25 research outputs found
Spontaneous Emergence of Multiple Drug Resistance in Tuberculosis before and during Therapy
The emergence of drug resistance in M. tuberculosis undermines the efficacy of tuberculosis (TB) treatment in individuals and of TB control programs in populations. Multiple drug resistance is often attributed to sequential functional monotherapy, and standard initial treatment regimens have therefore been designed to include simultaneous use of four different antibiotics. Despite the widespread use of combination therapy, highly resistant M. tb strains have emerged in many settings. Here we use a stochastic birth-death model to estimate the probability of the emergence of multidrug resistance during the growth of a population of initially drug sensitive TB bacilli within an infected host. We find that the probability of the emergence of resistance to the two principal anti-TB drugs before initiation of therapy ranges from 10â5 to 10â4; while rare, this is several orders of magnitude higher than previous estimates. This finding suggests that multidrug resistant M. tb may not be an entirely âman-madeâ phenomenon and may help explain how highly drug resistant forms of TB have independently emerged in many settings
Genome Analysis of Multi- and Extensively-Drug-Resistant Tuberculosis from KwaZulu-Natal, South Africa
The KZN strain family of Mycobacterium tuberculosis is a highly virulent strain endemic to the KwaZulu-Natal region of South Africa, which has recently experienced an outbreak of extensively-drug resistant tuberculosis. To investigate the causes and evolution of drug-resistance, we determined the DNA sequences of several clinical isolates - one drug-susceptible, one multi-drug resistant, and nine extensively drug-resistant - using whole-genome sequencing. Analysis of polymorphisms among the strains is consistent with the drug-susceptibility profiles, in that well-known mutations are observed that are correlated with resistance to isoniazid, rifampicin, kanamycin, ofloxacin, ethambutol, and pyrazinamide. However, the mutations responsible for rifampicin resistance in rpoB and pyrazinamide in pncA are in different nucleotide positions in the multi-drug-resistant and extensively drug-resistant strains, clearly showing that they acquired these mutations independently, and that the XDR strain could not have evolved directly from the MDR strain (though it could have arisen from another similar MDR strain). Sequencing of eight additional XDR strains from other areas of KwaZulu-Natal shows that they have identical drug resistant mutations to the first one sequenced, including the same polymorphisms at sites associated with drug resistance, supporting the theory that this represents a case of clonal expansion
Malaria vaccines and their potential role in the elimination of malaria
Research on malaria vaccines is currently directed primarily towards the development of vaccines that prevent clinical malaria. Malaria elimination, now being considered seriously in some epidemiological situations, requires a different vaccine strategy, since success will depend on killing all parasites in the community in order to stop transmission completely
The costâeffectiveness of prophylaxis strategies for individuals with advanced HIV starting treatment in Africa
Introduction Many HIVâpositive individuals in Africa have advanced disease when initiating antiretroviral therapy (ART) so have high risks of opportunistic infections and death. The REALITY trial found that an enhancedâprophylaxis package including fluconazole reduced mortality by 27% in individuals starting ART with CD4 <100 cells/mm3. We investigated the costâeffectiveness of this enhancedâprophylaxis package versus other strategies, including using cryptococcal antigen (CrAg) testing, in individuals with CD4 <200 cells/mm3 or <100 cells/mm3 at ART initiation and all individuals regardless of CD4 count. Methods The REALITY trial enrolled from June 2013 to April 2015. A decisionâanalytic model was developed to estimate the costâeffectiveness of six management strategies in individuals initiating ART in the REALITY trial countries. Strategies included standardâprophylaxis, enhancedâprophylaxis, standardâprophylaxis with fluconazole; and three CrAg testing strategies, the first stratifying individuals to enhancedâprophylaxis (CrAgâpositive) or standardâprophylaxis (CrAgânegative), the second to enhancedâprophylaxis (CrAgâpositive) or enhancedâprophylaxis without fluconazole (CrAgânegative) and the third to standardâprophylaxis with fluconazole (CrAgâpositive) or without fluconazole (CrAgânegative). The model estimated costs, lifeâyears and qualityâadjusted lifeâyears (QALY) over 48 weeks using three competing mortality risks: cryptococcal meningitis; tuberculosis, serious bacterial infection or other known cause; and unknown cause. Results Enhancedâprophylaxis was costâeffective at costâeffectiveness thresholds of US500 per QALY with an incremental costâeffectiveness ratio (ICER) of US113 per QALY in the CD4 <100 cells/mm3 population) and increased in all individuals regardless of CD4 count (US2.30. Conclusions The REALITY enhancedâprophylaxis package in individuals with advanced HIV starting ART reduces morbidity and mortality, is practical to administer and is costâeffective. Efforts should continue to ensure that components are accessed at lowest available prices
Late Presentation With HIV in Africa: Phenotypes, Risk, and Risk Stratification in the REALITY Trial.
