Target Product Profiles For Tuberculosis Preventive Treatment

Target product profiles
for tuberculosis
preventive treatment
Target product profiles
for tuberculosis
Target product profiles for tuberculosis preventive treatment
ISBN 978-92-4-001013-0 (electronic version)
ISBN 978-92-4-001014-7 (print version)
© World Health Organization 2020

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Contents
Acknowledgements iv
Abbreviations and acronyms v
Definitions vi
1 Introduction 1
2 Tuberculosis preventive treatment: background and current situation 1
3 Target product profiles for tuberculosis preventive treatment 3
3.1 New medicines and regimens for the treatment of tuberculosis infection 3
3.2 Objective and target audience 3
3.3 Methods 4
3.3.1 Baseline elements 4
3.3.2 Mathematical modelling 4
3.3.3 Cost-effectiveness analysis 5
3.3.4 Development of target product profiles 8
3.4 Description of the target product profiles for tuberculosis preventive treatment 9
3.4.1 Principles 9
3.4.2 Priority attributes 9
3.4.3 Desirable attributes 11
4 Cross-cutting aspects 18
5 Use case scenarios 19
5.1 Essential use case scenario 19
5.2 Intended use case scenarios 20
5.2.1 High- and low-transmission settings 20
5.2.2 Testing for tuberculosis infection 20
5.2.3 Rifampicin-susceptible and rifampicin-resistant strains 20
References 21
Annex 1. Treatment of tuberculosis infection for prevention of disease 24
Annex 2. Tuberculosis preventive treatment in special populations 27
Annex 3. Technical consultation on latent TB infection management: target regimen profiles,
17 September 2019, Montréal, Canada 30
Annex 4. WHO recommendations on TB preventive treatment (2020 update) 34
Annex 5. Long-acting drug formulations for the treatment of tuberculosis infection 36
Target product profiles for tuberculosis preventive treatment iii

Acknowledgements
This document was prepared by Christian Lienhardt (Institute for Research on Sustainable Development,
Montpellier, France) on the basis of consensus achieved at a technical consultation on target product
profiles for tuberculosis preventive treatment convened by the Global TB Programme of WHO on 17
September 2019 in Montréal, Canada.
WHO thanks Payam Nahid, Christian Lienhardt, Olivia Oxlade, Kevin Schwartzman, Dick Menzies and
Richard Chaisson for presenting or moderating discussions during the technical consultation and Kevin
Schwartzman, Nimalan Arinaminpathy, Juan Vesga Gaviria, Ntwali Placide Nsengiyumva, Jonathon
Campbell and Olivia Oxlade for conducting modelling for this document.
This document was finalized after consideration of all comments and suggestions made by members of the
scoping group: Jay Achar, Menonli Adjobimey, Faiz Ahmad Khan, Sevim Ahmedov, Teeb Al-Samarrai,
Nimalan Arinaminpathy, Cathy Bansbach, Draurio Barreira Cravo Neto, Grania Brigden, Jonathon
Campbell, Martina Casenghi, Richard Chaisson, Gavin Churchyard, Isabelle Cieren-Puiseux, Daniela
Cirillo, William Coggin, Timothy Evans, Unyeong Go, Celeste Gracia Edwards, David Hermann, Jeremy
Hill, Christian Lienhardt, Alberto Matteelli, Ariel Pablos Mendez, Richard Menzies, Payam Nahid,
Sumathi Nambiar, Thu Anh Nguyen, Olivia Oxlade, Madhukar Pai, Morten Ruhwald, Nicole Salazar-
Austin, Kevin Schwartzman, Susan Swindells, Ezio Távora dos Santos Filho, Anete Trajman, Andrew
Vernon, Juan Vesga Gaviria and Brenda Waning.
The contributions of various anonymous individuals during the public consultation are gratefully
acknowledged.
WHO secretariat: Saskia Den Boon, Dennis Falzon, Avinash Kanchar, Corinne Merle, Martina
Penazzato, Matteo Zignol and Lou Maureen Comia. Overall guidance and direction were provided by
Tereza Kasaeva, Director of the Global TB Programme.
The meeting, reviews and document were funded through grants provided by the Russian Federation
and the United States Agency for International Development (USAID).
iv Target product profiles for tuberculosis preventive treatment

Abbreviations and acronyms
ART antiretroviral treatment
CI confidence interval
DOT directly observed treatment
IPT isoniazid preventive treatment (or monotherapy)
MDR-TB multidrug-resistant tuberculosis
PLHIV people living with HIV
TB tuberculosis
TPP target product profile
TPT tuberculosis preventive treatment
USAID United States Agency for International Development
Target product profiles for tuberculosis preventive treatment v

Definitions
Note: The definitions listed below apply to this document. They may have different meanings in other
contexts.
Adolescent: A person aged 10–19 years
Adult: A person > 19 years of age
Bacteriologically confirmed TB: TB diagnosed in a biological specimen by smear microscopy, culture
or a WHO-approved molecular test such as Xpert MTB/RIF®
Child: A person < 10 years of age
Contact: Any person who has been exposed to a person with TB
Contact investigation: A systematic process for identifying people with previously undiagnosed TB
among the contacts of an index case. Contact investigation consists of identification, prioritization and
clinical evaluation. In many settings, the goal includes testing for TB infection to identify candidates for
preventive treatment.
High TB transmission setting: Setting with a high frequency of individuals with undetected or
undiagnosed active TB or in which infectious TB patients are present and there is a high risk of TB
transmission. TB patients are most infectious when they are untreated or inadequately treated.
Transmission is increased by aerosol-generating procedures and by the presence of highly susceptible
individuals.
Household contact: A person who shared the same enclosed living space as the index case for one or
more nights or for frequent or extended daytime periods during the 3 months before the start of current
treatment.
Incipient disease: Infection with viable Mycobacterium tuberculosis that is likely to progress to active
disease in the absence of further intervention but has not yet induced clinical symptoms, radiographic
abnormalities or microbiological evidence consistent with TB disease (1).
Index patient: The initially identified person of any age with new or recurrent TB in a specific household
or comparable setting in which others may have been exposed. An index case is the person on which a
contact investigation is centred but is not necessarily the source case.
Infant: A child < 1 year of age
Target product profile (TPP): The desired characteristics of a product for a particular disease or diseases.
The profile includes the intended use, target populations and other desired attributes of products,
including safety and efficacy. Such profiles usually guide product research and development.
TB preventive treatment (TPT): Treatment offered to individuals who are considered at risk of TB
disease in order to reduce that risk. Also referred to as “treatment of TB infection”, “treatment of latent
TB infection” or “TB preventive therapy”.
Tuberculosis (TB): The disease state due to M. tuberculosis. In this document, it is referred to as TB
disease in order to distinguish it from TB infection.
TB infection: Refers to a state of persistent immune response to stimulation by M. tuberculosis antigens
with no evidence of clinically manifest TB disease. This is commonly referred to as “latent” TB infection,
but, given that infection cannot always be considered latent, the term “TB infection” better reflects the
whole spectrum of infection to which the TPPs apply. TB infection should not be confused with TB
disease.
Underweight: Usually refers to a body mass index < 18.5 in adults and to a weight-for-age < –2 z-scores
in children < 10 years.
vi Target product profiles for tuberculosis preventive treatment

1 Introduction
Tuberculosis (TB) is a major yet preventable global health problem, with an estimated 10 million new
cases worldwide in 2018 that resulted in more than 1.5 million deaths, making it the leading infectious
disease cause of death worldwide (2). One quarter of the global population is estimated to be infected
with Mycobacterium tuberculosis (3). TB infection is classically defined as a “state of persistent immune
response to stimulation by M. tuberculosis antigens with no evidence of clinically manifested TB disease”.
The vast majority of infected people have no signs or symptoms and are not infectious, although they
are at risk of progression from infection to disease and becoming infectious. On average, 5–10% of
people who are infected will develop disease over the course of their lives, with the highest risk in the
first year after infection (4). Children aged < 2 years, adolescents (≥ 10 years) and people living with
HIV (PLHIV) are at high risk of TB disease after infection, including severe life-threatening forms such
as TB meningitis (5). As TB infection is more likely to progress rapidly to TB disease in children and
adolescents, household contacts of infectious TB patients in these age groups are at particular risk (6, 7).
Untreated HIV infection is the strongest risk factor for progression from TB infection to TB disease, with
an overall annual estimated risk of 10% (8), particularly in children (9, 10). For these reasons, prevention
of TB disease is a crucial component of the WHO End TB Strategy, which calls for 90% coverage of
treatment for TB infection among PLHIV and household contacts of infectious TB patients by 2035 (11).
The United Nations high-level meeting on TB, in September 2018, further emphasized the importance
of strengthening implementation of TB preventive treatment (TPT), with the goal of 30 million people,
including 4 million children < 5 years of age, receiving TPT by 2022 (12).
Although TPT has been available for more than 60 years and in spite of strong evidence of its effectiveness,
its uptake and scale-up have been slow, mainly because of the limitations of both available diagnostic
assays and regimens (long duration, cost, toxicity, adherence issues and operational aspects). Critical
gaps remain in achieving global targets: in the 16 countries with a high burden of TB or TB–HIV that
reported having provided treatment to PLHIV in 2018, TPT coverage reached only 49% (13). Globally,
TPT was initiated in only 27% of the 1.3 million household contact children aged < 5 years estimated to
be eligible for treatment. The availability of and access to new drugs or regimens that can be administered
for a shorter time and with fewer adverse events than the current 6–12-month TB preventive strategies
is essential to ensure wider-scale implementation.
Even with improved TPT options in the future, treatment of infection will remain essential for effective
TB control. Scaling-up of TPT would have to be accompanied by active case finding, better treatment for
TB disease and other measures to reduce transmission and unfavourable outcomes of disease episodes.
Parallel improvements in these areas and the development of new TB vaccines will be critical.
2 Tuberculosis preventive treatment:

background and current situation
The aim of treatment of TB infection is to prevent progression to TB disease by killing resident bacilli
in the host. Administration of isoniazid daily for 6–12 months has been the mainstay of treatment for
more than 50 years, with an efficacy of 54–88% (14, 15). Re-analysis of trials with isoniazid conducted
by the Public Health Service in the USA in the 1950s and 1960s showed that the benefit of isoniazid
increased progressively when administered for up to 9 or 10 months and stabilized thereafter, leading to
recommendation of a 9-month isoniazid regimen as adequate treatment (16). Further studies, however,
showed similar results with the 6- and 12-month regimens in non-HIV-infected people (17) (Annex 1).
Other treatments have been investigated, including rifampicin, isoniazid and rifampicin and isoniazid
and rifapentine, and proven to be safe and efficacious (17) (Table 1). A meta-analysis of several
Target product profiles for tuberculosis preventive treatment 1

randomized studies to compare 3–4 months of daily isoniazid and rifampicin with daily isoniazid alone
for 6–12 months in adults found that the two were equivalent in terms of efficacy, safety and mortality
(18). A randomized controlled trial in children < 15 years showed that 3–4 months of daily isoniazid and
rifampicin was at least equivalent to 9 months of daily isoniazid; no child in either group experienced
an episode of TB disease (19). Recently, a multicentre trial with 6859 people showed that 4 months of
daily rifampicin was not inferior to 9 months of daily isoniazid monotherapy for the prevention of TB
disease and was associated with a higher rate of treatment completion and better safety in both adults
and children (20, 21).
Table 1. Regimens for TB preventive treatment according to pooled efficacy, risk of

