BACKGROUND: The WHO has developed target product profiles (TPPs) describing the most appropriate qualities for future TPT regimens to assist developers in aligning the characteristics of new treatments with programmatic requirements.METHODS: A technical consultation group was convened by the WHO to determine regimen attributes with greatest potential impact for patients (i.e., improved risk/benefit profile) and populations (i.e., reduction in transmission and TB prevalence). The group categorised regimen attributes as 'priority´ or 'desirable´; and defined for each attribute the minimum requirements and optimal targets.RESULTS: Nine priority attributes were defined, including efficacy, treatment duration, safety, drug-drug interactions, barrier to emergence of drug resistance, target population, formulation, dosage, frequency and route of administration, stability and shelf life. Regimens meeting optimal targets were characterised, for example, as having superior efficacy, treatment duration of ≤2 weeks, and improved tolerability and safety profile compared with current regimens. The four desirable attributes included regimen cost, safety in special populations, treatment adherence and need for drug susceptibility testing in the index patient.DISCUSSION: It may be difficult for a single regimen to satisfy all characteristics so regimen developers may have to consider trade-offs. Additional operational aspects may be relevant to the feasibility and public health impact of new TPT regimens.

BACKGROUND: In 2018, the WHO Member States committed to providing TB preventive treatment (TPT) to at least 30 million people by 2022. However, only 6.3 million people had initiated TPT by the end of 2019. Major knowledge gaps and research needs in diagnosis, treatment and the programmatic management of TPT (PMTPT) require to be addressed urgently. METHODS: In September 2019, a group of stakeholders involved in PMTPT in high TB burden countries met to develop an action agenda to support the global expansion of PMTPT. RESULTS: Barriers at the health system level, and priorities for research to overcome these, were identified for each step of the PMTPT cascade. The need for data on TPT financing, gaps and coverage under national health insurance schemes, as well as the need for mathematical and cost-effectiveness modelling of the impact of TPT on TB incidence and mortality were highlighted. Specific research needs were identified for high-risk populations such as household contacts of any age and people living with HIV, as well as other people at risk. CONCLUSIONS: The meeting facilitated agreement on a set of actions needed to ensure that PMTPT continues to expand to achieve the End TB Strategy targets.

SETTING: Treatment for latent tuberculous infection (LTBI) reduces the risk of tuberculosis (TB) disease. Shorter, rifamycin-containing regimens have been shown to be as effective as 6 months of isoniazid and superior with regard to safety and completion rate. It is unknown whether preventive therapy with rifamycins increases resistance to the drugs used.OBJECTIVE : To determine whether treatment for LTBI with rifamycin-containing regimens leads to significant development of resistance against rifamycins.DESIGN: Systematic review and meta-analysis.RESULTS: We included six randomised-controlled trials of rifamycin-containing regimens for LTBI treatment that reported drug resistance. There was no statistically significant increased risk of rifamycin resistance after LTBI treatment with rifamycin-containing regimens compared to non-rifamycin-containing regimens (RR 3.45, 95%CI 0.72-16.56; P = 0.12) or placebo (RR 0.20, 95%CI 0.02-1.66; P = 0.13).CONCLUSION: Preventive treatment with rifamycin-containing regimens does not significantly increase rifamycin resistance. Programmatic management of LTBI requires the creation of sound surveillance systems to monitor drug resistance.

BACKGROUND Implementation of new tuberculosis (TB) diagnostic strategies in resource-constrained settings is challenging. We measured the impact of solid and liquid mycobacterial cultures on treatment practices for patients undergoing TB evaluation in Kampala, Uganda. METHODS We enrolled consecutive smear-negative, human immunodeficiency virus positive adults with cough of ⩾2 weeks from September 2009 to April 2010. Laboratory technicians performed mycobacterial cultures on solid and liquid media. We compared empiric treatment decisions with solid and liquid culture in terms of diagnostic yield and time to results, and assessed impact on patient management. RESULTS Of 200 patients enrolled, 26 (13%) had culture-confirmed TB: 22 (85%) on solid culture alone, 2 (8%) on liquid culture alone, and 2 (8%) on both solid and liquid culture. Thirty-four patients received empiric anti-tuberculosis treatment, but only 10 (29%) were culture-positive. Median time to a positive result on solid culture was 92 days (interquartile range [IQR] 69-148) compared to 106 days (IQR 66-157) for liquid culture. No patients initiated treatment following a positive result on liquid culture. CONCLUSION The introduction of mycobacterial culture did not influence care for patients undergoing evaluation for TB in Kampala, Uganda. Attention to contextual factors surrounding implementation is needed to ensure the effective introduction of new testing strategies in low-income countries.

