T h e NEW ENGL A ND JOUR NA L o f MEDICINE

ORIGINAL ARTICLE

Primary Isoniazid Prophylaxis against

Tuberculosis in HIV-Exposed Children
Shabir A. Madhi, M.D., Ph.D., Sharon Nachman, M.D., Avy Violari, M.D.,
Soyeon Kim, Sc.D., Mark F. Cotton, M.D., Ph.D., Raziya Bobat, M.D.,

Patrick Jean-Philippe, M.D., George McSherry, M.D, and Charles Mitchell,

M.D., for the P1041 Study Team

ABSTR ACT
RESULTS
BACKGROUND

Antiretroviral

therapy

was

The dual epidemic of humaninitiated in 98.9% of HIVimmunodeficiency

virusinfected children during the
(HIV) and tuberculosis is a study. Among HIV-infected
major cause of sickness andchildren,
protocol-defined
death in sub-Saharan Africa.tuberculosis or death occurred in
We conducted a double-blind,52 children (19.0%) in the
randomized,
placebo-isoniazid group and 53 (19.3%)
controlled
trial
ofin the placebo group (P=0.93).
preexposure
isoniazidAmong HIV-uninfected children,
prophylaxis
againstthere
was
no
significant
tuberculosis in HIV-infecteddifference in the combined
children
and
uninfectedincidence
of
tuberculosis
children exposed to HIVinfection, tuberculosis disease, or
during the perinatal period. death between the iso-niazid
group (39 children, 10%) and the
placebo group (45 children, 11%;
We randomly assigned 548P=0.44). The rate of tuberculosis
HIV-infected and 804 HIV-was 121 cases per 1000 childuninfected infants (91 to 120years (95% confidence interval
days of age) to isoniazid (10 [CI], 95 to 153) among HIVto 20 mg per kilogram ofinfected children as compared
body weight per day) orwith 41 per 1000 child-years
matching placebo for 96(95% CI, 31 to 52) among HIVweeks. All patients receiveduninfected children. There were
bacille
CalmetteGurinno significant differ-ences in
(BCG) vaccination againstclinical or severe laboratory toxic
tuberculosis within 30 dayseffects between treatment groups.
METHODS

after birth. HIV-infected

children had access toCONCLUSIONS
antiretroviral therapy. ThePrimary isoniazid prophylaxis
primary outcome measuresdid not improve tuberculosiswere tuberculosis disease anddiseasefree survival among
children
or
death
in
HIV-infectedHIV-infected
tuberculosis-infectionfree
children
and
latent
tuberculosis infection, tuber-survival among HIV-uninculosis disease, and death infected children immunized with
HIV-uninfected
childrenBCG vaccine. Despite access to
thera-py, the
within 96 to 108 weeks after antiretroviral
burden of tuberculosis remained
randomization.

high among
HIVinfected
children.
(Funded by
the
National
Institutes of
Health and
Secure the
Future;
ClinicalTria
ls.gov
number,
NCT00080
119.)

Pediatrics, State University of New York at

Stony Brook, Stony Brook (S.N.); the Center
for Biostatistics in AIDS Research,
From the Department of Science and
Department of Biostatistics, Harvard School
Technology/National Research Foundaof Public Health, Boston (S.K.); Henry
tion: Vaccine Preventable Diseases and
Jackson Foundation, Division of AIDS,
the Medical Research Council: RespiratoBethesda, MD (P.J.-P.); Pennsylva-nia State
ry and Meningeal Pathogens Research
University College of Medicine, Hershey
Unit (S.A.M.), and the Perinatal HIV Re(G.M.); and the University of Mi-ami, Miami
search Unit (A.V.), University of the Wit(C.M.). Address reprint re-quests to Dr.
watersrand, Johannesburg; Stellenbosch
Madhi at the Respiratory and Meningeal
University, Cape Town (M.F.C.); and the
Pathogens Research Unit, P.O. Box 90753,
University of KwaZulu Natal, Durban
Bertsham, Gauteng 2013, South Africa, or at
(R.B.)
madhis@rmpru.co.za.
all in South Africa; the Department of

Drs.
Madhi,
McSherry,
and Mitchell
con-tributed
equally to this
article.
N Engl J Med
2011;365:2131.
Copyright 2011
Massachusetts
Medical Society.

N ENGL J MED 365;1 NEJM.ORG JULY 7, 2011

21

T h e NEW ENGL A ND JOUR NA L o f MEDICINE

otherwise
immunocompet
children,
UBERCULO ent
MTB
infection
SIS
IS
HIGHLY in the first 2
ENDEMI years of life is
associ-ated
C
INwith a 43% risk
subof
the
Saharan
Africa, adevelopment of
situation tuber-culosis
aggravatedduring the next

by
the
6
ongoing 12
months.
epidemic
of humanAlso, the risk of
cultureimmu-

nodeficiency
virus type

confirmed
1tuberculosis is
1
(HIV-1).
Theincreased by a
factor of more
increased
burden
ofthan 20 among
HIV-infected
tuberculosis
chil-dren under
among adults in
2 years
of
areas with a
7,8
high prevalenceage.
of HIV infectionFurthermore,
is also associ-post-mortem
have
ated with highstudies
identified
rates
of
transmission oftuberculosis as
a leading cause
Mycobacteof death in
rium
HIV-infected
tuberculosis
in
(MTB)
tochildren
Africa,
household
members
andaccounting for
2-12 to 18% of
other contacts. deaths in these
5
Therefore, itchildren.9,10
has
beenIsoniazid has
proposed that inshown
areas such aseffectiveness in
South
Africa,preventing
tuberculosisprogression to
prevention
tuberculosis
strategies withdisease
in
isoniazid
children who
chemoprophy- had
known
laxis, which socontact
with
far
havepersons
with
targeted
onlyinfectious
11household
tuberculosis,
contacts
of13
adults
with but its role in
positive sputumpreexposure
smears for MTBprophylaxis has
been
acid-fast bacilli,not
in
be expanded toevaluated
HIV-infected
include
other
infants
or
high-risk
uninfected
groups.
children
exAmong

posed to HIV
during
the
perinatal period
both groups
at
increased
risk
for
tuberculosis.
Our study
evaluated the
safety
and
efficacy
of
isoniazid versus
placebo
for
preexposure
prophy-laxis
against
tuberculosis in
HIV-infected
children
and
uninfected
children
exposed to HIV
during
the
perinatal
period, when
treatment was
started at 3 to 4
months of age
and continued
for 96 weeks.

