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TRANSCRIPT
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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
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World Health Organization 2006
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GUIDELINES ON
CO-TRIMOXAZOLE PROPHYLAXIS
FOR HIV-RELATED INFECTIONS
AMONG CHILDREN,
ADOLESCENTS AND ADULTSIN RESOURCE-LIMITED SETTINGS
Recommendations
for a public health approach
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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
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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
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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
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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.
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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
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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
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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
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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
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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
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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.
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. 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.
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.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
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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].
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. 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.
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. 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].
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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).
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for hiV-related infections amonG children, adolescents and adults in resource-limited settinGs
. 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].
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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
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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
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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.
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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.
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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.
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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].
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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
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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].
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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.
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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 (
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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).
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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 (
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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.
Source: World Health Organization (45).
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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 (
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CLINICAL EVENT CLINICAL DIAGNOSIS DEFINITIVE DIAGNOSIS
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
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CLINICAL EVENT CLINICAL DIAGNOSIS DEFINITIVE DIAGNOSIS
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
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CLINICAL EVENT CLINICAL DIAGNOSIS DEFINITIVE 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
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CLINICAL EVENT CLINICAL DIAGNOSIS DEFINITIVE DIAGNOSIS
Unexplained anaemia(
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CLINICAL EVENT CLINICAL DIAGNOSIS DEFINITIVE DIAGNOSIS
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 (
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CLINICAL EVENT CLINICAL DIAGNOSIS DEFINITIVE DIAGNOSIS
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)
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CLINICAL EVENT CLINICAL DIAGNOSIS DEFINITIVE DIAGNOSIS
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
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CLINICAL EVENT CLINICAL DIAGNOSIS DEFINITIVE DIAGNOSIS
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)
No presumptive clinical
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)
No presumptive clinical
diagnosis
Histology, antigen detection
or culture rom clinical
specimen or blood culture
Recurrent non-typhoid
Salmonella bacteraemia
No presumptive clinical
diagnosis
Blood culture
Lymphoma (cerebralor B-cell non-Hodgkin)
or other solid HIV-
associated tumours
No presumptive clinicaldiagnosis
Histology o relevantspecimen or, or central
nervous system tumours,
neuroimaging techniques
Invasive cervical
carcinoma
No presumptive clinical
diagnosis
Histology or cytology
Visceral leishmaniasis No presumptive clinical
diagnosis
Diagnosed by histology
(amastigotes visualized)
or culture rom anyappropriate clinical
specimen
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CLINICAL EVENT CLINICAL DIAGNOSIS DEFINITIVE DIAGNOSIS
HIV-associatednephropathy
No presumptive clinicaldiagnosis
Renal biopsy
HIV-associated
cardiomyopathy
No presumptive clinical
diagnosis
Cardiomegaly and
evidence o poor
let ventricular
unction conrmed by
echocardiography
Source: World Health Organization (45).
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These criteria should be used or children younger than 15 years with conrmed
HIV inection.
CLINICAL EVENT CLINICAL DIAGNOSIS DEFINITIVE DIAGNOSIS
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
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CLINICAL EVENT CLINICAL DIAGNOSIS DEFINITIVE DIAGNOSIS
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
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CLINICAL EVENT CLINICAL DIAGNOSIS DEFINITIVE DIAGNOSIS
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
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CLINICAL EVENT CLINICAL DIAGNOSIS DEFINITIVE DIAGNOSIS
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
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CLINICAL EVENT CLINICAL DIAGNOSIS DEFINITIVE DIAGNOSIS
Symptomaticlymphocytic interstitial
pneumonia
No presumptive clinicaldiagnosis
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
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CLINICAL EVENT CLINICAL DIAGNOSIS DEFINITIVE DIAGNOSIS
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
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CLINICAL EVENT CLINICAL DIAGNOSIS DEFINITIVE DIAGNOSIS
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
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CLINICAL EVENT CLINICAL DIAGNOSIS DEFINITIVE DIAGNOSIS
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
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CLINICAL EVENT CLINICAL DIAGNOSIS DEFINITIVE DIAGNOSIS
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
No presumptive clinical
diagnosis
Diagnosed by central
nervous system
neuroimaging; histology orelevant specimen
Progressive multiocal
leukoencephalopathy
No presumptive clinical
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
No presumptive clinicaldiagnosis
Cardiomegaly andevidence o poor
let ventricular
unction conrmed by
echocardiography
Source: World Health Organization (45).
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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