Treatment Outcomes in Global Systematic Review and Patient Meta-Analysis of Children with Extensively Drug-Resistant Tuberculosis.

Extensively drug-resistant tuberculosis (XDR TB) has extremely poor treatment outcomes in adults. Limited data are available for children. We report on clinical manifestations, treatment, and outcomes for 37 children (<15 years of age) with bacteriologically confirmed XDR TB in 11 countries. These patients were managed during 1999-2013. For the 37 children, median age was 11 years, 32 (87%) had pulmonary TB, and 29 had a recorded HIV status; 7 (24%) were infected with HIV. Median treatment duration was 7.0 months for the intensive phase and 12.2 months for the continuation phase. Thirty (81%) children had favorable treatment outcomes. Four (11%) died, 1 (3%) failed treatment, and 2 (5%) did not complete treatment. We found a high proportion of favorable treatment outcomes among children, with mortality rates markedly lower than for adults. Regimens and duration of treatment varied considerably. Evaluation of new regimens in children is required.

Treatment and outcomes in children with multidrug-resistant tuberculosis: A systematic review and individual patient data meta-analysis.

BACKGROUND: An estimated 32,000 children develop multidrug-resistant tuberculosis (MDR-TB; Mycobacterium tuberculosis resistant to isoniazid and rifampin) each year. Little is known about the optimal treatment for these children. METHODS AND FINDINGS: To inform the pediatric aspects of the revised World Health Organization (WHO) MDR-TB treatment guidelines, we performed a systematic review and individual patient data (IPD) meta-analysis, describing treatment outcomes in children treated for MDR-TB. To identify eligible reports we searched PubMed, LILACS, Embase, The Cochrane Library, PsychINFO, and BioMedCentral databases through 1 October 2014. To identify unpublished data, we reviewed conference abstracts, contacted experts in the field, and requested data through other routes, including at national and international conferences and through organizations working in pediatric MDR-TB. A cohort was eligible for inclusion if it included a minimum of three children (aged <15 years) who were treated for bacteriologically confirmed or clinically diagnosed MDR-TB, and if treatment outcomes were reported. The search yielded 2,772 reports; after review, 33 studies were eligible for inclusion, with IPD provided for 28 of these. All data were from published or unpublished observational cohorts. We analyzed demographic, clinical, and treatment factors as predictors of treatment outcome. In order to obtain adjusted estimates, we used a random-effects multivariable logistic regression (random intercept and random slope, unless specified otherwise) adjusted for the following covariates: age, sex, HIV infection, malnutrition, severe extrapulmonary disease, or the presence of severe disease on chest radiograph. We analyzed data from 975 children from 18 countries; 731 (75%) had bacteriologically confirmed and 244 (25%) had clinically diagnosed MDR-TB. The median age was 7.1 years. Of 910 (93%) children with documented HIV status, 359 (39%) were infected with HIV. When compared to clinically diagnosed patients, children with confirmed MDR-TB were more likely to be older, to be infected with HIV, to be malnourished, and to have severe tuberculosis (TB) on chest radiograph (p < 0.001 for all characteristics). Overall, 764 of 975 (78%) had a successful treatment outcome at the conclusion of therapy: 548/731 (75%) of confirmed and 216/244 (89%) of clinically diagnosed children (absolute difference 14%, 95% confidence interval [CI] 8%-19%, p < 0.001). Treatment was successful in only 56% of children with bacteriologically confirmed TB who were infected with HIV who did not receive any antiretroviral treatment (ART) during MDR-TB therapy, compared to 82% in children infected with HIV who received ART during MDR-TB therapy (absolute difference 26%, 95% CI 5%-48%, p = 0.006). In children with confirmed MDR-TB, the use of second-line injectable agents and high-dose isoniazid (15-20 mg/kg/day) were associated with treatment success (adjusted odds ratio [aOR] 2.9, 95% CI 1.0-8.3, p = 0.041 and aOR 5.9, 95% CI 1.7-20.5, p = 0.007, respectively). These findings for high-dose isoniazid may have been affected by site effect, as the majority of patients came from Cape Town. Limitations of this study include the difficulty of estimating the treatment effects of individual drugs within multidrug regimens, only observational cohort studies were available for inclusion, and treatment decisions were based on the clinician's perception of illness, with resulting potential for bias. CONCLUSIONS: This study suggests that children respond favorably to MDR-TB treatment. The low success rate in children infected with HIV who did not receive ART during their MDR-TB treatment highlights the need for ART in these children. Our findings of individual drug effects on treatment outcome should be further evaluated.

