Tuberculosis Preventive Therapy Pipeline Report – 2020

Abstract

Overviews progress in the clinical development of TB preventive therapy, including an inventory of recently completed, ongoing, and planned clinical trials. Provides an in-depth review of studies of the 3HP TB preventive therapy regimen in people living with HIV and pregnant women. Outlines the future potential for long-acting formulations of TB preventive therapy.

Full text

Pipeline Report » 2020
Tuberculosis Preventive Therapy

PIPELINE REPORT 2020
2
TUBERCULOSIS PREVENTIVE
THERAPY
Mike Frick
Introductory Note
“Open a window” is an old tuberculosis (TB) prevenon adage, one that
remains good advice for prevenng TB in the household and, now, SARS-
CoV-2/COVID-19 too.1 While I was wring this year’s TB Prevenon Pipeline
Report at home in New York City—a me spent mostly indoors due to the
COVID-19 pandemic—my open window and its view of a small square of dirt
with a gingko tree, standing solitary yet resilient amid a stretch of concrete,
reminded me that prevenon can arise from the simplest of natural things: a
breeze, a patch of soil, the trunk and foliage of a tree. The nature metaphors
invoked throughout this year’s TB Prevenon Pipeline Report are not incidental.
Like so much of medical science, recent advances in TB prevenve therapy
(TPT) and TB vaccines originate in the natural world. Rifapenne and rifampicin,
the drugs at the center of shorter TPT regimens, were rst synthesized from a
compound discovered in a soil sample taken from the pine forests of southern
France.2 A key component of the M72/AS01E TB vaccine candidate—the QS-21
molecule—comes from the soapbark tree, a medicinal resource recognized in the
tradional knowledge of Indigenous Andean peoples.3
Tracing things back to their source is instrucve for demonstrang how much a
eld has grown from its roots. In recent years, TB prevenon science has traveled
by leaps. Researchers developing new TPT regimens are processing a bounty of
data from recently concluded clinical trials that have established a new standard
of care (reviewed in this chapter). For TB vaccine developers, successful
phase II studies have lled the ground for larger ecacy trials, most notably
a phase III trial of M72/AS01E (reviewed in a separate chapter available here).
Whatever our vantage point, it is a good me to watch the TB prevenon pipeline
closely, keeping our gaze on where prevenon science is going without forgeng
where it all began.

PIPELINE REPORT 2020
3
The Tuberculosis Preventive Therapy Pipeline
“The rst hay is in and all at once / in the silent evening summer has come”
—Aer the Spring, W.S. Merwin4
Regular readers of TAG’s Pipeline Report will noce the absence of familiar
study names from Tables 1 and 2. TAG last published a review of research on
TPT in 2018. That was the year the harvest came in with the conclusion of
several long-running TPT clinical trials. The bumper crop started with posive
results from the BRIEF-TB/A5279 phase III study. Conducted by the AIDS
Clinical Trials Group (ACTG), BRIEF-TB found that a one-month regimen of
daily isoniazid and rifapenne (1HP) was non-inferior to nine months of daily
isoniazid (9H) in prevenng TB, death from TB, or death from unknown cause.5
Other large prevenve therapy trials bore fruit soon aer. The IMPAACT
Network’s phase IV TB Apprise/P1078 study raised new quesons about
the standing recommendaon to give isoniazid prevenve therapy (IPT) to
pregnant women with HIV.6 And a series of trials supported by the government
of Canada—which took over 15 years to complete—showed that four months
of daily rifampicin (4R) is a safe and eecve alternave to 9H for prevenng
TB in both adults and children.7
The absence of these large trials from Tables 1 and 2, many of which TAG has
followed for the beer part of the last decade, signals that the TB prevenve
therapy eld has entered a new season. The current moment is less about
ancipang long-awaited results and more about making sense of the substanal
clinical trial data already on hand. The primary ndings from the three studies
summarized above have already spurred revisions to World Health Organizaon
(WHO) guidelines on TPT, which the agency updated in March 2020.8 Pung
primary outcomes into normave guidance is just the rst pass at unpacking
the knowledge generated by these clinical trials. Some of the most excing
advances in TB prevenve therapy in the past two years have come from
secondary analyses (of P1078 and BRIEF-TB), pharmacokinec invesgaons
(P2001), drug-drug interacon studies (DOLPHIN), biomarker research
(CORTIS), pediatric studies (TiTi), and studies evaluang the durability of
newer TPT regimens (WHIP3TB).
Results from the studies italicized in the previous paragraph are reviewed
below. These studies share a commitment to carefully designed, detail-oriented
invesgaon into the eecveness and safety of using newer TPT regimens
in vulnerable populaons: in the case of these studies, people living with HIV
(PLHIV) and pregnant women. Collecvely, the studies discussed here and many
of those listed in Tables 1 and 2 are about making TPT work for everyone. HIV
posive or HIV negave, pregnant or not, young or old, drug user or abstainer,
drinker or teetotaler, exposed to drug-resistant or drug-sensive TB—everyone
has a right to the highest aainable standard of TB prevenon. Honoring this
entlement means expanding the range of TPT opons available to people at
risk of TB in all of their diversity.
TAG’s Statement on WHO
Updated TB Prevenve Therapy
Guidance overviews major
takeaways from the updated
WHO guidelines on TPT.
Results from the CORTIS
study will be presented
at the 51st Union World
Conference on Lung Health in
late October 2020 and will be
discussed in the next issue of
TAG’s Pipeline Report.
Non-inferior to means tesng
whether an intervenon is no
worse than the control by a
prespecied amount (called
a noninferiority margin).
This is dierent from tesng
superiority or equivalence.

PIPELINE REPORT 2020
4
Table 1. Recently Completed Clinical Trials of TB Prevenve Therapy
Study Name
(Registry number)
■ Sponsor
and major
collaborators
■Phase
■Sample Size (N =)
Status Regimens and
Study Design Populaon Study
Locaon(s)
WHIP3TB
(NCT02980016)
■ Aurum Instute,
KNCV, USAID
■Phase III
■N = 4,027
Completed;
results
presented
at CROI in
March 2020
Part A: treatment
compleon of
3HP versus 6H
Part B:
eecveness of
3HP once versus
3HP once a year
for two years
(p3HP)
PLHIV ≥2 years
living in high-
TB-incidence
sengs
Ethiopia,
Mozambique,
South Africa
P2001
(NCT02651259)
■IMPAACT
■Phase I/II
■N = 50
Completed;
results
presented
at CROI in
March 2020
PK and safety
of 3HP
Pregnant and
postpartum
women with
and without
HIV and with
TB infecon
Hai,
Kenya,
Malawi,
Thailand,
Zimbabwe
DOLPHIN
(NCT03435146)
■ IMPAACT4TB
(Aurum Instute/
JHU/Unitaid)
■Phase I/II
■N = 60
Completed;
results
presented
at CROI in
March 2019
PK and safety
of 3HP given
with DTG-based
ART
Adults with
HIV on stable
DTG-based ART
South Africa
CORTIS
(NCT02735590)
■Phase II/III
■ University of
Cape Town
■N = 2,927
Completed;
results to be
presented
at TB Union
Conference in
October 2020
3HP versus no
intervenon
and acve
surveillance
for TB
HIV-negave
adults with a
gene-based
correlate of risk
suggesve of
incipient TB
South Africa
DORIIS
(NCT03886701)
■Phase I
■ Merck Sharp &
Dohme
■N = 11
Completed;
results
published
Drug-drug
interacon
study of 3HP
and doravirine,
a novel NNRTI
HIV-negave,
QFT-negave
adult volunteers
United States
ART: anretroviral therapy
CROI: Conference on Retroviruses and
Opportunisc Infecons
DTG: dolutegravir
IMPAACT: Internaonal Maternal Pediatric
Adolescent AIDS Clinical Trials Group
JHU: Johns Hopkins University
NNRTI: non-nucleoside reverse transcriptase inhibitor
PLHIV: people living with HIV
PK: pharmacokinecs
QFT: QuanFERON
TB: tuberculosis
USAID: U.S. Agency for Internaonal Development

