TB preventive therapy preferences among children and adolescents.

BACKGROUND: TB preventive therapy (TPT) is critical for ending TB, yet implementation remains poor. With new global guidelines expanding TPT eligibility and regimens, we aimed to understand TPT preferences among children, adolescents and caregivers.METHODS: We undertook a discrete choice experiment among 131 children, 170 adolescents and 173 caregivers, and conducted 17 in-depth interviews in 25 clinics in Cape Town, South Africa. The design included attributes for location, waiting time, treatment duration, dosing frequency, formulation/size, side effects, packaging and taste. Mixed-effects logistic regression models were used for analysis.RESULTS: Among children and caregivers, the number and size of pills, taste and side effects were important drivers of preferences. Among adolescents and caregivers, clinic waiting times and side effects were significant drivers of preferences. Adolescents expressed concerns about being stigmatised, and preferred services from local clinics to services delivered in the community. Dosing frequency and treatment duration were only significant drivers of choice among adolescents, and only if linked to fewer clinic visits.CONCLUSIONS: Introducing shorter TPT regimens in isolation without consideration of preferences and health services may not have the desired effect on uptake and completion. Developing TPT delivery models and formulations that align with preferences must be prioritised.

Reasons for poor uptake of TB preventive therapy in South Africa.

BACKGROUND: South Africa has one the highest TB and HIV burdens globally. TB preventive therapy (TPT) reduces the risk of TB disease and TB-related mortality in adults and children living with HIV and is indicated for use in TB-exposed HIV-negative individuals and children. TPT implementation in South Africa remains suboptimal. METHODS: We conducted a pragmatic review of TPT implementation using multiple data sources, including informant interviews (n = 134), semi-structured observations (n = 93) and TB patient folder reviews in 31 health facilities purposively selected across three high TB burden provinces. We used case descriptive analysis and thematic coding to identify barriers and facilitators to TPT implementation. RESULTS: TPT programme implementation was suboptimal, with inadequate monitoring even in health districts with well-functioning TB services. Health workers reported scepticism about TPT effectiveness, deprioritised TPT in practice and expressed divergent opinions about the cadres of staff responsible for implementation. Service- and facility-level barriers included ineffective contact tracing, resource shortages, lack of standardised reporting mechanisms and insufficient patient education on TPT. Patient-level barriers included socio-economic factors. CONCLUSIONS: Improving TPT implementation will require radically simplified and more feasible systems and training for all cadres of health workers. Partnership with communities to stimulate demand driven service uptake can potentially facilitate implementation.

CONTEXTE: L'Afrique du Sud a l'une des charges de TB et de VIH les plus élevées au monde. La thérapie préventive contre la TB (TPT) réduit le risque de TB maladie et de mortalité liée à la TB chez les adultes et les enfants vivant avec le VIH et est indiquée chez les personnes et les enfants séronégatifs exposés à la TB. La mise en œuvre du TPT en Afrique du Sud reste sous-optimale. MÉTHODES: Nous avons procédé à un examen pragmatique de la mise en œuvre du TPT à l'aide de plusieurs sources de données, notamment des entretiens avec des informateurs (n = 134), des observations semi-structurées (n = 93) et des examens de dossiers de patients atteints de TB dans 31 établissements de santé sélectionnés à dessein dans trois provinces fortement touchées par la TB. Nous avons utilisé une analyse descriptive des cas et un codage thématique pour identifier les obstacles et les facilitateurs de la mise en œuvre du programme TPT. RÉSULTATS: La mise en œuvre du programme TPT était sousoptimale, avec un suivi inadéquat, y compris dans les districts sanitaires où les services de lutte contre la TB fonctionnaient correctement. Les agents de santé ont fait part de leur scepticisme quant à l'efficacité de la TPT, n'ont pas accordé la priorité à la TPT dans la pratique et ont exprimé des opinions divergentes sur les cadres du personnel responsables de la mise en œuvre. Les obstacles au niveau des services et des établissements comprennent l'inefficacité de la recherche des contacts, la pénurie de ressources, l'absence de mécanismes de déclaration standardisés et l'insuffisance de l'éducation des patients sur la TPT. Les obstacles au niveau des patients comprenaient des facteurs socio-économiques. CONCLUSIONS: L'amélioration de la mise en œuvre des TPT nécessitera des systèmes radicalement simplifiés et plus réalisables ainsi qu'une formation pour tous les cadres du personnel de santé. Un partenariat avec les communautés pour stimuler l'adoption de services axés sur la demande peut potentiellement faciliter la mise en œuvre.