Impact of a district-wide health center strengthening intervention on healthcare utilization in rural Rwanda: Use of interrupted time series analysis.

BACKGROUND: Evaluations of health systems strengthening (HSS) interventions using observational data are rarely used for causal inference due to limited data availability. Routinely collected national data allow use of quasi-experimental designs such as interrupted time series (ITS). Rwanda has invested in a robust electronic health management information system (HMIS) that captures monthly healthcare utilization data. We used ITS to evaluate impact of an HSS intervention to improve primary health care facility readiness on health service utilization in two rural districts of Rwanda. METHODS: We used controlled ITS analysis to compare changes in healthcare utilization at health centers (HC) that received the intervention (n = 13) to propensity score matched non-intervention health centers in Rwanda (n = 86) from January 2008 to December 2012. HC support included infrastructure renovation, salary support, medical equipment, referral network strengthening, and clinical training. Baseline quarterly mean outpatient visit rates and population density were used to model propensity scores. The intervention began in May 2010 and was implemented over a twelve-month period. We used monthly healthcare utilization data from the national Rwandan HMIS to study changes in the (1) number of facility deliveries per 10,000 women, (2) number of referrals for high risk pregnancy per 100,000 women, and (3) the number of outpatient visits performed per 1,000 catchment population. RESULTS: PHIT HC experienced significantly higher monthly delivery rates post-HSS during the April-June season than comparison (3.19/10,000, 95% CI: [0.27, 6.10]). In 2010, this represented a 13% relative increase, and in 2011, this represented a 23% relative increase. The post-HSS change in monthly rate of high-risk pregnancies referred increased slightly in intervention compared to control HC (0.03/10,000, 95% CI: [-0.007, 0.06]). There was a small immediate post-HSS increase in outpatient visit rates in intervention compared to control HC (6.64/1,000, 95% CI: [-13.52, 26.81]). CONCLUSION: We failed to find strong evidence of post-HSS increases in outpatient visit rates or referral rates at health centers, which could be explained by small sample size and high baseline nation-wide health service coverage. However, our findings demonstrate that high quality routinely collected health facility data combined with ITS can be used for rigorous policy evaluation in resource-limited settings.

Pursuing equity in cancer care: implementation, challenges and preliminary findings of a public cancer referral center in rural Rwanda.

BACKGROUND: Cancer services are inaccessible in many low-income countries, and few published examples describe oncology programs within the public sector. In 2011, the Rwanda Ministry of Health (RMOH) established Butaro Cancer Center of Excellence (BCCOE) to expand cancer services nationally. In hopes of informing cancer care delivery in similar settings, we describe program-level experience implementing BCCOE, patient characteristics, and challenges encountered. METHODS: Butaro Cancer Center of Excellence was founded on diverse partnerships that emphasize capacity building. Services available include pathology-based diagnosis, basic imaging, chemotherapy, surgery, referral for radiotherapy, palliative care and socioeconomic access supports. Retrospective review of electronic medical records (EMR) of patients enrolled between July 1, 2012 and June 30, 2014 was conducted, supplemented by manual review of paper charts and programmatic records. RESULTS: In the program's first 2 years, 2326 patients presented for cancer-related care. Of these, 70.5% were female, 4.3% children, and 74.3% on public health insurance. In the first year, 66.3% (n = 1144) were diagnosed with cancer. Leading adult diagnoses were breast, cervical, and skin cancer. Among children, nephroblastoma, acute lymphoblastic leukemia, and Hodgkin lymphoma were predominant. As of June 30, 2013, 95 cancer patients had died. Challenges encountered include documentation gaps and staff shortages. CONCLUSION: Butaro Cancer Center of Excellence demonstrates that complex cancer care can be delivered in the most resource-constrained settings, accessible to vulnerable patients. Key attributes that have made BCCOE possible are: meaningful North-south partnerships, innovative task- and infrastructure-shifting, RMOH leadership, and an equity-driven agenda. Going forward, we will apply our experiences and lessons learned to further strengthen BCCOE, and employ the developed EMR system as a valuable platform to assess long-term clinical outcomes and improve care.

