Antiretroviral drugs to prevent breastfeeding HIV transmission

©2010 International Medical Press 1359-6535 (print) 2040-2058 (online) 537

Antiviral Therapy 2010 15:537–553 (doi: 10.3851/IMP1574)

Observational studies and randomized clinical trials demonstrating that antiretroviral prophylaxis of the breastfeeding infant or triple-drug antiretroviral prophy-laxis of the lactating mother can significantly affect the risk of postnatal transmission of HIV via breast milk have recently become available. In resource-limited countries, breastfeeding is a cornerstone of infant survival. While

shortening the duration of breastfeeding by HIV-infected women reduces postnatal HIV transmission, increasing data suggest this may also decrease overall infant survival. Thus, there is a crucial need for interventions to allow safer and more prolonged breastfeeding. This paper will critically review the results of studies of postnatal antiretroviral prophylaxis to prevent breast milk HIV transmission.

In 2008, an estimated 430,000 children were infected with HIV worldwide [1]. The vast majority of these infections were acquired by mother-to-child HIV trans-mission occurring in utero, intrapartum or through breastfeeding. Over 90% of these new paediatric infec-tions occurred in sub-Saharan Africa, where acquisition of HIV through breast milk accounts for an estimated 40% or more of new infections, but where breastfeed-ing has long been a cornerstone of child survival pro-grammes. HIV-infected mothers in this setting are faced with an agonizing choice: to breastfeed but risk trans-mitting HIV to their infant or to not breastfeed and risk their infant dying of malnutrition or other infectious diseases. Exclusive breastfeeding can lower the risk of postnatal HIV transmission compared to mixed feed-ing, but it does not eliminate risk [2,3].

In well-resourced countries, such as the United States, early identification of HIV infection in pregnant women through universal routine opt-out antenatal HIV testing, provision of antiretroviral therapy for HIV-infected women who need treatment for their own health, provision of antiretroviral prophylaxis if ther-apy is not yet required, elective caesarean delivery and complete avoidance of breastfeeding has dramatically reduced the risk of mother-to-child HIV transmission to approximately 1–2% [4].

More than a decade ago, clinical trials identified simple, effective and relatively inexpensive antiretroviral

interventions to prevent mother-to-child transmission during pregnancy and delivery that are applicable to resource-limited settings; however, implementation of these interventions has been slow. The proportion of pregnant women accessing antenatal HIV testing in mid- and low-resource countries has increased from 10% to 21% between 2007 and 2009, and the proportion of HIV-infected pregnant women receiving antiretroviral drugs for prevention of transmission has increased from 11% to 45% during the same period; however, almost one-quarter of pregnant women globally do not access any antenatal care and many countries continue to use less effective antiretroviral interventions, such as single-dose nevirapine alone, for prevention of transmission [5,6]. Importantly, although the current antepartum and peripartum antiretroviral prophylaxis regimens reduce the risk of in utero and intrapartum transmission, the subsequent risk of HIV transmission through breast-feeding remains high and can result in postnatal trans-mission rates >15% with prolonged breastfeeding [3].

The only method that can eliminate breastfeeding-associated HIV transmission is to completely avoid breastfeeding. This is recommended in settings in which replacement feeding is affordable and sustainable, clean water is widely available, hygiene and sanitary condi-tions are good, and deaths caused by infectious diar-rhoeal and respiratory diseases are relatively uncommon. This approach, however, is not feasible or safe in many

Review

Antiretroviral drugs to prevent breastfeeding HIV transmission

Lynne M Mofenson1*

1Pediatric, Adolescent and Maternal AIDS Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Rockville, MD, USA

*Corresponding author e-mail: [email protected]

Introduction

AVT-09-RV-1486_Mofenson.indd 537 25/6/10 11:12:31

©2010 International Medical Press538

LM Mofenson

resource-limited countries, where there are high rates of infant morbidity, mortality and malnutrition, and the high costs of formula, inadequate replacement foods to meet the nutritional needs of a growing infant, unsafe water supply, and stigma associated with not breastfeed-ing make replacement feeding untenable.

In the past year, exciting new results from randomized clinical trials have become available demonstrating that antiretroviral prophylaxis of the breastfeeding infant or the lactating mother can significantly decrease the risk of postnatal acquisition of HIV. Available data suggest that implementation of these postpartum antiretroviral interventions, combined with treatment of HIV-infected pregnant and lactating women who require treatment for their own health and antepartum and intrapartum anti-retroviral prophylaxis interventions for those not requir-ing treatment, could decrease mother-to-child transmis-sion rates in resource-limited countries to <4%.

The crucial need to provide antiretroviral therapy to pregnant and lactating women

Clinical trials of interventions to prevent mother-to-child transmission have largely focused on use of antiretro-viral drugs solely for prevention of transmission, without consideration of what might be optimal treatment for the mother. Given the inextricable link between mater-nal and infant survival, this approach is short-sighted, and only interventions that address maternal health as well as prevention of transmission are likely to provide maximal benefit.

Although this paper is focused on antiretroviral proph-ylaxis to prevent postnatal HIV transmission, prevention of mother-to-child transmission should begin during pregnancy and must consider maternal health status. A key issue related to choosing an antiretroviral regimen for an HIV- infected pregnant woman (or for a postpar-tum lactating woman) is whether the antiretroviral drugs are being provided for treatment (in which case combi-nation antiretroviral therapy should be provided and continued for life) or solely for prophylaxis of mother-to-child transmission (in which case less intensive regimens might be equally as effective as combination antiretro-viral therapy, and the antiretroviral drug therapy would be stopped when the risk of transmission has ceased).

The 2006 WHO guidelines on when to treat pregnant women recommended treating all women with WHO clinical stage 4; for women with WHO clinical stage 3, starting when CD4+ T-cell count is <350 cells/µl; but for women with WHO clinical stage 1 or 2, which consti-tute the vast majority of pregnant women, therapy was only recommended if CD4+ T-cell count was <200 cells/µl [7]. In 2009, WHO updated these guidelines to rec-ommend treatment for all HIV-infected adults, preg-nant and non-pregnant, with CD4+ T-cell count <350

cells/µl regardless of clinical stage and for those with WHO clinical stage 3 or 4 disease regardless of CD4+ T-cell count [8,9], based on results from a clinical trial from Haiti that demonstrated improved survival and decreased morbidity in non-pregnant adults initiating treatment at a CD4+ T-cell threshold of <350 cells/µl compared with <200 cells/µl [10].

In pregnant and lactating women, both maternal mortality as well as risk of mother-to-child transmission is associated with CD4+ T-cell count, and use of a higher CD4+ T-cell threshold to determine when to initiate life-long therapy is particularly important as it affects out-come for both mother and child. Looking specifically at postnatal transmission risk, in the absence of antiretro-viral prophylaxis, 12–18-month postnatal infection rates in infants uninfected at 4–6 weeks of age born to moth-ers with baseline CD4+ T-cell count <350 cells/µl were as high as 17%, whereas infants of mothers with CD4+ T-cell count >350 cells/µl had postnatal infection rates of 2–6% (Table 1) [11–15]. Data from Zambia indicate that approximately 92% of maternal deaths and 88% of perinatal or postnatal infections occur among women who would meet the new WHO criteria for treatment (CD4+ T-cell count <350 cells/µl or WHO clinical stage 3 or 4 disease) [16]. In a study in Kenya, overall maternal mortality at 1 and 2 years postpartum was 2% and 6%, respectively; all deaths occurred in women with CD4+ T-cell count <350 cells/µl at 32 weeks gestation (20/169; 12% died by 2 years postpartum), with no deaths in women with CD4+ T-cell count >350 cell/µl [17].

Because the majority of HIV-infected pregnant women are asymptomatic or have only mild symptoms (unlike adults enrolled in HIV care and treatment programmes who are often symptomatic) [18], it is critical that pro-grammes that provide care to pregnant (and lactating) women provide access to CD4+ T-cell lymphocyte assays to determine which women need to initiate antiretro-viral treatment for their own health benefit that would be continued for life. Interventions provided solely for prophylaxis of transmission, which stop after transmis-sion risk has ceased (upon complete cessation of breast-feeding), should therefore theoretically be restricted to women without clinical symptoms and with CD4+ T-cell count >350 cells/µl. In studies from Kenya and Côte d’Ivorie, approximately 52–65% of HIV-infected preg-nant women seen in antenatal clinics had CD4+ T-cell count >350 cells/µl [17,19].

Prevention of postnatal transmission through breastfeeding using antiretroviral drugs

Two types of antiretroviral interventions to prevent postnatal transmission have been evaluated in obser-vational studies and clinical trials in resource-limited settings: provision of antiretroviral drugs to infants


ARV drugs and breast milk HIV transmission

Antiviral Therapy 15.4 539

exposed to HIV during breastfeeding [20–25] and provision of combination antiretroviral prophylaxis to lactating women [25–32]. The design of these studies is shown in Table 2. Detailed comparative information for the infant prophylaxis studies is shown in Table 3, and for the maternal prophylaxis studies is shown in Table 4. Both of these strategies have been predicated on breastfeeding during the period of most benefit, followed by early weaning (for example, at or before age 6 months). Although the benefit of breastfeeding in terms of reducing infant mortality appears to be greatest in the first 6 months of life in resource-limited countries, significant benefit is furthermore observed throughout the first year of life [33]. Cessation of breastfeeding at age 6 months might be associated with increased morbidity and mortality in infants, as will be discussed later.

