Adjunctive dexamethasone for the treatment of hiv-infected adults with tuberculous meningitis (ACT HIV)

Study protocol for a randomised controlled trial [version 2; referees: 1 approved, 2 approved with reservations]

Joseph Donovan, Nguyen Hoan Phu, Nguyen Thi Hoang Mai, Le Tien Dung, Darma Imran, Erlina Burhan, Lam Hong Bao Ngoc, Nguyen Duc Bang, Do Chau Giang, Dang Thi Minh Ha, Jeremy Day, Le Thi Phuong Thao, Nguyen T.T. Thuong, Nguyen Nang Vien, Ronald B. Geskus, Marcel Wolbers, Raph L. Hamers, Reinout van Crevel, Mugi Nursaya, Kartika Maharani & 6 others Tran Tinh Hien, Kevin Baird, Nguyen Huu Lan, Evelyne Kestelyn, Nguyen Van Vinh Chau, Guy E. Thwaites

Research output: Contribution to journalArticleOtherpeer-review

4 Citations (Scopus)

Abstract

Background: Tuberculous meningitis (TBM) is the most severe form of tuberculosis. Co-infection with HIV increases the risk of developing TBM, complicates treatment, and substantially worsens outcome. Whether corticosteroids confer a survival benefit in HIV-infected patients with TBM remains uncertain. Hepatitis is the most common drug-induced serious adverse event associated with anti-tuberculosis treatment, occurring in 20% of HIV-infected patients. The suggested concentration thresholds for stopping anti-tuberculosis drugs are not evidence-based. This study aims to determine whether dexamethasone is a safe and effective addition to the first 6-8 weeks of anti-tuberculosis treatment of TBM in patients with HIV, and investigate alternative management strategies in a subset of patients who develop drug induced liver injury (DILI) that will enable the safe continuation of rifampicin and isoniazid therapy. Methods: We will perform a parallel group, randomised (1:1), double blind, placebo-controlled multi-centre Phase III trial, comparing the effect of dexamethasone versus placebo on overall survival in HIV-infected patients with TBM, in addition to standard anti-tuberculosis and antiretroviral treatment. The trial will be set in two hospitals in Ho Chi Minh City, Vietnam, and two hospitals in Jakarta, Indonesia. The trial will enrol 520 HIV-infected adults. An ancillary study will perform a randomised comparison of three DILI management strategies with the aim of demonstrating which strategy results in the least interruption in rifampicin and isoniazid treatment. An identical ancillary study will also be performed in the linked randomised controlled trial of dexamethasone in HIV-uninfected adults with TBM stratified by LTA4H genotype (LAST ACT). Discussion: Whether corticosteroids confer a survival benefit in HIV-infected patients remains uncertain, and the current evidence base for using corticosteroids in this context is limited. Interruptions in anti-tuberculosis chemotherapy is a risk factor for death from TBM. Alternative management strategies in DILI may allow the safe continuation of rifampicin and isoniazid therapy.

Original languageEnglish
Article number31
JournalWellcome Open Research
Volume3
DOIs
Publication statusPublished - 1 Jan 2018
Externally publishedYes

Keywords

  • Adrenal suppression
  • Dexamethasone
  • Diabetes
  • Drug-induced liver injury
  • HIV
  • Hyponatraemia
  • LTA4H
  • Strongyloides
  • Tuberculous meningitis

