Tuberculosis NEJM
Tuberculosis NEJM
Tuberculosis NEJM
n e w e ng l a n d j o u r na l
of
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review article
current concepts
Tuberculosis
Alimuddin Zumla, M.D., Ph.D., Mario Raviglione, M.D., Richard Hafner, M.D.,
and C. Fordham von Reyn, M.D.
espite the availability of a cheap and effective treatment, tuberculosis still accounts for millions of cases of active disease and deaths
worldwide. The disease disproportionately affects the poorest persons in
both high-income and developing countries.1 However, recent advances in diagnostics, drugs, and vaccines and enhanced implementation of existing interventions have
increased the prospects for improved clinical care and global tuberculosis control.
Epidemiol o gy
In 2011, there were 8.7 million new cases of active tuberculosis worldwide (13%
of which involved coinfection with the human immunodeficiency virus [HIV]) and
1.4 million deaths, including 430,000 deaths among HIV-infected patients1 representing a slight decrease from peak numbers in the mid-2000s (Fig. 1). It has been
estimated that there were 310,000 incident cases of multidrug-resistant tuberculosis, caused by organisms resistant to at least isoniazid and rifampin, among patients
who were reported to have tuberculosis in 2011 (Fig. 2). More than 60% of these
patients were in China, India, the Russian Federation, Pakistan, and South Africa.1,2
A total of 84 countries have reported cases of extensively drug-resistant tuberculosis,
a subset of multidrug-resistant tuberculosis with added resistance to all fluoroquin
olones plus any of the three injectable antituberculosis drugs, kanamycin, amikacin,
and capreomycin.1-3 Sub-Saharan Africa has the highest rates of active tuberculosis
per capita, driven primarily by the HIV epidemic.1 The absolute number of cases is
highest in Asia, with India and China having the greatest burden of disease globally.1 In the United States and most Western European countries, the majority of
cases occur in foreign-born residents and recent immigrants from countries in
which tuberculosis is endemic.4-6
From the Department of Infection, Division of Infection and Immunity, University College London Medical School,
London (A.Z.); STOP TB Department,
World Health Organization, Geneva
(M.R.); the Tuberculosis Clinical Research Branch, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health,
Bethesda, MD (R.H.); and the Section of
Infectious Disease and International
Health, Geisel School of Medicine at
Dartmouth, Hanover, NH (C.F.R.). Address reprint requests to Dr. Zumla at the
Division of Infection and Immunity, Centre for Clinical Microbiology, 2nd Fl., UCL
Royal Free Campus, Rowland Hill St.,
London NW3 OPE, United Kingdom, or
at a.zumla@ucl.ac.uk.
N Engl J Med 2013;368:745-55.
DOI: 10.1056/NEJMra1200894
Copyright 2013 Massachusetts Medical Society.
745
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All cases
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2.5
HIV-positive
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2000
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2010
nejm.org
current concepts
MDR-TB Cases
0299
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300029,999
30,00059,999
60,000
Data not shown
747
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748
current concepts
Recommended Regimen
Comments
Active disease
Newly diagnosed cases that are not
multidrug-resistant
Multidrug-resistant disease
Latent infection
Isoniazid at a dose of 300 mg daily for at least Recommended for 9 mo or more in HIV6 mo and preferably for 9 mo
infected persons; daily administration
for 6 mo also an option but with lower
efficacy; extension to 36 mo further re
duces risk among HIV-positive patients
in regions in which tuberculosis is
endemic
Isoniazid at a dose of 900 mg plus rifapentine Studied with directly observed therapy in preat a dose of 900 mg weekly for 3 mo (directly
dominantly HIV-uninfected persons; higher
observed therapy)
completion rates and equal efficacy, as
compared with isoniazid for 9 mo
Rifampin at a dose of 600 mg daily for 4 mo
Isoniazid at a dose of 300 mg plus rifampin at Effective alternative for HIV-infected persons
a dose of 600 mg daily for 3 mo
Isoniazid at a dose of 900 mg plus rifampin at Another effective alternative for HIV-infected
a dose of 600 mg twice weekly for 3 mo
persons
T r e atmen t
Latent Infection
constrained, high-burden countries receive preventive therapy with isoniazid for at least 6 months.
