Arv in Pediatrics

8/6/2019 Arv in Pediatrics

http://slidepdf.com/reader/full/arv-in-pediatrics 1/76

1

Pediatric AntiretroviralTherapy

International Center for AIDS Careand Treatment Programs

Columbia University

Mailman School of Public Health



2

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

International Center for AIDS Care and Treatment Programs, Columbia University



3

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




4

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



5

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




6

ART Eligibility




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




8

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


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



9

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




10

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.




11

Initiating ART




12

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




14

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




16

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?




17

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




18

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)




20

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




21

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




22

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




24

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




25

Zidovudine Toxicity

� Hematologic toxicity: granulocytopenia

and anemia

± May require dose reduction or interruption of therapy

� Gastrointestinal disturbance: anorexia,

nausea, vomiting

� Myositis, myopathy, mitochondrial disease




26

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




27

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




28

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




29

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




31

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




32

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




33

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




34

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




36

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




37

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




38

Monitoring Pediatric ART




39

How to Monitor ARV Therapy

� Clinical

� Laboratory

� Treatment adherence� Program adherence: keeping visit

appointments




40

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




41

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




42

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.




43

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




44

ART Toxicities




45

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




46

Possible causes of adverse

events among patients on ART� ART toxicity

� Immune reconstitution

� Intercurrent illness

� Disease progression

� Drug interaction

� Other?




47

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




48

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?




49

Step 2: Systematic Assessment

� Know the patient

� Know the drugs

� Know the timeframe




50

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?




51

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)




52

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?




53

Step 3: Managing Acute Drug

Toxicity

� Management should be based on

± Severity of event/potential for harm

± Implications for adherence




54

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




55

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)




57

Clinical Symptoms Requiring

Medication Switch




58

Laboratory Results Requiring

Medication Switch




59

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




60

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




62

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




63


First Line ARV

regime


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




64


Triple NRTI First

Line ARV regime


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




67

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.




68

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)


I l i i di t f



69

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




70

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




71

Role of the Multidisciplinary

Team




72

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.




73

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




75

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)


S mmar



76

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

Arv in Pediatrics

Documents

Transcript of Arv in Pediatrics