Journal Article > ResearchFull Text
Antimicrob Agents Chemother. 9 April 2025; Online ahead of print; DOI:10.1128/aac.01839-24
Ardizzoni E, Mulders W, De Diego Fuertes M, Hayrapetyan A, Mirzoyan A, et al.
Antimicrob Agents Chemother. 9 April 2025; Online ahead of print; DOI:10.1128/aac.01839-24
Risk factors for baseline bedaquiline (BDQ) resistance, amplification during treatment, and correlations with treatment outcomes are not fully understood. This cohort included Armenian patients with multidrug-resistant TB predominantly fluoroquinolone-resistant enrolled between 2013 and 2015 in a BDQ compassionate use program. BDQ resistance at baseline and during treatment was assessed using MGIT (pDSTMGIT), minimal inhibitory concentration in 7H11 (MIC7H11), and whole-genome sequencing. Risk factors, such as treatment effectiveness or stage of the disease, were analyzed for association with baseline BDQ resistance, acquired BDQ resistance, and treatment outcome. Among 39 patients, baseline BDQ resistance was 6% (2/33) by pDSTMGIT and 7% (2/29) by MIC7H11. All four baseline isolates with an Rv0678 mutation were phenotypically resistant. During treatment, 48% of the patients acquired BDQ resistance by pDSTMGIT, and 52% acquired mutations at various frequencies (97% in Rv0678). None of the factors significantly contributed to baseline or acquired BDQ resistance. Unfavorable treatment outcome (41%) was more frequent in the presence of acquired Rv0678 mutations [odds ratio (OR) 132, 95% confidence interval (CI) 7.43, 2375], phenotypic BDQ resistance (OR 176, 95% CI 6.48, 2423), or MIC increase above or below the critical concentration (both OR 84.3, 95% CI 2.93, 2423) during treatment. For these highly treatment-experienced patients, low baseline prevalence but high incidence of acquired BDQ resistance was observed. Acquisition of mutations in BDQ candidate resistance genes, regardless of their frequency, or increased MICs during treatment, even below the critical concentration, should be seen as a warning sign of resistance amplification and increased risk of unfavorable treatment outcome.
Journal Article > ResearchFull Text
Int J Tuberc Lung Dis. 1 January 2023; Volume 27 (Issue 1); 34-40.; DOI:10.5588/ijtld.22.0324
Zeng C, Mitnick CD, Hewison CCH, Bastard M, Khan PY, et al.
Int J Tuberc Lung Dis. 1 January 2023; Volume 27 (Issue 1); 34-40.; DOI:10.5588/ijtld.22.0324
BACKGROUND
The WHO provides standardized outcome definitions for rifampicin-resistant (RR) and multidrug-resistant (MDR) TB. However, operationalizing these definitions can be challenging in some clinical settings, and incorrect classification may generate bias in reporting and research. Outcomes calculated by algorithms can increase standardization and be adapted to suit the research question. We evaluated concordance between clinician-assigned treatment outcomes and outcomes calculated based on one of two standardized algorithms, one which identified failure at its earliest possible recurrence (i.e., failure-dominant algorithm), and one which calculated the outcome based on culture results at the end of treatment, regardless of early occurrence of failure (i.e., success-dominant algorithm).
METHODS
Among 2,525 patients enrolled in the multi-country endTB observational study, we calculated the frequencies of concordance using cross-tabulations of clinician-assigned and algorithm-assigned outcomes. We summarized the common discrepancies.
RESULTS
Treatment success calculated by algorithms had high concordance with treatment success assigned by clinicians (95.8 and 97.7% for failure-dominant and success-dominant algorithms, respectively). The frequency and pattern of the most common discrepancies varied by country.
CONCLUSION
High concordance was found between clinician-assigned and algorithm-assigned outcomes. Heterogeneity in discrepancies across settings suggests that using algorithms to calculate outcomes may minimize bias.
The WHO provides standardized outcome definitions for rifampicin-resistant (RR) and multidrug-resistant (MDR) TB. However, operationalizing these definitions can be challenging in some clinical settings, and incorrect classification may generate bias in reporting and research. Outcomes calculated by algorithms can increase standardization and be adapted to suit the research question. We evaluated concordance between clinician-assigned treatment outcomes and outcomes calculated based on one of two standardized algorithms, one which identified failure at its earliest possible recurrence (i.e., failure-dominant algorithm), and one which calculated the outcome based on culture results at the end of treatment, regardless of early occurrence of failure (i.e., success-dominant algorithm).
