Sex and age differences in Mycobacterium tuberculosis infection in Brazil.

Globally, the prevalence of tuberculosis (TB) disease is higher in males. This study examined the effect of sex and age on Mycobacterium tuberculosis (Mtb) infection. Demographic and exposure data were collected on household contacts of sputum smear-positive pulmonary TB patients in Brazil. Contacts with tuberculin skin test induration ⩾10 mm at baseline or 12 weeks were considered Mtb infected. The study enrolled 917 household contacts from 160 households; 508 (55.4%) were female, median age was 21.0 years (range 0.30-87.0) and 609 (66.4%) had Mtb infection. The proportion infected increased with age from 63.3% in girls <5 years to 75.4% in women ⩾40 years and from 44.9% in boys <5 years to 73.6% in men ⩾40 years. Multivariable modelling showed the odds of infection increased between age 5 and 14 years among female contacts (OR 1.5 per 5-year age increase; 95% CI 1.1-2.2; P = 0.02) and between ages 0-4 and 15-39 years among male contacts (OR 2.7, 95% CI 0.83-8.9 and 1.1, 95% CI 0.99-1.3 per 5-year age increase; P = 0.10, 0.07, respectively). The study suggests that the age at which Mtb infection increases most is different in females compared with males. Studies are needed to explore whether these findings are due to differences in host susceptibility, exposure outside the household or other factors.

Comparison of intermittent ethambutol with rifampicin-based regimens in HIV-infected adults with PTB, Kampala.

BACKGROUND: The human immunodeficiency virus (HIV) is a key factor responsible for the high rates of tuberculosis (TB) in sub-Saharan Africa. Treatment of TB with rifampicin (R, RMP) containing short-course regimens is highly effective in HIV-infected adults. We conducted a study to compare the efficacy and safety of intermittent ethambutol (E, EMB) with two RMP-containing regimens to treat pulmonary TB in HIV-infected patients. SETTING: National Tuberculosis Treatment Centre, Mulago Hospital, Kampala, Uganda. DESIGN: This was a prospective cohort compared to two non-randomised control groups. The study group and the two control arms were treated with 2 months of isoniazid (H), RMP, pyrazinamide (Z) and EMB followed by 6 E3H3 for the study group and 4HR or 6HR for controls. RESULTS: Between April 1993 and March 2000, 136 patients were enrolled in the 2EHRZ/E3H3 arm, 147 in the 2EHRZ/4HR arm and 266 in the 2EHRZ/6HR arm. The relapse rate was 18.2 per 100 person-years observation (PYO) for the study regimen compared to 9.7/100 PYO (P = 0.0063) and 4.8/100 PYO (P = 0.0001) in patients treated with 2 EHRZ/4HR or 2EHRZ/6HR, respectively. CONCLUSION: The 2EHRZ/6E3H3 regimen is safe and effective but has a significant risk of relapse.

Tuberculosis in household contacts of infectious cases in Kampala, Uganda.

Tuberculosis remains a serious threat to public health, especially in sub-Saharan Africa. To determine the host and environmental factors responsible for tuberculosis in African households, the authors performed a prospective cohort study of 1,206 household contacts of 302 index cases with tuberculosis enrolled in Uganda between 1995 and 1999. All contacts were systematically evaluated for active tuberculosis and risk factors for active disease. Among the 1,206 household contacts, 76 secondary cases (6%) of tuberculosis were identified. Of these cases, 51 were identified in the baseline evaluation, and 25 developed during follow-up. Compared with index cases, secondary cases presented more often with minimal disease. The risk for secondary tuberculosis was greater among young children than adults (10% vs. 1.9%) and among human immunodeficiency virus-seropositive than -seronegative contacts (23% vs. 3.3%). Host risk factors could not be completely separated from the effects of environmental risk factors, suggesting that a household may represent a complex system of interacting risks for tuberculosis.

Mycobacterium africanum subtype II is associated with two distinct genotypes and is a major cause of human tuberculosis in Kampala, Uganda.

