BACKGROUND: Evidence shows that isoniazid preventive therapy (IPT) reduces tuberculosis (TB) incidence among people with human immunodeficiency virus (HIV) with additive benefit beyond antiretroviral therapy alone, but its effectiveness in settings with high multidrug-resistant TB (MDR-TB) burden is unclear. We assessed the relationship between IPT and TB incidence among people with HIV (PWH) in Ukraine, a high-burden (32.6%) MDR-TB setting, and whether its effectiveness is maintained among virologically suppressed persons. METHODS: We analyzed national surveillance data for HIV and TB collected between 2018 and 2022. Complete IPT (n = 40 733) was defined as receipt of ≥146 days of therapy and no IPT (n = 91 022) as <28 days of therapy. We modeled TB incidence and death using Poisson regression adjusting for covariates related to receipt of IPT and TB incidence. The secondary outcome was multidrug resistance, and sensitivity analyses explored the influence of virologic suppression. RESULTS: Of 131 755 PWH who met inclusion criteria, 9089 (5.5%) died. Unadjusted TB incidence was 1.91 cases per 100 person-years in the No IPT group and 1.01 cases per 100 person-years in the Complete IPT group (adjusted incidence rate ratio [aIRR], 1.99). MDR-TB occurred in 29.1% and 30.7% of TB cases in the Complete and No IPT groups, respectively. Among virologically suppressed PWH, persons with no IPT had a higher TB incidence (aIRR, 1.38) than those who completed IPT. CONCLUSIONS: Completing IPT as part of a public health intervention can significantly reduce TB incidence among PWH, even in settings with high-burden MDR-TB and among the virologically suppressed.

INTRODUCTION: Age-adjusted mortality rates (AAMR) for cardiovascular diseases (CVD) increased in 2020 and 2021, and provisional data indicated an increase in 2022, resulting in substantial excess CVD deaths during the COVID-19 pandemic. Updated estimates using final data for 2022 are needed. METHODS: The National Vital Statistics System's final Multiple Cause of Death files were analyzed in 2024 to calculate AAMR from 2010 to 2022 and excess deaths from 2020 to 2022 for US adults aged ≥35 years, with CVD as the underlying cause of death. RESULTS: The CVD AAMR among adults aged ≥35 years in 2022 was 434.6 deaths per 100,000 (95% CI: 433.8, 435.5), which was lower than in 2021 (451.8 deaths per 100,000; 95% CI: 450.9, 452.7). The most recent year with a similarly high CVD AAMR as in 2022 was 2012 (434.7 deaths per 100,000 population, 95% CI: 433.8, 435.7). The CVD AAMR for 2022 calculated using provisional data over-estimated the AAMR calculated using final data by 4.6% (95% CI: 4.3%, 4.9%) or 19.9 (95% CI: 18.6, 21.2) deaths per 100,000 population. From 2020 to 2022, an estimated 190,661 (95% CI: 158,139, 223,325) excess CVD deaths occurred. CONCLUSIONS: In 2022, the CVD AAMR among adults aged ≥35 years did not increase, but rather declined from a peak in 2021, signaling improvements in adverse mortality trends that began in 2020, amid the COVID-19 pandemic. However, the 2022 CVD AAMR remains higher than observed before the COVID-19 pandemic, indicating an ongoing need for cardiovascular disease prevention, detection, and management.

INTRODUCTION: Cardiovascular disease (CVD) mortality increased during the initial years of the coronavirus disease 2019 (COVID-19) pandemic, but whether these trends endured in 2022 is unknown. The analysis describes temporal trends in CVD death rates from 2010 to 2022 and estimates excess CVD deaths from 2020 to 2022. METHODS: Using national mortality data from the National Vital Statistics System, deaths among adults aged ≥35 years were classified by underlying cause of death International Classification of Diseases 10(th) Revision codes for CVD (I00-I99), heart disease (I00-I09, I11, I13, I20-I51), and stroke (I60-I69). Analyses in Joinpoint software identified trends in CVD age-adjusted mortality rates (AAMR) per 100,000 and estimated the number of excess CVD deaths from 2020 to 2022. RESULTS: During 2010-2022, 10,951,403 CVD deaths occurred (75.6% heart disease, 16.9% stroke). The national CVD AAMR declined by 8.9% from 2010 to 2019 (456.6 to 416.0 per 100,000) and then increased by 9.3% from 2019 to 2022 to 454.5 per 100,000, which approximated the 2010 rate (456.7 per 100,000). From 2020 to 2022, 228,524 excess CVD deaths occurred, which was 9.0% more CVD deaths than expected based on trends from 2010 to 2019. Results varied by CVD subtype and population subgroup. CONCLUSIONS: Despite stabilization of the public health emergency, declines in CVD mortality rates reversed in 2020 and remained high in 2022, representing almost a decade of lost progress and over 228,000 excess CVD deaths. Findings underscore the importance of prioritizing prevention and management of CVD to improve outcomes.

