Received Isoniazid Preventive Therapy Research Articles

Contact screening of children exposed to active pulmonary tuberculosis: A hospital-based study in Navi Mumbai, India

Abstract Background: Contact investigation is a proactive method employed for active case-finding to improve the detection of active tuberculosis (TB) cases, constituting a crucial component of National TB Programs. Household contacts face a higher exposure risk than individuals in the general population. Although integrated into national policy, the execution of contact investigations is not regularly undertaken, and the outcomes of these investigations are inadequately characterized. Objective: To evaluate risk factors and determine the occurrence of TB disease among household contacts of individuals diagnosed with sputum smear-positive TB in Kamothe, Navi Mumbai, India. Materials and Methods: From December 2018 to November 2020, active screening was carried out for 120 household contact children aged up to 18 years, linked to 52 index cases receiving care at MGM Medical College and Hospital in Navi Mumbai, India. Results: Out of the 120 screened children, 10 (8.3%) showed symptoms, whereas 110 (91.6%) were asymptomatic. Among those exhibiting symptoms, 5 (50%) had abnormal chest X-ray findings. The diagnosis of TB was established in eight cases, including five with pulmonary TB, two with lymph node TB, and one with central nervous system TB. All confirmed TB-positive cases underwent antitubercular treatment, with children under 5 years receiving Isoniazid Preventive Therapy. Conclusion: The study resulted in a 6.67% incidence rate, offering an opportunity to initiate chemoprophylaxis among children. This research identified risk factors associated with the development of TB disease, encompassing female gender, underweight status, residing in crowded conditions, prolonged contact, and extended duration of exposure.

Maternal HIV Status and Risk of Infant Mycobacterium tuberculosis Infection as Measured by Tuberculin Skin Test.

The effect of maternal HIV on infant Mycobacterium tuberculosis (Mtb) infection risk is not well-characterized. Pregnant women with/without HIV and their infants were enrolled in a longitudinal cohort in Kenya. Mothers had interferon gamma-release assays (QFT-Plus) and tuberculin skin tests (TST) at enrollment in pregnancy; children underwent TST at 12 and 24 months of age. We estimated the incidence and correlates of infant TST-positivity using Cox proportional hazards regression. Among 322 infants, 170 (53%) were HIV-exposed and 152 (47%) were HIV-unexposed. Median enrollment age was 6.6 weeks [interquartile range (IQR): 6.1-10.0]; most received Bacillus Calmette-Guerin (320, 99%). Thirty-nine (12%) mothers were TST-positive; 102 (32%) were QFT-Plus-positive. Among HIV-exposed infants, 154 (95%) received antiretrovirals for HIV prevention and 141 (83%) of their mothers ever received isoniazid preventive therapy (IPT). Cumulative 24-month infant Mtb infection incidence was 3.6/100 person-years (PY) [95% confidence interval (CI): 2.4-5.5/100 PY]; 5.4/100 PY in HIV-exposed infants (10%, 17/170) versus 1.7/100 PY in HIV-unexposed infants (3.3%, 5/152) [hazard ratio (HR): 3.1 (95% CI: 1.2-8.5)]. More TST conversions occurred in the first versus second year of life [5.8 vs. 2.0/100 PY; HR: 2.9 (95% CI: 1.0-10.1)]. Infant TST-positivity was associated with maternal TST-positivity [HR: 2.9 (95% CI: 1.1-7.4)], but not QFT-Plus-positivity. Among HIV-exposed children, Mtb infection incidence was similar regardless of maternal IPT. Mtb infection incidence (by TST) by 24 months of age was ~3-fold higher among HIV-exposed children, despite high maternal IPT uptake. Overall, more TST conversions occurred in the first 12 months compared to 12-24 months of age, similar in both HIV-exposed and HIV-unexposed children.

Interferon Gamma Release Assay and Tuberculin Skin Test Performance in Pregnant Women Living With and Without HIV.

