Journal Article > ResearchFull Text
Lancet Microbe. 1 December 2023; Volume 4 (Issue 12); e972-e982.; DOI:10.1016/S2666-5247(23)00172-6
Derendinger B, Dippenaar A, de Vos M, Huo S, Alberts R, et al.
Lancet Microbe. 1 December 2023; Volume 4 (Issue 12); e972-e982.; DOI:10.1016/S2666-5247(23)00172-6
BACKGROUND
Bedaquiline is a life-saving tuberculosis drug undergoing global scale-up. People at risk of weak tuberculosis drug regimens are a priority for novel drug access despite the potential source of Mycobacterium tuberculosis-resistant strains. We aimed to characterise bedaquiline resistance in individuals who had sustained culture positivity during bedaquiline-based treatment.
METHODS
We did a retrospective longitudinal cohort study of adults (aged ≥18 years) with culture-positive pulmonary tuberculosis who received at least 4 months of a bedaquiline-containing regimen from 12 drug-resistant tuberculosis treatment facilities in Cape Town, South Africa, between Jan 20, 2016, and Nov 20, 2017. Sputum was programmatically collected at baseline (ie, before bedaquiline initiation) and each month to monitor treatment response per the national algorithm. The last available isolate from the sputum collected at or after 4 months of bedaquiline was designated the follow-up isolate. Phenotypic drug susceptibility testing for bedaquiline was done on baseline and follow-up isolates in MGIT960 media (WHO-recommended critical concentration of 1 μg/mL). Targeted deep sequencing for Rv0678, atpE, and pepQ, as well as whole-genome sequencing were also done.
FINDINGS
In total, 40 (31%) of 129 patients from an estimated pool were eligible for this study. Overall, three (8%) of 38 patients assessable by phenotypic drug susceptibility testing for bedaquiline had primary resistance, 18 (47%) gained resistance (acquired or reinfection), and 17 (45%) were susceptible at both baseline and follow-up. Several Rv0678 and pepQ single-nucleotide polymorphisms and indels were associated with resistance. Although variants occurred in Rv0676c and Rv1979c, these variants were not associated with resistance. Targeted deep sequencing detected low-level variants undetected by whole-genome sequencing; however, none were in genes without variants already detected by whole-genome sequencing. Patients with baseline fluoroquinolone resistance, clofazimine exposure, and four or less effective drugs were more likely to have bedaquiline-resistant gain. Resistance gain was primarily due to acquisition; however, some reinfection by resistant strains occurred.
INTERPRETATION
Bedaquiline-resistance gain, for which we identified risk factors, was common in these programmatically treated patients with sustained culture positivity. Our study highlights risks associated with implementing life-saving new drugs and shows evidence of bedaquiline-resistance transmission. Routine drug susceptibility testing should urgently accompany scale-up of new drugs; however, rapid drug susceptibility testing for bedaquiline remains challenging given the diversity of variants observed.
Bedaquiline is a life-saving tuberculosis drug undergoing global scale-up. People at risk of weak tuberculosis drug regimens are a priority for novel drug access despite the potential source of Mycobacterium tuberculosis-resistant strains. We aimed to characterise bedaquiline resistance in individuals who had sustained culture positivity during bedaquiline-based treatment.
METHODS
We did a retrospective longitudinal cohort study of adults (aged ≥18 years) with culture-positive pulmonary tuberculosis who received at least 4 months of a bedaquiline-containing regimen from 12 drug-resistant tuberculosis treatment facilities in Cape Town, South Africa, between Jan 20, 2016, and Nov 20, 2017. Sputum was programmatically collected at baseline (ie, before bedaquiline initiation) and each month to monitor treatment response per the national algorithm. The last available isolate from the sputum collected at or after 4 months of bedaquiline was designated the follow-up isolate. Phenotypic drug susceptibility testing for bedaquiline was done on baseline and follow-up isolates in MGIT960 media (WHO-recommended critical concentration of 1 μg/mL). Targeted deep sequencing for Rv0678, atpE, and pepQ, as well as whole-genome sequencing were also done.