hepatotoxicity and main adverse events
Drug Dosage Odds ratio (95% confidence interval) Adverse events
regimen
Efficacy Efficacy Hepatotoxicity
vs placeboa vs 6Ha vs 6Ha
6H or 9H Adults, 5 mg/kg; children, 6H: 0.61 Not applicable Not applicable Drug-induced liver injury,
10 mg/kg (maximum, (0.48–0.77); for 6H and not for 6H and not nausea, vomiting, abdominal
300 mg) available for 9H available for 9H pain, rash, peripheral
9H: 0.39 neuropathy, dizziness,
(0.19–0.83) drowsiness and seizure
3–4R Adults, 10 mg/kg; 0.48 (0.26–0.87) 0.78 (0.41–1.46) 0.03 (0.00–0.48) Influenza-like syndrome,
children, 10 mg/kg rash, drug-induced
(maximum if < 45 kg, liver injury, anorexia,
450 mg; maximum if nausea, abdominal
≥ 45 kg, 600 mg) pain, neutropenia,
thrombocytopenia and
renal reactions (e.g. acute
tubular necrosis and
interstitial nephritis)
3–4HR Adults, 10 mg/kg; 0.52 (0.33–0.84) 0.89 (0.65–1.23) 0.89 (0.52–1.55) Influenza-like syndrome,
children, 10 mg/kg rash, drug-induced
(maximum if < 45 kg, liver injury, anorexia,
450 mg; maximum if nausea, abdominal
≥ 45 kg, 600 mg) pain, neutropenia,
thrombocytopenia and
renal reactions (e.g. acute
tubular necrosis and
interstitial nephritis)
3HP Adults and children: Not available vs 9H: vs 9H: Hypersensitivity reactions,
rifapentine, 15–30 mg/kg petechial rash, drug-induced
(maximum, 900 mg)b; 0.44 (0.18–1.07) c
0.16 (0.10–0.27) liver injury, anorexia,
isoniazid, 15 mg/kg nausea, abdominal pain
(maximum, 900 mg) and hypotensive reactions
1HP Adults and adolescents Not available vs 9H: vs 9H: Nausea, vomiting, drug-
(≥ 13 years): 300 mg daily associated fever, anaemia,
for a weight of Risk difference: 0.47 (0.30–0.75) neutropenia, elevated liver
< 35 kg, 450 mg daily for 0.02 per 100 enzyme levels, peripheral
a weight of 35–45 kg and person-years neuropathy
600 mg for a weight of (−0.30–0.34)
> 45 kg) plus isoniazid at
a dose of 300 mg daily
(1-month group)
Adapted from reference 8
6H, isoniazid alone for 6 months; 9H, isoniazid alone for 9 months; 3–4R, rifampicin alone for 3–4 months; 3–4HR, isoniazid plus rifampicin for 4 months;
3HP, weekly rifapentine plus isoniazid for 3 months; 1HP, daily rifapentine plus isoniazid for 1 month
a
Data on efficacy and hepatotoxicity from references 17 and 22.
b
The following incremental adjustments are required for people weighing < 50 kg: 10.0–14.0 kg, 300 mg; 14.1–25.0 kg, 450 mg; 25.1–32.0 kg, 600 mg;
and 32.1–49.9 kg, 750 mg.
c
The comparison is with 9H.
A once-weekly, directly observed regimen of combined isoniazid and rifapentine for 3 months was shown
to be non-inferior to 9 months of daily self-administered isoniazid monotherapy and associated with
2 Target product profiles for tuberculosis preventive treatment

higher treatment-completion rates (82.1% vs. 69.0%) and less hepatotoxicity (0.4% vs. 2.7%) (23). Similar
results were observed in an extension of the study to children aged 2–17 years, and no hepatotoxic effects
attributed to treatment were observed in either study group (24).
A follow-up study in HIV-infected adults showed that 3 months of weekly rifapentine plus isoniazid
was as effective as 9 months of daily isoniazid monotherapy and was associated with a higher treatment
completion rate (89% vs. 64%) (25). The 3 months of weekly rifapentine plus isoniazid regimen was
also evaluated in South African adults with HIV infection and a positive tuberculin skin test who were
not receiving antiretroviral therapy (ART); the efficacy was shown to be similar to that of a 6-month
isoniazid regimen (26).
In a large post-marketing evaluation of 3 months of weekly rifapentine plus isoniazid in 16 TB
programmes and routine health care settings in the USA, completion was greater overall than the rates
reported from clinical trials and greater than that for other regimens among reportedly non-adherent
populations (27). A systematic review published in 2018 showed that the effectiveness, risk of adverse
events, risk of discontinuation due to adverse events and risk of death were similar with 3 months of
weekly rifapentine plus isoniazid and with other TB infection treatment regimens, including 6 months of
daily isoniazid monotherapy, 9 months of daily isoniazid monotherapy, 3–4 months of daily rifampicin
plus isoniazid and 2–3 months of daily rifampicin plus pyrazinamide (28).
A 1-month regimen of daily isoniazid plus rifapentine delivered to PLHIV aged ≥ 13 years living in areas
of high TB prevalence or who tested positive for TB infection, was shown to be non-inferior to 9 months
of isoniazid alone in a phase-III randomized, open-label, controlled trial (22). The regimen was also
found to be non-inferior to 9 months of daily isoniazid monotherapy in a subset of participants with a
positive test for TB infection (tuberculin skin test or interferon- release assay). Serious adverse events
occurred in 6% of the patients in the group receiving 1 month of daily rifapentine plus isoniazid and in
7% of those receiving 9 months of daily isoniazid monotherapy (P = 0.07). The treatment completion
rate was higher with 1 month of daily rifapentine plus isoniazid than with 9 months of daily isoniazid
monotherapy (97% vs 90%, P < 0.001). Most of the participants were on ART. Annex 2 describes studies
of TPT in special populations.
3 Target product profiles for tuberculosis

3.1 New medicines and regimens for the treatment of tuberculosis
infection
The development of short, safe, efficacious, easy-to-take regimens for the treatment of TB infection
and prevention of TB disease requires detailed information on the safety and toxicity of the regimen’s
components, their potential for drug–drug interactions, their propensity for development of resistance
and their use in specific patient populations such as PLHIV, pregnant women and children (29). The aim
of the TPPs is to identify the product attributes to be considered in developing the best, most suitable TB
prevention treatments (30). Thus, TPPs for the treatment of TB infection are expected to assist developers
in aligning the characteristics of new treatment regimens with national programme requirements. It
should be noted that target products are either an individual medicine or a combination of medicines.
3.2 Objective and target audience

The overall objective of the TPPs is to align developers’ performance and operational targets for new
TPT regimens with the needs of users. The target audience comprises the pharmaceutical industry,
academia, research institutions, product development partnerships, nongovernmental and civil society
organizations and donors.

3.3 Methods
The WHO Global TB Programme followed the WHO Standard procedures for the development of target
product profiles, preferred product characteristics and target regimen (31) and used a stepwise approach
to identify regimen features that could have an impact for both patients and populations. The activities
included a series of expert meetings, mathematical modelling, cost–effectiveness analysis and a wide
web-based consultation with stakeholders.
3.3.1 Baseline elements

After establishment of a scoping group, a systematic literature review and a rigorous analysis of the
different TPT treatments and regimens that are currently being developed were undertaken to assess
the context for developing TPPs for the treatment of TB infection and to prepare an initial draft of TPP
attributes. The scoping group then met in Montréal, Canada, in September 2019 to review the evidence
and baseline elements of the TPPs and to discuss potential targets. Teleconferences with the scoping
group and consultations with various stakeholders were held to adjust the proposed targets, with the
results of complementary analyses, described below (Annex 3).
3.3.2 Mathematical modelling

The TPPs for TPT are designed to improve TB control with the use of shorter, simpler, more tolerable,
more efficacious regimens that are affordable and accessible and can rapidly reduce morbidity and
mortality from TB disease. Individual treatment success rates, disease transmission, antimicrobial
resistance and operational factors may all determine whether a regimen can fulfil its role. To prioritize
certain characteristics when constructing and evaluating new preventive regimens, a mathematical
model was developed to identify the regimen properties that would best predict its epidemiological
impact in different settings. The following attributes were adopted as a minimal set of properties that
could influence the epidemiological impact:
• duration: length of administration of the regimen (months);

• efficacy against drug-susceptible TB: reduction in cumulative incidence that would be observed under
trial conditions during a 5-year follow-up, with and without preventive treatment;
• drug-resistant barrier: proportion of treated individuals with drug-susceptible infection who do not
acquire rifampicin-resistant infection as a result of receiving the regimen;1
• “forgiveness” for non-completion of the regimen: among those who interrupt treatment after
completing at least half the regimen, the proportion who nonetheless receive the full benefit of the
regimen; and
• ease of adherence: proportion of patients who complete the regimen.
The analysis was conducted for four countries representing different epidemiological conditions: Brazil,
India, Kenya and South Africa. In each country, the potential impact of achieving the United Nations
high-level meeting targets for preventive therapy was modelled for PLHIV and for household contacts
of notified TB cases. On the assumption that the coverage targets are fully met by 2022 and maintained
thereafter, impact was quantified as the percentage reduction in cumulative incidence of TB disease
between 2020 and 2035 from a base case of 6 months of isoniazid administered daily, with coverage
remaining at current levels during the same period.
The influence of each attribute on incidence of TB disease is shown in Fig. 1, which illustrates the modelled
impact of 1000 regimens representing different combinations of attributes on the continuum between
minimal and optimal scenarios. The regimen’s efficacy was found to be the attribute that best predicted a
1 It was assumed that a rifamycin-containing regimen would have half the efficacy against drug-resistant as against drug-
susceptible TB. For simplicity, a non-rifamycin-containing regimen (such as 6 months of daily isoniazid monotherapy) would
be considered as having no capacity to generate drug-resistant TB, thus effectively having a 100% drug-resistant barrier.

reduction in TB disease incidence in all countries. Ease of adherence was found to play a strong secondary
role, while remaining attributes, including forgiveness, were found to have only minimal influence on
incidence in these settings. Sensitivity analysis (not shown) showed that the relative roles of forgiveness
and adherence depend on the point in the regimen at which forgiveness is assumed to act (50%, as stated
above); however, these variations do not change the overall qualitative results shown in Fig. 1.
Fig. 1. Influence of each attribute on TB incidence
Partial Rank Correlation Coefficient (PRCC) for TB cases averted

Impact trend Impact trend
Efficacy
Ease-of-adherence
Forgiveness
DR-Barrier
Regimen duration Kenya South Africa
Efficacy
Ease-of-adherence
Forgiveness
DR-Barrier
Regimen duration India Brazil
0 0.2 0.4 0.6 0.8 1 0 0.2 0.4 0.6 0.8 1

PRCC PRCC
Bars represent PRCC between individual attributes and impact. Scatter plots show each attribute plotted against impact.
3.3.3 Cost–effectiveness analysis

On the basis of the results of the epidemiological modelling, a cost–effectiveness analysis was conducted.
The analysis was for Brazil and South Africa, which represent a relatively low-transmission, low-HIV
prevalence setting and a high-transmission, high-HIV prevalence setting. A bottom-up, or micro-
costing, approach was used to capture detailed costs for treatment of TB disease and TB infection in
the two countries by estimating use of health system personnel and resources for care of a typical or
“average” patient. For TB disease, it includes cost components such as personnel time to administer
clinical care, equipment for diagnosis, TB medication and other supplies, expressed in 2019 US$. For
TB infection, costs are assumed only for preventive treatment, which includes an initial medical visit,
treatment medication (assumed in this analysis to be 6 months of isoniazid administered daily in the
base case) and follow-up medical visits. Costs of treatment-related adverse events are considered on a
pro-rated basis for the entire cohort. Costs of diagnosing TB infection or excluding TB disease are not
included, i.e. it is assumed that people eligible for treatment have already been identified, regardless of
regimen.
Costs related to TB disease were calculated separately for patients with drug-susceptible- and drug-
resistant-TB. Costs for inpatient stays and outpatient visits and for monitoring treatment were included.
For treatment supervision, two treatment modes were considered, i.e. directly observed treatment
(DOT) and mixed DOT plus self-administered treatment. Costs for monitoring treatment, inpatient and
outpatient visits and corresponding proportions were obtained from national TB programmes and the
published literature.

To “anchor” the analysis, two novel preventive treatment regimens were modelled: a “minimal” and an
“optimal” regimen, with the attributes listed in Table 2.
Table 2. Regimen attributes and input costs
Attribute Baseline (isoniazid) Minimal Optimal
Regimen duration (months) 6 3 1
Efficacy 70% 70% 100%
Drug-resistance barrier 100% 95% 100%
Forgiveness 25% 50% 80%
Treatment completion 70% 80% 90%
Cost of regimen: medicationa US$ 3.45 US$ 3.45 US$ 3.45
Brazil: cost of regimen: visits, monitoring, adverse eventsb US$ 37.79 US$ 23.54 US$ 14.04
South Africa: cost of regimen: visits, monitoring, adverse eventsb US$ 41.53 US$ 26.56 US$ 16.57
Brazil: cost of DS-TB treatment US$ 866 US$ 866 US$ 866
Brazil: cost of MDR-TB treatment US$ 10 800 US$ 10 800 US$ 10 800
South Africa: cost of DS-TB treatment US$ 524 US$ 524 US$ 524
South Africa: cost of MDR-TB treatment US$ 9 527 US$ 9 527 US$ 9 527
DS, drug-susceptible; MDR, multi-drug-resistant

a
Medication costs for the two novel regimens assumed to be equal to those of 6 months of daily isoniazid monotherapy
b
For the minimal regimen, the rate of adverse events was assumed to be equivalent to that of 6 months of daily isoniazid monotherapy. With the optimal
regimen, it is assumed that there will be no adverse events that require additional monitoring, hospitalization or intervention.
Epidemiological modelling was used to project the costs of TPT and TB disease care through 2035 in
Brazil and South Africa, in the following scenarios:
• reported baseline TPT coverage with 6 months of daily isoniazid monotherapy;

• expansion of treatment with 6 months of daily isoniazid monotherapy to meet the United Nations
high-level meeting targets;
• TPT with a regimen with the “minimal” set of attributes, reaching the targets; and
• TPT with a regimen with the “optimal” set of attributes, reaching the targets.
The primary analysis included a rifamycin-containing regimen, but a rifamycin-free regimen was also
considered. No discounting was applied.
Epidemiological projections for Brazil and South Africa are shown in Table 3.

