Effectiveness of Bedaquiline Use beyond Six Months in Patients with Multidrug-Resistant Tuberculosis.

Rationale: Current recommendations for the treatment of rifampicin- and multidrug-resistant tuberculosis include bedaquiline (BDQ) used for 6 months or longer. Evidence is needed to inform the optimal duration of BDQ. Objectives: We emulated a target trial to estimate the effect of three BDQ duration treatment strategies (6, 7-11, and ⩾12 mo) on the probability of successful treatment among patients receiving a longer individualized regimen for multidrug-resistant tuberculosis. Methods: To estimate the probability of successful treatment, we implemented a three-step approach comprising cloning, censoring, and inverse probability weighting. Measurements and Main Results: The 1,468 eligible individuals received a median of 4 (interquartile range, 4-5) likely effective drugs. In 87.1% and 77.7% of participants, this included linezolid and clofazimine, respectively. The adjusted probability of successful treatment was 0.85 (95% confidence interval [CI], 0.81-0.88) for 6 months of BDQ, 0.77 (95% CI, 0.73-0.81) for 7-11 months, and 0.86 (95% CI, 0.83-0.88) for ⩾12 months. Compared with 6 months of BDQ, the ratio of treatment success was 0.91 (95% CI, 0.85-0.96) for 7-11 months and 1.01 (95% CI, 0.96-1.06) for ⩾12 months. Naive analyses that did not account for bias revealed a higher probability of successful treatment with ⩾12 months (ratio, 1.09 [95% CI, 1.05-1.14]). Conclusions: BDQ use beyond 6 months did not increase the probability of successful treatment among patients receiving longer regimens that commonly included new and repurposed drugs. When not properly accounted for, immortal person-time bias can influence estimates of the effects of treatment duration. Future analyses should explore the effect of treatment duration of BDQ and other drugs in subgroups with advanced disease and/or receiving less potent regimens.

All-oral longer regimens are effective for the management of multidrug-resistant tuberculosis in high-burden settings.

BACKGROUND: Recent World Health Organization guidance on drug-resistant tuberculosis treatment de-prioritised injectable agents, in use for decades, and endorsed all-oral longer regimens. However, questions remain about the role of the injectable agent, particularly in the context of regimens using new and repurposed drugs. We compared the effectiveness of an injectable-containing regimen to that of an all-oral regimen among patients with drug-resistant tuberculosis who received bedaquiline and/or delamanid as part of their multidrug regimen. METHODS: Patients with a positive baseline culture were included. 6-month culture conversion was defined as two consecutive negative cultures collected >15 days apart. We derived predicted probabilities of culture conversion and relative risk using marginal standardisation methods. RESULTS: Culture conversion was observed in 83.8% (526 out of 628) of patients receiving an all-oral regimen and 85.5% (425 out of 497) of those receiving an injectable-containing regimen. The adjusted relative risk comparing injectable-containing regimens to all-oral regimens was 0.96 (95% CI 0.88-1.04). We found very weak evidence of effect modification by HIV status: among patients living with HIV, there was a small increase in the frequency of conversion among those receiving an injectable-containing regimen, relative to an all-oral regimen, which was not apparent in HIV-negative patients. CONCLUSIONS: Among individuals receiving bedaquiline and/or delamanid as part of a multidrug regimen for drug-resistant tuberculosis, there was no significant difference between those who received an injectable and those who did not regarding culture conversion within 6 months. The potential contribution of injectable agents in the treatment of drug-resistant tuberculosis among those who were HIV positive requires further study.

Culture Conversion in Patients Treated with Bedaquiline and/or Delamanid. A Prospective Multicountry Study.