M
ET
H
O
DS
STUDY SITES

This
multicenter,
phase
23,
randomized,
double-blind,
placebocontrolled trial
of
isoniazid
was
undertaken
in
three
South
African centers
(Chris
Hani
Baragwanath
Hospital,
Johannesburg;
Tygerberg
Hospital,
University of

Stellenbosch, sites
had
Cape Town; andexisting
King
Edwardprograms for
VII
Hospital,the prevention
Durban)
andof mother-toone center inchild
Botswana
transmission
(Princess
of
HIV.
Marina
Children
inHospital,
fected
with
Gaborone).
HIV
were
Enrollment atgiven
the
Botswanaantiretroviral
site
be-gantreatment,
shortly beforewhich
the study wasprimarily
terminated. All included

stavudine,
lamivudine,
and lopinavir
ritonavir, per
countryspecific guidelines,
or
zidovudine,
lamivudine,
and lopinavir
ritonavir.

means of HIV-1
DNA
polymerasechain-reaction
(PCR) testing.
HIV-uninfected
in-fants
had
their
negative
status confirmed
by a second
negative DNA
PCR assay 24
weeks
after
randomization
and a negative
HIV
enzymelinked
immunosorbent
assay (ELISA)
at 18 months of
age. Participants
were
enrolled
between the 91st
and 120th days
of
life.
Eligibility
criteria included
re-ceipt of the
BCG vaccine by
30 days of age;
no his-tory of
tuberculosis in
the
infant,
known exposure
to
a
microbiologicall
y
confirmed
case of tuberculosis, or active
antituberculosis
treatment in the
mother at the
time
of the
infants
birth;
and no evidence
of failure to
thrive, recurrent
pneumonia,
chronic diarrhea,
or
immunosuppress
ive condi-tions
other than HIV
infection.

STUDY
ENROLLMEN
T AND
PARTICIPANT
S
Enrollment
occurred
between
December 2004
and June 2008.
Enrollment of
the
HIVuninfected
cohort
was
completed
in
June
2006.
Infants born to
HIV-infected
women
were
identified
through
programs for the
prevention
of
mother-to-child
transmission of
HIV. The HIVInfants
infection status
were randomly
of infants was
assigned
to
determined by

receive

daily

isoniazid, at aThe coprimary

dose of 10 toobjectives were
20 mg perto compare the
kilogram
ofisoniazid and
body weight, orplacebo groups
placebo. Otherwith respect to
aspects of theirtu-berculosiscare, includingdiseasefree
trimethoprim survival
sulfamethoxazo(hereafter
le prophylaxis,referred to as
are detailed indisease-free
survival)
the
HIVSupplementary among
infected
Appendix,
and
available withchildren
the full text oftuberculosisthis ar-ticle atinfectionfree
survival
NEJM.org.

uninfected
children
96
weeks after randomization.
The end point
for disease-free
survival
was
the
first
occurrence of
death from any
cause
or
tuberculosis
disease, and the
end point for
infec-tion-free
survival
was
the
first
occurrence of
death from any
(hereafter
cause,
referred to as tuberculosis
STUDY
OBJECTIVES infection-free
disease,
or
AND END
survival)
MTB inPOINTS
among
HIV22
N ENGL J

MED 365;1 NEJM.ORG

JULY 7, 2011

ISONIAZID PROPHYLAXIS IN HIV-EXPOSED CHILDREN

Table 1. Algorithm Used to Screen for and Diagnose Clinical Tuberculosis.*

Feature

Score
0

Weeks of illness (including cough)

Nutritional status (% weight for age)
Family history of tuberculosis
Tuberculin skin test

<2

24

>80%

6080%

None

Reported by family

No

Confirmed or suspected EPTB

No

* The algorithm is from the tuberculosis guidelines for South Africa.

>4
<60% or a drop of
2 percentiles
Sputum-confirmed

Negative

Fever not responding to treatment

for >2 wk

Reactive (5 or
10 mm)
Yes
Yes
14

Study participants with a score of 4 or more (excluding the tuberculin skin test) during screenings at
their routine visits every 3 months were screened further by means of a tuberculin skin test and a chest
radiograph.
15
1
Evaluation for malnutrition was performed according to World Health Organization guidelines on the
basis of z scores and clinical and laboratory evaluations.
1
A reactive skin test was defined as an induration of at least 5 mm in horizontal diameter in HIVinfected children and an induration of at least 10 mm in HIV-uninfected children.

Extrapulmonary tuberculosis (EPTB) included extrathoracic lymphadenopathy, joint or bone involvement,

abdominal mass, meningitis, and tuberculosis of the spine, diagnosed according to criteria that were prespecified in the
protocol.

fection. Secondary study objectives for the cohort of

HIV-infected children were to determine wheth-er
isoniazid prophylaxis decreased the incidence of
tuberculosis infection at 96 weeks and whether it
reduced the risk of HIV disease progression, defined as the first occurrence of worsening of the
Centers for Disease Control and Prevention (CDC)
clinical categorization of HIV infection or death. A
secondary objective for the cohort of HIV-uninfected children was to determine whether isonia-zid
prophylaxis improved disease-free survival.
TUBERCULOSIS INVESTIGATION AND
OUTCOME CATEGORIZATION

Participants were screened for symptoms of tuberculosis at each study visit and assessed further if
they had a score of 4 or more on the clinical algo14
rithm scale (Table 1), excluding scoring on the
tuberculin skin test. Children were also assessed
for pulmonary tuberculosis when presenting with
clinical or radiographic evidence of pneumonia or
at the discretion of the attending physician. For
children with MTB exposure, the study drug was
discontinued and open-label isoniazid was administered according to the guidelines in South
14
Africa.
Investigations for tuberculosis included collection of information on the status of sputum
smears in the index case, a history taking for

symptoms and signs

suggestive of MTB
infec-tion,
an
intradermal
tuberculin
skin test with the use of
RT23 2TU (Statens
Serum Institut), a chest
radiograph,
and
microbiologic
or
histopathologi-cal
evaluation as clinically
indicated. In children
suspected of having
pulmonary tuberculosis,
two gastric washings,
two
induced-sputum
samples, or both were
tested by means of
auramine staining and a
mycobacterial
culture
was tested with the use
of the Bactec method at
nationally
accredited
laboratories.
Mycobacterial isolates
were analyzed for drug
resistance with the use of
the
BACTEC
460
system
(Becton
Dickinson).
On the basis of

positive results of these evalu-ations, childrenbasis of a positive

received a diagnosis of definite, probable, or tuberculin
skin
test
possible tuberculosis (Table 2). Children whose (induration 5 mm in
health care providers initiated an-tituberculosishorizontal diam-eter in
treatment but who did not fulfill protocol-defined HIV-infected
children
criteria for a diagnosis of tuber-culosis were and 10 mm in HIVclassified as having non-algorithm tuberculosis.uninfected children), in
Latent tuberculosis infection was diagnosed on the the absence of evidence
N ENGL J MED 365;1

of active tuberculosis
disease, 96 weeks after
ran-domization. An endpoint review committee
of study-team clinicians
who were unaware of the
study-group assignments
reviewed all deaths and

NEJM.ORG JULY 7, 2011

23

T h e NEW ENGL A ND JOUR NA L o f MEDICINE

Table 2. Protocol-Defined Criteria for Categorization of Tuberculosis Disease and Infection.

