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Pediatric AntiretroviralTherapy
International Center for AIDS Careand Treatment Programs
Columbia University
Mailman School of Public Health
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Learning Objectives
� Identify the ARV-eligible child
� Prepare the family for ARV initiation
� Choose an effective 1st line regimen
� Create an appropriate follow-up schedule
for the newly initiated child
� Identify and manage ARV toxicities
� Recognize treatment failure
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Unifying Concepts
� The primary goal of ARV therapy is to
prevent clinical complications of HIV and to
prolong survival� Prescribing ARV regimens requires careful
assessment and preparation of the patient
followed by consistent support
� There are unique considerations for ARV
use in infants, children, and adolescents
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Antiretroviral Therapy in Children
� Similarities to adults
± Pathogenesis of HIV infection
± General virologic and immunologic principles
� Unique to infants and children
± Diagnostic issues
± Pharmacokinetic changes with age/maturation ± Natural history differences in disease progression,
immune function, viral replication
± Adherence issues particular to children and
adolescentsInternational Center for AIDS Care and Treatment Programs, Columbia University
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Children Are Not Small Adults
� Age-related differences between children &adults ± Body composition
± Renal excretion
± Liver metabolism ± Gastrointestinal function
� Drug metabolism in children varies with ageand maturation leads to differences in: ± Drug distribution and clearance
± Drug dosing and drug toxicities
� Pharmacokinetic (PK) data not consistently available inyoung children
� Variations in PK (between and within individuals) frequentlygreater in children
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ART Eligibility
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New WHO Criteria for Starting ART
in ChildrenWHO Pediatric
Stage
Availability of
CD4 cell assay
Age specific recommendation
<18months >18 months
IVa
CD4
Treat AllNo CD4
IIIaCD4
Treat All
Treat all except those
with TBb, LIP,OHL,
thrombocytopenia, also
take into account CD4
value
No CD4 Treat allb
II
CD4 CD4 guided
No CD4 TLC -guided
1
CD4 CD4 guided
No CD4 Do not treat
a- Stabilize any opportunistic infection prior to initiation of ART
b- in children with TB the CD 4 level and clinical status should be used todetermine the need and timing for initiation of ART in relation to TB treatment
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New WHO Age-Related CD4
Values for Starting ART in ChildrenImmunological
marker a
Age specific recommendations to initiate ARTb
<11mo 12-35mo 36-59mo >5 years
CD4%c 25 % 20% 15% 15%
CD4 countc 1500cells/mm3 750 cells/mm3 350cells/mm3 200cells/mm3
To Be used only in absence of CD4 assay:
Total
Lymphocyte
count
4000cells/mm3 3000cells/mm3 2500cells/mm3 1500cells/mm3
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a- Immunological markers supplement clinical staging
b-ART should be initiated at these cut-off levels regardless pf clinical stagec- CD4 is more accurate in children < 5 years
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Children > 13 years of age eligible
for ART� WHO stage 4 irrespective of CD4 cell
count
� WHO stage 3 HIV disease and CD4 < 350
� CD4 < 200 irrespective of WHO stage
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Special Circumstances: The
Rapidly Progressing Infant� In situations of rapidly deteriorating health status and lackof virologic test availability, a presumptive diagnosis canbe made on the following criteria: ± HIV exposed/ antibody positive
± < 18
months of age ± Symptomatic with at least two of:� Oral thrush
� Severe pneumonia
� Severe wasting/malnutrition
� Severe sepsis
± Recent HIV-related maternal death, advanced HIV disease in themother, and/or CD4<25% will also support this diagnosis
± It is important to confirm the diagnosis as soon as possible.
� A presumptive diagnosis then necessitates managementof presenting acute illnesses and management of the HIVincluding the initiation of ART when indicated.
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Initiating ART
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Preparing for ART
� Complex adherence challenges for children
± Requires collaboration of child, parent, and all
secondary caretakers ± Family needs support around long-term
therapy, changing regimens, and doses
± Issues of disclosure and multiple caretakers
complicate complete adherence ± Ongoing support for evolving adherence
needs as child develops with age
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Adherence Preparation
� ART should never be initiated without extensivepreparation of the child and the family
� ART is rarely an emergency and thereforeshould only be started once the family is ready
� Adherence Counseling must address: ± WHO will administer the medications
± WHAT medications will be given
± WHEN will medications be given
± HOW will medications be given� The multi-disciplinary team must work together
to identify any possible barriers to adherenceand address these before commencingtreatment
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Assess Patient Readiness
� Has the child tasted the medications?
