Comparison of QuantiFERON Gold In-Tube Versus Tuberculin Skin Tests on the Initiation of Tuberculosis Preventive Therapy Among Patients Newly Diagnosed With Human Immunodeficiency Virus in the North West Province of South Africa (the Teko Study): A Cluster Randomized Trial.

BACKGROUND: Tuberculosis (TB) preventive therapy (TPT) reduces the risk of TB disease in people with human immunodeficiency virus (HIV), yet uptake has been suboptimal in many countries. We assessed whether QuantiFERON Gold In-Tube (QGIT) during routine HIV care increased TB infection (TBI) testing and TPT prescriptions. METHODS: This parallel-arm, 1:1 cluster-randomized controlled trial compared the standard-of-care tuberculin skin test to QGIT in South Africa. We enrolled consenting, TPT-eligible adults diagnosed with HIV ≤30 days prior and used intention-to-treat analyses for the outcomes: proportion of patients with documented TBI results, proportion with documented TPT, and time from enrollment to outcomes. FINDINGS: We enrolled 2232 patients across 14 clinics from November 2014 to May 2017 (58% in intervention clinics). At 24 months of follow-up, more participants in intervention clinics had TBI results (69% vs 2%, P < .001) and TPT prescriptions (45% vs 30%, P = .13) than control clinics. Controlling for baseline covariates, intervention clinics had 60% (95% confidence interval, 51-68; P < .001) more participants with TBI results and 12% (95% confidence interval, -6 to 31; P = .18) more with TPT prescriptions. Among participants with results, those in intervention clinics received results and TPT faster (intervention: median of 6 and 29 days after enrollment vs control: 21 and 54 days, respectively). INTERPRETATION: In this setting, QGIT in routine HIV care resulted in more patients with TBI results. Clinicians also initiated more people with HIV on TPT in QGIT intervention clinics, and did so more quickly, than the control arm. CLINICAL TRIALS REGISTRATION: NCT02119130.

Pyrazinamide Safety, Efficacy, and Dosing for Treating Drug-Susceptible Pulmonary Tuberculosis: A Phase 3, Randomized, Controlled Clinical Trial.

RATIONALE: Optimizing pyrazinamide dosing is critical to improve treatment efficacy while minimizing toxicity during tuberculosis treatment. Study 31/ACTG A5349 represents the largest Phase 3 randomized controlled therapeutic trial to date for such investigation. OBJECTIVES: We sought to report pyrazinamide pharmacokinetic parameters, risk factors for lower pyrazinamide exposure, and relationships between pyrazinamide exposure with efficacy and safety outcomes. We aimed to determine pyrazinamide dosing strategies that optimize risks and benefits. METHODS: We analyzed pyrazinamide steady-state pharmacokinetic data using population nonlinear mixed-effects models. We evaluated the contribution of pyrazinamide exposure to long-term efficacy using parametric time-to-event models and safety outcomes using logistic regression. We evaluated optimal dosing with therapeutic windows targeting ≥95% durable cure and safety within the observed proportion of the primary safety outcome. MEASUREMENTS AND MAIN RESULTS: Among 2255 participants with 6978 plasma samples, pyrazinamide displayed 7-fold exposure variability (151-1053 mg·h/L). Body weight was not a clinically relevant predictor of drug clearance and thus did not justify the need for weight-banded dosing. Both clinical and safety outcomes were associated with pyrazinamide exposure, resulting in a therapeutic window of 231-355 mg·h/L for the control and 226-349 mg·h/L for the rifapentine-moxifloxacin regimen. Flat dosing of pyrazinamide at 1000 mg would have permitted an additional 13.1% (n=96) participants allocated to the control and 9.2% (n=70) to the rifapentine-moxifloxacin regimen dosed within the therapeutic window, compared to the current weight-banded dosing. CONCLUSIONS: Flat dosing of pyrazinamide at 1000 mg daily would be readily implementable and could optimize treatment outcomes in drug-susceptible tuberculosis. Clinical trial registration available at www. CLINICALTRIALS: gov, ID: NCT02410772. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Association between Covishield vaccine and menstrual disturbance. Findings from a cross-sectional study among participants of Zero TB cohort in India.

