Tuberculin skin test reversion following isoniazid preventive therapy reflects diversity of immune response to primary Mycobacterium tuberculosis infection.

RATIONALE: Healthy household contacts (HHC) of individuals with Tuberculosis (TB) with Tuberculin Skin Test (TST) conversions are considered to harbor latent Mycobacterium tuberculosis (Mtb), and at risk for TB. The immunologic, clinical, and public health implications of TST reversions that occur following Isoniazid preventive therapy (IPT) remain controversial. OBJECTIVES: To measure frequency of TST reversion following IPT, and variation in interferon-gamma (IFN-γ) responses to Mtb, in healthy Ugandan TB HHC with primary Mtb infection evidenced by TST conversion. METHODS: Prospective cohort study of healthy, HIV-uninfected, TST-negative TB HHC with TST conversions. Repeat TST was performed 12 months following conversion (3 months following completion of 9 month IPT course) to assess for stable conversion vs. reversion. Whole blood IFN-γ responses to Mtb antigen 85B (MtbA85B) and whole Mtb bacilli (wMtb) were measured in a subset (n = 27 and n = 42, respectively) at enrollment and TST conversion, prior to initiation of IPT. RESULTS: Of 122 subjects, TST reversion was noted in 25 (20.5%). There were no significant differences in demographic, clinical, or exposure variables between reverters and stable converters. At conversion, reverters had significantly smaller TST compared to stable converters (13.7 mm vs 16.4 mm, respectively; p = 0.003). At enrollment, there were no significant differences in IFN-γ responses to MtbA85B or wMTB between groups. At conversion, stable converters demonstrated significant increases in IFN-γ responses to Ag85B and wMtb compared to enrollment (p = 0.001, p<0.001, respectively), while there were no significant changes among reverters. CONCLUSIONS: TST reversion following IPT is common following primary Mtb infection and associated with unique patterns of Mtb-induced IFN-γ production. We have demonstrated that immune responses to primary Mtb infection are heterogeneous, and submit that prospective longitudinal studies of cell mediated immune responses to Mtb infection be prioritized to identify immune phenotypes protective against development of TB disease.

Mycobacterium tuberculosis specific CD8(+) T cells rapidly decline with antituberculosis treatment.

RATIONALE: Biomarkers associated with response to therapy in tuberculosis could have broad clinical utility. We postulated that the frequency of Mycobacterium tuberculosis (Mtb) specific CD8(+) T cells, by virtue of detecting intracellular infection, could be a surrogate marker of response to therapy and would decrease during effective antituberculosis treatment. OBJECTIVES: We sought to determine the relationship of Mtb specific CD4(+) T cells and CD8(+) T cells with duration of antituberculosis treatment. MATERIALS AND METHODS: We performed a prospective cohort study, enrolling between June 2008 and August 2010, of HIV-uninfected Ugandan adults (n = 50) with acid-fast bacillus smear-positive, culture confirmed pulmonary TB at the onset of antituberculosis treatment and the Mtb specific CD4(+) and CD8(+) T cell responses to ESAT-6 and CFP-10 were measured by IFN-γ ELISPOT at enrollment, week 8 and 24. RESULTS: There was a significant difference in the Mtb specific CD8(+) T response, but not the CD4(+) T cell response, over 24 weeks of antituberculosis treatment (p<0.0001), with an early difference observed at 8 weeks of therapy (p = 0.023). At 24 weeks, the estimated Mtb specific CD8(+) T cell response decreased by 58%. In contrast, there was no significant difference in the Mtb specific CD4(+) T cell during the treatment. The Mtb specific CD4(+) T cell response, but not the CD8(+) response, was negatively impacted by the body mass index. CONCLUSIONS: Our data provide evidence that the Mtb specific CD8(+) T cell response declines with antituberculosis treatment and could be a surrogate marker of response to therapy. Additional research is needed to determine if the Mtb specific CD8(+) T cell response can detect early treatment failure, relapse, or to predict disease progression.

