who policy on collaborative tb/hiv activities guidelines for national

WHO policy on collaborative TB/HIV activities

Guidelines for national programmes and other stakeholders

Annexes for webposting and CD-Rom distribution with the policy guidelines

This is an updated version of a document originally published in 2004 as Interim policy on collaborative TB/HIV activities (WHO/HTM/TB/2004.330; WHO/HTM/HIV/2004.1)

WHO Library Cataloguing-in-Publication Data

WHO policy on collaborative TB/HIV activities: guidelines for national programmes and other stakeholders.

Contents: Annexes for webposting and CD-ROM distribution with the policy guidelines

1.HIV infections. 2.Acquired immunodeficiency syndrome - prevention and control. 3.AIDS-related opportunistic infections - prevention and control. 4.Tuberculosis, Pulmonary - prevention and control. 5.National health programs. 6.Health policy. 7.Guidelines. I.World Health Organization.

ISBN 978 92 4 150300 6 (NLM classification: WC 503.5)

These guidelines were developed in compliance with the process for evidence gathering, assessment and formulation of recommendations, as outlined in the WHO handbook for guideline development (version March 2010).

© World Health Organization 2012

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Designed by Creative Lynx, Geneva, Switzerland

WHO/HTM/TB/2012.1 WHO/HIV/2012.1

WHO policy on collaborative TB/HIV activities

Guidelines for national programmes and other stakeholders

Annexes for webposting and CD-Rom distribution

with the policy guidelines

4

WHO policy on collaborative TB/HIV activities: Guidelines for national programmes and other stakeholders Annexes for webposting and CD-Rom distribution with the policy guidelines

Summary of declaration of interests

All members of the Policy Updating Group were asked to complete a World Health Organization (WHO) Declaration of interests for WHO consultants form. Five members of the group declared a conflict of interest. Constance Benson declared consulting, scientific and technical advisory work on antiretroviral therapy new drug development with Merck, GlaxoSmithKline and ViiV for less than US$ 5000 each. Pedro Cahn declared ongoing research support and consulting work with Abbott for an amount of US$ 3000. He declared receiving US$ 2000 from Bristol-Myers Squibb and US$ 2000 from Tibotec for serving on a speakers’ bureau. He also declared scientific advisory work for Merck, Pfizer, GlaxoSmithKline and Avexa for an amount of US$ 2000 each. Mark Harrington declared giving testimony to the Institute of Medicine of the United States National Academies in panels on multidrug-resistant TB in 2008 and 2009. Charles Holmes declared employment by Gilead up to January 2008 in the clinical research unit focusing on phase I studies of experimental antiretroviral drugs. He declared no financial or other interest in Gilead. Salim S. Abdool Karim declared receiving US$ 2500 from Merck to attend the advisory panel meeting on microbicides in March 2011.

The declared conflicts of interest were discussed within the WHO Steering Group and with the Policy Updating Group before deliberations on the policy document, and it was concluded that these conflicts would not prohibit any of the members from participating in the process. Declarations of interest were collected from all non-WHO reviewers. Four peer reviewers declared potential conflicts of interest. Helen Ayles declared an ongoing research grant for her research unit with Delft Diagnostic Systems of € 100 000 to develop a computer-aided diagnostic for reading digital chest X-rays as well as having received a digital chest X-ray unit for an amount of US$ 250 000. François Boillot declared being the owner, director of and employed by a consulting company providing services in international health including in TB/HIV issues. Susan Swindells declared consulting services (advisory board) with Pfizer in 2008 (US$ 1800) and 2009 (US$ 1750), with Merck in 2009 (US$ 3500), with Tibotec in 2009 (US$ 1500) and with Abbott Molecular in 2010 (US$ 1000). She also declared previous research support to her institution from Bristol Myers Squibb that ended in 2010 (US$ 14929), from Pfizer that ended in 2011 (US$ 28125) and ongoing research support from GlaxoSmithKline for an amount of US$ 104034 and US$ 60676. Jay K. Varma declared non-monetary support (supplies and equipment) in 2010 valued at approximately US$ 10 000 from Cellestis to the government research unit of China and collaborators in Inner Mongolia to examine the prevalence of TB in health-care workers in collaboration with the United States Centers for Disease Control and Prevention. The WHO Steering Group discussed these declarations and concluded that they would not exclude the reviewers from the process. All declarations of conflict of interests are retained on electronic file by the WHO Stop TB Department.

Acknowledgements

The development of these guidelines was financially supported by the Joint United Nations Programme on HIV/AIDS Unified Budget and Workplan (UNAIDS UBW) and the US President’s Emergency Plan for AIDS Relief (PEPFAR) through the United States Centers for Disease Control and Prevention (CDC) and the United States Agency for International Development (USAID). Partial support for the systematic reviews on TB and HIV service integration was provided by the Global Fund to Fight AIDS, TB and Malaria.

5


WHO policy on collaborative TB/HIV activities: Guidelines for national programmes and other stakeholders is based on the interim policy on collaborative TB/HIV activities published in 2004 by the World Health Organization (WHO) and written by Haileyesus Getahun, Jeroen van Gorkom, Anthony Harries, Mark Harington, Paul Nunn, Jos Perriens, Alasdair Reid and Marco Vitoria on behalf of the TB/HIV policy writing committee for the Global TB/HIV Working Group of the Stop TB Partnership. This updated policy was written by Delphine Sculier and Haileyesus Getahun (Stop TB Department, WHO) in collaboration with the WHO Steering Group.

WHO Steering Group

Rachel Baggaley (HIV/AIDS Department), Haileyesus Getahun (Stop TB Department), Reuben Granich (HIV/AIDS Department), Christian Gunneberg (Stop TB Department), Craig McClure (HIV/AIDS Department), Eyerusalem Negussie (HIV/AIDS Department), Delphine Sculier (Stop TB Department), Marco Vitoria (HIV/AIDS Department).

WHO consultants for systematic and GRADE reviews

Martina Penazzato (Italy), Amitabh Suthar (USA), Helena Legido-Quigley (UK).

Policy updating group

Yibeltal Assefa (Federal HIV/AIDS Prevention and Control Office, Ethiopia), Abdool Karim S. Abdool Salim (Centre for the AIDS Programme of Research in South Africa, South Africa), Rifat Atun (Global Fund to Fight AIDS, Tuberculosis and Malaria (The Global Fund), Switzerland), Constance Benson (University of California, San Diego, USA), Amy Bloom (United States Agency for International Development (USAID), USA), Pedro Cahn (Fundación Huésped, Argentina), Rolando Cedillos (Proyecto Regional VIH SIDA para Centroamérica, El Salvador), Richard E. Chaisson (Johns Hopkins Bloomberg School of Public Health Center for TB Research, USA), Jeremiah Chakaya (Kenya Medical Research Institute (KEMRI), Kenya), Lucy Chesire (Advocacy to Control TB Internationally, Kenya), Mean Chhi Vun (National Center for HIV/AIDS, Dermatology and Sexually Transmitted Diseases, Cambodia), Gavin Churchyard (Aurum Institute for Health Research, South Africa), William Coggin (Office of the US Global AIDS Coordinator (OGAC), USA), Riitta Dlodlo (International Union Against Tuberculosis and Lung Disease (The Union), Zimbabwe), Ade Fakoya, (The Global Fund, Switzerland), Peter Godfrey-Fausset (London School of Hygiene & Tropical Medicine, UK), Anthony Harries (The Union, UK), Mark Harrington (Treatment Action Group, USA), Diane Havlir (University of California, San Francisco, USA), Charles Holmes (OGAC, USA), Nina Kerimi (United Nations Office on Drugs and Crime, Kazakhstan), Robert Makombe (United States Centers for Disease Control and Prevention (CDC), Botswana), Bess Miller (Global AIDS Program, USA), Ya-Diul Mukadi (USAID, USA), Jintanta Ngamvithayapong-Yanai (Research Institute of Tuberculosis, Japan), Alasdair Reid (Joint United Nations Programme on HIV/AIDS, Switzerland), BB Rewari (National AIDS Control Organization, India), Ashurova Rukshona (National Center for Prevention and Control of AIDS, Tajikistan), Holger Schünemann (McMaster University Health Sciences Centre, Canada), Lakhbir Singh Chauhan (Central TB Division, Ministry of Health and Family Welfare, India), Joseph Sitienei (Division of Leprosy, TB and Lung Diseases, Kenya), Alena Skrahina (Republic Scientific and Practical Center of Pulmonology and Tuberculosis, Belarus), John Stover (Future Institutes, USA), Jeroen van Gorkom (KNCV Tuberculosis Foundation, Netherlands).

External peer reviewers

Helen Ayles (ZAMBART Project, Zambia), François-Xavier Blanc (Agence nationale de recherche sur le sida et les hépatites virales, France), François Boillot (Alter-Santé Internationale et Développement, France), John T. Brooks (CDC, USA), Kevin Cain (KEMRI/CDC, Kenya), Wafaa El-Sadr (Columbia University, New York, USA), Eric Goemare (Médecins Sans Frontières (MSF), South Africa), Yared Kebede Haile (KNCV Tuberculosis Foundation, Netherlands), Steve D. Lawn (University of Cape Town, South Africa), Gary Maartens (University of Cape Town, South Africa), Barbara J. Marston (CDC, USA), Elizabeth Marum (CDC, Zambia), Max Meis (KNCV Tuberculosis Foundation, Netherlands), Sue Perez (free lance consultant, USA), Eric S. Pevzner (CDC, USA), Yogan Pillay (Strategic Health Programme, Department of Health, South Africa), Peter Saranchuk (MSF, South Africa), Kenly Sikwese (Global Network of People Living with HIV/AIDS, Zambia), Susan Swindells (University of Nebraska Medical Center, USA), Javid Syed (Treatment Action Group, USA), Nonna Turusbekova (KNCV Tuberculosis Foundation, Netherlands), Marieke van der Werf (KNCV Tuberculosis Foundation, Netherlands), Eric van Praag (Family Health International, United Republic of Tanzania), Jay K. Varma (CDC, China), Lynne Wilkinson (MSF, South Africa), Rony Zachariah (MSF, Belgium).

WHO headquarters and regional offices

Leopold Blanc (Stop TB Department), Puneet Dewan (Regional Office for South-East Asia), Gottfried Hirnschall (HIV/AIDS Department), Khurshid Hyder (Regional Office for South-East Asia), Rafael Lopez Olarte (Regional Office for the Americas), Frank Lule (Regional Office for Africa), Mario Raviglione (Stop TB Department), Ying-Ru Lo (HIV/AIDS Department), Caoimhe Smyth (HIV/AIDS Department).

Editor

Karin Ciceri

Coordination

Delphine Sculier and Haileyesus Getahun (Stop TB Department, WHO).

6


Contents

Abbreviations 7

Annex 1: Earlier initiation of antiretroviral therapy prevents active tuberculosis in people living with HIV – summary of findings and evaluation of the quality of the evidence 8

Annex 2: Voluntary testing and counselling for HIV benefits patients with diagnosed and presumptive tuberculosis – summary of findings and evaluation of the quality of the evidence 18

Annex 3: Co-trimoxazole preventive therapy reduces morbidity and mortality in tuberculosis patients living with HIV – summary of findings and evaluation of the quality of the evidence 26

7


Abbreviations

AFB acid-fast bacilli

AIDS acquired immunodeficiency syndrome

ART antiretroviral therapy

CI confidence interval

CPT co-trimoxazole preventive therapy

GRADE grading of recommendations assessment, development and evaluation

HAART highly active antiretroviral therapy

HIV human immunodeficiency virus

HR hazard ratio

IPT isoniazid preventive therapy

IRR incidence rate ratio

NNRTI non-nucleoside reverse transcriptase inhibitor

NRTI nucleoside reverse transcriptase inhibitor

PI protease inhibitor

PICO population, intervention, comparison, outcome

RCT randomized controlled trial

RR risk ratio

SD standard deviation

TB tuberculosis

TB/HIV The intersecting epidemics of TB and HIV

TST tuberculin skin test

VCT voluntary counselling and testing

WHO World Health Organization

8


PICO question: Can earlier initiation of antiretroviral therapy (ART) at higher CD4 counts (>350 cells/mm3) be used to prevent active tuberculosis in people living with HIV? Should antiretroviral therapy be used to prevent active tuberculosis?

Population: adults and adolescents living with HIVIntervention: ART at CD4 counts >350 cells/mm3

Comparison: no ART or ART deferred until CD4 counts ≤350 cells/mm3

Outcomes: TB incidence rate

1. Outcomes of interest

Outcomes Relative importance(rank 1 9 most critical) Comment

Tuberculosis incidence rate 9 Critical

2. Literature search strategy and information retrievalStudies were identified using PubMed and the Cochrane Library databases. No systematic reviews were identified using the Cochrane database.

Annex 1Earlier initiation of antiretroviral therapy prevents active tuberculosis in people living with HIV – summary of findings and evaluation of the quality of the evidence

Pubmed Search (346+ citations)

(“Antiretroviral Therapy, Highly Active”[Majr] OR “Anti-HIV gents/therapeutic use”[Majr] OR “Anti-HIV

Agents/administration and dosage”[Majr]) AND (“Tuberculosis/prevention and contro;”[Majr]) OR

“Tuberculosis/epidemiology”[Majr] OR “AIDS-Related Opportunistic Infections/epidemiology”[Majr] OR “AIDS-Related

Opportunistic Infections/prevention and control”[Majr]

By title: 43

By abstract: 21

By article: 6*

9


Selection criteria

Studies were selected if:

• randomizedandquasi-randomizedcontrolledstudies, includinghistoricallycontrolled trialsorobservationaland cohort studies;

• participantswerepeoplelivingwithHIV;• incidenceratesforbothexposuregroupsofPICOquestionweregiven.

*Excluded observational studies:

• Tuberculosis incidence ratewasnotanoutcome:AiLian (2007),Detels (2001),Eng (2009),Girardi (2000),Losina(2007)andSantaro-Lopes(2002);

• Person-yearsforstudyarmsnotincluded:Lannoy(2008)andMiranda(2007);• InterventionwasnotART:Brodt(1997),Dore(2002),Elzi(2007),Gillini(2002),Ives(2001),Kirk(2000)andMuga(2007).

Investigators in the field were contacted by email. The NA-ACCORD and HIV-CASUAL collaborations shared abstracts which were included. ART-CC updated the data from their study which were included (Girardi et al., 2005). Three relevant studies which were not captured by the MEDLINE search were also included (Golub et al., 2007, Severe et al., 2010, Cohen et al., 2011). Therefore, five additional studies were added to the six studies identified by the literature search.

Table 1 summarizes the findings from the 11 studies meeting eligible criteria for the review. ART causes immune reconstitution, prevents the development of opportunistic infections and prevents other HIV-related conditions. Data from observational cohorts have demonstrated the benefits of ART in reducing rates of TB (1–3). Data from South Africa show that TB rates decrease in a stepwise fashion as a result of ART-induced immune reconstitution, with high rates persisting until CD4 counts recover to more than 500 cells/mm3 (4). The rates of TB for South Africans with CD4 counts less than 100 cells/mm3 were approximately 10 times the rate of South Africans with CD4 counts exceeding 500 cells/mm3. HIV-infected South Africans with CD4 counts more than 500 cells/mm3 had about a two-fold increased rate of TB compared with HIV-negative persons. Many people living with HIV in Africa start ART with CD4 counts less than 100 cells/mm3 (5). WHO treatment guidelines published in 2010 recommend initiating ART at CD4 counts ≤350 cells/mm3 regardless of the presence of signs and symptoms (6). Data from observational studies assessed in this review and that did not specify CD4 counts showed that ART halves TB incidence rates. When ART is used in CD4 count stratum 200–350 cells/mm3, TB incidence is reduced up to 88% in observational studies (7,8) and by half in randomized controlled trials (9). In CD4 stratum >350 cells/mm3, ART use reduces TB incidence rates by up to 75% in observational studies (7,8) and by half in randomized controlled trials (10). TB case ascertainment was either definite (culture-confirmed TB) or probable (AFB smear-positive or signs, symptoms and chest radiography consistent with TB or histological finding of caseating/necrotizing granulomas or clinical response to antituberculosis treatment). Observational studies also showed a greater reduction in TB risk (up to 90%) among patients receiving both ART and IPT (11,12).

