Variation in missed doses and reasons for discontinuation of anti-tuberculosis drugs during hospital treatment for drug-resistant tuberculosis in South Africa.

BACKGROUND: Updated World Health Organization (WHO) treatment guidelines prioritize all-oral drug-resistant tuberculosis (DR-TB) regimens. Several poorly tolerated drugs, such as amikacin and para-aminosalicylic acid (PAS), remain treatment options for DR-TB in WHO-recommended longer regimens as Group C drugs. Incomplete treatment with anti-TB drugs increases the risk of treatment failure, relapse, and death. We determined whether missed doses of individual anti-TB drugs, and reasons for their discontinuation, varied in closely monitored hospital settings prior to the 2020 WHO DR-TB treatment guideline updates. METHODS: We collected retrospective data on adult patients with microbiologically confirmed DR-TB between 2008 and 2015 who were selected for a study of acquired drug resistance in the Western Cape Province of South Africa. Medical records through mid-2017 were reviewed. Patients received directly observed treatment during hospitalization at specialized DR-TB hospitals. Incomplete treatment with individual anti-TB drugs, defined as the failure to take medication as prescribed, regardless of reason, was determined by comparing percent missed doses, stratified by HIV status and DR-TB regimen. We applied a generalized mixed effects model. RESULTS: Among 242 patients, 131 (54%) were male, 97 (40%) were living with HIV, 175 (72%) received second-line treatment prior to first hospitalization, and 191 (79%) died during the study period. At initial hospitalization, 134 (55%) patients had Mycobacterium tuberculosis with resistance to rifampicin and isoniazid (multidrug-resistant TB [MDR-TB]) without resistance to ofloxacin or amikacin, and 102 (42%) had resistance to ofloxacin and/or amikacin. Most patients (129 [53%]) had multiple hospitalizations and DST changes occurred in 146 (60%) by the end of their last hospital discharge. Incomplete treatment was significantly higher for amikacin (18%), capreomycin (18%), PAS (17%) and kanamycin (16%) than other DR-TB drugs (P<0.001), including ethionamide (8%), moxifloxacin (7%), terizidone (7%), ethambutol (7%), and pyrazinamide (6%). Among the most frequently prescribed drugs, second-line injectables had the highest rates of discontinuation for adverse events (range 0.56-1.02 events per year follow-up), while amikacin, PAS and ethionamide had the highest rates of discontinuation for patient refusal (range 0.51-0.68 events per year follow-up). Missed doses did not differ according to HIV status or anti-TB drug combinations. CONCLUSION: We found that incomplete treatment for second-line injectables and PAS during hospitalization was higher than for other anti-TB drugs. To maximize treatment success, interventions to improve person-centered care and mitigate adverse events may be necessary in cases when PAS or amikacin (2020 WHO recommended Group C drugs) are needed.

High mortality among patients hospitalized for drug-resistant tuberculosis with acquired second-line drug resistance and high HIV prevalence.

OBJECTIVES: We compared mortality between HIV-positive and HIV-negative South African adults with drug-resistant tuberculosis (DR-TB) and high incidence of acquired second-line drug resistance. METHODS: We performed a retrospective review of DR-TB patients with serial second-line TB drug susceptibility tests (2008-2015) who were hospitalized at a specialized TB hospital. We used Kaplan-Meier analysis and Cox models to examine associations with mortality. RESULTS: Of 245 patients, the median age was 33 years, 54% were male and 40% were HIV-positive, 96% of whom had ever received antiretroviral therapy (ART). At initial drug resistance detection, 99% of patients had resistance to at least rifampicin and isoniazid, and 18% had second-line drug resistance (fluoroquinolones and/or injectable drugs). At later testing, 88% of patients had acquired additional second-line drug resistance. Patient-initiated treatment interruptions (> 2 months) occurred in 47%. Mortality was 79%. Those with HIV had a shorter time to death (p = 0.02; log-rank): median survival time from DR-TB treatment initiation was 2.44 years [95% confidence interval (CI): 2.09-3.15] versus 3.99 years (95% CI: 3.12-4.75) for HIV-negative patients. HIV-positive patients who received ART within 6 months before DR-TB treatment had a higher mortality hazard than HIV-negative patients [adjusted hazard ratio (aHR) ratio = 1.82, 95% CI: 1.21-2.74]. By contrast, HIV-positive patients who did not receive ART within 6 months before DR-TB treatment did not have a significantly higher mortality hazard than HIV-negative patients (aHR = 1.09; 95% CI: 0.72-1.65), although those on ART had lower median CD4 counts than those not on ART (157 vs. 281 cells/µL, respectively; p = 0.02). CONCLUSIONS: A very high incidence of acquired second-line drug resistance and high overall mortality were observed, reinforcing the need to reduce the risk of acquired resistance and for more effective treatment.

