The risk of viral rebound in the year after delivery in women remaining on antiretroviral therapy

Objective: The objective of this study is to assess the risk of viral rebound in postpartum women on suppressive combination antiretroviral therapy (cART). Methods: Using data from the UK Collaborative HIV Cohort (UK CHIC) study and the UK and Ireland National Study of HIV in Pregnancy and Childhood (NSHPC), women with HIV-RNA 50 copies/ml or less at delivery in 2006–2011, who started life-long cART during pregnancy (n = 321) or conceived on cART (n = 618), were matched by age, duration on cART and time period, with at least one control (non-postpartum). The cumulative probability of viral rebound (HIV-RNA >200 copies/ml) was assessed by Kaplan–Meier analysis; adjusted hazard ratios (aHRs) for the 0–3 and 3–12 months postdelivery (cases)/pseudo-delivery (controls) were calculated in Cox proportional hazards models. Results: In postpartum women who conceived on cART, 5.9% [95% confidence interval (95% CI) 4.0–7.7] experienced viral rebound by 3 months, and 2.2% (1.4–3.0%) of their controls. The risk of viral rebound was higher in postpartum women than in controls during the first 3 months [aHR 2.63 (1.58–4.39)] but not during the 3–12 months postdelivery/pseudo-delivery. In postpartum women who started cART during pregnancy, 27% (22–32%) experienced viral rebound by 3 months, and 3.0% (1.6–4.4%) of their controls. The risk of viral rebound was higher in postpartum women than in controls during both postdelivery/pseudo-delivery periods [<3 months: aHR 6.63 (3.58–12.29); 3–12 months: aHR 4.05 (2.03–8.09)]. Conclusion: In women on suppressive cART, the risk of viral rebound is increased following delivery, especially in the first 3 months, which may be related to reduced adherence, indicating the need for additional adherence support for postpartum women

The impact of antiretroviral therapy used in pregnancy on the health of HIV-positive women

In the UK, antiretroviral therapy (ART) is used during the vast majority of pregnancies among women living with HIV. This thesis aims to examine some of the consequences of antenatal ART use on women’s health during and after pregnancy. Initially, a linkage was developed between two well established studies, the UK Collaborative HIV Cohort (UK CHIC) Study and the UK and Ireland’s National Study of HIV in Pregnancy and Childhood (NSHPC). The resultant dataset was used to assess pregnancy incidence in women attending HIV clinical care at UK CHIC sites in 2000- 2009. The overall pregnancy incidence increased. The rate of increase did not significantly differ between ethnic groups, age groups or according to ART use. In women starting life-long cART at least one year after HIV diagnosis, those who had previously used short-course cART in pregnancy were more likely to experience viral rebound and interrupt their treatment compared to those who had never previously used ART. Levels of the liver enzyme alanine transaminase (ALT) were assessed in women on combination ART (cART). The risk of liver enzyme elevation (LEE) was higher during pregnancy than at other times in women who started ART during pregnancy and in women who conceived on ART. The risk of viral rebound (HIV-RNA >200 copies/ml) whilst on cART was higher in women who had recently had a pregnancy than in similar women who had not recently been pregnant. In post-pregnant women remaining on cART, the risk of viral rebound was higher in women who had started cART during their pregnancy than in women who had conceived on cART. The findings presented in this thesis contribute to the evidence-base for the management of pregnant women living with HIV and highlight the need for close monitoring of toxicity in pregnancy and additional drug adherence support following pregnancy

Modelling-based evaluation of the costs, benefits and cost-effectiveness of multipathogen point-of-care tests for sexually transmitted infections in symptomatic genitourinary medicine clinic attendees

Objectives To quantify the costs, benefits and cost-effectiveness of three multipathogen point-of-care (POC) testing strategies for detecting common sexually transmitted infections (STIs) compared with standard laboratory testing. Design Modelling study. Setting Genitourinary medicine (GUM) services in England. Population A hypothetical cohort of 965 988 people, representing the annual number attending GUM services symptomatic of lower genitourinary tract infection. Interventions The decision tree model considered costs and reimbursement to GUM services associated with diagnosing and managing STIs. Three strategies using hypothetical point-of-care tests (POCTs) were compared with standard care (SC) using laboratory-based testing. The strategies were: A) dual POCT for Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG); B) triplex POCT for CT-NG and Mycoplasma genitalium (MG); C) quadruplex POCT for CT-NG-MG and Trichomonas vaginalis (TV). Data came from published literature and unpublished estimates. Primary and secondary outcome measures Primary outcomes were total costs and benefits (quality-adjusted life years (QALYs)) for each strategy (2016 GB, £) and associated incremental cost-effectiveness ratios (ICERs) between each of the POC strategies and SC. Secondary outcomes were inappropriate treatment of STIs, onward STI transmission, pelvic inflammatory disease in women, time to cure and total attendances. Results In the base-case analysis, POC strategy C, a quadruplex POCT, was the most cost-effective relative to the other strategies, with an ICER of £36 585 per QALY gained compared with SC when using microcosting, and cost-savings of £26 451 382 when using tariff costing. POC strategy C also generated the most benefits, with 240 467 fewer clinic attendances, 808 fewer onward STI transmissions and 235 135 averted inappropriate treatments compared with SC. Conclusions Many benefits can be achieved by using multipathogen POCTs to improve STI diagnosis and management. Further evidence is needed on the underlying prevalence of STIs and SC delivery in the UK to reduce uncertainty in economic analyses

