Disability, comorbidities and risk determinants at end of TB treatment in Kenya, Uganda, Zambia and Zimbabwe.

BACKGROUND: We examined the feasibility of assessing and referring adults successfully completing TB treatment for comorbidities, risk determinants and disability in health facilities in Kenya, Uganda, Zambia and Zimbabwe. METHODS: This was a cross-sectional study within national TB programmes. RESULTS: Health workers assessed 1,063 patients (78% of eligible) in a median of 22 min [IQR 16-35] and found it useful and feasible to accomplish in addition to other responsibilities. For comorbidities, 476 (44%) had HIV co-infection, 172 (16%) had high blood pressure (newly detected in 124), 43 (4%) had mental health disorders (newly detected in 33) and 36 (3%) had diabetes mellitus. The most common risk determinants were 'probable alcohol dependence' (15%) and malnutrition (14%). Disability, defined as walking <400 m in 6 min, was found in 151/882 (17%). Overall, 763 (72%) patients had at least one comorbidity, risk determinant and/or disability. At least two-thirds of eligible patients were referred for care, although 80% of those with disability needed referral outside their original health facility. CONCLUSIONS: Seven in 10 patients completing TB treatment had at least one comorbidity, risk determinant and/or disability. This emphasises the need for offering early patient-centred care, including pulmonary rehabilitation, to improve quality of life, reduce TB recurrence and increase long-term survival.

CONTEXTE: Nous avons examiné la faisabilité d'évaluer et de référer les adultes ayant terminé avec succès le traitement de la TB pour les comorbidités, les déterminants de risque et l'invalidité dans les établissements de santé au Kenya, en Ouganda, en Zambie et au Zimbabwe. MÉTHODES: Il s'agissait d'une étude transversale menée dans le cadre des programmes nationaux de lutte contre la TB. RÉSULTATS: Les agents de santé ont évalué 1 063 patients (78% des personnes éligibles) en médiane de 22 min (IQR 16­35) et ont jugé utile et réalisable d'accomplir cette tâche en plus de leurs autres responsabilités. Pour les comorbidités, 476 (44%) étaient co-infectés par le VIH, 172 (16%) souffraient d'hypertension artérielle (dont 124 nouvellement diagnostiqués), 43 (4%) présentaient des troubles de santé mentale (dont 33 nouvellement diagnostiqués) et 36 (3%) étaient diabétiques. Les déterminants de risque les plus courants étaient une « dépendance probable à l'alcool ¼ (15%) et la malnutrition (14%). L'invalidité, définie comme une marche <400 m en 6 min, a été observée chez 151/882 (17%) des patients. Dans l'ensemble, 763 (72%) des patients présentaient au moins une comorbidité, un déterminant de risque et/ou une invalidité. Au moins deux tiers des patients éligibles ont été référés pour des soins, bien que 80% de ceux souffrant d'invalidité aient besoin d'être référés en dehors de leur établissement de santé d'origine. CONCLUSIONS: Sept patients sur 10 ayant terminé le traitement de la TB présentaient au moins une comorbidité, un déterminant de risque et/ou une invalidité. Cela souligne la nécessité d'offrir des soins précoces centrés sur le patient, y compris une réadaptation pulmonaire, pour améliorer la qualité de vie, réduire la récurrence de la TB et augmenter la survie à long terme.

The interaction of monocyte chemoattractant protein-1 and tumour necrosis factor-alpha in Mycobacterium tuberculosis-induced HIV-1 replication at sites of active tuberculosis.

Tuberculosis (TB) is a prominent opportunistic infection in HIV-1-infected subjects and enhances HIV-1 replication. TB is associated with excess monocyte chemoattractant protein (MCP)-1 and tumour necrosis factor (TNF)-alpha activity in situ, both of which are implicated in transcriptional activation of HIV-1. The role of MCP-1 and TNF-alpha in activation of HIV-1 during TB and by Mycobacterium tuberculosis (MTB) in mononuclear cells from HIV-1/TB subjects with pleural TB was examined here. Extremely high levels of MCP-1 (as compared with TNF-alpha) protein and mRNA were found in pleural fluid and pleural fluid mononuclear cells. Levels of MCP-1 mRNA were sustained during in vitro culture of pleural fluid mononuclear cells. Neutralization of MCP-1 (but not TNF-alpha), resulted in inhibition of MTB induced HIV-1 gag/pol mRNA. Neutralization of both MCP-1 and TNF-alpha, however, abrogated the effect of anti-MCP-1 antibody on HIV-1 mRNA. LMP-420, a small molecular transcriptional inhibitor of both TNF-alpha and MCP-1 expression, did not reduce MTB-induced HIV-1 expression. These data imply that MCP-1 activity may be critical to activation of HIV-1 at sites of TB. An interplay of MCP-1 and TNF-alpha is also suggested.