The transmission patterns of drug-resistant tuberculosis (TB) remain poorly understood, despite over half a million incident cases in 2017. Modeling TB transmission networks can provide insight into the nature and drivers of transmission, but incomplete and non-random sampling of TB cases can pose challenges to making inferences from epidemiologic and molecular data. We conducted a quantitative bias analysis to assess the effect of missing cases on a transmission network inferred from Mtb sequencing data on extensively drug-resistant (XDR) TB cases in South Africa. We tested scenarios in which cases were missing at random, differentially by clinical characteristics, or differentially by transmission (i.e., cases with many links were under or over-sampled). Under the assumption cases were missing at random, cases in the complete, modeled network would have had a mean of 20 or more transmission links, which is far higher than expected, in order to reproduce the observed, partial network. Instead, we found that the most likely scenario involved undersampling of high-transmitting cases, and further models provided evidence for superspreading behavior. This is, to our knowledge, the first study to define and assess the support for different mechanisms of missingness in a study of TB transmission. Our findings should caution interpretation of results of future studies of TB transmission in high-incidence settings, given the potential for biased sampling, and should motivate further research aimed at identifying the specific host, pathogen, or environmental factors contributing to superspreading.

INTRODUCTION: Despite antiretroviral therapy (ART) scale-up among people living with HIV (PLHIV), those with advanced HIV disease (AHD) (defined in adults as CD4 count <200 cells/mm(3) or clinical stage 3 or 4), remain at high risk of death from opportunistic infections. The shift from routine baseline CD4 testing towards viral load testing in conjunction with "Test and Treat" has limited AHD identification. METHODS: We used official estimates and existing epidemiological data to project deaths from tuberculosis (TB) and cryptococcal meningitis (CM) among PLHIV-initiating ART with CD4 <200 cells/mm(3) , in the absence of select World Health Organization recommended diagnostic or therapeutic protocols for patients with AHD. We modelled the reduction in deaths, based on the performance of screening/diagnostic testing and the coverage and efficacy of treatment/preventive therapies for TB and CM. We compared projected TB and CM deaths in the first year of ART from 2019 to 2024, with and without CD4 testing. The analysis was performed for nine countries: South Africa, Kenya, Lesotho, Mozambique, Nigeria, Uganda, Zambia, Zimbabwe and the Democratic Republic of Congo. RESULTS: The effect of CD4 testing comes through increased identification of AHD and consequent eligibility for protocols for AHD prevention, diagnosis and management; algorithms for CD4 testing avert between 31% and 38% of deaths from TB and CM in the first year of ART. The number of CD4 tests required per death averted varies widely by country from approximately 101 for South Africa to 917 for Kenya. CONCLUSIONS: This analysis supports retaining baseline CD4 testing to avert deaths from TB and CM, the two most deadly opportunistic infections among patients with AHD. However, national programmes will need to weigh the cost of increasing CD4 access against other HIV-related priorities and allocate resources accordingly.

BACKGROUND: Obesity increases the risk for metabolic and cardiovascular disease, and this risk occurs at lower body mass index (BMI) thresholds in Asian adults than in White adults. The degree to which obesity prevalence varies across heterogeneous Asian American subgroups is unclear because most obesity estimates combine all Asian Americans into a single group. OBJECTIVE: To quantify obesity prevalence in Asian American subgroups among U.S. adults using both standard BMI categorizations and categorizations tailored to Asian populations. DESIGN: Cross-sectional. SETTING: United States, 2013 to 2020. PARTICIPANTS: The analytic sample included 2 882 158 adults aged 18 years or older in the U.S. Behavioral Risk Factor Surveillance System surveys (2013 to 2020). Participants self-identified as non-Hispanic White ([NHW] n = 2 547 965); non-Hispanic Black ([NHB] n = 263 136); or non-Hispanic Asian ([NHA] n = 71 057), comprising Asian Indian (n = 13 916), Chinese (n = 11 686), Filipino (n = 11 815), Japanese (n = 12 473), Korean (n = 3634), and Vietnamese (n = 2618) Americans. MEASUREMENTS: Obesity prevalence adjusted for age and sex calculated using both standard BMI thresholds (≥30 kg/m(2)) and BMI thresholds modified for Asian adults (≥27.5 kg/m(2)), based on self-reported height and weight. RESULTS: Adjusted obesity prevalence (by standard categorization) was 11.7% (95% CI, 11.2% to 12.2%) in NHA, 39.7% (CI, 39.4% to 40.1%) in NHB, and 29.4% (CI, 29.3% to 29.5%) in NHW participants; the prevalence was 16.8% (CI, 15.2% to 18.5%) in Filipino, 15.3% (CI, 13.2% to 17.5%) in Japanese, 11.2% (CI, 10.2% to 12.2%) in Asian Indian, 8.5% (CI, 6.8% to 10.5%) in Korean, 6.5% (CI, 5.5% to 7.5%) in Chinese, and 6.3% (CI, 5.1% to 7.8%) in Vietnamese Americans. The prevalence using modified criteria (BMI ≥27.5 kg/m(2)) was 22.4% (CI, 21.8% to 23.1%) in NHA participants overall and 28.7% (CI, 26.8% to 30.7%) in Filipino, 26.7% (CI, 24.1% to 29.5%) in Japanese, 22.4% (CI, 21.1% to 23.7%) in Asian Indian, 17.4% (CI, 15.2% to 19.8%) in Korean, 13.6% (CI, 11.7% to 15.9%) in Vietnamese, and 13.2% (CI, 12.0% to 14.5%) in Chinese Americans. LIMITATION: Body mass index estimates rely on self-reported data. CONCLUSION: Substantial heterogeneity in obesity prevalence exists among Asian American subgroups in the United States. Future studies and public health efforts should consider this heterogeneity. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute.

