Cost and impact of decentralized tuberculosis testing: a modeling analysis of price thresholds for molecular instruments in high-burden settings

RationaleHigh rates of recurrent tuberculosis after successful treatment have been reported from different high burden settings in Sub-Saharan Africa. However, little is known about the rate of smear-positive tuberculosis after treatment default. In particular, it is not known whether or not treatment defaulters continue to be or become again smear-positive and thus pose a potential for transmission of infection to others.ObjectiveTo investigate, in a high tuberculosis burden setting, the rate of re-treatment for smear-positive tuberculosis among cases defaulting from standardized treatment compared to successfully treated cases.MethodsRetrospective cohort study among smear-positive tuberculosis cases treated between 1996 and 2008 in two urban communities in Cape Town, South Africa. Episodes of re-treatment for smear-positive tuberculosis were ascertained via probabilistic record linkage. Survival analysis and Poisson regression were used to compare the rate of smear-positive tuberculosis after treatment default to that after successful treatment.ResultsA total of 2,136 smear-positive tuberculosis cases were included in the study. After treatment default, the rate of re-treatment for smear-positive tuberculosis was 6.86 (95% confidence interval [CI]: 5.59–8.41) per 100 person-years compared to 2.09 (95% CI: 1.81–2.41) after cure (adjusted Hazard Ratio [aHR]: 3.97; 95% CI: 3.00–5.26). Among defaulters, the rate was inversely associated with treatment duration and sputum conversion prior to defaulting. Smear grade at start of the index treatment episode (Smear3+: aHR 1.61; 95%CI 1.11–2.33) was independently associated with smear-positive tuberculosis re-treatment, regardless of treatment outcome.ConclusionsIn this high-burden setting, there is a high rate of subsequent smear-positive tuberculosis after treatment default. Treatment defaulters are therefore likely to contribute to the pool of infectious source cases in the community. Our findings underscore the importance of preventing treatment default, as a means of successful tuberculosis control in high-burden settings.

The utility of T-cell interferon-gamma (IFN-gamma) responses to Mycobacterium tuberculosis specific antigens [interferon-gamma release assays (IGRAs)] in high-burden settings remains unclear and there is growing evidence that IGRA performance varies across high tuberculosis (TB) burden vs. low TB burden settings. Here we review the evidence supporting the utility of IGRAs in specific subgroups and compare their performance in high-burden vs. low-burden settings. Although the IGRA, compared with the tuberculin skin test (TST), has greater specificity in BCG-vaccinated individuals, treatment of latent tuberculosis infection is not a priority in high-burden setting. Nevertheless, in high-burden settings, the TST performs reasonably well and correlates as well, or better, with proxy measures of exposure. IGRAs may still be useful in high-burden settings in specific subgroups at high risk of progression, including young children, HIV-infected individuals and healthcare workers, but this requires confirmation. Although the IGRAs cannot distinguish between latent and active TB, their utility as rule-out tests, when combined with smear microscopy or the TST, requires further study. Prospective studies are required in high-burden settings to confirm whether IFN-gamma responses are predictive of high risk of progression to active TB, particularly in HIV-infected individuals.

Effect of empirical treatment on outcomes of clinical trials of diagnostic assays for tuberculosis

Screening Strategies for Tuberculosis in Children With Kidney Disease: What Is Cost-Effective?

Rapid diagnosis of tuberculosis (TB) is an effective measure to eradicate this infectious disease worldwide. Traditional methods for screening TB patients do not provide an immediate diagnosis and thus delay treatment. There is an urgent need for the early detection of TB through point-of-care tests (POCTs). Several POCTs are widely available at primary healthcare facilities that assist in TB screening. In addition to the currently used POCTs, advancements in technology have led to the discovery of newer methods that provide accurate and fast information independent of access to laboratory facilities. In the present article, the authors tried to include and describe the potential POCTs for screening TB in patients. Several molecular diagnostic tests, such as nucleic acid amplification tests, including GeneXpert and TB-loop-mediated isothermal amplification, are currently being used as POCTs. Besides these methods, the pathogenic component of Mycobacterium tuberculosis can also be utilized as a biomarker for screening purposes through immunological assays. Similarly, the host immune response to infection has also been utilized as a marker for the diagnosis of TB. These novel biomarkers might include Mtb85, interferon-γ inducible protein-10, volatile organic compounds, acute-phase proteins, etc. Radiological tests have also been observed as POCTs in the TB screening POCT panel. Various POCTs are performed on samples other than sputum, which further eases the screening process. These POCTs should not require large-scale manpower and infrastructure. Hence, POCT should be able to identify patients with M. tuberculosis infection at the primary healthcare level only. There are several other advanced techniques that have been proposed as future POCTs and have been discussed in the present article.

