Incidence and geographic distribution of extensively drug-resistant tuberculosis in KwaZulu-Natal Province, South Africa

South Africa is experiencing a widespread drug-resistant tuberculosis epidemic, although data are limited regarding the current situation. This study finds that the extensively drugresistant tuberculosis (XDR-TB) incidence in KwaZulu-Natal increased to 3.5 cases/ 100,000 (776 cases) in 2011-2012. XDR-TB cases are widely distributed geographically, with the majority of districts experiencing a rise in incidence.This work was supported by: R01 AI089349, National Institutes of Health, NRG NSS (http://www.nih.gov/); 2007071, Doris Duke Charitable Foundation Clinical Scientist Development Award, NSS (http://www.ddcf.org/); 2007070, Doris Duke Charitable Foundation Clinical Scientist Development Award, NRG (http://www.ddcf.org/); K24 114444, K24 Career Development Award from the National Institute of Allergy and Infectious Diseases, NRG (http://www.niaid.nih.gov/Pages/default.aspx); P30 AI050409, Emory University Center for AIDS Research, NRG (http://www.cfar.emory.edu/); K23 AI083088, National Institutes of Health, JCMB (http:// www.nih.gov/); and P30 AI051519, Einstein- Montefiore Center for AIDS Research, JCMB (http:// www.einstein.yu.edu/centers/center-for-aidsresearch/).http://www.plosone.orgam201

Spatial patterns of extensively drug-resistant tuberculosis transmission in KwaZulu-Natal, South Africa

BACKGROUND : Transmission is driving the global drug-resistant tuberculosis (TB) epidemic; nearly three-quarters of drug-resistant TB cases are attributable to transmission. Geographic patterns of disease incidence, combined with information on probable transmission links, can define the spatial scale of transmission and generate hypotheses about factors driving transmission patterns. METHODS : We combined whole-genome sequencing data with home Global Positioning System coordinates from 344 participants with extensively drug-resistant (XDR) TB in KwaZulu-Natal, South Africa, diagnosed from 2011 to 2014. We aimed to determine if genomically linked (difference of ≤5 single-nucleotide polymorphisms) cases lived close to one another, which would suggest a role for local community settings in transmission. RESULTS : One hundred eighty-two study participants were genomically linked, comprising 1084 case-pairs. The median distance between case-pairs’ homes was 108 km (interquartile range, 64–162 km). Between-district, as compared to within-district, links accounted for the majority (912/1084 [84%]) of genomic links. Half (526 [49%]) of genomic links involved a case from Durban, the urban center of KwaZulu-Natal. CONCLUSIONS : The high proportions of between-district links with Durban provide insight into possible drivers of province-wide XDR-TB transmission, including urban–rural migration. Further research should focus on characterizing the contribution of these drivers to overall XDR-TB transmission in KwaZulu-Natal to inform design of targeted strategies to curb the drug-resistant TB epidemic.Grants from the US National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH): R01AI089349 (PI Gandhi and R01AI087465 (PI Gandhi). It was also supported in part by NIH/NIAID grants: K23AI083088 (PI Brust), K24AI114444 (PI Gandhi), K23AI134182 (PI Auld), Emory CFAR P30AI050409 (PI Curran), Einstein CFAR P30AI051519 (PI Goldstein), by Einstein/Montefiore ICTR UL1 TR001073 (PI Shamoon).https://academic.oup.com/jid2019-12-15hj2019Medical Microbiolog

Modeling missing cases and transmission links in networks of extensively drug-resistant tuberculosis in KwaZulu-Natal, South Africa