Improving district facility readiness: a 12-month evaluation of a data-driven health systems strengthening intervention in rural Rwanda.

BACKGROUND: While health systems strengthening (HSS) interventions are recommended by global health policy experts to improve population health in resource-limited settings, few examples exist of evaluations of HSS interventions conducted at the district level. In 2009, a partnership between Partners In Health (PIH), a non-governmental organization, and the Rwandan Ministry of Health (RMOH) was provided funds to implement and evaluate a district-level HSS intervention in two rural districts of Rwanda. DESIGN: The partnership provided limited funds to 14 health centers for targeted systems support in 2010; six others received support prior to the intervention (reference). RMOH health systems norms were mapped across the WHO HSS framework, scored from 0 to 10 and incorporated into a rapid survey assessing 11 domains of facility readiness. Stakeholder meetings allowed partnership leaders to review results, set priorities, and allocate resources. Investments included salary support, infrastructure improvements, medical equipment, and social support for patients. We compared facility domain scores from the start of the intervention to 12 months and tested for correlation between change in score and change in funding allocation to assess equity in our approach. RESULTS: We found significant improvements among intervention facilities from baseline to 12 months across several domains [infrastructure (+4, p=0.0001), clinical services (+1.2, p=0.03), infection and sanitation control (+0.6, p=0.03), medical equipment (+1.0, p=0.02), information use (+2, p=0.002)]. Composite score across domains improved from 6.2 at baseline to 7.4 at 12 months (p=0.002). Across facilities, 50% had composite scores greater than the average score among reference facilities (7.4) at 12 months compared to none at baseline. CONCLUSIONS: Rapid facility surveys, stakeholder engagement, and information feedback can be used for gap analysis and resource allocation. This approach can achieve effective use of limited resources, improve facility readiness, and ensure consistency of facility capacity to provide quality care at the district level.

Mentoring and quality improvement strengthen integrated management of childhood illness implementation in rural Rwanda.

OBJECTIVE: Integrated Management of Childhood Illness (IMCI) is the leading clinical protocol designed to decrease under-five mortality globally. However, impact is threatened by gaps in IMCI quality of care (QOC). In 2010, Partners In Health and the Rwanda Ministry of Health implemented a nurse mentorship intervention Mentoring and Enhanced Supervision at Health Centres (MESH) in two rural districts. This study measures change in QOC following the addition of MESH to didactic training. DESIGN: Prepost intervention study of change in QOC after 12 months of MESH support measured by case observation using a standardised checklist. Study sample was children age 2 months to 5 years presenting on the days of data collection (292 baseline, 413 endpoint). SETTING: 21 rural health centres in Rwanda. OUTCOMES: Primary outcome was a validated index of key IMCI assessments. Secondary outcomes included assessment, classification and treatment indicators, and QOC variability across providers. A mixed-effects regression model of the index was created. RESULTS: In multivariate analyses, the index significantly improved in southern Kayonza (ß-coefficient 0.17, 95% CI 0.12 to 0.22) and Kirehe (ß-coefficient 0.29, 95% CI 0.23 to 0.34) districts. Children seen by IMCI-trained nurses increased from 83.2% to 100% (p<0.001) and use of IMCI case recording forms improved from 65.9% to 97.1% (p<0.001). Correct classification improved (56.0% to 91.5%, p<0.001), as did correct treatment (78.3% to 98.2%, p<0.001). Variability in QOC decreased (intracluster correlation coefficient 0.613-0.346). CONCLUSIONS: MESH was associated with significant improvements in all domains of IMCI quality. MESH could be an innovative strategy to improve IMCI implementation in resource-limited settings working to decrease under-five mortality.

