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1.
Transpl Infect Dis ; 26(2): e14231, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38375954

RESUMEN

Observational studies of coronavirus disease 2019 (COVID-19) among transplant candidates and recipients remain important as immunocompromised patients formed a very small proportion of patients included in COVID-19 trials and large database analyses. We discuss methods that have been used in such analyses to evaluate the impact of vaccination on the risk of symptomatic COVID-19 in such patients and on the probability of developing post-acute sequelae of severe acute respiratory syndrome coronavirus 2 after the onset of infection. We also propose future directions for research and discuss the methods that will be useful to conduct such investigations. The study design and analytical issues that we consider have the potential to be helpful not only for COVID-19 research but also for other infections as well.


Asunto(s)
COVID-19 , SARS-CoV-2 , Humanos , COVID-19/complicaciones , Bases de Datos Factuales , Progresión de la Enfermedad , Huésped Inmunocomprometido , Estudios Observacionales como Asunto
2.
BMC Infect Dis ; 23(1): 656, 2023 Oct 04.
Artículo en Inglés | MEDLINE | ID: mdl-37794364

RESUMEN

BACKGROUND: Efforts to control the HIV epidemic can benefit from knowledge of the relationships between the characteristics of people who have transmitted HIV and those who became infected by them. Investigation of this relationship is facilitated by the use of HIV genetic linkage analyses, which allows inference about possible transmission events among people with HIV infection. Two persons with HIV (PWH) are considered linked if the genetic distance between their HIV sequences is less than a given threshold, which implies proximity in a transmission network. The tendency of pairs of nodes (in our case PWH) that share (or differ in) certain attributes to be linked is denoted homophily. Below, we describe a novel approach to modeling homophily with application to analyses of HIV viral genetic sequences from clinical series of participants followed in San Diego. Over the 22-year period of follow-up, increases in cluster size results from HIV transmissions to new people from those already in the cluster-either directly or through intermediaries. METHODS: Our analytical approach makes use of a logistic model to describe homophily with regard to demographic, clinical, and behavioral characteristics-that is we investigate whether similarities (or differences) between PWH in these characteristics are associated with their sequences being linked. To investigate the performance of our methods, we conducted on a simulation study for which data sets were generated in a way that reproduced the structure of the observed database. RESULTS: Our results demonstrated strong positive homophily associated with hispanic ethnicity, and strong negative homophily, with birth year difference. The second result implies that the larger the difference between the age of a newly-infected PWH and the average age for an available cluster, the lower the odds of a newly infected person joining that cluster. We did not observe homophily associated with prior diagnosis of sexually transmitted diseases. Our simulation studies demonstrated the validity of our approach for modeling homophily, by showing that the estimates it produced matched the specified values of the statistical network generating model. CONCLUSIONS: Our novel methods provide a simple and flexible statistical network-based approach for modeling the growth of viral (or other microbial) genetic clusters from linkage to new infections based on genetic distance.


Asunto(s)
Infecciones por VIH , Enfermedades de Transmisión Sexual , Humanos , Etnicidad , Hispánicos o Latinos , Modelos Estadísticos
3.
Transpl Infect Dis ; 25(6): e14167, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37922371

RESUMEN

BACKGROUND: Post-acute sequelae of coronavirus disease 2019 (COVID-19) (PASC), defined as prolonged symptoms following an episode of COVID-19, is not well-characterized in solid organ transplant recipients (SOTR). In this study, we aimed to assess the prevalence of PASC in SOTR, its descriptive characteristics, and associated risk factors. METHODS: We retrospectively identified SOTRs with acute COVID-19 between June 1, 2020 and April 15, 2022, and abstracted demographic and medical history, characteristics of acute COVID-19 illness, and COVID-19 vaccination status. We defined PASC as ongoing/new symptoms present at 6 weeks or longer following acute COVID-19 diagnosis. RESULTS: Among 208 SOTRs with acute COVID-19, 72 (35%) developed PASC. Common symptoms were respiratory symptoms (67%), headache (40%), and difficulty concentrating (10%). Severe acute COVID-19 disease and presence of respiratory symptoms were associated with higher odds of PASC in multivariable analyses, while receipt of at least one COVID-19 vaccination prior to transplantation was protective. CONCLUSION: We found that PASC occurs in about a third of SOTRs with acute COVID-19 and has similar symptoms as described previously in immunocompetent hosts. Pre-transplant vaccination may be protective. Further prospective multicenter studies are needed.


Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , Trasplante de Órganos , Receptores de Trasplantes , Humanos , COVID-19/epidemiología , Prueba de COVID-19 , Vacunas contra la COVID-19/administración & dosificación , Progresión de la Enfermedad , Síndrome Post Agudo de COVID-19/epidemiología , Estudios Retrospectivos
4.
N Engl J Med ; 381(3): 230-242, 2019 07 18.
Artículo en Inglés | MEDLINE | ID: mdl-31314967

RESUMEN

BACKGROUND: The feasibility of reducing the population-level incidence of human immunodeficiency virus (HIV) infection by increasing community coverage of antiretroviral therapy (ART) and male circumcision is unknown. METHODS: We conducted a pair-matched, community-randomized trial in 30 rural or periurban communities in Botswana from 2013 to 2018. Participants in 15 villages in the intervention group received HIV testing and counseling, linkage to care, ART (started at a higher CD4 count than in standard care), and increased access to male circumcision services. The standard-care group also consisted of 15 villages. Universal ART became available in both groups in mid-2016. We enrolled a random sample of participants from approximately 20% of households in each community and measured the incidence of HIV infection through testing performed approximately once per year. The prespecified primary analysis was a permutation test of HIV incidence ratios. Pair-stratified Cox models were used to calculate 95% confidence intervals. RESULTS: Of 12,610 enrollees (81% of eligible household members), 29% were HIV-positive. Of the 8974 HIV-negative persons (4487 per group), 95% were retested for HIV infection over a median of 29 months. A total of 57 participants in the intervention group and 90 participants in the standard-care group acquired HIV infection (annualized HIV incidence, 0.59% and 0.92%, respectively). The unadjusted HIV incidence ratio in the intervention group as compared with the standard-care group was 0.69 (P = 0.09) by permutation test (95% confidence interval [CI], 0.46 to 0.90 by pair-stratified Cox model). An end-of-trial survey in six communities (three per group) showed a significantly greater increase in the percentage of HIV-positive participants with an HIV-1 RNA level of 400 copies per milliliter or less in the intervention group (18 percentage points, from 70% to 88%) than in the standard-care group (8 percentage points, from 75% to 83%) (relative risk, 1.12; 95% CI, 1.09 to 1.16). The percentage of men who underwent circumcision increased by 10 percentage points in the intervention group and 2 percentage points in the standard-care group (relative risk, 1.26; 95% CI, 1.17 to 1.35). CONCLUSIONS: Expanded HIV testing, linkage to care, and ART coverage were associated with increased population viral suppression. (Funded by the President's Emergency Plan for AIDS Relief and others; Ya Tsie ClinicalTrials.gov number, NCT01965470.).


Asunto(s)
Antirretrovirales/uso terapéutico , Circuncisión Masculina , Infecciones por VIH/diagnóstico , Infecciones por VIH/tratamiento farmacológico , Tamizaje Masivo , Adolescente , Adulto , Botswana/epidemiología , Circuncisión Masculina/estadística & datos numéricos , Femenino , Infecciones por VIH/epidemiología , Infecciones por VIH/prevención & control , Humanos , Incidencia , Masculino , Administración Masiva de Medicamentos , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Población Rural , Factores Socioeconómicos , Carga Viral , Adulto Joven
5.
Clin Trials ; 19(4): 363-374, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35894099

RESUMEN

Network science methods can be useful in design, monitoring, and analysis of randomized trials for control of spread of infections. Their usefulness arises from the role of statistical network models in molecular epidemiology and in study design. Computational models, such as agent-based models that propagate disease on simulated contact networks, can be used to investigate the properties of different study designs and analysis plans. Particularly valuable is the use of these methods to assess how magnitude and detectability of intervention effects depend on both individual-level and network-level characteristics of the enrolled populations. Such investigation also provides an important approach to assessing consequences of study data being incomplete or measured with error. To address these goals, we consider two statistical network models: exponential random graph models and the more flexible congruence class models. We focus first on an historical use of these methods in design and monitoring of a cluster randomized trial in Botswana to evaluate the effect of combination HIV prevention modalities compared to standard of care on HIV incidence. We then present a framework for the design of a study of booster vaccine effects on infection with, and forward transmission of, SARS-CoV-2 variants. Motivation for the study is driven in part by guidance from the United Kingdom to base approval of booster vaccines with "strain changes" that target variants on results of neutralizing antibody tests and information about safety, but without requiring evidence of clinical efficacy. Using designs informed by our agent-based network models, we show it may be feasible to conduct a trial of novel SARS-CoV-2 vaccines in a single large campus to obtain useful information regarding vaccine efficacy against susceptibility and infectiousness. If needed, the sample size could be increased by extending the study to a small number of campuses. Novel network methods may be useful in developing pragmatic SARS-CoV-2 vaccine trials that can leverage existing infrastructure to reduce costs and hasten the development of results.


