Randomized controlled trial of Mycobacterium vaccae immunotherapy in non-human immunodeficiency virus-infected ugandan adults with newly diagnosed pulmonary tuberculosis. The Uganda-Case Western Reserve University Research Collaboration.

Adjunctive immunotherapy with heat-killed Mycobacterium vaccae was studied in a randomized, placebo-controlled trial of 120 non-human immunodeficiency virus-infected adults with newly diagnosed pulmonary tuberculosis. Patients were randomized to a single dose of M. vaccae or placebo 1 week after beginning chemotherapy and were followed up for 1 year. M. vaccae was safe and well tolerated. The rate of sputum culture conversion after 1 month of tuberculosis treatment was 35% in the M. vaccae group and only 14% in the placebo group (P=.01) but was comparable at 2 months and thereafter. Patients receiving M. vaccae had greater improvement on chest radiography at 6 months (91% vs. 77% for placebo recipients; P=.04) and 12 months (94% vs. 80%; P=.04) after initiation of tuberculosis treatment. These data provide evidence of an early increase in sputum culture conversion and greater radiographic improvement among patients who received M. vaccae. Further studies are warranted.

Instability of tuberculin and Candida skin test reactivity in HIV-infected Ugandans. The Uganda-Case Western Reserve University Research Collaboration.

Anergy testing has been used as an adjunct to tuberculin testing for assessing M. tuberculosis (MTB) infection and indications for isoniazid preventive therapy in HIV-infected persons. We examined factors associated with the stability of skin test responses to purified protein derivative (PPD) and candida antigens in a cohort of HIV-infected adults followed prospectively in a tuberculosis preventive therapy trial in Uganda. PPD-positive and anergic subjects in the placebo arms of the preventive therapy study underwent repeat skin testing and immunologic testing including measurement of MTB culture filtrate (CF)-stimulated interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) levels in whole-blood culture supernatants. Anergy was present in 27% of 4,058 HIV-infected subjects screened for the tuberculosis preventive therapy trial compared with 10% of 682 HIV-non-infected persons. On follow-up testing of enrolled subjects, 42% of 139 initially anergic subjects were no longer anergic; two thirds of these had PPD reactions >= 5 mm. Stability of anergy was associated with intercurrent opportunistic infections and AIDS-associated dermatitis at baseline. Thirty-five percent of 313 subjects with an initial positive PPD had a negative PPD test at follow-up, 26% of whom had a positive candida skin test at the same time as the negative PPD test. Baseline MTBCF-stimulated IFN-gamma levels were significantly higher among PPD-positive subjects who remained PPD-positive than in those who were falsely negative. We conclude first that anergy is unstable and second that anergy testing is unreliable in identifying HIV-infected adults who are not infected with MTB and should not be used routinely for this purpose in assessing indications for isoniazid preventive therapy.

Two-step tuberculin skin testing in HIV-infected persons in Uganda.

Identifying persons infected with both human immunodeficiency virus (HIV) and Mycobacterium tuberculosis (MTB) is often difficult because of the reduced sensitivity of tuberculin skin testing in HIV-infected persons. To determine the value of two-step tuberculin skin testing (TTST) as a method of increasing the sensitivity of tuberculin skin testing in HIV-infected persons, a consecutive sample of 58 HIV-infected persons being screened for a TB preventive therapy trial in Uganda with an initial purified protein derivative (PPD) response < 5 mm completed two-step tuberculin and candida skin testing. The mean change in PPD size between the two tests, placed a mean of 8 d apart, was +2.1 mm (SD 4.4 mm, range -4 to +16 mm). Seventeen subjects (29%) had a boosted response (PPD1 < 5 and PPD2 > or = 5). In a multiple logistic regression model, boosted responses were independently associated with a CD4 count between 200 and 500 microl(-1) (p = 0.02) and a higher body mass index (p = 0.05). TTST may be valuable in identifying MTB infection and in preventing misclassification of boosted responses as skin test conversions in HIV-infected persons, especially persons with CD4 counts between 200 and 500 microl(-1) from areas with a high prevalence of MTB infection or from areas with a low prevalence of MTB infection who have other risk factors for MTB infection.

