Pharmacokinetic and Pharmacodynamic Comparison of Once-Daily Efavirenz (400 mg vs. 600 mg) in Treatment-Naïve HIV-Infected Patients: Results of the ENCORE1 Study.

Daily efavirenz 400 mg (EFV400) was virologically noninferior to 600 mg (EFV600) at 48 weeks in treatment-naïve patients. We evaluated EFV400 and EFV600 pharmacokinetics (NONMEM v. 7.

Functional Expression of Aquaporin-2 Tagged with Photoconvertible Fluorescent Protein in mpkCCD Cells.

Background: Vasopressin induced trafficking of aquaporin-2 (AQP2) containing vesicles has been studied in kidney cell lines using conventional fluorescent proteins as tags. However, trafficking of fluorescent tagged AQP2, which resembles the vectorial translocation of native AQP2 from cytoplasm to apical membrane has not been demonstrated at real time. Using a photoconvertible fluorescent protein tag on AQP2 might allow the simultaneous tracking of two separate populations of AQP2 vesicle after subcellular local photoconversion.

Low birth weight and prenatal care in Colombia: a cross-sectional study.

Background: Low birth weight (LBW) is one of the most important factors affecting child morbidity and mortality worldwide; approximately one third of neonatal deaths are attributable to it. Most research and public health policy on LBW arise from developed nations, despite that most cases (96.5%) take place in developing countries.

The impact of blood-borne viruses on cause-specific mortality among opioid dependent people: An Australian population-based cohort study.

Background: Blood-borne viruses (BBV) are prevalent among people with opioid dependence but their association with cause-specific mortality has not been examined at the population-level.

Methods: We formed a population-based cohort of 29,571 opioid substitution therapy (OST) registrants in New South Wales, Australia, 1993-2007. We ascertained notifications of infection and death by record linkage between the Pharmaceutical Drugs of Addiction System (OST data), registers of hepatitis C (HCV), hepatitis B (HBV) and human immunodeficiency virus (HIV) diagnoses, and the National Death Index.

Efficacy and safety of efavirenz 400 mg daily versus 600 mg daily: 96-week data from the randomised, double-blind, placebo-controlled, non-inferiority ENCORE1 study.

Background: The week 48 primary analysis of the ENCORE1 trial established the virological non-inferiority and safety of efavirenz 400 mg compared with the standard 600 mg dose, combined with tenofovir and emtricitabine, as first-line HIV therapy. This 96-week follow-up of the trial assesses the durability of efficacy and safety of this treatment over 96 weeks.

Methods: ENCORE1 was a double-blind, placebo-controlled, non-inferiority trial done at 38 clinical sites in 13 countries.

Patterns of hepatitis C virus RNA levels during acute infection: the InC3 study.

Background: Understanding the patterns of HCV RNA levels during acute hepatitis C virus (HCV) infection provides insights into immunopathogenesis and is important for vaccine design. This study evaluated patterns of HCV RNA levels and associated factors among individuals with acute infection.

Methods: Data were from an international collaboration of nine prospective cohorts of acute HCV (InC3 Study).

Limited reporting of major harms in studies of initial combination antiretroviral therapy: a systematic review.

Objectives: Risk-benefit assessment of combination antiretroviral therapy (cART) requires consideration of all potential serious harms. Studies of initial cART may permit identification of associations between particular regimens and uncommon harms, but only if comprehensively reported in the public domain.

Design: Study-based, systematic review of published initial cART studies (in adult patients) for completeness of serious harms reporting.

Early antiretroviral therapy with raltegravir generates sustained reductions in HIV reservoirs but not lower T-cell activation levels.

Objective: The initiation of antiretroviral therapy (ART) during primary infection may offer clinical benefits for HIV-infected individuals by reducing HIV DNA reservoir size and chronic T-cell activation. Current evidence for the advantages of early ART, however, are mostly derived from cross-sectional studies, with the long-term benefits yet to be ascertained.

Design/methods: We conducted an open-label, nonrandomized study, monitoring for 3 years: plasma viral load (pVL), T-cell phenotypes, and peripheral CD4(+) T-cell associated total, integrated and 2-long terminal repeat HIV DNA species.

Raltegravir non-inferior to nucleoside based regimens in second-line therapy with lopinavir/ritonavir over 96 weeks: a randomised open label study for the treatment of HIV-1 infection.