Public health and hospital-based nursing intersection: Case study of drug-resistant tuberculosis patients.

OBJECTIVE: Public health nurses (PHN) are key partners in continuity of care for drug-resistant tuberculosis (DR-TB) patients. We examined complexities in DR-TB care transition between community- and hospital-based care. DESIGN: We conducted a case study using medical record data. Four patients were purposively selected to illustrate intersectional complexities in DR-TB care transition involving PHN. RESULTS: Case A (HIV negative male) received PHN care at a community-based facility 124 km from Cape Town. Cases B, C, and D (males living with HIV) received PHN community-based care, averaging 25 km from the hospital. Treatment failed in cases A, B, and C; they subsequently died. Case D was cured. All cases were granted leave of absence at least once while hospitalized. None returned when expected mainly due to lack of transport funds. PHN played critical roles regarding patients' return by conducting home visits, interacting with relatives, and assisting emergency officers to transport patients back to the hospital. PHN supported relatives to endure protracted patient hospitalizations. CONCLUSION: The role of PHN in continuity of DR-TB care in low-middle income countries is unambiguous. PHN are key partners in the DR-TB care cascade, namely facilitating retention in care between hospital and community-based care. Effective DR-TB control relies on effective partnerships among healthcare personnel, patients, and their families.

Bacterial and host determinants of cough aerosol culture positivity in patients with drug-resistant versus drug-susceptible tuberculosis.

A burgeoning epidemic of drug-resistant tuberculosis (TB) threatens to derail global control efforts. Although the mechanisms remain poorly clarified, drug-resistant strains are widely believed to be less infectious than drug-susceptible strains. Consequently, we hypothesized that lower proportions of patients with drug-resistant TB would have culturable Mycobacterium tuberculosis from respirable, cough-generated aerosols compared to patients with drug-susceptible TB, and that multiple factors, including mycobacterial genomic variation, would predict culturable cough aerosol production. We enumerated the colony forming units in aerosols (≤10 µm) from 452 patients with TB (227 with drug resistance), compared clinical characteristics, and performed mycobacterial whole-genome sequencing, dormancy phenotyping and drug-susceptibility analyses on M. tuberculosis from sputum. After considering treatment duration, we found that almost half of the patients with drug-resistant TB were cough aerosol culture-positive. Surprisingly, neither mycobacterial genomic variants, lineage, nor dormancy status predicted cough aerosol culture positivity. However, mycobacterial sputum bacillary load and clinical characteristics, including a lower symptom score and stronger cough, were strongly predictive, thereby supporting targeted transmission-limiting interventions. Effective treatment largely abrogated cough aerosol culture positivity; however, this was not always rapid. These data question current paradigms, inform public health strategies and suggest the need to redirect TB transmission-associated research efforts toward host-pathogen interactions.

Factors associated with tuberculosis diagnosis and treatment delays in Middle East and North Africa: a systematic review.

BACKGROUND: Political instability, economic sanctions and substandard quality of health care negatively affect tuberculosis (TB) control in the Middle East and North Africa (MENA) region. AIMS: We aimed to elucidate factors contributing to delays in TB diagnosis and treatment in MENA countries. METHODS: Two reviewers independently appraised eligible articles identified through comprehensive searching and extracted data which were subjected to meta-analysis. RESULTS: Delays in TB diagnosis were associated with older age and low income [(OR = 1.49; 95% CI: 1.31-1.70) and (OR = 1.26; 95% CI: 1.09-1.45)] respectively (n = 17 studies). Being female was associated with patient delay and health system delay [(OR = 1.24; 95% CI: 1.02-1.50) and (OR = 1.68; 95% CI: 1.18-2.38)] respectively. Knowledge and perception of TB, having employment and low levels of crowding were each protective against patient delay. The GRADE system rated the evidence as of low quality. CONCLUSION: This review provides evidence for facilitators and barriers to TB diagnosis and health system delays. For successful TB control in the MENA region, TB awareness and interventions targeting the elderly and those from lower-income settings, particularly directed at gender differences, are essential.

