501

Dosages of ARV drugs for adults and adolescents

Generic name Dose

Nucleoside reverse-transcriptase inhibitors (NRTIs)

Abacavir (ABC) 300 mg twice daily or 600 mg once daily

Emtricitabine (FTC) 200 mg once daily

Lamivudine (3TC) 150 mg twice daily or 300 mg once daily

Zidovudine (AZT) 300 mg twice daily

Nucleotide reverse-transcriptase inhibitors (NtRTIs)

Tenofovir disoproxil fumarate (TDF)

300 mg once dailya

Tenofovir alafenamide (TAF) 10 or 25 mg once dailyb

Non-nucleoside reverse-transcriptase inhibitors (NNRTIs)

Efavirenz (EFV) 400 mg or 600 mg once daily

Etravirine (ETV) 200 mg twice daily

Nevirapine (NVP) 200 mg once daily for 14 days followed by 200 mg twice daily

Protease inhibitors (PIs)

Atazanavir/ritonavir (ATV/r) 300 mg/100 mg once daily

Darunavir + ritonavir (DRV/r) 800 mg + 100 mg once daily or 600 mg + 100 mg twice daily

Lopinavir/ritonavir (LPV/r) 400 mg/100 mg twice daily

Considerations for individuals receiving TB therapy

In the presence of rifampicin, adjusted dose of LPV/r (double-dose LPV 800 mg + ritonavir 200 mg twice daily or super boosted with LPV 400 mg/ + ritonavir 100 mg twice daily plus additional doses of RTV 300 mg twice daily), with close monitoring. In the presence of rifabutin, no dose adjustment required. Rifapentine should not be used.

Integrase strand transfer inhibitors (INSTIs)

Dolutegravir (DTG) 50 mg once dailya

Raltegravir (RAL) 400 mg twice daily

Considerations for individuals receiving TB therapy

In the presence of rifampicin, adjusted dose of DTG (50 mg twice daily) and RAL (800 mg twice daily), with close monitoring DTG and RAL dose should remain twice daily for additional two weeks after the last dose of rifampicin. In the presence of rifabutin or rifapentine, no dose adjustment is required.

a DTG 50 mg and TLD (tenofovir 300 mg, lamivudine 300 mg, dolutegravir 50 mg, fixed-dose combination) can be used once daily for adolescents living with HIV weighing at least 30 kg. DTG 50-mg film-coated tablets can be used for children and adolescents weighing at least 20 kg. TDF 300 mg can be used for adolescents weighing at least 30 kg.

b TAF 25 mg and TAF + FTC + DTG (TAF 25 mg, emtricitabine 200 mg, dolutegravir 50 mg, fixed-dose combination) can be used once daily for adolescents living with HIV weighing at least 25 kg. The TAF dose is reduced to 10 mg when administered in the context of boosted regimens.

ANNEX 1: DOSAGES FOR ARV DRUGS

502 Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring

Weight-based dosing for ARV drug formulations for infants and children

Prescribing information and weight-based dosing of available ARV formulations for infants and childrenThis annex contains information on ARV drugs for which there are paediatric indications, formulations or sufficient information and evidence to provide guidance on prescribing and dosing for infants, children and adolescents. WHO has undertaken the work to develop and update simplified guidance on ARV drugs for children through the Paediatric Antiretroviral Working Group.1

For simplification and ease of implementation, doses are expressed by weight band rather than per kilogram or per square metre of body surface area. When this simplified weight-band dosing was developed, the expected body surface area of children from low- and middle-income countries in each weight band was carefully considered. The primary source of information for the guidance provided is the manufacturer’s package insert. This was supplemented with data from other clinical studies as well as expert paediatric pharmacology consultations. For ARV drug fixed-dose combinations, a dose-modelling tool (1) was used to predict the dose delivered for each component drug against the recommended dosing schedule. In some cases, the dose for a component in a particular weight band may be somewhat above or below the target dose recommended by the manufacturer. This is inevitable given the limitations imposed by a fixed-dose combination, but care was taken to minimize the number of children that would receive more than 25% above the maximum target dose or more than 5% below the minimum target dose. Pharmacokinetic efficacy and safety studies have also confirmed the overall safety of this dosing approach. For simplification, ARV drugs no longer considered preferred or alternative options for children have been removed from the dosing guidance.

In the context of increasing implementation of HIV virological testing at birth, and the shift towards treating infants earlier in an effort to reduce early mortality, these guidelines include additional weight-based dosing guidance for term infants less than four weeks old, including those weighing 2–3 kg. However, there is limited experience with initiating treatment for neonates living with HIV younger than two weeks and a paucity of pharmacokinetic data to fully inform accurate dosing for most drugs in neonates, who are undergoing rapid growth and maturation in renal and liver function. Limited pharmacokinetic data for preterm infants are available for AZT, NVP, 3TC and ABC; there is considerable uncertainty of appropriate dosing for NVP, RAL, 3TC and ABC for preterm and low-birth-weight infants. In addition, LPV/r solution should not be given to infants younger than two weeks old or to preterm infants until they have reached 42 weeks of gestational age, because of the risk of adverse effects that may occur in this population. The management of HIV treatment for preterm neonates remains challenging because of the lack of appropriate pharmacokinetic, safety and dosing information as well as suitable formulations.

1 Paediatric Antiretroviral Working Group members: Elaine Abrams (ICAP at Columbia University, USA); Pauline Amuge (Baylor College of Medicine Children’s Foundation, Uganda); Mo Archary (University of Kwazulu-Natal, South Africa); Adrie Bekker (University of Stellenbosch, South Africa); Brookie Best (University of San Diego, USA); David Burger (Radboud University Nijmegen Medical Centre, Netherlands); Esther Casas (MSF, South Africa); Luis Castaneda (Hospital de Ninos Benjamin Bloom, El Salvador); Diana Clarke (Boston Medical Center, USA); Polly Clayden (HIV i-Base, United Kingdom); Angela Colbers (Radboud University Nijmegen Medical Centre, Netherlands); Tim R. Cressey (PHPT-IRD Research Unit, Chang Mai University, Thailand); Roberto Delisa (European Medicines Agency); Paolo Denti (University of Cape Town, South Africa); Diana Gibb (MRC Clinical Trials Unit at University College London, United Kingdom); Rohan Hazra (National Institute of Child Health and Human Development, USA); Maria Kim (Baylor International Pediatric AIDS Initiative, Malawi); Shahin Lockman (Harvard T.H. Chan School of Public Health, USA); Fatima Mir (Agha Khan University, Pakistan); Mark H. Mirochnick (Boston Medical Center, USA); Elizabeth Obimbo (University of Nairobi/Kenyatta National Hospital); Thanyawee Puthanakit (Chulalongkorn University, Thailand); Natella Rakhmanina (Elizabeth Glazer Paediatric AIDS Foundation, USA); Pablo Rojo (Hospital de 12 Octubre Madrid, Spain); Vanessa Rouzier (GHESIKO); Ted Ruel (University of California, San Francisco, USA); Nadia Sam-Agudu (Institute of Human Virology, Nigeria); Mariam Sylla (EVA Network, Mali); and Anna Turkova (MRC Clinical Trials Unit at University College London, United Kingdom). Observers: Yodit Belew (United States Food and Drug Administration, USA); Helen Bygrave (Access Campaign MSF); Shaffiq Essajee (UNICEF, USA); Stephanie Hackett (United States Centers for Dsiease Control and Prevention, USA); Marc Lallemant (PHPT Foundation, Thailand); Linda Lewis (Clinton Health Access Initiative, USA); Lynne Mofenson (Elizabeth Glaser Paediatric AIDS Foundation, USA); Irene Mukui (Drugs for Neglected Diseases initiative, Geneva, Switzerland); Sandra Nobre (Medicines Patent Pool, Switzerland); Mary Ojoo (UNICEF, Denmark); George Siberry (United States Agency for International Development, USA); Nandita Sugandhi (ICAP at Columbia University, USA); Marissa Vicari (International AIDS Society, Switzerland); Melynda Watkins (Clinton Health Access Initiative, USA); and Hilary Wolf (Office of the United States Global AIDS Coordinator, Department of State, USA).