BACKGROUND: The association between covid-19 vaccine and menstrual disturbance is unclear. METHODS: An in-person cross-sectional survey among female members ≥ 18 years enrolled in an ongoing Zero TB prospective cohort in Northern India who had received one or two doses of covid-19 vaccine was conducted to study the characteristics and association of menstrual disturbance within six months of receiving Covishield. RESULTS: Between June 29 and September 5, 2021, 339 females ≥ 18 years of age were administered the survey. Median age was 30 (IQR: 22-39) years; 84 % were between 18 and 49 and 16 % were ≥ 50 years old. There were 152 college students, 27 healthcare workers, and 160 nuns. Forty-two women (12 %) had received one dose and 297 (88 %) had received two doses of Covishield. Overall, 66 (20 %) women reported experiencing menstrual disturbance after receiving Covishield vaccine. The problems included early menstruation: 6 % (n = 19/339); late menstruation: 4 % (n = 14/339); and heavier bleeding: 5 % (n = 17/339). Disturbances lasted for less than seven days and cycles normalized in 1-3 months. There was no post-menopausal bleeding. There was no significant difference in menstrual disturbance based on receiving one vs. two doses of Covishield (OR: 1.58; 95 % CI: 0.55-4.57; p = 0.381). History of SARS-CoV-2 infection was not associated with the development of menstrual disturbance among the vaccinees (OR: 0.63; 95 % CI: 0.24-1.73; p = 0.379). Presence of emotional disturbance at baseline (OR: 31; 95 % CI: 3.52-267; p = 0.002) or previous history of dysmenorrhea (OR: 41; 95 % CI: 8.7-196; p < 0.001) was associated with menstrual disturbance in the vaccinees, indicating their potential to confound or bias study results. CONCLUSION: Menstrual problems were reported by Covishield vaccinees, but they were minor and reversible within three months and do not constitute a ground for vaccine hesitancy. Studies designed to assess causal link taking care to avoid selection bias or confounding are needed.

Pharmacokinetic-Pharmacodynamic Evidence From a Phase 3 Trial to Support Flat-Dosing of Rifampicin for Tuberculosis.

BACKGROUND: The optimal dosing strategy for rifampicin in treating drug-susceptible tuberculosis (TB) is still highly debated. In the phase 3 clinical trial Study 31/ACTG 5349 (NCT02410772), all participants in the control regimen arm received 600 mg rifampicin daily as a flat dose. Here, we evaluated relationships between rifampicin exposure and efficacy and safety outcomes. METHODS: We analyzed rifampicin concentration time profiles using population nonlinear mixed-effects models. We compared simulated rifampicin exposure from flat- and weight-banded dosing. We evaluated the effect of rifampicin exposure on stable culture conversion at 6 months; TB-related unfavorable outcomes at 9, 12, and 18 months using Cox proportional hazard models; and all trial-defined safety outcomes using logistic regression. RESULTS: Our model-derived rifampicin exposure ranged from 4.57 mg · h/L to 140.0 mg · h/L with a median of 41.8 mg · h/L. Pharmacokinetic simulations demonstrated that flat-dosed rifampicin provided exposure coverage similar to the weight-banded dose. Exposure-efficacy analysis (n = 680) showed that participants with rifampicin exposure below the median experienced similar hazards of stable culture conversion and TB-related unfavorable outcomes compared with those with exposure above the median. Exposure-safety analysis (n = 722) showed that increased rifampicin exposure was not associated with increased grade 3 or higher adverse events or serious adverse events. CONCLUSIONS: Flat-dosing of rifampicin at 600 mg daily may be a reasonable alternative to the incumbent weight-banded dosing strategy for the standard-of-care 6-month regimen. Future research should assess the optimal dosing strategy for rifampicin, at doses higher than the current recommendation.

