Search

Abstract Background Despite HIV's evolution to a chronic disease, the burden of advanced HIV disease (AHD, defined as a CD4 count of

BackgroundEmerging evidence suggests that shortened, simplified treatment regimens for rifampicin-resistant tuberculosis (RR-TB) can achieve comparable end-of-treatment (EOT) outcomes to longer regimens. We compared a 6-month regimen containing bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) to a standard of care strategy using a 9- or 18-month regimen depending on whether fluoroquinolone resistance (FQ-R) was detected on drug susceptibility testing (DST).Methods and findingsThe primary objective was to determine whether 6 months of BPaLM is a cost-effective treatment strategy for RR-TB. We used genomic and demographic data to parameterize a mathematical model estimating long-term health outcomes measured in quality-adjusted life years (QALYs) and lifetime costs in 2022 USD ($) for each treatment strategy for patients 15 years and older diagnosed with pulmonary RR-TB in Moldova, a country with a high burden of TB drug resistance. For each individual, we simulated the natural history of TB and associated treatment outcomes, as well as the process of acquiring resistance to each of 12 anti-TB drugs. Compared to the standard of care, 6 months of BPaLM was cost-effective. This strategy was estimated to reduce lifetime costs by $3,366 (95% UI: [1,465, 5,742] p < 0.001) per individual, with a nonsignificant change in QALYs (-0.06; 95% UI: [-0.49, 0.03] p = 0.790). For those stopping moxifloxacin under the BPaLM regimen, continuing with BPaL plus clofazimine (BPaLC) provided more QALYs at lower cost than continuing with BPaL alone. Strategies based on 6 months of BPaLM had at least a 93% chance of being cost-effective, so long as BPaLC was continued in the event of stopping moxifloxacin. BPaLM for 6 months also reduced the average time spent with TB resistant to amikacin, bedaquiline, clofazimine, cycloserine, moxifloxacin, and pyrazinamide, while it increased the average time spent with TB resistant to delamanid and pretomanid. Sensitivity analyses showed 6 months of BPaLM to be cost-effective across a broad range of values for the relative effectiveness of BPaLM, and the proportion of the cohort with FQ-R. Compared to the standard of care, 6 months of BPaLM would be expected to save Moldova's national TB program budget $7.1 million (95% UI: [1.3 million, 15.4 million] p = 0.002) over the 5-year period from implementation. Our analysis did not account for all possible interactions between specific drugs with regard to treatment outcomes, resistance acquisition, or the consequences of specific types of severe adverse events, nor did we model how the intervention may affect TB transmission dynamics.ConclusionsCompared to standard of care, longer regimens, the implementation of the 6-month BPaLM regimen could improve the cost-effectiveness of care for individuals diagnosed with RR-TB, particularly in settings with a high burden of drug-resistant TB. Further research may be warranted to explore the impact and cost-effectiveness of shorter RR-TB regimens across settings with varied drug-resistant TB burdens and national income levels.

Abstract Background Adolescents who have acquired HIV perinatally (ALHIV) face unique challenges in taking lifelong antiretroviral therapy (ART), but little is known about what factors affect their adherence over the course of their lifelong treatment journey. Methods We conducted a qualitative study with ALHIV who had periods of poor adherence to ART in KwaZulu-Natal, South Africa using Participant-generated Visual Methodologies (PVM). Participants used photography to represent their perspectives and experiences. Results 14 individuals participated in the research process. We developed a framework and identified four social domains which combined with the adolescent’s own experiences and sense of self to either support or undermine adherence. Periods of non-adherence were reported by all participants. Participants described the importance of supportive relationships and households as well as the benefits of ART as supporting adherence. The fear of inadvertent disclosure of their HIV status and the side-effects of ART were barriers to adherence. Possible interventions to support adolescents in their treatment journey are identified. Conclusions Current models of adherence support fail to address the challenges to lifelong therapy ALHIV face. Ongoing education and honest communication with health care providers, interventions that build resilience together with peer support, have the potential to improve adherence in ALHIV.

Abstract Background People living with HIV need to take lifelong, combination antiretroviral therapy (cART), but there have been only limited explorations of how factors affecting adherence can change over the course of an individual’s lifetime. Methods We carried out a qualitative study of men and women living with HIV in KwaZulu, Natal, South Africa who were prescribed cART and who had periods of higher and lower adherence. Results 18 individuals participated in open-ended interviews. Using a dynamic theory of adherence, we identified factual, relational, and experiential factors that were associated with adherence and non-adherence to cART. Periods of non-adherence were commonly reported. Participants described relationships and experiences as being important influences on their ability to adhere to cART throughout their treatment journeys. Conclusions Periods of non-adherence to cART are common. While many cART counseling models are based on conveying facts to people prescribed cART, providing opportunities for supportive relationship where people can process their varied experiences is likely important to maintaining health for people living with HIV.