Effectiveness of a community-based intervention to prevent childhood TB in Lesotho.

BACKGROUND: Child contact management (CCM) is a recognized strategy to prevent TB; however, implementation is suboptimal. PREVENT was a cluster-randomized trial that evaluated the effectiveness and acceptability of a community-based intervention (CBI) to improve CCM in Lesotho.METHODS: Ten health facilities (HFs) were randomized to CBI or standard-of-care (SOC). CBI included nurse training/mentorship, health education by village health workers (VHW), adherence support, and multidisciplinary team meetings. Information on TB cases registered from February 2016 to June 2018 and their child contacts was abstracted. Outcomes were TB preventive treatment (TPT) initiation, TPT completion, and CBI acceptability. Generalized linear mixed models were used to test for differences between study arms and qualitative interview thematic analysis for acceptability.RESULTS: Among 547 registered children (CBI: n = 399; SOC: n = 148) of 426 adult TB patients, 46% were <2 years, 48% female, and 3% HIV-exposed/positive, with no significant differences between study arms. A total of 501 children initiated TPT-98% at CBI and 88% at SOC HFs (P < 0.0001). TPT completion was 82% in CBI vs. 59% in SOC sites (P = 0.048). Caregivers and providers reported that CBI was acceptable.CONCLUSION: The CBI was acceptable and significantly improved TPT initiation and completion in Lesotho, offering the opportunity to mitigate the threat of TB among children.

Adherence to Pre-exposure Prophylaxis in Black Men Who Have Sex with Men and Transgender Women in a Community Setting in Harlem, NY.

While oral pre-exposure prophylaxis (PrEP) has proven efficacious for HIV prevention, consistent use is necessary to achieve its intended impact. We compared effectiveness of enhanced PrEP (enPrEP) adherence support to standard of care (sPrEP) among Black MSM and TGW attending a community clinic in Harlem, NY. EnPrEP included peer navigation, in-person/online support groups, and SMS messages. Self-reported adherence over previous 30 days, collected in quarterly interviews, was defined as ≥ 57%. Crude and adjusted analyses examined factors associated with adherence. A total of 204 participants were enrolled and randomized; 35% were lost to follow-up. PrEP adherence was 30% at 12-months; no intervention effect was observed (p = 0.69). Multivariable regression analysis found that lower adherence was associated with low education and depressive symptoms. We found that an enhanced adherence intervention did not improve PrEP adherence. Findings point to the need for innovative methods to improve PrEP adherence among Black MSM and TGW.Clinical Trial Registration NCT02167386, June 19, 2014.

Tuberculosis preventive treatment preferences among care givers of children in Lesotho: a pilot study.

BACKGROUND: Shorter-duration regimens for preventing drug-susceptible tuberculosis (TB) have been shown to be safe and efficacious in children, and may improve acceptability, adherence, and treatment completion. While these regimens have been used in children in low TB burden countries, they are not yet widely used in high TB burden countries. SETTING: Five health facilities in one district in Lesotho, a high TB burden country. OBJECTIVE: Assess the preventive treatment preferences of care givers of child TB contacts. DESIGN: Qualitative data were collected using in-depth interviews with 12 care givers whose children completed preventive treatment, and analyzed using grounded theory. FINDINGS: Care givers were interested in being involved in the children's treatment decisions. Pill burden, treatment duration and related frequency of dosing were identified as important factors that influenced preventive treatment preferences among care givers. CONCLUSION: Understanding care giver preferences and involving them in treatment decisions may facilitate efforts to implement successful preventive treatment for TB among children in high TB burden countries.

Depressive symptoms and hazardous/harmful alcohol use are prevalent and correlate with stigma among TB-HIV patients in Lesotho.