Table 3. Epidemiological projections, Brazil and South Africa, 2018–2035
Baseline Scale up 6H Minimal TPT Optimal TPT
Brazil
No. of people on TPT 110 775 1 286 644 1 283 271 1 280 422
TB cases (drug-susceptible and MDR) 1 358 958 1 328 541 1 309 655 1 295 106
MDR-TB cases 46 714 45 753 45 733 44 824
TB deaths 187 208 183 212 180 681 178 750
DALYs 5 164 722 5 052 558 4 982 683 4 926 308
South Africa
No. of people on TPT 4 594 449 8 301 001 8 122 022 8 069 326
TB cases (drug-susceptible and MDR) 4 463,872 3 247 354 2 429 083 2 179 961
MDR-TB cases 185 817 152 312 146 274 124 892
TB deaths 852 281 641 033 493 689 448 153
DALYs 29 888 441 22 270 743 16 784 278 15 222 462
DALY, disability-adjusted life year; MDR, multidrug-resistant; TPT, TB preventive treatment; 6H, isoniazid alone for 6 months
The analysis suggests that the cost of scaling up TPT and of new regimens is largely outweighed by
savings due to fewer TB patients. In comparison with the baseline scenario, implementation of TPT
corresponding to the minimal regimen in Brazil was estimated to cost an additional US$ 32 million but
resulted in projected savings of US$ 56 million due to 49 000 fewer TB patients, hence net savings of
US$ 24 million (1.3%). In South Africa, the epidemiological impact and cost savings were much greater,
given the higher HIV prevalence, the high rate of transmission and the burden of drug-resistant TB.
Use of the minimal regimen to meet the United Nations high-level meeting targets was projected to cost
US$ 37 million as compared with baseline but to generate net savings of US$ 1.6 billion (34%), reflecting
2 million TB patients averted. Greater savings were projected with the optimal TPT regimen. The results
are summarized in Fig 2.

Fig. 2. Incremental cost projections, Brazil and South Africa, 2018–2035
Brazil
$ 14 M
0M
-20 M $ -24 M
-40 M
Incremental cost (in US$)
$ -60 M
-60 M
South Africa
0.00 B
-0.50 B
$ -911 M
-1.00 B
-1.50 B $ -1609 M
$ -2050 M
-2.00 B
6H vs baseline
Minimal vs baseline
Optimal vs baseline
Strategy
M, million; 6H, 6 months daily isoniazid monotherapy
In a sensitivity analysis, we considered an alternative scenario involving a rifamycin-sparing regimen.

This regimen, with a drug resistance barrier of 100% but with other characteristics of the “minimal”
regimen unchanged, resulted in modest additional gains. In comparison with the “minimal” rifamycin-
containing regimen, it was projected to avert 119 additional TB cases in Brazil and 4556 in South Africa,
leading to additional cost savings of US$ 4 million (0.3%) in Brazil and US$ 91 million (2%) in South
Africa. Additional savings in South Africa are largely driven by averting 9331 additional cases of drug-
resistant TB.
3.3.4 Development of target product profiles

The above results were used to prepare a first draft of the TPPs and related tables, which were revised by
the scoping group, with group discussions by webinar.

3.4 Description of the target product profiles for tuberculosis
3.4.1 Principles
The WHO standard procedures for the development of TPPs, preferred product characteristics and
target regimens (31) list the elements that should (obligatory) and could (optional) be part of any
TPP. At a minimum, they usually specify the following characteristics: the clinical indication of the
therapeutics or regimen; the goal to be met and the measure of efficacy; the target population for the
treatment; the level of implementation in the health care system; and the intended users. The targets
selected represent the most important performance and operational characteristics, the term “minimal”
being used for the lowest acceptable output for a characteristic, and “optimal” for its ideal target. The
“minimum requirements” include instructions for targets to improve current standard of care and which
therefore represent an acceptable minimum for a global health impact of a candidate regimen. These
criteria provide the context for defining clear minimal “go” or “no-go” decisions to be used throughout
development. The “optimal requirements” specify the performance and use characteristics of an “ideal”
product, the global health impact of which would be broader, deeper and potentially quicker.
The attributes that can be identified as specific, quantifiable targets for treatment of TB infection are listed
in the TPP tables, which include the respective regimen attributes and relevant minimum and optimum
targets to be met (see pp. 12–17). Annotations to both the minimum and the optimal categories provide
elements of the rationale for each attribute of the selected targets.
A number of regimen attributes or characteristics were identified and included as proposed targets.
Certain attributes are defined as “priority”, as their minimum targets should be met in order to make a
“go” or “no-go” decision, while others, which are less essential, could be considered potential trade-offs
and are defined as “desirable”. For example, if a new regimen were to be better tolerated or have greater
efficacy, a trade-off in a desirable area such as the number of drugs in the regimen or its duration could
be justified. Note that the “go” or “no-go” decision does not apply to desirable attributes.
This document outlines the minimal levels of acceptable performance and use characteristics for novel
TPT regimens and also the optimal performance for a number of priority and desirable attributes. The
minimal and optimal characteristics thus define a range: it is therefore expected that the resulting products
– regimens to treat TB infection – will have all the minimal characteristics of the priority attributes and
as many of the desirable attributes as possible. It is hoped that these criteria will provide a baseline for
developing candidates that are best suited for prevention of TB disease.
3.4.2 Priority attributes

Indication
Ideally, a new treatment for TB infection should be efficacious against all M. tuberculosis strains harboured
by an individual and be independent of their resistance profile. As contacts of infectious TB patients and
PLHIV are priorities for TB prevention and the vast majority of infected people harbour bacilli that
are susceptible to rifampicin, the “minimum” target scenario addresses mainly these populations. The
“optimal” scenario is the capacity to treat TB infection in all individuals, regardless of the resistance profile
of the M. tuberculosis strains they harbour: the proposed new TPT regimen would have to be efficacious
in recent contacts of both drug-susceptible and drug-resistant TB patients. In any case, TB disease must
be formally excluded, and treatment for TB infection should be given only to people without TB disease.
Efficacy
In clinical trials, the efficacy of treatment for TB infection is usually defined as the proportion of participants
who remain free of TB disease for a reasonable period of follow-up after treatment completion, which is
usually 2–5 years. The expected duration of protection provided by a regimen, however, depends on the
subject (as the risk of TB disease depends on age, sex and host immune response capacity) and on the

setting (i.e. high and low TB transmission areas, defining various degrees of reinfection and reactivation).
Observational studies showed a long average duration of protection; however, a meta-analysis indicated
that treatment was generally more efficacious in populations with low rather than high TB incidence
(odds ratio, 1.58; 95% confidence interval [CI], 1.01; 2.48) (17).
Duration of Treatment
Meta-analyses show that shorter regimens are generally associated with higher treatment completion
rates. This is important, as shorter regimens remove some of the specific barriers to completion of
isoniazid preventive treatment (17), because they are associated with better adherence.
Safety and tolerability

As the target population is likely to be healthy, safety and tolerability are particularly important attributes.
The main reported risk identified so far is hepatotoxicity, but other adverse events should be considered,
including cutaneous reactions, hypersensitivity reactions, gastrointestinal intolerance, peripheral
neuropathy and cardiotoxicity, as these can lead to temporary or permanent cessation of treatment.
Clearly, the safer the regimen, the easier it will be to implement, as it will not require careful, complex or
possibly expensive monitoring. Furthermore, more providers (front-line workers) will be able to use it.
Drug-drug interactions and metabolism

Targets are provided for the most common drug–drug interactions observed to date, with current TB
infection treatments given to PLHIV receiving ART. Other concurrent diseases should be considered as
well, especially with regard to reported increases in noncommunicable diseases that require long-term
treatment (diabetes, hypertension, post-transplant, rheumatological diseases) as well as infectious and
parasitic diseases in the tropics (e.g. malaria). It might not be possible to avoid all drug–drug interactions,
but they should be manageable with simple clinical algorithms.
Barrier to emergence of drug resistance

The likelihood of emergence of resistance to isoniazid has long been an argument against provision of
TB infection treatment in programmes, especially when isoniazid was provided as monotherapy for
long periods (6–12 months) (5, 8, 16). There is, however, no evidence that monotherapy for TB infection
creates resistance. Although a newly proposed regimen should not result in emergence of resistance, the
barrier to resistance should be considered for repeated dosing, for instance in PLHIV.
Target population
The target populations include PLHIV, household (and other close) recent contacts of confirmed infectious
TB cases, including neonates and young children, and other at-risk populations. These include patients
with immunosuppressive conditions such as poorly controlled diabetes mellitus, initiation of anti-TNF
treatment, chronic renal failure being treated with dialysis, preparation for organ or haematological
transplant and silicosis.
Formulation, dosage, frequency and route of administration

The aspects to be considered are the availability of a treatment regimen in a fixed-dose combination,
the availability of scored or dispersible, palatable tablets for easy treatment of children and the dosing
frequency (e.g. daily vs weekly). If a regimen is to be intermittent (e.g. once weekly), it is essential that it
retains its priority attributes. More frequent dosing (e.g. more than once a day) could be considered if it
significantly reduces the total duration of treatment and improves safety and tolerability or provides any
other substantial improvement that would offset the challenges associated with longer duration, such as
treatment adherence and completion. Development of fixed-dose combinations for PLHIVs should take
into consideration combinations with ART or co-trimoxazole.

Stability and shelf life
Currently available treatments are stable for at least 24 months. As TPT would have to be provided in
high-TB burden countries that are likely to be hot and humid, the medicines must be stable in all climate
zones and, preferably, not require a cold chain.
3.4.3 Desirable attributes

Cost of regimen
Projected treatment costs should be compatible with wide access and scale-up. An improved regimen
may decrease the costs for both programmes and patients if it is shorter, safer, better tolerated, requires
minimal to no monitoring and fewer clinical visits and reduces the management of adverse events
or toxicity. The price and the associated resources required to use the regimen should be set against
considerations of equity, non-discrimination and transparency, with the goal of affordable access for all,
ensuring that vulnerable and marginalized groups do not bear disproportionate costs.
Special populations
Formulations should be safe for pregnant women and women of reproductive age. Appropriate care
during the antenatal and postnatal periods and during delivery is necessary to reduce the risk of adverse
pregnancy outcomes.
Treatment adherence and completion

To maximize adherence to therapy, current guidelines recommend use of a broad range of patient-
centred care and case management strategies, including DOT or virtually observed therapy provided
with electronic or mobile health devices, education and incentives to encourage compliance with long
regimens. Studies have shown that shorter treatments (4 months of daily rifampicin monotherapy, 3
months of weekly rifapentine plus isoniazid, 1 month of daily rifapentine plus isoniazid) are associated
with higher completion rates than longer control regimens (19, 22, 24). For the minimum target, most
patients on a new regimen should be able to complete self-administered therapy, only selected populations
requiring DOT or virtually observed therapy. For the optimal target, self-administered therapy should
be the standard in all populations. Clinical follow-up and monitoring should be conducted to assess any
adverse events.
Drug susceptibility testing in index TB patients

When molecular diagnostic tests are available, a single, rapid, molecular test for rifampicin susceptibility
will suffice to assess the drug susceptibility profile of the bacilli population in an index patient and
confirm the suitability of the new regimen. In an optimal scenario, the new treatment regimen should be
usable in all conditions and settings, whatever the drug susceptibility profile of the index patient and, in
particular, irrespective of the likelihood of rifampicin-resistant TB transmission.

12
Summary tables of proposed attributes for TB preventive treatment
1. Priority attributes
Attribute Minimum Optimal Annotations
The minimal target should be considered a The optimal target should have a broader, For each variable, the rationale for why it is important and for the target value
potential “go” or “no go” decision point for deeper, quicker global health impact
the given “priority attribute”
Indication The regimen is indicated for the treatment The regimen is indicated for the treatment According to the latest WHO recommendations on TPT (2020) (13), populations prioritized for TPT
of TB infection to prevent development of of TB infection to prevent development of are as follows:
TB disease in at-risk individuals as defined TB disease in all individuals recognized • Adults and adolescents living with HIV who are unlikely to have active TB should receive TPT as
in current WHO guidelines. as being at risk of TB disease, regardless part of a comprehensive package of HIV care. Treatment should also be given to those on ART,
of the drug susceptibility profile of the to pregnant women and to those who have previously been treated for TB, irrespective of the
harboured bacilli population. degree of immunosuppression and even if testing for TB infection is unavailable.
• Infants living with HIV who are in contact with a person with TB and who are unlikely to have active
TB on an appropriate clinical evaluation or according to national guidelines should receive TPT.
• Children aged ≥ 12 months living with HIV who are considered unlikely to have active TB on an
appropriate clinical evaluation or according to national guidelines should be offered TPT as part
of a comprehensive package of HIV prevention and care if they live in a setting with high TB
transmission, regardless of contact with TB.
• Children aged < 5 years who are household contacts of people with bacteriologically confirmed
pulmonary TB and who are found not to have active TB on an appropriate clinical evaluation
or according to national guidelines should be given TPT even if testing for TB infection is

unavailable.
Children aged ≥ 5 years, adolescents and adults who are household contacts of people with
bacteriologically confirmed pulmonary TB who are found not to have active TB by an appropriate
clinical evaluation or according to national guidelines may be given TPT.
In selected high-risk household contacts of patients with MDR-TB, preventive treatment may be
considered after an individual risk assessment and sound clinical justification.
Efficacy A regimen with efficacy not inferior to the A regimen with efficacy superior to the To be effective, TPT regimens must be able to kill bacteria with low growth rates and those that
current standard of care for treatment of TB current standard of care regimen for undergo occasional growth spurts (sterilizing), in addition to killing those with high growth rates
infection (e.g. 6H or 3HP). treatment of TB infection, leading to (bactericidal). If not, the risk of reactivation will persist after prophylactic treatment has been
lifetime protection in areas of low risk of completed.
re-infection.
Efficacy in TB prevention is currently defined in clinical trials as occurrence-free (defined as a
combination of breakthrough TB disease and TB deaths) 2–5 years after treatment completion. The
targets provided take into consideration the odds of efficacy of the current 6H and 3HP regimens for
TB infection treatment vs placebo: 0.65 (0.50, 0.83) and 0.58 (0.30, 1.12), respectively (17).
Notes:
• The term “not inferior” refers to the results of investigational trials with the non-inferiority
design. Non-inferiority trials of new TPT regimens should be designed and conducted under the
most rigorous conditions in order to provide reliable results (including careful selection of the
control regimen and appropriate choice of the margins of non-inferiority (delta)) (32, 33).
• The expected efficacy and duration of imparted protection depends on the population (e.g. PLHIV;
children) and setting (i.e. high vs low TB transmission areas). Observational studies showed a
long average duration of protection (34); however, in a meta-analysis, treatment was generally
less efficacious in high- than in low-incidence populations (relative odds ratio, 1.58; 95% CI, 1.01;
2.48) (35).
Duration of < 3 months ≤ 2 weeks This attribute refers to the total duration of administration of treatment, whatever the frequency
treatment (e.g. 1 month daily or 3 months weekly).
Systematic reviews showed that shorter regimens were associated with higher treatment
completion rates (35, 36).
Treatment duration should be independent of the resistance profile of the strains harboured by the
individual (i.e. fully susceptible or resistant TB bacilli strains).

