Initiation, scale-up and outcomes of the Cambodian National MDR-TB programme 2006-2016: hospital and community-based treatment through an NGO-NTP partnership.

Introduction: Prolonged inpatient multidrug-resistant tuberculosis (MDR-TB) treatment for all patients is not sustainable for high-burden settings, but there is limited information on community-based treatment programme outcomes for MDR-TB.

Methods: The Cambodian Health Committee, a non-governmental organisation (NGO), launched the Cambodian MDR-TB programme in 2006 in cooperation with the National Tuberculosis Program (NTP) including a community-based treatment option as a key programme component. The programme was transferred to NTP oversight in 2011 with NGO clinical management continuing.

Controlling the seedbeds of tuberculosis: diagnosis and treatment of tuberculosis infection.

The billions of people with latent tuberculosis infection serve as the seedbeds for future cases of active tuberculosis. Virtually all episodes of tuberculosis disease are preceded by a period of asymptomatic Mycobacterium tuberculosis infection; therefore, identifying infected individuals most likely to progress to disease and treating such subclinical infections to prevent future disease provides a crucial opportunity to interrupt tuberculosis transmission and reduce the global burden of tuberculosis disease. Programmes focusing on single strategies rather than comprehensive programmes that deliver an integrated arsenal for tuberculosis control might continue to struggle.

Achieving high treatment success for multidrug-resistant TB in Africa: initiation and scale-up of MDR TB care in Ethiopia--an observational cohort study.

Background: In Africa, fewer than half of patients receiving therapy for multidrug-resistant TB (MDR TB) are successfully treated, with poor outcomes reported for HIV-coinfected patients.

Methods: A standardised second-line drug (SLD) regimen was used in a non-governmental organisation-Ministry of Health (NGO-MOH) collaborative community and hospital-based programme in Ethiopia that included intensive side effect monitoring, adherence strategies and nutritional supplementation. Clinical outcomes for patients with at least 24 months of follow-up were reviewed and predictors of treatment failure or death were evaluated by Cox proportional hazards models.

TB-IRIS, T-cell activation, and remodeling of the T-cell compartment in highly immunosuppressed HIV-infected patients with TB.

Objective: To investigate the impact of tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) upon immunological recovery and the T-cell compartment after initiation of TB and antiretroviral therapy (ART).

Design And Methods: We prospectively evaluated T-cell immunophenotypes by flow cytometry and cytokines by Luminex assays in a subset (n = 154) of highly immunosuppressed HIV-infected patients with TB from the Cambodian Early versus Late Introduction of Antiretrovirals randomized clinical trial. We compared findings from patients who developed TB-IRIS with findings from patients who did not develop TB-IRIS.

Causes and determinants of mortality in HIV-infected adults with tuberculosis: an analysis from the CAMELIA ANRS 1295-CIPRA KH001 randomized trial.

Background: Shortening the interval between antituberculosis treatment onset and initiation of antiretroviral therapy (ART) reduces mortality in severely immunocompromised human immunodeficiency virus (HIV)-infected patients with tuberculosis. A better understanding of causes and determinants of death may lead to new strategies to further enhance survival.

Methods: We assessed mortality rates, causes of death, and factors of mortality in Cambodian HIV-infected adults with CD4 count ≤200 cells/µL and tuberculosis, randomized to initiate ART either 2 weeks (early ART) or 8 weeks (late ART) after tuberculosis treatment onset in the CAMELIA clinical trial.

Plasma concentrations, efficacy and safety of efavirenz in HIV-infected adults treated for tuberculosis in Cambodia (ANRS 1295-CIPRA KH001 CAMELIA trial).

Objective: To assess efavirenz plasma concentrations and their association with treatment efficacy and tolerance of efavirenz 600 mg daily in HIV-tuberculosis co-infected patients.

Methods: HIV-infected adults with CD4+ T cell count ≤ 200/mm(3) received standard 6-month tuberculosis treatment and antiretroviral therapy including a daily-dose of 600 mg of efavirenz, irrespective of their body weight. Mid-dose blood samples were drawn both on tuberculosis treatment (week +2 and week +6 after antiretroviral therapy initiation, and week 22 of follow-up) and off tuberculosis treatment (week 50 of follow-up).

Plasma concentrations of efavirenz with a 600 mg standard dose in Cambodian HIV-infected adults treated for tuberculosis with a body weight above 50 kg.

