An attempt to reproduce a previous meta-analysis and a new analysis regarding the impact of directly observed therapy on tuberculosis treatment outcomes

Directly observed therapy (DOT) is almost universally used for the treatment of TB. Several meta-analyses using different methods have assessed the effectiveness of DOT compared to self-administered therapy (SAT). The results of these meta-analyses often conflict with some concluding DOT is superior and others that there is little or no difference. Meta-analyses can guide policymaking, but such analyses must be reliable. To assess the validity of a previous meta-analysis, we tried to reproduce it. We encountered problems with the previous analysis that did not allow for a meaningful reproduction. We describe the issues we encountered here. We then performed a new meta-analysis comparing the treatment outcomes of adults given treatment with SAT versus DOT. Outcomes in the new analysis are loss to follow-up, treatment failure, cure, treatment completed, and all-cause mortality. All data, documentation, and code used to generate our results is provided. Our new analysis included four randomized and three observational studies with 1603 and 1626 individuals respectively. The pooled relative risks (RR) are as follows: Lost to follow-up (RR = 1.2, 95% CI 0.9, 1.7), Treatment Failure (RR = 1.1, 95% CI 0.6, 2), Cure (RR = 0.9, 95% CI 0.8, 1.1), Treatment Completion (RR = 1, 95% CI 0.9, 1.1), Mortality (RR = 0.9, 95% CI 0.6, 1.3). Based on data from our new meta-analysis, the magnitude of the difference between DOT and SAT for all reported outcomes is small, and none of the differences are statistically significant

Systematic review of TST responses in people living with HIV in under-resourced settings: implications for isoniazid preventive therapy.

BACKGROUND: People living with HIV (PLWH) who have positive tuberculin skin tests (TST) benefit from isoniazid preventive therapy (IPT) whereas those testing TST-negative do not. Revised World Health Organization guidelines explicitly state that assessment of TST is not a requirement for initiation of IPT. However, it is not known what proportions of patients will benefit from IPT if implemented without targeting according to TST status. We therefore determined the proportions of PLWH who test TST-positive. METHODOLOGY/PRINCIPAL FINDINGS: We systematically reviewed the literature published between January 1990 and February 2012 to determine the proportions of patients without active tuberculosis attending HIV care services in low and middle-income countries who tested TST-positive (≥5 mm induration). Proportions were also determined for different CD4 count strata. Data from 19 studies with 9,478 PLWH from sub-Saharan Africa, Asia and Central and South America were summarized. The vast majority were not receiving antiretroviral therapy (ART). A sub-analysis was conducted of 5 studies (5,567 subjects) from high TB prevalence countries of PLWH with negative TB screens attending HIV care and treatment settings for whom CD4 stratified data were available. The median proportion of PLWH testing TST-positive overall was 22.8% (range, 19.5-32.6%). The median (range) proportions with CD4 cell counts of <200, 200-499 or ≥500 cells/µL who tested positive were 12.4% (8.2-15.3%), 28.4% (20.1-36.9%) and 37.4% (31.3-56.3%), respectively. Heterogeneity in the data precluded calculation of pooled summary estimates. CONCLUSIONS/SIGNIFICANCE: In most settings, if IPT is administered to PLWH pre-ART without assessment of TST status, only a minority of those treated are likely to benefit, especially among those with the lowest CD4 cell counts. This may be inefficient use of resources and cost-effectiveness analyses should take this into account. Local knowledge of TST response rates may help inform policies. New simple means of identifying those who will benefit from IPT are needed to permit appropriate targeting of this intervention

Defining adequate contact for transmission of Mycobacterium tuberculosis in an African urban environment