There are major differences between studies, particularly between maternal and infant prophylaxis studies, which make it difficult to compare absolute HIV transmission rates between the studies. Reports often lack a 95% confidence interval to help under-stand the range of transmission encompassed by the intervention. The patient populations significantly differ; for example, all the infant prophylaxis stud-ies except one (the Breastfeeding, Antiretroviral and Nutrition [BAN] study) enrolled women regardless of CD4+ T-cell count, whereas the three randomized tri-als of maternal prophylaxis (BAN, Kesho Bora and Mma Bana) restricted enrolment to women with CD4+

T-cell counts ≥200–250 cells/µl (Table 2). Antepartum antiretroviral drug administration and duration (when given) differs significantly between the studies, yet is clearly important in terms of reducing in utero infection and comparisons of cumulative infection risk. The three large infant prophylaxis studies (the Six Week Extended Nevirapine [SWEN] study, Post-Exposure Prophylaxis of the Infant [PEPI-Malawi] study and BAN) enrolled women who had not received any antepartum drugs, whereas all the maternal prophylaxis studies except one (BAN) provided antepartum drugs (of different dura-tions, ranging from initiation at 25–36 weeks gestation, making comparison even among maternal studies dif-ficult; Table 2). The duration of postnatal prophylaxis differs between studies, with two infant prophylaxis studies (SWEN and PEPI-Malawi) providing only 6–14 weeks of postnatal prophylaxis, whereas all of the eight maternal prophylaxis studies provided 6 months of postnatal prophylaxis (Table 2). The duration of breastfeeding, and hence the time at risk for postnatal infection, and rates of exclusive breastfeeding, which can affect postnatal transmission risk, differs between studies and is not specified in several maternal prophy-laxis studies (Tables 3 and 4). Several studies do not provide birth infection rates, making it difficult to com-pare the incremental benefit of interventions during the breastfeeding period because the proportion of infec-tions occurring in utero (and hence not affected by a postnatal intervention) cannot be determined (Tables 3 and 4). For example, the Mma Bana trial of maternal

Table 1. Postnatal infant HIV infection rates in studies with no extended postnatal antiretroviral intervention by baseline maternal CD4+ T-cell count

AZT, zidovudine; BF, breastfeeding; sdNVP, single-dose nevirapine.

Study details Median BF Maternal CD4+ Total number PostnatalStudy Transmission Treatment group duration, months T-cell count, cells/µl of women infection, % Reference

HIVNET 012 18-Month sdNVP arm, 18 <200 95 12.6 [11] transmission in n=607 200–349 105 5.4 uninfected at 56 days 350–499 152 1.6 ≥500 255 1.7 VTS, Ditrame 18-Month n=1,151 4 <200 119 15.3 [12] transmission in 200–349 234 11.3 uninfected at 4 weeks 350–499 320 6.3 ≥500 478 3.7PEPI-Malawi 18-Month Control arm 9 <200 150 12.7 [13] transmission in (sdNVP+1 week 200–349 222 13.7 uninfected at 6 weeks AZT), n=929 ≥350 557 5.6HIVNET 024 12-Month n=1,182 >12 <200 207 14.0 [14] transmission in 200–499 648 6.6 uninfected at 4 weeks >500 327 1.8Breastfeeding and 18-Month n=2,030 10 <200 183 17.4 [15]HIV International transmission in 200–499 844 9.2Transmission Study uninfected at 4 weeks >500 1,003 3.0


LM Mofenson


Study name

Study design Antepartum

Intrapartum

Postpartum

Postpartum

and location and enrolm

ent regim

en regim

en m

other regimen

infant regimen

Overall results for RCTs

Reference

Infant prophylaxis

Mashi; Botsw

ana Random

ized trial; Starting at 34 w

eeks; First random

ization; N

o ARV Second random

ization; Arm 1: BF,

At 7 months, H

IV infection higher in [20]

enrolled w

omen

Arm 1: AZT, Arm

2: AZT Arm

1: AZT; Arm 2:

sdN

VP+AZT through age BF than FF (9.1%

versus 5.6%), but

regardless of CD4

AZT+sdN

VP

6 months; Arm

2: FF, sdNVP+AZT

mortality low

er (4.9% versus 9.3%

);

through age 1 m

onth resulting in no difference in H

IV-free

survival (12.5% versus 12.9%

)

Mitra; Tanzania

Open-label non-

Starting at 36 weeks;

AZT/3TC AZT/3TC ×1 w

eek AZT/3TC ×1 w

eek, then 3TC N

o comparison group (see Table 3

[21]

random

ized; enrolled AZT/3TC

alone through age 6 months

for results)

w

omen regardless

of CD4

SIMBA; U

ganda, Random

ized trial; Starting at 36 w

eeks; AZT/ddI

AZT/ddI ×1 week

Randomized; Arm

1: daily NVP

No difference in H

IV [22]

Rwanda

enrolled wom

en AZT/ddI

through age 20 weeks; Arm

2: infection betw

een NVP and 3TC arm

s

regardless of CD4

daily 3TC through age 20 w

eeks (overall 2.4%

at 6 months)

SWEN

; Ethiopia, Random

ized trial N

o ARV Arm

1: sdNVP;

No ARV

Randomized; Arm

1: sdNVP; Arm

2: In infants uninfected at birth, low

er [23]

Uganda, India

(combined analysis

Arm

2: sdNVP

sdN

VP+ daily NVP

HIV infection in extended N

VP than

of three separate

from

age 7 days through 6 weeks

control arm at 6 w

eeks (2.5% versus

trials); enrolled w

omen

5.3%; P=0.009) but not 6 m

onths

regardless of CD4

(6.9% versus 9.0%

, P=0.16); Lower

rates of death in extended NVP than

control arm at 6 m

onths (1.1% versus

3.6%, P=0.016)

PEPI-Malaw

i, Random

ized trial; N

o ARV sdN

VP (if N

o ARV Arm

1: sdNVP+AZT ×1 w

eek; In infants uninfected at birth, low

er HIV

[24]

Malaw

i enrolled w

omen

presented early

Arm

2: sdNVP+AZT ×1 w

eek + infection in extended N

VP and NVP/AZT

regardless of CD4

enough to receive)

daily N

VP starting at age 7 days than control arm

at 14 weeks (2.8%

,

through 14 w

eeks; Arm 3:

2.8%, 8.4%

, respectively) and 9 months

sdN

VP+AZT ×1 week + daily

(5.2%, 6.4%

, 10.6%, respectively)

N

VP/AZT from age 7 days

but no significant difference between

through 14 w

eeks extended (N

VP versus NVP/AZT) arm

s

Infant or maternal

prophylaxis

BAN; M

alawi

Randomized trial;

Arm 1: no ARV;

Arm 1: AZT/3TC+

Arm 1: AZT/3TC ×1 w

eek; Arm

1: sdNVP+AZT/3TC ×1 w

eek; Infants uninfected at 2 w

eeks had [25]

enrolled w

omen w

ith Arm

2: no ARV; sdN

VP; Arm 2: AZT/

Arm 2: AZT/3TC ×1 w

eek, Arm

2: sdNVP+AZT/3TC

lower H

IV infection at 28 weeks than

CD4≥250

Arm 3: no ARV

3TC+sdNVP; Arm

3: then, from

7 days to ×1 w

eek; Arm 3: sdN

VP+ control arm

(6.4%) w

ith infant

AZT/3TC+sdN

VP 6 m

onths postpartum

AZT/3TC ×1 week, then daily N

VP prophylaxis (1.8%

, P<0.0001 versus control)

Table 2. Design and drug regim

ens for infant and maternal antiretroviral postnatal prophylaxis studies

ABC, abacavir; ARV, antiretrovirals; AZT, zidovudine; BAN, Breastfeeding, Antiretrovirals and N

utrition study; BF, breastfed; CD4, CD

4+ T-cell count, m

easured in cells/µl; ddI, didanosine; DREAM

, Drug Resource Enhancem

ent against AID

S and Malnutrition study; d4T, stavudine; EFV, efavirenz; FF, form

ula fed; KiBS, Kisumu Breastfeeding Study; LPV/RTV, lopinavir/ritonavir; N

FV, nelfinavir; NVP, nevirapine; PEPI-M

alawi, Post-Exposure Prophylaxis of the Infant study;

RCT, randomized controlled trial; sdN

VP, single-dose nevirapine; SIMBA, Stopping Infection from

Mother to Child via Breastfeeding in Africa study; SW

EN, Six W

eek Extended Nevirapine study; 3TC, lam

ivudine.




Stud

y na

me

Stud

y de

sign

Ante

part

um

Intr

apar

tum

Po

stpa

rtum

Po

stpa

rtum

and

loca

tion

and

enro

lmen

t re

gim

en

regi

men

m

othe

r reg

imen

in

fant

regi

men

O

vera

ll re

sults

for R

CTs

Refe

renc

e

AZT/

3TC/

NVP

(n=4

5),

from

age

7 d

ays

an

d m

ater

nal p

roph

ylax

is (3

.0%

m

odifi

ed 0

1/20

05 to

th

roug

h 6

mon

ths

P=0.

0032

ver

sus

cont

rol)

AZT/

3TC/

NFV

(n=1

41) a

nd

bu

t no

diff

eren

ce b

etw

een

02/2

006

to A

ZT/3

TC/

m

ater

nal a

nd in

fant

pro

phyl

axis

LPV/

RTV

(n=6

64);

Arm

3:

ar

ms

(P=0

.12)

AZ

T/3T

C ×1

wee

k

M

ater

nal p

roph

ylax

isDR

EAM

; Moz

ambi

que

Obs

erva

tiona

l;

Star

ting

at 2

5 w

eeks

; Co

ntin

ue

CD4<

350:

con

tinue

regi

men

sd

NVP

+AZT

×1

wee

k N

o co

mpa

rison

gro

up (s

ee T

able

3

[26,

27]

en

rolle

d w

omen

AZ

T/3T

C/N

VP

regi

men

lif

elon

g; C

D4>3

50:

fo

r res

ults

)

rega

rdle

ss o

f CD4

;

co

ntin

ue re

gim

en th

roug

h

wom

en c

hoos

e m

ode

6

mon

ths

post

part

um

of

feed

ing

Ki

BS; K

enya

O

bser

vatio

nal;

St

artin

g at

34–

36 w

eeks

; Co

ntin

ue

CD4<

200:

con

tinue

regi

men

sd

NVP

N

o co

mpa

rison

gro

up (s

ee T

able

3

[28]

en

rolle

d w

omen

AZ

T/3T

C/N

VP; m

id-2

005

regi

men

lif

elon

g; C

D4>2

00:

fo

r res

ults

)

rega

rdle

ss o

f CD4

m

odifi

ed if

CD4

>250

:

cont

inue

regi

men

AZ

T/3T

C/LP

V/RT

V

thro

ugh

6 m

onth

s

post

part

um

Mitr

a-Pl

us;

