Relapse after treatment with standardized all-oral short regimens for rifampicin-resistant tuberculosis (RR-TB): A systematic review and meta-analysis.

Background: Treatment for rifampicin-resistant tuberculosis (RR-TB) has been shortened to 12 months or less, with duration depending on the regimen used and treatment response. Treatment shortening has the potential to increase the risk of relapse, with a new episode of RR-TB after cure or completion. The proportion of relapses after standardized all-oral short (12 months or less) RR-TB regimens has not yet been systematically reviewed, which is the main objective of this review. Methods: This is a systematic review and meta-analysis. PubMed, Web of Science and Google scholar databases were systematically investigated to identify studies published between January 2018 and November 2023. Characteristics of studies, demographic data, baseline clinical condition, resistance profile, and definitions used for relapse, failure, and end-of-treatment outcomes are summarized in tables and graphs. Pooled proportions are estimated for relapse. Results: A total of ten studies were included in this review and meta-analysis, representing 1792 participants. Seven studies were clinical trials and two were cohorts. Five studies investigated all-oral six-month regimens composed of bedaquiline, pretomanid, and linezolid (BPaL). The remaining studies assessed other standardized all-oral short regimens, with treatment duration between 6 and 12 months. Post-treatment follow-up (PTFU) duration ranged from 6 to 30 months. The pooled proportion estimate of relapse was 2·0% (95 % CI, 1·0-3·0%) for all and BPaL-based regimens. Treatment extension due to poor treatment response was poorly documented. Conclusion: This review showed that the proportion of relapse in RR-TB patients treated with standardized short all-oral regimens was low. The low relapse proportion is similar to what was achieved for drug-susceptible Tuberculosis patients treated with first-line rifampicin-containing regimens. However, most data came from trial settings, and in some studies the post-treatment follow-up was short. Studies of large programmatic cohorts with longer post-treatment follow-up periods are needed to confirm the low relapse rate shown in the clinical trials.

Correction: Viraemic-time predicts mortality among people living with HIV on second-line antiretroviral treatment in Myanmar: A retrospective cohort study.

[This corrects the article DOI: 10.1371/journal.pone.0271910.].

Correction: Translating drug resistant tuberculosis treatment guidelines to reality in war-torn Kandahar, Afghanistan: A retrospective cohort study.

[This corrects the article DOI: 10.1371/journal.pone.0237787.].

Challenges and knowledge gaps in the management of non-tuberculous mycobacterial pulmonary disease in sub-Saharan African countries with a high tuberculosis burden: a scoping review.

INTRODUCTION: In sub-Saharan African (SSA) countries endemic for tuberculosis (TB), previous TB is a significant risk factor for non-tuberculous mycobacterial pulmonary disease (NTM-PD). The deployment of GeneXpert MTB/RIF in pulmonary TB diagnostic work-up regularly identifies symptomatic patients with a positive smear microscopy but negative GeneXpert, indicative of NTM presence. This scoping review outlines recent evidence for NTM-PD diagnosis and management in SSA. OBJECTIVE: The review's objective was to outline the risk factors, available diagnostics, management options and outcomes of NTM-PD in high-burden TB settings in SSA using the population-concept-context framework. DESIGN AND DATA SOURCES: We searched existing literature from PubMed, Web of Science, African Journals Online, Google Scholar and grey literature. Studies published between January 2005 and December 2022 were retained. Data were extracted into Rayyan software and Mendeley and summarised using Excel. RESULTS: We identified 785 potential articles, of which 105 were included in the full-text review, with 7 papers retained. Included articles used international criteria for diagnosing NTM-PD. Multiple papers were excluded due to non-application of the criteria, suggesting challenging application in the SSA setting. Identified risk factors include previous TB, smoking and mining. Most commonly, chest radiography and not CT was used for the radiological diagnosis of PD, which may miss early changes related to NTM-PD. Molecular methods for NTM species identification were employed in research settings, usually at referral centres, but were unavailable for routine care. Most studies did not report a standardised approach to treatment and they were not offered treatment for the specific disease, marking a lack of guidance in treatment decision-making. When treatment was provided, the outcome was often not reported due to the lack of implementation of standardised outcome definitions. CONCLUSIONS: These outlined challenges present a unique opportunity for researchers to undertake further studies in NTM-PD and proffer solutions more applicable to SSA.

