Early Bactericidal Activity Trial of Nitazoxanide for Pulmonary Tuberculosis.

This study was conducted in treatment-naive adults with drug-susceptible pulmonary tuberculosis in Port-au-Prince, Haiti, to assess the safety, bactericidal activity, and pharmacokinetics of nitazoxanide (NTZ). This was a prospective phase II clinical trial in 30 adults with pulmonary tuberculosis. Twenty participants received 1 g of NTZ orally twice daily for 14 days. A control group of 10 participants received standard therapy over 14 days. The primary outcome was the change in time to culture positivity (TTP) in an automated liquid culture system. The most common adverse events seen in the NTZ group were gastrointestinal complaints and headache. The mean change in TTP in sputum over 14 days in the NTZ group was 3.2 h ± 22.6 h and was not statistically significant (P = 0.56). The mean change in TTP in the standard therapy group was significantly increased, at 134 h ± 45.2 h (P < 0.0001). The mean NTZ MIC for Mycobacterium tuberculosis isolates was 12.3 µg/ml; the mean NTZ maximum concentration (Cmax) in plasma was 10.2 µg/ml. Negligible NTZ levels were measured in sputum. At the doses used, NTZ did not show bactericidal activity against M. tuberculosis Plasma concentrations of NTZ were below the MIC, and its negligible accumulation in pulmonary sites may explain the lack of bactericidal activity. (This study has been registered at ClinicalTrials.gov under identifier NCT02684240.).

Towards high-quality peri-operative care: a global perspective.

Article 25 of the United Nations' Universal Declaration of Human Rights enshrines the right to health and well-being for every individual. However, universal access to high-quality healthcare remains the purview of a handful of wealthy nations. This is no more apparent than in peri-operative care, where an estimated five billion individuals lack access to safe, affordable and timely surgical care. Delivery of surgery and anaesthesia in low-resource environments presents unique challenges that, when unaddressed, result in limited access to low-quality care. Current peri-operative research and clinical guidance often fail to acknowledge these system-level deficits and therefore have limited applicability in low-resource settings. In this manuscript, the authors priority-set the need for equitable access to high-quality peri-operative care and analyse the system-level contributors to excess peri-operative mortality rates, a key marker of quality of care. To provide examples of how research and investment may close the equity gap, a modified Delphi method was adopted to curate and appraise interventions which may, with subsequent research and evaluation, begin to address the barriers to high-quality peri-operative care in low- and middle-income countries.

Commonality versus specificity among adiposity traits in normal-weight and moderately overweight adults.

BACKGROUND: Many adiposity traits have been related to health complications and premature death. These adiposity traits are intercorrelated but their underlying structure has not been extensively investigated. We report on the degree of commonality and specificity among multiple adiposity traits in normal-weight and moderately overweight adult males and females (mean body mass index (BMI)=22.9 kg m(-2), s.d.=2.4). METHODS: A total of 75 healthy participants were assessed for a panel of adiposity traits including leg, arm, trunk, total fat masses and visceral adipose tissue (VAT) derived from dual energy X-ray absorptiometry (DXA), hepatic and muscle lipids from proton magnetic resonance spectroscopy, fat cell volume from an abdominal subcutaneous adipose tissue biopsy (n=36) and conventional anthropometry (BMI and waist girth). Spearman's correlations were calculated and were subjected to factor analysis. RESULTS: Arm, leg, trunk and total fat masses correlated positively (r=0.78-0.95) with each other. VAT correlated weakly with fat mass indicators (r=0.24-0.31). Intrahepatic lipids (IHL) correlated weakly with all fat mass traits (r=0.09-0.34), whereas correlations between DXA depots and intramyocellular lipids (IMCL) were inconsequential. The four DXA fat mass measures, VAT, IHL and IMCL depots segregated as four independent factors that accounted for 96% of the overall adiposity variance. BMI and waist girth were moderately correlated with the arm, leg, trunk and total fat and weakly with VAT, IHL and IMCL. CONCLUSION: Adiposity traits share a substantial degree of commonality, but there is considerable specificity across the adiposity variance space. For instance, VAT, IHL and IMCL are typically poorly correlated with each other and are poorly to weakly associated with the other adiposity traits. The same is true for BMI and waist girth, commonly used anthropometric indicators of adiposity. These results do not support the view that it will be possible to identify adequate anthropometric indicators of visceral, hepatic and muscle lipid content in normal-weight and moderately overweight individuals.