The population structure of 234 Mycobacterium tuberculosis complex strains obtained during 1995 and 1997 from tuberculosis patients living in Kampala, Uganda (East Africa), was analyzed by routine laboratory procedures, spoligotyping, and IS6110 restriction fragment length polymorphism (RFLP) typing. According to biochemical test results, 157 isolates (67%) were classified as M. africanum subtype II (resistant to thiophen-2-carboxylic acid hydrazide), 76 isolates (32%) were classified as M. tuberculosis, and 1 isolate was classified as classical M. bovis. Spoligotyping did not lead to clear differentiation of M. tuberculosis and M. africanum, but all M. africanum subtype II isolates lacked spacers 33 to 36, differentiating them from M. africanum subtype I. Moreover, spoligotyping was not sufficient for differentiation of isolates on the strain level, since 193 (82%) were grouped into clusters. In contrast, in the IS6110-based dendrogram, M. africanum strains were clustered into two closely related strain families (Uganda I and II) and clearly separated from the M. tuberculosis isolates. A further characteristic of both M. africanum subtype II families was the absence of spoligotype spacer 40. All strains of family I also lacked spacer 43. The clustering rate obtained by the combination of spoligotyping and RFLP IS6110 analysis was similar for M. africanum and M. tuberculosis, as 46% and 49% of the respective isolates were grouped into clusters. The results presented demonstrate that M. africanum subtype II isolates from Kampala, Uganda, belong to two closely related genotypes, which may represent unique phylogenetic branches within the M. tuberculosis complex. We conclude that M. africanum subtype II is the main cause of human tuberculosis in Kampala, Uganda.

Increased replication of HIV-1 at sites of Mycobacterium tuberculosis infection: potential mechanisms of viral activation.

Tuberculosis (TB) enhances HIV-1 replication and the progression to AIDS in dually infected patients. We employed pleural TB as a model to understand the interaction of the host with HIV-1 during active TB, at sites of Mycobacterium tuberculosis (MTB) infection. HIV-1 replication was enhanced both in the cellular (pleural compared with blood mononuclear cells) and acellular (pleural fluid compared with plasma) compartments of the pleural space. Several potential mechanisms for expansion of HIV-1 in situ were found, including augmentation in expression of tumor necrosis factor (TNF)-alpha and the HIV-1 noninhibitory beta-chemokine (MCP-1), low presence of HIV-1 inhibitory beta-chemokines (MIP-1 alpha, MIP-1 beta, and RANTES [regulated on activation, normal T expressed and secreted]), and upregulation in expression of the HIV-1 coreceptor, CCR5, by pleural fluid mononuclear cells. Thus, at sites of MTB infection, conditions are propitious both for transcriptional activation of HIV-1 in latently infected mononuclear cells, and facilitation of viral infection of newly recruited cells. These mechanisms may contribute to enhanced viral burden and dissemination during TB infection.

Duration of efficacy of treatment of latent tuberculosis infection in HIV-infected adults.

BACKGROUND: Treatment of latent infection is needed to protect HIV-infected individuals against tuberculosis. A previous report addressed short-term efficacy of three regimens in HIV-infected adults. We now report on long-term efficacy of the study regimens. METHODS: Three daily self-administered regimens were compared in a randomized placebo-controlled trial in 2736 purified protein derivative (PPD)-positive and anergic HIV-infected adults. PPD-positive subjects were treated with isoniazid (INH) for 6 months (6H), INH plus rifampicin for 3 months (3HR), INH plus rifampicin and pyrazinamide for 3 months (3HRZ), or placebo for 6 months. Anergic subjects were randomized to 6H or placebo. RESULTS: 6H initially protected against tuberculosis in PPD-positive individuals; however, benefit was lost within the first year of treatment. Sustained benefit was observed in persons receiving 3HR and 3HRZ. In a Cox regression analysis, the adjusted relative risk for tuberculosis compared with placebo was 0.67 [95% confidence interval (CI), 0.42-1.07] for 6H, 0.49 (95% CI, 0.29-0.82) for 3HR, and 0.41 (95% CI, 0.22-0.76) for 3HRZ. When the rifampicin-containing regimens were combined, the adjusted relative risk for tuberculosis compared with placebo was 0.46 (95% CI, 0.29-0.71). Among anergic subjects, a modest degree of protection with 6H was present (adjusted relative risk, 0.61; 95% CI, 0.32-1.16). Treatment of latent tuberculosis infection had no effect on mortality. CONCLUSION: Six months of INH provided short-term protection against tuberculosis in PPD-positive HIV-infected adults. Three month regimens including INH plus rifampicin or INH, rifampicin and pyrazinamide provided sustained protection for up to 3 years.

