Helen Ayles

Rapid detection of active and latent tuberculosis infection in HIV-positive individuals by enumeration of Mycobacterium tuberculosis-specific T cells.

Objectives: An accurate test for Mycobacterium tuberculosis infection is urgently needed. The tuberculin skin test (TST) lacks sensitivity, particularly in HIV-infected individuals, and has poor specificity because of antigenic cross-reactivity with Bacillus Calmette-Guérin (BCG) vaccination. ESAT-6 and CFP-10 are antigens expressed in M. tuberculosis, but not in Mycobacterium bovis BCG and most environmental mycobacteria. We investigated whether T cells specific for these antigens could serve as accurate markers of M. tuberculosis infection in an area of high tuberculosis and HIV prevalence. Methods: Using the rapid ex-vivo enzyme-linked immunospot (ELISPOT) assay for IFN-γ, we enumerated T cells specific for ESAT-6, CFP-10 and purified protein derivative (PPD) in blood samples from 50 Zambian tuberculosis patients, 75 healthy Zambian adults, and 40 healthy UK residents. TSTs were performed in 49 healthy Zambian adults. Results: All (100%; n = 11) and 90% (n = 39) of HIV-negative and HIV-positive tuberculosis patients, respectively, had detectable ESAT-6- or CFP-10-specific T cells. The ESAT-6/CFP-10-based ELISPOT assay was positive in 37 out of 54 HIV-negative healthy Zambians, suggesting a 69% prevalence of latent M. tuberculosis infection. Fewer HIV-positive Zambians possessed ESAT-6/CFP-10-specific T cells, but the impact of HIV infection was less on this assay than on the PPD-based ELISPOT or TST. Conclusion: The ESAT-6/CFP-10-based ELISPOT assay detects active tuberculosis in HIV-positive individuals with high sensitivity. It is more specific, and possibly more sensitive, than PPD-based methods of detecting latent M. tuberculosis infection, and may potentially improve the targeting of isoniazid preventative therapy to HIV-positive individuals with latent tuberculosis infection.

Development of a standardized screening rule for tuberculosis in people living with HIV in resource-constrained settings: individual participant data meta-analysis of observational studies.

Haileyesus Getahun and colleagues report the development of a simple, standardized tuberculosis (TB) screening rule for resource-constrained settings, to identify people living with HIV who need further investigation for TB disease.

The Effects of HIV on the Sensitivity of a Whole Blood IFN-γ Release Assay in Zambian Adults with Active Tuberculosis

Background Interferon gamma release assays (IGRA) are replacing the tuberculin skin test (TST) as a diagnostic tool for Mycobacterium tuberculosis infection. However research into the tests 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 tests performance. Principal Findings Patients 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. Conclusions QGIT 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.

Prevalence of Tuberculosis, HIV and Respiratory Symptoms in Two Zambian Communities: Implications for Tuberculosis Control in the Era of HIV

Background The Stop TB Partnership target for tuberculosis is to have reduced the prevalence of tuberculosis by 50% comparing 2015 to 1990. This target is challenging as few prevalence surveys have been conducted, especially in high burden tuberculosis and HIV countries. Current tuberculosis control strategies in high HIV prevalent settings are therefore based on limited epidemiological evidence and more evidence is needed from community-based surveys to inform improved policy formulation. Methods and Findings 8044 adults were sampled from 2 sub-districts (wards) in Lusaka province, Zambia. Questionnaires were used to screen for symptoms, respiratory samples were obtained for culture and oral secretions collected for HIV testing. 79 individuals were found to have Mycobacterium tuberculosis in their sputum, giving an adjusted overall prevalence of tuberculosis of 870/100,000 (95% CI 570–1160/100,000). The adjusted overall prevalence of HIV was 28.61% (95% CI 26.04–31.19). HIV- infection was significantly associated with prevalent tuberculosis (Adj OR 2.3, 95% CI 1.42–3.74) and the population attributable fraction of HIV for prevalent tuberculosis was 36%. Symptoms such as prolonged cough (adj OR 12.72, 95% CI 7.05–22.94) and fever (Adj OR 2.04, 95%CI 1.23–3.39), were associated with prevalent tuberculosis, but 8 (10%) individuals with prevalent tuberculosis denied having any symptoms at all and only 34 (43%) would have been classified as a TB suspect by current guidelines. Conclusions Undiagnosed tuberculosis is a challenge for tuberculosis control and new approaches are needed if we are to reach international targets. Epidemiological studies can inform screening algorithms for both detection and prevention of active tuberculosis.