Rationale: Bedaquiline and delamanid offer the possibility of more effective and less toxic treatment for multidrug-resistant (MDR) tuberculosis (TB). With this treatment, however, some patients remain at high risk for an unfavorable treatment outcome. The endTB Observational Study is the largest multicountry cohort of patients with rifampin-resistant TB or MDR-TB treated in routine care with delamanid- and/or bedaquiline-containing regimens according to World Health Organization guidance.Objectives: We report the frequency of sputum culture conversion within 6 months of treatment initiation and the risk factors for nonconversion.Methods: We included patients with a positive baseline culture who initiated a first endTB regimen before April 2018. Two consecutive negative cultures collected 15 days or more apart constituted culture conversion. We used generalized mixed models to derive marginal predictions for the probability of culture conversion in key subgroups.Measurements and Main Results: A total of 1,109 patients initiated a multidrug treatment containing bedaquiline (63%), delamanid (27%), or both (10%). Of these, 939 (85%) experienced culture conversion within 6 months. In adjusted analyses, patients with HIV had a lower probability of conversion (0.73; 95% confidence interval [CI], 0.62-0.84) than patients without HIV (0.84; 95% CI, 0.79-0.90; P = 0.03). Patients with both cavitary disease and highly positive sputum smear had a lower probability of conversion (0.68; 95% CI, 0.57-0.79) relative to patients without either (0.89; 95% CI, 0.84-0.95; P = 0.0004). Hepatitis C infection, diabetes mellitus or glucose intolerance, and baseline resistance were not associated with conversion.Conclusions: Frequent sputum conversion in patients with rifampin-resistant TB or MDR-TB who were treated with bedaquiline and/or delamanid underscores the need for urgent expanded access to these drugs. There is a need to optimize treatment for patients with HIV and extensive disease.

Community-based outreach associated with increased health utilization among Navajo individuals living with diabetes: a matched cohort study.

BACKGROUND: Navajo community members face high rates of diabetes mellitus and other chronic diseases. The Navajo Community Health Representative Outreach Program collaborated with healthcare providers and academic partners to implement structured and coordinated outreach to patients living with diabetes. The intervention, called Community Outreach and Patient Empowerment or COPE, provides home-based health coaching and community-clinic linkages to promote self-management and engagement in healthcare services among patients living with diabetes. The purpose of this study was to evaluate how outreach by Navajo Community Health Representatives ("COPE Program") affected utilization of health care services among patients living with diabetes. METHODS: De-identified data from 2010 to 2014 were abstracted from electronic health records at participating health facilities. In this observational cohort study, 173 cases were matched to 2880 controls. Healthcare utilization was measured as the number of times per quarter services were accessed by the patient. Changes in utilization over 4 years were modeled using a difference-in-differences approach, comparing the trajectory of COPE patients' utilization before versus after enrollment with that of the control group. The model was estimated using generalized linear mixed models for count outcomes, controlling for clustering at the patient level and the service unit level. RESULTS: COPE enrollees showed a 2.5% per patient per quarter (pppq) greater increase in total utilization (p = 0.001) of healthcare services than non-COPE enrollees; a 3.2% greater increase in primary care visits (p = 0.024); a 6.3% greater increase in utilization of counseling and behavioral health services (p = 0.013); and a 9.0% greater increase in pharmacy visits (p <  0.001). We found no statistically significant differences in utilization trends of inpatient, emergency room, specialty outpatient, dental, laboratory, radiology, or community encounter services among COPE participants versus control. CONCLUSIONS: A structured intervention consisting of Community Health Representative outreach and coordination with clinic-based providers was associated with a modest increase in health care utilization, including primary care and counseling services, among Navajo patients living with diabetes. Community health workers may provide an important linkage to enable patients to access and engage in clinic-based health care. TRIAL REGISTRATION: NCT03326206, registered 10/31/2017, retrospectively registered.

Community Outreach for Navajo People Living with Diabetes: Who Benefits Most?