Systematic review on cumulative HIV viraemia among people living with HIV receiving antiretroviral treatment and its association with mortality and morbidity.

BACKGROUND: We performed a systematic review to generate evidence on the association between cumulative human immunodeficiency virus (HIV) viraemia and health outcomes. METHODS: Quantitative studies reporting on HIV cumulative viraemia (CV) and its association with health outcomes among people living with HIV (PLHIV) on antiretroviral treatment (ART) were included. We searched MEDLINE via PubMed, Embase, Scopus and Web of Science and conference abstracts from 1 January 2008 to 1 August 2022. RESULTS: The systematic review included 26 studies. The association between CV and mortality depended on the study population, methods used to calculate CV and its level. Higher CV was not consistently associated with greater risk of acquire immunodeficiency syndrome-defining clinical conditions. However, four studies present a strong relationship between CV and cardiovascular disease. The risk was not confirmed in relation of increased hazards of stroke. Studies that assessed the effect of CV on the risk of cancer reported a positive association between CV and malignancy, although the effect may differ for different types of cancer. CONCLUSIONS: CV is associated with adverse health outcomes in PLHIV on ART, especially at higher levels. However, its role in clinical and programmatic monitoring and management of PLHIV on ART is yet to be established.

Advanced HIV disease and associated attrition after re-engagement in HIV care in Myanmar from 2003 to 2019: a retrospective cohort study.

BACKGROUND: The burden of advanced HIV disease (AHD) and predictors of outcomes among people living with HIV (PLHIV) re-engaging in care are not well known. METHODS: We conducted a retrospective cohort study of PLHIV who re-engaged in care after being lost to follow-up (LFU), from 2003 to 2019, in Myanmar. We calculated the incidence rates of attrition after re-engagement and performed Cox regression to identify risk factors for attrition. RESULTS: Of 44 131 PLHIV who started antiretroviral treatment, 12 338 (28.0%) were LFU at least once: 7608 (61.6%) re-engaged in care, 4672 (61.4%) with AHD at re-engagement. The death and LFU rates were 2.21-fold (95% CI 1.82 to 2.67) and 1.46-fold (95% CI 1.33 to 1.61) higher among patients who re-engaged with AHD (p>0.001). Death in patients who re-engaged with AHD was associated with male sex (adjusted HR [aHR] 2.63; 95% CI 1.31 to 5.26; p=0.006), TB coinfection (aHR 2.26; 95% CI 1.23 to 4.14; p=0.008) and sex work (aHR 7.49, 95% CI 2.29 to 22.52; p<0.001). History of intravenous drug use was identified as a predictor of being LFU. CONCLUSIONS: Re-engagement in HIV care in Myanmar is frequent and those who re-engage carry a high burden of AHD. As AHD at re-engagement is associated with higher attrition rates, implementation of differentiated interventions that enable earlier linkage to care and prompt identification and management of AHD in this population is necessary.

Middlebrook 7h11 reduces invalid results and turnaround time of phenotypic drug-susceptibility testing of M. tuberculosis.

Background: Phenotypic drug-susceptibility testing (pDST), which relies on growth inhibition in the drug-containing media, remains a challenge for fastidious Mycobacterium tuberculosis complex (MTBc) isolates due to insufficient growth on the growth controls (GC). Middlebrook 7H11 (M7H11) medium contains casein hydrolysate, which may favor the growth of such strains. Method: In this study, we tested whether M7H11 reduces invalid results due to insufficient growth on the GCs and the turnaround time (TAT) of pDST for MTBc compared to Middlebrook 7H10 (M7H10) without affecting the accuracy of the pDST results and how it differs between rifampicin- and isoniazid-susceptible non multi-drug resistant (non-MDR), MDR and MDR with additional resistance to fluoroquinolones (Pre-XDR) MTBc isolates. We compared the proportions of invalid pDST results due to lack of growth on the GCs, TATs of valid parallel drug-susceptibility testings as an indicator of speed of MTBc growth, and colony-forming unit (CFU) count on the most diluted GC of the parallel pDSTs after equal incubation periods as an indicator of growth abundance on M7H11 and M7H10. We also analyzed the agreement between the pDST results of the same drug or drugs in the same drug class, tested in parallel on both media. Results: For MDR and pre-XDR isolates, relative to M7H10, M7H11 significantly reduced the occurrence of invalid pDST results due to insufficient growth on the GCs (odds ratio [OR] = ∞ [95% confidence interval (CI) 1.9-∞], P = 0.004 for MDR, OR = ∞ [95% CI 3.3-∞], P = 0.0001 for pre-XDR) and the TAT of pDSTs (OR = 17 [95% CI 2.6-710.4], P = 0.0001 for MDR, OR = 9.3 [95% CI 4.0-26.5], P < 0.0001 for pre-XDR). The growth abundance of MTBc on M7H11 was significantly higher compared to M7H10 (17 CFU on M7H10 vs. 28 on M7H11), irrespective of drug-resistance profiles. The agreement between the pDST results between the two media was high (Cohen's k > 0.98). Conclusion: Our study findings suggest that M7H11 is preferred over M7H10 for pDSTs of MTBc isolates.

