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

22 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

33 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

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

55 a/ Entering to the CD4 cell Attachement to CD4 Infusion

66 Pathogenesis and mechanisms of ARVs b/ Reverse transcriptase HIV DNA

77 Pathogenesis and mechanisms of ARVs c/ Intergration

88 Pathogenesis and mechanisms of ARVs d/ Transcription HIV mRNA/Polyprotein

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

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

11 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 ARV drugs available in Vietnam

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 children Criteria 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 CD4 count <11 months 12–35 months 36 –59 months Not significant >35%>30%>25% Mild30-35%25-30%20-25% Advanced25-29%20-24%15-19% Severe < 25 % <20%<15% > 5 years > 500 cells 350 – 499 cells 200 – 349 cells <15%< 200 cells * Vietnam MOH, 2009 TLC of severe level < 4000< 3000< 2500< 2000

24 ART initiation in children ART 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 children Pre-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 children Evaluation 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 children Choosing ART regimen The 1 st 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 weeks is 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, whenever suspecting of anemia 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 and body 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, 1 st 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 or BW <10kg, 1 st trimester pregnant women, child with mental illness. Indication: When a child who 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 children Lab monitoring ActivitiesBaseline Time after ART 4 weeks 6 months 12 months every 6 months CD4 and % CD4 CBC/Hgb, ALT CBC for AZT regimen ALT for NVP regimen Pregnancy test When suspected Viral load (if patient can afford)

34 ART monitoring in children Adherence 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 children Monitoring ART outcome Findings of a good response to treatment: –Gained weight, height, active, obtain the growth milestone –Reduced risks for opportunistic infections. –Increased CD4 percentage 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 children Monitoring 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 ?