Tuberculosis Category

Microbiologic, Radiographic, Histologic, and Clinical Criteria

Definite tuberculosis

Mycobacterium tuberculosis cultured from any site, or positive auramine staining of a cerebrospinal fluid specimen

Probable tuberculosis

The presence of at least two clinical criteria in the algorithm shown in Table 1, plus either
positive auramine staining of an induced-sputum or gastric-washing smear or suggestive
histologic findings (caseating granuloma); or positive auramine staining of a gastricwashing or induced-sputum smear and a chest radiograph suggestive of tuberculosis*

Possible tuberculosis

An algorithm score 6 and a radiograph suggestive of tuberculosis, or a positive tuber

culin skin test (induration 5 mm in horizontal diameter) and a chest radiograph
suggestive of tuberculosis

Latent M. tuberculosis
infection

A positive tuberculin skin test at week 96 after randomization in the absence of active
tuberculosis (definite, probable, or possible)

1*

Radiographic findings that were considered to be suggestive of pulmonary tuberculosis included hilar
lymphadenopathy, alveolar consolidation, a miliary pattern of lesions, and cavitations in the lung parenchyma.

safety monitoring board

is provided in the Suppotentially tuberculosis-related primary and secplementary Appendix.
ondary end points.
KaplanMeier
Screening for safety was undertaken at schedestimates were used to
uled visits every 3 months while the participants
summa-rize
the
were receiving the study drug. Screening included
distribution of time to
serum liver enzyme tests, complete blood counts,
efficacy and safety end
and clinical neurologic evaluations for peripheral
points. Data on end
neuropathy with the use of a modified Denver
points were censored at
Developmental Screening Test, with severity
week
96,
with
grad-ing based on criteria from the Division of
allowance
for
the
Ac quired Immunodeficiency Syndrome at the
inclusion of end points
Na-tional Institute of Allergy and Infectious
for 12 additional weeks
16
Diseases (NIAID).
(up to 108 weeks after
randomization). LogSTUDY OVERSIGHT
rank tests were used to
The study was approved by the institutional re-view
compare
these
board of each participating center, the Med-icines
distributions between
Control Council in South Africa, and the Division of
the study groups. Cox
AIDS at the NIAID. The study was con-ducted in
regression was used for
accordance with Good Clinical Prac-tices guidelines
hazard
ratios
and
and the Declaration of Helsinki. Written informed
analyses adjusted for
consent was obtained from the legal guardians of the
covariates.
children before they un-derwent randomization. All
Analyses followed
authors vouch for the accuracy and completeness of
an intention-to-treat apthe analyses pre-sented and the adherence of the
proach unless otherwise
study and this report to the protocol, available at
specified. Data on chilNEJM.org.
dren whose guardians
declined further study
STATISTICAL ANALYSIS
follow-up
before
The study was designed and powered to evaluate
meeting a study end
study outcomes independently in the HIV-infected
point were censored at
and HIV-uninfected cohorts. A detailed descrip-tion
the date of the last
of the sample-size calculation (with a target sample
follow-up visit. All
of 500 HIV-infected and 800 HIV-unin-fected
testing was two-sided at
children) and of oversight by the data and
the 5% significance
level. To maintain the

significance level for

each cohort at 5%,
nominal P values of
0.0492 and 0.0493 for
between-group
differences in the HIVinfected and HIVuninfected
cohorts,
respectively,
were
required in the final
analysis of the primary
end points. All P values
presented
were
nominal. Data were
analyzed with the use
of
SAS
software,
version
9.1
(SAS
Institute).

RES
ULT
S
CHARACTERISTICS
OF THE
PARTICIPANTS

A total of 548 HIVinfected and 806 HIVunin-fected infants were

enrolled; the majority
(65%) were enrolled in
Johannesburg. Figure 1A
shows the disposition of
the 274 HIV-infected
infants enrolled in each
study group; the study
drug was initiated within
4
days
after
randomization, except

24

N ENGL J

MED 365;1
NEJM.ORG JULY 7,

2011

ISONIAZID PROPHYLAXIS IN HIV-EXPOSED CHILDREN

A HIV-Infected

B HIV-Uninfected
548 Children underwent randomization
359 Were from Johannesburg
132 Were from Cape Town
53 Were from Durban
4 Were from Botswana

806 Children underwent randomization

519 Were from Johannesburg
280 Were from Cape Town
7 Were from Durban

274 Were assigned to receive

INH
273 Received INH
1 Never received INH,
failed to return

274 Were assigned to receive

placebo
274 Received placebo

403 Were assigned to receive

INH
403 Received INH

403 Were assigned to receive

placebo
401 Received placebo
2 Did not receive placebo
1 Mother was HIVuninfected
1 Had randomization
error

75 Completed intervention
34 Were lost to follow-up
7Were unable to get to
the clinic
4Withdrew consent
5Were unwilling to adhere
to study requirements
18Could not be contacted
34 Discontinued intervention
11Had exposure to TB case
1Had laboratory toxicity
12Did not meet protocol
definition of clinical TB
1Had peripheral neuropathy
9Did not adhere to regimen
130 Did not complete intervention because of study
closure

81 Completed intervention
21 Were lost to follow-up
1Was unable to get to
the clinic
6Withdrew consent
1Was unwilling to adhere
to study requirements
13Could not be contacted
31 Discontinued intervention
11Had exposure to TB case
11Did not meet protocol
definition of clinical TB
2Disallowed concomitant
medication
1Discontinued following
hospitalization
6Did not adhere to regimen
141 Did not complete intervention because of study
closure

246 Completed intervention

56 Were lost to follow-up
24 Were unable to get to
the clinic
13 Withdrew consent
3 Were unwilling to adhere
to study requirements
16 Could not be contacted
101 Discontinued intervention
34 Had exposure to TB case
9 Did not meet protocol
definition of clinical TB
1 Had peripheral neuropathy
57 Did not adhere to regimen

261 Completed intervention

60 Were lost to follow-up
23 Were unable to get to
the clinic
16 Withdrew consent
2 Were unwilling to adhere
to study requirements
19 Could not be contacted
80 Discontinued intervention
26 Had exposure to TB case
8 Did not meet protocol
definition of clinical TB
46 Did not adhere to regimen

273 Were included in analysis

1 Was excluded from analysis

274Were included in analysis

403 Were included in analysis

401 Were included in analysis

2 Were excluded from analysis

Figure 1. Enrollment, Randomization, and Follow-up of the HIV-Infected and HIV-Uninfected Study Cohorts.
Four HIV-infected children (one in the isoniazid group and three in the placebo group) who were positive for HIV at baseline were
sub-sequently confirmed to be HIV-uninfected. Six HIV-uninfected children (two in the isoniazid group and four in the placebo
group) who were negative for HIV at baseline were subsequently confirmed to be HIV-infected. The numbers of participants lost to
follow-up or who discontinued the intervention denote those who were lost to follow-up or discontinued the intervention before a
primary end point oc-curred. The reasons for discontinuing the intervention are enumerated only for those not lost to follow-up.
INH denotes isoniazid, and TB tuberculosis.

ceived BCG vaccination

in 1 child who never received it and was excluded from the by 30 days of age, before
analysis. The disposition of the HIV-uninfected infants, including their positive HIV status
2 children who did not receive the study drug and were excluded was determined. The mafrom the analysis, is shown in Figure 1B.
jority of infants were
The baseline characteristics were generally well-balanced indigenous
Africans
between the two groups (Table 3) in both cohorts. Infants (97.0%). By chance, in the
underwent randomization at a median age of 96 days. All HIV-infected cohort, a
infants had rehigher
percentage
of
N ENGL J MED 365;1
NEJM.ORG JULY 7,

