Effect of compensatory evolution in the emergence and transmission of rifampicin-resistant Mycobacterium tuberculosis in Cape Town, South Africa: a genomic epidemiology study.

BACKGROUND: Experimental data show that drug-resistance-conferring mutations are often associated with a decrease in the replicative fitness of bacteria in vitro, and that this fitness cost can be mitigated by compensatory mutations; however, the role of compensatory evolution in clinical settings is less clear. We assessed whether compensatory evolution was associated with increased transmission of rifampicin-resistant tuberculosis in Khayelitsha, Cape Town, South Africa. METHODS: We did a genomic epidemiological study by analysing available M tuberculosis isolates and their associated clinical data from individuals routinely diagnosed with rifampicin-resistant tuberculosis in primary care and hospitals in Khayelitsha, Cape Town, South Africa. Isolates were collected as part of a previous study. All individuals diagnosed with rifampicin-resistant tuberculosis and with linked biobanked specimens were included in this study. We applied whole-genome sequencing, Bayesian reconstruction of transmission trees, and phylogenetic multivariable regression analysis to identify individual and bacterial factors associated with the transmission of rifampicin-resistant M tuberculosis strains. FINDINGS: Between Jan 1, 2008, and Dec 31, 2017, 2161 individuals were diagnosed with multidrug-resistant or rifampicin-resistant tuberculosis in Khayelitsha, Cape Town, South Africa. Whole-genome sequences were available for 1168 (54%) unique individual M tuberculosis isolates. Compensatory evolution was associated with smear-positive pulmonary disease (adjusted odds ratio 1·49, 95% CI 1·08-2·06) and a higher number of drug-resistance-conferring mutations (incidence rate ratio 1·38, 95% CI 1·28-1·48). Compensatory evolution was also associated with increased transmission of rifampicin-resistant disease between individuals (adjusted odds ratio 1·55; 95% CI 1·13-2·12), independent of other patient and bacterial factors. INTERPRETATION: Our findings suggest that compensatory evolution enhances the in vivo fitness of drug-resistant M tuberculosis genotypes, both within and between patients, and that the in vitro replicative fitness of rifampicin-resistant M tuberculosis measured in the laboratory correlates with the bacterial fitness measured in clinical settings. These results emphasise the importance of enhancing surveillance and monitoring efforts to prevent the emergence of highly transmissible clones capable of rapidly accumulating new drug resistance mutations. This concern becomes especially crucial at present, because treatment regimens incorporating novel drugs are being implemented. FUNDING: Funding for this study was provided by a Swiss and South Africa joint research award (grant numbers 310030_188888, CRSII5_177163, and IZLSZ3_170834), the European Research Council (grant number 883582), and a Wellcome Trust fellowship (to HC; reference number 099818/Z/12/Z). ZS-D was funded through a PhD scholarship from the South African National Research Foundation and RMW was funded through the South African Medical Research Council.

Tuberculosis Diagnosis and Preventive Monotherapy Among Children and Adolescents Exposed to Rifampicin-Resistant Tuberculosis in the Household.

Background: Children and adolescents with household exposure to multidrug- or rifampicin-resistant tuberculosis (MDR/RR-TB) are at high risk of developing TB disease. Tuberculosis preventive therapy (TPT) is recommended, but programmatic experience is limited, particularly for adolescents. Methods: We conducted a prospective cohort study to describe MDR/RR-TB diagnosis and TPT provision for individuals aged <18 years with MDR/RR-TB exposure. Participants were assessed for TB either in homes or health facilities, with referral for chest x-ray or specimen collection at clinician discretion. The TPT regimens included levofloxacin, isoniazid, or delamanid monotherapy for 6 months, based on source patient drug-resistance profile. Results: Between March 1, 2020 and July 31, 2021, 112 participants were enrolled; median age was 8.5 years, 57 (51%) were female, and 6 (5%) had human immunodeficiency virus. On screening, 11 (10%) were diagnosed with TB: 10 presumptive MDR/RR-TB and 1 drug-susceptible TB. Overall, 95 (94% of 101) participants started TPT: 79 with levofloxacin, 9 with isoniazid, and 7 with delamanid. Seventy-six (80%) completed TPT, 12 (13%) were lost to follow up, and 7 (7%) stopped TPT early due to adverse events. Potential adverse events were reported for 12 (13%) participants; none were serious. There were no further TB diagnoses (200 days median follow up). Conclusions: Post-MDR/RR-TB exposure management for children and adolescents resulted in significant MDR/RR-TB detection and both high TPT initiation and completion. Tuberculosis preventive monotherapy was well tolerated and there were no further TB diagnoses after initial assessment. Key factors supporting these outcomes included use of pediatric formulations for young children, monotherapy, and community-based options for assessment and follow up.