Enhancing formal educational and in-service training programs in rural Rwanda: a partnership among the public sector, a nongovernmental organization, and academia.

Global disparities in the distribution, specialization, diversity, and competency of the health workforce are striking. Countries with fewer health professionals have poorer health outcomes compared with countries that have more. Despite major gains in health indicators, Rwanda still suffers from a severe shortage of health professionals.This article describes a partnership launched in 2005 by Rwanda's Ministry of Health with the U.S. nongovernmental organization Partners In Health and with Harvard Medical School and Brigham and Women's Hospital. The partnership has expanded to include the Faculty of Medicine and the School of Public Health at the National University of Rwanda and other Harvard-affiliated academic medical centers. The partnership prioritizes local ownership and-with the ultimate goals of strengthening health service delivery and achieving health equity for poor and underserved populations-it has helped establish new or strengthen existing formal educational programs (conferring advanced degrees) and in-service training programs (fostering continuing professional development) targeting the local health workforce. Harvard Medical School and Brigham and Women's Hospital have also benefited from the partnership, expanding the opportunities for training and research in global health available to their faculty and trainees.The partnership has enabled Rwandan health professionals at partnership-supported district hospitals to acquire new competencies and deliver better health services to rural and underserved populations by leveraging resources, expertise, and growing interest in global health within the participating U.S. academic institutions. Best practices implemented during the partnership's first nine years can inform similar formal educational and in-service training programs in other low-income countries.

Prediction of severe disease in children with diarrhea in a resource-limited setting.

OBJECTIVE: To investigate the accuracy of three clinical scales for predicting severe disease (severe dehydration or death) in children with diarrhea in a resource-limited setting. METHODS: Participants included 178 children admitted to three Rwandan hospitals with diarrhea. A local physician or nurse assessed each child on arrival using the World Health Organization (WHO) severe dehydration scale and the Centers for Disease Control (CDC) scale. Children were weighed on arrival and daily until they achieved a stable weight, with a 10% increase between admission weight and stable weight considered severe dehydration. The Clinical Dehydration Scale was then constructed post-hoc using the data collected for the other two scales. Receiver Operator Characteristic (ROC) curves were constructed for each scale compared to the composite outcome of severe dehydration or death. RESULTS: The WHO severe dehydration scale, CDC scale, and Clinical Dehydration Scale had areas under the ROC curves (AUCs) of 0.72 (95% CI 0.60, 0.85), 0.73 (95% CI 0.62, 0.84), and 0.80 (95% CI 0.71, 0.89), respectively, in the full cohort. Only the Clinical Dehydration Scale was a significant predictor of severe disease when used in infants, with an AUC of 0.77 (95% CI 0.61, 0.93), and when used by nurses, with an AUC of 0.78 (95% CI 0.63, 0.93). CONCLUSIONS: While all three scales were moderate predictors of severe disease in children with diarrhea, scale accuracy varied based on provider training and age of the child. Future research should focus on developing or validating clinical tools that can be used accurately by nurses and other less-skilled providers to assess all children with diarrhea in resource-limited settings.

Shared learning in an interconnected world: innovations to advance global health equity.

The notion of "reverse innovation"--that some insights from low-income countries might offer transferable lessons for wealthier contexts--is increasingly common in the global health and business strategy literature. Yet the perspectives of researchers and policymakers in settings where these innovations are developed have been largely absent from the discussion to date. In this Commentary, we present examples of programmatic, technological, and research-based innovations from Rwanda, and offer reflections on how the global health community might leverage innovative partnerships for shared learning and improved health outcomes in all countries.