Cite this

Donovan, Joseph ; Phu, Nguyen Hoan ; Mai, Nguyen Thi Hoang ; Dung, Le Tien ; Imran, Darma ; Burhan, Erlina ; Ngoc, Lam Hong Bao ; Bang, Nguyen Duc ; Giang, Do Chau ; Ha, Dang Thi Minh ; Day, Jeremy ; Thao, Le Thi Phuong ; Thuong, Nguyen T.T. ; Vien, Nguyen Nang ; Geskus, Ronald B. ; Wolbers, Marcel ; Hamers, Raph L. ; Crevel, Reinout van ; Nursaya, Mugi ; Maharani, Kartika ; Hien, Tran Tinh ; Baird, Kevin ; Lan, Nguyen Huu ; Kestelyn, Evelyne ; Chau, Nguyen Van Vinh ; Thwaites, Guy E. / Adjunctive dexamethasone for the treatment of hiv-infected adults with tuberculous meningitis (ACT HIV) : Study protocol for a randomised controlled trial [version 2; referees: 1 approved, 2 approved with reservations]. In: Wellcome Open Research. 2018 ; Vol. 3.
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title = "Adjunctive dexamethasone for the treatment of hiv-infected adults with tuberculous meningitis (ACT HIV): Study protocol for a randomised controlled trial [version 2; referees: 1 approved, 2 approved with reservations]",
abstract = "Background: Tuberculous meningitis (TBM) is the most severe form of tuberculosis. Co-infection with HIV increases the risk of developing TBM, complicates treatment, and substantially worsens outcome. Whether corticosteroids confer a survival benefit in HIV-infected patients with TBM remains uncertain. Hepatitis is the most common drug-induced serious adverse event associated with anti-tuberculosis treatment, occurring in 20{\%} of HIV-infected patients. The suggested concentration thresholds for stopping anti-tuberculosis drugs are not evidence-based. This study aims to determine whether dexamethasone is a safe and effective addition to the first 6-8 weeks of anti-tuberculosis treatment of TBM in patients with HIV, and investigate alternative management strategies in a subset of patients who develop drug induced liver injury (DILI) that will enable the safe continuation of rifampicin and isoniazid therapy. Methods: We will perform a parallel group, randomised (1:1), double blind, placebo-controlled multi-centre Phase III trial, comparing the effect of dexamethasone versus placebo on overall survival in HIV-infected patients with TBM, in addition to standard anti-tuberculosis and antiretroviral treatment. The trial will be set in two hospitals in Ho Chi Minh City, Vietnam, and two hospitals in Jakarta, Indonesia. The trial will enrol 520 HIV-infected adults. An ancillary study will perform a randomised comparison of three DILI management strategies with the aim of demonstrating which strategy results in the least interruption in rifampicin and isoniazid treatment. An identical ancillary study will also be performed in the linked randomised controlled trial of dexamethasone in HIV-uninfected adults with TBM stratified by LTA4H genotype (LAST ACT). Discussion: Whether corticosteroids confer a survival benefit in HIV-infected patients remains uncertain, and the current evidence base for using corticosteroids in this context is limited. Interruptions in anti-tuberculosis chemotherapy is a risk factor for death from TBM. Alternative management strategies in DILI may allow the safe continuation of rifampicin and isoniazid therapy.",
keywords = "Adrenal suppression, Dexamethasone, Diabetes, Drug-induced liver injury, HIV, Hyponatraemia, LTA4H, Strongyloides, Tuberculous meningitis",
author = "Joseph Donovan and Phu, {Nguyen Hoan} and Mai, {Nguyen Thi Hoang} and Dung, {Le Tien} and Darma Imran and Erlina Burhan and Ngoc, {Lam Hong Bao} and Bang, {Nguyen Duc} and Giang, {Do Chau} and Ha, {Dang Thi Minh} and Jeremy Day and Thao, {Le Thi Phuong} and Thuong, {Nguyen T.T.} and Vien, {Nguyen Nang} and Geskus, {Ronald B.} and Marcel Wolbers and Hamers, {Raph L.} and Crevel, {Reinout van} and Mugi Nursaya and Kartika Maharani and Hien, {Tran Tinh} and Kevin Baird and Lan, {Nguyen Huu} and Evelyne Kestelyn and Chau, {Nguyen Van Vinh} and Thwaites, {Guy E.}",
year = "2018",
month = "1",
day = "1",
doi = "10.12688/wellcomeopenres.14006.2",
language = "English",
volume = "3",
journal = "Wellcome Open Research",
issn = "2398-502X",
publisher = "F1000Research",