To determine the treatment success rate among TB patients and associated factors in Anambra and Oyo, the two states with the largest burden of tuberculosis in Nigeria. A health facility record review for 2016 was conducted in the two states (Anambra and Oyo). A checklist was used to extract relevant information from the records kept in each of the selected DOTS facilities to determine TB treatment success rates. Treatment success rate was defined as the proportion of new smear-positive TB cases registered under DOTS in a given year that successfully completed treatment, whether with bacteriologic evidence of success ('cured') or without ('treatment completed'). Treatment success rate was classified into good (≥85%) and poor (<85%) success rates using the 85% national target for TB treatment outcome. Data were analysed using descriptive statistics and chi-square at P<0.05. There were 1281TB treatment enrollees in 2016 in Anambra and 3809 in Oyo (total=4835). An overall treatment success rate of 75.8% was achieved (Anambra-57.5%; Oyo-82.0%). The percentage cure rates were 61.5% for Anambra and 85.2% for Oyo. Overall, only 28.6% of the facilities in both states (Anambra-0.0%; Oyo-60.0%) had a good treatment success rate. More facilities in Anambra (100.0%) than Oyo (40.0%) had a poor treatment success rate (p<0.001), as did more private/FBO (100.0%) than public health facilities (60.0%) (p=0.009). All tertiary facilities had a poor treatment success rate followed by 87.5% of secondary health facilities and 56.5% of primary healthcare facilities (P=0.035). Treatment success and cure rates in Anambra state were below the 85.0% of the recommended target set by the WHO. Geographical location, and level/tier and type of facility were factors associated with this. Interventions are recommended to address these problems.

Although interferon-γ release assays (IGRAs) are intended for diagnosing latent tuberculosis (TB), we hypothesised that in a high-burden setting: 1) the magnitude of the response when using IGRAs can distinguish active TB from other diagnoses; 2) IGRAs may aid in the diagnosis of smear-negative TB; and 3) IGRAs could be useful as rule-out tests for active TB. We evaluated the accuracy of two IGRAs (QuantiFERON®-TB Gold In-tube (QFT-GIT) and T-SPOT®.TB) in 395 patients (27% HIV-infected) with suspected TB in Cape Town, South Africa. IGRA sensitivity and specificity (95% CI) were 76% (68-83%) and 42% (36-49%) for QFT-GIT and 84% (77-90%) and 47% (40-53%) for T-SPOT®.TB, respectively. Although interferon-γ responses were significantly higher in the TB versus non-TB groups (p<0.0001), varying the cut-offs did not improve discriminatory ability. In culture-negative patients, depending on whether those with clinically diagnosed TB were included or excluded from the analysis, the negative predictive value (NPV) of QFT-GIT, T-SPOT®.TB and chest radiograph in smear-negative patients varied between 85 and 89, 87 and 92, and 98% (for chest radiograph), respectively. Overall accuracy was independent of HIV status and CD4 count. In a high-burden setting, IGRAs alone do not have value as rule-in or -out tests for active TB. In smear-negative patients, chest radiography had better NPV even in HIV-infected patients.