503Annex 1: dosages for ARV drugs

Dosing for postnatal prophylaxis for infants exposed to HIV is also included here. These guidelines provide simplified dosing to administer enhanced or extended prophylaxis with NVP 50 mg scored dispersible tablets, which provide an alternative to NVP syrup. Finally, alternative ARV drugs were considered to address special situations in which stock-outs of NVP or AZT may affect the ability to effectively provide postnatal prophylaxis (including for enhanced and extended prophylaxis).

Since the WHO ARV drug guidelines were revised in 2018, integrase strand transfer inhibitors (INSTIs) have been included more prominently among the preferred regimens recommended by WHO, and DTG-based regimens have been recommended for all children with approved DTG dosing. At the time of this update in July 2021, the United States Food and Drug Administration and the European Medicines Agency have approved DTG for treatment-naive or treatment-experienced INSTI-naive children who are at least four weeks old and weigh at least 3 kg (2,3). These approvals were granted based on data generated by the IMPAACT P1093 registration trial (4) as well as the multicountry Odyssey trial (5), which also investigated the pharmacokinetics of DTG among children co-treated for TB.

– In November 2020, the United States Food and Drug Administration approved the first generic DTG 10 mg scored dispersible tablet. DTG dispersible tablets should be ideally dispersed in water or swallowed whole. Crushing, chewing or mixing with other foods or liquids can be considered as long as the entire tablet is ingested. DTG dispersible tablets are not bioequivalent to DTG film-coated tablets; 30 mg of DTG dispersible tablet is equivalent to 50 mg of DTG film-coated tablets (6).

– For infants who received RAL-containing ART for limited duration (such as no more than three months) and without evidence or suspicion of treatment failure, the Paediatric Antiretroviral Working Group concluded that switching to standard (once-daily) weight-appropriate DTG was reasonable while encouraging the generation of direct evidence to evaluate this approach. Of note, although DTG can be dosed twice daily for treating adults with suspected INSTI resistance, this approach cannot be safely extrapolated to children given differences in pharmacokinetics. Alternative regimens should be considered and, if possible, informed by appropriate HIV drug resistance testing.

– This annex includes guidance on dose adjustment for children receiving a DTG formulation during rifampicin-based TB co-treatment. For all weights and ages with approved DTG dosing, the United States Food and Drug Administration recommended administering the weight-based DTG dose twice daily if taken with rifampicin based on its customary approach of extrapolating drug–drug interaction data from adults. Direct pharmacokinetic data for children support the use of DTG twice daily for children weighing more than 25 kg (7). The DTG dose will need to remain twice daily for two weeks after the last dose of rifampicin has been given since the enzyme-inducing effect of rifampicin slowly fades away after discontinuing the drug. The Paediatric Antiretroviral Working Group highlights the need to continue to collect confirmatory evidence in lower weight bands but, as reflected in the dosing table, endorses immediate uptake of twice-daily dosing of DTG when taken with rifampicin for all children (at least four weeks old and weighing at least 3 kg) and to be continued for two weeks after cessation of rifampicin-based TB treatment.

RAL granules were added in 2018 with the goal of providing a suitable formulation to deliver RAL to neonates. Because of concerns about the complexity of administering the granule formulation, the Paediatric Antiretroviral Working Group endorsed the 25-mg chewable tablets as dispersible tablets for infants and children older than four weeks and weighing at least 3 kg. This decision was largely based on in vitro data on solubility and bioequivalence between RAL chewable tablets and granules (8) and considering the limited availability of alternative formulations for this age group. In this update of the dosing guidance, we also recommend appropriate dose adjustment for of RAL during rifampicin-based TB treatment, to be continued for two weeks after completion of rifampicin-based TB treatment.

504 Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring

In this 2021 update, we confirm dosing information for children for tenofovir alafenamide (TAF), fixed-dose combinations containing TAF were included for children weighing 25 kg or more with a 25-mg dose when used with unboosted regimens. This aligns with dosing approved by United States Food and Drug Administration (9). Studies to investigate dosing for children weighing less than 25 kg are ongoing, and more information will be made available as soon as approval is extended.

This dosing annex and the simplified dosing schedule will be regularly reviewed and updated as additional data and new formulations become available. Updated information on ARV drug dosing in children and rationale for dose simplification is available on the newly developed paediatric ARV dosing dashboard (10).

ARV drugs and formulations are available from several manufacturers, and the available dosage strengths of tablets, capsules and liquid formulations may vary from the information provided here. Several optimal dosage forms for children are currently being developed but have not yet received regulatory approval at the time these updated guidelines were published. National programme managers should ensure that products planned for use have received stringent regulatory approval and are of appropriate quality and stability. The current list of WHO prequalified drugs is available (11). The United States Food and Drug Administration has a current list of approved and tentatively approved ARV drugs (12). The policy of the Global Fund to Fight AIDS, Tuberculosis and Malaria on procurement and quality assurance is available (13).

General principlesWHO followed the following principles in developing the simplified tables.

• Using an age-appropriate fixed-dose combination is preferred for any regimen if such a formulation is available.

• Oral liquid or syrup formulations should be avoided if possible (except for neonatal treatment and prevention). Dispersible tablets (or granules) are the preferred solid oral dosage forms, since these formulations can be made into liquid at the point of use.

• If suitable dispersible fixed-dose combinations are not available and oral liquids must be used, children should be switched to a solid oral dosage form as soon as possible.

• Although dosing newborns generally requires using oral liquid formulations for administrating precise dosing, switching to solid oral dosage form as soon as possible is recommended.

• If children have to use adult formulations, care must be taken to avoid underdosing and overdosing. Using scored tablets is preferred to ensure accurate dosing, especially if adult dosage forms are used. Splitting unscored tablets should be avoided since the uniform distribution of active drug product cannot be assured in tablet fragments.

• Some tablets such as LPV/r or ATV/r heat-stable tablets are made in a special embedded matrix formulation (a proprietary melt extrusion technology that stabilizes drug molecules that are normally heat labile) and should not be cut, split, dissolved, chewed or crushed, since bioavailability is significantly reduced when they are not swallowed whole.

• Among children for whom an LPV/r-based regimen remains the appropriate treatment choice, LPV/r is available in a 40 mg/10 mg pellet or granule formulation for infants and young children. However, children weighing 10 kg or more should be transitioned to LPV/r heat-stable tablets as soon as they are able to swallow tablets whole to ease administration and improve palatability and to reduce pill burden.

• After the first four weeks of life, at each clinic visit, infants and children should be weighed and doses should be adjusted based on observed growth and change in body weight.

• Country programmes should consider the national regulatory status and local availability status of specific dosage forms when developing national recommendations for treating children.

• Research is ongoing for several ARV medications to establish dosing guidance for neonates, infants and young children. The age indications for each drug mentioned in the drug pages are based on current evidence and will be updated as new recommendations become available.

505Annex 1: dosages for ARV drugs

Tabl

e A1

.1 S

impl

ified

dos

ing

of c

hild

-fri

endl

y fix

ed-d

ose

solid

for

mul

atio

ns f

or t

wic

e-da

ily d

osin

g fo

r in

fant

s an

d ch

ildre

n fo

ur w

eeks

and

old

era

Dru

gSt

reng

th o

f pa

edia

tric

tab

lets

N

umbe

r of

tab

lets

by

wei

ght

band

mor

ning

and

eve

ning

Stre

ngth

of

adul

t ta

blet

Num

ber

of t

able

ts b

y w

eigh

t ba

nd

3–<

6 kg

6–<1

0 kg

10–<

14 k

g14

–<20

kg

20–<

25 k

g25

–<35

kg

AM

PMA

MPM

AM

PMA

MPM

AM

PMA

MPM

AZT

/3TC

Tabl

et (d

ispe

rsib

le)

60 m

g/30

mg

11

1.5

1.5

22

2.5

2.5

33

300

mg/

150

mg

11

ABC

/3TC

Tabl

et (d

ispe

rsib

le)

60 m

g/30

mgb

11

1.5

1.5

22

2.5

2.5

33

600

mg/

300

mg

0.5

0.5

Tabl

et (d

ispe

rsib

le)

120 

mg/

60 m

g0.