An estimated 19 million people are infected with rifampicin-resistant/multidrug-resistant strains of tuberculosis worldwide. There is little done to prevent these individuals from becoming sick with RR/MDR-TB, a disease that is associated with high rates of morbidity, mortality, and suffering. There are multiple phase III trials currently being conducted to assess the effectiveness of treatment of infection (i.e., “preventive therapy”) for RR/MDR-TB, but their results are likely years away. In the meantime, there is sufficient evidence to support a more comprehensive management of people who have been exposed to RR/MDR-TB so that they can maintain their health. We present a patient scenario and share our experience in implementing a systematic post-exposure management program in South Africa with the goal of inspiring similar programs in other high-burden RR/MDR-TB settings.

ObjectiveThe disease COVID-19 has caused a widespread global pandemic with ~3. 93 million deaths worldwide. In this work, we present three models—radiomics (MRM), clinical (MCM), and combined clinical–radiomics (MRCM) nomogram to predict COVID-19-positive patients who will end up needing invasive mechanical ventilation from the baseline CT scans.MethodsWe performed a retrospective multicohort study of individuals with COVID-19-positive findings for a total of 897 patients from two different institutions (Renmin Hospital of Wuhan University, D1 = 787, and University Hospitals, US D2 = 110). The patients from institution-1 were divided into 60% training, D1T (N = 473), and 40% test set D1V (N = 314). The patients from institution-2 were used for an independent validation test set D2V (N = 110). A U-Net-based neural network (CNN) was trained to automatically segment out the COVID consolidation regions on the CT scans. The segmented regions from the CT scans were used for extracting first- and higher-order radiomic textural features. The top radiomic and clinical features were selected using the least absolute shrinkage and selection operator (LASSO) with an optimal binomial regression model within D1T.ResultsThe three out of the top five features identified using D1T were higher-order textural features (GLCM, GLRLM, GLSZM), whereas the last two features included the total absolute infection size on the CT scan and the total intensity of the COVID consolidations. The radiomics model (MRM) was constructed using the radiomic score built using the coefficients obtained from the LASSO logistic model used within the linear regression (LR) classifier. The MRM yielded an area under the receiver operating characteristic curve (AUC) of 0.754 (0.709–0.799) on D1T, 0.836 on D1V, and 0.748 D2V. The top prognostic clinical factors identified in the analysis were dehydrogenase (LDH), age, and albumin (ALB). The clinical model had an AUC of 0.784 (0.743–0.825) on D1T, 0.813 on D1V, and 0.688 on D2V. Finally, the combined model, MRCM integrating radiomic score, age, LDH and ALB, yielded an AUC of 0.814 (0.774–0.853) on D1T, 0.847 on D1V, and 0.771 on D2V. The MRCM had an overall improvement in the performance of ~5.85% (D1T: p = 0.0031; D1Vp = 0.0165; D2V: p = 0.0369) over MCM.ConclusionThe novel integrated imaging and clinical model (MRCM) outperformed both models (MRM) and (MCM). Our results across multiple sites suggest that the integrated nomogram could help identify COVID-19 patients with more severe disease phenotype and potentially require mechanical ventilation.

Abstract Background Patient-centered care is pillar 1 of the “End TB” strategy, but little has been documented in the literature about what this means for people living with rifampicin-resistant (RR-TB). Optimizing care for such individuals requires a better understanding of the challenges they face and the support they need. Methods A qualitative study was done among persons living with RR-TB and members of their support network. A purposive sample was selected from a larger study population and open-ended interviews were conducted using a semi-standard interview guide. Interviews were recorded and transcribed and the content analyzed using an iterative thematic analysis based in grounded theory. Results 16 participants were interviewed from three different provinces. Four distinct periods in which support was needed were identified: 1) pre-diagnosis; 2) pre-treatment; 3) treatment; and 4) post-treatment. Challenges common in all four periods included: socioeconomic issues, centralized care, and the need for better counseling at multiple levels. Conclusions Beyond being a “very humiliating illness”, RR-TB robs people of their physical, social, economic, psychological, and emotional well-being far beyond the period when treatment is being administered. Efforts to tackle these issues are as important as new drugs and diagnostics in the fight against TB.

