Estimation of random effects and identifying heterogeneous genes in meta-analysis of gene expression studies.

Combining effect sizes from individual studies using random-effects meta-analysis models are commonly applied in high-dimensional gene expression data. However, unknown study heterogeneity can arise from inconsistencies in sample quality and experimental conditions. High heterogeneity of effect sizes can reduce statistical power of the models. In this study, we describe three hypothesis-testing frameworks for meta-analysis of microarray data, and review several existing meta-analytic techniques that have been used in the genomic setting. These include P-value-based methods, rank-based methods and effect-size-based methods. We then discuss limitations of some of these methods and describe random-effects-based methods in detail. We introduce two methods for estimating the inter-study variance in random-effects meta-analytic models and another method for identifying heterogeneous genes for gene expression data. We compared various methods with the standard and existing meta-analytic techniques in the genomic framework. We demonstrate our results through a series of simulations and application in Alzheimer's gene expression data.

Patient Comorbidity and Serious Adverse Events after Outpatient Colonoscopy: Population-based Study From Three States, 2006 to 2009.

BACKGROUND AND OBJECTIVE: Serious GI adverse events in the outpatient setting were examined for patients with a full spectrum of comorbid conditions and combinations of multiple comorbidities. DESIGN: This is a retrospective follow-up study. SETTING: Ambulatory surgery and hospital discharge data sets from California, Florida, and New York, 2006 to 2009, were used. PATIENTS: The outpatient colonoscopies of 4,234,084 adults aged 19 to 85 and over and payers were examined. MAIN OUTCOME: Thirty-day hospitalizations due to colonic perforations and GI bleeding, measured as cumulative outcomes, were investigated. RESULTS: About 24% of patients undergoing outpatient colonoscopy had a comorbid condition. In comparison with patients without comorbidities, the adjusted risks of adverse events were greater for patients with several single comorbidities and combinations of multiple comorbid conditions. Elderly patients and those treated in freestanding Ambulatory Surgery Centers had higher odds of colonic perforations and GI bleeding than younger patients and patients treated in hospital outpatient departments. LIMITATION: The study was constrained by limitations inherent in administrative data. CONCLUSIONS: Given the large number of outpatient colonoscopies performed in the United States, these procedures should be provided with caution to patients with chronic and multiple comorbidities and the elderly, because these populations are associated with higher rates of colonic perforations and GI bleeding.

Comparison of Low Back Pain Recovery and Persistence: A Descriptive Study of Characteristics at Pain Onset.

BACKGROUND: Persistent low back pain is a significant problem worldwide. Early identification and treatment of individuals at high risk for persistent low back pain have been suggested as strategies to decrease the rate of disability associated with this condition. PURPOSE: To examine and compare demographic, pain-related, psychological, and somatosensory characteristics in a cohort of participants with acute low back pain who later went on to experience persistent low back pain or whose pain resolved within the first 6 weeks after initial onset. METHODS: A descriptive study was conducted among men and women 18-50 years of age who had an acute episode of low back pain. Study questionnaires were administered to collect demographic information and measures of pain, coping, reactivity, mood, work history and satisfaction, and disability. A standardized protocol of quantitative sensory testing was performed on each participant at the painful area of their low back and at a remote site on their arm. RESULTS: The sample consisted of 48 participants, of whom 19 went on to develop persistent low back pain and 29 resolved. Compared to the resolved group, the persistent low back pain group was significantly older and had a lower level of educational attainment, a higher body mass index, and higher mean "least" pain score on the Brief Pain Inventory-Short Form. Significantly higher thermal detection thresholds at the painful and remote sites as well as signs of central sensitivity differentiated the persistent pain group from the resolved group during the acute stage of low back pain.

Acute Low Back Pain: Differential Somatosensory Function and Gene Expression Compared With Healthy No-Pain Controls.