50.

50.

51

11

11.

51.

51.

560

0 m

g/30

0 m

g0.

50.

5

a Fo

r inf

ants

you

nger

tha

n fo

ur w

eeks

old

, see

Tab

le A

1.4

for m

ore

accu

rate

dos

ing,

whi

ch is

red

uced

bec

ause

of t

he d

ecre

ased

abi

lity

to e

xcre

te a

nd m

etab

oliz

e m

edic

atio

ns. F

or in

fant

s w

ho a

re a

t le

ast f

our w

eeks

old

but

wei

gh le

ss t

han

3 kg

, the

imm

atur

ity

of r

enal

and

hep

atic

pat

hway

s of

elim

inat

ion

are

less

of a

con

cern

, but

unc

erta

inty

stil

l exi

sts

on t

he a

ppro

pria

te d

osin

g of

ARV

dru

gs fo

r pr

eter

m a

nd lo

w-b

irth

-wei

ght i

nfan

ts.

b Th

is fo

rmul

atio

n w

ill b

e ph

ased

out

of u

se o

ver t

ime,

and

pro

gram

mes

sho

uld

tran

siti

on t

o us

ing

the

120

mg/

60 m

g di

sper

sibl

e sc

ored

tab

lets

.

506 Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring

Tabl

e A1

.2 S

impl

ified

dos

ing

of c

hild

-fri

endl

y so

lid f

orm

ulat

ions

for

onc

e-da

ily d

osin

g fo

r in

fant

s an

d ch

ildre

n fo

ur w

eeks

and

old

era

Dru

gSt

reng

th o

f pae

diat

ric

tabl

et

Num

ber

of t

able

ts o

r ca

psul

es b

y w

eigh

t ba

nd o

nce

daily

Stre

ngth

of

adul

t ta

blet

Num

ber

of t

able

ts o

r ca

psul

es b

y w

eigh

t ba

nd o

nce

daily

3–<

6 kg

6–<1

0 kg

10–<

14 k

g14

–<20

kg

20–<

25 k

g25

–<35

kg

EFVb

Tabl

et (s

core

d) 2

00 m

g–

–1

1.5

1.5

-2

ABC

/3TC

Tabl

et (d

ispe

rsib

le) 6

0 m

g/30

mg

23

45

660

0 m

g/30

0 m

g1

Tabl

et (d

ispe

rsib

le) 1

20 m

g/60

mg

11.

52

2.5

3

TAF/

FTCc

Tabl

et 2

5 m

g/ 2

00 m

g–

––

––

25 m

g/20

0 m

g1

ATVd

Caps

ules

100

mg

––

22

230

0 m

g1e

Caps

ules

200

mg

––

11

1

DRV

fTa

blet

600

mg

––

–1

160

0 m

g1

Tabl

et 1

50 m

g–

––

44

RTVg

Tabl

et 2

5 m

g–

––

44

100

mg

1

Tabl

et 5

0 m

g–

––

22

507Annex 1: dosages for ARV drugs

Tabl

e A1

.2 S

impl

ified

dos

ing

of c

hild

-fri

endl

y so

lid f

orm

ulat

ions

for

onc

e-da

ily d

osin

g fo

r in

fant

s an

d ch

ildre

n fo

ur w

eeks

and

old

era (c

onti

nued

)

Dru

gSt

reng

th o

f pae

diat

ric

tabl

et

Num

ber

of t

able

ts o

r ca

psul

es b

y w

eigh

t ba

nd o

nce

daily

Stre

ngth

of

adul

t ta

blet

Num

ber

of t

able

ts o

r ca

psul

es b

y w

eigh

t ba

nd o

nce

daily

3–<

6 kg

6–<1

0 kg

10–<

14 k

g14

–<20

kg

20–<

25 k

g25

–<35

kg

DTG

hFi

lm-c

oate

d ta

blet

50

mg

––

––

150

mg

1

Dis

pers

ible

tabl

et 5

mg

13

45

6

Dis

pers

ible

sco

red

tabl

et 1

0 m

g0.

51.

52

2.5

3

a Se

e Ta

ble

A1.4

for d

osin

g re

com

men

datio

ns fo

r inf

ants

you

nger

than

four

wee

ks o

ld. D

oses

for t

his

age

grou

p ar

e re

duce

d to

acc

ount

for t

he d

ecre

ased

abi

lity

to e

xcre

te a

nd m

etab

oliz

e m

edic

atio

ns. F

or in

fant

s w

ho

are

at le

ast f

our w

eeks

old

but

wei

gh le

ss th

an 3

kg,

imm

atur

ity o

f ren

al a

nd h

epat

ic p

athw

ays

of e

limin

atio

n ar

e le

ss o

f a c

once

rn, b

ut u

ncer

tain

ty s

till e

xist

s on

the

appr

opria

te d

osin

g of

ARV

dru

gs fo

r pre

term

and

lo

w-b

irth-

wei

ght i

nfan

ts.

b EF

V is

not r

ecom

men

ded

for c

hild

ren

youn

ger t

han

thre

e ye

ars

and

wei

ghin

g le

ss th

an 1

0 kg

.c

At th

e tim

e of

this

upda

te, t

he U

nite

d St

ates

Foo

d an

d Dr

ug A

dmin

istr

atio

n ap

prov

ed T

AF

film

-coa

ted

tabl

ets

for c

hild

ren

olde

r tha

n si

x ye

ars

for u

se in

unb

oost

ed re

gim

ens

such

as

with

DTG

. The

Uni

ted

Stat

es

Food

and

Dru

g Ad

min

istr

atio

n te

ntat

ivel

y ap

prov

ed a

fixe

d-do

se c

ombi

natio

n co

ntai

ning

TA

F/FT

C/DT

G (T

AF

25 m

g, F

TC 2

00 m

g, D

TG 5

0 m

g) th

at c

an b

e us

ed o

nce

daily

for c

hild

ren

and

adol

esce

nts

livin

g w

ith H

IV

wei

ghin

g at

leas

t 25

kg.

d AT

V is

only

app

rove

d fo

r chi

ldre

n th

ree

mon

ths a

nd o

lder

. ATV

sin

gle-

stre

ngth

cap

sule

s sho

uld

be a

dmin

iste

red

with

RTV

100

mg

for a

ll w

eigh

t ban

ds 1

0 kg

and

abo

ve. A

TV p

owde

r for

mul

atio

n ha

s lim

ited

avai

labi

lity

in lo

w- a

nd m

iddl

e-in

com

e co

untr

ies

but e

nabl

es A

TV to

be

adm

inis

tere

d to

infa

nts

and

child

ren

as y

oung

as

thre

e m

onth

s. In

fant

s an

d ch

ildre

n w

eigh

ing

5–<1

5 kg

sho

uld

be a

dmin

iste

red

200

mg

of A

TV p

owde

r (fo

ur p

acke

ts, 5

0 m

g pe

r pac

ket)

with

80

mg

of R

TV o

ral s

olut

ion

(1 m

L) (1

4).

e AT

V 30

0 m

g w

ith R

TV 1

00 m

g fo

r 25–

<30

kg

is re

com

men

ded

base

d on

the

findi

ngs

from

the

PRIN

CE-2

stu

dy (1

5).