Obs

erva

tiona

l;

Star

ting

at 3

4 w

eeks

Co

ntin

ue

CD4<

200

or W

HO

sta

ge

AZT/

3TC

×1 w

eek

No

com

paris

on g

roup

(see

Tab

le 3

[2

9]Ta

nzan

ia

enro

lled

wom

en

(ear

lier i

f CD4

<200

): re

gim

en

3/4:

con

tinue

regi

men

for r

esul

ts)

re

gard

less

of C

D4

AZT/

3TC/

NVP

; 10/

2005

lifel

ong;

CD4

>200

: con

tinue

m

odifi

ed if

CD4

>200

:

regi

men

thro

ugh

6 m

onth

s

AZT/

3TC/

NFV

post

part

um

Amat

a; R

wan

da

Obs

erva

tiona

l;

Star

ting

at 2

8 w

eeks

; Co

ntin

ue

CD4<

350:

con

tinue

regi

men

sd

NVP

+AZT

×1

wee

k N

o co

mpa

rison

gro

up (s

ee T

able

3

[30]

en

rolle

d w

omen

CD

4<35

0 or

WH

O

regi

men

lif

elon

g; C

D4>3

50:

fo

r res

ults

)

rega

rdle

ss o

f CD4

; st

age

4: d

4T/3

TC/N

VP;

co

ntin

ue re

gim

en th

roug

h

w

omen

cho

ose

mod

e

CD4>

350

and

WH

O s

tage

6 m

onth

s po

stpa

rtum

of fe

edin

g 1/

2/3:

AZT

/3TC

/EFV

Ke

sho

Ra

ndom

ized

tria

l;

Star

ting

at 2

8–36

wee

ks;

Arm

1: A

ZT/3

TC/

Arm

1: C

ontin

ue

Arm

1: s

dNVP

+AZT

H

IV in

fect

ion

at b

irth

not d

iffer

ent

[31]

Bora

; Ken

ya,

enro

lled

wom

en w

ith

Arm

1: A

ZT/3

TC/L

PV/R

TV;

LPV/

RTV;

Arm

2:

AZT/

3TC/

LPV/

RTV

thro

ugh

×1

wee

k; A

rm 2

: sdN

VP+A

ZT

betw

een

ante

part

um m

ater

nal t

riple

So

uth

Afric

a,

CD4

200–

500

Arm

2: A

ZT

AZT+

sdN

VP

6 m

onth

s po

stpa

rtum

; ×1

wee

k (n

o po

stna

tal

prop

hyla

xis

vers

us A

ZT (1

.8%

Bu

rkin

a Fa

so

Ar

m 2

: AZT

/3TC

pr

ophy

laxi

s)

vers

us 2

.2%

, res

pect

ivel

y); H

IV in

fect

ion

×1

wee

k (n

o po

stna

tal

at

12

mon

ths

low

er w

ith m

ater

nal

prop

hyla

xis)

trip

le p

roph

ylax

is th

an A

ZT w

ith n

o

po

stna

tal p

roph

ylax

is (5

.5%

ver

sus

9.5%

)M

ma

Bana

Ra

ndom

ized

tria

l;

Star

ting

at 2

6–34

wee

ks:

Arm

1: A

ZT/3

TC/A

BC;

Arm

1: c

ontin

ue A

ZT/3

TC/A

BC

Arm

1: s

dNVP

+AZT

H

IV in

fect

ion

at 6

mon

ths

not d

iffer

ent

[32]

Stud

y; B

otsw

ana

enro

lled

wom

en w

ith

Arm

1: A

ZT/3

TC/A

BC;

Arm

2:

thro

ugh

6 m

onth

s po

stpa

rtum

; ×4

wee

ks; A

rm 2

: sdN

VP+A

ZT

betw

een

AZT/

3TC/

ABC

vers

us A

ZT/3

TC/

CD

4>20

0 Ar

m 2

: AZT

/3TC

/LPV

/RTV

AZ

T/3T

C/LP

V/RT

V Ar

m 2

: con

tinue

×4

wee

ks

LPV/

RTV

(1.8

% v

ersu

s 0.

4%; P

=0.5

3)

AZT/

3TC/

LPV/

RTV

thro

ugh

6

mon

ths

post

part

um

Tabl

e 2.

Con

tinu

ed


LM Mofenson


Baseline

m

edian maternal

Study name,

Maternal antepartum

and N

umber

CD4, cells/µl and

HIV transm

ission at H

IV transmission at

location and design

infant ARV prophylaxis of infants

HIV RN

A, copies/ml

Infant feeding birth and 4–6 w

eeks a 6–7 m

onths a H

IV or deatha

Reference

Mashi; Botsw

ana; M

other: AZT 34 weeks to

FF, 591; BF, 588 BF, CD4: 372; H

IV FF and BF; BF m

edian Birth: 3.3%

(19/558 BF); Cum

ulative at 7 months:

6.1% at 4 w

eeks; [20]

Randomized trial

delivery (±sdNVP);

RN

A: 4.35 log duration 5.9

Cumulative at 4 w

eeks: 4.6%

9.0% (51/541 BF);

12.9% at 12 m

onths

Infant: AZT to 6 months

months; 51%

(27/557 BF); Increm

ent Increm

ent from 4 w

eeks to

if BF (±sdN

VP)

EBF at 3 m

onths day 1 to 4 w

eeks: 1.3%

7 months: 4.4%

Mitra; Tanzania;

Mother: AZT/3TC 36

BF, 398 CD4: 411 (15.4%

BF only, m

edian Birth: N

D; Cum


4.5% (2.4–6.5) at

[21]O

bservational w

eeks to 1 week

CD4<200);

duration 18 weeks

Cumulative

4.9% (2.7–7.1);

6 weeks; 8.5%

postpartum; Infant:

H

IV RNA:

at 6 w

eeks: Increm

ent from 6 w

eeks (5.7–11.4)

AZT/3TC ×1 w

eek, then

not specified

3.8% (2.0–5.6)

to 6 months:

at 6 months

daily 3TC to 6 m

onths

1.2%

(0–2.4)

SIMBA; U

ganda, M

other: AZT/ddI 36 BF, 397

CD4: 427; HIV RN

A: BF only, m

edian N

o difference between arm

s; Cum


Not specified

[22]Rw

anda; w

eeks to 1 week

(199 randomized

Not specified at

duration Birth: 6.0%

(24/397 infants); 7.6%

(5–14; 30/397 infants);

Randomized trial

postpartum; Infant:

to 3TC, 198 to NVP

baseline 100–107 days

Cumulative at 4 w

eeks: Increm

ent from 4 w

eeks

random

ized at birth to

(~3.3 m

onths) 6.8%

; Increment from

to 6 m

onths: 0.8%

daily 3TC or NVP to

1 w

eek to 4 weeks: 0.8%

(3/358 infants)

6 months

(3/373 infants)

SWEN

; Ethiopia, M

other: Late presenter, BF, 2,074 (placebo

CD4: 397; HIV RN

A: BF only; m

ost Extended N

VP arm:

Extended NVP arm

: Extended N

VP arm:

[23]U

ganda, India; no antepartum

ARVs; 1,047, extended N

VP 16,457–17,400

weaned betw

een Birth: 4.7%

; Cumulative

Cumulative at 6 m

onths: 3.7%

at Random

ized trial Infant: sdN

VP, and 977); U

ninfected at

14 weeks (73%

BF) at 6 w

eeks: 7.2%;

11.6%; Increm

ent from

6 weeks; 8.1%

(com

bined analysis random

ized to daily birth and data

and 6 m

onths Increm

ent from day 1

6 weeks to

at 6 months

3 separate trials) placebo versus

at 6 months:

(31%

BF); to 6 w

eeks: 2.5%

6 months: 4.4%

extended N

VP from

placebo, 928; extended

54% EBF

day 8 to 6 weeks

NVP, 831

at 14 w

eeks

PEPI-Malaw

i, M

other: late presenter, BF, 3,016 (placebo, 989;

CD4: 379–401; HIV

BF only, most

Extended NVP or N

VP/AZT: Cum


Extended NVP arm

: [24]

Malaw

i; no antepartum

extended N

VP, 993; RN

A: not specified w

eaned between

Birth: 7.1% both; Cum

ulative 11.1%

extended NVP,

3.3% at 6 w

eeks; 6.6%

Randomized trial

ARVs; Infant: sdNVP

extended NVP/AZT, 980);

6 m

onths (90% BF)

at 6 weeks: 8.8%

12.3%

extended NVP/AZT;

at 6 months; 13.9%

at

+1 week AZT,

Uninfected at birth and

and 9 m

onths extended N

VP and 8.7%

Increment from

6 weeks

12 months; Extended

random

ized to daily data at 9 m

onths:

(29–32% BF);

NVP/AZT; Increm

ent from

to 6 months:

NVP/AZT arm

: 1.8% at

placebo versus N

VP placebo, 788; extended

61–64%

EBF at day 1 to 6 w

eeks: 2.3%

extended 6 w

eeks; 8.2%

versus N

VP/AZT from

NVP, 800; extended

6 m

onths 1.7%

extended NVP and

NVP, 3.6%

at 6 m

onths;

day 7 to 14 weeks

NVP/AZT, 801

1.6% N

VP/AZT extended N

VP/AZT 15.0%

at 12 months

BAN; M

alawi –

Mother: N

o antepartum

BF: infant NVP arm

, CD4: 440; H

IV RNA:

BF only; duration not Birth: enrolled at

Cumulative at 7 m

onths U

ninfected at 2 weeks:

[25]Infant prophylaxis

ARVs; Infant: sdNVP+

848 enrolled not specified

specified (counseled delivery, rates based on

(uninfected at 2 weeks):

Extended infant arm

; Randomized

AZT/3TC ×1 week, then

to wean at 6 m

onths) uninfected at 2 w

eeks; 1.8%

; Increment

NVP arm

, 2.9%

trial for wom

en daily N

VP to age

Cumulative at 6 w

eeks from

2 weeks

at 7 months

with CD4 >250

6 months

not specified

to 6 months: 1.8%

Table 3. Study results for infant antiretroviral postnatal prophylaxis studies

aRange values shown in parentheses are 95%

confidence intervals. ARV, antiretroviral; AZT, zidovudine; BAN, Breastfeeding, Antiretroviral and N

utrition study; BF, breastfed; CD4, CD

4+ T-cell count, m

easured in cells/µl; ddI, didanosine; EBF, exclusive breastfeeding; FF, form

ula fed; ND

, no data; NVP, nevirapine; PEPI-M

alawi, Post-Exposure Prophylaxis of the Infant study; sdN


Mother to Child via Breastfeeding in

Africa study; SWEN

, Six Week Extended N

evirapine study; 3TC, lamivudine.




