Journal Article > ReviewSubscription Only
Curr Opin HIV AIDS. 2019 January 1; Volume 14 (Issue 1); 21-27.; DOI:10.1097/COH.0000000000000517
Fargher J, Reuter A, Furin J
Curr Opin HIV AIDS. 2019 January 1; 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 > 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
Lancet Respir Med. 2017 March 15 (Issue 4)
Dheda K, Gumbo T, Maartens G, Dooley KE, McNerney R, et al.
Lancet Respir Med. 2017 March 15 (Issue 4)
Global tuberculosis incidence has declined marginally over the past decade, and tuberculosis remains out of control in several parts of the world including Africa and Asia. Although tuberculosis control has been effective in some regions of the world, these gains are threatened by the increasing burden of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis. XDR tuberculosis has evolved in several tuberculosis-endemic countries to drug-incurable or programmatically incurable tuberculosis (totally drug-resistant tuberculosis). This poses several challenges similar to those encountered in the pre-chemotherapy era, including the inability to cure tuberculosis, high mortality, and the need for alternative methods to prevent disease transmission. This phenomenon mirrors the worldwide increase in antimicrobial resistance and the emergence of other MDR pathogens, such as malaria, HIV, and Gram-negative bacteria. MDR and XDR tuberculosis are associated with high morbidity and substantial mortality, are a threat to health-care workers, prohibitively expensive to treat, and are therefore a serious public health problem. In this Commission, we examine several aspects of drug-resistant tuberculosis. The traditional view that acquired resistance to antituberculous drugs is driven by poor compliance and programmatic failure is now being questioned, and several lines of evidence suggest that alternative mechanisms-including pharmacokinetic variability, induction of efflux pumps that transport the drug out of cells, and suboptimal drug penetration into tuberculosis lesions-are likely crucial to the pathogenesis of drug-resistant tuberculosis. These factors have implications for the design of new interventions, drug delivery and dosing mechanisms, and public health policy. We discuss epidemiology and transmission dynamics, including new insights into the fundamental biology of transmission, and we review the utility of newer diagnostic tools, including molecular tests and next-generation whole-genome sequencing, and their potential for clinical effectiveness. Relevant research priorities are highlighted, including optimal medical and surgical management, the role of newer and repurposed drugs (including bedaquiline, delamanid, and linezolid), pharmacokinetic and pharmacodynamic considerations, preventive strategies (such as prophylaxis in MDR and XDR contacts), palliative and patient-orientated care aspects, and medicolegal and ethical issues.
Journal Article > ResearchFull Text
Int J Tuberc Lung Dis. 2014 October 3; Volume 19 (Issue 10); 1479-84.; DOI:10.5588/ijtld.14.0277
Furin J, Isaakidis P, Reid AJ, Kielmann K
Int J Tuberc Lung Dis. 2014 October 3; Volume 19 (Issue 10); 1479-84.; DOI:10.5588/ijtld.14.0277
OBJECTIVES
To understand the impact of past experiences of anti-tuberculosis treatment among patients co-infected with the human immunodeficiency virus and multidrug-resistant tuberculosis (MDR-TB) on perceptions and attitudes towards treatment.
METHODS
Qualitative study using in-depth interviews with 12 HIV-MDR-TB co-infected patients in Mumbai, India.
RESULTS
Patients reported unnecessarily long pathways to care and fatigue with diagnostic and treatment procedures. In particular, they expressed concerns over the lack of efficacy of their current treatment regimen based on their experiences with anti-tuberculosis treatment regimens in the past.
CONCLUSION
Patients reported negative experiences with previous HIV and anti-tuberculosis treatment. Access to early diagnosis and rapid initiation of integrated care for HIV-MDR-TB co-infected patients, with a strong, patient-centered support system, could help to combat the low morale and lack of faith in treatment described in this group of patients.
To understand the impact of past experiences of anti-tuberculosis treatment among patients co-infected with the human immunodeficiency virus and multidrug-resistant tuberculosis (MDR-TB) on perceptions and attitudes towards treatment.