Low vitamin D levels, prediabetes and prehypertension in healthy African American adults.

AIMS: To determine if customary lower serum vitamin D concentrations in healthy African American (AA) adults are associated with modest elevations in fasting plasma glucose (FPG) and/or resting blood pressure (BP). Numerous health disparities between African American (AA) and Caucasian American (CA) adults, especially those which increase cardiovascular morbidity and mortality, have been attributed to lower serum vitamin D concentrations in the AA. Prediabetes (PreDM) and prehypertension (PreHTN) are significantly more prevalent in healthy disease free CA adults with serum vitamin D concentrations below the 75th percentile for the Caucasian cohort. We hypothesized that despite overall lower serum vitamin D concentrations in AA, an increase in the prevalence for PreDM and PreHTN would be seen in those with low vitamin D levels. METHODS AND RESULTS: Disease free AA adults in the National Health and Nutrition Examination Survey 2001-2006 were assessed. PreDM and PreHTN were diagnosed using the ADA and JNC 7 criteria: (FPG) 100-125 mg/dL and resting systolic (SBP) 120-139 and/or diastolic (DBP) 80-89 mm Hg, respectively. Logistic regression was employed to assess effects of low vitamin D concentrations on the odds for PreDM and PreHTN (n = 621). Age, gender and BMI adjusted odds ratio for co-morbid PreDM and PreHTN in AA men (n = 343) and women (n = 278) with vitamin D levels ≤45.4 versus >45.4 nmol/L was 2.02 (1.11, 3.68), (p < 0.021). CONCLUSIONS: Evaluating serum vitamin D levels, with consideration for supplementation in seemingly healthy AA adults with prediabetes, prehypertension, or co-existing prediabetes and prehypertension, has merit.

Inhibition of multiplication of Toxoplasma gondii by human monocytes exposed to T-lymphocyte products.

The multiplication of Toxoplasma gondii was quantitated in human monocytes in vitro by phase-contrast microscopy. Toxoplasma multiplication was identical in monocytes from subjects byt was significantly inhibited in cells from both sources if the monocytes were preincubated with immune lymphocytes and toxoplasma monocytes were preincubated with immune lymphocytes and toxoplasma antigen. Supernates prepared from toxoplasma-immune lymphocytes incubated with toxoplasma antigen were also effective in inducing in monocytes the capacity to inhibit toxoplasma multiplication. Supernative acitivty was evident after lymphocytes and antigen were incubated for as little as 15 min. The instruction of monocytes was also repid and reversible. Monocytes were fully induced to inhibit toxoplasma multiplication after a 2 h exposure to an active supernate, but they lost their inhibitory capacity on culture in vitro for 48 h in the absece of immune cells or their products. The lymphocytes particupating in the monocyte induction were identified as t cells. The in vitro stimulation of monocytes appeared to exhibit some specificity, since no inhibition of toxopreotein derivative and lymphocytes from tuberculin-positive subjects, concanavalin a-stimulated lymphocytes, or their supermates. Supernates which induced monocytes to inhibit toxoplasma multiplication did not influence parasite growth in HeLa cells.

Neutrophils from human immunodeficiency virus (HIV)-seronegative donors induce HIV replication from HIV-infected patients' mononuclear cells and cell lines: an in vitro model of HIV transmission facilitated by Chlamydia trachomatis.