BackgroundThere are limited data on the experiences of children being treated for drug-resistant tuberculosis (DR-TB), and most work in the area has been done with older children and adolescents. Comprehensive explorations of the caregiver experiences in this area are also lacking.ObjectiveTo describe the experiences of being treated for drug-resistant tuberculosis of children and their caregivers.MethodsThis was a qualitative study done using focus group discussions (FGDs) among three different groups of participants: 1) health care providers involved in the care of children being treated for DR-TB (including physicians, nurses, and pharmacists)-herein referred to as providers; 2) household caregivers of children being treated for DR-TB-herein referred to as caregivers; and 3) children who were being treated for DR-TB-herein referred to as children. The population was a convenience sample and included children hospitalized between January 1, 2018, and June 30, 2020, ages 0-14 years old, as well as their caregivers and providers. Focus group transcripts and notes were analysed using a thematic network analysis based in grounded theory The analysis was iterative and the coding system developed focused on "stressful experiences" as well as ways to address them along the diagnostic and treatment journey. This paper follows the COREQ guidelines.Results16 children between the ages 7 and 14 years participated in 5 FGDs, 30 caregivers participated in 7 FGDs, and 12 providers participated in 3 FDGs. Data from the children and the caregivers were the focus of this analysis, although some themes were informed by the discussions with the providers as well. In general, it was reported that for a child diagnosed with DR-TB, there is a lived experience of stress that impacts their physical, mental, and social well-being. These pediatric patients and their families therefore develop strategies for coping with these disruptions to their lives. In general, there were major disruptive experiences that resulted from the process around receiving a diagnosis of DR-TB and second distinct set of stressful experiences that occurred during the treatment of DR-TB once the diagnosis had been made. These stresses occur in the physical, mental, and social realms, and families develop multiple strategies to cope with them, demonstrating resilience in the face of this disease.ConclusionAddressing the stresses experienced by children and their caregivers through child-friendly DR-TB testing, treatment, and counseling is not only essential for ending TB but also for enacting a human-rights based approach to child health in general. Children with DR-TB are a vulnerable population, and they have often been the last to benefit from advances in general pediatric care and in DR-TB care more specifically.

BackgroundLimited access to drug-susceptibility tests (DSTs) and delays in receiving DST results are challenges for timely and appropriate treatment of multi-drug resistant tuberculosis (TB) in many low-resource settings. We investigated whether data collected as part of routine, national TB surveillance could be used to develop predictive models to identify additional resistance to fluoroquinolones (FLQs), a critical second-line class of anti-TB agents, at the time of diagnosis with rifampin-resistant TB.Methods and findingsWe assessed three machine learning-based models (logistic regression, neural network, and random forest) using information from 540 patients with rifampicin-resistant TB, diagnosed using Xpert MTB/RIF and notified in the Republic of Moldova between January 2018 and December 2019. The models were trained to predict the resistance to FLQs based on demographic and TB clinical information of patients and the estimated district-level prevalence of resistance to FLQs. We compared these models based on the optimism-corrected area under the receiver operating characteristic curve (OC-AUC-ROC). The OC-AUC-ROC of all models were statistically greater than 0.5. The neural network model, which utilizes twelve features, performed best and had an estimated OC-AUC-ROC of 0.87 (0.83,0.91), which suggests reasonable discriminatory power. A limitation of our study is that our models are based only on data from the Republic of Moldova and since not externally validated, the generalizability of these models to other populations remains unknown.ConclusionsModels trained on data from phenotypic surveillance of drug-resistant TB can predict resistance to FLQs based on patient characteristics at the time of diagnosis with rifampin-resistant TB using Xpert MTB/RIF, and information about the local prevalence of resistance to FLQs. These models may be useful for informing the selection of antibiotics while awaiting results of DSTs.

