Diagnostic accuracy and effectiveness of the Xpert MTB/RIF assay for the diagnosis of HIV-associated lymph node tuberculosis.

Xpert MTB/RIF (Xpert) is recommended for human immunodeficiency virus (HIV)-associated pulmonary tuberculosis but not extrapulmonary tuberculosis. We assessed the performance of Xpert for HIV-associated lymph node tuberculosis (LNTB), the most common type of extrapulmonary tuberculosis. Among HIV-infected adults suspected of LNTB presenting for fine needle aspirate (FNA) at a South African hospital, we assessed the diagnostic accuracy of Xpert using either FNA culture or a composite of microscopy, culture, and cytology as the reference standard, and evaluated the impact of different diagnostics on patient management. Among 344 adults with valid FNA culture and Xpert results, 84 (24 %) were positive on microscopy, 149 (43 %) on culture, 152 (53 %) on Xpert, and 181 (57 %) had a cytology result suggestive of tuberculosis. Using liquid culture as the reference standard, the specificity of a single Xpert was suboptimal (88.2 %) but the sensitivity was high [93.3 %, 95 % confidence interval (CI) 87.6-96.6] and increased with decreasing CD4 count (from 87.0 % for CD4 >250 to 98.6 % for CD4 <100 cells/mm(3)). Using a composite reference standard reduced the sensitivity to 79.2 % but increased the specificity to 98.6 %. All Xpert-positive patients initiated treatment within one day, compared to 70 % of culture-positive but Xpert-negative and 13 % of culture- and Xpert-negative but cytology-positive patients. Xpert is accurate and effective and could be endorsed as the initial diagnostic for HIV-associated LNTB.

TB/HIV integration at primary care level: A quantitative assessment at 3 clinics in Johannesburg, South Africa.

BACKGROUND: In 2004 the World Health Organization WHO) released the Interim Policy on Collaborative TB/ HIV activities. According to the policy, for people living with HIV (PLWH), activities include intensified case finding, isoniazid preventive therapy (IPT) and infection control. For TB patients, activities included HIV counselling and testing HCT), prevention messages, and cotrimoxazole preventive therapy (CPT), care and support, and antiretroviral therapy ART) for those with HIV-associated TB. While important progress has been made in implementation, targets of the WHO Global Plan to Stop TB have not been reached. OBJECTIVE: To quantify TB/HIV integration at 3 primary healthcare clinics in Johannesburg, South Africa. METHODS: Routinely collected TB and HIV data from the HCT register, TB 'suspect' register, TB treatment register, clinic files and HIV electronic database, collected over a 3-month period, were reviewed. RESULTS: Of 1 104 people receiving HCT: 306 (28%) were HIV-positive; a CD4 count was documented for 57%; and few received TB screening or IPT. In clinic encounters among PLWH, 921 (15%) had documented TB symptoms; only 10% were assessed by smear microscopy, and few asymptomatic PLWH were offered IPT. Infection control was poorly documented and implemented. HIV status was documented for 155 (75%) of the 208 TB patients; 90% were HIV-positive and 88% had a documented CD4 count. Provision of CPT and ART was poorly documented. CONCLUSION: The coverage of most TB/HIV collaborative activities was below Global Plan targets. The lack of standardised recording tools and incomplete documentation impeded assessment at facility level and limited the accuracy of compiled data.

Symptom and digital chest X-ray TB screening in South African prisons: yield and cost-effectiveness.

BACKGROUND: Correctional inmates are at a high risk of tuberculosis (TB). The optimal approach to screening this population is unclear.METHODS: We retrospectively reviewed records from TB screening in 64 correctional facilities in South Africa between January 2015 and July 2016. Inmates received symptom screening (any of cough, fever, weight loss, or night sweats) combined with digital chest X-ray (CXR), when available. CXRs were assessed as 'abnormal' or with no abnormalities. Inmates with either a symptom or an 'abnormal' CXR were asked to provide a single spot sputum for Xpert® MTB/RIF testing. We estimated the incremental cost-effectiveness ratio (ICER) per additional TB case detected using CXR screening among asymptomatic inmates.RESULTS: Of 61 580 inmates, CXR screening was available for 41 852. Of these, 19 711 (47.1%) had TB symptoms. Among 22 141 inmates without symptoms, 1939/19 783 (9.8%) had an abnormal CXR, and 8 (1.2%) were Xpert-positive among those with Xpert tests done. Of 14 942 who received symptom screening only and had symptoms, 84% (12 616) had an Xpert result, and 105 (0.8%) were positive. The ICER for CXR screening was US$22 278.CONCLUSION: Having CXR in addition to symptom screening increased yield but added considerable cost. A major limitation of screening was the low specificity of the symptom screen.