METHODS
Qualitative study using in-depth interviews with 12 HIV-MDR-TB co-infected patients in Mumbai, India.
RESULTS
Patients reported unnecessarily long pathways to care and fatigue with diagnostic and treatment procedures. In particular, they expressed concerns over the lack of efficacy of their current treatment regimen based on their experiences with anti-tuberculosis treatment regimens in the past.
CONCLUSION
Patients reported negative experiences with previous HIV and anti-tuberculosis treatment. Access to early diagnosis and rapid initiation of integrated care for HIV-MDR-TB co-infected patients, with a strong, patient-centered support system, could help to combat the low morale and lack of faith in treatment described in this group of patients.
Journal Article > ResearchAbstract Only
Int J Tuberc Lung Dis. 2022 October 1; Volume 26 (Issue 10); 956-962.; DOI:DOI: 10.5588/ijtld.22.0115
Mangochi P, Bossard C, Catacutan C, Van Laeken D, Kwitonda C, et al.
Int J Tuberc Lung Dis. 2022 October 1; Volume 26 (Issue 10); 956-962.; DOI:DOI: 10.5588/ijtld.22.0115
BACKGROUND
Incarcerated individuals, especially in high HIV and TB burden settings, are at increased risk of latent TB infection and/or TB disease. We implemented a comprehensive HIV-TB intervention in a Malawi prison and studied its feasibility.
METHODS
Between February and December 2019, consenting individuals underwent screening for HIV, TB infection and TB disease. HIV-positive individuals without TB disease were treated with a fixed-dose combination of isoniazid, cotrimoxazole and vitamin B6 (INH-CTX-B6). HIV-negative persons with TB infection received 12 weeks of isoniazid and rifapentine (3HP).
RESULTS
Of 1,546 consenting individuals, 1,498 (96.9%) were screened and 1,427 (92.3%) included in the analysis: 96.4% were male, the median age was 31 years (IQR 25–38). Twenty-nine (2.1%) participants were diagnosed with TB disease, of whom 89.7% started and 61.5% completed TB treatment. Of the 1,427 included, 341 (23.9%) were HIV-positive, of whom 98.5% on antiretroviral therapy and 95% were started on INH-CTX-B6. Among 1,086 HIV-negative participants, 1,015 (93.5%) underwent the tuberculin skin test (TST), 670 (65.9%) were TST-positive, 666 (99.4%) started 3HP and 570 (85.5%) completed 3HP treatment.
CONCLUSION
A comprehensive TB screening and treatment package among incarcerated individuals was acceptable and feasible, and showed high prevalence of HIV, TB disease and TB infection. Treatment uptake was excellent, but treatment completion needs to be improved. Greater investment in comprehensive HIV-TB services, including access to shorter TB regimens and follow-up upon release, is needed for incarcerated individuals.
Incarcerated individuals, especially in high HIV and TB burden settings, are at increased risk of latent TB infection and/or TB disease. We implemented a comprehensive HIV-TB intervention in a Malawi prison and studied its feasibility.
METHODS
Between February and December 2019, consenting individuals underwent screening for HIV, TB infection and TB disease. HIV-positive individuals without TB disease were treated with a fixed-dose combination of isoniazid, cotrimoxazole and vitamin B6 (INH-CTX-B6). HIV-negative persons with TB infection received 12 weeks of isoniazid and rifapentine (3HP).
RESULTS
Of 1,546 consenting individuals, 1,498 (96.9%) were screened and 1,427 (92.3%) included in the analysis: 96.4% were male, the median age was 31 years (IQR 25–38). Twenty-nine (2.1%) participants were diagnosed with TB disease, of whom 89.7% started and 61.5% completed TB treatment. Of the 1,427 included, 341 (23.9%) were HIV-positive, of whom 98.5% on antiretroviral therapy and 95% were started on INH-CTX-B6. Among 1,086 HIV-negative participants, 1,015 (93.5%) underwent the tuberculin skin test (TST), 670 (65.9%) were TST-positive, 666 (99.4%) started 3HP and 570 (85.5%) completed 3HP treatment.