13
14
Safety and Safety: Incidence and severity of adverse Safety: Incidence and severity of adverse Hepatotoxicity and clinical hepatitis are serious adverse events associated with drugs that are
tolerability events better than the current standard of events better than the current safest currently used for the treatment or prevention of TB disease, either alone or in combination.
care treatment. treatment. Neuropathy is a frequent adverse event with isoniazid.
Requirement of no more than monthly No requirement for active clinical A standard meta-analysis gave odds ratios for hepatotoxicity with 6H and 9H vs no treatment of 1.10
clinical monitoring and no laboratory monitoring or for laboratory monitoring for (95% CI, 0.40; 3.17) and 1.70 (95% CI, 0.35; 8.05), respectively. Rifampicin-only and HP regimens
monitoring for drug toxicity necessary, drug toxicity and preferably no requirement resulted in lower rates of hepatotoxicity than 6H or 9H. Regimens containing pyrazinamide were more
except for special populations (e.g. pre- for additional monitoring or encounters for hepatotoxic than 6H or 12 weeks of HP.
existing kidney or liver disease, diabetes). special populations (e.g. pre-existing liver
disease, diabetes).
The target product should not require any
additional medication to allay toxicity (e.g. The target product should not require any
pyridoxine in IPT). additional medication to allay toxicity (e.g.
pyridoxine in IPT).
Tolerability: The frequency of adverse
events leading to treatment cessation Tolerability: No adverse events leading to
should be no worse than with current treatment cessation.
paired isoniazid and rifamycin regimens
(e.g., 3HP, 3HR, 1HP).
Drug–drug Can be used safely with any other No dose adjustment when given with any ART regimens may include drugs that are substrates of P450 or other metabolizing enzymes or that

interaction medication with minimal dose adjustment, other medication and can be used safely inhibit or induce P450 enzymes. As a benchmark, the target regimen should be free of the problems
and particularly with current first- and second- with any other drug. currently associated with use of rifamycins plus ART, which may complicate their use in PLHIV.
metabolism line ART, opioid substitution therapies,
hormone-based contraceptives and directly For the minimum target, dose adjustment of component drug(s) may be required to manage drug–drug
acting antivirals to treat viral hepatitis. interactions. Such adjustments would require that different dose sizes and formulations are readily
available.
For the optimistic target, no dose adjustments should be required, including for HIV therapies, so that
regimen can be used easily and in a standardized way in different populations.
Barrier to Potential for acquisition of resistance is Rate of in-vitro mutations conferring There is no evidence so far of a significant association between generation of resistance to TB
emergence no worse than with current regimens and resistance is lower than with rifampicin. drugs and the use of isoniazid or rifamycins for treatment of TB infection in the absence of TB
of drug current methods of excluding TB disease. disease (37, 38).
Fewer than two gene targets linked to
resistance development of resistance. Ideally, drugs included in preventive treatment should protect each other against emergence of
(propensity resistance. The drugs in the regimen should have no initial resistance, and mutants with resistance
to develop No cross-resistance with existing drugs. against the drugs should not be cross-resistant to drugs used in first- or second-line TB regimens. The
resistance, last attribute is extremely important to avoid compromising the use of potential new drugs. It would
generation be desirable that the target preventive treatment regimen does not generate resistance when used in
of cross- people infected with strains resistant to other commonly used TB treatments.
resistance) As a reference, the frequency of strains with mutations conferring resistance to rifampicin has been
estimated to be 2.25 x10-10 (39).
Target Populations with established high risk of All individuals in all age groups at risk of TB Minimum criteria address currently recommended target groups only (32).
population progression to TB disease, e.g. disease, irrespective of HIV status, whether
living in countries with high, medium or Optimistic criteria address all TB-infected populations who might be screened and in whom TB
• HIV-infected adults, adolescents disease has been formally ruled out.
and children aged ≥ 12 months (with low TB incidence, regardless of the drug
unknown or a positive tuberculin skin susceptibility profile of the harboured bacilli Note:
test) regardless of ART use; population, in whom TB disease has been • In children, pharmacokinetics and safety studies will be required in both the minimum and the
formally ruled out. optimistic scenarios, but efficacy trials in this population are not necessarily required. TB regimen
• HIV-negative children aged < 5 years
who are household contacts of people developers should consider initiating pharmacokinetics and safety studies for all paediatric age
with bacteriologically confirmed groups for drugs that show promising efficacy and safety in phase-2A trials in adults (40).
pulmonary TB; • Patients with end-stage renal and liver disease may require significant adjustments to doses and
• patients with immunosuppressive frequency of administration and may require more clinical and laboratory monitoring. It would
conditions such as initiation of anti-TNF be desirable, however, for the optimal TPT regimen to be usable in patients with severe renal or
treatment, chronic renal failure treated hepatic disease.
with dialysis, preparation for organ or
haematological transplant and silicosis.
In all these situations, TB disease is
formally ruled out.

15
16
Formulation, Formulation to be oral, with a daily intake Formulation to be oral, without a If the regimen consists of two or more drugs orally, fixed-dose combinations of proven bioavailability
dosage, as a maximum for all drugs in the regimen, requirement for weight adjustment, and bioequivalence for all components are optimal to facilitate use by all targeted recipients of TPT. For
frequency including paediatric forms (dispersible, including paediatric forms (dispersible, PLHIVs, fixed-dose combinations could combine TPT medicines with ART or co-trimoxazole.
and route of scored tablets, palatability). scored tablets). Ideally, a single pill per
day or week for the duration of treatment Dosing frequency:
administration If long-acting formulation: injection with • Daily intake is advantageous for PLHIVs, as they can be ingested with daily ART. In addition, daily
(depending on daily or weekly formulation).
or without oral lead-in no more than once treatment may be more forgiving of poor adherence than weekly treatment.
a month. No specific food requirements.
• Conversely, weekly intake might be more advantageous in terms of lower toxicity and clinical
Single dissolvable implant for complete Single injection of long-acting formulation requirements but may require stricter conditions of treatment adherence.
course of therapy. without oral lead-in to be given once or
twice or a single dissolvable implant with No special requirement for food or companion drugs; ideally, no restriction with alcohol.
long-lasting protection. Long-acting injection or implant formulations have strong practical and operational advantages, as
they cancel the requirement for DOT (41). A long-lasting or extended-release formulation could be
particularly suitable for long-term treatment of PLHIV who are at high risk of TB re-infection in high-
transmission settings. In addition, avoiding oral delivery and its associated first-pass metabolism
through the liver may have additional benefits in terms of drug–drug interactions.
Stability and Oral regimen: Stable to heat, humidity and Oral regimen: Stable to heat, humidity and Current therapies are stable for ≥ 2 years.
shelf life light, with a shelf life for all drugs ≥ 2 years. light, with a shelf life for all drugs ≥ 5 years.
Climatic zones:

No cold chain required. No cold chain required. I, temperate
Injectable: stable in all climate zones. If cold Injectable: stable in all climate zones, and II, subtropical, with possible humidity
chain required, to be compatible with current no cold chain required. III, hot and dry
vaccine cold chain requirements (2–8 °C).
IV, hot and humid
2. Desirable attributes
Cost of Projected cost of the drug(s) or treatment Projected cost of the drug(s) or treatment Access to essential medicines is part of the right to the highest attainable standard of health (“the
regimen courses should be compatible with wide course should be compatible with wide right to health”) and is well founded in international law. Economic factors that affect the price,
access. access and scale-up. demand and availability of regimens depend on factors including how well the new regimens meet or
surpass the attributes described herein (e.g. efficacy, safety, adherence).
An improved regimen may provide advantages in other costs to programmes and patients by being
e.g. shorter, better tolerated and/or requiring minimal to no monitoring, thus reducing non-drug costs.
The cost and associated resource demands to implement the regimen at the scale necessary to reduce
the global TB incidence should not upset the balance of health equity to the disadvantage of any
subpopulation in either low- or high-resource settings.
Special For women of reproductive age, For women of reproductive age and Formulations are required that are safe for pregnant women and women of reproductive age. A
populations pharmacokinetics and safety studies pregnant women, pharmacokinetics and study of 6H in HIV-infected pregnant and post-partum women showed that the risk of an adverse
support use of the regimen with minimal safety studies support use of the regimen pregnancy outcome (stillbirth or spontaneous abortion, low birth weight, preterm delivery or congenital
dose adjustment. without dose adjustment. anomalies) was greater when 6H was initiated during pregnancy than during the postpartum period
(42), whereas three observational studies suggested no higher risk of adverse pregnancy outcomes in
There must be no foetal toxicity in There must be no foetal toxicity in women who initiated IPT during pregnancy (43–45). According to the latest WHO guidelines (13), there
preclinical data. preclinical data. are insufficient grounds to change previous guidance, and systematic deferral of IPT to the post-partum
The drugs can be taken safely during The drugs can be taken safely during period would deprive women of its protective effect at a time when they are more vulnerable to TB.
breastfeeding and are compatible with breastfeeding and are compatible with Appropriate care during the antenatal and postnatal periods and during delivery is recommended to
common forms of hormone-based birth common forms of hormone-based birth reduce the risk of adverse pregnancy outcomes.
control for women of reproductive age who control for women of reproductive age who Note: As malformations and foetal loss were observed in experimental animals, use of alternatives to
wish not to become pregnant. wish not to become pregnant. rifapentine for TB treatment and prophylaxis in pregnancy is recommended.
Safe and tolerable for patients with co- Safe and tolerable for patients with co-
morbid conditions. morbid conditions.
Treatment At least as good adherence and chance Better adherence and chance of completion To maximize adherence to therapy, current guidelines recommend use of a broad range of patient-
adherence of treatment completion as with existing than with existing recommended short- centred care and case management strategies, including DOT, video-supported treatment, education
and recommended short-course regimens (4R, course regimens. and incentives.
completion 3HP).
Suitable for self-administration in For the minimum target, most patients on the new regimen should be able to complete therapy with
Suitable for self-administration in all populations (not for long-acting minimum support, only selected populations requiring DOT or virtually observed therapy or other
all populations (not for long-acting formulation). labour- or cost-intensive activities.
formulation).
For the optimal target, all populations should be able to complete therapy by self-administration,
without requiring DOT or other interventions.
Drug- Drug-susceptibility test available for the No need to test index TB patient. Where molecular diagnostic tests are available, a single, rapid molecular rifampicin-susceptibility test
susceptibility index TB patient when required. will suffice. Optimally, the new TPT regimen should be usable in all conditions and settings, particularly
testing in index in those in which there is a moderate-to-high likelihood of rifampicin-resistant TB transmission.
TB patients
1HP, 1 month daily rifapentine plus isoniazid; 3HP, 3 months weekly rifapentine plus isoniazid; 3HR, 3 months daily rifampicin plus isoniazid; 4R, 4 months daily rifampicin monotherapy; 6H, 6 months daily isoniazid monotherapy; 9H, 9 months

daily isoniazid monotherapy.
Annex 4 summarises the latest WHO recommendations on TB preventive treatment.
17
4 Cross-cutting aspects
Whatever priority and/or desirable targets are being met, the aspects listed below are to be considered
carefully before, or during, regimen development.
Safety
It is essential to keep in mind that, apart from HIV-infected or other immune-suppressed people, treatment
of TB infection is offered to individuals who are otherwise healthy and do not consider themselves affected
by any specific illness. Therefore, preventive treatment should be extremely safe and disrupt the lives of
these people as little as possible. As shorter regimens are associated with higher treatment completion
rates (18), any potential gain in completion from a shorter duration must not be offset by poorer safety
or tolerability.
Furthermore, any regimen that appears to be promising for TB prevention should be evaluated carefully
for safety and tolerability in the same populations as those likely to receive it. Therefore, clinical trials
should be performed to define the benefits and harms of TPT in vulnerable groups, including PLHIV,
children, pregnant and breast-feeding women, recent contacts of infectious TB patients and patients with
immunosuppressed conditions (46).
Diagnosis of TB infection
An efficacious preventive treatment, if coupled with a test to identify those at highest risk for disease
progression, especially in people co-infected with HIV, would be an important step to accelerate
progress towards TB elimination. TPT drug and regimen development should include consideration of
diagnostic technologies for identifying those at greatest risk of progression to TB disease (47,48).
Rule-out TB test
In every situation in which TPT is indicated and considered, it is imperative that TB disease be formally
ruled out. Inadvertent use of TPT in people with TB disease may generate drug resistance. Details of
appropriate strategies must be clearly explained at the time of scale-up.
Availability of drug-susceptibility testing for the index TB patient