METHODS
Among 2,525 patients enrolled in the multi-country endTB observational study, we calculated the frequencies of concordance using cross-tabulations of clinician-assigned and algorithm-assigned outcomes. We summarized the common discrepancies.
RESULTS
Treatment success calculated by algorithms had high concordance with treatment success assigned by clinicians (95.8 and 97.7% for failure-dominant and success-dominant algorithms, respectively). The frequency and pattern of the most common discrepancies varied by country.
CONCLUSION
High concordance was found between clinician-assigned and algorithm-assigned outcomes. Heterogeneity in discrepancies across settings suggests that using algorithms to calculate outcomes may minimize bias.
Journal Article > ResearchFull Text
Public Health Action. 21 June 2022; Volume 12 (Issue 2); 96-101.; DOI:10.5588/pha.22.0002
Kirakosyan O, Melikyan N, Falcao J, Khachatryan N, Atshemyan H, et al.
Public Health Action. 21 June 2022; Volume 12 (Issue 2); 96-101.; DOI:10.5588/pha.22.0002
BACKGROUND
Direct-acting antivirals (DAAs) are not widely used for patients with chronic hepatitis C virus (HCV) infection and multidrug- or rifampicin-resistant TB (MDR/RR-TB). We describe the implementation aspects of a new integrated model of care in Armenia and the perceptions of the healthcare staff and patients.
METHODS
We used qualitative methods, including a desktop review and semi-structured individual interviews with healthcare staff and with patients receiving HCV and MDR/RR-TB treatment.
RESULTS
The new integrated model resulted in simplified management of HCV and MDR/RR-TB at public TB facilities. Training on HCV was provided for TB clinic staff. All MDR/RR-TB patients were systematically offered HCV testing and those diagnosed with HCV, offered treatment with DAAs. Treatment monitoring was performed by TB staff in coordination with a hepatologist. The staff interviewed had a positive opinion of the new model. They suggested that additional training should be provided. Most patients were fully satisfied with the care received. Some were concerned about the increased pill burden.
CONCLUSION
Integrating HCV treatment into MDR/ RR-TB care was feasible and appreciated by patients and staff. This new model facilitated HCV diagnosis and treatment among people with MDR/RR-TB. Our results encourage piloting this model in other settings.
Direct-acting antivirals (DAAs) are not widely used for patients with chronic hepatitis C virus (HCV) infection and multidrug- or rifampicin-resistant TB (MDR/RR-TB). We describe the implementation aspects of a new integrated model of care in Armenia and the perceptions of the healthcare staff and patients.
METHODS
We used qualitative methods, including a desktop review and semi-structured individual interviews with healthcare staff and with patients receiving HCV and MDR/RR-TB treatment.
RESULTS
The new integrated model resulted in simplified management of HCV and MDR/RR-TB at public TB facilities. Training on HCV was provided for TB clinic staff. All MDR/RR-TB patients were systematically offered HCV testing and those diagnosed with HCV, offered treatment with DAAs. Treatment monitoring was performed by TB staff in coordination with a hepatologist. The staff interviewed had a positive opinion of the new model. They suggested that additional training should be provided. Most patients were fully satisfied with the care received. Some were concerned about the increased pill burden.
CONCLUSION
Integrating HCV treatment into MDR/ RR-TB care was feasible and appreciated by patients and staff. This new model facilitated HCV diagnosis and treatment among people with MDR/RR-TB. Our results encourage piloting this model in other settings.
Journal Article > LetterFull Text
Am J Respir Crit Care Med. 1 February 2015; Volume 191 (Issue 3); 355-358.; DOI:10.1164/rccm.201407-1302LE
Bastard M, Bonnet MMB, du Cros PAK, Khamraev AK, Hayrapetyan A, et al.
Am J Respir Crit Care Med. 1 February 2015; Volume 191 (Issue 3); 355-358.; DOI:10.1164/rccm.201407-1302LE
Journal Article > Short ReportFull Text
Clin Infect Dis. 2 November 2019; Volume 71 (Issue 2); 415-418.; DOI:10.1093/cid/ciz1084
Seung KJ, Khan PY, Franke MF, Ahmed SM, Aiylchiev S, et al.
