Drop-offs in the isoniazid preventive therapy cascade among children living with HIV in western Kenya, 2015–2019

Introduction: Isoniazid preventive therapy (IPT) can reduce the risk of tuberculosis (TB) in children living with HIV (CLHIV), but data on the outcomes of the IPT cascade in CLHIV are limited. Methods: We evaluated the IPT cascade among CLHIV aged <15 years and newly enrolled in HIV care in eight HIV clinics in western Kenya. Medical record data were abstracted from September 2015 through July 2019. We assessed the proportion of CLHIV completing TB symptom screening, IPT eligibility assessment, IPT initiation and completion. TB incidence rate was calculated stratified by IPT initiation and completion status. Risk factors for IPT non-initiation and non-completion were assessed using Poisson regression with generalized linear models. Results: Overall, 856 CLHIV were newly enrolled in HIV care, of whom 98% ([95% CI 97–99]; n = 841) underwent screening for TB symptoms and IPT eligibility. Of these, 13 (2%; 95% CI 1–3) were ineligible due to active TB and 828 (98%; 95% CI 97–99) were eligible. Five hundred and fifty-nine (68%; 95% CI 64–71) of eligible CLHIV initiated IPT; median time to IPT initiation was 3.6 months (interquartile range [IQR] 0.5–10.2). Overall, 434 (78%; 95% CI 74–81) IPT initiators completed. Attending high-volume HIV clinics (aRR = 2.82; 95% CI 1.20–6.62) was independently associated with IPT non-initiation. IPT non-initiation had a trend of being higher among those enrolled in the period 2017–2019 versus 2015–2016 (aRR = 1.91; 0.98–3.73) and those who were HIV virally non-suppressed (aRR = 1.90; 95% CI 0.98–3.71). Being enrolled in 2017–2019 versus 2015–2016 (aRR = 1.40; 1.01–1.96) was independently associated with IPT non-completion. By 24 months after IPT screening, TB incidence was four-fold higher among eligible CLHIV who never initiated (8.1 per 1000 person years [PY]) compared to CLHIV who completed IPT (2.1 per 1000 PY; rate ratio [RR] = 3.85; 95% CI 1.08–17.15), with a similar trend among CLHIV who initiated but did not complete IPT (8.2/1000 PY; RR = 4.39; 95% CI 0.82–23.56). Conclusions: Despite high screening for eligibility, timely IPT initiation and completion were suboptimal among eligible CLHIV in this programmatic cohort. Targeted programmatic interventions are needed to address these drop-offs from the IPT cascade by ensuring timely IPT initiation after ruling out active TB and enhancing completion of the 6-month course to reduce TB in CLHIV

Accuracy of digital chest x-ray analysis with artificial intelligence software as a triage and screening tool in hospitalized patients being evaluated for tuberculosis in Lima, Peru.

Tuberculosis (TB) transmission in healthcare facilities is common in high-incidence countries. Yet, the optimal approach for identifying inpatients who may have TB is unclear. We evaluated the diagnostic accuracy of qXR (Qure.ai, India) computer-aided detection (CAD) software versions 3.0 and 4.0 (v3 and v4) as a triage and screening tool within the FAST (Find cases Actively, Separate safely, and Treat effectively) transmission control strategy. We prospectively enrolled two cohorts of patients admitted to a tertiary hospital in Lima, Peru: one group had cough or TB risk factors (triage) and the other did not report cough or TB risk factors (screening). We evaluated the sensitivity and specificity of qXR for the diagnosis of pulmonary TB using culture and Xpert as primary and secondary reference standards, including stratified analyses based on risk factors. In the triage cohort (n = 387), qXR v4 sensitivity was 0.91 (59/65, 95% CI 0.81-0.97) and specificity was 0.32 (103/322, 95% CI 0.27-0.37) using culture as reference standard. There was no difference in the area under the receiver-operating-characteristic curve (AUC) between qXR v3 and qXR v4 with either a culture or Xpert reference standard. In the screening cohort (n = 191), only one patient had a positive Xpert result, but specificity in this cohort was high (>90%). A high prevalence of radiographic lung abnormalities, most notably opacities (81%), consolidation (62%), or nodules (58%), was detected by qXR on digital CXR images from the triage cohort. qXR had high sensitivity but low specificity as a triage in hospitalized patients with cough or TB risk factors. Screening patients without cough or risk factors in this setting had a low diagnostic yield. These findings further support the need for population and setting-specific thresholds for CAD programs

Significant benefits of AIP testing and clinical screening in familial isolated and young-onset pituitary tumors

Context Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs). Objective To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients. Design 12-year prospective, observational study. Participants & Setting We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases. Interventions & Outcome AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310). Results Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650). Conclusions Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course

Totality of outcomes: A different paradigm in assessing interventions for treatment of tuberculosis

Conventional analytic methods used for tuberculosis (TB) outcomes research use standardized outcomes definitions and assess safety and efficacy separately. These methods are subject to important limitations. Conventionally utilized outcome definitions fail to capture important aspects of patients' treatment experience and obscure meaningful differences between patients.Assessing safety and efficacy separately fails to yield an objective riskâbenefit comparison to guide clinical practice. We propose to address these issues through an analytic approach based on prioritized outcomes. This approach enables a more comprehensive and integrated assessment of TB interventions. It simultaneously considers a âtotality of outcomesâ, including clinical benefit, adverse events, and quality of life. These composite outcomes are ranked terms of overall desirability and compared using statistical methods for ordinal outcomes. Here we discuss the application of this approach to TB research, the considerations involved with prioritizing TB treatment outcomes, and the statistical methods involved in comparing prioritized outcomes. Keywords: Tuberculosis, Treatment outcome, Riskâbenefit assessmen

Association between Mycobacterium tuberculosis complex phylogenetic lineage and acquired drug resistance.