Survival of HIV patients with tuberculosis started on simultaneous or deferred HAART in the THRio cohort, Rio de Janeiro, Brazil

Background: The timing of highly active antiretroviral therapy (HAART) after a tuberculosis diagnosis in HIV-infected patients can affect clinical outcomes and survival. We compared survival after tuberculosis diagnosis in HIV-infected adults who initiated HAART and tuberculosis therapy simultaneously to those who delayed the start of HAART for at least two months. Methods: The THRio cohort includes 17,983 patients receiving HIV care in 29 public clinics in Rio de Janeiro, Brazil. HAART-naïve patients at the time of a new TB diagnosis between September 2003 and June 2008 were included. Survival was measured in days from diagnosis of TB. We compared survival among patients who initiated HAART within 60 days of TB treatment (simultaneous – ST) to those who started HAART >60 days of TB treatment or never started (deferred – DT). Kaplan–Meier plots and Cox proportional hazards regression analyses were conducted. Results: Of 947 patients diagnosed with TB, 572 (60%) were HAART naïve at the time of TB diagnosis; 135 were excluded because of missing CD4 count results. Among the remaining 437 TB patients, 56 (13%) died during follow-up: 25 (10%) among ST patients and 31 (16%) in DT group (p = 0.08). ST patients had lower median CD4 counts at TB diagnosis than DT patients (106 vs. 278, p < 0.001). Cox proportional hazards utilizing propensity score analysis showed that DT patients were more likely to die (adjusted HR = 1.89; 95% CI: 1.05–3.40; p = 0.03). Conclusion: HAART administered simultaneously with TB therapy was associated with improved survival after TB diagnosis. HAART should be given to patients with HIV-related TB as soon as clinically feasible. .

Physician adherence to guidelines for tuberculosis and HIV care in Rio de Janeiro, Brazil

BACKGROUND: Tuberculosis is the most common opportunistic infection among HIV-infected patients in Brazil. Brazil's national policy for HIV care recommends screening for latent tuberculosis (TB) and implementing isoniazid preventive therapy (IPT). OBJECTIVES: We compared physician adherence to TB screening and other prevention and care policies among HIV primary care clinics in Rio de Janeiro City. METHODS: Data on performance of CD4 counts, viral load testing, tuberculin skin testing (TST) and IPT were abstracted from patient charts at 29 HIV clinics in Rio de Janeiro as part of the TB/HIV in Rio (THRio) study. Data on use of pneumocystis jiroveci pneumonia (PCP) prophylaxis were also abstracted from a convenience sample of 150 patient charts at 10 HIV clinics. Comparisons were made between rates of adherence to TB guidelines and other HIV care guidelines. RESULTS: Among the subset of 150 patients with confirmed HIV infection in 2003, 96 percent had at least one reported CD4 counts result; 93 percent had at least one viral load result reported; and, PCP prophylaxis was prescribed for 97 percent of patients with CD4 counts < 200 cells/mm³ or when clinically indicated. In contrast, 67 patients (45 percent) had a TST performed (all eligible); and only 11 percent (17) of eligible patients started IPT. Among 12,027 THRio cohort participants between 2003 and 2005, the mean number of CD4 counts and viral load counts was 2.5 and 1.9, respectively, per patient per year. In contrast, 49 percent of 8,703 eligible patients in THRio had a TST ever performed and only 53 percent of eligible patients started IPT. CONCLUSION: Physicians are substantially more compliant with HIV monitoring and PCP prophylaxis than with TB prophylaxis guidelines. Efforts to improve TB control in HIV patients are badly needed.

A implantação da estratégia DOTS na cidade do Rio de Janeiro / Implementation of the DOTS strategy in the city of Rio de Janeiro

Introdução: o objetivo deste estudo foi descrever a implementação da estratégia DOTS (Estratégia de Tratamento Diretamente Observado de Curta duração) nos centros de saúde na cidade do Rio de Janeiro, apresentando os resultados obtidos após dois anos de desenvolvimento de projetos-piloto. Métodos: análise dos dados contidos nos "Livros de Registro e Controle do Tratamento", regularmente notificados à Secretaria Municipal de Saúde do Rio de Janeiro, visando avaliar o impacto do tratamento diretamente observado (DOT) nos índices de cura e o efeito da implementação da estratégia DOTS na qualidade do programa de controle da tuberculose (PCT). Resultados: De Janeiro de 1999 a Dezembro de 2001, 3657 casos de TB foram registrados nas áreas onde a estratégia DOTS foi implantada. Destes, 1730 receberam DOT e 1927 receberam tratamento auto-administrado (TAA). Entre os caos novos, 81% dos que receberam DOT e 71% dos que receberam TAA foram tratados com sucesso (OR 1,66, IC 95%: 1,3 -1,8), p<0,01. As taxas de negativação da baciloscopia do escarro após 2 e 3 meses de tratamento foram de 84% e 91% respectivamente para aqueles que receberam DOT e 75% e 83% para o grupo em TAA. Nos centros de saúde onde a estratégia DOTS foi implantada houve, em 3 anos, melhora geral dos índices de cura e de abandono, assim como dos percentuais de baciloscopias realizadas para acompanhamento do tratamento. Conclusão: Pacientes que receberam DOTS tiveram maior chance de cura do que aqueles que receberam TAA. A implantação da estratégia DOTS melhorou a qualidade do PCT.