Summary: Background: South Africa has a high burden of rifampicin-resistant tuberculosis (including multidrug-resistant [MDR] tuberculosis), with increasing rifampicin-monoresistant (RMR) tuberculosis over time. Resistance acquisition during first-line tuberculosis treatment could be a key contributor to this burden, and HIV might increase the risk of acquiring rifampicin resistance. We assessed whether HIV during previous treatment was associated with RMR tuberculosis and resistance acquisition among a retrospective cohort of patients with MDR or rifampicin-resistant tuberculosis. Methods: In this retrospective cohort study, we included all patients routinely diagnosed with MDR or rifampicin-resistant tuberculosis in Khayelitsha, Cape Town, South Africa, between Jan 1, 2008, and Dec 31, 2017. Patient-level data were obtained from a prospective database, complemented by data on previous tuberculosis treatment and HIV from a provincial health data exchange. Stored MDR or rifampicin-resistant tuberculosis isolates from patients underwent whole-genome sequencing (WGS). WGS data were used to infer resistance acquisition versus transmission, by identifying genomically unique isolates (single nucleotide polymorphism threshold of five). Logistic regression analyses were used to assess factors associated with RMR tuberculosis and genomic uniqueness. Findings: The cohort included 2041 patients diagnosed with MDR or rifampicin-resistant tuberculosis between Jan 1, 2008, and Dec 31, 2017; of those, 463 (22·7%) with RMR tuberculosis and 1354 (66·3%) with previous tuberculosis treatment. In previously treated patients, HIV positivity during previous tuberculosis treatment versus HIV negativity (adjusted odds ratio [OR] 2·07, 95% CI 1·35–3·18), and three or more previous tuberculosis treatment episodes versus one (1·96, 1·21–3·17) were associated with RMR tuberculosis. WGS data showing MDR or rifampicin-resistant tuberculosis were available for 1169 patients; 360 (30·8%) isolates were identified as unique. In previously treated patients, RMR tuberculosis versus MDR tuberculosis (adjusted OR 4·96, 3·40–7·23), HIV positivity during previous tuberculosis treatment (1·71, 1·03–2·84), and diagnosis in 2013–17 (1·42, 1·02–1·99) versus 2008–12, were associated with uniqueness. In previously treated patients with RMR tuberculosis, HIV positivity during previous treatment (adjusted OR 5·13, 1·61–16·32) was associated with uniqueness as was female sex (2·50 [1·18–5·26]). Interpretation: These data suggest that HIV contributes to rifampicin-resistance acquisition during first-line tuberculosis treatment and that this might be driving increasing RMR tuberculosis over time. Large-scale prospective cohort studies are required to further quantify this risk. Funding: Swiss National Science Foundation, South African National Research Foundation, and Wellcome Trust.

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 (

Background There are few data on the on post-treatment experiences of people who have been successfully treated for rifampicin-resistant (RR-)TB. Objective To describe the experiences and impact of RR-TB disease and therapy on post-treatment life of individuals who were successfully treated. Methods In this qualitative study in-depth interviews were conducted among a purposively selected sample from a population of individuals who were successfully treated for RR-TB between January 2008 and December 2018. Interview transcripts and notes were analysed using a thematic network analysis which included grounded theory and a framework for understanding pathophysiological mechanisms for post-TB morbidity and mortality. The analysis was iterative and the coding system developed focused on disease, treatment and post-treatment experiences of individuals. This paper follows the COREQ guidelines. Results For all 12 participants interviewed, the development of RR-TB disease, its diagnosis and the subsequent treatment were a major disruption to their lives as well as a transformative experience. On diagnosis of RR-TB disease, participants entered a liminal period in which their lives were marked with uncertainty and dominated by physical and mental suffering. Irrespective of how long ago they had completed their treatment, they all remembered with clarity the signs and symptoms of the disease and the arduous treatment journey. Post-treatment participants reported physical, social, psychological and economic changes as consequences of their RR-TB disease and treatment. Many participants reported a diminished ability to perform physical activities and, once discharged from the RR-TB hospital, inadequate physical rehabilitation. For some, these physical limitations impacted on their social life, and ultimately on their psychological health as well as on their ability to earn money and support their families. Conclusion The experiences and impact of RR-TB disease and therapy on post-treatment life of individuals successfully treated, highlights gaps in the current health care system that need to be addressed to improve the life of individuals post-treatment. A more holistic and long-term view of post-TB health, including the provision of comprehensive medical and social services for post-treatment care of physical ailments, social re-integration and the mitigation of the perceived fear and risk of getting TB again could be a central part of person-centred TB care.

Background: Limited data exist on the use of bedaquiline and delamanid in adolescents with rifampicin-resistant tuberculosis (RR-TB). We describe RR-TB treatment of adolescents (10–19 years) with injectable-free regimens containing these drugs in Khayelitsha, South Africa. Methods: This retrospective study included adolescents initiating injectable-free RR-TB treatment regimens containing bedaquiline and/or delamanid from February 2015 to June 2018. We report adverse events (AEs) of interest, sputum culture conversion (SCC), and final end-of-treatment outcomes. Findings: Twenty-two patients were included; median age at treatment initiation was 17 years (interquartile range [IQR] 15-18), and six (27%) were HIV-positive (median CD4 count 191 cells/mm3 [IQR 157-204]). Eight (36%) patients had RR-TB with fluoroquinolone resistance; ten (45%), eight (36%), and four (18%) patients received regimens containing bedaquiline, delamanid, or the combination of bedaquiline and delamanid, respectively. The median durations of exposure to bedaquiline and delamanid were 5·6 (IQR 5·5-8·4) and 9·4 (IQR 5·9-14·4) months, respectively. There were 49 AEs of interest which occurred in 17 (77%) patients. Fourteen (64%) patients had pulmonary TB with positive sputum cultures at bedaquiline and/or delamanid initiation; among these SCC at month 6 was 79%. Final end-of-treatment outcomes for the 22 adolescent were: 17 (77%) successfully treated, two (9%) lost-to-follow-up, two (9%) treatment failed, and one (5%) died. Interpretation: This study found that injectable-free regimens containing bedaquiline and/or delamanid in a programmatic setting were effective and well tolerated in adolescents and should be routinely provided for RR-TB treatment in this age group as recommended by the World Health Organisation.

