aids who ctx

8/8/2019 Aids Who Ctx

1/68

GUIDELINES ON

CO-TRIMOXAZOLE PROPHYLAXIS

FOR HIV-RELATED INFECTIONS

AMONG CHILDREN,

ADOLESCENTS AND ADULTS

IN RESOURCE-LIMITED SETTINGS

Recommendations

for a public health approach

Strengthening health services to fght HIV/AIDSHIV/AIDS Programme


2/68

World Health Organization 2006

All rights reserved. Publications o the World Health Organization can be obtained rom WHO Press, World Health

Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel: +41 22 791 3264; ax: +41 22 791 4857; email:

[email protected]). Requests or permission to reproduce or translate WHO publications whether or sale or or

noncommercial distribution should be addressed to WHO Press, at the above address (ax: +41 22 791 4806;

email: [email protected]).

The designations employed and the presentation o the material in this publication do not imply the expression o

any opinion whatsoever on the part o the World Health Organization concerning the legal status o any country,

territory, city or area or o its authorities, or concerning the delimitation o its rontiers or boundaries. Dotted lines on

maps represent approximate border lines or which there may not yet be ull agreement.

The mention o specifc companies or o certain manuacturers products does not imply that they are endorsed or

recommended by the World Health Organization in preerence to others o a similar nature that are not mentioned.

Errors and omissions excepted, the names o proprietary products are distinguished by initial capital letters.

All reasonable precautions have been taken by WHO to veriy the inormation contained in this publication. However,

the published material is being distributed without warranty o any kind, either express or implied. The responsibilit y

or the interpretation and use o the material lies with the reader. In no event shall the World Health Organization be

liable or damages arising rom its use.


3/68

GUIDELINES ON

CO-TRIMOXAZOLE PROPHYLAXIS

FOR HIV-RELATED INFECTIONS

AMONG CHILDREN,

ADOLESCENTS AND ADULTSIN RESOURCE-LIMITED SETTINGS

Recommendations

for a public health approach


4/68Guidelines on co-trimoxazole prophyla xis

for hiV-related infections amonG children, adolescents and adults in resource-limited settinGs

These guidelines could not have been created without the participation o numerous experts.

The World Health Organization expresses its gratitude to the writing committee that developed this document.

Members o the writing committee were Murtada Sesay Bpharm (UNICEF), Rhehab Chimzizi (Lilongwe, Malawi),

Tawee Chotpitayasunondh (Queen Sirikit National Institute o Child Health, Bangkok, Thailand), Siobhan Crowley

(Department o HIV/AIDS, World Health Organization), Chris Duncombe (HIV Netherlands Australia Thailand

Research Collaboration (HIV-NAT), Bangkok, Thailand), Wafaa El Sadr (Columbia University, New York, NY, USA),

Robert Gass (UNICEF), Diane Gibb (Medical Research Council, London, United Kingdom), Kate Grimwade (City

General Hospital, Stoke-on-Trent, United Kingdom), Senait Kebede (WHO Regional Ofce or Arica, World Health

Organization) Nagalingeshwaran Kumarasamy (YRG Centre or AIDS Research & Education, India), Sylvia Ojoo

(Kenyatta National Hospital, Nairobi, Kenya) and Renee Ridzon (Bill & Melinda Gates Foundation, Seattle, WA,

USA).

This publication was developed through an expert consultation process that took account o current scientifc

evidence and the state o the art in co-trimoxazole prophylaxis or HIV inection in the context o resource-limited

settings.

WHO also wishes to acknowledge the comments and contributions by Xavier Anglaret, Amy Bloom, Nguy Chi,

Chiumbe Chintu, Anniek De Baets, Kevin de Cock, Joseph Drabo, Sergie Eho li, Aires Fernandes, Tendani Galoathi,

Julian Gold, Gregg Gonsalves, Stephen Graham, Catherine Hankins, Robert Josiah, Rita Kabra, Jon Kaplan,

George Ki-zerbo, Charles Kouanack, Maria Grazia Lain, Chewe Luo, Shabir Madhi, Jean Ellie Malkin, Mariana

Mardaresceau, Anaky Marie-France, Antonieta Medina Lara, Jonathan Mermim, Lulu Muhe, Hilda Mujuru, Paula

Munderi, Peter Mwaba, Cheikh Ndour, Ngashi Ngongo, Kike Osinusi, Christopher Plowe, Hak Chan Roeun, Fabio

Scano, Goa Tau, Donald Thea, Valdilea Veloso, Christine Watera, Wilson Were, Yazdan Yazdanpanah, Rony

Zachariah and Heather Zar.

WHO also wish to thank the Bill and Melinda Gates Foundation or supporting the elaboration o these guidelines.

This work was coordinated by Charles Gilks and Marco Vitoria, Department o HIV/AIDS, World Health Organization.

Acknowledgements


5/68

1. Acronyms and abbreviations ..........................................................................................4

2. Development o these guidelines ...................................................................................5

2.1 Objective o this document .....................................................................................52.2 Target audience ......................................................................................................5

3. Statement on the strength o the evidence used in the recommendations ....................6

4. Introduction ....................................................................................................................7

5. Background and new evidence ......................................................................................85.1 Co-trimoxazole prophylaxis among inants and children .......................................85.2 Co-trimoxazole prophylaxis among adolescents and adults .................................95.3 Co-trimoxazole prophylaxis in pregnant women .................................................. 105.4 Discontinuing co-trimoxazole prophylaxis among people

receiving antiretroviral therapy ............................................................................. 105.5 Bacterial resistance to co-trimoxazole.................................................................. 125.6 Cross-resistance o co-trimoxazole with suladoxine/pyr imethamine ................... 12

6. Recommendations on the use o co-trimoxazole prophylaxis among inants and children .. 136.1 Initiation o primary co-trimoxazole prophylaxis in inants and children ............... 136.2 Doses o co-trimoxazole in inants and children ................................................... 156.3 Secondary co-trimoxazole prophylaxis in inants and children ............................166.4 Discontinuation o primary co-trimoxazole prophylaxis in inants and children....166.5 Discontinuation o secondary co-trimoxazole prophylaxis ................................... 18

7. Recommendations on the use o primary co-trimoxazole prophylaxis

among adults and adolescents .................................................................................... 197.1 Adults and adolescents among whom co-tr imoxazole prophylaxis

is contraindicated ................................................................................................. 197.2 Initiation o primary co-trimoxazole prophylaxis among adults and adolescents . 197.3 Co-trimoxazole prophylaxis among pregnant women ..........................................207.4 Doses o co-tr imoxazole among adults and adolescents ....................................217.5 Secondary co-trimoxazole prophylaxis among adults and adolescents ..............217.6 Discontinuing co-trimoxazole prophylaxis among adults and adolescents .........21

8. Recommendations common to inants, children, adults and adolescents ...................268.1 Timing the initiation o co-trimoxazole in relation to initiating antiretroviral therapy .... 26

8.2 Clinical and laboratory monitoring o co-tr imoxazole prophylaxis ........................268.3 Treatment o bacterial and opportunistic inectionsamong people taking co-trimoxazole prophylaxis ...............................................27

8.4 Preventing and treating malaria among people taking co-trimoxazole prophylaxis .. 27

Annex 1. WHO clinical staging o HIV disease in inants and children .............................29Annex 2. WHO clinical staging o HIV disease among adults and adolescents .............. 31Annex 3. Criteria or recognizing HIV-related clinical events among adults and adolescents .. 33Annex 4. Criteria for recognizing HIV-related clinical events among children living with HIV ...43Annex 5. Grading o adverse drug events ........................................................................54Annex 6. Summary o major studies o co-trimoxazole prophylaxis ................................56

Reerences .........................................................................................................................60

CONTENTS




1. ACRONYMS AND AbbREVIATIONS

AIDS acquired immunodeciency syndrome

HIV human immunodeciency virus

PCP Pneumocystis jiroveci pneumonia

(ormerly Pneumocystis carinii pneumonia)

TB tuberculosis

UNAIDS Joint United Nations Programme on HIV/AIDS

WHO World Health Organization


7/68

2. DEVELOPMENT OF THESE GUIDELINES

Co-trimoxazole prophylaxis is a simple, well-tolerated and cost-eective interventionor people living with HIV. It should be implemented as an integral component o the

HIV chronic care package and as a key element o preantiretroviral therapy care.

Co-trimoxazole prophylaxis needs to continue ater antiretroviral therapy is initiated

until there is evidence o immune recovery (see subsections 6.4 and 7.6).

In May 2005, WHO convened an Expert Consultation on Cotrimoxazole Prophylaxis in

HIV Inection. The meeting objectives were to review available data on co-trimoxazole

prophylaxis, including operational issues and research priorities, and to exchange

regional and country experiences. The meeting report(1) ormulated recommendations

or the initiation and discontinuation o co-trimoxazole prophylaxis in inants, children,

adults and adolescents.

