Transcript Pediatric Antiretroviral Therapy

Pediatric Antiretroviral
Therapy
Learning Objectives
 Describe the WHO clinical and immunological
criteria for ART initiation in infants and children
 Describe preparation of the family for ART
 Know the preferred regimens, and how to
identify and manage toxicities
 Know how to follow up and support children and
families
 Recognize treatment failure
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Principles of ART in the Pediatric
Setting
 The primary goal of ARV therapy is to prevent
clinical complications of HIV and to prolong
survival
 Maximal and durable suppression and replication of
HIV
 Restoration and/or preservation of immune function
 Reduction of HIV-related morbidity and mortality
 Preserve normal growth and development
 Improvement of quality of life of family and child
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Antiretroviral Therapy in Children:
Children Are Not Small Adults
 Age-related differences between children & adults
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Body composition
Renal excretion
Liver metabolism
Gastrointestinal function
 Drug metabolism in children varies with age and
maturation leads to differences in:
 Drug distribution and clearance
 Drug dosing and drug toxicities
• Pharmacokinetic (PK) data not consistently available in
young children
• Variations in PK (between and within individuals) frequently
greater in children
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Antiretroviral Therapy in Children:
Differences from Adults
 HIV Disease
 Disease progression is rapid in infants and young
children
 Different clinical staging
 Immunologic Classification
 Criteria for ART initiation different for children
 CD4 percentage is more accurate in children < 6
years of age
 Special psychosocial needs
 Children have feelings and fears which they may not
verbalize
 Caregivers’ attitudes influence the child
 Disclosure issues
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Antiretroviral Therapy in Children:
Differences from Adults
 Dynamic nature of developmental stages
 Infants accepting of medications but this changes as
they become oppositional toddlers
 Adolescents’ oppositional behavior and feelings of
invincibility
 Antiretrovirals
 Pediatric drug formulations not available for all drugs
 Adverse events occur much less frequently in children
 Drug dosages based on child size (weight and body
surface area)
 Developmental challenges in drug administration
 Drug storage – some pediatric formulations need to
be refrigerated
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Antiretroviral Therapy in Children:
Similarities with Adults
 Drug adherence is the most critical factor in
treatment success
 Poor adherence results in drug resistance and
treatment failure
 Immune reconstitution syndrome can occur
 ART should be provided with comprehensive
care
 Multidisciplinary teams
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WHO Criteria for ART Initiation in Infants
and Children < 13 years
 Children with WHO Stage IV
 Children with WHO stage III
 In children > 12 months with TB, LIP, OHL, CD4 can
be used to guide ART initiation
 Children with WHO Stages I and II should only
initiate ART if they have evidence of severe
immune suppression
 Children with severe immune suppression
independent of WHO stage
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What is the criteria for Severe Immune
Suppression in Children?
 CD4 number and percent differ between children and
adults:
 Normal values differ by age
 CD4 percent is the preferred value to assess immune
status in young children < 5 years
 Any child with severe immune suppression is eligible for
ART independent of WHO stage
Immunological
markera
CD4%
CD4 count
WHO Age-Related CD4 Values for Starting ART in Infants &
Children
<11mo
12-35mo
36-59mo
>5 years
<25 %
<20%
<15%
<15%
<1500cells/mm3
<750 cells/mm3
<350cells/mm3
<200cells/mm3
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WHO Criteria for Starting ART in an Infant <18
months with Presumptive Diagnosis of Severe
HIV Disease
 HIV antibody positive and
 Diagnosis of Stage IV or AIDS indicator condition
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OR
 Symptomatic with ≥ 2 of the following:
• Oral thrush
• Severe pneumonia
• Severe sepsis
 Supporting factors
 Recent maternal death
 Advanced HIV disease in the mother
 CD4 < 20%
 Laboratory confirmation should be sought as soon as
possible depending on available resources
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Eligibility Criteria for Children >13 years
of age
 Use adult Criteria
 WHO Stage 4 irrespective of CD4 cell
count
 WHO Stage 3 disease and CD4 < 350
 CD4 < 200 irrespective of Clinical Stage