Implementing a Substance-Use Screening and Intervention Program for People Living with Rifampicin-Resistant Tuberculosis: Pragmatic Experience from Khayelitsha, South Africa.

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.

Whole-Genome Sequencing Has the Potential To Improve Treatment for Rifampicin-Resistant Tuberculosis in High-Burden Settings: a Retrospective Cohort Study.

Treatment of multidrug-resistant or rifampicin-resistant tuberculosis (MDR/RR-TB), although improved in recent years with shorter, more tolerable regimens, remains largely standardized and based on limited drug susceptibility testing (DST). More individualized treatment with expanded DST access is likely to improve patient outcomes. To assess the potential of TB drug resistance prediction based on whole-genome sequencing (WGS) to provide more effective treatment regimens, we applied current South African treatment recommendations to a retrospective cohort of MDR/RR-TB patients from Khayelitsha, Cape Town. Routine DST and clinical data were used to retrospectively categorize patients into a recommended regimen, either a standardized short regimen or a longer individualized regimen. Potential regimen changes were then described with the addition of WGS-derived DST. WGS data were available for 1274 MDR/RR-TB patient treatment episodes across 2008 to 2017. Among 834 patients initially eligible for the shorter regimen, 385 (46%) may have benefited from reduced drug dosage or removing ineffective drugs when WGS data were considered. A further 187 (22%) patients may have benefited from more effective adjusted regimens. Among 440 patients initially eligible for a longer individualized regimen, 153 (35%) could have been switched to the short regimen. Overall, 305 (24%) patients had MDR/RR-TB with second-line TB drug resistance, where the availability of WGS-derived DST would have allowed more effective treatment individualization. These data suggest considerable benefits could accrue from routine access to WGS-derived resistance prediction. Advances in culture-free sequencing and expansion of the reference resistance mutation catalogue will increase the utility of WGS resistance prediction.

Potential contribution of HIV during first-line tuberculosis treatment to subsequent rifampicin-monoresistant tuberculosis and acquired tuberculosis drug resistance in South Africa: a retrospective molecular epidemiology study.

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.

"This is not my body": Therapeutic experiences and post-treatment health of people with rifampicin-resistant tuberculosis.

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.

Rifampicin-Monoresistant Tuberculosis Is Not the Same as Multidrug-Resistant Tuberculosis: a Descriptive Study from Khayelitsha, South Africa.

