Estimating Post-treatment Recurrence After Multidrug-Resistant Tuberculosis Treatment Among Patients With and Without Human Immunodeficiency Virus: The Impact of Assumptions About Death and Missing Follow-up.

BACKGROUND: Quantification of recurrence risk following successful treatment is crucial to evaluating regimens for multidrug- or rifampicin-resistant (MDR/RR) tuberculosis (TB). However, such analyses are complicated when some patients die or become lost during post-treatment follow-up. METHODS: We analyzed data on 1991 patients who successfully completed a longer MDR/RR-TB regimen containing bedaquiline and/or delamanid between 2015 and 2018 in 16 countries. Using 5 approaches for handling post-treatment deaths, we estimated 6-month post-treatment TB recurrence risk overall and by HIV status. We used inverse-probability weighting to account for patients with missing follow-up and investigated the impact of potential bias from excluding these patients without applying inverse-probability weights. RESULTS: The estimated TB recurrence risk was 7.4/1000 (95% credible interval: 3.3-12.8) when deaths were handled as non-recurrences and 7.6/1000 (3.3-13.0) when deaths were censored and inverse-probability weights were applied to account for the excluded deaths. The estimated risks of composite recurrence outcomes were 25.5 (15.3-38.1), 11.7 (6.4-18.2), and 8.6 (4.1-14.4) per 1000 for recurrence or (1) any death, (2) death with unknown or TB-related cause, or (3) TB-related death, respectively. Corresponding relative risks for HIV status varied in direction and magnitude. Exclusion of patients with missing follow-up without inverse-probability weighting had a small impact on estimates. CONCLUSIONS: The estimated 6-month TB recurrence risk was low, and the association with HIV status was inconclusive due to few recurrence events. Estimation of post-treatment recurrence will be enhanced by explicit assumptions about deaths and appropriate adjustment for missing follow-up data.

Estimating post-treatment recurrence after multidrug-resistant tuberculosis treatment among patients with and without HIV: the impact of assumptions about death and missing follow-up.

Background: Quantification of recurrence risk following successful treatment is crucial to evaluating regimens for multidrug- or rifampicin-resistant (MDR/RR) tuberculosis (TB). However, such analyses are complicated when some patients die or become lost during post-treatment-follow-up. Methods: We analyzed data on 1,991 patients who successfully completed a longer MDR/RR-TB regimen containing bedaquiline and/or delamanid between 2015 and 2018 in 16 countries. Using five approaches for handling post-treatment deaths, we estimated the six-month post-treatment TB recurrence risk overall, and by HIV status. We used inverse-probability-weighting to account for patients with missing follow-up and investigated the impact of potential bias from excluding these patients without applying inverse-probability weights. Results: The estimated TB recurrence risk was 6.6 per 1000 (95% confidence interval (CI):3.2,11.2) when deaths were handled as non-recurrences, and 6.7 per 1000 (95% CI:2.8,12.2) when deaths were censored and inverse-probability weights were applied to account for the excluded deaths. The estimated risk of composite recurrence outcomes were 24.2 (95% CI:14.1,37.0), 10.5 (95% CI:5.6,16.6), and 7.8 (95% CI:3.9,13.2) per 1000 for recurrence or 1) any death, 2) death with unknown or TB-related cause, 3) TB-related death, respectively. Corresponding relative risks for HIV status varied in direction and magnitude. Exclusion of patients with missing follow-up without inverse-probability-weighting had a small but apparent impact on estimates. Conclusion: The estimated six-month TB recurrence risk was low, and the association with HIV status was inconclusive due to few recurrence events. Estimation of post-treatment recurrence will be enhanced by explicit assumptions about deaths and appropriate adjustment for missing follow-up data.

Mapping tuberculosis prevalence in Ethiopia using geospatial meta-analysis.