Systemic immune activation and microbial translocation in dual HIV/tuberculosis-infected subjects.

BACKGROUND: Systemic immune activation is a strong predictor of progression of human immunodeficiency virus type 1 (HIV-1) disease and a prominent feature of infection with Mycobacterium tuberculosis. OBJECTIVE: To understand the role of systemic immune activation and microbial translocation in HIV/tuberculosis dually infected patients over the full spectrum of HIV-1 immunodeficiency, we studied circulating sCD14 and lipopolysaccharide (LPS) and their relationship to HIV-1 activity. METHODS: Two cohorts of HIV/tuberculosis subjects defined by CD4 T-cell count at time of diagnosis of tuberculosis were studied: those with low (<350/µL) and those with high (≥ 350/µL) CD4 T-cell count. Circulating soluble CD14 (sCD14) and LPS were assessed. RESULTS: Levels of sCD14 were higher in HIV/tuberculosis with high (≥ 350/µL) as compared to low CD4 T-cell count (P < .001). Whereas sCD14 levels remained elevated in HIV/tuberculosis subjects with lower CD4 T-cell counts despite treatment of tuberculosis, in HIV/tuberculosis patients with higher CD4 T-cell count (≥ 350/µL), levels declined regardless of whether highly active antiretroviral therapy (HAART) was included with the anti-tuberculosis regimen. Circulating LPS levels in HIV/tuberculosis patients with CD4 T-cell count ≥ 350/µL were unaffected by treatment of tuberculosis with or without HAART. CONCLUSION: During HIV/tuberculosis, systemic immune activation is dissociated from microbial translocation. Changes in circulating sCD14 and LPS are dependent on CD4 T-cell count.

CD8+ T cells provide an immunologic signature of tuberculosis in young children.

RATIONALE: The immunologic events surrounding primary Mycobacterium tuberculosis infection and development of tuberculosis remain controversial. Young children who develop tuberculosis do so quickly after first exposure, thus permitting study of immune response to primary infection and disease. We hypothesized that M. tuberculosis-specific CD8(+) T cells are generated in response to high bacillary loads occurring during tuberculosis. OBJECTIVES: To determine if M. tuberculosis-specific T cells are generated among healthy children exposed to M. tuberculosis and children with tuberculosis. METHODS: Enzyme-linked immunosorbent spot assays were used to measure IFN-γ production in response to M. tuberculosis-specific proteins ESAT-6/CFP-10 by peripheral blood mononuclear cells and CD8(+) T cells isolated from Ugandan children hospitalized with tuberculosis (n = 96) or healthy tuberculosis contacts (n = 62). MEASUREMENTS AND MAIN RESULTS: The proportion of positive CD8(+) T-cell assays and magnitude of CD8(+) T-cell responses were significantly greater among young (<5 yr) tuberculosis cases compared with young contacts (P = 0.02, Fisher exact test, P = 0.01, Wilcoxon rank-sum, respectively). M. tuberculosis-specific T-cell responses measured in peripheral blood mononuclear cells were equivalent between groups. CONCLUSIONS: Among young children, M. tuberculosis-specific CD8(+) T cells develop in response to high bacillary loads, as occurs during tuberculosis, and are unlikely to be found after M. tuberculosis exposure. T-cell responses measured in peripheral blood mononuclear cells are generated after M. tuberculosis exposure alone, and thus cannot distinguish exposure from disease. In young children, IFN-γ-producing M. tuberculosis-specific CD8(+) T cells provide an immunologic signature of primary M. tuberculosis infection resulting in disease.

Effects of antiretroviral therapy on immune function of HIV-infected adults with pulmonary tuberculosis and CD4+ >350 cells/mm3.