HIV and pregnancy may affect latent TB infection (LTBI) diagnostics. Tuberculin skin test (TST) and newer generation QuantiFERON-TB Gold Plus (QFT-Plus) evaluations in pregnant women living with HIV (WLHIV) and without HIV are lacking. In this cross-sectional study, pregnant women underwent TST and QFT-Plus testing during antenatal care in Kenya. We estimated LTBI prevalence and TST and QFT-Plus performances. Diagnostic agreement was assessed with kappa statistic, participant characteristics associated with LTBI and HIV were assessed with generalized linear models, and QFT-Plus quantitative responses were assessed with Mann-Whitney U test. We enrolled 400 pregnant women (200 WLHIV/200 HIV-negative women) at median 28 weeks gestation (interquartile range 24-30). Among WLHIV (all on antiretroviral therapy), the median CD4 count was 464 cells/mm3 (interquartile range 325-654); 62.5% (125) had received isoniazid preventive therapy. LTBI prevalence was 35.8% and similar among WLHIV and HIV-negative women. QFT-Plus testing identified 3-fold more women with LTBI when compared with TST (32% vs. 12%, P < 0.0001). QFT-Plus positivity prevalence was similar regardless of HIV status, although TB-specific antigen responses were lower in WLHIV than in HIV-negative women with LTBI (median QFT-TB1 1.05 vs. 2.65 IU/mL, P = 0.035; QFT-TB2 1.26 vs. 2.56 IU/mL, P = 0.027). TST positivity was more frequent among WLHIV than among HIV-negative women (18.5% vs 4.6%; P < 0.0001). QFT-Plus assay had higher diagnostic yield than TST for LTBI in WLHIV and HIV-negative women despite lower TB-specific antigen responses in WLHIV. Higher TST positivity was observed in WLHIV. LTBI diagnostic performance in the context of pregnancy and HIV has implications for clinical use and prevention studies, which rely on these diagnostics for TB infection entry criteria or outcomes.

Plasma Kynurenine-to-Tryptophan Ratio, a Highly Sensitive Blood-Based Diagnostic Tool for Tuberculosis in Pregnant Women Living With Human Immunodeficiency Virus (HIV).

BackgroundFor pregnant women living with human immunodeficiency virus (HIV), concurrent active tuberculosis (TB) disease increases the risk of maternal mortality and poor pregnancy outcomes. Plasma indoleamine 2,3-dioxygenase (IDO) activity measured by kynurenine-to-tryptophan (K/T) ratio has been proposed as a blood-based TB biomarker. We investigated whether plasma K/T ratio could be used to diagnose active TB among pregnant women with HIV.MethodsUsing an enzyme-linked immunosorbent assay (ELISA), we measured K/T ratio in 72 pregnant women with and active TB and compared them to 117 pregnant women with HIB but without TB, matched by age and gestational age.ResultsPlasma K/T ratio was significantly elevated during pregnancy compared to sampling done after pregnancy (P < .0001). Pregnant women who had received isoniazid preventive therapy (IPT) before enrollment had decreased plasma K/T ratio compared to those who had not received IPT (P = .0174). Plasma K/T ratio was elevated in women with active TB at time of diagnosis compared to those without TB (P < .0001). Using a cutoff of 0.100, plasma K/T ratio gave a diagnostic sensitivity of 94% (95% confidence interval [CI]: 82–95), specificity of 90% (95% CI: 80–91), positive predictive value (PPV) 85% and negative predictive value (NPV) 98%. A receiver operating characteristic curve (ROC) gave an area under the curve of 0.95 (95% CI: .92–.97, P < .0001).In conclusion, plasma K/T ratio is a sensitive blood-based diagnostic test for active TB disease in pregnant women living with HIV. Plasma K/T ratio should be further evaluated as an initial TB diagnostic test to determine its impact on patient care.

Choice architecture-based prescribing tool for TB preventive therapy: a pilot study in South Africa.

All people with HIV who screen negative for active tuberculosis (TB) should receive isoniazid preventive therapy (IPT). IPT implementation remains substantially below the 90% WHO target. This study sought to further understanding of IPT prescription by piloting a simplified prescribing approach. Primary care clinics in Matlosana, South Africa. This was a mixed-methods implementation study. Nine providers were recruited and underwent training on 2018 WHO guidelines. A simplified prescribing tool containing antiretroviral therapy (ART) and IPT prescriptions was introduced into the workflow for 2 weeks. Prescription data were collected from file review. Interviews were conducted with prescribers. During the study period, 41 patients were evaluated for ART initiation; 34 (83%) files used the simplified prescribing tool. Thirty-seven (90%) patients were eligible for same-day ART and IPT initiation, of whom 36 (97%) received IPT prescription. Qualitative interviews identified the following barriers to IPT prescription: cognitive burden, extensive documentation, limited management support, paucity of training, stock-outs, and patient-related factors. Provider acceptability of the tool was favorable, with unanimous recommendation to colleagues on the basis of streamlining documentation and reminding to prescribe. This simplified prescribing device for IPT was feasible to implement. Streamlining documentation and reminding providers to prescribe can reduce work-flow barriers to IPT provision.

