Efavirenz in pregnancy

Clinical guidelines from the National Department of Health (DoH), South Africa, for prevention of mother-tochild transmission (PMTCT), revised in 2010, recommend that HIV-positive pregnant women with a CD4 count of 350 cells/μl or less commence lifelong antiretroviral therapy (ART).¹ DoH guidance for women initiating ART in pregnancy in the public sector – on which the overwhelming majority of HIV-positive South Africans rely for their care – recommends they receive nevirapine with tenofovir and lamivudine or emtricitabine at any stage of gestation. In cases where a woman is already receiving ART with an efavirenz-based regimen, it is recommended that this should be substituted for nevirapine if she is still in the first trimester of pregnancy. Efavirenz is therefore contraindicated in pregnant women at any time during pregnancy; for those already receiving the drug, it is only switched in the first trimester. The concern about the use of efavirenz in pregnancy dates back to preclinical studies. It is the only antiretroviral with preclinical primate data and in turn has the strongest US Food and Drug Administration (FDA) category and the most scrutiny during pregnancy.² The drug also has the most conflicting recommendations, both from guidelines and product labelling. This article is a summary of what we know (and do not know) about using efavirenz in pregnancy. We argue that reconsideration of the risk and benefits of this evidence, which has informed South African guidance, is warranted

Has the phasing out of stavudine in accordance with changes in WHO guidelines led to a decrease in single-drug substitutions in first-line antiretroviral therapy for HIV in sub-Saharan Africa?

This version is the Accepted Manuscript and is published in final edited form as: AIDS. 2017 January 02; 31(1): 147–157. doi:10.1097/QAD.0000000000001307OBJECTIVE: We assessed the relationship between phasing out stavudine in first-line antiretroviral therapy (ART) in accordance with WHO 2010 policy and single-drug substitutions (SDS) (substituting the nucleoside reverse transcriptase inhibitor in first-line ART) in sub-Saharan Africa. DESIGN: Prospective cohort analysis (International epidemiological Databases to Evaluate AIDS-Multiregional) including ART-naive, HIV-infected patients aged at least 16 years, initiating ART between January 2005 and December 2012. Before April 2010 (July 2007 in Zambia) national guidelines called for patients to initiate stavudine-based or zidovudine-based regimen, whereas thereafter tenofovir or zidovudine replaced stavudine in first-line ART. METHODS: We evaluated the frequency of stavudine use and SDS by calendar year 2004-2014. Competing risk regression was used to assess the association between nucleoside reverse transcriptase inhibitor use and SDS in the first 24 months on ART. RESULTS: In all, 33 441 (8.9%; 95% confience interval 8.7-8.9%) SDS occurred among 377 656 patients in the first 24 months on ART, close to 40% of which were amongst patients on stavudine. The decrease in SDS corresponded with the phasing out of stavudine. Competing risks regression models showed that patients on tenofovir were 20-95% less likely to require a SDS than patients on stavudine, whereas patients on zidovudine had a 75-85% decrease in the hazards of SDS when compared to stavudine. CONCLUSION: The decline in SDS in the first 24 months on treatment appears to be associated with phasing out stavudine for zidovudine or tenofovir in first-line ART in our study. Further efforts to decrease the cost of tenofovir and zidovudine for use in this setting is warranted to substitute all patients still receiving stavudine

Gender differences in survival among adult patients starting antiretroviral therapy in South Africa: a multicentre cohort study.

Increased mortality among men on antiretroviral therapy (ART) has been documented but remains poorly understood. We examined the magnitude of and risk factors for gender differences in mortality on ART

Switching to second-line antiretroviral therapy in resource-limited settings: comparison of programmes with and without viral load monitoring.

In high-income countries, viral load is routinely measured to detect failure of antiretroviral therapy (ART) and guide switching to second-line ART. Viral load monitoring is not generally available in resource-limited settings. We examined switching from nonnucleoside reverse transcriptase inhibitor (NNRTI)-based first-line regimens to protease inhibitor-based regimens in Africa, South America and Asia

Estimating the impact of antiretroviral treatment on adult mortality trends in South Africa: A mathematical modelling study

Substantial reductions in adult mortality have been observed in South Africa since the mid-2000s, but there has been no formal evaluation of how much of this decline is attributable to the scale-up of antiretroviral treatment (ART), as previous models have not been calibrated to vital registration data. We developed a deterministic mathematical model to simulate the mortality trends that would have been expected in the absence of ART, and with earlier introduction of ART

Epitaxial growth and properties of lead-free ferroelectric Na0.5Bi0.5TiO3 thin films grown by pulsed laser deposition on various single crystal substrates