Ba

selin

e m

edia

n

Ti

min

g of

mat

erna

l

mat

erna

l CD4

,

Stud

y na

me,

tr

iple

ART

cells

/µl a

nd H

IV

H

IV tr

ansm

issio

n at

H

IV tr

ansm

issio

n at

loca

tion

and

desig

n ad

min

istra

tion

Num

ber o

f inf

ants

RN

A, c

opie

s/m

l In

fant

feed

ing

birt

h an

d 4–

6 w

eeks

a 6–

7 m

onth

sa H

IV o

r dea

th

Refe

renc

e

DREA

M; M

ozam

biqu

e;

Med

ian

26.8

wee

ks

985

Mot

hers

enr

olle

d;

CD4:

489

; HIV

FF

and

BF;

BF

dura

tion

Bi

rth:

ND;

Cum

ulat

ive

at

Cum

ulat

ive

at 6

mon

ths:

5.3

%;

Not

spe

cifie

d [2

6]

Obs

erva

tiona

l ge

stat

ion

to

707

Infa

nts

test

ed a

t RN

A: 4

.27

log

not s

peci

fied

4

wee

ks: 3

.8%

(3.1

–4.5

) In

crem

ent f

rom

4 w

eeks

to

6

mon

ths

1 m

onth

, 467

infa

nts

(cou

nsel

led

to w

ean

6

mon

ths:

1.5

% (0

.9–2

.1)

po

stpa

rtum

if B

F te

sted

at 6

mon

ths;

Did

at 6

mon

ths)

not s

peci

fy %

FF

vers

us B

F

DREA

M; M

ozam

biqu

e;

25 W

eeks

ges

tatio

n

FF, 8

91 (d

ata

on 8

09

Not

spe

cifie

d FF

and

BF;

BF

dura

tion

Bi

rth:

ND;

Cum

ulat

ive

at

Cum

ulat

ive

at 6

mon

ths:

2.2

%

Not

spe

cifie

d;

[27]

Obs

erva

tiona

l to

6 m

onth

s

infa

nts)

; BF,

341

infa

nts

not s

peci

fied

4

wee

ks: 1

.2%

(4/3

41 B

F)

(0.6

–3.8

; 6/2

66 B

F); I

ncre

men

t In

fant

mor

talit

y at

po

stpa

rtum

if B

F te

sted

at 1

mon

th, 2

51

(c

ouns

elle

d to

wea

n

from

4 w

eeks

to 6

mon

ths:

6

mon

ths:

2.8

5 pe

r

infa

nts

test

ed a

t 6 m

onth

s

at 6

mon

ths)

0.8%

(0.1

–2.8

; 2/2

51 B

F)

100

pers

on-y

ears

KiBS

; Ken

ya;

34 W

eeks

ges

tatio

n

BF, 4

97 in

fant

s CD

4: 3

94 (2

4%

BF o

nly;

Dur

atio

n no

t Bi

rth:

2.4

% (1

.4–4

.2);

Cu

mul

ativ

e at

6 m

onth

s: 5

.0%

N

ot s

peci

fied

[28]

Obs

erva

tiona

l to

6 m

onth

s

CD4≤

250)

; sp

ecifi

ed (c

ouns

elle

d to

Cu

mul

ativ

e at

6 w

eeks

:

(3.4

–6.3

); In

crem

ent

po

stpa

rtum

HIV

RN

A: 4

.5 lo

gw

ean

at 6

mon

ths)

3.

9% (2

.5–6

.0);

Incr

emen

t fr

om 1

wee

k an

d 6

mon

ths:

2.6

%

fr

om d

ay 1

to

6

wee

ks: 1

.5%

Mitr

a-Pl

us; T

anza

nia;

34

Wee

ks g

esta

tion

50

1 M

othe

rs e

nrol

led,

441

CD

4: 4

15 (1

7.5%

BF

onl

y; M

edia

n

Birt

h: N

D; C

umul

ativ

e at

Cu

mul

ativ

e at

6 m

onth

s: 5

.0%

8.

6% (6

–11.

2) a

t [2

9]

Obs

erva

tiona

l to

6 m

onth

s w

ith d

ata;

BF

441

infa

nts

CD4<

200)

; du

ratio

n 24

wee

ks

6 w

eeks

: 4.1

% (2

.2–6

.0;

(2.9

–7.1

; 22/

397

infa

nts)

; Inc

rem

ent

6 m

onth

s; 12

.8%

po

stpa

rtum

HIV

RN

A: 1

4,62

1

18/4

23 in

fant

s)

from

6 w

eeks

to 6

mon

ths:

1.0

%

(9.6

–16)

at 1

2 m

onth

s

Amat

a; R

wan

da;

28 W

eeks

ges

tatio

n

562

Mot

hers

enr

olle

d, 5

51

CD4:

Mea

n 49

8

FF (5

7%) a

nd B

F (4

3%);

BF

; Birt

h: 1

.3%

(3/2

27 in

fant

s);

BF: C

umul

ativ

e at

9 m

onth

s:

BF: 4

.9%

(3–9

; 7/2

16

[30]

Obs

erva

tiona

l to

7 m

onth

s

deliv

ered

, 532

infa

nts

aliv

e

(IQR

326–

659)

; BF

dur

atio

n no

t Cu

mul

ativ

e at

6 w

eeks

: 1.

8% (0

.7–4

.8; 4

/227

infa

nts)

;

infa

nts)

at 9

mon

ths

po

stpa

rtum

if B

F af

ter 2

day

s; BF

227

infa

nts

HIV

RN

A: N

ot

spec

ified

; (co

unse

lled

1.

3% (0

.4–4

.1);

Incr

emen

t In

crem

ent f

rom

6 w

eeks

to

sp

ecifi

ed

to w

ean

at 6

mon

ths)

fr

om b

irth

to 6

wee

ks: 0

%

6 m

onth

s: 0

.5%

(1/2

27 B

F)

Mm

a Ba

na S

tudy

; 26

–34

Wee

ks

BF, 5

60 m

othe

rs e

nrol

led,

CD

4: 3

93–4

03;

BF o

nly;

71%

BF

for

Birt

h: M

ater

nal t

riple

-dru

g

Cum

ulat

ive

at 6

mon

ths:

1.1

%

Not

spe

cifie

d; In

fant

[3

1]

Bots

wan

a; R

ando

miz

ed

gest

atio

n to

55

3 in

fant

s w

ith 6

mon

th

HIV

RN

A:

≥5 m

onth

s bu

t <1%

pr

ophy

laxi

s ar

ms

com

bine

d:

(0.5

–2.0

); In

crem

ent f

rom

m

orta

lity

at 6

mon

ths:

com

para

tive

tria

l for

6

mon

ths

da

ta

9,10

0–13

,300

af

ter 6

mon

ths;

93%

0.

7% (4

/553

infa

nts)

; No

bi

rth

to 6

mon

ths:

0.4

%

2.5%

wom

en w

ith C

D4>2

00

post

part

um;

re

port

ed E

BF

6-w

eek

data

but

no

intr

apar

tum

M

edia

n du

ratio

n

to

wea

ning

tr

ansm

issio

n; th

us, i

ncre

men

t

11

wee

ks

fr

om b

irth

to 4

wee

ks: 0

%

Kesh

o Bo

ra; K

enya

, 28

–36

Wee

ks

BF: m

ater

nal t

riple

-dru

g

CD4:

335

; HIV

FF

(23%

) and

BF

(77%

);

Birt

h: 1

.8%

(0.8

–3.7

);

Cum

ulat

ive

at 6

mon

ths:

4.9

%

Mat

erna

l trip

le-d

rug

[3

2]

Sout

h Af

rica,

Bur

kina

ge

stat

ion

to

prop

hyla

xis

arm

, 413

RN

A: N

ot

med

ian

dura

tion

Cu

mul

ativ

e at

6 w

eeks

: 3.3

(3

.1–7

.5);

Incr

emen

t fro

m

prop

hyla

xis

arm

: 8.3

%

Faso

; Ran

dom

ized

tria

l for

6.

5 m

onth

s m

othe

rs e

nrol

led,

402

sp

ecifi

ed

21.4

wee

ks; 4

6% E

BF

(1.9

–5.6

); In

crem

ent f

rom

6

wee

ks to

6 m

onth

s: 1

.6%

(6

–11.

5) a

t 6 m

onth

s; 10

.4%

wom

en w

ith C

D4 2

00–5

00 p

ostp

artu

m

live

birt

hs

at

3 m

onth

s bi

rth

to 6

wee

ks: 1

.5%

(7.7

–13.

9) a

t 12

mon

ths

BAN

; Mal

awi –

Mat

erna

l CD

4>25

0;

BF: m

ater

nal t

riple

-dru

g

CD4:

428

; HIV

BF

onl

y; d

urat

ion

not

Birt

h: E

nrol

led

at d

eliv

ery;

Cu

mul

ativ

e at

7 m

onth

s U

ninf

ecte

d at

2 w

eeks

:

[25]

prop

hyla

xis

arm

; De

liver

y to

pr

ophy

laxi

s ar

m,

RNA:

Not

sp

ecifi

ed (c

ouns

elle

d to

Ra

tes

base

d on

uni

nfec

ted

(u

ninf

ecte

d at

2 w

eeks

): 3.

