with minimum risk at the high end of normal, around 24 kg/m2. The odds ratio (OR) for PTD associated with low BMI within the normal range (19 kg/m2) was 2.84 (95%CI = 1.61–5.01); ORs for higher BMI in the overweight (29 kg/m2) and obese (34 kg/m2) ranges were 1.42 (95%CI = 1.10–1.84) and 2.01 (95% CI = 1.20–3.39) respectively, relative to 24 kg/m2). BMI categories obscured the preterm delivery risk associated with low-normal, overweight, and obese BMI. We found that higher BMI up to around 24 kg/m2 is increasingly protective of preterm delivery, beyond which a higher body mass index becomes detrimental. Current NHLBI/WHO BMI categories may be inadequate for identifying women at higher risk for PTD

The guideline implementability research and application network (GIRAnet): an international collaborative to support knowledge exchange: study protocol

<p>Abstract</p> <p>Background</p> <p>Modifying the format and content of guidelines may facilitate their use and lead to improved quality of care. We reviewed the medical literature to identify features desired by different users and associated with guideline use to develop a framework of implementability and found that most guidelines do not contain these elements. Further research is needed to develop and evaluate implementability tools.</p> <p>Methods</p> <p>We are launching the Guideline Implementability Research and Application Network (GIRAnet) to enable the development and testing of implementability tools in three domains: Resource Implications, Implementation, and Evaluation. Partners include the Guidelines International Network (G-I-N) and its member guideline developers, implementers, and researchers. In phase one, international guidelines will be examined to identify and describe exemplar tools. Indication-specific and generic tools will populate a searchable repository. In phase two, qualitative analysis of cognitive interviews will be used to understand how developers can best integrate implementability tools in guidelines and how health professionals use them for interpreting and applying guidelines. In phase three, a small-scale pilot test will assess the impact of implementability tools based on quantitative analysis of chart-based behavioural outcomes and qualitative analysis of interviews with participants. The findings will be used to plan a more comprehensive future evaluation of implementability tools.</p> <p>Discussion</p> <p>Infrastructure funding to establish GIRAnet will be leveraged with the in-kind contributions of collaborating national and international guideline developers to advance our knowledge of implementation practice and science. Needs assessment and evaluation of GIRAnet will provide a greater understanding of how to develop and sustain such knowledge-exchange networks. Ultimately, by facilitating use of guidelines, this research may lead to improved delivery and outcomes of patient care.</p

Factors linked to severe thrombocytopenia during antiviral therapy in patients with chronic hepatitis c and pretreatment low platelet counts

<p>Abstract</p> <p>Background</p> <p>Baseline low platelet count (< 150,000/μL) increases the risk of on-treatment severe thrombocytopenia (platelet count < 50,000/μL) in patients with chronic hepatitis C (CHC) undergoing antiviral therapy, which may interrupt treatment. The purpose of this study was to identify risk factors for severe thrombocytopenia during treatment for CHC in patients with baseline thrombocytopenia.</p> <p>Methods</p> <p>Medical records were reviewed for 125 patients with CHC treated with antiviral therapy according to the standard of care, with regular follow-up examinations. Early platelet decline was defined as platelet decrease during the first 2 weeks of therapy.</p> <p>Results</p> <p>Severe thrombocytopenia developed in 12.8% of patients with baseline thrombocytopenia, and predicted a higher therapeutic dropout rate. Multivariate analysis revealed baseline platelet count < 100,000/μL and rapid early platelet decline (> 30% decline in the first 2 weeks) were significantly associated with severe thrombocytopenia (<it>P </it>< 0.001 and 0.003, odds ratios, 179.22 and 45.74, respectively). In these patients, baseline PLT ≥ 100,000/μL and lack of rapid early platelet decline predicted absence of severe thrombocytopenia (negative predictive values were 95.1% and 96.6%, respectively). In contrast, baseline platelet count < 100,000/μL combined with rapid early platelet decline predicted severe thrombocytopenia (positive predictive value was 100%).</p> <p>Conclusions</p> <p>For patients with CHC on antiviral therapy, baseline platelet counts < 100,000/μL and rapid early platelet decline can identify patients at high risk of developing on-treatment severe thrombocytopenia.</p