Tab

le 1

: Sum

mar

y o

f st

udie

s o

n an

tiret

rovi

ral t

her

apy

(AR

T) f

or

pre

vent

ion

of

tub

ercu

losi

s (T

B)

Aut

ho

r (Y

ear)

Met

ho

ds/

des

ign

Po

pul

atio

nP

artic

ipan

tsIn

terv

entio

nFo

llow

-up

TB e

pis

od

es a

nd c

ase

as

cert

ainm

ent

Bad

ri (7

) (2

002)

Obs

erva

tiona

l co

hort

HIV

pat

ient

s at

tend

ing

New

S

omer

set H

ospi

tal a

dult

HIV

cl

inic

, Uni

vers

ity o

f Cap

e To

wn,

be

twee

n 19

92 a

nd 2

001.

Thi

s is

a m

ajor

pub

lic h

ealth

-car

e fa

cilit

y.

Incl

usio

n: a

ged

>15

ye

ars.

Exc

lusi

on: a

cute

op

portu

nist

ic in

fect

ion,

si

gnifi

cant

labo

rato

ry

abno

rmal

ities

, cur

rent

ev

iden

ce o

f act

ive

subs

tanc

e ab

use,

pr

egna

ncy

or la

ctat

ion,

TB

at b

asel

ine

visi

t, us

e of

IP

T in

the

6 m

onth

s pr

ior

to b

asel

ine,

and

trea

tmen

t w

ith im

mun

e-m

odul

atin

g or

sy

stem

ic c

hem

othe

rape

utic

ag

ents

HA

AR

T (d

efine

d as

2

NR

TIs

plus

one

of

the

follo

win

g: (i

) an

NN

RTI

, (ii)

a P

I, or

(ii

i) a

third

NR

TI)

For p

atie

nts

on A

RT,

eve

ry

2–3

mon

ths,

clin

ical

, im

mun

olog

ical

and

vi

rolo

gica

l inf

orm

atio

n w

as

take

n, o

r mor

e fre

quen

tly

if cl

inic

ally

indi

cate

d.

For p

atie

nts

not o

n A

RT,

fo

llow

-up

was

eve

ry 3

–6

mon

ths.

Mea

n fo

llow

-up

in

thos

e ex

pose

d to

AR

T w

as

sign

ifica

ntly

gre

ater

than

in

the

cont

rols

(16.

8 (S

D 8

.3)

vs 1

3.2

(SD

15.

5) m

onth

s).

2 ca

ses

durin

g 10

0.1

pers

on-y

ears

on

AR

T w

ith b

asel

ine

CD

4 co

unts

>35

0 ce

lls/m

m3 ;

14

case

s du

ring

388.

3 pe

rson

-yea

rs o

ff A

RT

with

ba

selin

e C

D4

coun

ts >

350.

Adj

uste

d R

R w

as

0.36

(95%

CI 0

.10

to 1

.74)

for t

his

CD

4 st

ratu

m.

2 ca

ses

durin

g 12

1.2

pers

on-y

ears

on

AR

T w

ith b

asel

ine

CD

4 co

unts

200

–350

; 27

case

s du

ring

225

pers

on-y

ears

off

AR

T w

ith b

asel

ine

CD

4 co

unts

200

–350

. Adj

uste

d R

R w

as 0

.12

(95%

0.0

3 to

0.5

3) fo

r thi

s C

D4

stra

tum

.

Acr

oss

all C

D4

stra

ta, o

f the

9 T

B c

ases

on

AR

T, 5

wer

e de

finite

(cul

ture

/aut

opsy

co

nfirm

ed) a

nd 4

wer

e pr

obab

le (p

rese

nce

of A

FB o

r his

tolo

gica

l find

ing

of c

asea

ting

gran

ulom

ata)

. Of t

he 8

2 TB

cas

es o

ff A

RT,

48

wer

e pr

obab

le a

nd 3

4 w

ere

defin

ite.

del A

mo

(8)

(201

1)

Obs

erva

tiona

l co

hort

This

ana

lysi

s fro

m th

e H

IV-C

AUS

AL

Col

labo

ratio

n in

clud

es 1

1 ob

serv

atio

nal

coho

rts fr

om 1

996

to 2

007.

Th

e co

horts

are

in th

e U

K, t

he

Net

herla

nds,

Fra

nce,

Spa

in

and

the

US

A.

HIV

-infe

cted

indi

vidu

als

who

wer

e ag

ed ≥

18 y

ears

, an

tiret

rovi

ral n

aive

, with

out

AID

S, n

ot p

regn

ant,

and

in

who

m C

D4

coun

ts a

nd v

iral

load

wer

e m

easu

red

with

in

6 m

onth

s of

eac

h ot

her a

t ba

selin

e. In

divi

dual

s w

ith

TB d

urin

g th

e fir

st m

onth

of

follo

w u

p w

ere

excl

uded

(p

reva

lent

TB

cas

e).

Com

bine

d A

RT

(defi

ned

as a

re

gim

en in

clud

ing

>3

AR

Ts, 2

rito

navi

r-bo

oste

d P

Is, o

r 1

NN

RTI

and

1

boos

ted

PI)

For e

ach

patie

nt, f

ollo

w-u

p en

ded

at th

e ea

rlies

t of:

TB d

iagn

osis

, dea

th, 1

2 m

onth

s af

ter t

he m

ost r

ecen

t la

bora

tory

mea

sure

men

t, pr

egna

ncy

(if k

now

n),

or th

e co

hort-

spec

ific

adm

inis

trativ

e en

d of

follo

w-

up.

The

over

all h

azar

d ra

tio o

f TB

for c

ombi

ned

AR

T w

as 0

.56

(95%

CI 0

.44–

0. 7

2).

The

haza

rd ra

tios

wer

e si

mila

r for

indi

vidu

als

with

bas

elin

e C

D4

coun

ts >

350

(0.5

0, 9

5% C

I 0.

36–0

.69)

and

200

–350

(0.4

5, 9

5% C

I 0.2

7,

0.74

).

TB c

ases

wer

e di

agno

sed

acco

rdin

g to

st

anda

rd c

linic

al p

ract

ice

in E

urop

e an

d th

e U

SA

.

Gira

rdi (13

)

(200

5)

Obs

erva

tiona

l co

hort

The

AR

T C

ohor

t Col

labo

ratio

n (A

RT-

CC

) is

an in

tern

atio

nal

colla

bora

tion

of c

ohor

t stu

dies

fro

m E

urop

e an

d N

orth

A

mer

ica.

Thi

s st

udy

incl

uded

12

coh

orts

.

Ant

iretro

vira

l-nai

ve s

ubje

cts

had

to b

e ag

ed ≥

16 y

ears

. D

ata

wer

e fro

m s

ubje

cts

who

sta

rted

AR

T be

twee

n 19

96 a

nd 2

008

(AR

T-C

C

upda

ted

the

data

pre

sent

ed

in th

e 20

05 a

rticl

e). F

ollo

w-

up w

as c

enso

red

at 3

yea

rs

from

sta

rt of

AR

T

HA

AR

T (d

efine

d as

at

leas

t 3 d

rugs

, in

clud

ing

PIs

, N

NR

TIs

and

NR

TIs)

Dat

a on

HA

AR

T re

gim

en

(PI/N

NR

TI/N

RTI

-bas

ed),

CD

4 co

unt,

vira

l loa

d,

gend

er, a

ge, y

ear o

f HA

AR

T in

itiat

ion

and

risk

grou

p (M

SM

, inj

ectio

n dr

ug u

ser,

hete

rose

xual

, blo

od-p

rodu

ct

reci

pien

t, ot

her/n

ot k

now

n)

wer

e co

llect

ed

676

case

s du

ring

124

669

pers

on-y

ears

on

HA

AR

T w

ith b

asel

ine

CD

4 co

unts

≤35

0; 5

8 ca

ses

durin

g 23

420

per

son-

year

s on

HA

AR

T w

ith b

asel

ine

CD

4 co

unts

351

–500

.

The

IRR

was

0.4

6 (9

5% C

I 0.3

5, 0

.60)

for

high

er v

s lo

wer

bas

elin

e C

D4

coun

ts a

t HA

AR

T in

itiat

ion.

All

TB c

ases

und

erw

ent a

ntitu

berc

ulos

is

treat

men

t. S

ince

the

stan

dard

of m

edic

al

care

is to

con

firm

TB

prio

r to

star

ting

antit

uber

culo

sis

treat

men

t, in

vest

igat

ors

indi

cate

that

all

the

TB c

ases

wer

e cu

lture

-co

nfirm

ed.

10WHO

pol

icy

on c

olla

bora

tive

TB/H

IV a

ctiv

ities

: Gui

delin

es fo

r nat

iona

l pro

gram

mes

and

oth

er s

take

hold

ers

Anne

xes

for w

ebpo

stin

g an

d CD

-Rom

dis

tribu

tion

with

the

polic

y gu

idel

ines

Tab

le 1

: Sum

mar

y o

f st

udie

s o

n an

tiret

rovi

ral t

her

apy

(AR

T) f

or

pre

vent

ion

of

tub

ercu

losi

s (T

B)

Aut

ho

r (Y

ear)

Met

ho

ds/

des

ign

Po

pul

atio

nP

artic

ipan

tsIn

terv

entio

nFo

llow

-up

TB e

pis

od

es a

nd c

ase

as

cert

ainm

ent

Gol

ub (12)

(200

9)

Obs

erva

tiona

l co

hort

HIV

pat

ient

s re

ceiv

ing

prim

ary

HIV

car

e at

two

clin

ics

affil

iate

d w

ith th

e U

nive

rsity

of t

he

Witw

ater

sran

d: th

e Pe

rinat

al

HIV

Res

earc

h U

nit (

PH

RU

) in

Sow

eto,

a la

rge,

urb

an s

ettin

g,

and

the

Tint

swal

o H

ospi

tal,

a re

mot

e, ru

ral c

linic

in

Mpu

mal

anga

Pro

vinc

e.

HIV

-infe

cted

adu

lts a

ged

>18

yea

rs. N

o ex

clus

ion

crite

ria li

sted

HA

AR

T (n

ot d

efine

d)

and/

or IP

TTi

me

betw

een

visi

ts is

sc

hedu

led

to b

e 4–

7 m

onth

s, b

ut p

atie

nts

may

vi

sit t

he c

linic

at a

ny ti

me.

Fo

llow

-up

data

col

lect

ion

focu

ses

on c

linic

al

diag

nose

s, s

ympt

oms

and

long

itudi

nal d

ata

incl

udin

g he

ight

and

wei

ght,

smok

ing

stat

us, a

lcoh

ol

cons

umpt

ion

and

mea

sure

s of

soc

ioec

onom

ic s

tatu

s.

Labo

rato

ry te

sts

incl

ude

CD

4 an

d fu

ll bl

ood

coun

ts

at re

crui

tmen

t and

eve

ry 6

m

onth

s.

200

case

s of

TB

dur

ing

2815

une

xpos

ed

pers

on-y

ears

; 44

case

s du

ring

952

pers

on-

year

s on

HA

AR

T; 1

cas

e du

ring

93 p

erso

n-ye

ars

on IP

T an

d A

RT.

The

IRR

for H

AA

RT

was

0.

65 (0

.46–

0.91

). Th

e IR

R fo

r IP

T an

d H

AA

RT

was

0.1

5 (0

.00–

0.85

). Th

e ad

just

ed H

R fo

r H

AA

RT

was

0.3

6 (0

.25,

0.5

1). T

he a

djus

ted

HR

fo

r IP

T an

d H

AA

RT

was

0.1

1 (0

.02,

0.7

8).

Gol

ub (11)

(200

7)

Obs

erva

tiona

l co

hort

Bas

elin

e m

edic

al re

cord

s w

ere

anal

ysed

for a

2-y

ear p

erio

d (fr

om 1

Sep

tem

ber 2

003

to 1

S

epte

mbe

r 200

5) in

29

publ

ic

clin

ics

in R

io d

e Ja

neiro

, Bra

zil.

Patie

nts

who

had

mad

e at

le

ast o

ne v

isit

to o

ne o

f the

cl

inic

s (fr

om 1

Sep

tem

ber

2003

to 1

Sep

tem

ber 2

005)

an

d w

ho re

ceiv

ed th

eir

prim

ary

care

from

the

clin

ics

wer

e in

clud

ed. P

atie

nts

who

at

tend

ed th

e cl

inic

to c

olle

ct

antir

etro

vira

l med

icat

ions

pr

escr

ibed

by

a pr

ivat

e ph

ysic

ian

wer

e ex

clud

ed,

as w

ere

patie

nts

who

die

d be

fore

1 S

epte

mbe

r 200

3.

AR

T (n

ot d

efine

d)

and/

or IP

TFo

llow

-up

ende

d at

TB

di

agno

sis

or th

e ea

rlier

of

thei

r las

t vis

it

to a

n H

IV c

linic

, the

dat

e of

ad

min

istra

tive

cens

orin

g or

de

ath.

Info

rmat

ion

colle

cted

in

clud

ed a

ge, s

ex, d

ate

of

HIV

dia

gnos

is, t

reat

men

t hi

stor

y (a

ntire

trovi

ral d

rugs

, IP

T), d

ates

of o

ppor

tuni

stic

di

seas

es in

clud

ing

TB, a

nd

resu

lts o

f dia

gnos

tic te

sts

incl

udin

g C

D4

coun

ts, H

IV

vira

l loa

ds a

nd T

ST.

155

case

s du

ring

3865

une

xpos

ed p

erso

n-ye

ars;

221

cas

es d

urin

g 11

627

pers

on-y

ears

on

AR

T; 1

0 ca

ses

durin

g 12

53 p

erso

n-ye

ars

on A

RT

and

IPT.

IRR

for A

RT

was

0.4

8 (0

.39,

0.

59).

IRR

for A

RT

and

IPT

was

0.2

0 (0

.09,

0.

91).

Adj

uste

d H

R w

as 0

.41

(0.3

1, 0

.54)

for

AR

T. A

djus

ted

HR

was

0.2

4 (0

.11,

0.5

3) fo

r A

RT

and

IPT.

Jone

s (14)

(200

0)

Obs

erva

tiona

l co

hort

The

Adu

lt/A

dole

scen

t S

pect

rum

of H

IV D

isea

se

proj

ect i

s a

mul

ticen

tre

obse

rvat

iona

l coh

ort s

tudy

in

clud

ing

site

s in

Atla

nta,

GA

; D

alla

s, H

oust

on, a

nd S

an

Ant

onio

, TX;

Den

ver,

CO

; D

etro

it, M

I; Lo

s A

ngel

es, C

A;

Sea

ttle,

WA

; New

Orle

ans,

LA

; N

ew Y

ork,

NY;

and

Bay

amon

, P

uerto

Ric

o.

HIV

-infe

cted

per

sons

ar

e id

entifi

ed a

t the

ir fir

st

heal

th-c

are

enco

unte

r re

gard

less

of t

he s

tage

of

thei

r HIV

infe

ctio

n. A

ll pa

tient

s ag

ed >

13 y

ears

w

ho w

ere

infe

cted

with

H

IV a

nd w

ho a

ttend

ed

parti

cipa

ting

clin

ics

durin

g th

e st

udy

perio

d w

ere

elig

ible

for e

nrol

men

t.