� How does the child¶s developmental level
influence ability to take medications?
� Have the health providers observed
medication administration?
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Initiating ART
� Never prescribe ARVs in the absence of
adherence preparation and support
� Pay attention to other medications and treatments
in order to avoid interactions with ARVs
� NEVER prescribe monotherapy or dual therapy
� Never add a single drug to a failing regimen
� If ARVs are to be discontinued, stop all treatmentsas instructed
� Be attentive to the dosages as the child grows
and develops
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Before ART
� Consider any medical contraindications to
first line regimens using
± Medical history ± Symptom checklist
± Physical examination
± Laboratory studies (renal function, liver
function, and CBC)
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First Line Regimens
Preferred pediatric first line regimes:
� Children under the age of 3
AZT+3TC+NVP or
d4T+3TC+NVP or ABC+3TC+NVP
� Children older than 3 years (>10kg)
AZT+3TC+NVP/EFV or
d4T+3TC+NVP/EFV or ABC+3TC+NVP/EFV
Additional dual NRTI backbone include ABC+ AZT or ABC+d4T
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Special Circumstances
� WHO recommends Triple NRTI as alternative
option for initial therapy under certain
circumstances
±AZT+3TC+ABC or d4T + 3TC +ABC ± Infants and children receiving TB treatment where
NVP or PI cannot be used because of interactions
with rifampin
± Pregnant adolescent with CD4 cell > 250/mm3 in
which both NVP and EFV are contraindicated and PI
based regimes are not available
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Dosing for Pediatric ARVs
� Dosing is weight dependent and must beadjusted for significant weight gain/loss
± Refer to ICAP pediatric dosing charts
� Check weight and height at each visit andadjust dosage when necessary
± Failure to adjust for weight gain can lead to
underdosage and development of resistance
± Failure to adjust for weight loss can lead tooverdosing and toxicity
� Review dose changes and reasons for
changes with family
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Zidovudine (AZT)
� Formulation
±Syrup:10 mg/ml
±Capsules: 100 mg; 250mg
±Tablet: 300mg
� May be crushed and combined with food
� Light sensitive, needs to be stored in aglass jar
� Should not be used with d4T because of
possible antagonism
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Zidovudine Toxicity
� Hematologic toxicity: granulocytopenia
and anemia
± May require dose reduction or interruption of therapy
� Gastrointestinal disturbance: anorexia,
nausea, vomiting
� Myositis, myopathy, mitochondrial disease
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Lamivudine (3TC)
� Formulation
± Oral solution: 10 mg/ml
± Tablet:150
mg� Generally well tolerated
� Store solution at room temperature
� Tablet can be mixed with water or foodand taken immediately
� Use within one month of opening the bottle
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Lamivudine Toxicity
� Side effects are uncommon and include
headache, nausea, and abdominal pain
� Rarely neutropenia, pancreatitis, andelevated LFTs
� In the case of life threatening pancreatitis
all drugs should be discontinued until
resolution of toxicity and restarted with
careful monitoring
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Stavudine (d4T)
� Formulation
± Oral solution: 1mg/ml
± Capsules:15mg, 2
0mg,
30mg
� Solution must be refrigerated
� Capsules may be opened and mixed with
small amount of food
� Should not be used with AZT because of
possible antagonism
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Stavudine Toxicity
� Most frequent side effect is headache and GIdisturbance
� Lactic acidosis and severe hepatomegaly withsteatosis, including fatal cases, have been
reported with d4T use. ± Increased risk when used with ddI
± Discontinue treatment if suspected
� Peripheral neuropathy (less common in children)
� Increasingly associated with metabolicabnormalities, particularly lipoatrophy
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Abacavir Toxicity
� Most common side effects are headache,
GI upset, and rash
� Potentially fatal hypersensitivity reactionoccurs in a small proportion of children
receiving the drug (3%)
± Symptoms include rash, fatigue, nausea,
vomiting, cough, pharyngitis, and dyspnea
± ABC must be stopped permanently if this
occurs and do not rechallenge