0%;

Mat

erna

l trip

le-d

rug

Rand

omiz

ed tr

ial f

or

6 m

onth

s 85

1 m

othe

rs e

nrol

led

spec

ified

w

ean

at 6

mon

ths)

at

2 w

eeks

; Cum

ulat

ive

at

Incr

emen

t fro

m 2

wee

ks to

pr

ophy

laxi

s ar

m: 4

.7%

wom

en w

ith C

D4>2

50

post

part

um

6

wee

ks: n

ot s

peci

fied

6 m

onth

s: 3

.0%

at

7 m

onth

s

Tabl

e 4.

Stu

dy re

sult

s fo

r m

ater

nal a

ntire

trov

iral p

ostn

atal

pro

phyl

axis

stu

dies

a Ran

ge v

alue

s sh

own

in p

aren

thes

es a

re 9

5% c

onfid

ence

inte

rval

s. AR

T, an

tire

trov

iral t

hera

py; B

AN, B

reas

tfee

ding

, Ant

iretr

ovira

l and

Nut

ritio

n st

udy;

BF,

brea

stfe

d; C

D4,

CD

4+ T-

cell

coun

t m

easu

red

in c

ells

/µl;

DRE

AM, D

rug

Reso

urce

En

hanc

emen

t ag

ains

t AI

DS

and

Mal

nutr

itio

n st

udy;

EBF

, exc

lusi

ve b

reas

tfee

ding

; FF,

form

ula

fed;

IQR,

inte

rqua

rtile

rang

e; K

iBS,

Kis

umu

Brea

stfe

edin

g St

udy;

ND

, no

data

.


LM Mofenson


prophylaxis (Tables 2 and 4), which reported the lowest rate of infant infection of all studies to date (cumulative infection 1% at age 6 months) had a median mater-nal CD4+ T-cell count at enrolment of approximately 400 cells/µl, baseline HIV RNA levels prior to initia-tion of prophylaxis of 9,100–13,300 copies/ml, median duration of antepartum prophylaxis of 11 weeks, a pro-portion of infants exclusively breastfeed through age 6 months of 93%, and an adherence rate to maternal prophylaxis of 93% [32]. By contrast, in the maternal prophylaxis arm of the Kesho Bora trial (Tables 2 and 4), where the 6-month cumulative HIV infection rate was 4.9%, the median maternal CD4+ T-cell count at enrolment was 335 cell/µl, median duration of antepar-tum prophylaxis was 6 weeks, and only 48% of infants exclusively breastfed to 3 months [31]. Thus, it is dif-ficult to make direct comparisons even between studies of similar interventions.

Given these caveats, the currently available data suggest that provision of antiretroviral drugs to the breastfeeding infant could have comparable efficacy to provision of maternal combination antiretroviral prophylaxis to the lactating mother. Tables 3 and 4 pro-vide data on six infant prophylaxis studies and eight maternal prophylaxis studies aimed at reducing postna-tal transmission that have been published or presented at meetings as of February 2010, and includes data on the timing and type of prophylaxis, numbers enrolled, maternal CD4+ T-cell count and HIV RNA level (when available), infant feeding and duration of feeding, trans-mission rates at birth, 4–6 weeks and 6–7 months, the incremental risk of early (before 4–6 weeks) and late (between 4–6 weeks and 6–7 months) postnatal infec-tion (when available) and rates of HIV or death (HIV-free survival, when available) [20–32].

Because of differences among the studies in admin-istration of maternal antepartum antiretroviral drugs, comparison of cumulative rates of transmission is mis-leading when trying to compare the effect of the inter-ventions to reduce breast milk transmission. This is because the infection rate at birth, reflecting in utero infection, will be lower if the mother has received drugs during pregnancy than if she received no drugs, and fur-ther will be lower with longer than with shorter dura-tion of antepartum drug administration. Therefore, when considering the effect of the postpartum interven-tion, the better comparison is the rate of infection at 4–6 weeks or 6–7 months in infants who are uninfected at birth; however, many of the maternal prophylaxis studies do not provide information on infection rates at birth, and, as a result, only the comparison of late post-natal infection occurring between 4–6 weeks and 6–7 months was possible between maternal and infant strat-egies. Another problem is that the duration of the actual postnatal intervention also differs between the studies.

Specifically, two large infant prophylaxis randomized trials provided 6 and 14 weeks of prophylaxis, whereas all the maternal studies provided 6 months of prophy-laxis; thus, comparisons of late transmission might also be misleading.

In the four maternal prophylaxis and the four infant prophylaxis studies with adequate information for a meaningful comparison of early postnatal infection rates (that is, studies that provided transmission rates at birth to allow assessment of in utero infection and 4–6 week data to allow description of the increment in infection between birth and 4–6 weeks of age), the rate of infec-tion at age 4–6 weeks in infants uninfected at birth with maternal prophylaxis was 0% in Amata and Mma Bana studies, 1.5% in the Kisumu Breastfeeding Study (KiBS), and 1.5% in the Kesho Bora study (Table 4) [28,30–32], and with infant prophylaxis was 0.8% in the Stopping Infection from Mother to Child via Breastfeeding in Africa (SIMBA) study, 1.3% in the Mashi study, 1.7% in the PEPI-Malawi study and 2.5% in the SWEN study (Table 3) [20,22–24]. Thus, the early (between birth and age 4–6 weeks) postnatal infection rates appear rela-tively similar with either maternal (range 0–1.5%) or infant (range 0.8–2.5%) interventions.

Although the ability to evaluate late postnatal infection between 4–6 weeks and 6–7 months of age is possible for most of the studies, it is important to note that in some of the infant prophylaxis studies the intervention stops at 6–14 weeks. In the mater-nal prophylaxis studies, the rates of late postnatal infection are 0.4% (Mma Bana study), 0.5% (Amata study), 0.8% (Drug Resource Enhancement against AIDS and Malnutrition [DREAM] study [27]), 1.0% (Mitra-Plus study), 1.5% (DREAM study [26]), 1.6% (Kesho Bora study), and 2.6% (KiBS study; Table 4) [25–32]. In the infant prophylaxis studies, in which infant prophylaxis was given for 6 months as in the maternal studies allowing a comparison of prophylaxis over similar time periods, the rates of late postnatal infection were 0.8% (SIMBA study), 1.2% (Mitra study) and 4.4% (Mashi study; Table 3) [20–22]. Of note, the one infant prophylaxis study with the highest rate of late infection (4.4%) gave infant zidovudine prophylaxis, whereas all the others used nevirapine or lamivudine [20]. The late infection rate in the PEPI-Malawi study, where infant prophy-laxis stopped at 14 weeks, was 2.3% [24]. The SWEN study only administered 6 weeks of infant prophy-laxis and therefore no prophylaxis was being received during the period of late transmission risk (after age 6 weeks) [23]. Thus, in the evaluable studies, the late (4–6 weeks to 6 months) postnatal infection rates also appear relatively similar with either maternal (range 0.4–2.6%) or infant (range 0.8–4.4%) interventions. In studies that provided data on the end point of HIV




or death, comparisons at age 6–7 months ranged from 4.7–8.6% in the maternal prophylaxis studies and 2.9–8.5% in infant prophylaxis studies.

Taken together, the early and late postnatal infection rates appear relatively low and similar with either mater-nal or infant interventions if being compared during similar periods of prophylaxis. The Mitra study of infant prophylaxis and Mitra-Plus study of maternal prophy-laxis provide a non-randomized comparison of interven-tions, as both studies were conducted sequentially in the same clinics, both provided some maternal antepartum antiretroviral prophylaxis, and both provided the same duration (6 months) of postnatal prophylaxis (Table 2) [21,29]. The cumulative transmission risk at 6 months was 4.9% with infant prophylaxis in Mitra and 5.0% with maternal prophylaxis in Mitra-Plus, and the risk of late transmission between 6 weeks and 6 months was 1.2% with infant prophylaxis and 1.0% with maternal prophylaxis (Tables 3 and 4).

Data from a randomized comparison of maternal and infant interventions for prevention of postnatal transmission is available from the BAN study, which compared 6 months of maternal prophylaxis or infant nevirapine prophylaxis to a control short-course arm with no maternal or infant prophylaxis during breast-feeding (Table 2) [25]; this study evaluated an intra-partum and postpartum intervention (no maternal antenatal drugs were received) and enrolled women with CD4+ T-cell counts >250 cells/µl. Postnatal trans-mission rates at age 28 weeks (7 months) in infants uninfected at age 2 weeks were 6.4% in the control arm compared with 3.0% in the maternal prophylaxis arm (P=0.0032 versus control) and 1.8% in the infant nevirapine arm (P<0.0001 versus control; Table 2). Although the transmission rate in the infant nevirap-ine arm appeared lower than in the maternal prophy-laxis arm, there was no significant difference between maternal and infant prophylaxis arms (P=0.12) and the study was not powered to detect a difference between the two experimental arms.

The data from these studies also indicate the importance of providing antiretroviral drugs during the antepartum period, and that longer antepartum prophylaxis is more effective than shorter prophylaxis. In the maternal prophylaxis studies where initiation of antiretroviral prophylaxis started at 25–34 weeks gestation, overall 6–7 month transmission rates were 1–5% (Table 4) [26–32]. In the infant prophylaxis studies in which maternal antepartum prophylaxis was given but started significantly later, at 34–36 weeks gestation, overall 6–7 month transmission rates were 5–9% [20–22], whereas in the infant prophylaxis studies where no maternal antepartum drugs were received, overall 6 month transmission rates were approximately 11–12% [23,24] (Table 3). Thus, for

optimal prevention of mother-to-child transmission, it is crucially important to identify HIV-infected women early in pregnancy and initiate prophylaxis by at least 28 weeks gestation, if not earlier.