Incidence and predictors of loss to follow-up among human immunodeficiency virus-infected adult patients on anti-retroviral therapy at Hadiya zone public hospitals, southern Ethiopia: a retrospective cohort study

Loss to follow-up from anti-retroviral therapy (ART) is common and can have adverse health impacts. This study aimed to assess the incidence and predictors of loss to follow-up among adult patients on ART treatment at Hadiya zone public hospitals. An institution-based retrospective cohort study was conducted in public hospitals in Hadiya zone, Ethiopia, from 2014 to 2018. Kaplan-Meier failure curves were used to estimate the probability of loss to follow-up after ART initiation. The Cox proportional hazard model was used to assess predictors associated with loss to follow-up after ART initiation. The incidence rate of loss to follow-up among advanced and not advanced disease of adult HIV-infected patients was 11.9/100 person-years (95% CI 9.47–14.99) and 8.6/100 person-years (95% CI 6.37–11.67), respectively. Baseline CD4 cell count < 200 cells/mm³ (AHR = 3.4, 95% CI: 1.87, 6.18), advanced disease at ART initiation (AHR = 0.33, 95% CI: 0.18, 0.58), not receiving isoniazid preventive therapy (AHR = 2.5, 95% CI: 1.64, 3.94), fair or poor adherence to medication (AHR = 2.8, 95% CI: 1.87, 4.34) and ambulatory or bedridden functional status (AHR = 2.4, 95% CI: 1.33, 4.18) were significantly associated. The overall incidence rate of loss to follow-up was high. Loss to follow-up was associated with low CD4 cell count, advanced disease stage, not receiving IPT, fair or poor adherence and ambulatory or bedridden functional status. Therefore, interventions should be strengthened to reduce loss to follow-up by addressing the identified risk factors.

Incidence and predictors of loss to follow up among adult HIV patients on antiretroviral therapy in University of Gondar Comprehensive Specialized Hospital: A competing risk regression modeling.

Loss to follow up after the initiation of antiretroviral therapy (ART) is common in Africa, particularly in Ethiopia and it is a considerable obstacle for the effectiveness of the ART program. Mortality is a competing risk of loss to follow up but it is often overlooked and there is limited evidence about the incidence and predictors of loss to follow up in the presence of competing events. To assess the Incidence and predictors of loss to follow up among adult HIV patients on ART in University of Gondar Comprehensive Specialized Hospital between January 1, 2015, and December 31, 2018. Institution based retrospective follow up study was conducted in University of Gondar Comprehensive Specialized Hospital. A Gray's test and cumulative incidence curve were used to compare the cumulative incidence function of loss to follow up. Bivariable and multivariable competing risk regression models were fitted to identify the predictors of lost to follow up and those variables with p-value <0.05 in the multivariable analysis was considered as significant predictors of lost to follow up. A total of 531 adult HIV patients on ART were included in the analysis. The incidence rate of loss to follow up in this study was 10.90 (95% CI: 8.9-13.2) per 100 person years. Being age group 15-30 years (aSHR = 2.01; 95%CI;1.11-3.63), being daily laborer(aSHR = 2.60; 95%CI;1.45-4.66), not receiving cotrimoxazole preventive therapy (aSHR = 2.66; 95%CI;1.68-4.21), not receiving isoniazid preventive therapy(aSHR = 4.57; 95% CI;1.60-13.08), ambulatory functional status (aSHR = 1.61; 95% CI; 1.02-2.51) and taking AZT-3TC-NVP medication at start of ART(aSHR = 2.01; 95% CI; 1.16-3.78) were significant predictors of lost to follow up. In this study the incidence of lost to follow up was high. Young people, daily laborer, ambulatory patients and those taking AZT-3TC-NVP as well as those who did not take opportunistic prophylaxis were at higher risk of loss to follow up. Therefore, giving special attention to the high-risk groups for lost to follow up highlighted in this study could decrease the rate of LTFU.