BACKGROUND: Human immunodeficiency virus (HIV)-tuberculosis coinfection is associated with heightened immune activation, viral replication, and T cell dysfunction. We compared changes in T cell activation and function between patients receiving concurrent treatment for HIV-tuberculosis coinfection and those receiving treatment for tuberculosis alone. METHODS: HIV-infected adults with tuberculosis and CD4(+) T cell counts >350 cells/mm(3) were randomized to receive tuberculosis treatment alone (control arm; n = 36) or 6 months of antiretroviral therapy (ART) concurrent with tuberculosis treatment (intervention arm; n = 38). HIV viral load, T cell subsets, T cell activation, and cytokine production were measured at enrollment and every 3 months for 12 months. RESULTS: Differences in absolute CD4(+) and CD8(+) T cell counts were not observed between arms. Viral load was reduced while participants received ART; control patients maintained viral load at baseline levels. Both arms had significant reductions in T cell expression of CD38 and HLA-DR. Interferon-γ production in response to mitogen increased significantly in the intervention arm. CONCLUSIONS: In HIV-infected adults with tuberculosis and CD4(+) T cell counts >350 cells/mm(3), both tuberculosis treatment and concurrent HIV-tuberculosis treatment reduce T cell activation and stabilize T cell counts. Concurrent ART with tuberculosis treatment does not provide additional, sustained reductions in T cell activation among individuals with preserved immunologic function.

Tuberculosis treatment in HIV infected Ugandans with CD4 counts>350 cells/mm reduces immune activation with no effect on HIV load or CD4 count.

BACKGROUND: Both HIV and TB cause a state of heightened immune activation. Immune activation in HIV is associated with progression to AIDS. Prior studies, focusing on persons with advanced HIV, have shown no decline in markers of cellular activation in response to TB therapy alone. METHODOLOGY: This prospective cohort study, composed of participants within a larger phase 3 open-label randomized controlled clinical trial, measured the impact of TB treatment on immune activation in persons with non-advanced HIV infection (CD4>350 cells/mm3) and pulmonary TB. HIV load, CD4 count, and markers of immune activation (CD38 and HLA-DR on CD4 and CD8 T cells) were measured prior to starting, during, and for 6 months after completion of standard 6 month anti-tuberculosis (TB) therapy in 38 HIV infected Ugandans with smear and culture confirmed pulmonary TB. RESULTS: Expression of CD38, and co-expression of CD38 and HLA-DR, on CD8 cells declined significantly within 3 months of starting standard TB therapy in the absence of anti-retroviral therapy, and remained suppressed for 6 months after completion of therapy. In contrast, HIV load and CD4 count remained unchanged throughout the study period. CONCLUSION: TB therapy leads to measurable decreases in immune activation in persons with HIV/TB co-infection and CD4 counts>350 cells/mm3.

Low risk sexual and drug-using behaviors among Latina women with AIDS in Los Angeles County.

Latina women represent nearly half of all females diagnosed with AIDS in Los Angeles County, yet little is known about their risk behaviors compared to women of other race/ethnicities. Compared to white and African American women with AIDS, Latinas with AIDS had fewer lifetime male sexual partners (P < .0001); reported fewer sexually transmitted diseases (OR = 0.24; 95% CI: 0.1, 0.5); were less likely to trade sex for drugs/money (OR = 0.18; 95% CI: 0.07, 0.5); and were less likely to report exposure to HIV via injection drug use (OR = 0.3; 95% CI: 0.09, 0.99). Latinas were also more likely to be single mothers (OR = 3.02; 95% CI: 1.4, 6.4); less likely to receive public assistance (OR = 0.33; 95% CI: 0.16, 0.70); were less likely to have completed high-school (OR = 0.11; 95% CI: .04, .31) and were more likely to never have had health insurance (OR = 2.44; 95% CI: 1.15, 5.18). The data demonstrate low-risk behaviors for Latinas and underscores the challenge of delivering effective HIV prevention to women without traditional risk profiles.

Early and extended early bactericidal activity of linezolid in pulmonary tuberculosis.