OBJECTIVES: Low back pain (LBP) is the second most frequently diagnosed pain condition in the United States, and although a majority of individuals have resolution of pain during the acute period, an estimated 40% of individuals will experience persistent pain. Given the heterogenous nature of LBP, this study sought to describe and compare somatosensory and molecular (gene expression) profiles between individuals with acute LBP and healthy no-pain controls. METHODS: Using a previously established protocol, we comprehensively assessed somatosensory parameters among 31 no-pain control participants and 31 participants with acute LBP. Samples of whole blood were drawn to examine mRNA expression of candidate genes involved in the transduction, maintenance, and modulation of pain. RESULTS: The acute LBP group exhibited increased pain sensitivity to cold stimuli, mechanical stimuli, including mechanical temporal summation at both the painful back area and remote location suggesting a mechanism of enhanced central nervous system excitability. In addition, deep tissue-specific peripheral sensitization was suggested due to significant differences in pressure pain threshold of the painful back area, but not the remote body site. Several genes that were differentially expressed were significantly associated with somatosensory alterations identified in the acute LBP group. DISCUSSION: Acute LBP participants showed selective pain sensitivity enhancement and differential gene expression profiles compared with pain-free controls. Further research to characterize pain-associated somatosensory changes in the context of altered mRNA expression levels may provide insight on the molecular underpinnings of maladaptive chronic pain.

Gene Expression in HIV-Associated Neurocognitive Disorders: A Meta-Analysis.

OBJECTIVES: To identify differentially expressed (DE) genes in HIV-associated neurocognitive disorders (HAND) patients in comparison with HIV-infected patients without HAND and controls. DESIGN: A meta-analysis of publicly available gene expression data from HIV postmortem brain tissue studies. METHODS: We selected studies using clearly defined inclusion and exclusion criteria. Within study data preprocessing and individual analyses were performed for each brain region. The following meta-analytic methods were applied: combining P values, combining effect sizes with and without a permutation method. The DE genes were defined with a false discovery rate less than 5% using Benjamini-Hochberg method. RESULTS: Our meta-analysis on 3 studies encompasses analyses of over 48 postmortem brains [25 HAND, 7 HIV encephalitis (HIVE), 8 HIV-infected patients, and 8 controls]. Overall, 411 genes in white matter were DE in HAND with HIVE patients when comparing with controls. Of these, 94 genes were significantly expressed in all statistical methods. These 94 genes participate in significant pathways such as immune system, interferon response, or antigen presentation. Sixty-six of the 94 genes were significantly upregulated with log2 intensities greater than 2-fold. Strong examples of the highly upregulated genes were PSMB8-AS1, APOL6, TRIM69, PSME1, CTSB, HLA-E, GPNMB, UBE2L6, PSME2, NET1, CAPG, B2M, RPL38, GBP1, and PLSCR1. Only BTN3A2 was expressed in HAND with HIVE patients as compared with HAND patients without HIVE. CONCLUSION: A number of genes were DE in our meta-analysis that were not identified in the individual analyses. The meta-analytic approach has increased statistical power for identifying DE genes in HAND.

Evaluation of the performance of smoothing functions in generalized additive models for spatial variation in disease.

Generalized additive models (GAMs) with bivariate smoothing functions have been applied to estimate spatial variation in risk for many types of cancers. Only a handful of studies have evaluated the performance of smoothing functions applied in GAMs with regard to different geographical areas of elevated risk and different risk levels. This study evaluates the ability of different smoothing functions to detect overall spatial variation of risk and elevated risk in diverse geographical areas at various risk levels using a simulation study. We created five scenarios with different true risk area shapes (circle, triangle, linear) in a square study region. We applied four different smoothing functions in the GAMs, including two types of thin plate regression splines (TPRS) and two versions of locally weighted scatterplot smoothing (loess). We tested the null hypothesis of constant risk and detected areas of elevated risk using analysis of deviance with permutation methods and assessed the performance of the smoothing methods based on the spatial detection rate, sensitivity, accuracy, precision, power, and false-positive rate. The results showed that all methods had a higher sensitivity and a consistently moderate-to-high accuracy rate when the true disease risk was higher. The models generally performed better in detecting elevated risk areas than detecting overall spatial variation. One of the loess methods had the highest precision in detecting overall spatial variation across scenarios and outperformed the other methods in detecting a linear elevated risk area. The TPRS methods outperformed loess in detecting elevated risk in two circular areas.

Delivery system characteristics and their association with quality and costs of care: implications for accountable care organizations.