Background The risk of infection from respiratory pathogens increases according to the contact rate between the infectious case and susceptible contact, but the definition of adequate contact for transmission is not standard. In this study we aimed to identify factors that can explain the level of contact between tuberculosis cases and their social networks in an African urban environment. Methods This was a cross-sectional study conducted in Kampala, Uganda from 2013 to 2017. We carried out an exploratory factor analysis (EFA) in social network data from tuberculosis cases and their contacts. We evaluated the factorability of the data to EFA using the Kaiser-Meyer-Olkin Measure of Sampling Adequacy (KMO). We used principal axis factoring with oblique rotation to extract and rotate the factors, then we calculated factor scores for each using the weighted sum scores method. We assessed construct validity of the factors by associating the factors with other variables related to social mixing. Results Tuberculosis cases (N = 120) listed their encounters with 1154 members of their social networks. Two factors were identified, the first named “Setting” captured 61% of the variance whereas the second, named ‘Relationship’ captured 21%. Median scores for the setting and relationship factors were 10.2 (IQR 7.0, 13.6) and 7.7 (IQR 6.4, 10.1) respectively. Setting and Relationship scores varied according to the age, gender, and nature of the relationship among tuberculosis cases and their contacts. Family members had a higher median setting score (13.8, IQR 11.6, 15.7) than non-family members (7.2, IQR 6.2, 9.4). The median relationship score in family members (9.9, IQR 7.6, 11.5) was also higher than in non-family members (6.9, IQR 5.6, 8.1). For both factors, household contacts had higher scores than extra-household contacts (p < .0001). Contacts of male cases had a lower setting score as opposed to contacts of female cases. In contrast, contacts of male and female cases had similar relationship scores. Conclusions In this large cross-sectional study from an urban African setting, we identified two factors that can assess adequate contact between tuberculosis cases and their social network members. These findings also confirm the complexity and heterogeneity of social mixing

Determination of circulating Mycobacterium tuberculosis strains and transmission patterns among pulmonary TB patients in Kawempe municipality, Uganda, using MIRU-VNTR

<p>Abstract</p> <p>Background</p> <p>Mycobacterial interspersed repetitive units - variable number of tandem repeats (MIRU-VNTR) genotyping is a powerful tool for unraveling clonally complex <it>Mycobacterium tuberculosis </it>(MTB) strains and detection of transmission patterns. Using MIRU-VNTR, MTB genotypes and their transmission patterns among patients with new and active pulmonary tuberculosis (PTB) in Kawempe municipality in Kampala, Uganda was determined.</p> <p>Results</p> <p>MIRU-VNTR genotyping was performed by PCR-amplification of 15 MTB-MIRU loci from 113 cultured specimens from 113 PTB patients (one culture sample per patient). To determine lineages, the genotypes were entered into the MIRU-VNTR<it>plus </it>database [<url>http://www.miru-vntrplus.org/</url>] as numerical codes corresponding to the number of alleles at each locus. Ten different lineages were obtained: Uganda II (40% of specimens), Uganda I (14%), LAM (6%), Delhi/CAS (3%), Haarlem (3%), Beijing (3%), Cameroon (3%), EAI (2%), TUR (2%) and S (1%). Uganda I and Uganda II were the most predominant genotypes. Genotypes for 29 isolates (26%) did not match any strain in the database and were considered unique. There was high diversity of MIRU-VNTR genotypes, with a total of 94 distinct patterns. Thirty four isolates grouped into 15 distinct clusters each with two to four isolates. Eight households had similar MTB strains for both index and contact cases, indicating possible transmission.</p> <p>Conclusion</p> <p>MIRU-VNTR genotyping revealed high MTB strain diversity with low clustering in Kawempe municipality. The technique has a high discriminatory power for genotyping MTB strains in Uganda.</p

Tuberculosis Treatment in HIV Infected Ugandans with CD4 Counts >350 Cells/mm3 Reduces Immune Activation with No Effect on HIV Load or CD4 Count

Both HIV and TB cause a state of heightened immune activation. Immune activation in HIV is associated with progression to AIDS. Prior studies, focusing on persons with advanced HIV, have shown no decline in markers of cellular activation in response to TB therapy alone.) and pulmonary TB. HIV load, CD4 count, and markers of immune activation (CD38 and HLA-DR on CD4 and CD8 T cells) were measured prior to starting, during, and for 6 months after completion of standard 6 month anti-tuberculosis (TB) therapy in 38 HIV infected Ugandans with smear and culture confirmed pulmonary TB.Expression of CD38, and co-expression of CD38 and HLA-DR, on CD8 cells declined significantly within 3 months of starting standard TB therapy in the absence of anti-retroviral therapy, and remained suppressed for 6 months after completion of therapy. In contrast, HIV load and CD4 count remained unchanged throughout the study period.