Elevated HIV seroprevalence and risk behavior among Ugandan TB suspects: implications for HIV testing and prevention.

OBJECTIVES: Voluntary counseling and testing (VCT) for the human immunodeficiency virus (HIV) is recommended for persons treated for tuberculosis (TB). Opportunities to diagnose HIV may be missed by limiting HIV testing to only persons diagnosed with TB. Among TB suspects in Uganda, we determined HIV prevalence, risk behaviors, and willingness to refer family for VCT. METHODS: Consenting adult patients presenting for evaluation at a referral TB clinic received same-day VCT. TB diagnosis data were abstracted from clinical records. RESULTS: Among 665 eligible patients, 565 (85%) consented to VCT. Among these, 238 (42%) were HIV-positive. Of the HIV-infected patients, 37% had received a non-TB diagnosis. HIV seroprevalence was higher in patients with a non-TB diagnosis (49%) than those diagnosed with TB (39%) (P = 0.02). Fewer than 6% of HIV-infected patients reported always using condoms with sexual partners. The majority of patients (86%) reported being 'very willing' to refer family members for VCT. CONCLUSIONS: Over 35% of HIV-infected cases in our population would have been undetected if HIV testing was limited to cases with diagnosed TB. The high HIV seroprevalence in both TB and non-TB cases merits HIV testing for all patients evaluated at TB clinics. HIV-infected TB suspects reporting high-risk behavior are at risk for HIV transmission, and should receive risk-reduction counseling.

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.

HIV-1-related pleural tuberculosis: elevated production of IFN-gamma, but failure of immunity to Mycobacterium tuberculosis.

BACKGROUND: Pleural tuberculosis can resolve spontaneously, suggesting that the inflammatory process may represent a protective immune response. However, pleural tuberculosis is strongly associated with HIV infection. It has been suggested that cell-mediated immune responses may be reduced, and direct bacterial invasion may have a role in pathogenesis, in HIV-positive cases. To test this hypothesis, we compared production of the pro-inflammatory cytokines, interferon (IFN)-gamma and tumour necrosis factor(TNF)-alpha, production of the immunosuppressive cytokine, interleukin (IL)-10, and mycobacterial culture positivity, in HIV-negative and HIV-positive patients with pleural tuberculosis. METHODS: Cytokine levels were measured in serum and pleural fluid, and in supernatants of blood and pleural fluid stimulated in vitro using mycobacterial antigens. Intracellular IFN-gamma and TNF-alpha production was measured after stimulation with phorbol myristate acetate and ionomycin in vitro. RESULTS: IFN-gamma was strikingly elevated in serum and pleural fluid in HIV-positive, compared to HIV-negative subjects (P < or = 0.02). TNF-alpha was elevated, but this was not statistically significant. IL-10 levels were higher in serum (P < 0.001), but similar in pleural fluid. IFN-gamma responses to soluble mycobacterial antigen in vitro were reduced in peripheral blood (P = 0.006), but not pleural fluid, of HIV-positive subjects. Intracellular cytokine staining suggested that CD8+ T cells were a major source of IFN-gamma in HIV-positive subjects. The proportion of subjects with a positive culture for Mycobacterium tuberculosis from pleural fluid was higher in the HIV-positive group. CONCLUSIONS: HIV-positive patients with pleural tuberculosis show elevated production of IFN-gamma, for which CD8+ T cells may be a major source. Mycobacterium tuberculosis can proliferate despite high levels of pro-inflammatory cytokines.

Evaluation of suspected tuberculous pleurisy: clinical and diagnostic findings in HIV-1-positive and HIV-negative adults in Uganda.

SETTING: National Tuberculosis Treatment Centre, Mulago Hospital, Kampala, Uganda. OBJECTIVES: To compare clinical and radiographic presentation, and diagnostic methods, in adults with tuberculous pleurisy who are negative and positive for the human immunodeficiency virus (HIV). DESIGN: Adults with suspected pleural tuberculosis were screened by clinical examination, thoracocentesis and closed pleural biopsy. Biopsy material was cultured on Middlebrook 7H-10 solid medium and in BACTEC 12B radiometric vials. Pleural fluid was cultured using Löwenstein-Jensen slants, BACTEC and Kirchner liquid medium. RESULTS: Of 156 individuals enrolled, 142 had tuberculosis, of whom 80% were HIV-positive. Among those with tuberculosis, HIV-positive patients bad a more severe and longer illness. The size of effusions was similar in HIV-positive and HIV-negative patients. A higher proportion of HIV-positive patients had parenchymal infiltrates but this difference was not statistically significant. Pleural fluid lymphocytosis was present in all HIV-negative and 97% of the HIV-positive patients. HIV-positive patients had lower pleural fluid lymphocyte counts. Pleural fluid cultures were more often positive in HIV-positive patients. BACTEC and Kirchner liquid media gave higher yields than solid media. CONCLUSION: HIV-positive patients with tuberculous pleurisy had a more severe illness than HIV-negative patients. Mycobacterial cultures from HIV-positive patients were more often positive, suggesting more mycobacterial extension from the lungs into the pleural space. Liquid culture media were superior to solid media with regard to diagnostic yield and time until diagnosis.