f DRV

in c

ombi

natio

n w

ith R

TV s

houl

d be

use

d fo

r chi

ldre

n ol

der t

han

thre

e ye

ars,

onc

e da

ily w

hen

this

is us

ed w

ithou

t pre

viou

s ex

posu

re to

PIs

. Alth

ough

the

appr

oved

dos

ing

for 3

0–<

35 k

g is

675

mg,

pre

limin

ary

data

from

adu

lt st

udie

s su

gges

t tha

t eve

n lo

wer

DRV

dos

es m

ay b

e ef

fect

ive,

and

the

600

mg

dose

was

ther

efor

e ex

tend

ed to

the

entir

e 25

- to

<35

kg

wei

ght b

and.

g RT

V sh

ould

onl

y be

use

as

a bo

ostin

g ag

ent i

n co

mbi

natio

n w

ith A

TV o

r DRV

or t

o su

per-

boos

t LPV

/r w

hen

give

n w

ith c

onco

mita

nt ri

fam

pici

n fo

r TB

(see

Tab

le A

1.5)

.h

At th

e tim

e of

this

upda

te, t

he U

nite

d St

ates

Foo

d an

d Dr

ug A

dmin

istr

atio

n ap

prov

ed 5

mg

disp

ersi

ble

tabl

ets

and

tent

ativ

ely

appr

oved

10-

mg

scor

ed d

ispe

rsib

le ta

blet

s fo

r tre

atm

ent-

naiv

e or

trea

tmen

t-ex

perie

nced

IN

STI-n

aive

chi

ldre

n at

leas

t fou

r wee

ks o

ld a

nd w

eigh

ing

at le

ast 3

kg,

bas

ed o

n da

ta fr

om th

e IM

PAAC

T 10

93 tr

ial (

4) a

nd O

DYSS

EY (1

6). T

he U

nite

d St

ates

Foo

d an

d Dr

ug A

dmin

istr

atio

n an

d Eu

rope

an M

edic

ines

Ag

ency

app

rove

d si

mpl

ified

dos

ing

of th

e DT

G 5

0 m

g fil

m-c

oate

d ta

blet

s fo

r all

child

ren

wei

ghin

g ≥

20 k

g. D

TG d

ispe

rsib

le ta

blet

s an

d DT

G fi

lm-c

oate

d ta

blet

s ar

e no

t bio

equi

vale

nt; 3

0 m

g of

DTG

dis

pers

ible

tabl

et

corr

espo

nds

to 5

0 m

g of

DTG

film

-coa

ted

tabl

ets.

DTG

50

mg

film

-coa

ted

tabl

ets

are

pref

erre

d fo

r chi

ldre

n w

ho h

ave

reac

hed

20 k

g (u

nles

s th

ey c

anno

t sw

allo

w t

able

ts).

Safe

ty m

onito

ring

rem

ains

impo

rtan

t gi

ven

the

curr

ent l

imite

d ex

peri

ence

wit

h th

is d

osin

g. F

or a

dole

scen

ts li

ving

wit

h H

IV w

eigh

ing

mor

e th

an 3

0 kg

, a fi

xed-

dose

form

ulat

ion

of T

DF

300

mg,

3TC

300

mg

and

DTG

50

mg

(TLD

) can

be

used

and

is p

refe

rred

.

508 Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring

Tabl

e A1

.3 S

impl

ified

dos

ing

of c

hild

-fri

endl

y so

lid a

nd o

ral l

iqui

d fo

rmul

atio

ns f

or t

wic

e-da

ily d

osin

g fo

r in

fant

s an

d ch

ildre

n fo

ur w

eeks

of

age

and

olde

ra

Dru

gSt

reng

th o

f pa

edia

tric

tab

lets

N

umbe

r of

tab

lets

or

mL

by w

eigh

t-ba

nd m

orni

ng (A

M) a

nd e

veni

ng (P

M)

Stre

ngth

of

adul

t ta

blet

N

umbe

r of

tab

lets

by

wei

ght

band

3–<

6 kg

6–<1

0 kg

10–<

14 k

g14

–<20

kg

20–<

25 k

g25

–<35

kg

AM

PMA

MPM

AM

PMA

MPM

AM

PMA

MPM

Solid

for

mul

atio

ns

AZT

Tabl

et (d

ispe

rsib

le)

60 m

g1

11.

51.

52

22.

52.

53

330

0 m

g1

1

ABC

Tabl

et (d

ispe

rsib

le)

60 m

g 1

11.

51.

52

22.

52.

53

330

0 m

g1

1

LPV/

rb Ta

blet

100

mg/

25 m

g–

––

–2

12

22

2–

33

Pelle

ts 4

0 m

g/10

mg

22

33

44

55

66

––

Gra

nule

s 40

mg/

10 m

g sa

chet

22

33

44

55

66

––

DRV

cTa

blet

75

mg

––

––

––

55

55

400

mg

11

RTVd

Tabl

et 2

5 m

g–

––

––

–2

22

210

0 m

g1

1

Tabl

et 5

0 m

g–

––

––

–1

11

1

RALe

Chew

able

tabl

ets

25 m

g1

12

23

34

46

640

0 m

g1

1

Chew

able

tabl

ets

100

mg

––

––

––

11

1.5

1.5

509Annex 1: dosages for ARV drugs

Tabl

e A1

.3 S

impl

ified

dos

ing

of c

hild

-fri

endl

y so

lid a

nd o

ral l

iqui

d fo

rmul

atio

ns f

or t

wic

e-da

ily d

osin

g fo

r in

fant

s an

d ch

ildre

n fo

ur w

eeks

of

age

and

olde

ra (c

onti

nued

)

Dru

gSt

reng

th o

f or

al li

quid

N

umbe

r of

tab

lets

or

mL

by w

eigh

t-ba

nd m

orni

ng (A

M) a

nd e

veni

ng (P

M)

Stre

ngth

of

adul

t ta

blet

N

umbe

r of

tab

lets

by

wei

ght

band

3–<

6 kg

6–<1

0 kg

10–<

14 k

g14

–<20

kg

20–<

25 k

g25

–<35

kg

AM

PMA

MPM

AM

PMA

MPM

AM

PMA

MPM

Liqu

id f

orm

ulat

ions

AZT

10 m

g/m

L6

mL

6 m

L9

mL

9 m

L12

mL

12 m

L–

––

––

––

ABC

f20

mg/

mL

3 m

L3

mL

4 m

L4

mL

6 m

L6

mL

––

––

––

–

3TC

10 m

g/m

L3

mL

3 m

L4

mL

4 m

L6

mL

6 m

L–

––

––

––

LPV/

rb80

mg/

20 m

g/m

L1

mL

1 m

L1.

5 m

L1.

5 m

L2

mL

2 m

L2.

5 m

L2.

5 m

L3

mL

3 m

L–

––

DRV

c10

0 m

g/m

L–

––

–2.

5 m

L2.

5 m

L3.

5 m

L3.

5 m

L–

––

––

RTVd

80 m

g/m

L–

––

–0.

5 m

L0.

5 m

L0.

6 m

L0.

