Ab Schaap

The benefits to communities and individuals of screening for active tuberculosis disease: a systematic review [State of the art series. Case finding/screening. Number 2 in the series].

BACKGROUNDnScreening for tuberculosis (TB) disease aims to improve early TB case detection. The ultimate goal is to improve outcomes for people with TB and to reduce Mycobacterium tuberculosis transmission in the community through improved case detection, reduction in diagnostic delays and early treatment. Before screening programmes are recommended, evidence is needed of individual and/or community-level benefits.nnnMETHODSnWe conducted a systematic review of the literature to assess the evidence that screening for TB disease 1) initially increases the number of TB cases initiated on anti-tuberculosis treatment, 2) identifies cases earlier in the course of disease, 3) reduces mortality and morbidity, and 4) impacts on TB epidemiology.nnnRESULTSnA total of 28u2009798 publications were identified by the search strategy: 27u2009087 were excluded on initial screening and 1749 on full text review, leaving 62 publications that addressed at least one of the study questions. Screening increases the number of cases found in the short term. In many settings, more than half of the prevalent TB cases in the community remain undiagnosed. Screening tends to find cases earlier and with less severe disease, but this may be attributed to case-finding studies using more sensitive diagnostic methods than routine programmes. Treatment outcomes among people identified through screening are similar to outcomes among those identified through passive case finding. Current studies provide insufficient evidence to show that active screening for TB disease impacts on TB epidemiology.nnnCONCLUSIONnIndividual and community-level benefits from active screening for TB disease remain uncertain. So far, the benefits of earlier diagnosis on patient outcomes and transmission have not been established.

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

BACKGROUNDnSouthern 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.nnnMETHODSnZAMSTAR 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.nnnFINDINGSnPrevalence 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).nnnINTERPRETATIONnAlthough 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.nnnFUNDINGnBill & Melinda Gates Foundation.

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.

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 [aORu200a=u200a6.2, 95%CI: 2.0–19.2 and aORu200a=u200a3.4, 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 [aORu200a=u200a3.1, 95%CI: 1.1–8.7], being HIV positive [aORu200a=u200a3.1, 95%CI: 1.7–5.8], not BCG vaccinated [aORu200a=u200a7.7, 95%CI: 2.8–20.8], and having a history of migration [aORu200a=u200a5.2, 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 (aPAFu200a=u200a42% 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.

Annual risk of tuberculous infection using different methods in communities with a high prevalence of TB and HIV in Zambia and South Africa.

Background The annual risk of tuberculous infection (ARTI) is a key epidemiological indicator of the extent of transmission in a community. Several methods have been suggested to estimate the prevalence of tuberculous infection using tuberculin skin test data. This paper explores the implications of using different methods to estimate prevalence of infection and ARTI. The effect of BCG vaccination on these estimates is also investigated. Methodology/Principal Findings Tuberculin surveys among school children in 16 communities in Zambia and 8 in South Africa (SA) were performed in 2005, as part of baseline data collection and for randomisation purposes of the ZAMSTAR study. Infection prevalence and ARTI estimates were calculated using five methods: different cut-offs with or without adjustments for sensitivity, the mirror method, and mixture analysis. A total of 49,835 children were registered for the surveys, of which 25,048 (50%) had skin tests done and 22,563 (90%) of those tested were read. Infection prevalence was higher in the combined SA than Zambian communities. The mirror method resulted in the least difference of 7.8%, whereas that estimated by the cut-off methods varied from 12.2% to 17.3%. The ARTI in the Zambian and SA communities was between 0.8% and 2.8% and 2.5% and 4.2% respectively, depending on the method used. In the SA communities, the ARTI was higher among the younger children. BCG vaccination had little effect on these estimates. Conclusions/Significance ARTI estimates are dependent on the calculation method used. All methods agreed that there were substantial differences in infection prevalence across the communities, with higher rates in SA. Although TB notification rates have increased over the past decades, the difference in cumulative exposure between younger and older children is less dramatic and a rise in risk of infection in parallel with the estimated incidence of active tuberculosis cannot be excluded.

Risk Factors Associated with Positive QuantiFERON-TB Gold In-Tube and Tuberculin Skin Tests Results in Zambia and South Africa