INTRODUCTION: The Community Outreach and Patient Empowerment (COPE) intervention provides integrated outreach through community health representatives (CHRs) to people living with diabetes in Navajo Nation. The aim of this study was to identify groups for whom the intervention had the greatest effect on glycated hemoglobin A1c (HbA1c). METHODS: We analyzed de-identified data extracted from routine health records dated from December 1, 2010, through August 31, 2014, to compare net change in HbA1c among COPE patients and non-COPE patients. We used linear mixed models to assess whether the intervention was modified by age, sex, preferred language, having a primary care provider, baseline HbA1c, or having a mental health condition. RESULTS: Age, having a primary care provider, and baseline HbA1c significantly modified HbA1c levels. Among patients aged 64 or younger, COPE participation was associated with a net decrease in HbA1c of 0.77%; among patients aged 65 or older, the net decrease was 0.49% (P = .03). COPE participation was associated with a steeper decrease in HbA1c among patients without a primary care physician (net decrease, 0.99%) than among patients with a primary care provider (net decrease, 0.57%) (P = .03). COPE patients with a baseline HbA1c >9% had a net decrease of 0.70%, while those with a baseline HbA1c ≤9% had a net decrease of 0.34% (P = .01). We found no significant differences based on sex, preferred language, or having a mental health condition. CONCLUSION: Findings suggest that the COPE intervention was robust and equitable, benefiting all groups living with diabetes in Navajo Nation, but conferring the greatest benefit on the most vulnerable.

The endTB observational study protocol: treatment of MDR-TB with bedaquiline or delamanid containing regimens.

BACKGROUND: At a time when programs were struggling to design effective regimens for the treatment of multidrug-resistant tuberculosis (MDR-TB), the marketing authorization of bedaquiline and delamanid was a critical development in the MDR-TB treatment landscape. However, despite their availability for routine programmatic use, the uptake of these drugs has remained slow; concerns included a lack of evidence on safety and efficacy and the need to protect the new drugs from the development of acquired resistance. As part of the endTB Project, we aimed to address these barriers by generating evidence on safety and efficacy of bedaquiline or delamanid based MDR-TB regimens. METHODS: This is a protocol for a multi-center prospective cohort study to enroll 2600 patients from April 2015 through September 2018 in 17 countries. The protocol describes inclusion of patients started on treatment with bedaquiline- or delamanid- containing regimens under routine care, who consented to participate in the endTB observational study. Patient follow-up was according to routine monitoring schedules recommended for patients receiving bedaquiline or delamanid as implemented at each endTB site. Therefore, no additional tests were performed as a part of the study. Data were to be collected in a customized, open-source electronic medical record (EMR) system developed as a part of the endTB Project across all 17 countries. DISCUSSION: The endTB observational study will generate evidence on safety and efficacy of bedaquiline- and delamanid-containing regimens in a large, extremely heterogeneous group of MDR-TB patients, from 17 epidemiologically diverse countries. The systematic, prospective data collection of repeated effectiveness and safety measures, and analyses performed on these data, will improve the quality of evidence available to inform MDR-TB treatment and policy decisions. Further, the resources available to countries through implementation of the endTB project will have permitted countries to: gain experience with the use of these drugs in MDR-TB regimens, improve local capacity to record and report adverse events (pharmacovigilance), and enhance significantly the body of data available for safety evaluation of these drugs and other novel treatments. TRIAL REGISTRATION: This study was registered on 24 August 2017 at clincaltrials.gov (Registration number: NCT03259269).

Integrating community health representatives with health care systems: clinical outcomes among individuals with diabetes in Navajo Nation.

BACKGROUND: We studied the impact of Community Outreach and Patient Empowerment (COPE) intervention to support Community Health Representatives (CHR) on the clinical outcomes of patients living with diabetes in the Navajo Nation extending into the States of Arizona, Utah, and New Mexico. The COPE intervention integrated CHRs into healthcare teams by providing a structured approach to referrals and home visits. METHODS: We abstracted routine clinical data from the Indian Health Service's information system on individuals with diabetes mellitus seen at participating clinical sites from 2010 to 2014. We matched 173 COPE participants to 2880 patients with similar demographic and clinical characteristics who had not participated in COPE. We compared the changes in clinical outcomes between the two groups using linear mixed models. RESULTS: Over the four years of the study, COPE patients had greater improvements in glycosylated hemoglobin (- 0.56%) than non-COPE participants (+ 0.07%) for a difference in differences of 0.63% (95% confidence interval (CI): 0.50, 0.76). Low-density lipoprotein fell more steeply in the COPE group (- 10.58 mg/dl) compared to the non-COPE group (- 3.18 mg/dl) for a difference in differences of 7.40 mg/dl (95%CI: 2.00, 12.80). Systolic blood pressure increased slightly more among COPE (2.06 mmHg) than non-COPE patients (0.61 mmHg). We noted no significant change for body mass index in either group. CONCLUSION: Structured outreach by Community Health Representatives as part of an integrated care team was associated with improved glycemic and lipid levels in the target Navajo population. TRIAL REGISTRATION: Trial registration: NCT03326206. Registered 31 October 2017 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/study/NCT03326206.