Risk factors for relapse in human immunodeficiency virus type 1 infected adults with pulmonary tuberculosis.

SETTING: A study conducted by the Uganda-Case Western Reserve University Research Collaboration in Kampala, Uganda, a country with high incidence rates of tuberculosis (TB) and human immunodeficiency virus type 1 (HIV-1) infection. OBJECTIVE: To assess clinical, microbiologic and radiographic factors associated with risk for relapse in HIV-infected adults treated for initial episodes of pulmonary TB. DESIGN: Nested case-control study within a randomized prospective clinical trial comparing the safety and efficacy of thiacetazone- and rifampicin-containing regimens for TB treatment in HIV-infected adults. RESULTS: The analysis was based on 119 patients who completed therapy. Median follow-up for all subjects was 22.3 months. Ten patients relapsed a median of 12.7 months after the end of therapy; seven of these were initially treated with the thiacetazone (T)-containing regimen. Each relapse case was matched to four controls by length of follow-up after initial TB treatment. In a univariate analysis risk for relapse was associated with treatment with the T-containing regimen (OR = 4.2, P = 0.08), age > or = 30 yrs (OR = 2.9, P = 0.16), and irregular compliance (OR = 3.6, P = 0.1). Baseline anergy on Mantoux tuberculin skin testing, cavitary disease, radiographic extent of disease and sputum bacillary burden, two month culture negativity, and residual cavitary disease at the end of treatment did not differ between relapses and controls. CONCLUSION: Older HIV-1 infected patients, those with poor treatment compliance, and those being treated with T-containing regimens, may be at increased risk for relapse after TB treatment and require closer post-treatment surveillance. Risk for relapse in HIV-infected adults with pulmonary TB after treatment with a nine month rifampicin-containing regimen was low (3.1 per 100 person-years observation) compared with those treated with a thiacetazone-containing regimen (10.1 per 100 person-years observation).

Reduced sensitivity of tuberculosis serodiagnosis in patients with AIDS in Uganda.

SETTING: The diagnostic utility of serodiagnosis of tuberculosis in HIV-infected persons was studied in Kampala, Uganda. OBJECTIVE: This study was undertaken to evaluate the utility of a recently described serologic assay for the diagnosis of tuberculosis in HIV-infected patients. DESIGN: The study was undertaken as a cross-sectional survey of 349 subjects, including human immunodeficiency virus-infected and uninfected patients with tuberculosis and control subjects. Serum from each subject was assayed by enzyme-linked immunosorbent assay (ELISA) for IgG antibody to the 30,000 dalton antigen of Mycobacterium tuberculosis. RESULTS: Test sensitivity dropped from 0.62 in non HIV-infected tuberculous patients to 0.28 in HIV-infected patients. CONCLUSIONS: ELISA serodiagnosis of tuberculosis may have a markedly decreased utility in populations where HIV infection is prevalent.

Influence of tuberculosis on human immunodeficiency virus (HIV-1): enhanced cytokine expression and elevated beta 2-microglobulin in HIV-1-associated tuberculosis.

Tuberculosis results in activation of T cells and macrophages that may harbor latent human immunodeficiency virus (HIV-1). Although such activation is beneficial to the host in terms of mycobacterial disease, it may be deleterious in terms of HIV-1. In Ugandan HIV-1-seropositive patients with pulmonary tuberculosis, antigen-induced blastogenesis and production of tumor necrosis factor-alpha (a cytokine that induces expression of HIV-1 in latently infected cells) were 3-10 times greater than in controls. The mean serum beta 2-microglobulin level was 5.22 mg/L in recently diagnosed patients, significantly greater than levels in HIV-negative patients with tuberculosis or asymptomatic HIV-1-seropositive subjects. beta 2-microglobulin was significantly lower in subjects who had completed at least 2 months of antituberculous therapy. These observations suggest that HIV-1-associated tuberculosis is accompanied by immune activation that may result in increased HIV expression and accelerated progression to AIDS.