HA

AR

T (d

efine

d as

trip

le th

erap

y w

ith 2

NR

TIs

and

an N

NR

TI o

r PI,

or

any

com

bina

tion

incl

udin

g a

PI)

On

succ

essi

ve 6

-mon

th

follo

w-u

p in

terv

als,

med

ical

re

cord

s ar

e re

view

ed fo

r ill

ness

es, A

IDS

-defi

ning

co

nditi

ons,

pre

scrip

tions

, la

bora

tory

test

s an

d m

edic

al

care

util

izat

ion.

TB

inci

denc

e w

as a

sses

sed

by e

xam

inin

g th

e fir

st p

rosp

ectiv

e oc

curr

ence

of T

B fr

om

Janu

ary

1996

to J

une

1998

.

45 c

ases

dur

ing

6250

une

xpos

ed p

erso

n-ye

ars;

7 c

ases

dur

ing

3684

per

son-

year

s on

H

AA

RT.

The

IRR

was

0.2

(0.1

, 0.5

).

11

WHO

pol

icy

on c

olla

bora

tive

TB/H

IV a

ctiv

ities

: Gui

delin

es fo

r nat

iona

l pro

gram

mes

and

oth

er s

take

hold

ers

Anne

xes

for w

ebpo

stin

g an

d CD

-Rom

dis

tribu

tion

with

the

polic

y gu

idel

ines

Tab

le 1

: Sum

mar

y o

f st

udie

s o

n an

tiret

rovi

ral t

her

apy

(AR

T) f

or

pre

vent

ion

of

tub

ercu

losi

s (T

B)

Aut

ho

r (Y

ear)

Met

ho

ds/

des

ign

Po

pul

atio

nP

artic

ipan

tsIn

terv

entio

nFo

llow

-up

TB e

pis

od

es a

nd c

ase

as

cert

ainm

ent

Lau

(15)

(201

0)

Obs

erva

tiona

l co

hort

The

Nor

th A

mer

ican

AID

S

Coh

ort C

olla

bora

tion

on

Res

earc

h an

d D

esig

n (N

A-A

CC

OR

D) i

nclu

des

22

rese

arch

gro

ups,

repr

esen

ting

mor

e th

an 6

0 st

udy

site

s.

HIV

-infe

cted

pat

ient

s w

ho

rece

ived

med

ical

car

e be

twee

n Ja

nuar

y 19

96 a

nd

Dec

embe

r 200

5 an

d ha

d no

his

tory

of a

n A

IDS

-de

finin

g ill

ness

and

wer

e A

RT-

naiv

e.

HA

AR

T (d

efine

d as

a re

gim

en

cont

aini

ng a

t lea

st

3 A

RT

drug

s,

one

of w

hich

had

to

be

a P

I, an

N

NR

TI, a

baca

vir/

teno

fovi

r, an

in

tegr

ase

inhi

bito

r , o

r mar

aviro

c/en

fuvi

rtide

)

Indi

vidu

als

cont

ribut

ed

pers

on-ti

me

star

ting

from

th

e m

onth

of i

nitia

tion

of H

AA

RT

up u

ntil

TB

diag

nosi

s, lo

ss to

follo

w-u

p

(last

con

tribu

ted

CD

4 co

unt),

or a

dmin

istra

tive

cens

orin

g.

124

case

s du

ring

149

011

pers

on-y

ears

on

HA

AR

T w

ith b

asel

ine

CD

4 co

unts

≤35

0; 1

3 ca

ses

durin

g 27

601

per

son-

year

s on

HA

AR

T w

ith b

asel

ine

CD

4 co

unts

351

–500

. The

IR

R w

as 0

.57

(95%

CI 0

.32,

1.0

0) fo

r ear

lier

HA

AR

T; 8

cas

es d

urin

g fo

llow

-up

for p

erso

ns

on H

AA

RT

with

bas

elin

e C

D4

coun

ts >

500.

Of

the

145

TB c

ases

, 98

wer

e cu

lture

-pos

itive

, 39

wer

e cu

lture

-neg

ativ

e an

d 8

wer

e of

unk

now

n cu

lture

sta

tus.

For

the

TB c

ases

that

wer

e no

t pos

itive

, TB

dia

gnos

is w

as e

stab

lishe

d by

sig

ns, s

ympt

oms

and

ches

t rad

iogr

aphy

co

nsis

tent

with

TB

, pat

holo

gy w

ith n

ecro

tizin

g gr

anul

omas

and

AFB

, pos

itive

NA

AT a

nd/o

r cl

inic

al re

spon

se to

ant

itube

rcul

osis

ther

apy.

Lede

rger

ber

(16)

(200

0)

Obs

erva

tiona

l co

hort

The

Sw

iss

HIV

Coh

ort S

tudy

en

rols

HIV

-infe

cted

per

sons

ag

ed >

16 y

ears

in B

asel

, Ber

n,

Gen

eva,

Lau

sann

e, L

ugan

o, S

t G

all a

nd Z

uric

h.

All

parti

cipa

nts

who

sta

rted

pote

nt A

RT

betw

een

Sep

tem

ber 1

995

and

Dec

embe

r 199

7; h

ad a

C

D4

coun

t and

a v

iral l

oad

durin

g th

e 3

mon

ths

befo

re

star

ting;

and

mad

e ≥1

fo

llow

- up

visi

t >1

mon

th

afte

r sta

rting

AR

T.

Pote

nt A

RT

(defi

ned

as c

ombi

natio

n tre

atm

ent w

ith

at le

ast 3

dru

gs,

incl

udin

g at

leas

t 1

PI)

Dat

a ar

e co

llect

ed

at 6

-mon

th in

terv

als.

M

edic

atio

ns a

re re

gist

ered

by

mon

th o

f ini

tiatio

n an

d di

scon

tinua

tion.

7 ca

ses

durin

g 89

7 un

expo

sed

pers

on-y

ears

; 6

case

s du

ring

2727

per

son-

year

s on

AR

T. T

he

IRR

was

0.2

8 (9

5% C

I 0.0

9, 0

.84)

.

Mor

eno

(17)

(200

8)

Obs

erva

tiona

l co

hort

CoR

IS-M

D is

an

open

m

ultic

entre

hos

pita

l-bas

ed

coho

rt st

udy

with

in S

pain

’s

HIV

Res

earc

h N

etw

ork

of

Exc

elle

nce.

All

HIV

-infe

cted

sub

ject

s ag

ed >

18 y

ears

, with

at

leas

t 6 m

onth

s of

follo

w-u

p,

seen

at a

ny ti

me

betw

een

1 Ja

nuar

y 19

97 a

nd 3

0 Ju

ne 2

003

in a

ny o

f the

pa

rtici

patin

g ce

ntre

s.

HA

AR

T (d

efine

d as

AR

T re

gim

ens

incl

udin

g 2

NR

TIs

plus

eith

er a

n N

NR

TI o

r a P

I, or

3

NR

TIs)

Dat

a w

ere

colle

cted

for:

sex,

ag

e, tr

ansm

issi

on c

ateg

ory,

pe

riod

of o

bser

vatio

n, C

D4

coun

t, vi

ral l

oad,

AID

S

diag

nosi

s, tr

eatm

ent s

tatu

s at

ent

ry a

nd o

ver t

ime,

and

vi

tal s

tatu

s. M

edia

n fo

llow

-up

was

4.1

yea

rs (I

QR

, 2.

0–6.

4) in

HA

AR

T-na

ive

and

2.9

year

s (1

.5–4

.6) i

n H

AA

RT.

129

case

s du

ring

5215

une

xpos

ed p

erso

n-ye

ars;

75

case

s du

ring

7825

per

son-

year

s on

H

AA

RT.

The

IRR

was

0.2

6 (9

5% C

I 0.1

6, 0

.40)

.

12WHO

pol

icy

on c

olla

bora

tive

TB/H

IV a

ctiv

ities

: Gui

delin

es fo

r nat

iona

l pro

gram

mes

and

oth

er s

take

hold

ers

Anne

xes

for w

ebpo

stin

g an

d CD

-Rom

dis

tribu

tion

with

the

polic

y gu

idel

ines

Tab

le 1

: Sum

mar

y o

f st

udie

s o

n an

tiret

rovi

ral t

her

apy

(AR

T) f

or

pre

vent

ion

of

tub

ercu

losi

s (T

B)

Aut

ho

r (Y

ear)

Met

ho

ds/

des

ign

Po

pul

atio

nP

artic

ipan

tsIn

terv

entio

nFo

llow

-up

TB e

pis

od

es a

nd c

ase

as

cert

ainm

ent

Coh

en (10)

(2

011)

Ran

dom

ized

co

ntro

lled

trial

The

trial

had

glo

bal

repr

esen

tatio

n w

ith 1

3 si

tes

in B

otsw

ana,

Bra

sil,

Indi

a,

Ken

ya, M

alaw

i, S

outh

Afri

ca,

Thai

land

, the

Uni

ted

Sta

tes

and

Zim

babw

e.

HIV

-ser

odis

cord

ant c

oupl

es

in w

hich

the

HIV

-infe

cted

pa

rtner

is A

RT-

naiv

e an

d ha

s a

CD

4 co

unt b

etw

een

350

and

550

cells

/mm

3

The

AR

T re

gim

ens

in th

is s

tudy

wer

e co

nsis

tent

with

W

HO

gui

delin

es

All

parti

cipa

nts

com

plet

ed

mon

thly

follo

w-u

p vi

sits

th

roug

hout

the

stud

y. F

or

thos

e on

AR

T, la

bora

tory

and

ad

here

nce

mea

sure

men

ts

took

pla

ce. F

or th

ose

not

on A

RT

labo

rato

ry a

nd

coun

selli

ng to

ok p

lace

.

33 c

ases

am

ong

the

877

adul

ts in

itiat

ing

AR

T w

ith C

D4

coun

ts <

350

cells

/µL;

17

case

s am

ong

the

886

peop

le in

itiat

ing

AR

T w

ith C

D4

coun

ts >

350

cells

/µL.

Thi

s tra

nsla

ted

into

an

RR

0.5

1 (0

.28–

0.91

).a

Sev

ere

(9)

(201

0)R

ando

miz

ed

cont

rolle

d tri

alTh

e st

udy

was

con

duct

ed a

t th

e ce

ntre

of t

he H

aitia

n G

roup

fo

r the

Stu

dy o

f Kap

osi’s

S

arco

ma

and

Opp

ortu

nist

ic

Infe

ctio

ns in

Por

t-au-

Prin

ce,

Hai

ti

HIV

-infe

cted

par

ticip

ants

ag

ed ≥

18 y

ears

with

CD

4 co

unts

from

200

and

350

ce

lls/m

m3 w

ithin

45

days

be

fore

enr

olm

ent w

ere

incl

uded

. Par

ticip

ants

with

a

hist

ory

of a

n A

IDS

-defi

ning

ill

ness

or w

ho h

ad re

ceiv

ed

AR

T pr

evio

usly

wer

e ex

clud

ed

Trea

tmen

t inc

lude

d la

miv

udin

e,

zido

vudi

ne, a

nd

efav

irenz

Adh

eren

ce w

as m

easu

red

ever

y 6

mon

ths

usin

g a

ques

tionn

aire

. Adv

erse

ev

ents

wer

e m

onito

ring

usin

g D

AID

S c

riter

ia.

Com

plet

e bl

ood

coun

t, liv

er e

nzym

e te

sts

and

seru

m c

hem

ical

test

s w

ere

repe

ated

eve

ry 3

mon

ths

for p

artic

ipan

ts o

n A

RT.

C

D4

resu

lts w

ere

colle

cted

6-

mon

thly.

36 c

ases

of T

B a

mon

g th

e 39

3 pe

ople

who

w

ere

rand

omiz

ed to

def

er A

RT

until

thei

r CD

4 co

unts

wer

e <

200;

18

case

s of

TB

am

ong

the

380

peop

le w

ho w

ere

rand

omiz

ed to

initi

ate

AR

T im

med

iate

ly (i

.e. b

etw

een

200

and

350)

. Th

is tr

ansl

ated

into

an

RR

of 0

.52

(0.3

0–0.

89).b

AFB,

aci

d-fa

st b

acilli

; ART

, ant

iretro

vira

l the

rapy

; HAA

RT, h

ighl

y ac

tive

antir

etro

vira

l the

rapy

; HIV

, hum

an im

mun

odefi

cien

cy v

irus;

IPT,

ison

iazid

pre

vent

ive

ther

apy;

IQR,

inte

rqua

rtile

rang

e; IR

R,

inci

denc

e ra

te ra

tio; N

AAT,

nuc

leic

aci

d am

plifi

catio

n te

st; N

NRTI

, non

-nuc

leos

ide

reve

rse

trans

crip

tase

inhi

bito

r; NR

TI, n

ucle

osid

e re

vers

e tra

nscr

ipta

se in

hibi

tor;

PI, p

rote

ase

inhi

bito

r; RR

, ris

k ra

tio; S

D, s

tand

ard

devi

atio

n; T

B, tu

berc

ulos

is; T

ST, t

uber

culin

ski

n te

st

a

The

AIDS

Clin

ical

Tria

ls G

roup

defi

nitio

n fo

r con

firm

ed o

r pro

babl

e TB

was

use

d:

•ConfirmedpulmonaryTB:M

ycob

acte

rium

tube

rcul

osis

cul

ture

d fro

m s

putu

m, b

ronc

ho-a

lveo

lar l

avag

e flu

id o

r lun

g tis

sue.

•ProbablepulmonaryTB:(i)clinicalsyndromeconsistentwithpulmonaryTB,including>1ofthefollowing:fever>38°C,nightsweats,productivecough,haemoptysis,weightloss;

and(ii)AFBsmearfromsputum,gastricaspirate,broncho-alveolarlavagefluidorlungtissue;orAFBidentifiedonhistopathologyoflungtissueand

M. a

vium

com

plex

and

oth

er a

typi

cal

myc

obac

teria

exc

lude

d; a

nd(iii)abnormalchestX-rayconsistentwithpulmonaryTB;a

nd(iv)specificmulti-drugantituberculoustherapyinitiated.

•ConfirmedextrapulmonaryTB:positivecultureforM

. tub

ercu

losi

s fro

m e

xtra

pulm

onar

y si

te.

• ProbableextrapulmonaryTB:(i)positiveAFBsmearorapositivehistopathologyfromanextrapulmonarysite;a

nd(ii)>1ofthefollowingsignsorsymptomsconsistentwithaclinical

syndromeforextrapulmonaryTB:fever>38°C,nightsweats,malaise,weightlossand/oradenopathy;a

nd(iii)specificmulti-drugantituberculoustherapyinitiated.

bTheAmericanThoracicSociety’scasedefinitionwasused:twoofthefollowingthreecriteriaweremet:(i)>1offever(temperature>38ºC)foratleast1week,nightsweatsforatleast

1 week,weightloss(>10%bodyweight),cough,dyspnoea,haemoptysisorlymphadenopathyforatleast4weeks;(ii)AFBvisibleinsputum,M

. tub

ercu

losi

s cu

lture

d fro

m s

putu

m, o

r hi

stop

atho

logi

cal fi

ndin

gs in

bio

psy

sam

ples

con

sist

ent w

ith m

ycob

acte

rial d

isea

se; a

nd(iii)achestradiographinterpretedashighlysuggestiveofTBbytwoindependentradiologists.Clinical

responsetoantituberculosismedicationswasdefinedasresolutionofclinicalsymptomsandsigns,anda50%decreaseinthesizeoftheeffusion,infiltrateorhilaradenopathyat8weeks,as

judg

ed b

y an

inde

pend

ent r

adio

logi

st.

13

WHO

pol

icy

on c

olla

bora

tive

TB/H

IV a

ctiv

ities

: Gui

delin

es fo

r nat

iona

l pro

gram

mes

and

oth

er s

take

hold

ers

Anne

xes

for w

ebpo

stin

g an

d CD

-Rom

dis

tribu

tion

with

the

polic

y gu

idel

ines

14


3. GRADE profileThe quality of evidence across a body of evidence was assessed using the GRADE approach. For systematic reviews, the GRADE approach defines the quality of a body of evidence as the extent to which one can be confident that an estimate of effect or association is close to the quantity of specific interest.