Asunto(s)
COVID-19 , Infecciones por VIH , COVID-19/epidemiología , COVID-19/prevención & control , Vacunas contra la COVID-19/uso terapéutico , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , SARS-CoV-2 , Vacunación
6.
Clin Infect Dis ; 73(5): 842-849, 2021 09 07.
Artículo en Inglés | MEDLINE | ID: mdl-34492694

RESUMEN

BACKGROUND: Ending the human immunodeficiency virus (HIV) epidemic requires knowledge of key drivers of spread of HIV infection. METHODS: Between 1996 and 2018, 1119 newly and previously diagnosed, therapy-naive persons with HIV (PWH) from San Diego were followed. A genetic distance-based network was inferred using pol sequences, and genetic clusters grew over time through linkage of sequences from newly observed infections. Cox proportional hazards models were used to identify factors associated with the rate of growth. These results were used to predict the impact of a hypothetical intervention targeting PWH with incident infection. Comparison was made to the Centers for Disease Control and Prevention (CDC) Ending the HIV Epidemic (EHE) molecular surveillance strategy, which prioritizes clusters recently linked to all new HIV diagnoses and does not incorporate data on incident infections. RESULTS: Overall, 219 genetic linkages to incident infections were identified over a median follow-up of 8.8 years. Incident cluster growth was strongly associated with proportion of PWH in the cluster who themselves had incident infection (hazard ratio, 44.09 [95% confidence interval, 17.09-113.78]). The CDC EHE molecular surveillance strategy identified 11 linkages to incident infections a genetic distance threshold of 0.5%, and 24 linkages at 1.5%. CONCLUSIONS: Over the past 2 decades, incident infections drove incident HIV cluster growth in San Diego. The current CDC EHE molecular detection and response strategy would not have identified most transmission events arising from those with incident infection in San Diego. Molecular surveillance that includes detection of incident cases will provide a more effective strategy for EHE.


Asunto(s)
Epidemias , Infecciones por VIH , VIH-1 , Infecciones por VIH/diagnóstico , Infecciones por VIH/epidemiología , VIH-1/genética , Humanos
7.
Artículo en Inglés | MEDLINE | ID: mdl-33085643

RESUMEN

Genetic sequence data of pathogens are increasingly used to investigate transmission dynamics in both endemic diseases and disease outbreaks. Such research can aid in the development of appropriate interventions and in the design of studies to evaluate them. Several computational methods have been proposed to infer transmission chains from sequence data; however, existing methods do not generally reliably reconstruct transmission trees because genetic sequence data or inferred phylogenetic trees from such data contain insufficient information for accurate estimation of transmission chains. Here, we show by simulation studies that incorporating infection times, even when they are uncertain, can greatly improve the accuracy of reconstruction of transmission trees. To achieve this improvement, we propose a Bayesian inference methods using Markov chain Monte Carlo that directly draws samples from the space of transmission trees under the assumption of complete sampling of the outbreak. The likelihood of each transmission tree is computed by a phylogenetic model by treating its internal nodes as transmission events. By a simulation study, we demonstrate that accuracy of the reconstructed transmission trees depends mainly on the amount of information available on times of infection; we show superiority of the proposed method to two alternative approaches when infection times are known up to specified degrees of certainty. In addition, we illustrate the use of a multiple imputation framework to study features of epidemic dynamics, such as the relationship between characteristics of nodes and average number of outbound edges or inbound edges, signifying possible transmission events from and to nodes. We apply the proposed method to a transmission cluster in San Diego and to a dataset from the 2014 Sierra Leone Ebola virus outbreak and investigate the impact of biological, behavioral, and demographic factors.