PIPELINE REPORT 2020
5
In short: the TB prevenve therapy eld is anything but a monoculture.
The studies reviewed here will be succeeded in a few years’ me when ongoing
clinical trials report results. Some of the most ancipated studies are three
evaluang prevenve therapy for people exposed to drug-resistant TB (Table 3),
an area of pracce completely barren of clinical trial data. Looking even further
ahead, sciensts are sowing ideas that, when matured, will radically alter TPT
past its familiar form of daily pill taking involving isoniazid, rifampicin, rifapenne,
or combinaons thereof. Preparaons are now underway to study long-acng,
injectable formulaons of exisng drugs and to apply drugs approved for other
TB indicaons as prophylaxis (e.g., bedaquiline, delamanid). The chapter closes
with an overview of these excing developments.
WHIP3TB: is taking a single round of 3HP enough to prevent TB in PLHIV?
The 3HP regimen is poised to supplant IPT as the preferred TPT regimen (for TB
programs that can access it, anyway: see TAG’s An Acvist’s Guide to Rifapenne for
a discussion of rifapenne accessibility challenges). The expected shi from IPT
to 3HP became more likely when the WHIP3TB trial reported results at the 2020
Conference on Retroviruses and Opportunisc Infecons (CROI). WHIP3TB was
a two-part, randomized, pragmac trial funded by the US Agency for Internaonal
Development, sponsored by the KNCV Tuberculosis Foundaon, and conducted
by the Aurum Instute. The trial enrolled 4,027 PLHIV in Ethiopia, Mozambique,
and South Africa. Most parcipants were adults, though anyone age two years
and older living with HIV and on anretroviral treatment (ART) was eligible to
enroll.9 Part A of the study was an observaonal, randomized comparison of 3HP
to six months of daily isoniazid (6H) in terms of treatment compleon (secondary
objecves evaluated the two regimens with respect to TB incidence and all-cause
mortality over 12 months). Invesgators measured compleon by pill counts self-
reported by study parcipants. Results showed that a far greater percentage of
people taking 3HP completed therapy compared with those on 6H: 90.4% versus
50.5%, a risk dierence of 39.5 (95% condence interval [CI]: 35–44.9). In other
words, parcipants taking 3HP were 1.79 (95% CI: 1.62–1.97) mes as likely to
complete therapy as those receiving 6H.10
Part B of WHIP3TB was a randomized, controlled trial that evaluated the
eecveness and safety of giving 3HP once versus giving 3HP twice—once a year
for two years, an approach called periodic 3HP, or p3HP. (Secondary objecves of
part B compared 3HP and p3HP in terms of TB incidence over months 12–24 of
follow-up, all-cause mortality, serious adverse events, and incidence of rifampicin-
resistant TB.) Invesgators observed similar TB incidence among parcipants
taking p3HP and 3HP over 24 months of follow-up.11 In the p3HP arm, there
were 37 cases of TB per 3,070 person-years of follow-up (an incidence rate
of 1.12/100 person-years) compared to 39 cases per 3,094 person-years
of follow-up (1.26/100 person-years) in the 3HP arm. TB incidence did not
dier by subgroups (country, CD4 count, QFT status). There were more study-
dened serious adverse events (SAEs) reported in the p3HP group than among
parcipants taking either 3HP or 6H, and the most common SAE was hepas.
The 3HP regimen consists
of 12 once-weekly doses of
rifapenne and isoniazid.
Person-years is a type of
measurement that looks at
both the number of people in
a study and how much me
each person spent in the
study. It esmates how much
“me at risk” parcipants
contributed to a study.
QFT refers to the
QuanFERON-TB Gold (or
Gold Plus) test, an interferon-
gamma release assay (IGRA)
manufactured by Qiagen.
IGRAs are used to test for TB
infecon. They detect cell-
mediated immune responses
to TB angens (but do not
measure infecon directly).

PIPELINE REPORT 2020
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The WHIP3TB results provide yet another demonstraon that people are more
likely to complete 3HP than either of the longer isoniazid-only opons (6H, 9H).
The part B ndings further suggest that there is no need for PLHIV to take more
than one course of 3HP, even if they live in countries with high TB incidence.
(Importantly, all WHIP3TB study parcipants were taking ART to treat HIV. As
with earlier studies of IPT in PLHIV, the combinaon of ART and TPT will beer
protect against TB than either intervenon alone.) A press release by the Aurum
Instute during the CROI Conference put it this way: “A single course of 3HP
provides lasng protecon against TB and does not need to be repeated year
aer year.”12 This is good news for the prospects of TB eliminaon, because
it will be easier and cheaper to scale up 3HP given as a single, rather than
repeat, course of therapy.
Table 2. Ongoing and Planned Clinical Trials of TB Prevenve Therapy
Study Name
(Registry number)
■ Sponsor
and major
collaborators
■Phase
■Sample Size (N =)
Status Regimens and
Study Design Populaon Study
Locaon(s)
3HP vs 1HP
(NCT03785106)
■Phase III
■HIV-NAT
■N = 2,500
Enrolling
Safety and ecacy
of 3HP vs. 1HP
(sub-study: PK
of rifapenne,
DTG, and TAF)
Adults with HIV
and TB infecon
(QFT or TST posive
or HHC)
Thailand
TBTC Study 35
(NCT03730181)
■ TBTC,
IMPAACT4TB
(Aurum Instute/
JHU/Unitaid),
Sano
■Phase I/II
■N = 72
Enrolling
PK and safety
of 3HP using
dispersible HP
formulaons
(Sano)
Children aged
0–12 years with
TB infecon (HHC
with posive TST
or IGRA) with
and without HIV
(children with
HIV on EFV- or
RAL-based ART)
South Africa
ASTERoiD/TBTC
Study 37
(NCT03474029)
■TBTC
■Phase III
■N = 3,400
Enrolling
Safety and
eecveness
of 6P vs. rifamycin-
based standard-
of-care regimens
(3HP, 4R, or 3HR)
People ≥12 years
of age with posive
TST or IGRA and at
high risk of disease
progression (PLHIV
eligible)
United States
2R2
(NCT03988933)
■ McGill University,
CIHR
■Phase II
■N = 1359
Enrolling
Safety and
treatment
compleon of
two high-dose
rifampicin regimens
(20 or 30 mg/kg)
taken daily for 2
months vs. 4R
People ≥ 10 years
of age with posive
TST or IGRA, or other
indicaon for TPT
(PLHIV eligible
Canada,
Indonesia,
Vietnam