Infection with a sexually transmitted disease (STD) increases the risk for human immunodeficiency virus (HIV) infection. Polymorphonuclear leukocytes (PMNs) are recruited into the genital tract by STD pathogens, such as Chlamydia trachomatis. Semen of HIV-infected men contains HIV associated with mononuclear cells. This study investigated the interaction among PMNs from HIV-uninfected persons, C. trachomatis, and HIV-infected cells and examined the mechanisms for enhanced HIV replication. We demonstrated that PMNs from HIV-seronegative donors induced HIV replication in mononuclear cells from 17 HIV-infected patients in medium without exogenous IL-2. HIV in the cell-free supernatants from cocultures of PMNs and patients' peripheral blood mononuclear cells (PBMCs) was replication competent, as indicated by their capacity to propagate HIV in a second round of culture using PBMCs from HIV-seronegative individuals and by the fact that proviral DNA was found in these cells. PMNs from HIV-seronegative donors increased HIV replication over 100-fold in chronically HIV-infected cell lines of the monocytic, T, and B cell lineages. Moreover, PMNs increased U1 cells' production of p24 antigen by as much as ninefold when compared with U1 cells cocultured with PBMCs. The addition of C. trachomatis to PMN and U1 coculture increased HIV replication by an additional ninefold at 24 h, whereas C. trachomatis alone had no effect on p24 antigen production by U1 cells. Thus, C. trachomatis serves not only to recruit PMNs, but also to interact with PMNs to increase HIV replication. HIV replication is triggered by contact of HIV-infected cells with PMNs, by the generation of reactive oxygen intermediates (ROIs), and by soluble factors such as TNF-alpha and IL-6. This is based on the findings that production of p24 antigen, IL-6, and TNF-alpha induced by PMNs is abrogated by disrupting or partitioning PMNs from HIV-infected cells; is inhibited by superoxide dismutase and catalase, enzymes that destroy ROIs; is enhanced by differentiated HL60 cells capable of producing ROIs; and is induced by PMNs tested negative for CMV. Furthermore, the production of ROIs is independent of HIV infection of mononuclear cells, since PMNs cocultured with HIV-uninfected parental monocytic and T cell lines generated ROIs. Therefore, the increased risk for acquiring HIV infection associated with chlamydia cervicitis may be related to the local recruitment of PMNs by C. trachomatis and the induction of infectious virus from mononuclear cells present in semen. These observations provide a rationale for strategies to reduce HIV transmission by control of STD.

Genetic control of chloroform toxicity in mice.

Mouse strain differences suggest intermediate or multifactorial gentic control of chloroform-induced renal toxicity and death. The chloroform dose lethal to 50 percent of animals was four times higher in C57BL/6J males than in DBA/2J males. Twice as much chloroform accumulated in the kidneys of the sensitive as the resistant strain. First generation offspring were midway between parental strains for both parameters.

Subchronic oral toxicity studies of Se-methylselenocysteine, an organoselenium compound for breast cancer prevention.

Se-methylselenocysteine (MSC) is an organoselenium compound being developed for breast cancer chemoprevention. To characterize MSC toxicity, CD rats received daily gavage doses of 0, 0.5, 1.0, or 2.0 mg/kg/day (0, 3, 6, or 12 mg/m(2)/day), and beagle dogs received daily gavage doses of 0, 0.15, 0.3, or 0.6 mg/kg/day (0, 3, 6, or 12 mg/m(2)/day) for 28 days. In rats, MSC induced dose-related hepatomegaly in both sexes; mild anemia, thrombocytopenia, and elevated liver enzymes were observed in high dose females only. Microscopic pathology included hepatocellular degeneration (high dose males, all doses in females); arrested spermatogenesis (high dose males); and atrophy of corpora lutea (middle and high dose females). In dogs, MSC induced mild anemia in middle and high dose males, and in high dose females. Toxicologically significant microscopic lesions in dogs were seen only in the liver (peliosis and vacuolar degeneration in high dose males, midzonal necrosis in males in all dose groups). Based on liver pathology seen in female rats in all dose groups, the no observed adverse effect level (NOAEL) for MSC in rats is <0.5mg/kg/day. Based on alterations in hematology parameters and liver morphology in male dogs in all dose groups, the NOAEL for MSC in dogs is <0.15 mg/kg/day.

A SAS program for calculating cumulative incidence of events (with confidence limits) and number at risk at specified time intervals with partially censored data.

Correct analysis and interpretation of longitudinal (cohort) studies with partially censored time-to-event data requires that the cumulative count of events and censored observations as well as the number at risk be calculated at appropriate time points (for example, every year), by baseline group or stratum. We present here a simple SAS program, for use in situations in which competing risks do not need to be accounted for, that calculates, by baseline group or stratum, the cumulative event count, cumulative event probability (with upper and lower 95% confidence limits), and number at risk at selected time points that can be chosen by the user. We demonstrate the use of the program in the analysis of longitudinal time-to-event data from a prospective study, the Atherosclerosis Risk In Communities (ARIC) Study, for four groups and a 10-year follow-up. The SAS code presented here is easy to follow and modify and can be incorporated quickly by the user for immediate use. It provides an especially valuable tool for less experienced SAS users.

Antigen-specific immunosuppression in visceral leishmaniasis is cell mediated.