2011

25

children of mixed ancestry

were enrolled in the
isoniazid group. A history
of maternal tuberculosis
was reported for 7.1% and
7.2% of HIV-infected and
HIV-uninfected
participants, respectively. Four
participants in the HIV-

T h e NEW ENGL A ND JOUR NA L o f MEDICINE

first end point

met.
Eight
infected cohort,
participants
who
initially
with previous
had a positive
protocolHIV PCR test,
defined
were
subsequently
found to be
HIV-neg-ative
on PCR assay.
At study entry,
65.3% of HIVinfected infants
were
asymptomatic
(CDC clinical
category N) and
26.2%
were
mildly
symptomatic
(category
A)
(Table
3).
Among children
who
were
confirmed to be
HIV-infected,
the
median
CD4+
lymphocyte
percentage and
HIV-1 viral load
were 28% and
625,000 copies
per
milliliter,
respec-tively, at
study entry, and
171
children
(31.5%)
had
already started
to
receive
antiretroviral
treatment (Table
3).
EFFICACY

HIV-Infected
Cohort
Primary
end
points
are
detailed in Table
4. Partici-pants
who
reached
more than one
end point were
categorized
according to the

tuberculosis
died, and only
tuberculosis
end points were
included in the
efficacy
analysis
for
these
participants.
Either protocoldefined
tuberculosis or
death occurred
in 52 children
(19.0%) in the
isoniazid group
as
compared
with
53
children (19.3)
in the placebo
group (hazard
ratio, 0.98; 95%
confidence
interval [CI],
0.67 to 1.44)
(Fig. 1 in the
Supplementary
Appendix).
Tuberculosis
ac-counted for
31 (59.6%) of
the primary end
points in the
isoniazid group
and for 38
(71.7%) in the
placebo group
(P=0.40);
death
accounted for
21 (40.4%) and
15 (28.3%) of
the primary end
points in the
two
groups,
respectively (P
=0.12). The results
were
similar
when
the
analysis
was
adjusted
for status with
respect
to
antiretroviral
treatment
at
baseline
and

maternal historyiniti ated on

of tuberculosis.antiretroviral
Overall, 98.9%treatment
of HIV-infectedduring
the
children werestudy.
The
Table 3.
Baselin
e
Demog
raphic
and
Clinical
Charac
teristic
s of
Childre
n
Rando
mly
Assign
ed to
Isoniazi
d or
Placeb
o.*

results
of
analyses of the
secondary end
points

Characteristic

HIV-Infected Children
Total
(N=547)

HI

Isoniazid
Group
(N=273)

Placebo
Group
(N=274)

97

95

91 to 120

91 to 120

Total
(N=804)

Age days
Median
Range

96
91 to 120

96

91 to 120

Weight-for-age z score
Median

0.58

0.61

0.54

0.35

Range

4.29 to 3.07

3.44 to 3.07

4.29 to 3.03

2.83 to 3.9

237 (43.3)

114 (41.8)

123 (44.9)

411(51.1

536 (98.0)

264 (96.7)

272 (99.3)

775 (96.4

11(2.0)

9 (3.3)

2 (0.7)

29 (3.6)

504 (92.1)

254 (93.0)

250 (91.2)

792 (98.5

Brick house

345 (63.3)

162 (59.3)

183 (67.3)

468 (58.2

Shack or wooden structure

198 (36.3)

109 (39.9)

89 (32.7)

336 (41.8

2 (0.4)

2 (0.7)

Male sex no. (%)

Race or ethnic group no. (%)
Indigenous African
Mixed ancestry or other
Biologic mother as primary caregiver
no. (%)
Housing type no. (%)

Hostel

Household size no. of members

Median

2 to 15

2 to 15

2 to 15

2 to 21

Ever breast-fed

73 (13.3)

37 (13.6)

36 (13.1)

48 (6.0)

Breast-fed at baseline

29 (5.3)

15 (5.5)

14 (5.1)

7 (0.9)

Range

Breast-feeding no. (%)

26

N ENGL J MED 365;1

NEJM.ORG JULY 7, 2011

ISONIAZID PROPHYLAXIS IN HIV-EXPOSED CHILDREN

Table 3. (Continued.)
Characteristic

HIV-Infected Children
Total
(N=547)

Isoniazid
Group
(N=273)

HIV-Uninfected Children
Placebo
Group
(N=274)

Total
(N=804)

Isoniazid
Group
(N=403)

Placebo
Group
(N=401)

Maternal history of tuberculosis

no. (%)
During index pregnancy

2 (0.4)

2 (0.7)

6 (0.7)

4 (1.0)

2 (0.5)

Before index pregnancy

37 (6.8)

14 (5.1)

23 (8.4)

51 (6.3)

29 (7.2)

22 (5.5)

Any history of tuberculosis

39 (7.1)

14 (5.1)

25 (9.1)

57 (7.1)

33 (8.2)

24 (6.0)

Within 7 days after birth

513 (93.8)

255 (93.4)

258 (94.2)

787 (97.9)

395 (98.0)

8 to 29 days after birth

34 (6.2)

18 (6.6)

16 (5.8)

17 (2.1)

354 (65.3)

178 (65.7)

176 (64.9)

142 (26.2)

74 (27.3)

68 (25.1)

37 (6.8)

16 (5.9)

21 (7.7)

5 (0.9)

2 (0.7)

3 (1.1)

HIV-uninfected

4 (0.7)

1 (0.4)

3 (1.1)

Missing data

BCG vaccination no. (%)

392 (97.8)

8 (2.0)

9 (2.2)

CDC clinical HIV category no. (%)

CD4+ cells %
Median
Range

28
6 to 58

29

28

6 to 53

6 to 58

CD4+ category no. (%)

<20%

111(21.5)

56 (21.7)

55 (21.3)

2024%

86 (16.7)

40 (15.5)

46 (17.8)

2534%

187 (36.2)

90 (34.9)

97 (37.6)

35%

132 (25.6)

72 (27.9)

60 (23.3)

31

15

16

Median

625,000

710,000

482,000

Interquartile range

46,000 to
750,000

97,905 to
750,000

258,000 to
750,000

171 (31.5)

78 (28.7)

93 (34.3)

Missing data or HIV-uninfected

Plasma HIV-1 RNA copies/ml

Antiretroviral treatment at or before

study entry no. (%)

1*

Percentages may not add to 100 because of rounding. BCG denotes bacille CalmetteGurin, CDC Centers for
Disease Control and Prevention, HIV human immunodeficiency virus, and HIV-1 human immunodeficiency virus type 1.
Housing type was not provided for two HIV-infected participants in the placebo group.
Category N denotes asymptomatic, A mildly symptomatic, B moderately symptomatic, and C severely symptomatic.
Participants with missing data and HIV-uninfected participants were excluded from the percentages.