Turning Off the Tap: Using the FAST Approach to Stop the Spread of Drug-Resistant Tuberculosis in the Russian Federation.

Background: We report the association of the FAST strategy (find cases actively, separate safely, and treat effectively) with reduction of hospital-based acquisition of multidrug-resistant tuberculosis in the Russian Federation. Methods: We used preintervention and postintervention cohorts in 2 Russian hospitals to determine whether the FAST strategy was associated with a reduced odds of converting MDR tuberculosis within 12 months among patients with tuberculosis susceptible to isoniazid and rifampin at baseline. Results: Sixty-three of 709 patients (8.9%) with isoniazid and rifampin-susceptible tuberculosis acquired MDR tuberculosis; 55 (12.2%) were in the early cohort, and 8 (3.1%) were in the FAST cohort. The FAST strategy was associated with a reduced odds (adjusted odds ratio, 0.16; 95% confidence interval, .07-.39) and 9.2% absolute reduction in the risk of MDR tuberculosis acquisition. Conclusion: Use of the FAST strategy in 2 Russian hospitals was associated with significantly less MDR tuberculosis 12 months after implementation.

Exogenous factors matter when interpreting the results of an impact evaluation: a case study of rainfall and child health programme intervention in Rwanda.

OBJECTIVE: Public health interventions are often implemented at large scale, and their evaluation seems to be difficult because they are usually multiple and their pathways to effect are complex and subject to modification by contextual factors. We assessed whether controlling for rainfall-related variables altered estimates of the efficacy of a health programme in rural Rwanda and have a quantifiable effect on an intervention evaluation outcomes. METHODS: We conducted a retrospective quasi-experimental study using previously collected cross-sectional data from the 2005 and 2010 Rwanda Demographic and Health Surveys (DHS), 2010 DHS oversampled data, monthly rainfall data collected from meteorological stations over the same period, and modelled output of long-term rainfall averages, soil moisture, and rain water run-off. Difference-in-difference models were used. RESULTS: Rainfall factors confounded the PIH intervention impact evaluation. When we adjusted our estimates of programme effect by controlling for a variety of rainfall variables, several effectiveness estimates changed by 10% or more. The analyses that did not adjust for rainfall-related variables underestimated the intervention effect on the prevalence of ARI by 14.3%, fever by 52.4% and stunting by 10.2%. Conversely, the unadjusted analysis overestimated the intervention's effect on diarrhoea by 56.5% and wasting by 80%. CONCLUSION: Rainfall-related patterns have a quantifiable effect on programme evaluation results and highlighted the importance and complexity of controlling for contextual factors in quasi-experimental design evaluations.

Aggressive Regimens Reduce Risk of Recurrence After Successful Treatment of MDR-TB.