Quantitative bacillary response to treatment in Mycobacterium tuberculosis infected and M. africanum infected adults with pulmonary tuberculosis.

Data regarding possible differences in microbiological response to therapy of disease caused by Mycobacterium tuberculosis and M. africanum are limited. Presenting clinical characteristics and sputum bacillary load during standard short-course chemotherapy in patients with newly-diagnosed pulmonary tuberculosis due to M. tuberculosis (n = 7) and M. africanum (n = 6) were compared. Changes in sputum bacillary load were measured using quantitative acid-fast bacilli smears, colony forming unit assay, and time until positive culture in the BACTEC radiometric system. Presentation and response to short course chemotherapy were comparable between patients infected with M. tuberculosis and those infected with M. africanum.

Safety and bactericidal activity of rifalazil in patients with pulmonary tuberculosis.

Rifalazil, also known as KRM-1648 or benzoxazinorifamycin, is a new semisynthetic rifamycin with a long half-life of approximately 60 h. Rifalazil has potent bactericidal activity against Mycobacterium tuberculosis in vitro and in animal models of tuberculosis (TB). Prior studies in healthy volunteers showed that once-weekly doses of 25 to 50 mg of rifalazil were well tolerated. In this randomized, open-label, active-controlled phase II clinical trial, 65 subjects with sputum smear-positive pulmonary TB received one of the following regimens for the first 2 weeks of therapy: 16 subjects received isoniazid (INH) (5 mg/kg of body weight) daily; 16 received INH (5 mg/kg) and rifampin (10 mg/kg) daily; 17 received INH (5 mg/kg) daily plus 10 mg of rifalazil once weekly; and 16 received INH (5 mg/kg) daily and 25 mg of rifalazil once weekly. All subjects were then put on 6 months of standard TB therapy. Pretreatment and day 15 sputum CFU of M. tuberculosis were measured to assess the bactericidal activity of each regimen. The number of drug-related adverse experiences was low and not significantly different among treatment arms. A transient decrease in absolute neutrophil count to less than 2,000 cells/mm(3) was detected in 10 to 20% of patients in the rifalazil- and rifampin-containing treatment arms without clinical consequences. Decreases in CFU counts were comparable among the four treatment arms; however, the CFU results were statistically inconclusive due to the variability in the control arms. Acquired drug resistance did not occur in any patient. Studies focused on determining a maximum tolerated dose will help elucidate the full anti-TB effect of rifalazil.

Macrophage-activating cytokines in human immununodeficiency virus type 1-infected and -uninfected patients with pulmonary tuberculosis.

Tuberculosis (TB) is the most common opportunistic infection in human immunodeficiency virus type 1 (HIV-1)-infected patients globally and occurs throughout the course of HIV-1 disease. Here the production of interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha by peripheral blood mononuclear cells (PBMC) of HIV-1-infected versus -uninfected patients with newly diagnosed pulmonary TB (PTB) was compared. Findings were correlated with cytokine profiles, clinical presentation, and expression of inducible nitric oxide (iNOS). Most HIV-1/PTB patients with a CD4 cell count of 200-500 cells/microL had high IFN-gamma production and radiographic evidence of atypical PTB. Low IFN-gamma production and radiographic evidence of reactivated PTB characterized both HIV-1/PTB patients with a CD4 cell count >or=500 cells/microL and HIV-1-uninfected patients. TNF-alpha levels were similar in all HIV-1/PTB patients, regardless of CD4 cell count. Induction of iNOS in PBMC was low and was associated with low IFN-gamma production. These data underscore the potential pathogenic role of macrophage-activating cytokines in TB in HIV-1-infected patients.