This article has been accepted for publication in Clinical Infectious Diseases Published by Oxford University PressBackground: Severely immunocompromised human immunodeficiency virus (HIV)-infected individuals have high mortality shortly after starting antiretroviral therapy (ART). We investigated predictors of early mortality and "late presenter" phenotypes. Methods: The Reduction of EArly MortaLITY (REALITY) trial enrolled ART-naive adults and children â„5 years of age with CD4 counts .1). Results: Among 1711 included participants, 203 (12%) died. Mortality was independently higher with older age; lower CD4 count, albumin, hemoglobin, and grip strength; presence of World Health Organization stage 3/4 weight loss, fever, or vomiting; and problems with mobility or self-care at baseline (all P < .04). Receiving enhanced antimicrobial prophylaxis independently reduced mortality (P = .02). Of five late-presenter phenotypes, Group 1 (n = 355) had highest mortality (25%; median CD4 count, 28 cells/”L), with high symptom burden, weight loss, poor mobility, and low albumin and hemoglobin. Group 2 (n = 394; 11% mortality; 43 cells/”L) also had weight loss, with high white cell, platelet, and neutrophil counts suggesting underlying inflammation/infection. Group 3 (n = 218; 10% mortality) had low CD4 counts (27 cells/”L), but low symptom burden and maintained fat mass. The remaining groups had 4%-6% mortality. Conclusions: Clinical and laboratory features identified groups with highest mortality following ART initiation. A screening tool could identify patients with low CD4 counts for prioritizing same-day ART initiation, enhanced prophylaxis, and intensive follow-up. Clinical Trials Registration: ISRCTN43622374.REALITY was funded by the Joint Global Health Trials Scheme (JGHTS) of the UK Department for International Development, the Wellcome Trust, and Medical Research Council (MRC) (grant number G1100693). Additional funding support was provided by the PENTA Foundation and core support to the MRC Clinical Trials Unit at University College London (grant numbers MC_UU_12023/23 and MC_UU_12023/26). Cipla Ltd, Gilead Sciences, ViiV Healthcare/GlaxoSmithKline, and Merck Sharp & Dohme donated drugs for REALITY, and ready-to-use supplementary food was purchased from Valid International. A. J. P. is funded by the Wellcome Trust (grant number 108065/Z/15/Z). J. A. B. is funded by the JGHTS (grant number MR/M007367/1). The Malawi-LiverpoolâWellcome Trust Clinical Research Programme, University of Malawi College of Medicine (grant number 101113/Z/13/Z) and the Kenya Medical Research Institute (KEMRI)/Wellcome Trust Research Programme, Kilifi (grant number 203077/Z/16/Z) are supported by strategic awards from the Wellcome Trust, United Kingdom. Permission to publish was granted by the Director of KEMRI. This supplement was supported by funds from the Bill & Melinda Gates Foundation
âTwo Steps Forward, One Step Backâ: Zimbabwean Migration and South Africaâs Regularising Programme (the ZDP)
South Africaâs announcement and implementation of a legalising amnesty
under the Zimbabwe Documentation Project (ZDP) in 2010 was lauded as a step away
from the laissez-faire approach to Zimbabwean immigration. The amnesty, granting
migrants stay, work, study and business operation rights in the country on 4-year
permits, was clouded by uncertainties and exclusions and implementation hassles. This
article explores this legalising amnesty in relation to trends in Zimbabwean immigration
over the years, noting in particular the complexity and fluidity in migration
patterns. The article highlights these complexities and how they expose the limitations
of any ad hoc and short-term approach to managing complex immigration flows. It
argues that such an approach fails to recognise differences in migration trends over time
and space, sources of migration and migrantâs strategies, and, more importantly, that
these factors result in different migrants with differing needs. As way of conclusion, the
article suggests that any progressive immigration strategy on Zimbabwean immigration
should not only build on the BTemporary Immigration Exemption Status for
Zimbabweans^ of 2009 and embrace ideals of diversity, inclusivity and openness but
also draw upon existing efforts at regional cooperation and integration.http://link.springer.com/journal/121342018-05-30hb2016Anthropology and Archaeolog