6 m

L–

––

––

RALe

10 m

g/m

L

(Ora

l gra

nule

s fo

r su

spen

sion

: 100

mg/

sach

et)

3 m

L3

mL

5 m

L5

mL

8 m

L8

mL

10 m

L10

mL

––

––

–

a Se

e Ta

ble

A1.4

for d

osin

g re

com

men

datio

ns fo

r inf

ants

you

nger

than

four

wee

ks. D

oses

for t

his a

ge g

roup

are

redu

ced

to a

ccou

nt fo

r the

dec

reas

ed a

bilit

y to

exc

rete

and

met

abol

ize m

edic

atio

ns. F

or in

fant

s who

are

at

leas

t fou

r wee

ks o

ld b

ut w

eigh

less

than

3 k

g, im

mat

urity

of r

enal

and

hep

atic

path

way

s of e

limin

atio

n ar

e le

ss o

f a c

once

rn, b

ut u

ncer

tain

ty st

ill e

xist

s on

the

dosin

g of

ARV

dru

gs fo

r pre

term

and

low

-birt

h-w

eigh

t inf

ants

.b

Alth

ough

ABC

dos

e re

pres

ents

a s

igni

fican

t inc

reas

e co

mpa

red

with

the

neon

atal

dos

e, th

is do

se w

as d

esig

ned

to m

atch

the

reco

mm

ende

d do

se fo

r the

sol

id fo

rmul

atio

n ab

ove.

c LP

V/r l

iqui

d re

quire

s a

cold

cha

in d

urin

g tr

ansp

ort a

nd s

tora

ge. T

he L

PV/r

heat

-sta

ble

tabl

et fo

rmul

atio

n m

ust b

e sw

allo

wed

who

le a

nd s

houl

d no

t be

split

, che

wed

, dis

solv

ed o

r cru

shed

. Adu

lt 20

0/50

mg

tabl

ets

coul

d be

use

d fo

r chi

ldre

n w

eigh

ing

14–<

25 k

g (o

ne ta

blet

in th

e m

orni

ng a

nd o

ne in

the

even

ing)

and

for c

hild

ren

wei

ghin

g 25

–<35

kg

(tw

o ta

blet

s in

the

mor

ning

and

one

in th

e ev

enin

g). T

he L

PV/r

pelle

t fo

rmul

atio

n sh

ould

not

be

used

for i

nfan

ts y

oung

er th

an th

ree

mon

ths.

Mor

e de

tails

on

the

adm

inis

trat

ion

of L

PV/r

pelle

ts a

re a

vaila

ble

(17)

. Thi

s do

sing

sch

edul

e ap

plie

s to

equ

ival

ent s

olid

dos

age

form

s su

ch a

s LP

V/r g

ranu

les,

whi

ch c

an b

e us

ed fr

om tw

o w

eeks

of a

ge. S

ince

the

supp

ly is

cur

rent

ly c

onst

rain

ed, b

oth

pelle

ts a

nd g

ranu

les

shou

ld b

e di

scou

rage

d fo

r chi

ldre

n w

eigh

ing

mor

e th

an 1

4 kg

, who

sho

uld

rece

ive

LPV/

r 10

0/25

mg

tabl

ets

inst

ead.

Info

rmat

ion

on L

PV/r

form

ulat

ions

for c

hild

ren

is av

aila

ble

(18)

.d

DRV

to b

e us

ed fo

r chi

ldre

n ol

der t

han

thre

e ye

ars

mus

t be

adm

inis

tere

d w

ith 0

.5 m

L of

RTV

80

mg/

mL

oral

sus

pens

ion

if th

ey w

eigh

less

than

15

kg a

nd w

ith R

TV 5

0 m

g (u

sing

25

mg

or 5

0 m

g so

lid fo

rmul

atio

n) fo

r ch

ildre

n w

eigh

ing

15–<

30 k

g. R

TV 1

00-m

g ta

blet

s ca

n be

use

d as

a b

oost

er if

low

er-s

tren

gth

RTV

tabl

ets

are

not a

vaila

ble,

bas

ed o

n lim

ited

expe

rienc

e su

gges

ting

good

acc

epta

bilit

y an

d to

lera

bilit

y.e

RTV

shou

ld o

nly

be u

sed

at th

is do

se a

s a

boos

ting

agen

t in

com

bina

tion

with

ATV

or D

RV.

f RA

L gr

anul

es a

re a

ppro

ved

from

birt

h. T

he fe

asib

ility

and

acc

epta

bilit

y of

suc

h fo

rmul

atio

ns h

ave

not b

een

wid

ely

inve

stig

ated

, and

con

cern

s ha

ve b

een

rais

ed a

bout

adm

inis

trat

ion

in re

sour

ce-li

mite

d se

ttin

gs.

Beca

use

of th

e ad

min

istr

atio

n ch

alle

nges

pre

sent

ed b

y th

e gr

anul

e fo

rmul

atio

n, th

e Pa

edia

tric

Ant

iretr

ovira

l Wor

king

Gro

up e

ndor

sed

the

use

of th

e 25

mg

chew

able

tabl

ets

as d

ispe

rsib

le fo

r inf

ants

and

chi

ldre

n ol

der t

han

four

wee

ks a

nd w

eigh

ing

at le

ast 3

kg.

Thi

s w

as la

rgel

y ba

sed

on in

vitr

o da

ta o

n so

lubi

lity

and

bioe

quiv

alen

ce b

etw

een

tabl

ets

and

gran

ules

(19)

and

on

cons

ider

ing

the

limite

d av

aila

bilit

y of

ade

quat

e al

tern

ativ

es fo

r thi

s ag

e gr

oup.

How

ever

, the

find

ings

from

a fe

asib

ility

and

acc

epta

bilit

y as

sess

men

t con

duct

ed in

Sou

th A

fric

a de

mon

stra

te th

at a

dmin

iste

ring

RAL

gran

ules

in ru

ral s

ettin

gs is

feas

ible

as

long

as

it is

su

ppor

ted

by a

dequ

ate

trai

ning

and

cou

nsel

ling.

510 Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring

Tabl

e A1

.4 D

rug

dosi

ng o

f liq

uid

form

ulat

ions

for

infa

nts

youn

ger

than

fou

r w

eeks

of

agea

Dru

gSt

reng

th o

f ora

l sol

utio

n2–

<3

kg3–

<4

kg4–

<5

kg

AM

PMA

MPM

AM

PM

AZT

10 m

g/m

L1

mL

1 m

L1.

5 m

L1.

5 m

L2

mL

2 m

L

ABC

20 m

g/m

L0.

4 m

L0.

4 m

L0.

5 m

L0.

5 m

L0.

6 m

L0.

6 m

L

NVP

10 m

g/m

L1.

5 m

L1.

5 m

L2

mL

2 m

L3

mL

3 m

L

3TC

10 m

g/m

L0.

5 m

L0.

5 m

L0.

8 m

L0.

8 m

L1

mL

1 m

L

LPV/

rb80

mg/

20 m

g/m

L0.

6 m

L0.

6 m

L0.

8 m

L0.

8 m

L1

mL

1 m

L

Gra

nule

s 40

mg/

10 m

g sa

chet

––

22

22

RAL

10 m

g/m

L (O

ral g

ranu

les

for

susp

ensi

on: 1

00 m

g/sa

chet

)c

<1

wee

k0.

4 m

L (o

nce

daily

)c0.

5 m

L (o

nce

daily

)c0.

7 m

L (o

nce

daily

)c

>1 w

eek

0.8

mL

0.8

mL

1 m

L1

mL

1.5

mL

1.5

mL

a To

avo

id d

ose

chan

ges

over

a s

hort

per

iod

of t

ime

and

to m

inim

ize

the

likel

ihoo

d of

err

ors,

all

ARV

dru

gs e

xcep

t for

RA

L (d

ose

chan

ge a

fter

wee

k 1)

, sho

uld

be d

osed

bas

ed o

n w

eigh

t whe

n tr

eatm

ent

star

ts a

nd m

aint

aine

d un

til fo

ur w

eeks

of a

ge (w

eigh

t gai

n is

lim

ited

duri

ng t

he fi

rst f

our w

eeks

of l

ife).

Phar

mac

okin

etic

dat

a fo

r pre

term

infa

nts

are

avai

labl

e on

ly fo

r AZT

; the

re a

re li

mite

d da

ta

and

cons

ider

able

unc

erta

inty

of a

ppro

pria

te d

osin

g fo

r NVP

, RA

L an

d 3T

C fo

r pre

term

and

low

-bir

th-w

eigh

t inf

ants

. In

addi

tion

, LPV

/r s

olut

ion

shou

ld n

ot b

e gi

ven

to p

rete

rm in

fant

s un

til t

hey

have

re

ache

d 42

wee

ks g

esta

tion

al a

ge, b

ecau

se o

f the

ris

k of

adv

erse

eff

ects

. Thi

s gu

idan

ce w

ill b

e up

date

d w

hen

mor

e ev

iden

ce o

n so

lid L

PV/r

form

ulat

ions

is a

vaila

ble

from

ong

oing

tria

ls.

b D

o no

t use

LPV

/r s

olut

ion

for i

nfan

ts a

ged

youn

ger t

han

2 w

eeks

of a

ge. L

PV/r

pel

lets

sho

uld

not b

e us

ed fo

r inf

ants

you

nger

tha

n th

ree

mon

ths.