To examine the usefulness of an interferon-gamma release assay (IGRA) for the diagnosis of smear-negative tuberculosis (TB) in China. A total of 624 patients with presumed pulmonary TB were enrolled prospectively and categorised as smear-negative TB, smear-positive TB or no TB. All patients were tested using T-SPOT.TB. Both the smear-negative and smear-positive TB groups had significantly more spot-forming cells (SFCs) than the no TB group (all P < 0.001), while the smear-negative group had fewer SFCs than the smear-positive TB group (P < 0.001). The specificity of T-SPOT.TB was 60.4% (95%CI 53.4-67.1). The sensitivities of T-SPOT.TB in the smear-negative and smear-positive TB groups were respectively 81.4% (95%CI 75.7-86.0) and 93.2% (95%CI 87.6-96.4). The sensitivity in the smear-negative TB group was much lower than that in the smear-positive TB (P < 0.05). The sensitivity of T-SPOT.TB was lower due the paucibacillary nature of the samples, and the specificity was lower due to the high prevalence of latent tuberculous infection in the smear-negative TB patients. The T-SPOT.TB test should only be used as a supplementary test and not as a single test to rule in or rule out smear-negative TB.

The World Health Organization's 2035 vision is to reduce tuberculosis (TB) associated mortality by 95%. While low-burden, well-equipped industrialised economies can expect to see this goal achieved, it is challenging in the low- and middle-income countries that bear the highest burden of TB. Inadequate diagnosis leads to inappropriate treatment and poor clinical outcomes. The roll-out of the Xpert(®) MTB/RIF assay has demonstrated that molecular diagnostics can produce rapid diagnosis and treatment initiation. Strong molecular services are still limited to regional or national centres. The delay in implementation is due partly to resources, and partly to the suggestion that such techniques are too challenging for widespread implementation. We have successfully implemented a molecular tool for rapid monitoring of patient treatment response to anti-tuberculosis treatment in three high TB burden countries in Africa. We discuss here the challenges facing TB diagnosis and treatment monitoring, and draw from our experience in establishing molecular treatment monitoring platforms to provide practical insights into successful optimisation of molecular diagnostic capacity in resource-constrained, high TB burden settings. We recommend a holistic health system-wide approach for molecular diagnostic capacity development, addressing human resource training, institutional capacity development, streamlined procurement systems, and engagement with the public, policy makers and implementers of TB control programmes.

Introduction: Integrated testing of TB and HIV can improve health outcomes and save costs. The GeneXpert (GX) instrument, a multi-disease testing platform, can allow for simultaneous HIV and TB testing. However, utilization of the platform for integrated testing remains suboptimal, and there are operational barriers to implementing integrated TB and HIV testing. Methods: We evaluated the implementation of TB and HIV testing on the GX instrument for early infant detection (EID) of HIV and tuberculosis (TB) testing in thirteen health facilities in Lesotho. The data collection process used a survey questionnaire, semi-structured interviews, and a review of records at each health facility. Data was collected for the period 2017 and 2019. Results: All thirteen health facilities had at least one GX instrument for TB or EID testing. In 2017, the average utilization rate for the GX instrument for TB and EID testing was 63% and 24%, while in 2019, the average utilization rate was 61% for TB testing and 27% for EID. However, none of the health facilities included testing for TB and HIV on the same GX instrument simultaneously. In general, utilization rates were sufficiently low that all the HIV and TB tests undertaken in 2017 and 2019 could have been performed using only the instruments currently dedicated to TB testing. All except for three sites (Scott, Motebang and Maluti) where the testing rates were high. Conclusion and Policy Implications: Much progress has been made in integrating TB and HIV activities in Africa. However, there is a missed opportunity for the integration of testing for TB and HIV on the GX instrument, which could save costs. This evaluation highlights areas that need more focus and more detailed diagnostic network optimization exercises to improve service delivery and allocate stocks, staff, equipment, and training. Better coordination of donor support or increased flexibility in reporting of use will be important to maximize the use of resources, where integration may be more effective than purchasing new equipment. Monitoring and evaluation should be a routine part of the implementation and should be budgeted and demanded by policymakers and donors. Health facilities may require additional resources and technical support to improve data collection, analysis, and dissemination. In conclusion, areas highlighted in this evaluation merit further exploration, such as the need to understand integrated testing models, including what works, why, and for which target groups. This will allow for effective targeted interventions to improve testing coverage across several diseases especially taking advantage of the multi-disease testing platforms.