BACKGROUND: Implementation of accountable care organizations (ACOs) is currently underway, but there is limited empirical evidence on the merits of the ACO model. PURPOSE: The aim was to study the associations between delivery system characteristics and ACO competencies, including centralization strategies to manage organizations, hospital integration with physicians and outpatient facilities, health information technology, infrastructure to monitor community health and report quality, and risk-adjusted 30-day all-cause mortality and case-mixed-adjusted inpatient costs for the Medicare population. METHODOLOGY: Panel data (2006-2009) were assembled from Florida and multiple sources: inpatient hospital discharge, vital statistics, the American Hospital Association, the Healthcare Information and Management Systems Society, and other databases. We applied a panel study design, controlling for hospital and market characteristics. PRINCIPAL FINDINGS: Hospitals that were in centralized health systems or became more centralized over the study period had significantly larger reductions in mortality compared with hospitals that remained freestanding. Surprisingly, tightly integrated hospital-physician arrangements were associated with increased mortality; as such, hospitals may wish to proceed cautiously when developing specific types of alignment with local physician organizations. We observed no statistically significant differences in the growth rate of costs across hospitals in any of the health systems studied relative to freestanding hospitals. Although we observed quality improvement in some organizational types, these outcome improvements were not coupled with the additional desired objective of lower cost growth. This implies that additional changes not present during our study period, potentially changes in provider payment approaches, are essential for achieving the ACO objectives of higher quality of care at lower costs. PRACTICE IMPLICATIONS: Provider organizations implementing ACOs should consider centralizing service delivery as a viable strategy to improve quality of care, although the strategy did not result in lower cost growth.

Polypectomy techniques, endoscopist characteristics, and serious gastrointestinal adverse events.

BACKGROUND: A use of polypectomy techniques by endoscopist specialty (primary care, surgery, and gastroenterology) and experience (volume), and associations with serious gastrointestinal adverse events, were examined. METHODS: A retrospective follow-up study with ambulatory surgery and hospital discharge datasets from Florida, 1999-2001, was used. Thirty-day hospitalizations due to colonic perforations and gastrointestinal bleeding were investigated for 323,585 patients. RESULTS: Primary care endoscopists and surgeons used hot biopsy forceps/ablation, while gastroenterologists provided snare polypectomy or complex colonoscopy. Low-volume endoscopists were more likely to use simpler rather than complex procedures. For hot forceps/ablation and snare polypectomy, low- and medium-volume endoscopists reported higher odds of adverse events. For complex colonoscopy, higher odds of adverse events were reported for primary care endoscopists (1.74 [95% CI, 1.18-2.56]) relative to gastroenterologists. CONCLUSIONS: Endoscopists regardless of specialty and experience can safely use cold biopsy forceps. For hot biopsy and snare polypectomy, low volume, but not specialty, contributed to increased odds of adverse events. For complex colonoscopy, primary care specialty, but not low volume, added to the odds of adverse events. Comparable outcomes were reported for surgeons and gastroenterologists. Cross-training and continuing medical education of primary care endoscopists in high-volume endoscopy settings are recommended for complex colonoscopy procedures.

Association of polypectomy techniques, endoscopist volume, and facility type with colonoscopy complications.

BACKGROUND AND OBJECTIVE: Serious GI adverse events in the outpatient setting were examined by polypectomy technique, endoscopist volume, and facility type (ambulatory surgery center and hospital outpatient department). DESIGN: Retrospective follow-up study. SETTING: Ambulatory surgery and hospital discharge datasets from Florida (1997-2004) were used. PATIENTS: A total of 2,315,126 outpatient colonoscopies performed in patients of all ages and payers were examined. MAIN OUTCOME: Thirty-day hospitalizations because of colonic perforations and GI bleeding, measured as cumulative and specific outcomes, were investigated. RESULTS: Compared with simple colonoscopy, the adjusted risks of cumulative adverse events were greater with the use of cold forceps (1.21 [95% CI, 1.01-1.44]), ablation (3.75 [95% CI, 2.97-4.72]), hot forceps (5.63 [95% CI, 4.97-6.39]), snares (7.75 [95% CI, 6.95-8.64]), or complex colonoscopy (8.83 [95% CI, 7.70-10.12]). Low-volume endoscopists had higher risks of adverse events (1.18 [95% CI, 1.07-1.30]). A higher risk of adverse events was associated with procedures performed in ambulatory surgery centers (1.27 [95% CI, 1.16-1.40]). Important findings were also reported for the analyses stratified by specific outcomes and procedures. LIMITATION: The study was constrained by limitations inherent in administrative data pertaining to a single state. CONCLUSIONS: As the complexity of polypectomy increases, a higher risk of adverse events is reported. Using lower risk procedures when clinically appropriate or referring patients to high-volume endoscopists can reduce the rates of perforations and GI bleeding. Given the large number of colonoscopies performed in the United States, it is critical that the rates of adverse events be considered when choosing procedures.