8.
J Infect Dis ; 222(10): 1670-1680, 2020 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-32492145

RESUMEN

BACKGROUND: Phylogenetic mapping of HIV-1 lineages circulating across defined geographical locations is promising for better understanding HIV transmission networks to design optimal prevention interventions. METHODS: We obtained near full-length HIV-1 genome sequences from people living with HIV (PLWH), including participants on antiretroviral treatment in the Botswana Combination Prevention Project, conducted in 30 Botswana communities in 2013-2018. Phylogenetic relationships among viral sequences were estimated by maximum likelihood. RESULTS: We obtained 6078 near full-length HIV-1C genome sequences from 6075 PLWH. We identified 984 phylogenetically distinct HIV-1 lineages (molecular HIV clusters) circulating in Botswana by mid-2018, with 2-27 members per cluster. Of these, dyads accounted for 62%, approximately 32% (n = 316) were found in single communities, and 68% (n = 668) were spread across multiple communities. Men in clusters were approximately 3 years older than women (median age 42 years, vs 39 years; P < .0001). In 65% of clusters, men were older than women, while in 35% of clusters women were older than men. The majority of identified viral lineages were spread across multiple communities. CONCLUSIONS: A large number of circulating phylogenetically distinct HIV-1C lineages (molecular HIV clusters) suggests highly diversified HIV transmission networks across Botswana communities by 2018.


Asunto(s)
Infecciones por VIH/prevención & control , Infecciones por VIH/transmisión , Infecciones por VIH/virología , VIH-1/genética , Adolescente , Adulto , Antirreumáticos/uso terapéutico , Botswana , Pruebas Diagnósticas de Rutina , Femenino , Genoma Viral , Genotipo , Infecciones por VIH/tratamiento farmacológico , VIH-1/clasificación , Humanos , Masculino , Persona de Mediana Edad , Filogenia , Proyectos de Investigación , Alineación de Secuencia , Adulto Joven
9.
Stat Med ; 39(15): 2051-2066, 2020 07 10.
Artículo en Inglés | MEDLINE | ID: mdl-32293756

RESUMEN

Characterization of HIV viral rebound after the discontinuation of antiretroviral therapy is central to HIV cure research. We propose a parametric nonlinear mixed effects model for the viral rebound trajectory, which often has a rapid rise to a peak value followed by a decrease to a viral load set point. We choose a flexible functional form that captures the shapes of viral rebound trajectories and can also provide biological insights regarding the rebound process. Each parameter can incorporate a random effect to allow for variation in parameters across individuals. Key features of viral rebound trajectories such as viral set points are represented by the parameters in the model, which facilitates assessment of intervention effects and identification of important pretreatment interruption predictors for these features. We employ a stochastic expectation-maximization (StEM) algorithm to incorporate HIV-1 RNA values that are below the lower limit of assay quantification. We evaluate the performance of our model in simulation studies and apply the proposed model to longitudinal HIV-1 viral load data from five AIDS Clinical Trials Group treatment interruption studies.


Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Algoritmos , Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Humanos , Dinámicas no Lineales , ARN Viral , Carga Viral
10.
Stat Med ; 39(24): 3255-3271, 2020 10 30.
Artículo en Inglés | MEDLINE | ID: mdl-32875624

RESUMEN

Development of methods to accurately estimate human immunodeficiency virus (HIV) incidence rate remains a challenge. Ideally, one would follow a random sample of HIV-negative individuals under a longitudinal study design and identify incident cases as they arise. Such designs can be prohibitively resource intensive and therefore alternative designs may be preferable. We propose such a simple, less resource-intensive study design and develop a weighted log likelihood approach which simultaneously accounts for selection bias and outcome misclassification error. The design is based on a cross-sectional survey which queries individuals' time since last HIV-negative test, validates their test results with formal documentation whenever possible, and tests all persons who do not have documentation of being HIV-positive. To gain efficiency, we update the weighted log likelihood function with potentially misclassified self-reports from individuals who could not produce documentation of a prior HIV-negative test and investigate large sample properties of validated sub-sample only versus pooled sample estimators through extensive Monte Carlo simulations. We illustrate our method by estimating incidence rate for individuals who tested HIV-negative within 1.5 and 5 years prior to Botswana Combination Prevention Project enrolment. This article establishes that accurate estimates of HIV incidence rate can be obtained from individuals' history of testing in a cross-sectional cohort study design by appropriately accounting for selection bias and misclassification error. Moreover, this approach is notably less resource-intensive compared to longitudinal and laboratory-based methods.


