INTRODUCTION TO ANTIRETROVIRAL THERAPY (ART) IN CHILDREN: INITIATION AND MONITORING

1. INTRODUCTION TO ANTIRETROVIRAL THERAPY (ART) IN CHILDREN: INITIATION AND MONITORING HAIVN Harvard Medical School AIDS Initiatives in Vietnam

2. Learning objectives By the end of the presentation, participants will be able to understand: • ARVs available in Vietnam and their mechanisms of action • ART principles • Undesirable effects of ARVs. • Considerations in pediatric ART. • When and what to start ART in children • How to monitor ART in children

3. Contents • Pathogenesis and mechanisms of ARVs. • ARV drugs available in Vietnam. • ART principles • ARV undesirable effects. • Considerations in pediatric ART. • ART initiation in children • ART monitoring in children

4. Pathogenesis and mechanisms of ARVs Weiss, R. Nature, 2001

5. Pathogenesis and mechanisms of ARVs a/ Entering to the CD4 cell Attachement to CD4 Infusion

6. Pathogenesis and mechanisms of ARVs b/ Reverse transcriptase HIV DNA

7. Pathogenesis and mechanisms of ARVs c/ Intergration

8. Pathogenesis and mechanisms of ARVs d/ Transcription HIV mRNA/Polyprotein

9. Pathogenesis and mechanisms of ARVs e/ Assemble and budding Action of Protease and recombination of virus

10. Fusion/Entry Inhibitors (2) Protease Inhibitors (10) Pathogenesis and mechanisms of ARVs Reverse Transcriptase Inhibitors (14) Integration Inhibitors (1)

11. ARV drugs available in Vietnam AntiRetroViral drugs – ARVs could be classified as 3 main groups: a/ Reverse transcriptase inhibitors: • Nucleoside Reverse Transcriptase Inhibitors = NRTIs. • Non - Nucleoside Reverse Transcriptase Inhibitors = NNRTIs. b/ Protease Inhibitors = PIs c/ Infusion inhibitors: enfuvirtide

12. ARV drugs available in Vietnam • Reverse transcriptase inhibitors: Mechanism of action: • Inhibit reverse transcriptase • Similar to Nucleoside (structure unit of ADN) or not • Replace viral nucleosides in DNA strand • Block reverse transcriptase • Inhibit the viral replication.

13. Reverse transcriptase inhibitors • NRTIs are available: • Zidovudine (AZT, ZDV, Retrovir) • Didanosine (ddI, Videx) • Lamivudine (3TC, Epivir) • Abacavir (ABC, Ziagen ) • Stavudine (d4T, Zerit) • Tenofovir Fixed dose combination (FDC) • AZT + 3TC = Combivir, Lamzidivir • AZT + 3TC + ABC = Trizivir • D4T + 3TC + NVP = Junior • NNRTIs are available: • Nevirapine (NVP, Viramune) • Efavirenz (EFV, Stocrin, Sustiva) Fixed dose combination (FDC) AZT + 3TC + NVP = Triamune, GPOvir

14. ARV drugs available in Vietnam • Protease Inhibitors: Mechanism: • Inhibit the protease which cleaves proteins for synthesizing a virus Available: • Lopinavir/Ritonavir (LPV/r, Aluvia) • Atazanavir

15. ART principles • Goals of ART: • To inhibit viral replication, to retain virus load under detection limit. • To restore the immune sysetem, reduce the opportunistic infections. • To improve the quality of life, prolong the survive for the children. • To maintain the physical and mental development and growth. • The regimen always include at least 3 drugs: • Current regimens recommended: • Two NRTIs combine with one NNRTI, or: • Two NRTIs combine with one PI.

16. ART principles • ART is one of the comprehensive treatment factors including nutritional, social and psychological components. • ART is for life; adherence is essential to prevent drug resistance. • Opportunistic infections prophylaxis is needed when the immune system is not recovered.

17. What is adherence? • ART is lifelong treatment • 100% adhere to the treatment • Maximize the treatment efficacy • Avoid the side effects • Prevent drug resistance. • Treament adherence: 5 right things • Right medications • Right dosages. • At right time • In right ways. • Under right conditions EVERY DAY AND FOR LIFE WIH ARVs !!!