Development of normative neuropsychological performance in Thailand for the assessment of HIV-associated neurocognitive disorders.

International studies of HIV-associated neurocognitive disorder (HAND) are needed to determine the viral and host factors associated with cognitive impairment particularly as more than 80% of HIV+ subjects reside in resource-limited settings. Recent diagnostic nomenclature of HAND requires comparison of cognitive performance specifically to local normative data. To evaluate this need for local norms, we compared normative data obtained locally in Thailand to Western norms. The current study examined cognitive performance in 477 seronegative Thai participants (male = 211, female = 266) who completed a battery of tests sensitive to cognitive changes in HIV. The cohort was divided into three age brackets (20-34; 35-49; 50-65 years) and four educational levels (no education or primary education, less than secondary certificate, high-school/associates degree, bachelor's degree or greater). The Thai cohort was compared (using analysis of covariance, ANCOVA) on a number of measures to a seronegative US cohort (n = 236; male = 198, female = 38) to examine cultural differences in performance. Normative data are provided with age and education stratification. The Thai and US groups performed significantly differently on all neuropsychological measures with the exception of verbal fluency. The Thai group performed better on measures of verbal learning (p < .001) and memory (p < .001) and measures of psychomotor speed (p < .001). Education was a more powerful predictor of performance in the Thai cohort than in the US group. These results highlight the continued need for the development of normative data within local populations. The use of Western norms as a comparison group could lead to inaccurate identification of HAND in culturally distinct groups.

High virologic response rate after second-line boosted protease inhibitor-based antiretroviral therapy regimens in children from a resource limited setting.

BACKGROUND: Limited data exist for the efficacy of second-line antiretroviral therapy among children in resource limited settings. We assessed the virologic response to protease inhibitor-based ART after failing first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens. METHODS: A retrospective chart review was conducted at 8 Thai sites of children who switched to PI -based regimens due to failure of NNRTI -based regimens. Primary endpoints were HIV RNA < 400 copies/ml and CD4 change over 48 weeks. RESULTS: Data from 241 children with median baseline values before starting PI-based regimens of 9.1 years for age, 10% for CD4%, and 4.8 log10 copies/ml for HIV RNA were included; 104 (41%) received a single ritonavir-boosted PI (sbPI) with 2 NRTIs and 137 (59%) received double-boosted PI (dbPI) with/without NRTIs based on physician discretion. SbPI children had higher baseline CD4 (17% vs. 6%, p < 0.001), lower HIV RNA (4.5 vs. 4.9 log10 copies/ml, p < 0.001), and less frequent high grade multi-NRTI resistance (12.4% vs 60.5%, p < 0.001) than the dbPI children. At week 48, 81% had HIV RNA < 400 copies/ml (sbPI 83.1% vs. dbPI 79.8%, p = 0.61) with a median CD4 rise of 9% (+7%vs. + 10%, p < 0.005). However, only 63% had HIV RNA < 50 copies/ml, with better viral suppression seen in sbPI (76.6% vs. 51.4%, p 0.002). CONCLUSION: Second-line PI therapy was effective for children failing first line NNRTI in a resource-limited setting. DbPI were used in patients with extensive drug resistance due to limited treatment options. Better access to antiretroviral drugs is needed.

HIV risk behavior among HIV-infected men who have sex with men in Bangkok, Thailand.

