Module IV: Paediatric ART Treatment

An Introduction to Antiretroviral Therapy

Key questions:What are ARVs?Why do we give ARVs to HIV infected children and adolescents?How do ARVs reduce the replication of HIV?What are the different ARV drug classes and types?What factors affect success of ART in children?

Why do we give ARVs to HIV infected children and adolescents?Suppress HIV replication and prevent disease progression.Restore and/or preserve the immune system reducing the risk of opportunistic Infections.Promote optimal growth and development

To reduce the HIV related morbidity & mortality of children and improve survival and quality of life. What do ARVs do?

Why do we learn about the structure and life cycle of the Virus?Understanding the structure helps us to know structures in the virus that helps it multiply in the human cell

Understanding the Life cycle helps us to know how the virus multiplies, where the ARV drugs work and how they are classified

Structure Of Human Immunodeficiency VirusHIV Core proteins1.P24 surrounds protein CoreEnzymes2.Reverse Transcriptaseconverts viral single-stranded RNAinto double stranded (DNA)3.Integrase. Integration of the viralDNA into the hosts chromosomalDNA.4.Protease splits generated macroproteins into smaller viral proteinswhich are then incorporated intothe new viral particles

HIV STRUCTURE

gp41

p17

p24

Core Proteins

RNA

Envelope Proteins

Matrix Protein

Envelope

gp120

HIV life cycle shows where the ARVs work

HIVLIFECYCLE

Insertion in Host Genome

HIVRNA

HIVmRNA

HIVRNA

HIVRNA

S. S. HIVDNA

HIVprecursorproteins

NEW VIRUS

RIBOSOMES

HIV LG. PROTEINS

REVERSETRANSCRIPTASE

INFECTING VIRUS

ASSEMBLY

D. S. HIVDNA

REVERSETRANSCRIPTION

INTEGRATION

Steps in HIV life cycleFusion and entry into human cell.

Reverse Transcription RNA-DNA.

Integration into host genome

Transcription and Translation of virus components

Budding and maturation of new virus particles

Video of Life cycle

What are the different classes of ARVs?

Nucleoside Reverse Transcriptase Inhibitors (NRTI)

Non- Nucleoside Reverse Transcriptase Inhibitors (NNRTI)

Protease Inhibitors (PI)

Integrase Inhibitors

Fusion Inhibitors (FI)

Which three classes are commonly used in Uganda?

Nucleoside Reverse Transcriptase inhibitors (NRTI) Fixed Dose CombinationsAZT/3TC/NVP (Douvir N) AZT/3TC (Combivir or Duovir)D4T/3TC/NVP (triomune)D4T/3TCAZT/3TC/ABC(Trizivir)

ABC/3TC(Epzicom)Tenofovir/Emtricabine(Truvada) Single Drugs: Zidovudine (AZT)Stavudine (D4T)Lamuvudine (3TC)Didanosine (DDI)Abacavir (ABC)TenofovirEmtricabineZaltacibine

Non Nucleoside Reverse Transcriptase InhibitorsNevirapine (NVP)

Efavirenz (EFV)

Delarvirdine (DLV)

Protease Inhibitorslopinavir/ritonavir (Kaletra/ Aluvia)RitonavirLopinavirAtazanavirDarunavirSaquinavir Nelfinavir Indinavir

New Classes

Entry/ Fuzion InhibitorsT20/ Fuzeon / Enfuvertide

Integrase InhibitorsRaltegravir

Principles of Paediatric Antiretroviral TherapyInitiate therapy with at least three drugs in a potent regimen Include at least two new agents when changing a therapy. Avoid using drugs previously used in a failing regimen (recycling) unless you have done resistance testingKeep doses at the upper end of dosing range Check childrens weights and adjust drug dosages at each visitMaximize adherence to ARTRationally sequence drugs to preserve future treatment options

What factors affect the success of ART?

PotencyToxicity / Interaction10 OR 20 ResistanceVirusDrugNon-AdherencePatientClinician, Nurse, Counsellor

Activity: Do you know the basics about ARVs?

Let us practice with a T/F quiz competition

Management of ART

Key questions:When should HIV+ve children be started on ART?What 1st line regimens are used to start ART?When do we substitute drugs in the 1st line regimen?How do we monitor children on ART?How do we make a decision to switch from a 1st line to 2nd line regimen? What 2nd line ARV regimens are used in Uganda?How can we identify an Immune Reconstitution Inflammatory (IRIS) event?