Effect of household and community interventions on the burden of tuberculosis in southern Africa: the ZAMSTAR community-randomised trial.

BACKGROUND Southern Africa has had an unprecedented increase in the burden of tuberculosis, driven by the HIV epidemic. The Zambia, South Africa Tuberculosis and AIDS Reduction (ZAMSTAR) trial examined two public health interventions that aimed to reduce the burden of tuberculosis by facilitating either rapid sputum diagnosis or integrating tuberculosis and HIV services within the community. METHODS ZAMSTAR was a community-randomised trial done in Zambia and the Western Cape province of South Africa. Two interventions, community-level enhanced tuberculosis case-finding (ECF) and household level tuberculosis-HIV care, were implemented between Aug 1, 2006, and July 31, 2009, and assessed in a 2×2 factorial design between Jan 9, 2010, and Dec 6, 2010. All communities had a strengthened tuberculosis-HIV programme implemented in participating health-care centres. 24 communities, selected according to population size and tuberculosis notification rate, were randomly allocated to one of four study groups using a randomisation schedule stratified by country and baseline prevalence of tuberculous infection: group 1 strengthened tuberculosis-HIV programme at the clinic alone; group 2, clinic plus ECF; group 3, clinic plus household intervention; and group 4, clinic plus ECF and household interventions. The primary outcome was the prevalence of culture-confirmed pulmonary tuberculosis in adults (≥18 years), defined as Mycobacterium tuberculosis isolated from one respiratory sample, measured 4 years after the start of interventions in a survey of 4000 randomly selected adults in each community in 2010. The secondary outcome was the incidence of tuberculous infection, measured using tuberculin skin testing in a cohort of schoolchildren, a median of 4 years after a baseline survey done before the start of interventions. This trial is registered, number ISRCTN36729271. FINDINGS Prevalence of tuberculosis was evaluated in 64,463 individuals randomly selected from the 24 communities; 894 individuals had active tuberculosis. Averaging over the 24 communities, the geometric mean of tuberculosis prevalence was 832 per 100,000 population. The adjusted prevalence ratio for the comparison of ECF versus non-ECF intervention groups was 1·09 (95% CI 0·86-1·40) and of household versus non-household intervention groups was 0·82 (0·64-1·04). The incidence of tuberculous infection was measured in a cohort of 8809 children, followed up for a median of 4 years; the adjusted rate ratio for ECF versus non-ECF groups was 1·36 (95% CI 0·59-3·14) and for household versus non-household groups was 0·45 (0·20-1·05). INTERPRETATION Although neither intervention led to a statistically significant reduction in tuberculosis, two independent indicators of burden provide some evidence of a reduction in tuberculosis among communities receiving the household intervention. By contrast the ECF intervention had no effect on either outcome. FUNDING Bill & Melinda Gates Foundation.

Validation of brief screening tools for depressive and alcohol use disorders among TB and HIV patients in primary care in Zambia