The quality rating across studies has four levels: high, moderate, low, or very low. Randomized trials are categorized as high quality but can be downgraded. Observational studies are categorized as low but can be upgraded. Factors that decrease the quality of evidence include design limitations, inconsistency among studies, indirectness of evidence and imprecision of effect measures, among other biases. Factors that can increase the quality level of a body of evidence include a large magnitude of effect, plausible confounding reducing a demonstrated effect and a dose-response gradient.

The GRADE Profiler software was used to perform the GRADE analyses (GRADE profiler version 3.2.2).

Tab

le 2

: Sh

oul

d a

ntir

etro

vira

l th

erap

y (A

RT)

be

used

to

pre

vent

act

ive

tub

ercu

losi

s (T

B)?

Set

ting

s: A

ll

Bib

liogr

aphy

: Bad

ri et

al.

(200

2), C

ohen

et a

l. (2

011)

, del

Am

o et

al.

(201

1), G

olub

et a

l. (2

007)

, Gol

ub e

t al.

(200

9), J

ones

et a

l. (2

000)

, Led

erge

rber

et a

l. (1

999)

, Mor

eno

et a

l. (2

008)

, Sev

ere

et a

l. (2

010)

Qua

lity

asse

ssm

ent

Sum

mar

y o

f fin

din

gs

Impo

rtan

ce

No

of

pat

ient

sE

ffec

t

Qual

ityNo

of

stud

ies

Desi

gnLi

mita

tions

Inco

nsis

tenc

yIn

dire

ctne

ssIm

prec

isio

nOt

her

cons

ider

atio

nsAR

TCo

ntro

lRe

lativ

e (9

5% C

I)Ab

solu

te

TB in

cid

ence

, bas

elin

e C

D4

coun

ts 2

00–3

50 (

ob

serv

atio

nal)

2Ob

serv

atio

nal

stud

ies1

No s

erio

us

limita

tions

No s

erio

us

inco

nsis

tenc

ySe

rious

in

dire

ctne

ss2

No s

erio

us

impr

ecis

ion

Stro

ng

asso

ciat

ion3

Not r

epor

ted

Not r

epor

ted

RR 0

.39

(0.2

4–0.

63)4

Not e

stim

ated

sin

ce

rate

dat

a us

edLO

WCR

ITIC

AL

TB in

cid

ence

, bas

elin

e C

D4

coun

ts 2

00–3

50 (

rand

om

ized

co

ntro

lled

tri

als)

1Ra

ndom

ized

cont

rolle

d tri

al5

No s

erio

us

limita

tions

No s

erio

us

inco

nsis

tenc

yNo

ser

ious

in

dire

ctne

ssNo

ser

ious

im

prec

isio

nNo

ne18

/380

36/3

93RR

0.5

2 (0

.30–

0.89

)6

44 fe

wer p

er 1

000

(from

10

fewe

r to

64

fewe

r)HI

GHCR

ITIC

AL

TB in

cid

ence

, bas

elin

e C

D4

coun

ts >

350

(ob

serv

atio

nal)

2Ob

serv

atio

nal

stud

ies1

No s

erio

us

limita

tions

No s

erio

us

inco

nsis

tenc

ySe

rious

in

dire

ctne

ss2

No s

erio

us

impr

ecis

ion

Stro

ng

asso

ciat

ion3

Not r

epor

ted

Not r

epor

ted

RR 0

.49

(0.3

6–0.

68)4

Not e

stim

ated

sin

ce

rate

dat

a us

edLO

WCR

ITIC

AL

TB in

cid

ence

, bas

elin

e C

D4

coun

ts >

350

(ran

do

miz

ed c

ont

rolle

d t

rial

s)

1Ra

ndom

ized

cont

rolle

d tri

al7

No s

erio

us

limita

tions

No s

erio

us

inco

nsis

tenc

yNo

ser

ious

in

dire

ctne

ssNo

ser

ious

im

prec

isio

nNo

ne17

/886

33/8

77RR

0.5

1 (0

.29–

0.91

)6

18 fe

wer p

er 1

000

(from

3 fe

wer t

o 27

fe

wer)

HIGH

CRIT

ICAL

TB in

cid

ence

, bas

elin

e C

D4

coun

ts n

ot

pro

vid

ed

5Ob

serv

atio

nal

stud

ies8

No s

erio

us

limita

tions

No s

erio

us

inco

nsis

tenc

yNo

ser

ious

in

dire

ctne

ssNo

ser

ious

im

prec

isio

nSt

rong

as

soci

atio

n213

2/15

188

(0.9

%)9

381/

1517

7 (2

.5%

)9RR

0.4

7 (0

.41–

0.53

)4No

t est

imat

ed s

ince

ra

te d

ata

used

MOD

ERAT

ECR

ITIC

AL

TB in

cid

ence

, AR

T an

d IP

T (b

asel

ine

CD

4 co

unts

no

t p

rovi

ded

)

2Ob

serv

atio

nal

stud

ies10

serio

us11

No s

erio

us

inco

nsis

tenc

yNo

ser

ious

in

dire

ctne

ssNo

ser

ious

im

prec

isio

nVe

ry s

trong

as

soci

atio

n1211

/134

6 (0

.8%

)935

5/66

80

(5.3

%)9

RR 0

.15

(0.0

8–0.

28)4

Not e

stim

ated

sin

ce

rate

dat

a us

edM

ODER

ATE

CRIT

ICAL

1delAmoetal.(2011)andBadrietal.(2002).

2delAmoetal(2011)studyconductedinEuropeandNorthAmerica,

setti

ngs

with

low

TB

trans

mis

sion

.

3LargemagnitudeofeffectasdefinedbyGRADE(RRestimate<0.5).

4Themeasureofeffectisanincidencerateratio.

5Severeetal.(2010).

6

The

mea

sure

of e

ffect

is a

risk

ratio

.

7Cohenetal.(2011).

8Golubetal.(2007),Golubetal.(2009),Morenoetal.(2008),Ledergerber

etal.(2000),andJonesetal.(2000).

9NumeratorisTBcases,denominatorisperson-yearsatrisk.

10Golubetal.(2007)andGolubetal.(2009).

11Antiretroviraltherapynotdefinedineitherstudy(Golubetal.2007and

Golubetal.2009).

12VerylargemagnitudeofeffectasdefinedbyGRADE(RRestimate<0.2).

15

WHO

pol

icy

on c

olla

bora

tive

TB/H

IV a

ctiv

ities

: Gui

delin

es fo

r nat

iona

l pro

gram

mes

and

oth

er s

take

hold

ers

Anne

xes

for w

ebpo

stin

g an

d CD

-Rom

dis

tribu

tion

with

the

polic

y gu

idel

ines

16


4. Risk and benefits assessment

Recommendation: People living with HIV with CD4 counts >350 cells/mm3 should receive ART to prevent active TB

Population: People living with HIV with CD4 counts >350 cells/mm3

Intervention: Antiretroviral therapy

Factor Decision Explanation

Quality of evidence High The reduction in tuberculosis incidence is supported by HIGH quality randomized trial

evidence

Benefits or desired effects

Strong (benefits outweigh risks)

Reduction in tuberculosis incidence.

Additional benefits of ART in reducing mortality, other HIV related morbidity, and HIV transmission

Risks or undesired effects

Reduction in tuberculosis incidence.

Additional benefits of ART in reducing mortality, other HIV related morbidity, and HIV transmission

Values and preferences Variable

Improved quality of HIV treatment and care.

Also prevents life-threatening opportunistic infections, increases survival, and prevents HIV transmission to others

Life-long therapy with issues of adherence and side effects in the long term.

High pill burden when ART taken with other preventive or curative treatment.

Costs Weak

Costs will increase as the volume of patients will at least double, with impact on drug and non-drug costs.

Evidence on long run cost savings only demonstrated by mathematical modelling.

Cheaper interventions exist such as isoniazid preventive therapy which is yet to be scaled-up

Feasibility Weak

A move to CD4 threshold >350 for ART initiation will at least double the number of eligible patients to start ART. In a context of low uptake, late presentation for treatment and limited resources in majority of high HIV prevalence settings, it can generate confusing messaging, competing forces in terms of infrastructure demand and very serious issues of equity towards patients with lower CD4 counts and who have not accessed yet ART

Not recommended

17


5. References1. Miranda A et al. Impact of antiretroviral therapy on the incidence of tuberculosis: the Brazilian experience,

1995–2001. PLoSONE, 2007;2(9):e826.

2. Santoro-Lopes G et al. Reduced risk of tuberculosis among Brazilian patients with advanced human immunodeficiency virus infection treated with highly active antiretroviral therapy. ClinicalInfectiousDiseases, 2002 Feb 15;34(4):543-6.

3. Girardi E et al. Impact of combination antiretroviral therapy on the risk of tuberculosis among persons with HIV infection. AIDS, 2000, 14(13):1985–1991.

4. Lawn SD et al. Short-term and long-term risk of tuberculosis associated with CD4 cell recovery during antiretroviral therapy in South Africa. AIDS, 2009, 23(13):1717–1725.

5. Egger M, ed. Outcomes of ART in resource-limited and industrialized countries. 14thConferenceonretrovirusesandopportunisticinfections(CROI2007), Los Angeles, USA, CROI.

6. AntiretroviraltherapyforHIVinfectioninadultsandadolescents:recommendationsforapublichealthapproach, 2010 revision. Geneva, World Health Organization, 2010.

7. Badri M, Wilson D, Wood R. Effect of highly active antiretroviral therapy on incidence of tuberculosis in South Africa: a cohort study. Lancet, 2002, 359(9323):2059–2064.

8. Del Amo J, Hernan, M. (HIV-CASUAL). Combined antiretroviral therapy and the incidence of tuberculosisamongHIV-positiveindividualsinhigh-incomecountries [personal communication], 2011.

9. Severe P et al. Early versus standard antiretroviral therapy for HIV-infected adults in Haiti. NewEnglandJournalofMedicine, 2010, 363(3):257–265.

10. Cohen MS et al. Prevention of HIV-1 Infection with Early Antiretroviral Therapy. New England Journal ofMedicine, 2011, 365(6):493–505.

11. Golub JE et al. The impact of antiretroviral therapy and isoniazid preventive therapy on tuberculosis incidence in HIV-infected patients in Rio de Janeiro, Brazil. AIDS, 2007, 21(11):1441–1418.

12. Golub JE et al. Isoniazid preventive therapy, HAART and tuberculosis risk in HIV-infected adults in South Africa: a prospective cohort. AIDS, 2009, 23(5):631–636.

13. Girardi E et al. Incidence of Tuberculosis among HIV-infected patients receiving highly active antiretroviral therapy in Europe and North America. ClinicalInfectiousDiseases, 2005, 41(12):1772–1782.

14. Jones JL et al. HIV-associated tuberculosis in the era of highly active antiretroviral therapy. The Adult/Adolescent Spectrum of HIV Disease Group. InternationalJournalofTuberculosisandLungDisease, 2000, 4(11):1026–1031.

15. Lau B, Zhang, J. (NA-ACCORD). Incidence of Tuberculosis after HAART Initiation in HIV-infected persons [personal communication], 2011.

16. Ledergerber B et al. AIDS-related opportunistic illnesses occurring after initiation of potent antiretroviral therapy: the Swiss HIV Cohort Study. JAMA, 1999, 282(23):2220–2226.

17. Moreno S et al. Incidence and risk factors for tuberculosis in HIV-positive subjects by HAART status. InternationalJournalofTuberculosisandLungDisease, 2008, 12(12):1393–1400.

18


PICO question: What are the benefits of HIV testing and counselling in patients with presumptive and diagnosed tuberculosis and among the partners and family members of patients who are found to be HIV-positive?

Population: people with presumptive and diagnosed TB, and the partners and family members of patients who are found to be HIV positiveIntervention: HIV testing and counsellingComparison: no HIV testing and counsellingOutcomes: yield of positive HIV cases



Among presumptive and confirmed TB patients

HIV cases (yield of positive HIV and TB cases by clinical settings and by epidemiological settings)

9 critical

Improved access to prevention, care and treatment

(reduced morbidity and mortality events due to TB and HIV diseases)

9 critical

Among partners and family members

HIV cases 9 critical

Improved access to prevention, care and treatment 8 critical

2. Literature search strategy and information retrievalStudies were identified using PubMed, EMBASE, Web of Science, Google Scholar and the Cochrane Library databases. Proceedings and abstracts from international conferences (CROI, IAS, ICAAC, World AIDS Conference) were searched.

Selection criteria

Studies were included if:

• randomizedandquasi-randomizedcontrolledtrials,includinghistoricallycontrolledtrialsorobservationalandcohort studies;

• participantsbeingpresumedorconfirmedTBcasesor/andpartnersandfamilymembersofthosewhoturntobe HIV positive;

• comparisonbeingaddressedwas:routineHIVtestingvs.noHIVtesting.

Annex 2Voluntary counselling and testing for HIV benefits patients with diagnosed and presumptive tuberculosis – summary of findings and evaluation of the quality of the evidence

19


Most data that can be found on this topic is circumstantial evidence, most likely because it is deemed unethical to compare groups in which HIV testing is offered against one in which it is not. This would deprive people of the right to then make choices about treatment.

The only study which has a comparison group was carried out in Malawi and compared patients after the introduction of voluntary counselling and testing (VCT) and co-trimoxazole prophylaxis therapy (CPT) to patients before (1); unfortunately, there was no stratification and therefore it is not amenable to GRADE appraisal.

It is now clear that people with HIV-associated TB fare a lot worse than those with HIV or TB separately. Treatment for HIV is becoming increasingly available, and evidence shows that even just CPT is beneficial in decreasing morbidity and mortality. Knowledge of HIV status is also beneficial for sexual partners and unborn children. Thus it is hard to imagine the need for evidence to be collected to prove that testing patients with TB for HIV is beneficial.

A large number of studies show that testing for HIV in confirmed TB patients (mostly) and in presumptive TB patients and their contacts (occasionally) yields a high number of new diagnoses of HIV. The assumption is that this allows newly diagnosed HIV-positive people to receive CPT and ART, thus hypothetically decreasing their morbidity and mortality and preventing HIV transmission. These same descriptive studies also show that often after diagnosis, either the HIV treatment is not offered or available, or it is not taken up. According to the HIV/AIDS universal access report, only 17% of the estimated number of TB patients living with HIV were receiving ART, a figure considerably lower than the estimated coverage rate of antiretroviral therapy for all HIV patients in low- and middle-income countries (2).

Table 1 summarizes the 24 studies retrieved from the systematic literature search. It shows that in these studies HIV testing in TB patients can yield positive results anywhere between 6.3% and 77% depending on the epidemiologic setting. Although 6.3% appears low, consideration should be given to the fact that HIV is a transmissible, 100% fatal disease without available treatment and prevention measures. A few of the studies addressed the issue of contacts or cases with presumptive TB, although they yield very little data. In one study carried out in Kenya on presumptive TB patients, 61% diagnosed with TB were also HIV-positive, whereas 63% without TB were positive (3). Another study in Uganda (4) found that 39% patients diagnosed with TB were also HIV-positive, whereas 49% of those who had no active TB were HIV-positive. The yield of HIV-positive results among those with presumptive TB was 39% in Guinea-Bissau and 61% in Zimbabwe (5,6).

Only one study addressed the issue of testing close contacts of TB patients and on doing so found that 13.8% of contacts of TB patients living with HIV were HIV-infected, whereas 2.5% of contacts of HIV-negative TB patients were HIV-infected (7). One study attempted to quantify the benefit of testing by looking at relative risk of death of a cohort of patients in one programme before and after the introduction of VCT (1). It found the adjusted relative risk of death to be 0.81 (p<0.001).