When are children supposed to start ART?1. Determine eligibility for ARTClinicallyImmunologically 2. Determine the readiness of the child to start ARVsDisclosure if appropriateAdherence counselingSocial life and current responsibilitiesBeing in and out of schoolFamily support Availability of trusted treatment supporter (Buddy)

3. Do a Pre-treatment (Baseline) AssessmentFull clinical assessment for infections & clinical stagingNeuro developmental assessment (include Tanner staging)Weight, length/height, head circumferenceDo HbCD4+ count Viral load (where available)4. Identify and prepare the main parent/caregiver Educate on giving the child ARVs and continuing with home careCounsel on caring for and living with an HIV infected child

Comparing 2006 and 2010 guidelines- What has changed?20062010

Immune markerAge-specific recommendation to initiate ART

START ARVSWHO clinical Stage 3 or 4?CD4 count

HIV + Rapid testHIV stage 4 conditionsAny 2 of the followingOral thrushSevere pneumoniaSevere sepsisRecent HIV related maternal death or CD4 %

Choosing a RegimenThe first line regimen is the best chance to achieve maximum and sustained viral suppression

Examples of Combinations to be avoidedTDF+DDILow potencyInteractionsTDF+ABCEarly treatment failure d4T+ddIMitochondrial ToxicityD4T +AZTCompetition for same site

Monitoring children on ART Rationale of monitoring

Assess effectiveness: Improvement or Treatment failure

Assess safety: Toxicity, Tolerability, Drug interactionsAssess adherence to the drugsTaking the correct regimen, correct dose, at the right time

How do we monitor children on ART? Clinical

Laboratory

Psychosocial

1st Visit after ART initiationReview understanding of HIV: disease process and adherence strategies

Observe accurate dosing and administration of drugs by caregiver

Full clinical assessment

Return visit in 2 weeks

Monthly clinical monitoringInterval medical history, symptom checkWt,Ht, physical exam, nutritional assessmentSide effects/toxicity, IRIS Assess adherenceAsk for demonstration of dose and administration of medication at each visitRecalculate doseDispense more dosesClinical monitoring

Laboratory monitoringImmunological testingCD4 counts: done every 6 months or if there are other features suggesting treatment failure

Virological testing- Done every 6 12 months if available

Lab monitoring

Lab test for diagnosis and monitoringBaseline ( entry into care)Initiation of 1st or 2nd regimenEvery six monthsAs required or symptom directedHIV diagnostic testing.Hb...WBC and differential.CD4% or absolute CD4 count....Preg. Test in adols.Chemistry.VL .OI screening..

*Psychosocial MonitoringProgress at schoolRelationships with family members, friendsAttitude to daily drug taking, adherenceProgress of disclosureDevelopment into adolescence sexual awareness, behavioural issues

What is substitution?

Substitution is the process of replacing one drug with another.

When or why do we substitute drugs in the 1st line regimen?

Main reasons for substitution of an ARV drug: Toxicity PregnancyDevelopment of OI like TB, Hep B., etcChange in treatment guidelines

Examples of substitution

DrugsReason to change the drugWhat to substitute withAZTAnaemia (toxicity)ABC or D4TEFVpregnancyNVPNVPTB treatmentEFVSteven Johnsons syndrome (toxicity)

When do we switch from 1st line to a 2nd line regimen?

Switch from one ARV regimen to another when there is Treatment Failure

Parameters used to assess ARV Treatment Failure include:Clinical Immunological Virological

Remember:

Always consult and discuss the case with a colleague before you substitute a drug or switch a regimen!

Immunological failure or not?Patient takes D4T+3TC+NVP for 1 year and 6 months.CD4 was measured at baseline (50 cells/ml), month 6 (143) , month 12 (247) , month 18 (220).Is this failure or not? Not enough indications to say its failure. CD4 physiological variation more probable. Look also at CD4%; less variable. In case of doubt, and before deciding on treatment switch, do another CD4 test (same machine, same lab) +/- 1 or 2 months later

What 2nd line to Use

National ART Paediatric Guidelines help us to:Decide when to start ARVsDecide on the 1st line regimen to useDecide the ARV regimen to use in special clinical conditions Identify a failing regimenDecide a 2nd line regimen to switch to

IRIS (Immune reconstitution Inflammatory Syndrome)DefinitionsPreviously quiescent diseases which become symptomatic or worse after the introduction of HAART (unmasking type)ORWorsening of symptoms of OIs that were already under effective treatment (TB, AC,CMV), shortly after starting HAART (paradoxical worsening)

How does IRIS come about?There is a quiescent disease like TB, MAC and a failed immune system.