International audienceThe epitaxial growth of lead-free ferroelectric Na0.5Bi0.5TiO3 (NBT) thin films on various single crystal substrates was successfully achieved, using the pulsed laser deposition technique (PLD). The present work is divided in two parts, focused on: (i) the growth of NBT layers on c- and r-sapphire (Al2O3) substrates, with and without introducing a CeO2 buffer layer, and (ii) the growth of NBT layers on bare (001)SrTiO3 substrates, with and without introducing a LaNiO3 layer, that could be used as a bottom electrode. In the first part, it was shown that the introduction of a CeO2 buffer layer completely modifies the out-of-plane growth orientation of the NBT films, as well as their microstructure. Indeed, (001)NBT films epitaxially grow only on r-Al2O3 substrates buffered with epitaxial (001)CeO2 layers, while, growing simply NBT on top of bare c or r-Al2O3 substrates, or on top of CeO2/c-Al2O3 heterostructures leads to polycrystalline or textured films. In the second part, we demonstrate that (001)-oriented NBT layers deposited on either bare (001)SrTiO3 or (001)SrTiO3 substrates (STO) covered with (001)LaNiO3 (LNO) are systematically epitaxially grown. Furthermore, the microstructure of the samples is strongly affected by the introduction of the LaNiO3 layer

Mutations in the EXT1 and EXT2 genes in hereditary multiple exostoses.

Hereditary multiple exostoses (EXT; MIM 133700) is an autosomal dominant bone disorder characterized by the presence of multiple benign cartilage-capped tumors (exostoses). Besides suffering complications caused by the pressure of these exostoses on the surrounding tissues, EXT patients are at an increased risk for malignant chondrosarcoma, which may develop from an exostosis. EXT is genetically heterogeneous, and three loci have been identified so far: EXT1, on chromosome 8q23-q24; EXT2, on 11p11-p12; and EXT3, on the short arm of chromosome 19. The EXT1 and EXT2 genes were cloned recently, and they were shown to be homologous. We have now analyzed the EXT1 and EXT2 genes, in 26 EXT families originating from nine countries, to identify the underlying disease-causing mutation. Of the 26 families, 10 families had an EXT1 mutation, and 10 had an EXT2 mutation. Twelve of these mutations have never been described before. In addition, we have reviewed all EXT1 and EXT2 mutations reported so far, to determine the nature, frequency, and distribution of mutations that cause EXT. From this analysis, we conclude that mutations in either the EXT1 or the EXT2 gene are responsible for the majority of EXT cases. Most of the mutations in EXT1 and EXT2 cause premature termination of the EXT proteins, whereas missense mutations are rare. The development is thus mainly due to loss of function of the EXT genes, consistent with the hypothesis that the EXT genes have a tumor- suppressor function

Microwave excitations associated with a wavy angular dependence of the spin transfer torque : model and experiments

The spin transfer torque (STT) can lead to steady precession of magnetization without any external applied field in magnetic spin valve where the magnetic layer have very different spin diffusion length. This effect is associated with an unusual angular dependence of the STT, called "wavy" (WAD-STT), predicted in the frame of diffusive models of spin transfer. In this article, we present a complete experimental characterization of the magnetization dynamics in the presence of a WAD-STT. The results are compared to the prediction of the magnetization dynamics obtained by single domain magnetic simulations (macrospin approximation). The macrospin simulations well reproduced the main static and dynamical experimental features (phase diagram, R(I) curves, dependence of frequency with current and field) and suggest that the dynamical excitations observed experimentally are associated with a large angle out-of-plane precession mode. The present work validates the diffusive models of the spin transfer and underlines the role of the spin accumulation and the spin relaxation effects on the STT

Elevation and cholera: an epidemiological spatial analysis of the cholera epidemic in Harare, Zimbabwe, 2008-2009

BACKGROUND: In highly populated African urban areas where access to clean water is a challenge, water source contamination is one of the most cited risk factors in a cholera epidemic. During the rainy season, where there is either no sewage disposal or working sewer system, runoff of rains follows the slopes and gets into the lower parts of towns where shallow wells could easily become contaminated by excretes. In cholera endemic areas, spatial information about topographical elevation could help to guide preventive interventions. This study aims to analyze the association between topographic elevation and the distribution of cholera cases in Harare during the cholera epidemic in 2008 and 2009. METHODS: We developed an ecological study using secondary data. First, we described attack rates by suburb and then calculated rate ratios using whole Harare as reference. We illustrated the average elevation and cholera cases by suburbs using geographical information. Finally, we estimated a generalized linear mixed model (under the assumption of a Poisson distribution) with an Empirical Bayesian approach to model the relation between the risk of cholera and the elevation in meters in Harare. We used a random intercept to allow for spatial correlation of neighboring suburbs. RESULTS: This study identifies a spatial pattern of the distribution of cholera cases in the Harare epidemic, characterized by a lower cholera risk in the highest elevation suburbs of Harare. The generalized linear mixed model showed that for each 100 meters of increase in the topographical elevation, the cholera risk was 30% lower with a rate ratio of 0.70 (95% confidence interval=0.66-0.76). Sensitivity analysis confirmed the risk reduction with an overall estimate of the rate ratio between 20% and 40%. CONCLUSION: This study highlights the importance of considering topographical elevation as a geographical and environmental risk factor in order to plan cholera preventive activities linked with water and sanitation in endemic areas. Furthermore, elevation information, among other risk factors, could help to spatially orientate cholera control interventions during an epidemic