Patterns of transmission of drug-resistant tuberculosis (TB) remain poorly understood, despite over half a million incident cases worldwide in 2017. Modeling TB transmission networks can provide insight into drivers of transmission, but incomplete sampling of TB cases can pose challenges for inference from individual epidemiologic and molecular data. We assessed the effect of missing cases on a transmission network inferred from Mycobacterium tuberculosis sequencing data on extensively drug-resistant TB cases in KwaZulu-Natal, South Africa, diagnosed in 2011–2014. We tested scenarios in which cases were missing at random, missing differentially by clinical characteristics, or missing differentially by transmission (i.e., cases with many links were under- or oversampled). Under the assumption that cases were missing randomly, the mean number of transmissions per case in the complete network needed to be larger than 20, far higher than expected, to reproduce the observed network. Instead, the most likely scenario involved undersampling of high-transmitting cases, and models provided evidence for super-spreading. To our knowledge, this is the first analysis to have assessed support for different mechanisms of missingness in a TB transmission study, but our results are subject to the distributional assumptions of the network models we used. Transmission studies should consider the potential biases introduced by incomplete sampling and identify host, pathogen, or environmental factors driving super-spreading.This work was presented at the Seventh International Conference on Infectious Disease Dynamics (Epidemics7), Charleston, South Carolina, December 3–6, 2019.The National Institute of Allergy and Infectious Diseases, US National Institutes of Health, the National Institute of Allergy and Infectious Diseases, the Emory Center for AIDS Research, the Einstein Center for AIDS Research and the Einstein/Montefiore Institute for Clinical and Translational Research.https://academic.oup.com/ajehj2021Medical Microbiolog

Pre-detection history of extensively drug-resistant tuberculosis in KwaZulu-Natal, South Africa

Antimicrobial-resistant (AMR) infections pose a major threat to global public health. Similar to other AMR pathogens, both historical and ongoing drug-resistant tuberculosis (TB) epidemics are characterized by transmission of a limited number of predominant Mycobacterium tuberculosis (Mtb) strains. Understanding how these predominant strains achieve sustained transmission, particularly during the critical period before they are detected via clinical or public health surveillance, can inform strategies for prevention and containment. In this study, we employ whole-genome sequence (WGS) data from TB clinical isolates collected in KwaZulu-Natal, South Africa to examine the pre-detection history of a successful strain of extensively drug-resistant (XDR) TB known as LAM4/KZN, first identified in a widely reported cluster of cases in 2005. We identify marked expansion of this strain concurrent with the onset of the generalized HIV epidemic 12 y prior to 2005, localize its geographic origin to a location in northeastern KwaZulu-Natal ∼400 km away from the site of the 2005 outbreak, and use protein structural modeling to propose a mechanism for how strain-specific rpoB mutations offset fitness costs associated with rifampin resistance in LAM4/KZN. Our findings highlight the importance of HIV coinfection, high preexisting rates of drug-resistant TB, human migration, and pathoadaptive evolution in the emergence and dispersal of this critical public health threat. We propose that integrating wholegenome sequencing into routine public health surveillance can enable the early detection and local containment of AMR pathogens before they achieve widespread dispersal.The National Institute of Allergy and Infectious Disease and National Institutes of Health.https://www.pnas.orgpm2020Medical Microbiolog

Clofazimine pharmacokinetics in patients with TB: dosing implications

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Directly Observed Antiretroviral Therapy in Substance Abusers Receiving Methadone Maintenance Therapy Does Not Cause Increased Drug Resistance

Direct observation of antiretroviral therapy (DOT) can increase adherence rates in HIV-infected substance users, but whether this affects the development of antiretroviral drug resistance has not been fully explored. We conducted a 24-week randomized controlled trial of methadone clinic-based antiretroviral DOT compared with treatment as usual (TAU) among antiretroviral-experienced substance users. To examine the development of new resistance mutations, we identified all participants with an amplifiable resistance test at both baseline and either week 8 or week 24. We compared the development of new drug resistance mutations between participants in the two arms of the trial. Among the 77 participants enrolled in the parent trial, antiretroviral DOT was efficacious for improving adherence and decreasing HIV viral load. Twenty-one participants had a detectable HIV viral load at both baseline and a second time point. Of these, nine developed new drug resistance mutations not seen at baseline (three in the DOT arm and six in the TAU arm; p = 0.27). Overall, five subjects in the TAU arm developed major mutations correlating with their current antiretroviral regimen, while no subjects in the DOT arm developed such mutations. Direct observation of antiretroviral therapy was associated with improved adherence and viral suppression among methadone maintained HIV-infected substance users, but was not associated with an increase in the development of antiretroviral drug resistance. DOT should be considered for substance users attending methadone maintenance clinics who are at high risk of nonadherence