PIPELINE REPORT 2020
7
Study Name
(Registry number)
■ Sponsor
and major
collaborators
■Phase
■Sample Size (N =)
Status Regimens and
Study Design Populaon Study
Locaon(s)
DOLPHIN Too
(NCT03435146)
■ IMPAACT4TB
(Aurum Instute/
JHU/Unitaid), ViiV
■Phase I/II
■N = 75
Planned
PK and safety of
3HP and IPT given
with DTG-based
ART
Adults with HIV
starng ART for
the rst me
South Africa
YODA
(NCT03510468)
■Phase I
■ NIH Clinical
Center
■N = 75
Enrolling
Drug-drug
interacon study of
3HP and TAF
HIV-negave,
QFT-negave
adult volunteers
United States
3HP with
DTG + DRV/c
(NCT02771249)
■Phase I
■ NIH Clinical
Center
■N = 75
Enrolling
Drug-drug
interacon study
of 3HP and DTG +
DRV/c
HIV-negave,
QFT-negave
adult volunteers
United States
A5372
(NCT04272242)
■ACTG, ViiV
■Phase II
■N = 72
Enrolling
PK and safety of
1HP given with
DTG-based ART
(twice daily vs.
once daily)
Adults with HIV on
stable DTG-based
ART with posive
TST or IGRA, or other
indicaon for TPT
Brazil,
Thailand,
United States
One to Three
(NA)
■ IMPAACT4TB
(Aurum Instute/
JHU/Unitaid)
■Phase III
■N ≈ 686
Planned
Treatment
compleon of 1HP
vs. 3HP
Adults and adolescents
(aged ≥13 years) either
HHCs (any HIV status)
or PLHIV on EFV- or
DTG-based ART
Select
IMPAACT4TB
project
countries
Rifapenne with
bictegravir and TAF
(NCT04551573)
■ Yale University,
Gilead
■Phase I
■N = 24
Planned
Drug-drug
interacon study
of rifapenne (daily
and once-weekly)
with bictegravir
and TAF
HIV-negave, QFT-
negave adult
volunteers
United States

PIPELINE REPORT 2020
8
Study Name
(Registry number)
■ Sponsor
and major
collaborators
■Phase
■Sample Size (N =)
Status Regimens and
Study Design Populaon Study
Locaon(s)
Ultra Curto
(NA)
■ NIH, JHU, Fiocruz,
FMT-HVD, Sano
■Phase IV
■N = 500
Planned
Treatment success
and safety of 1HP
vs. 3HP
HIV-negave adults and
adolescents (aged ≥ 15
years) with posive TST
or IGRA
Brazil
DOLPHIN Kids
(NA)
■ IMPAACT4TB
(Aurum Instute/
JHU/Unitaid), ViiV
■Phase I/II
■N = 100–140
Planned
PK and safety of
3HP given with
DTG-based ART
Children and
adolescents with
HIV aged 4 weeks
to 18 years
South Africa
IMPAACT P2024
(NA)
■IMPAACT
■Phase I/II
■N = NA
Planned
PK and safety of
1HP given with
DTG- and EFV-
based ART
Children ≤ 15 years
with and without
HIV (children with
HIV on DTG- or
EFV-based ART)
NA
IMPAACT P2025
(NA)
■IMPAACT
■Phase IV
■N = 1104
Planned
Safety, PK, and
opmal ming of
3HP and 1HP
Pregnant and
postpartum women
with HIV and QFT-
posive or recent HHC
on EFV- or DTG-based
ART
(possible subset of HIV-
negave women for
safety and ecacy)
NA
ACTG: AIDS Clinical Trials Group
ART: anretroviral therapy
DTG: dolutegravir
DRV/c: darunavir boosted with cobicistat
EFV: efavirenz
HHC: household contact (of people with TB disease)
HIV-NAT: HIV Netherlands Australia Thailand
Research Collaboraon
IGRA: interferon-gamma release assay
IPT: isoniazid prevenve therapy
IMPAACT: Internaonal Maternal Pediatric
Adolescent AIDS Clinical Trials Group
JHU: Johns Hopkins University
NA: Not available
NIH: U.S. Naonal Instutes of Health
NNRTI: non-nucleoside reverse transcriptase inhibitor
PK: pharmacokinecs
QFT: QuanFERON
RAL: raltegravir
TAF: tenofovir alafenamide
TB: tuberculosis
TBTC: Tuberculosis Trials Consorum,
U.S. Centers for Disease Control and Prevenon
TST: tuberculosis skin test

PIPELINE REPORT 2020
9
DOLPHIN: Is 3HP safe to take with dolutegravir-based ART?
Just as 3HP is increasingly seen as the preferred TPT opon, dolutegravir-based
ART (i.e., the TLD regimen) is fast becoming rst-line therapy for HIV in most
countries.13 Prevenng TB in PLHIV will therefore require using TPT regimens
that are compable with dolutegravir. The compability of TPT and ART must
be demonstrated, not assumed. All of the currently available short-course TPT
regimens incorporate either rifapenne (3HP, 1HP) or rifampicin (3HR, 4R).
Rifapenne and rifampicin belong to the rifamycin family of drugs; these drugs
can speed up the body’s metabolism of anretrovirals (ARVs), including
dolutegravir.14 Consequently, it may be necessary to increase the dose of
dolutegravir while taking rifamycin-based TPT in order to keep drug levels high
enough to maintain viral suppression of HIV.
The single-arm phase I/II DOLPHIN study assessed the safety and PK of
coadministering 3HP and TLD in adults with HIV on stable ART. As summarized in
TAG’s An Acvist’s Guide to Rifapenne, the DOLPHIN study sought to answer two
quesons: (1) Is it safe to take 3HP with dolutegravir-based ART? (2) If yes, does
the dose of dolutegravir need to be adjusted?15 In answer to the rst queson, the
study showed that giving 3HP with TLD is safe. Invesgators recorded only three
grade 3 AEs (one involving a parcipant who withdrew before starng 3HP). The
remaining 60 parcipants all completed a full course of 3HP; there were no deaths
in the study.16
Regarding the second queson: 3HP increased dolutegravir clearance by 37%,
which resulted in an average decrease in daily dolutegravir exposures of 26%
(measured as AUC).17 This drop in dolutegravir exposures was not enough to
warrant increasing the dose of dolutegravir. More specically, the mean trough
concentraons of dolutegravir in the presence of 3HP, while reduced, exceeded
the average concentraon corresponding to a 10 mg dose of dolutegravir in
the SPRING-1 study.18 Even a 10 mg daily dose of dolutegravir—40 mg lower
than the currently recommended dose—is associated with substanal anviral
eect.19 Therefore, the fact that dolutegravir trough concentraons in DOLPHIN
were above those achieved with 10 mg in earlier studies suggests there is no
need to raise dolutegravir doses in the presence of 3HP. All parcipants received
the standard once-a-day 50 mg dose of dolutegravir throughout the study and
maintained viral suppression while taking 3HP. (One parcipant had a detectable
HIV viral load during the follow-up phase of the study, but this occurred four
weeks aer compleng 3HP.)20
The DOLPHIN study provides reassurance that 3HP and TLD can be
coadministered with relave ease, but the story does not end here. Parcipants
entered the study already on ART and with viral suppression. The compability
of 3HP and dolutegravir in this populaon does not necessarily apply to people
SPRING-1 (NCT00951015)
was a phase IIb dose-ranging
study that compared 10 mg,
25 mg, and 50 mg daily doses
of dolutegravir.
The DOLPHIN study was
funded by Unitaid under the
IMPAACT4TB project and
conducted by invesgators at
Johns Hopkins University and
the Aurum Instute.
PK stands for
pharmacokinecs, which
involves studying what
the body does to a drug by
looking at things like how a
drug moves through the body
or how the drug concentraon
and distribuon change over
me.
AUC or area under the
curve is a PK measure of
how much drug reaches the
bloodstream in a given period
of me. Mostly simply, it can
be thought of as total drug
exposure.
The TLD regimen is composed
of the anretroviral drugs
dolutegravir, lamivudine, and
tenofovir disoproxil fumarate.