Clin Infect Dis. 2 November 2019; Volume 71 (Issue 2); 415-418.; DOI:10.1093/cid/ciz1084
Delamanid should be effective against highly resistant strains of Mycobacterium tuberculosis, but uptake has been slow globally. In the endTB (expand new drug markets for TB) Observational Study, which enrolled a large, heterogeneous cohorts of patients receiving delamanid as part of a multidrug regimen, 80% of participants experienced sputum culture conversion within 6 months.
Journal Article > ResearchFull Text
Int J Tuberc Lung Dis. 1 February 2014; Volume 18 (Issue 2); 160-167.; DOI:10.5588/ijtld.13.0369
Sanchez-Padilla E, Marquer C, Kalon S, Qayyum S, Hayrapetyan A, et al.
Int J Tuberc Lung Dis. 1 February 2014; Volume 18 (Issue 2); 160-167.; DOI:10.5588/ijtld.13.0369
SETTING
Armenia, a country with a high prevalence of drug-resistant tuberculosis (DR-TB).
OBJECTIVE
To identify factors related to default from DR-TB treatment in Yerevan.
DESIGN
Using a retrospective cohort design, we compared defaulters with patients who were cured, completed or failed treatment. Patients who initiated DR-TB treatment from 2005 to 2011 were included in the study. A qualitative survey was conducted including semi-structured interviews with defaulters and focus group discussions with care providers.
RESULTS
Of 381 patients, 193 had achieved treatment success, 24 had died, 51 had failed treatment and 97 had defaulted. The number of drugs to which the patient was resistant at admission (aRR 1.16, 95%CI 1.05–1.27), the rate of treatment interruption based on patient's decision (aRR 1.03, 95%CI 1.02–1.05), the rate of side effects (aRR 1.18, 95%CI 1.09–1.27), and absence of culture conversion during the intensive phase (aRR 0.47, 95%CI 0.31–0.71) were independently associated with default from treatment. In the qualitative study, poor treatment tolerance, a perception that treatment was inefficient, lack of information, incorrect perception of being cured, working factors and behavioural problems were factors related to treatment default.
CONCLUSION
In addition to economic reasons, poor tolerance of and poor response to treatment were the main factors associated with treatment default.
Armenia, a country with a high prevalence of drug-resistant tuberculosis (DR-TB).
OBJECTIVE
To identify factors related to default from DR-TB treatment in Yerevan.
DESIGN
Using a retrospective cohort design, we compared defaulters with patients who were cured, completed or failed treatment. Patients who initiated DR-TB treatment from 2005 to 2011 were included in the study. A qualitative survey was conducted including semi-structured interviews with defaulters and focus group discussions with care providers.
RESULTS
Of 381 patients, 193 had achieved treatment success, 24 had died, 51 had failed treatment and 97 had defaulted. The number of drugs to which the patient was resistant at admission (aRR 1.16, 95%CI 1.05–1.27), the rate of treatment interruption based on patient's decision (aRR 1.03, 95%CI 1.02–1.05), the rate of side effects (aRR 1.18, 95%CI 1.09–1.27), and absence of culture conversion during the intensive phase (aRR 0.47, 95%CI 0.31–0.71) were independently associated with default from treatment. In the qualitative study, poor treatment tolerance, a perception that treatment was inefficient, lack of information, incorrect perception of being cured, working factors and behavioural problems were factors related to treatment default.
CONCLUSION
In addition to economic reasons, poor tolerance of and poor response to treatment were the main factors associated with treatment default.
Journal Article > ResearchFull Text
J Infect Dis. 13 October 2014; Volume 211 (Issue 10); DOI:10.1093/infdis/jiu551
Bastard M, Sanchez-Padilla E, Hewison CCH, Hayrapetyan A, Khurkhumal S, et al.
J Infect Dis. 13 October 2014; Volume 211 (Issue 10); DOI:10.1093/infdis/jiu551
The success of the current treatment regimen for multidrug-resistant tuberculosis (MDR-TB) is poor partly due to a high defaulter rate. Many studies explored predictors of poor outcomes, but very few assessed the impact of treatment interruptions on MDR-TB treatment outcomes.