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Prior to ART Initiation-Clinical Evaluation
 Confirm HIV Diagnosis and Eligibility
 Laboratory confirmation as soon as possible
 WHO Clinical and Immunological Staging Criteria
 Baseline growth measurements
 Height and weight on all children
 Head circumference for children < 2 years of age
 Baseline neurodevelopmental status
 Screen for and treat any inter-current or opportunistic
infection
 Ensure access to nutrition and prophylaxis
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Prior to ARV Initiation – Laboratory
Evaluation
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CD4 count
Full blood count
Liver function test: Alanine transaminase
Kidney function: Serum creatinine
TB screening
 History
 Mantoux test and Chest x-ray if available
 When indicated: syphilis serology, Hepatitis B
virus screening, pregnancy test
 When available: viral load
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Prior to ART Initiation-Adherence
Preparation
 Identify and fully counsel care givers
 Confirm availability of support services (family,
social, inpatients care etc)
 Consistent caregiver for administration, supervision
of medication
 Identify barriers to treatment for the care taker
and address where possible
 Prepare family and child for adherence
 Completion of adherence/counseling sessions – may
vary at each site
 Address disclosure where appropriate
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Barriers to address before starting ART
 Drug taste, volume & burden
 Poverty and financial variables in generaltransportation, employment and work schedule,
food availability
 No identified caregiver
 Lack of Disclosure
 Lack of emotional support
 Lack of belief in HIV as the cause of illness and
the efficacy of treatment
 Caregiver is too sick to provide care
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Medical Contraindications to ART
 Severe Anemia (Hb<6.9 gdl) Contraindication to AZT, replace
with d4T
 Severe Neutropenia (ANC<250 mm3) AZT use requires close
monitoring. Can substitute d4T if ANC falls
 Severe Renal Insufficiency (Creatinine > 3 times normal)
Contraindication to ARV use. Patient not eligible for ART
 Severe Hepatic Insufficiency (LFTs > 5 times normal)
Contraindication to NVP use. Use EFV in children older than 3,
PI treatment suggested for small children
 History of prior ARV use Potential for ARV resistance. Consult
for expert management
 Current use of rifampin containing TB regimen- Interactions
with NVP. If CD4 is high, consider deferring ART or use ritonavir
containing regimen for children under 3 and EFV containing
regimen for children older than 3
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Pediatric First-Line Regimens in
Ethiopia
Children less than 3 years of age:
(ZDV or d4T) + 3TC + NVP
Children older than 3 years of age:
(ZDV or d4T) + 3TC + NVP
or
(ZDV or d4T) + 3TC + EFV
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Special Circumstances
WHO recommends Triple NRTI
 (AZT+3TC+ABC or d4T + 3TC +ABC)
as alternative option for initial therapy under
certain circumstances:
 Infants and children < 3 years 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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Zidovudine (AZT)
 Formulation
 Syrup:10 mg/ml
 Capsules: 100 mg; 250mg
 Tablet: 300mg
 May be crushed and combined with food
 Syrup is light sensitive, needs to be stored in a
glass jar
 Should not be used with d4T because of
possible antagonism
 Side effects
 Common- anemia, granulocytopenia, GI upset
 Less Common-myopathy and mitochondrial disease 21
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 food and
taken immediately
 Use within one month of opening the bottle
 Side effects
 Generally rare, include headache, nausea, rarely
pancreatitis and elevated LFTs
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Stavudine (d4T)
 Formulation
 Oral solution: 1mg/ml
 Capsules: 15mg, 20mg, 30 mg
 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
 Side effects Common: headache and GI disturbance, peripheral neuropathy
is less common
 Less Common: metabolic abnormalities, particularly lipoatrophy
 Life threatening: Lactic acidosis and severe hepatomegaly with
steatosis, including fatal cases, have been reported with d4T use
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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
 Side effects
 Common: skin rash, do not escalate dose
 Life threatening :Liver toxicity can occur but is less common than
in adults, can be fatal, discontinue for grade 3 toxicity, Steven
Johnson Syndrome
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Efavirenz (EFV)
 Formulation