Mor

e de

tails

on

adm

inis

teri

ng L

PV/r

pel

lets

is

avai

labl

e (1

7). B

ecau

se o

f lac

k of

clin

ical

dat

a to

fully

info

rm t

he u

se o

f LPV

/r g

ranu

les

for n

ewbo

rns,

the

se d

osin

g re

com

men

dati

ons

wer

e de

velo

ped

base

d on

the

cur

rent

Uni

ted

Stat

es F

ood

and

Dru

g A

dmin

istr

atio

n ap

prov

al (s

uppo

rtin

g us

e of

LPV

/r g

ranu

les

from

tw

o w

eeks

) and

con

side

ring

the

sub

stan

tial u

ncer

tain

ty, e

spec

ially

for n

eona

tes

wei

ghin

g 2–

3 kg

. If n

o ot

her f

orm

ulat

ion

exis

ts, o

ne

sach

et t

wic

e a

day

coul

d be

con

side

red

for n

eona

tes

olde

r tha

n tw

o w

eeks

who

wei

gh 2

–3 k

g to

min

imiz

e th

e ris

k of

pot

entia

l tox

icit

y w

ith

over

dosi

ng.

c RA

L gr

anul

es fo

r ora

l sus

pens

ion

shou

ld b

e us

ed fo

r new

born

s w

eigh

ing

at le

ast 2

kg

and

be a

dmin

iste

red

once

a d

ay d

urin

g th

e fir

st w

eek

of li

fe a

nd t

wic

e a

day

afte

rwar

ds (2

0).

511Annex 1: dosages for ARV drugs

Tabl

e A1

.5 A

RV d

rug

dose

adj

ustm

ent

for

child

ren

rece

ivin

g ri

fam

pici

n-co

ntai

ning

TB

trea

tmen

ta

Dru

gSt

reng

th o

f pa

edia

tric

tab

lets

or

ora

l liq

uid

Num

ber

of t

able

ts o

r m

L by

wei

ght-

band

mor

ning

(AM

) and

eve

ning

(PM

)St

reng

th o

f ad

ult

tabl

et

Num

ber

of t

able

ts b

y w

eigh

t ba

nd

3–<

6 kg

6–<1

0 kg

10–<

14 k

g14

–<20

kg

20–<

25 k

g25

–<35

kg

AM

PMA

MPM

AM

PMA

MPM

AM

PMA

MPM

DTG

b5

mg

disp

ersi

ble

tabl

ets

11

33

44

55

6 6

50 m

g

film

-coa

ted

tabl

ets

11

10 m

g sc

ored

di

sper

sibl

e ta

blet

s0.

50.

51.

51.

52

22.

52.

53

3

50 m

g fil

m-c

oate

d ta

blet

s–

––

––

––

–1

1

RAL

10 m

g/m

L (O

ral g

ranu

les

for

susp

ensi

on: 1

00 m

g/sa

chet

)

6 m

L6

mL

10 m

L10

mL

16 m

L16

mL

20 m

L20

mL

––

400

mg

22

Chew

able

tabl

ets

25 m

g2

24

46

68

8–

–

Chew

able

tabl

ets

100

mg

––

––

––

22

33

LPV/

rc (w

ith

addi

tiona

l RTV

)O

ral s

olut

iond 8

0/

20 m

g/m

L1

mL

1 m

L1.

5 m

L1.

5 m

L2

mL

2 m

L2.

5 m

L2.

5 m

L3

mL

3 m

L–

––

Pelle

tse 4

0 m

g/10

mg

22

33

44

55

66

––

–

Gra

nule

s 40

mg/

10 m

g sa

chet

22

33

44

55

66

––

–

Tabl

et 1

00 m

g/25

mg

––

––

21

22

22

100

mg/

25 m

g3

3

512 Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring

Tabl

e A1

.5 A

RV d

rug

dose

adj

ustm

ent

for

child

ren

rece

ivin

g ri

fam

pici

n-co

ntai

ning

TB

trea

tmen

ta (c

onti

nued

)

Dru

gSt

reng

th o

f pa

edia

tric

tab

lets

or

ora

l liq

uid

Num

ber

of t

able

ts o

r m

L by

wei

ght-

band

mor

ning

(AM

) and

eve

ning

(PM

)St

reng

th o

f ad

ult

tabl

et

Num

ber

of t

able

ts b

y w

eigh

t ba

nd

3–<

6 kg

6–<1

0 kg

10–<

14 k

g14

–<20

kg

20–<

25 k

g25

–<35

kg

AM

PMA

MPM

AM

PMA

MPM

AM

PMA

MPM

RTVf

Tabl

et 1

00 m

g–

––

–1

11

21

210

0 m

g2

2

Tabl

et 5

0 m

g–

––

–2

23

33

3

Tabl

et 2

5 m

g–

––

–4

46

66

6

Ora

l sol

utio

n 80

mg/

mL

0.8

mL

0.8

mL

1.2

mL

1.2

mL

1.5

mL

1.5

mL

2 m

L2

mL

2.3

mL

2.3

mL

––

–

Pow

der 1

00 m

g/pa

cket

––

11

11

12

12

––

–

a Th

e ad

apte

d do

se o

f the

ARV

dru

gs n

eeds

to

cont

inue

unt

il tw

o w

eeks

aft

er r

ifam

pici

n tr

eatm

ent e

nds,

sin

ce t

he e

nzym

e-in

duci

ng e

ffec

t of r

ifam

pici

n sl

owly

fade

s aw

ay a

fter

dis

cont

inui

ng t

he d

rug.

b Th

e U

nite

d St

ates

Foo

d an

d D

rug

Adm

inis

trat

ion

reco

mm

ende

d ad

min

iste

ring

the

wei

ght-

base

d D

TG d

ose

twic

e da

ily if

tak

en w

ith

rifa

mpi

cin

base

d on

its

cust

omar

y ap

proa

ch o

f ext

rapo

lati

ng d

rug–

drug

inte

ract

ion

data

from

adu

lts.

Dir

ect p

harm

acok

inet

ic d

ata

in c

hild

ren

supp

ort t

he u

se o

f DTG

tw

ice

daily

for c

hild

ren

wei

ghin

g m

ore

than

25

kg (2

1). T

he P

aedi

atri

c A

ntir

etro

vira

l Wor

king

Gro

up

high

light

s th

e ne

ed t

o co

ntin

ue t

o co

llect

con

firm

ator

y ev

iden

ce fo

r low

er w

eigh

t ban

ds b

ut e

ndor

ses

imm

edia

te u

ptak

e of

tw

ice-

daily

dos

ing

of D

TG w

hen

take

n w

ith

rifa

mpi

cin

for a

ll ch

ildre

n (a

t le

ast f

our w

eeks

of a

ge a

nd w

eigh

ing

at le

ast 3

kg)

.c

The

LPV/

r hea

t-st

able

tab

let f

orm

ulat

ion

mus

t be

swal

low

ed w

hole

and

sho

uld

not b

e sp

lit, c

hew

ed, d

isso

lved

or c

rush

ed. A

n ad

ult 2

00/5

0 m

g ta

blet

cou

ld b

e us

ed fo

r chi

ldre

n w

eigh

ing

14–<

25 k

g (o

ne t

able

t in

the

mor

ning

and

one

in t

he e

veni

ng) a

nd fo

r chi

ldre

n 25

–<35

kg

(tw

o ta

blet

s in

the

mor

ning

and

one

in t

he e

veni

ng).

d LP

V/r l

iqui

d re

quir

es a

col

d ch

ain

duri

ng t

rans

port

and

sto

rage

.e

The

LPV/

r pel

let f

orm

ulat

ion

shou

ld n

ot b

e us

ed fo

r inf

ants

you

nger

tha

n th

ree

mon

ths.