.1 Objective o this document

In high-income countries, co-trimoxazole prophylaxis among children (both those exposed

to HIV1 and those living with HIV) and adults and adolescents living with HIV has been thestandard o care or many years. WHO and UNAIDS have not produced guidelines or

national programmes in resource-limited settings. In the absence o clear guidelines,

countries and programmes have been slow in adopting co-trimoxazole prophylaxis, a lie-

saving, simple and inexpensive intervention. The objective o these guidelines is to provide

global technical and operational recommendations or the use o co-trimoxazole prophylaxis

in HIV-exposed children, children living with HIV and adolescents and adults living with HIV

in the context o scaling up HIV care in resource-limited settings.

All HIV-exposed inants born to mothers living with HIV must receive co-trimoxazole

prophylaxis, commencing at 46 weeks o age (or at frst encounter with health

care system) and continued until HIV inection can be excluded.

. Target audience

This publication is primarily intended or use by national HIV/AIDS programme managers,

managers o nongovernmental organizations delivering HIV/AIDS care services and other

policy-makers who are involved in planning HIV/AIDS care strategies in resource-limited

countries. It should also be useul to clinicians in resource-limited settings.

1 Defnit ion o HIV exposure: inants and children born to mothers living with HIV until HIV inection in the inant

or child is reliably excluded and the inant or child is no longer exposed through breasteeding. For those 18 months o age, HIV inection can be

excluded by negative HIV antibody testing at least six weeks ater complete cessation o all breasteeding.




The recommendations contained in these guidelines are based on levels o

evidence rom randomized clinical trials, high-quality scientic studies, observational

cohort data and, where sucient evidence is not available, on expert opinion

(Table 1). The strength o the recommendations is intended to guide the degree to

which regional and country programmes consider the recommendations.

These recommendations do not explicitly consider cost-eectiveness, although

the realities o human resources, health system inrastructure and socioeconomic

issues need to be taken into account when adapting these recommendations to

regional and country programmes.

Table 1. Grading o recommendations and levels o evidence

STRENGTH OF THERECOMMENDATION

LEVEL OF EVIDENCE AVAILABLEFOR THE RECOMMENDATION

A. Recommended should be

ollowed

B. Consider applicable in most

situations

C. Optional

I. At least one randomized controlled trial

with clinical laboratorial or programmatic

endpoints

II. At least one high-quality study or several

adequate studies with clinical, laboratory

or programmatic endpoints

III. Observational cohort data, one or more

case-controlled or analytical studies

adequately conducted

IV. Expert opinion based on evaluation o

other evidence

Sources: BHIVA Writing Committee on behal o the BHIVA Executive Committee (2); Task Force on Community

Preventive Services (3); WHO Health Evidence Network (4); EDM guidelines: evidence-based medicine (5).

3. STATEMENT ON THE STRENGTH OF THE EVIDENCE USED

IN THE RECOMMENDATIONS


9/68

Co-trimoxazole, a xed-dose combination o sulamethoxazole and trimethoprim,

is a broad-spectrum antimicrobial agent that targets a range o aerobic gram-

positive and gram-negative organisms, ungi and protozoa. The drug is widely

available in both syrup and solid ormulations at low cost (a ew US cents per day)

in most places, including resource-limited settings. Co-trimoxazole is on the

essential medicines list (6) o most countries.

Providing co-trimoxazole has been part o the standard o care or preventing

Pneumocystis jiroveci pneumonia (PCP) (ormerly Pneumocystis carinii pneumonia)

and toxoplasmosis since the early 1990s. Although WHO/UNAIDS issued a

provisional statement on the use o co-trimoxazole prophylaxis in sub-Saharan

Arica in 2000, most countries have not implemented this intervention widely. The

reasons or the slow implementation o co-trimoxazole prophylaxis programmes

include the dierence in causation and burden o HIV-related inections between

well-resourced and resource-limited countries, the potential or drug resistance

and the lack o guidelines. Until more recently, there has also been concern over

the limited evidence base or the ecacy o co-trimoxazole prophylaxis, particularly

in areas with high levels o bacterial resistance to the drug.

4. INTRODUCTION




5. bACkGROUND AND NEw EVIDENCE

Data on the eectiveness o co-trimoxazole in reducing morbidity and mortality

among individuals living with HIV in resource-limited countries comes rom

randomized clinical trials, observational cohort studies and programme analyses

rom several Arican countries (with varying levels o co-trimoxazole resistance),

India and Thailand. There are limited data rom the Caribbean and Latin America.

Recently, more data have become available rom resource-limited settings on the

ecacy o co-trimoxazole prophylaxis in reducing morbidity and mortality among

adults and children living with HIV.

.1 Co-trimoxazole prophylaxis among inants and children

Across a large number o clinical and postmortem studies in all settings, PCP has been

identied as the leading cause o death in inants with HIV inection, accounting or 5060%

o AIDS diagnoses in inants (7,8). The incidence peaks in the rst six months o lie (912).

Because o diculty in diagnosing HIV inection in inants, co-trimoxazole prophylaxis is

recommended or all HIV-exposed children born to mothers living with HIV starting at 46

weeks ater birth and continuing until HIV inection has been excluded and the inant is no

longer at risk o acquiring HIV through breasteeding.

Data rom randomized clinical trials and observational studies demonstrate the

eectiveness o co-trimoxazole in preventing PCP in inants and reducing morbidity

and mortality among inants and children living with or exposed to HIV.

Among children ater inancy, a randomized clinical trial conducted in Lusaka, Zambiaprovided strong evidence that daily co-trimoxazole prophylaxis is eective in reducing

mortality and morbidity (7). This was demonstrated despite high levels oin vitro resistance

o common bacterial inections to co-trimoxazole (6080%). In this study, 534 children living

with HIV (mean age 4.4 years; 32% 12 years and 15% older than 10 years) were randomized

to receive co-trimoxazole (240 mg daily or children 15 years and 480 mg or children older

than 5 years) or matching placebo. Mortality declined 43% and the rate o hospital admissions

23% in the co-trimoxazole group versus placebo. No evidence indicated that the eectiveness

decreased over a median ollow-up time o 20 months in the trial, and the benet o co-

trimoxazole was demonstrated at all ages and all levels o CD4 percentage. However, most

o these children had symptoms (WHO clinical stages 2, 3 or 4 or HIV disease) at baseline

and only 16% had a CD4% >20%. The main protective eect was the reduction o mortality


11/68

and hospital admissions due to pneumonia (presumed to be bacterial). P. jiroveci was not

demonstrated as a common causative organism in these older children (only 1 o 119

nasopharyngeal aspirates positive or P. jiroveci). O note, malaria is less common in Lusakathan in other countries in the region, and the ecacy o co-trimoxazole prophylaxis against

malaria could not be determined in this trial. However, another study showed that co-

trimoxazole reduced malaria in HIV-uninected children in Mali (13).

. Co-trimoxazole prophylaxis among adolescents and adults

Randomized clinical trials, studies using historical controls and observational cohort

studies have demonstrated the eectiveness o co-trimoxazole prophylaxis in reducing

mortality and morbidity across varying levels o background resistance to co-trimoxazole

and prevalence o malaria.

Consistent evidence rom all studies that include CD4 cell count supports the eectiveness

o co-trimoxazole prophylaxis among people with CD4 counts




An observational study conducted in Uganda (19) assessed the impact o daily co-

trimoxazole prophylaxis on rates o malaria, diarrhoea, hospital admission and death. In

this study, 509 individuals living with HIV-1 and 1522 HIV-negative household memberswere enrolled and ollowed up with weekly home visits. Ater ve months, participants living

with HIV were oered co-trimoxazole prophylaxis and ollowed or a urther 1.5 years.

Mortality declined 45% rom all causes and morbidity rom malaria and diarrhoeal diseases

declined ater co-trimoxazole prophylaxis was provided to those living with HIV. This study

also demonstrated the benet o co-trimoxazole prophylaxis among untreated amily

members uninected with HIV. Mortality and the incidence o diarrhoea and malaria among

HIV-uninected children o adults treated with co-trimoxazole were lower than in the children

o untreated adults living with HIV (20). A second study rom Uganda, with a similar study

design, also demonstrated a reduction in mortality and malaria (12).

. Co-trimoxazole prophylaxis in pregnant women

In a study o the prevention o mother-to-child transmission in Zambia (21), birth outcomes

rom 1075 pregnant women living with HIV were analysed beore and ater co-trimoxazole

was introduced as the standard o care or pregnant women in Zambia. There were

signicant improvements in bir th outcomes, with reductions in chorioamnionitis, prematurity

and neonatal mortality ollowing the introduction o routine co-trimoxazole prophylaxis or

women living with HIV who had CD4 cell counts


13/6811

prophylaxis (10 children). No episodes o PCP were reported during a median ollow-up

time o 4.1 years (range 0.37.7) with no prophylaxis. There are no data rom resource-

limited settings on the saety o stopping co-trimoxazole prophylaxis among children.