Viraemic-time predicts mortality among people living with HIV on second-line antiretroviral treatment in Myanmar: A retrospective cohort study.

INTRODUCTION: Despite HIV viral load (VL) monitoring being serial, most studies use a cross-sectional design to evaluate the virological status of a cohort. The objective of our study was to use a simplified approach to calculate viraemic-time: the proportion of follow-up time with unsuppressed VL above the limit of detection. We estimated risk factors for higher viraemic-time and whether viraemic-time predicted mortality in a second-line antiretroviral treatment (ART) cohort in Myanmar. METHODS: We conducted a retrospective cohort analysis of people living with HIV (PLHIV) who received second-line ART for a period >6 months and who had at least two HIV VL test results between 01 January 2014 and 30 April 2018. Fractional logistic regression assessed risk factors for having higher viraemic-time and Cox proportional hazards regression assessed the association between viraemic-time and mortality. Kaplan-Meier curves were plotted to illustrate survival probability for different viraemic-time categories. RESULTS: Among 1,352 participants, 815 (60.3%) never experienced viraemia, and 172 (12.7%), 214 (15.8%), and 80 (5.9%) participants were viraemic <20%, 20-49%, and 50-79% of their total follow-up time, respectively. Few (71; 5.3%) participants were ≥80% of their total follow-up time viraemic. The odds for having higher viraemic-time were higher among people with a history of injecting drug use (aOR 2.01, 95% CI 1.30-3.10, p = 0.002), sex workers (aOR 2.10, 95% CI 1.11-4.00, p = 0.02) and patients treated with lopinavir/ritonavir (vs. atazanavir; aOR 1.53, 95% CI 1.12-2.10, p = 0.008). Viraemic-time was strongly associated with mortality hazard among those with 50-79% and ≥80% viraemic-time (aHR 2.92, 95% CI 1.21-7.10, p = 0.02 and aHR 2.71, 95% CI 1.22-6.01, p = 0.01). This association was not observed in those with viraemic-time <50%. CONCLUSIONS: Key populations were at risk for having a higher viraemic-time on second-line ART. Viraemic-time predicts clinical outcomes. Differentiated services should target subgroups at risk for a higher viraemic-time to control both HIV transmission and mortality.

Person-centred care and short oral treatment for rifampicin-resistant tuberculosis improve retention in care in Kandahar, Afghanistan.

OBJECTIVES: To describe the effect of adaptations to a person-centred care with short oral regimens on retention in care for rifampicin-resistant TB (RR-TB) in Kandahar province, Afghanistan. METHODS: The study included people with RR-TB registered in the programme between 01 October 2016 and 18 April 2021. From 19 November 2019, the programme implemented a trial investigating the safety and effectiveness of short oral RR-TB regimens. During the trial, person-centred care was adapted. We included the data from people living with RR-TB treated in the period before and after the care model was adapted and applied Kaplan-Meier statistics to compare rates of retention in care. RESULTS: Of 236 patients registered in the RR-TB programme, 146 (61.9%) were registered before and 90 (38.1%) after the model of care was adapted. Before adaptations enhancing person-centred care, pre-treatment attrition was 23.3% (n = 34/146), whilst under the adapted care model it was 5.6% (n = 5/90). Attrition on treatment was 22.3% (n = 25/112) before adaptations, whilst during the study period none of the participants were lost-to-follow-up on treatment and 3.3% died (n = 3/90). CONCLUSIONS: As person-centred care delivery and treatment regimens were adapted to better fit-specific contextual challenges and the needs of the target population, retention in care improved amongst people with RR-TB in Kandahar, Afghanistan.