Three regimens are effective for the prevention
of active tuberculosis in HIV-infected persons:
daily isoniazid for 6 to 9 months, daily rifampin
and isoniazid for 3 months, and rifampin and iso
niazid twice weekly for 3 months.43,44 Rifampincontaining regimens have higher rates of drug
toxicity than those that do not include rifam
pin.44-46 The difficulty of diagnosing active tuberculosis in patients with HIV coinfection accounts
in part for the slow adoption of isoniazid preventive therapy in clinical practice. Only patients
with a positive tuberculin skin test who are receiving preventive therapy with isoniazid have decreased rates of active tuberculosis and death,46
and protection against tuberculosis wanes within
a few months after cessation of isoniazid therapy. A trial in Botswana recently showed that 36
months of preventive therapy with isoniazid, as
compared with 6 months of therapy, reduced the
subsequent rate of tuberculosis by 43%.47 However, compliance with such a long-term regimen
may be poor.44 A daily regimen of rifapentine
749
750
Increased doses of rifampin and rifapentine
Multiple trials
SQ109
Linezolid
of
Sutezolid
PA-824
n e w e ng l a n d j o u r na l
AZD 5847
PA-824 combined with moxifloxacin and pyrazinamide is being studied A nitroimidazole with the same mechanism of action as delamanid;
in a phase 2b trial (8 wk) for treatment of drug-sensitive and
when combined with moxifloxacin and pyrazinamide, has high
drug-resistant disease
bactericidal activity at 14 days, suggesting promise for treatment
of sensitive and resistant disease
A marketed oxazolidinone that improved sputum-culture conversion
at 4 mo in a group receiving immediate versus delayed linezolid;
for both linezolid regimens, 89% of patients had sputum-culture
conversion on solid medium by 6 mo; high rate of peripheral neuropathy, including some cases of optic neuropathy
Delamanid (OPC-67683)
A nitroimidazole with activity against replicating bacilli through inhibition of mycolic acid synthesis; active against nonreplicating bacilli
through generation of reactive nitrogen intermediates; shown to
improve sputum-culture conversion at 8 wk
Higher doses of rifamycins may permit shorter regimens with standard drugs
Bedaquiline (TMC207)
RIFAQUIN
Standard 6-mo regimen vs. two 4-mo regimens including moxifloxacin Results in 2014 have potential to shorten standard therapy to 4 mo
Standard 6-mo regimen vs. 4-mo regimen including gatifloxacin
Comments
REMox
Description
OFLOTUB III
The
m e dic i n e
* A full listing of all trial references or clinical trial numbers is provided in the Supplementary Appendix at NEJM.org. ACTG 5279 denotes Ultra-Short-Course Rifapentine/Isoniazid for the
Prevention of Active Tuberculosis in HIV-Infected Individuals with Latent Tuberculosis Infection, OFLOTUB Randomized, Open-Label, Controlled Trial of a 4-Month Gatifloxacin-Containing
Regimen versus Standard Regimen for the treatment of Adult Patients with Pulmonary Tuberculosis, PROMPT Prevention of Early Mortality by Presumptive Tuberculosis Treatment,
REMEMBER Reducing Early Mortality and Morbidity by Empiric Tuberculosis Treatment, REMox Rapid Evaluation of Moxifloxacin in Tuberculosis, and RIFAQUIN International
Multicenter Trial to Evaluate High-Dose Rifapentine and a Quinolone in the Treatment of Pulmonary Tuberculosis.
current concepts
Tuberculosis leads to an increase in HIV replication and accelerates progression of HIV infection,
with attendant high mortality. Early initiation of
antiretroviral therapy results in a reduction in
mortality; among patients with tuberculosis who
do not receive antiretroviral therapy, those with
very low numbers of CD4+ cells have a high
short-term risk of death.50-52 WHO recommends
that antiretroviral therapy be started within the
751
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The treatment of multidrug-resistant tuberculosis is based on expert opinion and requires the
creation of combination drug regimens chosen
from five hierarchical groups of first-line and
second-line drugs58,59 (Table S1 in the Supplementary Appendix). Such therapy is associated
with a high risk of intolerance and serious toxic
effects. Regimens may be chosen on a standardized or empirical basis and then switched to individualized therapy after data regarding drugsusceptibility testing become available. However,
reliable drug-susceptibility testing is not widely
available in regions in which tuberculosis is endemic, particularly for second-line drugs. WHO
treatment guidelines for multidrug-resistant tuberculosis recommend that the intensive phase of
therapy be administered for at least 8 months.58,59
A fluoroquinolone and an injectable agent should
routinely be included to provide a regimen with
at least four second-line drugs that will have certain or nearly certain effectiveness, as well as
pyrazinamide.