Comprehensive and integrated district health systems strengthening: the Rwanda Population Health Implementation and Training (PHIT) Partnership.

BACKGROUND: Nationally, health in Rwanda has been improving since 2000, with considerable improvement since 2005. Despite improvements, rural areas continue to lag behind urban sectors with regard to key health outcomes. Partners In Health (PIH) has been supporting the Rwanda Ministry of Health (MOH) in two rural districts in Rwanda since 2005. Since 2009, the MOH and PIH have spearheaded a health systems strengthening (HSS) intervention in these districts as part of the Rwanda Population Health Implementation and Training (PHIT) Partnership. The partnership is guided by the belief that HSS interventions should be comprehensive, integrated, responsive to local conditions, and address health care access, cost, and quality. The PHIT Partnership represents a collaboration between the MOH and PIH, with support from the National University of Rwanda School of Public Health, the National Institute of Statistics, Harvard Medical School, and Brigham and Women's Hospital. DESCRIPTION OF INTERVENTION: The PHIT Partnership's health systems support aligns with the World Health Organization's six health systems building blocks. HSS activities focus across all levels of the health system - community, health center, hospital, and district leadership - to improve health care access, quality, delivery, and health outcomes. Interventions are concentrated on three main areas: targeted support for health facilities, quality improvement initiatives, and a strengthened network of community health workers. EVALUATION DESIGN: The impact of activities will be assessed using population-level outcomes data collected through oversampling of the demographic and health survey (DHS) in the intervention districts. The overall impact evaluation is complemented by an analysis of trends in facility health care utilization. A comprehensive costing project captures the total expenditures and financial inputs of the health care system to determine the cost of systems improvement. Targeted evaluations and operational research pieces focus on specific programmatic components, supported by partnership-supported work to build in-country research capacity. DISCUSSION: Building on early successes, the work of the Rwanda PHIT Partnership approach to HSS has already seen noticeable increases in facility capacity and quality of care. The rigorous planned evaluation of the Partnership's HSS activities will contribute to global knowledge about intervention methodology, cost, and population health impact.

Prevention of mother-to-child transmission of HIV: cost-effectiveness of antiretroviral regimens and feeding options in Rwanda.

BACKGROUND: Rwanda's National PMTCT program aims to achieve elimination of new HIV infections in children by 2015. In November 2010, Rwanda adopted the WHO 2010 ARV guidelines for PMTCT recommending Option B (HAART) for all HIV-positive pregnant women extended throughout breastfeeding and discontinued (short course-HAART) only for those not eligible for life treatment. The current study aims to assess the cost-effectiveness of this policy choice. METHODS: Based on a cohort of HIV-infected pregnant women in Rwanda, we modelled the cost-effectiveness of six regimens: dual ARV prophylaxis with either 12 months breastfeeding or replacement feeding; short course HAART (Sc-HAART) prophylaxis with either 6 months breastfeeding, 12 months breastfeeding, or 18 months breastfeeding; and Sc-HAART prophylaxis with replacement feeding. Direct costs were modelled based on all inputs in each scenario and related unit costs. Effectiveness was evaluated by measuring HIV-free survival at 18 months. Savings correspond to the lifetime costs of HIV treatment and care avoided as a result of all vertical HIV infections averted. RESULTS: All PMTCT scenarios considered are cost saving compared to "no intervention." Sc-HAART with 12 months breastfeeding or 6 months breastfeeding dominate all other scenarios. Sc-HAART with 12 months breastfeeding allows for more children to be alive and HIV-uninfected by 18 months than Sc-HAART with 6 months breastfeeding for an incremental cost per child alive and uninfected of 11,882 USD. This conclusion is sensitive to changes in the relative risk of mortality by 18 months for exposed HIV-uninfected children on replacement feeding from birth and those who were breastfed for only 6 months compared to those breastfeeding for 12 months or more. CONCLUSION: Our findings support the earlier decision by Rwanda to adopt WHO Option B and could inform alternatives for breastfeeding duration. Local contexts and existing care delivery models should be part of national policy decisions.