}

Donovan, J, Phu, NH, Mai, NTH, Dung, LT, Imran, D, Burhan, E, Ngoc, LHB, Bang, ND, Giang, DC, Ha, DTM, Day, J, Thao, LTP, Thuong, NTT, Vien, NN, Geskus, RB, Wolbers, M, Hamers, RL, Crevel, RV, Nursaya, M, Maharani, K, Hien, TT, Baird, K, Lan, NH, Kestelyn, E, Chau, NVV & Thwaites, GE 2018, 'Adjunctive dexamethasone for the treatment of hiv-infected adults with tuberculous meningitis (ACT HIV): Study protocol for a randomised controlled trial [version 2; referees: 1 approved, 2 approved with reservations]', Wellcome Open Research, vol. 3, 31. https://doi.org/10.12688/wellcomeopenres.14006.2

Adjunctive dexamethasone for the treatment of hiv-infected adults with tuberculous meningitis (ACT HIV) : Study protocol for a randomised controlled trial [version 2; referees: 1 approved, 2 approved with reservations]. / Donovan, Joseph; Phu, Nguyen Hoan; Mai, Nguyen Thi Hoang; Dung, Le Tien; Imran, Darma; Burhan, Erlina; Ngoc, Lam Hong Bao; Bang, Nguyen Duc; Giang, Do Chau; Ha, Dang Thi Minh; Day, Jeremy; Thao, Le Thi Phuong; Thuong, Nguyen T.T.; Vien, Nguyen Nang; Geskus, Ronald B.; Wolbers, Marcel; Hamers, Raph L.; Crevel, Reinout van; Nursaya, Mugi; Maharani, Kartika; Hien, Tran Tinh; Baird, Kevin; Lan, Nguyen Huu; Kestelyn, Evelyne; Chau, Nguyen Van Vinh; Thwaites, Guy E.

In: Wellcome Open Research, Vol. 3, 31, 01.01.2018.

Research output: Contribution to journalArticleOtherpeer-review

TY - JOUR

T1 - Adjunctive dexamethasone for the treatment of hiv-infected adults with tuberculous meningitis (ACT HIV)

T2 - Study protocol for a randomised controlled trial [version 2; referees: 1 approved, 2 approved with reservations]

AU - Donovan, Joseph

AU - Phu, Nguyen Hoan

AU - Mai, Nguyen Thi Hoang

AU - Dung, Le Tien

AU - Imran, Darma

AU - Burhan, Erlina

AU - Ngoc, Lam Hong Bao

AU - Bang, Nguyen Duc

AU - Giang, Do Chau

AU - Ha, Dang Thi Minh

AU - Day, Jeremy

AU - Thao, Le Thi Phuong

AU - Thuong, Nguyen T.T.

AU - Vien, Nguyen Nang

AU - Geskus, Ronald B.

AU - Wolbers, Marcel

AU - Hamers, Raph L.