PIPELINE REPORT 2020
10
who may be starng ART for the rst me together with 3HP. For this so-called
ART-naïve populaon, DOLPHIN Too will assess the safety and PK of iniang
3HP and TLD simultaneously. DOLPHIN Too will enroll two addional groups of
parcipants: 25 people will receive TLD plus daily IPT, and a separate cohort of 50
will take TLD with 3HP.21 Invesgators will then compare safety, PK, and HIV viral
loads among people starng TLD for the rst me taking either IPT (the old TPT
standard of care) or 3HP (the newer standard of care) over 24 weeks. A separate
study, DOLPHIN Kids, will examine drug-drug interacons between 3HP and
dolutegravir in children.22
Aside from 3HP, there is a need to study whether other rifamycin-based TPT
regimens are safe to take with dolutegravir. Toward this end, ACTG study A5372
will evaluate potenal drug-drug interacons when giving dolutegravir with 1HP.23
The 1HP regimen may have dierent eects on dolutegravir than 3HP because
of its daily dosing and higher total quanty of rifapenne taken (because the 1HP
regimen is taken daily, it requires more rifapenne than 3HP).
P2001: Does the dose of 3HP need to be adjusted for pregnancy?
Other recent PK invesgaons have looked at the eects of pregnancy on 3HP.
Pregnant individuals were excluded from earlier 3HP trials.24 The resulng gap in
evidence has preempted the WHO from recommending 3HP during pregnancy,
though the regimen would be ideal in this context as its 3-month duraon means
women could complete it in full before delivery. To ll this evidenary gap, the
IMPAACT Network conducted P2001, a phase I/II study of the PK, tolerability,
and safety of 3HP in pregnant and postpartum women. The trial enrolled 50
women, 20 of whom were living with HIV. All parcipants had a risk factor for
TB, either because they shared a household with someone with TB or were
living with HIV and had a posive QFT test.25
In presenng P2001 results at the 2020 CROI Conference, primary invesgator
Jyo Mathad described the study’s purpose as “providing the data needed to
extend the use of the 3HP regimen to pregnant women.”26 To accomplish this,
P2001 sought to determine the eect of pregnancy on rifapenne PK and to
collect some inial safety data. It is important to note that the study was not
powered to demonstrate safety (more on this later). The primary objecve of
the study was to esmate the populaon PK of rifapenne and desacetyl-
rifapenne in pregnant women (second or third trimester) and postpartum
women. The analysis compared rifapenne clearance in parcipants to historical
controls. Invesgators hypothesized that rifapenne clearance in pregnant
and postpartum women would be within 25% of the clearance observed in
non-pregnant cohorts. The researchers also looked at whether results varied
by HIV status and stage of pregnancy.27
DOLPHIN Too is an extension
of the DOLPHIN study
protocol and listed under
the same ClinicalTrials.
gov idener number
(NCT03435146).
Desacetyl-rifapenne is
the acve metabolite of
rifapenne.
TAG is using the word
“women” to review P2001
and P1078 ndings and not
the gender-neutral “pregnant
individuals/persons” preferred
by our style guide because
this is the term the trialists
themselves used in designing,
conducng, and analyzing the
two studies.
A historical control involves
comparing newly collected
data to data from older
studies (as opposed to a study
enrolling a concurrent control
group). The data used as
historical controls in P2001
came from two studies of 3HP
conducted by the TB Trials
Consorum in non-pregnant
individuals: TBTC Study 26
(NCT00023452) and TBTC
Study 29B (NCT00694629).

PIPELINE REPORT 2020
11
P2001 enrolled parcipants into two cohorts of 25 people, 10 PLHIV in each.
Women in cohort 1 entered the study in their second trimester, and those in
cohort 2 entered during their third trimester. The study found that in both the
second and third trimesters, women living with HIV cleared rifapenne faster
than HIV-negave women.28 On average, women with HIV had 30% lower drug
exposure (measured as AUC). Despite this higher clearance, rifapenne exposures
remained within the drug’s therapeuc range. Among HIV-negave parcipants,
rifapenne clearance was 35% higher postpartum compared with during
pregnancy. Among HIV-posive women, there was no dierence in rifapenne
clearance during pregnancy versus postpartum. In both groups, clearance was
similar to that in non-pregnant historical controls. Consequently, invesgators
concluded that there is no need to change the dose of rifapenne for either
pregnant or postpartum women irrespecve of HIV status.29 Further analyses
of isoniazid exposures as well as PK data on the two drugs in breastmilk and
among infants born to women in the trial are forthcoming.
Although not powered for safety, the study did collect informaon on maternal
and infant outcomes. In terms of maternal safety, all 50 women completed 3HP in
full, no women developed TB disease, and there were no deaths or drug-related
SAEs. One woman in the study died from trauma (placental abrupon); her death
occurred 10 weeks aer compleng 3HP. In terms of infant safety, 22 infants
were born to women sll taking 3HP at the me of birth. No infants developed
TB or had an SAE related to 3HP. Rates of low birth weight and premature
birth in P2001 were similar to the frequency of these events among women
in the general populaon of the countries where the study took place.30
P2001 provides reassurance that pregnant and postpartum women can receive
the same dose of rifapenne as non-pregnant people when taking 3HP. As
TAG’s TB project co-director Lindsay McKenna commented, “These ndings
bring us closer to unlocking a new, potenally safer TPT opon for pregnant
women, a populaon especially vulnerable to TB.”31 Closer, yes—but not yet all
the way. McKenna connued: “A randomized clinical trial powered to determine
opmal ming and safety of 3HP and other rifapenne-containing TB prevenon
regimens during pregnancy is necessary and should be iniated with urgency.
Such a study should be a priority for the IMPAACT network to carry forward.”32
The PK data collected in P2001 are convincing; the safety data are encouraging,
but preliminary. Thoroughly characterizing the safety of 3HP in pregnant women
will require a larger study. It will also be important to study 3HP in pregnant
women taking dolutegravir-based ART, as all of the parcipants in P2001 were
on efavirenz-based regimens. At this point, it is unclear whether the higher
rifapenne clearance seen in women with HIV was due to HIV status or perhaps
an eect of efavirenz-based ART.33 The planned P2025 study by the IMPAACT
Network will invesgate many of these quesons in a four-arm trial of 3HP and
1HP in pregnant and postpartum women living with HIV who are taking either
efavirenz- or dolutegravir-based ART.34
P2001 took place in the
following countries: Hai,
Kenya, Malawi, Thailand,
and Zimbabwe.