18. Undesirable effects of ARVs • Including: • Side effects • Interactions.

19. Side effects of ARVs • 4 grades of ARV side effects: mild, moderate, severe and life threatening: • Grade 1(mild): Symptomatic treatment, keep the regimen unchanged. • Grade 2 (moderate): • Keep on ARVs, symptomatic treatment, change the offensive drug if the patient does not get better. • Lipodystrophy or peripheral neuropathy: change the offensive drug. • Grade 3 (severe): Do not change ARV regimen, just change the drug that induce the side effects. • Grade 4 (life threatening): • Stop ARVs, symptomatic management. • If the symptoms get better, change the ARVs that induces the toxicity.

20. ARV interactions Some ARVs can interact each other or with other drugs: • Reduce the concentration: E.g: Rifampicin reduces the plasma NVP concentration. • Or increase the toxicity: E.g: • d4T + ddI: ↑ toxicities (neurology, lactic acidosis, liver steatosis) • d4T + AZT: antagonist. • ddI + IDV: each should be taken with empty stomach, but never keep these 2 drugs taken together.

21. Considerations in pediatric ART • ARVs for children are prepared in 2 forms: • Liquid formulation: for children < 3 year-old, or < 10 kg. • Pills: capsules or tablets prepared with various strength: Fixed dose combination of 3 drugs: pills for better adherence. • Pediatric dosages should be calculated with body weight or skin area. • Choose drug formulation appropriate to the body weight, do not chop/divide pills. • It is required to instruct how to divide and calculate the drug doses. • It is necessary to store liquid of d4T, ddI and LPV/r in a fridge.

22. ART initiation in childrenCriteria for initiating ART • For those with confirmed HIV infection: • Children < 12 months : • Treat immediately, regardless of clinical staging or CD4. • Children ≥ 12 months : • Clinical stage 3, 4, regardless CD4 count. • Treat for TB, LIP, OHL, thombocytopenia first if CD4 > “severe” level. • Clinical stage 2 &CD4 (or total lymphocyte count) < “Severe“ level • Clinical stage 1 & CD4 < “ Severe“ level by age. • Children < 18 months with diagnosis of severe clinical HIV/AIDS disease.

23. Immunological staging * Vietnam MOH, 2009

24. ART initiation in childrenART readiness Pre- ART assessment: • Clinical and immunological staging. • Screening for TB and other OIs, specialized consultations as needed. • OI Management, if available. • Blood testing for choosing proper regimen: CBC/Hgb, ALT/AST. • Past medical history of ART (mother to child): reasons, regimen; adhrerence, progress. • Nutritions, family situation, willingness for ART. • Proposed an ART regimen. • Inform caregivers about the schedule for ART. • Cotrimoxazole and other prophylaxes if indicated.

25. ART initiation in childrenPre-ART counseling • Progression of HIV, benefits of treatment, ARVs will be indicated. • The importance of adherence and the methods to enhance the adherence. • The regimens– How to calculate the dose and how to store the drugs. • How to manage side effects. • Make plan for caregivers, how to monitor patients at health facilities or at home.

26. ART initiation in childrenEvaluation of ART readiness • Understandings of caregivers about HIV basics, ART, adherence. • Provide the counseling if patient has not got enought the understanding. • Reduce the time for counseling if patient is in emergency situation. • Check for personal information: residence, address, social supports. • Caregiver signs in the consent form for participating the ART program. • Emergency cases: Provide ARV and make plan for every counseling sections, or put patient as a inpatient.

27. ART initiation in childrenChoosing ART regimen • The 1st line regimen is indicated for every naive child. • Preferred regimen: AZT + 3TC + NVP • Alternative regimens: d4T + 3TC + NVP AZT/d4T + 3TC + EFV AZT/d4T + 3TC + ABC • If patient was on PMTCT regimen includes NVP, do not use NVP within 12 months. • Preferred regimen: AZT + 3TC + LPV/r • Alternative regimens: d4T + 3TC + LPV/r ABC + 3TC + LPV/r AZT/d4T + 3TC + NVP

28. Regimen AZT + 3TC + NVP • Indications: Naïve patient to NVP or has taken for >12 months • Remember: • NVP dose at the first 2 weeksis always as a half dose, increasing the dose after 2 weeks. • Take drug every 12 hours, with food or empty stomach. • Blood examinations: Hgb, ALT:pre ART, after 1, 6 months, wheneversuspecting ofanemia or liver toxicity. • Do not use this regimen if Hgb < 80 g/l; • If a patient is on ART, Hgb < 70 g/l then change AZT • Be careful if ATL elevated> 2,5 times, patients are on TB Rx with rifampicin regimen.