By article: 24Appraisable by GRADE methodology 0

By title: 51

By abstract: 33

Pubmed Search (“Tuberculosis”[Mesh] AND “HIV Infections”[Mesh]) AND “Testing”[Mesh] 149

Tab

le 1

: Sum

mar

y o

f st

udie

s o

n te

stin

g f

or

HIV

infe

ctio

n in

TB

pat

ient

s, p

eop

le w

ith s

usp

ecte

d T

B a

nd c

ont

acts

of

TB p

atie

nts

Aut

ho

r an

d y

ear

(ref

eren

ce)

Co

untr

yB

ackg

roun

d

HIV

pre

vale

nce

(14–

59ye

ars)

Typ

e o

f st

udy

Sam

ple

siz

eTe

stin

g s

ite

and

per

sonn

elH

IV t

estin

g

upta

ke%

tes

ted

HIV

-p

osi

tive

CP

T up

take

AR

T up

take

Aye

new

A, 2

010

(8)

Eth

iopi

a2%

Cas

e-co

ntro

l 28

2 TB

pat

ient

s–

70.6

%36

.2%

––

Njo

zing

NB

, 20

10 (9

)C

amer

oon

5.1%

Ret

rosp

ectiv

e co

hort

2270

TB

pat

ient

sC

ouns

ello

rs

with

in T

B u

nits

94.7

%68

.5%

47%

50.3

%

Vija

y S

, 200

9 (10)

Indi

a0.

3%P

rosp

ectiv

e co

hort

5299

TB

pat

ient

s (4

701

unkn

own

HIV

sta

tus)

Phy

sici

an re

ferr

al

to in

tegr

ated

co

unse

lling

and

te

stin

g ce

ntre

s

66%

6.4%

(of

prev

ious

ly

undi

agno

sed)

–37

%

Low

SY,

200

9 (11)

Sin

gapo

re0.

2%R

etro

spec

tive

493

TB p

atie

nts

–37

.3%

8.2%

––

Nat

eniy

om S

, 20

08 (12)

Thai

land

1.4%

Pro

spec

tive

coho

rt10

86 T

B p

atie

nts

(100

0 un

know

n H

IV s

tatu

s)

Trai

ned

nurs

es

and

soci

al

wor

kers

in T

B

clin

ics

93%

11%

36%

42%

Pope

DS

, 200

8 (13)

Sou

th A

frica

18.1

%C

lust

er-

rand

omiz

ed75

4 TB

pat

ient

sTB

nur

se in

TB

cl

inic

13.8

%36

–42%

19%

21%

Van

Rie

A, 2

008

(14)

Dem

ocra

tic

Rep

ublic

of t

he

Con

go

(opt

-in v

s op

t-ou

t)12

46 T

B p

atie

nts

VCT

clin

ic v

s pr

imar

y ca

re

cent

re v

s TB

nu

rse

95–9

8%18

.8%

89.8

%–

Cha

kaya

JM

, 20

08 (15)

Ken

ya7.

1-8.

3%R

etro

spec

tive

coho

rt46

428

TB

patie

nts

Hea

lth-c

are

wor

kers

in T

B

care

ser

vice

s

31.5

–59%

55%

85%

28%

Mor

bidi

ty a

nd

Mor

talit

y W

eekl

y R

epor

t, 20

08

(16)

Zam

bia

13.1

%D

escr

iptiv

e41

48 T

B p

atie

nts

VCT

offs

ite, V

CT

onsi

te, P

ITC

by

TB s

taff

50%

72%

––

20WHO

pol

icy

on c

olla

bora

tive

TB/H

IV a

ctiv

ities

: Gui

delin

es fo

r nat

iona

l pro

gram

mes

and

oth

er s

take

hold

ers

Anne

xes

for w

ebpo

stin

g an

d CD

-Rom

dis

tribu

tion

with

the

polic

y gu

idel

ines

Tab

le 1

: Sum

mar

y o

f st

udie

s o

n te

stin

g f

or

HIV

infe

ctio

n in

TB

pat

ient

s, p

eop

le w

ith s

usp

ecte

d T

B a

nd c

ont

acts

of

TB p

atie

nts

Aut

ho

r an

d y

ear

(ref

eren

ce)

Co

untr

yB

ackg

roun

d

HIV

pre

vale

nce

(14–

59ye

ars)

Typ

e o

f st

udy

Sam

ple

siz

eTe

stin

g s

ite

and

per

sonn

elH

IV t

estin

g

upta

ke%

tes

ted

HIV

-p

osi

tive

CP

T up

take

AR

T up

take

Jere

ne D

, 20

07(17)

Eth

iopi

a2%

–19

0 TB

pat

ient

sTr

aine

d co

unse

llor a

t TB

cl

inic

in h

ospi

tal

58%

20.6

%–

–

Mor

bidi

ty a

nd

Mor

talit

y W

eekl

y R

epor

t, 20

06

(18)

Guy

ana

–D

escr

iptiv

e17

4 TB

pat

ient

s of

unk

now

n st

atus

–91

%10

%–

–

van

der W

erf M

J,

2005

(19)

Ukr

aine

–P

rosp

ectiv

e91

4 TB

pat

ient

sTB

phy

sici

ans

84%

6.3%

––

Chi

mzi

zi R

B,

2004

(20)

Mal

awi

12%

Eva

luat

ion

of

proj

ect

2397

TB

pat

ient

sC

ouns

ello

rs in

la

bora

tory

, war

d or

VC

T un

it

59%

68%

97%

–

Chi

mzi

zi R

B,

2004

(21)

Mal

awi

12%

Des

crip

tive

1103

TB

pat

ient

sC

ouns

ello

rs in

la

bora

tory

, war

d or

VC

T un

it

91%

77%

69%

Zach

aria

h R

, Jan

20

03 (22)

Mal

awi

12%

Coh

ort s

tudy

1049

TB

pat

ient

sH

ospi

tal H

IV

VCT

unit

91%

77%

94%

Zach

aria

h R

, M

ay 2

003

(1)

Mal

awi

12%

Coh

ort s

tudy

1986

TB

pat

ient

sH

ospi

tal H

IV

VCT

unit

91%

77%

93%

Abo

uya

L, 1

998

(23)

Côt

e d’

Ivoi

re–

Coh

ort s

tudy

w

ith h

isto

rical

co

ntro

ls

1959

4 TB

pa

tient

sP

hysi

cian

s,

nurs

es a

nd

soci

al w

orke

rs

91.8

%43

.2%

––

Ban

erje

e A

, 19

97 (24)

Mal

awi

12%

Ret

rosp

ectiv

e20

5 TB

pat

ient

s–

54%

66%

––

21

WHO

pol

icy

on c

olla

bora

tive

TB/H

IV a

ctiv

ities

: Gui

delin

es fo

r nat

iona

l pro

gram

mes

and

oth

er s

take

hold

ers

Anne

xes

for w

ebpo

stin

g an

d CD

-Rom

dis

tribu

tion

with

the

polic

y gu

idel

ines

Tab

le 1

: Sum

mar

y o

f st

udie

s o

n te

stin

g f

or

HIV

infe

ctio

n in

TB

pat

ient

s, p

eop

le w

ith s

usp

ecte

d T

B a

nd c

ont

acts

of

TB p

atie

nts

Aut

ho

r an

d y

ear

(ref

eren

ce)

Co

untr

yB

ackg

roun

d

HIV

pre

vale

nce

(14–

59ye

ars)

Typ

e o

f st

udy

Sam

ple

siz

eTe

stin

g s

ite

and

per

sonn

elH

IV t

estin

g

upta

ke%

tes

ted

HIV

-p

osi

tive

CP

T up

take

AR

T up

take

Stu

die

s in

clud

ing

pre

sum

ptiv

e TB

pat

ient

s

Pors

krog

A,

2011

(6)

Gui

nea-

Bis

sau

9%P

rosp

ectiv

e co

hort

86 w

ith

pres

umpt

ive

TBVC

T un

it51

%39

%–

–

Dim

airo

M, 2

010

(5)

Zim

babw

e–

Pro

spec

tive

coho

rt ne

sted

w

ithin

clu

ster

ra

ndom

ized

tria

l

1195

with

pr

esum

ptiv

e TB

VCT

unit

and

stud

y cl

inic

95%

61%

–15

%

Odh

iam

bo J

, 20

08 (3

)K

enya

7.1–

8.3%

Pilo

t stu

dy-

desc

riptiv

e54

57 w

ith

pres

umpt

ive

TB

Clin

ical

offi

cers

an

d TB

nur

ses

in

TB c

linic

s

89%

61–6

3%–

83%

Srik

antia

h P,

20

07 (4

)U

gand

a5.

4%P

rosp

ectiv

e co

hort

665

with

pr

esum

ptiv

e TB

Trai

ned

coun

sello

rs a

t TB

clin

ic

85%

42%

––

Mun

thal

i L, 2

006

(25)

Mal

awi

12%

Cro

ss-s

ectio

nal

surv

ey56

5 w

ith

pres

umpt

ive

TB–

95%

56%

––

Stu

die

s in

clud

ing

co

ntac

ts

Sug

gara

vets

iri P

, 20

03(7

)Th

aila

nd1.

4%D

escr

iptiv

e49

9 TB

pat

ient

s

1200

TB

co

ntac

ts

–74

.2%

39.5

%

13.8

% (i

f con

tact

ca

se H

IV-

posi

tive)

2.5%

(if c

ase

HIV

-neg

ativ

e)

––

Ran

ges

13.8

–98%

6.3–

77%

21–8

3%

ART,antiretroviraltherapy;CPT,co-trimoxazolepreventivetherapy;PICT,providerinitiatedcounsellingandtesting;VCT,voluntarycounsellingandtesting;%,percentage

22WHO

pol

icy

on c

olla

bora

tive

TB/H

IV a

ctiv

ities

: Gui

delin

es fo

r nat

iona

l pro

gram

mes

and

oth

er s

take

hold

ers

Anne

xes

for w

ebpo

stin

g an

d CD

-Rom

dis

tribu

tion

with

the

polic

y gu

idel

ines

23


In all studies, the prevalence of HIV was found to be higher in TB patients, those with presumptive TB and possibly even among TB contacts than the expected national adult HIV prevalence. One study highlighted higher rates of mortality among HIV-positive TB patients (29%) compared to those with TB only (8%) (24). Interestingly, 34% of those who refused testing died, but a possible bias is that anybody very unwell and suspicious of having HIV is possibly more likely not to test.

3. GRADE profileThe quality of evidence across a body of evidence was assessed using the GRADE approach but risk ratios could not be calculated as none of the studies available assessed the question of interest. GRADE profiles were therefore not produced.


Recommendation: Routine HIV testing should be offered to all patients with presumptive and confirmed TB, their partners and family members

Population: TB patients, patients with presumptive TB, and their partners and family members

Intervention: Routine HIV testing


Quality of evidence Low

There is a wealth of evidence documenting that TB and HIV coinfection has a worse outcome than TB alone. There is plenty of evidence that the population in question (patients with presumptive and confirmed TB) has a high prevalence of HIV and that those with HIV have high prevalence of TB. There is little evidence that contacts of HIV-positive TB patients have high prevalence of HIV.

Unfortunately, there are no randomized controlled trials or high-quality studies for GRADE appraisal.

Benefits

or desired effects Strong

Knowledge about status is a prerequisite for HIV prevention, treatment, care and support, including CPT and ART, which reduce morbidity and mortality. Even those who test negative have increased awareness, allowing them to avoid risk-taking behaviour, promote safer sexual behaviour and practices, and encourage their partners to do the same and/or be on ART and anti-TB treatment if indicated.


False-positive results; false negative results.

Stigma of HIV diagnosis once known.

Values and preferences Strong

Improved individual and family care

Better health for individual, partners, family and community

Prevent HIV transmission to loved ones

Stigma and problem of disclosure might lead to low uptake

Costs StrongTesting using rapid tests is inexpensive and incorporated in health package.

Savings by decreasing HIV and TB transmission and resulting morbidity and mortality.

Feasibility Strong

Structure for testing already in place and working.

Increased workload on health workers – actually less in the long term if fewer people have TB and HIV

Feasibility studies from India and Rwanda showed that it is feasible to routinely test TB patients for HIV (26,27)

Strength of recommendationStrong

24


5. References1. Zachariah R et al. Voluntary counselling, HIV testing and adjunctive cotrimoxazole reduces mortality in

tuberculosis patients in Thyolo, Malawi. AIDS, 2003, 17(7):1053–1061.

2. Towardsuniversalaccess:scalinguppriorityHIV/AIDSinterventionsinthehealthsector.Progressreport2010. Geneva, World Health Organization, 2010.

3. Odhiambo J et al. Provider-initiated HIV testing and counselling for TB patients and suspects in Nairobi, Kenya. InternationalJournalofTuberculosisandLungDisease, 12(3 Suppl 1):63–68.

4. Srikantiah P et al. Elevated HIV seroprevalence and risk behavior among Ugandan TB suspects: implications for HIV testing and prevention. InternationalJournalofTuberculosisandLungDisease, 2007, 11(2):168–174.

5. Dimairo M et al. The risk and timing of tuberculosis diagnosed in smear-negative TB suspects: a 12 month cohort study in Harare, Zimbabwe. PLoSONE, 2010, 5(7):e11849.

6. Porskrog A et al. Enhanced tuberculosis identification through 1-month follow-up of smear-negative tuberculosis suspects. InternationalJournalofTuberculosisandLungDisease, 2011, 15(4):459–464.

7. Suggaravetsiri P et al. Integrated counseling and screening for tuberculosis and HIV among household contacts of tuberculosis patients in an endemic area of HIV infection: Chiang Rai, Thailand. International JournalofTuberculosisandLungDisease, 2003, 7(12 Suppl 3):S424–431.

8. Ayenew A et al. Predictors of HIV testing among patients with tuberculosis in North West Ethiopia: a case-control study. PLoSONE, 2010, 5(3):e9702.

9. Njozing NB et al. Assessing the accessibility of HIV care packages among tuberculosis patients in the Northwest Region, Cameroon. BMCPublicHealth, 2010, 10:129.

10. Vijay S et al. Feasibility of provider-initiated HIV testing and counselling of tuberculosis patients under the TB control programme in two districts of South India. PLoSONE, 2009, 4(11):e7899.

11. Low SY, Eng P. Human immunodeficiency virus testing in patients with newly-diagnosed tuberculosis in Singapore. SingaporeMedicalJournal, 2009, 50(5):479–481.

12. Nateniyom S et al. Provider-initiated diagnostic HIV counselling and testing in tuberculosis clinics in Thailand. InternationalJournalofTuberculosisandLungDisease, 2008, 12(8):955–961.

13. Pope DS et al. A cluster-randomized trial of provider-initiated (opt-out) HIV counseling and testing of tuberculosis patients in South Africa. JAIDS, 2008, 48(2):190–195.

14. Van Rie A et al. Counseling and testing TB patients for HIV: evaluation of three implementation models in Kinshasa, Congo. InternationalJournalofTuberculosisandLungDisease, 2008, 12(3 Suppl 1):73–78.

15. Chakaya JM et al. National scale-up of HIV testing and provision of HIV care to tuberculosis patients in Kenya. InternationalJournalofTuberculosisandLungDisease, 2008, 12(4):424–429.

16. Provider-initiated HIV testing and counseling of TB patients—Livingstone District, Zambia, September 2004–December 2006. MMWR, 2008, 57(11):285–289.

17. Jerene D, Endale A, Lindtjorn B. Acceptability of HIV counselling and testing among tuberculosis patients in south Ethiopia. BMCInternationalHealthandHumanRights, 2007, 7:4.

18. HIV counseling, testing, and care of tuberculosis patients at chest clinics—Guyana, 2005–2006. MMWR, 2006, 55(31):849–851.

19. van der Werf MJ et al. HIV testing practices of TB patients after introduction of a new testing policy in Kiev City, Ukraine. InternationalJournalofTuberculosisandLungDisease, 2005, 9(7):733–739.