Yield of undetected tuberculosis and human immunodeficiency virus coinfection from active case finding in urban Uganda.

OBJECTIVES: To determine the yield of undetected active tuberculosis (TB), TB and human immunodeficiency virus (HIV) coinfection and the number needed to screen (NNS) to detect a case using active case finding (ACF) in an urban community in Kampala, Uganda. METHODS: In a door-to-door survey conducted in Rubaga community from January 2008 to June 2009, residents aged ≥15 years were screened for chronic cough (≥2 weeks) and tested for TB disease using smear microscopy and/or culture. Rapid testing was used to screen for HIV infection. The NNS to detect one case was calculated based on population screened and undetected cases found. RESULTS: Of 5102 participants, 3868 (75.8%) were females; the median age was 24 years (IQR 20-30). Of 199 (4%) with chronic cough, 160 (80.4%) submitted sputum, of whom 39 (24.4%, 95%CI 17.4-31.5) had undetected active TB and 13 (8.1%, 95%CI 6.7-22.9) were TB-HIV co-infected. The NNS to detect one TB case was 131 in the whole study population, but only five among the subgroup with chronic cough. CONCLUSION: ACF obtained a high yield of previously undetected active TB and TB-HIV cases. The NNS in the general population was 131, but the number needed to test in persons with chronic cough was five. These findings suggest that boosting the identification of persons with chronic cough may increase the overall efficiency of TB case detection at a community level.

Relapse more common than reinfection in recurrent tuberculosis 1-2 years post treatment in urban Uganda.

OBJECTIVE: To determine the proportion of recurrent tuberculosis (TB) due to relapse with the patient's initial strain or reinfection with a new strain of Mycobacterium tuberculosis 1-2 years after anti-tuberculosis treatment in Uganda, a sub-Saharan TB-endemic country. DESIGN: Records of patients with culture-confirmed TB who completed treatment at an urban Ugandan clinic were reviewed. Restriction fragment length polymorphism (RFLP) patterns were used to determine relapse or reinfection. Associations between human immunodeficiency virus (HIV) positivity and type of TB recurrence were determined. RESULTS: Of 1701 patients cured of their initial TB episode with a median follow-up of 1.24 years, 171 (10%) had TB recurrence (8.4 per 100 person-years). Rate and risk factors for recurrence were similar to other studies from sub-Saharan Africa. Insertion sequence (IS) 6110-based RFLP of paired isolates from 98 recurrences identified 80 relapses and 18 reinfections. Relapses among HIV-positive and -negative patients were respectively 79% and 85% of recurrences. CONCLUSIONS: Relapse was more common and presented earlier than reinfection in both HIV-positive and -negative TB patients 1-2 years after completing treatment. These findings impact both the choice of retreatment drug regimen, as relapsing patients are at higher risk for acquired drug resistance, and clinical trials of new TB regimens with relapse as clinical endpoint.

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.

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.

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.

Role of Ethambutol in the Consolidation Phase of Tuberculosis Treatment Regimens

The purpose of this study is to evaluate the safety and efficacy of anti-TB chemotherapy regimen utilizing an ethambutol-containing continuation phase for the treatment of newly diagnosed pulmonary tuberculosis in HIV-infected adults. The aim was to find a suitable alternative to thiacetazone in the continuation phase given the high cost of regimens utilizing rifampicin throughout the continuation phase and concerns about the high frequency of cutaneous hypersensitivity drug reactions in HIV-infected patients treated with thiacetazone-containing regimens. The result showed that treatment with 2EHRZ/6H3E3 was well tolerated with few significant side effects. The relapse rate of 13.6 400 PYO is comparable to reported relapse rates with standard thiacetazone-containing regimens in HIV-infected adults; but is higher than more expensive regimens utilizing rigampicin throughout the continuation phase. These data have important implications for TB control programs in developing countries with high TB and HIV infection rates