PIPELINE REPORT 2020
12
P1078 secondary analyses: should pregnant women with HIV start IPT during
pregnancy or aer delivery?
The urgency behind McKenna’s call for a randomized clinical trial to determine
the safety and opmal ming of 3HP in pregnant and postpartum women
originates in the experience of an earlier IMPAACT study. P1078 was a phase IV
trial that evaluated the safety of immediate (during pregnancy) versus deferred
(postpartum) IPT in 956 HIV-posive women. Most TB in women occurs in
women of reproducve age. When TB and pregnancy coincide, there is a higher
risk of adverse maternal, pregnancy, and infant outcomes. Although vulnerable
to TB, pregnant women were excluded from earlier clinical trials of IPT.35 This
exclusion held across decades of research on IPT.36 Despite the resulng lack of
safety and ecacy data from clinical trials, the prevailing medical consensus and
longstanding WHO recommendaon were that pregnant women, parcularly
those with HIV or TB infecon, receive IPT. Generang high-quality evidence to
back up this recommendaon is especially important since physiological changes
during pregnancy and the early postpartum period alter how the body processes
many drugs.37 Medicines that work one way in non-pregnant people may have
dierent safety proles, may require dierent dosing strategies, or may be
contraindicated enrely in pregnant people.
P1078 sought to close this decades-long evidence-pracce gap. Invesgators
hypothesized that starng IPT during pregnancy would be noninferior to
deferring IPT to 12 weeks aer delivery. And it was; the trial’s primary outcome
was a composite safety measure of maternal adverse events. There were 72 of
these events in the group of women starng IPT during pregnancy (15.1%) and
73 in the deferred group (15.2%) for a risk dierence of 0.10 (95% CI: −4.77 to
4.98).38 This met the trial’s denion of noninferiority. Addionally, both groups
had low rates of TB. However, things got more complicated when it came to
secondary outcomes, parcularly a composite adverse pregnancy outcome.
Here, more women in the group starng IPT during pregnancy experienced
an event considered an adverse pregnancy outcome than in the deferred
group (23.6% versus 17.0%, a risk dierence of 6.7 [95% CI: 0.8–11.9]).39
When analyzed individually, the various adverse pregnancy outcomes did
not dier signicantly between the immediate and deferred IPT groups,
but when analyzed together, as the composite outcome, they did.
Some may interpret this nding to mean that pregnant women should wait
to start IPT unl aer they give birth—the opposite of long-established pracce.
For their part, the study invesgators reacted in the reasonable, understated prose
of academic medicine: “This was a new nding.... that highlights a safety concern
that warrants further examinaon.”
Composite measures combine
dierent endpoints of
interest into a single outcome
measure.
The composite adverse
pregnancy outcome in P1078
included the following events:
sll birth, spontaneous
aboron, low birth weight,
preterm delivery, and infant
congenital anomalies.

PIPELINE REPORT 2020
13
To further interrogate this nding, P1078 invesgators presented a secondary
analysis of the adverse pregnancy outcomes at the 2020 CROI Conference.40
The secondary analysis adjusted for factors (covariates) associated with the
dierent pregnancy outcomes. (These covariates included things like maternal
age, ARV regimen, CD4 count, QFT status, twin pregnancy, mid-upper arm
circumference, etc.) The adjusted analysis evaluated three composite outcomes
comprised of dierent combinaons of adverse pregnancy events. For all three
composite adverse pregnancy outcomes, the odds of experiencing an event were
higher in the group of women starng IPT during pregnancy compared to the
deferred group. In other words, starng IPT during pregnancy was independently
associated with a higher risk of adverse pregnancy outcomes aer adjusng for
known risk factors. The adjusted analysis also indicated that the odds of low birth
weight were 1.68 mes higher among women in the immediate versus deferred
IPT group (odds rao = 1.68 [95% CI: 1.10–2.59]).41
The P1078 study team presented an addional set of secondary analyses at
the AIDS2020 conference looking at the risk of hepatotoxicity.42 Sixty-three
women in the trial experienced a hepatotoxic event; most events occurred at least
one week postpartum. The eect of immediate versus deferred IPT on risk of
hepatotoxicity diered by ARV regimen. Women taking efavirenz-based ART were
more likely to experience hepatoxicity if they iniated IPT postpartum rather than
during pregnancy (the opposite was true for women taking nevirapine-based ART).
Starng cotrimoxazole therapy aer 12 weeks post-delivery was also associated
with a higher risk of liver toxicity. Most importantly, invesgators observed a
2.5-fold higher risk of hepatotoxicity among women with a CYP2B6 genotype
associated with slow efavirenz metabolism compared with women with a CYP2B6
genotype associated with moderate or fast efavirenz clearance (risk rao = 2.5,
95% CI: 1.42–4.56).43 The two major takeaways from this analysis are (1) the
importance of monitoring for hepatoxicity in the postpartum period and (2) the
need to consider ARV regimen, CYP2B6 genotype, and cotrimoxazole use when
deciding whether to use IPT in pregnant and postpartum women living with HIV.
Where does this leave pregnant women with HIV at risk of TB? The WHO
reviewed data from the P1078 primary analysis for its updated TPT guidance
released in March 2020. Ulmately, the WHO guideline development group did
not change the original recommendaon that pregnant women with HIV receive
IPT during pregnancy to prevent maternal and infant TB. Pregnancy does not
disqualify women with HIV from receiving IPT. In making this decision, the GDG
evaluated the P1078 ndings alongside the totality of other evidence (most of it
from observaonal studies that did not conrm the ndings of P1078). The group
Cotrimoxazole is an
anbioc that consists of
two drugs—trimethoprim and
sulfamethoxazole—and is taken
by PLHIV to prevent serious
bacterial infecons such as
pneumonia or toxoplasmosis.
Hepatotoxicity, or liver toxicity,
occurs when drugs or other
chemicals damage the liver.

PIPELINE REPORT 2020
14
considered that “a systemac deferral of IPT to the postpartum period in pregnant
women living with HIV would deprive them of signicant protecon when they
are highly vulnerable to TB.”44 Although the P1078 results did not change WHO
guidance, the primary and secondary analyses add important context to a choice
many women will have to make. Women and their healthcare providers may weigh
the risks and benets of deferring IPT dierently knowing that there may be
higher odds of adverse pregnancy outcomes when IPT is started during pregnancy.
One day, hopefully soon, pregnant women will have the opon to choose from a
wider array of TPT regimens with well-characterized safety and PK data.
The results of P1078 are complex and nuanced, but the trial’s larger implicaon is
clear: more research in pregnant women, earlier. The eld is playing catch-up with
regimens like 3HP and 1HP, which are already approved but have just recently
been studied in pregnant women.45 Future TPT regimens must be developed in
a way that generates safety and PK data in pregnant and postpartum women as
soon as feasible. Women at risk of TB cannot aord to repeat the experience of
IPT where 66 years separates the introducon of a regimen and its systemac
study in pregnant women. The consequences of this exclusion, which applies to
other research areas including HIV, is summarized by the opening statement of a
report from the PHASES project (Pregnancy + HIV/AIDS Seeking Equitable Study):
“Pregnant women are among those most in need of safe and eecve prevenves
and treatments for HIV and its co-infecons. Yet, because they are commonly
excluded from research, they are among the least likely to have robust, mely
evidence to inform decisions around the use of needed medicaons. The resulng
evidence gaps have put pregnant women and their children in harm’s way.”46
How sciensts include those most vulnerable to a parcular disease in a
research agenda says a lot about how commied a scienc eld is to health
equity. The safety, PK, and drug-drug interacon studies reviewed in this year’s
dispatch from the TB prevenve therapy pipeline are not the sideshow to larger
trials but the main event. If PLHIV, pregnant women, and other groups such as
children or people who use drugs are most at risk of TB, then they should also
be well represented in research to prevent TB. Too oen their inclusion comes
later—historically, much later. More recently, sciensts, funders, acvists, and
representaves from TB-aected communies have moved closer to realizing
the earlier and equitable inclusion of special populaons in TPT research. Future
installments of TAG’s Pipeline Report will reveal whether this progress
is momentary or lasng.
The PHASES project report
contains 12 recommendaons
for generang more research
in pregnant women on
HIV and its coinfecons
in ways that uphold the
ethical values of protecons,
access, and respect.