20. Chimzizi RB et al. Counselling, HIV testing and adjunctive cotrimoxazole for TB patients in Malawi: from research to routine implementation. InternationalJournalofTuberculosisandLungDisease, 2004, 8(8):938–944.

25


21. Chimzizi R et al. Voluntary counselling, HIV testing and adjunctive cotrimoxazole are associated with improved TB treatment outcomes under routine conditions in Thyolo District, Malawi. InternationalJournalofTuberculosisandLungDisease, 2004, 8(5):579–585.

22. Zachariah R et al. Voluntary counselling, HIV testing and sexual behaviour among patients with tuberculosis in a rural district of Malawi. InternationalJournalofTuberculosisandLungDisease, 2003, 7(1):65–71.

23. Abouya L et al. The Côte d’Ivoire national HIV counseling and testing program for tuberculosis patients: implementation and analysis of epidemiologic data. AIDS, 1998, 12(5):505–512.

24. Banerjee A et al. HIV testing and tuberculosis treatment outcome in a rural district in Malawi. Transactions of theRoyalSocietyofTropicalMedicineandHygiene, 1997, 91(6):707–708.

25. Munthali L et al. Using tuberculosis suspects to identify patients eligible for antiretroviral treatment. International JournalofTuberculosisandLungDisease, 2006, 10(2):199–202.

26. Thomas BE et al. Perceptions of tuberculosis patients on provider-initiated HIV testing and counseling—a study from south India. PLoSONE, 2009, 4(12):e8389.

27. Gasana M et al. Integrating tuberculosis and HIV care in rural Rwanda. InternationalJournalofTuberculosisandLungDisease, 2008, 12(3 Suppl 1):39–43.

26


PICO question: Does the administration of routine CPT compared with no CPT reduce the number of illness episodes and deaths in TB patients living with HIV?

Population: TB patients living with HIVIntervention: CPTComparison: no CPT or placeboOutcomes: mortality, morbidity/hospital admissions/adverse events



Mortality (deaths occurring during the follow up period) 9 Critical

Morbidity/hospital admissions

(as defined by the trial researchers)

9 Critical

Adverse events (leading to hospitalization or treatment cessation)

9 Critical

2. Literature search strategy and information retrievalStudies were identified using PubMed, EMBASE, Web of Science, Google Scholar and the Cochrane Library databases. Proceedings and abstracts from international conferences (CROI, IAS, ICAAC, World AIDS Conference) were searched.

Annex 3Co-trimoxazole preventive therapy (CPT) reduces morbidity and mortality in tuberculosis patients living with HIV – summary of findings and evaluation of the quality of the evidence

Pubmed Search (“Tuberculosis”[Mesh] AND “HIV Infections”[Mesh]) AND “Cotrimoxazole”[Mesh] 55

By title: 35

By abstract: 8

By article: 7

27


Selection criteria

Studies were selected if:

• randomizedandquasi-randomizedcontrolledtrials,includinghistoricallycontrolledtrialsorobservationalandcohort studies;

• participantsbeingpeoplelivingwithHIVwithactiveTB(studiesthatincludeparticipantsbothwithandwithoutactiveTBdiseasewereconsideredwherethedataforthosewithTBdiseasecouldbeextracted);

• comparisonbeingaddressedwas:routineCPTvs.placeboornoCPT.

Table 1 summarizes the findings from the two randomized controlled trials (RCTs) and the six observational studies, using historical controls or observational cohorts, identified by the systematic literature search. All studies were conducted in Africa.

Co-trimoxazole, a fixed-dose combination of sulfamethoxazole and trimethoprim, is a broad-spectrum antimicrobial agent that has been used since the mid-1980s to prevent Pneumocystisjirovecci pneumonia and toxoplasmosis in people living with HIV. It is also effective against other bacterial and parasitic diseases and it reduces the incidence of malaria in people living with HIV.

Data on CPT among TB patients living with HIV showed that survival of those receiving CPT is improved up to 18 months after diagnosis of TB disease in observational studies and up to 24 months of follow-up in one of the two RCTs (1). The number needed to treat to prevent one death during TB treatment was 24 in one observational study using historical controls conducted in South Africa (2) and 12.5 in another cohort study evaluating the benefit of a combination of HIV testing and provision of CPT in Malawi (3). All studies showed that adverse reactions, defined as those causing cessation of CPT or hospitalization, were infrequent with few patients having to definitely stop prophylaxis. Only one RCT studied the effect of CPT on morbidity through hospital admission for all diseases that could potentially have been prevented by CPT (septicaemia, enteritis, chest infection, urinary tract infection and toxoplasmosis) (4). The rate of admissions was significantly lower in the co-trimoxazole group (2.7/100 person-years) than in the placebo group (8.7/100 person-years; P=0.001). This trial also showed that the mortality rate was significantly lower in patients with CD4 counts ≤350 cells/mm3 receiving CPT than those receiving a placebo (hazard ratio: 0.44, 95% CI: 0.29–0.66). There is also a wealth of evidence on the benefits of CPT in reducing mortality and morbidity among people living with HIV without TB and their household members.

Tab

le 1

: Sum

mar

y o

f st

udie

s o

n co

-tri

mo

xazo

le p

reve

ntiv

e th

erap

y (C

PT)

in H

IV-i

nfec

ted

TB

pat

ient

s

Mw

aung

ulu

2004

(5)

(Mal

awi)

Nun

n 20

08 (

1)(Z

amb

ia)

Gri

mw

ade

2005

(2)

(So

uth

Afr

ica)

Kal

ou

2005

(6)

(Cô

te d

’Ivo

ire)

Met

ho

ds/

des

ign

A c

ohor

t stu

dy w

ith a

retro

spec

tive

cont

rol g

roup

.D

oubl

e-bl

ind

plac

ebo

cont

rolle

d ra

ndom

ized

clin

ical

tri

al.

Coh

ort s

tudy

usi

ng h

isto

rical

co

ntro

ls.

Con

trolle

d ra

ndom

ized

clin

ical

tria

l usi

ng

retro

spec

tive

data

from

a p

revi

ous

stud

y.

Po

pul

atio

nTB

pat

ient

s re

gist

ered

in 1

999

and

2000

in K

aron

ga D

istri

ct, M

alaw

i; 33

5 an

d 36

2 re

spec

tivel

y, o

f who

m

70%

wer

e H

IV-p

ositi

ve.

Two

grou

ps o

f HA

AR

T-na

ive

adul

ts w

ith H

IV in

fect

ion:

pa

tient

s ne

wly

dia

gnos

ed a

s ha

ving

TB

and

rece

ivin

g an

ti-TB

trea

tmen

t eith

er fo

r the

firs

t tim

e or

for

retre

atm

ent a

fter r

elap

se; p

revi

ousl

y tre

ated

pat

ient

s no

t rec

eivi

ng tr

eatm

ent.

Lusa

ka, Z

ambi

a, U

nive

rsity

Te

achi

ng H

ospi

tal (

UTH

) che

st c

linic

.

1003

pat

ient

s w

ere

rand

omiz

ed: 8

35 (4

16 C

PT,

419

pl

aceb

o) re

ceiv

ed a

nti-T

B tr

eatm

ent;

762

(376

CP

T,

386

plac

ebo)

wer

e ne

wly

dia

gnos

ed p

revi

ousl

y un

treat

ed p

atie

nts

and

73 (4

0 C

PT,

33

plac

ebo)

wer

e re

ceiv

ing

a re

treat

men

t reg

imen

; 168

(CP

T 84

pla

cebo

) w

ere

not o

n tre

atm

ent b

ut h

ad b

een

treat

ed in

the

past

.

Adu

lts tr

eate

d fo

r TB

bet

wee

n 19

98 a

nd 2

000

(con

trol g

roup

: 20

04)

All

adul

ts s

tarti

ng tr

eatm

ent f

or

TB b

etw

een

June

200

1 an

d Ju

ne

2002

irre

spec

tive

of

HIV

sta

tus

(inte

rven

tion

grou

p: 1

321)

.

HIV

-1-in

fect

ed p

atie

nts

with

new

ly d

iagn

osed

, sp

utum

-sm

ear p

ositi

ve fo

r Mycobacterium

tube

rcul

osis

pul

mon

ary

infe

ctio

n.

All

patie

nts

rece

ived

a s

tand

ard

TB re

gim

en

with

or w

ithou

t CP

T. P

atie

nts

in th

e C

PT

arm

w

ere

com

pare

d w

ith th

ose

in th

e pl

aceb

o ar

m

at th

e st

art o

f tre

atm

ent,

and

sim

ilarly

wer

e co

mpa

red

with

the

patie

nts

of b

oth

arm

s to

ea

ch o

ther

12

mon

ths

afte

r ini

tiatio

n of

the

treat

men

t.

Of t

he 4

4 pa

tient

s (2

3 m

ales

, 52%

) elig

ible

fo

r ana

lysi

s in

this

stu

dy, 2

5 (5

6.8%

) wer

e on

co

mbi

ned

treat

men

t of T

B (C

PT

grou

p) a

nd 1

9 (4

3.2%

) wer

e on

sta

ndar

d tre

atm

ent o

f TB

onl

y (p

lace

bo g

roup

); 3

2/44

(70%

) wer

e in

fect

ed

with

HIV

-1, a

nd 3

0% w

ere

dual

ly s

ero-

reac

tive

to H

IV-1

and

HIV

-2.

Inte

rven

tion

CP

T (9

60 m

g O

D) w

as g

iven

to

HIV

pat

ient

s en

rolle

d si

nce

Janu

ary

2000

.

Red

uced

dos

es w

ere

give

n to

ch

ildre

n.

Cas

e as

certa

inm

ent,

follo

w u

p an

d ca

re w

ere

iden

tical

in th

e 2

year

s ex

cept

that

in 2

000

CP

T w

as

adm

inis

tere

d to

HIV

pat

ient

s.

CP

T w

as g

iven

from

the

time

a pa

tient

was

iden

tified

as

HIV

-po

sitiv

e un

til 1

2 m

onth

s af

ter

regi

stra

tion.

Inte

ntio

n to

trea

t ana

lysi

s

Ran

dom

ized

par

ticip

ants

in a

1:1

ratio

to re

ceiv

e a

supp

ly o

f pre

-labe

lled

trial

med

icin

e (i)

CP

T or

(ii

) mat

chin

g pl

aceb

o; (2

tabl

ets

to b

e ta

ken

daily

). E

ach

CP

T (4

00 m

g su

lfam

etho

xazo

le a

nd 8

0 m

g tri

met

hopr

im).

All

adul

ts s

tarti

ng T

B tr

eatm

ent

betw

een

June

200

1 an

d Ju

ne 2

002

wer

e of

fere

d C

PT

prop

hyla

xis

(960

mg

OD

for 6

m

onth

s) d

urin

g TB

trea

tmen

t irr

espe

ctiv

e of

HIV

sta

tus.

960

mg

OD

of C

PT

or p

lace

bo s

tarti

ng 1

m

onth

into

sta

ndar

d tre

atm

ent o

f TB

.

Ana

lysi

sIn

tent

ion

to tr

eat a

naly

sis

Inte

ntio

n to

trea

t ana

lysi

sIn

tent

ion

to tr

eat a

naly

sis

Inte

ntio

n to

trea

t ana

lysi

s

28WHO

pol

icy

on c

olla

bora

tive

TB/H

IV a

ctiv

ities

: Gui

delin

es fo

r nat

iona

l pro

gram

mes

and

oth

er s

take

hold

ers

Anne

xes

for w

ebpo

stin

g an

d CD

-Rom

dis

tribu

tion

with

the

polic

y gu

idel

ines

Tab

le 1

: Sum

mar

y o

f st

udie

s o

n co

-tri

mo

xazo

le p

reve

ntiv

e th

erap

y (C

PT)

in H

IV-i

nfec

ted

TB

pat

ient

s

Mw

aung

ulu

2004

(5)

(Mal

awi)

Nun

n 20

08 (

1)(Z

amb

ia)

Gri

mw

ade

2005

(2)

(So

uth

Afr

ica)

Kal

ou

2005

(6)

(Cô

te d

’Ivo

ire)

Par

ticip

ants

In

clus

ion

crite

ria:

patie

nts

with

pos

itive

cul

ture

s,

smea

rs, b

iops

ies

for A

FB.

Use

d on

ly H

IV te

st d

ata

that

wer

e av

aila

ble

<16

day

s af

ter t

he

patie

nts

was

regi

ster

ed fo

r ant

i-TB

tre

atm

ent.

The

inte

rven

tion

was

lim

ited

to

HIV

-pos

itive

TB

pat

ient

s.

Exc

lusi

on

crite

ria:

P

regn

ancy

, bre

astfe

edin

g, c

hild

ag

ed <

2 ye

ars,

pre

viou

s re

actio

ns

to s

ulfo

nam

ide

drug

s.

Incl

usio

n cr

iteri

a:

new

ly d

iagn

osed

, pre

viou

sly

untre

ated

pat

ient

s w

ith

smea

r-pos

itive

pul

mon

ary

tube

rcul

osis

rece

ivin

g an

ti-TB

trea

tmen

t (af

ter 1

yea

r, pa

tient

s re

ceiv

ing

a re

treat

men

t reg

imen

wer

e al

so e

ligib

le) a

nd c

linic

ally

he

alth

y pe

ople

pre

viou

sly

treat

ed fo

r TB

but

no

long

er

rece

ivin

g an

y tre

atm

ent.

Exc

lusi

on

crite

ria:

W

HO

sta

ge 4

HIV

dis

ease

s th

at w

ere

unlik

ely

to

surv

ive

mor

e th

an 2

wee

ks a

s w

ell a

s th

ose

with

a

hist

ory

of s

ulph

onam

ide

alle

rgy

and

thos

e w

ho n

eede

d tre

atm

ent w

ith o

r wer

e al

read

y re

ceiv

ing

CP

T fo

r oth

er

indi

catio

ns.

Incl

usio

n cr

iteri

a:A

ll ad

ult p

atie

nts

with

TB

(age

d 13

yea

rs o

r old

er) t

reat

ed in

the

com

mun

ity fr

om J

anua

ry 1

998

to

Dec

embe

r 200

0 (c

ontro

ls).

All

new

ly re

gist

ered

TB

pat

ient

s (S

epte

mbe

r 200

1 –

June

200

2)

Exc

lusi

on

crite

ria:

P

regn

ancy

, pat

ient

s w

ho d

eclin

ed

cons

ent t

o th

e tre

atm

ent.

Incl

usio

n cr

iteri

a:

patie

nts

who

wer

e ne

wly

dia

gnos

ed to

be

sput

um-s

mea

r pos

itive

for p

ulm

onar

y TB

. P

lasm

a sp

ecim

ens

shou

ld b

e av

aila

ble

at th

e be

ginn

ing

and

at 1

2 m

onth

s fo

llow

ing

star

t of

ther

apy,

pat

ient

s m

ust h

ave

been

cur

ed fo

r TB

, as

det

erm

ined

by

a sm

ear-n

egat

ive

or c

ultu

re-

nega

tive

resu

lt, a

fter 4

mon

ths

of tr

eatm

ent

for T

B.

Follo

w-u

pS

urvi

val w

as a

sses

sed

at 1

-2-8

-12

-18

mon

ths

afte

r reg

istra

tion

as

TB p

atie

nt.

Tota

l of 1

012.

6 pe

rson

-yea

rs o

f fol

low

-up.

Fol

low

-up

from

the

time

of ra

ndom

izat

ion

rang

ed fr

om 0

to 4

6 m

onth

s. E

very

4 w

eeks

up

to 1

6 w

eeks

and

eve

ry 8

w

eeks

ther

eafte

r unt

il th

e cl

ose

of th

e tri

al.

1 ye

ar a

fter T

B d

iagn

osis

and

tra

ced

at 6

mon

ths

afte

r end

of

treat

men

t.