Objective: To determine the durability over 96 weeks of safety and efficacy of lopinavir/ritonavir (LPV/r) and raltegravir (RAL) which was demonstrated to have non-inferior efficacy relative to a regimen of LPV/r with nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs) (Control) in primary analysis at 48 weeks.

Design: Open label, centrally randomised trial.

Setting: Recruitment was from 37 primary and secondary care sites from Africa, Asia, Australia, Europe and Latin America.

Factors associated with hepatitis C virus RNA levels in early chronic infection: the InC3 study.

Improved understanding of natural history of hepatitis C virus (HCV) RNA levels in chronic infection provides enhanced insights into immunopathogenesis of HCV and has implications for the clinical management of chronic HCV infection. This study assessed factors associated with HCV RNA levels during early chronic infection in a population with well-defined early chronic HCV infection. Data were from an international collaboration of nine prospective cohorts studying acute HCV infection (InC(3) study).

Opioid substitution therapy is associated with increased detection of hepatitis C virus infection: a 15-year observational cohort study.

Background: Strategies are needed to enhance screening of hepatitis C virus (HCV) infection among people who inject drugs to improve engagement in HCV treatment, and stem the growing burden of HCV-related morbidity and mortality.

Methods: We linked routinely collected data on enrolment in opioid substitution therapy (OST) and HCV notifications. We calculated rates of incident HCV notifications, and compared rates in and out of OST.

Cerebrospinal fluid exposure of efavirenz and its major metabolites when dosed at 400 mg and 600 mg once daily: a randomized controlled trial.

Background: The optimal penetration of antiretroviral agents into the central nervous system may be a balance between providing adequate drug exposure to inhibit human immunodeficiency virus (HIV) replication while avoiding concentrations associated with neuronal toxicities.

Methods: Cerebrospinal fluid (CSF) exposure of efavirenz and the metabolites 7-hydroxy (7OH) and 8-hydroxy (8OH) efavirenz were assessed after at least 12 weeks of therapy in HIV-infected subjects randomized to commence antiretroviral regimens containing efavirenz at either 400 mg or 600 mg once daily.

Results: Of 28 subjects (14 and 14 on efavirenz 400 mg and 600 mg, respectively), CSF HIV RNA was undetectable in all.

Effect of amyloid-β (Aβ) immunization on hyperphosphorylated tau: a potential role for glycogen synthase kinase (GSK)-3β.

Aims: Active amyloid-β (Aβ) immunotherapy in Alzheimer's disease (AD) induces removal of Aβ and phosphorylated tau (ptau). Glycogen synthase kinase (GSK)-3β is a kinase, responsible for phosphorylation of tau, activation of which can be induced by phosphorylated double-stranded RNA-dependent protein kinase (pPKR). Using a post-mortem cohort of immunized AD cases, we investigated the effect of Aβ immunization on GSK-3β expression and pPKR.

Effect of active Aβ immunotherapy on neurons in human Alzheimer's disease.

Amyloid β peptide (Aβ) immunization of Alzheimer's disease (AD) patients has been reported to induce amyloid plaque removal, but with little impact on cognitive decline. We have explored the consequences of Aβ immunotherapy on neurons in post mortem brain tissue. Eleven immunized (AN1792, Elan Pharmaceuticals) AD patients were compared to 28 non-immunized AD cases.

Comparison of central and local HIV-1 RNA quantification from two international clinical trials.

Local and centrally measured plasma HIV RNA (pVL) were assessed for agreement in two trials, ENCORE1 and SECOND-LINE. The proportion less than 200 copies/ml at week 48 was qualitatively similar [ENCORE1 2.5% (95% confidence interval, 95% CI –1.

Examining the quality of name code record linkage: what is the impact on death and cancer risk estimates? A validation study.

Objective: To examine the validity and impact of record linkage using name code compared to full name records.

Methods: A registry of 45,419 opioid substitution clients (1985-2007) was linked with national population-based death and cancer registries using registrant's name, date of birth, sex, state, postcode and date of death. Records were linked using full name and then using the first two letters of the given and surname (2×2 name code).

Interferon lambda 3 genotype predicts hepatitis C virus RNA levels in early acute infection among people who inject drugs: the InC(3) study.