The impacts of corruption on firm performance: some lessons from 40 African countries

The current evidence-base regarding the impacts of corruption on firm performance is based largely on studies of individual countries and contains mixed results. Therefore, the aim of this paper is to achieve a better insight into this relationship by reporting the results of a firm-level analysis of the impacts of corruption on firm performance using World Bank Enterprise Survey (WBES) data across 40 African countries. The clear result is that corruption significantly enhances rather than harms annual sales, employment and productivity growth rates. The outcome is to re-theorize participation in acts of corruption as beneficial for the individual firms engaged in such activity, while recognizing the wider evidence that this is not an optimal strategy at the aggregate country level. The outcome will be to advance knowledge about how corruption needs to be tackled. To eliminate corruption, it is shown here to be necessary for public authorities to recognize that corruption is an efficient strategy at the firm level and to adopt measures to alter the cost/benefit ratio confronting individual enterprises, and at the same time, to address the country-level formal institutional deficiencies that characterize many developing countries and result in the prevalence of corruption

In silico assessment of potential druggable pockets on the surface of α1-Antitrypsin conformers

The search for druggable pockets on the surface of a protein is often performed on a single conformer, treated as a rigid body. Transient druggable pockets may be missed in this approach. Here, we describe a methodology for systematic in silico analysis of surface clefts across multiple conformers of the metastable protein α1-antitrypsin (A1AT). Pathological mutations disturb the conformational landscape of A1AT, triggering polymerisation that leads to emphysema and hepatic cirrhosis. Computational screens for small molecule inhibitors of polymerisation have generally focused on one major druggable site visible in all crystal structures of native A1AT. In an alternative approach, we scan all surface clefts observed in crystal structures of A1AT and in 100 computationally produced conformers, mimicking the native solution ensemble. We assess the persistence, variability and druggability of these pockets. Finally, we employ molecular docking using publicly available libraries of small molecules to explore scaffold preferences for each site. Our approach identifies a number of novel target sites for drug design. In particular one transient site shows favourable characteristics for druggability due to high enclosure and hydrophobicity. Hits against this and other druggable sites achieve docking scores corresponding to a Kd in the µM–nM range, comparing favourably with a recently identified promising lead. Preliminary ThermoFluor studies support the docking predictions. In conclusion, our strategy shows considerable promise compared with the conventional single pocket/single conformer approach to in silico screening. Our best-scoring ligands warrant further experimental investigation

Suppressor of cytokine signaling (SOCS)5 ameliorates influenza infection via inhibition of EGFR signaling

© Kedzierski et al. Influenza virus infections have a significant impact on global human health. Individuals with suppressed immunity, or suffering from chronic inflammatory conditions such as COPD, are particularly susceptible to influenza. Here we show that suppressor of cytokine signaling (SOCS) five has a pivotal role in restricting influenza A virus in the airway epithelium, through the regulation of epidermal growth factor receptor (EGFR). Socs5-deficient mice exhibit heightened disease severity, with increased viral titres and weight loss. Socs5 levels were differentially regulated in response to distinct influenza viruses (H1N1, H3N2, H5N1 and H11N9) and were reduced in primary epithelial cells from COPD patients, again correlating with increased susceptibility to influenza. Importantly, restoration of SOCS5 levels restricted influenza virus infection, suggesting that manipulating SOCS5 expression and/or SOCS5 targets might be a novel therapeutic approach to influenza

Exclusion of mutations in the PRNP, JPH3, TBP, ATN1, CREBBP, POU3F2 and FTL genes as a cause of disease in Portuguese patients with a Huntington-like phenotype