Current service delivery systems do not reach all people in need of antiretroviral therapy (ART). In order to inform the operational and service delivery section of the WHO 2013 consolidated antiretroviral guidelines, our objective was to summarize systematic reviews on integrating ART delivery into maternal, newborn, and child health (MNCH) care settings in countries with generalized epidemics, tuberculosis (TB) treatment settings in which the burden of HIV and TB is high, and settings providing opiate substitution therapy (OST); and decentralizing ART into primary health facilities and communities. A summary of systematic reviews. The reviewers searched PubMed, Embase, PsycINFO, Web of Science, CENTRAL, and the WHO Index Medicus databases. Randomized controlled trials and observational cohort studies were included if they compared ART coverage, retention in HIV care, and/or mortality in MNCH, TB, or OST facilities providing ART with MNCH, TB, or OST facilities providing ART services separately; or primary health facilities or communities providing ART with hospitals providing ART. The reviewers identified 28 studies on integration and decentralization. Antiretroviral therapy integration into MNCH facilities improved ART coverage (relative risk [RR] 1.37, 95% confidence interval [CI] 1.05-1.79) and led to comparable retention in care. ART integration into TB treatment settings improved ART coverage (RR 1.83, 95% CI 1.48-2.23) and led to a nonsignificant reduction in mortality (RR 0.55, 95% CI 0.29-1.05). The limited data on ART integration into OST services indicated comparable rates of ART coverage, retention, and mortality. Partial decentralization into primary health facilities improved retention (RR 1.05, 95% CI 1.01-1.09) and reduced mortality (RR 0.34, 95% CI 0.13-0.87). Full decentralization improved retention (RR 1.12, 95% CI 1.08-1.17) and led to comparable mortality. Community-based ART led to comparable rates of retention and mortality. Integrating ART into MNCH, TB, and OST services was often associated with improvements in ART coverage, and decentralization of ART into primary health facilities and communities was often associated with improved retention. Neither integration nor decentralization was associated with adverse outcomes. These data contributed to recommendations in the WHO 2013 consolidated antiretroviral guidelines to integrate ART delivery into MNCH, TB, and OST services and to decentralize ART.

Clinically diagnosed tuberculosis and mortality in high burden settings: a systematic review and meta-analysis

Despite ART scale-up, tuberculosis (TB) remains a leading cause of HIV-related deaths worldwide and much of this disease may remain unascertained. In patients receiving ART, TB incidence is highest during the first few months of treatment (many cases of which were prevalent disease missed by baseline screening) and long-term rates remain several-fold higher than background. We identify three groups of patients starting ART for which different interventions are required to reduce TB-related deaths. First, diagnostic screening is needed in patients who have undiagnosed active TB so that timely anti-tuberculosis treatment can be started. This may be greatly facilitated by new diagnostic assays such as the Xpert MTB/RIF assay and a novel point-of-care urine test for lipoarabinomannan (LAM). Second, patients with a diagnosis of active TB need optimised case management, which includes early initiation of ART (with early timing now defined by randomised controlled trials), trimethoprim-sulphamethoxazole prophylaxis and treatment of co-morbidity. Third, in high TB burden settings, all remaining patients who are TB-free at enrolment have high ongoing risk of developing TB and require optimised immune recovery (with ART ideally started early in the course of HIV infection), isoniazid preventive therapy and infection control to reduce infection risk. Further specific measures are needed to address multi-drug resistant TB (MDR-TB) and there are now new promising developments in antimycobacterial agents. Finally, in high burden settings, scale-up of all these interventions requires nationally and locally tailored models of care that are patient-centred and provide integrated health care delivery for TB, HIV and other co-morbidities.