Rifampin monoresistance (RMR; rifampin resistance and isoniazid susceptibility) accounts for 38% of all rifampin-resistant tuberculosis (RR-TB) in South Africa and is increasing. We aimed to compare RMR-TB with multidrug-resistant TB (MDR-TB) in a setting with high TB, RR-TB, and HIV burdens. Patient-level clinical data and stored RR Mycobacterium tuberculosis isolates from 2008 to 2017 with available whole-genome sequencing (WGS) data were used to describe risk factors associated with RMR-TB and to compare RR-conferring mutations between RMR-TB and MDR-TB. A subset of isolates with particular RR-conferring mutations were subjected to semiquantitative rifampin phenotypic drug susceptibility testing. Among 2,041 routinely diagnosed RR-TB patients, 463 (22.7%) had RMR-TB. HIV-positive individuals (adjusted odds ratio [aOR], 1.4; 95% confidence interval [CI], 1.1 to 1.9) and diagnosis between 2013 and 2017 versus between 2008 and 2012 (aOR, 1.3; 95% CI, 1.1 to 1.7) were associated with RMR-TB. Among 1,119 (54.8%) patients with available WGS data showing RR-TB, significant differences in the distribution of rpoB RR-conferring mutations between RMR and MDR isolates were observed. Mutations associated with high-level RR were more commonly found among MDR isolates (811/889 [90.2%] versus 162/230 [70.4%] among RMR isolates; P < 0.0001). In particular, the rpoB L430P mutation, conferring low-level RR, was identified in 32/230 (13.9%) RMR isolates versus 10/889 (1.1%) in MDR isolates (P < 0.0001). Among 10 isolates with an rpoB L430P mutation, 7 were phenotypically susceptible using the critical concentration of 0.5 µg/ml (range, 0.125 to 1 µg/ml). The majority (215/230 [93.5%]) of RMR isolates showed susceptibility to all other TB drugs, highlighting the potential benefits of WGS for simplified treatment. These data suggest that the evolution of RMR-TB differs from MDR-TB with a potential contribution from HIV infection.

Outcomes of Children Born to Pregnant Women With Drug-resistant Tuberculosis Treated With Novel Drugs in Khayelitsha, South Africa: A Report of Five Patients.

This brief report presents a series of 5 pregnant women treated for rifampicin-resistant tuberculosis with the novel drugs bedaquiline, delamanid, and linezolid as part of an optimized backbone regimen and reviews the outcomes of the children born to them. Although the case series is small, all children had excellent birth outcomes suggesting pregnant women should not be denied access to novel therapies for RR-TB.

Delamanid for rifampicin-resistant tuberculosis: a retrospective study from South Africa.

Experience with delamanid (Dlm) is limited, particularly among HIV-positive individuals. We describe early efficacy and safety data from a programmatic setting in South Africa.This was a retrospective cohort study of patients receiving Dlm-containing treatment regimens between November 2015 and August 2017. We report 12-month interim outcomes, sputum culture conversion (SCC) by months 2 and 6, serious adverse events (SAEs) and QT intervals corrected using the Frederica formula (QTcF).Overall, 103 patients were initiated on Dlm; 79 (77%) were HIV positive. The main indication for Dlm was intolerance to second-line anti-tuberculosis (TB) drugs (n=58, 56%). There were 12 months of follow-up for 46 patients; 28 (61%) had a favourable outcome (cure, treatment completion or culture negativity). Positive cultures were found for 57 patients at Dlm initiation; 16 out of 31 (52%) had SCC within 2 months and 25 out of 31 (81%) within 6 months. There were 67 SAEs reported in 29 patients (28%). There were four instances of QTcF prolongation >500 ms in two patients (2%), leading to permanent discontinuation in one case; however, no cardiac arrhythmias occurred.This large cohort of difficult-to-treat patients receiving Dlm for rifampicin-resistant TB treatment in a programmatic setting with high HIV prevalence had favourable early treatment response and tolerated treatment well. Dlm should remain available, particularly for those who cannot be treated with conventional regimens or with limited treatment options.

DOT or SAT for Rifampicin-resistant tuberculosis? A non-randomized comparison in a high HIV-prevalence setting.

BACKGROUND: Daily directly-observed therapy (DOT) is recommended for rifampicin-resistant tuberculosis (RR-TB) patients throughout treatment. We assessed the impact of self-administered treatment (SAT) in a South African township with high rates of RR-TB and HIV. METHODS: Community-supported SAT for patients who completed the intensive phase was piloted in five primary care clinics in Khayelitsha. We compared final treatment outcomes among RR-TB patients initiating treatment before (standard-of-care (SOC)-cohort, January 2010-July 2013) and after the implementation of the pilot (SAT-cohort, January 2012-December 2014). All patients with outcomes before January 1, 2017 were considered in the analysis of outcomes. RESULTS: One-hundred-eighteen patients in the SOC-cohort and 174 patients in the SAT-cohort had final RR-TB treatment outcomes; 70% and 73% were HIV-co-infected, respectively. The proportion of patients with a final outcome of loss to follow-up (LTFU) did not differ whether treated in the SOC (25/118, 21.2%) or SAT-cohort (31/174, 17.8%) (P = 0.47). There were no significant differences in the time to 24-month LTFU among HIV-infected and uninfected patients (HR 0.90, 95% CI: 0.51-1.6, P = 0.71), or among patients enrolled in the SOC-cohort versus the SAT-cohort (HR 0.83, 95% CI: 0.49-1.4, P = 0.50) who received at least 6-months of RR-TB treatment. CONCLUSION: The introduction of SAT during the continuation phase of RR-TB treatment does not adversely affect final RR-TB treatment outcomes in a high TB and HIV-burden setting. This differentiated, patient-centred model of care could be considered in RR-TB programmes to decrease the burden of DOT on patients and health facilities.