BACKGROUND: Reliable and detailed data on the prevalence of tuberculosis (TB) with sub-national estimates are scarce in Ethiopia. We address this knowledge gap by spatially predicting the national, sub-national and local prevalence of TB, and identifying drivers of TB prevalence across the country. METHODS: TB prevalence data were obtained from the Ethiopia national TB prevalence survey and from a comprehensive review of published reports. Geospatial covariates were obtained from publicly available sources. A random effects meta-analysis was used to estimate a pooled prevalence of TB at the national level, and model-based geostatistics were used to estimate the spatial variation of TB prevalence at sub-national and local levels. Within the MBG Plugin Framework, a logistic regression model was fitted to TB prevalence data using both fixed covariate effects and spatial random effects to identify drivers of TB and to predict the prevalence of TB. RESULTS: The overall pooled prevalence of TB in Ethiopia was 0.19% [95% confidence intervals (CI): 0.12%-0.28%]. There was a high degree of heterogeneity in the prevalence of TB (I2 96.4%, P <0.001), which varied by geographical locations, data collection periods and diagnostic methods. The highest prevalence of TB was observed in Dire Dawa (0.96%), Gambela (0.88%), Somali (0.42%), Addis Ababa (0.28%) and Afar (0.24%) regions. Nationally, there was a decline in TB prevalence from 0.18% in 2001 to 0.04% in 2009. However, prevalence increased back to 0.29% in 2014. Substantial spatial variation of TB prevalence was observed at a regional level, with a higher prevalence observed in the border regions, and at a local level within regions. The spatial distribution of TB prevalence was positively associated with population density. CONCLUSION: The results of this study showed that TB prevalence varied substantially at sub-national and local levels in Ethiopia. Spatial patterns were associated with population density. These results suggest that targeted interventions in high-risk areas may reduce the burden of TB in Ethiopia and additional data collection would be required to make further inferences on TB prevalence in areas that lack data.

Safety and Effectiveness Outcomes From a 14-Country Cohort of Patients With Multi-Drug Resistant Tuberculosis Treated Concomitantly With Bedaquiline, Delamanid, and Other Second-Line Drugs.

BACKGROUND: Concomitant use of bedaquiline (Bdq) and delamanid (Dlm) for multi-drug/rifampicin resistant tuberculosis (MDR/RR-TB) has raised concerns about a potentially poor risk-benefit ratio. Yet this combination is an important alternative for patients infected with strains of TB with complex drug resistance profiles or who cannot tolerate other therapies. We assessed safety and treatment outcomes of MDR/RR-TB patients receiving concomitant Bdq and Dlm, along with other second-line anti-TB drugs. METHODS: We conducted a multi-centric, prospective observational cohort study across 14 countries among patients receiving concomitant Bdq-Dlm treatment. Patients were recruited between April 2015 and September 2018 and were followed until the end of treatment. All serious adverse events and adverse events of special interest (AESI), leading to a treatment change, or judged significant by a clinician, were systematically monitored and documented. RESULTS: Overall, 472 patients received Bdq and Dlm concomitantly. A large majority also received linezolid (89.6%) and clofazimine (84.5%). Nearly all (90.3%) had extensive disease; most (74.2%) had resistance to fluoroquinolones. The most common AESI were peripheral neuropathy (134, 28.4%) and electrolyte depletion (94, 19.9%). Acute kidney injury and myelosuppression were seen in 40 (8.5%) and 24 (5.1%) of patients, respectively. QT prolongation occurred in 7 patients (1.5%). Overall, 78.0% (358/458) had successful treatment outcomes, 8.9% died, and 7.2% experienced treatment failure. CONCLUSIONS: Concomitant use of Bdq and Dlm, along with linezolid and clofazimine, is safe and effective for MDR/RR-TB patients with extensive disease. Using these drugs concomitantly is a good therapeutic option for patients with resistance to many anti-TB drugs.

Safety of Treatment Regimens Containing Bedaquiline and Delamanid in the endTB Cohort.

BACKGROUND: Safety of treatment for multidrug-resistant tuberculosis (MDR/RR-TB) can be an obstacle to treatment completion. Evaluate safety of longer MDR/RR-TB regimens containing bedaquiline and/or delamanid. METHODS: Multicentre (16 countries), prospective, observational study reporting incidence and frequency of clinically relevant adverse events of special interest (AESIs) among patients who received MDR/RR-TB treatment containing bedaquiline and/or delamanid. The AESIs were defined a priori as important events caused by bedaquiline, delamanid, linezolid, injectables, and other commonly used drugs. Occurrence of these events was also reported by exposure to the likely causative agent. RESULTS: Among 2296 patients, the most common clinically relevant AESIs were peripheral neuropathy (26.4%), electrolyte depletion (26.0%), and hearing loss (13.2%) with an incidence per 1000 person months of treatment, 1000 person-months of treatment 21.5 (95% confidence interval [CI]: 19.8-23.2), 20.7 (95% CI: 19.1-22.4), and 9.7 (95% CI: 8.6-10.8), respectively. QT interval was prolonged in 2.7% or 1.8 (95% CI: 1.4-2.3)/1000 person-months of treatment. Patients receiving injectables (N = 925) and linezolid (N = 1826) were most likely to experience events during exposure. Hearing loss, acute renal failure, or electrolyte depletion occurred in 36.8% or 72.8 (95% CI: 66.0-80.0) times/1000 person-months of injectable drug exposure. Peripheral neuropathy, optic neuritis, and/or myelosuppression occurred in 27.8% or 22.8 (95% CI: 20.9-24.8) times/1000 patient-months of linezolid exposure. CONCLUSIONS: AEs often related to linezolid and injectable drugs were more common than those frequently attributed to bedaquiline and delamanid. MDR-TB treatment monitoring and drug durations should reflect expected safety profiles of drug combinations. CLINICAL TRIALS REGISTRATION: NCT02754765.