Given two presumably similarly effective interven-tions, the choice of intervention to prevent mother-to-child transmission for women who do not require treatment for their own health will involve weigh-ing a number of different considerations, including relative costs, feasibility, and risks and benefits of the interventions (Table 5). Few studies have evaluated the cost-effectiveness of these two interventions [34]. When administering maternal triple-drug combination therapy solely for prevention of transmission, the risks of maternal drug toxicities, treatment interruption fol-lowing prolonged exposure to three drug combination prophylaxis during pregnancy and breastfeeding (pre-suming treatment stops after cessation of breastfeed-ing), and of fetal exposure to multiple drugs, need to be weighed against the incremental benefit in prevent-ing transmission compared to less complex regimens in the population of women who do not yet need treat-ment for their own health. Infant prophylaxis is less expensive but might be programmatically more difficult to implement if combined with use of zidovudine plus single-dose nevirapine plus a ‘tail’ to reduce nevirapine resistance and prevent in utero/intrapartum infection. None of the studies to date have been adequately pow-ered to address the comparative efficacy and safety of maternal versus infant prophylaxis, and although there are studies planned (Table 6), data will not be available for several years.

Safety of infant and maternal antiretroviral prophylaxis

Table 7 summarizes toxicity reports from the infant and maternal prophylaxis studies. Evaluation of safety can be best assessed in the randomized clinical trials. The SWEN and PEPI-Malawi large randomized clini-cal trials of 6 and 14 weeks of extended daily infant nevirapine prophylaxis (Table 2), respectively, together enrolled 5,090 infants [23,24]. There were no signifi-cant differences in infant adverse events (including rash and hepatic events) between the experimental and con-trol arms (control arm was single-dose nevirapine in SWEN and single-dose nevirapine plus 1 week of infant zidovudine in PEPI-Malawi). The SWEN trial found significantly lower infant mortality at 6 months in the extended nevirapine group compared with the control arm, whereas the PEPI-Malawi trial found similar rates of mortality at 9 months between the two extended infant prophylaxis arms and the control arm (Table 7).

In the PEPI-Malawi trial, infants in the extended dual nevirapine/zidovudine prophylaxis arm had a


LM Mofenson


significantly higher number of infant adverse events deemed possibly related to study drug (primarily neu-tropaenia) compared with the control group (Table 7) [24]. Thus, the addition of zidovudine potentially increased toxicity of the extended infant prophylaxis, without increasing efficacy, as there was no significant difference in efficacy between the two extended proph-ylaxis arms [24]. The Mashi trial randomized infants to formula feeding with 1 month of infant zidovudine or to infant breastfeeding with 6 months of infant zidovu-dine. There were significantly higher rates of grade 3 or 4 signs or symptoms in infants receiving 6 months ver-sus 1 month of zidovudine and higher rates of grade 3 or

4 laboratory abnormalities, particularly neutropaenia, similar to the PEPI-Malawi trial (Table 7) [20]. Finally, the SIMBA trial compared extended infant prophylaxis with daily lamivudine or daily nevirapine; there were no significant differences in serious adverse events or mortality between the two study arms [22].

The BAN trial compared 6 months of maternal triple-drug combination prophylaxis and 6 months of infant daily nevirapine prophylaxis to a control intervention of single-dose nevirapine with 1 week of zidovudine/lamivudine (Table 2). Mothers in the triple-drug com-bination prophylaxis arm had significantly higher rates of grade 3 or 4 neutropaenia than those in the infant

Infant antiretroviral prophylaxis (combined with AZT/sdNVP Maternal antiretroviral prophylaxis (given duringFactor with 1-week antiretroviral ‘tail’ to prevent resistance) pregnancy and through breastfeeding postpartum)

Comparative Similar effectiveness to maternal triple-drug combination Same as adjacent.efficacy prophylaxis for prevention of in utero infection in women with high CD4 (Kesho Bora trial in women with CD4 200–500, transmission at birth 2.2% with AZT/sdNVP regimen versus 1.8% with maternal triple-drug regimen). No study with adequate power to provide comparative efficacy of infant versus maternal postnatal prophylaxis in women with CD4>350, although available data suggest at minimum similar efficacy. Cost Inexpensive. More expensive.Pregnancy No indication of adverse effect on pregnancy outcome. Potential increase in preterm delivery or low birth weight outcome safety with maternal triple-drug regimen seen in some studies in resource-limited and resource-rich countries.Maternal safety Use of intrapartum sdNVP can be associated with NVP Possible higher rates of haematological toxicity. resistance in mother, hence need for AZT/3TC (or other Effect on maternal health of interruption of drugs drug) ‘tail’ to prevent resistance. No maternal drugs postpartum. after prolonged use during pregnancy and breastfeeding and of repeated courses with subsequent pregnancies is a concern. No data on prophylaxis extended past 6 months.Infant safety Up to 6 months of daily NVP prophylaxis is safe. No data Infant exposed to subtherapeutic levels of antiretroviral on more prolonged prophylaxis yet. drugs in maternal milk, although BAN trials suggests similar safety between infant and maternal prophylaxis.Resistance If infant is receiving prophylaxis during breastfeeding and If mother is receiving triple-drug during breastfeeding and becomes infected, drug resistance likely. infant becomes infected, drug resistance is likely.Choice of drug Extended prophylaxis with infant NVP as effective as More complicated: NVP hepatotoxicity a concern; in NVP/AZT (PEPI-Malawi study) resource-rich countries, protease-inhibitor-based regimens used for prophylaxis; use of EFV for prolonged periods postpartum a concern regarding risk for teratogenicity should woman become pregnant again.Complexity Use of AZT/sdNVP and ‘tail’ is more complex. Use of single regimen during pregnancy and postpartum might be easier to implement.Assessment of CD4 prior to initiation important to determine which CD4 prior to initiation important as maternal drugs are mother for women require treatment for own health. CD4 could be stopped after infection risk ceases (should not stop treatment need obtained and antepartum AZT (or postnatal NVP) initiated drugs if maternal CD4<350). Regimen likely to be(for example, while waiting for result; women with CD4<350 can then different for women with CD4>350 where NVP cannot beCD4 count) be switched to cART for own health which also provides safely used. postnatal prophylaxis.

Table 5. Issues relating to choice of infant versus maternal postnatal antiretroviral prophylaxis for preventing breast milk HIV transmission for women with CD4>350 cells/µl who do not require treatment for their own health

AZT, zidovudine; BAN, Breastfeeding, Antiretroviral and Nutrition study; cART, combination antiretroviral therapy; CD4, CD4+ T-cell count, measured in cells/µl; EFV, efavirenz; NVP, nevirapine; PEPI-Malawi, Post-Exposure Prophylaxis of the Infant study; sdNVP, single-dose nevirapine; 3TC, lamivudine




Stud

y na

me

In

fant

feed

ing

An

tepa

rtum

In

trap

artu

m

Post

part

um

Post

part

um

and

loca

tion

Stud

y de

sign

and

enro

lmen

t re

gim

en

regi

men

m

othe

r reg

imen

in

fant

regi

men

Co

mm

ents

ANRS

-PEP

; Bur

kina

Po

stpa

rtum

inte

rven

tion

BF

; n=1

,500

In

fant

enr

olle

d

Infa

nt e

nrol

led

In

fant

enr

olle

d po

stpa

rtum

Ar

m 1

: sdN

VP a

t birt

h;

To s

tart

in 2

010

Faso

, Sou

th A

fric

a,

com

parin

g in

fant

pro

phyl

axis

(in

pla

nnin

g)

post

part

um

post

part

um

3T

C fr

om d

ay 7

to

Uga

nda,

Zam

bia

durin

g BF

for 9

mon

ths

to

9 m

onth

s; Ar

m 2

: sdN

VP

no

pro

phyl

axis

at b

irth;

pla

cebo

from

day

7 to

9 m

onth

s

Prom

otin

g M

ater

nal

For w

omen

who

do

not r

equi

re

BF a

nd F

F; R

esou

rce

CD

4>35

0 st

artin

g

Arm

1: s

dNVP

+TDF

/FTC

CD

4>35

0; P

ostp

artu

m

Post

part

um

Star

t: U

S/So

uth

Infa

nt S

urvi

val

trea

tmen

t for

ow

n he

alth

lim

ited:

app

roxi

mat

ely

at

14

wee

ks;

(for

7 d

ays

ra

ndom

izat

ion

at d

ay 7

: Arm

3:

rand

omiz

atio

n at

day

7:

Amer

ica,

late

fall

Ever

ywhe

re

(CD4

>350

); W

ill a

ddre

ss:

8,00

0 m

othe

r–in

fant

An

tepa

rtum

po

stpa

rtum

); Ar

m 2

: in

fant

NVP

pro

phyl

axis

to

Arm

3: s

dNVP

+AZT

×7

20

09; R

esou

rce-

(PRO

MIS

E-

Wha

t is

optim

al a

ntep

artu

m/

pairs

; ra

ndom

izat

ion;

Arm

1:

AZT/

3TC/

LPV/

RTV

(for

ce

ssat

ion

of B

F (u

p to

da

ys; N

VP fr

om d

ay 7

to

limite

d co

untr

ies,

IMPA

ACT

1077

);

post

part

um re

gim

en to

U

S/So

uth

Amer

ica:

AZ

T; A

rm 2

: mat

erna

l 7

days

pos

tpar

tum

) 18

mon

ths)

with

no

mat

erna

l

cess

atio

n of

BF

(up

to

sum

mer

201

0

Mul

tiple

cou

ntrie

s

prev

ent M

TCT?

Is it

saf

e fo

r 2,

000

mot

hers

tr

iple

-dru

g pr

ophy

laxi

s

ARV;

Arm

4: m

ater

nal

18 m

onth

s); A

rm 4

:

in A

fric

a, A

sia,

m

othe

rs to

sto

p tr

iple

-dru

g

AZT/

3TC/

LPV/

RTV

tr

iple

-dru

g pr

ophy

laxi

s: T

DF/

sdN

VP+A

ZT ×

7 da

ys;

Sout

h Am

eric

a, U

S pr

ophy

laxi

s af

ter r

ecei

ving

it

FT

C/LP

V/RT

V to

ces

satio

n In

fant

hea

lth

on

ly fo

r PM

TCT?