Asunto(s)
Infecciones por VIH , Botswana , Estudios de Cohortes , Estudios Transversales , VIH , Infecciones por VIH/diagnóstico , Infecciones por VIH/epidemiología , Humanos , Incidencia , Funciones de Verosimilitud , Estudios Longitudinales
11.
BMC Med ; 15(1): 223, 2017 12 29.
Artículo en Inglés | MEDLINE | ID: mdl-29287587

RESUMEN

BACKGROUND: Interventions in infectious diseases can have both direct effects on individuals who receive the intervention as well as indirect effects in the population. In addition, intervention combinations can have complex interactions at the population level, which are often difficult to adequately assess with standard study designs and analytical methods. DISCUSSION: Herein, we urge the adoption of a new paradigm for the design and interpretation of intervention trials in infectious diseases, particularly with regard to emerging infectious diseases, one that more accurately reflects the dynamics of the transmission process. In an increasingly complex world, simulations can explicitly represent transmission dynamics, which are critical for proper trial design and interpretation. Certain ethical aspects of a trial can also be quantified using simulations. Further, after a trial has been conducted, simulations can be used to explore the possible explanations for the observed effects. CONCLUSION: Much is to be gained through a multidisciplinary approach that builds collaborations among experts in infectious disease dynamics, epidemiology, statistical science, economics, simulation methods, and the conduct of clinical trials.


Asunto(s)
Ensayos Clínicos como Asunto , Enfermedades Transmisibles/terapia , Simulación por Computador , Proyectos de Investigación , Ensayos Clínicos como Asunto/ética , Humanos
12.
Clin Trials ; 14(2): 201-210, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-28124579

RESUMEN

BACKGROUND: Several cluster-randomized trials are underway to investigate the implementation and effectiveness of a universal test-and-treat strategy on the HIV epidemic in sub-Saharan Africa. We consider nesting studies of pre-exposure prophylaxis within these trials. Pre-exposure prophylaxis is a general strategy where high-risk HIV- persons take antiretrovirals daily to reduce their risk of infection from exposure to HIV. We address how to target pre-exposure prophylaxis to high-risk groups and how to maximize power to detect the individual and combined effects of universal test-and-treat and pre-exposure prophylaxis strategies. METHODS: We simulated 1000 trials, each consisting of 32 villages with 200 individuals per village. At baseline, we randomized the universal test-and-treat strategy. Then, after 3 years of follow-up, we considered four strategies for targeting pre-exposure prophylaxis: (1) all HIV- individuals who self-identify as high risk, (2) all HIV- individuals who are identified by their HIV+ partner (serodiscordant couples), (3) highly connected HIV- individuals, and (4) the HIV- contacts of a newly diagnosed HIV+ individual (a ring-based strategy). We explored two possible trial designs, and all villages were followed for a total of 7 years. For each village in a trial, we used a stochastic block model to generate bipartite (male-female) networks and simulated an agent-based epidemic process on these networks. We estimated the individual and combined intervention effects with a novel targeted maximum likelihood estimator, which used cross-validation to data-adaptively select from a pre-specified library the candidate estimator that maximized the efficiency of the analysis. RESULTS: The universal test-and-treat strategy reduced the 3-year cumulative HIV incidence by 4.0% on average. The impact of each pre-exposure prophylaxis strategy on the 4-year cumulative HIV incidence varied by the coverage of the universal test-and-treat strategy with lower coverage resulting in a larger impact of pre-exposure prophylaxis. Offering pre-exposure prophylaxis to serodiscordant couples resulted in the largest reductions in HIV incidence (2% reduction), and the ring-based strategy had little impact (0% reduction). The joint effect was larger than either individual effect with reductions in the 7-year incidence ranging from 4.5% to 8.8%. Targeted maximum likelihood estimation, data-adaptively adjusting for baseline covariates, substantially improved power over the unadjusted analysis, while maintaining nominal confidence interval coverage. CONCLUSION: Our simulation study suggests that nesting a pre-exposure prophylaxis study within an ongoing trial can lead to combined intervention effects greater than those of universal test-and-treat alone and can provide information about the efficacy of pre-exposure prophylaxis in the presence of high coverage of treatment for HIV+ persons.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/prevención & control , Profilaxis Pre-Exposición , África del Sur del Sahara , Simulación por Computador , Femenino , Infecciones por VIH/diagnóstico , Infecciones por VIH/tratamiento farmacológico , Humanos , Funciones de Verosimilitud , Masculino , Tamizaje Masivo , Ensayos Clínicos Controlados Aleatorios como Asunto , Proyectos de Investigación , Medición de Riesgo
13.
Am J Epidemiol ; 184(3): 239-48, 2016 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-27416841