Visceral leishmaniasis is associated with an antigen-specific immunosuppression during the acute disease. Patients become responsive to Leishmania antigen in both in vivo and in vitro assays after successful antimony therapy. The cell type involved in the suppression of lymphocyte reactivity to Leishmania antigen was studied by selective depletion of mononuclear cell (MNC) populations and in co-cultivation experiments. Adherent cells were depleted on plastic and by passage on nylon wool columns. High-avidity Fc+ cells were depleted by adherence to BSA-anti-BSA complexes and OKT4+ and OKT8+ cells were depleted by treatment with monoclonal antibody (anti-OKT4+ and OKT8+) and complement. Depletion of MNC preparations of adherent cells, high-avidity Fc+ cells, OKT4+ cells and OKT8+ cells failed to restore the lymphocyte reactivity to Leishmania antigen. Antimony therapy was associated with restoration of the proliferative responses of unseparated MNC (before treatment 460 +/- 76 cpm and after treatment 4,293 +/- 1,442 cpm). Co-culture of frozen cells obtained before chemotherapy with autologous MNC obtained after treatment reduced the response of posttreatment cells to Leishmania antigen by 80%. We conclude that the antigenic specific suppression of lymphocyte proliferation in visceral leishmaniasis is cell mediated.

Absence of gamma interferon and interleukin 2 production during active visceral leishmaniasis.

The lymphocytes from eight patients with active visceral leishmaniasis (VL), a disease associated with marked immunologic dysfunction, were examined for ability to produce interleukin 2 (IL-2) and gamma interferon during in vitro cultivation. It was found that both IL-2 and gamma interferon production, in response to leishmania antigen, was absent during the active disease, but was restored after successful chemotherapy. Untreated VL patients produced IL-2 and gamma interferon when stimulated with phytohemagglutinin (PHA). Six patients with either active cutaneous or mucosal leishmaniasis, a disease not associated with immunosuppression, showed high levels of gamma interferon in response to leishmania antigen and PHA. Since IL-2 and gamma interferon have been shown to have important roles in the immune response and in the killing of leishmania, their absence may represent a key defect in the immune response in VL.

Burns in the Third World: an unmet need.

Burns continue to present a significant public health problem, resulting in scores of preventable deaths and disability everyyear. The burden of burns disproportionately falls to the world's poor residing in low and middle-income countries (LMICs). Those who are burnt require timely access to acute burns management, including definitive surgical care. The current lack of access to safe and affordable surgical care with anaesthesia worldwide means that some 5 billion people do not have access to acute burns management, including definitive surgical care for burns, when needed most. Major limitations to access to burn care at healthcare facilities in LMICs include a lack of appropriately trained staff (including surgeons), appropriate equipment and resources. Burn prevention measures have been successful in reducing the incidence of burns and deaths in many developed countries, however there is currently a paucity of robust understanding of what works in LMICs to prevent burns. A combined effort to implement proven burn prevention strategies and address the unmet need for access to safe and affordable surgical care with anaesthesia is required to reduce the global burden of burns that still exists.

Les brûlures demeurent un problème de santé publique, en raison du nombre de décès et de handicaps préventibles survenant annuellement. Le risque de brûlure est particulièrement élevé parmi la population pauvre des pays en développement (PED). Les brûlés doivent recevoir des soins adaptés, y compris chirurgicaux, en temps et heure. Le manque actuel de structures chirurgicales (et anesthésiques) sécurisées et financièrement abordables place les 5 milliards d'humains les plus à risque en dehors des structures de prise en charge des brûlés. Les limitations à l'accès aux soins pour brûlés dans les PED comprennent l'absence de soignants entraînés (chirurgiens inclus), d'équipement, de moyens. Si les mesures de prévention ont permis de réduire l'incidence des brûlures et de leur mortalité dans nombre pays développés, on ne sait actuellement clairement ce qui serait efficace dans les PED. Des actions préventives combinées au développement de structures capables de prendre en charge correctement (à un coût raisonnable pour les patients) les brûlés sont nécessaire pour réduire le risque et les conséquences des brûlures, toujours très élevés dans les PED.

Dehydroretronecine-induced skin tumors in mice.

Female Swiss mice susceptible to skin tumors received 6 sc injections and/or topical applications of dehydroretronecine, a metabolite of the pyrrolizidine alkaloid monocrotaline, and were observed for 15 months for tumor development. Of 92 animals examined, 63 had tumors at the site of application or injection; 47 of these had skin tumors, mainly basal cell and squamous cell carcinomas. These data indicate that dehydroretronecine is a proximate carcinogen capable of causing a high incidence of skin tumours in mice at the site of sc injection or topical application.

Prevalence of latent prostate carcinoma in two U.S. populations.