Mor

e de

tails

on

adm

inis

teri

ng L

PV/r

pel

lets

is a

vaila

ble

(17)

. The

dos

ing

sche

dule

pro

vide

d ap

plie

s to

equ

ival

ent

solid

dos

age

form

s th

at m

ay b

ecom

e av

aila

ble

such

as

LPV/

r gra

nule

s, w

hich

the

Uni

ted

Stat

es F

ood

and

Dru

g A

dmin

istr

atio

n ha

s ap

prov

ed fo

r fro

m t

wo

wee

ks o

f life

.f S

ugge

sted

RTV

dos

e fo

r sup

er-b

oost

ing

to a

chie

ve t

he s

ame

dose

as

LPV

in m

g, in

a ra

tio

equa

l or a

ppro

achi

ng t

o 1:

1. T

his

dosi

ng a

ppro

ach

is s

uppo

rted

by

a st

udy

that

exp

lore

d th

is a

ppro

ach

for

youn

g ch

ildre

n re

ceiv

ing

LPV/

r (22

). RT

V or

al s

olut

ion

dosi

ng is

bas

ed o

n th

e do

sing

tes

ted

in t

he t

rial t

hat s

uppo

rts

the

use

of s

uper

-boo

stin

g.

513Annex 1: dosages for ARV drugs

Tabl

e A1

.6 S

impl

ified

dos

ing

of is

onia

zid

and

co-t

rim

oxaz

ole

prop

hyla

xis

for

infa

nts

and

child

ren

at le

ast

four

w

eeks

old

Dru

gSt

reng

th o

f pa

edia

tric

tab

let

or o

ral l

iqui

d

Num

ber

of t

able

ts o

r m

L by

wei

ght

band

onc

e da

ilySt

reng

th o

f ad

ult

tabl

etN

umbe

r of

tab

lets

by

wei

ght

band

3–<

6 kg

6–<1

0 kg

10–<

14 k

g14

–<20

kg

20–<

25 k

g25

–<35

kg

Ison

iazi

d10

0 m

g0.

51

1.5

22.

530

0 m

g1

Co-t

rimox

azol

e (s

ulfa

met

hoxa

zole

an

d tr

imet

hopr

im)

Susp

ensi

on 2

00 m

g/

40 p

er 5

mL

2.5

mL

5 m

L5

mL

10 m

L10

mL

––

Tabl

ets

(dis

pers

ible

) 10

0 m

g/20

mg

12

24

4–

–

Tabl

ets

(sco

red)

40

0 m

g/80

mg

–0.

50.

51

140

0 m

g/80

mg

2

Tabl

ets

(sco

red)

80

0 m

g/16

0 m

g–

––

0.5

0.5

800

mg/

160

mg

1

Ison

iazi

d/

(sul

fam

etho

xazo

le

and

trim

etho

prim

)/B6

Tabl

ets

(sco

red)

30

0 m

g/(8

00 m

g/

160

mg)

/25

mg

––

–0.

50.

530

0 m

g/

(800

mg/

16

0 m

g)/

25 m

g

1

514 Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring

Tabl

e A1

.7 S

impl

ified

age

-bas

ed A

RV d

rug

dosi

ng f

or a

dmin

iste

ring

enh

ance

d an

d pr

olon

ged

post

nata

l pr

ophy

laxi

sa

Dru

gSt

reng

th

0–6

wee

ks6–

12 w

eeks

12 w

eeks

to

6 m

onth

s9–

24 m

onth

s

AM

PMA

MPM

AM

PMA

MPM

NVP

b50

mg

scor

ed d

ispe

rsib

le

tabl

ets

0.5

_0.

5_

0.5

_1

_

NVP

10 m

g/m

L1.

5 m

L_

2 m

L_

3 m

L_

4 m

L_

AZT

10 m

g/m

L1.

5 m

L1.

5 m

L6

mL

6 m

L_

__

_

a In

spe

cial

circ

umst

ance

s w

ith

stoc

k-ou

t of N

VP a

nd/o

r AZT

, alte

rnat

ive

ARV

dru

gs c

ould

be

used

: RA

L w

ith

trea

tmen

t dos

ing,

3TC

or L

PV/r

bas

ed o

n ev

iden

ce g

athe

red

thro

ugh

the

PRO

MIS

E tr

ial:

3TC

was

adm

inis

tere

d as

follo

ws:

7.5

mg

once

dai

ly fo

r neo

nate

s w

eigh

ing

2–<

4 kg

, 25

mg

once

dai

ly fo

r inf

ants

wei

ghin

g 4–

<8

kg a

nd 5

0 m

g on

ce d

aily

for c

hild

ren

wei

ghin

g m

ore

than

8 k

g; L

PV/r

was

ad

min

iste

red

twic

e da

ily a

fter

the

firs

t wee

k of

life

acc

ordi

ng t

o th

e fo

llow

ing

dosi

ng s

chem

e: 4

0/10

mg

once

dai

ly fo

r neo

nate

s w

eigh

ing

2–<

4 kg

and

80/

20 m

g on

ce d

aily

for i

nfan

ts w

eigh

ing

mor

e th

an 4

kg

(23)

.b Th

is s

impl

ified

dos

ing

was

dev

elop

ed w

ith

a W

HO

gen

eric

too

l bas

ed o

n pr

evio

usly

est

ablis

hed

NVP

pro

phyl

actic

tar

gets

.

515Annex 1: dosages for ARV drugs

Optimal ARV drug formulary for childrenIn recent years, a number of improved ARV drug formulations have become available, such as dispersible, scored fixed-dose combination tablets that have replaced traditional liquid formulations. These products have greatly simplified the delivery of HIV treatment for children in low-income settings; however, the proliferation of options has resulted in a multiplicity of formulations across regimens and weight bands. Generic manufacturers use economies of scale to maintain affordable pricing, but fragmentation of demand across too many duplicative products creates instability in the reliable supply of ARV dosage forms for children and complicates procurement and supply chain management.

Partners of the ARV Procurement Working Group (24) and of the Global Accelerator for Paediatric Formulations Network (16) provide formulary guidance to programmes on selecting optimal ARV drugs for children, which have been defined using a robust set of criteria. The formulary was first developed in 2011 but is routinely revised to correspond to current WHO guidelines and available products. The current Optimal Formulary was revised in December 2020 and released in April 2021 (25). It now includes seven products that deliver recommended and appropriate first and second-line regimens across all weight bands for children. Programmes are encouraged to procure dosage forms for children that are included in the Optimal ARV Formulary for Children. During periods of transition or in special circumstances (neonatal treatment, TB co-treatment and third-line ART), dosage forms included on the ARV Limited-use Formulary are sufficient to provide appropriate dosing across weight bands for children (26).

The need for new formulationsAs part of the Global Accelerator for Paediatric Formulations Network, the work of the Paediatric Antiretroviral Working Group and the Paediatric ARV Drug Optimization (27,28) groups continue to highlight the urgent need for better age-appropriate formulations for infants and children living with HIV. An additional solid fixed-dose combination formulation is under the final stage of approval (ABC/3TC/LPV/r granules). In addition, the availability of co-formulated DRV/r in a heat-stable fixed-dose combination is critical to facilitate treatment sequencing and uptake of future second- and third-line regimens for children. Several formulations containing approved ARV drugs for children have been formally given priority and are listed in Table A1.6. Finally, additional formulations containing newer drugs for which there is currently no indication for children were considered, and the central future role of DTG and TAF in optimizing dose, sequencing and harmonization across age groups was highlighted.

In moving towards promoting drug optimization for children and adolescents, WHO will continue to work to simplify prescribing, dispensing and dosing guidance and work with the pharmaceutical industry (originator and generic) and other partners to develop more practical recommendations on the range of formulations required to safely accelerate the scaling up of ART for children.