FINDINGS
In total, 40 (31%) of 129 patients from an estimated pool were eligible for this study. Overall, three (8%) of 38 patients assessable by phenotypic drug susceptibility testing for bedaquiline had primary resistance, 18 (47%) gained resistance (acquired or reinfection), and 17 (45%) were susceptible at both baseline and follow-up. Several Rv0678 and pepQ single-nucleotide polymorphisms and indels were associated with resistance. Although variants occurred in Rv0676c and Rv1979c, these variants were not associated with resistance. Targeted deep sequencing detected low-level variants undetected by whole-genome sequencing; however, none were in genes without variants already detected by whole-genome sequencing. Patients with baseline fluoroquinolone resistance, clofazimine exposure, and four or less effective drugs were more likely to have bedaquiline-resistant gain. Resistance gain was primarily due to acquisition; however, some reinfection by resistant strains occurred.
INTERPRETATION
Bedaquiline-resistance gain, for which we identified risk factors, was common in these programmatically treated patients with sustained culture positivity. Our study highlights risks associated with implementing life-saving new drugs and shows evidence of bedaquiline-resistance transmission. Routine drug susceptibility testing should urgently accompany scale-up of new drugs; however, rapid drug susceptibility testing for bedaquiline remains challenging given the diversity of variants observed.
Journal Article > ResearchFull Text
Lancet Microbe. 6 June 2023; Volume S2666-5247 (Issue 23); 00110-6.; DOI:10.1016/S2666-5247(23)00110-6
Goig GA, Menardo F, Salaam-Dreyer Z, Dippenaar A, Streicher EM, et al.
Lancet Microbe. 6 June 2023; Volume S2666-5247 (Issue 23); 00110-6.; DOI:10.1016/S2666-5247(23)00110-6
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.
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.
Journal Article > ResearchFull Text
Open Forum Infect Dis. 21 February 2023; Volume 10 (Issue 3); ofad087.; DOI:10.1093/ofid/ofad087
Apolisi I, Cox HS, Tyeku N, Daniels J, Mathee S, et al.
Open Forum Infect Dis. 21 February 2023; Volume 10 (Issue 3); ofad087.; DOI:10.1093/ofid/ofad087
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.
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.
Journal Article > LetterFull Text
Int J Tuberc Lung Dis. 1 December 2022; Volume 26 (Issue 12); 1180-1182.; DOI:10.5588/ijtld.22.0335
Memani B, Furin J, Cox HS, Reuter A
Int J Tuberc Lung Dis. 1 December 2022; Volume 26 (Issue 12); 1180-1182.; DOI:10.5588/ijtld.22.0335
Journal Article > LetterFull Text
Int J Tuberc Lung Dis. 1 November 2022; Volume 26 (Issue 11); 1092-1093.; DOI:10.5588/ijtld.22.0445
Furin J, Reuter A, Eyde L, Cox HS
Int J Tuberc Lung Dis. 1 November 2022; Volume 26 (Issue 11); 1092-1093.; DOI:10.5588/ijtld.22.0445
Journal Article > LetterFull Text
Int J Tuberc Lung Dis. 1 October 2022; Volume 26 (Issue 10); 986-988.; DOI:10.5588/ijtld.22.0264
Tyeku N, Apolisi I, Daniels J, Beko B, Memani B, et al.
Int J Tuberc Lung Dis. 1 October 2022; Volume 26 (Issue 10); 986-988.; DOI:10.5588/ijtld.22.0264
Journal Article > Short ReportFull Text
Lancet Infect Dis. 13 March 2018; Volume 18 (Issue 9); DOI:10.1016/S1473-3099(18)30104-X
Cox HS, Hughes J, Black JM, Nicol MP
Lancet Infect Dis. 13 March 2018; Volume 18 (Issue 9); DOI:10.1016/S1473-3099(18)30104-X
Treatment for drug-resistant tuberculosis is largely delivered through standardised, empirical combination regimens in low-resource, high-burden settings. However, individualised treatment, guided by detailed drug susceptibility testing, probably results in improved individual outcomes and is the standard of care in well-resourced settings. Driven by the urgent need to scale up treatment provision, new tuberculosis drugs, incorporated into standardised regimens, are being tested. Although standardised regimens are expected to improve access to treatment in high-burden settings, they are also likely to contribute to the emergence of resistance, even with good clinical management. We argue that a balance is required between the need to improve treatment access and the imperative to minimise resistance amplification and provide the highest standard of care, through a precision medicine approach. In tuberculosis, as in other diseases, we should aim to reduce the entrenched inequalities that manifest as different standards of care in different settings.