On starting ART, the immune system begins to recover and mount an attack on these quiescent diseases. This makes the symptoms of the quiescent disease appear or re-appear if it was previously there

Comparison between IRIS and Treatment failure

ParameterIRISTreatment FailureOpportunistic infectionsWorsenWorsen CD4+ countsIncreaseDecreaseViral loadDecreaseIncrease

Treatment of IRISContinue ART (sometimes stop needed due to interactions or patients condition too bad)Treat the IRIS according to the presenting OI with the standard treatment for that condition e.g. TB (if already on Rx , intensification may be required) Add corticosteroids in case of severe inflammatory response e.g. dyspnoea due to large thoracic LN, or severe CNS (e.g. prednisolone 20-40 mg/day, 2 weeks-1 month)Use mechanical measures (drainage)Use of NSAID (ASA)

Activity: Case # 1 John is a one year old, HIV +ve child who was started on AZT+3TC and NVP at 2 months of age. The child has been adherent to his treatment. His CD4+ has fallen from 500 to 150 cells over 6 months. He was well until 2 weeks ago when he developed oral thrush. He has been treated with Ketoconazole with no improvement. Qn1: What is the Treatment stage?Qn2: Would you switch therapy in the child and why?

Qn3: what ARV regimen would you give?

Stage 3Length on treatment >24 weeks, Adherent to treatment yesThen switch because there is clinical and immunological failure.ABC +3TC+LPV/r

Activity: Case # 2Na-gundi is a 4 year old girl who has been on AZT+3TC+ NVP forthe past 3 months, and she has not missed her drugs. Hermother reports that she has developed symptoms of cough anddifficulty in breathing. Her mother also reports that she thinksthat Na-gundi gets a bit hot especially in the afternoon andsweats a lot at night. Na-gundi was treated with IV ceftriaxonefor 5 days with no improvement. Qn1: What could be the diagnosis in Na-gundi? Qn2: What other investigations would you do ?

Qn 3: Would you switch treatment in this child and why?

NoDuration on treatment= 12 weeksAdherence goodIf she has confirmed TB IRIS, substitute NVP for EfavirezIRIS TB PneumoniaSputum ZNCXRMantoux testEarly CD4+ counts

Practical 3Mukonogum is an 8 year old boy. He has been on AZT+3TC + NVP for 3 years now. He has been adherent and doing very well until 1 month ago when he developed skin rashes and pneumonia. His CD4 count when he started treatment was 200. His CD4 as per last month was 300. It was repeated 2 days ago and it was 90 cells/mm .From this information do you think Mukonogum is failing on his first line regimen?If yes, which regimen are you likely to switch him to?What factors do you need to clarify on before you initiate him on the second line?

Yes - Duration on ART >24 weeks, Adherent-Yes, Clinical failure- yes , Immunological failure-YesABC+ 3TC + LPV/RtrFactors for clarification: Adherence Tolerability (e.g. side effects)Pharmacokinetic issues(food/fasting requirementsDrug-drug interactionsPotency of current ARTsPrior ART experiencePotential for or known resistance

******HIV gains entry into the CD4 cell by binding onto receptors on the outside of the CD4 cell and fusing with the lipid outer layer of the cell.Gag: group specific antigen: core structural proteinsEnv gp120 and 41Pol: RT, integrase, proteaseRev (REgulator of Viral expression) and tat (TransActivator of Transcriptiondoubles transcription) control replicationNef downregulates expression of MHC 1 molecules, blocks apoptosisvpu, vpr prevents cells from mitosis, vif are accessory genes that contribute to viral replicationOnce inside the cell, HIV removes its outer coating, exposing its RNA, and releases reverse transcriptase enzyme to convert the HIV RNA to DNA.HIV DNA then enters the nucleus of the CD4 cell and is integrated into the host (CD4) DNAHIV gains entry into the CD4 cell by binding onto receptors on the outside of the CD4 cell and fusing with the lipid outer layer of the cell.Once inside the cell, HIV removes its outer coating, exposing its RNA, and releases reverse transcriptase enzyme to convert the HIV RNA to DNA.HIV DNA then enters the nucleus of the CD4 cell and is integrated into the host (CD4) DNA

***************Regimen 5:PI based regimen (LPV/R)NVP used for PMTCTOn anti TBKaposis Sarcoma

*******Check for school attendance record and enquire about stigmatization at school.Disclosure issues become more important as the child grows and begins to question more and more.The older child should be allowed to take charge of their drug-taking which can only be achieved after full disclosure and counseling.Tailor-made regimens to suit teen-agers may be considered.**************