Automated chest radiography and mass systematic screening for tuberculosis.

BACKGROUND: Systematic screening for TB using automated chest radiography (ACR) with computer-aided detection software (CAD4TB) has been implemented at scale in Karachi, Pakistan. Despite evidence supporting the use of ACR as a pre-screen prior to Xpert® MTB/RIF diagnostic testing in presumptive TB patients, there has been no data published on its use in mass screening in real-world settings.METHOD: Screening was undertaken using mobile digital X-ray vehicles at hospital facilities and community camps. Chest X-rays were offered to individuals aged ≥15 years, regardless of symptoms. Those with a CAD4TB score of ≥70 were offered Xpert testing. The association between Xpert positivity and CAD4TB scores was examined using data collected between 1 January and 30 June 2018 using a custom-built data collection tool.RESULTS: Of the 127 062 individuals screened, 97.2% had a valid CAD4TB score; 11 184 (9.1%) individuals had a CAD4TB score ≥70. Prevalence of Xpert positivity rose from 0.7% in the <50 category to 23.5% in the >90 category. The strong linear association between CAD4TB score and Xpert positivity was found in both community and hospital settings.CONCLUSION: The strong association between CAD4TB scores and Xpert positivity provide evidence that an ACR-based pre-screening performs well when implemented at scale in a high-burden setting.

Impact of adverse drug reactions on the incremental cost-effectiveness of bedaquiline for drug-resistant tuberculosis.

BACKGROUND: Adverse drug reactions (ADRs) are common during standard, long-course treatment for multidrug-resistant and rifampicin-resistant tuberculosis (MDR-/RR-TB). In particular, second-line injectables (SLIs) are associated with permanent hearing loss, acute renal injury and electrolyte imbalance. We adapted an established Markov model for ambulatory treatment to estimate the impact of the toxicity profile on the incremental cost-effectiveness ratio (ICER) for a proposed MDR-/RR-TB regimen replacing the SLI with bedaquiline (BDQ). METHODS: Treatment effectiveness was evaluated in disability-adjusted life-years (DALYs). Clinical outcomes and ingredient costs from a provider perspective were derived from the South African public-sector treatment program or extracted from the literature. Costs and effectiveness were discounted at 3% per year over 10 years. RESULTS: A BDQ-based MDR-/RR-TB regimen compared with the SLI regimen had a mean ICER of US$516 per DALY averted using the standard Markov model. Costs for both regimens increased and effectiveness decreased for the SLI regimen once adjusted for toxicity. The resulting ICER for the BDQ-based regimen was cost saving (US$96/patient) and more effective (0.96 DALYs averted) after adjusting for ADRs. CONCLUSION: Decision-analysis models of treatment for MDR-/RR-TB, including new drug regimens, should consider the costs of managing ADRs and their sequelae.

Direct costs of managing adverse drug reactions during rifampicin-resistant tuberculosis treatment in South Africa.

OBJECTIVE: To estimate the provider costs of managing adverse drug reactions (ADRs) to standard long-course treatment for multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB) according to South African guidelines. METHODS: We parameterised a published Markov health state model for MDR/RR-TB with guidelines-based, bottom-up public-sector provider costing of ADR management. Frequency of ADR occurrence was extracted from the literature. Costs were estimated over 10 years, discounted 3% annually and tested using probabilistic sensitivity analysis. RESULTS: On average, guidelines-based costing of moderate ADRs weighted by the frequency of occurrence was US$135.76 (standard deviation [SD] US$17.18) and the cost of serious ADRs was US$521.29 (SD US$55.99). We estimated that the incremental costs of ADR management were US$380.17 annually per patient initiating MDR/RR-TB treatment. The incremental costs of ADR management for the public health sector in South Africa was US$4.76 million, 8.3% of the estimated cohort costs of MDR/RR-TB treatment ($57.55 million) for the 2015 cohort of 12 527 patients. CONCLUSIONS: Management of multiple ADRs and serious ADRs, which are common during the first 6 months of standard, long-course MDR/RR-TB treatment, substantially increases provider treatment costs. These results need to be taken into account when comparing regimen costs, and highlight the urgent need to identify drug regimens with improved safety profiles.

Persistently high early mortality despite rapid diagnostics for drug-resistant tuberculosis cases in South Africa.