Journal Article > ResearchFull Text
PLOS One. 1 December 2011; Volume 6 (Issue 12); DOI:10.1371/journal.pone.0028066
Isaakidis P, Cox HS, Varghese B, Montaldo C, Da Silva E, et al.
PLOS One. 1 December 2011; Volume 6 (Issue 12); DOI:10.1371/journal.pone.0028066
India carries one quarter of the global burden of multi-drug resistant TB (MDR-TB) and has an estimated 2.5 million people living with HIV. Despite this reality, provision of treatment for MDR-TB is extremely limited, particularly for HIV-infected individuals. Médecins Sans Frontières (MSF) has been treating HIV-infected MDR-TB patients in Mumbai since May 2007. This is the first report of treatment outcomes among HIV-infected MDR-TB patients in India.
Journal Article > ResearchFull Text
Int J Tuberc Lung Dis. 1 February 2015; Volume 19 (Issue 2); 172-178.; DOI:10.5588/ijtld.14.0421
Sinanovic E, Ramma L, Vassall A, Azevedo VD, Wilkinson LS, et al.
Int J Tuberc Lung Dis. 1 February 2015; Volume 19 (Issue 2); 172-178.; DOI:10.5588/ijtld.14.0421
SETTING
The cost of multidrug-resistant tuberculosis (MDR-TB) treatment is a major barrier to treatment scale-up in South Africa.
OBJECTIVE
To estimate and compare the cost of treatment for rifampicin-resistant tuberculosis (RR-TB) in South Africa in different models of care in different settings.
DESIGN
We estimated the costs of different models of care with varying levels of hospitalisation. These costs were used to calculate the total cost of treating all diagnosed cases of RR-TB in South Africa, and to estimate the budget impact of adopting a fully or partially decentralised model vs. a fully hospitalised model.
RESULTS
The fully hospitalised model was 42% more costly than the fully decentralised model (US$13 432 vs. US$7753 per patient). A much shorter hospital stay in the decentralised models of care (44–57 days), compared to 128 days of hospitalisation in the fully hospitalised model, was the key contributor to the reduced cost of treatment. The annual total cost of treating all diagnosed cases ranged from US$110 million in the fully decentralised model to US$190 million in the fully hospitalised model.
CONCLUSION
Following a more decentralised approach for treating RR-TB patients could potentially improve the affordability of RR-TB treatment in South Africa.
The cost of multidrug-resistant tuberculosis (MDR-TB) treatment is a major barrier to treatment scale-up in South Africa.
OBJECTIVE
To estimate and compare the cost of treatment for rifampicin-resistant tuberculosis (RR-TB) in South Africa in different models of care in different settings.
DESIGN
We estimated the costs of different models of care with varying levels of hospitalisation. These costs were used to calculate the total cost of treating all diagnosed cases of RR-TB in South Africa, and to estimate the budget impact of adopting a fully or partially decentralised model vs. a fully hospitalised model.
RESULTS
The fully hospitalised model was 42% more costly than the fully decentralised model (US$13 432 vs. US$7753 per patient). A much shorter hospital stay in the decentralised models of care (44–57 days), compared to 128 days of hospitalisation in the fully hospitalised model, was the key contributor to the reduced cost of treatment. The annual total cost of treating all diagnosed cases ranged from US$110 million in the fully decentralised model to US$190 million in the fully hospitalised model.
CONCLUSION
Following a more decentralised approach for treating RR-TB patients could potentially improve the affordability of RR-TB treatment in South Africa.
Journal Article > LetterFull Text
Eur Respir J. 1 December 2015; Volume 46 (Issue 6); DOI:10.1183/13993003.01374-2015
Hughes J, Isaakidis P, Andries A, Mansoor H, Cox V, et al.
Eur Respir J. 1 December 2015; Volume 46 (Issue 6); DOI:10.1183/13993003.01374-2015