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

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

Predictors of virological failure among people living with HIV receiving first line antiretroviral treatment in Myanmar: retrospective cohort analysis.

BACKGROUND: Progress toward the global target for 95% virological suppression among those on antiretroviral treatment (ART) is still suboptimal. We describe the viral load (VL) cascade, the incidence of virological failure and associated risk factors among people living with HIV receiving first-line ART in an HIV cohort in Myanmar treated by the Médecins Sans Frontières in collaboration with the Ministry of Health and Sports Myanmar. METHODS: We conducted a retrospective cohort study, including adult patients with at least one HIV viral load test result and having received of at least 6 months' standard first-line ART. The incidence rate of virological failure (HIV viral load ≥ 1000 copies/mL) was calculated. Multivariable Cox's regression was performed to identify risk factors for virological failure. RESULTS: We included 25,260 patients with a median age of 33.1 years (interquartile range, IQR 28.0-39.1) and a median observation time of 5.4 years (IQR 3.7-7.9). Virological failure was documented in 3,579 (14.2%) participants, resulting in an overall incidence rate for failure of 2.5 per 100 person-years of follow-up. Among those who had a follow-up viral load result, 1,258 (57.1%) had confirmed virological failure, of which 836 (66.5%) were switched to second-line treatment. An increased hazard for failure was associated with age ≤ 19 years (adjusted hazard ratio, aHR 1.51; 95% confidence intervals, CI 1.20-1.89; p < 0.001), baseline tuberculosis (aHR 1.39; 95% CI 1.14-1.49; p < 0.001), a history of low-level viremia (aHR 1.60; 95% CI 1.42-1.81; p < 0.001), or a history of loss-to-follow-up (aHR 1.24; 95% CI 1.41-1.52; p = 0.041) and being on the same regimen (aHR 1.37; 95% CI 1.07-1.76; p < 0.001). Cumulative appointment delay was not significantly associated with failure after controlling for covariates. CONCLUSIONS: VL monitoring is an important tool to improve programme outcomes, however limited coverage of VL testing and acting on test results hampers its full potential. In our cohort children and adolescents, PLHIV with history of loss-to-follow-up or those with low-viremia are at the highest risk of virological failure and might require more frequent virological monitoring than is currently recommended.

Translating drug resistant tuberculosis treatment guidelines to reality in war-torn Kandahar, Afghanistan: A retrospective cohort study.

INTRODUCTION: Afghanistan is affected by one of the world's longest protracted armed conflicts, frequent natural disasters, disease outbreaks and large population movements and it suffers from a high burden of tuberculosis (TB), including rifampicin-resistant TB (RR-TB). The study shows Médecins Sans Frontières' experiences with care for patients with RR-TB in Kandahar Province. We describe the uptake of RR-TB treatment, how World Health Organisation criteria for the choice between the short and an individualized regimen were implemented, and treatment outcomes. METHODS: This is a retrospective cohort analysis of routinely collected data from RR-TB patients enrolled in care from 2016 until 2019. Descriptive analysis was performed to present characteristics of patients and treatment outcomes. Multivariable Cox analysis was performed to identify risk factors for having an unfavourable treatment outcome. RESULTS: Out of 146 enrolled RR-TB patients, 112 (76.7%) started treatment: 41 (36.6%) and 71 (63.4%) with the short and individualized treatment regimen, respectively. Of 82 with results for fluoroquinolone susceptibility, 39 (47.6%) had fluoroquinolone-resistant TB. Seven patients with initially fluoroquinolone-resistant TB and three pregnant women started the short regimen and 18 patients eligible for the short regimen started the injectable-free individualized regimen. Overall, six-month smear and culture conversion were 98.7% and 97.1%, respectively; treatment success was 70.1%. Known initial fluoroquinolone resistance (aHR 3.77, 95%CI:1.53-9.27) but not choice of regimen predicted having an unfavourable outcome. CONCLUSION: Even though criteria for the choice of treatment regimen were not applied strictly, we have achieved acceptable outcomes in this cohort. To expand RR-TB care, treatment regimens should fit provision at primary health care level and take patient preferences into account.

