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 > ResearchFull Text
Public Health Action. 21 June 2022; Volume 12 (Issue 2); 55-57.; DOI:10.5588/pha.21.0083
Memani B, Beko B, Dumile N, Mohr-Holland E, Daniels J, et al.
Public Health Action. 21 June 2022; Volume 12 (Issue 2); 55-57.; DOI:10.5588/pha.21.0083
Patients initiated on drug-resistant TB (DR-TB) treatment in 2019 in Khayelitsha, South Africa, with a loss to follow-up outcome were evaluated to better understand reasons for loss to follow-up and to determine if any had returned to care. Of a total of 187 patients, 28 (15%) were lost to follow-up (LTFU), 24 (86%) of whom were traced: 20/24 (83%) were found when they re-presented to facilities and 8/28 (29%) were linked back to DR-TB care. People with DR-TB continue to seek care even after being LTFU; thus better coordination between different components of the healthcare system are required to re-engage with these patients. Interventions to mitigate the socio-economic challenges of people on DR-TB treatment are needed. Many people who were LTFU and symptomatic were willing to re-engage with DR-TB care, which highlights the importance of for compassionate interventions to welcome them back.
Journal Article > ReviewSubscription Only
Curr Opin HIV AIDS. 1 January 2019; Volume 14 (Issue 1); 21-27.; DOI:10.1097/COH.0000000000000517
Fargher J, Reuter A, Furin J
Curr Opin HIV AIDS. 1 January 2019; Volume 14 (Issue 1); 21-27.; DOI:10.1097/COH.0000000000000517
PURPOSE OF REVIEW
More than two billion people are infected with Mycobacterium tuberculosis and few of them are ever offered therapy in spite of such treatment being associated with reduced rates of morbidity and mortality. This article reviews the current recommendations on the diagnosis and treatment of TB infection (or what is commonly referred to as 'prophylaxis' or 'preventive therapy' of latent TB) and discusses barriers to implementation that have led to low demand for this life-saving therapeutic intervention.
RECENT FINDINGS
Treatment of infection for both TB and drug-resistant TB is well tolerated and effective, and several new, shorter regimens - including rfiapenitine-based regimens of 1 month and 12 weeks duration - have been shown to be effective. Not all persons infected with TB go on to develop disease and the risk is the highest in the first 2 years after infection. Given this, additional work is needed to better identify those at the highest risk of developing active TB.
SUMMARY
Practitioners should offer newer, shorter regimens to persons who are infected with TB and at high risk of developing disease, including people living with HIV and household contacts of people living with TB who are age 5 years and under. This includes individuals who have been exposed to drug-resistant forms of disease. Socioeconomic risk factors may play a key role in the development of TB disease and should also be addressed.
More than two billion people are infected with Mycobacterium tuberculosis and few of them are ever offered therapy in spite of such treatment being associated with reduced rates of morbidity and mortality. This article reviews the current recommendations on the diagnosis and treatment of TB infection (or what is commonly referred to as 'prophylaxis' or 'preventive therapy' of latent TB) and discusses barriers to implementation that have led to low demand for this life-saving therapeutic intervention.
RECENT FINDINGS
Treatment of infection for both TB and drug-resistant TB is well tolerated and effective, and several new, shorter regimens - including rfiapenitine-based regimens of 1 month and 12 weeks duration - have been shown to be effective. Not all persons infected with TB go on to develop disease and the risk is the highest in the first 2 years after infection. Given this, additional work is needed to better identify those at the highest risk of developing active TB.
SUMMARY
Practitioners should offer newer, shorter regimens to persons who are infected with TB and at high risk of developing disease, including people living with HIV and household contacts of people living with TB who are age 5 years and under. This includes individuals who have been exposed to drug-resistant forms of disease. Socioeconomic risk factors may play a key role in the development of TB disease and should also be addressed.
Journal Article > ResearchFull Text
Lancet Infect Dis. 2 May 2022; Online ahead of print; DOI:10.1016/S1473-3099(21)00811-2
Ndjeka N, Campbell JR, Meintjes GA, Maartens G, Schaaf HS, et al.
Lancet Infect Dis. 2 May 2022; Online ahead of print; DOI:10.1016/S1473-3099(21)00811-2
BACKGROUND
There is a need for short and safe all-oral treatment of rifampicin-resistant tuberculosis. We compared outcomes up to 24 months after treatment initiation for patients with rifampicin-resistant tuberculosis in South Africa treated with a short, all-oral bedaquiline-containing regimen (bedaquiline group), or a short, injectable-containing regimen (injectable group).