Such therapy should be administered for at
least 20 months in patients who have not received previous treatment for multidrug-resistant tuberculosis and for up to 30 months in
those who have received previous treatment. An
observational study showed that a shorter regimen, with treatment given for 9 to 12 months
(the so-called Bangladesh regimen), had acceptable efficacy with fewer adverse reactions60 in a
population with no previous exposure to secondline drugs. This regimen is being more widely
evaluated in the ongoing Standardized Treatment Regimen of Antituberculosis Drugs for
Patients with Multidrug-Resistant Tuberculosis
(STREAM) trial.61 Since most of the recommended drugs have serious side effects that render
treatment particularly difficult, expert consultation is always advised for the treatment of multidrug-resistant tuberculosis (Table S2 in the
Supplementary Appendix).
Extensively drug-resistant tuberculosis is extremely difficult to diagnose and treat in countries in which the disease is endemic. The condition has been associated with death rates as high
current concepts
C onclusions
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References
1. Global tuberculosis report 2012. Ge-
754
current concepts
tion, 2011 (http://whqlibdoc.who.int/
publications/2011/9789241501569_eng
.pdf).
41. Moore DA, Evans CA, Gilman RH, et
al. Microscopic-observation drug-susceptibility assay for the diagnosis of TB.
N Engl J Med 2006;355:1539-50.
42. WHO policy on collaborative TB/HIV
activities. Geneva: World Health Organization, 2012 (http://whqlibdoc.who.int/
publications/2012/9789241503006_eng
.pdf).
43. Martinson NA, Barnes GL, Moulton
LH, et al. New regimens to prevent tuberculosis in adults with HIV infection.
N Engl J Med 2011;365:11-20.
44. Guidelines for intensified tuberculosis case-finding and isoniazid preventive
therapy for people living with HIV in
resource-constrained settings. Geneva:
World Health Organization, 2011 (http://
whqlibdoc.who.int/publications/2011
/9789241500708_eng.pdf).
45. Sterling TR, Villarino ME, Borisov AS,
et al. Three months of rifapentine and
isoniazid for latent tuberculosis infection. N Engl J Med 2011;365:2155-66.
46. Akolo C, Adetifa I, Shepperd S, Volmink J. Treatment of latent tuberculosis
infection in HIV infected persons. Cochrane Database Syst Rev 2010;1:
CD000171.
47. Samandari T, Agizew TB, Nyirenda S,
et al. 6-Month versus 36-month isoniazid
preventive treatment for tuberculosis in
adults with HIV infection in Botswana: a
randomised, double-blind, placebo-controlled trial. Lancet 2011;377:1588-98.
48. Lawn SD, Wood R. Antiretroviral
therapy for control of the HIV-associated
MDR and XDR tuberculosis epidemic in
South Africa. Am J Respir Crit Care Med
2010;182:1567.
49. Combs DL, OBrien RJ, Geiter LJ.
USPHS Tuberculosis Short-Course Chemotherapy Trial 21: effectiveness, toxicity
and acceptability: the report of the final
results. Ann Intern Med 1990;112:397-406.
50. Abdool Karim SS, Naidoo K, Grobler
A, et al. Integration of antiretroviral therapy with tuberculosis treatment. N Engl J
Med 2011;365:1492-501.
51. Havlir DV, Kendall MA, Ive P, et al.
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Supplementary Appendix
This appendix has been provided by the authors to give readers additional information about their work.
Supplement to: Zumla A, Raviglione M, Hafner R, von Reyn CF. Tuberculosis. N Engl J Med 2013;368:745-55.
DOI: 10.1056/NEJMra1200894
PAGE NO.