516 Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring

Box

A1.1

 Ant

icip

ated

sim

plifi

ed d

osin

g fo

r fo

rmul

atio

ns u

nder

dev

elop

men

t

Dru

gSt

reng

th o

f pae

diat

ric

tabl

ets

or

ora

l liq

uid

Num

ber

of t

able

ts o

r m

L by

wei

ght-

band

mor

ning

(AM

) and

eve

ning

(PM

)

3–<

6 kg

6–<1

0 kg

10–<

14 k

g14

–<20

kg

20–<

25 k

g25

–<35

kg

AM

PMA

MPM

AM

PMA

MPM

AM

PMA

MPM

ABC

/3TC

/LPV

/r 30

mg/

15 m

g/40

mg/

10 m

g gr

anul

es2

23

34

45

56

6–

DRV

/r12

0 m

g/20

mg

tabl

et–

––

–2

23

33

34

4

ABC

/3TC

/DTG

aD

ispe

rsib

le 6

0 m

g/30

mg/

5 m

g ta

blet

–3

45

6–

a Th

is d

osag

e fo

rm is

the

one

iden

tifie

d by

the

PA

DO

4 gr

oup

(28)

as

the

mos

t lik

ely

to d

eliv

er a

ppro

pria

te d

ose

base

d on

the

bes

t ava

ilabl

e in

form

atio

n.

517Annex 1: dosages for ARV drugs

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(https://www.who.int/groups/antiretroviral-drug-optimization, accessed 1 June 2021).

2. Annex 1. Summary of product characteristics. Tivicay. Amsterdam: European Medicines Agency; 2020 (https://www.ema.europa.eu/en/documents/product-information/tivicay-epar-product-information_en.pdf, accessed 1 June 2021).

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6. Dolutegravir tablet for oral suspension. Washington (DC): United States Food and Drug Administration; 2020 (https://www.accessdata.fda.gov/drugsatfda_docs/pepfar/214521PI.pdf, accessed 1 June 2021).

7. Jacobs TG, Svensson EM, Musiime V, Rojo P, Dooley KE, McIlleron H. Pharmacokinetics of antiretroviral and tuberculosis drugs in children with HIV/TB co-infection: a systematic review. J Antimicrob Chemother. 2020;75:3433–57.

8. Teppler H, Thompson K, Chain A, Mathe M, Nachman S, Clarke D. Crushing of raltegravir (RAL) chewable tablets for administration in infants and young children. International Workshop on HIV Pediatrics, Paris, France, 21–22 July 2017.

9. GENVOYA® (elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets, for oral use. Washington (DC): United States Food and Drug Administration; 2017 (https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/207561s013lbl.pdf, accessed 1 June 2021).

10. Paediatric ARV dosing dashboard [website]. Geneva: World Health Organization; 2021 (https://www.who.int/groups/antiretroviral-drug-optimization, accessed 1 June 2021).

11. World Health Organization prequalification [website]. Geneva: World Health Organization; 2021 (http://apps.who.int/prequal, accessed 1 June 2021).

12. Quick reference guide for PEPFAR Database; interactive database for antiretroviral (ARV) drugs tentatively approved or approved that are eligible for procurement. Washington (DC): United States Food and Drug Administration; 2021 (https://www.fda.gov/InternationalPrograms/PEPFAR/ucm119231.htm, accessed 1 June 2021).

13. Sourcing and management of health products [website]. Geneva: Global Fund to Fight AIDS, Tuberculosis and Malaria; 2021 (https://www.theglobalfund.org/en/sourcing-management/quality-assurance/medicines, accessed 1 June 2021.

14. REYATAZ® (atazanavir) oral powder. Washington (DC): United States Food and Drug Administration; 2018 (https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021567s042,206352s007lbl.pdf, accessed 1 June 2021).

518 Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring

15. Cotton MF, Liberty A, Torres-Escobar I, Gonzalez-Tome MI, Lissens J, Zaru L et al. Safety and efficacy of atazanavir powder and ritonavir in HIV-1-infected infants and children from 3 months to <11 years of age: the PRINCE-2 Study. Pediatr Infect Dis J. 2018;37:e149–56.

16. A randomised trial of dolutegravir (DTG)-based antiretroviral therapy vs. standard of care (SOC) in children with HIV infection starting first-line or switching to second-line ART. Bethesda (MD): ClinicalTrials.gov; 2020 (https://clinicaltrials.gov/ct2/show/NCT02259127, accessed 1 June 2021).

17. WHO, Interagency Task Team (IATT) on Prevention of HIV Infection in Pregnant Women, Mothers and their Children, UNICEF). Fact sheet on lopinavir and ritonavir (LPV/R) oral pellets: 40 mg/10 mg per capsule bottle pack containing 120 capsules. Geneva: World Health Organization; 2015 (https://apps.who.int/iris/handle/10665/193543, accessed 1 June 2021).

18. Lopinavir/ritonavir 40 mg/10 mg pellets and granules and 100/25 mg tablets. ARV Procurement Working Group; 2020 (https://www.arvprocurementworkinggroup.org/lpv-r-supply, accessed 1 June 2021).

19. Fillekes Q, Mulenga V, Kabamba D, Kankasa C, Thomason MJ, Cook A et al. Pharmacokinetics of nevirapine in HIV-infected infants weighing 3 kg to less than 6 kg taking paediatric fixed dose combination tablets. AIDS. 2012;26:1795–800.

20. ISENTRESS® (raltegravir) film-coated tablets, for oral use, ISENTRESS® HD (raltegravir) film-coated tablets, for oral use, ISENTRESS® (raltegravir) chewable tablets, for oral use, ISENTRESS® (raltegravir) for oral suspension. Washington (DC): United States Food and Drug Administration; 2020 (https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/022145s042,203045s016,205786s008lblrpl.pdf, accessed 1 June 2021).

21. Bollen PDJ, Moore CL, Mujuru HA, Makumbi S, Kekitiinwa AR, Kaudha E et al. Simplified dolutegravir dosing for children with HIV weighing 20 kg or more: pharmacokinetic and safety substudies of the multicentre, randomised ODYSSEY trial. Lancet HIV. 2020;7:e533–44.

22. Rabie H, Denti P, Lee J, Masango M, Coovadia A, Pillay S et al. Lopinavir-ritonavir super-boosting in young HIV-infected children on rifampicin-based tuberculosis therapy compared with lopinavir-ritonavir without rifampicin: a pharmacokinetic modelling and clinical study. Lancet HIV. 2018:S2352-3018(18)30293-5.

23. Nagot N, Kankasa C, Tumwine JK, Meda N, Hofmeyr GJ, Vallo R, et al. Extended pre-exposure prophylaxis with lopinavir–ritonavir versus lamivudine to prevent HIV-1 transmission through breastfeeding up to 50 weeks in infants in Africa (ANRS 12174): a randomised controlled trial. The Lancet. 2016 Feb 6;387(10018):566-73.

24. ARV Procurement Working Group [website]. ARV Procurement Working Group; 2021 (https://arvprocurementworkinggroup.org/en, accessed 1 June 2021).

25. Global Accelerator for Paediatric Formulations Network (GAP-f) [website]. Geneva: World Health Organization; 2021 (https://www.who.int/initiatives/gap-f, accessed 1 June 2021).

26. The 2021 optimal formulary and limited-use list for antiretroviral drugs for children. Geneva: World Health Organization; 2021 (https://www.who.int/publications/i/item/9789240023529, accessed 1 June 2021).

27. Meeting report: Paediatric Antiretroviral Drug Optimization (PADO) Meeting 4. Geneva: World Health Organization; 2018 (https://cdn.who.int/media/docs/default-source/hq-hiv-hepatitis-and-stis-library/pado4.pdf?sfvrsn=26d4169c_5, accessed 1 June 2021).

28. Penazzato M, Townsend CL, Rakhmanina N, Cheng Y, Archary M, Cressey TR et al. Prioritising the most needed paediatric antiretroviral formulations: the PADO4 list. Lancet HIV. 2019;6:e623–31.