Risk factors for in-hospital mortality among children with tuberculosis: the 25-year experience in Peru.

OBJECTIVE: We examined factors associated with in-hospital death among children with tuberculosis (TB). We hypothesized that a negative response to tuberculin skin testing (TST) would predict decreased survival. METHODS: This retrospective cohort comprised 2392 children ages 0 to 14 years hospitalized with TB at a Peruvian referral hospital over the 25-year study period. Detailed chart abstraction captured clinical history including TB contacts, physical examination findings, diagnostic data, treatment regimen, and hospitalization outcome. We used Cox proportional hazards regression analyses to determine risk factors for mortality. RESULTS: Of 2392 children, 2 (0.1%) were known to be HIV-positive, 5 (0.2%) had documented multidrug-resistant TB, and 266 (11%) died. The median time from hospitalization to death was 16 days (interquartile range: 4-44 days). Reaction of <5 mm induration on TST predicted death in a multivariable analysis (hazard ratio [HR]: 3.01; 95% confidence interval [CI]: 2.15-4.21; P < .0001). Younger age, period of admission, alteration of mental status (HR: 3.25; 95% CI: 2.48-4.27; P < .0001), respiratory distress (HR: 1.40; 95% CI: 1.07-1.83; P = .01), peripheral edema (HR: 1.97; 95% CI: 1.42-2.73; P < .0001), and hemoptysis (HR: 0.57; 95% CI: 0.32-1.00; P = .05) were associated with mortality. Treatment regimens that contained rifampicin (HR: 0.47; 95% CI: 0.33-0.68; P < .0001) were associated with improved survival. CONCLUSIONS: Negative reaction to TST is highly predictive of death among children with active TB. In children with clinical and radiographic findings suggestive of TB, a negative TST should not preclude or delay anti-TB therapy.

Excellent clinical outcomes and high retention in care among adults in a community-based HIV treatment program in rural Rwanda.

BACKGROUND: Access to antiretroviral therapy (ART) has rapidly expanded; as of the end of 2010, an estimated 6.6 million people are receiving ART in low-income and middle-income countries. Few reports have focused on the experiences of rural health centers or the use of community health workers. We report clinical and programatic outcomes at 24 months for a cohort of patients enrolled in a community-based ART program in southeastern Rwanda under collaboration between Partners In Health and the Rwandan Ministry of Health. METHODS AND FINDINGS: A retrospective medical record review was performed for a cohort of 1041 HIV+ adult patients initiating community-based ART between June 1, 2005, and April 30, 2006. Key programatic elements included free ART with direct observation by community health worker, tuberculosis screening and treatment, nutritional support, a transportation allowance, and social support. Among 1041 patients who initiated community-based ART, 961 (92.3%) were retained in care, 52 (5%) died and 28 (2.7%) were lost to follow-up. Median CD4 T-cell count increase was 336 cells per microliter [interquartile range: (IQR): 212-493] from median 190 cells per microliter (IQR: 116-270) at initiation. CONCLUSIONS: A program of intensive community-based treatment support for ART in rural Rwanda had excellent outcomes in 24-month retention in care. Having committed to improving access to HIV treatment in sub-Saharan Africa, the international community, including country HIV programs, should set high programmatic outcome benchmarks.

High human immunodeficiency virus-free survival of infants born to human immunodeficiency virus-positive mothers in an integrated program to decrease child mortality in rural Rwanda.

We retrospectively examined infant mortality and human immunodeficiency virus (HIV)-free survival among 211 infants who received a comprehensive package of health services, including breast milk substitution and clean water access, to prevent maternal-to-child transmission of HIV and improve child survival. The cumulative 12-month infant survival probability was 0.97 (95% confidence interval: 0.94-0.99). The cumulative 12- to 18-month HIV-free survival probability was 0.95 (confidence interval: 0.91-0.97).

Effect of directly observed therapy for highly active antiretroviral therapy on virologic, immunologic, and adherence outcomes: a meta-analysis and systematic review.

