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2.
Am J Epidemiol ; 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31063192

RESUMO

Effect estimates from randomized trials and observational studies may not be directly comparable because of differences in study design, other than randomization, and in data analysis. We propose a three-step procedure to facilitate meaningful comparisons of effect estimates from randomized trials and observational studies: 1) harmonization of the study protocol (eligibility criteria, treatment strategies, outcome, start and end of follow-up, causal contrast) so that the studies target the same causal effect, 2) harmonization of the data analysis to estimate the causal effect, and 3) sensitivity analyses to investigate the impact of discrepancies that could not be accounted for in the harmonization process. To illustrate our approach, we compared estimates of the effect of immediate with deferred initiation of antiretroviral therapy in individuals positive to the human immunodeficiency virus from the START randomized trial and the observational HIV-CAUSAL Collaboration.

3.
Nat Commun ; 10(1): 412, 2019 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-30679439

RESUMO

Understanding HIV remission in rare individuals who initiated antiretroviral therapy (ART) soon after infection and then discontinued, may inform HIV cure interventions. Here we describe features of virus and host of a perinatally HIV-1 infected child with long-term sustained virological control. The child received early limited ART in the Children with HIV Early antiRetroviral therapy (CHER) trial. At age 9.5 years, diagnostic tests for HIV are negative and the child has characteristics similar to uninfected children that include a high CD4:CD8 ratio, low T cell activation and low CCR5 expression. Virus persistence (HIV-1 DNA and plasma RNA) is confirmed with sensitive methods, but replication-competent virus is not detected. The child has weak HIV-specific antibody and T cell responses. Furthermore, we determine his HLA and KIR genotypes. This case aids in understanding post-treatment control and may help design of future intervention strategies.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Suspensão de Tratamento , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Criança , Citocinas/análise , DNA Viral , Feminino , Genótipo , Anticorpos Anti-HIV/sangue , Infecções por HIV/imunologia , HIV-1/genética , HIV-1/patogenicidade , Humanos , Imunidade Celular , Imunofenotipagem , Recém-Nascido , Fosfoproteínas/genética , Gravidez , RNA Viral , Receptores CCR5/metabolismo , Receptores KIR/genética , Receptores KIR3DL1/genética , Carga Viral , Produtos do Gene gag do Vírus da Imunodeficiência Humana/genética
4.
PLoS One ; 14(1): e0209911, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30689664

RESUMO

BACKGROUND: Comparison of changes in body composition, adipokines and inflammatory markers after initial therapy with a nucleos(t)ide reverse transcriptase inhibitor (N(t)RTI)- sparing or containing regimen are scarce. DESIGN: Randomised Clinical Trial. METHODS: This is the body composition substudy of NEAT 001/ANRS 143, a randomised trial comparing darunavir/ritonavir (DRV/r) plus either raltegravir (RAL) or tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in 805 ART naïve HIV-infected adults. The primary endpoint was percentage change in limb fat at week 96. Secondary endpoints were associations among these changes and metabolic markers (IL-6, insulin, leptin, adiponectin, FGF-23). RESULTS: 126 subjects (61 DRV/r + RAL and 65 DRV/r + TDF/FTC) were included. The rate of change in BMI between groups for RAL versus TDF/FTC at week 96 was 1.5% per 48-week period (p = 0.015). The rate of change in limb fat mass, trunk fat mass, total body fat and total lean mass was for RAL versus TDF/FTC at week 96 was 2.5% (p = 0.38), 7.3% ((p = 0.021), 4.9% (p = 0.061) and 1.3% (p = 0.12) respectively. Baseline insulin and leptin levels were correlated with baseline limb fat and trunk fat mass [r = 0.31 (p = 0.0043)/r = 0.28 (p = 0.0011) for limb fat, and r = 0.63 (p<0.0001)/r = 0.50(p<0.0001) for trunk fat]. After adjustment, a 10% faster increase in leptin between baseline and week 48 was associated with a more rapid increase in limb fat at week 48 (0.5% per 48 weeks, p<0.001), total body fat mass (0.6% per 48 weeks, p<0.001), and trunk fat mass (0.3% per 48 weeks, p = 0.0026). CONCLUSIONS: After week 96 a N(t)RTI sparing regimen of DRV/r + RAL produced a numerically greater percentage increase in body composition variables with only change in trunk fat mass and BMI being significant.