Inhibition of isoniazid-induced expression of Mycobacterium tuberculosis antigen 85 in sputum: potential surrogate marker in tuberculosis chemotherapy trials.

Mycobacterium tuberculosis antigen 85 is induced in vitro by isoniazid (INH); its sustained induction in sputum during tuberculosis (TB) therapy predicts relapse. In this trial, rifampin or rifalazil inhibited the induction of sputum antigen 85 by INH in a dose-dependent fashion. This approach may facilitate the evaluation of new TB drugs.

A whole blood bactericidal assay for tuberculosis.

The bactericidal activity of orally administered antituberculosis (anti-TB) drugs was determined in a whole blood culture model of intracellular infection in which microbial killing reflects the combined effects of drug and immune mechanisms. Rifampin (Rif) was the most active compound studied and reduced the number of viable bacilli by >4 logs. Isoniazid (INH), 2 quinolones, and pyrazinamide (PZA) showed intermediate levels of activity. Ethambutol exerted only a bacteristatic effect; amoxicillin/clavulanate was inactive. The combination of INH-Rif-PZA showed strong activity against 11 drug-sensitive isolates (mean, -3.8 log) but no activity against 12 multidrug-resistant (MDR) strains. The combination of levofloxacin-PZA-ethambutol had intermediate bactericidal activity against MDR isolates (mean, -1.2 log) but failed to equal that of INH-Rif-PZA against sensitive isolates (P<.001). The whole blood BACTEC method (Becton Dickinson) may be useful for the early clinical evaluation of new anti-TB drugs and in the management of individual patients.

Expression of IL-18 by Mycobacterium avium-infected human monocytes; association with M. avium virulence.

Disseminated Mycobacterium avium infection is the most frequent bacterial infection in patients with advanced AIDS and also associated with interferon-gamma (IFN-gamma) or IL-12 receptor deficiency. IFN-gamma is a key cytokine in host defence against M. avium infection. Expression of IL-18, a potent IFN-gamma inducer, and IFN-gamma by human monocytes after infection with M. avium was examined. Monocytes were co-cultured with isogenic smooth-transparent (SmT: virulent) or smooth-domed (SmD: avirulent) M. avium strains (10 organisms per monocyte). Infection with the SmD strain induced significantly higher concentration of IL-18 and IFN-gamma in culture supernatants than did the SmT strain. IFN-gamma production in response to M. avium was partially inhibited by anti-human IL-18 MoAb. Both recombinant human IL-12 (77 +/- 42 pg/ml, control versus 1492 +/- 141 pg/ml, cultures with IL-12 1 ng/ml) and IL-18 (126 +/- 37 pg/ml, control versus 2683 +/- 864 pg/ml, cultures with IL-18 10 ng/ml) augmented M. avium-induced IFN-gamma production. Freshly isolated uninfected monocytes expressed constitutive levels of IL-18. Following infection with M. avium, enhancement of IL-18 mRNA expression peaked at 3-6 h. IL-18 protein was detected in monocyte lysates as early as 1 h after infection with both SmT and SmD M. avium strains by Western blotting. Higher IL-18 expression by monocytes infected with the avirulent strain may result in more IFN-gamma production, thus modulating its pathogenicity. Local induction of IL-18 may be important both for M. avium pathogenicity and host defence and become a potential candidate for immunotherapy.

Impact of tuberculosis (TB) on HIV-1 activity in dually infected patients.

