EDCTP Alumni Network

Fostering excellence and collaboration in the next generation of researchers

Call Senior Fellowship (SF)
Programme EDCTP2
Start Date 2020-04-01
End Date 2025-03-31
Project Code TMA2018SF-2467
Status Active

Title

The Individualized Multi-/Extensively Drug-Resistant Tuberculosis Treatment Strategy Study (InDEX)

Host Organisation

Institution Country
Centre for the Aids Programme of Research in South Africa (CAPRISA) South Africa
Call Senior Fellowship (SF)
Programme EDCTP1
Start Date 2013-01-01
End Date 2014-12-31
Project Code TA.2011.40200.044
Status Completed

Title

Improving retreatment success of tuberculosis

Objectives

To determine if a moxifloxacin-containing regimen [isoniazid (H), rifampin (R), pyrazinamide (Z), moxifloxacin (M)] of 24 weeks duration is superior to a control regimen [isoniazid (H), rifampicin(R), pyrazinamide(Z), ethambutol(E)] of 32 weeks duration in improving treatment outcomes in patients with recurrent TB

Host Organisation

Institution Country
University of KwaZulu-Natal (UKZN) South Africa

Participants

Name Institution Country
Gavin John Churchyard Aurum Institute for Health Research South Africa
Wafaa El-Sadr Columbia University United States
Sarah Fortune Harvard School of Public Health United States
Gerald Friedland Yale University United States
William Jacobs Albert Einstein College of Medicine United States
Salim S. Abdool Karim University of KwaZulu-Natal (UKZN) United States

Study Design

Randomised controlled trial

Sites

CAPRISA eThekwini Clinical Research Site (eCRS)

Phd Study

Title University Start Date End Date
Improving Retreatment Success in TB University of KwaZulu-Natal (UKZN) 2014-02-03 2016-12-30

Current Organisation

Centre for the AIDS Programme of Research in South Africa

Current Job Title

Deputy Director

Students Supervised

Type Name Title University Start Date End Date
Postgraduate Rubeshan Perumal Dr University of KwaZulu-Natal 2012 2019
Postgraduate Amrita Daftary Dr Columbia University, NY 2013 2016
Postgraduate Marian Loveday Dr Medical Research Council 2014 2016

Memberships

Role Committee/board Start Date End Date
Member Bedaquiline Access Program 2013 2019
Member Southern African HIV Clinicians society 2014
SA MRC Silver Award for lifetime contribution to research SA Medical Research Council 2018
Protocol Team Adult Aids Clinical Trials Group – Study A5289, A5300 2008 2013
Protocol Co-chair Adult Aids Clinical Trials Group – Study A5319
Member The Academy of Science of South Africa (ASSAf) 2014
Member DSMB STREAM Study, international 2015
Member International Union against TB and Lung Disease Ethics Advisory 2015
Member International Society of Infectious Diseases 2015
Board Member South African HIV Clinicians Society 2016
Member India TB Research Consortium 2017
Member International Aids Society 2013

Education

Institution Degree Year
University of Durban-Westville, South Africa BS 1979-12-30
university of Natal, South Africa MBBS
College of South Africa, South Africa Diploma
University of Witwatersrand, South Africa Diploma
University of Witwatersrand, South Africa Diploma
University of Witwatersrand, South Africa Diploma
Columbia University, United States MS
University of KwaZulu-Natal, South Africa PhD

Areas Of Specialisation

Tuberculosis (TB)

Grants

Grant Code:
U2GGH001142
Source of funding:
CDC
Amount:
16685929.00
Role:
Co-Project Director
Start Date:
2014-01-01
End Date:
2019-01-01
Grant Code:
BR-C 13/0056
Source of funding:
BroadReach/USAID
Amount:
776177.04
Role:
Co-Principal Investigator
Start Date:
2013-01-01
End Date:
2016-01-01
Grant Code:
1R21TW011077
Source of funding:
NIH
Amount:
455168.00
Role:
Sub Principal Investigator
Start Date:
2018-01-01
End Date:
2020-01-01
Grant Code:
UM1AI069469
Source of funding:
NIH
Amount:
11259308.00
Role:
Co-Investigator
Start Date:
2013-01-01
End Date:
2020-01-01
Grant Code:
Extra Mural Unit
Source of funding:
MRC
Amount:
314228.25
Role:
Co-Principal Investigator
Start Date:
2016-01-01
End Date:
2019-01-01
Grant Code:
R01 AI124413
Source of funding:
NIH
Amount:
2688420.00
Role:
Principal Investigator
Start Date:
2016-01-01
End Date:
2021-01-01

Publications

Authors:
Naidoo A
Naidoo K
Ramsuran V
Reddy M
Padayatchi N
Date:
2017-08-23
Journal:
Pharmacogenomics and Personalized Medicine 2017 August; 10: 233-234. doi: 10.2147/PGPM.S146787. PMC5574687
Content:

Open access full text article.