5.
AIDS ; 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30325764

RESUMO

INTRODUCTION: There are few data on the frequency of virological remission in African individuals after treatment with antiretroviral therapy (ART) in primary HIV infection (PHI). METHODS: We studied participants (n = 82) from South Africa and Uganda in SPARTAC, the first trial of treatment interruption (TI) in African individuals with PHI randomized to deferred ART or 48 weeks of immediate ART. All were female and infected with non-B HIV subtypes, mainly C. We measured HIV DNA in CD4 T cells, CD4 count, plasma viral load (pVL), cell-associated HIV RNA and T cell activation and exhaustion. We explored associations with clinical progression and time to pVL rebound after TI (n = 22). Data were compared with non-African SPARTAC participants. RESULTS: Pre-therapy pVL and integrated HIV DNA were lower in Africans compared with non-Africans (median 4.16 vs 4.72 log10 copies/ml and 3.07 vs 3.61 log10 copies/million CD4 T-cells respectively; p < 0.001). Pre-ART HIV DNA in Africans was associated with clinical progression (p = 0.001, HR per log10 copies/million CD4 T cells increase (95% CI) 5.38 (1.95-14.79)) and time to pVL rebound (p = 0.034, HR per log10 copies/ml increase 4.33 (1.12-16.84)). After TI, Africans experienced longer duration of viral remission than non-Africans (p < 0.001; HR 3.90 (1.75-8.71). Five of 22 African participants (22.7%) maintained VL < 400 copies/ml over a median of 188 weeks following TI. CONCLUSION: We find evidence of greater probability of virological remission following TI among African participants, although we are unable to differentiate between sex, ethnicity and viral subtype. The finding warrants further investigation.

6.
Artigo em Inglês | MEDLINE | ID: mdl-30298747

RESUMO

BACKGROUND: In this study, we aimed to quantify KREC (kappa-deleting recombination excision circles) levels and naïve B-cell output in healthy HIV-uninfected children, compared with HIV-infected South African children, before and after starting ART (anti-retroviral therapy). SETTING: Samples were acquired from a Child Wellness Clinic (n=288 HIV-uninfected South African children, 2 weeks - 12 years) and the Children with HIV and Early Antiretroviral Therapy (CHER) trial (n=153 HIV-infected South African children, 7 weeks - 8 years). METHODS: Naïve B-cell output was estimated using a mathematical model combining KREC levels to reflect B-cell emigration into the circulation, flow cytometry measures of naïve un-switched B-cells to quantify total body naïve B-cells, and their rates of proliferation using the intracellular marker Ki67. RESULTS: Naïve B-cell output increases from birth to 1 year, followed by a decline and plateau into late childhood. HIV-infected children on or off ART had higher naïve B-cell outputs than their uninfected counterparts (p=0.01 and p=0.04). CONCLUSIONS: This is the first study to present reference ranges for measurements of KRECs and naïve B-cell output in healthy and HIV-infected children. Comparison between HIV-uninfected healthy children and HIV-infected children suggest that HIV may increase naïve B-cell output. Further work is required to fully understand the mechanisms involved and clinical value of measuring naïve B-cell output in children. .