Long-term bedaquiline-related treatment outcomes in patients with extensively drug-resistant tuberculosis from South Africa.

Optimal treatment regimens for patients with extensively drug-resistant tuberculosis (XDR-TB) remain unclear. Long-term prospective outcome data comparing XDR-TB regimens with and without bedaquiline from an endemic setting are lacking.We prospectively followed-up 272 South African patients (49.3% HIV-infected; median CD4 count 169 cells·µL-1) with newly diagnosed XDR-TB between 2008 and 2017. Outcomes were compared between those who had not received bedaquiline (pre-2013; n=204) and those who had (post-2013; n=68; 80.9% received linezolid in addition).The 24-month favourable outcome rate was substantially better in the bedaquiline versus the non-bedaquiline group (66.2% (45 out of 68) versus 13.2% (27 out of 204); p<0.001). In addition, the bedaquiline group exhibited reduced 24-month rates of treatment failure (5.9% versus 26.0%; p<0.001) and default (1.5% versus 15.2%; p<0.001). However, linezolid was withdrawn in 32.7% (18 out of 55) of patients in the bedaquiline group because of adverse events. Admission weight >50 kg, an increasing number of anti-TB drugs and bedaquiline were independent predictors of survival (the bedaquiline survival effect remained significant in HIV-infected persons, irrespective of CD4 count).XDR-TB patients receiving a backbone of bedaquiline and linezolid had substantially better favourable outcomes compared to those not using these drugs. These data inform the selection of XDR-TB treatment regimens and roll-out of newer drugs in TB-endemic countries.

Regulatory T Cells Subvert Mycobacterial Containment in Patients Failing Extensively Drug-Resistant Tuberculosis Treatment.

RATIONALE: The advent of extensively drug-resistant (XDR) tuberculosis (TB) and totally drug-resistant TB, with limited or no treatment options, has facilitated renewed interest in host-directed immunotherapy, particularly for therapeutically destitute patients. However, the selection and utility of such approaches depend on understanding the host immune response in XDR-TB, which hitherto remains unexplored. OBJECTIVES: To determine the host immunological profile in patients with XDR-TB, compared with drug-sensitive TB (DS-TB), using peripheral blood and explanted lung tissue. METHODS: Blood and explanted lung tissue were obtained from patients with XDR-TB (n = 31), DS-TB (n = 20), and presumed latent TB infection (n = 20). T-cell phenotype (T-helper cell type 1 [Th1]/Th2/Th17/regulatory T cells [Tregs]) was evaluated in all patient groups, and Treg function assessed in XDR-TB nonresponders by coculturing PPD-preprimed effector T cells with H37Rv-infected monocyte-derived macrophages, with or without autologous Tregs. Mycobacterial containment was evaluated by counting colony-forming units. MEASUREMENTS AND MAIN RESULTS: Patients failing XDR-TB treatment had an altered immunophenotype characterized by a substantial increase in the frequency (median; interquartile range) of CD4+CD25+FoxP3+ Tregs (11.5%; 5.9-15.2%) compared with DS-TB (3.4%; 1.6-5.73%; P < 0.001) and presumed latent TB infection (1.8%; 1.2-2.3%; P < 0.001), which was unrelated to disease duration. Tregs isolated from patients with XDR-TB suppressed T-cell proliferation (up to 90%) and subverted containment of H37Rv-infected monocyte-derived macrophages (by 30%; P = 0.03) by impairing effector T-cell function through a mechanism independent of direct cell-to-cell contact, IL-10, TGF (transforming growth factor)-ß, and CTLA-4 (cytotoxic T-lymphocyte-associated protein 4). CONCLUSIONS: Collectively, these data suggest that Tregs may be contributing to immune dysfunction, and bacterial persistence, in patients with XDR-TB. The relevant cellular pathways may serve as potential targets for immunotherapeutic intervention.