A single, rapid, molecular test for susceptibility to rifampicin should be carried out on the index TB
patient to rule out rifampicin-resistant TB. In optimal conditions, however, the new TPT regimen should
be usable in all conditions and settings, particularly where there is a moderate-to-high likelihood of
rifampicin-resistant TB transmission, and delivered without requiring the susceptibility profile of the
presumed source case.
Adherence to preventive therapy

Once high-risk individuals with TB infection have been identified, TB control programmes
must ensure optimal adherence to treatment. Strategies to support adherence include remote
use of digital techniques (through mobile phones) (49). Long-acting formulations may be
alternatives to these techniques. In all cases, self-administered treatment is the preferred mode
of delivery.
Monitoring
Clinical monitoring is essential to identify and manage adverse events and drug–drug interactions
rapidly and to detect any TB disease. TB disease must be excluded before TB preventive treatment is
initiated, and regular follow-up is required to ensure early identification of people who develop active TB
while receiving TB preventive treatment (13).

Scalability, health equity and access
These are key elements for the success of the End TB Strategy. The reported limited use of TB infection
treatment to household contacts of TB cases globally at the time of isoniazid monotherapy is an example to
keep in mind. Recent experience with scaling up 3HP should be considered fully for further information.
This is one of the objectives of the Unitaid-funded IMPAACT4TB project, which provides access to 3HP
for PLHIV and children < 5 years, in order to establish an affordable, quality-assured, less toxic, shorter
therapy suitable for wide introduction in the countries most affected by TB (50).
The TPPs presented here include the attributes that are considered essential for novel TPT, i.e. efficacy,
safety, toxicity, lack of drug–drug interactions and a barrier to emergence of drug resistance. It might be
difficult to satisfy all these characteristics in a single regimen, however, and regimen developers might
have to consider trade-offs, such as increasing efficacy and safety rather than shortening treatment
duration, or increasing dosing frequency (e.g. once a day rather than once a week) if it significantly
reduces the duration of treatment, or improvements in safety and tolerability that would offset the
challenges associated with longer duration (e.g. treatment adherence and completion).
For an infectious disease such as TB, with a large global burden and continuing person-to-person
transmission, the efficacy of new TPT regimen(s) will depend heavily on operational factors that also
affect a regimen’s ability to fulfil its role (e.g. access to diagnostics, capacity to rule out TB disease, access
to new treatments, education of health care workers, patients and contacts). While the TPPs indicate the
attributes to be considered at the developmental stage, these should not be dissociated from the factors to
be considered at the implementation stage in the framework of overall TB-oriented activities, including
enhanced detection and treatment of TB disease (all forms), provision of antiretrovirals to PLHIV, BCG
vaccine coverage and sustained infection control activities.
5 Use case scenarios

5.1 Essential use case scenario
Under an essential (baseline) use case scenario, the preferred (optimal) TPT regimen should:
• be indicated for treatment of all individuals and age groups with TB infection at risk of developing TB
disease, irrespective of HIV status;
• be safe, tolerable and efficacious in individuals of all ages (including neonates, infants and young
children, women of reproductive age and pregnant and lactating women) and for patients with a wide
range of co-morbid conditions, including HIV infection, other infectious or tropical diseases and
chronic diseases;
• not result in drug–drug interactions, specifically with antiretrovirals, drugs metabolized by P450 liver
enzymes, pro-arrhythmic QT-prolonging drugs, contraceptive medicines and others;
• be delivered exclusively orally by a simple dosing schedule (preferably once daily, with no food
restrictions, no requirement for weight adjustment and in a fixed-dose combination) and be child-
friendly (e.g. dispersible, scored and palatable formulations with few pills); parenteral formulations to
be considered for long-acting formulations (see Annex 5);
• be affordable and available, particularly in low- and middle-income countries;
• contain medicines that may be prescribed in decentralized settings; and
• be simple to use and easy to monitor for efficacy in TB prevention by simple checks.

5.2 Intended use case scenarios
5.2.1 High- and low-transmission settings
Although there should be no difference in regimens for treatment of TB infection in different settings,
consideration should be given to the different situations in low-incidence and high-incidence settings.
In high-incidence settings with continuous TB transmission and concurrent HIV epidemics, the protective
effect of TPT may be transient, given the potential for re-infection, but it is particularly valuable during
periods of high vulnerability, such as infection of young household contacts or PLHIV (2). Thus,
treatment of TB infection will depend strongly on the capacity to initiate and sustain targeted campaigns
for the prevention of TB in these high-risk groups. This should complement sustained provision of ART,
which is a highly effective measure against TB and other opportunistic infections in PLHIV.
In low-incidence settings with minimal TB transmission, the protection provided by TPT is more
durable, given the limited risk of re-infection, but has a reduced population benefit because of low
TB transmission. In deciding whether to recommend preventive therapy, clinicians should weigh the
probable benefits and harms of treatment (once TB disease has been ruled out), considering the risk
of subsequent progression to disease and the potential toxicity of therapy, which require consideration
of the patient’s age and comorbid conditions. Recent contacts of infectious individuals and migrants
arriving from endemic areas within the preceding 2 years are often considered high-risk populations.
In these situations, all means should be available to (i) rule out TB disease; (ii) test for TB infection
in a reliable way; and (iii) initiate therapy, assess the risk of subsequent progression to TB disease and
monitor treatment adherence and completion.
5.2.2 Testing for TB infection

For formal demonstration of TB infection, recent WHO guidelines (13) stipulate that “testing for TB
infection by tuberculin skin test or interferon- release assay is not a requirement for initiating preventive
treatment in PLHIV or child household contacts aged < 5 years”. This is not the case, however, for adults,
adolescents and children aged ≥ 5 years who are household contacts of bacteriologically confirmed
pulmonary TB cases, who should be tested for TB infection before treatment is provided, or for migrants
arriving from endemic areas, who should all be tested for TB infection in a reliable way. The strategy
therefore differs according to population group, and different use case scenarios may be developed for
global use and scale-up of treatments. It is hoped that cheap, rapid, accurate point-of care-diagnostic tests
for TB infection and incipient disease will become available for further refinement of the TB prevention
strategy.
5.2.3 Rifampicin-susceptible and -resistant strains

As mentioned in the introduction, a practical approach of extended scale-up and access to treatment of
TB infection under programmatic conditions in high-risk populations might have a drastic impact on
TB incidence and mortality, in addition to optimized case-finding and treatment. Thus, TB preventive
treatment regimens are intended for all patients infected with M. tuberculosis, whether the infection is
susceptible or resistant to rifampicin or to other oral first-line drugs that may be used in the regimen
(e.g. isoniazid) or to second-line drugs included in drug-resistant TB treatment (fluoroquinolones,
bedaquiline, delamanid). The potential use case scenario may thus be either (i) that treatment of TB
infection is intended for all individuals infected with M. tuberculosis strains whether susceptible or
resistant to rifampicin or to other oral first-line drugs potentially used in disease-susceptible regimen
(e.g. isoniazid) or to second-line drugs included in drug-resistant TB treatment (fluoroquinolones,
bedaquiline, delamanid), or (ii) that contacts of known drug-resistant TB cases with no TB disease
require specific drugs or regimens for TB preventive treatment. The scenario will therefore strongly
depend on the class of the drugs proposed in the TPT.

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20. Menzies D, Adjobimey M, Ruslami R, Trajman A, Sow O, et al. Four months of rifampin or nine
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Annex 1.
Treatment of tuberculosis infection for
prevention of tuberculosis disease
Background and current situation.
The aim of treatment of TB infection is to prevent progression to active clinical disease by killing
potential resident bacilli in the host. Isoniazid administered daily for 6–12 months has been the mainstay
of treatment for more than half a century, with an efficacy of 54–88% (1, 2). A re-analysis of the United
States Public Health Service trials conducted in the 1950s–1960s showed that the benefit of isoniazid
increased progressively when administered for up to 9 or 10 months and stabilized thereafter, leading to
recommendation of the 9-month isoniazid regimen as adequate treatment (3). Further studies, however,
showed similarities between the 6- and 12-month regimens in non-HIV-infected people. A meta-analysis
of 11 isoniazid trials involving 73 375 HIV-uninfected people showed that, as compared with placebo, the
risk of progression to TB disease at 6 months (relative risk, 0.44; 95% CI, 0.27; 0.73) was similar to that
at 12 months (relative risk, 0.38; 95% CI, 0.28; 0.50) (4). A meta-analysis of placebo-controlled studies
found that the odds of subsequent TB disease in individuals with TB infection was 0.65 (95% credible
interval, 0.50; 0.83) after treatment with isoniazid for 6 months and 0.50 (0.41; 0.62) after treatment with
isoniazid for 12 months as compared with placebo (5) (Table A1.1).
Table A1.1. Odds ratios for the prevention of TB disease and treatment rankings,
derived from a network meta-analysis
Regimen Odds ratio vs placebo (95% CrI) Odds ratio vs no treatment (95% CrI)
No treatment 1.62 (1.06–2.47) 1 (reference)
Placebo 1 (reference) 0.62 (0.41–0.94)
INH 3-4m 0.93 (0.55–1.50) 0.57 (0.31–1.02)
INH 6m 0.65 (0.50–0.83) 0.40 (0.26–0.60)
INH 9m 0.75 (0.35–1.62) 0.46 (0.22–0.95)
INH 12m 0.50 (0.41–0.62) 0.31 (0.21–0.47)
RPT-INH 3m 0.58 (0.30–1.12) 0.36 (0.18–0.73)
RMP 0.41 (0.19–0.85) 0.25 (0.11–0.57)
RMP-INH 1m 1.05 (0.37–2.77) 0.65 (0.23–1.71)
RMP-INH 3-4m 0.53 (0.36–0.78) 0.33 (0.20–0.54)
Adapted from reference 5.

CrI, credible interval; INH, isoniazid; RMP, rifampicin; RPT, rifapentine.
Other treatment regimens have been investigated and proven to be safe and efficacious, including
rifampicin, isoniazid and rifampicin, and isoniazid and rifapentine regimens. In the network meta-
analysis of preventive therapies cited above, daily rifampicin for 3–4 months was found to reduce the
risk of incident TB by 59% as compared with placebo (odds ratio, 0.41; 95% credible interval, 0.19;
0.85). A multicentre clinical trial in which 4 months of self-administered rifampicin was compared with