OBJECTIVE: To describe the timing and predictors of mortality among multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB) patients reported in the South African electronic drug-resistant TB register (EDRweb), 2012-2014. DESIGN: We present time-to-event survival analysis and Cox proportional hazards regression. Identity numbers were matched to the National Vital Statistics Register. RESULTS: Of the 20 653 patients included in the analysis (median age 35 years, interquartile range 28-43), over half were male (n = 10 944, 53.0%). Most were human immunodeficiency virus (HIV) positive (n = 14 174, 68.9%), most of whom were on antiretroviral therapy (ART; n = 12 471, 88.0%). At 24 months, 4689 patients had died (22.7%); 2072 deaths (44.2%) were reported within 12 weeks of initiating treatment for MDR/RR-TB. From week 12 to week 24, there were 717 deaths/18 048 persons; 59.5% of mortality occurred within the first 24 weeks. During the first 12 weeks, the adjusted hazard rate (aHR) for mortality was highest among patients with a missing baseline culture result (aHR 3.78, 95%CI 2.94-4.86) and among HIV-positive, ART-naïve patients (aHR 3.40, 95%CI 2.90-3.99). Patients initiating MDR/RR-TB treatment within 4 weeks of diagnosis had higher mortality than those with delayed initiation (aHR 1.57, 95%CI 1.41-1.75). CONCLUSION: In EDRweb, mortality is highest in the first few weeks after MDR/RR-TB treatment initiation.

Successes, challenges and lessons from a novel deployment of Xpert(®) MTB/RIF at a major South African public event [Short Communication].

In a mobile deployment of Xpert(®) MTB/RIF (Xpert) at the public event for 2012 South African World TB Day, Xpert testing was offered to tuberculosis (TB) symptomatic clients from gold mining and surrounding communities. Considerations before implementation included effective TB symptom screening; safe, effective sputum collection; uninterrupted electricity supply; stringent instrument verification and provision of on-site results. Public event Xpert testing is feasible; however, the case-finding rate was very low (0.7%). We recommend exploring enhanced symptom screening algorithms to improve pre-test probability, cost-effectiveness analysis, exploring alternate electrical fail-safes and on-site data connectivity and improving management of client expectations.

Point-of-care Xpert® MTB/RIF for smear-negative tuberculosis suspects at a primary care clinic in South Africa.

OBJECTIVE: To assess the clinical utility and cost of point-of-care Xpert® MTB/RIF for the diagnosis of smear-negative tuberculosis (TB). DESIGN: Cohort study of smear-negative TB suspects at a South African primary care clinic. Participants provided one sputum sample for fluorescent smear microscopy and culture and an additional sample for Xpert. Outcomes of interest were TB diagnosis, linkage to care, patient and provider costs. RESULTS: Among 199 smear-negative TB suspects, 16 were positive by Xpert, 15 by culture and 7 by microscopy. All cases identified by Xpert began anti-tuberculosis treatment the same or next day; only one of five Xpert-negative culture-positive cases started treatment after 34 days. Xpert at point of care offered similar diagnostic yield but a faster turnaround time than smear and culture performed at a centralized laboratory. Compared to smear plus culture, Xpert (at US$9.98 per cartridge) was US$3 less expensive per valid result (US$21 vs. US$24) and only US$6 more costly per case identified (US$266 vs. US$260). CONCLUSION: Xpert is an effective method of diagnosing smear-negative TB. It is cost saving for patients, especially if performed at point of care, but it is costly for health care providers. Data-driven studies are needed to determine its cost-effectiveness in resource-poor settings with diverse diagnostic practices.

False-positive rifampicin resistance on Xpert® MTB/RIF: case report and clinical implications.

The World Health Organization had endorsed Xpert® MTB/RIF (Xpert) as the initial diagnostic for multidrug-resistant tuberculosis (TB) or TB suspects co-infected with the human immunodeficiency virus. We investigated an unexpected case of rifampicin (RMP) resistance on Xpert using repeat Xpert, smear microscopy, MTBDRplus assay, culture, drug susceptibility testing, spoligotyping and rpoB gene sequencing. A false-positive result was most likely, given the wild type rpoB gene sequence and exclusion of both mixed infection and mixture of drug-susceptible and drug-resistant populations. When decentralising Xpert, test performance characteristics need to be understood by health care workers and methods of confirmation of RMP resistance need to be accessible.

Antiretroviral therapy initiation during tuberculosis treatment and HIV-RNA and CD4 T-lymphocyte responses.