Identifiers:
Authors:
Naidoo A
Naidoo K
McIlleron H
Essack S
Padayatchi N
Date:
2017-11-30
Journal:
Journal of Clinical Pharmacology 2017 November; 57(11):1369-1386. doi: 10.1002/jcph.968. PMC5663285
Content:

Moxifloxacin, an 8-methoxy quinolone, is an important drug in the treatment of multidrug-resistant tuberculosis and is being investigated in novel drug regimens with pretomanid, bedaquiline, and pyrazinamide, or rifapentine, for the treatment of drug-susceptible tuberculosis. Early results of these studies are promising. Although current evidence does not support the use of moxifloxacin in treatment-shortening regimens for drug-susceptible tuberculosis, it may be recommended in patients unable to tolerate standard first-line drug regimens or for isoniazid monoresistance. Evidence suggests that the standard 400-mg dose of moxifloxacin used in the treatment of tuberculosis may be suboptimal in some patients, leading to worse tuberculosis treatment outcomes and emergence of drug resistance. Furthermore, a drug interaction with the rifamycins results in up to 31% reduced plasma concentrations of moxifloxacin when these are combined for treatment of drug-susceptible tuberculosis, although the clinical relevance of this interaction is unclear. Moxifloxacin exhibits extensive interindividual pharmacokinetic variability. Higher doses of moxifloxacin may be needed to achieve drug exposures required for improved clinical outcomes. Further study is, however, needed to determine the safety of proposed higher doses and clinically validated targets for drug exposure to moxifloxacin associated with improved tuberculosis treatment outcomes. We discuss in this review the evidence for the use of moxifloxacin in drug-susceptible tuberculosis and explore the role of moxifloxacin pharmacokinetics, pharmacodynamics, and drug interactions with rifamycins, on tuberculosis treatment outcomes when used in first-line tuberculosis drug regimens.

Identifiers:
Authors:
Naidoo A
Chirehwa M
McIlleron H
Naidoo K
Essack S
Yende-Zuma N
Kimba-Phongi E
Adamson J
Govender K
Padayatchi N
Denti P
Date:
2017-05-01
Journal:
Journal of Antimicrobial Chemotherapy 2017 May; 72(5):1441-49. doi: 10.1093/jac/dkx004. PMC5890691
Content:

Objectives: We compared the pharmacokinetics of moxifloxacin during rifampicin co-treatment or when dosed alone in African patients with drug-susceptible recurrent TB.

Methods: Patients in the intervention arm of the Improving Retreatment Success (IMPRESS) randomized controlled TB trial received 400 mg of moxifloxacin, with rifampicin, isoniazid and pyrazinamide in the treatment regimen. Moxifloxacin concentrations were measured in plasma during rifampicin-based TB treatment and again 4 weeks after treatment completion, when given alone as a single dose. Moxifloxacin concentration-time data were analysed using non-linear mixed-effects models.

Results: We included 58 patients; 42 (72.4%) were HIV co-infected and 40 (95%) of these were on efavirenz-based ART. Moxifloxacin pharmacokinetics was best described using a two-compartment disposition model with first-order lagged absorption and elimination using a semi-mechanistic model describing hepatic extraction. Oral clearance (CL/F) of moxifloxacin during rifampicin-based TB treatment was 24.3 L/h for a typical patient (fat-free mass of 47 kg), resulting in an AUC of 16.5 mg·h/L. This exposure was 7.8% lower than the AUC following the single dose of moxifloxacin given alone after TB treatment completion. In HIV-co-infected patients taking efavirenz-based ART, CL/F of moxifloxacin was increased by 42.4%, resulting in a further 30% reduction in moxifloxacin AUC.

Conclusions: Moxifloxacin clearance was high and plasma concentrations low in our patients overall. Moxifloxacin AUC was further decreased by co-administration of efavirenz-based ART and, to a lesser extent, rifampicin. The clinical relevance of the low moxifloxacin concentrations for TB treatment outcomes and the need for moxifloxacin dose adjustment in the presence of rifampicin and efavirenz co-treatment need further investigation.