BACKGROUND: HIV infection is associated with high mortality among people with TB. Antiretroviral therapy (ART) reduces TB incidence and mortality among people living with HIV (PLHIV). Since 2005, Kenya has scaled up TB and HIV prevention, diagnosis and treatment. We evaluated the impact of these services on trends and TB treatment outcomes.METHODS: Using Microsoft Excel (2016) and Epi-Info 7, we analysed Kenya Ministry of Health TB surveillance data from 2008 to 2018 to determine trends in TB notifications, TB classification, HIV and ART status, and TB treatment outcomes.RESULTS: Among the 1,047,406 people reported with TB, 93% knew their HIV status, and 37% of these were HIV-positive. Among persons with TB and HIV, 69% received ART. Between 2008 and 2018, annual TB notifications declined from 110,252 to 96,562, and HIV-coinfection declined from 45% to 27%. HIV testing and ART uptake increased from 83% to 98% and from 30% to 97%, respectively. TB case fatality rose from 3.5% to 3.9% (P <0.018) among HIV-negative people and from 5.1% to 11.2% (P <0.001) among PLHIV on ART.CONCLUSION: TB notifications decreased in settings with suboptimal case detection. Although HIV-TB services were scaled-up, HIV-TB case fatality rose significantly. Concerted efforts are needed to address case detection and gaps in quality of TB care.

INTRODUCTION: Providing more convenient and patient-centred options for service delivery is a priority within global HIV programmes. These efforts improve patient satisfaction and retention and free up time for providers to focus on new HIV diagnoses or severe illness. Recently, the coronavirus disease 2019 (COVID-19) pandemic precipitated expanded eligibility criteria for these differentiated service delivery (DSD) models to decongest clinics and protect patients and healthcare workers. This has resulted in dramatic scale-up of DSD for antiretroviral therapy, cotrimoxazole and tuberculosis (TB) preventive treatment. While TB treatment among people living with HIV (PLHIV) has traditionally involved frequent, facility-based management, TB treatment can also be adapted within DSD models. Such adaptations could include electronic tools to ensure appropriate clinical management, treatment support, adherence counselling and adverse event (AE) monitoring. In this commentary, we outline considerations for DSD of TB treatment among PLHIV, building on best practices from global DSD model implementation for HIV service delivery. DISCUSSION: In operationalizing TB treatment in DSD models, we consider the following: what activity is being done, when or how often it takes place, where it takes place, by whom and for whom. We discuss considerations for various programme elements including TB screening and diagnosis; medication dispensing; patient education, counselling and support; clinical management and monitoring; and reporting and recording. General approaches include multi-month dispensing for TB medications during intensive and continuation phases of treatment and standardized virtual adherence and AE monitoring. Lastly, we provide operational examples of TB treatment delivery through DSD models, including a conceptual model and an early implementation experience from Zambia. CONCLUSIONS: COVID-19 has catalysed the rapid expansion of differentiated patient-centred service delivery for PLHIV. Expanding DSD models to include TB treatment can capitalize on existing platforms, while providing high-quality, routine treatment, follow-up and patient education and empowerment.

BACKGROUND: Diabetes mellitus (DM) is a leading contributor to morbidity and mortality in the United States (US). Prior DM prevalence estimates in Asian Americans are predominantly from Asians aggregated into a single group, but the Asian American population is heterogenous. OBJECTIVE: To evaluate self-reported DM prevalence in disaggregated Asian American subgroups to inform targeted management and prevention. DESIGN: Serial cross-sectional analysis. PARTICIPANTS: Respondents to the US Behavioral Risk Factor Surveillance System surveys who self-identify as non-Hispanic Asian American (NHA, N=57,001), comprising Asian Indian (N=11,089), Chinese (N=9458), Filipino (N=9339), Japanese (N=10,387), and Korean Americans (N=2843), compared to non-Hispanic White (NHW, N=2,143,729) and non-Hispanic Black (NHB, N=215,957) Americans. MAIN MEASURES: Prevalence of self-reported DM. Univariate Satterthwaite-adjusted chi-square tests compared the differences in weighted DM prevalence by sociodemographic and health status. KEY RESULTS: Self-reported fully adjusted DM prevalence was 8.7% (95% confidence interval 8.2-9.3) in NHA, compared to 14.3% (14.0-14.6) in NHB and 10.0% (10.0-10.1) in NHW (p<0.01 for difference). In NHA subgroups overall, DM prevalence was 14.4% (12.6-16.3) in Filipino, 13.4% (10.9-16.2) in Japanese, 10.7% (9.6-11.8) in Asian Indian, 5.1% (4.2-6.2) in Chinese, and 4.7% (3.4-6.3) in Korean Americans (p<0.01). Among those aged ≥65 years, DM prevalence was highest in Filipino (35.0% (29.4-41.2)) and Asian Indian (31.5% (25.9-37.8)) Americans. Adjusted for sex, education, and race/ethnicity-specific obesity category, NHA overall had a 21% higher DM prevalence compared to NHW (prevalence ratio 1.21 [1.14-1.27]), while prevalence ratios were 1.42 (1.24-1.63) in Filipinos and 1.29 (1.14-1.46) in Asian Indians. CONCLUSIONS: Adjusted self-reported DM prevalence is higher in NHA compared with NHW. Disaggregating NHA reveals heterogeneity in self-reported DM prevalence, highest in Filipino and Asian Indian Americans.