Background: The optimal dose of efavirenz for HIV-infected patients receiving a tuberculosis regimen including rifampicin remains debated, especially for subjects weighing over 50 kg. To address this issue, we measured plasma efavirenz concentrations from Cambodian adults with tuberculosis enrolled in the CAMELIA randomized trial (ClinicalTrials.gov number, NCT01300481) 6 weeks after the onset of antiretroviral therapy.

Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis.

Background: Tuberculosis remains an important cause of death among patients infected with the human immunodeficiency virus (HIV). Robust data are lacking with regard to the timing for the initiation of antiretroviral therapy (ART) in relation to the start of antituberculosis therapy.

Methods: We tested the hypothesis that the timing of ART initiation would significantly affect mortality among adults not previously exposed to antiretroviral drugs who had newly diagnosed tuberculosis and CD4+ T-cell counts of 200 per cubic millimeter or lower.

Treatment strategies for HIV-infected patients with tuberculosis: ongoing and planned clinical trials.

Currently, there are limited data to guide the management of highly active antiretroviral therapy (HAART) for human immunodeficiency virus type 1 (HIV-1)-infected patients with active tuberculosis (TB), the leading cause of death among individuals with acquired immunodeficiency syndrome (AIDS) in resource-limited areas. Four trials to take place in Southeast Asian, African, and South American countries will address the unresolved question of the optimal timing for initiation of HAART in patients with AIDS and TB: (1) Cambodian Early versus Late Introduction of Antiretrovirals (CAMELIA [ANRS 1295/NIH-CIPRA KH001]), (2) Adult AIDS Clinical Trials Group A5221, (3) START, and (4) a trial sponsored by the World Health Organization/Special Programme for Research and Training in Tropical Diseases. Two other clinical questions regarding patients with TB and HIV-1 coinfection are also undergoing evaluation: (1) the benefits of short-term HAART when CD4 cell counts are >350 cells/mm(3) (PART [NIH 1 R01 AI051219-01A2]) and (2) the efficacy of a once-daily HAART regimen in treatment-naive patients (BKVIR [ANRS 129]).

Aspartic acid homozygosity at codon 57 of HLA-DQ beta is associated with susceptibility to pulmonary tuberculosis in Cambodia.

After infection with Mycobacterium tuberculosis, clinical disease usually remains latent, contained by the host immune response. Although polymorphisms of HLA loci have been hypothesized to play a major role in the breakdown of latency, a functional link has not been established. Molecular-based HLA-typing methods were used to test the association of sets of HLA alleles encoding an aspartic acid at codon 57 of the HLA-DQ beta-chain (HLA-DQ beta57-Asp) with susceptibility to tuberculosis in a cohort of 436 pulmonary tuberculosis patients and 107 healthy controls from Cambodia.

Mycobacterium tuberculosis recall antigens suppress HIV-1 replication in anergic donor cells via CD8+ T cell expansion and increased IL-10 levels.

Mycobacterium tuberculosis (MTb) is the leading cause of death in the setting of AIDS. MTb enhances the pathogenicity and accelerates the course of HIV disease and, furthermore, infection with HIV-1 increases the risk of reactivation or reinfection with MTb. In this study, we show that host-specific recall responses to one pathogen, MTb, has a direct effect upon the regulation of a second pathogen, HIV-1.

Ethnic-specific genetic associations with pulmonary tuberculosis.

Several susceptibility-associated genetic polymorphisms have been proposed to explain differential susceptibility to tuberculosis (TB) disease progression in different populations. Here, polymorphisms in the natural resistance-associated macrophage protein 1 (NRAMP1), vitamin D receptor, tumor necrosis factor-alpha, interleukin (IL)-1, and IL-10 genes were evaluated in 358 Cambodian patients with pulmonary TB and 106 tuberculin-positive control subjects. Heterozygosity for the -1082 polymorphism of the IL-10 promoter and heterozygosity for 2 linked polymorphic NRAMP1 variants, D543N and 3' untranslated region, were associated with TB susceptibility and resistance, respectively.

Antigen-specific and persistent tuberculin anergy in a cohort of pulmonary tuberculosis patients from rural Cambodia.

Purified protein derivative (PPD) skin testing is used to identify persons infected with Mycobacterium tuberculosis (Mtb) and to assess cell-mediated immune responses to Mtb. However, lack of skin induration to intradermal injection of PPD or PPD anergy is observed in a subset of patients with active tuberculosis (TB). To investigate the sensitivity and persistence of PPD reactivity and its in vitro correlates during active TB disease and after successful chemotherapy, we evaluated the distribution of skin size induration after intradermal injection of PPD among 364 pulmonary TB patients in Cambodia.