BACKGROUND: We sought to determine whether treatment with a "long aggressive regimen" was associated with lower rates of relapse among patients successfully treated for pulmonary multidrug-resistant tuberculosis (MDR-TB) in Tomsk, Russia. METHODS: We conducted a retrospective cohort study of adult patients that initiated MDR-TB treatment with individualized regimens between September 2000 and November 2004, and were successfully treated. Patients were classified as having received "aggressive regimens" if their intensive phase consisted of at least 5 likely effective drugs (including a second-line injectable and a fluoroquinolone) used for at least 6 months post culture conversion, and their continuation phase included at least 4 likely effective drugs. Patients that were treated with aggressive regimens for a minimum duration of 18 months post culture conversion were classified as having received "long aggressive regimens." We used recurrence as a proxy for relapse because genotyping was not performed. After treatment, patients were classified as having disease recurrence if cultures grew MDR-TB or they re-initiated MDR-TB therapy. Data were analyzed using Cox proportional hazard regression. RESULTS: Of 408 successfully treated patients, 399 (97.5%) with at least 1 follow-up visit were included. Median duration of follow-up was 42.4 months (interquartile range: 20.5-59.5), and there were 27 recurrence episodes. In a multivariable complete case analysis (n = 371 [92.9%]) adjusting for potential confounders, long aggressive regimens were associated with a lower rate of recurrence (adjusted hazard ratio: 0.22, 95% confidence interval, .05-.92). CONCLUSIONS: Long aggressive regimens for MDR-TB treatment are associated with lower risk of disease recurrence.

Impact of HIV on mortality among patients treated for tuberculosis in Lima, Peru: a prospective cohort study.

BACKGROUND: Human immunodeficiency virus (HIV)-associated tuberculosis deaths have decreased worldwide over the past decade. We sought to evaluate the effect of HIV status on tuberculosis mortality among patients undergoing treatment for tuberculosis in Lima, Peru, a low HIV prevalence setting. METHODS: We conducted a prospective cohort study of patients treated for tuberculosis between 2005 and 2008 in two adjacent health regions in Lima, Peru (Lima Ciudad and Lima Este). We constructed a multivariate Cox proportional hazards model to evaluate the effect of HIV status on mortality during tuberculosis treatment. RESULTS: Of 1701 participants treated for tuberculosis, 136 (8.0%) died during tuberculosis treatment. HIV-positive patients constituted 11.0% of the cohort and contributed to 34.6% of all deaths. HIV-positive patients were significantly more likely to die (25.1 vs. 5.9%, P < 0.001) and less likely to be cured (28.3 vs. 39.4%, P = 0.003). On multivariate analysis, positive HIV status (hazard ratio [HR] = 6.06; 95% confidence interval [CI], 3.96-9.27), unemployment (HR = 2.24; 95% CI, 1.55-3.25), and sputum acid-fast bacilli smear positivity (HR = 1.91; 95% CI, 1.10-3.31) were significantly associated with a higher hazard of death. CONCLUSIONS: We demonstrate that positive HIV status was a strong predictor of mortality among patients treated for tuberculosis in the early years after Peru started providing free antiretroviral therapy. As HIV diagnosis and antiretroviral therapy provision are more widely implemented for tuberculosis patients in Peru, future operational research should document the changing profile of HIV-associated tuberculosis mortality.

Rainfall variation and child health: effect of rainfall on diarrhea among under 5 children in Rwanda, 2010.

BACKGROUND: Diarrhea among children under 5 years of age has long been a major public health concern. Previous studies have suggested an association between rainfall and diarrhea. Here, we examined the association between Rwandan rainfall patterns and childhood diarrhea and the impact of household sanitation variables on this relationship. METHODS: We derived a series of rain-related variables in Rwanda based on daily rainfall measurements and hydrological models built from daily precipitation measurements collected between 2009 and 2011. Using these data and the 2010 Rwanda Demographic and Health Survey database, we measured the association between total monthly rainfall, monthly rainfall intensity, runoff water and anomalous rainfall and the occurrence of diarrhea in children under 5 years of age. RESULTS: Among the 8601 children under 5 years of age included in the survey, 13.2 % reported having diarrhea within the 2 weeks prior to the survey. We found that higher levels of runoff were protective against diarrhea compared to low levels among children who lived in households with unimproved toilet facilities (OR = 0.54, 95 % CI: [0.34, 0.87] for moderate runoff and OR = 0.50, 95 % CI: [0.29, 0.86] for high runoff) but had no impact among children in household with improved toilets. CONCLUSION: Our finding that children in households with unimproved toilets were less likely to report diarrhea during periods of high runoff highlights the vulnerabilities of those living without adequate sanitation to the negative health impacts of environmental events.