Lessons learned: Retrospective assessment of outcomes and management of patients with advanced HIV disease in a semi-urban polyclinic in Epworth, Zimbabwe.

INTRODUCTION: HIV continues to be one of the leading causes of infectious death worldwide and presentation with advanced HIV disease is associated with increased morbidity and mortality. Recommendations for the management of advanced HIV disease include prompt screening and treatment of opportunistic infections, rapid initiation of ART and intensified adherence support. We present treatment outcomes of a cohort of patients presenting with advanced HIV disease in a semi-urban Zimbabwean polyclinic. METHODS: Retrospective cohort analysis of adult patients enrolled for care at Epworth polyclinic, Zimbabwe between 2007 and end June 2016. Treatment outcomes at 6 and 12 months were recorded. Multivariate logistical regression analysis was undertaken to identify risk factors for presentation with advanced HIV Disease (CD4 count less than 200 cells/mm3 or WHO stage 3 or 4) and risks for attrition at 12 months. RESULTS: 16,007 anti-retroviral therapy naive adult patients were included in the final analysis, 47.4% of whom presented with advanced HIV disease. Patients presenting with advanced HIV disease had a higher mortality rate at 12 months following enrollment compared to early stage patients (5.11% vs 0.45%). Introduction of a package of differentiated care for patients with a CD4 count of less than 100 cells/mm3 resulted in diagnosis of cryptococcal antigenaemia in 7% of patients and a significant increase in the diagnosis of TB, although there was no significant difference in attrition at 6 or 12 months for these patients compared to those enrolled prior to the introduction of the differentiated care. CONCLUSIONS: The burden of advanced HIV disease remained high over the study period in this semi-urban polyclinic in Zimbabwe. Introduction of a package of differentiated care for those with advanced HIV disease increased the diagnosis of opportunistic infections and represents a model of care which can be replicated in other polyclinics in the resource constrained Zimbabwean context.

Implications of differentiated care for successful ART scale-up in a concentrated HIV epidemic in Yangon, Myanmar.

INTRODUCTION: National AIDS Programme in Myanmar has made significant progress in scaling up antiretroviral treatment (ART) services and recognizes the importance of differentiated care for people living with HIV. Indeed, long centred around the hospital and reliant on physicians, the country's HIV response is undergoing a process of successful decentralization with HIV care increasingly being integrated into other health services as part of a systematic effort to expand access to HIV treatment. This study describes implementation of differentiated care in Médecins Sans Frontières (MSF)-supported programmes and reports its outcomes. METHODS: A descriptive cohort analysis of adult patients on antiretroviral treatment was performed. We assessed stability of patients as of 31 December 2014 and introduced an intervention of reduced frequency of physicians' consultations for stable patients, and fast tract ART refills. We measured a number of saved physician's visits as the result of this intervention. Main outcomes, remained under care, death, lost to follow up, treatment failure, were assessed on 31 December 2015 and reported as rates for different stable groups. RESULTS: On 31 December 2014, our programme counted 16, 272 adult patients enrolled in HIV care, of whom 80.34% were stable. The model allowed for an increase in the average number of patients one medical team could care for - from 745 patients in 2011 to 1, 627 in 2014 - and, thus, a reduction in the number of teams needed. An assessment of stable patients enrolled on ART one year after the implementation of the new model revealed excellent outcomes, aggregated for stable patients as 98.7% remaining in care, 0.4% dead, 0.8% lost to follow-up, 0.8% clinical treatment failure and 5.8% with immunological treatment failure. CONCLUSIONS: Implementation of a differentiated model reduced the number of visits between stable clients and physicians, reduced the medical resources required for treatment and enabled integrated treatment of the main co-morbidities. We hope that these findings will encourage other stakeholders to implement innovative models of HIV care in Myanmar, further expediting the scale up of ART services, the decentralization of treatment and the integration of care for the main HIV co-morbidities in this context.

