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1.
Clin Infect Dis ; 73(2): 183-191, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32277809

RESUMO

BACKGROUND: We evaluated the efficacy, pharmacokinetics (PK), and safety of clofazimine (CFZ) in patients living with human immunodeficiency virus (HIV) with cryptosporidiosis. METHODS: We performed a randomized, double-blind, placebo-controlled study. Primary outcomes in part A were reduction in Cryptosporidium shedding, safety, and PK. Primary analysis was according to protocol (ATP). Part B of the study compared CFZ PK in matched individuals living with HIV without cryptosporidiosis. RESULTS: Twenty part A and 10 part B participants completed the study ATP. Almost all part A participants had high viral loads and low CD4 counts, consistent with failure of antiretroviral (ARV) therapy. At study entry, the part A CFZ group had higher Cryptosporidium shedding, total stool weight, and more diarrheal episodes compared with the placebo group. Over the inpatient period, compared with those who received placebo, the CFZ group Cryptosporidium shedding increased by 2.17 log2 Cryptosporidium per gram stool (95% upper confidence limit, 3.82), total stool weight decreased by 45.3 g (P = .37), and number of diarrheal episodes increased by 2.32 (P = .87). The most frequent solicited adverse effects were diarrhea, abdominal pain, and malaise. One placebo and 3 CFZ participants died during the study. Plasma levels of CFZ in participants with cryptosporidiosis were 2-fold lower than in part B controls. CONCLUSIONS: Our findings do not support the efficacy of CFZ for the treatment of cryptosporidiosis in a severely immunocompromised HIV population. However, this trial demonstrates a pathway to assess the therapeutic potential of drugs for cryptosporidiosis treatment. Screening persons living with HIV for diarrhea, and especially Cryptosporidium infection, may identify those failing ARV therapy. CLINICAL TRIALS REGISTRATION: NCT03341767.


Assuntos
Pesquisa Biomédica , Criptosporidiose , Cryptosporidium , Infecções por HIV , Adulto , Clofazimina/uso terapêutico , Criptosporidiose/complicações , Criptosporidiose/tratamento farmacológico , Diarreia , HIV , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Humanos
2.
Arch Virol ; 162(1): 213-226, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27718073

RESUMO

Rotavirus A strains detected in diarrhoeal children commonly possess any one of the genotypes G1, G2, G3, G4, and G9, with a recent increase in G12 detection globally. G12P[6] strains possessing short RNA (DS-1-like) and long RNA (Wa-like) migration patterns accounted for 27 % of the strains circulating in Blantyre, Malawi, between 2007 and 2008. To understand how the G12P[6] strains with two distinct genetic backgrounds emerged in Malawi, we conducted whole-genome analysis of two long-RNA and two short-RNA strains. While the former had a typical Wa-like genotype constellation of G12-P[6]-I1-R1-C1-M1-A1-N1-T1-E1-H1, the latter was found to have G12-P[6]-I2-R2-C2-M1-A2-N2-T2-E2-H2: a VP3 gene mono-reassortant on the DS-1-like backbone. Phylogenetic and Bayesian Markov chain Monte Carlo analyses showed that the short-RNA G12P[6] strains were generated around 2006 by reassortment between an African Wa-like G12P[6] strain donating three genes (the VP7, VP4, and VP3 genes) and a G2P[4] strain similar to the one circulating in Thailand or the United States of America that donated the remaining eight genes. On the other hand, the long-RNA strains were generated as a result of reassortment events within Wa-like G12 and non-G12 strains commonly circulating in Africa; only the VP4 gene was from a Malawian G8P[6] strain. In conclusion, this study uncovered the evolutionary pathways through which two distinct G12P[6] strains emerged in Malawi.


Assuntos
Genoma Viral , Genótipo , RNA Viral/genética , Infecções por Rotavirus/virologia , Rotavirus/isolamento & purificação , Análise por Conglomerados , Evolução Molecular , Humanos , Malaui , Filogenia , Vírus Reordenados/genética , Rotavirus/classificação , Rotavirus/genética , Análise de Sequência de DNA , Homologia de Sequência
3.
J Clin Microbiol ; 53(6): 1951-4, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25854480

RESUMO

We evaluated quantitative real-time PCR to establish the diagnosis of rotavirus gastroenteritis in a high-disease-burden population in Malawi using enzyme immunoassay as the gold standard diagnostic test. In 146 children with acute gastroenteritis and 65 asymptomatic children, we defined a cutoff point in the threshold cycle value (26.7) that predicts rotavirus-attributable gastroenteritis in this population. These data will inform the evaluation of direct and indirect rotavirus vaccine effects in Africa.