7.
J Acquir Immune Defic Syndr ; 79(2): 269-276, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30211778

RESUMO

BACKGROUND: Future strategies aiming to achieve HIV-1 remission are likely to target individuals with small reservoir size. SETTING: We retrospectively investigated factors associated with HIV-1 DNA levels in European, perinatally HIV-infected children starting antiretroviral therapy (ART) <6 months of age. METHODS: Total HIV-1 DNA was measured from 51 long-term suppressed children aged 6.3 years (median) after initial viral suppression. Factors associated with log10 total HIV-1 DNA were analyzed using linear regression. RESULTS: At ART initiation, children were aged median [IQR] 2.3 [1.2-4.1] months, CD4% 37 [24-45] %, CD8% 28 [18-36] %, log10 plasma viral load (VL) 5.4 [4.4-5.9] copies per milliliter. Time to viral suppression was 7.98 [4.6-19.3] months. After suppression, 13 (25%) children had suboptimal response [≥2 consecutive VL 50-400 followed by VL <50] and/or experienced periods of virological failure [≥2 consecutive VL ≥400 followed by VL <50]. Median total HIV-1 DNA was 43 [6195] copies/10 PBMC. Younger age at therapy initiation was associated with lower total HIV-1 DNA (adjusted coefficient [AC] 0.12 per month older, P = 0.0091), with a month increase in age at ART start being associated with a 13% increase in HIV DNA. Similarly, a higher proportion of time spent virally suppressed (AC 0.10 per 10% higher, P = 0.0022) and the absence of viral failure/suboptimal response (AC 0.34 for those with fail/suboptimal response, P = 0.0483) were associated with lower total HIV-1 DNA. CONCLUSIONS: Early ART initiation and a higher proportion of time suppressed are linked with lower total HIV-1 DNA. Early ART start and improving adherence in perinatally HIV-1-infected children minimize the size of viral reservoir.

8.
Int J STD AIDS ; 29(13): 1330-1336, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30049254

RESUMO

Routine infectious diseases screening of Sudanese pregnant women has been patchy due to scarcity of healthcare resources and social stigma. We sought to determine the seroprevalence of HIV, hepatitis B, and syphilis among pregnant women attending antenatal care (ANC) at El Obeid Maternity Hospital in western Sudan. We also explored the association between these infections and a set of socio-demographic and maternal variables. Unlinked anonymous testing for HIV-1/2 antibodies, hepatitis B surface antigen, and Treponema pallidum antibodies was performed on residual blood samples collected during routine ANC (August 2016-March 2017). Seroprevalence of HIV was 1.13% (5/444; 95% CI 0.37-2.61%), hepatitis B 2.93% (13/444; 95% CI 1.57-4.95%), and syphilis 7.43% (33/444; 95% CI 5.17-10.28%). On bivariate analysis, there were no statistically significant associations between hepatitis B, syphilis, or a composite outcome including any of the three infections and age, stage of pregnancy, gravidity, parity, previous mode of delivery, history of blood transfusion, or husband polygamy. Urgent action is needed to scale up routine maternal screening for HIV, hepatitis B, and syphilis on an opt-out basis. Further research into the socio-demographic and behavioural determinants of these infections as well as their clinical outcomes is needed.

9.
Artigo em Inglês | MEDLINE | ID: mdl-29957674

RESUMO

BACKGROUND: Future strategies aiming to achieve HIV-1 remission are likely to target individuals with small reservoir size. SETTING: We retrospectively investigated factors associated with HIV-1 DNA levels in European, perinatally HIV-infected children starting ART <6 months of age. METHODS: Total HIV-1 DNA was measured from 51 long-term suppressed children 6.3 years (median) after initial viral suppression. Factors associated with log10 total HIV-1 DNA were analyzed using linear regression. RESULTS: At ART initiation, children were aged median [IQR] 2.3 [1.2,4.1] months, CD4% 37 [24,45] %, CD8% 28 [18,36] %, log10 plasma viral load (VL) 5.4 [4.4,5.9] copies/ml. Time to viral suppression was 7.98 [4.6,19.3] months. Following suppression, 13 (25%) children had suboptimal response [≥2 consecutive VL50-400 followed by VL<50] and/or experienced periods of virological failure [≥2 consecutive VL≥400 followed by VL<50]. Median total HIV-1 DNA was 43 [6,195] copies/10 PBMC.Younger age at therapy initiation was associated with lower total HIV-1 DNA (adjusted coefficient [AC] 0.12 per month older, p=0.0091), with a month increase in age at ART start being associated with a 13% increase in HIV DNA. Similarly, a higher proportion of time spent virally suppressed (AC 0.10 per 10% higher, p=0.0022) and absence of viral failure/suboptimal response (AC 0.34 for those with fail/ suboptimal response, p=0.0483) were associated with lower total HIV-1 DNA. CONCLUSION: Early ART initiation and a higher proportion of time suppressed are linked with lower total HIV-1 DNA. Early ART start and improving adherence in perinatally HIV-1 infected children minimize the size of viral reservoir.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal.