CONCLUSION
A comprehensive TB screening and treatment package among incarcerated individuals was acceptable and feasible, and showed high prevalence of HIV, TB disease and TB infection. Treatment uptake was excellent, but treatment completion needs to be improved. Greater investment in comprehensive HIV-TB services, including access to shorter TB regimens and follow-up upon release, is needed for incarcerated individuals.
Journal Article > CommentaryFull Text
Lancet Respir Med. 2020 September 1; Volume 8 (Issue 9); 844-846.; DOI:10.1016/S2213-2600(20)30311-8
Keene CM, Mohr-Holland E, Cassidy T, Scott V, Nelson AM, et al.
Lancet Respir Med. 2020 September 1; Volume 8 (Issue 9); 844-846.; DOI:10.1016/S2213-2600(20)30311-8
Journal Article > LetterFull Text
Int J Tuberc Lung Dis. 2021 May 1; Volume 25 (Issue 5); 409-412.; DOI:10.5588/ijtld.21.0010
Mohr-Holland E, Daniels J, Douglas-Jones B, Mema N, Scott V, et al.
Int J Tuberc Lung Dis. 2021 May 1; Volume 25 (Issue 5); 409-412.; DOI:10.5588/ijtld.21.0010
Journal Article > CommentaryFull Text
Lancet Infect Dis. 2019 March 1; Volume 19 (Issue 3); 224-225.; DOI:10.1016/S1473-3099(18)30742-4
Acquah R, Furin J
Lancet Infect Dis. 2019 March 1; Volume 19 (Issue 3); 224-225.; DOI:10.1016/S1473-3099(18)30742-4
A universal regimen. At times this appears to be the Holy Grail in tuberculosis treatment. For decades, policy makers, public health specialists, and donors have argued that in order to control—and these days to “End TB”—a simplified approach that offers everyone the same regimen is our best bet. They argue that countries, programmes, and the people who work in them, are incapable of managing complexity when it comes to tackling tuberculosis. Fears abound that recommending anything other than a basic treatment algorithm will lead to mismanagement and a tuberculosis crisis worse that what we see now. Never mind that such an approach erases patient individuality and unique human treatment needs. “Keep it simple” remains the mantra in tuberculosis control to this day.
Journal Article > ResearchFull Text
Lancet Microbe. 2021 November 1; Volume 2 (Issue 11); e584-e593.; DOI:10.1016/S2666-5247(21)00144-0
Cox HS, Salaam-Dreyer Z, Goig GA, Nicol MP, Menardo F, et al.
Lancet Microbe. 2021 November 1; Volume 2 (Issue 11); e584-e593.; DOI:10.1016/S2666-5247(21)00144-0
BACKGROUND
South Africa has a high burden of rifampicin-resistant tuberculosis (including multidrug-resistant [MDR] tuberculosis), with increasing rifampicin-monoresistant (RMR) tuberculosis over time. Resistance acquisition during first-line tuberculosis treatment could be a key contributor to this burden, and HIV might increase the risk of acquiring rifampicin resistance. We assessed whether HIV during previous treatment was associated with RMR tuberculosis and resistance acquisition among a retrospective cohort of patients with MDR or rifampicin-resistant tuberculosis.
METHODS
In this retrospective cohort study, we included all patients routinely diagnosed with MDR or rifampicin-resistant tuberculosis in Khayelitsha, Cape Town, South Africa, between Jan 1, 2008, and Dec 31, 2017. Patient-level data were obtained from a prospective database, complemented by data on previous tuberculosis treatment and HIV from a provincial health data exchange. Stored MDR or rifampicin-resistant tuberculosis isolates from patients underwent whole-genome sequencing (WGS). WGS data were used to infer resistance acquisition versus transmission, by identifying genomically unique isolates (single nucleotide polymorphism threshold of five). Logistic regression analyses were used to assess factors associated with RMR tuberculosis and genomic uniqueness.