Page 2
TABLE S1
GROUPS OF FIRST AND SECOND-LINE ANTI-TUBERCULOSIS DRUGS
Page 3
TABLE S2
MDR-TB TREATMENT DRUGS AND RELATED TOXICITIES
Page 4
TABLE S3
CANDIDATE TUBERCULOSIS DRUGS IN CLINICAL TRIALS
Page 6
FIGURE S1
RISKS OF Mycobacterium tuberculosis INFECTION AND DISEASE
Page 8
FIGURE S2
CLASSIFYING THE TUBERCULIN SKIN TEST REACTION
Page 9
FIGURE S3
GLOBAL TB VACCINE PIPELINE
Page 10
Page 11
Current Concepts
TUBERCULOSIS
ALIMUDDIN ZUMLA,M.D.,Ph.D., MARIO RAVIGLIONE,M.D., RICHARD HAFNER,M.D., AND C. FORDHAM VON REYNM.D.
From the Department of Infection, Center for Clinical Microbiology, Division of Infection and Immunity, University
College London Medical School, University College London, U.K. (A.Z); STOP TB Department, World Health
Organisation, Avenue Appia 20, 1211 Geneva 27, Switzerland (M.R); Tuberculosis Clinical Research Branch, Division of
AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and
Human Services, Bethesda, MD 20892-7628, USA (R.H); Section of Infectious Disease and International Health, Geisel
School of Medicine at Dartmouth, Hanover, NH 03756, USA (C.FvR).
TABLE S1
GROUPS OF FIRST AND SECOND-LINE ANTI-TUBERCULOSIS DRUGS
GROUP NAME
ANTI-TUBERCULOSIS AGENT
ABBREVIATION
Isoniazid
Rifampin/Rifampicin
Ethambutol
Pyrazinamide
H (Inh)
R (Rif)
E (Emb)
Z (Pza)
Kanamycin
Amikacin
Capreomycin
Km
Amk
Cm
Fluoroquinolones
Levofloxacin
Moxifloxacin
Gatifloxacin
Ofloxacin
Lfx
Mfx
Gfx
Ofx
Ethionamide
Prothionamide
Cycloserine
Terizidone
Para-aminosalicylic acid
Eto
Pto
Cs
Trd
Pas
Clofazimine
Linezolid
Amoxicillin/Clavulanate
Imipenem/Cilastin
Clarithromycin
Cfz
Lzd
Amx/Clv
Ipm/Cln
Clr
TABLE S2
GROUP
Group 1
First-line Agents
Generally well tolerated
DRUG
Pyrazinamide (Pza)*
Ethambutol (Emb)*
Group 2
Injectable Agents
Group 3
Fluoroquinolones
Aminoglycosides:
Kanamycin (Km)*
Amikacin (Amk)
Cyclic polypeptide:
Capreomycin (Cm)
Moxifloxacin (Mfx)*
Levofloxacin (Lfx)
Ofloxacin (Ofx)
Group 4
Bacteriostatic Second-line
Agents (in order of
preference)
Ethionamide (Eto)
Prothionamide (Pto)*
Cycloserine (Cs)
Terizidone (Trd)
COMMENTS
GROUP
DRUG
Para-aminosalicylic
acid (Pas)
Group 5
Agents with unclear role in
MDR-TB Treatment (use
only as needed for regimen
to have at least 4 highprobability active secondline drugs)
COMMENT
S
- High-dose pyridoxine (150-300
mg/day) should
be added
- Weak static activity only, but helps to prevent
emergence of resistance
- Granular form and divided dosing are usually
better tolerated
- Unlikely to have activity against katG mutant
strains, but may be active against most inhA
mutant strains
- Pyridoxine should be added
2011 WHO guidelines for choice of combination regimens for MDR treatment: Initiate treatment with Pza and four second-line drugs likely to be effective based on patient
treatment history, local resistance and drug use patterns, and available DST of strains from patient or close contacts. Combination should include a fluoroquinolone (preferably Mfx
or Lfx), an injectable drug, and eto (or pto) as first choices, if appropriate. Other drugs from Group 4 should be added in the order listed above to achieve combination goals. If other
drugs are still needed, they are chosen from Group 5, and in that case, use of two Group 5 drugs may be considered. Addition of more drugs has not been demonstrated to add benefit
in treatment of extensive disease. Intensive phase with at least five drugs (including an injecta ble and Pza) is continued for at least 8 months.