Concordance of resistance profiles in households of patients with multidrug-resistant tuberculosis.

We estimated the proportion of household contacts whose drug-susceptibility test results matched those of the purported source patient with multidrug-resistant tuberculosis. Ninety-nine (88.4%) contacts had isolates resistant to isoniazid and rifampin, and 41 (36.6%) contacts had isolates with results that also matched the purported source for ethambutol, streptomycin, and pyrazinamide.

Improving outcomes for multidrug-resistant tuberculosis: aggressive regimens prevent treatment failure and death.

BACKGROUND: Evidence is sparse regarding the optimal construction of regimens to treat multidrug-resistant (MDR) tuberculosis disease due to strains of Mycobacterium tuberculosis resistant to at least both isoniazid and rifampin. Given the low potency of many second-line antituberculous drugs, we hypothesized that an aggressive regimen of at least 5 likely effective drugs during the intensive phase, including a fluoroquinolone and a parenteral agent, would be associated with a reduced risk of death or treatment failure. METHODS: We conducted a retrospective cohort study of patients initiating MDR tuberculosis treatment between 2000 and 2004 in Tomsk, Russian Federation. We used a multivariate Cox proportional hazards model to assess whether monthly exposure to an aggressive regimen was associated with the risk of death or treatment failure. RESULTS: Six hundred fourteen individuals with confirmed MDR tuberculosis were eligible for analysis. On multivariable analysis that adjusted for extensively drug-resistant (XDR) tuberculosis-MDR tuberculosis isolates resistant to fluoroquinolones and parenteral agents-we found that monthly exposure to an aggressive regimen was significantly associated with a lower risk of death or treatment failure (hazard ratio, 0.52 [95% confidence interval, .29-.94]; P = .030). CONCLUSIONS: Receipt of an aggressive treatment regimen was a robust predictor of decreased risk of death or failure during MDR tuberculosis treatment. These findings further support the use of this regimen definition as the benchmark for the standard of care of MDR tuberculosis patients and should be used as the basis for evaluating novel therapies.

Beyond 'Screen & Refer': Understanding Families' Use of Resources for Health-related Social Needs Identified via Primary Care.

OBJECTIVE: As health-related social needs (HRSN) screening increases, attention to families' resource preferences lags. This study of a pediatric primary care intervention (DULCE) with reliable HRSN screening and resource connection explored whether resources adequately addressed families' needs and, when HRSN persisted, families' reasons for declining resources. METHODS: This retrospective cohort, mixed-methods study analyzed data from 989 families that received care at seven pediatric clinics implementing DULCE in three states. DULCE screens for seven HRSN around the 1-month and 4-month well-child visits; we calculated the percent of initial and ongoing positive screens. For positive rescreens, we calculated the percent that had all eligible or wanted resources and that were interested in further resources. We also analyzed case notes, which elicited families' resource preferences, and explored demographic characteristics associated with ongoing HRSN. RESULTS: Half of enrolled families (508 of 989) initially screened positive for HRSN; 124 families had positive rescreens; 26 expressed interest in further assistance. Most families with ongoing concrete supports needs accessed all eligible resources (60-100%); 20-58% had everything they wanted. Fewer families with ongoing maternal depression and intimate partner violence accessed all eligible resources (48% and 18%, respectively); most reported having all wanted resources (76% and 90%, respectively). Families declined resources due to lack of perceived need, the HRSN resolving, or families addressed HRSN themselves. White families were more likely to rescreen positive. CONCLUSIONS: Pediatric medical homes must honor family-centered decision-making while empowering families to accept beneficial resources. Healthcare systems should advocate for resources that families need and want.

Primary Care-Based Housing Program Reduced Outpatient Visits; Patients Reported Mental And Physical Health Benefits.