RATIONALE: Linezolid, the first oxazolidinone approved for clinical use, has effective in vitro and promising in vivo activity against Mycobacterium tuberculosis. OBJECTIVES: To evaluate the early and extended early bactericidal activity of linezolid in patients with pulmonary tuberculosis. METHODS: Randomized open label trial. Thirty patients with newly diagnosed smear-positive pulmonary tuberculosis (10 per arm) were assigned to receive isoniazid (300 mg daily) and linezolid (600 mg twice daily or 600 mg once daily) for 7 days. Sputum for quantitative culture was collected for 2 days before and then daily during 7 days of study drug administration. Bactericidal activity was estimated by measuring the decline in bacilli during the first 2 days (early bactericidal activity) and the last 5 days of study drug administration (extended early bactericidal activity). MEASUREMENTS AND MAIN RESULTS: The mean early bactericidal activity of isoniazid (0.67 log10 cfu/ml/d) was greater than that of linezolid twice and once daily (0.26 and 0.18 log10 cfu/ml/d, respectively). The extended early bactericidal activity of linezolid between Days 2 and 7 was minimal. CONCLUSIONS: Linezolid has modest early bactericidal activity against rapidly dividing tubercle bacilli in patients with cavitary pulmonary tuberculosis during the first 2 days of administration, but little extended early bactericidal activity. Clinical trial registered with www.clinicaltrials.gov (NCT00396084).

Demographic characteristics and sexual behaviors associated with methamphetamine use among MSM and non-MSM diagnosed with AIDS in Los Angeles County.

Demographic and behavioral factors associated with methamphetamine use are presented for 455 men who have sex with men (MSM) and 228 non-MSM diagnosed with AIDS in Los Angeles County (LAC) from 2000 to 2004, as there are limited population-based data for these subgroups. Lifetime methamphetamine use was 35% for MSM, 14% for non-MSM, 50% for white MSM, and 35% for black MSM. Methamphetamine use in the previous 12 months among MSM (11%) and non-MSM (0.4%) was less than lifetime use. Compared to MSM with no history of methamphetamine use in a multivariate analysis, MSM methamphetamine users were more likely to be non-Latino (white or black) (OR = 2.8, 95% CI: 1.6, 4.9) compared to Latino and reported > or = 10 sexual partners in the previous 12 months (OR = 3.1, 95% CI: 1.7, 5.6). These data indicate that methamphetamine has been widely used by both MSM and non-MSM with AIDS in LAC and that lifetime use is associated with sexual risk behaviors among MSM.

Associations of race/ethnicity with HIV prevalence and HIV-related behaviors among young men who have sex with men in 7 urban centers in the United States.

Using data from a multisite venue-based survey of male subjects aged 15 to 22 years, we examined racial/ethnic differences in demographics, partner type, partner type-specific condom use, drug use, and HIV prevalence in 3316 US black, multiethnic black, Latino, and white men who have sex with men (MSM). We further estimated associations of these factors with HIV infection and their influence on racial/ethnic disparities in HIV prevalence. HIV prevalences were 16% for both black and multiethnic black participants, 6.9% for Latinos, and 3.3% for whites. Paradoxically, potentially risky sex and drug-using behaviors were generally reported most frequently by whites and least frequently by blacks. In a multiple logistic regression analysis, positive associations with HIV included older age, being out of school or work, sex while on crack cocaine, and anal sex with another male regardless of reported condom use level. Differences in these factors did not explain the racial/ethnic disparities in HIV prevalence, with both groups of blacks experiencing more than 9 times and Latinos experiencing approximately twice the fully adjusted odds of infection compared with whites. Understanding racial/ethnic disparities in HIV risk requires information beyond the traditional risk behavior and partnership type distinctions. Prevention programs should address risks in steady partnerships, target young men before sexual initiation with male partners, and tailor interventions to men of color and of lower socioeconomic status.

Frequent failed early HIV detection in a high prevalence area: implications for prevention.