Journal Article > ResearchFull Text
PLOS One. 8 March 2018; Volume 13 (Issue 3); DOI:10.1371/journal.pone.0193491
Bastard M, Sanchez-Padilla E, du Cros PAK, Khamraev AK, Parpieva N, et al.
PLOS One. 8 March 2018; Volume 13 (Issue 3); DOI:10.1371/journal.pone.0193491
The emergence of resistance to anti-tuberculosis (DR-TB) drugs and the HIV epidemic represent a serious threat for reducing the global burden of TB. Although data on HIV-negative DR-TB treatment outcomes are well published, few data on DR-TB outcomes among HIV co-infected people is available despite the great public health importance.
Journal Article > ResearchFull Text
Arch Dis Child. 6 December 2018; Volume 104 (Issue 7); 622-628.; DOI:10.1136/archdischild-2018-315411
Huerga H, Sanchez-Padilla E, Melikyan N, Atshemyan H, Ulumyan A, et al.
Arch Dis Child. 6 December 2018; Volume 104 (Issue 7); 622-628.; DOI:10.1136/archdischild-2018-315411
OBJECTIVE
We aimed to measure the prevalence and incidence of latent tuberculosis infection (LTBI) and tuberculosis (TB) disease in children in close contact with patients with drug-resistant TB (DR-TB) in a country with high DR-TB prevalence.
DESIGN AND SETTING
This is a prospective cohort study of paediatric contacts of adult patients with pulmonary DR-TB in Armenia. Children were screened using tuberculin skin test, interferon-gamma release assay and chest X-ray at the initial consultation, and were reassessed every 3–6 months for a period of 24 months. Children did not receive preventive treatment.
MAIN OUTCOME MEASURES
Prevalence and incidence of LTBI and TB disease; factors associated with prevalent LTBI.
RESULTS
At initial evaluation, 3 of the 150 children included were diagnosed with TB disease (2.0%). The prevalence of LTBI was 58.7%. The incidence of LTBI was 19.9 per 100 children per year, and was especially high during the first 6 months of follow-up (33.3 per 100 children per year). No additional cases with incident disease were diagnosed during follow-up. After adjustment, prevalent LTBI was significantly associated with the child’s age, sleeping in the same house, higher household density, the index case’s age, positive smear result and presence of lung cavities.
CONCLUSIONS
Children in close contact with patients with DR-TB or in contact with very contagious patients had an increased risk of prevalent LTBI. Although none of the children developed TB disease during a 2-year follow-up period, screening for symptoms of TB disease, based on the prevalence of disease at recruitment, together with follow-up and repeated testing of non-infected contacts, is highly recommended in paediatric contacts of patients with DR-TB.
We aimed to measure the prevalence and incidence of latent tuberculosis infection (LTBI) and tuberculosis (TB) disease in children in close contact with patients with drug-resistant TB (DR-TB) in a country with high DR-TB prevalence.
DESIGN AND SETTING
This is a prospective cohort study of paediatric contacts of adult patients with pulmonary DR-TB in Armenia. Children were screened using tuberculin skin test, interferon-gamma release assay and chest X-ray at the initial consultation, and were reassessed every 3–6 months for a period of 24 months. Children did not receive preventive treatment.
MAIN OUTCOME MEASURES
Prevalence and incidence of LTBI and TB disease; factors associated with prevalent LTBI.
RESULTS
At initial evaluation, 3 of the 150 children included were diagnosed with TB disease (2.0%). The prevalence of LTBI was 58.7%. The incidence of LTBI was 19.9 per 100 children per year, and was especially high during the first 6 months of follow-up (33.3 per 100 children per year). No additional cases with incident disease were diagnosed during follow-up. After adjustment, prevalent LTBI was significantly associated with the child’s age, sleeping in the same house, higher household density, the index case’s age, positive smear result and presence of lung cavities.
CONCLUSIONS
Children in close contact with patients with DR-TB or in contact with very contagious patients had an increased risk of prevalent LTBI. Although none of the children developed TB disease during a 2-year follow-up period, screening for symptoms of TB disease, based on the prevalence of disease at recruitment, together with follow-up and repeated testing of non-infected contacts, is highly recommended in paediatric contacts of patients with DR-TB.