Outcomes, infectiousness, and transmission dynamics of patients with extensively drug-resistant tuberculosis and home-discharged patients with programmatically incurable tuberculosis: a prospective cohort study.

BACKGROUND: The emergence of programmatically incurable tuberculosis threatens to destabilise control efforts. The aim of this study was to collect prospective patient-level data to inform treatment and containment strategies. METHODS: In a prospective cohort study, 273 South African patients with extensively drug-resistant tuberculosis, or resistance beyond extensively drug-resistant tuberculosis, were followed up over a period of 6 years. Transmission dynamics, infectiousness, and drug susceptibility were analysed in a subset of patients from the Western Cape using whole-genome sequencing (WGS; n=149), a cough aerosol sampling system (CASS; n=26), and phenotypic testing for 18 drugs (n=179). FINDINGS: Between Oct 1, 2008, and Oct 31, 2012, we enrolled and followed up 273 patients for a median of 20·3 months (IQR 9·6-27·8). 203 (74%) had programmatically incurable tuberculosis and unfavourable outcomes (treatment failure, relapse, default, or death despite treatment with a regimen based on capreomycin, aminosalicylic acid, or both). 172 (63%) patients were discharged home, of whom 104 (60%) had an unfavourable outcome. 54 (31%) home-discharged patients had failed treatment, with a median time to death after discharge of 9·9 months (IQR 4·2-17·4). 35 (20%) home-discharged cases were smear-positive at discharge. Using CASS, six (23%) of 26 home-discharged cases with data available expectorated infectious culture-positive cough aerosols in the respirable range (<5 µm), and most reported inter-person contact with suboptimal protective mask usage. WGS identified 17 (19%) of the 90 patients (with available sequence data) that were discharged home before the diagnosis of 20 downstream cases of extensively drug-resistant tuberculosis with almost identical sequencing profiles suggestive of community-based transmission (five or fewer single nucleotide polymorphisms different and with identical resistance-encoding mutations for 14 drugs). 11 (55%) of these downstream cases had HIV co-infection and ten (50%) had died by the end of the study. 22 (56%) of 39 isolates in patients discharged home after treatment failure were resistant to eight or more drugs. However, five (16%) of 31 isolates were susceptible to rifabutin and more than 90% were likely to be sensitive to linezolid, bedaquiline, and delamanid. INTERPRETATION: More than half of the patients with programmatically incurable tuberculosis were discharged into the community where they remained for an average of 16 months, were at risk of expectorating infectious cough aerosols, and posed a threat of transmission of extensively drug-resistant tuberculosis. Urgent action, including appropriate containment strategies, is needed to address this situation. Access to delamanid, bedaquiline, linezolid, and rifabutin, when appropriate, must be accelerated along with comprehensive drug susceptibility testing. FUNDING: UK Medical Research Council, South African Medical Research Council, South African National Research Foundation, European & Developing Countries Clinical Trials Partnership, Oppenheimer Foundation, Newton Fund, Biotechnology and Biological Sciences Research Council, King Abdullah University of Science & Technology.

The diagnostic accuracy of the MTBDRplus and MTBDRsl assays for drug-resistant TB detection when performed on sputum and culture isolates.

Although molecular tests for drug-resistant TB perform well on culture isolates, their accuracy using clinical samples, particularly from TB and HIV-endemic settings, requires clarification. The MTBDRplus and MTBDRsl line probe assays were evaluated in 181 sputum samples and 270 isolates from patients with culture-confirmed drug-sensitive-TB, MDR-TB, or XDR-TB. Phenotypic culture-based testing was the reference standard. Using sputum, the sensitivities for resistance was 97.7%, 95.4%, 58.9%, 61.6% for rifampicin, isoniazid, ofloxacin, and amikacin, respectively, whereas the specificities were 91.8%, 89%, 100%, and 100%, respectively. MTBDRsl sensitivity differed in smear-positive vs. smear-negative samples (79.2% vs. 20%, p < 0.0001 for ofloxacin; 72.9% vs. 37%, p = 0.0023 for amikacin) but not by HIV status. If used sequentially, MTBDRplus and MTBDRsl could rule-in XDR-TB in 78.5% (22/28) and 10.5% (2/19) of smear-positive and smear-negative samples, respectively. On culture isolates, the sensitivity for resistance to rifampicin, isoniazid, ofloxacin, and amikacin was 95.1%, 96.1%, 72.3% and 76.6%, respectively, whereas the specificities exceeded 96%. Using a sequential testing approach, rapid sputum-based diagnosis of fluoroquinolone or aminoglycoside-resistant TB is feasible only in smear-positive samples, where rule-in value is good. Further investigation is required in samples that test susceptible in order to rule-out second-line drug resistance.