RESUMEN

Little is known about how combining efficacious interventions for human immunodeficiency virus (HIV) prevention could lead to HIV elimination. We used an agent-based simulation model, the HIV calibrated dynamic model, to assess the potential for HIV elimination in South Africa. We examined several scenarios (from continuation of the current status quo to perfect achievement of targets) with differing combinations of male condom use, adult male circumcision, HIV testing, and early antiretroviral therapy (ART). We varied numerous parameters, including the proportion of adult males circumcised, the frequency of condom use during sex acts, acceptance of HIV testing, linkage to health care, criteria for ART initiation, ART viral suppression rates, and loss to follow-up. Maintaining current levels of combination prevention would lead to increasing HIV incidence and prevalence in South Africa, while the perfect combination scenario was projected to eliminate HIV on a 50-year time scale from 2013 to 2063. Perfecting testing and treatment, without changing condom use or circumcision rates, resulted in an 89% reduction in HIV incidence but not elimination. Universal adult male circumcision alone resulted in a 21% incidence reduction within 20 years. Substantial decreases in HIV incidence are possible from sufficient uptake of both primary prevention and ART, but with continuation of the status quo, HIV elimination in South Africa is unlikely within a 50-year time scale.


Asunto(s)
Serodiagnóstico del SIDA/normas , Fármacos Anti-VIH/uso terapéutico , Circuncisión Masculina/normas , Condones/estadística & datos numéricos , Erradicación de la Enfermedad/métodos , Infecciones por VIH/prevención & control , Prevención Primaria/métodos , Serodiagnóstico del SIDA/estadística & datos numéricos , Adulto , Fármacos Anti-VIH/normas , Quimioprevención/métodos , Quimioprevención/normas , Circuncisión Masculina/estadística & datos numéricos , Simulación por Computador , Femenino , Infecciones por VIH/diagnóstico , Infecciones por VIH/epidemiología , Infecciones por VIH/transmisión , Heterosexualidad , Humanos , Incidencia , Masculino , Modelos Biológicos , Prevalencia , Prevención Primaria/estadística & datos numéricos , Sudáfrica/epidemiología
14.
Biometrics ; 72(4): 1066-1077, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-27060877

RESUMEN

Semi-parametric methods are often used for the estimation of intervention effects on correlated outcomes in cluster-randomized trials (CRTs). When outcomes are missing at random (MAR), Inverse Probability Weighted (IPW) methods incorporating baseline covariates can be used to deal with informative missingness. Also, augmented generalized estimating equations (AUG) correct for imbalance in baseline covariates but need to be extended for MAR outcomes. However, in the presence of interactions between treatment and baseline covariates, neither method alone produces consistent estimates for the marginal treatment effect if the model for interaction is not correctly specified. We propose an AUG-IPW estimator that weights by the inverse of the probability of being a complete case and allows different outcome models in each intervention arm. This estimator is doubly robust (DR); it gives correct estimates whether the missing data process or the outcome model is correctly specified. We consider the problem of covariate interference which arises when the outcome of an individual may depend on covariates of other individuals. When interfering covariates are not modeled, the DR property prevents bias as long as covariate interference is not present simultaneously for the outcome and the missingness. An R package is developed implementing the proposed method. An extensive simulation study and an application to a CRT of HIV risk reduction-intervention in South Africa illustrate the method.


Asunto(s)
Análisis por Conglomerados , Modelos Estadísticos , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Simulación por Computador , Interpretación Estadística de Datos , Infecciones por VIH , Humanos , Riesgo , Resultado del Tratamiento
15.
J Neurovirol ; 21(5): 525-34, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26002840

RESUMEN

Distal leg epidermal nerve fiber density (ENFD) is a validated predictor of HIV sensory neuropathy (SN) risk. We assessed how ENFD is impacted by initiation of first-time antiretroviral therapy (ART) in subjects free of neuropathy and how it is altered when mitochondrial toxic nucleoside medications are used as part of ART. Serial changes in proximal thigh and distal leg ENFD were examined over 72 weeks in 150 Thai subjects randomized to a regimen of stavudine (d4T) switching to zidovudine (ZDV) at 24 weeks vs ZDV vs tenofovir (TDF) for the entire duration of study, all given in combination with nevirapine. We found individual variations in ENFD change, with almost equal number of subjects who decreased or increased their distal leg ENFD over 72 weeks and no relationship to nucleoside backbone or to development of neuropathic signs or symptoms. Lower baseline distal leg ENFD and greater increases in mitochondrial oxidative phosphorylation complex I (CI) activity were associated with larger increases in distal leg ENFD over 72 weeks. Distal leg ENFD correlated with body composition parameters (body surface area, body mass index, height) as well as with blood pressure measurements. Assessed together with a companion cross-sectional study, we found that mean distal leg ENFD in all HIV+ subjects was lower than in HIV- subjects but similar among HIV+ groups whether ART-naïve or on d4T with/without neuropathy/neuropathic symptoms. The utility of ENFD as a useful predictor of small unmyelinated nerve fiber damage and neuropathy risk in HIV may be limited in certain populations.