Five-year impact of different multi-year mass drug administration strategies on childhood Schistosoma mansoni-associated morbidity:A combined analysis from the schistosomiasis consortium for operational research and evaluation cohort studies in the Lake Victoria Regions of Kenya and Tanzania

The WHO recommends mass treatment with praziquantel as the primary approach for; Schistosoma mansoni; -related morbidity control in endemic populations. The Schistosomiasis Consortium for Operational Research and Evaluation implemented multi-country, cluster-randomized trials to compare effectiveness of community-wide and school-based treatment (SBT) regimens on prevalence and intensity of schistosomiasis. To assess the impact of two different treatment schedules on; S. mansoni; -associated morbidity in children, cohort studies were nested within the randomized trials conducted in villages in Kenya and Tanzania having baseline prevalence ≥ 25%. Children aged 7-8 years were enrolled at baseline and followed to ages 11-12 years. Infection intensity and odds of infection were reduced both in villages receiving four years of annual community-wide treatment (CWT) and those who received biennial SBT over 4 years. These regimens were also associated with reduced odds of undernutrition and reduced odds of portal vein dilation at follow-up. However, neither hemoglobin levels nor the prevalence of the rare abnormal pattern C liver scores on ultrasound improved. For the combined cohorts, growth stunting worsened in the areas receiving biennial SBT, and maximal oxygen uptake as estimated by fitness testing scores declined under both regimens. After adjusting for imbalance in starting prevalence between study arms, children in villages receiving annual CWT had significantly greater decreases in infection prevalence and intensity than those villages receiving biennial SBT. Although health-related quality-of-life scores improved in both study arms, children in the CWT villages gained significantly more. We conclude that programs using annual CWT are likely to achieve better overall; S. mansoni; morbidity control than those implementing only biennial SBT

Attraction of the Invasive Halyomorpha halys (Hemiptera: Pentatomidae) to Traps Baited with Semiochemical Stimuli Across the United States

A recent identification of the two-component aggregation pheromone of the invasive stink bug species, Halyomorpha halys (Stål), in association with a synergist, has greatly improved the ability to accurately monitor the seasonal abundance and distribution of this destructive pest. We evaluated the attraction of H. halys to black pyramid traps baited with lures containing the pheromone alone, the synergist methyl (2E,4E,6Z)-decatrienoate (MDT) alone, and the two lures in combination. Traps were deployed around areas of agricultural production including fruit orchards, vegetables, ornamentals, or row crops in Delaware, Maryland, North Carolina, New Jersey, New York, Ohio, Oregon, Pennsylvania, Virginia, and West Virginia from mid-April to mid-October, 2012 and 2013. We confirmed that H. halys adults and nymphs are attracted to the aggregation pheromone season long, but that attraction is significantly increased with the addition of the synergist MDT. H. halys adults were detected in April with peak captures of overwintering adults in mid- to late May. The largest adult captures were late in the summer, typically in early September. Nymphal captures began in late May and continued season long. Total captures declined rapidly in autumn and ceased by mid-October. Captures were greatest at locations in the Eastern Inland region, followed by those in the Eastern Coastal Plain and Pacific Northwest. Importantly, regardless of location in the United States, all mobile life stages of H. halys consistently responded to the combination of H. halys aggregation pheromone and the synergist throughout the entire season, suggesting that these stimuli will be useful tools to monitor for H. halys in managed system

SCORE studies on the impact of drug treatment on morbidity due to <i>Schistosoma mansoni</i> and <i>Schistosoma haematobium</i> infection