Introduction: The objective of this study is to describe the implementation of DOTS (Directly Observed Treatment, Short course) strategy in health centers in the city of the Rio de Janeiro presenting the results 2 years after teh development of pilot projects. Methods: analysis of data recorded on the "TB treatment and outcome registration books", regularly reported to the City Health Secretariat, to evaluate the results of the directly observed therapy (DOT) on the treatment success rates and the effect of DOTS implementation on the equality of the TB control program. Results: From January 1999 to December 2001, 3,657 TB cases were registered in the areas where the DOTS strategy was implemented. Of these, 1,730 received directly observed treatment (DOT) and 1,927 received self-administered treatment (SAT). In the DOT group 81% of the new cases were treated successfully, whereas in the SAT 71% of the new cases were treated successfully (OR1,66, 95% CI:1,3 -1,8, p <0,01). The sputum smear conversion rates for the new cases after 2 and 3 months' treatment were respectively 84% and 91% for the group on DOT and 75% and 83% for those on SAT. In the health centers where the DOTS strategy was implemented there was a general improvement on the cure and default rates, and also on the proportion of patients monitored bacteriologically during treatment. Conclusion: patients receiving DOT were much more likely to complete treatment than those receiving SAT. The implementation of the DOTS strategy improved the quality of the TB control program.

Servicio de orientacion y deteccion de VIH vinculado a un programa comunitario antituberculoso en una poblacion de alto riesgo / Wide-spread HIV counseling and testing linked to a community based tuberculosis control program in a high-risk population

La finalidad del trabajo que aqui se describe fue evaluarel tamizaje comunitario para la deteccion de los casos de infeccion por VIH vinculado a un programa de lucha anticuberculosa en una poblacion de alto riesgo de ambas infecciones. De mayo de 1990 a agosto de 1992, trabajadores de salud comunitarios se comunicaron con adultos en domicilios y dispensarios de Cite Soleil, Haiti, para ofrecerles servicios institucionales de asesoramiento individual y de deteccion de VIH y de tuberculosis. A todas las personas que aceptaron la prueba se les dio asesoramiento posterior sobre VIH. Las que tenian tuberculosis activa recibieron tratamiento y a las que tenian enfermedad latente mas infeccion por VIH se les dio la oportunidad de participar en un ensayo clinico sobre quimioprofilaxis antituberculosa. La elevada prevalencia de infeccion por VIH en la poblacion examinada, al compararsela con otros grupos sometidos a tamizaje en la misma comunidad, indica que las personas en alto riesgo de infeccion por VIH buscaron selectivamente o aceptaron someterse a las pruebas de tamizaje ofrecidas en los dispensarios de tuberculosis. Asimismo, a muchas personas se les diagnostico tuberculosis activa en una fase mas temprana de la enfermedad de lo que hubiera sido posible sin un programa de tamizaje. En general, los resultados indican que cuando el tamizaje comunitario para la deteccion de VIH es parte de un programa de lucha antituberculosa, el resultado puede ser una mejor focalizacion de destinatarios para las pruebas de deteccion de ambas infecciones

Widespread HIV counseling and testing linked to a community-based tuberculosis control program in a high-risk population