 Syrup: 30mg/ml (for children > 3 years)
 Capsules: 50mg, 100mg, 200 mg
 Not indicated for children under 3 years of age
 Syrup requires higher dose than capsules
 Capsules can be mixed with sweet foods or jam to
disguise peppery taste
 Can be given with food but avoid high-fat meals which
decrease absorption by 50%
 Best given at bedtime to reduce CNS side effects
 Should not be prescribed for adolescent females who
are at risk for becoming pregnant because of
teratogenicity
 Side effects
 Common: Rash is generally milder
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Pediatric ARV’s: Important
Principles
 Dosing is weight dependent and must be
adjusted for significant weight gain/loss
 Always use three drugs together, never use
mono- or dual drug therapy
 Check weight and height at each visit and adjust
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 to
overdosing and toxicity
 Review dose changes and reasons for changes
with family
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Pediatric ARV’s: Important
Principles (2)
 Instruct family that drugs are to be stopped only with the
guidance of the team
 Keep the regimens simple and switch to pills as soon as
possible
 Make sure the caregiver understands how to administer
the drug at the correct dose at each visit
 Some capsules can be opened and taken immediately
with food or water
 Some tablets can be crushed and given immediately with
water or little food
 Can change to adult combination drugs when child
reaches appropriate weight
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Pediatric Considerations for ARV Dosing
 WHO Guidelines break down dosing
recommendations based on Tanner stages of
sexual development regardless of chronological
age
 Dosages for HIV and OI prophylaxis follow
pediatric schedules for persons in Tanner stages
1, 2, 3
 Adult schedules should be followed in Tanner
stages 4 & 5
 Close monitoring for those in stage 3 to ensure
that there is no underdosing
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Calculating Doses
 Some drugs are based on weight
 mg/kg
 Some drugs are based on Body Surface Area
 mg/m2
Wt (kg) XL (cm)
3600
 Use standardized weight dosing chart
since this is more convenient and reduces
chance of errors
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Weight based dosing
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Has simplified treatment dramatically
Very easy to use
Can use in all settings
Reduces the chances of dosing errors
Has been validated and is approved by WHO
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ICAP Pediatric ARV Dosing Chart
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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
 Stavudine (d4T) liquid requires
refrigeration. Families can be taught to
open capsules but this may be complex.
Zidovudine may be preferable
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Sd-NVP Exposure and Development of
Resistance Mutations
 The development of NNRTI-related resistance mutations after sdNVP is common
 Occurs in both mother and infected infant
 Risk of developing resistance is related to maternal health status,
viral subtype, assay sensitivity, concomitant ARV
 More common with low CD4, high viral load
 Mutations ‘fade’ from detection with time post-exposure but may
be archived
 It appears that if NVP-based ART is started > 6 months after sd-NVP
the mother will have a good treatment outcome
 In the 15 infants exposed to sd-NVP significant proportion were likely
to develop failure
 Small numbers, difficult to generalize
 Infants who are infected after receiving PMTCT should be monitored
closely
 Get mothers into care early and provide HAART for those with advanced
disease
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Lockman S. et al, NEJM 2007, 356: 135-147
How to Monitor ARV Therapy
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Clinical
Laboratory
Treatment adherence
Program adherence: keeping visit appointments
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Clinical Monitoring
 Biweekly visits for the first month
 Assess adherence, side effects/toxicity, immune
reconstitution and growth
 Symptom checklist and targeted physical exam
 Review and recalculate dose, if needed, at each visit
based on weight
 Escalate dose of NVP
 Dispense two weeks of medication
 To decrease burden on the family, follow-up visits can
be combined with other health care visits
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Clinical Monitoring (2)
 Monthly visits after the month if adherence is
excellent
 At each visit:
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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
 CD4 count and percent
 Every 6 months to monitor ART efficacy