.. Stopping among adults and adolescents

Randomized clinical trials conducted in well-resourced countries have demonstrated that

co-trimoxazole prophylaxis used or PCP prophylaxis may be saely stopped ollowing

immune recovery in response to antiretroviral therapy (24,25). In resource-limited settings,

data are more limited, particularly in the absence o CD4 count monitoring, and there are

no randomized trials. Some experts suggest the use o similar CD4 cell count criteria or

stopping co-trimoxazole prophylaxis as those used in well-resourced countries.

In a small study rom India (26), co-trimoxazole prophylaxis was stopped when the CD4 count

was >200 cells per mm3, and no participant developed PCP or toxoplasmosis. Similar results

were reported rom a study in Thailand (27) in which 179 people who had never received

antiretroviral therapy commenced antiretroviral therapy with non-nucleoside reverse transcriptase

inhibitors were ollowed or 216 weeks. The median time to achieve a CD4 count >200 cells per

mm3 or participants with a baseline CD4 count o >100 cells per mm 3 was 24 weeks. For those

with a baseline CD4 count 200 cells per

mm3

was 96 weeks. There were no cases o PCP among 169 participants who stopped co-trimoxazole during the 216 weeks o ollow-up rom study entry (10 participants did not reach

the CD4 cell target o 200 cells per mm3). These studies also reported that some participants

with low baseline CD4 counts might never achieve a CD4 cell count >200 cells per mm3.

Data on stopping co-trimoxazole prophylaxis among people receiving antiretroviral therapy in

the absence o CD4 count monitoring are not available. Inormation rom studies o people

receiving antiretroviral therapy and their CD4 cell count response during ollow-up may

infuence recommendations on i and when co-trimoxazole prophylaxis should be stopped

based on the duration o antiretroviral therapy in the absence o CD4 count monitoring. TheDevelopment o Antiretroviral Therapy in Arica (DART) study in Uganda examined the CD4

response ollowing commencement o antiretroviral therapy. The median time to achieve a

CD4 count >200 cells per mm3 was 24 weeks among those who commenced antiretroviral

therapy with CD4 counts greater than 100 cells per mm3. Among those with baseline CD4

counts below 50 cells per mm3, the median time to CD4 increase to >200 cells per mm 3 was

72 weeks. These data are comparable those in the study in Thailand.

The lack o data rom randomized clinical trials on stopping co-trimoxazole in the absence

o CD4 count monitoring, the limited number o participants in observational studies andthe absence o a control group in these studies caution against this approach until such

data are available.




. Bacterial resistance to co-trimoxazole

Co-trimoxazole has antimicrobial activity against a wide range o pathogens includingPneumococcus spp., non-typhoidal Salmonella, Isospora, Cyclospora, Nocardia, Plasmodium

alciparum, Toxoplasma gondii and PCP.

Co-trimoxazole has been used widely as treatment or common inections in many resource-

limited settings and, as a result, co-trimoxazole resistance among these pathogens has

increased in these settings. Resistance o non-typhoidal Salmonella and Pneumococcus

isolates to co-trimoxazole has been reported to be 44% and 52% respectively in Uganda

(19) and approximately 80% and 90% respectively in Malawi (28).

The ecacy o co-trimoxazole prophylaxis has not been aected by the background

prevalence o co-trimoxazole resistance and appears to be similar in geographical areas in

which background prevalence o co-trimoxazole resistance is high (South Arica, Uganda

and Zambia) and low (Cte dIvoire).

The impact o co-trimoxazole use in the evolution o drug resistance is uncertain. There is

concern that implementing wide and prolonged use o co-trimoxazole prophylaxis could be

associated with the development o drug resistance in common pathogens, such as

increased penicillin-resistant Pneumococcus (29). Data rom Uganda (20) ound no

signicant changes in the bacterial resistance patterns o stool pathogens isolated rom theamily members o individuals on co-trimoxazole prophylaxis over a two-year period.

However, one study rom Malawi (30) showed a signicant increase in resistance o

pharyngeal and aecal isolates rom those receiving co-trimoxazole prophylaxis.

. Cross-resistance o co-trimoxazole with suladoxine/pyrimethamine

Co-trimoxazole has been shown to be 99.5% eective in preventing malaria versus 95%

eectiveness with suladoxine/pyrimethamine, and both have about 80% therapeutic ecacy

or the treatment o malaria (13). Cross-resistance between co-trimoxazole and suladoxine/pyrimethamine is a potential concern when co-trimoxazole prophylaxis is used in areas where

suladoxine/pyrimethamine is the rst-line agent or treating malaria. Analysis o malaria

parasites rom children in Mali who had received at least one month o co-trimoxazole

prophylaxis detected no resistance-conerring mutations. Similarly, the study in Uganda (20)

ound no signicant dierence between either the proportion o malarial episodes with

resistant organisms or the incidence o suladoxine/pyrimethamineresistant malaria beore

and ater co-trimoxazole prophylaxis was introduced. There is no evidence to date on the

ecacy o suladoxine/pyrimethamine in treating breakthrough episodes o malaria among

people taking co-trimoxazole prophylaxis. As co-trimoxazole is 99.5% eective in preventing

malaria, adherence to co-trimoxazole should be assessed i breakthrough episodes occur

and the need or adherence should be reinorced.


15/681

.1 Initiation o primary co-trimoxazole prophylaxis in inants and children

.1.1 Children among whom co-trimoxazole prophylaxis is contraindicated

Children with a history o severe adverse reaction (grade 4 reactions, see Table 7) to co-

trimoxazole or other sula drugs and children with glucose-6-phosphate dehydrogenase

deciency should not be prescribed co-trimoxazole prophylaxis. In resource-limited

settings, routine testing or glucose-6-phosphate dehydrogenase deciency is not

recommended. Dapsone 2 mg/kg once daily, i available, is an alternative. Some children

cannot tolerate either co-trimoxazole or dapsone. No alternative recommendation can be

made in resource-limited settings or children who cannot tolerate either.

.1. HIV-exposed inants and children

In resource-limited settings, co-trimoxazole prophylaxis is recommended or all HIV-

exposed inants starting at 46 weeks o age (or at rst encounter with the health care

system) and continued until HIV inection can be excluded. Co-trimoxazole is also

recommended or HIV-exposed breasteeding children o any age, and co-trimoxazole

prophylaxis should be continued until HIV inection can be excluded by HIV antibody testing

(beyond 18 months o age) or virological testing (beore 18 months o age) at least six

weeks ater complete cessation o breasteeding [A-III]. Programme eorts should ocus

on co-trimoxazole prophylaxis in the rst six months o lie, when the risk o PCP isgreatest.

.1. Inants and children documented to be living with HIV

All children younger than one year o age documented to be living with HIV should receive

co-trimoxazole prophylaxis regardless o symptoms or CD4 percentage [A-II]. Ater one

year o age, initiation o co-trimoxazole prophylaxis is recommended or symptomatic

children (WHO clinical stages 2, 3 or 4 or HIV disease) or children with CD4




Table . Initiation o co-trimoxazole prophylaxis in inants and children

SITUATION

HIV-EXPOSED

INFANTSAND CHILDRENa

INFANTS AND CHILDRENCONFIRMEDbTO BE LIVING WITH HIV

5 YEARS

Co-trimoxazole

prophylaxis is universally

indicated, starting at

our to six weeks aterbirth and maintained

until cessation o risk

o HIV transmission

and exclusion o HIV

inection [A-III]

Co-trimoxazole

prophylaxis

is indicated

regardless oCD4 percentage

or clinical status

[A-II]c

WHO clinical

stages 2, 3 and

4 regardless o

CD4 percentageOR

Any WHO stage

and CD4 25% should remain on co-trimoxazole

prophylaxis until they reach ve years o age [A-IV].


17/681

. Doses o co-trimoxazole in inants and children

Table . Co-trimoxazole ormulations and dosage or inantsand children living with HIV or exposed to HIV

RECOMMENDED

DAILY DOSAGEa

SUSPENSION

(5 ML OF

SYRUP

200 MG/

40 MG)

CHILD

TABLET

(100 MG/

20 MG)

SINGLE-

STRENGTH

ADULT

TABLET

(400 MG/

80 MG)

DOUBLE-

STRENGTH

ADULT

TABLET

(800 MG/

160 MG)

14 years800 mg

sulamethoxazole/160 mg trimethoprim

Two tablets One tablet

Frequency once a day

a Some countries may use weight bands to determine dosing. Age and the corresponding weight bands (based

on the children with HIV antibiotic prophylaxis trial (CHAP trial (7)) are:

AGES WEIGHT

30 kg

b Splitting tablets into quarters is not considered best practice. This should be done only i syrup is not available.

c Children o these ages (6 months14 years) may swallow crushed tablets.




. Secondary co-trimoxazole prophylaxis in inants and children

Children with a history o treated PCP should be administered secondary co-trimoxazoleprophylaxis with the same regimen recommended or primary prophylaxis (16)[A-III].