The aim of the work reported here was to evaluate community-wide screening for HIV infection that was linked to a tuberculosis control program in a population at high risk for both infections. Between May 1990 and August 1992, adults in Cité Soleil, Haiti, were recruited by community health workers at their homes and in clinics for individual, clinic-based counseling and testing for HIV and tuberculosis. All of the screened subjects were offered post-test HIV counseling. Those with active tuberculosis received treatment, while those with latent tuberculosis and HIV infection were offered an opportunity to participate in a trial of antituberculosis chemoprophylaxis. The 10 611 individuals screened for HIV represented 10.0 percent of the adult population in Cité Soleil. HIV infection was detected in 1 629 (15.4 percent) and active tuberculosis in 242 (2.3 percent). Latent M. tuberculosis infection was found in 4 800 (67.5 percent) of 7 309 community residents who completed tuberculosis screening, 781 (16.3 percent) of whom were coinfected with HIV. The high prevalence of HIV infection found in this screened population, as compared to other groups undergoing HIV screening in the same community, suggests that people at high risk for HIV infection selectively sought or accepted tuberculosis clinic screening. Also, many people with active tuberculosis were identified earlier in the course of their disease than they would have been in the absence of a screening program. Overall, the results indicate that community-based screening for HIV infection within a tuberculosis control program can result in effective targeting of screening for both infections

Widespread HIV counseling and testing linked to a community-based tuberculosis control program in a high-risk population

The aim of the work reported here was to evaluate community-wide screening for HIV infection that was linked to a tuberculosis control program in a population at high risk for both infections. Between May 1990 and August 1992, adults in Cité Soleil, Haiti, were recruited by community health workers at their homes and in clinics for individual, clinic-based counseling and testing for HIV and tuberculosis. All of the screened subjects were offered post-test HIV counseling. Those with active tuberculosis received treatment, while those with latent tuberculosis and HIV infection were offered an opportunity to participate in a trial of antituberculosis chemoprophylaxis. The 10 611 individuals screened for HIV represented 10.0 percent of the adult population in Cité Soleil. HIV infection was detected in 1 629 (15.4 percent) and active tuberculosis in 242 (2.3 percent). Latent M. tuberculosis infection was found in 4 800 (67.5 percent) of 7 309 community residents who completed tuberculosis screening, 781 (16.3 percent) of whom were coinfected with HIV. The high prevalence of HIV infection found in this screened population, as compared to other groups undergoing HIV screening in the same community, suggests that people at high risk for HIV infection selectively sought or accepted tuberculosis clinic screening. Also, many people with active tuberculosis were identified earlier in the course of their disease than they would have been in the absence of a screening program. Overall, the results indicate that community-based screening for HIV infection within a tuberculosis control program can result in effective targeting of screening for both infections

This article will also be published in Spanish in the Bol. OSP. Vol. 120(5), 1996

Servicio de orientacion y deteccion de VIH vinculado a un programa comunitario antituberculoso en una poblacion de alto riesgo / Wide-spread HIV counseling and testing linked to a community based tuberculosis control program in a high-risk population

La finalidad del trabajo que aqui se describe fue evaluarel tamizaje comunitario para la deteccion de los casos de infeccion por VIH vinculado a un programa de lucha anticuberculosa en una poblacion de alto riesgo de ambas infecciones. De mayo de 1990 a agosto de 1992, trabajadores de salud comunitarios se comunicaron con adultos en domicilios y dispensarios de Cite Soleil, Haiti, para ofrecerles servicios institucionales de asesoramiento individual y de deteccion de VIH y de tuberculosis. A todas las personas que aceptaron la prueba se les dio asesoramiento posterior sobre VIH. Las que tenian tuberculosis activa recibieron tratamiento y a las que tenian enfermedad latente mas infeccion por VIH se les dio la oportunidad de participar en un ensayo clinico sobre quimioprofilaxis antituberculosa. La elevada prevalencia de infeccion por VIH en la poblacion examinada, al compararsela con otros grupos sometidos a tamizaje en la misma comunidad, indica que las personas en alto riesgo de infeccion por VIH buscaron selectivamente o aceptaron someterse a las pruebas de tamizaje ofrecidas en los dispensarios de tuberculosis. Asimismo, a muchas personas se les diagnostico tuberculosis activa en una fase mas temprana de la enfermedad de lo que hubiera sido posible sin un programa de tamizaje. En general, los resultados indican que cuando el tamizaje comunitario para la deteccion de VIH es parte de un programa de lucha antituberculosa, el resultado puede ser una mejor focalizacion de destinatarios para las pruebas de deteccion de ambas infecciones

Este articulo se publico en ingles en el Bull. PAHO. Vol. 30(1), 1996