Journal Article > ResearchFull Text
AIDS Care. 2005 July 1; Volume 17 (Issue 5); DOI:10.1080/09540120412331319714
Jelsma J, Maclean E, Hughes J, Tinise X, Darder M
AIDS Care. 2005 July 1; Volume 17 (Issue 5); DOI:10.1080/09540120412331319714
The health authorities have recently accepted the routine provision of highly active antiretroviral therapy to persons living with AIDS in South Africa. There is a need to investigate the impact of HAART on the health-related quality of life of people living with HIV/AIDS (PLWHA) in a resource-poor environment, as this will have an influence on compliance and treatment outcome. The aim of this study was to explore whether HAART is efficacious in improving the self-reported health-related quality of life (HRQoL) in a group of PWLA in WHO Stages 3 and 4 living in a resource-poor community. A quasi-experimental, prospective repeated measures design was used to monitor the HRQoL over time in participants recruited to an existing HAART programme. The HRQoL of 117 participants was determined through the use of the Xhosa version of the EQ-5D and measurements were taken at baseline, one, six and 12 months. At the time of the 12-month questionnaire, 95 participants had been on HAART for 12 months. Not all participants attended all follow-up visits, but only two participants had withdrawn from the HAART programme, after two or three months. At baseline, the rank order of problems reported in all domains of the EQ-5D was significantly greater than at 12 months. The mean score on the global rating of health status increased significantly (p < 0.001) from a mean of 61.7 (SD = 22.7) at baseline to 76.1 at 12 months (SD = 18.5) It is concluded that, even in a resource-poor environment, HRQoL can be greatly improved by HAART, and that the possible side effects of the drugs seem to have a negligible impact on the wellbeing of the subjects. This bodes well for the anticipated roll-out of HAART within the public health sector in South Africa.
Journal Article > Short ReportFull Text
Lancet Infect Dis. 2018 March 13; Volume 18 (Issue 9); DOI:10.1016/S1473-3099(18)30104-X
Cox HS, Hughes J, Black JM, Nicol MP
Lancet Infect Dis. 2018 March 13; 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
Int J Tuberc Lung Dis. 2014 April 1; Volume 18 (Issue 4); 441-448.; DOI:10.5588/ijtld.13.0742
Cox HS, Hughes J, Daniels J, Azevedo VD, McDermid C, et al.
Int J Tuberc Lung Dis. 2014 April 1; Volume 18 (Issue 4); 441-448.; DOI:10.5588/ijtld.13.0742
SETTING: Khayelitsha, South Africa, a peri-urban township with high burdens of tuberculosis (TB), drug-resistant tuberculosis (DR-TB), and human immunodeficiency virus (HIV) infection.
OBJECTIVE: To describe case detection and patient outcomes in a community-based DR-TB programme.
DESIGN: DR-TB management was integrated into primary health care in Khayelitsha from 2007 onwards. Implementation was incremental, and included training and clinician support, counselling and home visits, tuberculous infection control, a local in-patient service, and routine monitoring. Patients received treatment rapidly through their local clinic, and were only hospitalised if clinically unwell.
RESULTS: DR-TB case notification (any rifampicin resistance) increased from 28 per 100 000 population per year (2005–2007) to 55/100 000/year in 2009–2011 (72% HIV-infected). From 2008 to 2011, 754 patients received treatment (86% of those diagnosed). The median time between diagnostic sputum and treatment decreased over the years of implementation to 27 days in 2011 (P < 0.001). Treatment success was 52% in 2010, with 31% default, 13% death and 4% treatment failure. Two-year survival was 65%, with poorer survival in those with HIV (HR 2.0, 95%CI 1.4–2.8), second-line drug resistance (HR 3.3, 95%CI 2.2–4.8), and diagnosis in earlier programme years (HR 1.4, 95%CI 1.1–2.0).
CONCLUSION: Community-based DR-TB management is feasible, and contributes to improved case detection, reduced treatment delay and improved survival. Treatment outcomes remain poor, highlighting the poor efficacy, tolerability and lengthy duration of current treatment.
OBJECTIVE: To describe case detection and patient outcomes in a community-based DR-TB programme.
DESIGN: DR-TB management was integrated into primary health care in Khayelitsha from 2007 onwards. Implementation was incremental, and included training and clinician support, counselling and home visits, tuberculous infection control, a local in-patient service, and routine monitoring. Patients received treatment rapidly through their local clinic, and were only hospitalised if clinically unwell.