10.
J Int AIDS Soc ; 21(5): e25106, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29722482

RESUMO

INTRODUCTION: Early antiretroviral therapy (ART) has improved neurodevelopmental outcomes of HIV-infected (HIV-positive) children; however, little is known about the longer term outcomes in infants commencing early ART or whether temporary ART interruption might have long-term consequences. In the children with HIV early antiretroviral treatment (CHER) trial, HIV-infected infants ≤12 weeks of age with CD4 ≥25% were randomized to deferred ART (ART-Def); immediate time-limited ART for 40 weeks (ART-40W) or 96 weeks (ART-96W). ART was restarted in the time-limited arms for immunologic/clinical progression. Our objective was to compare the neurodevelopmental profiles in all three arms of Cape Town CHER participants. METHODS: A prospective, longitudinal observational study was used. The Griffiths mental development scales (GMDS), which includes six subscales and a global score, were performed at 11, 20, 30, 42 and 60 months, and the Beery-Buktenica developmental tests for visual motor integration at 60 months. HIV-exposed uninfected (HEU) and HIV-unexposed (HU) children were enrolled for comparison. Mixed model repeated measures were used to compare groups over time, using quotients derived from standardized British norms. RESULTS: In this study, 28 ART-Def, 35 ART-40W, 33 ART-96W CHER children, and 34 HEU and 39 HU controls were enrolled. GMDS scores over five years were similar between the five groups in all subscales except locomotor and general Griffiths (interaction p < 0.001 and p = 0.02 respectively), driven by early lower scores in the ART-Def arm. At 60 months, scores for all groups were similar in each GMDS scale. However, Beery visual perception scores were significantly lower in HIV-infected children (mean standard scores: 75.8 ART-Def, 79.8 ART-40W, 75.9 ART-96W) versus 84.4 in HEU and 90.5 in HU (p < 0.01)). CONCLUSIONS: Early locomotor delay in the ART-Def arm resolved by five years. Neurodevelopmental outcomes at five years in HIV-infected children on early time-limited ART were similar to uninfected controls, apart from visual perception where HIV-infected children scored lower. Poorer visual perception performance warrants further investigation.