. Discontinuation o primary co-trimoxazole prophylaxis

in inants and children

..1 HIV-exposed inants and children confrmed to be HIV uninected

Co-trimoxazole prophylaxis can be discontinued when HIV inection has been denitely

excluded by a conrmed negative HIV virological test six weeks ater complete cessation o

breasteeding in an inant 18 months o age and six weeks ater complete cessation o breasteeding [A-I].

.. Children living with HIV in the context o antiretroviral therapyrelated

immune recovery

Given that children living with HIV have a high risk o bacterial inections, the general

recommendation is that, among children conrmed to be living with HIV in resource-limited

settings, co-trimoxazole should be continued irrespective o immune recovery in response

to antiretroviral therapy [A-IV].

Data suggest that the risk o developing PCP ater immune restoration in response to

antiretroviral therapy is suciently low to withdraw co-trimoxazole i it was initiated primarily

or PCP prophylaxis (23). Children older than ve years who are stable on antiretroviral

therapy, with good adherence, secure access to antiretroviral therapy and with CD4 and

clinical evidence o immune recovery can be reassessed and consideration can be given

to discontinuing co-trimoxazole prophylaxis in accordance with the recommendations or

adults and adolescents [C-IV]. I children have been prescribed dapsone prophylaxis, the

same discontinuation recommendations apply.

Co-trimoxazole prophylaxis (or dapsone i the child cannot tolerate co-trimoxazole) should

be recommenced i the CD4 percentage alls below the age-related initiation threshold or i

new or recurrent WHO clinical stage 2, 3 or 4 conditions occur [A-IV].


19/681

Table . Summary o recommendations or discontinuing primary co-trimoxazole

among inants and children

TARGET POPULATION RECOMMENDATIONS

HIV-exposed childrenDiscontinue co-trimoxazole prophylaxis ater HIV inection

is excluded [A-I]

Inants and children

living with HIV

Maintain on co-trimoxazole prophylaxis until age ve years

irrespective o clinical and immune response [A-IV]

Children older than ve years can be reassessed and

consideration can be given to discontinuing co-trimoxazole

prophylaxis in accordance with the recommendations or

adults and adolescents [C-IV]

Severe adverse reactions to co-trimoxazole in children are uncommon, In the

CHAP study (7), 534 children were randomized to co-trimoxazole or placebo. No

child on co-trimoxazole developed rash.

.. Discontinuation or co-trimoxazole adverse reactions

Co-trimoxazole prophylaxis may need to be discontinued in the event o an adverse drug

reaction. Although severe reactions to co-trimoxazole are uncommon, these may include

extensive exoliative rash, Stevens-Johnson syndrome or severe anaemia or

pancytopaenia.

There are insucient data on co-trimoxazole desensitization (rechallenge ollowing an

adverse reaction to co-trimoxazole commencing with low doses o co-trimoxazole andgradual dose escalation) among children to make any recommendations on its use in

resource-limited settings.

Everyone starting co-trimoxazole and their guardians and caregivers should be provided

with verbal or writ ten inormation on potential adverse eects and advised to stop the drug

and report to their nearest health acility i co-trimoxazole-related adverse events are

suspected (Table 7).




. Discontinuation o secondary co-trimoxazole prophylaxis

The saety o discontinuing secondary co-trimoxazole prophylaxis among children livingwith HIV has had limited assessment and has been studied only in high income countries

(23). The general recommendation is that secondary co-trimoxazole prophylaxis should not

be discontinued, irrespective o clinical and immune response to antiretroviral therapy (15)

[B-III].

Based on evidence that secondary co-trimoxazole prophylaxis can be saely stopped

among adults and adolescents guided by immune recovery in response to antiretroviral

therapy assessed using CD4 cell count (3337), discontinuation o secondary co-

trimoxazole prophylaxis may be considered among children older than ve years with

evidence o immune recovery in response to antiretroviral therapy in accordance with the

recommendation or discontinuation o primary prophylaxis [C-IV].


21/681

7. RECOMMENDATIONS ON THE USE OF PRIMARY CO-TRIMOXAZOLE

PROPHYLAXIS AMONG ADULTS AND ADOLESCENTS

.1 Adults and adolescents among whom co-trimoxazole prophylaxis

is contraindicated

Adults and adolescents with a history o severe adverse reaction (grade 4; see Table 7) to

co-trimoxazole or other sula drugs should not be prescribed co-trimoxazole prophylaxis.

In situations in which co-trimoxazole cannot be continued or should not be initiated,

dapsone 100 mg per day, i available, can be used as an alternative. Dapsone is less

eective than co-trimoxazole in preventing PCP and also lacks the broad antimicrobial

activity o co-trimoxazole. It is thereore desirable to attempt desensitization (section 7.4.3)

to co-trimoxazole, i easible in the clinical setting, among individuals with a previous non-

severe reaction, beore substituting dapsone [A-IV]. However, co-trimoxazole desensitization

should not be attempted among individuals with a previous severe (grade 4) reaction to

co-trimoxazole or other sula-containing drugs.

. Initiation o primary co-trimoxazole prophylaxis among adults

and adolescents

These recommendations include a degree o fexibility to enable decisions on the most

appropriate threshold o CD4 count or clinical disease stage or initiation o co-trimoxazole

prophylaxis to be made at the country level or even the local level, taking into account

variation in the burden o HIV, disease spectrum and the capacity and inrastructure o

health systems.

In settings in which co-trimoxazole prophylaxis is initiated based on WHO clinical staging

criteria only, co-trimoxazole prophylaxis is recommended or all symptomatic people with

mild, advanced or severe HIV disease (WHO clinical stages 2, 3 or 4) [A-I]. Where CD4 cell

testing is available, co-trimoxazole prophylaxis is recommended or everyone with a CD4

cell count




Some countries may also opt to treat everyone living with HIV (universal option), because

o operational simplicity and data suggesting a reduction o severe events irrespective o

CD4 count or clinical stage [C-III]. This strategy may be considered in settings with highprevalence o HIV and limited health inrastructure. However, lielong use o co-trimoxazole

prophylaxis or all people living with HIV needs to be weighed against the challenges o

maintaining long-term adherence and the potential or emergence o drug-resistant

pathogens.

Table . Initiation o co-trimoxazole prophylaxis among adults and adolescents

living with HIV

BASED ON WHO CLINICALSTAGING CRITERIA ALONE (WHEN

CD4 COUNT IS NOT AVAILABLE)

BASED ON WHO CLINICALSTAGING AND CD4 CELL COUNT

CRITERIAa

WHO clinical stage 2, 3 or 4 [A-I]

Any WHO clinical stage

and CD4< 350 cells per mm3 b[A-III]

OR

WHO clinical stage 3 or 4 irrespective o

CD4 level [A-I]

Universal option:Countries may choose to adopt universal co-trimoxazole or everyone

living with HIV and any CD4 count or clinical stage. This strategy may be considered in

settings with high prevalence o HIV and limited health inrastructure [C-III].

a Expanded access to CD4 testing is encouraged to guide the initiation o antiretroviral therapy and to monitor the

progress o antiretroviral therapy.

b Countries may choose to adopt a CD4 threshold o


23/681

woman requires co-trimoxazole prophylaxis during pregnancy, it should be started

regardless o the stage o pregnancy [A-III]. I a woman living with HIV is receiving co-

trimoxazole prophylaxis and resides in a malarial zone, it is not necessary or her to haveadditional suladoxine/pyrimethaminebased intermittent presumptive therapy or malaria

[B-IV]. Breasteeding women should continue to receive co-trimoxazole prophylaxis.

. Doses o co-trimoxazole among adults and adolescents

The dose o co-trimoxazole among adults and adolescents living with HIV is one double-

strength tablet or two single-strength tablets once daily: the total daily dose is 960 mg (800

mg sulamethoxazole + 160 mg trimethoprim) [A-I].2

. Secondary co-trimoxazole prophylaxis among adults and adolescents

Adults and adolescents with a history o treated PCP should be administered secondary

co-trimoxazole prophylaxis with the same regimen recommended or primary prophylaxis

(10). [A-III].

. Discontinuing co-trimoxazole prophylaxis among adults and adolescents

The discontinuation o co-trimoxazole prophylaxis among individuals living with HIV may beconsidered in the context o drug toxicity and immune recovery in response to antiretroviral

therapy. Discontinuation should be based on clinical judgement, including both clinical and

laboratory parameters.

..1 Discontinuation based on antiretroviral therapyrelated immune recovery

Studies in well-resourced settings have demonstrated the saety o discontinuing co-

trimoxazole as prophylaxis against PCP and toxoplasmosis among people with immune

recovery (CD4 >200 cells per mm3) in response to antiretroviral therapy. Emerging data in

resource-limited settings have demonstrated similar ndings (24,25). However, no

randomized clinical trials have assessed the saety and timing o the discontinuation o co-

trimoxazole prophylaxis ollowing immune recovery in response to antiretroviral therapy in

resource-limited settings.