BACKGROUND: TB is the leading cause of mortality among people living with HIV (PLHIV), for whom isoniazid preventive therapy (IPT) has a proven mortality benefit. Despite WHO recommendations, countries have been slow in scaling up IPT. This study describes processes, challenges, solutions, outcomes and lessons learned during IPT scale-up in Kenya.METHODS: We conducted a desk review and analyzed aggregated Ministry of Health (MOH) IPT enrollment data from 2014 to 2018 to determine trends and impact of program activities. We further analyzed IPT completion reports for patients initiated from 2015 to 2017 in 745 MOH sites in Nairobi, Central, Eastern and Western Kenya.RESULTS: IPT was scaled up 75-fold from 2014 to 2018: the number of PLHIV covered increased from 9,981 to 749,890. The highest percentage increases in the cumulative number of PLHIV on IPT were seen in the quarters following IPT pilot projects in 2014 (49%), national launch in 2015 (54%), and HIV treatment acceleration in 2016 (158%). Among 250,069 patients initiating IPT from 2015 to 2017, 97.5% completed treatment, 0.2% died, 0.8% were lost to follow-up, 1.0% were not evaluated, and 0.6% discontinued treatment.CONCLUSIONS: IPT can be scaled up rapidly and effectively among PLHIV. Deliberate MOH efforts, strong leadership, service delivery integration, continuous mentorship, stakeholder involvement, and accountability are critical to program success.

BACKGROUND: Drug susceptibility testing (DST) patterns of Mycobacterium tuberculosis (MTB) from patients with rifampicin-resistant tuberculosis (RR-TB) or multidrug-resistant TB (MDR-TB; or resistant to rifampicin and isoniazid (INH)), are important to guide preventive therapy for their household contacts (HHCs). METHODS: As part of a feasibility study done in preparation for an MDR-TB preventive therapy trial in HHCs, smear, Xpert MTB/RIF, Hain MTBDRplus, culture and DST results of index MDR-TB patients were obtained from routine TB programs. A sputum sample was collected at study entry and evaluated by the same tests. Not all tests were performed on all specimens due to variations in test availability. RESULTS: Three hundred eight adults with reported RR/MDR-TB were enrolled from 16 participating sites in 8 countries. Their median age was 36 years, and 36% were HIV-infected. Routine testing on all 308 were confirmed as having RR-TB, but only 75% were documented as having MDR-TB. The majority of those not classified as having MDR-TB were because only rifampicin resistance was tested. At study entry (median 59 days after MDR-TB treatment initiation), 280 participants (91%) were able to produce sputum for the study, of whom 147 (53%) still had detectable MTB. All but 2 of these 147 had rifampicin DST done, with resistance detected in 89%. Almost half (47%) of the 147 specimens had INH DST done, with 83% resistance. Therefore, 20% of the 280 study specimens had MDR-TB confirmed. Overall, DST for second-line drugs were available in only 35% of the 308 routine specimens and 15% of 280 study specimens. CONCLUSIONS: RR-TB was detected in all routine specimens but only 75% had documented MDR-TB, illustrating the need for expanded DST beyond Xpert MTB/RIF to target preventive therapy for HHC.

SETTING: Peri-urban health facilities providing HIV and TB care in Zambia. OBJECTIVE: To evaluate 1) the impact of Xpert(®) MTB/RIF on time-to-diagnosis, treatment initiation, and outcomes among adult people living with HIV (PLHIV) on antiretroviral therapy (ART); and 2) the diagnostic performance of Xpert and Determine™ TB-LAM Ag assays. DESIGN: Quasi-experimental study design with the first cohort evaluated per standard-of-care (SOC; first sputum tested using smear microscopy) and the second cohort per an algorithm using Xpert as initial test (intervention phase; IP). Xpert testing was provided onsite in Chongwe District, while samples were transported 5-10 km in Kafue District. TB was confirmed using mycobacterial culture. RESULTS: Among 1350 PLHIV enrolled, 156 (15.4%) had confirmed TB. Time from TB evaluation to diagnosis (P = 0.018), and from evaluation to treatment initiation (P = 0.03) was significantly shorter for IP than for SOC. There was no difference in all-cause mortality (7.0% vs. 8.6%). TB-LAM Ag showed higher sensitivity with lower CD4 cell count: 81.8% at CD4 < 50 cells/mm(3) vs. 31.7% overall. CONCLUSION: Xpert improved time to diagnosis and treatment initiation, but there was no difference in all-cause mortality. High sensitivity of Determine TB-LAM Ag at lower CD4 count supports increased use in settings providing care to PLHIV, particularly with advanced HIV disease.