Huntington disease (HD) is an autosomal dominant neurodegenerative disorder characterised by chorea, cognitive impairment, dementia and personality changes, caused by the expansion of a CAG repeat in the HD gene. Often, patients with a similar clinical presentation do not carry expansions of the CAG repeat in this gene [Huntington disease-like (HDL) patients]. We report the genetic analysis of 107 Portuguese patients with an HDL phenotype. The HDL genes PRNP and JPH3, encoding the prion protein and junctophilin-3, respectively, were screened for repeat expansions in these patients. Given the partial clinical overlap of SCA17, DRPLA and neuroferritinopathy with HD, their causative genes (TBP, ATN1, and FTL, respectively) were also analysed. Finally, repeat expansions in two candidate genes, CREBBP and POU3F2, which encode the nuclear transcriptional coactivator CREB-binding protein and the CNS-specific transcription factor N-Oct-3, respectively, were also studied. Expansions of the repetitive tracts of the PRNP, JPH3, TBP, ATN1, CREBBP and POU3F2 genes were excluded in all patients, as were sequence alterations in the FTL gene. Since none of the genes already included in the differential diagnosis of HD was responsible for the disease in our sample, the genetic heterogeneity of the HDL phenotype is still open for investigation.Fundação para a Ciência e a Tecnologia (FCT) and FEDER (grant CBO/33485/99). BIC included in grant CBO/33485/99, respectivel

Treatment switches during pregnancy among HIV-positive women on antiretroviral therapy at conception

Objectives: To describe antiretroviral therapy (ART) use and clinical status, at start of and during pregnancy, for HIV-positive women receiving ART at conception, including the proportion conceiving on drugs (efavirenz and didanosine) not recommended for use in early pregnancy.Methods: Women with a pregnancy resulting in a live-birth after 1995 (n = 1537) were identified in an observational cohort of patients receiving HIV care at 12 clinics in the UK by matching records with national pregnancy data. Treatment and clinical data were analysed for 375 women conceiving on ART, including logistic regression to identify factors associated with changing regimen during pregnancy.Results: Of the 375 women on ART, 39 (10%) conceived on dual therapy, 306 (82%) on triple therapy and 30 (8%) on more than three drugs. In total, 116 (31%) women conceived on a regimen containing efavirenz or didanosine (69 efavirenz, 54 didanosine, seven both). Overall, 38% (143) changed regimen during pregnancy, of whom 44% (n = 51) had a detectable viral load around that time. Detectable viral load was associated with increased risk of regimen change [adjusted odds ratio 2.97, 95% confidence interval (CI) (1.70-5.19)], while women on efavirenz at conception were three times more likely to switch than women on other drugs [3.40, (1.84-6.25)]. Regimen switching was also associated with year at conception [0.89, (0.83-0.96)].Conclusion: These findings reinforce the need for careful consideration of ART use among women planning or likely to have a pregnancy in order to reduce viral load before pregnancy and avoid drugs not recommended for early antenatal use. (C) 2011 Wolters Kluwer Health | Lippincott Williams & Wilkin

Quantification of Age-Dependent Somatic CAG Repeat Instability in Hdh CAG Knock-In Mice Reveals Different Expansion Dynamics in Striatum and Liver

Age at onset of Huntington's disease (HD) is largely determined by the CAG trinucleotide repeat length in the HTT gene. Importantly, the CAG repeat undergoes tissue-specific somatic instability, prevalent in brain regions that are disease targets, suggesting a potential role for somatic CAG repeat instability in modifying HD pathogenesis. Thus, understanding underlying mechanisms of somatic CAG repeat instability may lead to discoveries of novel therapeutics for HD. Investigation of the dynamics of the CAG repeat size changes over time may provide insights into the mechanisms underlying CAG repeat instability.To understand how the HTT CAG repeat length changes over time, we quantified somatic instability of the CAG repeat in Huntington's disease CAG knock-in mice from 2-16 months of age in liver, striatum, spleen and tail. The HTT CAG repeat in spleen and tail was very stable, but that in liver and striatum expanded over time at an average rate of one CAG per month. Interestingly, the patterns of repeat instability were different between liver and striatum. Unstable CAG repeats in liver repeatedly gained similar sizes of additional CAG repeats (approximately two CAGs per month), maintaining a distinct population of unstable repeats. In contrast, unstable CAG repeats in striatum gained additional repeats with different sizes resulting in broadly distributed unstable CAG repeats. Expanded CAG repeats in the liver were highly enriched in polyploid hepatocytes, suggesting that the pattern of liver instability may reflect the restriction of the unstable repeats to a unique cell type.Our results are consistent with repeat expansion occurring as a consequence of recurrent small repeat insertions that differ in different tissues. Investigation of the specific mechanisms that underlie liver and striatal instability will contribute to our understanding of the relationship between instability and disease and the means to intervene in this process