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Nevirapine (NVP)
� Formulation
± Oral solution: 10 mg/ml
± Tablet: 200 mg
� Can be given with food
� Store suspension at room temperature;
must be shaken well
� NVP is initiated at a lower dose and
increased in a stepwise fashion
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Nevirapine Toxicity
Nevirapine hepatotoxicity
� Liver toxicity can occur but is less common
than in adults, can be fatal� Discontinue for grade 3 toxicity:
substitution with efavirenz has been
successful in adults, but little data is
available for children
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Nevirapine Toxicity
� Nevirapine Rash
� Usually occurs during first 2 ± 6 weeks of
therapy
� For mild to moderate rash without systemicsymptoms, continue treatment with close
observation
� For severe rash (2-5%) Stevens Johnson
Syndrome (fever, oral lesions, conjunctivitis,blistering), discontinue drug
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Efavirenz Toxicity
� Should not be prescribed for adolescent
females who are at risk for becoming
pregnant because of teratogenicity
� Associated with CNS side effects which
last approximately 10-14 days
� Rash is more frequent in children than
adults but it is generally milder
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Special Considerations in
Prescribing First Line Regimens
� Never prescribe efavirenz to a child under the age of 3.
Proper dosing has not been determined for any child <3yrs
or <10kg.
� Stavudine (d4T) liquid requires refrigeration. Families canbe taught to open capsules but this may be complex.
Zidovudine may be preferable.
� In children who were previously exposed to NVP as a
pMTCT regimen, NNRTI resistance may develop. While thisresistance generally fades within the first year, this may
impact the efficacy of the NNRTI-based regimen
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Monitoring Pediatric ART
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How to Monitor ARV Therapy
� Clinical
� Laboratory
� Treatment adherence� Program adherence: keeping visit
appointments
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Clinical Monitoring
� Weekly visits for the first 8 weeks.
± Assess adherence, side effects/toxicity,immune reconstitution and growth
± Symptom checklist and targeted physicalexam
± Review and recalculate dose, if needed, ateach visit based on weight
± Dispense one week of medication ± To decrease burden on the family, f/u visits
can be combined with other health care visits
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Clinical Monitoring-Cont¶d
� Monthly visits after the first 8 weeks if adherence is excellent.
� At each visit:
± Interim history ± Symptom checklist
± Targeted physical exam
± Growth and nutritional assessment
± Developmental assessment
± Psychosocial assessment ± Adherence with caregiver and older child when appropriate
± ARV prescription (recalculate doses)
± Referral for support services as needed
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Laboratory Monitoring
� Baseline labs should include renalfunction, liver function, CBC, and CD4
� CD4 count and percent should be
obtained every 6 months to monitor ARTefficacy
� Abnormal findings on history or physical
may warrant additional laboratory testing� Abnormal lab results may indicate ART
toxicities, intercurrent illnesses, and/or advancing disease.
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Defining ART Success
� Mild or no reported side effects� Excellent adherence
� Improved clinical status in 6 months
± Improved growth
± Improvement in neurological symptoms and
development
± No new AIDS defining illness
± Fewer intercurrent illnesses
� Improved or stabilized immune status in 6
months
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ART Toxicities
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ART Toxicities
� In general, ART is well tolerated
� The majority of patients tolerate ART with mild tono side effects or toxicities
� Drug-related adverse events can be ± acute (occurring right after initiation)
± sub-acute (occurring 1-2 weeks after initiation)
± chronic (after prolonged use).
� It is important to differentiate betweencomplications of HIV disease and toxicitiesrelated to medication
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Possible causes of adverse
events among patients on ART� ART toxicity
� Immune reconstitution
� Intercurrent illness
� Disease progression
� Drug interaction
� Other?