BACKGROUND: Study A5274 was an open-label trial of people with HIV (PLHIV) with CD4 cell count <50 cells/µL who were randomized to empirical TB treatment vs. isoniazid preventive therapy (IPT) in addition to antiretroviral therapy (ART). We evaluated health-related quality of life (HRQoL) by study arm, changes over time, and association with sociodemographic and clinical factors.METHODS: Participants aged >13 years were enrolled from outpatient clinics in 10 countries. HRQoL was assessed at Weeks 0, 8, 24 and 96 with questions about daily activity, hospital or emergency room visits, and general health status. We used logistic regression to examine HRQoL by arm and association with sociodemographic and clinical factors.RESULTS: Among 850 participants (424 empiric arm, 426 IPT arm), HRQoL improved over time with no difference between arms. At baseline and Week 24, participants with WHO Stage 3 or 4 events, or those who had Grade 3 or 4 signs/symptoms, were significantly more likely to report poor HRQoL using the composite of four HRQoL measures.CONCLUSION: HRQoL improved substantially in both arms during the study period. These findings show that ART, TB screening, and IPT can not only reduce mortality, but also improve HRQoL in PLHIV with advanced disease.

Transmission patterns of drug-resistant tuberculosis (TB) remain poorly understood, despite over half a million incident cases in 2017. Modeling TB transmission networks can provide insight into drivers of transmission, but incomplete sampling of TB cases can pose challenges for inference from individual epidemiologic and molecular data. We assessed the effect of missing cases on a transmission network inferred from Mycobacterium tuberculosis sequencing data on extensively drug-resistant TB cases in KwaZulu-Natal, South Africa diagnosed in 2011-2014. We tested scenarios in which cases were missing at random, differentially by clinical characteristics or by transmission (i.e., cases with many links were under or over-sampled). Under the assumption cases were missing randomly, the mean number of transmissions per case in the complete network needed to be larger than 20, far higher than expected, to reproduce the observed network. Instead, the most likely scenario involved undersampling of high-transmitting cases and models provided evidence for superspreading. This is the first study to assess support for different mechanisms of missingness in a TB transmission study, but our results are subject to the distributional assumptions of the network models we used. Transmission studies should consider the potential biases introduced by incomplete sampling and identify host, pathogen, or environmental factors driving superspreading.

BACKGROUND: South Africa has among the highest incidence of multidrug-resistant tuberculosis (MDR-TB) and more than 70% of patients are HIV co-infected. MDR-TB treatment is associated with frequent adverse events (AEs). Although guidelines recommend concurrent treatment of MDR-TB and HIV, safety data on concurrent therapy are limited. METHODS: We conducted a prospective observational study of MDR-TB patients with and without HIV-coinfection in South Africa between 2011 and 2015. Participants received standardized MDR-TB and HIV regimens. Participants were followed monthly for the duration of MDR-TB therapy and screened for clinical and laboratory AEs. Audiometry was performed monthly during the intensive phase; color discrimination testing was performed every 2 months. RESULTS: We enrolled 150 HIV-infected and 56 HIV-uninfected participants. Nearly all experienced at least one clinical (93%) or laboratory (96%) AE. The most common clinical AEs were peripheral neuropathy (50%) and difficulty sleeping (48%); the most common laboratory AEs were hypokalemia (47%) and decreased creatinine clearance (46%). Among 19 clinical and lab AEs examined, there were no differences by HIV status, except for diarrhea (27% HIV-infected vs. 13% HIV-uninfected, P = 0.03). Hearing loss was experienced by 72% of participants (8% severe loss). Fourteen percent experienced color discrimination loss (4% severe loss). There were no differences in frequency or severity of hearing or vision loss by HIV status. CONCLUSIONS: AEs were common, but not more frequent or severe among MDR-TB/HIV co-infected participants receiving concurrent antiretroviral therapy. Given the favorable treatment outcomes associated with concurrent treatment, antiretroviral therapy initiation should not be delayed in MDR-TB patients with HIV-coinfection.

Background: The American Thoracic Society, U.S. Centers for Disease Control and Prevention, European Respiratory Society, and Infectious Diseases Society of America jointly sponsored this new practice guideline on the treatment of drug-resistant tuberculosis (DR-TB). The document includes recommendations on the treatment of multidrug-resistant TB (MDR-TB) as well as isoniazid-resistant but rifampin-susceptible TB.Methods: Published systematic reviews, meta-analyses, and a new individual patient data meta-analysis from 12,030 patients, in 50 studies, across 25 countries with confirmed pulmonary rifampin-resistant TB were used for this guideline. Meta-analytic approaches included propensity score matching to reduce confounding. Each recommendation was discussed by an expert committee, screened for conflicts of interest, according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology.Results: Twenty-one Population, Intervention, Comparator, and Outcomes questions were addressed, generating 25 GRADE-based recommendations. Certainty in the evidence was judged to be very low, because the data came from observational studies with significant loss to follow-up and imbalance in background regimens between comparator groups. Good practices in the management of MDR-TB are described. On the basis of the evidence review, a clinical strategy tool for building a treatment regimen for MDR-TB is also provided.Conclusions: New recommendations are made for the choice and number of drugs in a regimen, the duration of intensive and continuation phases, and the role of injectable drugs for MDR-TB. On the basis of these recommendations, an effective all-oral regimen for MDR-TB can be assembled. Recommendations are also provided on the role of surgery in treatment of MDR-TB and for treatment of contacts exposed to MDR-TB and treatment of isoniazid-resistant TB.