Asunto(s)
Antirretrovirales/efectos adversos , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/etiología , Enfermedades del Sistema Nervioso Periférico/patología , Células Receptoras Sensoriales/patología , Adulto , Estudios Transversales , Femenino , Humanos , Pierna , Masculino , Factores de Riesgo , Piel/inervación , Estavudina/efectos adversos , Tenofovir/efectos adversos , Tailandia , Zidovudina/efectos adversos
16.
Stat Med ; 34(28): 3750-9, 2015 Dec 10.
Artículo en Inglés | MEDLINE | ID: mdl-26215657

RESUMEN

Since 1990, the World Health Organization has recommended HIV surveillance among pregnant women as an essential surveillance activity for countries with generalized HIV epidemics. Despite the widespread availability and potential usefulness of antenatal HIV surveillance, analyses of such data present important challenges. Within an individual clinic, the HIV status of its attendees may be correlated because of similarities in HIV risk among women close in age. Between-clinic correlation may also arise as women often seek antenatal care at clinics located close to their home, and individuals living in nearby communities may share important characteristics or behaviours related to susceptibility. A general estimating equation-based approach for spatially-correlated, binary data such as that antenatal HIV surveillance based on a pairwise composite likelihood has been described. We present an extended version of this model that can accommodate penalized spline estimators and apply it to antenatal HIV surveillance data collected in 2011 in Botswana to estimate the effects of proximity to the 'hotspot' of the country's HIV epidemic and age on HIV prevalence. Finally, we compare the results with a logistic regression analysis, which ignores potential correlation of responses.


Asunto(s)
Infecciones por VIH/epidemiología , Infecciones por VIH/prevención & control , Funciones de Verosimilitud , Adolescente , Adulto , Botswana/epidemiología , Femenino , Humanos , Persona de Mediana Edad , Vigilancia de la Población , Embarazo , Atención Prenatal , Prevalencia , Adulto Joven
17.
PLoS Comput Biol ; 9(3): e1002973, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23555210

RESUMEN

We propose a Bayesian approach for estimating branching tree mixture models to compare drug-resistance pathways (i.e. patterns of sequential acquisition of resistance to individual antibiotics) that are observed among Mycobacterium tuberculosis isolates collected from treatment-naïve and treatment-experienced patients. Resistant pathogens collected from treatment-naïve patients are strains for which fitness costs of resistance were not sufficient to prevent transmission, whereas those collected from treatment-experienced patients reflect both transmitted and acquired resistance, the latter of which may or may not be associated with lower transmissibility. The comparison of the resistance pathways constructed from these two groups of drug-resistant strains provides insight into which pathways preferentially lead to the development of multiple drug resistant strains that are transmissible. We apply the proposed statistical methods to data from worldwide surveillance of drug-resistant tuberculosis collected by the World Health Organization over 13 years.


Asunto(s)
Antituberculosos/farmacología , Modelos Biológicos , Mycobacterium tuberculosis/efectos de los fármacos , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Antituberculosos/uso terapéutico , Teorema de Bayes , Biología Computacional , Bases de Datos Factuales , Humanos , Cadenas de Markov , Pruebas de Sensibilidad Microbiana , Tuberculosis Resistente a Múltiples Medicamentos/epidemiología , Tuberculosis Resistente a Múltiples Medicamentos/microbiología , Tuberculosis Resistente a Múltiples Medicamentos/transmisión
18.
J Neurovirol ; 19(2): 137-43, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23483520

RESUMEN

Although HIV-associated dementia (HAD) occurs in less than 5 % of individuals with access to combination antiretroviral therapy, rates of milder forms of HIV-associated neurocognitive disorder (HAND) are much higher. We sought to define an optimal cut point for the International HIV Dementia Scale (IHDS) in Thailand for the identification of symptomatic HAND, defined as both HAD and mild neurocognitive disorder. We then sought to determine if adding a simple test from a larger neuropsychological battery could improve the performance characteristics for identifying symptomatic HAND. In this study, subjects comprising 75 seropositive adults in Bangkok, Thailand, completed neuropsychological tests and underwent a full neurological assessment. HAND diagnoses were determined by consensus conference using the 2007 Frascati criteria, blinded to the IHDS results. The optimal IHDS cut point was determined by receiver operating characteristic analysis with cross-validation. Individual neuropsychological tests were then evaluated and combined with the IHDS to test performance characteristics. The IHDS was poor at detecting symptomatic HAND at the optimized cut point of ≤ 10 (sensitivity, 53.3 %; specificity, 89.8 %). Trail Making Test A was most effective in improving performance characteristics when combined with the IHDS, with net sensitivity of 86 % and specificity of 79 %. In this setting, the IHDS performed poorly in identifying symptomatic HAND, but was substantially improved by the addition of Trail Making Test A, which typically requires less than 2 min to complete. This combination should be validated in a larger setting since it may address the critical need for HAND screening instruments in international settings.