Excluded were seven and six HIV-infected participants with missing data from the isoniazid and placebo groups, respectively. HIVuninfected participants were excluded from the percentages. The range was 400 to 750,000 for both study groups.
HIV-uninfected participants were excluded from the percentages.

incidence of tuberculosis
isoniazid
group
(10 was 121 cases per 1000
were consistent with lack of efficacy. In addition, a post hoc participants, 3.7%) and child-years (95% CI, 95
analysis of the composite end point of probable or definite the pla-cebo group (11 to 153).
tuberculosis showed no significant difference in incidence participants, 4.0%; P=
between the
0.83).
The
overall
N ENGL J MED 365;1

NEJM.ORG JULY 7, 2011

27

T h e NEW ENGL A ND JOUR NA L o f MEDICINE

Table 4. Summary of First End Point Met toward Primary Outcome Measures in Children Randomly Assigned to Isoniazid or Placebo.*

End Point

HIV-Infected Children
Total
(N=547)

Isoniazid
Group
(N=273)

105 (19.2)

HIV-Uninfected Children

Placebo
Group
(N=274)

P Value

Total
(N=804)

52 (19.0)

53 (19.3)

0.93

84 (10.4)

39 (9.7)

45 (11.2)

0.40

no. (%)
Primary end point: tuberculosis
disease or death

Isoniazid
Group
(N=403)

Placebo
Group
(N=401) P Value

no. (%)
0.44

Specific end points

Protocol-defined tuberculosis

69 (12.6)

31 (11.4)

38 (13.9)

59 (7.3)

28 (6.9)

31 (7.7)

Definite PTB

8 (1.5)

5 (1.8)

3 (1.1)

14 (1.7)

8 (2.0)

6 (1.5)

Probable PTB

8 (1.5)

5 (1.8)

3 (1.1)

9 (1.1)

3 (0.7)

6 (1.5)

Possible PTB

48 (8.8)

21 (7.7)

27 (9.9)

36 (4.5)

17 (4.2)

19 (4.7)

Definite EPTB

3 (0.5)

Probable EPTB and possible PTB

Death without prior tuberculosis

2 (0.4)
36 (6.6)

0
0
21 (7.7)

3 (1.1)

2 (0.7)

4 (0.5)

2 (0.5)

2 (0.5)

21 (2.6)

9 (2.2)

12 (3.0)

15 (5.5)

Latent tuberculosis

* Percentages for specific outcomes may not add to the total percentages because of rounding.
P values are for the log-rank test.
P=0.85 in an analysis adjusted for status with respect to antiretroviral treatment at baseline and maternal history of tuberculosis.

Protocol-defined tuberculosis included any episode that fulfilled the protocol-specified criteria for possible, probable, or definite
tuberculo-sis, as confirmed by the end-point review committee. EPTB denotes extrapulmonary tuberculosis, and PTB pulmonary
tuberculosis.

One HIV-infected participant with possible pulmonary tuberculosis later fulfilled the criteria for probable pulmonary tuberculosis.

Latent tuberculosis was evaluated at 96 weeks of age by means of a tuberculin skin test (with an induration 10 mm in
horizontal diameter considered to be reactive). The outcome was not evaluated for HIV-infected children because most children
had not completed 96 weeks in the study when the study ended.

The overall incidence of

Details on compliance with study follow-up, HIV-AIDS tuberculosis was 41 cases
disease progression, and mortality rates and causes of death per 1000 child-years (95%
are provided in the Supple-mentary Appendix. Self-reported CI, 31 to 52). Six HIVcompliance at scheduled visits (defined as no missed dosesuninfected children (three
since the last visit) ranged from 74 to 92% across visits and each in the isoniazid and
did not differ significantly between the study groups.
placebo groups) died of
either gastroenteritis or
HIV-Uninfected Cohort
unknown reasons (Table 1 in
The rate of loss to followup at 96 weeks was
14.4% (95% CI, 12.0 to
17.0) in the cohort of
children with-out HIV
infection,
with
no
significant
difference
between the isoniazid and
placebo groups (P=0.58).
Eighty-four
children
(10.4%)
reached
a
primary end point, a
composite of tuberculosis
disease,
latent
tuberculosis infection, or

d
e
a
t
h
.
T
h
e
e
s
ti
m
a
t

e
d
h
a
z
a
r
d
r
a
ti
o
f
o

the
Supplemen-tary
Appendix). Survival did not
differ significantly between
the study groups (P>0.99).
Self-reported compliance at
scheduled visits ranged from
62 to 82% across visits and
was similar in the two
groups.

r the
isonia
zid
group
as
comp
ared
with
the
placeb
o
group
was
0.85
(95%

C
I
,
0
.
5
5
t
o
1
.
3
0

) (Table 4, and Fig. 1 in

the
Supplementary
Appen-dix). There was no
significant
difference
between study groups (P
=0.44)
(Table
4).
Analyses of all secondary
end points showed lack of
efficacy of isoniazid
prophylaxis as compared
with placebo.

28

N ENGL J MED 365;1

DRUGSUSCEPTIBI
LITY
TESTING

Overall,
isoniazid
resistance was
identified in 5
of 19 children
(26.3%; 95%
CI, 9.2 to
51.2)
with
culture-

confirmed
tuberculosis
who
were
tested
for
susceptibility.
Of these 5
children,
2
children
(1
HIV-infected
and 1 HIVuninfected)
were in the

stratified
according
to
HIV
status
(Table 2 in the
Supplementary
SAFETY
Appendix).
Rates of grade 3 or With
the
higher clinical or exception of
laboratory
abnormalities
were NEJM.ORG JULY 7,
2011
similar in the two
study
groups,

isoniazid group and

3
(all
HIVuninfected) were in
the placebo group.

ISONIAZID PROPHYLAXIS IN HIV-EXPOSED CHILDREN

isoniazid. Our prophylaxis does not

pri-mary
study showed prevent
grade
3no benefit of tuberculosis.
In
peripheral
addition,
the
metaisoniazid
as
neuropathy
inpreexpo-sure analysis showed no
overall
one HIV-infectedprophylaxis in significant
reduction in morchild
in
theimproving
17
isoniazid group,disease-free
tality.
These data
all grade 3 orsurvival among are corroborated by
higher
toxicHIV-infected our study, in which
effects resolved,children
or isoniazid prophylaxis
prevent
allowing for theinfection-free failed to
among
resumption
ofsurvival among tuberculosis
HIV-infected
children
treatment
withHIV-uninfected
without a history of
the
randomlychildren.
MTB exposure.
assigned
studySimilar-ly,
a The other major
hoc published study of
drug.
Allpost
analysis
that
reportable serious
isoniazid prophylaxis
the in
adverse
eventsincluded
HIV-infected
are shown incomposite
children was underof taken in Cape Town,
Table 3 in theoutcome
protocolSupplementary
South
Africa.
defined
Appendix.
Isoniazid pro-phylaxis
tuberculosis,
was associated with a
death, or non- 54% reduction in allD
cause mortality and a
Ialgorithm
72% reduction in the
Stuberculosis
showed
no incidence
of
C
signifi-cant
tuberculosis,
U
Sdifferences in prompting early trial
termination by the
Soutcome
between
the data
and
safety
I
isoniazid group
18
O
monitoring board.
(24.2%) and the
N
There were marked
placebo group
differences between
P=
The prevention of(24.1%,
the
HIV-infected
among
tuberculosis
in0.93)
children enrolled in
perinatally
ex-HIV-infected our study and those in
posed
HIV-children.
the Cape Town study,
meta- limiting
infected
and A
a
direct
of
HIV-uninfected analysis
comparison of the
of
infants in areastrials
findings from the two
tuberculosis
with
high
studies. The children
pro-phylaxis in
incidences
of
HIV-infected enrolled by Zar et al.
tuberculosis and
adults showed as com-pared with our
HIV
infection,that iso-niazid cohort were older
such as southernreduced
the (median age, 24.7
Africa, is a majorincidence
of months vs. 96 days),
pub-lic
healthtuberculosis (by had been treated for
challenge.
The62%) in those tu-berculosis in some
before
only
currentwith a positive cases
alternative
totuberculin skin enrollment (16%
BCG vaccinationtest but was
N ENGL J MED
for
preventingineffective in
365;1
tuberculosis
isthose with a
17