RESULTS: DR-TB case notification (any rifampicin resistance) increased from 28 per 100 000 population per year (2005–2007) to 55/100 000/year in 2009–2011 (72% HIV-infected). From 2008 to 2011, 754 patients received treatment (86% of those diagnosed). The median time between diagnostic sputum and treatment decreased over the years of implementation to 27 days in 2011 (P < 0.001). Treatment success was 52% in 2010, with 31% default, 13% death and 4% treatment failure. Two-year survival was 65%, with poorer survival in those with HIV (HR 2.0, 95%CI 1.4–2.8), second-line drug resistance (HR 3.3, 95%CI 2.2–4.8), and diagnosis in earlier programme years (HR 1.4, 95%CI 1.1–2.0).
CONCLUSION: Community-based DR-TB management is feasible, and contributes to improved case detection, reduced treatment delay and improved survival. Treatment outcomes remain poor, highlighting the poor efficacy, tolerability and lengthy duration of current treatment.
Journal Article > ResearchFull Text
PLOS One. 2015 November 10; Volume 10 (Issue 11); e0142873.; DOI:10.1371/journal.pone.0142873
Daniels J, Khogali MA, Mohr E, Cox V, Moyo S, et al.
PLOS One. 2015 November 10; Volume 10 (Issue 11); e0142873.; DOI:10.1371/journal.pone.0142873
SETTING
Khayelitsha, South Africa, with high burdens of rifampicin-resistant tuberculosis (RR-TB) and HIV co-infection.
OBJECTIVE
To describe time to antiretroviral treatment (ART) initiation among HIV-infected RR-TB patients initiating RR-TB treatment and to assess the association between time to ART initiation and treatment outcomes.
DESIGN
A retrospective cohort study of patients with RR-TB and HIV co-infection not on ART at RR-TB treatment initiation.
RESULTS
Of the 696 RR-TB and HIV-infected patients initiated on RR-TB treatment between 2009 and 2013, 303 (44%) were not on ART when RR-TB treatment was initiated. The median CD4 cell count was 126 cells/mm3. Overall 257 (85%) patients started ART during RR-TB treatment, 33 (11%) within 2 weeks, 152 (50%) between 2-8 weeks and 72 (24%) after 8 weeks. Of the 46 (15%) who never started ART, 10 (21%) died or stopped RR-TB treatment within 4 weeks and 16 (37%) had at least 4 months of RR-TB treatment. Treatment success and mortality during treatment did not vary by time to ART initiation: treatment success was 41%, 43%, and 50% among patients who started ART within 2 weeks, between 2-8 weeks, and after 8 weeks (p = 0.62), while mortality was 21%, 13% and 15% respectively (p = 0.57). Mortality was associated with never receiving ART (adjusted hazard ratio (aHR) 6.0, CI 2.1-18.1), CD4 count ≤100 (aHR 2.1, CI 1.0-4.5), and multidrug-resistant tuberculosis (MDR-TB) with second-line resistance (aHR 2.5, CI 1.1-5.4).
CONCLUSIONS
Despite wide variation in time to ART initiation among RR-TB patients, no differences in mortality or treatment success were observed. However, a significant proportion of patients did not initiate ART despite receiving >4 months of RR-TB treatment. Programmatic priorities should focus on ensuring all patients with RR-TB/HIV co-infection initiate ART regardless of CD4 count, with special attention for patients with CD4 counts ≤ 100 to initiate ART as soon as possible after RR-TB treatment initiation.
Khayelitsha, South Africa, with high burdens of rifampicin-resistant tuberculosis (RR-TB) and HIV co-infection.
OBJECTIVE
To describe time to antiretroviral treatment (ART) initiation among HIV-infected RR-TB patients initiating RR-TB treatment and to assess the association between time to ART initiation and treatment outcomes.
DESIGN
A retrospective cohort study of patients with RR-TB and HIV co-infection not on ART at RR-TB treatment initiation.
RESULTS
Of the 696 RR-TB and HIV-infected patients initiated on RR-TB treatment between 2009 and 2013, 303 (44%) were not on ART when RR-TB treatment was initiated. The median CD4 cell count was 126 cells/mm3. Overall 257 (85%) patients started ART during RR-TB treatment, 33 (11%) within 2 weeks, 152 (50%) between 2-8 weeks and 72 (24%) after 8 weeks. Of the 46 (15%) who never started ART, 10 (21%) died or stopped RR-TB treatment within 4 weeks and 16 (37%) had at least 4 months of RR-TB treatment. Treatment success and mortality during treatment did not vary by time to ART initiation: treatment success was 41%, 43%, and 50% among patients who started ART within 2 weeks, between 2-8 weeks, and after 8 weeks (p = 0.62), while mortality was 21%, 13% and 15% respectively (p = 0.57). Mortality was associated with never receiving ART (adjusted hazard ratio (aHR) 6.0, CI 2.1-18.1), CD4 count ≤100 (aHR 2.1, CI 1.0-4.5), and multidrug-resistant tuberculosis (MDR-TB) with second-line resistance (aHR 2.5, CI 1.1-5.4).