9 months of daily isoniazid therapy in 6859 people, 4 months of daily rifampicin was non-inferior to 9
months of isoniazid for the prevention of TB disease and was associated with a higher rate of treatment
completion and better safety (6). In an additional 829 children aged < 18 years recruited in a companion
trial, treatment with 4 months of rifampicin resulted in similar rates of safety and efficacy but a better rate
of adherence than 9 months of isoniazid (85.3% vs 76.4%, adjusted difference in the rates of treatment
completion, 13.4 % [95% CI, 7.5; 19.3]) (7).
Several randomized studies have been conducted to compare 3–4 months of daily isoniazid and rifampicin
with daily isoniazid alone. A meta-analysis of five randomized controlled trials in adults showed that
daily therapy with isoniazid plus rifampicin for 3 or 4 months and standard therapy with isoniazid for
6–12 months were equivalent in terms of efficacy, severe side-effects and mortality (8). The trials were
significantly heterogeneous with regard to the outcome of severe adverse drug reactions, but a sub-
analysis of only high-quality studies indicated that the two regimens were equally safe. A randomized
controlled trial in children < 15 years showed that 3–4 months of isoniazid plus rifampicin was at least
equivalent to 9 months of daily isoniazid monotherapy (9). No child in either group experienced a clinical
episode of TB disease.
In an open-label, registration-quality clinical trial conducted in Brazil, Canada, Spain and the USA, 3
months of weekly rifapentine plus isoniazid was shown to be non-inferior to 9 months of daily isoniazid
monotherapy (10). Further, the 3 months of weekly rifapentine plus isoniazid regimen was associated
with higher treatment completion rates (82.1% vs 69.0%) and less hepatotoxicity (0.4% vs 2.7%),
although permanent discontinuation of the regimen due to side-effects was more frequent with the 3
months of weekly rifapentine plus isoniazid regimen (4.9% vs 3.7%). Similar results were observed in
an extension of the study involving 1058 children aged 2–17 years, and no hepatotoxic effects attributed
to treatment were observed in either study group (11). A follow-up study involving 399 HIV-infected
adults showed that 3 months of weekly rifapentine plus isoniazid was as effective as 9 months of daily
isoniazid monotherapy and was associated with a higher treatment completion rate (89% vs 64%) (12).
The weekly isoniazid–rifapentine regimen was also evaluated in South African adults with HIV infection
and a positive tuberculin skin test, who were not receiving ART; the efficacy of that regimen was shown
to be similar to a 6-month isoniazid regimen (13).
In a post-marketing evaluation of 3 months of weekly rifapentine plus isoniazid in 16 TB programmes
and routine health care settings in the USA involving 3288 participants, completion of 3 months of
weekly rifapentine plus isoniazid was better overall than the rates reported from clinical trials, and better
than with other regimens in reportedly non-adherent populations (14). Further, a systematic review
published in 2018 showed that 3 months of weekly rifapentine plus isoniazid was similar to other TB
infection regimens (6 months of daily isoniazid monotherapy, 9 months of daily isoniazid monotherapy,
3–4 months of isoniazid plus rifampicin and 2–33 months of daily rifampicin plus pyrazinamide) in
effectiveness, risk of adverse events, risk of discontinuation due to adverse events and risk of death but
resulted in higher completion rates (15).
In a study conducted in 2019, 1 month of daily rifapentine plus isoniazid delivered to HIV-infected
patients aged ≥ 13 years living in areas of high TB prevalence or who had evidence of TB infection was
shown to be non-inferior to 9 months of daily isoniazid monotherapy in a phase-III randomized, open-
label, controlled trial (16). The primary end-point was a first diagnosis of TB or death from TB or an
unknown cause. A total of 3000 patients were enrolled and followed for a median of 3.3 years. The primary
end-point was reported in 32 of 1488 patients (2%) receiving 1 month of daily rifapentine plus isoniazid
and in 33 of 1498 patients (2%) receiving 9 months of daily isoniazid monotherapy, for incidence rates
of 0.65 per 100 person-years and 0.67 per 100 person-years, respectively (rate difference, −0.02 per 100
person-years; 95% CI, −0.30; 0.34). The 1 month of daily rifapentine plus isoniazid regimen was also
found to be non-inferior to 9 months of daily isoniazid monotherapy in the subset of participants with a
positive test for TB infection (tuberculin skin test or Interferon-γ release assay). Serious adverse events
occurred in 6% of the patients receiving 1 month of daily rifapentine plus isoniazid and in 7% of those

given 9 months of daily isoniazid monotherapy (P = 0.07). The treatment completion rate was higher
with 1 month of daily rifapentine plus isoniazid than with 9 months of daily isoniazid monotherapy (97%
vs 90%, P < 0.001). Most of the participants were on ART.
References
1. Horsburgh CR Jr, Rubin EJ. Latent tuberculosis infection in the United States. N Engl J Med.
2011;364:1441–8.
2. Akolo C, Adetifa I, Shepperd S, Volmink J. Treatment of latent tuberculosis infection in HIV
infected persons. Cochrane Database Syst Rev. 2010;(1):CD000171.
3. Comstock GW. How much isoniazid is needed for prevention of tuberculosis among
immunocompetent adults? Int J Tuberc Lung Dis. 1999;3:847–50.
4. Smieja MJ, Marchetti CA, Cook DJ, Smaill FM. Isoniazid for preventing tuberculosis in non-HIV
infected persons. Cochrane Database Syst Rev 2000; 2: CD001363.
5. Zenner D, Beer N, Harris RJ, Lipman MCI, Stagg,HR, van der Werf MJ. Treatment of latent
tuberculosis infection: an updated network meta-analysis. Ann Intern Med.2017;167(4):248–55.
6. Menzies D, Adjobimey M, Ruslami R, Trajman A, Sow O, et al. Four months of rifampin or nine
months of isoniazid for latent tuberculosis in adults. N Engl J Med. 2018;379:440–53.
7. Diallo T, Adjobimey M, Ruslami R, Trajman A, Sow O, et al. Safety and side effects of rifampin
versus isoniazid in children. N Engl J Med. 2018;379:454–63.
8. Ena J, Valls V. Short-course therapy with rifampin plus isoniazid, compared with standard therapy
with isoniazid, for latent tuberculosis infection: a metaanalysis. Clin Infect Dis. 2005;40:670–6.
9. Spyridis NP, Spyridis PG, Gelesme A, Sypsa V, Valianatou M, Metsou F, et al. The effectiveness of a
9-month regimen of isoniazid alone versus 3- and 4-month regimens of isoniazid plus rifampin for
treatment of latent tuberculosis infection in children: results of an 11-year randomized study. Clin
Infect Dis. 2007;45:715–22.
10. Sterling TR, Villarino ME, Borisov AS, Shang N, Gordin F, Bliven-Sizemore E, et al. Three months
of rifapentine and isoniazid for latent tuberculosis infection. N Engl J Med. 2011;365:2155–66.
11. Villarino ME, Scott NA, Weis SE, Weiner M, Conde MB, Jones B, et al. Treatment for preventing
tuberculosis in children and adolescents: a randomized clinical trial of a 3-month, 12-dose regimen
of a combination of rifapentine and isoniazid. JAMA Pediatr. 2015;169:247–55.
12. Sterling TR, Scott NA, Miro JM, Calvet G, La Rose A, Infante R, et al. Three months of weekly
rifapentine and isoniazid for treatment of M. tuberculosis infection in HIV coinfected persons.
AIDS. 2016;30(10):1607–15.
13. Martinson NA, Barnes GL, Moulton LH, Msandiwa R, Hausler H, Ram M, et al. New regimens to
prevent tuberculosis in adults with HIV infection. N Engl J Med. 2011;365:11–20.
14. Sandul AL, Nwana N, Holcombe JM, Lobato MN, Marks S, Webb R, et al. High rate of treatment
completion in program settings with 12-dose weekly isoniazid and rifapentine for latent
Mycobacterium tuberculosis infection. Clin Infect Dis. 2017;65(7):1085–93.
15. Njie GJ, Morris SB, Woodruff RZW, Moro RN, Vernon A, Borisov AS. Isoniazid–rifapentine for
latent tuberculosis infection: a systematic review and meta-analysis. Am J Prev Med. 2018;55(2):244–
52.
16. Swindells S, Ramchandani R, Gupta A, Benson CA, Leon-Cruz J, Mwelase N, et al. One month of
rifapentine plus isoniazid to prevent HIV-related tuberculosis. N Engl J Med. 2019;380:1001–11.

Annex 2.
Tuberculosis preventive treatment
in special populations
1. Contacts of MDR-TB cases
Contacts of patients with known MDR-TB are at high risk of infection with a drug-resistant organism
(1). Limited evidence is available for deciding on the optimal approach for individuals who are likely
to have TB infection with drug-resistant bacteria. An observational study in Micronesia showed that
contacts of MDR-TB patients who received preventive therapy in a regimen including moxifloxacin or
levofloxacin with either ethambutol or ethionamide did not develop MDR-TB, while 20% of infected
contacts who refused treatment developed the disease (2). In a prospective study in South Africa, six of
186 (3.2%) children who were contacts of MDR-TB and received 6 months of ofloxacin with isoniazid
and ethambutol developed TB, which was a substantially lower rate than in “historical” controls (3).
Three randomized controlled trials of preventive therapy after household exposure to MDR-TB are being
conducted currently, with various regimens. The V-QUIN trial is a comparison of levofloxacin with
placebo in infected contacts of MDR-TB patients in Viet Nam. The TB CHAMP trial is a comparison
of the same regimens but with a dispersible formulation for children < 5 years in South Africa. The
PHOENIx study in Africa, Asia and South America is a comparison of delamanid with isoniazid. The
results of the three studies will not be available until after 2020. Details are provided in Table A2.1.
Table A2.1. Ongoing clinical trials for the treatment of TB infection in contacts of MDR-
TB patients
TB-CHAMP V-QUIN Phoenix
Intervention Levofloxacin (novel paediatric Levofloxacin vs placebo daily for 6 Delamanid vs standard dose isoniazid
dispersible formulation) vs placebo months daily for 26 weeks
daily for 6 months
Design Cluster randomized; superiority Cluster randomized; superiority Cluster randomized; superiority
Community-based Community-based Community-based
Target 0–5 years, regardless of Tuberculin skin test + Children 0–5 years regardless of HIV and
population interferon- release assay result TB infection status
or HIV status No age limit
HIV negative adults, adolescents and
children aged >5 tuberculin skin test or
interferon- release assay positive
HIV positive adults, adolescents and
children aged >5 regardless of TB
infection status
Assumptions Levofloxacin decreases TB Levofloxacin decreases TB incidence Delamanid decreases TB incidence by
incidence from 7% to 3.5%. by 70% from 3% in untreated. 50%, from 5% to 2.5%.
80% power 80% power 90% power
Sample size 778 households 1326 households 2158 adults ≥ 18 years with confirmed
MDR-TB
1556 contacts 2785 contacts
3452 contacts
Sites South Africa Viet Nam NTP ACTG and IMPAACT sites
Timelines Completed and intended to be Planned end of data collection in Estimated completion in mid-2025
published by end 2020 March 2020
Funder BMRC, Wellcome Trust, DFiD, SA Australian MRC DAIDS, ACTH, IMPAACT
MRC SHIP
Trial http://www.isrctn.com/ https://anzctr.org.au/Trial/ https://clinicaltrials.gov/ct2/show/
websites ISRCTN92634082 Registration/TrialReview. NCT03568383
aspx?id=369817

2. TB preventive treatment in PLHIV
In a Cochrane database review of 12 randomized clinical trials of TB infection treatment in 8578
randomized PLHIV, preventive therapy with any anti-TB drug administered for 6–12 months versus
placebo resulted in an overall 32% reduction in the incidence of TB disease (relative risk, 0.68; 95%
CI, 0.54; 0.85) (4). The effect was greater for people with a positive tuberculin skin test (62% reduction;
relative risk, 0.38; 95% CI, 0.25; 0.57) than for those with a negative tuberculin skin test (11% reduction;
relative risk, 0.89; 95% CI, 0.64; 1.24). Because of the uncertain performance and limitations of existing
diagnostic tests for TB infection in PLHIV, the treatment recommendations in this special population do
not require systematic testing for infection.
The benefit provided by IPT in PLHIV was shown to remain in the presence of concurrent ART (4).
Further, while in South Africa the protective effect of isoniazid against TB disease among PLHIV was
found to wane over time (5), in Côte d’Ivoire, 6 months of IPT had a durable protective effect (up to 6
years of follow-up) in reducing mortality of PLHIV (by 37%), even in those with a high CD4 cell counts
and who had started ART (6). The probable additive effect of IPT and ART suggests that receiving both
treatments is a better option than receiving either therapy alone. In Brazil, a country with low rates of
transmission of TB, isoniazid therapy for 6 months has long-term protective benefits in HIV-infected
adults (7). In settings with high TB prevalence and transmission, daily isoniazid preventive therapy for
36 months for PLHIV was shown to reduce the risk for TB disease by 38% more than 6 months of daily
isoniazid (8).
Short-course preventive therapy with 3 months of weekly rifapentine plus isoniazid could transform
TB control, but drug interactions with antiretrovirals pose potential challenges. Co-administration of
efavirenz and daily rifapentine (600 mg), with or without isoniazid, did not reduce exposure to efavirenz
that could jeopardize antiviral activity (9). Administration of 3 months of weekly rifapentine plus
isoniazid with raltegravir was found to be safe and well tolerated in healthy volunteers (10). One of the
most urgent remaining questions about acceptability is whether rifapentine can be safely given with
dolutegravir, which is purported to be the most widely prescribed integrase inhibitor in the world and a
key component of WHO-recommended first-line regimens for HIV infection (11, 12). Recent data from
DOLPHIN, a single-arm study of the safety and pharmacokinetics of 3 months of weekly rifapentine plus
isoniazid with dolutegravir (ART in adults with HIV infection (13)), showed that co-administration was
well tolerated, with no adverse events of grade > 3 after 3 months of weekly rifapentine plus isoniazid,
and all participants maintained viral suppression (14).
References
1. Becerra M, Appleton S, Franke M, Chalco K, Arteaga F, Bayona J, et al. Tuberculosis burden in
households of patients with multidrug-resistant and extensively drug-resistant tuberculosis: a
retrospective cohort study. Lancet. 2011;377:147–52.
2. Bamrah S, Brostrom R, Dorina F, Setik L, Song R, Kawamura LM, et al. Treatment for LTBI in
contacts of MDR-TB patients, Federated States of Micronesia, 2009–2012. Int J Tuberc Lung Dis.
2014;18:912–8.
3. Seddon JA, Hesseling AC, Finlayson H, Fielding K, Cox H, Hughes J, et al. Preventive therapy
for child contacts of multidrug-resistant tuberculosis: a prospective cohort study. Clin Infect Dis.
2013;57:1676–84.
4. Rangaka MX, Wilkinson RJ, Glynn JR, Boulle A, van Cutsem G, Goliath R, et al. Isoniazid plus
antiretroviral therapy to prevent tuberculosis: a randomized double-blind, placebo-controlled trial.
Lancet. 2014;384:682–90.
5. Churchyard GJ, Fielding KL, Grant AD. A trial of mass isoniazid preventive therapy for tuberculosis
control. N Engl J Med. 2014;370:1662–3.