To identify the frequency of and factors associated with early detection of HIV infection in Los Angeles County, data were evaluated from interviews of a population-based sample of adult persons with AIDS. Early detection was defined as greater than 5 years between the first reported positive HIV test and an AIDS diagnosis. The associations between early detection and sociodemographic and behavioral factors were assessed for the period January 1997 through June 2002. Over the study period, only 20% (253/1268) of persons interviewed met the criterion for early detection. Early HIV detection was less likely for women (adjusted odds ratio [AOR] = 0.6, 95% confidence interval [CI]: 0.4, 0.9), blacks (AOR = 0.5, 95% CI: 0.4, 0.8), foreign-born Latinos (AOR = 0.2, 95% CI: 0.1, 0.3), U.S.-born Latinos (AOR = 0.3, 95% CI: 0.2, 0.6, and heterosexuals (AOR = 0.5, 95% CI: 0.3, 0.7). Trends of increasing early detection with older age groups (p < 0.001) and higher educational levels (p < 0.001) were also observed. Our findings indicate an overall low level of early HIV detection and suggest that major sociodemographic and risk group disparities exist in the likelihood of early detection among HIV-infected persons in Los Angeles. These differences have important implications for reducing the level of community HIV transmission and for improving individual health outcomes among people with HIV. Aggressive efforts are needed to expand HIV testing and early detection for women, minorities, heterosexuals, younger age groups, and persons of lower education. Links to treatment and behavioral intervention programs should accompany such expanded testing efforts.

The effect of partner characteristics on HIV infection among African American men who have sex with men in the Young Men's Survey, Los Angeles, 1999-2000.

Previous studies have documented disparities in HIV prevalence by race among men who have sex with men (MSM), even after adjusting for traditional risk factors. In this analysis of data collected for the 1999-2000 Los Angeles Young Men's Survey, a cross-sectional venue-based survey of MSM aged 23-29, we investigated whether information on male sex-partner characteristics accounts for some of the racial/ethnic differences in HIV prevalence. In this sample of survey participants, we observed that African American MSM reported similar or lower levels of HIV risk behaviors compared with White MSM but much higher HIV prevalence (26% vs. 7.4%, respectively). In an unadjusted logistic regression model, African American participants had 4.4 times higher odds of HIV infection compared with White participants. In a multiple logistic regression model adjusting for participant behaviors, we observed elevation of the relative odds of HIV infection for African Americans compared with Whites (odds ratio [OR] = 6.9, 95% confidence limits [CL] = 2.5, 19). In a fully adjusted model, controlling for the effects of having older partners and more African American partners, we observed a 20% reduction in the relative odds of HIV for African American participants compared with White participants (OR = 5.5, 95% CL = 1.8, 17). Our findings suggest that differences in male partner types, namely older and African American partners, may account for some of the observed racial disparity in HIV infection, especially for African American MSM compared with White MSM in Los Angeles.

HIV risk behaviors among African American men in Los Angeles County who self-identify as heterosexual.

There are limited data on high-risk behaviors among heterosexual African American men with HIV infection. Risk behaviors were examined in a case-control study of HIV-infected (n = 90) and uninfected (n = 272) African American men who self-identified as heterosexual. Of men who self-identified as heterosexual, 31% (n = 28) of the infected men and 16% (n = 43) of the uninfected men reported having had anal sex with men. Among the heterosexual men reporting anal sex with men, 100% of the infected and 67% of the uninfected men reported inconsistent condom use during anal sex with men. Few of the infected (12%) and uninfected (2%) men reported oral sex with other men. Of the men who self-identified as heterosexual, 46% of those who were HIV-positive and 37% of those who were HIV-negative reported anal sex with women with infrequent condom use. An increasing risk for HIV was associated with decreasing age at first sexual experience (chi2, 9.3; p = .002). A history of injecting drugs (odds ratio [OR], 3.1; 95% confidence intervals [CIs], 1.8, 5.4) and amphetamine (OR, 4.3; 95% CIs, 1.1, 16.7) and methamphetamine (OR, 2.9; 95% CIs, 1.4, 6.3) use were associated with HIV. Innovative HIV prevention strategies are needed that move beyond the traditional gay versus straight model to effectively access hard-to-reach African American men who self-identify as heterosexual.