CONCLUSIONS
Despite wide variation in time to ART initiation among RR-TB patients, no differences in mortality or treatment success were observed. However, a significant proportion of patients did not initiate ART despite receiving >4 months of RR-TB treatment. Programmatic priorities should focus on ensuring all patients with RR-TB/HIV co-infection initiate ART regardless of CD4 count, with special attention for patients with CD4 counts ≤ 100 to initiate ART as soon as possible after RR-TB treatment initiation.
Journal Article > LetterFull Text
Eur Respir J. 2015 December 1; 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. 2015 December 1; Volume 46 (Issue 6); DOI:10.1183/13993003.01374-2015
Journal Article > ResearchFull Text
Lancet Infect Dis. 2022 May 2; 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. 2022 May 2; 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 > LetterAbstract
Lancet Infect Dis. 2013 January 1; Volume 13 (Issue 1); DOI:10.1016/S1473-3099(12)70299-2
Cox HS, Ford NP, Hughes J, Goemaere E
Lancet Infect Dis. 2013 January 1; Volume 13 (Issue 1); DOI:10.1016/S1473-3099(12)70299-2
Journal Article > ResearchAbstract Only
Lancet Infect Dis. 2021 November 12; Volume S1473-3099 (Issue 21); 00470-00479.; DOI:10.1016/S1473-3099(21)00470-9
Ismail N, Omar SV, Moultrie H, Bhyat Z, Conradie F, et al.
Lancet Infect Dis. 2021 November 12; Volume S1473-3099 (Issue 21); 00470-00479.; DOI:10.1016/S1473-3099(21)00470-9
BACKGROUND
Bedaquiline improves outcomes of patients with rifampicin-resistant and multidrug-resistant (MDR) tuberculosis; however, emerging resistance threatens this success. We did a cross-sectional and longitudinal analysis evaluating the epidemiology, genetic basis, and treatment outcomes associated with bedaquiline resistance, using data from South Africa (2015-19).
METHODS
Patients with drug-resistant tuberculosis starting bedaquiline-based treatment had surveillance samples submitted at baseline, month 2, and month 6, along with demographic information. Culture-positive baseline and post-baseline isolates had phenotypic resistance determined. Eligible patients were aged 12 years or older with a positive culture sample at baseline or, if the sample was invalid or negative, a sample within 30 days of the baseline sample submitted for bedaquiline drug susceptibility testing. For the longitudinal study, the first surveillance sample had to be phenotypically susceptible to bedaquiline for inclusion. Whole-genome sequencing was done on bedaquiline-resistant isolates and a subset of bedaquiline-susceptible isolates. The National Institute for Communicable Diseases tuberculosis reference laboratory, and national tuberculosis surveillance databases were matched to the Electronic Drug-Resistant Tuberculosis Register. We assessed baseline resistance prevalence, mutations, transmission, cumulative resistance incidence, and odds ratios (ORs) associating risk factors for resistance with patient outcomes.
FINDINGS
Between Jan 1, 2015, and July 31, 2019, 8041 patients had surveillance samples submitted, of whom 2023 were included in the cross-sectional analysis and 695 in the longitudinal analysis. Baseline bedaquiline resistance prevalence was 3·8% (76 of 2023 patients; 95% CI 2·9-4·6), and it was associated with previous exposure to bedaquiline or clofazimine (OR 7·1, 95% CI 2·3-21·9) and with rifampicin-resistant or MDR tuberculosis with additional resistance to either fluoroquinolones or injectable drugs (pre-extensively-drug resistant [XDR] tuberculosis: 4·2, 1·7-10·5) or to both (XDR tuberculosis: 4·8, 2·0-11·7). Rv0678 mutations were the sole genetic basis of phenotypic resistance. Baseline resistance could be attributed to previous bedaquiline or clofazimine exposure in four (5·3%) of 76 patients and to primary transmission in six (7·9%). Odds of successful treatment outcomes were lower in patients with baseline bedaquiline resistance (0·5, 0·3-1). Resistance during treatment developed in 16 (2·3%) of 695 patients, at a median of 90 days (IQR 62-195), with 12 of these 16 having pre-XDR or XDR.