Minimal Diversity of Drug-Resistant Mycobacterium tuberculosis Strains, South Africa

Multidrug- (MDR) and extensively drug-resistant tuberculosis (XDR TB) are commonly associated with Beijing strains. However, in KwaZulu-Natal, South Africa, which has among the highest incidence and mortality for MDR and XDR TB, data suggest that non-Beijing strains are driving the epidemic. We conducted a retrospective study to characterize the strain prevalence among drug-susceptible, MDR, and XDR TB cases and determine associations between strain type and survival. Among 297 isolates from 2005–2006, 49 spoligotype patterns were found. Predominant strains were Beijing (ST1) among drug-susceptible isolates (27%), S/Quebec (ST34) in MDR TB (34%) and LAM4/KZN (ST60) in XDR TB (89%). More than 90% of patients were HIV co-infected. MDR TB and XDR TB were independently associated with mortality, but TB strain type was not. We conclude that, although Beijing strain was common among drug-susceptible TB, other strains predominated among MDR TB and XDR TB cases. Drug-resistance was a stronger predictor of survival than strain type. Download MP3  Length: 1:5

pncA Gene Mutations Associated with Pyrazinamide Resistance in Drug-Resistant Tuberculosis, South Africa and Georgia

Although pyrazinamide is commonly used for tuberculosis treatment, drug-susceptibility testing is not routinely available. We found polymorphisms in the pncA gene for 70% of multidrug-resistant and 96% of extensively drug-resistant Mycobacterium tuberculosis isolates from South Africa and Georgia. Assessment of pyrazinamide susceptibility may be prudent before using it in regimens for drug-resistant tuberculosis

Extensively drug-resistant tuberculosis hotspots and sociodemographic associations in Durban, South Africa

BACKGROUND : Extensively drug-resistant tuberculosis (XDR-TB) incidence is driven by transmission of resistant strains in KwaZulu-Natal, South Africa. Data suggests cases may be spatially clustered; we therefore sought to identify hotspots and describe these communities. METHODS : We enrolled XDR-TB patients diagnosed from 2011–2014 in eThekwini. GPS coordinates for participant homes were collected and hotspots were identified based on population-adjusted XDR-TB incidence. Sociodemographic features of hotspots were characterized using census data. For a subset of participants, we mapped XDR-TB case non-home congregate locations and compared to results including only homes. RESULTS : Among 132 participants, 75 (57%) were female and 87 (66%) lived in urban or suburban locations. Fifteen of 197 census tracts were identified as XDR-TB hotspots with ≥ 95% confidence. Four spatial mapping methods identified one large hotspot in northeastern eThekwini. Hotspot communities had higher percentages of low educational attainment (12% vs 9%), higher unemployment (29.3% vs 20.4%), and lower percentage of homes with flush toilets (36.4% vs 68.9%). Mapping congregate locations, including workplaces, for 43 (33%) participants shifted case density towards Durban. CONCLUSIONS : In eThekwini, XDR-TB case homes were clustered into hotspots with more indicators of poverty than non-hotspots. Prevention efforts targeting hotspot communities and congregate settings may be effective in reducing community transmission.A grant from the US National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH): R01AI089349 (PI Gandhi) and R01AI087465 (PI Gandhi). It was also supported in part by NIH/NIAID grants: K23AI083088 (PI Brust), K23AI134182 (PI Auld), K24AI114444 (PI Gandhi), R01AI138646 (PI Gandhi), Emory CFAR P30AI050409 (PI Curran), Einstein CFAR P30AI124414 (PI Goldstein), by Einstein/Montefiore ICTR UL1 TR001073 (PI Shamoon), and by NIH/NHLBI T32 HL116271 (PI Guidot).https://www.ingentaconnect.com/content/iuatld/ijtldhj2020Medical Microbiolog