6. Badje A, Moh R, Gabillard D, Guéhi C, Kabran M, Ntakpé JB, et al. Effect of isoniazid preventive
therapy on risk of death in West African, HIV-infected adults with high CD4 cell counts: long-term
follow-up of the Temprano ANRS 12136 trial. Lancet Glob Health. 2017;5(11):e1080–9.
7. Golub JE, Cohn S, Saraceni V, Cavalcante SC, Pacheco AG, Moulton LH, et al. Long-term protection
from isoniazid preventive therapy for tuberculosis in HIV-infected patients in a medium-burden
tuberculosis setting: the TB/HIV in Rio (THRio) study. Clin Infect Dis. 2015;60:639–45.
8. Den Boon S, Matteelli A, Ford N, Getahun H. Continuous isoniazid for the treatment of latent
tuberculosis infection in people living with HIV. AIDS. 2016;30(5):797–801.
9. Podany A, Bao Y, Swindells S, Chaisson RE, Andersen JW, Mwelase T, et al. Efavirenz
pharmacokinetics and pharmacodynamics in HIV-infected persons receiving rifapentine and
isoniazid for tuberculosis prevention. Clin Infect Dis. 2015:61:1322–7.
10. Weiner M, Egelund EF, Engle M, Kiser M, Prihoda TJ, Gelfond JA, et al. Pharmacokinetic interaction
of rifapentine and raltegravir in healthy volunteers. J Antimicrob Chemother. 2014;69(4):1079–85.
11. ViiV Healthcare receives EU marketing authorization for Juluca (dolutegravir/rilpivirine),
the first 2-drug regimen, once-daily, single-pill for the treatment of HIV. Press release, 21 May
2018. Research Triangle (NC): ViiV Healthcare Ltd; 2018 (https://viivhealthcare.com/en-gb/
media/press-releases/2018/may/viiv-healthcare-receives-eu-marketing-authorisation-for-juluca-
dolutegravirrilpivirine-the-first-2-drug-regimen-once-daily-single-pill-for-the-treatment-of-hiv/).
12. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection.
Geneva: World Health Organization; 2016 (http://www.who.int/hiv/pub/arv/arv-2016/en/).
13. Identifier: NCT03435146, Safety, tolerability, DDI short course treatment of LTBI infection with
high-dose rifapentine isoniazid in HIV+ patients (IMPAACT4TB); 2018 February 15. Bethesda
(MD): National Library of Medicine; 2000 (https://clinicaltrials.gov/ct2/show/NCT03435146).
14. Dooley K, Churchyard G, Savic R, Gupta A, Mazinke MA, Zhang N, et al. Safety and PK of
weekly rifapentine/isoniazid (3HP) in adults with HIV on dolutegravir. Abstract 80. Conference
on Retroviruses and Opportunistic Infections, Seattle (WA), 4–7 March 2019 (http://www.
croiconference.org/sessions/safety-pk-weekly-rifapentineisoniazid-3hp-adults-hiv-dolutegravir).

Annex 3.
Technical consultation on latent TB infection
management: target regimen profiles,
17 September 2019, Montréal, Canada
Agenda
Target regimen profiles for treatment of TB infection
Chair: Payam Nahid
8:30–8:45 Introductions and meeting objectives Matteo Zignol
8:45–9:00 Declaration of Interests, management of conflict and roles Dennis Falzon
Current situation and gaps in treatment of TB infection
9:00–9:15 Background on WHO LTBI guidance uptake and updates Dennis Falzon
9:15–9:45 Available treatments and the development pipeline – solutions and gaps Payam Nahid
9:45–10:00 The conceptual framework for TRP of TB infection Christian Lienhardt
Olivia Oxlade,
10:00-10:30 Modelling input parameters to inform TRP for TB infection
Kevin Schwartzman
10:30-11:00 Break
I. Attributes for the TRPs
11:00-11:30 Description of the first set of attributes of the TRPs Christian Lienhardt
11:30-13:00 Discussion Dick Menzies (moderator)
13:00-14:00 Lunch
II. Attributes for the TRPs
14:00-14:30 Description of the second set of attributes of the TRPs Christian Lienhardt
14:30-16:00 Discussion Richard Chaisson (moderator)
16:00-16:20 Break
Conclusion and next steps
16:20-17:15 Recap, summary of actions and next steps Christian Lienhardt
17:15-17:30 Closure and thanks Dennis Falzon

List of participants
Jay Achar, Médecins Sans Frontières, UK and Ireland
Mênonli Adjobimey, Programme National contre la Tuberculose, Benin
Sevim Ahmedov, USAID, USA
Teeb Al-Samarrai, President’s Emergency Plan for AIDS Relief, USA
Cathy Bansbach, Bill & Melinda Gates Foundation, USA
Draurio Barreira Cravo Neto, Unitaid, Switzerland
Grania Brigden, Union, France
Jonathon Campbell, McGill University, Canada
Martina Casenghi, Elizabeth Glaser Pediatric AIDS Foundation, Switzerland
Dick Chaisson, Johns Hopkins University, USA
Gavin Churchyard, Aurum Institute, South Africa
Isabelle Cieren-Puiseux, Sanofi, France
Daniela Cirillo, San Raffaele Scientific Institute Milan, Italy
William Coggin, United States Centers for Disease Control and Prevention, USA
Dennis Falzon, WHO Global TB Programme, Switzerland
Celeste Garcia Edwards, Global Fund to Fight AIDS, Tuberculosis and Malaria, Switzerland
Unyeong Go, Korea Centers for Disease Control and Prevention, Republic of Korea
Jeremy Hill, KNCV Tuberculosis Foundation, The Netherlands
Avinash Kanchar, WHO Global TB Programme, Switzerland
Christian Lienhardt, Institut de Recherche pour le Développement, France
Alberto Matteelli, University of Brescia, Italy
Dick Menzies, McGill University, Canada
Corinne Merle, Special Programme for Research and Training in Tropical Diseases, Switzerland
Payam Nahid, University of California at San Francisco, USA
Thu Anh Nguyen, The University of Sydney, Australia
Olivia Oxlade, McGill University, Canada
Madhu Pai, McGill University, Canada
Martina Penazzato, WHO HIV Department, Switzerland
Morten Ruhwald, FIND, Switzerland
Nicole Salazar-Austin, Johns Hopkins University, USA
Kevin Schwartzman, McGill University, Canada
Sue Swindells, University of Nebraska Medical Center, USA
Ezio Távora dos Santos Filho, Union/ Vital Strategies, Brazil
Anete Trajman, McGill University, Canada
Andy Vernon, United States Centers for Disease Control and Prevention, USA
Brenda Waning, Global Drug Facility, Switzerland
Matteo Zignol, WHO Global TB Programme, Switzerland

Statements of conflicts of interest
The following participants declared no interests that could conflict with the objectives of the meeting:
Menonli Adjobimey, Grania Brigden, Jonathon Campbell, William Coggin, Celeste Garcia Edwards,
Timothy Evans, Unyeong Go, Jeremy Hill, Christian Lienhardt, Alberto Matteelli, Richard (Dick)
Menzies, Sumathi Nambiar, Olivia Oxlade, Nicole Salazar-Austin, Kevin Schwartzman, Susan Swindells,
Anete Trajman, Brenda Waning.
The following participants declared interests that might be relevant to the objectives of the meeting:
Jay Achar declared that his employer, Médecins Sans Frontières, has an interest in various aspects of
global policy that influence TB control and receives external funding from Unitaid, the Dutch National
Lottery and other sources for implementation of the endTB project and the TBPRACTECAL clinical
trial.
Faiz Ahmad Khan declared that he is co-investigator in a 2-month trial of high-dose vs normal dose
rifampicin in TB infection, which is supported by the Canadian Institute of Health Research. He is
also principal investigator in a study to assess the accuracy of artificial intelligence for computer-aided
diagnosis of TB in digital chest radiography (CA$ 487 000 operating costs). No funding is provided
by the developers or companies of the software being evaluated. Delft (CAD4TB) & QURE.AI provide
technical assistance in use of their software, and QURE.AI provided access to their software free of
charge for evaluation. The companies have no influence or input on study design or reporting. He was
also a member of a WHO steering committee for a consultation on the use of CXR in TB diagnosis.
Martina Casenghi is in the project management leadership for the CaP TB project, funded by Unitaid.
The project includes operational research on models of care for delivery of TB preventive treatment to
child contacts. The 3RH regimen will be used. The study is led by the Institut pour la Recherche et le
Développement, and she is a co-investigator. As a representative of one of the stakeholders supporting the
roll-out of TPT in endemic countries, she has been invited to stakeholders’ meetings and consultations.
Her contributions have included ensuring that the specific needs of the paediatric population are taken
into consideration by donors and public health organizations.
Dick Chaisson has benefited from direct and institutional (Johns Hopkins University) funding in recent
years, which includes a total of about US$ 2.6 million in research grants from the National Institutes of
Health, the US Centers for Disease Control and Prevention (US CDC), Chao Foundation, Unitaid and
Aurum Institute; US$ 5000 from Sanofi for technical consulting (Johns Hopkins University); and about
US$ 5000 for speaking honoraria from the National Institutes of Health, the US CDC, Stop-TB Japan, the
Portuguese Infectious Disease Society and several universities in the USA.
Gavin Churchyard declared ongoing research support from Unitaid, USAID, the National Institutes
of Health and Sanofi. Unitaid provided a grant of US$ 59 million for scaling up use of 3HP and
implementation research. USAID provided a grant of US$ 14.2 million to evaluate 3HP given once or
annually. The National Institutes of Health provided minimal salary support for the PHOENIx trial.
Sanofi donated 3HP for the WHIP3TB trial.
Daniela Cirillo declared that the Supranational TB Laboratory in Milan where she works is developing
new diagnostics for drug-resistant TB. She declares current research support from FIND (US$ 26 000);
participation in a national expert group to establish use of bedaquiline in Italy (€ 1000; 2014); support
for standardization of the drug-susceptibility methods for bedaquiline by Janssen (US$ 10 000; 2014);
and support for the drug-susceptibility methods for delamanid from Otsuka (US$ 25 000; 2014). The
Ospedale San Raffaele in which the laboratory is based, has a service agreement with the TB Alliance
(US$ 19 800).

Payam Nahid declared an active Federal US CDC contract to support clinical trial units in San Francisco,
USA, and Hanoi, Viet Nam.
Thu Anh Nguyen works fulltime in Viet Nam for the Woolcock Institute of Medical Research, an
Australian non-profit organization. Operational research is being conducted on TB infection with
funding from Australia National Health and Medical Research Council.
Madhukar Pai serves as the Chair of the Stop TB Partnership’s Public Private Mix Working Group;
the Access Advisory Committee of TB Alliance (New York City (NY), USA); the Scientific Advisory
Committee of FIND, Geneva, Switzerland; and the SAGE IVD and STAG TB committees of WHO,
Geneva, Switzerland.
Morten Ruhwald declared that he works for FIND, which collaborates with industry (e.g. Cepheid,
Hain, Alere, Roche) in the development, evaluation and distribution of novel diagnostics. No income is
received or will be received from these companies. Industry partnerships are approved and monitored by
an independent scientific advisory committee on the basis of due diligence and their ability to meet TPPs
and public sector requirements. FIND has not allocated any financial value to the know-how or access to
equipment gained by these projects.
Ezio Távora dos Santos Filho declared that he delivered a talk at the Regional IAS Conference in April
2018 in Mexico City, Mexico, on advanced tools for treatment of TB infection, without endorsing any
particular study. He also declared that, as a TB advocate, he has participated in many discussions with
the Global TB Community Advisory Board and the Brazilian National TB CAB on implementation of
new methods for treatment of TB infection. The Brazilian TB CAB is raising awareness about 3HP and
TB infection.
Andrew Vernon declared that he heads a clinical research group (TBTC) at the US CDC, which conducts
trials. The group has conducted studies on TB infection, and studies are under way with rifapentine
(e.g. TBTC Study 31). During the past two decades, TBTC has accepted support from commercial and
pharmaceutical companies in the form of drug supplies and funding for pharmacokinetics testing.
Most recently, TBTC collaborated with the US National Institutes of Health and Sanofi in undertaking a
phase 3 multi-centre trial of daily rifapentine. Sanofi provided medicines and funded pharmacokinetics
testing but was not involved in the design or conduct of the study. In 2007–2017, Sanofi Aventis made
contributions to the CDC Foundation (about US$ 3 million total) to facilitate or support TBTC work
on rifapentine (e.g. pharmacokinetics studies, two to three staff contracts, travel for invited speakers,
preparation of data to support regulatory filings). These funds have not otherwise benefited Dr Vernon
or the research group and represent a small proportion of overall costs for the studies. In his capacity as
a TB researcher and clinician at US CDC he has participated in both internal and external meetings on
developing guidelines for the treatment of active and latent TB in the USA. His attendance was only in the
context of CDC employment and never on behalf of any commercial or nongovernmental organization.
Exempted:
Funding agencies: Sevim Ahmedov, Teeb Al-Samarrai, Cathy Bansbach, Draurio Barreira Cravo Neto,
Celeste Garcia Edward
Drug manufacturer: Isabelle Cieren-Puiseux

