Journal Article > ResearchFull Text
Antimicrob Agents Chemother. 2021 August 30; Volume 65 (Issue 11); e00364-21.; DOI:10.1128/AAC.00364-21
Salaam-Dreyer Z, Streicher EM, Sirgel FA, Menardo F, Borrell S, et al.
Antimicrob Agents Chemother. 2021 August 30; Volume 65 (Issue 11); e00364-21.; DOI:10.1128/AAC.00364-21
Rifampicin mono-resistant TB (RMR-TB, rifampicin resistance and isoniazid susceptibility) constitutes 38% of all rifampicin-resistant TB (RR-TB) in South Africa and is increasing. We aimed to compare RMR-TB with multidrug-resistant TB (MDR-TB) within a high TB, RR-TB and HIV burden setting. Patient-level clinical data and stored RR-TB isolates from 2008-2017 with available whole genome sequencing (WGS) data were used to describe risk factors associated with RMR-TB and to compare rifampicin-resistance (RR) conferring mutations between RMR-TB and MDR-TB. A subset of isolates with particular RR-conferring mutations were subjected to semi-quantitative rifampicin phenotypic drug susceptibility testing. Among 2,041 routinely diagnosed RR-TB patients, 463 (22.7%) had RMR-TB. HIV-positive individuals (adjusted Odds Ratio 1.4, 95% CI 1.1-1.9) and diagnosis between 2013-2017 versus 2008-2012 (aOR 1.3, 1.1-1.7) 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-TB and MDR-TB isolates were observed. Mutations associated with high-level RR were more commonly found among MDR-TB isolates (811/889, 90.2% versus 162/230, 70.4% among RMR-TB, p<0.0001). In particular, the rpoB L430P mutation, conferring low-level RR, was identified in 32/230 (13.9%) RMR-TB versus 10/889 (1.1%) in MDR-TB (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 0.125-1 μg/ml). The majority (215/230, 93.5%) of RMR-TB 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.
Journal Article > CommentaryFull Text
Lancet Respir Med. 2020 September 1; Volume 8 (Issue 9); 844-846.; DOI:10.1016/S2213-2600(20)30311-8
Keene CM, Mohr-Holland E, Cassidy T, Scott V, Nelson AM, et al.
Lancet Respir Med. 2020 September 1; Volume 8 (Issue 9); 844-846.; DOI:10.1016/S2213-2600(20)30311-8
Journal Article > LetterFull Text
Int J Tuberc Lung Dis. 2021 May 1; Volume 25 (Issue 5); 409-412.; DOI:10.5588/ijtld.21.0010
Mohr-Holland E, Daniels J, Douglas-Jones B, Mema N, Scott V, et al.
Int J Tuberc Lung Dis. 2021 May 1; Volume 25 (Issue 5); 409-412.; DOI:10.5588/ijtld.21.0010
Journal Article > ResearchFull Text
Trop Med Infect Dis. 2022 January 31; Volume 7 (Issue 2); 21.; DOI: 10.3390/tropicalmed7020021
Reuter A, Beko B, Memani B, Furin J, Daniels J, et al.
Trop Med Infect Dis. 2022 January 31; Volume 7 (Issue 2); 21.; DOI: 10.3390/tropicalmed7020021
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.
Journal Article > Case Report/SeriesFull Text
Pediatr Infect Dis J. 2021 May 1; Volume 40 (Issue 5); e191-e192.; DOI:10.1097/INF.0000000000003069
Mohr-Holland E, Daniels J, Furin J, Loveday M, Mudaly V, et al.
Pediatr Infect Dis J. 2021 May 1; Volume 40 (Issue 5); e191-e192.; DOI:10.1097/INF.0000000000003069
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.
Journal Article > CommentaryFull Text
J Adolesc Health. 2023 March 1; Volume 72 (Issue 3); 323-331.; DOI:10.1016/j.jadohealth.2022.10.036
Chiang SS, Waterous PM, Atieno VF, Bernays S, Bondarenko Y, et al.
J Adolesc Health. 2023 March 1; Volume 72 (Issue 3); 323-331.; DOI:10.1016/j.jadohealth.2022.10.036
Journal Article > ResearchFull Text
Lancet Microbe. 2021 November 1; Volume 2 (Issue 11); e584-e593.; DOI:10.1016/S2666-5247(21)00144-0
Cox HS, Salaam-Dreyer Z, Goig GA, Nicol MP, Menardo F, et al.
Lancet Microbe. 2021 November 1; Volume 2 (Issue 11); e584-e593.; DOI:10.1016/S2666-5247(21)00144-0
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.
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.