Active TB in HIV-1-infected subjects is associated with increased HIV-1-related immunodeficiency and mortality. We assessed plasma viral load in HIV-1-infected patients with pulmonary TB (HIV/TB) and non-TB symptomatic HIV-1-infected patients (HIV). HIV-1 load was higher in HIV/TB compared with HIV at higher CD4 counts (> 500/microl) (P < 0.01), but not at lower CD4 counts (< 500/microl). We also evaluated the status of HIV-1 gene expression in peripheral blood mononuclear cells (PBMC) and serum from HIV/TB and CD4-matched healthy HIV-infected patients (HIV/C) by reverse transcriptase-polymerase chain reaction over a range of CD4 (> 900/microl to < 200/microl). HIV-1 RNA in serum and PBMC correlated to one another, and both were markedly higher in HIV/TB compared with HIV/C with higher CD4 counts. Also, during a longitudinal study of anti-tuberculous chemoprophylaxis in HIV-1-infected patients, 10 subjects who developed TB had serologies before, at the time, and after the diagnosis of TB. These HIV/TB patients had an increase in viral load (average 2.5-fold) at the time of diagnosis of TB (P < 0.05). Overall, these data indicate that the transcriptional activity of HIV-1 is enhanced in HIV-1-infected patients with active TB, especially during early HIV-1 disease. As TB often is an early HIV-1 opportunistic infection, it may particularly favour early viral replication and dissemination, and therefore contribute to progression of HIV-1 disease.

Augmentation of apoptosis and interferon-gamma production at sites of active Mycobacterium tuberculosis infection in human tuberculosis.

Pleural tuberculosis (TB) was employed as a model to study T cell apoptosis at sites of active Mycobacterium tuberculosis (MTB) infection in human immunodeficiency virus (HIV)-coinfected (HIV/TB) patients and patients infected with TB alone. Apoptosis in blood and in pleural fluid mononuclear cells and cytokine immunoreactivities in plasma and in pleural fluid were evaluated. T cells were expanded at the site of MTB infection, irrespective of HIV status. Apoptosis of CD4 and non-CD4 T cells in the pleural space occurred in both HIV/TB and TB. Interferon (IFN)-gamma levels were increased in pleural fluid, compared with plasma. Spontaneous apoptosis correlated with specific loss of MTB-reactive, IFN-gamma-producing pleural T cells. Immunoreactivities of molecules potentially involved in apoptosis, such as tumor necrosis factor-alpha, Fas-ligand, and Fas, were increased in pleural fluid, compared with plasma. These data suggest that continued exposure of immunoreactive cells to MTB at sites of infection may initiate a vicious cycle in which immune activation and loss of antigen-responsive T cells occur concomitantly, thus favoring persistence of MTB infection.

Efficacy of an unsupervised 8-month rifampicin-containing regimen for the treatment of pulmonary tuberculosis in HIV-infected adults. Uganda-Case Western Reserve University Research Collaboration.

SETTING: National Tuberculosis Treatment Centre, Mulago Hospital, Kampala, Uganda. OBJECTIVE: To assess the efficacy of a daily, self-administered 8-month rifampicin-containing regimen for the treatment of pulmonary tuberculosis (TB) in human immunodeficiency virus (HIV) infected adults. DESIGN: Treatment outcomes in patients with pulmonary TB treated with a single 8-month regimen and followed in a prospective epidemiological study. RESULTS: Two hundred and sixty-five HIV-infected and 26 non-HIV-infected adults with initial episodes of pulmonary tuberculosis were treated with 2 months of daily isoniazid (INH), rifampicin (RMP), ethambutol and pyrazinamide followed by 6 months of daily INH + RMP. Median follow-up was 17.8 months. Ninety-five per cent of the HIV-infected and all of the non-HIV-infected patients who had sputum examined were sputum culture negative after 2 months of treatment. Twenty-two HIV-infected and no non-HIV-infected patients died during treatment. Relapse rates were 8.4% (5.9 per 100 person-years of observation [PYO], 95%CI 3.2-8.6) among HIV-infected patients and 4.5% (2.1/100 PYO, 95%CI 0-7.8) for non-HIV-infected patients. Adverse drug reactions occurred in 37% of the HIV-infected patients; most were minor and self-limiting. CONCLUSION: An 8-month RMP-containing regimen was well tolerated and effective in the treatment of HIV-infected adults with initial episodes of pulmonary TB. Relapse rates were similar to those reported with 6-month short-course regimens in HIV-infected individuals. Decisions about the duration of anti-tuberculosis treatment for HIV-infected adults must balance programme resources and the likelihood of poor compliance with longer regimens with the potential for a modest decrease in relapses with longer treatment.