The prevalence of latent prostate carcinoma, the suspected precursor of invasive carcinoma, was studied in 500 autopsy specimens from New Orleans, Louisiana, and found to be similar in both whites and blacks. The tumors were subdivided into latent infiltrative type (LIT) and latent noninfiltrative type tumor was measured by photographic techniques. A good correlation between size and histology was found: The mean size of LIT tumors was significanty greater than that of LNT tumors. Age-versus-size plots revealed a subset of large LIT lesions in blacks that was not found among whites of the same ages. This subset may account for the excess of invasive carcinomas in blacks. These results suggest that many latent carcinomas lack promotional stimuli to become invasive.

Chemoprevention of gastric dysplasia: randomized trial of antioxidant supplements and anti-helicobacter pylori therapy.

BACKGROUND: Previous research has identified a high risk of gastric carcinoma as well as a high prevalence of cancer precursor lesions in rural populations living in the province of Nariño, Colombia, in the Andes Mountains. METHODS: A randomized, controlled chemoprevention trial was conducted in subjects with confirmed histologic diagnoses of multifocal nonmetaplastic atrophy and/or intestinal metaplasia, two precancerous lesions. Individuals were assigned to receive anti-Helicobacter pylori triple therapy and/or dietary supplementation with ascorbic acid, beta-carotene, or their corresponding placebos. Gastric biopsy specimens taken at baseline were compared with those taken at 72 months. Relative risks of progression, no change, and regression from multifocal nonmetaplastic atrophy and intestinal metaplasia were analyzed with multivariate polytomous logistic regression models to estimate treatment effects. All statistical tests were two-sided. RESULTS: All three basic interventions resulted in statistically significant increases in the rates of regression: Relative risks were 4.8 (95% confidence interval [CI] = 1.6-14.2) for anti-H. pylori treatment, 5. 1 (95% CI = 1.7-15.0) for beta-carotene treatment, and 5.0 (95% CI = 1.7-14.4) for ascorbic acid treatment in subjects with atrophy. Corresponding relative risks of regression in subjects with intestinal metaplasia were 3.1 (95% CI = 1.0-9.3), 3.4 (95% CI = 1.1-9.8), and 3.3 (95% CI = 1.1-9.5). Combinations of treatments did not statistically significantly increase the regression rates. Curing the H. pylori infection (which occurred in 74% of the treated subjects) produced a marked and statistically significant increase in the rate of regression of the precursor lesions (relative risks = 8.7 [95% CI = 2.7-28.2] for subjects with atrophy and 5.4 [95% CI = 1.7-17.6] for subjects with intestinal metaplasia). CONCLUSIONS: In the very high-risk population studied, effective anti-H. pylori treatment and dietary supplementation with antioxidant micronutrients may interfere with the precancerous process, mostly by increasing the rate of regression of cancer precursor lesions, and may be an effective strategy to prevent gastric carcinoma.

Exceptional chemopreventive activity of low-dose dehydroepiandrosterone in the rat mammary gland.

To determine if the chemopreventive activity of dehydroepiandrosterone (DHEA) in the rat mammary gland can be dissociated from its toxicity, two studies were conducted in which low doses of DHEA were administered alone and in combination with other agents to rats treated with N-methyl-N-nitrosourea. Beginning 1 week prior to administration of 35 mg N-methyl-N-nitrosourea per kg body weight, groups of 20 female Sprague-Dawley rates were fed AIN-76A diet supplemented with DHEA alone (800 or 400 mg/kg diet), DHEA + tamoxifen (80 or 40 microgram/kg diet), DHEA + carbenoxolone (3500 or 1750 mg/kg diet), or DHEA + tamoxifen + carbenoxolone. When administered alone at either 800 or 400 mg/kg diet, DHEA reduced mammary cancer incidence from >70% in dietary controls to 0%; mammary cancer incidence from >70% in dietary controls to 0%; mammary cancer incidence in all DHEA combination regimens was also < or = 5%. The dose levels of DHEA used induced no toxicity or alteration in body weight gain. These results indicate that dietary supplementation with low doses of DHEA has chemopreventive efficacy greater than or equal to that of endocrine ablation. This protection may be mediated by the induction of differentiation in the mammary parenchyma.

Chemoprevention of rat prostate carcinogenesis by early and delayed administration of dehydroepiandrosterone.