Delivering HIV care in challenging operating environments: the MSF experience towards differentiated models of care for settings with multiple basic health care needs.

INTRODUCTION: Countries in the West and Central African regions struggle to offer quality HIV care at scale, despite HIV prevalence being relatively low. In these challenging operating environments, basic health care needs are multiple, systems are highly fragile and conflict disrupts health care. Médecins Sans Frontières (MSF) has been working to integrate HIV care in basic health services in such settings since 2000. We review the implementation of differentiated HIV care and treatment approaches in MSF-supported programmes in South Sudan (RoSS), Central African Republic (CAR) and Democratic Republic of Congo (DRC). METHODS: A descriptive analysis from CAR, DRC and RoSS programmes reviewing methodology and strategies of HIV care integration between 2010 and 2015 was performed. We describe HIV care models integrated within the provision of general health care and highlight best practices and challenges. RESULTS: Services included provision of general health care, with out-patient care (range between countries 43,343 and 287,163 consultations/year in 2015) and in-patient care (range 1076-16,595 in 2015). By the end of 2015 antiretroviral therapy (ART) initiations reached 12-255 patients/year. A total of 1101 and 1053 patients were on ART in CAR and DRC, respectively. In RoSS 186 patients were on ART when conflict recommenced late in 2013. While ART initiation and monitoring were mostly clinically driven in the early phase of the programmes, DRC implemented CD4 monitoring and progressively HIV viral load (VL) monitoring during study period. Attacks to health care facilities in CAR and RoSS disrupted service provision temporarily. Programmatic challenges include: competing health priorities influencing HIV care and need to integrate within general health services. Differentiated care approaches that support continuity of care in these programmes include simplification of medical protocols, multi-month ART prescriptions, and community strategies such as ART delivery groups, contingency plans and peer support activities. CONCLUSIONS: The principles of differentiated HIV care for high-quality ART delivery can successfully be applied in challenging operating environments. However, success heavily depends on specific adaptations to each setting.

Modelling the effect of short-course multidrug-resistant tuberculosis treatment in Karakalpakstan, Uzbekistan.

BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) is a major threat to global TB control. MDR-TB treatment regimens typically have a high pill burden, last 20 months or more and often lead to unsatisfactory outcomes. A 9-11 month regimen with seven antibiotics has shown high success rates among selected MDR-TB patients in different settings and is conditionally recommended by the World Health Organization. METHODS: We construct a transmission-dynamic model of TB to estimate the likely impact of a shorter MDR-TB regimen when applied in a low HIV prevalence region of Uzbekistan (Karakalpakstan) with high rates of drug resistance, good access to diagnostics and a well-established community-based MDR-TB treatment programme providing treatment to around 400 patients. The model incorporates acquisition of additional drug resistance and incorrect regimen assignment. It is calibrated to local epidemiology and used to compare the impact of shorter treatment against four alternative programmatic interventions. RESULTS: Based on empirical outcomes among MDR-TB patients and assuming no improvement in treatment success rates, the shorter regimen reduced MDR-TB incidence from 15.2 to 9.7 cases per 100,000 population per year and MDR-TB mortality from 3.0 to 1.7 deaths per 100,000 per year, achieving comparable or greater gains than the alternative interventions. No significant increase in the burden of higher levels of resistance was predicted. Effects are probably conservative given that the regimen is likely to improve success rates. CONCLUSIONS: In addition to benefits to individual patients, we find that shorter MDR-TB treatment regimens also have the potential to reduce transmission of resistant strains. These findings are in the epidemiological setting of treatment availability being an important bottleneck due to high numbers of patients being eligible for treatment, and may differ in other contexts. The high proportion of MDR-TB with additional antibiotic resistance simulated was not exacerbated by programmatic responses and greater gains may be possible in contexts where the regimen is more widely applicable.

Risk factors for unstructured treatment interruptions and association with survival in low to middle income countries.