Maintenance therapy includes only the other drugs (typically a fluoroquinolone, Eto or Pto, and Cs or Trd). Total duration of therapy is at least 20 months in the absence of prior MDR
treatment, but longer with previous MDR therapy (approximately 28-30 months). If available, DST should be obtained for fluoroquinolones and aminoglycosides. DST for other listed
drugs is not reproducible or reliable (except for detection of inhA and KatG mutations). Regimen changes are made based on clinical and bacteriologic indicators of response and DST
results.
HIV co-infection: All HIV co-infected patients treated for MDR-TB should begin antiretroviral therapy regardless of CD4+ cell count as soon as possible, but within 8 weeks of TB
treatment initiation, and within 2 weeks for those with a CD4+ T cell count of less than 50 per cubic millimeter.
* Drugs included in the (modified) Bangladesh Regimen: Intensive phase consists of at least four months of Pza, Emb, Mfx, Clz, Km, high dose Inh, and Pto.
Maintenance phase includes Pza, Emb, Mfx, and Cfz to complete nine to twelve months total duration.
TABLE S3
CANDIDATE TUBERCULOSIS DRUGS IN CLINICAL TRIALS
CLASS
DRUG
Fluoroquinolone
Moxifloxacin
TRIAL
PHASE
3
Gatifloxacin
MECHANISM OF ACTION
Bayer/GATB
-Inhibition of Topoisomerase IV
and DNA gyrase
WHO
Janssen;
generics now
available
Levofloxacin
2
Nitroimidazole
DEVELOPER
COMMENTS
Delamanid
(OPC-67683)
Otsuka
PA-824
GATB
Diarylquinoline
Bedaquiline
(TMC-207)
Janssen
Oxazolidinone*
Sutezolid
(PNU 100480)
Pfizer
-Inhibition of translation
by binding at the A site of
peptidyl transferase center
AZD 5847
Ethylenediamine SQ109
Astra
Zeneca
2
2
Sequella
-Inhibition of MmpL3 transporter - Phase 2b MAMS trial will evaluate four new treatment regimens
including SQ109, an increased dose of Rif, and Mfx, in early 2013
of trehalose mycolate across cell
membrane for incorporation into - Appears to have high barrier to development of resistance
cell wall
* Two other oxazoldinones now in late clinical trials for other indications have substantial activity against Mycobacterium tuberculosis: Tedazolid (Trius) and Radezolid (Rib-X)
EBA = Early bactericidal activity. GATB = The Global Alliance for Tuberculosis Drug Development
FIGURE S1
RISKS OF Mycobacterium tuberculosis INFECTION AND DISEASE
Percentages represent the estimated risk of progression from latent infection to active disease in a general population. The right side of the
Figure depicts the relative risk of developing active tuberculosis after new exposure for subjects with and without prior mycobacterial
experience including BCG, LTBI, or active tuberculosis. The risk of disease after new exposure is shown as 1X for nave subjects and is
higher or lower depending on prior mycobacterial experience.
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FIGURE S2
CLASSIFYING THE TUBERCULIN SKIN TEST (TST) REACTION
TST INDURATION
INTERPRETATION
5mm induration
10mm induration
15mm induration
Note:
Targeted TST programs should be conducted amongst high risk groups
TST reaction may be negative in patients with LTBI
Rule out active TB disease before treating LTBI
FIGURE S3
GLOBAL TB VACCINE PIPELINE
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OFLOTUB III -- A Controlled Trial of a 4-Month Quinolone-Containing Regimen for the Treatment of Pulmonary Tuberculosis
ClinicalTrials.gov Identifier: NCT00216385.
RIFAQUIN
-- An international multicentre controlled clinical trial to evaluate high dose RIFApentine and a QUINolone in the
treatment of pulmonary tuberculosis RIFAQUIN. International Standard Randomised Controlled Trial Number
Register Identifier: ISRCTN44153044.
DELAMANID -- (Ref 65) -- Gler MT, Skripconoka V, Sanchez-Garavito E, et al. Delamanid for multidrug-resistant pulmonary
tuberculosis. N Engl J Med. 2012 Jun 7;366(23):2151-60.