METHODS
Patients with rifampicin-resistant tuberculosis, aged 18 years or older, eligible for a short regimen starting treatment between Jan 1 and Dec 31, 2017, with a bedaquiline-containing or WHO recommended injectable containing treatment regimen of 9–12 months, registered in the drug-resistant tuberculosis database (EDRWeb), and with known age, sex, HIV status, and national identification number were eligible for study inclusion; patients receiving linezolid, carbapenems, terizidone or cycloserine, delamanid, or para-aminosalicylic acid were excluded. Bedaquiline was given at a dose of 400 mg once daily for two weeks followed by 200 mg three times a week for 22 weeks. To compare regimens, patients were exactly matched on HIV and ART status, previous tuberculosis treatment history, and baseline acid-fast bacilli smear and culture result, while propensity score matched on age, sex, province of treatment, and isoniazid-susceptibility status. We did binomial linear regression to estimate adjusted risk differences (aRD) and 95% CIs for 24-month outcomes, which included: treatment success (ie, cure or treatment completion without evidence of recurrence) versus all other outcomes, survival versus death, disease free survival versus survival with treatment failure or recurrence, and loss to follow-up versus all other outcomes.
FINDINGS
Overall, 1387 (14%) of 10152 patients with rifampicin-resistant tuberculosis treated during 2017 met inclusion criteria; 688 in the bedaquiline group and 699 in the injectable group. Four patients (1%) had treatment failure or recurrence, 44 (6%) were lost to follow-up, and 162 (24%) died in the bedaquiline group, compared with 17 (2%), 87 (12%), and 199 (28%), respectively, in the injectable group. In adjusted analyses, treatment success was 14% (95% CI 8–20) higher in the bedaquiline group than in the injectable group (70% vs 57%); loss to follow-up was 4% (1–8) lower in the bedaquiline group (6% vs 12%); and disease-free survival was 2% (0–5) higher in the bedaquiline group (99% vs 97%). The bedaquiline group had 8% (4–11) lower risk of mortality during treatment (17·0% vs 22·4%), but there was no difference in mortality post-treatment.
INTERPRETATION
Patients in the bedaquiline group experienced significantly higher rates of treatment success at 24 months. This finding supports the use of short bedaquiline-containing regimens in eligible patients.
FUNDING
WHO Global TB Programme.
There is a need for short and safe all-oral treatment of rifampicin-resistant tuberculosis. We compared outcomes up to 24 months after treatment initiation for patients with rifampicin-resistant tuberculosis in South Africa treated with a short, all-oral bedaquiline-containing regimen (bedaquiline group), or a short, injectable-containing regimen (injectable group).
METHODS
Patients with rifampicin-resistant tuberculosis, aged 18 years or older, eligible for a short regimen starting treatment between Jan 1 and Dec 31, 2017, with a bedaquiline-containing or WHO recommended injectable containing treatment regimen of 9–12 months, registered in the drug-resistant tuberculosis database (EDRWeb), and with known age, sex, HIV status, and national identification number were eligible for study inclusion; patients receiving linezolid, carbapenems, terizidone or cycloserine, delamanid, or para-aminosalicylic acid were excluded. Bedaquiline was given at a dose of 400 mg once daily for two weeks followed by 200 mg three times a week for 22 weeks. To compare regimens, patients were exactly matched on HIV and ART status, previous tuberculosis treatment history, and baseline acid-fast bacilli smear and culture result, while propensity score matched on age, sex, province of treatment, and isoniazid-susceptibility status. We did binomial linear regression to estimate adjusted risk differences (aRD) and 95% CIs for 24-month outcomes, which included: treatment success (ie, cure or treatment completion without evidence of recurrence) versus all other outcomes, survival versus death, disease free survival versus survival with treatment failure or recurrence, and loss to follow-up versus all other outcomes.
FINDINGS
Overall, 1387 (14%) of 10152 patients with rifampicin-resistant tuberculosis treated during 2017 met inclusion criteria; 688 in the bedaquiline group and 699 in the injectable group. Four patients (1%) had treatment failure or recurrence, 44 (6%) were lost to follow-up, and 162 (24%) died in the bedaquiline group, compared with 17 (2%), 87 (12%), and 199 (28%), respectively, in the injectable group. In adjusted analyses, treatment success was 14% (95% CI 8–20) higher in the bedaquiline group than in the injectable group (70% vs 57%); loss to follow-up was 4% (1–8) lower in the bedaquiline group (6% vs 12%); and disease-free survival was 2% (0–5) higher in the bedaquiline group (99% vs 97%). The bedaquiline group had 8% (4–11) lower risk of mortality during treatment (17·0% vs 22·4%), but there was no difference in mortality post-treatment.
INTERPRETATION
Patients in the bedaquiline group experienced significantly higher rates of treatment success at 24 months. This finding supports the use of short bedaquiline-containing regimens in eligible patients.
FUNDING
WHO Global TB Programme.
Journal Article > Case Report/SeriesFull Text
N Engl J Med. 30 May 2019; Volume 380 (Issue 22); 2178-2180.; DOI:10.1056/NEJMc1815121
de Vos M, Ley SD, Wiggins KB, Derendinger B, Dippenaar A, et al.
N Engl J Med. 30 May 2019; Volume 380 (Issue 22); 2178-2180.; DOI:10.1056/NEJMc1815121