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.

Culture Conversion at 6 Months in Patients Receiving Delamanid-containing Regimens for the Treatment of Multidrug-resistant Tuberculosis.

Delamanid should be effective against highly resistant strains of Mycobacteriumtuberculosis, but uptake has been slow globally. In the endTB (expand new drug markets for TB) Observational Study, which enrolled a large, heterogeneous cohorts of patients receiving delamanid as part of a multidrug regimen, 80% of participants experienced sputum culture conversion within 6 months. Clinical Trials Registration. NCT02754765.

Intensive phase treatment outcome and associated factors among patients treated for multi drug resistant tuberculosis in Ethiopia: a retrospective cohort study.

BACKGROUND: Multi-drug resistant Tuberculosis (MDR-TB) is a strain of Mycobacterium tuberculosis that is resistant to at least Rifampicin and Isoniazid drugs. The treatment success rate for MDR-TB cases is lower than for drug susceptible TB. Globally only 55% of MDR-TB patients were successfully treated. Monitoring the early treatment outcome and better understanding of the specific reasons for early unfavorable and unknown treatment outcome is crucial for preventing the emergence of further drug-resistant tuberculosis. However, this information is scarce in Ethiopia. Therefore, this study aimed to determine the intensive phase treatment outcome and contributing factors among patients treated for MDR-TB in Ethiopia. METHODS: A 6 year retrospective cohort record review was conducted in fourteen TICs all over the country. The records of 751 MDR-TB patients were randomly selected using simple random sampling technique. Data were collected using a pre-tested and structured checklist. Multivariable multinomial logistic regression was undertaken to identify the contributing factors. RESULTS: At the end of the intensive phase, 17.3% of MDR-TB patients had an unfavorable treatment outcome, while 16.8% had an unknown outcome with the remaining having a favorable outcome. The median duration of the intensive phase was 9.0 months (IQR 8.04-10.54). Having an unfavorable intensive phase treatment outcome was found significantly more common among older age [ARRR = 1.047, 95% CI (1.024, 1.072)] and those with a history of hypokalemia [ARRR = 0.512, 95% CI (0.280, 0.939)]. Having an unknown intensive phase treatment outcome was found to be more common among those treated under the ambulatory care [ARRR = 3.2, 95% CI (1.6, 6.2)], rural dwellers [ARRR = 0.370, 95% CI (0.199, 0.66)], those without a treatment supporter [ARRR = 0.022, 95% CI (0.002, 0.231)], and those with resistance to a limited number of drugs. CONCLUSION: We observed a higher rate of unfavorable and unknown treatment outcome in this study. To improve favorable treatment outcome more emphasis should be given to conducting all scheduled laboratory monitoring tests, assignment of treatment supporters for each patient and ensuring complete recording and reporting which could be enhanced by quarterly cohort review. Older aged and rural patients need special attention. Furthermore, the sample referral network should be strengthened.

The Burden of HIV/AIDS in Ethiopia from 1990 to 2016: Evidence from the Global Burden of Diseases 2016 Study.