Identifiers:
Authors:
Perumal P
Padayatchi N
Yende-Zuma N
Naidoo A
Govender D
Naidoo K
Date:
2019-02-28
Journal:
Clinical Infectious Diseases 2019 February.pii: ciz152. https://doi.org/10.1093/cid/ciz152
Content:

BACKGROUND: The substitution of moxifloxacin for ethambutol produced promising results for improved tuberculosis (TB) treatment outcomes.

METHOD: We conducted an open-label randomized trial to test whether a moxifloxacin-containing treatment regimen was superior to the standard regimen for the treatment of recurrent TB. The primary and secondary outcomes were sputum culture conversion rate at the end of 8 weeks and the proportion of participants with a favourable outcome, respectively.

RESULTS: We enrolled 196 participants; 69.9% were male and 70.4% were co-infected with HIV. There was no significant difference between the study groups in the proportion of patients achieving culture conversion at the end of 8 weeks [83.0% (Moxifloxacin) vs 78.5% (Control), p=0.463], however the median time to culture conversion was significantly shorter (6.0 weeks, IQR 4.0 - 8.3) in the moxifloxacin group than the control group (7.9 weeks, IQR 4.0- 11.4) (p=0.018). A favourable end-of-treatment outcome was reported in 86 participants (87.8%) in the moxifloxacin group and 93 participants (94.9%) in the control group, for an adjusted absolute risk difference of -5.5 (95% CI -13.8 to 2.8, p=0.193) percentage points. There was a significantly higher proportion of participants with grade 3 or 4 adverse events [43.9% (43/98) vs 25.5% (25/98), p=0.011] and serious adverse events [27.6% (27/98) vs 12.2% (12/98), p=0.012] in the moxifloxacin group.

CONCLUSION: Replacement of ethambutol with moxifloxacin did not significantly improve culture conversion rates at the end of 8 weeks or treatment success, and was associated with a higher incidence of adverse events.

Identifiers:
Authors:
Naidoo A
McIlleron H
Naidoo K
Yende-Zuma N
Singh R
Ncgapu S
Adamson J
Govender K
Denti P
Padayatchi N
Date:
2019-02-15
Journal:
Pharmacogenomics 2019 February. doi: 10.2217/pgs-2018-0166
Content:

AIM: We report the prevalence and effect of genetic variability on pharmacokinetic parameters of isoniazid and rifampicin.

MATERIALS & METHODS: Genotypes for SLCO1B1, NAT2, PXR, ABCB1 and UGT1A genes were determined using a TaqMan® Genotyping OpenArray™. Nonlinear mixed-effects models were used to describe drug pharmacokinetics.

RESULTS: Among 172 patients, 18, 43 and 34% were classified as rapid, intermediate and slow NAT2 acetylators, respectively. Of the 58 patients contributing drug concentrations, rapid and intermediate acetylators had 2.3- and 1.6-times faster isoniazid clearance than slow acetylators. No association was observed between rifampicin pharmacokinetics and SLCO1B1, ABCB1, UGT1A or PXR genotypes.

CONCLUSION: Clinical relevance of the effects of genetic variation on isoniazid concentrations and low first-line tuberculosis drug exposures observed require further investigation.

Identifiers:
Authors:
Naidoo A
Ramsuran V
Chirehwa M
Denti P
McIlleron H
Naidoo K
Yende-Zuma N
Singh R
Ngcapu S
Chaudhry M
Pepper MS
Padayatchi N
Date:
2018-01-30
Journal:
Pharmacogenomics 2018 January; 19(1):17-29. doi: 10.2217/pgs-2017-0144. PMC5753622
Content:

AIM: We assessed the effect of genetic variability in UGT1A and ABCB1 genes on moxifloxacin pharmacokinetics.

METHODS: Genotypes for selected UGT1A and ABCB1 SNPs were determined using a TaqMan® Genotyping OpenArray and high-resolution melt analysis for rs8175347. A nonlinear mixed-effects model was used to describe moxifloxacin pharmacokinetics.

RESULTS:Genotypes of UGT1A SNPs, rs8175347 and rs3755319 (20.6% lower and 11.6% increased clearance, respectively) and ABCB1 SNP rs2032582 (40% reduced bioavailability in one individual) were significantly associated with changes in moxifloxacin pharmacokinetic parameters.