People exposed to COVID-19 have a risk of developing disease, and health care workers are at risk at a time when they are badly needed during a health care crisis. Hydroxychloroquine and chloroquine have been used as treatment and are being considered as prophylaxis. Our patient developed COVID-19 while on hydroxychloroquine and although more work is needed, this calls into question the role of these medications as preventive therapy.

BackgroundThere are few data on the on the care experiences of pregnant women with rifampicin-resistant TB.ObjectiveTo describe the treatment journeys of pregnant women with RR-TB-including how their care experiences shape their identities-and identify areas in which tailored interventions are needed.MethodsIn this qualitative study in-depth interviews were conducted among a convenience sample from a population of pregnant women receiving treatment for RR-TB. This paper follows COREQ guidelines. A thematic network analysis using an inductive approach was performed to analyze the interview transcripts and notes. The analysis was iterative and a coding system developed which focused on the care experiences of the women and how these experiences affected their perceptions of themselves, their children, and the health care system in which treatment was received.ResultsSeventeen women were interviewed. The women described multiple challenges in their treatment journeys which required them to demonstrate sustained resilience (i.e. to "be brave"). Care experiences required them to negotiate seemingly contradictory identities as both new mothers-"givers of life"-and RR-TB patients facing a complicated and potentially deadly disease. In terms of their "pregnancy identity" and "RR-TB patient identity" that emerged as part of their care experiences, four key themes were identified that appeared to have elements that were contradictory to one another (contradictory areas). These included: 1) the experience of physical symptoms or changes; 2) the experience of the "mothering" and "patient" roles; 3) the experience of the care they received for their pregnancy and their RR-TB; and 4) the experience of community engagement. There were also three areas that overlapped with both roles and during which identity was negotiated/reinforced and they included: 1) faith; 2) socioeconomic issues; and 3) long-term concerns over the child's health. At times, the health care system exacerbated these challenges as the women were not given the support they needed by health care providers who were ill-informed or angry and treated the women in a discriminatory fashion. Left to negotiate this confusing time period, the women turned to faith, their own mothers, and the fathers of their unborn children.ConclusionThe care experiences of the women who participated in this study highlight several gaps in the current health care system that must be better addressed in both TB and perinatal services in order to improve the therapeutic journeys for pregnant women with RR-TB and their children. Suggestions for optimizing care include the provision of integrated services, including specialized counseling as well as training for health care providers; engagement of peer support networks; provision of socioeconomic support; long-term medical care/follow-up for children born to women who were treated for RR-TB; and inclusion of faith-based services in the provision of care.

Substance use (SU) is associated with poor rifampicin-resistant tuberculosis (RR-TB) treatment outcomes. In 2017, a SBIRT (SU screening-brief intervention-referral to treatment) was integrated into routine RR-TB care in Khayelitsha, South Africa. This was a retrospective study of persons with RR-TB who were screened for SU between 1 July 2018 and 30 September 2020 using the ASSIST (Alcohol, Smoking and Substance Involvement Screening Test). Here we describe outcomes from this program. Persons scoring moderate/high risk received a brief intervention and referral to treatment. Overall, 333 persons were initiated on RR-TB treatment; 38% (n = 128) were screened for SU. Of those, 88% (n = 113/128) reported SU; 65% (n = 83/128) had moderate/high risk SU. Eighty percent (n = 103/128) reported alcohol use, of whom 52% (n = 54/103) reported moderate/high risk alcohol use. Seventy-seven persons were screened for SU within ≤2 months of RR-TB treatment initiation, of whom 69%, 12%, and 12% had outcomes of treatment success, loss to follow-up and death, respectively. Outcomes did not differ between persons with no/low risk and moderate/high risk SU or based on the receipt of naltrexone (p > 0.05). SU was common among persons with RR-TB; there is a need for interventions to address this co-morbidity as part of “person-centered care”. Integrated, holistic care is needed at the community level to address unique challenges of persons with RR-TB and SU.