The Schistosomiasis Consortium for Operational Research (SCORE) was funded in 2008 to improve the evidence base for control and elimination of schistosomiasis-better understanding of the systemic morbidities experienced by children in schistosomiasis-endemic areas and the response of these morbidities to treatment, being essential for updating WHO guidelines for mass drug administration (MDA) in endemic areas. This article summarizes the SCORE studies that aimed to gauge the impact of MDA-based treatment on schistosomiasis-related morbidities. Morbidity cohort studies were embedded in the SCORE's larger field studies of gaining control of schistosomiasis in Kenya and Tanzania. Following MDA, cohort children had less undernutrition, less portal vein dilation, and increased quality of life in Year 5 compared with baseline. We also conducted a pilot study of the Behavioral Assessment System for Children (BASC-2) in conjunction with the Kenya gaining control study, which demonstrated beneficial effects of treatment on classroom behavior. In addition, the SCORE's Rapid Answers Project performed systematic reviews of previously available data, providing two meta-analyses related to morbidity. The first documented children's infection-related deficits in school attendance and achievement and in formal tests of learning and memory. The second showed that greater reductions in egg output following drug treatment correlates significantly with reduced odds of most morbidities. Overall, these SCORE morbidity studies provided convincing evidence to support the use of MDA to improve the health of school-aged children in endemic areas. However, study findings also support the need to use enhanced metrics to fully assess and better control schistosomiasis-associated morbidity

Whole Blood Interferon-Gamma Responses to Mycobacterium tuberculosis Antigens in Young Household Contacts of Persons with Tuberculosis in Uganda

Due to immunologic immaturity, IFN-gamma-producing T cell responses may be decreased in young children compared to adults, thus we hypothesized that IFN-gamma responses to mycobacterial antigens in household contacts exposed to Mycobacterium tuberculosis (Mtb) would be impaired in young children relative to adults. The objective of this study was to compare whole blood IFN-gamma production in response to mycobacterial antigens between children and adults in Uganda.We studied household contacts of persons with culture-positive pulmonary tuberculosis (TB) enrolled in a cohort study conducted in Kampala, Uganda. Whole blood IFN-gamma production in response to Mtb culture-filtrate antigens was measured by ELISA and compared between infants (<2 years old, n = 80), young children (2 <5 years old, n = 216), older children (5 <15 years old, n = 443) and adults (> or =15 years old, n = 528). We evaluated the relationship between IFN-gamma responses and the tuberculin skin test (TST), and between IFN-gamma responses and epidemiologic factors that reflect exposure to Mtb, and the effect of prior BCG vaccination on IFN-gamma responses. Young household contacts demonstrated robust IFN-gamma responses comparable to those of adults that were associated with TST and known risk factors for infection. There was no effect of prior BCG immunization on the IFN-gamma response.Young children in a TB endemic setting can mount robust IFN-gamma responses generally comparable to those of adults, and as in adults, these responses correlated with the TST and known epidemiologic risk factors for Mtb infection

Circumcision of Male Children for Reduction of Future Risk for HIV: Acceptability among HIV Serodiscordant Couples in Kampala, Uganda

The ultimate success of medical male circumcision for HIV prevention may depend on targeting male infants and children as well as adults, in order to maximally reduce new HIV infections into the future.We conducted a cross-sectional study among heterosexual HIV serodiscordant couples (a population at high risk for HIV transmission) attending a research clinic in Kampala, Uganda on perceptions and attitudes about medical circumcision for male children for HIV prevention. Correlates of willingness to circumcise male children were assessed using generalized estimating equations methods.318 HIV serodiscordant couples were interviewed, 51.3% in which the female partner was HIV uninfected. Most couples were married and cohabiting, and almost 50% had at least one uncircumcised male child of ≤18 years of age. Overall, 90.2% of male partners and 94.6% of female partners expressed interest in medical circumcision for their male children for reduction of future risk for HIV infection, including 79.9% of men and 87.6% of women who had an uncircumcised male child. Among both men and women, those who were knowledgeable that circumcision reduces men's risk for HIV (adjusted prevalence ratio [APR] 1.34 and 1.14) and those who had discussed the HIV prevention effects of medical circumcision with their partner (APR 1.08 and 1.07) were significantly (p≤0.05) more likely to be interested in male child circumcision for HIV prevention. Among men, those who were circumcised (APR 1.09, p = 0.004) and those who were HIV seropositive (APR 1.09, p = 0.03) were also more likely to be interested in child circumcision for HIV prevention.A high proportion of men and women in Ugandan heterosexual HIV serodiscordant partnerships were willing to have their male children circumcised for eventual HIV prevention benefits. Engaging both parents may increase interest in medical male circumcision for HIV prevention