Impact of pulmonary tuberculosis on survival of HIV-infected adults: a prospective epidemiologic study in Uganda.

BACKGROUND: Retrospective cohort studies of tuberculosis suggest that active tuberculosis accelerates the progression of HIV infection. The validity of these findings has been questioned because of their retrospective design, diverse study populations, variable compliance with anti-tuberculous therapy and use of anti-retroviral medication. To assess the impact of tuberculosis on survival in HIV infection we performed a prospective study among HIV-infected Ugandan adults with and without tuberculosis. METHODS: In a prospective cohort study, 230 patients with HIV-associated tuberculosis and 442 HIV-infected subjects without tuberculosis were followed for a mean duration of 19 months for survival. To assess changes in viral load over 1 year, 20 pairs of tuberculosis cases and controls were selected and matched according to baseline CD4 lymphocyte count, age, sex and tuberculin skin test status. RESULTS: During the follow-up period, 63 out of of 230 tuberculosis cases (28%) died compared with 85 out of 442 controls (19%), with a crude risk ratio of 1.4 [95% confidence interval (CI), 1.07-1.87]. Most deaths occurred in patients with CD4 lymphocyte counts < 200 x 10(6) cells/l at baseline (n = 99) and occurred with similar frequency in the tuberculosis cases (46%) and the controls (44%). When the CD4 lymphocyte count was > 200 x 10(6)/l, however, the relative risk of death in HIV-associated tuberculosis was 2.1 (95% CI, 1.27-3.62) compared with subjects without tuberculosis. For subjects with a CD4 lymphocyte count > 200 x 10(6)/l, the 1-year survival proportion was slightly lower in the cases than in the controls (0.91 versus 0.96), but by 2 years the survival proportion was significantly lower in the cases than in the controls (0.84 versus 0.91; P < 0.02; log-rank test). For subjects with a CD4 lymphocyte count of 200 x 10(6) cells/l or fewer, the survival proportion at 1 year for the controls was lower than cases (0.59 versus 0.64), but this difference was not statistically significant (P = 0.53; logrank test). After adjusting for age, sex, tuberculin skin test status, CD4 lymphocyte count, and history of HIV-related infections, the overall relative hazard for death associated with tuberculosis was 1.81 (95% CI, 1.24-2.65). In a nested Cox regression model, the relative hazard for death was 3.0 (95% CI, 1.62-5.63) for subjects with CD4 lymphocyte counts > 200 x 10(6)/l and 1.5 (95% CI, 0.99-2.40) for subjects with a CD4 lymphocyte count of 200 x 10(6)/l or fewer. CONCLUSION: The findings from this prospective study indicate that active tuberculosis exerts its greatest effect on survival in the early stages of HIV infection, when there is a reserve capacity of the host immune response. These observations provide a theoretical basis for the treatment of latent tuberculous infection in HIV-infected persons.

Pulmonary mononuclear cell responses to antigens of Mycobacterium tuberculosis in healthy household contacts of patients with active tuberculosis and healthy controls from the community.