chemoprophylaxi negative test,

s, especially withsuggesting that

v
s
.
0
%
)
,
w
e
r
e
m
o
r
e
l
i
k
e
l
y
t
o
b
e
s
e
v
e
r
e
l
y
i
m
m
u
n
o
c
o
m
p
r
o
m
i
s

e
d
(
C
D
C
c
a
t
e
g
o
r
y
B
o
r
C
,
8
8
%
v
s
.
8
%
)
,
w
e
r
e
l
e
s
s
l
i
k
e
l
y
t
o

b
e
re
ce
iv
in
g
a
nt
ir
et
ro
vi
ra
l
tr
ea
tm
e
nt
at
st
u
d
y
e
nt
ry
(9
%
vs
.
3
1
%
),
h
a
d
lo
w
er
C
D
4
+
p
er
ce
nt
a
g
es
(2
0
%
vs

2
8
%
)
,

(
m
e
d
i
a
n

a
n
d
w
e
r
e
m
o
r
e
s
e
v
e
r
e
l
y
m
a
l
n
o
u
r
i
s
h
e
d
a
t
s
t
u
d
y
e
n
t
r

z
s
c
o
r
e
,

1
.
5
6
v
s
.

0
.
5
8
)
.
I
n
a
d
d
i
t
i
o
n
,
9
%
o
f
c
h

il
dr
e
n
in
th
e
st
u
d
y
b
y
Z
ar
et
al
.
h
a
d
a
re
ac
ti
v
e
tu
b
er
c
ul
in
sk
in
te
st
at
st
u
d
y
e
nt
ry
,
p
os
si
bl
y
in
di
ca
ti
n
g
pr

e
v
i
o
u
s

y
s
i
s

M
T
B

a
n
t
i
t
u
b
e
r
c
u
l
o
s
i
s

i
n
f
e
c
t
i
o
n
.
C
o
n
t
r
a
r
y
t
o
t
h
e
f
i
n
d
i
n
g
s
o
f
t
h
e
m
e
t
a
a
n
a
l

o
f

p
r
o
p
h
y
l
a
x
i
s
i
n
H
I
V
i
n
f
e
c
t
e
d
a
d
u
l
t
s
w
i
t
h

a
n
o
nr
ea
ct
iv
e
tu
be
rc
ul
in
sk
in
te
st,
17

th
e
st
u
d
y
b
y
Z
ar
et
al
.
sh
o
w
ed
a
4
9
%
re
d
uc
ti
o
n
in
m
or
ta
lit
y
an
d
a
6
8
%
re
d
uc
ti
o
n

i
n

v
e

t
h
e

t
u
b
e
r
c
u
l
i
n

i
n
c
i
d
e
n
c
e
o
f
t
u
b
e
r
c
u
l
o
s
i
s
a
m
o
n
g
c
h
i
l
d
r
e
n
w
i
t
h
a
n
o
n
r
e
a
c
t
i

s
k
i
n
t
e
s
t
.
1
8

A
c
l
i
n
i
c
a
l
l
y
r
e
l
e
v
a
n
t
a
s
p
e
c
t
o
f
t
h
e

fi
n
di
n
gs
b
y
Z
ar
et
al
.
is
th
at
th
e
ca
us
es
of
de
at
h
in
b
ot
h
gr
o
u
ps
w
er
e
pr
i
m
ar
il
y
at
tri
b
ut
ed
to
se
ps
is
(4
4
%
),
p
ne
u
m
o
ni
a
(2
2
%

)
,
a
n
d
g
a
s
t
r
o
e
n
t
e
r
i
t
i
s
(
9
%
)
,
n
o
t
d
i
r
e
c
t
l
y
t
o
t
u
b
e
r
c
u
l
o
s
i
s
.
H
o
w
e

v
e
r
,
t
u
b
e
r
c
u
l
o
s
i
s
c
o
u
l
d
h
a
v
e
p
r
e
d
i
s
p
o
s
e
d
t
h
e
c
h
i
l
d
r
e
n
t
o
b
a
c
t
e
r
i

al
in
fe
ct
io
n.
19

In
ad
di
ti
o
n,
th
e
gr
ea
te
st
di
ff
er
en
ce
in
su
rv
iv
al
o
bs
er
ve
d
be
t
w
ee
n
th
e
gr
o
u
ps
oc
cu
rr
ed
pr
i
m
ar
il
y
w
it
hi
n
3
0
da
ys

a
f
t
e
r
r
a
n
d
o
m
i
z
a
t
i
o
n
,
w
i
t
h
m
a
r
g
i
n
a
l
d
i
f
f
e
r
e
n
c
e
s
b
e
t
w
e
e
n
t
h
e
g
r
o
u

p
s
t
h
e
r
e
a
f
t
e
r
.
T
h
e
s
t
u
d
y
a
l
s
o
e
n
r
o
l
l
e
d
4
4
.
8
%
o
f
t
h
e
c
h
i
l
d
r
e
n
d
u
r

in
g
th
e
co
ur
se
of
h
os
pi
ta
li
za
ti
o
n
fo
r
an
ac
ut
e
ill
ne
ss
.