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.

Antimicrobial-resistant (AMR) infections pose a major threat to global public health. Similar to other AMR pathogens, both historical and ongoing drug-resistant tuberculosis (TB) epidemics are characterized by transmission of a limited number of predominant Mycobacterium tuberculosis (Mtb) strains. Understanding how these predominant strains achieve sustained transmission, particularly during the critical period before they are detected via clinical or public health surveillance, can inform strategies for prevention and containment. In this study, we employ whole-genome sequence (WGS) data from TB clinical isolates collected in KwaZulu-Natal, South Africa to examine the pre-detection history of a successful strain of extensively drug-resistant (XDR) TB known as LAM4/KZN, first identified in a widely reported cluster of cases in 2005. We identify marked expansion of this strain concurrent with the onset of the generalized HIV epidemic 12 y prior to 2005, localize its geographic origin to a location in northeastern KwaZulu-Natal approximately 400 km away from the site of the 2005 outbreak, and use protein structural modeling to propose a mechanism for how strain-specific rpoB mutations offset fitness costs associated with rifampin resistance in LAM4/KZN. Our findings highlight the importance of HIV coinfection, high preexisting rates of drug-resistant TB, human migration, and pathoadaptive evolution in the emergence and dispersal of this critical public health threat. We propose that integrating whole-genome sequencing into routine public health surveillance can enable the early detection and local containment of AMR pathogens before they achieve widespread dispersal.

BACKGROUND: Tuberculosis (TB) is the leading infectious cause of death globally and drug-resistant TB strains pose a serious threat to controlling the global TB epidemic. The clinical features, locations, and social factors driving transmission in settings with a high incidence of drug-resistant TB are poorly understood. METHODS: We measured a network of genomic links using Mycobacterium tuberculosis (Mtb) whole genome sequences. RESULTS: Cases with 2-3 months of cough or who spent time in urban locations, were more likely to be linked in the network, while cases with sputum smear-positive disease were less likely to be linked than those with smear-negative disease. Associations persisted using different thresholds to define genomic links and irrespective of assumptions about the direction of transmission. CONCLUSIONS: Identifying factors that lead to many transmissions, including contact with urban areas, can suggest settings instrumental in transmission and indicate optimal locations and groups to target with interventions.

BACKGROUND In KwaZulu-Natal, South Africa, the incidence of extensively drug-resistant tuberculosis (XDR-TB) is driven by the transmission of resistant strains. As data suggest that cases may be spatially clustered, we sought to identify 'hotspots' and describe these communities. METHODS We enrolled XDR-TB patients diagnosed from 2011 to 2014 in eThekwini. Global positioning system (GPS) coordinates for participant homes were collected and hotspots were identified based on population-adjusted XDR-TB incidence. The sociodemographic features of hotspots were characterised using census data. For a subset of participants, we mapped non-home XDR-TB congregate locations and compared these with results including only homes. RESULTS Among 132 participants, 75 (57%) were female and 87 (66%) lived in urban or suburban locations. Fifteen of 197 census tracts were identified as XDR-TB hotspots with >/=95% confidence. Four spatial mapping methods identified one large hotspot in northeastern eThekwini. Hotspot communities had higher proportions of low educational attainment (12% vs. 9%) and unemployment (29.3% vs. 20.4%), and lower proportion of homes with flush toilets (36.4% vs. 68.9%). The case density shifted towards downtown Durban when congregate locations (e.g., workplaces) for 43 (33%) participants were mapped. CONCLUSIONS In eThekwini, XDR-TB case homes were clustered into hotspots with more poverty indicators than non-hotspots. Prevention efforts targeting hotspot communities and congregate settings may be effective in reducing community transmission..

BACKGROUND: We assessed multidrug-resistant tuberculosis (MDR-TB) cases and their household contacts (HHCs) to inform the development of an interventional clinical trial. METHODS: We conducted a cross-sectional study of adult MDR-TB cases and their HHCs in eight high-TB-burden countries. HHCs underwent symptom screening, chest radiography (CXR), sputum TB bacteriology, TB infection (TBI) testing (tuberculin skin test and interferon gamma release assay) and HIV testing. RESULTS: From October 2015 to April 2016, 1016 HHCs from 284 MDR-TB cases were enrolled. At diagnosis, 69% of MDR-TB cases were acid fast bacilli sputum smear-positive and 43% had cavitary disease; at study entry 35% remained smear-positive after a median MDR-TB treatment duration of 8.8 weeks. Nine HHCs were diagnosed with TB prior to entry and excluded. Of the remaining 1007 HHCs, 41% were male and the median age was 25 years. 121 (12%) HHC had new TB identified: 17 (2%) were confirmed; 33 (3%) probable; and 71 (7%) possible TB. TBI prevalence (defined as either TST or IGRA positivity) was 72% and varied by age, test used, and country. Of 1007 HHCs, 775 (77%) were considered high-risk per these mutually exclusive groups: 102 (10%) <5 years; 63 (6%) 5 and HIV-infected; and 610 (61%) 5 years, HIV-negative/unknown, and TBI positive. Only 21 (2%) HHCs were on preventive therapy. CONCLUSIONS: The majority of HHCs in these high-burden countries were at high risk of TB disease and infection, yet few were receiving routine preventive therapy. Trials of novel preventive therapies are urgently needed to inform treatment policy and practice.