11.
PLoS One ; 13(4): e0196239, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29684092

RESUMO

BACKGROUND: Weekends off antiretroviral therapy (ART) may help engage HIV-1-infected young people facing lifelong treatment. BREATHER showed short cycle therapy (SCT; 5 days on, 2 days off ART) was non-inferior to continuous therapy (CT) over 48 weeks. Planned follow-up was extended to 144 weeks, maintaining original randomisation. METHODS: BREATHER was an open-label, non-inferiority trial. Participants aged 8-24yrs with virological suppression on efavirenz-based first-line ART were randomised 1:1, stratified by age and African/non-African sites, to remain on CT or change to SCT. The Kaplan-Meier method was used to estimate the proportion of participants with viral rebound (confirmed VL≥50 copies/mL) under intent-to-treat at 48 weeks (primary outcome), and in extended follow-up at 96, 144, and 192 weeks. SCT participants returned to CT following viral rebound, 3 VL blips or discontinuation of efavirenz. FINDINGS: Of 199 participants (99 SCT, 100 CT), 97 per arm consented to extended follow-up. Median follow-up was 185.3 weeks (IQR 160.9-216.1). 69 (70%) SCT participants remained on SCT at last follow-up. 105 (53%) were male, baseline median age 14 years (IQR 12-18), median CD4 count 735 cells/µL (IQR 576-968). 16 SCT and 16 CT participants had confirmed VL≥50 copies/mL by the end of extended follow-up (HR 1.00, 95% CI 0.50-2.00). Estimated difference in percentage with viral rebound (SCT minus CT) by week 144 was 1.9% (90% CI -6.6-10.4; p = 0.72) and was similar in a per-protocol analysis. There were no significant differences between arms in proportions of participants with grade 3/4 adverse events (18 SCT vs 16 CT participants; p = 0.71) or ART-related adverse events (10 vs 12; p = 0.82). 20 versus 8 serious adverse events (SAEs) were reported in 16 SCT versus 4 CT participants, respectively (p = 0.005 comparing proportions between groups; incidence rate ratio 2.49, 95%CI 0.71-8.66, p = 0.15). 75% of SAEs (15 SCT, 6 CT) were hospitalisations for a wide range of conditions. 3 SCT and 6 CT participants switched to second-line ART following viral failure (p = 0.50). CONCLUSIONS: Sustainable non-inferiority of virological suppression in young people was shown for SCT versus CT over median 3.6 years. Standard-dose efavirenz-based SCT is a viable option for virologically suppressed HIV-1 infected young people on first-line ART with 3-monthly VL monitoring. TRIAL REGISTRATION: EudraCT 2009-012947-40 ISRCTN 97755073 ClinicalTrials.gov NCT01641016.


Assuntos
Benzoxazinas/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores da Transcriptase Reversa/uso terapêutico , Adolescente , Benzoxazinas/farmacologia , Criança , Esquema de Medicação , Feminino , Seguimentos , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Humanos , Masculino , Inibidores da Transcriptase Reversa/farmacologia , Resultado do Tratamento , Carga Viral , Adulto Jovem
13.
BMC Med ; 16(1): 37, 2018 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-29519240

RESUMO

BACKGROUND: Hyperlactataemia (HL) is a biomarker of disease severity that predicts mortality in patients with sepsis and malaria. Lactate clearance (LC) during resuscitation has been shown to be a prognostic factor of survival in critically ill adults, but little data exist for African children living in malaria-endemic areas. METHODS: In a secondary data analysis of severely ill febrile children included in the Fluid Expansion as Supportive Therapy (FEAST) resuscitation trial, we assessed the association between lactate levels at admission and LC at 8 h with all-cause mortality at 72 h (d72). LC was defined as a relative lactate decline ≥ 40% and/or lactate normalisation (lactate < 2.5 mmol/L). RESULTS: Of 3170 children in the FEAST trial, including 1719 children (57%) with Plasmodium falciparum malaria, 3008 (95%) had a baseline lactate measurement, 2127 (71%) had HL (lactate ≥ 2.5 mmol/L), and 1179 (39%) had severe HL (≥ 5 mmol/L). Within 72 h, 309 children (10.3%) died, of whom 284 (92%) had baseline HL. After adjustment for potential confounders, severe HL was strongly associated with mortality (Odds Ratio (OR) 6.96; 95% CI 3.52, 13.76, p < 0.001). This association was not modified by malaria status, despite children with malaria having a higher baseline lactate (median 4.6 mmol/L vs 3 mmol/L; p < 0.001) and a lower mortality rate (OR = 0.42; p < 0.001) compared to non-malarial cases. Sensitivity and specificity analysis identified a higher lactate on admission cut-off value predictive of d72 for children with malaria (5.2 mmol/L) than for those with other febrile illnesses (3.4 mmol/L). At 8 h, 2748/3008 survivors (91%) had a lactate measured, 1906 (63%) of whom had HL on admission, of whom 1014 (53%) fulfilled pre-defined LC criteria. After adjustment for confounders, LC independently predicted survival after 8 h (OR 0.24; 95% CI 0.14, 0.42; p < 0.001). Absence of LC (< 10%) at 8 h was strongly associated with death at 72 h (OR 4.62; 95% CI 2.7, 8.0; p < 0.001). CONCLUSIONS: Independently of the underlying diagnosis, HL is a strong risk factor for death at 72 h in children admitted with severe febrile illnesses in Africa. Children able to clear lactate within 8 h had an improved chance of survival. These findings prompt the more widespread use of lactate and LC to identify children with severe disease and monitor response to treatment. TRIAL REGISTRATION: ISRCTN69856593 Registered 21 January 2009.