The general recommendation is to continue co-trimoxazole prophylaxis among adults living

with HIV indenitely [A-IV].

Some countries may consider adopting a CD4 countguided discontinuation o co-

trimoxazole as prophylaxis against PCP and toxoplasmosis among people with immune

recovery and CD4 >200 cells per mm3 in response to antiretroviral therapy or at least six

months [B-I].

There is an option to give one single-strength tablets (80 mg per dose or 00 mg sulamethoxazole + 80 mg

trimethoprim) taken twice daily, as this may assist in preparing individuals or initiating the twice-daily antiret-

roviral therapy regimens that are commonly available in resource-limited set tings.


24/68


25/68

Table . Summary o recommendations or discontinuing primary co-trimoxazole

among adults and adolescents

TARGETPOPULATION

RECOMMENDATIONS

Adults and

adolescents

living with HIV

CD4 testing

not available

(clinical

assessmentonly)

Do not discontinue co-trimoxazole prophylaxis,

particularly in settings where bacterial inections

and malaria are common HIV-related events [A-IV]

Consider discontinuing co-trimoxazole

prophylaxis among people with evidence o

good clinical response to antiretroviral therapy(absence o clinical symptoms ater at least one

year o therapy), good adherence and secure

access to antiretroviral therapy [C-IV]

CD4 testingavailable

(clinical and

immunological

assessment)

In countries where co-trimoxazole prophylaxis

is recommended only or preventing PCP and

toxoplasmosis, it can be discontinued among

those with evidence o immune recovery in

response to antiretroviral therapy (CD4 >200cells per mm3ater at least six months o

antiretroviral therapy) [B-I]

In countries with a high incidence o bacterial

inections and malaria, discontinue co-trimoxazole

prophylaxis among people with evidence o

immune recovery related to antiretroviral therapy

(CD4 >350 cells per mm3 ater at least six months

o antiretroviral therapy) [C-IV]

.. Discontinuation based on co-trimoxazole adverse events

Severe adverse reactions to co-trimoxazole are uncommon. I non-severe adverse events

occur, every eort should be made to continue prophylaxis with co-trimoxazole because o

its superior ecacy in preventing PCP and bacterial inections compared with dapsone

among adults (3941). It also protects against toxoplasmosis, malaria and some enteric

pathogens. Except in cases o severe adverse reaction, co-trimoxazole should be

temporarily interrupted or two weeks and then desensitization should be attempted, i

indicated and easible. I using dapsone is necessary, the dose or adults and adolescentsis 100 mg per day. Some people cannot tolerate either co-trimoxazole or dapsone. No

alternative recommendation can be made in resource-limited settings.




For people in settings with limited laboratory capacity, the potential side eects associated

with co-trimoxazole prophylaxis (skin rash, bone marrow toxicity and hepatotoxicity) can be

monitored clinically [B-IV].

Everyone starting co-trimoxazole should be provided with verbal or written inormation on

potential adverse eects and advised to stop the drug and report to their nearest clinic i

co-trimoxazole-related adverse events are suspected.

Table . Co-trimoxazole toxicity grading scale or adults and adolescents

TOXICITY CLINICAL DESCRIPTION RECOMMENDATION

GRADE 1 Erythema

Continue co-trimoxazole

prophylaxis with careul and

repeated observation and ollow-

up. Provide symptomatic

treatment, such as

antihistamines, i available

GRADE Diuse maculopapular rash,

dry desquamation

Continue co-trimoxazole

prophylaxis with careul and

repeated observation and ollow-

up. Provide symptomatic

treatment, such as

antihistamines, i available

GRADE Vesiculation, mucosal ulceration

Co-trimoxazole should be

discontinued until the adverse

eect has completely resolved

(usually two weeks), and then

reintroduction or desensitizationcan be considered

GRADE

Exoliative dermatitis, Stevens-

Johnson syndrome or erythema

multiorme, moist desquamation

Co-trimoxazole should be

permanently discontinued

.. Co-trimoxazole desensitization

Given the importance o co-trimoxazole and the lack o an equally eective and widely

available alternative, desensitization is an important component o managing adults and

adolescents with HIV inection. It can be attempted two weeks ater a non-severe (grade 3 or

less) co-trimoxazole reaction that has resulted in a temporary interruption o co-trimoxazole.


27/68

Co-trimoxazole desensitization has been shown be successul in most individuals with

previous hypersensitivity and rarely causes serious reactions (4244). Desensitization should

not be attempted in individuals with a history o grade 4 reaction to previous co-trimoxazoleor other sula drugs [B-IV]. It is recommended to commence an antihistamine regimen o

choice one day prior to starting the regimen and to continue daily until completing the dose

escalation. On the rst day o the regimen, the step 1 dose o co-trimoxazole is given and

subsequently increased one step each day. I a severe reaction occurs, the desensitization

regimen is terminated. I a minor reaction occurs, repeat the same step or an additional day.

I the reaction subsides, advance to the next step; i the reaction worsens, the desensitization

regimen is terminated.

Table 8. Protocol or co-trimoxazole desensitization among adults and adolescents

STEP DOSE

DAY 1 80 mg sulamethoxazole + 16 mg trimethoprim (2 ml o oral suspensiona)

DAY 160 mg sulamethoxazole + 32 mg trimethoprim (4 ml o oral suspensiona)

DAY 240 mg sulamethoxazole + 48 mg trimethoprim (6 ml o oral suspensiona)

DAY 320 mg sulamethoxazole + 64 mg trimethoprim (8 m o oral suspensiona)

DAY One single-strength sulamethoxazole-trimethoprim tablet

(400 mg sulamethoxazole + 80 mg trimethoprim)

DAY

ONWARDS

Two single-strength sulamethoxazole-trimethoprim tablets or one double

strength tablet (800 mg sulamethoxazole + 160 mg trimethoprim)

a Co-trimoxazole oral suspension is 40 mg trimethoprim + 200 mg sulamethoxazole per 5 ml.

.. Discontinuing secondary co-trimoxazole prophylaxis

among adults and adolescentsRecommendations or discontinuing and restarting secondary prophylaxis among adults

and adolescents are the same as or the recommendations or primary prophylaxis. These

recommendations are supported by observational studies (3335) and rom a randomized

trial in a well-resourced setting (36) as well as a combined analysis o eight European

prospective cohorts (37)[C-I].




8.1 Timing the initiation o co-trimoxazole in relation to initiating

antiretroviral therapy

Since the most common initial side eect o co-trimoxazole and antiretroviral therapy

(especially nevirapine and eavirenz) is rash, it is recommended to start co-trimoxazole

prophylaxis rst and to initiate antiretroviral therapy two weeks later i the individual is stable

on co-trimoxazole and has no rash [A-IV].

8. Clinical and laboratory monitoring o co-trimoxazole prophylaxis

The saety o co-trimoxazole in long-term use has been established. Drug-related adverse events

are uncommon and typically occur within the rst ew weeks o starting prophylaxis. Clinicalmonitoring should be carried out regularly, ideally at a minimum o three monthly intervals, with

individuals encouraged to report adverse symptoms as soon as they are noted [A-III].

No specifc laboratory monitoring is required among children, adolescents and

adults receiving co-trimoxazole prophylaxis [A-III].

Particular interest should be paid to skin reactions and symptoms such as nausea, vomiting

or jaundice. Skin reaction is the most common co-trimoxazole-related adverse event and is

diagnosed clinically. Attention should be paid to other medications the person is receiving

with possible overlapping toxicity (such as eavirenz, nevirapine and isoniazid).

Co-trimoxazole and dapsone can induce haemolytic anaemia among people with glucose-

6-phosphate dehydrogenase deciency. These drugs should not be prescribed to individuals,

particularly children, with known or suspected glucose-6-phosphate dehydrogenase

deciency. Routine testing or glucose-6-phosphate dehydrogenase deciency in resource-

limited settings is not recommended.

No specic laboratory monitoring is required in individuals receiving co-trimoxazole

prophylaxis. I available, laboratory monitoring should be based on symptoms and signs

(such as ull blood counts i anaemia is suspected and liver unction tests i hepatic

dysunction is suspected) [A-III].

Six-monthly CD4 count monitoring is recommended, i available, to guide when to initiate

antiretroviral therapy. Once antiretroviral therapy is initiated, monitoring should continue

according to the standard o care or antiretroviral therapy management or the setting

involved [A-III].

8 RECOMMENDATIONS COMMON TO INFANTS, CHILDREN,

ADULTS AND ADOLESCENTS


29/68

In general, the impact o co-trimoxazole prophylaxis on antiretroviral therapy toxicity is

minimal. Among people on zidovudine-containing antiretroviral therapy regimens, the

impact o overlapping blood toxicity with co-trimoxazole prophylaxis is not signicant(except or people with advanced HIV disease), and no additional laboratory monitoring is

needed [B-III].