INTERPRETATION
Bedaquiline resistance was associated with poorer treatment outcomes. Rapid assessment of bedaquiline resistance, especially when patients were previously exposed to bedaquiline or clofazimine, should be prioritised at baseline or if patients remain culture-positive after 2 months of treatment. Preventing resistance by use of novel combination therapies, current treatment optimisation, and patient support is essential.
Bedaquiline improves outcomes of patients with rifampicin-resistant and multidrug-resistant (MDR) tuberculosis; however, emerging resistance threatens this success. We did a cross-sectional and longitudinal analysis evaluating the epidemiology, genetic basis, and treatment outcomes associated with bedaquiline resistance, using data from South Africa (2015-19).
METHODS
Patients with drug-resistant tuberculosis starting bedaquiline-based treatment had surveillance samples submitted at baseline, month 2, and month 6, along with demographic information. Culture-positive baseline and post-baseline isolates had phenotypic resistance determined. Eligible patients were aged 12 years or older with a positive culture sample at baseline or, if the sample was invalid or negative, a sample within 30 days of the baseline sample submitted for bedaquiline drug susceptibility testing. For the longitudinal study, the first surveillance sample had to be phenotypically susceptible to bedaquiline for inclusion. Whole-genome sequencing was done on bedaquiline-resistant isolates and a subset of bedaquiline-susceptible isolates. The National Institute for Communicable Diseases tuberculosis reference laboratory, and national tuberculosis surveillance databases were matched to the Electronic Drug-Resistant Tuberculosis Register. We assessed baseline resistance prevalence, mutations, transmission, cumulative resistance incidence, and odds ratios (ORs) associating risk factors for resistance with patient outcomes.
FINDINGS
Between Jan 1, 2015, and July 31, 2019, 8041 patients had surveillance samples submitted, of whom 2023 were included in the cross-sectional analysis and 695 in the longitudinal analysis. Baseline bedaquiline resistance prevalence was 3·8% (76 of 2023 patients; 95% CI 2·9-4·6), and it was associated with previous exposure to bedaquiline or clofazimine (OR 7·1, 95% CI 2·3-21·9) and with rifampicin-resistant or MDR tuberculosis with additional resistance to either fluoroquinolones or injectable drugs (pre-extensively-drug resistant [XDR] tuberculosis: 4·2, 1·7-10·5) or to both (XDR tuberculosis: 4·8, 2·0-11·7). Rv0678 mutations were the sole genetic basis of phenotypic resistance. Baseline resistance could be attributed to previous bedaquiline or clofazimine exposure in four (5·3%) of 76 patients and to primary transmission in six (7·9%). Odds of successful treatment outcomes were lower in patients with baseline bedaquiline resistance (0·5, 0·3-1). Resistance during treatment developed in 16 (2·3%) of 695 patients, at a median of 90 days (IQR 62-195), with 12 of these 16 having pre-XDR or XDR.
INTERPRETATION
Bedaquiline resistance was associated with poorer treatment outcomes. Rapid assessment of bedaquiline resistance, especially when patients were previously exposed to bedaquiline or clofazimine, should be prioritised at baseline or if patients remain culture-positive after 2 months of treatment. Preventing resistance by use of novel combination therapies, current treatment optimisation, and patient support is essential.
Journal Article > Short ReportAbstract
Lancet. 2019 September 14; Volume 394; DOI:10.1016/S0140-6736(19)32045-8
Reuter A, Hughes J, Furin J
Lancet. 2019 September 14; Volume 394; DOI:10.1016/S0140-6736(19)32045-8
Children bear a substantial burden of suffering when it comes to tuberculosis. Ironically, they are often left out of the scientific and public health advances that have led to important improvements in tuberculosis diagnosis, treatment, and prevention over the past decade. This Series paper describes some of the challenges and controversies in paediatric tuberculosis, including the epidemiology and treatment of tuberculosis in children. Two areas in which substantial challenges and controversies exist (ie, diagnosis and prevention) are explored in more detail. This Series paper also offers possible solutions for including children in all efforts to end tuberculosis, with a focus on ensuring that the proper financial and human resources are in place to best serve children exposed to, infected with, and sick from all forms of tuberculosis.
Journal Article > LetterFull Text
Int J Tuberc Lung Dis. 2020 April 2; Volume 24 (Issue 5); DOI:10.5588/ijtld.20.0205
Cox V, Wilkinson LS, Grimsrud A, Hughes J, Reuter A, et al.
Int J Tuberc Lung Dis. 2020 April 2; Volume 24 (Issue 5); DOI:10.5588/ijtld.20.0205