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Distinguishing ART Toxicity
� Timing of the event ± When was ART initiated
� Some toxicities occur more frequently close to the time of initiation while others are associated with chronic treatment
� Constellation of signs & symptoms ± Progressive vs. acute
± Single vs. multiple organ systems
� Three step process ± Clinical Formulation
± Systematic assessment
± Management
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Step 1: Clinical Formulation
� What are the most likely causes of the new
symptoms or findings?
� How severe is the new symptom/finding, and
which potential diagnosis has the most seriousconsequences?
� Is this symptom or finding compatible with the
side effect of an individual drug?
� What additional information do you need?
± Will laboratory studies be useful?
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Step 2: Systematic Assessment
� Know the patient
� Know the drugs
� Know the timeframe
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Know the Patient
� History of presenting signs and symptoms
� Is the patient adherent to ART? Has her
adherence changed recently?
� What other medicines has she been on?
� Has she stopped or started any other prescribed
or non-prescribed medicines or substances?
� Does she have any sick contacts?� Are there any other changes in her life?
� Does she have access to food and clean water?
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Know the Drugs
� What medicines/substances is the patienttaking?
� Know individual toxicities and druginteraction profiles
± ART ± Medicines for OI prophylaxis (e.g. cotrimoxazole,
isoniazid, fluconazole):
± Medicines for other conditions (e.g. TB)
± Other medicine or substances taken regularly (e.g.
alcohol, hormonal contraceptives) ± Other remedies including herbal, natural, or traditional
treatments and teas
± Vitamins (including lack of vitamins)
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Know the Timeframe
� Exactly when did the patient start ART?
± Discuss with parent medicine by medicine
± Review chart
± Check pharmacy records
� When did the patient begin or discontinue other
medications or therapies?
� What was the exact timing of onset of symptom
or findings?
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Step 3: Managing Acute Drug
Toxicity
� Management should be based on
± Severity of event/potential for harm
± Implications for adherence
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Assessing Severity
� Grade degree of severity using toxicity tables
and clinical judgment
± Potentially life threatening
� Requires immediate management
± Static or Progressive� Rapid vs. chronic evolution
± Impact on adherence� Mild toxicity/side effect may have significant impact on
adherence
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After Severity is Assessed,
There are Three Options:
� Continue the medication and observeclosely
± Example: early nausea from zidovudine (AZT)
� Hold the medication
± Example: hepatitis from nevirapine (NVP)
� Switch the medication
± Example: severe peripheral neuropathy fromstavudine (d4T)
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Clinical Symptoms Requiring
Medication Switch
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Laboratory Results Requiring
Medication Switch
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Sy mptomati c Lactic Acidosis
� Rare but potentially fatal complication of ARV use ± most often associated with NRTI (especially d4T
and the combination of d4T + DDI).
� No single diagnostic sign or symptom; often
presents as symptom complex. ± Fatigue, abdominal pain, nausea/vomiting, weightloss, dyspnea, pancreatitis
� Specialized laboratory testing can confirm thepresence of lactic acidosis
± Anion gap, lactate level� Symptomatic lactic acidosis ± stop therapy
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Remember :
� Clinical judgment is important:
± Something other than ART may be causingthe adverse effect
± Lab error might confound the assessment of toxicity severity
± Every individual is unique and might not fitprecisely into a table or guideline
± Again, response to management may be theonly way to determine if symptoms/problemsare really a result of ART toxicity
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Switching single drug for toxicity
First Line ARV
regime
Major potential toxicities Drug substitution
AZT/3TC/NVP
ABC/3TC/NVP
AZT-anemia, gastro-
intestinal intolerance,
neutropenia
Switch AZT d4T or
ABC
ABC-hypersensitivity Switch ABC AZT
NVP-severe
hepatotoxicity
Switch NVP EFV
NVP-severe rash but not
life threatening
Switch NVP EFV
NVP-severe life
threatening rash ( Steven
Johnson Syndrome)
Switch NVP EFV
with close monitoring
or Triple NRTI or PI
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Switching single drug for toxicity
First Line ARV
regime
Major potential toxicities Drug substitution
d4T/3TC/EFV
AZT/3TC/EFV
ABC/3TC/EFV
d4T-lactic acidosis Switch d4T AZT or
ABC
d4T-peripheral
neuropathy
Switch d4T AZT
d4T-lipoatrophy Switch d4T ABC
AZT-anemia, GI
intolerance , neutropenia
Switch AZT d4T
or ABC
ABC- hypersensitivity Switch ABC AZT
EFV-CNS toxicity and
potential for
teratogenicity
Switch EFV NVP
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Switching single drug for toxicity
Triple NRTI First
Line ARV regime
Major potential toxicities Drug substitution
AZT/3TC/ABC
d4T/3TC/ABC
AZT-anemia, gastro-
intestinal intolerance,
neutropenia
Switch AZT d4T
ABC- hypersensitivity Switch ABC NNRTI
or PI based regime
d4T-lactic acidosis Switch d4T AZT
d4T-peripheral
neuropathy or
pancreatitis
Switch d4T AZT
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Why is the Regimen Failing?