Annex 4.
WHO recommendations on TB preventive
treatment (2020 update)
These recommendations (1) are listed below as a reference to the current status of TB preventive
treatment. They do not preclude further recommendations based on new data and evidence.
A. Identifying populations for LTBI testing and treatment
People living with HIV
1. Adults and adolescents living with HIV who are unlikely to have active TB should receive TB preventive treatment as part of a
comprehensive package of HIV care. Treatment should also be given to those on antiretroviral treatment, to pregnant women and to those
who have previously been treated for TB, irrespective of the degree of immunosuppression and even if LTBI testing is unavailable.
2. Infants aged < 12 months living with HIV who are in contact with a person with TB and who are unlikely to have active TB on an
appropriate clinical evaluation or according to national guidelines should receive TB preventive treatment.
3. Children aged ≥ 12 months living with HIV who are considered unlikely to have active TB on an appropriate clinical evaluation or according
to national guidelines should be offered TB preventive treatment as part of a comprehensive package of HIV prevention and care if they live
in a setting with high TB transmission, regardless of contact with TB.
4. All children living with HIV who have successfully completed treatment for TB disease may receive TB preventive treatment.
Household contacts (regardless of HIV status)
5. Children aged < 5 years who are household contacts of people with bacteriologically confirmed pulmonary TB and who are found not to
have active TB on an appropriate clinical evaluation or according to national guidelines should be given TB preventive treatment even if LTBI
testing is unavailable.
6. Children aged ≥ 5 years, adolescents and adults who are household contacts of people with bacteriologically confirmed pulmonary TB
who are found not to have active TB by an appropriate clinical evaluation or according to national guidelines may be given TB preventive
treatment.
7. In selected high-risk household contacts of patients with multidrug-resistant tuberculosis, preventive treatment may be considered based
on individualized risk assessment and a sound clinical justification.
Other people at risk
8. People who are initiating anti-TNF treatment, or receiving dialysis, or preparing for an organ or haematological transplant, or who have
silicosis should be systematically tested and treated for LTBI.
9. Systematic LTBI testing and treatment may be considered for prisoners, health workers, immigrants from countries with a high TB burden,
homeless people and people who use drugs.
10. Systematic LTBI testing and treatment is not recommended for people with diabetes, people who engage in the harmful use of alcohol,
tobacco smokers and underweight people unless they also belong to other risk groups included in the above recommendations.
B. Algorithms to rule out active TB disease
11. Adults and adolescents living with HIV should be screened for TB according to a clinical algorithm. Those who do not report any of the
symptoms of current cough, fever, weight loss or night sweats are unlikely to have active TB and should be offered preventive treatment,
regardless of their ART status.
12. Adults and adolescents living with HIV who are screened for TB according to a clinical algorithm and who report any of the symptoms
of current cough, fever, weight loss or night sweats may have active TB and should be evaluated for TB and other diseases and offered
preventive treatment if active TB is excluded.
13. Chest radiography may be offered to people living with HIV on ART and preventive treatment given to those with no abnormal
radiographic findings.
14. Infants and children living with HIV who have poor weight gain, fever or current cough or who have a history of contact with a person
with TB should be evaluated for TB and other diseases that cause such symptoms. If TB disease is excluded after an appropriate clinical
evaluation or according to national guidelines, these children should be offered TB preventive treatment, regardless of their age.
15. The absence of any symptoms of TB and the absence of abnormal chest radiographic findings may be used to rule out active TB disease
among HIV-negative household contacts aged ≥ 5 years and other risk groups before preventive treatment.
C. Testing for LTBI
16. Either a tuberculin skin test (TST) or interferon-gamma release assay (IGRA) can be used to test for LTBI.

D. Treatment options for LTBI
17. The following options are recommended for the treatment of LTBI regardless of HIV status: 6 or 9 months of daily isoniazid, or a 3-month
regimen of weekly rifapentine plus isoniazid, or a 3 month regimen of daily isoniazid plus rifampicin. A 1-month regimen of daily rifapentine
plus isoniazid or 4 months of daily rifampicin alone may also be offered as alternatives.
18. In settings with high TB transmission, adults and adolescents living with HIV who have an unknown or a positive LTBI test and are
unlikely to have active TB disease should receive at least 36 months of daily isoniazid preventive therapy (IPT). Daily IPT for 36 months should
be given whether or not the person is on ART, and irrespective of the degree of immunosuppression, history of previous TB treatment and
pregnancy in settings considered to have a high TB transmission as defined by national authorities.
Recommended dosages of drugs for the treatment of TB infection
Regimen Dose by weight band

6 or 9 months of daily isoniazid Age 10 years & older: 5 mg/kg per day
monotherapy (6H, 9H)
Age <10 years: 10 mg/kg per day (range, 7–15 mg)
Four months of daily rifampicin (4R) Age 10 years & older: 10 mg/kg per day
Age >10 years: 15 mg/kg per day (range, 10–20 mg)
Three months of daily rifampicin Isoniazid:
plus isoniazid (3HR) Age 10 years & older: 5 mg/kg per day
Rifampicin:
Age 10 years & older: 10 mg/kg per day
Three months of rifapentine plus Age 2–14 years
isoniazid weekly (12 doses) (3HP)
Medicine, formulation 10–15 kg 16–23 kg 24–30 kg 31–34 kg > 34 kg
Isoniazid, 100 mg* 3 5 6 7 7
Rifapentine, 150 mg 2 3 4 5 5
Age > 14 years
Medicine, formulation 30–35 kg 36–45 kg 46–55 kg 56–70 kg > 70 kg
Isoniazid, 300 mg 3 3 3 3 3
Rifapentine, 150 mg 6 6 6 6 6
* 300-mg formulation can be used to reduce pill burden
One month of rifapentine plus Age ≥ 13 years (regardless of weight band)
isoniazid daily (30 doses) (1HP)
Isoniazid, 300 mg/day
Rifapentine, 600 mg/day
Six months of levofloxacin daily Age > 14 years, by body weight: < 46 kg, 750 mg/day; > 45 kg, 1 g/day
(preventive treatment of MDR-TB)
Age < 15 years (range, approximately 15–20 mg/kg per day), by body weight: 5–9 kg, 150 mg/day;
10–15 kg, 200–300 mg/day; 16–23 kg, 300–400 mg/day; 24–34 kg, 500–750 mg/day
Notes:
Regimens based on isoniazid and rifampicin may be used for people of all ages. There are no or very limited data on the efficacy and safety of rifapentine in children
< 2 years, and the 3 months of weekly rifapentine plus isoniazid regimen is recommended only for use in children aged ≥ 2 years. Data from the trial of 1 month of
daily rifapentine plus isoniazid relates only to people aged ≥ 13 years. The Guideline Development Group considered that extrapolation of effects to children aged
2–12 years is reasonable, although the daily dose of rifapentine for this age group has yet to be established. The suitability of this regimen for people aged < 13
years should be reviewed once the results of studies of pharmacokinetics and safety in children of all ages become available in the near future.
In addition to PLHIV on ART, other populations that may be commonly at risk of drug–drug interactions with rifampicin include women of reproductive age
on contraceptive medicines (who should be counselled about potential interactions and consider non-hormonal birth control while receiving rifampicin) and
opiate users on substitution therapy with methadone.
Contacts of patients with laboratory confirmed isoniazid-resistant, rifampicin-susceptible TB may be offered a 4-month regimen of daily rifampicin.
Individuals at risk for peripheral neuropathy, such as those with malnutrition, chronic alcohol dependence, HIV infection, renal failure or diabetes, or who are
pregnant or breastfeeding, should receive pyridoxine (vitamin B6) when taking isoniazid-containing regimens. The dose of isoniazid might have to be reduced
from that proposed to avoid toxicity if there is a high population prevalence of “slow acetylators”. Combination tablets of co-trimoxazole, isoniazid and
pyridoxine could be useful for PLHIV; however, lack of availability of pyridoxine should not be considered a reason to withhold TPT.
Reference
1. WHO consolidated guidelines on tuberculosis: Module 1: Prevention - tuberculosis preventive
treatment. Geneva, World Health Organization. 2020.

Annex 5.
Long-acting drug formulations for the
treatment of tuberculosis infection
Adherence and completion rates for TB preventive treatment are low in many programmes, which
represent major obstacles to the effectiveness of this strategy. An important, novel solution could be
long-acting, extended-release, injectable anti-TB drugs that can be administered periodically in
a clinic, thus eliminating the problems of suboptimal adherence and treatment completion (1). This
strategy might be particularly important for vulnerable populations, including children, adolescents and
pregnant women. The potential of a single administration, providing a “one shot cure”, would render
DOT requirements obsolete. In addition, the avoidance of oral delivery and the associated first metabolic
passage through the liver might have additional benefits in terms of drug–drug interactions and would
improve bioavailability.
Rifapentine, delamanid, bedaquiline and rifabutin have pharmacological and physicochemical
characteristics that make them appealing candidates for long-acting administration with the drug
nanoparticle suspension approach (half-life > 12 h, therapeutic concentrations < 1000 ng/mL and
water solubility < 50 mg/mL). The activity of a long-acting injectable bedaquiline formulation has been
demonstrated in a paucibacillary mouse model of TBI (1).
Coupled with a field-friendly diagnostic test to identify those at highest risk for progression to disease,
a long-acting, extended-release TB formulation could enable a test-and-treat strategy that would greatly
increase the possibility of TB elimination.
Reference
1. Kaushik A, Ammerman NC, Tyagi S, Saini V, Vervoort I, Lachau-Durand S, et al. Activity of a long-
acting injectable bedaquiline formulation in a paucibacillary mouse model of latent tuberculosis
infection. Antimicrob Agents Chemother. 2019;63:e00007–19.

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Target product profiles for tuberculosis preventive treatment iii

iv Target product profiles for tuberculosis preventive treatment

Target product profiles for tuberculosis preventive treatment v

vi Target product profiles for tuberculosis preventive treatment

2 Tuberculosis preventive treatment:

Target product profiles for tuberculosis preventive treatment 1

Table 1. Regimens for TB preventive treatment according to pooled efficacy, risk of

2 Target product profiles for tuberculosis preventive treatment

3 Target product profiles for tuberculosis

3.2 Objective and target audience

Target product profiles for tuberculosis preventive treatment 3

3.3.1 Baseline elements

3.3.2 Mathematical modelling

• duration: length of administration of the regimen (months);

4 Target product profiles for tuberculosis preventive treatment

Fig. 1. Influence of each attribute on TB incidence

Partial Rank Correlation Coefficient (PRCC) for TB cases averted

0 0.2 0.4 0.6 0.8 1 0 0.2 0.4 0.6 0.8 1

3.3.3 Cost–effectiveness analysis

Target product profiles for tuberculosis preventive treatment 5

Table 2. Regimen attributes and input costs

Attribute Baseline (isoniazid) Minimal Optimal

Regimen duration (months) 6 3 1

Efficacy 70% 70% 100%

Drug-resistance barrier 100% 95% 100%

Forgiveness 25% 50% 80%

Treatment completion 70% 80% 90%

Cost of regimen: medicationa US$ 3.45 US$ 3.45 US$ 3.45

DS, drug-susceptible; MDR, multi-drug-resistant

• reported baseline TPT coverage with 6 months of daily isoniazid monotherapy;

6 Target product profiles for tuberculosis preventive treatment

Baseline Scale up 6H Minimal TPT Optimal TPT

MDR-TB cases 46 714 45 753 45 733 44 824

TB deaths 187 208 183 212 180 681 178 750

DALYs 5 164 722 5 052 558 4 982 683 4 926 308

TB deaths 852 281 641 033 493 689 448 153

DALYs 29 888 441 22 270 743 16 784 278 15 222 462

Target product profiles for tuberculosis preventive treatment 7

M, million; 6H, 6 months daily isoniazid monotherapy

In a sensitivity analysis, we considered an alternative scenario involving a rifamycin-sparing regimen.

3.3.4 Development of target product profiles

8 Target product profiles for tuberculosis preventive treatment

3.4.2 Priority attributes

Target product profiles for tuberculosis preventive treatment 9

Safety and tolerability

Drug-drug interactions and metabolism

Barrier to emergence of drug resistance

Formulation, dosage, frequency and route of administration

10 Target product profiles for tuberculosis preventive treatment

3.4.3 Desirable attributes

Treatment adherence and completion

Drug susceptibility testing in index TB patients

Target product profiles for tuberculosis preventive treatment 11

Target product profiles for tuberculosis preventive treatment

Target product profiles for tuberculosis preventive treatment