B
ec
au
se
th
e
pr
o
gr
es
si
o
n
fr
o
m
M
T
B
in
fe
ct
io
n
to
ac
ti
ve
di
se
as
e
ta
ke

s
1
t
o
3
m
o
n
t
h
s
t
o
b
e
m
a
n
i
f
e
s
t
e
d
,
2
1

t
h
e
m
e
c
h
a
n
i
s
m
b
y
w
h
i
c
h
i
s
o

n
i
a
z
i
d
p
r
o
p
h
y
l
a
x
i
s
p
r
e
v
e
n
t
e
d
t
u
b
e
r
c
u
l
o
s
i
s
a
n
d
i
m
p
r
o
v
e
d
s
u
r
v
i
v
a

l
in
th
e
st
u
d
y
b
y
Z
ar
et
al
.
re
m
ai
ns
u
ne
xpl
ai
ne
d.
It
is
p
os
si
bl
e,
h
o
w
ev
er
,
th
at
th
e
re
d
uc
ti
o
n
in
th
e
in
ci
de
nc
e
of
tu
be
rc
ul

o
s
i
s
o
b
s
e
r
v
e
d
i
n
t
h
e
i
s
o
n
i
a
z
i
d
g
r
o
u
p
b
y
Z
a
r
e
t
a
l
.
w
a
s
t
h
e
r
e
s

u
l
t
o
f
t
r
e
a
t
m
e
n
t
o
f
u
n
r
e
c
o
g
n
i
z
e
d
u
n
d
e
r
l
y
i
n
g
p
r
i
m
a
r
y
t
u
b
e
r
c
u
l

os
is
in
th
e
en
ro
ll
ed
ch
il
dr
en
,
as
w
as
o
bs
er
ve
d
in
ea
rl
y
st
u
di
es
of
is
o
ni
az
id
,

ra
th
er
th
an
th
e
re
su
lt
of
pr
o
p
h
yl
ax
is
ag
ai
ns
t
M

T
B

u
r

i
n
f
e
c
t
i
o
n

s
t
u
d
y
.

a
n
d
i
t
s
p
r
o
g
r
e
s
s
i
o
n
,
w
h
i
c
h
w
a
s
t
h
e
o
b
j
e
c
t
i
v
e
i
n
o

P
o
s
s
i
b
l
e
r
e
a
s
o
n
s
w
h
y
i
s
o
n
i
a
z
i
d
p
r
o
p
h
y
l
a
x
i
s
w
a
s
i
n
e

ff
ec
ti
v
e
in
c
hi
ld
re
n
w
it
h
o
ut
k
n
o
w
n
M
T
B
e
x
p
osu
re
in
o
ur
st
u
d
y
in
cl
u
d
e
a
su
b
o
pt
i
m
al
d
os
e
of
th
e
dr
u

g
,
i
s
o
n
i
a
z
i
d
r
e
s
i
s
t
a
n
c
e
,
l
a
c
k
o
f
c
o
m
p
l
i
a
n
c
e
w
i
t
h
t
h
e
m
e
d
i
c

a
t
i
o
n
r
e
g
i
m
e
n
,
a
n
d
i
s
s
u
e
s
r
e
g
a
r
d
i
n
g
t
h
e
s
p
e
c
i
f
i
c
i
t
y
o
f
t
h
e

s
tu
d
y
e
n
d
p
oi
nt
s.
A
di
sc
us
si
o
n
of
th
es
e
fa
ct
or
s
is
a
v
ai
la
bl
e
in
th
e
S
u
p
pl
e
m
e
nt
ar
y
A
p
p
e
n
di
x.
F
in
al
ly
,a

l
i
m
i
t
a
t
i
o
n
o
f
o
u
r
s
t
u
d
y
i
s
r
e
l
a
t
e
d
t
o
p
o
s
s
i
b
l
e
c
h
a
n
g
e
s

i
n
t
h
e
e
p
i
d
e
m
i
o
l
o
g
y
o
f
t
u
b
e
r
c
u
l
o
s
i
s
a
n
d
i
n
m
o
r
t
a
l
i
t
y
a

m
o
n
g
H
I
V
in
fe
ct
ed
ch
il
dr
en

NEJM.ORG JULY 7, 2011

29

T h e NEW ENGL A ND JOUR NA L o f MEDICINE

placebo group
would reach a
because
ofprimary
end
increased accesspoint over the
to antiretroviral96-week
treat-ment. Theperiod,
an
overall rate of aincidence
primary
endsimilar to that
point
amongobserved in our
HIV-infected study.
children in our In
study was 22%conclusion, in
over a period ofour
study
96
weeks,isoniazid
which is belowprophy-laxis as
the 40% ratecompared with
that
weplacebo
was
originally
safe but inefestimated. Wefective
as
therefore
preexposure
continued
prophylaxis
enrolling
against tubercuchildren
afterlosis in HIVthe initial targetinfected
and
enrollment
ofHIV-uninfected
500 participantschildren.
had
beenHowever, the
reached.
Theresults of our
futility analysis,study
are
nevertheless, specific to a
indicated
thatsetting such as
even with theSouth
Africa
most optimisticwith a high
estimates, it wasdual bur-den of
unlikely that thetuberculosis
HIV
study
wasand
infection. Much
adequately
has
powered
toin-sight
gained
show significantbeen
the
differences ininto
the primary endepidemiology
points betweenof tuberculosis
southern
the two groups.in
Our study wasAfrica in the
era
of
anadequately
tiretroviral
powered
(91.7%)
totreatment. In a
detect a 50%study
conducted
in
rela-tive
Cape
Town
reduction
in
primary
endfrom 2004 to
the
points
among2007,
incidence
of
HIV-infected
culturechildren on the
basis of anconfirmed
estimate
thattuberculosis
25% of thewas 1596 cases
100,000
children in theper

HIV-infected
7

infants.
In
addition,
the
incidence
of
hospitalization
for
cultureconfirmed and
all categories of
pulmonary
tuberculosis in
Johannes-

burg, before themanage-ment

introduction ofof tuberculosis
antiretroviral in HIV-exposed
treatment, waschildren.
3028
per
The content of
100,000
andthis article is solely
10,016
perthe responsibility of
the authors and
100,000,
does not necessarily
respectively, inrepresent
the
children under 5official views of the
8National

Institutes

years of age. of Health.

The burden of Overall support
for the International
tuberculosis
MaternalPediatric
among
HIV-Adolescent AIDS
infected
Clinical
Trials
children
(121(IMPAACT) Group
provided by
cases per 1000was
grants from the
child-years) inNIAID
(U01
the
our
studyAI068632),
remained highEunice Kennedy
Shriver
National
despite access toInstitute of Child
an-tiretroviral Health and Human
treatment.
ADevelopment
(NICHD), and the
high burden ofNational Institute of
tuberculo-sis
Mental
Health
was
also(AI068632). This
work was supported
identified
by the Statistical
among
HIV-and Data Analysis
exposed
un-Center at the
Harvard School of
infected
Public
Health,
children
(41under NIAID cocases per 1000operative
agreements with the
child-years).
Pediatric
AIDS
These findingsClinical
Trials
underscore theGroup (5 U01
need to exploreAI41110) and the
IMPAACT Group
al-ternative
(1 U01 AI068616).
options for theSup-port of the sites
prevention andwas provided by

NIAID and the

NICHD
International and Domestic
Pediatric
and
Maternal
HIV
Clinical
Trials
Network (NICHD
contract
number
N01-DK-9001/HHSN267200
800001C).
The
study was also
funded by a grant
from the Secure the
Future Fund, a
philanthropy
program sponsored
by
Bristol-Myers
Squibb.
Disclosure forms
provided by the
authors
are
available with the
full text of this
article at NEJM.org.
We thank the
parents and legal
guardians
for
allowing
their
children
to
participate in the
clinical trial; the
health care work-ers
for providing care
to the participants;
other members of
the P1041 team for
assisting in the
conduct of the
study; Peter R.
Donald, M.D., and
H. Simon Schaaf,
M.D., for their
critical re-view of
the manuscript; and
Anneke Hesseling,
M.D.,
for
her
contribution
to
drug-susceptibility
testing.