Time to ART Initiation among Patients Treated for Rifampicin-Resistant Tuberculosis in Khayelitsha, South Africa: Impact on Mortality and Treatment Success.

SETTING: Khayelitsha, South Africa, with high burdens of rifampicin-resistant tuberculosis (RR-TB) and HIV co-infection. OBJECTIVE: To describe time to antiretroviral treatment (ART) initiation among HIV-infected RR-TB patients initiating RR-TB treatment and to assess the association between time to ART initiation and treatment outcomes. DESIGN: A retrospective cohort study of patients with RR-TB and HIV co-infection not on ART at RR-TB treatment initiation. RESULTS: Of the 696 RR-TB and HIV-infected patients initiated on RR-TB treatment between 2009 and 2013, 303 (44%) were not on ART when RR-TB treatment was initiated. The median CD4 cell count was 126 cells/mm3. Overall 257 (85%) patients started ART during RR-TB treatment, 33 (11%) within 2 weeks, 152 (50%) between 2-8 weeks and 72 (24%) after 8 weeks. Of the 46 (15%) who never started ART, 10 (21%) died or stopped RR-TB treatment within 4 weeks and 16 (37%) had at least 4 months of RR-TB treatment. Treatment success and mortality during treatment did not vary by time to ART initiation: treatment success was 41%, 43%, and 50% among patients who started ART within 2 weeks, between 2-8 weeks, and after 8 weeks (p = 0.62), while mortality was 21%, 13% and 15% respectively (p = 0.57). Mortality was associated with never receiving ART (adjusted hazard ratio (aHR) 6.0, CI 2.1-18.1), CD4 count ≤100 (aHR 2.1, CI 1.0-4.5), and multidrug-resistant tuberculosis (MDR-TB) with second-line resistance (aHR 2.5, CI 1.1-5.4). CONCLUSIONS: Despite wide variation in time to ART initiation among RR-TB patients, no differences in mortality or treatment success were observed. However, a significant proportion of patients did not initiate ART despite receiving >4 months of RR-TB treatment. Programmatic priorities should focus on ensuring all patients with RR-TB/HIV co-infection initiate ART regardless of CD4 count, with special attention for patients with CD4 counts ≤ 100 to initiate ART as soon as possible after RR-TB treatment initiation.

Impact of Decentralized Care and the Xpert MTB/RIF Test on Rifampicin-Resistant Tuberculosis Treatment Initiation in Khayelitsha, South Africa.

Background. Globally, case detection and treatment access are poor for rifampicin-resistant tuberculosis (RR-TB). The Xpert MTB/RIF test has the potential to increase detection and reduce time to treatment (TTT). However, these benefits are dependent on health system capacity to provide treatment. Methods. We retrospectively assessed the impact of Xpert on treatment initiation and TTT in the context of decentralized RR-TB care in Khayelitsha, Cape Town, using routine programmatic data. Community-based treatment was introduced progressively from 2008. Before 2007, diagnosis relied on phenotypic resistance (culture). During 2007-2008, the line probe assay (LPA) was introduced, followed by Xpert in 2012. Results. Before decentralization (2003-2006), median TTT was 71 days (interquartile range [IQR], 49-134; n = 158). The LPA introduction during 2007-2008 was associated with reduced median TTT from 76 to 50 days (P < .0001, n = 257). Between January 2009 and June 2013, 938 RR-TB cases were diagnosed (74% human immunodeficiency virus [HIV]-infected). Decentralization during 2008-2011 was associated with declining TTT (P < .0001, test for trend), a decline to 28 days in 2011 (IQR, 16-40; n = 173). Xpert was associated with a further reduction to 8 days in 2013 (IQR, 5-25; n = 89; P < .0001). Treatment initiation remained unchanged with Xpert and was lower among HIV-infected (2010-2013); 87.9% (445 of 506) compared with 96.9% (188 of 194) for HIV-uninfected (P < .0001) patients. Conclusions. Improved case detection and rapid treatment initiation are required to interrupt transmission and reduce mortality. In this setting, decentralization was associated with high treatment initiation and reduced TTT. Xpert implementation significantly enhanced the reduction in TTT and has the potential to reduce transmission.