How

can

we

of

BF

(up

to 1

8 m

onth

s);

rand

omiz

atio

n: B

F, in

fant

m

aint

ain

heal

th o

f uni

nfec

ted

M

ater

nal H

ealth

rand

omiz

atio

n un

infe

cted

and

in

fant

s af

ter w

eani

ng?

to

sto

p or

con

tinue

mat

erna

l <1

2 m

onth

s at

tim

e of

BF

Re

sour

ce-l

imite

d co

untr

ies:

trip

le-d

rug

ARV:

If F

F, ce

ssat

ion;

Arm

1:

An

tepa

rtum

/intr

apar

tum

/

on m

ater

nal t

riple

-dru

g Co

trim

oxaz

ole

to

po

stpa

rtum

inte

rven

tion

in

pr

ophy

laxi

s an

d CD

4>35

0,

18 m

onth

s: A

rm 2

:

w

omen

with

CD4

>350

,

rand

omiz

e at

day

7–1

2;

Cotr

imox

azol

e pl

aceb

o

se

quen

tial r

ando

miz

atio

ns;

if

BF, o

n m

ater

nal t

riple

- to

18

mon

ths

U

S/So

uth

Amer

ica:

onl

y

drug

pro

phyl

axis,

rand

omiz

e

pa

rtic

ipat

e in

the

Mat

erna

l

at c

essa

tion

of B

F; U

S/So

uth

H

ealth

rand

omiz

atio

n

Amer

ica:

If tr

iple

-dru

g

pr

ophy

laxi

s du

ring

preg

nanc

y

an

d CD

4>40

0, ra

ndom

ize

af

ter d

eliv

ery

ANRS

122

00;

An

tepa

rtum

/intr

apar

tum

/ BF

and

FF;

n=u

nkno

wn

St

artin

g at

20

wee

ks;

Arm

1: T

DF/F

TC/E

FV;

If BF

, con

tinue

6–9

mon

ths

Ar

m 1

: AZT

×1

wee

k?

In p

lann

ing,

to

Côte

d’Iv

oire

po

stpa

rtum

inte

rven

tion

Arm

1: M

ater

nal

Arm

2:

post

part

um; A

rm 1

: Ar

m 2

: AZT

×1

wee

k?

star

t 201

0

co

mpa

ring

two

trip

le-d

rug

regi

men

: TDF

/FTC

/EFV

; AZ

T/3T

C/LP

V/RT

V TD

F/FT

C/EF

V; A

rm 2

:

re

gim

ens

to p

reve

nt M

TCT;

Arm

2: M

ater

nal

AZ

T/3T

C/LP

V/RT

V

Ra

ndom

ized

tria

l

regi

men

: AZT

/3TC

/LPV

/RTV

(n

on-i

nfer

iorit

y de

sign)

Tabl

e 6.

Pla

nned

stu

dies

on

prev

enti

on o

f m

othe

r-to

-chi

ld H

IV t

rans

mis

sion

ANRS

, Age

nce

Nat

iona

le d

e Re

cher

ches

sur

le S

ida;

ARV

, ant

iretr

ovira

ls; A

ZT, z

idov

udin

e; B

F, br

east

fed;

CD

4, C

D4+

T-ce

ll co

unt,

mea

sure

d in

cel

ls/µ

l; EF

V, e

favi

renz

; FF,

form

ula

fed;

FTC

: em

tric

itab

ine;

LPV

/RTV

, lop

inav

ir/rit

onav

ir; M

TCT,

mot

her-

to-c

hild

tra

nsm

issi

on; N

VP, n

evira

pine

; PEP

, pos

t-ex

posu

re p

roph

ylax

is; P

MTC

T, pr

even

tion

of

mot

her-

to-c

hild

tra

nsm

issi

on; s

dNVP

, sin

gle-

dose

nev

irapi

ne; T

DF,

teno

fovi

r; 3

TC, l

amiv

udin

e.


LM Mofenson


N

umber of

Postnatal m

othersStudy

Design prophylaxis type

and/or infants M

aternal toxicities and adverse events Infant toxicities and adverse events

Mashi

Randomized

Infant 1,200 M

others, G

rade 3 or 4 toxicities in all mothers (n=1,200; all

Grade 3 or 4 toxicities by 7 m

onths in FF with AZT ×1 m

onth arm (n=602)

trial

prophylaxis 1,179 live-born

mothers received AZT antepartum

and sdNVP or

and BF with AZT ×6 m

onths arm (n=598), respectively:

infants

placebo intrapartum);

≥1 Clinical event: 17.6%, 13.1%

(P=0.03);

≥1 Clinical event: 2.8%

in overall group ≥1 Laboratory event: 14.8%

, 24.7% (P<0.001);

≥1 H

ospitalization: 20.3%, 15.6%

(P=0.04);

Toxicity leading to cessation of AZT: 1.7%, 9.2%

(P=0.001 haemoglobin:

0.8%

, 1.0%; neutrophils: 0.3%

, 7.7%)

Mitra

Observational

Infant 398 Infants

Did not report specific toxicities Did not report specific toxicities, but state that no SAE w

as considered

prophylaxis

related to study medication;

M

ortality (6 months): 3.7%

SIMBA

Randomized

Infant 397 Infants

Did not report specific toxicities G

rade 3 or 4 toxicities by 7 months in 3TC arm

(n=199) and NVP arm

trial

prophylaxis

(n=198), respectively:

≥1 Event: 15%

, 22%;

M


, 4%SW

EN

Randomized

Infant 2,074 Infants

Not part of study

Grade 3 or 4 SAE by 7 m

onths in sdNVP arm

(n=1,047) and extended NVP

trial,

prophylaxis

arm

(n=977), respectively:

≥1 Event: 39.9%, 38.4%

;

Neutrophils: grade 3, 8.9%

, 10.4%; grade 4, 5.0%

, 3.3%;

ALT: grade 3, 0%

, 0%; grade 4, 0.1%

, 0%;

Rash: grade 3, 0.5%

, 0.7%; grade 4, 0%

, 0%;

M


, 1.1% (P=0.02)

PEPI-Malaw

i Random

ized Infant

3,016 Infants N

ot part of study G

rade 3 or 4 SAE in control arm (n=1,003), extended N

VP arm (n=1,016)

trial

prophylaxis

or extended N

VP/AZT arm (n=997), respectively:

≥1 Possibly related SAE: 3.4%

, 4.3%, 6.2%

(primarily neutropaenia; P=0.02);

≥1 Probably related SAE: 0.1%

, 0.6%, 0.5%

;

Mortality (9 m

onths): 9%, 7%

, 6%BAN

Random

ized Infant or

2,637 Mother–

Grade 3 or 4 toxicities by 28 w

eeks in control arm (n=668),

Grade 3 or 4 toxicities by 28 w

eeks in control arm (n=668), m

aternal triple-

trial m

aternal infant pairs

maternal triple-drug prophylaxis arm

(n=851) and infant drug prophylaxis (n=851) arm

and infant prophylaxis arm (n=848),

triple-drug

prophylaxis arm (n=848), respectively:

respectively:

prophylaxis

H

aemoglobin: 1.7%

, 1.6%, 0.8%

; H

aemoglobin: 21.6%

, 19.4%, 21.0%

;

N

eutrophils: 2.3%, 6.2%

, 2.8% (P<0.001);

Neutrophils: 0.8%

, 0.5%, 1.1%

;

ALT: 0.5%

, 1.6%, 0.4%

; ALT: 1.0%

, 0.4%, 0.6%

;

N

VP hypersensitivity: 0%, 0.7%

, 0%;

NVP hypersensitivity: 0%

, 0.1%,1.9%

;

M

ortality (28 weeks): 0%

, 0.3%, 0%

M

ortality (28 weeks): 1.0%

, 1.1%, 0.8%

Table 7. Toxicities reported in infant and maternal antiretroviral prophylaxis studies

ABC, abacavir; ALT, alanine transaminase; AZT, zidovudine; BAN

, Breastfeeding, Antiretroviral and Nutrition study; BF, breastfed; D

REAM, D

rug Resource Enhancement against AID

S and Malnutrition study; FF, form

ula fed; KiBs, Kisumu

Breastfeeding Study; LPV/RTV, lopinavir/ritonavir; NVP, nevirapine; PEPI-M

alalwi, Post-Exposure Prophylaxis of the Infant study; SAE, serious adverse event; sdN


Mother to Child

via Breastfeeding in Africa study; SWEN

, Six Week Extended N

evirapine study; 3TC, lamivudine.




Tabl

e 7.

Con

tinu

ed

N

umbe

r of

Post

nata

l m

othe

rsSt

udy

Desig

n pr

ophy

laxi

s ty

pe

and/

or in

fant

s M

ater

nal t

oxic

ities

and

adv

erse

eve

nts

Infa

nt to

xici

ties

and

adve

rse

even

ts

DREA

M

Obs

erva

tiona

l M

ater

nal

Di

d no

t rep

ort s

peci

fic to

xici

ties

Onl

y re

port

ed h

aem

oglo

bin

and

mor

talit

y:

trip

le-d

rug

H

aem

oglo

bin

<8 m

g/dl

: 4.9

% if

FF,

6.8%

if B

F;

prop

hyla

xis

Mor

talit

y (6

mon

ths)

: 2.7

% if

FF,

2.9%

if B

FKi

BS

Obs

erva

tiona

l M

ater

nal

502

Mot

her–

Di

d no

t rep

ort s

peci

fic to

xici

ties

Did

not r

epor

t spe

cific

toxi

citie

s

tr

iple

-dru

g

infa

nt p

airs

prop

hyla

xis

Mitr

a-Pl

us

Obs

erva

tiona

l M

ater

nal

441

Mot

her–

Ra

sh (a

ny):

6.5%

;

Did

not r

epor

t spe

cific

toxi

citie

s;

prop

hyla

xis

infa

nt p

airs

G

rade

3 o

r 4 ra

sh: 1

.6%

; M

orta

lity:

6 m

onth

s, 4.

3%; 1

2 m

onth

s, 8.

5%, 1

8 m

onth

s, 9.