DELAMANID -- Safety and Efficacy Trial of Delamanid for 6 Months in Patients With Multidrug Resistant Tuberculosis.
ClinicalTrials.gov Identifier: NCT01424670 (Phase 3 trial by Otsuka).
PA-824 -- Diacon AH, Dawson R, du Bois J, et al. Phase II dose-ranging trial of the early bactericidal activity of PA-824. Antimicrob
Agents Chemother. 2012 Jun;56(6):3027-31.
PA-824 -- Singh R, Manjunatha U, Boshoff HI, et al. PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release.
Science. 2008 Nov 28;322(5906):1392-5.
PA-824 -- (Ref 66) -- Diacon AH, Dawson R, von Groote-Bidlingmaier et al. 14-day bactericidal activity of PA-824, bedaquiline,
pyrazinamide, and moxifloxacin combinations: a randomised trial Lancet. 2012 Sep 15;380(9846):986-93.
PA-824 -- Evaluation of 8 weeks treatment With the Combination of Moxifloxacin, PA-824 and Pyrazinamide in Patients With Drug
Sensitive and Multi Drug-Resistant Pulmonary Tuberculosis (TB). ClinicalTrials.gov Identifier: NCT01498419 (ongoing Phase IIB trial
for the Global Alliances PA-824+PZA+moxifloxacin combination).
PA-824 -- Evaluation of Early Bactericidal Activity in Pulmonary Tuberculosis With Clofazimine (C)-TMC207 (J)-PA-824(Pa)Pyrazinamide(Z). ClinicalTrials.gov Identifier: NCT01691534. (Not yet initiated).
LINEZOLID -- (Ref 67) -- Lee M, Lee J, Carroll MW, et al . Linezolid for treatment of chronic extensively drug-resistant tuberculosis. N
Engl J Med. 2012;367(16):1508-18.
SUTEZOLID -- A Study Of PNU-100480 In Newly Diagnosed, Treatment Sensitive Patients With Pulmonary Tuberculosis To Assess Early
Bactericidal Activity (EBA) And Whole Blood Activity (WBA). ClinicalTrials.gov Identifier: NCT01225640
-- Wallis RS, Friedrich SO, Diacon AH, et al. Bactericidal Activity in Sputum and Blood of PNU-100480(Sutezolid,U-480)
and its Major Metabolite (PNU101603,U-603) in Patients with Pulmonary TB. ICAAC 201 abs A-1264.
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-- Dose Escalation Study of SQ109 in Healthy Adult Volunteers. ClinicalTrials.gov Identifier: NCT00866190
-- Dose Escalation Study of SQ109 in Healthy Adult Volunteers, International Consortium for Trials of
Chemotherapeutic Agents in Tuberculosis, 2012 Meeting: http://www.intertb.sgul.ac.uk/2012-meeting.
SQ-109 -- A multiple arm, multiple stage (MAMS), phase 2, open label, randomized, controlled clinical trial to evaluate four
treatment regimens including two doses of SQ109, an increased dose of rifampicin, and moxifloxacin in adult
subjects with newly diagnosed, smear-positive pulmonary tuberculosis - PanACEA-MAMS-TB-01.
Pan-African Clinical Trials Registry Identifier: PACTR201205000383208.
ACTG 5290 -- (Ref 55) -- Rifampin-Based Tuberculosis Treatment Versus Rifabutin-Based Tuberculosis Treatment in HIV.
http://clinicaltrials.gov/ct2/show/NCT01601626.
PROMPT -- (Ref 56) -- Prevention of Early Mortality by Presumptive Tuberculosis (TB) Treatment (PrOMPT).
ClinicalTrials.gov Identifier: NCT01417988.
REMEMBER (ACTG 5274) -- (Ref 57) -- Reducing Early Mortality & Morbidity by Empiric Tuberculosis (TB) Treatment.
AC ClinicalTrials.gov Identifier: NCT01380080.
ACTG 5279 -- Evaluating the Safety and Effectiveness of Short-Course Rifapentine/Isoniazid for the Prevention of Active
Tuberculosis in HIV-Infected Individuals With Latent Tuberculosis Infection. ClinicalTrials.gov Identifier: NCT01404312.
13