SETTING: Limited data exist on the prevalence and correlates, including stigma, of mental health conditions, including depressive symptoms and alcohol use, among patients co-infected with tuberculosis (TB) and the human immunodeficiency virus (HIV) in sub-Saharan Africa, despite their negative impact on health outcomes. OBJECTIVE: To assess the prevalence and correlates of depressive symptoms and hazardous/harmful alcohol use among TB-HIV patients in the Start TB patients on ART and Retain on Treatment (START) study. DESIGN: START, a mixed-methods cluster-randomized trial, evaluated a combination intervention package vs. standard of care (SOC) to improve treatment outcomes in TB-HIV co-infected patients in Lesotho. Moderate/severe depressive symptoms and hazardous/harmful alcohol use were measured using baseline questionnaire data collected from April 2013 to March 2015. Demographic, psychosocial, and TB- and HIV-related knowledge and attitudes, including stigma, were assessed for association with both conditions using generalized linear mixed models. RESULTS: Among 371 participants, 29.8% reported moderate/severe depressive symptoms, and 24.7% reported hazardous/harmful alcohol use; 7% reported both. Depressive symptoms were significantly associated with less education, more difficulty understanding written medical information, non-disclosure of TB, greater TB stigma, and the SOC study arm. Hazardous/harmful alcohol use was significantly associated with male sex, as well as greater TB and external HIV stigma. CONCLUSION: Prevalence of depressive symptoms and hazardous/harmful alcohol use were high, suggesting a need for routine screening for, and treatment of, mental health disorders in TB-HIV patients.

Pulmonary tuberculosis diagnostic practices among people living with the human immunodeficiency virus in Lesotho.

SETTING: Twelve health facilities in Berea District, Lesotho, that participated in the Start TB Patients on ART and Retain on Treatment (START) Study, a mixed-methods cluster-randomized trial evaluating a combination intervention package to improve early initiation of antiretroviral therapy (ART) and anti-tuberculosis treatment success among patients with tuberculosis (TB) and human immunodeficiency virus (HIV). OBJECTIVE: To assess TB and HIV diagnostic practices among TB-HIV patients. DESIGN: A standardized survey assessed services at each facility at baseline. Routine clinical data were abstracted for all newly registered adult TB-HIV patients during the study period. Descriptive statistics were used to assess TB diagnostic practices, timing of the HIV diagnosis, and ART status at TB treatment initiation. RESULTS: Between April 2013 and March 2015, 1233 TB-HIV patients were enrolled. Among 1215 patients with available data, 87.2% had pulmonary TB, of which 34.8% were bacteriologically confirmed, 40.9% tested negative and 24.3% were not tested. Among 1138 patients with available data, 53.3% had an existing HIV diagnosis, of whom 39.3% were ART-naïve. CONCLUSIONS: The majority of pulmonary TB patients were clinically diagnosed, and many were unaware of their HIV status or were ART-naïve despite known status. The Test and Treat Strategy holds promise to prevent TB and reduce TB-related mortality among people living with HIV; however, enhanced TB diagnostic capacity and improved HIV case detection are urgently needed.

Characteristics and costs of multidrug-resistant tuberculosis in-patient care in the United States, 2005-2007.

OBJECTIVE: A population-based study of 135 multidrug-resistant tuberculosis (MDR-TB) patients reported to the Centers for Disease Control and Prevention (CDC) during 2005-2007 found 73% were hospitalized. We analyzed factors associated with hospitalization. METHODS: We assessed statistically significant multivariable associations with US in-patient TB diagnosis, frequency of hospitalization, length of hospital stay, and in-patient direct costs to the health care system. RESULTS: Of 98 hospitalized patients, 83 (85%) were foreign-born. Blacks, diabetics, or smokers were more likely, and patients with disseminated disease less likely, to receive their TB diagnosis while hospitalized. Patients aged ⩾65 years, those with the acquired immune-deficiency syndrome (AIDS), or with private insurance, were hospitalized more frequently. Excluding deaths, length of stay was greater for patients aged ⩾65 years, those with extensively drug-resistant TB (XDR-TB), those residing in Texas, those with AIDS, those who were unemployed, or those who had TB resistant to all first-line medications vs. others. Average hospitalization cost per XDR-TB patient (US$285 000) was 3.5 times that per MDR-TB patient (US$81 000), in 2010 dollars. Hospitalization episode costs for MDR-TB rank third highest and those for XDR-TB highest among the principal diagnoses. CONCLUSIONS: Hospitalization was common and remains a critical care component for patients who were older, had comorbidities, or required complex management due to XDR-TB. MDR-TB in-patient costs are among the highest for any disease.