1344. Interferon Gamma Release Assay (IGRA) Responses in HIV-Infected and -Uninfected Women in Pregnancy

BackgroundPregnancy and HIV-associated immunologic changes may affect latent TB infection (LTBI) interferon-gamma release assay (IGRA) QuantiFERON TB Gold Plus (QFT-Plus) diagnostic performance.MethodsIn this ongoing study, HIV-infected and -uninfected women 20–34 weeks gestation without TB in the past year are enrolled from antenatal clinics in western Kenya and tested with QFT-Plus. Mean quantitative IFN- γ responses to mitogen, and M. tuberculosis antigens (TB1 [primarily CD4+] and TB2 [addition of CD8+ response]) were compared using two-sample t-tests. Proportions for categorical variables were compared using univariate logistic regression.ResultsAmong 306 women (HIV+ 127 [41.5%], HIV− 179 [58.5%]) enrolled between January 2018 and March 2019, median maternal and gestational age were 25 years (IQR 21–28) and 28 weeks (IQR 24–32), respectively. Among HIV-infected women at enrollment, 99.2% were on ART, median CD4 count was 440 cells/mm3 (IQR 235–703), 37.5% were virally suppressed, and 60.6% reported having received isoniazid preventive therapy (IPT). Overall, 95 (31.1%) women were QFT-Plus positive (HIV+ 38 [29.9%], HIV− 57 [31.8%], OR 0.90, 95% CI 0.54–1.48, P = 0.671); 190 (62.1%) were negative (HIV+ 81 [63.8%], HIV− 109 [60.9%]), and 21 had indeterminate results (HIV+ 8 [6.3%], HIV− 13 [7.3%], OR 0.83, 95% CI 0.33–2.09, P = 0.690). Mean response to mitogen was similar between HIV-infected and -uninfected women (6.0 vs. 6.1 IU/mL, P = 0.663]. Among QFT-Plus positive women, HIV+ women had significantly lower TB1 responses than HIV− women (HIV+ 2.7 vs. 4.2 IU/mL, P = 0.035). Mean TB2 responses had a similar pattern, but did not reach statistical significance (HIV+ 3.1 vs. 4.3 IU/mL, P = 0.107). Both TB1 and TB2 were positive for 82 women (86.3%), 4 women were only TB1 positive (4.2%), and 8 women were only TB2 positive (8.4%).ConclusionAmong pregnant women, HIV-infection was not associated with increased prevalence of QFT+ responses. However, among QFT-positive women, TB1 responses were lower in HIV-positive women with a similar trend observed for TB2 responses. These findings suggest that HIV-associated immunologic changes may influence QFT test performance.Disclosures All authors: No reported disclosures.

Isoniazid Preventive Therapy in HIV-Infected Pregnant and Postpartum Women

BackgroundThe safety, efficacy, and appropriate timing of isoniazid therapy to prevent tuberculosis in pregnant women with human immunodeficiency virus (HIV) infection who are receiving antiretroviral therapy are unknown.MethodsIn this multicenter, double-blind, placebo-controlled, noninferiority trial, we randomly assigned pregnant women with HIV infection to receive isoniazid preventive therapy for 28 weeks, initiated either during pregnancy (immediate group) or at week 12 after delivery (deferred group). Mothers and infants were followed through week 48 after delivery. The primary outcome was a composite of treatment-related maternal adverse events of grade 3 or higher or permanent discontinuation of the trial regimen because of toxic effects. The noninferiority margin was an upper boundary of the 95% confidence interval for the between-group difference in the rate of the primary outcome of less than 5 events per 100 person-years.ResultsA total of 956 women were enrolled. A primary outcome event occurred in 72 of 477 women (15.1%) in the immediate group and in 73 of 479 (15.2%) in the deferred group (incidence rate, 15.03 and 14.93 events per 100 person-years, respectively; rate difference, 0.10; 95% confidence interval [CI], −4.77 to 4.98, which met the criterion for noninferiority). Two women in the immediate group and 4 women in the deferred group died (incidence rate, 0.40 and 0.78 per 100 person-years, respectively; rate difference, −0.39; 95% CI, −1.33 to 0.56); all deaths occurred during the postpartum period, and 4 were from liver failure (2 of the women who died from liver failure had received isoniazid [1 in each group]). Tuberculosis developed in 6 women (3 in each group); the incidence rate was 0.60 per 100 person-years in the immediate group and 0.59 per 100 person-years in the deferred group (rate difference, 0.01; 95% CI, −0.94 to 0.96). There was a higher incidence in the immediate group than in the deferred group of an event included in the composite adverse pregnancy outcome (stillbirth or spontaneous abortion, low birth weight in an infant, preterm delivery, or congenital anomalies in an infant) (23.6% vs. 17.0%; difference, 6.7 percentage points; 95% CI, 0.8 to 11.9).ConclusionsThe risks associated with initiation of isoniazid preventive therapy during pregnancy appeared to be greater than those associated with initiation of therapy during the postpartum period. (Funded by the National Institutes of Health; IMPAACT P1078 TB APPRISE ClinicalTrials.gov number, NCT01494038.)

Incidence and predictors of tuberculosis among HIV-positive children at Adama Referral Hospital and Medical College, Oromia, Ethiopia: a retrospective follow-up study.