PIPELINE REPORT 2020
15
Table 3: Clinical Trials of Tuberculosis Prevenve Therapy for People Exposed to
Drug-Resistant TB
Study Name
(Registry number)
■ Sponsor and major
collaborators
■Phase
■Sample Size (N =)
Status Regimens
and Study
Design
Populaon Study
Locaon(s)
TB CHAMP
ISRCTN92634082
■ South African MRC,
Wellcome Trust, U.K.
MRC,
■Phase III
■ N = 1,556 child HHCs
from 778 households
Acve, not
enrolling
Safety and
ecacy of
6 months
of daily
levooxacin
vs. placebo
HIV-posive or
HIV-negave
children (aged 0–5
years) who are
HHCs of adults with
MDR-TB
South Africa
V-QUIN
ACTRN12616000215426
■ Australian NHMRC,
government of Vietnam
■Phase III
■ N = 2785 HHCs from
1326 households
Acve,
enrolling
Safety and
ecacy of
6 months
of daily
levooxacin
vs. placebo
Household contacts
of people with
MDR-TB;
rst phase
restricted to people
aged ≥15 years
(PLHIV eligible)
Vietnam
PHOENIx MDR-TB/
A5300B/I2003B
(NCT03568383)
■ ACTG, IMPAACT
■ Phase III
■ N = 3,452 HHCs from
1,726 households
Enrolling
6 months
(26 weeks)
of daily
delamanid
vs. 6H
High-risk adult,
adolescent, and
child household
contacts of adults
with MDR-TB
(PLHIV eligible)
Botswana,
Brazil,
Hai, India,
Kenya, Peru,
Philippines,
South Africa,
Tanzania,
Thailand,
Uganda,
Zimbabwe
ACTG: AIDS Clinical Trials Group
DFID: U.K. Department for Internaonal Development
HHC: household contact (of people with tuberculosis
disease)
IMPAACT: Internaonal Maternal Pediatric Adolescent
AIDS Clinical Trials Group
MDR-TB: muldrug-resistant tuberculosis
MRC: Medical Research Council
NHMRC: Naonal Health and Medical Research
Council (Australia)

PIPELINE REPORT 2020
16
The future of TPT is long-acng
Since the advent of IPT, prevenve therapy for TB has required swallowing pills—
a lot of pills. Even the 12-week 3HP regimen requires taking either 120 pills
(Sano formulaon) or 48 pills (Macleods formulaon). In the future, familiar TPT
regimens such as 3HP and 1HP may assume new forms as long-acng, injectable
nanoparcle suspensions. Instead of lling a prescripon for pill boles or blister
packs, people taking TPT would receive an injecon or two (or perhaps three)
into muscle or subcutaneous ssue. The injecon would deliver a drug depot
that would gradually release drug at a rate that provides a meaningful therapeuc
concentraon for weeks or even months.
Momentum for developing long-acng, injectable (LAI) formulaons of TPT
and TB treatments has been building slowly but steadily for several years.
The LEAP TB working group wrote a target product prole that lays out the
minimum expectaons and ideal standards for TB LAI technologies.47 LEAP
and associated invesgators also evaluated exisng TB drugs for their potenal
to be reposioned as LAIs. Not every drug is suitable for long-acng applicaons.
Compounds must have the right mix of qualies with respect to low water
solubility (water-soluble nanoparcles dissolve and release drug too quickly), high
potency (meaning the drug can sll work without a high plasma concentraon),
and a long half-life (which prevents the drug from clearing the body too rapidly).
TB drugs that possess the right combinaon of solubility, potency, and half-life
include rifapenne, delamanid, bedaquiline, and rifabun.48 The rst three unlock
the potenal to apply LAI technologies to TPT. Rifapenne is the backbone of
exisng short-course TPT regimens (3HP, 1HP), delamanid is being studied as
prophylaxis for people exposed to MDR-TB (in the PHOENix trial), and there
are murmurings of using bedaquiline as prevenve therapy (read on).
The momentum pushing forward this work accelerated in 2020 when Unitaid
announced a $32 million, 5-year award to a consorum led by the University of
Liverpool and known as LONGEVITY. The LONGEVITY project seeks to develop
and commercialize long-acng medicines for TB prevenon (isoniazid and
rifapenne), malaria treatment (atovaquone), and hepas C cure (glecaprevir
and pibrentasvir).49 The TB work will inially focus on creang an LAI version of
the powerful rifapenne and isoniazid combinaon. Reformulang rifapenne as
an LAI will be the easy part; isoniazid is trickier. Isoniazid is highly water soluble
(among the drugs in the TB LEAP assessment, isoniazid was more soluble than any
drug except pyrazinamide). The LONGEVITY team will therefore need to develop
a novel isoniazid prodrug before beginning phase I trials (scheduled for 2024).
Other important issues must be worked out during the development process—
for example, can rifapenne and isoniazid nanoparcle suspensions be delivered
together in a single vial, or will they require separate injecons? The eventual
clinical trials will invesgate safety, tolerability, and dosing schedules (the team
is aspiring toward one or two injecons of rifapenne-isoniazid, each designed
to work over a month).
The Long-Acng/Extended
Release Anretroviral
Resource Program (LEAP) is an
NIH-funded eort to support
the development of long-
acng ARVs for HIV.
A prodrug is a compound that
is converted by the body into
acve drug substance aer its
administraon
The LONGEVITY consorum
includes the University of
Liverpool, CHAI, Tandem
Nano Ltd, University of
Nebraska, Johns Hopkins
University, the Medicines
Patent Pool, and TAG.
A drug depot delivered by
injecon places a localized
mass of drug material in
muscle or ssue where it
is gradually released and
absorbed by the body over an
extended period of me.