CONCLUSION:Genetic variation in UGT1A as represented by rs8175347 to a lesser extent rs3755319 and the ABCB1 rs2032582 SNP is modestly associated with the interindividual variability reported in moxifloxacin pharmacokinetics and exposure. Clinical relevance of the effects of genetic variation on moxifloxacin pharmacokinetic requires further investigation.

Identifiers:
Authors:
Naidoo K
Dookie N
Naidoo K
Yende-Zuma N
Chimukangara B
Bhushan A
Govender D
Gengiah S
Padayatchi N
Date:
2018-09-05
Journal:
Infection and Drug Resistance 2018 Sept; 11:1413-21. doi: 10.2147/IDR.S150644. PMC6130302
Content:

Background: Recurrent tuberculosis (TB) following TB treatment completion in HIV-infected individuals remains a major public health burden. We assessed the role of various risk factors in mediating the development of recurrent TB and subsequent resistance to antiretroviral therapy and anti-TB drugs.

Patients and methods: We analyzed secondary demographic, clinical, and laboratory data from medical records of five HIV-infected TB patients enrolled between 2009 and 2014 in a prospective observational study investigating TB recurrence. Paired clinical isolates of Myco-bacterium tuberculosis were typed by IS6110 restriction fragment length polymorphism analysis to determine the mechanism of TB recurrence. Plasma samples were genotyped to determine acquisition of HIV drug resistance mutations on antiretroviral treatment (ART).

Results: All five patients were HIV-coinfected, with a previous history of TB infection and prior exposure to anti-TB treatment, and residual lung damage, and demonstrated poor treatment adherence - significant risk factors linked to the development of recurrent TB disease. Furthermore, three of the five patients had multiple episodes of drug-susceptible TB infection with subsequent drug-resistant TB infection. Genotyping of the initial and recurrent M. tuberculosis isolates demonstrated three cases of recurrent TB because of relapse and two because of reinfection. All five patients had no mutations at ART initiation; however, by the end of the study follow-up, all patients developed dual class resistance.

Conclusion: This series demonstrates the complexity of recurrent TB in HIV coinfection. We highlight the challenges of managing coinfected patients and the increased propensity for the development of drug resistance. We report on the role of various risk factors mediating the development of resistance and subsequent clinical impact. This report underscores the need for structural clinical and adherence interventions for the management of complex treatment and dosing.

Identifiers:

Projects

Fellow:
Nesri Padayatchi
Collaborators:
Name Country Institution
Nesri Padayatchi South Africa Centre for the AIDS Programme of Research in South Africa (CAPRISA)
Objectives:
The goals of this research are to understand adherence and retention in care for multi-and extensively drug-resistant tuberculosis (M/XDR-TB) patients using a mixed methods approach.
Sites:
King DinuZulu Hospital in Durban, South Africa.
Study Design:
200 participants; Adult patients with newly diagnosed active pulmonary multi- and extremely-drug resistance tuberculosis (M/XDR-TB) (≥ 18 years old).
Subjects:
200 participants; Adult patients.
Outcomes:
Primary Outcome Measures : 1. Medication adherence based on electronic monitoring [ Time Frame: 6 months ] An electronic monitoring system (e.g., Wisepill technologies) will be used to measure adherence to antiretroviral therapy and treatment of multi- and extremely-drug resistant tuberculosis. Secondary Outcome Measures : 1. Medication adherence based on self-report [ Time Frame: 6 months ] Quantitative adherence will be measured using 30 day and 7 day recall. Average adherence to both antiretroviral therapy and tuberculosis treatment will be calculated for each patient 2. Sociomedical risk factors associated with six-month adherence to ART or TB medications [ Time Frame: 6 months ] Barriers and facilitators to medication adherence and retention in care for M/XDR-TB HIV patients will be identified through in-depth interviews and focus group discussions with patients and health care workers. To identify sociomedical risk factors associated with six-month adherence to ART or TB medications we will first identified risk factors associated with adherence in bivariate analysis and then multiple logistic regression models will be constructed including variables which are statistically significant and/or associated with >10% change in effect measure.
Start Date:
2016-01-01
End Date:
2019-12-30
Fellow:
Nesri Padayatchi
Collaborators:
Name Country Institution
Neel Rajnikant Gandhi United States Emory University
Koleka Mlisana South Africa University of KwaZulu-natal
Kogieleum Naidoo South Africa CAPRISA
Nesri Pdayatchi South Africa CAPRISA
Objectives:
The goal of The CONTEXT study is to characterize casual contact and migration in XDR TB transmission in South Africa using geospatial, social network and genomic analyses.
Sites:
King DinuZulu Hospital, Durban, South Africa
Study Design:
The knowledge and integrated methodology created from this study will catalyze the significant declines in global TB incidence needed to achieve the global EndTB 2035 goals.
Subjects:
The Role of Casual Contact and Migration in XDR TB Transmission in South Africa: a Geospatial, Genomic and Social Network study
Outcomes:
Findings from this study will lead to a better understanding of XDR TB transmission patterns in South Africa, which is critical for targeting interventions to curb the ongoing XDR TB epidemic and to characterize potential TB transmission routes due to commuting and migration patterns in a high HIV prevalence setting. Aim 1: To determine the proportion of XDR TB that develops through casual contact and identify locations where transmission occurs using genomic, social network, and geospatial analyses. Aim 2: To characterize migration patterns among persons diagnosed with XDR TB in Durban to determine how migration creates opportunities for XDR TB dissemination. Aim 3: To quantify the proportion of XDR TB cases from throughout KwaZulu-Natal province that are genomically linked to cases in Durban using whole genome sequencing.
Start Date:
2018-01-17
End Date:
2022-12-31
Fellow:
Nesri Padayatchi
Collaborators:
Name Country Institution
Nesri Padayatchi South Africa Centre for the AIDS Programme of Research in South Africa (CAPRISA)
Objectives:
The primary objective is to determine if a moxifloxacin-containing regimen, substituting moxifloxacin for ethambutol, of 24 weeks duration is superior to a control regimen of 24 weeks duration in improving treatment outcomes in patients with recurrent TB and shortens the duration of TB treatment.
Sites:
CAPRISA eThekwini Clinical Research Site (eCRS) Durban, KwaZulu Natal, South Africa
Study Design:
197 participants; 18 Years and older.
Subjects:
An Open Label Randomized Controlled Clinical Trial Comparing a 24Week Oral Regimen Containing Moxifloxacin With a 24 Week Standard Drug Regimen for the Treatment of Smear-positive Pulmonary Tuberculosis in Patients Previously Treated for TB.
Outcomes:
Primary Outcome Measures : A moxifloxacin-containing regimen, substituting moxifloxacin for ethambutol, is superior to a control regimen in improving treatment outcomes [ Time Frame: Up to 2 years ] The primary objective is to determine if a moxifloxacin-containing regimen, [isoniazid (H), rifampicin (R), pyrazinamide (Z), moxifloxacin (M)], substituting moxifloxacin for ethambutol, of 24 weeks duration is superior to a control regimen [isoniazid (H), rifampicin(R), pyrazinamide (Z), ethambutol(E)] of 24 weeks duration in improving treatment outcomes in patients with recurrent TB and shortens the duration of TB treatment.
Start Date:
2013-11-01
End Date:
2017-07-17
Fellow:
Nesri Padayatchi
Collaborators:
Name Country Institution
Nesri Padayatchi South Africa Centre for the AIDS Programme of Research in South Africa (CAPRISA)
Kogieleum Naidoo South Africa Centre for the AIDS Programme of Research in South Africa (CAPRISA)
Max R O’Donnell United States Columbia University Medical Center
Objectives:
This is a randomized controlled clinical trial comparing treatment success of a gene-derived individualized drug-resistant Tuberculosis regimen to a standard Tuberculosis regimen based on South African National Tuberculosis guidelines.
Sites:
King Dinuzulu Hospital Durban, Kwa-Zulu Natal, South Africa
Study Design:
Study Type : Interventional (Clinical Trial) Allocation: Randomized Intervention Model: Parallel Assignment Intervention Model Description: Patients randomized to the intervention receive a individualized tuberculosis treatment based on whole genome sequencing and the patients randomized to the control receive the standard of care tuberculosis treatment. Masking: None (Open Label) Primary Purpose: Treatment
Subjects:
448 Adults (>18 years) with pulmonary tuberculosis
Outcomes:
Primary Outcome Measures : 1. Culture negative survival rate [ Time Frame: 24 months ] To determine if a gene-derived individualized treatment approach in patients with drug-resistant TB will improve culture negative survival rates at 6 months post treatment initiation. 2. Culture negative survival rate [ Time Frame: 30 months ] To determine if a gene-derived individualized treatment approach in patients with drug-resistant TB will improve culture negative survival rates at 6 months post treatment initiation.
Start Date:
2017-06-14
End Date:
2021-12-31

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