8. Treatment o bacterial and opportunistic inections

among people taking co-trimoxazole prophylaxis

Despite the lack o data, it is recommended to use an alternative antibiotic (where available)

or treating breakthrough bacterial inections among individuals living with HIV receiving

co-trimoxazole prophylaxis, while continuing co-trimoxazole [A-IV]. For toxoplasmosis and

PCP inections, prophylaxis should be suspended and ull active treatment initiated

according to national guidelines. Co-trimoxazole prophylaxis should be recommenced

ater the treatment course [A-III].

8. Preventing and treating malaria

among people taking co-trimoxazole prophylaxis

Among children, adults and adolescents receiving co-trimoxazole prophylaxis, breakthrough

episodes o malaria should be treated, i possible, with antimalarial therapy that does not

include suladoxine/pyrimethamine [A-III]. There is no evidence to date on the ecacy o

suladoxine/pyrimethamine in treating episodes o malaria among people taking co-

trimoxazole prophylaxis.

In malaria-endemic areas, intermittent presumptive therapy or malaria is recommended or

pregnant women. Given the benets o co-trimoxazole in preventing and treating malaria,

intermittent presumptive therapy is not recommended or pregnant women receiving co-

trimoxazole prophylaxis [A-III]. Similarly, suladoxine/pyrimethaminebased intermittent

presumptive therapy or malaria is not necessary or inants or children on co-trimoxazole

prophylaxis [A-III].




9 OPERATIONAL CONSIDERATIONS

The ollowing are considered key to the successul scaling up o co-trimoxazole prophylaxis

in resource-limited settings:

integrating the recommendation or co-trimoxazole prophylaxis into existing HIV-related

treatment guidelines;

implementing co-trimoxazole prophylaxis as an integral part o the chronic care package

or all individuals living with HIV and as a key element o preantiretroviral therapy care

and being part o the monitoring and evaluation process in preparation or initiating

antiretroviral therapy;

developing and implementing explicit policies in countries on the use o co-trimoxazole

prophylaxis or children, adolescents and adults;

giving priority to guidelines or co-trimoxazole prophylaxis or all HIV-exposed inants

and people with TB who are living with HIV;

assessing legal and policy options to secure co-trimoxazole or prophylaxis at reduced

cost or ree o charge;

ensuring the availability o appropriate and aordable doses and ormulations or

children;

ensuring eective and integrated management o procurement and supplies at all levels(national, district, community and household);

ensuring that programmes to scale up co-trimoxazole prophylaxis are decentralized,

available at the community level and are used to improve the quality o HIV chronic care

and are linked to preparedness or and initiation o antiretroviral therapy; and

establishing surveillance systems to monitor the ecacy o co-trimoxazole prophylaxis,

bacterial resistance to co-trimoxazole and malaria resistance to suladoxine/

pyrimethamine.


31/68

CLINICAL STAGE 1

AsymptomaticPersistent generalized lymphadenopathy

CLINICAL STAGE 2

Unexplaineda persistent hepatosplenomegaly

Papular pruritic eruptions

Extensive wart virus inection

Extensive molluscum contagiosum

Fungal nail inections

Recurrent oral ulcerations

Unexplaineda persistent parotid enlargement

Lineal gingival erythema

Herpes zoster

Recurrent or chronic upper respiratory tract inections (otitis media, otorrhoea, sinusitis

or tonsillitis)

CLINICAL STAGE 3

Unexplaineda moderate malnutrition not adequately responding to standard therapy

Unexplaineda persistent diarrhoea (14 days or more)

Unexplaineda persistent ever

(above 37.5C intermittent or constant, or longer than one month)

Persistent oral candidiasis (ater rst 68 weeks o lie)

Oral hairy leukoplakia

Acute necrotizing ulcerative gingivitis or periodontitis

Lymph node TB

Pulmonary TB

Severe recurrent bacterial pneumoniaSymptomatic lymphoid interstitial pneumonitis

Chronic HIV-associated lung disease including brochiectasis

Unexplaineda anaemia (




CLINICAL STAGE 4b

Unexplaineda severe wasting, stunting or severe malnutrition not responding tostandard therapy

Pneumocystis pneumonia

Recurrent severe bacterial inections (such as empyema, pyomyositis, bone or joint

inection, meningitis, but excluding pneumonia)

Chronic herpes simplex inection (orolabial or cutaneous o more than one months

duration or visceral at any site)

Extrapulmonary TB

Kaposis sarcoma

Oesophageal candidiasis (or candidiasis o trachea, bronchi or lungs)

Central nervous system toxoplasmosis (ater one month o lie)

HIV encephalopathy

Cytomegalovirus inection (retinitis or cytomegalovirus inection aecting another

organ, with onset at age older than one month)

Extrapulmonary cryptococcosis (including meningitis)

Disseminated endemic mycosis (extrapulmonary histoplasmosis or coccidiomycosis)

Chronic cryptosporidiosis

Chronic isosporiasisDisseminated non-tuberculous mycobacterial inection

HIV-associated tumours, including cerebral or B-cell non-Hodgkin lymphoma

Progressive multiocal leukoencephalopathy

Symptomatic HIV-associated nephropathy or symptomatic HIV-associated

cardiomyopathy

a Unexplained reers to where the condition is not explained by other conditions.

b Some additional specic conditions can also be included in regional classications, such as the reactivation

o American trypanosomiasis (meningoencephalitis and/or myocarditis) in the WHO Region o the Americas,

penicilliosis in Asia and HIV-associated rectovaginal stula in Arica.

Source: World Health Organization (45).


33/681

CLINICAL STAGE 1

AsymptomaticPersistent generalized lymphadenopathy

CLINICAL STAGE 2

Unexplaineda moderate weight loss (10% o presumed or measured body weight) b

Unexplaineda chronic diarrhoea or longer than one month

Unexplaineda persistent ever (above 37.5C intermittent or constant or longer

than one month)

Persistent oral candidiasis

Oral hairy leukoplakia

Pulmonary TB

Severe bacterial inections (such as pneumonia, empyema, pyomyositis,

bone or joint inection, meningitis or bacteraemia)

Acute necrotizing ulcerative stomatitis, gingivitis or periodontitis

Unexplaineda anaemia (




CLINICAL STAGE 4c

HIV wasting syndromePneumocystis pneumonia

Recurrent severe bacterial pneumonia

Chronic herpes simplex inection (orolabial, genital or anorectal o more than

one months duration or visceral at any site)

Oesophageal candidiasis (or candidiasis o trachea, bronchi or lungs)

Extrapulmonary TB

Kaposis sarcoma

Cytomegalovirus inection (retinitis or inection o other organs)

Central nervous system toxoplasmosis

HIV encephalopathy

Extrapulmonary cryptococcosis including meningitis

Disseminated non-tuberculous mycobacterial inection

Progressive multiocal leukoencephalopathy

Chronic cryptosporidiosis

Chronic isosporiasis

Disseminated mycosis (extrapulmonary histoplasmosis or coccidiomycosis)

Recurrent septicaemia (including non-typhoidal Salmonella)Lymphoma (cerebral or B-cell non-Hodgkin)

Invasive cervical carcinoma

Atypical disseminated leishmaniasis

Symptomatic HIV-associated nephropathy or symptomatic HIV-associated

cardiomyopathy

a Unexplained reers to where the condition is not explained by other conditions.

b Assessment o body weight among pregnant woman needs to consider the expected weight gain o

pregnancy.

c Some additional specic conditions can also be included in regional classications, such as the reactivation

o American trypanosomiasis (meningoencephalitis and/or myocarditis) in the WHO Region o the Americas

and penicilliosis in Asia.



35/68

ANNEX 3. CRITERIA FOR RECOGNIZING HIV-RELATED CLINICAL

EVENTS AMONG ADULTS AND ADOLESCENTS

CLINICAL EVENT CLINICAL DIAGNOSIS DEFINITIVE DIAGNOSIS

CLINICAL STAGE 1Asymptomatic No HIV-related symptoms

reported and no signs on

examination

Not applicable

Persistent generalized

lymphadenopathy

Painless enlarged lymph

nodes >1 cm in two or

more non-contiguous sites

(excluding inguinal) in the

absence o known causeand persisting or >3

months

Histology

CLINICAL STAGE 2

Moderate unexplained

weight loss (





Recurrent oralulcerations (two or more

episodes in last six

months)

Aphthous ulceration,typically painul with a halo

o infammation and a yellow-

grey pseudomembrane

Clinical diagnosis

Papular pruritic eruption Papular pruritic lesions,

oten with marked post-

infammatory pigmentation

Clinical diagnosis

Seborrhoeic dermatitis Itchy scaly skin condition,

particularly aecting hairyareas (scalp, axillae, upper

trunk and groin)

Clinical diagnosis

Fungal nail inections Paronychia (painul red

and swollen nail bed) or

onycholysis (separation o

the nail rom the nail bed)

o the ngernails (white

discoloration especially

involving the proximal part

o nail plate with thickening

and separation o the nail

rom the nail bed)

Fungal culture o the nail or

nail plate material

CLINICAL STAGE 3

Severe unexplained

weight loss (more than

10% o body weight)

Reported unexplained

weight loss (>10% o body

weight) and visible thinningo ace, waist and extremities

with obvious wasting or body

mass index


37/68


Unexplained persistentever (intermittent or

constant and lasting or

longer than one month)

Fever or night sweats ormore than one month, either

intermittent or constant with

reported lack o response

to antibiotics or antimalarial

agents, without other

obvious oci o disease

reported or ound on

examination. Malaria must

be excluded in malariousareas.