INTRODUCTION: Directly observed therapy of highly active antiretroviral therapy (DOT-HAART) is a feasible adherence intervention. Prospective DOT-HAART studies have shown mixed results, and optimal target groups have yet to be defined. We performed a meta-analysis and systematic review to assess the effect of DOT-HAART on adherence and virologic and immunologic response. METHODS: We performed a comprehensive search through August 2009 to identify peer-reviewed controlled studies that involved outpatient DOT-HAART among adults and reported at least 1 outcome assessed in this meta-analysis. Random-effects meta-analyses were performed; differences in effect on virologic suppression were examined using stratified meta-analyses and meta-regression on several study characteristics. RESULTS: Seventeen studies met inclusion criteria. Compared with control groups, DOT-HAART recipients were more likely to achieve an undetectable viral load (random effects risk ratio 1.24, 95% confidence interval (CI): 1.08 to 1.41), a greater increase in CD4 cell count (random effects weighted mean difference 43 cells/microL, 95% CI: 12 to 74 cells/microL), and HAART adherence of > or =95% (random effects risk ratio 1.17, 95% CI: 1.03 to 1.32). Results varied with respect to virologic response. DOT-HAART did not have a significant effect on virologic suppression when restricted to randomized controlled studies. Post-treatment effect was not observed in a limited number of studies. CONCLUSIONS: DOT-HAART had a significant effect on virologic, immunologic, and adherence outcomes, although its efficacy was not supported when restricting analysis to randomized controlled trials. DOT-HAART shows greatest treatment effect when targeting individuals with greater risk of nonadherence and when delivering the intervention that maximizes participant convenience and provides enhanced adherence support. Further investigation is needed to assess the postintervention effect and cost-effectiveness of DOT-HAART.

Community-based therapy for children with multidrug-resistant tuberculosis.

OBJECTIVES: The goals were to describe the management of multidrug-resistant tuberculosis among children, to examine the tolerability of second-line antituberculosis agents among children, and to report the outcomes of children treated for multidrug-resistant tuberculosis in poor urban communities in Lima, Peru, a city with high tuberculosis prevalence. METHODS: A retrospective analysis of data for 38 children <15 years of age with multidrug-resistant tuberculosis, either documented with drug sensitivity testing of the child's tuberculosis isolate or suspected on the basis of the presence of clinical symptoms for a child with a household contact with documented multidrug-resistant tuberculosis, was performed. All 38 children initiated a supervised individualized treatment regimen for multidrug-resistant tuberculosis between July 1999 and July 2003. Each child received 18 to 24 months of therapy with > or =5 first- or second-line drugs to which their Mycobacterium tuberculosis strain was presumed to be sensitive. RESULTS: Forty-five percent of the children had malnutrition or anemia at the time of diagnosis, 29% had severe radiographic findings (defined as bilateral or cavitary disease), and 13% had extrapulmonary disease. Forty-five percent of the children were hospitalized initially because of the severity of illness. Adverse events were observed for 42% of the children, but no events required suspension of therapy for >5 days. Ninety-five percent of the children (36 of 38 children) achieved cures or probable cures, 1 child (2.5%) died, and 1 child (2.5%) defaulted from therapy. CONCLUSIONS: Multidrug-resistant tuberculosis disease among children can be treated successfully in resource-poor settings. Treatment is well tolerated by children, and severe adverse events with second-line agents are rare.

Treatment of multidrug-resistant tuberculosis during pregnancy: long-term follow-up of 6 children with intrauterine exposure to second-line agents.

Treatment of gestational multidrug-resistant tuberculosis (MDR-TB) is controversial. We describe follow-up of 6 children exposed to second-line antituberculous agents in utero. Each child (average age, 3.7 years) underwent comprehensive clinical evaluation. One child had MDR-TB diagnosed. There was no evidence of significant late-presentation toxicity among the children. The results suggest that aggressive management of gestational MDR-TB may benefit both mother and child.