Assuntos
Estado Terminal/mortalidade , Febre/mortalidade , Ácido Láctico/metabolismo , Malária/mortalidade , Sepse/mortalidade , África Oriental , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Malária/complicações , Masculino , Prognóstico , Fatores de Risco , Sepse/complicações
14.
Clin Infect Dis ; 66(9): 1467-1469, 2018 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-29177461

RESUMO

Randomized clinical trials are the most reliable approaches to evaluating the effects of new treatments and vaccines. During the 2014-2015 West African Ebola epidemic, many argued that such trials were neither ethical nor feasible in an environment of limited health infrastructure and severe disease with a high fatality rate. Consensus among the numerous organizations providing help to the affected areas was never achieved, resulting in fragmented collaboration, delayed study initiation, and ultimately failure to provide definitive evidence on the efficacy of treatments and vaccines. Randomized trials were in fact approved by local ethics boards and initiated, demonstrating that randomized trials, even in such difficult circumstances, are feasible. Improved planning and collaboration among research and humanitarian organizations, and affected communities, in the interepidemic periods are needed to ensure that questions regarding the efficacy of vaccines and treatments can be definitively answered during future public health emergencies.

15.
Front Immunol ; 8: 1162, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28979264

RESUMO

OBJECTIVES: Early treatment of HIV-infected children and adults is important for optimal immune reconstitution. Infants' immune systems are more plastic and dynamic than older children's or adults', and deserve particular attention. This study aimed to understand the response of the HIV-infected infant immune system to early antiretroviral therapy (ART) and planned ART interruption and restart. METHODS: Data from HIV-infected children enrolled the CHER trial, starting ART aged between 6 and 12 weeks, were used to explore the effect of ART on immune reconstitution. We used linear and non-linear regression and mixed-effects models to describe children's CD4 trajectories and to identify predictors of CD4 count during early and interrupted ART. RESULTS: Early treatment arrested the decline in CD4 count but did not fully restore it to the levels observed in HIV-uninfected children. Treatment interruption at 40 or 96 weeks resulted in a rapid decline in CD4 T-cells, which on retreatment returned to levels observed before interruption. Naïve CD4 T-cell count was an important determinant of overall CD4 levels. A strong correlation was observed between thymic output and the stable CD4 count both before and after treatment interruption. CONCLUSION: Early identification and treatment of HIV-infected infants is important to stabilize CD4 counts at the highest levels possible. Once stabilized, children's CD4 counts appear resilient, with good potential for recovery following treatment interruption. The naïve T-cell pool and thymic production of naive cells are key determinants of children's CD4 levels.