BackgroundInterferon gamma release assays (IGRA) are replacing the tuberculin skin test (TST) as a diagnostic tool for Mycobacterium tuberculosis infection. However research into the test's performance in the high HIV-TB burden setting is scarce. This study aimed to define the sensitivity of an IGRA, QuantiFERON-TB® Gold In-Tube (QGIT), in adult Zambian patients with active smear-positive tuberculosis. Secondary outcomes focussed on the effect of HIV on the test's performance.Principal FindingsPatients attending government health clinics were recruited within 1 month of starting treatment for TB. Subjects were tested with QGIT and TST. T lymphocyte counts were estimated (CD3+, CD4+, CD8+). QGIT was performed for 112 subjects. 83/112 were QGIT positive giving an overall sensitivity of 74% [95%CI: 66,82]. A marked decrease in sensitivity was observed in HIV positive patients with 37/59 (63%) being QGIT positive compared to 31/37 (84%) HIV negative patients [chi2 p = 0.033]. Low CD4+ count was associated with increases in both indeterminate and false-negative results. Low CD4+ count in combination with high/normal CD8+ count was associated with false-negative results. TST was recorded for 92 patients, 62/92 were positive, giving a sensitivity of 67% [95%CI: 58,77]. Although there was little difference in the overall sensitivities, agreement between TST and QGIT was poor.ConclusionsQGIT was technically feasible with results in HIV negative subjects comparable to those achieved elsewhere. However, where under-treated HIV is prevalent, an increased proportion of both indeterminate and false-negative QGIT results can be expected in patients with active TB. The implications of this for the diagnosis of LTBI by QGIT is unclear. The diagnostic and prognostic relevance of IGRAs in high burden settings needs to be better characterised.

Men and women with undiagnosed tuberculosis (TB) in high burden countries may have differential factors influencing their healthcare seeking behaviors and access to TB services, which can result in delayed diagnoses and increase TB-related morbidity and mortality. A convergent, parallel, mixed-methods study design was used to explore and evaluate TB care engagement among adults (≥18 years) with newly diagnosed, microbiologically-confirmed TB attending three public health facilities in Lusaka, Zambia. Quantitative structured surveys characterized the TB care pathway (time to initial care-seeking, diagnosis, and treatment initiation) and collected information on factors influencing care engagement. Multinomial multivariable logistic regression was used to determine predicted probabilities of TB health-seeking behaviors and determinants of care engagement. Qualitative in-depth interviews (IDIs; n = 20) were conducted and analyzed using a hybrid approach to identify barriers and facilitators to TB care engagement by gender. Overall, 400 TB patients completed a structured survey, of which 275 (68.8%) and 125 (31.3%) were men and women, respectively. Men were more likely to be unmarried (39.3% and 27.2%), have a higher median daily income (50 and 30 Zambian Kwacha [ZMW]), alcohol use disorder (70.9% [AUDIT-C score ≥4] and 31.2% [AUDIT-C score ≥3]), and a history of smoking (63.3% and 8.8%), while women were more likely to be religious (96.8% and 70.8%) and living with HIV (70.4% and 36.0%). After adjusting for potential confounders, the probability of delayed health-seeking ≥4 weeks after symptom onset did not differ significantly by gender (44.0% and 36.2%, p = 0.14). While the top reasons for delayed healthcare-seeking were largely similar by gender, men were more likely to report initially perceiving their symptoms as not being serious (94.8% and 78.7%, p = 0.032), while women were more likely to report not knowing the symptoms of TB before their diagnosis (89.5% and 74.4%; p = 0.007) and having a prior bad healthcare experience (26.4% and 9.9%; p = 0.036). Notably, women had a higher probability of receiving TB diagnosis ≥2 weeks after initial healthcare seeking (56.5% and 41.0%, p = 0.007). While men and women reported similar acceptability of health-information sources, they emphasized different trusted messengers. Also, men had a higher adjusted probability of stating that no one influenced their health-related decision making (37.9% and 28.3%, p = 0.001). In IDIs, men recommended TB testing sites at convenient community locations, while women endorsed an incentivized, peer-based, case-finding approach. Sensitization and TB testing strategies at bars and churches were highlighted as promising approaches to reach men and women, respectively. This mixed-methods study found important differences between men and women with TB in Zambia. These differences suggest the need for gender-tailored TB health promotion, including addressing harmful alcohol use and smoking among men, and sensitizing HCWs to prolonged delays in TB diagnosis among women, and also using gender-specific approaches as part of community-based, active case-finding strategies to improve TB diagnosis in high burden settings.