2%

Se

vere

hep

atot

oxic

ity: 0

.5%

Amat

a O

bser

vatio

nal

Mat

erna

l 53

2 M

othe

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LM Mofenson


prophylaxis or control arms (Table 7) [25]. Infant haematological and liver adverse events were similar in all three study arms but rash events were significant greater in the infant prophylaxis arm, although the proportion with rash only was 1.8%; all rash events resolved with change from daily nevirapine to daily lamivudine infant prophylaxis.

The Kesho Bora randomized trial compared antepartum and extended postpartum maternal tri-ple-drug combination therapy to a control arm of zidovudine/single-dose nevirapine without extended postpartum prophylaxis (Table 2). There were no sig-nificant differences in serious adverse events in moth-ers or infants between study arms or in maternal or infant mortality (Table 7) [31].

The Mma Bana study compared two different maternal combination antiretroviral prophylaxis interventions (zidovudine/lamivudine/abacavir versus zidovudine/ lamivudine/lopinavir/ritonavir; Table 2). There was no significant difference in the number of women or infants with grade 3 or 4 diagnoses, grade 3 or 4 laboratory events, or maternal and infant mortality at 6 months between the arms (Table 7) [32]. The rate of preterm delivery, however, was significantly higher in the lopinavir/ritonavir arm than the triple nucleo-side arm, 23% versus 15%, respectively (P=0.04). The rate of low birth weight infants was also higher, 17% versus 13%, although this difference was not statisti-cally significant. There have been some other reports of increased rates of preterm delivery or low birth weight with use of combination triple-drug prophylaxis in other resource-limited countries (Côte d’Ivoire and South Africa) [35,36]. In resource-rich countries, there are conflicting reports regarding pregnancy outcome and use of triple-drug prophylaxis [37,38].

The combined data suggest that daily infant nevi-rapine prophylaxis, studied in 3,016 infants in the SWEN, PEPI-Malawi, SIMBA and BAN trials, appears safe for the infant compared with control interven-tions, with the exception of a higher number of rashes seen in the BAN study only (although the incidence of grade 3 or 4 rash in BAN was <2%). Use of zidovu-dine for infant prophylaxis, either alone or in com-bination with nevirapine, is associated with higher rates of haematological toxicity in infants. Similarly, maternal prophylaxis, studied in 1,824 mother–infant pairs in the Kesho Bora, BAN and Mma Bana trials, appears safe for both the mother and the infant com-pared with control interventions, although the rate of maternal neutropaenia might be increased (BAN trial). There was, however, a concerning increase in the rate of preterm delivery in infants born to moth-ers receiving extended maternal prophylaxis with a lopinavir/ritonavir-based combination drug regimen in the Mma Bana trial, and enhanced surveillance for

adverse pregnancy outcome as use of maternal triple-drug prophylaxis increases is warranted.

Drug resistance with infant or maternal antiretroviral prophylaxis of postnatal transmission

There are concerns regarding potential drug resistance in infants infected postnatally, despite either infant or maternal antiretroviral prophylaxis interventions, and further studies are needed to better define risk.

High rates of nevirapine resistance were seen in breastfed infants in the SWEN study of 6 weeks of infant nevirapine prophylaxis: 92% of infants who became infected during the first 6 weeks of life (that is, dur-ing the period of extended prophylaxis) had nevirapine resistance compared with 38% exposed to single-dose nevirapine only [39]. Although the addition of zidovu-dine to the infant nevirapine prophylaxis regimen in the PEPI-Malawi study did result in lower nevirapine resist-ance among infants infected despite prophylaxis (62% had resistance mutations with extended nevirapine plus zidovudine compared to 86% with extended nevirap-ine prophylaxis; P=0.015), this was only if prophylaxis was discontinued before age 6 weeks, and resistance was still observed in a significant proportion of infected infants [40].

Antiretroviral drug resistance has also been observed in infants infected despite prophylaxis with maternal triple-drug combinations. Three studies have now iden-tified multiclass drug resistance (mutations conferring resistance to nucleoside analogue reverse transcriptase inhibitor drugs as well as to the non-nucleoside drug class) in breastfeeding infants who have become infected despite maternal triple-drug prophylaxis [41–43]

It is known that some antiretroviral drugs enter breast milk, and that the concentration of drug in milk varies by drug. The drug lamivudine appears to concentrate in breast milk, and is present at levels 3–5× that in mater-nal plasma, whereas zidovudine appears to be present at levels similar to or somewhat less than maternal plasma [44]. Nevirapine levels are only approximately 60–75% of maternal plasma, and the protease inhibi-tors that have been studied have reported very limited data on breast milk [45]. Thus, breastfeeding infants who become infected could be ingesting subtherapeutic levels of antiretroviral drugs present in the breast milk of mothers receiving combination drug prophylaxis, and could therefore develop drug-resistant virus.

Although the development of resistance in infants infected despite infant or maternal antiretroviral proph-ylaxis is concerning, it should be noted that the proven efficacy of antiretroviral prophylaxis of the infant or mother to prevent postnatal MTCT means that such regimens remain an attractive choice overall. That is,




although a larger proportion of children who become infected while receiving prophylaxis will develop resist-ance, the absolute number of children who develop resistance is small because the breastfeeding prophy-laxis prevents a substantial number of infections.

Duration of prophylaxis

Both maternal and infant antiretroviral interventions evaluated to date are predicated upon early weaning of the infant, generally at or prior to age 6 months. How-ever, increasing data, including that from the infant and maternal prophylaxis trials, suggest that shortening the duration of breastfeeding to 6 months could be asso-ciated with increased risk of malnutrition and infant mortality caused by infectious diseases. Although some of the studies are problematic (for example, by using historical controls or not accounting for seasonality of diarrhoeal illness), the cumulative data suggest that shortening breastfeeding duration is problematic in many settings. In the postnatal prophylaxis trials, it is clear that HIV transmission risk resumes once prophy-laxis is stopped if breastfeeding continues [20,23,24]; therefore, evaluation of the safety, additional efficacy and cost-effectiveness of more extended postnatal prophylaxis to allow for more prolonged breastfeeding is warranted. Several planned clinical trials are evalu-ating longer durations of infant prophylaxis, rang-ing from 9 to 18 months (ANRS-PEP, PROMISE and ANRS 12200; Table 6).

In the Zambia Exclusive Breastfeeding trial, early abrupt cessation of breastfeeding at 4 months by HIV-infected mothers in Zambia did not improve the rate of HIV-free survival among children born to HIV-infected mothers and was harmful to HIV-infected infants [46]. In the PEPI-Malawi infant prophylaxis study, where weaning at 6 months of age was recommended, there was a significantly higher incidence of gastroenteritis and infant mortality in the period immediately fol-lowing breastfeeding cessation when compared to an historical control with continued breastfeeding [47]. In a study of 118 infants born to women receiving triple- drug antiretroviral therapy during pregnancy and breastfeeding in rural Uganda, the median duration of breastfeeding was 5 months. In multivariate analysis, there was a sixfold greater risk of death among infants breastfed for <6 months independent of maternal CD4+ T-cell count closest to delivery, maternal marital status or maternal death (adjusted hazard ratio =6.19; 95% confidence interval 1.41–27.00; P=0.015) [48]. Simi-larly, in the KiBS open-label study of maternal triple-drug prophylaxis, an increase in serious gastroenteri-tis events, hospitalizations and growth faltering were observed following early breastfeeding cessation around 6 months of age [49]. Additionally, in the Mashi study,

discontinuation of breastfeeding was the primary risk factor for serious infant morbidity [20]. Finally, in an outbreak of diarrhoeal disease associated with heavy rains in Botswana in 2006, a cross-sectional survey found that one-third of children <5 years of age had diarrhoea, which increased levels of acute malnutrition and mortality among children [50]. Breastfeeding was found to be protective, whereas age under 2 years and being HIV-exposed was a risk factor for diarrhoea; this was particularly relevant because national policy in Botswana at that time was for HIV-infected mothers to formula-feed their infants.

WHO has recently revised their guidelines for infant feeding by HIV-infected women, based in part on the clinical trials demonstrating the effectiveness of infant and maternal antiretroviral prophylaxis to reduce post-natal HIV transmission [51]. It is now recommended that national or subnational guidelines be developed to support either breastfeeding accompanied by postna-tal infant nevirapine or maternal triple-drug antiretro-viral prophylaxis for women with CD4+ T-cell count >350 cells/µl or antiretroviral treatment for women with CD4+ T-cell count <350 cells/µl, or avoidance of all breastfeeding, based on economic and cultural fac-tors, available health services, local epidemiology and infant mortality rates [51]. If breastfeeding is recom-mended on the national level, exclusive breastfeeding through age 6 months, followed by continued breast-feeding with addition of complementary foods through age 12 months is recommended; gradual weaning over 1 month is recommended, with discontinuation of anti-retroviral prophylaxis 1 week after complete cessation of breastfeeding.

Conclusions

Prevention of mother-to-child HIV transmission during breastfeeding remains a challenge but we now have new antiretroviral-based prophylaxis approaches that can allow safer and more prolonged breastfeeding by HIV-infected women. There is a crucial need to initiate anti-retroviral therapy among pregnant and lactating HIV-infected women who meet existing criteria for treatment; this intervention would have substantial effect on both maternal mortality and HIV transmission to the infant. In women who do not require treatment, both infant anti-retroviral prophylaxis and maternal combination triple-drug prophylaxis appear to have similar efficacy and both approaches appear relatively safe; however, each has pros and cons that countries will need to consider when choos-ing which to implement on a population basis. Longer duration of prophylaxis than has been studied to date (6 months) appears advisable in terms of infant survival. Pharmacovigilance to evaluate the safety of longer term use of these interventions as well as to evaluate the effect


LM Mofenson


of maternal prophylaxis on pregnancy outcome will be crucial as these interventions are implemented.

Acknowledgements

The author would like to thank Elaine Abrams for her thoughtful input and comments on this manuscript.

Disclosure statement

The author declares no competing interests.

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Accepted for publication 5 April 2010


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Antiretroviral drugs to prevent breastfeeding HIV transmission