OBJECTIVESTuberculosis (TB) is common in children with human immunodeficiency virus (HIV), but its effect on the survival of HIV-infected children is not well understood. Therefore, the aim of this study was to assess the incidence and predictors of active TB among HIV-positive children at Adama Referral Hospital and Medical College, Oromia, Ethiopia.METHODSA retrospective study was conducted over 5 years using a checklist to gather data from 428 randomly selected pediatric patient charts. The checklist was adapted from the standardized antiretroviral therapy (ART) follow-up form currently used by the institution’s ART clinic. Data were analyzed by bivariate and multivariable analysis using Cox regression proportional hazards models, as appropriate. Survival was calculated and compared using the Kaplan-Meier and log-rank tests.RESULTSOf the 466 charts reviewed, 428 patient records were included in the analysis. A total of 67 new TB cases were observed during the follow-up period. Hence, the incidence rate in this cohort was found to be 6.03 per 100 child-years of observation. A baseline hemoglobin level <10 g/dL (adjusted hazard ratio [aHR], 7.04; 95% confidence interval [CI], 1.03 to 48.15), moderate wasting (aHR, 2.86; 95% CI, 1.02 to 7.99), and not receiving isoniazid preventive therapy (aHR, 8.23; 95% CI, 2.11 to 32.06) were among the independent predictors of TB occurrence.CONCLUSIONSThe incidence of TB was high, particularly in pre-ART patients receiving chronic care for HIV. Close followup of HIV-positive children is crucial to protect them against the development of TB. Initiating isoniazid preventive therapy, averting malnutrition, and managing anemia are also of significant importance.

Immunologic-based Diagnosis of Latent Tuberculosis Among Children Younger Than 5 Years of Age Exposed and Unexposed to Tuberculosis in Tanzania.

Childhood tuberculosis (TB) is acquired after exposure to an infectious TB case, often within the household. We prospectively screened children 6-59 months of age, exposed and unexposed to an infectious TB case within the same household, for latent tuberculosis infection (LTBI), in Dar es Salaam, Tanzania. We collected medical data and clinical specimens (to evaluate for helminths, TB and HIV coinfections) and performed physical examinations at enrollment and at 3-month and 6-month follow-up surveys. LTBI was assessed using QuantiFERON-TB Gold (QFT) at enrollment and at 3 months. In total, 301 children had complete data records (186 with TB exposure and 115 without known TB exposure). The median age of children was 26 months (range: 6-58); 52% were females, and 4 were HIV positive. Eight children (3%) developed TB during the 6-month follow-up. We found equal proportions of children with LTBI among those with and without exposure: 20% (38/186) versus 20% (23/115) QFT-positive, and 2% (4/186) versus 4% (5/115) indeterminate QFT. QFT conversion rate was 7% (22 children) and reversion 8% (25 children). Of the TB-exposed children, 72% initiated isoniazid preventive therapy, but 61% of parents/caregivers of children with unknown TB exposure and positive QFT refused isoniazid preventive therapy. In this high burden TB setting, TB exposure from sources other than the household was equally important as household exposure. Nearly one third of eligible children did not receive isoniazid preventive therapy. Evaluation for LTBI in children remains an important strategy for controlling TB but should not be limited to children with documented TB exposure.

High prevalence and incidence of tuberculosis in people living with the HIV in Mandalay, Myanmar, 2011-2017.

Two human immunodeficiency virus (HIV) clinics providing antiretroviral therapy (ART), Mandalay, Myanmar. To assess prevalent TB at enrolment, incident TB during follow-up and associated risk factors in adult people living with HIV (PLHIV) between 2011 and 2017. Cohort study using secondary data. Of 11 777 PLHIV, 2911 (25%) had prevalent TB at or within 6 weeks of enrolment. Independent risk factors for prevalent TB were being male or single/widowed, daily alcohol consumption, CD4 count 200 cells/μl and anaemia. During 6 years follow-up in 8866 PLHIV with no prevalent TB, the rate of new TB was 2.9 per 100 person-years (95%CI 2.6-3.1). Cumulative TB incidence was 9.6%, with 370 (72%) of 517 new TB cases occurring in the first year. Independent risk factors for incident TB were being male and anaemia. Incident TB was highest in the first year of ART, in PLHIV with CD4 counts 200 cells/μl and those not receiving isoniazid preventive therapy (IPT). Incident TB declined with time on ART and rising CD4 counts. Prevalent and incident TB were high in PLHIV in the Mandalay clinics. Consideration should be given to earlier TB diagnosis using more sensitive diagnostic tools, effective ART and scaling up IPT.

Burden, spectrum and outcomes of children with tuberculosis diagnosed at a district-level hospital in South Africa.