BACKGROUND:Peripheral blood interferon-gamma release assays (IGRAs) have sub-optimal sensitivity and specificity for diagnosis of active pulmonary tuberculosis (TB). However, assessment of local immune responses has been reported to improve the accuracy of TB diagnosis. METHODS:We enrolled HIV-infected adults with cough ≥2 weeks' duration admitted to Mulago Hospital in Kampala, Uganda and referred for bronchoscopy following two negative sputum acid-fast bacillus smears. We performed an ELISPOT-based IGRA (T-SPOT.TB®, Oxford Immunotec, Oxford, UK) using peripheral blood and bronchoalveolar lavage (BAL) fluid mononuclear cells, and determined the accuracy of IGRAs using mycobacterial culture results as a reference standard. RESULTS:94 HIV-infected patients with paired peripheral blood and BAL IGRA results were included. The study population was young (median age 34 years [IQR 28-40 years]) and had advanced HIV/AIDS (median CD4+ T-lymphocyte count 60 cells/µl [IQR 22-200 cells/µl]). The proportion of indeterminate IGRA results was higher in BAL fluid than in peripheral blood specimens (34% vs. 14%, difference 20%, 95% CI 7-33%, p = 0.002). BAL IGRA had moderate sensitivity (73%, 95% CI 50-89%) but poor specificity (48%, 95% CI 32-64%) for TB diagnosis. Sensitivity was similar (75%, 95% CI 57-89%) and specificity was higher (78%, 95% CI 63-88%) when IGRA was performed on peripheral blood. CONCLUSIONS:BAL IGRA performed poorly for the diagnosis of smear-negative TB in a high HIV/TB burden setting. Further studies are needed to examine reasons for the large proportion of indeterminate results and low specificity of BAL IGRA for active TB in high HIV/TB burden settings.

OBJECTIVEWe describe chest radiograph (CXR) findings in a population with a high prevalence of human immunodeficiency virus (HIV) and tuberculosis (TB) in order to identify radiological features associated with TB; to compare CXR features between HIV-seronegative and HIV-seropositive patients with TB; and to correlate CXR findings with CD4 T-cell count.METHODSConsecutive adult patients admitted to a national referral hospital with a cough of duration of 2 weeks or longer underwent diagnostic evaluation for TB and other pneumonias, including sputum examination and mycobacterial culture, bronchoscopy and CXR. Two radiologists blindly reviewed CXRs using a standardised interpretation form.RESULTSSmear or culture-positive TB was diagnosed in 214 of 403 (53%) patients. Median CD4+ T-cell count was 50 cells mm(-3) [interquartile range (IQR) 14-150]. TB patients were less likely than non-TB patients to have a normal CXR (12% vs 20%, p = 0.04), and more likely than non-TB patients to have a diffuse pattern of opacities (75% vs 60%, p = 0.003), reticulonodular opacities (45% vs 12%, p < 0.001), nodules (14% vs 6%, p = 0.008) or cavities (18% vs 7%, p = 0.001). HIV-seronegative TB patients more often had consolidation (70% vs 42%, p = 0.007) and cavities (48% vs 13%, p < 0.001) than HIV-seropositive TB patients. TB patients with a CD4+ T-cell count of ≤ 50 cells mm(-3) less often had consolidation (33% vs 54%, p = 0.006) and more often had hilar lymphadenopathy (30% vs 16%, p = 0.03) compared with patients with CD4 51-200 cells mm(-3).CONCLUSIONAlthough different CXR patterns can be seen in TB and non-TB pneumonias there is considerable overlap in features, especially among HIV-seropositive and severely immunosuppressed patients. Providing clinical and immunological information to the radiologist might improve the accuracy of radiographic diagnosis of TB.