We assessed prevalence of sexually transmitted infection (STIs), sexual risk behaviors, and factors associated with risk behaviors among HIV-infected MSM attending a public STI clinic serving MSM in Bangkok, Thailand. Between October 2005-October 2007, 154 HIV-infected MSM attending the clinic were interviewed about sexual risk behaviors and evaluated for STIs. Patients were examined for genital ulcers and had serologic testing for syphilis and PCR testing for chlamydia and gonorrhea. Results showed that sexual intercourse in the last 3 months was reported by 131 men. Of these, 32% reported anal sex without a condom. STIs were diagnosed in 41%. Factors associated with having sex without a condom were having a steady male partner, having a female partner and awareness of HIV status <1 month. Sexual risk behaviors and STIs were common among HIV-infected MSM in this study. This highlights the need for increased HIV prevention strategies for HIV-infected MSM.

National program scale-up and patient outcomes in a pediatric antiretroviral treatment program, Thailand, 2000-2007.

BACKGROUND: There are limited reports of public sector scale-up of antiretroviral treatment (ART) for HIV-infected children. We describe patient outcomes for HIV-infected children initiating ART in Thailand from 2000 to 2005. METHODS: ART-naive patients <15 years old initiating ART from January 2000 to December 2005 were included; follow-up was through March 2007. Survival probabilities were estimated with Kaplan-Meier and hazard ratios for death and loss to follow-up (LTFU) with Cox proportional hazards models. RESULTS: Analysis included 3409 children. Median follow-up time was 1.7 years (interquartile range = 1.0-2.5). Median age at ART initiation was 7.3 years, weight-for-age z score was -2.0, CD4% was 5.0%. ART was initiated in 1428 (41.9%) children at regional/university hospitals and in 689 (20.2%) at district/community hospitals. At last visit, 346 (10.1%) were LTFU and 305 (9.0%) had died. Age <1 (P = 0.008), weight-for-age z score <-2.0 (P < 0.001), CD4% <5% (P < 0.001), and clinical stage C (P < 0.001) were associated with death; district/community hospital patients had a lower hazard of death (P = 0.011). Clinical stage C (P = 0.052) and regional/university hospital (P < 0.001) were associated with increased LTFU. CONCLUSIONS: Pediatric ART has been successfully scaled-up in Thailand, including to district/community hospitals. Late entry to care is associated with poorer outcomes, and earlier ART initiation should be prioritized.

Neurocognitive impairment and psychiatric comorbidity in well-controlled human immunodeficiency virus-infected Thais from the 2NN Cohort Study.

This research is a cross-sectional study to determine the frequency of neurocognitive impairment and psychiatric comorbidity among Thais maintained on highly active antiretroviral therapy (HAART) with undetectable plasma human immunodeficiency virus (HIV) RNA in the 2NN Cohort. Sixty-four subjects were evaluated with neurological examinations, neuropsychological testing, and psychiatric questionnaires. Twenty-four subjects (37.5%) were found to have neurocognitive impairment, with 13 (20.3%), 10 (15.6%), and 1 (1.6%) classified as asymptomatic neurocognitive disorder (ANI), mild neurocognitive disorder (MND), and HIV-associated dementia (HAD), respectively. Three subjects (4.7%) had depression and no cases had significant symptoms of anxiety. A notable proportion of well-controlled individuals exhibited neurocognitive impairment. Anxiety and depression were uncommon.

Immunologic markers as predictors of tuberculosis-associated immune reconstitution inflammatory syndrome in HIV and tuberculosis coinfected persons in Thailand.

This study analyzes immunologic markers to predict and diagnose tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) in HIV and TB coinfected adults who initiated antiretroviral therapy (ART) in Thailand. T helper 1 cytokines interleukin (IL)-2, IL-12, and interferon-gamma (IFN-gamma) levels in response to PPD and RD1 antigens were assessed prior to ART, at weeks 6, 12, and 24 of treatment, and at time of TB-IRIS. Of 126 subjects, 22 (17.5%) developed TB-IRIS; 14 (64%) subjects received steroid treatment and 3 (14%) received NSAIDs; none of the subjects died. Median interval between ART initiation and TB-IRIS development was 14 days. IFN-gamma, IL-2, and IL-12 responses did not differ between TB-IRIS and no TB-IRIS subjects (p > 0.05). More research into the immunopathogenesis of TB-IRIS and diagnostic potential of cytokine markers is warranted.

Clinical case definition and manifestations of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome.