Journal Article > ResearchFull Text
Lancet Infect Dis. 13 February 2018; Volume 18 (Issue 5); 536-544.; DOI:10.1016/S1473-3099(18)30100-2
Ferlazzo G, Mohr E, Laxmeshwar C, Hewison CCH, Hughes J, et al.
Lancet Infect Dis. 13 February 2018; Volume 18 (Issue 5); 536-544.; DOI:10.1016/S1473-3099(18)30100-2
BACKGROUND
Bedaquiline and delamanid have been approved for treatment of multidrug-resistant (MDR) tuberculosis in the past 5 years. Because of theoretical safety concerns, patients have been unable to access the two drugs in combination. Médecins Sans Frontières has supported the use of combination bedaquiline and delamanid for people with few treatment options since 2016. We describe early safety and efficacy of regimens containing the bedaquiline and delamanid combination in patients with drug-resistant tuberculosis in Yerevan, Armenia; Mumbai, India; and Khayelitsha, South Africa.
METHODS
We retrospectively analysed a cohort of all patients who received 6-12 months of oral bedaquiline and delamanid in combination (400 mg bedaquiline once per day for 2 weeks, then 200 mg bedaquiline three times per week and 100 mg delamanid twice per day) in MSF-supported projects. We report serious adverse events, QTc corrected using the Fridericia formula (QTcF) interval data, and culture conversion data during the first 6 months of treatment.
FINDINGS
Between Jan 1, 2016, and Aug 31, 2016, 28 patients (median age 32·5 years [IQR 28·5-40·5], 17 men) were included in the analysis. 11 (39%) of 28 patients were HIV-positive. 24 patients (86%) had isolates resistant to fluoroquinolones; 14 patients (50%) had extensively drug-resistant tuberculosis. No patient had an increase of more than 500 ms in their QTcF interval. Four patients (14%) had six instances of QTcF increase of more than 60 ms from baseline but none permanently discontinued the drugs. 16 serious adverse events were reported in seven patients. Of 23 individuals with positive baseline cultures, 17 (74%) converted to negative by month 6 of treatment.
INTERPRETATION
Use of the bedaquiline and delamanid combination appears to reveal no additive or synergistic QTcF-prolonging effects. Access to bedaquiline and delamanid in combination should be expanded for people with few treatment options while awaiting the results of formal clinical trials.
Bedaquiline and delamanid have been approved for treatment of multidrug-resistant (MDR) tuberculosis in the past 5 years. Because of theoretical safety concerns, patients have been unable to access the two drugs in combination. Médecins Sans Frontières has supported the use of combination bedaquiline and delamanid for people with few treatment options since 2016. We describe early safety and efficacy of regimens containing the bedaquiline and delamanid combination in patients with drug-resistant tuberculosis in Yerevan, Armenia; Mumbai, India; and Khayelitsha, South Africa.
METHODS
We retrospectively analysed a cohort of all patients who received 6-12 months of oral bedaquiline and delamanid in combination (400 mg bedaquiline once per day for 2 weeks, then 200 mg bedaquiline three times per week and 100 mg delamanid twice per day) in MSF-supported projects. We report serious adverse events, QTc corrected using the Fridericia formula (QTcF) interval data, and culture conversion data during the first 6 months of treatment.
FINDINGS
Between Jan 1, 2016, and Aug 31, 2016, 28 patients (median age 32·5 years [IQR 28·5-40·5], 17 men) were included in the analysis. 11 (39%) of 28 patients were HIV-positive. 24 patients (86%) had isolates resistant to fluoroquinolones; 14 patients (50%) had extensively drug-resistant tuberculosis. No patient had an increase of more than 500 ms in their QTcF interval. Four patients (14%) had six instances of QTcF increase of more than 60 ms from baseline but none permanently discontinued the drugs. 16 serious adverse events were reported in seven patients. Of 23 individuals with positive baseline cultures, 17 (74%) converted to negative by month 6 of treatment.
INTERPRETATION
Use of the bedaquiline and delamanid combination appears to reveal no additive or synergistic QTcF-prolonging effects. Access to bedaquiline and delamanid in combination should be expanded for people with few treatment options while awaiting the results of formal clinical trials.