The Khayelitsha subdistrict has the highest burden of reported tuberculosis (TB) cases in Cape Town, Western Cape Province, South Africa. To characterise the TB burden, spectrum and treatment outcomes among children managed at a district-level hospital, the Khayelitsha District Hospital. Retrospective medical record review of all children (age <13 years) diagnosed with TB in January-July 2014. A lay health care worker completed daily surveillance and supported linkage to TB care. Symptoms and investigations at presentation, TB disease spectrum, referral pathways and outcomes were reported. Most children were aged 2 years (84/99, 85%), 18/96 (19%) were infected with the human immunodeficiency virus, 31/91 (34%) were malnourished and 80/99 (81%) had pulmonary TB only. The majority of the children (63/80, 79%) presented with cough of acute onset (<2 weeks). Only 5/36 (14%) eligible child contacts had documentation of receiving isoniazid preventive therapy. Twelve (13%) children had bacteriologically confirmed pulmonary TB. Overall, 93/97 (96%) children successfully continued TB care after hospital discharge. Favourable TB treatment outcomes were recorded in only 77 (78%) children. Children with TB managed at this district-level hospital were young, and frequently had acute symptoms and substantial comorbidities. Missed opportunities for TB prevention were identified. Linkage to care support resulted in excellent continuation of TB care; however, treatment outcomes could be further improved.

Implications of a school outbreak of multidrug-resistant tuberculosis in Northern China.

In this study, we identified a multidrug-resistant tuberculosis (MDR-TB) outbreak in a high school in northern China. The aim of this work was to describe TB transmission, drug resistance and treatment outcomes for this patient cluster. In January 2017, pulmonary TB was identified in a 17-year-old boy in northern China. Subsequently, a total of 11 TB cases were identified during 6-month follow-up of attendees of the same school. Of five students with latent TB infection (LTBI) receiving isoniazid preventive therapy (IPT), two pulmonary TB cases (40.0%) emerged in March and April, for an active case rate not significantly different from that of the non-IPT group (4/16, 25.0%, P = 0.598). All TB patients were first treated with a standardised first-line treatment regimen administered by the local TB hospital, with 11 of 12 active TB patients exhibiting poor treatment outcomes. Further data demonstrated that all nine patient isolates collected during this outbreak were MDR-TB and shared a common genotypic profile. In conclusion, our data demonstrate that diagnostic delay for the index MDR-TB case of this outbreak played a primary role in transmission of MDR-TB infection within a school setting. Importantly, IPT failed to prevent progression of MDR-TB from LTBI to active TB.

Xpert MTB/RIF assay did not improve diagnosis of pulmonary tuberculosis among child contacts in Rwanda.

IntroductionTo report on the diagnostic yield using the Xpert MTB/RIF assay on gastric lavage samples from children (<15 years) who were household contacts of tuberculosis (TB) cases in Kigali, Rwanda.MethodsA cross-sectional study was conducted among 216 child contacts of index cases with sputum smear-positive TB over a 7 month period, from 1st August 2015 to 29th February 2016. Child contacts with tuberculosis-related symptoms or abnormal chest X-ray had sputum collected by gastric lavage on two consecutive days and samples were examined by smear microscopy, Xpert MTB/RIF assay and solid culture.ResultsOf the 216 child contacts, 94 (44%) were less than 5 years of age. Most of them 84 (89%) were receiving isoniazid preventive therapy at the time of screening. Thirty seven out of 216 children had TB-related symptoms. Only 4 (10.8%) were clinically diagnosed with TB; and none had bacteriologically confirmed tuberculosis.ConclusionThe use of Xpert MTB/RIF assay did not contribute to bacteriological confirmation of active TB in child contacts in this study. The low prevalence of tuberculosis in child contacts in this study may reflect the high coverage of preventive therapy in young (<5 years) child contacts. The low sensitivity of Xpert MTB/RIF assay in contacts may also suggest likely reflection of paucibacillary disease.

Addressing tuberculosis control in fragile states: Urban DOTS experience in Kabul, Afghanistan, 2009-2015.

Tuberculosis (TB) is a major public health problem in Afghanistan, but experience in implementing effective strategies to prevent and control TB in urban areas and conflict zones is limited. This study shares programmatic experience in implementing DOTS in the large city of Kabul. We analyzed data from the 2009–2015 reports of the National TB Program (NTP) for Kabul City and calculated treatment outcomes and progress in case notification using rates, ratios, and confidence interval. Urban DOTS was implemented by the NTP in partnership with United States Agency for International Development (USAID)-funded TB projects, the World Health Organization (WHO), and the private sector. Between 2009 and 2015, the number of DOTS-providing centers in Kabul increased from 22 to 85. In total, 24,619 TB patients were enrolled in TB treatment during this period. The case notification rate for all forms of TB increased from 59 per 100,000 population to 125 per 100,000. The case notification rate per 100,000 population for sputum-smear-positive TB increased from 25 to 33. The treatment success rate for all forms of TB increased from 31% to 67% and from 47% to 77% for sputum-smear-positive TB cases. The treatment success rate for private health facilities increased from 52% in 2010 to 80% in 2015. In 2013, contact screening was introduced, and the TB yield was 723 per 100,000—more than two times higher than the estimated national prevalence of 340 per 100,000. Contact screening contributed to identifying 2,509 child contacts of people with TB, and 76% of those children received isoniazid preventive therapy. The comprehensive urban DOTS program significantly improved service accessibility, TB case finding, and treatment outcomes in Kabul. Public- and private-sector involvement also improved treatment outcomes; however, the treatment success rate remains higher in private health facilities. While the treatment success rate increased significantly, it remains lower than the national average, and more efforts are needed to improve treatment outcomes in Kabul. We recommend that the urban DOTS approach be replicated in other countries and cities in Afghanistan with settings similar to Kabul.