BACKGROUND: The International Network for the Study of HIV-associated IRIS (INSHI) recently published criteria for tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) diagnosis. The performance of this definition and clinical manifestations of TB-IRIS were studied. METHODS: Antiretroviral therapy-naive HIV/TB Thai patients receiving antituberculous therapy were enrolled during 2006-2007 and prospectively followed through 24 weeks of antiretroviral therapy. Patients were defined as having paradoxical TB-IRIS if they fulfilled the 'study definition' by French 2004 and were confirmed by an external reviewer. All were later compared by the classification according to 'INSHI-2008'. RESULTS: For the 126 patients, median baseline CD4 cell count was 43 cells/microl and HIV-1 RNA was 5.9 log(10) Y copies/ml. Seventy-three (58%) had extrapulmonary/disseminated TB. Twenty-two (18%) and 21 (17%) fulfilled TB-IRIS criteria according to the study definition and INSHI-2008 definition, respectively. Two (2%) were diagnosed by study definition only and one (1%) by INSHI-2008 definition only. Twenty (16%) were concordantly diagnosed by both definitions and 103 (82%) were consistently negative. Eighteen (82%) had worsening of a preexisting site, whereas four (18%) had TB-IRIS in a new location. Lymph node enlargement (73%) and fever (59%) were common in TB-IRIS. Sensitivity and specificity of INSHI-2008 was 91% (95% confidence interval, 72-98%) and 99% (95% confidence interval, 95-99.8%), respectively. Positive predictive value was 95% and negative predictive value was 98%. By multivariate analysis, factors predicting TB-IRIS were extrapulmonary TB (odds ratio, 8.63) and disseminated TB (odds ratio, 4.17). CONCLUSION: There was high concordance between the INSHI-2008 and French 2004 definition for TB-IRIS diagnosis in HIV/TB patients with relatively high rate of paradoxical TB-IRIS. This suggests that lack of HIV-1 RNA and CD4 cell count monitoring does not impede the ability to diagnose TB-IRIS.

National expansion of antiretroviral treatment in Thailand, 2000-2007: program scale-up and patient outcomes.

OBJECTIVE: Thailand began a national antiretroviral (ARV) treatment program in 2000, and all government and some private and university hospitals now provide treatment to eligible HIV-infected patients. We describe program scale-up and patient outcomes from 2000 to 2007. METHODS: Data from 839 hospitals in all 76 provinces of Thailand were included in this analysis. Outcomes were assessed for patients initiating ARV treatment from January 2000 to December 2005. Follow-up data through March 2007 were included; lost to follow-up was defined as >3 months late for a follow-up visit. A Cox proportional hazard model was used to assess risk factors for death; the Kaplan-Meier method was used to estimate survival probabilities. RESULTS: Outcome data are reported for 58,008 patients. Among these, 52.2% were male; at treatment initiation, the median age was 34 years, the median CD4 count was 41 cells per cubic millimeter, and 50.5% had AIDS. The initial regimen was nevirapine and 2 nonnucleoside reverse transcriptase inhibitors for 92.4% of patients; median follow-up time was 1.6 years (interquartile range = 0.8-2.4 years). Lost to follow-up occurred in 8.8% of patients. Overall 1-year survival was 0.89 (95% confidence interval = 0.88 to 0.89). Death was significantly associated with male sex, age >40 years, baseline CD4 count <100 cells per cubic millimeter, symptomatic HIV or AIDS, receipt of services at a district or community hospital, and treatment initiation before 2005. CONCLUSIONS: National ARV treatment programs can be scaled up rapidly with good patient outcomes. Treatment outcomes among patients in Thailand are comparable to those reported in smaller cohorts in other countries, and survival rates have improved since 2004.

External quality assessment program on CD4+ T-lymphocyte counts for persons with HIV/AIDS in Thailand: history and accomplishments.

A CD4 count External Quality Assessment (EQA) program is important for the clinical monitoring of persons infected with HIV/AIDS. The purpose of the present study was to evaluate the CD4 EQA performance program of the flow cytometer laboratories that perform routine CD4 counts for these patients in Thailand. Stabilized whole blood samples were sent to participating laboratories to determine the percentage and absolute counts of CD4+ T-lymphocytes using their routine procedures. The data were analyzed and reports sent to the participants within one month. Most participating laboratories produced results that were within two standard deviations (SD) of the mean, while the average inter-laboratory coefficients of variation were less than 8% for CD4+ T-lymphocytes. This program was found to improve the reliability of CD4+ T-lymphocyte determinations. This test is becoming increasingly important as Thailand and other Southeast Asian countries scale up their national programs that provide access to antiretroviral therapy for persons living with HIV/AIDS.