12 m

onth

s af

ter i

nitia

tion

of th

e an

ti-TB

tre

atm

ent.

Out

com

es

Num

ber

of

illne

ss

epis

od

es a

nd

dea

ths

avo

ided

.

Ove

rall

case

-fata

lity

rate

fell

from

37

% to

29%

.

Unc

hang

ed in

the

HIV

-neg

ativ

e pa

tient

s bu

t fel

l in

HIV

-pos

itive

pa

tient

s fro

m 4

3% to

24%

.

A to

tal o

f 310

(147

CP

T 16

3 pl

aceb

o) p

artic

ipan

ts d

ied,

co

rres

pond

ing

to m

orta

lity

rate

s of

27.

3 an

d 34

.4 p

er

100

pers

on-y

ears

.

In th

e C

ox re

gres

sion

ana

lysi

s, th

e H

R fo

r dea

th

(CP

T:pl

aceb

o) w

as 0

.79

(95%

con

fiden

ce in

terv

al 0

.63

to 0

.99)

. CP

T w

as a

ssoc

iate

d w

ith a

21%

redu

ctio

n in

all

caus

e m

orta

lity.

The

effe

ct o

f CP

T w

aned

with

tim

e, p

ossi

bly

owin

g to

falli

ng a

dher

ence

leve

ls; i

n a

per-p

roto

col a

naly

sis

base

d on

pat

ient

s w

ho s

pent

at

leas

t 90%

of t

heir

time

at ri

sk s

uppl

ied

with

the

stud

y m

edic

ine,

the

HR

was

0.6

5 (0

.45

to 0

.93)

.

The

NN

T to

pre

vent

one

dea

th w

as 1

41.8

(95%

CI

71.7

–588

.7).

Ana

lysi

s by

CD

4 co

unt o

n th

e su

bset

of p

artic

ipan

ts

with

dat

a av

aila

ble

show

ed n

o ev

iden

ce o

f diff

eren

ce

in b

enefi

t acc

ordi

ng to

the

leve

l of i

mm

unos

uppr

essi

on

(P>

0.5,

test

for h

eter

ogen

eity

); n

o di

ffere

nce

in b

enefi

t by

age

or s

ex.

Mor

talit

y at

6 m

onth

s w

as 2

9%

low

er in

the

grou

p gi

ven

CP

T th

an in

the

cont

rol g

roup

. The

N

NT

to p

reve

nt o

ne d

eath

dur

ing

the

perio

d of

TB

trea

tmen

t was

24

. The

ben

efit w

as s

een

acro

ss

all t

ypes

of T

B b

ut w

as o

nly

evid

ent i

n ne

w p

atie

nts;

pat

ient

s be

ing

retre

ated

had

sim

ilar

outc

omes

in b

oth

grou

ps.

Pers

iste

ntly

ele

vate

d le

vels

of H

IV-1

VL

wer

e do

cum

ente

d am

ong

HIV

-1-in

fect

ed p

atie

nts

with

TB

des

pite

suc

cess

ful t

reat

men

t of T

B.

The

incr

ease

in p

lasm

a H

IV-1

VL

may

hel

p to

ex

plai

n th

e hi

gh m

orta

lity

obse

rved

am

ong

HIV

-1- i

nfec

ted

patie

nts

who

suc

cess

fully

co

mpl

ete

treat

men

t of T

B.

29

WHO

pol

icy

on c

olla

bora

tive

TB/H

IV a

ctiv

ities

: Gui

delin

es fo

r nat

iona

l pro

gram

mes

and

oth

er s

take

hold

ers

Anne

xes

for w

ebpo

stin

g an

d CD

-Rom

dis

tribu

tion

with

the

polic

y gu

idel

ines

Tab

le 1

: Sum

mar

y o

f st

udie

s o

n co

-tri

mo

xazo

le p

reve

ntiv

e th

erap

y (C

PT)

in H

IV-i

nfec

ted

TB

pat

ient

s

Mw

aung

ulu

2004

(5)

(Mal

awi)

Nun

n 20

08 (

1)(Z

amb

ia)

Gri

mw

ade

2005

(2)

(So

uth

Afr

ica)

Kal

ou

2005

(6)

(Cô

te d

’Ivo

ire)

Sec

ond

ary

out

com

es

Mo

rbid

ity/h

osp

ital

adm

issi

ons

N

AN

AN

AN

A

Ad

vers

e ev

ents

(d

efine

d a

s th

ose

ca

usin

g c

essa

tion

of

the

ther

apy

or

ho

spita

lizat

ion)

NA

Sus

pect

ed a

dver

se e

vent

s le

adin

g to

a p

lann

ed

inte

rrup

tion

of tr

ial m

edic

ine

occu

rred

in 1

8 pa

tient

s (1

2 C

PT,

6 p

lace

bo);

all

exce

pt 6

(all

CP

T) re

sum

ed

the

trial

med

icin

e. T

he re

actio

ns le

adin

g to

per

man

ent

disc

ontin

uatio

n w

ere

Ste

vens

–Joh

nson

syn

drom

e an

d an

aem

ia, i

tchy

rash

, sw

olle

n fa

ce a

nd li

ps, p

erip

hera

l ne

urop

athy

, and

ana

emia

(2 c

ases

).

Adv

erse

eve

nts

wer

e in

frequ

ent

and

min

or (o

nly

2 pa

rtici

pant

s st

oppe

d tre

atm

ent f

or th

is

reas

on).

Perc

eive

d ad

vers

e re

actio

ns

wer

e gi

ven

as th

e re

ason

for

stop

ping

pro

phyl

axis

by

23

patie

nts

but o

nly

2 si

gnifi

cant

ad

vers

e re

actio

ns w

ere

iden

tified

. O

ne p

atie

nt d

evel

oped

Ste

vens

–Jo

hnso

n sy

ndro

me

whi

le s

till

taki

ng a

nti-T

B tr

eatm

ent;

this

im

prov

ed o

n ce

ssat

ion

of

both

pro

phyl

axis

and

ant

i-TB

m

edic

atio

n. A

sec

ond

patie

nt

(kno

wn

to b

e H

IV-p

ositi

ve)

deve

lope

d ea

rly e

xfol

iativ

e de

rmat

itis

at 9

mon

ths

afte

r TB

di

agno

sis.

NA

Loss

to

fo

llow

up

NA

No

info

rmat

ion

on 7

8 (3

7 C

PT,

41

plac

ebo)

(9.3

%)

parti

cipa

nts

afte

r ran

dom

izat

ion.

429

parti

cipa

nts

No

loss

to fo

llow

up

Co

mm

ents

Ana

lyse

s in

clud

ing

all T

B p

atie

nts

wer

e al

so p

erfo

rmed

.Pa

tient

s pr

evio

usly

trea

ted

for T

B s

houl

d be

exc

lude

d.11

5 pa

tient

s re

sulte

d H

IV-p

ositi

ve

(8.8

%).

30WHO

pol

icy

on c

olla

bora

tive

TB/H

IV a

ctiv

ities

: Gui

delin

es fo

r nat

iona

l pro

gram

mes

and

oth

er s

take

hold

ers

Anne

xes

for w

ebpo

stin

g an

d CD

-Rom

dis

tribu

tion

with

the

polic

y gu

idel

ines

Tab

le 1

: Sum

mar

y o

f st

udie

s o

n co

-tri

mo

xazo

le p

reve

ntiv

e th

erap

y (C

PT)

in H

IV-i

nfec

ted

TB

pat

ient

s

Zach

aria

h 2

003

(Mal

awi)

(3)

Wik

tor

1999

(I

vory

Co

ast)

(4)

Ch

imzi

zi 2

004

(Mal

awi)

(7)

Met

ho

ds/

des

ign

Coh

ort s

tudy

usi

ng h

isto

rical

con

trols

Ran

dom

ized

dou

ble

blin

d ca

se-c

ontro

l C

ohor

t stu

dy u

sing

rout

inel

y co

llect

ed p

rogr

amm

e da

ta.

Po

pul

atio

nA

coh

ort o

f TB

pat

ient

s re

gist

ered

und

er ro

utin

e pr

ogra

mm

e co

nditi

ons

in a

rura

l dis

trict

of M

alaw

i.

A to

tal o

f 198

6 pa

tient

s w

ere

regi

ster

ed in

the

stud

y: 1

061

(inte

rven

tion)

and

925

(con

trol).

Bet

wee

n 1

July

199

9 an

d 30

Ju

ne 2

000

all T

B p

atie

nts

wer

e st

arte

d on

sta

ndar

dize

d an

ti-TB

tre

atm

ent,

and

offe

red

VCT.

Bet

wee

n O

ctob

er, 1

995,

and

Apr

il, 1

998,

wer

e en

rolle

d 77

1 H

IV-1

and

HIV

-1 &

HIV

-2 d

ually

ser

orea

ctiv

e pa

tient

s w

ho h

ad s

putu

m-s

mea

r-pos

itive

pul

mon

ary

TB (m

edia

n ag

e 32

yea

rs [r

ange

18–

64],

atte

ndin

g

Abi

djan

’s fo

ur la

rges

t out

patie

nt T

B tr

eatm

ent c

entre

s.

Two

rura

l dis

trict

s in

Mal

awi:

Thyo

lo (1

103

pts)

, w

here

VC

T is

offe

red

to a

ll TB

pat

ient

s an

d ad

junc

tive

CP

T to

HIV

-pos

itive

s, a

nd M

ulan

je

(123

9), w

here

no

such

inte

rven

tions

are

offe

red.

Inte

rven

tion

Patie

nts

foun

d to

be

HIV

-pos

itive

wer

e of

fere

d C

PT

(480

mg

BD

), pr

ovid

ed th

ere

wer

e no

con

train

dica

tions

.P

atie

nts

wer

e ra

ndo

mly

ass

igne

d o

ne d

aily

tab

let

of

CP

T (n

=38

6) o

r p

lace

bo

(n=

385)

1 m

ont

h a

fter

th

e st

art

of

a st

and

ard

6-m

ont

h T

B r

egim

en.

In T

hyol

o D

istri

ct, a

ll TB

pat

ient

s re

gist

ered

bet

wee

n Ju

ly 1

999

and

June

200

0 w

ere

offe

red

VCT,

and

th

ose

foun

d to

be

HIV

-pos

wer

e gi

ven

CP

T (4

80 m

g B

D),

prov

ided

ther

e w

ere

no c

ontra

indi

catio

ns.

Ana

lysi

sIn

tent

ion-

to-tr

eat

Inte

ntio

n-to

-trea

tIn

tent

ion-

to-tr

eat

Par

ticip

ants

In

clus

ion

crite

ria:

B

etw

een

1 Ju

ly 1

999

and

30 J

une

2000

, all

TB p

atie

nts

who

wer

e re

gist

ered

in T

hyol

o di

stric

t, at

eith

er th

e go

vern

men

t hos

pita

l or

the

mis

sion

hos

pita

l, w

ere

enro

lled

into

the

VCT

and

adju

nctiv

e C

PT

treat

men

t stu

dy (i

nter

vent

ion

grou

p).

Bet

wee

n 1

July

199

8 an

d 30

Jun

e 19

99, a

ll TB

pat

ient

s w

ho w

ere

regi

ster

ed in

the

sam

e tw

o ho

spita

ls in

the

dist

rict w

ere

star

ted

on th

e sa

me

stan

dard

ized

ant

i-TB

trea

tmen

t (co

ntro

l gro

up).

Exc

lusi

on

crite

ria:

K

now

n al

lerg

ies

to s

ulfo

nam

ide

drug

s, p

regn

ancy

, bre

ast-

feed

ing

until

2 m

onth

s an

d ch

ildre

n ag

ed le

ss th

an 2

yea

rs

(bec

ause

of u

ncer

tain

ty a

bout

HIV

-ser

osta

tus)

.

Incl

usio

n cr

iteri

a:

All

thos

e ag

ed 1

8 ye

ars

or o

lder

who

live

d in

Abi

djan

, w

ho h

ad s

putu

m-s

mea

r-pos

itive

TB

, and

who

wer

e H

IV-1

se

ropo

sitiv

e or

HIV

-1 a

nd H

IV-2

dua

lly s

eror

eact

ive.

Exc

lusi

on

crite

ria:

H

IV-2

-ser

opos

itive

pat

ient

s be

caus

e of

low

mor

talit

y ris

k,

preg

nant

wom

en,

patie

nts

with

pre

viou

sly

treat

ed tu

berc

ulos

is, t

hose

al

lerg

ic to

CP

T,

and

thos

e re

ceiv

ing

CP

T pr

ophy

laxi

s fo

r pre

vent

ion

of a

re

curr

ence

of t

oxop

lasm

osis

.

Incl

usio

n cr

iteri

a:

Sm

ear p

ositi

ve P

TB a

nd E

PTB

, sm

ear n

egat

ive

PTB

an

d E

PTB

. Ret

reat

men

t pat

ient

s (B

oth

arm

s), H

IV

posi

tive

test

(int

erve

ntio

n ar

m).

Exc

lusi

on

crite

ria:

Pa

tient

s w

ere

not g

iven

CP

T if

preg

nant

or a

llerg

ic

to C

PT.

Follo

w-u

pU

ntil

end

of T

B tr

eatm

ent

24 m

onth

sN

A

31

WHO

pol

icy

on c

olla

bora

tive

TB/H

IV a

ctiv

ities

: Gui

delin

es fo

r nat

iona

l pro

gram

mes

and

oth

er s

take

hold

ers

Anne

xes

for w

ebpo

stin

g an

d CD

-Rom

dis

tribu

tion

with

the

polic

y gu

idel

ines

Tab

le 1

: Sum

mar

y o

f st

udie

s o

n co

-tri

mo

xazo

le p

reve

ntiv

e th

erap

y (C

PT)

in H

IV-i

nfec

ted

TB

pat

ient

s

Zach

aria

h 2

003

(Mal

awi)

(3)

Wik

tor

1999

(I

vory

Co

ast)

(4)

Ch

imzi

zi 2

004

(Mal

awi)

(7)

Num

ber

of

illne

ss

epis

od

es a

nd

dea

ths

avo

ided

.

Dea

th w

as d

efine

d as

a d

eath

at a

ny ti

me

durin

g th

e 8–

12

mon

ths

of tr

eatm

ent f

rom

wha

teve

r cau

se.

The

crud

e re

lativ

e ris

k (R

R) o

f dea

th b

y th

e en

d of

trea

tmen

t in

the

inte

rven

tion

com

pare

d gr

oup

with

the

cont

rol g

roup

was

0.7

8 (9

5% C

I, 0.

69–0

.89;

p=

0.00

1). A

djus

ted

for t

ype

and

cate

gory

of

TB

as

wel

l as

anti-

TB tr

eatm

ent,

the

RR

was

0.8

1 (9

5% C

I, 0.

75–0

.87;

p=

0.0

01).

The

deat

h ra

te fo

r all

regi

ster

ed T

B p

atie

nts

was

4.0

per

100

pe

rson

-mon

ths

of fo

llow

-up

in th

e in

terv

entio

n gr

oup

and

5.3

in th

e co

ntro

l gro

up, c

orre

spon

ding

to a

25%

redu

ctio

n in

risk

of

dea

th (9

5% C

I, 12

.3–3

5.8)

. Adj

uste

d fo

r typ

e an

d ca

tego

ry

of T

B a

s w

ell a

s an

ti-TB

trea

tmen

t, th

e H

R w

as 0

.76

(95%

CI,

0.69

–0.8

3).

The

NN

T to

pre

vent

one

dea

th (b

y pr

ovid

ing

VCT

plus

CP

T)

durin

g th

e co

urse

of a

nti-T

B tr

eatm

ent w

as 1

2.5.

51 p

atie

nts

in th

e C

PT

grou

p (1

3.8/

100

pers

on-y

ears

) and

86

in th

e pl

aceb

o gr

oup

(25.