Introduction The utility of T-cell based interferon-gamma release assays for the diagnosis of latent tuberculosis infection remains unclear in settings with a high burden of tuberculosis. Objectives To determine risk factors associated with positive QuantiFERON-TB Gold In-Tube (QFT-GIT) and tuberculin skin test (TST) results and the level of agreement between the tests; to explore the hypotheses that positivity in QFT-GIT is more related to recent infection and less affected by HIV than the TST. Methods Adult household contacts of tuberculosis patients were invited to participate in a cross-sectional study across 24 communities in Zambia and South Africa. HIV, QFT-GIT and TST tests were done. A questionnaire was used to assess risk factors. Results A total of 2,220 contacts were seen. 1,803 individuals had interpretable results for both tests, 1,147 (63.6%) were QFT-GIT positive while 725 (40.2%) were TST positive. Agreement between the tests was low (kappau200a=u200a0.24). QFT-GIT and TST results were associated with increasing age (adjusted OR [aOR] for each 10 year increase for QFT-GIT 1.15; 95% CI: 1.06–1.25, and for TST aOR: 1.10; 95% CI 1.01–1.20). HIV positivity was less common among those with positive results on QFT-GIT (aOR: 0.51; 95% CI: 0.39–0.67) and TST (aOR: 0.61; 95% CI: 0.46–0.82). Smear positivity of the index case was associated with QFT-GIT (aOR: 1.25; 95% CI: 0.90–1.74) and TST (aOR: 1.39; 95% CI: 0.98–1.98) results. We found little evidence in our data to support our hypotheses. Conclusion QFT-GIT may not be more sensitive than the TST to detect risk factors associated with tuberculous infection. We found little evidence to support the hypotheses that positivity in QFT-GIT is more related to recent infection and less affected by HIV than the TST.

Mortality impact of AIDS in Addis Ababa, Ethiopia

Objective: To measure the impact of HIV on mortality in Addis Ababa, Ethiopia. Design: A retrospective review of burials at three cemeteries, 1987–2001 and a prospective surveillance of burials at all (n = 70) cemeteries, February–May, 2001. Methods: The age, sex, and date of burial were recorded; in the absence of denominators, we compared the ratio of deaths of persons 25–49 versus 5–14 years of age per calendar year, using logistic regression, adjusting for sex and site. The age- and sex- specific mortality were calculated and compared with pre-HIV mortality in 1984. Results: Of 17 519 deaths, retrospectively reviewed, complete data were available for 6342 (47%) females and 7269 (53%) males. During 1987–2001, the ‘25-49’ versus ‘5–14’ group all-cause mortality ratio increased by 8.5% per calendar year (P < 0.05). A total of 5101 deaths were recorded in the prospective surveillance. Crude mortality rates were 9.5/1000 per year (men) and 7.1/1000 per year (women). In comparison with 1984, 5.0-times as many men and 5.3-times as many women died in the age group 35–39 years. Attributing the increase in mortality in ages 15–60 to HIV in the period 1984–2001, Ethiopian men and women have a probability of 18.8 and 17.8%, respectively, of dying of HIV before age 60. Conclusion: Burials increased significantly among the ‘25–49, versus the ‘5-14’ group, during the period 1987–2001. This trend, and a five-times higher mortality in 2001 than in 1984 in those aged 35–39 years demonstrate a severe impact of HIV on mortality. Continuing surveillance of burials is recommended.

Restricted randomization of ZAMSTAR: a 2 × 2 factorial cluster randomized trial

Background A small number of clusters and substantial variation between clusters increase the chance of unbalanced randomization in cluster randomized trials. Baseline imbalances between groups may distort intervention effects. When adjusting for imbalances in the cluster-level analysis, this results in loss of degrees of freedom. Variance reduction that can be achieved through stratification and blocking is limited. Restricted randomization is an alternative approach that ensures balanced allocation. Purpose We present the randomization scheme used in the ZAMSTAR trial of tuberculosis control interventions in Southern Africa. Methods We used stratification and restriction to randomize 24 clusters (16 Zambian, 8 South African) into four intervention groups in a 2 × 2 factorial design. Stratification was by country and tuberculous infection prevalence and restriction by tuberculous infection prevalence, HIV prevalence, urban/rural, social context, and geographical location. Balance was defined in terms of covariate-specific tolerance thresholds for the measure of imbalance. For binary (0/1) covariates we defined imbalance = max(Si) - min(Si), where, Si was the number of 1s in group i = 1,2,3,4. For continuous covariates we defined imbalance = (max(Mi) - min(Mi))/ min(Mi ), where, M i was the average in group i = 1,2,3,4. We used simulation to estimate the restriction factor (proportion of unacceptable allocations) both for individual covariates and overall. Simulation was also used to investigate the validity of the restricted randomization design, with the use of the validity matrix, by monitoring the probability that any given pair of clusters is allocated to the same intervention group. Results There were 3 657 930 400 possible ways of allocating the 24 clusters to the four groups after stratification. With a combined restriction factor of 0.998 this still left 7 million acceptable allocations. The final allocation was selected at a public ceremony from a randomly-generated list of acceptable allocations. The design of the allocation process was observed to be valid. Limitations The restricted randomization scheme significantly decreased the total number of available allocations of clusters into intervention groups. Conclusion Our restricted randomization was successful in that it achieved good balance while preserving the impartiality and validity of the trial. Clinical Trials 2008; 5: 316—327. http://ctj.sagepub.com

Evaluation of the Capilia TB Assay for Culture Confirmation of Mycobacterium tuberculosis Infections in Zambia and South Africa

ABSTRACT The performance and cost of the Capilia TB assay were evaluated for use in a resource-limited setting. The sensitivity and specificity were 99.6% and 99.5%, respectively. The incremental costs of the Capilia test were estimated to be

Lay diagnosis of causes of death for monitoring AIDS mortality in Addis Ababa, Ethiopia

1.46 and