REFERENCES

1. Nunn

epidemiol

of
P,ogy
Reid A, Detuberculos
Cock KM.is in a
peri-urban
Tuberculosis andcommunit
y in South
HIV
infection: Africa: the
the globalneed for
set-ting.
JageInfect Disspecific
2007;196:Su interventio
Clin
ppl
1:S5-ns.
Infect Dis
S14.

2. Lawn

2006;42:1
040-7.

SD, Bekker
Midde
LG,
Middelkoo lkoop K,
p K, MyerBekker
L, Wood R.LG, Myer
Impact ofL, Dawson
R, Wood
HIV
infection onR. Rates
of
the

3.

tuberculos D is
oe infecti
transmissi de on in
on
tons childr
children L, en
and
A hospit
adolescent dualised
s in ac with
communit T, tuy with aW bercul
high
es osis in
prevalence le South
of
HIVy Africa
infection D, . Int J
among
C Tuber
adults.
ooc
Clin Infectpe Lung
Dis
r Dis
2008;47:3 P 2000;
49-55.
A. 4:448Madhi H 54.
IV
SA,
Huebner -1
co
RE,

4.

5. W
ood
R,
Johns
toneRobe
rtson
S,
Uys
P, et
al.
Tuber
culosi
s
trans
missi
on to
youn
g
childr
en in
a
South
Afric

an
comm
unity:
modeli
ng
househ
old
and
comm
unity
infection
risks.
Clin
Infect
Dis
2010;5
1:4018.

6.

M
arais
BJ,
Gie
RP,

Schaaf HS,from
a
et al. TheSouth
natural
African
history ofpopulation
childhood -based
intrastudy
thoracic
highlights
tuberculosisthe need
: a criticalfor
review ofimproved
literature tubercufrom
thelosis
precontrol
chemothera strategies.
py era. Int JClin Infect
Tuberc
Dis
Lung Dis2009;48:1
2004;8:392 08-14.
-402.

8. Madhi
7. Hesseli SA,

ng
AC,Petersen K,
Cotton MF,Madhi A,
Jennings T,Khoosal M,
et al. HighKlugman
incidence KP.
of
Increased
tuberculosis
disease
among
burden and
HIVantibiotic
infected
resistance
infants:
evidence of bacteria

30

causing ill Ansari

severe
ne NA,
communit ss Komb
y-acquired es e AH,
lower
: aKenyo
respiratory de n TA,
tract
sc et al.
infections ri Pathol
in humanpt ogy
imiv and
munodefic e causes
iency virusne of
type
1-cr death
infected opin a
chil-dren. sy se-ries
Clin Infectst of
Dis
udhuma
2000;31:1 y. n
70-6.
L immu
an nodefi
Chintu
ce ciency
C,
t virusMudenda 20positi
V, Lucas02ve and
S, et al.; -negat
Lung
36ive
diseases at0: pediat
necropsy 98ric
in African5- referra
chil-dren 90l
dying
. hospit
from
al
respiratory

9.

N NGL
EJ

ME
D

admi
ssion
s in
Bots
wana
.
Pedia
tr
Infec
t Dis
J
2003
;22:4
3-7.

11.
Hsu
KH.
Thirt
y
years
after
isoni
azid:
its
impa
ct on
tuber
culos
is in
child
ren
and

adoles
cents.
JAMA
1984;
251:1
283-5.

12.
Smiej
a MJ,
March
etti
CA,
Cook
DJ,
Smaill
FM.
Isonia
zid for
preven
ting
tu-

365; NEJM.ORG
1
JULY 7, 2011

ISONIAZID PROPHYLAXIS IN HIV-EXPOSED CHILDREN

www.ucdm
berculosis in non-HIVc.ucdavis.e
infected
persons.du/clinicalt
Cochrane Database Systrials/
Rev 2000;2: CD001363. documents/
DAIDS_A
Hsu
KH.E_Grading
Isoniazid
in
theTable
prevention and treatment_FinalDec2
of tuberculosis: a 20-004.pdf.)
year study of the
A
effectiveness in children.
C,
JAMA 1974;229:528-33. kolo

13.

17.

Adetifa
I,
The South
Shepperd S,
African National Tubercu- Volmink
J.
losis Control Programme. Treatment of
Practical guide-lines,
latent
2004.
tuberculosis
(http://www.kznhealth.gov infection
in
.za/
HIV infected
chrp/documents/Guideline persons.
s/Guidelines
Cochrane
%20National/Tuberculosis Database Syst
/SA%20TB%20
Rev
Guidelines%202004.pdf.) 2010;1:CD00

14.

15.

Management 0171.
of severe malnutrition: a
Z
manual for physiciansar HJ, Cotton
and other senior healthMF, Strauss
workers. Geneva: WorldS,
et
al.
Health
Organization,Effect
of
1999.
isoniazid
(http://www.who.int/
prophylaxis
nutrition/publications/se on mortal-ity
veremalnutrition/
and incidence
en/manage_severe_maln of
utrition_eng.pdf.)
tuberculosis

18.

16.

DAIDS/RSC. in chil-dren
HIV:
Toxicity tables, 2004.with
randomised
(http://

controlled
trial.
BMJ
2007;334:136
.

19.

M
oore
DP,
Klugman KP,
Madhi SA.
Role
of
Streptococcu
s pneumoniae
in
hospitalization
for
acute
communityacquired
pneumonia
associated
with culturecon-firmed
Mycobacteriu
m
Every
article
publish
ed by
the
Journal
is now
availabl
e at
NEJM.
JOURNAL
org,
AT NEJM
beginni

tuberculosis
in chil-dren:
a
pneumococc
al conjugate
vaccine
probe study.
Pediatr
Infect Dis J
2010;29:
1099-04.

Cotton
MF,
Wasserman E,
Smit
J,
Whitelaw A,
Zar HJ. High
incidence of
an-timicrobial
resistant
organisms
including
extended
spectrum betalactamase pro
ducing
Enterobacteria
ceae
and
methi cillinresistant
Staphylococcu
s aureus in
nasopharyngea
l and blood
isolates
of
HIV-infected
children from
Cape Town,
South Africa.
BMC Infect
Dis 2008;8:40.

20.

M
arais BJ, Gie
RP, Schaaf
HS, Beyers
N,
Donald
PR,
Starke
JR.
Childhood
pul-monary
tuberculosis:
old wisdom
and
new
challenges.
Am J Respir
Crit
Care
Med
2006;173:107
8-90.

21.

M
ount
FW,
Ferebee SH.
Preventive
ef-fects
of
isoniazid in
the treatment
of pri-mary
tuberculosis
in children. N
Engl J Med
1961;265:713
-21.
Copyright
2011
Massachusetts
Medical Society.

ng with e, and browsing of

the first titles and tables of
article contents is easy and
publishe available to all.
d in
Individual
January
subscribers are
1812. entitled to free 24The
hour access to 50
entire archive articles per
archive
year. Access to
is fully
content in the
searchabl archive is available

on a per-article being
basis and is also provided

through
many

institutio
nal

subscriptions.

N ENGL J MED 365;1

NEJM.ORG JULY 7,

2011

31

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.