SETTING: A large human immunodeficiency virus (HIV) clinic in South Africa. OBJECTIVE: To examine the effect of initiating antiretroviral therapy (ART) on CD4 and viral response at different time periods during anti-tuberculosis treatment (<14 days, 15-60 days, or ≥60 days) using prospectively collected clinical data. METHODS: Cohort data analysis for 1499 patients with tuberculosis (TB) and HIV co-infection classified according to timing of ART after the initiation of anti-tuberculosis treatment. RESULTS: In adjusted modified Poisson regression models, CD4 and viral responses showed no significant differences according to timing of ART initiation (failure to increase CD4 by 6 months, <14 days vs. >60 days: RR 1.02, 95%CI 0.85-1.22; 15-60 days vs. >60 days: RR 1.00, 95%CI 0.86-1.15; failure to suppress virus by 6 months, <14 days vs. >60 days: RR 0.98, 95%CI 0.59-1.63; 15-60 days vs. >60 days: RR 0.96, 95%CI 0.66-1.41 and viral rebound at 12 months, 14 days vs. >60 days: RR 1.43, 95%CI 0.50-4.12; 15-60 days vs. >60 days: RR 1.14, 95%CI 0.39-3.34). Similar estimates were found in analysis restricted to patients with severe immunosuppression. CONCLUSION: Concerns over the overlapping impact of anti-tuberculosis treatment with ART on ART response should not be a reason for delaying ART in patients with HIV-associated TB.

Effects of anticoagulants and temperature on expression of activation markers CD11b and HLA-DR on human leukocytes.

A whole-blood model was used to evaluate the effects of temperature and anticoagulant on the expression of activation markers HLA-DR and CD11b on peripheral leukocytes. Venous blood, anticoagulated with either EDTA or heparin, was obtained from six healthy blood donors and 13 hospitalized patients (8 human immunodeficiency virus type 1-seropositive individuals with concurrent pulmonary tuberculosis and 5 patients with pneumonia). A preliminary evaluation was carried out with whole blood from two of the normal donors, and cells were stained immediately for HLA-DR and CD11b markers or stained after incubation at room temperature or 37 degreesC for 18 h with or without the addition of the cytokines gamma interferon (IFN-gamma), granulocyte-macrophage colony-stimulating factor (GM-CSF), IFN-gamma plus GM-CSF, tumor necrosis factor beta, or interleukin-6. Of the cytokines tested, the combination of IFN-gamma and GM-CSF had the most pronounced modulation of marker expression on polymorphonuclear neutrophils (PMN), in particular, HLA-DR expression, which required induction for its detection. These cytokines were therefore used in further evaluations that considered the above-mentioned effects in the presence of disease. Results indicated that the expression of activation markers on PMN and lymphocytes in whole blood are influenced by the temperature of incubation and the choice of anticoagulant and the effects noted were dependent on (i) the particular cell surface marker, (ii) the cell type being studied, and (iii) the presence or absence of disease. It is therefore recommended that ex vivo whole-blood models for evaluating phenotype or immune function be carefully evaluated for the above-mentioned effects.

Influence of antimicrobial chemotherapy on spirometric parameters and pro-inflammatory indices in severe pulmonary tuberculosis.

Patients who have completed a treatment for severe pulmonary tuberculosis (TB) are often left with severe respiratory disability. There have been few prospective studies assessing the effect of treatment on lung function in such patients. The influence of antimicrobial chemotherapy on lung function was investigated over a six month period in patients with newly diagnosed pulmonary TB to test the hypothesis that treatment improves lung function, as well as to identify factors that may influence lung function outcome. Seventy-six patients were recruited into the study, of whom 74 completed the treatment programme. Forty-two were current smokers and 13 seropositive for the human immunodeficiency virus. Improvement in lung function occurred in 54% of patients, but residual airflow limitation or a restrictive pattern was evident in 28% and 24% of patients, respectively. The extent of lung infiltration (radiographic score) both at the outset and after chemotherapy was significantly and negatively related to forced expiratory volume in one second (FEV1) (% pred) (r=-0.41, and r=-0.46, respectively). The post-treatment serum C-reactive protein and alpha1-protease inhibitor levels were negatively associated with FEV1 (% pred) (r=-0.30 and r=-0.35, respectively). These findings demonstrate that, while antimicrobial chemotherapy may lead to improved lung function in patients with pulmonary tuberculosis, a large proportion of patients has residual impairment. The most significant factor influencing post-treatment lung function status, as measured by forced expiratory volume in one second (% predicted), is the pretreatment and post-treatment radiographic score, which acts as a marker of the extent of pulmonary parenchymal involvement in tuberculosis.