Documented temperature>37.5C with negative

blood culture, negative

Ziehl-Nielsen stain,

negative malaria slide,

normal or unchanged chest

X-ray and no other obvious

ocus o inection

Oral candidiasis Persistent or recurring

creamy white curd-like

plaques that can be scraped

o (pseudomembranous) or

red patches on the tongue,

palate or lining o mouth,

usually painul or tender(erythematous orm)

Clinical diagnosis

Oral hairy leukoplakia Fine white small linear or

corrugated lesions on lateral

borders o the tongue, which

do not scrape o

Clinical diagnosis





Pulmonary TB(current)

Chronic symptoms: (lastingless than 23 weeks) cough,

haemoptysis, shortness o

breath, chest pain, weight

loss, ever, night sweats

and no clinical evidence o

extrapulmonary disease

Discrete peripheral lymph

node Mycobacteriumtuberculosis inection

(especially cervical) is

considered a less severe

orm o extrapulmonary

tuberculosis

One or more sputumsmear positive or

acid-ast bacilli and/or

radiographic abnormalities

consistent with active TB

and/or culture positive

or Mycobacterium

tuberculosis

Severe bacterial

inection (such as

pneumonia, meningitis,empyema, pyomyositis,

bone or joint inection,

bacteraemia or severe

pelvic infammatory

disease)

Fever accompanied by

specic symptoms or signs

that localize inection, andresponse to appropriate

antibiotic

Isolation o bacteria

rom appropriate clinical

specimens (usually sterilesites)

Acute necrotizing

ulcerative gingivitis or

necrotizing ulcerative

periodontitis

Severe pain, ulcerated

gingival papillae, loosening

o teeth, spontaneous

bleeding, bad odour and

rapid loss o bone and/or

sot tissue

Clinical diagnosis


39/68


Unexplained anaemia(





Pneumocystispneumonia

Dyspnoea on exertion ornonproductive cough o

recent onset (within the past

three months), tachypnoea

and ever AND chest X-ray

evidence o diuse bilateral

interstitial inltrates AND

no evidence o a bacterial

pneumonia, bilateral

crepitations on auscultationwith or without reduced air

entry

Cytology orimmunofuorescent

microscopy o induced

sputum or bronchoalveolar

lavage or histology o lung

tissue

Recurrent bacterial

pneumonia

Current episode plus one

or more previous episodes

in the past six months.

Acute onset (


41/68


Extrapulmonary TB Systemic illness (suchas ever, night sweats,

weakness and weight

loss). Other evidence

or extrapulmonary

or disseminated TB

varies by site: pleural,

pericardial, peritoneal

involvement, meningitis,

mediastinal or abdominallymphadenopathy or osteitis

Discrete peripheral lymph

node Mycobacterium

tuberculosis inection is

considered a less severe

orm o extrapulmonary TB

Mycobacteriumtuberculosis isolation or

compatible histology rom

appropriate site

OR

radiological evidence o

miliary TB (diuse uniormly

distributed small miliaryshadows or micronodules

on chest X-ray)

Kaposi sarcoma Typical gross appearancein skin or oropharynx o

persistent, initially fat,

patches with a pink or

blood-bruise colour, skin

lesions that usually develop

into violaceous plaques or

nodules

Macroscopic appearanceat endoscopy or

bronchoscopy or by

histology

Cytomegalovirus

disease (other than liver,

spleen or lymph node)

Retinitis only: may be

diagnosed by experienced

clinicians. Typical eye

lesions on undoscopic

examination: discrete

patches o retinal whitening

with distinct borders,

spreading centriugally, oten

ollowing blood vessels,

associated with retinalvasculitis, haemorrhage and

necrosis

Compatible histology

or cytomegalovirus

demonstrated in

cerebrospinal fuid

by culture or DNA (by

polymerase chain reaction)





Central nervous systemtoxoplasmosis

Recent onset o aocal nervous system

abnormality or reduced

level o consciousness AND

response within 10 days to

specic therapy

Positive serum toxoplasmaantibody AND (i available)

single or multiple

intracranial mass lesion on

neuroimaging (computed

tomography or magnetic

resonance imaging)

HIV encephalopathy Clinical nding o disabling

cognitive and/or motor

dysunction interering with

activities o daily living,

progressing over weeks

or months in the absence

o a concurrent illness or

condition other than HIV

inection which might explain

the ndings

Diagnosis o exclusion: and

(i available) neuroimaging

(computed tomography

or magnetic resonance

imaging)

Extrapulmonarycryptococcosis

(including meningitis)

Meningitis: usually subacute,ever with increasing severe

headache, meningism,

conusion, behavioural

changes that responds to

cryptococcal therapy

Isolation o Cryptococcusneoormans rom

extrapulmonary site or

positive cryptococcal

antigen test on

cerebrospinal fuid or blood

Disseminated

non-tuberculous

mycobacterial inection

No presumptive clinical

diagnosis

Diagnosed by nding

atypical mycobacterial

species rom stool, blood,body fuid or other body

tissue, excluding the lung


43/681


Progressive multiocalleukoencephalopathy

PML

No presumptive clinicaldiagnosis

Progressive nervoussystem disorder (cognitive

dysunction, gait/speech

disorder, visual loss, limb

weakness and cranial

nerve palsies) together with

hypodense white matter

lesions on neuroimaging

or positive polyomavirus

JC (JVC) polymerase chainreaction on cerebrospinal

fuid

Cryptosporidiosis (with

diarrhoea lasting more

than one month)


diagnosis

Cysts identied on

modied Ziehl-Nielsen

stain microscopic

examination o unormed

stool

Chronic isosporiasis No presumptive clinicaldiagnosis

Identication o Isospora

Disseminated mycosis

(coccidiomycosis or

histoplasmosis)


diagnosis

Histology, antigen detection

or culture rom clinical

specimen or blood culture

Recurrent non-typhoid

Salmonella bacteraemia


diagnosis

Blood culture

Lymphoma (cerebralor B-cell non-Hodgkin)

or other solid HIV-

associated tumours


Histology o relevantspecimen or, or central

nervous system tumours,

neuroimaging techniques

Invasive cervical

carcinoma


diagnosis

Histology or cytology

Visceral leishmaniasis No presumptive clinical

diagnosis

Diagnosed by histology

(amastigotes visualized)

or culture rom anyappropriate clinical

specimen





HIV-associatednephropathy


Renal biopsy

HIV-associated

cardiomyopathy


diagnosis

Cardiomegaly and

evidence o poor

let ventricular

unction conrmed by

echocardiography



45/68

These criteria should be used or children younger than 15 years with conrmed

HIV inection.


CLINICAL STAGE 1

Asymptomatic No HIV-related symptoms

reported and no signs on

examination

Not applicable

Persistent generalized

lymphadenopathy

Persistent swollen or enlarged

lymph nodes >1 cm at twoor more non-contiguous sites

(excluding inguinal), without

known cause

Clinical diagnosis

CLINICAL STAGE 2

Unexplained persistent

hepatosplenomegaly

Enlarged liver and spleen

without obvious cause

Clinical diagnosis

Papular pruritic eruptions Papular pruritic vesicular

lesions

Clinical diagnosis

Fungal nail inections Fungal paronychia (painul,

red and swollen nail bed)

or onycholysis (painless

separation o the nail rom

the nail bed); proximal white

subungual onchomycosis

is uncommon without

immunodeciency

Clinical diagnosis

Angular cheilitis Splits or cracks on lips at

the angle o the mouth with

depigmentation, usually

responding to antiungal

treatment but may recur

Clinical diagnosis

ANNEX 4. CRITERIA FOR RECOGNIZING HIV-RELATED CLINICAL

EVENTS AMONG CHILDREN LIVING wITH HIV





Lineal gingival erythema Erythematous band thatollows the contour o

the ree gingival line;

may be associated with

spontaneous bleeding

Clinical diagnosis

Extensive wart virus

inection

Characteristic warty skin

lesions; small feshy grainy

bumps, oten rough, fat on

sole o eet (plantar warts);

acial, more than 5% o body

area or disguring

Clinical diagnosis

Extensive molluscum

contagiosum inection

Characteristic skin lesions:

small fesh-coloured, pearly

or pink, dome-shaped or

umbilicated growths may be

infamed or red; acial, more

than 5% o body area or

disguring. Giant molluscummay indicate more advanced

immunodeciency

Clinical diagnosis

Recurrent oral ulcerations

(two or more in six

months)