BACKGROUND: Household contacts (HHCs) of individuals with multidrug-resistant tuberculosis (MDR-TB) are at high risk of infection and subsequent disease. There is limited evidence on the willingness of MDR-TB HHCs to take MDR-TB preventive therapy (TPT) to decrease their risk of TB disease. METHODS: In this cross-sectional study of HHCs of MDR and rifampicin resistant (RR)-TB index cases from 16 clinical research sites in eight countries, enrollees were interviewed to assess willingness to take a hypothetical, newly-developed MDR TPT if offered. In order to identify factors associated with willingness to take MDR TPT, a marginal logistic model was fitted using generalized estimating equations to account for household-level clustering. RESULTS: From 278 MDR/RR-TB index case households, 743 HHCs were enrolled; the median age of HHCs was 33 years (IQR 22-49) and 62% were women. HHC willingness to take hypothetical MDR TPT was high (79%) and remained high even with the potential for mild side effects (70%). Increased willingness was significantly associated with current employment or schooling [adjusted Odds Ratio (aOR) 1.83, 95% confidence interval (95%CI) 1.07-3.13], appropriate TB-related knowledge (aOR 2.22, 95%CI 1.23-3.99), confidence in taking TPT (aOR 7.16, 95%CI 3.33-15.42), and being comfortable telling others about taking MDR TPT (aOR 2.29, 95%CI 1.29-4.06). CONCLUSIONS: The high percentage of HHCs of MDR/RR-TB index cases willing to take hypothetical MDR TPT provides important evidence for the potential uptake of effective MDR TPT when implemented. Identified HHC-level variables associated with willingness may inform education and counseling efforts to increase HHC confidence in and uptake of MDR TPT.

The current tuberculosis (TB) case reporting system for the United States, the Report of Verified Case of TB (RVCT), has minimal capture of multidrug-resistant (MDR) TB treatment and adverse events. Data were abstracted in five states using the form for 13 MDR TB patients during 2012–2015. The Centers for Disease Control and Prevention Guidelines for Evaluating Public Health Surveillance Systems were used to evaluate attributes of the form. Unstructured interviews with pilot sites and stakeholders provided qualitative feedback. The form was acceptable, simple, stable, representative, and provided high-quality data but was not flexible or timely. For the 13 patients on whom data were collected, the median duration of treatment with an injectable medication was 216 days (IQR 203–252). Six (46%) patients reported a side effect requiring a medication change and eight (62%) had a side effect present at treatment completion. A standardized MDR TB supplemental surveillance form was well received by stakeholders whose feedback was critical to making modifications. The finalized form will be implemented nationally in 2020 and will provide MDR TB treatment and morbidity data in the United States to help ensure patients with MDR TB receive the most effective treatment regimens with the least toxic drugs.

SETTING: The household contacts (HHCs) of multidrug-resistant tuberculosis (MDR-TB) index cases are at high risk of tuberculous infection and disease progression, particularly if infected with the human immunodeficiency virus (HIV). HIV testing is important for risk assessment and clinical management. METHODS: This was a cross-sectional, multi-country study of adult MDR-TB index cases and HHCs. All adult and child HHCs were offered HIV testing if never tested or if HIV-negative >1 year previously when last tested. We measured HIV testing uptake and used logistic regression to evaluate predictors. RESULTS: A total of 1007 HHCs of 284 index cases were enrolled in eight countries. HIV status was known at enrolment for 226 (22%) HHCs; 39 (4%) were HIV-positive. HIV testing was offered to 769 (98%) of the 781 remaining HHCs; 544 (71%) agreed to testing. Of 535 who were actually tested, 26 (5%) were HIV-infected. HIV testing uptake varied by site (median 86%, range 0-100%; P < 0.0001), and was lower in children aged <18 years than in adults (59% vs. 78%; adjusted for site P < 0.0001). CONCLUSIONS: HIV testing of HHCs of MDR-TB index cases is feasible and high-yield, with 5% testing positive. Reasons for low test uptake among children and at specific sites-including sites with high HIV prevalence-require further study to ensure all persons at risk for HIV are aware of their status.

For three decades, drug-resistant tuberculosis (TB) has posed grave challenges to patients, communities and global TB control efforts. Treatment of multidrug-resistant (MDR)-TB (i.e. TB resistant to at least isoniazid and rifampicin) and extensively drug-resistant (XDR)-TB (i.e. MDR-TB with additional resistance to fluoroquinolones and second-line injectable TB drugs) has relied on medications that are less potent and more toxic than first-line TB therapy. Consequently, drug-resistant TB treatment takes 2 years to complete and has been associated with frequent and severe side-effects. Treatment outcomes remain abysmal despite this prolonged therapy, with only 54% of MDR-TB patients and 30% of XDR-TB patients achieving cure [1]. When considering the full cascade of individuals estimated to have drug-resistant TB, only 12% of MDR-TB and 6.8% of XDR-TB patients are cured (figure 1).