Background And Objectives: Hepatitis C virus (HCV) RNA level in acute HCV infection is predictive of spontaneous clearance. This study assessed factors associated with HCV RNA levels during early acute infection among people who inject drugs with well-defined acute HCV infection.

Study Design: Data were from International Collaboration of Incident HIV and Hepatitis C in Injecting Cohorts (InC(3)) Study, an international collaboration of nine prospective cohorts studying acute HCV infection.

Update 2014: advances to optimize 6-mercaptopurine and azathioprine to reduce toxicity and improve efficacy in the management of IBD.

Background: The thiopurine drugs, 6-mercaptopurine (6-MP) and azathioprine (AZA), remain as a mainstay therapy in inflammatory bowel disease (IBD). Differences in metabolism of these drugs lead to individual variation in thiopurine metabolite levels that can determine its therapeutic efficacy and development of adverse reactions. In this update, we will review thiopurine metabolic pathway along with the up-to-date approaches in administering thiopurine medications based on the current literature.

Trends in mortality after diagnosis of hepatitis C virus infection: an international comparison and implications for monitoring the population impact of treatment.

Background & Aims: People living with hepatitis C virus (HCV) are at increased risk of all-cause and liver-related mortality, although successful treatment has been shown to reduce this risk. The aim of this study was to provide baseline data on trends in cause-specific mortality and to establish an international surveillance system for evaluating the population level impact of HCV treatments.

Methods: Population level HCV diagnosis databases from Scotland (1997-2010), Australia (New South Wales [NSW]) (1997-2006), and Canada (British Columbia [BC]) (1997-2003) were linked to corresponding death registries using record linkage.

Bone mineral density over 96 weeks in adults failing first-line therapy randomized to raltegravir/lopinavir/ritonavir compared with standard second-line therapy.

Objective: To compare bone mineral density (BMD) changes over 96 weeks in adults virologically failing standard first-line therapy, randomized to raltegravir plus lopinavir/ritonavir (RAL + LPV/r) or conventional 2-3 nucleoside/nucleotide reverse transcriptase inhibitors [N(t)RTIs] + LPV/r second-line therapy.

Methods: Participants underwent dual-energy x-ray absorptiometry at baseline and weeks 48 and 96 to measure total hip and lumbar spine BMD. Analyses were adjusted for gender, body mass index, and smoking.

A new method for assessing how sensitivity and specificity of linkage studies affects estimation.

Background: While the importance of record linkage is widely recognised, few studies have attempted to quantify how linkage errors may have impacted on their own findings and outcomes. Even where authors of linkage studies have attempted to estimate sensitivity and specificity based on subjects with known status, the effects of false negatives and positives on event rates and estimates of effect are not often described.

Methods: We present quantification of the effect of sensitivity and specificity of the linkage process on event rates and incidence, as well as the resultant effect on relative risks.

Dynamics of HCV RNA levels during acute hepatitis C virus infection.

Understanding viral dynamics during acute hepatitis C virus (HCV) infection can provide important insights into immunopathogenesis and guide early treatment. The aim of this study was to investigate the dynamics of HCV RNA and alanine transaminase (ALT) levels during recent HCV infection in the Australian Trial in Acute Hepatitis C (ATAHC). ATAHC was a prospective study of the natural history of recently acquired HCV infection.

Zebrafish embryo model of Bartonella henselae infection.

Bartonella henselae (Bh) is an emerging zoonotic pathogen that has been associated with a variety of human diseases, including bacillary angiomatosis that is characterized by vasoproliferative tumor-like lesions on the skin of some immunosuppressed individuals. The study of Bh pathogenesis has been limited to in vitro cell culture systems due to the lack of an animal model. Therefore, we wanted to investigate whether the zebrafish embryo could be used to model human infection with Bh.

A prospective study of hepatitis C incidence in Australian prisoners.

Aims: To document the relationships between injecting drug use, imprisonment and hepatitis C virus (HCV) infection.

Design: Prospective cohort study.

Setting: Multiple prisons in New South Wales, Australia.

Metabolically Stable tert-Butyl Replacement.

Susceptibility to metabolism is a common issue with the tert-butyl group on compounds of medicinal interest. We demonstrate an approach of removing all the fully sp(3) C-Hs from a tert-butyl group: replacing some C-Hs with C-Fs and increasing the s-character of the remaining C-Hs. This approach gave a trifluoromethylcyclopropyl group, which increased metabolic stability.