BACKGROUND: The burden of HIV/AIDS in Ethiopia has not been comprehensively assessed over the last two decades. In this study, we used the 2016 Global Burden of Diseases, Injuries and Risk factors (GBD) data to analyze the incidence, prevalence, mortality and Disability-adjusted Life Years Lost (DALY) rates of Human Immunodeficiency Virus / Acquired Immune Deficiency Syndrome (HIV/AIDS) in Ethiopia over the last 26 years. METHODS: The GBD 2016 used a wide range of data source for Ethiopia such as verbal autopsy (VA), surveys, reports of the Federal Ministry of Health and the United Nations (UN) and published scientific articles. The modified United Nations Programme on HIV/AIDS (UNAIDS) Spectrum model was used to estimate the incidence and mortality rates for HIV/AIDS. RESULTS: In 2016, an estimated 36,990 new HIV infections (95% uncertainty interval [UI]: 8775-80262), 670,906 prevalent HIV cases (95% UI: 568,268-798,970) and 19,999 HIV deaths (95% UI: 16426-24412) occurred in Ethiopia. The HIV/AIDS incidence rate peaked in 1995 and declined by 6.3% annually for both sexes with a total reduction of 77% between 1990 and 2016. The annualized HIV/AIDS mortality rate reduction during 1990 to 2016 for both sexes was 0.4%. CONCLUSIONS: Ethiopia has achieved the 50% reduction of the incidence rate of HIV/AIDS based on the Millennium Development Goals (MDGs) target. However, the decline in HIV/AIDS mortality rate has been comparatively slow. The country should strengthen the HIV/AIDS detection and treatment programs at community level to achieve its targets during the Sustainable Development Program (SDGs)-era.

Tuberculosis Burden in Ethiopia from 1990 to 2016: Evidence from the Global Burden of Diseases 2016 Study.

BACKGROUND: The burden of Tuberculosis (TB) has not been comprehensively evaluated over the last 25 years in Ethiopia. In this study, we used the 2016 Global Burden of Diseases, Injuries and Risk Factors (GBD) data to analyze the incidence, prevalence and mortality rates of tuberculosis (TB) in Ethiopia over the last 26 years. METHODS: The GBD 2016 is a mathematical modeling using different data source for Ethiopia such as verbal autopsy (VA), prevalence surveys and annual case notifications. Age and sex specific causes of death for TB were estimated using the Cause of Death Ensemble Modeling (CODEm). We used the available data such as annual notifications and prevalence surveys as an input to estimate incidence and prevalence rates respectively using DisMod-MR 2.1, a Bayesian meta-regression tool. RESULTS: In 2016, we estimated 219,186 (95%UI: 182,977-265,292) new, 151,602 (95% UI: 126,054-180,976) prevalent TB cases and 48,910(95% UI: 40,310-58,195) TB deaths. The age-standardized TB incidence rate decreased from 201.6/100,000 to 88.5/100,000 (with a total decline of 56%) between 1990 to 2016. Similarly, the age-standardized TB mortality rate declined from 393.8/100,000 to 100/100,000 between 1990 and 2016(with a total decline of 75%). CONCLUSIONS: Ethiopia has achieved the 50% reduction of most of the Millennium Development Goals (MDGs) targets related to TB. However, the decline of TB incidence and prevalence rates has been comparatively slow. The country should strengthen the TB case detection and treatment programs at community level to achieve its targets during the Sustainable Development Program (SDGs)-era.

Assessment of national tuberculosis and HIV collaborative program implementation status in health care settings of Ethiopia.

BACKGROUND: Ethiopia has adopted the World Health Organization recommendation for TB and HIV collaborative activities since 2004. These collaborative activities have been scaled up in a phased manner and covered large number of health facilities across the nation. However, there is scarcity of information on implementation of these collaborative activities in Ethiopia. OBJECTIVE: To assess the status of implementation of TB and HIV collaborative activities in health facility settings of Ethiopia. METHODS: A cross sectional study mainly quantitative supplemented by qualitative methods was undertaken from May 10 to July 10, 2014 in 132 selected health facilities. Statistical analysis was performed using SPSS version 20. RESULT: About 81% of the respondents in the selected health facilities reported the screening of People Living with HIV in care for TB at every follow up visit, whereas, only 28.7% of those health facilities reported the screening of PLWHIV for TB at enrolment to HIV chronic care. About half of the public health facilities assessed were not implementing Isoniazid Preventive Therapy and only 18.2% of eligible clients were getting this Preventive Therapy. Among the co-infected patients, 32% were not linked to chronic care services and 45.3% were not getting ART during TB treatment. On the other hand, about two thirds of the co-infected patients are getting the Cotrimoxazole Prophylaxis Therapy. CONCLUSION: Most of anti-TB and HIV collaborative activities were not implemented as expected in the health facilities. Thus it needs integration from the ministry to the health facilities level in order to improve the collaborative activities.