Assuntos
Infecções Assintomáticas , Gastroenterite/diagnóstico , Infecções por Rotavirus/diagnóstico , Rotavirus/genética , Carga Viral/normas , Pré-Escolar , Gastroenterite/epidemiologia , Gastroenterite/virologia , Humanos , Técnicas Imunoenzimáticas , Lactente , Recém-Nascido , Malaui , Reação em Cadeia da Polimerase em Tempo Real , Infecções por Rotavirus/epidemiologia , Infecções por Rotavirus/virologia
4.
J Med Virol ; 83(3): 540-50, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21264877

RESUMO

In an effort to reduce the high mortalities associated with rotavirus infections, a number of African countries are considering introducing human rotavirus vaccines. The demonstrated safety and efficacy of the live-attenuate human rotavirus vaccines in several clinical trials worldwide has accelerated such initiatives. Although the percentage-mortality rates for Sierra Leone are top of the list for rotavirus-associated deaths in Africa, no study has reported the prevalent strains circulating within this country. In this study, stool specimens were collected from 128 Sierra Leonean children presenting with diarrhea in 2005. Almost 37.5% (48/128) were rotavirus positive by EIA, of which 89.6% (43/48) revealed a short electropherotype, and a further 6.98% (3/48) could not be assigned a PAGE pattern. Genotyping analysis revealed G2P[4] (30.23%), G2P[6] (13.95%), G8P[6] (11.63%), G2P[8] (4.65%), G8P[4] (4.65%), and G8P[8] (2%) strains. About 11% were only assigned VP7 genotypes (G2), while 20.9% had mixed G and P types. The frequent detection of G2 rotaviruses could be of concern considering data generated from some studies that suggests lower efficacy of Rotarix® vaccine against G2 rotaviruses. This underscores the need for extensive and continuous regional strain surveillance to support rotavirus vaccines introduction and guide future vaccine development efforts. Such information will be useful before considering administration of specific rotavirus vaccine candidates in countries like Sierra Leone where little is known about circulating rotavirus strains.


Assuntos
Infecções por Rotavirus/epidemiologia , Infecções por Rotavirus/virologia , Rotavirus/genética , Adolescente , Antígenos Virais/genética , Antígenos Virais/imunologia , Proteínas do Capsídeo/genética , Criança , Pré-Escolar , Fezes/virologia , Genótipo , Humanos , Lactente , Recém-Nascido , Tipagem Molecular , Filogenia , Rotavirus/classificação , Rotavirus/imunologia , Serra Leoa
5.
Vaccine ; 36(47): 7142-7148, 2018 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-29887320

RESUMO

INTRODUCTION: Despite increased use of vaccine in routine immunisation, rotavirus remains a major cause of acute gastroenteritis (AGE) in low-income countries. We describe rotavirus prevalence and hospitalisation in Malawi pre and four years post vaccine introduction; provide updated vaccine effectiveness (VE) estimates; and assess rotavirus vaccine indirect effects. METHODS: Children under five years of age presenting to a referral hospital in Blantyre with AGE were recruited. Stool samples were tested for rotavirus using Enzyme Immunoassay. The change in rotavirus prevalence was evaluated using Poisson regression. Time series analysis was used to further investigate trends in prevalence over time. VE against rotavirus diarrhoea of any severity was estimated using logistic regression. Indirect effects were estimated by evaluating rotavirus prevalence in unvaccinated children over time, and by comparing observed reductions in incidence of rotavirus hospitalisation to those expected based on vaccine coverage and trial efficacy estimates. RESULTS: 2320 children were included. Prevalence of rotavirus in hospitalised infants (<12 months) with AGE decreased from 69/139(49.64%) prior to vaccine introduction to 197/607(32.45%) post-vaccine introduction (adjusted RR 0.67[95% CI 0.55, 0.82]). Prevalence in children aged 12-23 months demonstrated a less substantial decline: 15/37(40.54%) pre- and 122/352(34.66%) post-vaccine introduction (adjusted RR 0.85, 95% CI 0.57, 1.28). Adjusted VE was 61.89%(95% CI 28.04-79.82), but lower in children aged 12-23 months (31.69% [95% CI -139.03 to 80.48]). In hospitalised infants with rotavirus disease, the observed overall effect of the vaccine was 9% greater than expected according to vaccine coverage and efficacy estimates. Rotavirus prevalence among unvaccinated infants declined post-vaccine introduction (RR 0.70[95% CI 0.55-0.80]). CONCLUSIONS: Following rotavirus vaccine introduction in Malawi, prevalence of rotavirus in hospitalised children with AGE has declined significantly, with some evidence of an indirect effect in infants. Despite this, rotavirus remains an important cause of severe diarrhoea in Malawian children, particularly in the second year of life.


Assuntos
Diarreia/prevenção & controle , Gastroenterite/prevenção & controle , Hospitalização/estatística & dados numéricos , Infecções por Rotavirus/prevenção & controle , Vacinas contra Rotavirus/uso terapêutico , Doença Aguda/epidemiologia , Diarreia/epidemiologia , Diarreia/virologia , Fezes/virologia , Feminino , Gastroenterite/epidemiologia , Gastroenterite/virologia , Humanos , Imunoensaio , Incidência , Lactente , Malaui/epidemiologia , Masculino , Distribuição de Poisson , Prevalência , Rotavirus/imunologia , Infecções por Rotavirus/epidemiologia , Fatores de Tempo , Cobertura Vacinal , Vacinas Atenuadas/uso terapêutico
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