Screening for housing instability has increased as health systems move toward value-based care, but evidence on how health care-based housing interventions affect patient outcomes comes mostly from interventions that address homelessness. In this mixed-methods evaluation of a primary care-based housing program in Boston, Massachusetts, for 1,139 patients with housing-related needs that extend beyond homelessness, we found associations between program participation and health care use. Patients enrolled in the program between October 2018 and March 2021 had 2.5 fewer primary care visits and 3.6 fewer outpatient visits per year compared with those who were not enrolled, including fewer social work, behavioral health, psychiatry, and urgent care visits. Patients in the program who obtained new housing reported mental and physical health benefits, and some expressed having stronger connections to their health care providers. Many patients attributed improvements in mental health to compassionate support provided by the program's housing advocates. Health care-based housing interventions should address the needs of patients facing imminent housing crises. Such interventions hold promise for redressing health inequities and restoring dignity to the connections between historically marginalized patient populations and health care institutions.

Sustaining and scaling a clinic-based approach to address health-related social needs.

Objective: Scaling evidence-based interventions (EBIs) from pilot phase remains a pressing challenge in efforts to address health-related social needs (HRSN) and improve population health. This study describes an innovative approach to sustaining and further spreading DULCE (Developmental Understanding and Legal Collaboration for Everyone), a universal EBI that supports pediatric clinics to implement the American Academy of Pediatrics' Bright Futures™ guidelines for infants' well-child visits (WCVs) and introduces a new quality measure of families' HRSN resource use. Methods: Between August 2018 and December 2019, seven teams in four communities in three states implemented DULCE: four teams that had been implementing DULCE since 2016 and three new teams. Teams received monthly data reports and individualized continuous quality improvement (CQI) coaching for six months, followed by lighter-touch support via quarterly group calls (peer-to-peer learning and coaching). Run charts were used to study outcome (percent of infants that received all WCVs on time) and process measures (percent of families screened for HRSN and connected to resources). Results: Integrating three new sites was associated with an initial regression of outcome: 41% of infants received all WCVs on time, followed by improvement to 48%. Process performance was sustained or improved: among 989 participating families, 84% (831) received 1-month WCVs on time; 96% (946) were screened for seven HRSN, 54% (508) had HRSN, and 87% (444) used HRSN resources. Conclusion: An innovative, lighter-touch CQI approach to a second phase of scale-up resulted in sustainment or improvements in most processes and outcomes. Outcomes-oriented CQI measures (family receipt of resources) are an important addition to more traditional process-oriented indicators.

Comparative effectiveness of adding delamanid to a multidrug-resistant tuberculosis regimen comprised of three drugs likely to be effective.

Clarity about the role of delamanid in longer regimens for multidrug-resistant TB is needed after discordant Phase IIb and Phase III randomized controlled trial results. The Phase IIb trial found that the addition of delamanid to a background regimen hastened culture conversion; the results of the Phase III trial were equivocal. We evaluated the effect of adding delamanid for 24 weeks to three-drug MDR/RR-TB regimens on two- and six-month culture conversion in the endTB observational study. We used pooled logistic regression to estimate the observational analogue of the intention-to-treat effect (aITT) adjusting for baseline confounders and to estimate the observational analogue of the per-protocol effect (aPP) using inverse probability of censoring weighting to control for time-varying confounding. At treatment initiation, 362 patients received three likely effective drugs (delamanid-free) or three likely effective drugs plus delamanid (delamanid-containing). Over 80% of patients received two to three Group A drugs (bedaquiline, linezolid, moxifloxacin/levofloxacin) in their regimen. We found no evidence the addition of delamanid to a three-drug regimen increased two-month (aITT relative risk: 0.90 (95% CI: 0.73-1.11), aPP relative risk: 0.89 (95% CI: 0.66-1.21)) or six-month culture conversion (aITT relative risk: 0.94 (95% CI: 0.84, 1.02), aPP relative risk: 0.93 (95% CI: 0.83, 1.04)). In regimens containing combinations of three likely effective, highly active anti-TB drugs the addition of delamanid had no discernible effect on culture conversion at two or six months. As the standard of care for MDR/RR-TB treatment becomes more potent, it may become increasingly difficult to detect the benefit of adding a single agent to standard of care MDR/RR-TB regimens. Novel approaches like those implemented may help account for background regimens and establish effectiveness of new chemical entities.