� Inadequate adherence is the most common cause of treatment failure in children
� Issues to consider with regard to adherence: ± Who administers drug?
± How is drug administered? ± Is it the drug?
� Resistance to specific agents may have a significantimpact on treatment efficacy. ± Resistance to specific drugs can develop secondary to
inadequate adherence, inadequate drug levels and selection of pre-existing mutations with selective pressure of presentregimen.
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Clinical indications of treatment
failure
� Lack of or decline in growth rate in childrenwho show an initial response to treatment(WHO Stage III or IV)
� Loss of neurodevelopmental milestones or development of encephalopathy (WHO StageIV)
� Occurrence of new opportunistic infections or malignancies or recurrence of infections ,such as oral candidiasis that is refractory totreatment or esophageal candidiasis (WHOStage III or IV)
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Immunologic indicators of
treatment failure� Lack of improvement in CD4 cell percentage
or absolute count
� Return of CD4 percent or absolute to pre-therapy baseline or below, in the absence of
other concurrent infection explaining transientCD4decrease
� > 50% fall from peak level on therapy of CD4 percentage or absolute in the absence of other concurrent infection explaining transient
CD4 decrease, particularly if CD4 valuesdeclines below age±related threshold for initiating therapy
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Early vs. Late Change to Second
Line Regimen� Early changes to a second line regime leaves
fewer drug class options for treatment of subsequent failure (a single NNRTI mutationresults in cross class resistance)
� Late change to a second line regime (using justclinical and or CD4 criteria may provide agreater opportunity for drug resistancemutations to develop before regime change
� The advantage of the alternative triple NRTI firstline regime is that treatment failure can bemanaged with a wider choice of drugs becausedrugs from two classes will have been spared
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Role of the Multidisciplinary
Team
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Side Effects of Medicines
� Non-clinicians may be the first to hear about amedication toxicity. They should be able to: ± recognize serious toxicities
± advise the patient to see a clinician promptly ± inform clinician directly of these toxicities
± discuss occurrence and management in themultidisciplinary team meetings
� Providers should note patient symptoms/signsin the medical record. Decisions and follow-upshould be discussed in multidisciplinary teammeetings.
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Adherence Assessment and
Support� Assess adherence at every visit and contact(clinician, counselors etc)
� Determine if medicines are being taken correctly
(over or under-dosing)� Evaluate timing of food intake and medication
� Determine whether vomiting, diarrhea, andtrouble swallowing are affecting medicine intake
� Identify social issues that may impact adherence� Discuss adherence at multidisciplinary team
meetings
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Documentation and Coordination of
Care� A complete medication history and record
should exist for all patients.
� Careful documentation of toxicities shouldappear in the medical record: presentation,
confirmation, management strategy,
response/resolution
� This documentation should be shared with other
providers (e.g., TB clinic, ANC)
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Summary
� ART can provide life sustaining support for the HIVinfected child
� Using clinical staging and CD4 count can help identifythe eligible child
� In the case of rapidly progressing disease, clinical judgment may identify the eligible child before diagnosis
is confirmed� There are unique adherence challenges for children on
ART
� Families need additional support from the MDT aroundadherence and frequently changing dosage
requirements� A child on ART must be monitored carefully in order to
identify adverse events early and respond appropriately
� The multi-disciplinary team plays an important role inassessing adherence and in monitoring the child on ART