Lifestyle, attitudes and needs of uncured XDR-TB patients living in the communities of South Africa: a qualitative study.

OBJECTIVE: Patient-level data are required to inform strategies interrupting transmission and default in patients with extensively drug-resistant TB (XDR-TB) to improve models of care and identify potential routes of transmission. We therefore explored the experiences, lifestyle, attitudes and needs of patients with uncured XDR-TB, who failed or interrupted therapy, living without treatment in the community. METHODS: We conducted in-depth interviews with 12 community-based patients from South Africa. Family members were interviewed when patients were unavailable. Interviews were analysed using inductive thematic analysis. RESULTS: The thematic experiences identified from the interviews were as follows: (i) living with but not being cured of XDR-TB, (ii) altered lifestyle in the community, (iii) experiences with community health care, (iv) local community members, and (v) wants and needs. Patients identified mistrust in health care, futility of treatment regimens, a need for a purpose in life and subsistence as major concerns. Restriction of living in the community for patients whose treatment had failed resulted in self-imposed isolation. Defaulters focused more on the never-ending drug regimen and bad experiences with health care contributing to non-adherence. Family members emphasised an under-recognised experience of unforeseen burden, obligation, worry and discomfort. Lack of knowledge and lack of concern about transmission was evident. CONCLUSION: Current models of care are not adequately meeting the needs of patients with uncured XDR-TB and relatives. These data inform the need for community-based palliative care, vocational facilities to improve economic opportunities, home-based infection control and improved psychosocial support to increase patient adherence, reduce transmission, provide income and relieve the burden on family members.

High frequency of resistance, lack of clinical benefit, and poor outcomes in capreomycin treated South African patients with extensively drug-resistant tuberculosis.

BACKGROUND: There are limited data about the epidemiology and treatment-related outcomes associated with capreomycin resistance in patients with XDR-TB. Capreomycin achieves high serum concentrations relative to MIC but whether capreomycin has therapeutic benefit despite microbiological resistance remains unclear. METHODS: We reviewed the susceptibility profiles and outcomes associated with capreomycin usage in patients diagnosed with XDR-TB between August 2002 and October 2012 in two provinces of South Africa. Patients whose isolates were genotypically tested for capreomycin resistance were included in the analysis. RESULTS: Of 178 XDR-TB patients 41% were HIV-infected. 87% (154/178) isolates contained a capreomycin resistance-conferring mutation [80% (143/178) rrs A1401G and 6% (11/178) were heteroresistant (containing both the rrs A1401G mutation and wild-type sequences)]. Previous MDR-TB treatment, prior usage of kanamycin, or strain type was not associated with capreomycin resistance. 92% (163/178) of XDR-TB patients were empirically treated with capreomycin. Capreomycin resistance decreased the odds of sputum culture conversion. In capreomycin sensitive and resistant persons combined weight at diagnosis was the only independent predictor for survival (p=<0.001). By contrast, HIV status and use of co-amoxicillin/clavulanic acid were independent predictors of mortality (p=<0.05). Capreomycin usage was not associated with survival or culture conversion when the analysis was restricted to those whose isolates were resistant to capreomycin. CONCLUSION: In South Africa the frequency of capreomycin conferring mutations was extremely high in XDR-TB isolates. In those with capreomycin resistance there appeared to be no therapeutic benefit of using capreomycin. These data inform susceptibility testing and the design of treatment regimens for XDR-TB in TB endemic settings.