Re-inventing adherence: toward a patient-centered model of care for drug-resistant tuberculosis and HIV.

BACKGROUND: Despite renewed focus on molecular tuberculosis (TB) diagnostics and new antimycobacterial agents, treatment outcomes for patients co-infected with drug-resistant TB and human immunodeficiency virus (HIV) remain dismal, in part due to lack of focus on medication adherence as part of a patient-centered continuum of care. OBJECTIVE: To review current barriers to drug-resistant TB-HIV treatment and propose an alternative model to conventional approaches to treatment support. DISCUSSION: Current national TB control programs rely heavily on directly observed therapy (DOT) as the centerpiece of treatment delivery and adherence support. Medication adherence and care for drug-resistant TB-HIV could be improved by fully implementing team-based patient-centered care, empowering patients through counseling and support, maintaining a rights-based approach while acknowledging the responsibility of health care systems in providing comprehensive care, and prioritizing critical research gaps. CONCLUSION: It is time to re-invent our understanding of adherence in drug-resistant TB and HIV by focusing attention on the complex clinical, behavioral, social, and structural needs of affected patients and communities.

Risk factors for transmission of tuberculosis among United States-born African Americans and Whites.

SETTING: Tuberculosis (TB) patients and their contacts enrolled in nine states and the District of Columbia from 16 December 2009 to 31 March 2011. OBJECTIVE: To evaluate characteristics of TB patients that are predictive of tuberculous infection in their close contacts. DESIGN: The study population was enrolled from a list of eligible African-American and White TB patients from the TB registry at each site. Information about close contacts was abstracted from the standard reports of each site. RESULTS: Close contacts of African-American TB patients had twice the risk of infection of contacts of White patients (adjusted risk ratio [aRR] 2.1, 95%CI 1.3-3.4). Close contacts of patients whose sputum was positive for acid-fast bacilli on sputum smear microscopy had 1.6 times the risk of tuberculous infection compared to contacts of smear-negative patients (95%CI 1.1-2.3). TB patients with longer (>3 months) estimated times to diagnosis did not have higher proportions of infected contacts (aRR 1.2, 95%CI 0.9-1.6). CONCLUSION: African-American race and sputum smear positivity were predictive of tuberculous infection in close contacts. This study did not support previous findings that longer estimated time to diagnosis predicted tuberculous infection in contacts.

HIV counseling and testing in tuberculosis contact investigations in the United States and Canada.

BACKGROUND: Determining the human immunodeficiency virus (HIV) status of tuberculosis (TB) patients and contacts is important. Despite existing guidelines, not all patients are tested, and testing of contacts is rarely performed. METHODS: In a study conducted at nine US/Canadian sites, we introduced formal procedures for offering HIV testing to TB patients and contacts. Data were collected via interviews and medical record review. Characteristics associated with offering and accepting HIV testing were examined. RESULTS: Of 651 TB patients, 601 (92%) were offered testing, 511 (85%) accepted, and 51 (10%) were HIV-infected. Of 4152 contacts, 3099 (75%) were offered testing, 1202 (39%) accepted, and 24 (2%) were HIV-infected. Contacts aged 15-64 years, non-Whites, foreign-born persons, smokers, those with positive TB screening, and household contacts were more likely to be offered testing, whereas contacts exposed to HIV-negative patients were less likely to be offered testing. Contacts aged 15-64 years, smokers, drug/alcohol users, diabetics, and those with positive TB screening were more likely to accept testing. Foreign-born persons, Blacks, Hispanics, and contacts exposed to HIV-positive patients were less likely to accept testing. CONCLUSIONS: High rates of HIV were detected among patients and contacts. Despite structured procedures to offer HIV testing, some patients and most contacts did not accept testing. Strategies are needed to improve testing acceptance rates.