 Hemoglobin at 1 month for those on AZT
 Thereafter, if symptoms indicate
 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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Attending to ART Toxicities
 In general, ART is well tolerated
 Similar to adult ART care, high level of attention
needs to be given to potential adverse effects
such as: ART toxicity, immune reconstitution,
intercurrent illness, disease progression, drug
interaction
 Please refer to detailed toxicity information
covered in the adult sections
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Attending to ART Toxicities (2)
 Remember:
 Clinical judgment is important:
 Something other than ART may be causing the
adverse effect
 Lab error might confound the assessment of toxicity
severity
 Every individual is unique and might not fit precisely
into a table or guideline
 Response to management plan may be the only way
to determine if symptoms/problems are due to ART
toxicity
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Switching Single Drug for Toxicity
First- line
drug
Major potential toxicity
Drug substitution
ABC
Hypersensitivity reaction—DO NOT
RECHALLENGE
AZT
Lactic acidosis
ABC
Severe gastro-intestinal intolerance
d4T or ABC
Severe anemia or neutropenia
d4T or ABC
Lactic acidosis
ABC
AZT
d4T
Lipoatrophy / metabolic syndrome
Peripheral neuropathy
AZT or ABC
Pancreatitis
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Switching Single Drug for Toxicity
First- line drug
Major potential toxicity
Drug substitution
Persistent severe CNS toxicity
NVP
Potential teratogenicity
NVP
Severe hepatotoxicity
EFV
Hypersensitivity
DO NOT RECHALLENGE:
use
Triple NNRTI (disadvantage,
EFV
NVP
Severe life threatening rash
(Stevens Johnson Syndrome)
may be less potent)
PI (disadvantage, premature start of
2nd line ARV drug)
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Recognizing Treatment Failure
 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 significant
impact 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 present
regimen
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Clinical Indications of Treatment Failure
 Lack of or decline in growth rate in children who
show an initial response to treatment (WHO
Stage III or IV)
 Loss of neurodevelopmental milestones or
development of encephalopathy (WHO Stage
IV)
 Occurrence of new opportunistic infections or
malignancies or recurrence of infections, such
as oral candidiasis that is refractory to treatment
or esophageal candidiasis (WHO Stage III or IV)
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Immunologic Indicators of Treatment
Failure
 Development of age-related severe
immunodeficiency after initial immune recovery
 Despite > 24 weeks of treatment
 Confirmed with at least one subsequent CD4
measurement
 Lack of improvement in CD4 cell percentage or
absolute count despite >24 weeks of treatment
 Rapid rate of decline to or below threshold of
age-related severe immunodeficiency
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Second-Line Regimens
 ART sequencing based on resistance patterns
associated with specific agents
 Goal is to replace failing first-line regimen with a
second that has minimal potential for cross
resistance
 Choices balance potency, toxicity, formulation,
and cost
 As new data becomes available, these may
change
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Pediatric Second-Line Regimens:
Regimen Sequencing
First-line:
(ZDV or d4T) + 3TC
+ NVP or EFV
Second-line:
ABC + ddI
+ LPV/r
First-line:
ZDV or d4T + 3TC
+ ABC
Second-line:
ABC + ddI
+ LPV/r
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Abacavir (ABC)
 Formulation
 Oral solution: 20mg/ml
 Tablet: 300mg
 Can be given with food
 Tablet can be crushed and mixed with small
amount of water or food and immediately
ingested
 Side effects
 Common- headache, GI upset,
 Life threatening-rare (<3%) fatal hypersensitivity
reaction, do not rechallenge
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Didanosine (ddI)
 Formulation
 25, 50, 100, 200 mg tabs
 10 mg/ml liquid
 For proper buffer dose, 2 tabs must be used
 Administer on empty stomach 1 hour before or 2
hours after meal; don’t take with acidic drinks but
can take with water
 This may make administration of regimen difficult, as
drugs may not all be taken together
 Side effects
 Common: GI intolerance
 Serious: peripheral neuropathy, pancreatitis
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Lopinavir/ritonavir (Kaletra)
 Formulation – dose based on lopinavir
 Solution: 80/20 mg/ml
 Capsule: 133.3/33.3 mg
 Must take with food
 Can be stored at room temperature once dispensed –
stable for 60 days
 Bad taste – can be masked with sweets, peanut butter