4/10

0 pe

rson

-yea

rs) d

ied

(dec

reas

e In

risk

46%

[95%

CI 2

3–62

], p<

0·00

1).

Adj

uste

d fo

r typ

e an

d ca

tego

ry o

f TB

, TB

trea

tmen

t re

gim

en a

nd s

ite o

f reg

istra

tion,

the

rela

tive

risks

fo

r all

TB p

atie

nts

in T

hyol

o co

mpa

red

with

thos

e in

M

ulan

je w

ere:

- Tre

atm

ent s

ucce

ss R

R 1

.23

(95%

CI 1

.19–

1.26

, p=

0.

001)

;

- Dea

th R

R 0

.84

(95%

CI 0

.78–

0.91

, p=

0.00

1);

- “O

ther

out

com

es”

(def

ault,

tran

sfer

out

, unk

now

n an

d, fo

r sm

ear-p

ositi

ve p

atie

nts,

failu

re) R

R 0

.27

(95%

CI 0

.23–

0.32

, p=

0.0

01).

Sec

ond

ary

out

com

es

Mo

rbid

ity/h

osp

ital

adm

issi

ons

NA

29 p

atie

nts

on C

PT

(8.2

/100

per

son-

year

s) a

nd 4

7 on

pl

aceb

o (1

5.0/

100

pers

on-y

ears

) wer

e ad

mitt

ed to

ho

spita

l at l

east

onc

e af

ter r

ando

miz

atio

n (d

ecre

ase

43%

[10–

64])

, p=

0.02

). Th

e ra

te o

f adm

issi

ons

for a

ll di

seas

es th

at c

ould

pot

entia

lly h

ave

been

pre

vent

ed b

y C

PT

(sep

ticae

mia

, ent

eriti

s, c

hest

infe

ctio

n, u

rinar

y-tra

ct

infe

ctio

n, a

nd to

xopl

asm

osis

) was

sig

nific

antly

low

er fo

r pa

tient

s in

the

CP

T gr

oup

(2.7

/100

per

son-

year

s) th

an

in th

e pl

aceb

o gr

oup

(8.7

/100

per

son-

year

s; H

R 0

.3

[0.2

–0.7

], p=

0.00

1).

Ther

e w

ere

sign

ifica

ntly

few

er a

dmis

sion

s fo

r sep

ticae

mia

an

d en

terit

is in

the

CP

T gr

oup

than

in th

e pl

aceb

o gr

oup.

NA

Ad

vers

e ev

ents

, d

efine

d a

s th

ose

ca

usin

g c

essa

tion

of

the

ther

apy

or

ho

spita

lizat

ion

Of 6

93 p

atie

nts

on C

PT,

14

(2%

) had

a d

erm

atol

ogic

al re

actio

n.

No

reac

tions

wer

e se

rious

or i

nvol

ved

muc

osal

mem

bran

es, a

nd

all w

ere

reve

rsib

le o

n di

scon

tinui

ng tr

eatm

ent.

All

derm

atol

ogic

al

reac

tions

occ

urre

d in

the

first

2 m

onth

s of

trea

tmen

t, w

ith 9

(6

4%) o

ccur

ring

durin

g th

e fir

st m

onth

. In

13 p

atie

nts,

CP

T w

as

disc

ontin

ued

inde

finite

ly, a

nd in

one

pat

ient

it w

as re

-sta

rted

(by

mis

take

) with

out p

robl

ems.

Abo

ut 1

6 %

of p

atie

nts

in th

e pl

aceb

o gr

oup

and

12%

in

the

CP

T gr

oup

had

at le

ast o

ne s

ever

e cl

inic

al a

dver

se

even

t.

Abo

ut 8

% o

f the

pat

ient

s in

eac

h gr

oup

had

a se

vere

to

xic

effe

ct b

ased

on

labo

rato

ry m

easu

rem

ents

.

Rat

es o

f lab

orat

ory

and

clin

ical

adv

erse

eve

nts

wer

e si

mila

r in

the

two

grou

ps.

NA

32WHO

pol

icy

on c

olla

bora

tive

TB/H

IV a

ctiv

ities

: Gui

delin

es fo

r nat

iona

l pro

gram

mes

and

oth

er s

take

hold

ers

Anne

xes

for w

ebpo

stin

g an

d CD

-Rom

dis

tribu

tion

with

the

polic

y gu

idel

ines

Tab

le 1

: Sum

mar

y o

f st

udie

s o

n co

-tri

mo

xazo

le p

reve

ntiv

e th

erap

y (C

PT)

in H

IV-i

nfec

ted

TB

pat

ient

s

Zach

aria

h 2

003

(Mal

awi)

(3)

Wik

tor

1999

(I

vory

Co

ast)

(4)

Ch

imzi

zi 2

004

(Mal

awi)

(7)

Loss

to

fo

llow

up

19 m

isse

d, 6

tran

sfer

red,

3 a

bsco

nded

, 36

died

, 53

refu

sed

VCT

A to

tal o

f 984

pat

ient

s w

ere

invi

ted

to p

artic

ipat

e, o

f w

hom

771

(78.

4%) w

ere

enro

lled.

The

mai

n re

ason

s fo

r

non-

enro

lmen

t wer

e no

t ret

urni

ng to

the

TB c

linic

(74%

), tra

nsfe

r by

the

TB-c

linic

phy

sici

ans

to a

non

-stu

dy c

linic

(2

2%) o

r dea

th b

efor

e en

rolm

ent (

4%).

NA

Co

mm

ents

The

inte

rven

tion

bein

g ev

alua

ted

cons

ider

ed th

e co

mbi

natio

n of

C

PT

and

VCT.

The

ana

lysi

s is

ther

efor

e no

t res

trict

ed to

the

use

of C

PT

only.

No

sign

ifica

nt b

enefi

t in

smea

r-pos

itive

TB

pat

ient

s.

On

Apr

il 19

98, b

ased

on

a re

view

of t

he a

vaila

ble

resu

lts,

and

sinc

e it

was

thou

ght n

o lo

nger

eth

ical

to c

ontin

ue

to e

nrol

new

pat

ient

s, th

e dr

ug s

afet

y m

onito

ring

boar

d re

com

men

ded

susp

ensi

on o

f enr

olm

ent:

ALL

stu

dy

patie

nts

rece

ived

ope

n-la

bel C

PT

Ant

ibio

tic s

ensi

tivity

test

ing

reve

aled

that

6/7

(86%

) is

olat

es o

f non

-typh

oid

salm

onel

la w

ere

sens

itive

to C

PT.

Med

ian

CD

4-ce

ll co

unt 3

17ce

lls/L

)

BD,twicedaily;CPT,co-trimoxazolepreventivetherapy;EPTB,extrapulmonarytuberculosis;HR,hazardratio;NNT,numberneededtotreat;OD,oncedaily;

PTB,pulmonarytuberculosis;RR,riskratioTB,tuberculosis;VCT,voluntarycounsellingandtesting;VL,viralload.

33

WHO

pol

icy

on c

olla

bora

tive

TB/H

IV a

ctiv

ities

: Gui

delin

es fo

r nat

iona

l pro

gram

mes

and

oth

er s

take

hold

ers

Anne

xes

for w

ebpo

stin

g an

d CD

-Rom

dis

tribu

tion

with

the

polic

y gu

idel

ines

34


3. GRADE profileThe quality of evidence across a body of evidence was assessed using the GRADE approach. For purposes of systematic reviews, the GRADE approach defines the quality of a body of evidence as the extent to which one can be confident that an estimate of effect or association is close to the quantity of specific interest (8). The quality of a body of evidence involves consideration of within-study risk of bias (methodological quality), directness of evidence, heterogeneity, precision of effect estimates and risk of publication bias. The GRADE system entails an assessment of the quality of a body of evidence for each individual outcome.

The quality rating across studies has four levels: high, moderate, low or very low. Randomized trials are categorized as high-quality but can be downgraded; similarly, observational studies can be upgraded. Factors that decrease the quality of evidence include limitations in design, indirectness of evidence, unexplained heterogeneity or inconsistency of results, imprecision of results, or high probability of publication bias. Factors that can increase the quality level of a body of evidence include a large magnitude of effect, if all plausible confounding would reduce a demonstrated effect and if there is a dose-response gradient. The GRADE Profiler software was used to perform the GRADE analyses (GRADE pro 2008).

Given the availability of two randomized controlled trials and the unlikelihood of achieving a better quality of evidence by including the observational studies, the GRADE analyses were restricted to the two randomized controlled trials available as follows.

35


Table 2Question: Should routine co-trimoxazole preventive therapy (CPT) be used in HIV-infected individuals with active TB?Settings: High TB/HIV prevalence settingsBibliography: Nunn A, 2008 (1) Wiktor SZ, 1999 (4)

Routine CPT prophylaxis for HIV-infected individuals with active TB

Patient or population: HIV-infected individuals with active TB

Settings: High TB/HIV prevalence settings

Intervention: Routine CPT prophylaxis

Outcomes Illustrative comparative risks* (95% CI)

Relative effect(95% CI)

No of participants(studies)

Quality of the evidence(GRADE)

Comments

Assumed risk Corresponding risk

Control Routine CPT prophylaxis

Mortality

Medical record

Follow-up: 332–538 patient-years

Study population RR 0.70 (0.6 to 0.83)

1711(2 studies)

++++high1

309 per 1000 216 per 1000(185 to 256)

Medium risk population

300 per 1000 210 per 1000(180 to 249)

Morbidity/hospital admission

Medical and hospital record


Study population HR 0.54 (0.39 to 0.74)

698(1 study)

+++-moderate2

259 per 1000 140 per 1000(101 to 192)

Adverse events

Medical record


58 per 1000 46 per 1000(31 to 67)

RR 0.79 (0.54 to 1.15)

1599(2 studies)

+++-moderate3

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI, confidence interval; RR, risk ratio; HR, hazard ratio

GRADE Working Group grades of evidence

High quality: Further research is very unlikely to change our confidence in the estimate of effect.

Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Very low quality: We are very uncertain about the estimate.

1 PatientswerenotonHAARTandthiscouldbeconsideredasasignificantdifferencebetweenthetrialsubjectsandthepatientsforwhomtherecommendationisintended;however,thisislikely to be a minor issue therefore the studies were not downgraded.

2 Onlyonestudyavailable.

3 WideCI.

36


Table 3aQuestion: Should routine co-trimoxazole preventive therapy (CPT) be used in HIV-infected individuals with active TB and CD4 count <200 cells/mm3?Settings: High TB/HIV prevalence settingsBibliography: Wiktor SZ, 1999 (4)

Routine CPT prophylaxis for HIV infected individuals with active TB and CD4 count <200 cells/mm3

Patient or population: HIV infected individuals with active TB and CD4 count <200 cells/mm3







Comments



Mortality

Medical record



175(1 study)

++--low1,2

645 per 1000 303 per 1000(213 to 426)

Low risk population

200 per 1000 94 per 1000(66 to 132)

High risk population

700 per 1000 329 per 1000(231 to 462)

Hospital admission




161(1 study)

++--low1,2

403 per 1000 177 per 1000(105 to 302)


500 per 1000 220 per 1000(130 to 375)


CI, confidence interval; RR, risk ratio







2 SmallsamplesizeandwideCI.

37


Table 3bQuestion: Should routine co-trimoxazole preventive therapy (CPT) be used in HIV-infected individuals with active TB and CD4 count >200 cells/mm3?Settings: High TB/HIV prevalence settingsBibliography: Wiktor SZ, 1999 (4)

Routine CPT prophylaxis for HIV-infected individuals with active TB and CD4 count >200 cells/mm3

Patient or population: HIV-infected individuals with active TB and CD4 count >200 cells/mm3







Comments



Mortality

Medical record

Follow-up: 251 patient-years


502(1 study)

++--low1,2

116 per 1000 56 per 1000(30 to 103)

Low risk population

100 per 1000 48 per 1000(26 to 89)

High risk population

400 per 1000 192 per 1000(104 to 356)

Hospital admission




485(1 study)

++--low1,2

62 per 1000 37 per 1000(17 to 84)


200 per 1000 120 per 1000(54 to 270)


CI, confidence interval; RR, risk ratio







2 SmallsamplesizeandwideCI.

38



Recommendation: Routine co-trimoxazole preventive therapy (CPT) should be administered in all HIV-infected patients with active TB disease regardless of their CD4 count

Population: HIV-infected patients with active TB disease irrespective of their CD4 count

Intervention: Standard routine CPT administration


Quality of evidence High

The reduction in mortality is supported by the HIGH quality of the evidence.

The intervention shows decrease in morbidity and hospital admission (LOW quality of the evidence) with no significant increase in adverse events (MODERATE quality of the evidence)

Lack of specific evidence in HIV infected patients on ART

Benefits

or desired effects

Strong (benefits outweigh risks)

Reduction in mortality

Reduction in morbidity (bacterial infection, malaria, etc.) including among HIV-uninfected household members of people living with HIV receiving CPT (but not exclusively HIV-infected TB patients)


Additional drug-related adverse events

Resistance rates to CPT among common pathogens may increase, although this was not the case on diarrhoeal pathogens in Uganda and on falciparum parasites in Mali (studies conducted among people living with HIV receiving ART – not exclusively HIV-infected TB patients – and their household members)

Values and preferences Strong

Improve quality of HIV care

Prevention of life-threatening opportunistic infections

Health-care workers would probably prefer standard policy regarding CPT irrespective of antituberculosis treatment

Costs Strong

CPT is inexpensive and available

Unlikely to increase cost significantly

Avoiding additional hospitalization: potentially cost-saving

Feasibility Strong

Routine CPT provision is part of HIV general care

Continuation of standard provision is very feasible

Downside is that CPT is a common antibiotic for people with and without HIV and it is often difficult to maintain regular supply for those in need.

Strength of recommendationStrong

39


5. References1. Nunn AJ et al. Role of co-trimoxazole prophylaxis in reducing mortality in HIV infected adults being treated for

tuberculosis: randomised clinical trial. BMJ, 2008, 337:a257.

2. Grimwade K et al. Effectiveness of cotrimoxazole prophylaxis on mortality in adults with tuberculosis in rural South Africa. AIDS, 2005, 19(2):163–168.

3. Zachariah R et al. Voluntary counselling, HIV testing and adjunctive cotrimoxazole reduces mortality in tuberculosis patients in Thyolo, Malawi. AIDS, 2003, 17(7):1053–1061.

4. Wiktor SZ et al. Efficacy of trimethoprim-sulphamethoxazole prophylaxis to decrease morbidity and mortality in HIV-1-infected patients with tuberculosis in Abidjan, Côte d’Ivoire: a randomised controlled trial. Lancet, 1999, 353(9163):1469–1475.

5. Mwaungulu FB et al. Cotrimoxazole prophylaxis reduces mortality in human immunodeficiency virus-positive tuberculosis patients in Karonga District, Malawi. BulletinoftheWorldHealthOrganization, 2004, 82(5):354–363.

6. Kalou M et al. Changes in HIV RNA viral load, CD4+ T-cell counts, and levels of immune activation markers associated with anti-tuberculosis therapy and cotrimoxazole prophylaxis among HIV-infected tuberculosis patients in Abidjan, Côte d’Ivoire. JournalofMedicalVirology, 2005, 75(2):202–208.

7. Chimzizi R et al. Voluntary counselling, HIV testing and adjunctive cotrimoxazole are associated with improved TB treatment outcomes under routine conditions in Thyolo District, Malawi. InternationalJournalofTuberculosisandLungDisease, 2004, 8(5):579–585.

8. Atkins D et al. Grading quality of evidence and strength of recommendations. BMJ, 2004, 328(7454):1490.

9789241503006

For further information contact:

World Health Organization20, Avenue Appia CH-1211 Geneva 27 SwitzerlandStop TB DepartmentE-mail: [email protected] site: www.who.int/tb

Department of HIV/AIDSEmail: [email protected] site: www.who.int/hiv

who policy on collaborative tb/hiv activities guidelines for national

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