FOLLOWING THE CLINICAL TRIALS by the Singapore Tuberculosis Service and the British Medical Research Council in the 1970s, the 6-month ‘short-course’ tuberculosis (TB) regimen, based on isoniazid, rifampicin, and pyrazinamide, was widely adopted in the 1980s.1,2 However, for patients undergoing retreatment for TB disease, there was no clear evidence-based treatment regimen. In an effort to fill this gap, in 1991 the World Health Organization (WHO) endorsed the ‘Category II’ regimen, an 8-month regimen with the addition of streptomycin, as a retreatment regimen for patients with TB disease relapse, treatment failure, or treatment after an interruption of at least 2 months.3 Despite this endorsement, it was already recognized that the addition of a single drug to a failing regimen set the stage for the amplification of drug resistance and poor clinical outcomes.4–6 Nearly two decades later, in the face of mounting data pointing to its ineffectiveness, in 2010 the WHO recommended against using the Category II regimen.7 This reversal remains highly relevant for the 19% of retreatment cases estimated to have drug resistance in the context of relapsed or recurrent disease in 2016.8

BACKGROUND: Current guidelines recommend evaluation of the household contacts (HHCs) of individuals with multidrug-resistant tuberculosis (MDR-TB); however, implementation of this policy is challenging. OBJECTIVE: To describe the resource utilization and operational challenges encountered when identifying and characterizing adult MDR-TB index cases and their HHCs. DESIGN: Cross-sectional study of adult MDR-TB index cases and HHCs at 16 clinical research sites in eight countries. Site-level resource utilization was assessed with surveys. RESULTS: Between October 2015 and April 2016, 308 index cases and 1018 HHCs were enrolled. Of 280 index cases with sputum collected, 94 were smear-positive (34%, 95%CI 28-39), and of 201 with chest X-rays, 87 had cavitary disease (43%, 95%CI 37-50) after a mean duration of treatment of 8 weeks. Staff required 512 attempts to evaluate the 308 households, with a median time per attempt of 4 h; 77% (95%CI 73-80) of HHCs were at increased risk for TB: 13% were aged <5 years, 8% were infected with the human immunodeficiency virus, and 79% were positive on the tuberculin skin test/interferon-gamma release assay. One hundred and twenty-one previously undiagnosed TB cases were identified. Issues identified by site staff included the complexity of personnel and participant transportation, infection control, personnel safety and management of stigma. CONCLUSION: HHC investigations can be high yield, but are labor-intensive.

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.

Background: Transmission is driving the global drug-resistant tuberculosis epidemic; nearly three-quarters of drug-resistant tuberculosis cases are attributable to transmission. Geographic patterns of disease incidence, combined with information on probable transmission links, can define the spatial scale of transmission and generate hypotheses about factors driving transmission patterns. Methods: We combined whole-genome sequencing data with home GPS coordinates from 344 participants with extensively drug-resistant (XDR) tuberculosis in KwaZulu-Natal, South Africa diagnosed from 2011-2014. We aimed to determine if genomically linked (</=5 single nucleotide polymorphisms [SNP] differences) cases lived close to one another, which would suggest a role for local community settings in transmission. Results: 182 study participants were genomically linked, comprising 1084 case-pairs. The median distance between case-pairs' homes was 108 km (IQR: 64-162 km). Between-district, as compared to within-district, links accounted for the majority (912/1084, 84%) of genomic links. Half (526, 49%) of genomic links involved a case from Durban, the urban center of KwaZulu-Natal. Conclusions: The high proportions of between-district links with Durban provide insight into possible drivers of province-wide XDR-tuberculosis transmission, including urban-rural migration. Further research should focus on characterizing the contribution of these drivers to overall XDR-tuberculosis transmission in KwaZulu-Natal to inform design of targeted strategies to curb the drug-resistant tuberculosis epidemic.

More than 10 million new cases of tuberculosis (TB) are diagnosed worldwide each year. The majority of these cases occur in low- and middle-income countries where the TB epidemic is predominantly driven by transmission. Efforts to 'end TB' will depend upon our ability to halt ongoing transmission. However, recent studies of new approaches to interrupt transmission have demonstrated inconsistent effects on reducing population-level TB incidence. TB transmission occurs across a wide range of settings, that include households and hospitals, but also community-based settings. While home-based contact investigations and infection control programmes in hospitals and clinics have a successful track record as TB control activities, there is a gap in our knowledge of where, and between whom, community-based transmission of TB occurs. Novel tools, including molecular epidemiology, geospatial analyses and ventilation studies, provide hope for improving our understanding of transmission in countries where the burden of TB is greatest. By integrating these diverse and innovative tools, we can enhance our ability to identify transmission events by documenting the opportunity for transmission-through either an epidemiologic or geospatial connection-alongside genomic evidence for transmission, based upon genetically similar TB strains. A greater understanding of locations and patterns of transmission will translate into meaningful improvements in our current TB control activities by informing targeted, evidence-based public health interventions.