Latent tuberculous infection in the United States and Canada: who completes treatment and why?

OBJECTIVES: To assess latent tuberculous infection (LTBI) treatment completion rates in a large prospective US/Canada multisite cohort and identify associated risk factors. METHODS: This prospective cohort study assessed factors associated with LTBI treatment completion through interviews with persons who initiated treatment at 12 sites. Interviews were conducted at treatment initiation and completion/cessation. Participants received usual care according to each clinic's procedure. Multivariable models were constructed based on stepwise assessment of potential predictors and interactions. RESULTS: Of 1515 participants initiating LTBI treatment, 1323 had information available on treatment completion; 617 (46.6%) completed treatment. Baseline predictors of completion included male sex, foreign birth, not thinking it would be a problem to take anti-tuberculosis medication, and having health insurance. Participants in stable housing who received monthly appointment reminders were more likely to complete treatment than those without stable housing or without monthly reminders. End-of-treatment predictors of non-completion included severe symptoms and the inconvenience of clinic/pharmacy schedules, barriers to care and changes of residence. Common reasons for treatment non-completion were patient concerns about tolerability/toxicity, appointment conflicts, low prioritization of TB, and forgetfulness. CONCLUSIONS: Less than half of treatment initiators completed treatment in our multisite study. Addressing tangible issues such as not having health insurance, toxicity concerns, and clinic accessibility could help to improve treatment completion rates.

Risk factors for treatment default in close contacts with latent tuberculous infection.

OBJECTIVE: 1) To characterize risk factors for non-completion of latent tuberculous infection treatment (LTBIT), and 2) to assess the impact of LTBIT regimens on subsequent risk of tuberculosis (TB). METHODS: Close contacts of adults aged ⩾15 years with pulmonary TB were prospectively enrolled in a multi-center study in the United States and Canada from January 2002 to December 2006. Close contacts of TB patients were screened and cross-matched with TB registries to identify those who developed active TB. RESULTS: Of 3238 contacts screened, 1714 (53%) were diagnosed with LTBI. Preventive treatment was recommended in 1371 (80%); 1147 (84%) initiated treatment, of whom 723 (63%) completed it. In multivariate analysis, study site, initial interview sites other than a home or health care setting and isoniazid preventive treatment (IPT) were significantly associated with non-completion of LTBIT. Fourteen TB cases were identified in contacts, all of whom initiated IPT: two TB cases among persons who received ⩾6 months of IPT (66 cases/100 000 person-years [py]), and nine among those who received 0-5 months (median 2 months) of IPT (792 cases/100 000 py, P < 0.001); data on duration of IPT were not available for three cases. CONCLUSION: Only 53% (723/1371) of close contacts for whom IPT was recommended actually completed treatment. Close contacts were significantly less likely to complete LTBIT if they took IPT. Less than 6 months of IPT was associated with increased risk of active TB.

Can a peer-based intervention impact adherence to the treatment of latent tuberculous infection?

OBJECTIVE: To assess the effectiveness of a peer-based intervention on adherence to and completion of latent tuberculous infection (LTBI) treatment. METHODS: Patients prescribed self-administered LTBI treatment were enrolled in a randomized controlled trial of an experimental, peer-based adherence support intervention. Primary outcomes were treatment adherence and completion. Adherence was assessed through self-report, electronic monitoring devices and clinic visits. RESULTS: Of 250 participants, 70% were male; 71% were Black and 20% Latino; the mean age was 40 years; 67% were foreign-born and 39% were married. No significant baseline differences were noted between the intervention groups. Treatment completion was 61% in the intervention group compared to 57% in the controls (P = 0.482). The corresponding completion rate for other clinic patients was 44%. Foreign birth, marriage and history of mental illness were associated with non-completion of treatment after controlling for the intervention group; increased completion rates were found among foreign-born married persons and older participants. A substantial difference in adherence rates was observed between the intervention groups. Adherence among non-completers decreased early, while adherence among completers remained constant. CONCLUSIONS: The peer-based intervention was not significantly associated with LTBI treatment completion, but was associated with greater adherence. Findings suggest the importance of interventions to support adherence that target early non-adherence with LTBI treatment, particularly in the first 2 months, when there is a substantial risk of default.