A feasibility study of immediate versus deferred antiretroviral therapy in children with HIV infection.

OBJECTIVE: To evaluate the feasibility of a large immediate versus deferred antiretroviral therapy (ART) study in children. METHODS: We conducted an open-label pilot randomized clinical trial study in 43 Thai children with CD4 15 to 24% of starting generic AZT/3TC/NVP immediately (Arm 1) or deferring until CD4 < 15% or CDC C (Arm 2). Primary endpoints were recruitment rate, adherence to randomized treatment and retention in trial. Secondary endpoints were % with CDC C or CD4 < 15%. Children were in the trial until the last child reached 108 weeks. Intention to treat and on treatment analyses were performed. RESULTS: Recruitment took 15 months. Twenty-six of 69 (37.7%) were not eligible due mainly to low CD4%. Twenty four and 19 were randomized to arms 1 and 2 respectively. All accepted the randomized arm; however, 3 in arm 1 stopped ART and 1 in arm 2 refused to start ART. Ten/19 (53%) in arm 2 started ART. At baseline, median age was 4.8 yrs, CDC A:B were 36:7, median CD4 was 19% and viral load was 4.8 log. All in arm 1 and 17/19 in arm 2 completed the study (median of 134 weeks). No one had AIDS or death. Four in immediate arm had tuberculosis. Once started on ART, deferred arm children achieved similar CD4 and viral load response as the immediate arm. Adverse events were similar between arms. The deferred arm had a 26% ART saving. CONCLUSION: Almost 40% of children were not eligible due mainly to low CD4% but adherence to randomized treatment and retention in trial were excellent. A larger study to evaluate when to start ART is feasible.

Directly observed therapy and improved tuberculosis treatment outcomes in Thailand.

BACKGROUND: The World Health Organization (WHO) recommends that tuberculosis (TB) patients receive directly observed therapy (DOT). Randomized controlled trials have not consistently shown that this practice improves TB treatment success rates. In Thailand, one of 22 WHO-designated high burden TB countries, patients may have TB treatment observed by a health care worker (HCW), family member, or no one. We studied whether DOT improved TB treatment outcomes in a prospective, observational cohort. METHODS AND FINDINGS: We prospectively collected epidemiologic data about TB patients treated at public and private facilities in four provinces in Thailand and the national infectious diseases hospital from 2004-2006. Public health staff recorded the type of observed therapy that patients received during the first two months of TB treatment. We limited our analysis to pulmonary TB patients never previously treated for TB and not known to have multidrug-resistant TB. We analyzed the proportion of patients still on treatment at the end of two months and with treatment success at the end of treatment according to DOT type. We used propensity score analysis to control for factors associated with DOT and treatment outcome. Of 8,031 patients eligible for analysis, 24% received HCW DOT, 59% family DOT, and 18% self-administered therapy (SAT). Smear-positive TB was diagnosed in 63%, and 21% were HIV-infected. Of patients either on treatment or that defaulted at two months, 1601/1636 (98%) patients that received HCW DOT remained on treatment at two months compared with 1096/1268 (86%) patients that received SAT (adjusted OR [aOR] 3.8; 95% confidence interval [CI] 2.4-6.0) and 3782/3987 (95%) patients that received family DOT (aOR 2.1; CI, 1.4-3.1). Of patients that had treatment success or that defaulted at the end of treatment, 1369/1477 (93%) patients that received HCW DOT completed treatment compared with 744/1074 (69%) patients that received SAT (aOR 3.3; CI, 2.4-4.5) and 3130/3529 (89%) patients that received family DOT (aOR 1.5; 1.2-1.9). The benefit of HCW DOT compared with SAT was similar, but smaller, when comparing patients with treatment success to those with death, default, or failure. CONCLUSIONS: In Thailand, two months of DOT was associated with lower odds of default during treatment. The magnitude of benefit was greater for DOT provided by a HCW compared with a family member. Thailand should consider increasing its use of HCW DOT during TB treatment.