PIPELINE REPORT 2020
17
Why long-acng, and why now? Unitaid framed its investment in the LONGEVITY
project primarily in public health terms by poinng out that when daily oral
medicines “are not taken consistently, treatments fail and illness spreads.
Poor adherence can also allow drug-resistant microbes to develop.”50 In Unitaid’s
vision, long-acng formulaons may also “free paents from daily pills, make it
easier for them to start and stay on treatment, and reduce the burden on health
systems.” For diseases that carry signicant sgma, such as TB, “long-acng
medicines can provide people with a more discreet treatment.”51 All of these
benets are potenal, and realizing these potenalies will depend on developing
long-acng TPT formulaons in close consort with communies to ensure that
the resulng products meet 3AQ standards.
The development of TPT LAIs is draing o the success of similar techniques
applied to other diseases. Long-acng/extended-release technologies are
commonly used for contracepon (e.g., Depo-Provera) and management of
schizophrenia (many an-psychoc drugs are available in LAI forms). More
recently, and closer to home for TB, the HIV eld is preparing for the rst
U.S. Food and Drug Administraon approval of a once-a-month, LAI ARV
combinaon (cabotegravir and rilpivirine). In addion, a large clinical trial
among 4,570 cisgender men and transgender women who have sex with men
showed that long-acng cabotegravir (CAB LA) was noninferior to TDF/FTC
(Truvada™) as pre-exposure prophylaxis (PrEP) for HIV.52
The TB eld should carefully watch the recepon of long-acng cabotegravir
as ART and PrEP. Just as people experience pill fague from having to take daily
medicaon, they may also re of repeat, large injecons. In two clinical trials
of long-acng cabotegravir and rilpivirine (ATLAS and FLAIR), 81% and 86%
of parcipants reported injecon-site reacons.53 In the CAB LA study, 80% of
parcipants receiving CAB LA experienced injecon-site pain or tenderness.54
Sll, overall acceptability of both approaches was high. In an editorial introducing
the ATLAS and FLAIR results in the New England Journal of Medicine, Judith
Currier wrote, “For many, freedom from the need for daily oral therapy is a major
advance, even at the cost of having to receive monthly injecons.”55 Whether this
holds over me remains to be seen. Researchers will also need to demonstrate
acceptability in key populaons such as people who inject drugs. Since TPT is
not taken for life, trading longer oral regimens for shorter injectable regimens
may present an even easier choice. But preserving choice is key: not everyone
likes geng a shot, and prevenon works best when people who receive it—
people who are by denion not sick and who by choosing therapy are acng
to avert a future potenal risk to themselves and others—have a range of
opons from which to choose.
Developing LAIs guided by paent preferences and values is an especially
important undertaking in TB, where civil society and community groups only
recently won a years-long struggle to drop injectable drug agents from drug-
resistant TB therapy. New LAIs for prevenon and the decades-old injectable
agents for drug-resistant TB are not the same, but negave associaons may
carry over from past experience.
3AQ is a human rights
standard established by
the right to health and the
right to science. It requires
that any health goods
and scienc benets
be available, accessible
(aordable), acceptable to
users, and of quality.
TAG’s 2020 Pipeline Report
chapters on Anretroviral
Treatment and PrEP and
Microbicides review the latest
research advancements
related to long-acng
cabotegravir/rilpivirine
and CAB LA.
The LONGEVITY project
is opening with a series
of surveys to understand
community and paent
preferences for long-acng
TB prevenve technologies.

PIPELINE REPORT 2020
18
Looking even further ahead, beyond rifapenne-based TPT, the LONGEVITY
project may work with bedaquiline and delamanid if either drug is recommended
by the WHO as TB prophylaxis within the 2020–2024 project period (possible
for delamanid, less likely for bedaquiline). Janssen has already developed a
bedaquiline LAI and has funded its early evaluaon in a mouse model of TB.56
The injectable bedaquiline performed well in a paucibacillary mouse model of
latent tuberculosis infecon that compared giving one, two, or three monthly
injecons of bedaquiline to the equivalent oral doses. Most notably, a single
bedaquiline LAI injecon had detectable anbioc acvity out to 12 weeks.57
Addional research and development is required before studying bedaquiline
LAI in humans, but the inial mouse data are promising. In an interview with
TAG conducted in April 2020, Gavin Churchyard, CEO of the Aurum Instute,
raised an intriguing idea: “Could we couple the rifapenne injectable with the
bedaquiline long-acng formulaon, which has been evaluated in mice and shown
to have durable protecon up to three months?”58 Coupling LAI rifapenne and
bedaquiline would bring together two drugs that are always used apart due to
drug-drug interacons that would need to be overcome.59 A lot of work lies ahead,
but Churchyard expressed the opmism evident throughout the enre TPT eld:
“The innovaon is not done. We can look forward to many new
excing developments.”
Paucibacillary refers to
having a low bacterial count
or burden, in this case to
simulate the condions
of TB infecon (as opposed
to the higher bacterial counts
of TB disease).
Endnotes
1. World Health Organizaon. Q&A: venlaon and air condioning in public spaces and buildings and COVID-19
[Internet]. 2020 July 29. hps://www.who.int/news-room/q-a-detail/q-a-venlaon-and-air-condioning-in-
public-spaces-and-buildings-and-covid-19.
2.
Margalith P, Berea G. Rifamycin XI taxonomic study on streptomyces mediterranei nov. sp. Mycopathologia et
mycologia applicata. 1960;13(4):321–30. doi: 10.1007/BF02089930.
3. For a detailed review of the natural provenance of QS-21and its applicaon to TB vaccine development, see: Frick
M. The TB vaccine pipeline. M72/AS01E: between nature and licensure. New York: Treatment Acon Group; 2019.
hps://www.treatmentacongroup.org/resources/pipeline-report/2019-pipeline-report/.
4. Merwin W.S. “Aer the spring.” In: Travels. New York: Knopf; 1993.
5. Swindells S, Ramchandani R, Gupta A, et al. One month of rifapenne plus isoniazid to prevent HIV-related
tuberculosis. N Engl J Med. 2019;380(11):1001–11. doi: 10.1056/NEJMoa1806808.
6. Gupta A, Montepiedra G, Aaron L, et al. Isoniazid prevenve therapy in HIV-infected pregnant and postpartum
women. N Engl J Med. 2019;381(14):1333–46. doi. 10.1056/NEJMoa1813060.
7. Menzies D, Adjobimey M, Ruslami R, et al. N Engl J Med. 2018;379(5):440–53. doi: 10.1056/NEJMoa1714283.
8. World Health Organizaon. WHO consolidated guidelines on tuberculosis: module 1: prevenon: tuberculosis
prevenve treatment. Geneva: World Health Organizaon; March 2020. hps://www.who.int/publicaons/i/item/
who-consolidated-guidelines-on-tuberculosis-module-1-prevenon-tuberculosis-prevenve-treatment.
9. Churchyard G, Cardenas V, Chihota V, et al. Eecveness of 3HP annually vs once for HIV-posive people: the
WHIP3TB trial (Abstract 143). Presented at: Conference on Retroviruses and Opportunisc Infecons; 2020 March
8–11; Boston, MA. hps://www.croiconference.org.
10. Ibid.
11. Ibid.
12. Aurum Instute (Press Release). Shorter regimen for prevenng TB found to have lasng protecve eect in
people living with HIV. 2020 April 28. hps://www.auruminstute.org/component/content/arcle/46-press-
releases/internaonal-news/115-shorter-regimen-for-prevenng-tb-found-to-have-lasng-protecve-eect-in-
people-living-with-hiv.