Asunto(s)
Complejo SIDA Demencia/psicología , Disfunción Cognitiva/psicología , Proyectos de Investigación/estadística & datos numéricos , Prueba de Secuencia Alfanumérica/estadística & datos numéricos , Complejo SIDA Demencia/diagnóstico , Complejo SIDA Demencia/virología , Adulto , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/virología , Femenino , Humanos , Masculino , Curva ROC , Índice de Severidad de la Enfermedad , Tailandia
19.
Stat Med ; 32(6): 978-94, 2013 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-22941582

RESUMEN

The development of HIV resistance mutations reduces the efficacy of specific antiretroviral drugs used to treat HIV infection and cross-resistance within classes of drugs is common. Recursive partitioning has been extensively used to identify resistance mutations associated with a reduced virologic response measured at a single time point; here we describe a statistical method that accommodates a large set of genetic or other covariates and a longitudinal response. This recursive partitioning approach for continuous longitudinal data uses the kernel of a U-statistic as the splitting criterion and avoids the need for parametric assumptions regarding the relationship between observed response trajectories and covariates. We propose an extension of this approach that allows longitudinal measurements to be monotone missing at random by making use of inverse probability weights. We assess the performance of our method using extensive simulation studies and apply them to data collected by the Forum for Collaborative HIV Research as part of an investigation of the viral genetic mutations associated with reduced clinical efficacy of the drug abacavir.


Asunto(s)
Biomarcadores/análisis , Interpretación Estadística de Datos , Estudios Longitudinales , Simulación por Computador , Didesoxinucleósidos/uso terapéutico , Farmacorresistencia Viral/genética , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/genética , Infecciones por VIH/virología , VIH-1/crecimiento & desarrollo , Humanos
20.
J Infect Dis ; 205(1): 87-96, 2012 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-22180621

RESUMEN

BACKGROUND: The benefits of antiretroviral therapy during early human immunodeficiency virus type 1 (HIV-1) infection remain unproved. METHODS: A5217 study team randomized patients within 6 months of HIV-1 seroconversion to receive either 36 weeks of antiretrovirals (immediate treatment [IT]) or no treatment (deferred treatment [DT]). Patients were to start or restart antiretroviral therapy if they met predefined criteria. The primary end point was a composite of requiring treatment or retreatment and the log(10) HIV-1 RNA level at week 72 (both groups) and 36 (DT group). RESULTS: At the June 2009 Data Safety Monitoring Board (DSMB) review, 130 of 150 targeted participants had enrolled. Efficacy analysis included 79 individuals randomized ≥72 weeks previously. For the primary end point, the IT group at week 72 had a better outcome than the DT group at week 72 (P = .005) and the DT group at week 36 (P = .002). The differences were primarily due to the higher rate of progression to needing treatment in the DT group (50%) versus the IT (10%) group. The DSMB recommended stopping the study because further follow-up was unlikely to change these findings. CONCLUSIONS: Progression to meeting criteria for antiretroviral initiation in the DT group occurred more frequently than anticipated, limiting the ability to evaluate virologic set point. Antiretrovirals during early HIV-1 infection modestly delayed the need for subsequent treatment. CLINICAL TRIALS REGISTRATION: NCT00090779.


Asunto(s)
Adenina/análogos & derivados , Fármacos Anti-VIH/uso terapéutico , Desoxicitidina/análogos & derivados , Infecciones por VIH/tratamiento farmacológico , VIH-1/aislamiento & purificación , Lopinavir/uso terapéutico , Organofosfonatos/uso terapéutico , Ritonavir/uso terapéutico , Carga Viral , Adenina/uso terapéutico , Adulto , Desoxicitidina/uso terapéutico , Progresión de la Enfermedad , Esquema de Medicación , Combinación de Medicamentos , Quimioterapia Combinada , Emtricitabina , Femenino , Infecciones por VIH/sangre , Infecciones por VIH/virología , VIH-1/genética , Humanos , Masculino , ARN Viral/sangre , Tenofovir , Resultado del Tratamiento
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