The health needs of adolescents and young adults (AYAs) have been neglected in tuberculosis (TB) care, control, and research. AYAs, who are distinct from younger children and older adults, undergo dynamic physical, psychological, emotional, cognitive, and social development. Five domains of adolescent well-being are crucial to a successful transition between childhood and adulthood: (1) Good health; (2) connectedness and contribution to society; (3) safety and a supportive environment; (4) learning, competence, education, skills, and employability; and (5) agency and resilience. This review summarizes the evidence of the impact of TB disease and treatment on these five domains of AYA well-being.

Drug-resistant forms of tuberculosis (DR-TB) are a significant cause of global morbidity and mortality and the treatment of DR-TB is characterized by long and toxic regimens that result in low rates of cure. There are few formal studies documenting the quality of DR-TB treatment services provided globally, but the limited data that do exist show there is a quality crisis in the field. This paper reviews current issues impacting quality of care in DR-TB, including within the areas of patient-centeredness, safety, effectiveness and equity. Specific issues affecting DR-TB quality of care include: 1) the use of regimens with limited efficacy, significant toxicity, and high pill burden; 2) standardized treatment without drug susceptibility testing; 3) non-quality assured medications and drug stock outs; 4) lack of access to newer and repurposed drugs; 5) high rates of adverse events coupled with minimal monitoring and management; 6) care provided by multiple providers in the private sector; 7) depression, anxiety, and stress; and 8) stigma and discrimination. The paper discusses potential ways to improve quality in each of these areas and concludes that many of these issues arise from the traditional “public health approach” to TB and will only transformed when a human-rights based approach is put into practice. Keywords: Tuberculosis, Quality, Drug resistance, Human rights

Peripheral neuropathy (PN) is a serious condition affecting the nerves that is commonly seen in patients with tuberculosis (TB). Causes of PN in patients with TB are multiple, and can include TB itself, other co-morbid conditions, such as Human Immune-deficiency virus (HIV) disease, malnutrition, or diabetes mellitus (DM), and several anti-tuberculous medications. The condition can manifest with a variety of symptoms, and a diagnosis can usually be made on a clinical basis. Treatment and prognosis of PN vary depending on the underlying cause, but often the condition can lead to permanent disability in individuals with TB. For this reason, primary prevention is key as is early identification and management of symptoms. Treatment can include withdrawal of possible offending agents, vitamin supplementation, physical therapy, analgesics, and targeted agents, including tricyclic antidepressants, selective serotonin reuptake inhibitors, and gabapentin. Additional research is needed to better describe the morbidity and disability associated with PN in persons with TB and to improve management strategies for persons at risk for and affected by this condition. Case review: RM is a 47 year-old man who is in his third month of treatment for drug-resistant TB (DR-TB). His treatment regimen consists of kanamycin (1 gm intramuscular daily), levofloxacin (1000 mg by mouth daily), cycloserine (750 mg by mouth daily), ethionamide (750 mg by mouth daily), pyrazinamide (1500 mg by mouth daily), and Para-Amino Salicylate (12 gm by mouth daily). He is HIV-infected with a CD4 count of 470 cell/µl and on a stable antiretroviral therapy regimen of tenofovir, lamivudine, and efavirenz, which he started 8 weeks ago. He works in a platinum mine, denies smoking, reports drinking beer “on the weekend” and denies other drugs. He presents for his 3 month clinical visit for his DR-TB follow-up and states he is doing well, but he does report some “burning” in the bottom of his feet.

BackgroundAn 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 findingsTo 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 ConclusionsThis 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.

Little is known about the treatment experiences of pregnant women with rifampin-resistant tuberculosis. We conducted qualitative interviews with 10 women who had this condition; 9 reported facing discrimination from healthcare providers. Our findings underscore an urgent need to ensure a human-rights–based, patient-centered approach for women with rifampin-resistant tuberculosis who are pregnant.

Multidrug-resistant tuberculosis (MDR-TB) is on the rise, and is difficult to treat. The approval of two new drugs, bedaquiline and delamanid, and growing evidence for the use of linezolid, offer renewed hope for addressing MDR-TB. However, access to these medicines remains a significant challenge. These drugs have not been registered for TB in most settings; barriers to preapproval access persist; and high pricing and intellectual property restrictions limit access. Many unanswered research questions about optimal use of these drugs also limit access, particularly for vulnerable populations. This review outlines challenges in accessing drugs encountered from the perspective of clinicians, patients and affected communities, and offers potential solutions.