PIPELINE REPORT 2020
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13. i360. Tenofovir, lamivudine, and dolutegravir (TLD) transion. Durham, NC: i360; 2019. hps://www.i360.
org/sites/default/les/media/documents/linkages-tld-transion-informaon.pdf.
14. See, for example, the eects of rifampicin on dolutegravir concentraons: Dooley K, Sayre P, Borland J, et al.
Safety, tolerability, and pharmacokinecs of the HIV integrase inhibitor dolutegravir given twice daily with
rifampin or once daily with rifabun: results of a phase 1 study among healthy subjects. J Acquir Immune Dec
Syndr. 2013;62(1):21–7. doi: 10.1097/QAI/0b013e318276cda9.
15. Frick M. An acvist’s guide to rifapenne.
16. Dooley K, Savic R, Gupte A, et al. Once-weekly rifapenne and isoniazid for tuberculosis prevenon in paents
with HIV taking dolutegravir-based anretroviral therapy: a phase 1/2 trial. Lancet HIV. 2020;7(6):e401–9. doi:
10.1016/S2352-3018(20)30032-1.
17. Ibid.
18. Hans-Jürgen S, Reynes J, Lazzarin A, et al. Dolutegravir in anretroviral-naïve adults with HIV-1: 96-week results
from a randomized dose-ranging study. AIDS. 2013;27(11):1771–8. doi: 10.1097/QAD.0b013e3283612419.
19. In an early monotherapy trial of dolutegravir, the 10 mg dose had “anviral responses [that] were similar to or
higher than those seen in short-term studies of other anretrovirals…” See: Min S, Sloan L, DeJesus E, et al.
Anviral acvity, safety, and pharmacokinecs/pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-
1-infected adults. AIDS. 2011;25(14):1737–45. doi: 10.1097/QAD.0b013e32834a1dd9.
20. Dooley K, et al. Once-weekly rifapenne and isoniazid.
21. ClinicalTrials.gov [Internet]. Bethesda (MD): Naonal Library of Medicine (U.S.) 2000. Idener NCT03435146,
Safety, tolerability, DDI short course treatment of LTBI infecon with high-dose rifapenne and isoniazid or
standard isoniazid prevenve therapy in HIV+ paents (DOLPHIN & DOLPHIN TOO) (IMPAACT4TB). Cited: 2020
September 22. hps://clinicaltrials.gov/.
22. Salazar-Ausn N. Pediatric TPT research gaps. Presentaon to: WHO HIVTB Implementaon for Impact Working
Group; 2020 May 20; virtual meeng.
23. ClinicalTrials.gov [Internet]. Bethesda (MD): Naonal Library of Medicine (U.S.) 2000. Idener NCT04272242,
Drug-drug interacons between rifapenne and dolutegravir in HIV/LTBI co-infected individuals. Cited: 2020
September 22. hps://clinicaltrials.gov/.
24. Gupta A, Hughes M, Garcia-Prats A, McInre K, Hesseling A. Inclusion of key populaons in clinical trials of new
antuberculosis treatments: current barriers and recommendaons for pregnant and lactang women, children,
and HIV-infected persons. PLoS Med. 2019;16(8):e1002882. doi: 10.1371/journal.pmed.1002882.
25. Mathad J, Savic R, Brio P, et al. Rifapenne pharmacokinecs and safety in pregnant women with and without
HIV on 3HP (Abstract 144). Presented at: Conference on Retroviruses and Opportunisc Infecons; 2020 March
8–11; Boston, MA. hps://www.croiconference.org.
26. Ibid.
27. Ibid.
28. Ibid.
29. Ibid.
30. Ibid.
31. Lindsay McKenna quoted in: Treatment Acon Group. CROI 2020 TB round up [Internet]. 2020 March 16.
hps://www.treatmentacongroup.org/statement/croi-2020-tb-round-up/.
32. Ibid.
33. Mathad J. Rifapenne pharmacokinecs and safety.
34. McKenna, Lindsay (Treatment Acon Group and IMPAACT TB Scienc Commiee, New York, NY). Personal
communicaon with: Mike Frick (Treatment Acon Group, New York, USA). 2020 September 15.
35. Gupta A, Mathad J, Abdel-Rahman S, et al. Toward earlier inclusion of pregnant and postpartum women in
tuberculosis drug trials: consensus statement from an internaonal expert panel. Clin Infect Dis. 2016:62(6):761–
9. doi: 10.1093/cid/civ991.
36. McKenna L, Frick M, Lee C, et al. A community perspecve on the inclusion of pregnant women in tuberculosis
drug trials. Clin Infect Dis. 2017;65(8):1383–8. doi: 10.1093/cid/cix533.
37. Gupta A, et al. Toward earlier inclusion of pregnant and postpartum women.
38. Gupta A, et al. Isoniazid prevenve therapy.

PIPELINE REPORT 2020
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39. Ibid.
40. Theron G, Chakhtoura N, Montepeidra G, et al. Adjusted analysis of the eect of isoniazid prevenve therapy on
adverse pregnancy outcomes in women with HIV (Abstract 727). Presented at: Conference on Retroviruses and
Opportunisc Infecons; 2020 March 8–11; Boston, MA. hps://www.croiconference.org.
41. Ibid.
42. Gupta A. Risk factors for hepatoxicity in HIV-infected women receiving isoniazid prevenve therapy in pregnancy
and postpartum (Abstract OAB05). Presented at: AIDS2020; 2020 July 6–10; San Francisco, CA.
hps://caendee.abstractsonline.com/meeng/9289/presentaon/74.
43. Ibid.
44. World Health Organizaon. WHO consolidated guidelines on tuberculosis.
45. Gupta A. Inclusion of key populaons in trials of antuberculosis treatments.
46. PHASES Working Group. Ending the evidence gap for pregnant women around HIV & coinfecons: a call to
acon. Chapel Hill, NC: July 2020. hp://www.hivpregnancyethics.org/.
47. Swindells S, Siccardi M, Barre S, et al. Long-acng formulaons for the treatment of latent tuberculosis infecon:
opportunies and challenges. Int J Tuberc Lung Dis. 2018;22(2):125–32.
48. Ibid.
49. Unitaid. Repurposing key medicines as long-acng formulaons could revoluonize prevenon and treatment
[Internet]. N.D. hps://unitaid.org/project/long-acng-medicines-for-malaria-tuberculosis-and-hepas-c/#en.
50. Unitaid. Unitaid invests in long-acng medicines to simplify treatment and prevenon for HIV, TB, malaria and
HCV [Internet]. 2020 January 30. hps://unitaid.org/news-blog/unitaid-invests-in-long-acng-medicines-to-
simplify-treatment-and-prevenon-for-hiv-tb-malaria-and-hcv/#en.
51. Ibid.
52. Jeerys R. The anretroviral therapy pipeline 2020. New York: Treatment Acon Group; 2020.
hps://www.treatmentacongroup.org/resources/pipeline-report/2020-pipeline-report/.
53. Ibid.
54. Jeerys R. PrEP and microbicides pipeline 2020. New York: Treatment Acon Group; 2020.
hps://www.treatmentacongroup.org/resources/pipeline-report/2020-pipeline-report/
55. Currier J. Monthly injectable anretroviral therapy—version 1.0 of a new treatment approach. N Engl J Med.
2020;382(12):1164–5. doi: 10.1056/NEJMe2002199.
56. Kaushik A, Ammerman N, Tyagi S, et al. Acvity of a long-acng injectable bedaquiline formulaon in a
paucibacillary mouse model of latent tuberculosis infecon. Anmicrob Agents Chemother. 2019;63(4):e00007-
19. doi: 10.1128/AAC.00007-19.
57. Ibid.
58. Churchyard, Gavin (Aurum Instute, Johannesburg, South Africa). Interview with: Mike Frick (Treatment Acon
Group, New York, NY). 2020 May 6.
59. Svensson E, Murray S, Karlsson M, Dooley K. Rifampin and rifapenne signicantly reduce concentraons of
bedaquiline, a new an-TB drug. J Anmicrob Chemother. 2015;70(4):1106–14. doi. 10.1093/jac/dku504.