Long-term outcomes of patients with extensively drug-resistant tuberculosis in South Africa: a cohort study.

BACKGROUND: Long-term treatment-related outcomes in patients with extensively drug-resistant (XDR) tuberculosis are unknown. We followed up a cohort of patients to address knowledge gaps. METHODS: Between March, 2008, and August, 2012, we prospectively followed up a cohort of 107 patients from three provinces in South Africa, who had been diagnosed with XDR tuberculosis between August 2002, and February, 2008. Available isolates from 56 patients were genotyped to establish strain type and used for extended susceptibility testing. FINDINGS: All patients were treated empirically as inpatients with a median of eight drugs (IQR six to ten). 44 patients (41%) had HIV. 36 (64%) of 56 isolates were resistant to at least eight drugs, and resistance to an increasing number of drugs was associated with the Beijing genotype (p=0·01). After 24 months of follow-up, 17 patients (16%) had a favourable outcome (ie, treatment cure or completion), 49 (46%) had died, seven (7%) had defaulted (interruption of treatment for at least 2 consecutive months), and 25 (23%) had failed treatment. At 60 months, 12 patients (11%) had a favourable outcome, 78 (73%) had died, four (4%) had defaulted, and 11 (10%) had failed treatment. 45 patients were discharged from hospital, of whom 26 (58%) had achieved sputum culture conversion and 19 (42%) had failed treatment. Median survival of patients who had failed treatment from time of discharge was 19·84 months (IQR 4·16-26·04). Clustering of cases and transmission within families containing a patient who had failed treatment and been discharged were shown with genotypic methods. Net sputum culture conversion occurred in 22 patients (21%) and median time to net culture conversion was 8·7 months (IQR 5·6-26·4). Independent predictors of probability of net culture conversion were no history of multidrug-resistant tuberculosis (p=0·0007) and use of clofazamine (p=0·0069). Independent overall predictors of survival were net culture conversion (p<0·0001) and treatment with clofazamine (p=0·021). Antiretroviral therapy was also a predictor of survival in patients with HIV (p=0·003). INTERPRETATION: In South Africa, long-term outcomes in patients with XDR tuberculosis are poor, irrespective of HIV status. Because appropriate long-stay or palliative care facilities are scarce, substantial numbers of patients with XDR tuberculosis who have failed treatment and have positive sputum cultures are being discharged from hospital and are likely to transmit disease into the wider community. Testing of new combined regimens is needed urgently and policy makers should implement interventions to minimise disease spread by patients who fail treatment. FUNDING: European and Developing Countries Clinical Trials Partnership, South African National Research Foundation (SARChI), and the South African Medical Research Council.

A historical review of XDR tuberculosis in the Western Cape province of South Africa.

There are limited data on the temporal relationship between the regional introduction of multidrug-resistant tuberculosis (MDR-TB) treatment and the subsequent development of extensively drug-resistant TB (XDR-TB). The first XDR-TB case in the Western Cape province of South Africa was recorded in 1992, approximately 5 - 7 years after the regional introduction of MDR-TB-like treatment. Between 1990 and 2002 we identified 48 patients with XDR-TB in the Cape Metropole region of the Western Cape province. Patients were predominantly HIV-uninfected and median survival was 10.8 months. XDR-TB has therefore been present in the Western Cape at least since 1992. These data inform public health policy relevant to the introduction of new anti-TB drug regimens.

Dissociative identity disorder associated with mania and change in handedness.

OBJECTIVE: To investigate the overlap between dissociative and bipolar disorders with reference to their neurophysiological foundations. BACKGROUND: Case reports of anomalous lateralization and shifts in handedness associated with both affective and dissociative conditions have intermittently surfaced in the literature. The two disorders are, however, usually considered to be distinct psychopathological entities. METHOD: A case of co-occurring bipolar disorder and dissociative identity disorder (DID) is presented. RESULTS: The "switch" in personality coincided with manic or hypomanic symptoms and was associated with a change in handedness. CONCLUSIONS: A parallel between the "personality" shifts that characterize DID and the mood fluctuations that underlie bipolar disorder is drawn, suggesting some nosological overlap between the two disorders. The possibility that these two psychiatric conditions share a similar neurophysiological architecture is also raised.