29. Regimen d4T + 3TC + NVP • Indications: When a child can not be on AZT. • Remember: • NVP dose for first 2 weeks should be a half. • Take drugs every 12 hours with food or without food. • ALT should be done before ART, after 1 month and then every after 6 months. • Be careful if a case if ATL> 2,5 normal range, or if a patient is on ART regimen including rifampicin.

30. Regimen AZT + 3TC + EFV • Indications: When a child is not indicated for d4T and NVP, a child > 3 years old andbody weight >10kg who is on TB treatment with rifampicin regimen. • Remember: • AZT + 3TC: Take every 12hours, EFV at bed time or after meal 2-3 hours. • Check CBC for Hgb: pre-ART, after 1 month,after 6 months, or whenever suspecting of anemia. • Contra-indication when Hgb < 80 g/l. • If a child is on ART, now develops Hgb < 70 g/l, replaced by AZT. • Contra-indicated this regimen if a child is under age of 3, under <10kg, 1st trimester (3 months) pregnant women, a child who has a mental illness.

31. Regimen d4T + 3TC + EFV • Indications: When a child is not on NVP and AZT, or a patient who is on TB drugs, but > 3moths old and > 10kg. • Remember: • Take d4T + 3TC every 12 hours, take EFV at bed time and after meal 2-3 hours. • Contra-indication for a child <3 years old orBW <10kg, 1st trimester pregnant women, child with mental illness. • Indication: When a childwho can not use NVP and EFV,a child is on TB regimen including rifampicin but<3 years old& <10kg. • Remember: This regimen is not widely recommended. Regimen AZT/d4T + 3TC + ABC

32. ART monitoring in children Monitoring clinical progress: • Physical and mental assessment. • Monitor and detect: • ARV side effects. • Opportunistic infections. • IRIS. • Treatment failure. • Hospitalization, consultation, referral as needed. • For females:Check the pregnancy in order to change efavirenz for the first 12 week of pregnancy.

33. ART monitoring in childrenLab monitoring

34. ART monitoring in childrenAdherence monitoring • Adherence assessment at every visit: • Listen to the report from caregiver, put the questions, ask about how to manage in case a patient forgot to take a dose. • Counting the drugs, clinical and lab monitoring. • If adherence is not good: • Check why patient is not good adherence. • How to manage the barriers/obstacles for adherence. • What to do when a patient missed a dose: • Take drug as soon as remember missing a dose. • Calculate the time taking the drug to the next dose: • If it is> 4 hours:Take the dose as planned as before. • If it is< 4 hours:wait until the duration between 2 doses should be enough for 4 hours. • If missing more than 2 doses:ask the doctors.

35. ART monitoring in childrenMonitoring ART outcome • Findings of agood response to treatment: • Gained weight, height, active, obtain the growth milestone • Reduced risks for opportunistic infections. • Increased CD4percentage and absolute number. • If a child who is good response to the treatment: • Continue the regimen, adjust the dose for every visit. • Continue to provide counseling, support for adherence and nutrition. • Drug filling and make the appointment for the next visit.

36. ART monitoring in childrenMonitoring ART outcome • If a patient dose not respond to the treatment or develops a new opportunistic infection: • Provide adherence counseling, increase the adherence support. • Provide counseling and support for nutrition. • Try to find out the reasons: • Side effects • Interaction • IRIS, or • Treatment failure.

37. Key points (1) • ARVs available in Vietnam include: • NRTIs: d4T, AZT, 3TC, TDF, ddI, ABC • NNRTIs: NVP, EFV • PIs: LPV/r (Aluvia), ATV/r • Main goal of ART: To inhibit viral replication, to retain virus load under detection limit. • The regimen always include at least 3 drugs. • 2NRTIs + NNRTI, or 2NRTI + PI. • ART is for life, adherence is essential. • Calculate doses according to the body weight or skin area. • Always remember and look up side effects and interactions.

38. Key points (2) • ART criteria • with confirmed HIV infection • < 12 months • ≥ 12 months: Clinical stage 3, 4 and/or CD4 count/TLC at “severe” level • Diagnosis of severe clincal HIV/AIDS disease • Ensure ART readiness before starting ART • Preferred first line regimens: • For naïve patient: AZT + 3TC + NVP • For patient <12 month exposed to NVP in PMTCT: AZT + 3TC + LPV/r • ART monitoring should be based on clinical assessment, lab tests and adherence.

39. Thank you! Questions ?