Tuberculosis burden in households of patients with multidrug-resistant and extensively drug-resistant tuberculosis: a retrospective cohort study.

BACKGROUND: Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis have emerged as major global health threats. WHO recommends contact investigation in close contacts of patients with MDR and XDR tuberculosis. We aimed to assess the burden of tuberculosis disease in household contacts of such patients. METHODS: We undertook a retrospective cohort study of household contacts of patients treated for MDR or XDR tuberculosis in Lima, Peru, in 1996-2003. The primary outcome was active tuberculosis in household contacts at the time the index patient began MDR tuberculosis treatment and during the 4-year follow-up. We examined whether the occurrence of active tuberculosis in the household contacts differed by resistance pattern of the index patient: either MDR or XDR tuberculosis. FINDINGS: 693 households of index patients with MDR tuberculosis were enrolled in the study. In 48 households, the Mycobacterium tuberculosis isolate from the index patient was XDR. Of the 4503 household contacts, 117 (2·60%) had active tuberculosis at the time the index patient began MDR tuberculosis treatment-there was no difference in prevalence between XDR and MDR tuberculosis households. During the 4-year follow-up, 242 contacts developed active tuberculosis-the frequency of active tuberculosis was nearly two times higher in contacts of patients with XDR tuberculosis than it was in contacts of patients with MDR tuberculosis (hazard ratio 1·88, 95% CI 1·10-3·21). In the 359 contacts with active tuberculosis, 142 (40%) had had isolates tested for resistance against first-line drugs, of whom 129 (90·9%, 95% CI 85·0-94·6) had MDR tuberculosis. INTERPRETATION: In view of the high risk of disease recorded in household contacts of patients with MDR or XDR tuberculosis, tuberculosis programmes should implement systematic household contact investigations for all patients identified as having MDR or XDR tuberculosis. If shown to have active tuberculosis, these household contacts should be suspected as having MDR tuberculosis until proven otherwise. FUNDING: The Charles H Hood Foundation, the David Rockefeller Center for Latin American Studies at Harvard University, and the Bill & Melinda Gates Foundation.

Benefits of a Universal Intervention in Pediatric Medical Homes to Identify and Address Health-Related Social Needs: An Observational Cohort Study.

OBJECTIVE: Compare rates of identification of families with health-related social needs (HRSN) and connection to resources by targeted versus universal, pediatric clinic-based interventions. METHODS: This observational cohort study included 1677 families that received care (January 2017-May 2020) at 8 pediatric medical homes in 3 states implementing Developmental Understanding and Legal Collaboration for Everyone (DULCE)-a universal, evidence-based intervention that addresses HRSN for families with infants. We divided the cohort into 2 groups using 4 common risk criteria in targeted programs serving families with infants; 862 families had no high-risk characteristics (Risk Criteria Absent [RCA]); 815 families had high-risk characteristics (Risk Criteria Present [RCP]). We compared both groups by prevalence of HRSN and connection to supports and estimated the performance of high-risk criteria to identify HRSN. RESULTS: DULCE identified 990 families with HRSN, compared to an estimated 274 families, if a risk-targeted approach had been used. More than half of RCA families had HRSN, 11% used resources at enrollment, and 42.5% accessed resources through DULCE. Simultaneously, 68.8% of RCP families had ongoing HRSN although 46.0% used resources at enrollment; 63.9% accessed additional resources through DULCE. Commonly used risk criteria had a sensitivity of 55.3% (95% confidence interval [CI], 52.2%-58.5%), specificity of 61.1% (95% CI, 57.2%-64.9%), positive predictive value of 68.8% (95% CI, 65.4%-72.0%), and negative predictive value of 46.9% (95% CI, 43.5%-50.4%). CONCLUSIONS: Risk criteria commonly used to identify families for targeted interventions are imperfect proxies for HRSN. Universal, medical home-based approaches can play a key role in supporting families with infants.