16.
Clin Infect Dis ; 64(7): 939-946, 2017 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-28362936

RESUMO

Background: In the Fluid Expansion as a Supportive Treatment (FEAST) trial, an unexpectedly high proportion of participants from eastern Uganda presented with blackwater fever (BWF). Methods: We describe the prevalence and outcome of BWF among trial participants and compare the prevalence of 3 malaria-protective red blood cell polymorphisms in BWF cases vs both trial (non-BWF) and population controls. Results: Of 3170 trial participants, 394 (12.4%) had BWF. The majority (318 [81.0%]) presented in eastern Uganda and were the subjects of further analysis. BWF cases typically presented with both clinical jaundice (254/318 [80%]) and severe anemia (hemoglobin level <5 g/dL) (238/310 [77%]). Plasmodium falciparum parasitemia was less frequent than in non-BWF controls, but a higher proportion were positive for P. falciparum histidine rich protein 2 (192/246 [78.0%]) vs 811/1154 [70.3%]; P = .014), suggesting recent antimalarial treatment. Overall, 282 of 318 (88.7%) received transfusions, with 94 of 282 (33.3%) and 9 of 282 (3.4%) receiving 2 or 3 transfusions, respectively. By day 28, 39 of 318 (12.3%) BWF cases and 154 of 1554 (9.9%) non-BWF controls had died (P = .21), and 7 of 255 (3.0%) vs 13/1212 (1%), respectively, had severe anemia (P = .036). We found no association with G6PD deficiency. The prevalence of both the sickle cell trait (10/218 [4.6%]) and homozygous α+thalassemia (8/216 [3.7%]) were significantly lower among cases than among population controls (334/2123 [15.7%] and 141/2114 [6.6%], respectively), providing further support for the role of malaria. Conclusions: We report the emergence of BWF in eastern Uganda, a condition that, according to local investigators, was rare until the last 7 years. We speculate that this might relate to the introduction of artemisinin-based combination therapies. Further studies investigating this possibility are urgently required.


Assuntos
Febre Hemoglobinúrica/diagnóstico , Febre Hemoglobinúrica/epidemiologia , Fatores Etários , Biomarcadores , Febre Hemoglobinúrica/complicações , Febre Hemoglobinúrica/parasitologia , Pré-Escolar , Eritrócitos/metabolismo , Eritrócitos/parasitologia , Feminino , Glucosefosfato Desidrogenase/genética , Hemoglobinopatias/complicações , Hemoglobinopatias/genética , Humanos , Lactente , Masculino , Mutação , Avaliação de Resultados da Assistência ao Paciente , Fenótipo , Polimorfismo Genético , Prevalência , Índice de Gravidade de Doença , Avaliação de Sintomas , Uganda/epidemiologia , Urinálise
17.
PLoS One ; 12(4): e0172607, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28445471

RESUMO

BACKGROUND: Improving the effectiveness and efficiency of research informed consent is a high priority. Some express concern about longer, more complex, written consent forms creating barriers to participant understanding. A recent meta-analysis concluded that randomized comparisons were needed. METHODS: We conducted a cluster-randomized non-inferiority comparison of a standard versus concise consent form within a multinational trial studying the timing of starting antiretroviral therapy in HIV+ adults (START). Interested sites were randomized to standard or concise consent forms for all individuals signing START consent. Participants completed a survey measuring comprehension of study information and satisfaction with the consent process. Site personnel reported usual site consent practices. The primary outcome was comprehension of the purpose of randomization (pre-specified 7.5% non-inferiority margin). RESULTS: 77 sites (2429 participants) were randomly allocated to use standard consent and 77 sites (2000 participants) concise consent, for an evaluable cohort of 4229. Site and participant characteristics were similar for the two groups. The concise consent was non-inferior to the standard consent on comprehension of randomization (80.2% versus 82%, site adjusted difference: 0.75% (95% CI -3.8%, +5.2%)); and the two groups did not differ significantly on total comprehension score, satisfaction, or voluntariness (p>0.1). Certain independent factors, such as education, influenced comprehension and satisfaction but not differences between consent groups. CONCLUSIONS: An easier to read, more concise consent form neither hindered nor improved comprehension of study information nor satisfaction with the consent process among a large number of participants. This supports continued efforts to make consent forms more efficient. TRIAL REGISTRATION: Informed consent substudy was registered as part of START study in clinicaltrials.gov #NCT00867048, and EudraCT # 2008-006439-12.