Two in vivo bioassays were conducted to evaluate the efficacy of dehydroepiandrosterone (DHEA) as an inhibitor of prostate carcinogenesis in rats. Prostate adenocarcinomas were induced in male Wistar-Unilever rats by a sequential regimen of cyproterone acetate and testosterone propionate, followed by a single i.v. injection of N-methyl-N-nitrosourea (MNU) and chronic androgen stimulation. In the first experiment, DHEA (1000 or 2000 mg/kg diet) was administered continuously to rats beginning 1 week before MNU exposure. In the second experiment, continuous administration of DHEA (2000 mg/kg diet) was begun either 1 week before, 20 weeks after, or 40 weeks after MNU exposure. Controls received basal diet without added DHEA. Studies were terminated at 13 months after MNU administration, and prostate cancer incidence was determined by histopathological evaluation of step sections of accessory sex glands. In the first study, continuous dietary administration of DHEA beginning 1 week before MNU resulted in a dose-related inhibition of prostate cancer induction. In the second experiment, comparable reductions in prostate cancer incidence were observed in groups exposed to DHEA beginning 1 week before, 20 weeks after, and 40 weeks after carcinogen exposure. These data demonstrate that nontoxic doses of DHEA confer significant protection against prostate carcinogenesis in rats. The efficacy of delayed administration of DHEA suggests that the compound confers protection against later stages of prostate cancer induction and can suppress the progression of existing preneoplastic lesions to invasive disease.

Triple vessel coronary artery endarterectomy and reconstruction: results in 144 patients.

Coronary artery endarterectomy and reconstruction are valuable adjuncts to conventional bypass surgery when attempting to revascularize "diffusely" diseased coronary arteries. One hundred forty-four consecutive patients were operated on through February 1986, all of whom required endarterectomy and reconstruction of the left anterior descending, left circumflex and right coronary arteries. There were 130 men (90%), ranging in age from 29 to 83 years (average 55.8), whose left ventricular ejection fraction ranged from 0.20 to 0.75 (average 0.54). One hundred thirty-one patients (91%) had angina preoperatively, which was Canadian Cardiovascular Society class III or IV in 85 (59%). Fifteen operations (10%) were repeat procedures. All operations were performed using intermittent ischemic arrest. There was an average of 5.0 grafts per patient (range 3 to 8), with an average of 3.8 endarterectomized vessels per patient (range 3 to 7). There were 14 surgical deaths (10%), all cardiac in origin. Statistically significant (p less than 0.01) risk factors for increased operative mortality included repeat surgery, ejection fraction less than or equal to 0.30 and age greater than or equal to 70 years. The operative mortality rate in 106 low risk patients (male gender, age less than 70 years, ejection fraction greater than 0.30, first operation) was 3.8% (4 patients). Nonfatal complications included 13 perioperative myocardial infarctions (10%). Long-term follow-up data are available for all 102 surviving patients for an average of 30 months (range 7 to 92). There were 12 late deaths 1 to 52 months postoperatively. The 5 year actuarial survival rate is 71% for the entire group and 87% for the 106 low risk patients.(ABSTRACT TRUNCATED AT 250 WORDS)

CD4 deficit and tuberculosis risk persist with delayed antiretroviral therapy: 5-year data from CIPRA HT-001.

SETTING: Port-au-Prince, Haiti. OBJECTIVE: To determine long-term effects of early vs. delayed initiation of antiretroviral therapy (ART) on immune recovery and tuberculosis (TB) risk in human immunodeficiency virus (HIV) infected individuals. DESIGN: Open-label randomized controlled trial of immediate ART in HIV-infected adults with CD4 counts between 200 and 350 cells/mm(3) vs. deferring ART until the CD4 count was <200 cells/mm(3). The primary comparisons were CD4 counts over time and risk for incident TB, with 5 years of follow-up. RESULTS: A total of 816 participants were enrolled, with 408 in each treatment arm. The early treatment group started ART within 2 weeks, while the deferred treatment group started ART a median of 1.3 years after enrollment. After 5 years, the mean CD4 count in the early treatment group was significantly higher than in the deferred treatment group (496 cells/mm(3), 95% confidence interval [CI] 477-515 vs. 373 cells/mm(3), 95%CI 357-389; P < 0.0001). TB risk was higher in the deferred treatment group (unadjusted HR 2.41, 95%CI 1.56-3.74; P < 0.0001) and strongly correlated with lower CD4 counts in time-dependent multivariate analysis. CONCLUSION: Delays in ART initiation for HIV-infected adults with CD4 counts of 200-350 cells/mm(3) can result in long-term immune dysfunction and persistent increased risk for TB.