BACKGROUND: Antiretroviral therapy (ART) treatment interruptions lead to poor clinical outcomes with unplanned or unstructured TIs (uTIs) likely to be underreported. This study describes; uTIs, their risk factors and association with survival. METHODS: Analysis of ART programmatic data from 11 countries across Asia and Africa between 2003 and 2013 where an uTI was defined as a ≥90-day patient initiated break from ART calculated from the last day the previous ART prescription would have run out until the date of the next ART prescription. Factors predicting uTI were assessed with a conditional risk-set multiple failure time-to-event model to account for repeated events per subject. Association between uTI and mortality was assessed using Cox proportional hazards, with a competing risks extension to test for the influence of lost to follow-up (LTFU). RESULTS: 40,632 patients were included from 11 countries across 33 sites (17 Africa, 16 Asia). Median duration of follow-up was 1.61 years (IQR 0.54-3.31 years), 3386 (8.3 %) patients died, and 3453 (8.5 %) were LTFU. There were 14,817 uTIs, with 10,162 (25 %) patients having more than one uTI. In the adjusted model males were at lower risk of uTI (aHR 0.94, p < 0.01, and age 20-59 was protective compared to <20 years (20-39 years aHR 0.87, p < 0.01; 40-59 years aHR 0.86, p < 0.01). Preserved immune function, as measured by higher CD4 cell count, was associated with a reduced rate of uTI compared to CD4 <200 cells/µL (CD4 200-350 cells/µL aHR 0.89, p < 0.01; CD4 >350 cells/µL aHR 0.87, p < 0.01), whereas advanced clinical disease was associated with increased uTI rate (WHO stage 3 aHR 1.10, p < 0.01; WHO stage 4 aHR 1.21, p < 0.01). There was no relationship between uTI and mortality after adjusting for disease status and considering LTFU as a competing risk. CONCLUSIONS: uTIs were frequent in people in ART programs in low-middle income countries and associated with younger age, female gender and advanced HIV. uTI did not predict survival when loss to follow-up was considered a competing risk. Further evaluation of uTI predictors and interventions to reduce their occurrence is warranted.

Risk factors for mortality during antiretroviral therapy in older populations in resource-limited settings.

INTRODUCTION: An increasing proportion of adult patients initiating antiretroviral therapy (ART) in resource-limited settings are aged > 50 years. Older populations on ART appear to have heightened risk of death, but little is known about factors influencing mortality in this population. METHODS: We performed a retrospective observational multisite cohort study including all adult patients (≥ 15 years) initiating ART between 2003 and 2013 in programmes supported by Médecins Sans Frontières across 12 countries in Asia, Africa and Europe. Patients were stratified into two age groups, > 50 years and 15 to 50 years. A Cox proportional hazards model was used to explore factors associated with mortality. RESULTS: The study included 41,088 patients: 2591 (6.3%) were aged > 50 years and 38,497 (93.7%) were aged 15 to 50 years. The mortality rate was significantly higher in the age group > 50 years [367 (14.2%) deaths; mortality rate 7.67 deaths per 100 person-years (95% confidence interval, CI: 6.93 to 8.50)] compared to the age group 15 to 50 years [3788 (9.8%) deaths; mortality rate 4.18 deaths per 100 person-years (95% CI: 4.05 to 4.31)], p < 0.0001. Higher CD4 levels at baseline were associated with significantly reduced mortality rates in the 15 to 50 age group but this association was not seen in the > 50 age group. WHO Stage 4 conditions were more strongly associated with increased mortality rates in the 15 to 50 age group compared to populations > 50 years. WHO Stage 3 conditions were associated with an increased mortality rate in the 15 to 50 age group but not in the > 50 age group. Programme region did not affect mortality rates in the > 50 age group; however being in an Asian programme was associated with a 36% reduced mortality rate in populations aged 15 to 50 years compared to being in an African programme. There was a higher overall incidence of Stage 3 WHO conditions in people > 50 years (12.8/100 person-years) compared to those 15 to 50 years (8.1/100 person-years) (p < 0.01). The rate of Stage 4 WHO conditions was similar (5.8/100 versus 6.1/100 respectively, p = 0.52). Mortality rates on ART associated with the majority of specific WHO conditions were similar between the 15 to 50 and > 50 age groups. CONCLUSIONS: Older patients on ART in resource-limited settings have increased mortality rates, but compared to younger populations this appears to be less influenced by baseline CD4 count and WHO clinical stage. HIV treatment programmes in resource-limited settings need to consider risk factors associated with mortality on ART in older populations, which may differ to those related to younger adults.