Programmatic treatment outcomes in HIV-infected and uninfected drug-resistant TB patients in Khayelitsha, South Africa.

BACKGROUND: South Africa has high burdens of HIV, TB and drug-resistant TB (DR-TB, rifampicin-resistance). Treatment outcome data for HIV-infected versus uninfected patients is limited. We assessed the impact of HIV and other factors on DR-TB treatment success, time to culture conversion, loss-from-treatment and overall mortality after second-line treatment initiation. METHODS: A retrospective cohort analysis was conducted for patients initiated on DR-TB treatment from 2008 to 2012, within a community-based, decentralised programme in Khayelitsha, South Africa. RESULTS: Among 853 confirmed DR-TB patients initiating second-line treatment, 605 (70.9%) were HIV infected. HIV status did not impact on time to sputum culture conversion nor did it impact treatment success; 48.1% (259/539) and 45.9% (100/218), respectively (p=0.59). In a multivariate model, HIV was not associated with treatment success. Death during treatment was higher among HIV-infected patients, but overall mortality was not significantly higher. HIV-infected patients with CD4 <=100 cells/ml were significantly more likely to die after starting treatment. CONCLUSIONS: Response to DR-TB treatment did not differ with HIV infection in a programmatic setting with access to antiretroviral treatment (ART). Earlier ART initiation at a primary care level could reduce mortality among HIV-infected patients presenting with low CD4 counts.

Loss from treatment for drug resistant tuberculosis: risk factors and patient outcomes in a community-based program in Khayelitsha, South Africa.

BACKGROUND: A community based drug resistant tuberculosis (DR-TB) program has been incrementally implemented in Khayelitsha, a high HIV and TB burden community in South Africa. We investigated loss from treatment (LFT), and post treatment outcomes of DR-TB patients in this setting. METHODOLOGY: LFT, defined as interruption of treatment for ≥2 consecutive months was assessed among patients initiating DR-TB treatment for the first time between January 2009 and July 2011. Patients were traced through routine data sources to identify those who subsequently restarted treatment and those who died. Additional information on patient status and survival after LTF was obtained from community DR-TB counselors and from the national death registry. Post treatment outcomes were observed until July 2013. RESULTS: Among 452 patients initiating treatment for the first time within the given period, 30% (136) were LFT, with 67% retention at 18 months. Treatment was restarted in 27 (20%) patients, with additional resistance recorded in 2/25 (8%), excluding two with presumed DR-TB. Overall, 34 (25%) patients died, including 11 who restarted treatment. Males and those in the age category 15-25 years had a greater hazard of LFT; HR 1.93 (95% CI 1.35-2.75), and 2.43 (95% CI 1.52-3.88) respectively. Older age (>35 years) was associated with a greater hazard of death; HR 3.74 (1.13- 12.37) post treatment. Overall two-year survival was 62%. It was lower (45%) in older patients, and was 92% among those who received >12 months treatment. CONCLUSION: LFT was high, occurred throughout the treatment period and was particularly high among males and those aged 15-25 years. Overall long term survival was poor. High rates of LFT should however not preclude scale up of community based care given its impact in increasing access to treatment. Further research is needed to support retention of DR-TB patients on treatment, even within community based treatment programs.