Aphthous ulceration,

typically with a halo o

infammation and yellow-

grey pseudomembrane

Clinical diagnosis

Unexplained parotid

enlargement

Asymptomatic bilateral

swelling that may

spontaneously resolve and

recur, in the absence o any

other known cause, usually

painless

Clinical diagnosis


47/68


Herpes zoster Painul rash with fuid-lled blisters, dermatomal

distribution, can be

haemorrhagic on

erythematous background

and can become large and

confuent. Does not cross

the midline

Clinical diagnosis

Recurrent upper

respiratory tract inection

Current event with at least

one episode in the past six

months. Symptom complex:

ever with unilateral ace

pain and nasal discharge

(sinusitis) or painul swollen

eardrum (otitis media), sore

throat with productive cough

(bronchitis), sore throat

(pharyngitis) and barkingcroup-like cough. Persistent

or recurrent ear discharge

Clinical diagnosis

CLINICAL STAGE 3

Unexplained moderate

malnutrition

Weight loss: low weight-

or-age, up to 2 standard

deviations rom the mean,

not explained by poor or

inadequate eeding and orother inections, and not

adequately responding to

standard management

Documented loss o body

weight o 2 standard

deviations rom the mean,

ailure to gain weight on

standard management andno other cause identied

during investigation

Unexplained persistent

diarrhoea

Unexplained persistent (14

days or more) diarrhoea

(loose or watery stool, three

or more times daily), not

responding to standardtreatment

Stools observed and

documented as unormed.

Culture and microscopy

reveal no pathogens


48/68


49/68


Pulmonary TB

Nonspecic symptoms, suchas chronic cough, ever,

night sweats, anorexia and

weight loss. In the older

child also productive cough

and haemoptysis. History

o contact with adult with

smear-positive pulmonary

TB. No response to standard

broad-spectrum antibiotictreatment

One or more sputumsmear positive or

acid-ast bacilli and/or

radiographic abnormalities

consistent with active TB

and/or culture positive

or Mycobacterium

tuberculosis

Severe recurrent bacterial

pneumonia

Cough with ast breathing,

chest in drawing, nasal

faring, wheezing and

grunting. Crackles

or consolidation on

auscultation. Responds to

course o antibiotics. Currentepisode plus one or more in

previous six months

Isolation o bacteria

rom appropriate clinical

specimens (induced

sputum, bronchoalveolar

lavage, lung aspirate)

Acute necrotizing

ulcerative gingivitis

or stomatitis, or acute

necrotizing ulcerative

periodontitis

Severe pain, ulcerated

gingival papillae, loosening

o teeth, spontaneous

bleeding, bad odour and

rapid loss o bone and/or

sot tissue

Clinical diagnosis





Symptomaticlymphocytic interstitial

pneumonia


Chest X-ray: bilateralreticulonodular interstitial

pulmonary inltrates

present or more than

two months with no

response to antibiotic

treatment and no other

pathogen ound. Oxygen

saturation persistently


51/68


CLINICAL STAGE 4Unexplained severe

wasting, stunting or

severe malnutrition not

adequately responding to

standard therapy

Persistent weight loss

not explained by poor

or inadequate eeding,

other inections and not

adequately responding

in two weeks to standard

therapy. Characterized by:

visible severe wasting o

muscles, with or without

oedema o both eet and/

or weight-or-height o 3

standard deviations rom the

mean, as dened by WHO

Integrated Management o

Childhood Illness guidelines

Documented weight loss

o more than 3 standard

deviations rom the mean

with or without oedema

Pneumocystis pneumonia

(PCP)

Dry cough, progressive

diculty in breathing,

cyanosis, tachypnoea and

ever; chest indrawing or

stridor (severe or very severe

pneumonia as in the WHO

Integrated Management

o Childhood Illness

guidelines). Usually o rapid

onset especially in inants

under six months o age.

Response to high-dose co-

trimoxazole with or without

prednisolone. Chest X-ray:

typical bilateral perihilar

diuse inltrates

Cytology or

immunofuorescent

microscopy o induced

sputum or bronchoalveolar

lavage or histology o lung

tissue





Recurrent severebacterial inection,

such as empyema,

pyomyositis, bone or joint

inection or meningitis

but excluding pneumonia

Fever accompanied byspecic symptoms or signs

that localize inection.

Responds to antibiotics.

Current episode plus one or

more in previous six months

Culture o appropriateclinical specimen

Chronic herpes simplex

inection; (orolabial or

cutaneous o more than

one months duration or

visceral at any site)

Severe and progressive

painul orolabial, genital, or

anorectal lesions caused

by herpes simplex virus

inection present or more

than one month

Culture and/or histology

Oesophageal candidiasis

(or candidiasis o

trachea, bronchi or lungs)

Diculty in swallowing

or pain on swallowing

(ood and fuids). In young

children, suspect particularly

i oral candidiasis observed

and ood reusal occurs and/or diculties or crying when

eeding

Macroscopic appearance

at endoscopy, microscopy

o specimen rom tissue or

macroscopic appearance

at bronchoscopy or

histology

Extrapulmonary or

disseminated TB

Systemic illness usually

with prolonged ever, night

sweats and weight loss.

Clinical eatures o organs

involved, such as sterile

pyuria, pericarditis, ascites,pleural eusion, meningitis,

arthritis and orchitis.

Responds to standard anti-

TB therapy

Positive microscopy

showing acid-ast bacilli or

culture o Mycobacterium

tuberculosis rom blood or

other relevant specimen

except sputum orbronchoalveolar lavage.

Biopsy and histology


53/681


Kaposi sarcoma Typical appearance in skinor oropharynx o persistent,

initially fat, patches with a

pink or blood-bruise colour,

skin lesions that usually

develop into nodules

Not required but may beconrmed by:

typical red-purple

lesions seen on

bronchoscopy or

endoscopy

dense masses in lymph

nodes, viscera or lungs

by palpation or radiology

histology

Cytomegalovirus retinitis

or cytomegalovirus

inection aecting

another organ, with onset

at age older than one

month

Retinitis only.

Cytomegalovirus retinitis

may be diagnosed by

experienced clinicians:

typical eye lesions on serial

undoscopic examination;

discrete patches o retinal

whitening with distinctborders, spreading

centriugally, oten ollowing

blood vessels, associated

with retinal vasculitis,

haemorrhage and necrosis

Denitive diagnosis

required or other sites.

Histology. Cerebrospinal

fuid polymerase chain

reaction

Central nervous system

toxoplasmosis onset ater

age one month

Fever, headache, ocal

nervous system signs

and convulsions. Usually

responds within 10 days to

specic therapy

Computed tomography

scan (or other

neuroimaging) showing

single or multiple lesions

with mass eect or

enhancing with contrast

Extrapulmonary

cryptococcosis

(including meningitis)

Meningitis: usually subacute,

ever with increasing severe

headache, meningism,

conusion, behavioural

changes that respond to

cryptococcal therapy

Cerebrospinal fuid

microscopy (India ink

or Gram stain), serum

or cerebrospinal fuid

cryptococcal antigen test

or culture


54/68


55/68


Chronic cryptosporidiosis No presumptive clinicaldiagnosis

Cysts identied onmodied Ziehl-Nielsen

microscopic examination

o unormed stool

Chronic isosporidiosis No presumptive clinical

diagnosis

Identication o Isospora

spp.

Cerebral or B-cell non-

Hodgkin lymphoma


diagnosis

Diagnosed by central

nervous system

neuroimaging; histology orelevant specimen

Progressive multiocal

leukoencephalopathy


diagnosis

Progressive neurological

disorder (cognitive

dysunction, gait/speech

disorder, visual loss,

limb weakness and

cranial nerve palsies)

together with hypodense

white matter lesions

on neuro-imaging or

positive polyomavirus JC

polymerase chain reaction

on cerebrospinal fuid

HIV-associated

nephropathy

No presumptive clincial

diagnosis

Renal biopsy

HIV-associatedcardiomyopathy


Cardiomegaly andevidence o poor

let ventricular

unction conrmed by

echocardiography





PARAMETER OR

FEATURE

GRADE 1 GRADE 2 GRADE 3 GRADE 4

BLOOD

Haemoglobin (g/dl)

(age >2 years)

10.010.9 7.09.9 15.0 timesnormal

Gamma-glutamyl

transerase

1.14.9 times

normal

5.09.9 times

normal

10.015.0

times normal

>15.0 times

normal

Pancreatic amylase 1.11.4 times

normal

1.51.9 times

normal

2.03.0 times

normal

>3.0 times

normal

Abdominal pain Mild

Moderate

no treatment

needed

Moderate

no treatment

needed

Severe

hospital and

treatment

aids who ctx

Documents