Rapid urine-based screening for tuberculosis to reduce AIDS-related mortality in hospitalized patients in Africa (the STAMP trial): study protocol for a randomised controlled trial

BackgroundHIV-associated tuberculosis (TB) co-infection remains an enormous burden to international public health. Post-mortem studies have highlighted the high proportion of HIV-positive adults admitted to hospital with TB. Determine TB-LAM and Xpert MTB/RIF assays can substantially increase diagnostic yield of TB within one day of hospital admission. However, it remains unclear if this approach can impact clinical outcomes. The STAMP trial aims to test the hypothesis that the implementation a urine-based screening strategy for TB can reduce all cause-mortality among HIV-positive patients admitted to hospital when compared to current, sputum-based screening.MethodsThe trial is a pragmatic, individually randomised, multi-country (Malawi and South Africa) clinical trial with two study arms (1:1 recruitment). Unselected HIV-positive patients admitted to medical wards, irrespective of presentation, meeting the inclusion criteria and giving consent will be randomized to screening for TB using either: (i) ‘standard of care’- testing of sputum using the Xpert MTB/RIF assay (Xpert) or (ii) ‘intervention’- testing of sputum using Xpert and testing of urine using (a) Determine TB-LAM lateral-flow assay and (b) Xpert following concentration of urine by centrifugation. Patients will be excluded if they have received TB treatment in the previous 12 months, if they have received isoniazid preventive therapy in the last 6 months, if they are aged <18 years or they live outside the pre-specified geographical area. Results will be provided to the responsible medical team as soon as available to inform decisions regarding TB treatment. Both the study and routine medical team will be masked to study arm allocation. 1300 patients will be enrolled per arm (equal numbers at the two trial sites). The primary endpoint is all-cause mortality at 56 days. An economic analysis will be conducted to project long-term outcomes for shorter-term trial data, including cost-effectiveness.DiscussionThis pragmatic trial assesses an intervention to reduce the high mortality caused by HIV-associated TB, which could feasibly be scaled up in high-burden settings if shown to be efficacious and cost-effective. We discuss the challenges of designing a trial to assess the impact on mortality of laboratory-based TB screening interventions given frequent initiation of empirical treatment and a failure of several previous clinical trials to demonstrate an impact on clinical outcomes. We also elaborate on the practical and ethical issues of ‘testing a test’ in general.Trial registrationISRCTN Registry (ISRCTN71603869) prospectively registered 08 May 2015; the South African National Controlled Trials Registry (DOH-27-1015-5185) prospectively registered October 2015.

Risk of Active Tuberculosis in HIV-Infected Patients in Taiwan with Free Access to HIV Care and a Positive T-Spot.TB Test.

BackgroundInterferon-gamma release assays (IGRAs) have been used to identify individuals at risk for developing active tuberculosis (TB). However, data regarding the risk of TB development in HIV-infected patients testing positive for IGRAs remain sparse in the era of combination antiretroviral therapy.MethodsBetween 2011 and 2013, 608 HIV-infected patients without active TB undergoing T-Spot.TB testing were enrolled in this prospective observational study at a university hospital designated for HIV care in Taiwan with a declining TB incidence from 72 per 100,000 population in 2005 to 53 per 100,000 population in 2012. All of the subjects were followed until September 30, 2014. The national TB registry was accessed to identify any TB cases among those lost to follow-up.ResultsT-Spot.TB tested negative in 534 patients (87.8%), positive in 64 patients (10.5%), and indeterminate in 10 patients (1.6%). In multivariate analysis, positive T-Spot.TB was significantly associated with older age (adjusted odds ratio [AOR], 1.172 per 10-year increase; 95% confidence interval [CI], 1.022-1.344, P=0.023), past history of TB (AOR, 13.412; 95% CI, 6.106-29.460, P<0.001), and higher CD4 counts at enrollment (AOR, per 50-cell/μl increase, 1.062; 95% CI, 1.017-1.109, P=0.007). Of the 64 patients testing positive for T-Spot.TB, none received isoniazid preventive therapy and all but 5 received combination antiretroviral therapy at the end of follow-up with the latest CD4 count and plasma HIV RNA load being 592.8 cells/μL and 1.85 log10 copies/mL, respectively. One patient (1.6%) developed active TB after 167 person-years of follow-up (PYFU), resulting in an incidence rate of 0.599 per 100 PFYU. None of the 534 patients testing negative for T-Spot.TB developed TB after 1380 PYFU, nor did the 24 patients with old TB and positive T-Spot.TB tests develop TB after 62.33 PYFU.ConclusionsThe risk of developing active TB in HIV-infected patients with positive T-Spot.TB receiving combination antiretroviral therapy is low in Taiwan where the national TB program has led to a sustained decrease in TB incidence.