BackgroundDevelopment of resistance to antituberculosis drugs during treatment (i.e., acquired resistance) can lead to emergence of resistant strains and consequent poor clinical outcomes. However, it is unknown whether Mycobacterium tuberculosis complex species and lineage affects the likelihood of acquired resistance.MethodsWe analyzed data from the U.S. National Tuberculosis Surveillance System and National Tuberculosis Genotyping Service for tuberculosis cases during 2004-2011 with assigned species and lineage and both initial and final drug susceptibility test results. We determined univariate associations between species and lineage of Mycobacterium tuberculosis complex bacteria and acquired resistance to isoniazid, rifamycins, fluoroquinolones, and second-line injectables. We used Poisson regression with backward elimination to generate multivariable models for acquired resistance to isoniazid and rifamycins.ResultsM. bovis was independently associated with acquired resistance to isoniazid (adjusted prevalence ratio = 8.46, 95% CI 2.96-24.14) adjusting for HIV status, and with acquired resistance to rifamycins (adjusted prevalence ratio = 4.53, 95% CI 1.29-15.90) adjusting for homelessness, HIV status, initial resistance to isoniazid, site of disease, and administration of therapy. East Asian lineage was associated with acquired resistance to fluoroquinolones (prevalence ratio = 6.10, 95% CI 1.56-23.83).ConclusionsWe found an association between mycobacterial species and lineage and acquired drug resistance using U.S. surveillance data. Prospective clinical studies are needed to determine the clinical significance of these findings, including whether rapid genotyping of isolates at the outset of treatment may benefit patient management

Assessing the impact of antiretroviral therapy on tuberculosis notification rates among people with HIV: a descriptive analysis of 23 countries in sub-Saharan Africa, 2010–2015

Abstract Background HIV is a major driver of the tuberculosis epidemic in sub-Saharan Africa. The population-level impact of antiretroviral therapy (ART) scale-up on tuberculosis rates in this region has not been well studied. We conducted a descriptive analysis to examine evidence of population-level effect of ART on tuberculosis by comparing trends in estimated tuberculosis notification rates, by HIV status, for countries in sub-Saharan Africa. Methods We estimated annual tuberculosis notification rates, stratified by HIV status during 2010–2015 using data from WHO, the Joint United Nations Programme on HIV/AIDS, and the United Nations Population Division. Countries were included in this analysis if they had ≥4 years of HIV prevalence estimates and ≥ 75% of tuberculosis patients with known HIV status. We compared tuberculosis notification rates among people living with HIV (PLHIV) and people without HIV via Wilcoxon rank sum test. Results Among 23 included countries, the median annual average change in tuberculosis notification rates among PLHIV during 2010–2015 was -5.7% (IQR -6.9 to -1.7%), compared to a median change of -2.3% (IQR -4.2 to -0.1%) among people without HIV (p-value = 0.0099). Among 11 countries with higher ART coverage, the median annual average change in TB notification rates among PLHIV was -6.8% (IQR -7.6 to -5.7%) compared to a median change of -2.1% (IQR -6.0 to 0.7%) for PLHIV in 12 countries with lower ART coverage (p = 0.0106). Conclusion Tuberculosis notification rates declined more among PLHIV than people without HIV, and have declined more in countries with higher ART coverage. These results are consistent with a population-level effect of ART on decreasing TB incidence among PLHIV. To further reduce TB incidence among PLHIV, additional scale-up of ART as well as greater use of isoniazid preventive therapy and active case-finding will be necessary

Tuberculosis household accompaniment to improve the contact management cascade: A prospective cohort study.

BackgroundAppropriate management of people exposed in the home to tuberculosis is essential to prevent morbidity. These household contacts, particularly children, should receive preventive therapy to prevent them from falling ill. However, few people receive preventive therapy worldwide. We sought to determine whether a community-based accompaniment intervention could improve tuberculosis contact management.MethodsWe conducted a prospective cohort study of household contacts of tuberculosis patients who initiated treatment during September 2015-June 2016 in Lima, Peru. Enrolled households received an intervention comprising home visits, transport vouchers, assistance coordinating evaluation procedures, and adherence support during preventive therapy. To evaluate the impact of the intervention, we conducted retrospective chart reviews of all patients initiating treatment during 6-month baseline and intervention periods.ResultsWe enrolled 314 household contacts of 109 index patients. Of these, 283 (90%) completed evaluation, and 4 (1%) were diagnosed with tuberculosis. Preventive therapy was prescribed for 35/38 (92%) contacts 0-19 years old who were eligible under Peruvian guidelines. Preventive therapy was also prescribed for 6/26 (23%) contacts with unknown eligibility due to lack of a tuberculin skin test (TST), and 20/69 (29%) who were ineligible either because of a negative TST result or exposure to a drug-resistant or extrapulmonary case. Of the 61 contacts who were prescribed preventive therapy, 57 (93%) initiated treatment, and 51 (91%) completed treatment. The proportion of contacts who completed evaluation increased from 42% during the baseline period to 71% during the evaluation period (risk ratio [RR] = 1.73, 95% confidence interval [95% CI]: 1.41-2.13). The proportion of contacts who initiated preventive therapy increased from 15% to 40% (RR = 2.45, 95% CI: 1.42-4.22).ConclusionAccompaniment of TB patient households greatly improved the evaluation of household contacts for TB and increased the use of preventive therapy