FINDINGS
The cohort included 2041 patients diagnosed with MDR or rifampicin-resistant tuberculosis between Jan 1, 2008, and Dec 31, 2017; of those, 463 (22·7%) with RMR tuberculosis and 1354 (66·3%) with previous tuberculosis treatment. In previously treated patients, HIV positivity during previous tuberculosis treatment versus HIV negativity (adjusted odds ratio [OR] 2·07, 95% CI 1·35-3·18), and three or more previous tuberculosis treatment episodes versus one (1·96, 1·21-3·17) were associated with RMR tuberculosis. WGS data showing MDR or rifampicin-resistant tuberculosis were available for 1169 patients; 360 (30·8%) isolates were identified as unique. In previously treated patients, RMR tuberculosis versus MDR tuberculosis (adjusted OR 4·96, 3·40-7·23), HIV positivity during previous tuberculosis treatment (1·71, 1·03-2·84), and diagnosis in 2013-17 (1·42, 1·02-1·99) versus 2008-12, were associated with uniqueness. In previously treated patients with RMR tuberculosis, HIV positivity during previous treatment (adjusted OR 5·13, 1·61-16·32) was associated with uniqueness as was female sex (2·50 [1·18-5·26]).
INTERPRETATION
These data suggest that HIV contributes to rifampicin-resistance acquisition during first-line tuberculosis treatment and that this might be driving increasing RMR tuberculosis over time. Large-scale prospective cohort studies are required to further quantify this risk.
South Africa has a high burden of rifampicin-resistant tuberculosis (including multidrug-resistant [MDR] tuberculosis), with increasing rifampicin-monoresistant (RMR) tuberculosis over time. Resistance acquisition during first-line tuberculosis treatment could be a key contributor to this burden, and HIV might increase the risk of acquiring rifampicin resistance. We assessed whether HIV during previous treatment was associated with RMR tuberculosis and resistance acquisition among a retrospective cohort of patients with MDR or rifampicin-resistant tuberculosis.
METHODS
In this retrospective cohort study, we included all patients routinely diagnosed with MDR or rifampicin-resistant tuberculosis in Khayelitsha, Cape Town, South Africa, between Jan 1, 2008, and Dec 31, 2017. Patient-level data were obtained from a prospective database, complemented by data on previous tuberculosis treatment and HIV from a provincial health data exchange. Stored MDR or rifampicin-resistant tuberculosis isolates from patients underwent whole-genome sequencing (WGS). WGS data were used to infer resistance acquisition versus transmission, by identifying genomically unique isolates (single nucleotide polymorphism threshold of five). Logistic regression analyses were used to assess factors associated with RMR tuberculosis and genomic uniqueness.
FINDINGS
The cohort included 2041 patients diagnosed with MDR or rifampicin-resistant tuberculosis between Jan 1, 2008, and Dec 31, 2017; of those, 463 (22·7%) with RMR tuberculosis and 1354 (66·3%) with previous tuberculosis treatment. In previously treated patients, HIV positivity during previous tuberculosis treatment versus HIV negativity (adjusted odds ratio [OR] 2·07, 95% CI 1·35-3·18), and three or more previous tuberculosis treatment episodes versus one (1·96, 1·21-3·17) were associated with RMR tuberculosis. WGS data showing MDR or rifampicin-resistant tuberculosis were available for 1169 patients; 360 (30·8%) isolates were identified as unique. In previously treated patients, RMR tuberculosis versus MDR tuberculosis (adjusted OR 4·96, 3·40-7·23), HIV positivity during previous tuberculosis treatment (1·71, 1·03-2·84), and diagnosis in 2013-17 (1·42, 1·02-1·99) versus 2008-12, were associated with uniqueness. In previously treated patients with RMR tuberculosis, HIV positivity during previous treatment (adjusted OR 5·13, 1·61-16·32) was associated with uniqueness as was female sex (2·50 [1·18-5·26]).
