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. 2015 February 1; 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. 2015 February 1; 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 > ResearchFull Text
PLOS One. 2011 December 1; 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. 2011 December 1; 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 > LetterSubscription Only
N Engl J Med. 2008 November 27; Volume 359 (Issue 22); 2398-400.; DOI:10.1056/NEJMc0805644
Cox HS, Sibilia C, Feuerriegel S, Kalon S, Polonsky JA, et al.
N Engl J Med. 2008 November 27; Volume 359 (Issue 22); 2398-400.; DOI:10.1056/NEJMc0805644
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 > CommentaryAbstract
Lancet Infect Dis. 2011 April 1; Volume 11 (Issue 4); DOI:10.1016/S1473-3099(11)70036-6
Cox HS, Ford NP, Keshavjee S, McDermid C, von Schoen-Angerer T, et al.
Lancet Infect Dis. 2011 April 1; Volume 11 (Issue 4); DOI:10.1016/S1473-3099(11)70036-6
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 > CommentaryFull Text
Bull World Health Organ. 2015 July 1; Volume 93 (Issue 7); 491-497.; DOI:10.2471/BLT.14.138925
Cox HS, Furin J, Mitnick CD, Daniels C, Cox V, et al.
Bull World Health Organ. 2015 July 1; Volume 93 (Issue 7); 491-497.; DOI:10.2471/BLT.14.138925
Approximately half a million people are thought to develop multidrug-resistant tuberculosis annually. Barely 20% of these people currently receive recommended treatment and only about 10% are successfully treated. Poor access to treatment is probably driving the current epidemic, via ongoing transmission. Treatment scale-up is hampered by current treatment regimens, which are lengthy, expensive, poorly tolerated and difficult to administer in the settings where most patients reside. Although new drugs provide an opportunity to improve treatment regimens, current and planned clinical trials hold little promise for developing regimens that will facilitate prompt treatment scale-up. In this article we argue that clinical trials, while necessary, should be complemented by timely, large-scale, operational research that will provide programmatic data on the use of new drugs and regimens while simultaneously improving access to life-saving treatment. Perceived risks - such as the rapid development of resistance to new drugs - need to be balanced against the high levels of mortality and transmission that will otherwise persist. Doubling access to treatment and increasing treatment success could save approximately a million lives over the next decade.
Journal Article > ResearchFull Text
Antimicrob Agents Chemother. 2021 August 30; Volume 65 (Issue 11); e00364-21.; DOI:10.1128/AAC.00364-21
Salaam-Dreyer Z, Streicher EM, Sirgel FA, Menardo F, Borrell S, et al.
Antimicrob Agents Chemother. 2021 August 30; Volume 65 (Issue 11); e00364-21.; DOI:10.1128/AAC.00364-21
Rifampicin mono-resistant TB (RMR-TB, rifampicin resistance and isoniazid susceptibility) constitutes 38% of all rifampicin-resistant TB (RR-TB) in South Africa and is increasing. We aimed to compare RMR-TB with multidrug-resistant TB (MDR-TB) within a high TB, RR-TB and HIV burden setting. Patient-level clinical data and stored RR-TB isolates from 2008-2017 with available whole genome sequencing (WGS) data were used to describe risk factors associated with RMR-TB and to compare rifampicin-resistance (RR) conferring mutations between RMR-TB and MDR-TB. A subset of isolates with particular RR-conferring mutations were subjected to semi-quantitative rifampicin phenotypic drug susceptibility testing. Among 2,041 routinely diagnosed RR-TB patients, 463 (22.7%) had RMR-TB. HIV-positive individuals (adjusted Odds Ratio 1.4, 95% CI 1.1-1.9) and diagnosis between 2013-2017 versus 2008-2012 (aOR 1.3, 1.1-1.7) were associated with RMR-TB. Among 1,119 (54.8%) patients with available WGS data showing RR-TB, significant differences in the distribution of rpoB RR-conferring mutations between RMR-TB and MDR-TB isolates were observed. Mutations associated with high-level RR were more commonly found among MDR-TB isolates (811/889, 90.2% versus 162/230, 70.4% among RMR-TB, p<0.0001). In particular, the rpoB L430P mutation, conferring low-level RR, was identified in 32/230 (13.9%) RMR-TB versus 10/889 (1.1%) in MDR-TB (p<0.0001). Among 10 isolates with an rpoB L430P mutation, 7 were phenotypically susceptible using the critical concentration of 0.5 μg/ml (range 0.125-1 μg/ml). The majority (215/230, 93.5%) of RMR-TB isolates showed susceptibility to all other TB drugs, highlighting the potential benefits of WGS for simplified treatment. These data suggest that the evolution of RMR-TB differs from MDR-TB with a potential contribution from HIV infection.