Previous research has documented an increased risk of subfertility in areas of sub-Saharan Africa, as well as an ecological association between urogenital schistosomiasis prevalence and decreased fertility. This pilot project examined reproductive patterns and the potential effects of childhood urogenital Schistosoma haematobium infection and individual treatment experience on adult subfertility among women who were long-term residents in an S. haematobium-endemic region of coastal Kenya.We analyzed findings from 162 in-depth interviews with women of childbearing age in a rural, coastal community, linking them, if possible, to their individual treatment records from previous multi-year longitudinal studies of parasitic infections. Reproductive histories indicated a much local higher local rate of subfertility (44%) than worldwide averages (8-12%). Although, due to the very high regional prevalence of schistosomiasis, a clear relationship could not be demonstrated between a history of S. haematobium infection and adult subfertility, among a convenience sub-sample of 61 women who had received documented treatment during previous interventional trials, a significant association was found between age at first anti-schistosomal treatment and later fertility in adulthood, with those women treated before age 21 significantly less likely to have subfertility (P = 0.001).The high subfertility rate documented in this pilot study suggests the importance of programs to prevent and treat pelvic infections in their early stages to preclude reproductive tract damage. The available documented treatment data also suggest that early anti-schistosomal treatment may prevent the fertility-damaging effects of urogenital schistosomiasis, and lend support for programs that provide universal treatment of children in S. haematobium-endemic regions.

The past decade has seen the emergence of new diagnostics and drugs for tuberculosis, a disease that kills over 1.8 million people each year. However, these new tools are yet to reach scale, and access remains a major challenge for patients in low and middle income countries. Urgent action is needed if we are committed to ending the TB epidemic. This means raising the level of ambition, embracing innovation, increasing financial investments, addressing implementation gaps, and ensuring that new technologies reach those who need them to survive. Otherwise, the promise of innovative technologies will never be realized.

Two new drugs—bedaquiline and delamanid—have recently been approved by stringent regulatory authorities to treat multidrug-resistant tuberculosis (TB) and recommended by the World Health Organization for use under defined programmatic conditions. Introducing the medications in TB programs worldwide has not kept pace with the need for these drugs. In response, the DR-TB STAT (Drug-Resistant TB Scale-up Treatment Action Team) task force was formed in April 2015 to monitor progress and help overcome challenges. Information was collected from multiple sources and assessed monthly. Some progress has been made in introducing bedaquiline: as of October 2015, a total of 1,258 persons were on the medication under programmatic conditions. For delamanid, >100 patients, but few under programmatic conditions, have received the medication. Coordinated global action might help assist making these medications accessible for persons who need them most.

PROBLEM: The category II retreatment regimen for management of tuberculosis in previously treated patients was first introduced in the early 1990s. It consists of 8 months of total therapy with the addition of streptomycin to standard first-line medications. A review of 6500 patients on category II therapy in Georgia showed poor outcomes and high rates of streptomycin resistance. APPROACH: The National Tuberculosis Program used an evidence-based analysis of national data to convince policy-makers that category II therapy should be eliminated from national guidelines in Georgia. LOCAL SETTING: The World Health Organization tuberculosis case-notification rate in Georgia is 102 per 100 000 population. All patients receive culture and drug susceptibility testing as a standard part of tuberculosis diagnosis. In 2009, routine surveillance found multidrug-resistant tuberculosis in 10.6% of newly diagnosed patients and 32.5% of previously treated cases. RELEVANT CHANGES: Category II retreatment regimen is no longer used in Georgia. Treatment is guided by results of drug susceptibility testing - using rapid, molecular tests where possible - for all previously treated tuberculosis patients. LESSONS LEARNT: There was little resistance to policy change because the review was initiated and led by the National Tuberculosis Program. This experience can serve as a successful model for other countries to make informed decisions about the use of category II therapy.

El tratamiento de la tuberculosis pulmonar (TB) es esencialmente farmacológico, pero debido a la aparición de resistenciaa drogas, el tratamiento se ha dificultado. En ese contexto la cirugía pulmonar es una importante estrategia coadyuvantepara el tratamiento de la tuberculosis multidrogo resistente (TB MDR). Objetivo. Describir las características clínicas,resultados y complicaciones en una serie de 304 pacientes con TB MDR sometidos a terapia quirúrgica. Materiales ymétodos. Entre mayo de 1999 y enero del 2007 un total de 336 intervenciones quirúrgicas fueron realizadas en 304pacientes, pertenecientes al Programa Nacional de Control de la Tuberculosis, los cuales fueron operados por un equipoquirúrgico del Ministerio de salud, en el Hospital Nacional Hipólito Unanue y en un Centro Privado de Lima. Resultados. Lamayoría de casos fueron de sexo masculino (60%) y el promedio de edad fue 28 años. Los pacientes tuvieron resistenciaa una mediana de 5 drogas. Las lesiones cavitarias fueron las más frecuentes (91.8%) y la lobectomía fue el procedimientoquirúrgico más utilizado (68.4%). La morbilidad postoperatoria ocurrió en 12,8% de los casos y la mortalidad post-operatoriafue de 2%. Los pacientes fueron seguidos hasta 79,3 meses y la curación fue alcanzada en el 77,2% de los casos.Conclusiones. La cirugía pulmonar coadyuvante es una alternativa efectiva para la curación en pacientes con TB MDR.Esta estrategia debe ser incluida como parte de los programas de tratamiento de la TB MDR.