Bronchoscopy is useful for diagnosing smear-negative tuberculosis in HIV-infected patientsTo the Editors:Tuberculosis (TB) is the leading cause of morbidity and mortality in HIV-infected patients in sub-Saharan Africa [1], in part because limited availability of diagnostic tests hinders early, directed treatment.Studies have demonstrated a substantial yield of bronchoscopy for diagnosing HIVassociated opportunistic pulmonary diseases, but few studies have explicitly considered whether bronchoscopy adds to the sensitivity of sputum culture in identifying Mycobacterium tuberculosis, or whether bronchoscopy shortens the time needed to diagnose TB.Although bronchoscopy is unavailable in many HIV and TB endemic settings, where it is available its usefulness for TB diagnosis is uncertain.Thus, we examined the performance of bronchoscopy to diagnose TB and other pulmonary diseases in HIV-infected inpatients with cough in Kampala, Uganda.We performed a prospective cross-sectional study enrolling consecutive HIV-infected patients aged o18 yrs hospitalised at Mulago Hospital with cough of o2 weeks but ,6 months duration.After providing informed consent, patients underwent a standard evaluation including chest radiography, sputum acid-fast bacillus (AFB) microscopy and bronchoscopy with bronchoalveolar lavage (BAL) if they were AFB smearnegative, according to previously described protocols [2].Trained technicians examined BAL by smear and/or culture for mycobacteria, Pneumocystis jirovecii, and other fungi.Specific pneumonia treatment was recorded.Patients were seen at a 2-month follow-up visit, after which a pulmonologist and a medical officer assigned final diagnoses based on all diagnostic information and according to a standardised protocol.A final diagnosis of pulmonary TB was based on a positive sputum mycobacterial culture (using Lowenstein-Jensen media), positive BAL AFB smear or BAL mycobacterial culture, or a clinical response to TB treatment at the 2-month follow-up visit.

SETTING: Mulago Hospital, Kampala, Uganda.OBJECTIVE: To evaluate the diagnostic performance of fluorescence microscopy (FM) for diagnosing pulmonary tuberculosis (TB) in a high human immunodeficiency virus (HIV) prevalence setting.DESIGN: Consecutive in-patients with cough for >2 weeks submitted two sputum specimens for smear microscopy. Smears were examined by conventional light microscopy (CM) and FM. The performance of the two methods was compared using mycobacterial culture as a reference standard.RESULTS: A total of 426 patients (82% HIV infected) were evaluated. FM identified 11% more smear-positive patients than CM (49% vs. 38%, P < 0.001). However, positive FM results were less likely than positive CM results to be confirmed by culture when smears were read as either 'scanty' (54% vs. 90%, P < 0.001) or 1+ (82% vs. 91%, P = 0.02). Compared to CM, the sensitivity of FM was higher (72% vs. 64%, P = 0.005), and the specificity lower (81% vs. 96%, P < 0.001). In receiver operating characteristic analysis, maximum area under the curve for FM was obtained at a threshold of >4 acid-fast bacilli/100 fields (sensitivity 68%, specificity 90%).CONCLUSION: Although FM increases the sensitivity of sputum smear microscopy, additional data on FM specificity and on the clinical consequences associated with false-positive FM results are needed to guide implementation of this technology in high HIV prevalence settings.

SETTING:Thirteen primary health care (PHC) facilities in the Stellenbosch District, South Africa.OBJECTIVE:To assess the use of a sputum register to evaluate the tuberculosis (TB) diagnostic process and the initiation of TB treatment in selected PHC facilities in a country with a centralised laboratory system.DESIGN:This prospective study was conducted between April 2004 and March 2005. The names of all individuals submitting sputum samples for TB testing were noted in a newly introduced sputum register. We classified all TB suspects with two positive smears as TB cases and consulted TB treatment registers until 3 months after sputum submission to determine how many had started treatment.RESULTS:A total of 4062 persons aged > or =15 years submitted sputum samples, of whom 2484 were TB suspects. There were 2037 suspects with at least two results, 367 (18%) had at least two positive smears and 64 (17%) of these did not start treatment (initial defaulters). Over the entire diagnostic process, up to 5% of TB cases were missed, and up to 26% did not start treatment and were not reported.CONCLUSION:By correcting diagnostic weaknesses identified in the sputum register, PHC facilities will be able to detect, treat and cure a higher percentage of TB patients.