 A very “forgiving” drug
 Side effects
 Common: abdominal pain, nausea, headache, increase in blood
lipids
 Less Common: hyperglycemia, fat redistribution
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Role of the Multidisciplinary Team
 Non-clinicians may be the first to hear about a
medication toxicity. Their finding need to be
communicated to providers who should note
patient symptoms/signs in the medical record
 Decisions and follow-up should be discussed in
multidisciplinary team meetings
 Adherence needs to be discussed at every visit
and contact (clinician, counselors etc)
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Patient Education
 The parent/patient should be aware of what to
expect when starting ART and while receiving
ART
 The parent/patient should be aware of possible
side effects
 The parent/patient should know what to do if she
believes she is experiencing a side effect
(especially if this happens when the clinic is
closed)
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Case Study
 A 6 month old baby girl, Mulu, presents to the
clinic 12 days after her appointment date
 Mother complains Mulu has had a cough and
diarrhea for the last 2 weeks
 Mother was enrolled in PMTCT program and
both baby and mother took Nevirapine
 Baby was enrolled at the HIV clinic at 4 weeks
and started on cotrimoxazole prophylaxis
 Exclusively breastfed for 6 months, weaned with
no breastfeeding for last 2 weeks
 Weight gain normal for first 6 months
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Case Continuation
 Adherence to care has been poor with mother
missing many appointment dates
 Diarrhea has been persistent with loose watery
stools passed 6 times each day for the last 2
weeks
 Little improvement on oral rehydration therapy
 Cough has been progressive
 Unresponsive to Amoxicillin
 Fever, lethargy and poor feeding
 Chart shows 1st DNA PCR was negative at 6
weeks of age
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Clinical Exam
 Vitals: Weight 5.4 kg (1 month ago was 6.4 kg),
Temperature 37.8 C
 Some wasting present with mild dehydration
 Child irritable and listless
 Chest exam finds left sided bronchial breathing
 Rest of the exam is unremarkable
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Growth Chart
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Case Continuation
 Chest X-ray showed left lower lobe pneumonia
 Prescribe Erythromycin
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Oral rehydration therapy for diarrhea
Cotrimoxazole prophylaxis
Nutritional counseling and advice
Multidisciplinary team meeting planned
Follow up in 2 weeks
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Case Continuation
 Mother does not return till her 7 month visit
 Baby’s cough resolved, however diarrhea has
persisted
 No fever or vomiting noted
 Weight has dropped to 5.2 kg despite mother
following nutritional advice
 She is adherent to cotrimoxazole
 Stool studies from previous visit were normal
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Case Continuation
 Clinician is concerned this infant might have HIV
and need ART
 He sends DNA PCR, CD4, LFTs, CBC and
chemistry
 Oral rehydration therapy for diarrhea
 He sends mother for adherence training in
anticipation of starting ART at next visit
 Cotrimoxazole prophylaxis
 Nutritional counseling and advice
 Follow up in 2 weeks
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Case Continuation
 At her next visit her weight is unchanged (5.2Kg)
and diarrhea is still present
 DNA PCR is positive, CD4% done at 7 months
of age is 20%
 Baselines tests were within normal
 Is she eligible for ART?
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Clinical Question
 Considerations for starting ART
 Is family appropriately prepared?
 Does mother understand critical importance of good
adherence?
 Are there any clinical or laboratory contraindications
to specific drugs?
 What ART would you start?
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Case Conclusion
 Adherence counseling done and mother understands
importance
 She is put on:
 AZT: 6ml twice a day
 3TC: 3ml twice a day and
 NVP: 6ml once a day
 At next visit 1 week later, she has no new complaints
and is tolerating her medications,
 2 weeks later she has gained 500gm
 Since infant is tolerating medications well  escalate the dose of
NVP to 6ml twice a day
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Summary
 ART can provide life sustaining support for the HIV
infected child
 Using clinical staging and CD4 count can help identify
the 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 for adherence 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 in 63
assessing adherence and in monitoring the child on ART