BackgroundThis study was conducted to evaluate the diagnostic accuracy and determine the optimum cut-off scores for clinical use of the Center for Epidemiological Studies Depression scale (CES-D) and Alcohol Use Disorders Identification Test (AUDIT) against a reference psychiatric diagnostic interview, in TB and anti-retroviral therapy (ART) patients in primary care in Zambia.MethodsThis was a cross-sectional study in 16 primary level care clinics. Consecutive sampling was used to select 649 participants who started TB treatment or ART in the preceding month. Participants were first interviewed using the CES-D and AUDIT, and subsequently with a psychiatric diagnostic interview for current major depressive disorder (MDD) and alcohol use disorders (AUDs) using the Mini-International Neuropsychiatric Interview (MINI). The diagnostic accuracy was calculated using the Area Under the Receiver Operating Characteristic curve (AUROC). The optimum cut-off scores for clinical use were calculated using sensitivity and positive predictive value (PPV).ResultsThe CES-D and AUDIT had high internal consistency (Cronbachs alpha = 0.84; 0.98 respectively). Confirmatory factor analysis showed that the four-factor CES-D model was not a good fit for the data (Tucker-Lewis Fit Index (TLI) = 0.86; standardized root-mean square residual (SRMR) = 0.06) while the two-factor AUDIT model fitted the data well (TFI = 0.99; SRMR = 0.04). Both the CES-D and AUDIT demonstrated good discriminatory ability in detecting MINI-defined current MDDs and AUDs (AUROC for CES-D = 0.78; AUDIT = 0.98 for women and 0.75 for men). The optimum CES-D cut-off score in screening for current MDD was 22 (sensitivity 73%, PPV 76%) while that of the AUDIT in screening for AUD was 24 for women (sensitivity 60%, PPV 60%), and 20 for men (sensitivity 55%, PPV 50%).ConclusionsThe CES-D and AUDIT showed high discriminatory ability in measuring MINI-defined current MDD and AUD respectively. They are suitable mental health screening tools for use among TB and ART patients in primary care in Zambia.

Protocol-driven primary care and community linkages to improve population health in rural Zambia: the Better Health Outcomes through Mentoring and Assessment (BHOMA) project

IntroductionZambia’s under-resourced public health system will not be able to deliver on its health-related Millennium Development Goals without a substantial acceleration in mortality reduction. Reducing mortality will depend not only upon increasing access to health care but also upon improving the quality of care that is delivered. Our project proposes to improve the quality of clinical care and to improve utilization of that care, through a targeted quality improvement (QI) intervention delivered at the facility and community level.Description of implementationThe project is being carried out 42 primary health care facilities that serve a largely rural population of more than 450,000 in Zambia’s Lusaka Province. We have deployed six QI teams to implement consensus clinical protocols, forms, and systems at each site. The QI teams define new clinical quality expectations and provide tools needed to deliver on those expectations. They also monitor the care that is provided and mentor facility staff to improve care quality. We also engage community health workers to actively refer and follow up patients.Evaluation designProject implementation occurs over a period of four years in a stepped expansion to six randomly selected new facilities every three months. Three annual household surveys will determine population estimates of age-standardized mortality and under-5 mortality in each community before, during, and after implementation. Surveys will also provide measures of childhood vaccine coverage, pregnancy care utilization, and general adult health. Health facility surveys will assess coverage of primary health interventions and measures of health system effectiveness.DiscussionThe patient-provider interaction is an important interface where the community and the health system meet. Our project aims to reduce population mortality by substantially improving this interaction. Our success will hinge upon the ability of mentoring and continuous QI to improve clinical service delivery. It will also be critical that once the quality of services improves, increasing proportions of the population will recognize their value and begin to utilize them.

HPTN 071 (PopART): A Cluster-Randomized Trial of the Population Impact of an HIV Combination Prevention Intervention Including Universal Testing and Treatment: Mathematical Model

Background The HPTN 052 trial confirmed that antiretroviral therapy (ART) can nearly eliminate HIV transmission from successfully treated HIV-infected individuals within couples. Here, we present the mathematical modeling used to inform the design and monitoring of a new trial aiming to test whether widespread provision of ART is feasible and can substantially reduce population-level HIV incidence. Methods and Findings The HPTN 071 (PopART) trial is a three-arm cluster-randomized trial of 21 large population clusters in Zambia and South Africa, starting in 2013. A combination prevention package including home-based voluntary testing and counseling, and ART for HIV positive individuals, will be delivered in arms A and B, with ART offered universally in arm A and according to national guidelines in arm B. Arm C will be the control arm. The primary endpoint is the cumulative three-year HIV incidence. We developed a mathematical model of heterosexual HIV transmission, informed by recent data on HIV-1 natural history. We focused on realistically modeling the intervention package. Parameters were calibrated to data previously collected in these communities and national surveillance data. We predict that, if targets are reached, HIV incidence over three years will drop by >60% in arm A and >25% in arm B, relative to arm C. The considerable uncertainty in the predicted reduction in incidence justifies the need for a trial. The main drivers of this uncertainty are possible community-level behavioral changes associated with the intervention, uptake of testing and treatment, as well as ART retention and adherence. Conclusions The HPTN 071 (PopART) trial intervention could reduce HIV population-level incidence by >60% over three years. This intervention could serve as a paradigm for national or supra-national implementation. Our analysis highlights the role mathematical modeling can play in trial development and monitoring, and more widely in evaluating the impact of treatment as prevention.