Journal Article > ResearchFull Text
Int J Tuberc Lung Dis. 2022 February 1; Volume 26 (Issue 2); 150-157.; DOI:10.5588/ijtld.21.0494
Mohr-Holland E, Daniels J, Reuter A, Rodriguez CA, Mitnick CD, et al.
Int J Tuberc Lung Dis. 2022 February 1; Volume 26 (Issue 2); 150-157.; DOI:10.5588/ijtld.21.0494
BACKGROUND
Data suggest that treatment with newer TB drugs (linezolid [LZD], bedaquiline [BDQ] and delamanid [DLM]), used in Khayelitsha, South Africa, since 2012, reduces mortality due to rifampicin-resistant TB (RR-TB).
METHODS
This was a retrospective cohort study to assess 6-month mortality among RR-TB patients diagnosed between 2008 and 2019.
RESULTS
By 6 months, 236/2,008 (12%) patients died; 12% (78/651) among those diagnosed in 2008-2011, and respectively 8% (49/619) and 15% (109/738) with and without LZD/BDQ/DLM in 2012-2019. Multivariable analysis showed a small, non-significant mortality reduction with LZD/BDQ/DLM use compared to the 2008-2011 period (aOR 0.79, 95% CI 0.5-1.2). Inpatient treatment initiation (aOR 3.2, 95% CI 2.4-4.4), fluoroquinolone (FQ) resistance (aOR 2.7, 95% CI 1.8-4.2) and female sex (aOR 1.5, 95% CI 1.1-2.0) were also associated with mortality. When restricted to 2012-2019, use of LZD/BDQ/DLM was associated with lower mortality (aOR 0.58, 95% CI 0.39-0.87).
CONCLUSIONS
While LZD/BDQ/DLM reduced 6-month mortality between 2012 and 2019, there was no significant effect overall. These findings may be due to initially restricted LZD/BDQ/DLM use for those with high-level resistance or treatment failure. Additional contributors include increased treatment initiation among individuals who would have otherwise died before treatment due to universal drug susceptibility testing from 2012, an effect that also likely contributed to higher mortality among females (survival through to care-seeking).
Data suggest that treatment with newer TB drugs (linezolid [LZD], bedaquiline [BDQ] and delamanid [DLM]), used in Khayelitsha, South Africa, since 2012, reduces mortality due to rifampicin-resistant TB (RR-TB).
METHODS
This was a retrospective cohort study to assess 6-month mortality among RR-TB patients diagnosed between 2008 and 2019.
RESULTS
By 6 months, 236/2,008 (12%) patients died; 12% (78/651) among those diagnosed in 2008-2011, and respectively 8% (49/619) and 15% (109/738) with and without LZD/BDQ/DLM in 2012-2019. Multivariable analysis showed a small, non-significant mortality reduction with LZD/BDQ/DLM use compared to the 2008-2011 period (aOR 0.79, 95% CI 0.5-1.2). Inpatient treatment initiation (aOR 3.2, 95% CI 2.4-4.4), fluoroquinolone (FQ) resistance (aOR 2.7, 95% CI 1.8-4.2) and female sex (aOR 1.5, 95% CI 1.1-2.0) were also associated with mortality. When restricted to 2012-2019, use of LZD/BDQ/DLM was associated with lower mortality (aOR 0.58, 95% CI 0.39-0.87).
CONCLUSIONS
While LZD/BDQ/DLM reduced 6-month mortality between 2012 and 2019, there was no significant effect overall. These findings may be due to initially restricted LZD/BDQ/DLM use for those with high-level resistance or treatment failure. Additional contributors include increased treatment initiation among individuals who would have otherwise died before treatment due to universal drug susceptibility testing from 2012, an effect that also likely contributed to higher mortality among females (survival through to care-seeking).
Journal Article > ResearchFull Text
Antimicrob Agents Chemother. 2021 October 18; Volume 65 (Issue 11); e0036421.; DOI:10.1128/AAC.00364-21
Salaam-Dreyer Z, Streicher EM, Sirgel FA, Menardo F, Borrell S, et al.
Antimicrob Agents Chemother. 2021 October 18; Volume 65 (Issue 11); e0036421.; DOI:10.1128/AAC.00364-21
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.
Journal Article > ResearchFull Text
E Clinical Medicine. 2020 March 1; Volume 20; 100290.; DOI:10.1016/j.eclinm.2020.100290
Mohr-Holland E, Reuter A, Furin J, Garcia-Prats AJ, De Azevedo V, et al.
E Clinical Medicine. 2020 March 1; Volume 20; 100290.; DOI:10.1016/j.eclinm.2020.100290
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.
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.