Isoniazid plus antiretroviral therapy to prevent tuberculosis: a randomised double-blind, placebo-controlled trial

Antiretroviral therapy reduces the risk of tuberculosis, but tuberculosis is more common in people with HIV than in people without HIV. We aimed to assess the effect of isoniazid preventive therapy on the risk of tuberculosis in people infected with HIV-1 concurrently receiving antiretroviral therapy. For this pragmatic randomised double-blind, placebo-controlled trial in Khayelitsha, South Africa, we randomly assigned (1:1) patients to receive either isoniazid preventive therapy or a placebo for 12 months (could be completed during 15 months). Randomisation was done with random number generator software. Participants, physicians, and pharmacy staff were masked to group assignment. The primary endpoint was time to development of incident tuberculosis (definite, probable, or possible). We excluded tuberculosis at screening by sputum culture. We did a modified intention-to-treat analysis and excluded all patients randomly assigned to groups who withdrew before receiving study drug or whose baseline sputum culture results suggested prevalent tuberculosis. This study is registered with ClinicalTrials.gov, number NCT00463086. 1329 participants were randomly assigned to receive isoniazid preventive therapy (n=662) or placebo (n=667) between Jan 31, 2008, and Sept 31, 2011, and contributed 3227 person-years of follow-up to the analysis. We recorded 95 incident cases of tuberculosis; 37 were in the isoniazid preventive therapy group (2·3 per 100 person-years, 95% CI 1·6-3·1), and 58 in the placebo group (3·6 per 100 person-years, 2·8-4·7; hazard ratio [HR] 0·63, 95% CI 0·41-0·94). Study drug was discontinued because of grade 3 or 4 raised alanine transaminase concentrations in 19 of 662 individuals in the isoniazid preventive therapy group and ten of the 667 individuals in the placebo group (risk ratio 1·9, 95% CI 0·90-4·09). We noted no evidence that the effect of isoniazid preventive therapy was restricted to patients who were positive on tuberculin skin test or interferon gamma release assay (adjusted HR for patients with negative tests 0·43 [0·21-0·86] and 0·43 [0·20-0·96]; for positive tests 0·86 [0·37-2·00] and 0·55 [0·26-1·24], respectively). Without a more predictive test or a multivariate algorithm that predicts benefit, isoniazid preventive therapy should be recommended to all patients receiving antiretroviral therapy in moderate or high incidence areas irrespective of tuberculin skin test or interferon gamma release assay status. Department of Health of South Africa, the Wellcome Trust, Médecins Sans Frontières, European and Developing Countries Clinical Trials Partnership, Foundation for Innovation and New Diagnostics, the European Union, and Hasso Plattner (Institute of Infectious Diseases and Molecular Medicine, University of Cape Town).

Adherence to isoniazid preventive therapy in Indonesian children: A quantitative and qualitative investigation.

BackgroundIt is recommended that young child contacts of sputum smear positive tuberculosis cases receive isoniazid preventive therapy (IPT) but reported adherence is low and risk factors for poor adherence in children are largely unknown.MethodsWe prospectively determined rates of IPT adherence in children < 5 yrs in an Indonesian lung clinic. Possible risk factors for poor adherence, defined as ≤3 months prescription collection, were calculated using logistic regression. To further investigate adherence barriers in-depth interviews were conducted with caregivers of children with good and poor adherence.ResultsEighty-two children eligible for IPT were included, 61 (74.4%) of which had poor adherence. High transport costs (OR 3.3, 95% CI 1.1-10.2) and medication costs (OR 20.0, 95% CI 2.7-414.5) were significantly associated with poor adherence in univariate analysis. Access, medication barriers, disease and health service experience and caregiver TB and IPT knowledge and beliefs were found to be important determinants of adherence in qualitative analysis.ConclusionAdherence to IPT in this setting in Indonesia is extremely low and may result from a combination of financial, knowledge, health service and medication related barriers. Successful reduction of childhood TB urgently requires evidence-based interventions that address poor adherence to IPT.