INTRODUCTION:Directly-observed therapy (DOT) is recommended for drug-resistant tuberculosis (DR-TB) patients during their entire treatment duration. However, there is limited published evidence on implementation of direct observation (DO) in the field. This study aims to detail whether DO was followed with DR-TB patients in a Médecins Sans Frontières (MSF) tuberculosis program in Mumbai, India. METHODS:This was a cross-sectional, mixed-methods study. Existing qualitative data from a purposively-selected subset of 12 patients, 5 DOT-providers and 5 family members, were assessed in order to determine how DO was implemented. A questionnaire-based survey of DR-TB patients, their DOT-providers and MSF staff was completed between June and August 2014. Patients were defined as"following Strict DO" and "following DO" if a DOT-provider had seen the patient swallow his/her medications "every day" or "most of the days" respectively. If DO was not followed, reasons were also recorded. The qualitative data were analysed for theme and content and used to supplement the questionnaire-based data. RESULTS:A total of 70 DR-TB patients, 65 DOT-providers and 21 MSF health staff were included. Fifty-five per cent of the patients were HIV-co-infected and 41% had multidrug-resistant-TB plus additional resistance to a fluoroquinolone. Among all patients, only 14% (10/70) and 20% (14/70) self-reported "following Strict DO" and "following DO" respectively. Among DOT-providers, 46% (30/65) reported that their patients "followed DO". MSF health staff reported none of the patients "followed DO". Reasons for not implementing DO included the unavailability of DOT-provider, time spent, stigma and treatment adverse events. The qualitative data also revealed that "Strict DO" was rarely followed and noted the same reasons for lack of implementation. CONCLUSION:This mixed-methods study has found that a majority of patients with DR-TB in Mumbai did not follow DO, and this was reported by patients and care-providers. These data likely reflect the reality of DO implementation in many high-burden settings, since this relatively small cohort was supported and closely monitored by a skilled team with access to multiple resources. The findings raise important concerns about the necessity of DO as a "pillar" of DR-TB treatment which need further validation in other settings. They also suggest that patient-centred adherence strategies might be better approaches for supporting patients on treatment.

BackgroundLittle is known about the treatment of multidrug-resistant tuberculosis (MDR-TB) in HIV-co-infected adolescents. This study aimed to present the intermediate outcomes of HIV-infected adolescents aged 10-19 years receiving second-line anti-TB treatment in a Médecins Sans Frontières (MSF) project in Mumbai, India.MethodsA retrospective review of medical records of 11 adolescents enrolled between July 2007 and January 2013 was undertaken. Patients were initiated on either empirical or individualized second-line ambulatory anti-TB treatment under direct observation.ResultsThe median age was 16 (IQR 14-18) years and 54% were female. Five (46%) adolescents had pulmonary TB (PTB), two (18%) extrapulmonary disease (EPTB) and four (36%) had both. Median CD4 count at the time of MDR-TB diagnosis was 162.7 cells/µl (IQR: 84.8-250.5). By January 2013, eight patients had final and 3 had interim outcomes. Favourable results were seen in four (36.5%) patients: one was cured and three were still on treatment with negative culture results. Seven patients (64%) had poor outcomes: four (36.5%) died and three (27%) defaulted. Three of the patients who died never started on antiretroviral and/or TB treatment and one died 16 days after treatment initiation. Two of the defaulted died soon after default. All patients (100%) on-treatment experienced adverse events (AEs): two required permanent discontinuation of the culprit drug and two were hospitalized due to AEs. No patient required permanent discontinuation of the entire second-line TB or antiretroviral regimens.ConclusionsEarly mortality and mortality after default were the most common reasons for poor outcomes in this study. Early mortality suggests the need for rapid diagnosis and prompt treatment initiation, and adolescents might benefit from active contact-tracing and immediate referral. Default occurred at different times, suggesting the need for continuous, intensified and individualized psychosocial support for co-infected adolescents. Operational research among co-infected adolescents will be especially important in designing effective interventions for this vulnerable group.