Can we control tuberculosis in high HIV prevalence settings

The overlap between the epidemiology of HIV and tuberculosis and consequent rapid rise in numbers of patients with tuberculosis in many African countries has put a huge burden on health systems. The stigma of HIV has increased the existing stigma surrounding tuberculosis. There are three mechanisms by which we may reduce the number of cases of tuberculosis in a community: reducing transmission of tuberculosis, reducing reactivation of latent tuberculosis infection and reducing HIV transmission. Reinforcing the existing health service to find more cases, active case-finding in communities or enhanced case-finding in specific groups will reduce transmission of tuberculosis. However, health services that find it difficult to find cases efficiently will also find it difficult to support patients throughout treatment to achieve a cure. Partnership with traditional healers, community-based organizations and private practitioners could reduce this burden. Reactivation of tuberculosis among people living with HIV can be reduced by tuberculosis preventive therapy or by antiretroviral therapy. Programmes that identify people living with HIV can also implement enhanced tuberculosis case-finding increasing the benefits of the programme. However, the impact of widespread use of antiretroviral therapy may be to increase the number of people in a community who are mildly immunocompromised and the incidence of tuberculosis at a community level might rise. Any strategy that successfully reduces HIV transmission will benefit tuberculosis control, since around a third of all HIV-positive individuals will develop tuberculosis before they die. To control tuberculosis in high HIV prevalence settings, we must strengthen health systems to include not only expansion of the DOTS strategy but also full-blooded implementation of voluntary counselling and testing, enhanced and active tuberculosis case-finding, preventive therapy and better care for people living with HIV including antiretroviral therapy. The approach needed to control tuberculosis needs also to be integrated into broader development and poverty reduction goals.

The Association between Household Socioeconomic Position and Prevalent Tuberculosis in Zambia: A Case-Control Study

Background Although historically tuberculosis (TB) has been associated with poverty, few analytical studies from developing countries have tried to: 1. assess the relative impact of poverty on TB after the emergence of HIV; 2. explore the causal mechanism underlying this association; and 3. estimate how many cases of TB could be prevented by improving household socioeconomic position (SEP). Methods and Findings We undertook a case-control study nested within a population-based TB and HIV prevalence survey conducted in 2005–2006 in two Zambian communities. Cases were defined as persons (15+ years of age) culture positive for M. tuberculosis. Controls were randomly drawn from the TB-free participants enrolled in the prevalence survey. We developed a composite index of household SEP combining variables accounting for four different domains of household SEP. The analysis of the mediation pathway between household SEP and TB was driven by a pre-defined conceptual framework. Adjusted Population Attributable Fractions (aPAF) were estimated. Prevalent TB was significantly associated with lower household SEP [aOR = 6.2, 95%CI: 2.0–19.2 and aOR = 3.4, 95%CI: 1.8–7.6 respectively for low and medium household SEP compared to high]. Other risk factors for prevalent TB included having a diet poor in proteins [aOR = 3.1, 95%CI: 1.1–8.7], being HIV positive [aOR = 3.1, 95%CI: 1.7–5.8], not BCG vaccinated [aOR = 7.7, 95%CI: 2.8–20.8], and having a history of migration [aOR = 5.2, 95%CI: 2.7–10.2]. These associations were not confounded by household SEP. The association between household SEP and TB appeared to be mediated by inadequate consumption of protein food. Approximately the same proportion of cases could be attributed to this variable and HIV infection (aPAF = 42% and 36%, respectively). Conclusions While the fight against HIV remains central for TB control, interventions addressing low household SEP and, especially food availability, may contribute to strengthen our control efforts.