Protective immunity against Mycobacterium tuberculosis requires CD4+ lymphocyte-mediated immune responses and IFN-gamma activity. As the primary portal of entry of M. tuberculosis is the lung, pulmonary immune responses against multiple M. tuberculosis Ags were compared between both M. tuberculosis-exposed tuberculin skin test-positive healthy household contacts (HHC) of patients with active sputum smear and culture-positive tuberculosis and tuberculin skin test-positive healthy control individuals from the community (CC). Frequencies of M. tuberculosis Ag-specific IFN-gamma-producing cells, IFN-gamma concentrations in culture supernatants, and DNA synthesis in bronchoalveolar cells (BAC) and PBMC were studied in HHC (n = 10) and CC (n = 15). Using enzyme-linked immunospot assay we found higher frequencies of IFN-gamma-producing cells with specificity to M. tuberculosis-secreted Ag 85 (Ag 85) in BAC from HHC than in BAC from CC (p < 0.022) and relative to autologous PBMC, indicating compartmentalization of Ag 85-specific cells to the lungs. Further, IFN-gamma-producing cells with specificity to components A and B of Ag 85 were specifically compartmentalized to the lungs in HHC (p < 0. 05). IFN-gamma concentrations in culture supernatants of BAC and Ag-specific DNA synthesis were low and comparable in the two subject groups. Increased immune responses to Ag 85 at the site of repeated exposure to M. tuberculosis (the lung) may represent an important component of protective immunity against M. tuberculosis. Correlates of protective immunity against M. tuberculosis are required for assessment of the efficiency of anti-tuberculous vaccines.

Quantitative sputum bacillary load during rifampin-containing short course chemotherapy in human immunodeficiency virus-infected and non-infected adults with pulmonary tuberculosis.

SETTING: National Tuberculosis (TB) Treatment Centre, Mulago Hospital and Joint Clinical Research Centre, Kampala, Uganda. OBJECTIVE: To compare the quantitative sputum bacillary load between TB patients infected with the human immunodeficiency virus (HIV) and those non-infected, during treatment with standard short course chemotherapy (SCC). DESIGN: To compare clinical characteristics and quantitative sputum bacillary load as measured by quantitative acid-fast bacilli (AFB) smears, colony forming unit (cfu) assay and time until positive culture in the BACTEC radiometric liquid system between 14 HIV-infected and 22 non-HIV-infected adults with initial episodes of smear-positive pulmonary TB at baseline and during treatment with standard four-drug SCC. RESULTS: Other than cavitation (P = 0.042) and adenopathy (P = 0.03), which were more common among non-HIV-infected and HIV-infected patients, respectively, there were no significant differences in baseline demographic, clinical, radiological and laboratory characteristics between the groups. Mean pretreatment sputum bacillary burden (6.5+/-0.51 log10 AFB/ml, 5.91+/-0.91 log10 cfu/ml and 1.8+/-1.7 days until positive BACTEC culture for HIV-infected patients and 6.32+/-0.85 log10 AFB/ml, 5.58+/-0.68 log10 cfu/ml and 1+/-1.2 days until positive BACTC culture for non-HIV-infected patients) were comparable between HIV-infected and non-HIV-infected patients. Clinical and bacteriological responses to standard SCC and treatment outcome did not differ between the groups. CONCLUSION: Quantitative sputum bacillary load at baseline and during SCC did not differ significantly between HIV-infected and non-HIV-infected adults with initial episodes of smear-positive TB.

Correlates of protective immunity to Mycobacterium tuberculosis in humans.

Correlates of protective immunity to Mycobacterium tuberculosis in humans are desirable for identifying protective antigens, demonstrating the immunogenicity of a vaccine candidate and its potential efficacy, and permitting optimization of the dose, vehicle, adjuvant, and schedule of immunization. Potential correlates can be proposed on the basis of animal models and ex vivo/in vitro studies in humans. Most critical is their validation; ultimate validation will require correlation with protection in a phase III efficacy trial of an effective vaccine. Other approaches, however, can allow selection of the most promising correlates for inclusion in phase I and II and, ultimately, phase III vaccine trials. Current data from experimental models and studies of patients with pulmonary tuberculosis and their household contacts indicate that Mycobacterium tuberculosis-stimulated whole-blood production of interferon-gamma, although imperfect, is the best available correlate. Nonetheless, further refinement of this assay and additional studies of more complex assays that model M. tuberculosis killing and cytotoxic T lymphocyte activity are warranted. During planning of a vaccine trial, the best available correlates of immunity can be selected for inclusion.