Acceptance of treatment for latent tuberculosis infection: prospective cohort study in the United States and Canada.

SETTING: An estimated 300 000 individuals are treated for latent tuberculosis infection (LTBI) in the United States and Canada annually. Little is known about the proportion or characteristics of those who decline treatment. OBJECTIVE: To define the proportion of individuals in various groups who accept LTBI treatment and to identify factors associated with non-acceptance of treatment. DESIGN: Persons offered LTBI treatment at 30 clinics in 12 Tuberculosis Epidemiologic Studies Consortium sites were prospectively enrolled. Multivariate regression models were constructed based on manual stepwise assessment of potential predictors. RESULTS: Of 1692 participants enrolled from March 2007 to September 2008, 1515 (89.5%) accepted treatment and 177 (10.5%) declined. Predictors of acceptance included believing one could personally spread TB germs, having greater TB knowledge, finding clinic schedules convenient and having low acculturation. Predictors of non-acceptance included being a health care worker, being previously recommended for treatment and believing that taking medicines would be problematic. CONCLUSION: This is the first prospective multisite study to examine predictors of LTBI treatment acceptance in general clinic populations. Greater efforts should be made to increase acceptance among health care workers, those previously recommended for treatment and those who expect problems with LTBI medicines. Ensuring convenient clinic schedules and TB education to increase knowledge could be important for ensuring acceptance.

Lessons from a randomised clinical trial for multidrug-resistant tuberculosis.

BACKGROUND: The treatment of multidrug-resistant tuberculosis (MDR-TB) is currently based upon expert opinion and findings from case series, rather than upon randomised clinical trials (RCTs). OBJECTIVE: To describe the challenges encountered during an RCT for the treatment of MDR-TB. METHODS: Tuberculosis Trials Consortium Study 30 was a pilot, Phase I/II, double-blind, placebo-controlled, RCT of the safety and tolerability of 16 weeks of daily, low-dose linezolid treatment for MDR-TB. RESULTS: A total of 36 patients, 56% of the target of 64 patients, consented to participate, for an average of 0.69 enrolments per week. Of the 36 patients enrolled, only 25 (69%) completed at least 90 doses of study treatment. Among the 12 (33%) patients who did not complete all 112 doses of the study treatment, the median time to study withdrawal was 15 days (range 0-92). After the study, we discovered discordance between treatment assignment and study drug for at least 9 (25%) of the 36 patients. CONCLUSIONS: Recruitment and retention in this MDR-TB clinical trial posed substantial challenges, suggesting the need for a large, multidisciplinary group of study staff to support the participants. Withdrawal tended to occur early in study treatment. The discrepancy in assigned study medication reflects the need for stronger administrative controls for study drugs.

Predictors of latent tuberculosis infection treatment completion in the United States: an inner city experience.

BACKGROUND: Few studies have examined predictors of latent tuberculosis infection (LTBI) treatment completion in inner city populations in the United States. OBJECTIVE: To assess LTBI treatment completion rates and predictors in an inner city cohort. METHODS: Data from control groups of two sequentially conducted randomized controlled trials of LTBI treatment were analyzed for treatment completion rates. Participants in Study A (n = 191), conducted in 1996-1999, self administered daily isoniazid (INH) for 6-12 months, while participants in Study B (n = 123), conducted in 2002-2005, self administered daily INH for 9 months. RESULTS: Overall, 44.6% of participants completed therapy, with significantly higher completion rates in Study B than Study A (37.0% vs. 56.1%, P = 0.001). Marriage and alcohol use were significant predictors of completion (aOR = 2.153, 95%CI 1.301-3.562) and non-completion (aOR = 0.530, 95%CI 0.320-0.877), respectively; multivariate analysis indicated increased completion among married persons of foreign birth and among alcohol users who were homeless. Knowledge of and attitudes to tuberculosis were not significant predictors. CONCLUSIONS: The design provided an opportunity to assess predictors of LTBI treatment completion in this inner city population. Social circumstances were the strongest predictors of treatment completion, suggesting that tangible social services may be more effective than educational programs in encouraging treatment completion.