AU - Crevel, Reinout van

AU - Nursaya, Mugi

AU - Maharani, Kartika

AU - Hien, Tran Tinh

AU - Baird, Kevin

AU - Lan, Nguyen Huu

AU - Kestelyn, Evelyne

AU - Chau, Nguyen Van Vinh

AU - Thwaites, Guy E.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Background: Tuberculous meningitis (TBM) is the most severe form of tuberculosis. Co-infection with HIV increases the risk of developing TBM, complicates treatment, and substantially worsens outcome. Whether corticosteroids confer a survival benefit in HIV-infected patients with TBM remains uncertain. Hepatitis is the most common drug-induced serious adverse event associated with anti-tuberculosis treatment, occurring in 20% of HIV-infected patients. The suggested concentration thresholds for stopping anti-tuberculosis drugs are not evidence-based. This study aims to determine whether dexamethasone is a safe and effective addition to the first 6-8 weeks of anti-tuberculosis treatment of TBM in patients with HIV, and investigate alternative management strategies in a subset of patients who develop drug induced liver injury (DILI) that will enable the safe continuation of rifampicin and isoniazid therapy. Methods: We will perform a parallel group, randomised (1:1), double blind, placebo-controlled multi-centre Phase III trial, comparing the effect of dexamethasone versus placebo on overall survival in HIV-infected patients with TBM, in addition to standard anti-tuberculosis and antiretroviral treatment. The trial will be set in two hospitals in Ho Chi Minh City, Vietnam, and two hospitals in Jakarta, Indonesia. The trial will enrol 520 HIV-infected adults. An ancillary study will perform a randomised comparison of three DILI management strategies with the aim of demonstrating which strategy results in the least interruption in rifampicin and isoniazid treatment. An identical ancillary study will also be performed in the linked randomised controlled trial of dexamethasone in HIV-uninfected adults with TBM stratified by LTA4H genotype (LAST ACT). Discussion: Whether corticosteroids confer a survival benefit in HIV-infected patients remains uncertain, and the current evidence base for using corticosteroids in this context is limited. Interruptions in anti-tuberculosis chemotherapy is a risk factor for death from TBM. Alternative management strategies in DILI may allow the safe continuation of rifampicin and isoniazid therapy.

AB - Background: Tuberculous meningitis (TBM) is the most severe form of tuberculosis. Co-infection with HIV increases the risk of developing TBM, complicates treatment, and substantially worsens outcome. Whether corticosteroids confer a survival benefit in HIV-infected patients with TBM remains uncertain. Hepatitis is the most common drug-induced serious adverse event associated with anti-tuberculosis treatment, occurring in 20% of HIV-infected patients. The suggested concentration thresholds for stopping anti-tuberculosis drugs are not evidence-based. This study aims to determine whether dexamethasone is a safe and effective addition to the first 6-8 weeks of anti-tuberculosis treatment of TBM in patients with HIV, and investigate alternative management strategies in a subset of patients who develop drug induced liver injury (DILI) that will enable the safe continuation of rifampicin and isoniazid therapy. Methods: We will perform a parallel group, randomised (1:1), double blind, placebo-controlled multi-centre Phase III trial, comparing the effect of dexamethasone versus placebo on overall survival in HIV-infected patients with TBM, in addition to standard anti-tuberculosis and antiretroviral treatment. The trial will be set in two hospitals in Ho Chi Minh City, Vietnam, and two hospitals in Jakarta, Indonesia. The trial will enrol 520 HIV-infected adults. An ancillary study will perform a randomised comparison of three DILI management strategies with the aim of demonstrating which strategy results in the least interruption in rifampicin and isoniazid treatment. An identical ancillary study will also be performed in the linked randomised controlled trial of dexamethasone in HIV-uninfected adults with TBM stratified by LTA4H genotype (LAST ACT). Discussion: Whether corticosteroids confer a survival benefit in HIV-infected patients remains uncertain, and the current evidence base for using corticosteroids in this context is limited. Interruptions in anti-tuberculosis chemotherapy is a risk factor for death from TBM. Alternative management strategies in DILI may allow the safe continuation of rifampicin and isoniazid therapy.

KW - Adrenal suppression

KW - Dexamethasone

KW - Diabetes

KW - Drug-induced liver injury

KW - HIV

KW - Hyponatraemia

KW - LTA4H

KW - Strongyloides

KW - Tuberculous meningitis

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U2 - 10.12688/wellcomeopenres.14006.2

DO - 10.12688/wellcomeopenres.14006.2

M3 - Article

VL - 3

JO - Wellcome Open Research

JF - Wellcome Open Research

SN - 2398-502X

M1 - 31

ER -