Assuntos
Infecções por HIV/psicologia , Consentimento Livre e Esclarecido , Adulto , Antirretrovirais/uso terapêutico , Compreensão , Feminino , Infecções por HIV/tratamento farmacológico , Serviços de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Satisfação do Paciente , Ensaios Clínicos Controlados Aleatórios como Assunto , Inquéritos e Questionários
18.
Clin Infect Dis ; 64(3): 389-390, 2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-28013262
19.
J Acquir Immune Defic Syndr ; 74(2): 185-192, 2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-27749603

RESUMO

BACKGROUND: Improvements in cognitive function are described after initiation of combination antiretroviral therapy (cART), with sparse data on differences between cART strategies. METHODS: We assessed changes in cognition, over 96 weeks, in therapy-naive HIV-positive adults randomized to darunavir/ritonavir (800/100 mg once daily) with either raltegravir (400 mg twice daily, Arm1) or tenofovir/emtricitabine (245/200 mg once daily, Arm2). Seven cognitive tests were administered at baseline and week (W) 96. Changes from baseline in individual cognitive test scores and composite score (NPZ) were assessed. Comparisons between treatment arms were by intention to treat and associations with immunological and virological parameters by regression models. FINDINGS: Of 343 subjects enrolled, 208 completed the W96 cognitive assessment. Baseline median (interquartile range) CD4 count and plasma HIV RNA were 348 (282-398) cells per microliter and 4.7 (4.2-5.1) log10 copies per milliliter, respectively. At W96, numbers with plasma HIV RNA undetectable and remaining on randomized cART were 85 (92%) and 110 (96%), and 84 (90%) and 107 (93%) in Arm1 and Arm2, respectively. Overall performance significantly improved by W96 in 5 of 7 individual tests and in NPZ. Mean changes in NPZ were 0.28 versus 0.21 for Arm1 and 2, respectively (P = 0.37). No statistically significant differences between study treatment arms were observed in individual cognitive domains apart from attention (greater improvement in Arm1, P = 0.0499). At W96, NPZ score increase was associated with increase in CD4 (P = 0.001) but not HIV RNA area under curve (P = 0.60). INTERPRETATION: Subsequent to the initiation of cART, immunological recovery rather than type of antiretroviral therapy is the major driver of changes in cognitive function.


Assuntos
Complexo AIDS Demência/tratamento farmacológico , Complexo AIDS Demência/patologia , Antirretrovirais/administração & dosagem , Terapia Antirretroviral de Alta Atividade/métodos , Cognição/fisiologia , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Resultado do Tratamento
20.
Open Forum Infect Dis ; 4(4): ofx262, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29308409

RESUMO

Background: The Strategic Timing of AntiRetroviral Treatment (START) trial demonstrated that immediate (at CD4+ >500 cells/µL) vs deferred (to CD4+ <350 cells/µL or AIDS) antiretroviral therapy (ART) initiation reduced risk for AIDS and serious non-AIDS (SNA). We investigated associations of inflammation, coagulation, and vascular injury biomarkers with AIDS, SNA or death, and the effect of immediate ART initiation. Methods: Biomarkers were measured from stored plasma prior to randomization and at month 8. Associations of baseline biomarkers with event risk were estimated with Cox regression, pooled across groups, adjusted for age, gender, and treatment group, and stratified by region. Mean changes over 8 months were estimated and compared between the immediate and deferred ART arms using analysis of covariance models, adjusted for levels at entry. Results: Baseline biomarker levels were available for 4299 START participants (92%). Mean follow-up was 3.2 years. Higher levels of IL-6 and D-dimer were the only biomarkers associated with risk for AIDS, SNA or death, as well as the individual components of SNA and AIDS events (HRs ranged 1.37-1.41 per 2-fold higher level), even after adjustment for baseline CD4+ count, HIV RNA level, and other biomarkers. At month 8, biomarker levels were lower in the immediate arm by 12%-21%. Conclusions: These data, combined with evidence from prior biomarker studies, demonstrate that IL-6 and D-dimer consistently predict clinical risk across a broad spectrum of CD4 counts for those both ART-naïve and treated. Research is needed to identify disease-modifying treatments that target inflammation beyond the effects of ART.

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