INTERPRETATION
These data suggest that HIV contributes to rifampicin-resistance acquisition during first-line tuberculosis treatment and that this might be driving increasing RMR tuberculosis over time. Large-scale prospective cohort studies are required to further quantify this risk.
Journal Article > ResearchFull Text
Int J Tuberc Lung Dis. 2022 February 1; Volume 26 (Issue 2); 150-157.; DOI:10.5588/ijtld.21.0494
Mohr-Holland E, Daniels J, Reuter A, Rodriguez CA, Mitnick CD, et al.
Int J Tuberc Lung Dis. 2022 February 1; Volume 26 (Issue 2); 150-157.; DOI:10.5588/ijtld.21.0494
BACKGROUND
Data suggest that treatment with newer TB drugs (linezolid [LZD], bedaquiline [BDQ] and delamanid [DLM]), used in Khayelitsha, South Africa, since 2012, reduces mortality due to rifampicin-resistant TB (RR-TB).
METHODS
This was a retrospective cohort study to assess 6-month mortality among RR-TB patients diagnosed between 2008 and 2019.
RESULTS
By 6 months, 236/2,008 (12%) patients died; 12% (78/651) among those diagnosed in 2008-2011, and respectively 8% (49/619) and 15% (109/738) with and without LZD/BDQ/DLM in 2012-2019. Multivariable analysis showed a small, non-significant mortality reduction with LZD/BDQ/DLM use compared to the 2008-2011 period (aOR 0.79, 95% CI 0.5-1.2). Inpatient treatment initiation (aOR 3.2, 95% CI 2.4-4.4), fluoroquinolone (FQ) resistance (aOR 2.7, 95% CI 1.8-4.2) and female sex (aOR 1.5, 95% CI 1.1-2.0) were also associated with mortality. When restricted to 2012-2019, use of LZD/BDQ/DLM was associated with lower mortality (aOR 0.58, 95% CI 0.39-0.87).
CONCLUSIONS
While LZD/BDQ/DLM reduced 6-month mortality between 2012 and 2019, there was no significant effect overall. These findings may be due to initially restricted LZD/BDQ/DLM use for those with high-level resistance or treatment failure. Additional contributors include increased treatment initiation among individuals who would have otherwise died before treatment due to universal drug susceptibility testing from 2012, an effect that also likely contributed to higher mortality among females (survival through to care-seeking).
Data suggest that treatment with newer TB drugs (linezolid [LZD], bedaquiline [BDQ] and delamanid [DLM]), used in Khayelitsha, South Africa, since 2012, reduces mortality due to rifampicin-resistant TB (RR-TB).
METHODS
This was a retrospective cohort study to assess 6-month mortality among RR-TB patients diagnosed between 2008 and 2019.
RESULTS
By 6 months, 236/2,008 (12%) patients died; 12% (78/651) among those diagnosed in 2008-2011, and respectively 8% (49/619) and 15% (109/738) with and without LZD/BDQ/DLM in 2012-2019. Multivariable analysis showed a small, non-significant mortality reduction with LZD/BDQ/DLM use compared to the 2008-2011 period (aOR 0.79, 95% CI 0.5-1.2). Inpatient treatment initiation (aOR 3.2, 95% CI 2.4-4.4), fluoroquinolone (FQ) resistance (aOR 2.7, 95% CI 1.8-4.2) and female sex (aOR 1.5, 95% CI 1.1-2.0) were also associated with mortality. When restricted to 2012-2019, use of LZD/BDQ/DLM was associated with lower mortality (aOR 0.58, 95% CI 0.39-0.87).
CONCLUSIONS
While LZD/BDQ/DLM reduced 6-month mortality between 2012 and 2019, there was no significant effect overall. These findings may be due to initially restricted LZD/BDQ/DLM use for those with high-level resistance or treatment failure. Additional contributors include increased treatment initiation among individuals who would have otherwise died before treatment due to universal drug susceptibility testing from 2012, an effect that also likely contributed to higher mortality among females (survival through to care-seeking).