1. Antiretroviral Therapy in Children With Drug Resistance Virus By Kulkanya Chokephaibulkit, MD Department of Pediatrics Faculty of Medicine Siriraj Hospital Mahidol University By Kulkanya Chokephaibulkit, MD Department of Pediatrics Faculty of Medicine Siriraj Hospital Mahidol University

2. Recommended Drug Regimen to Start Preferred Options  AZT/ABC/d4T+3TC+ NVP/EFV For infants exposed to SD-NVP consider  AZT/d4T/ABC+3TC+ LPV/r THAILAND (2007)  AZT/d4T+3TC+ NVP / EFV (in > 3yo) First choice  2NRTIs+ LPV/r or NFV or  2NRTIs+EFV or NVP Preferred  2NRTIs+ LPV/r or ATV/r  2NRTI + EFV (or NVP in < 3Y) Choices of 2NRTI  AZT+3TC/FTC  ABC+3TC/FTC  ddI+FTC  TDF+3TC/FTC (>18yo)  May use AZT+ABC, AZT+ddI WHO (2008)EU (2004)USA (2008) AIDSinfo.nih.gov Sharland M. HIV Med 2004 www.who.intinfo.nih.gov

3. Children Do Not Response to HAART As Well As Adults VL and CD4 At 12 Months After Initiation of HAART Judd A. CID 2007;45:918-24.

4. In Usual Practice in UK By 6 Years of Treatment N=4306 Virological failure 38% >1 major mutation 27% Mutation > 2 drug classes 20% >>PI with RTV had lower risk of resistance The UK Collaborative Group on HIV Drug Resistance, UK CHIC Study Group

5. Survival of children who started HAART in Takeo and Siem Reap. Janssens B. Pediatrics 2008;120:e1134-1140. Effectiveness of HAART in HIV-Positive Children: Evaluation at 12 Months in a Routine Program in Cambodia Factors associated with VL>400 after 12 M of HAART is being orphans

6. Predictors of Long-Term Viral Failure Among Ugandan Children and Adults Treated With Antiretroviral Therapy Kamya MR. JAIDS 2007;46:187-93. Predictors of Virologic Failure at 12 Months 454 Adults Started on First- Line Therapy 222 Children and Adolescents Started on First-Line Therapy Multivariate Analysis OR (95% CI)P P Male gender1.48 (0.77to 2.83)0.242.44 (1.20 to 4.93)0.01 WHO stage -Stage III vs. stage I-II -Stage IV vs. stage I-II 0.93 (0.35 to 2.45) 1.19 (0.041 to 3.43) 0.88 0.75 2.68 (0.71 to 10.2) 1.04 (0.16 to 6.72) 0.15 0.96 d4T-3TC-NVP vs. ZDV- 3TC-EFV 2.59 (1.20 to 5.59)0.022.46 (1.23 to 4.90)0.01 Baseline CD4 <5% or <100 cell/mm3 (adults) 1.34 (0.74 to 2.40)0.332.69 (1.28 to 5.63)0.009

7. Clinical Criteria for Treatment Failure US and Thai –Progressive neuroldevelopmental deterioration –Growth failure –Severe / recurrent infection / illness WHO –New stage 4 condition (very same to AIDS) –May consider in new stage 3 condition

8. Immunologic Criteria for Treatment Failure US –For severe immunologic stage, CD4 response <5% (or < 50 cells) after 1 yr of Rx –CD4 decline >5% or to less than baseline Thai –Change in immunologic classification –In those with CD4 5% –Rapid decline (30% in 6 mo) WHO –CD4 decline to <15% in 1-3 yo., <10% in 3-5 yo., <100 cells in < 5 yo.

9. Failure Rate of NVP-Based VS EFV-Based regimens in Thai children (Siriraj Hospital): Median F/U = 3 yr 10/449/232/341/38- No. of failure needed to EFVNVPEFVNVP ExperienceNaive 1824 - Median duration of Rx before switching (mo.) (22.7%)(39%)(5.8%)(2.6%)switch from NNRTI All were switched to boosted PI or double boosted PI

10. Virologic Criteria for Treatment Failure US –Incomplete response to RX (VL decline 6 mo in experienced cases) or VL still > 400 after 6 mo –Viral rebound ( Increase >0.5log (3-fold) in >2 yo or >0.7 log (5-fold) in <2 yo) Thai –Same as US WHO –No criteria. However, if CD4 and clinical criteria are conflicting, then use HIV-RNA >100,00 copies/mL as consideration to change treatment

11. Some Facts Some patients who were on HAART may maintain clinical and immunological benefit up to 3 years despite detectable virus >> Patients who have persistent improvement of CD4 despite persistent viremia, should be considered to continue ART. However, if appropriate regimen is available, it is preferred to change before more resistance developed

12. Treatment Failure Defined by Immunologic Markers Alone May Result in Unnecessary Regimen Change in Resource-Limited Settings In 54 adherent, clinically stable patients with immunologic failure (category 3) –HIV-1 RNA >400 copies in 30 (56%) cases Median HIV-1 RNA: 93,686 copies/mL (range: 2611-694,993) –HIV-1 RNA <400 copies in 24 (44%) cases Basenero A, Castelnuovo B, Birabwa E, et al. 4th IAS, July 22-25, 2007; Sydney, Australia. Abstract WEAB102.

13. Number of Children Taking ART Under NHSO Was 7,908 (September 2008) www.nhso.go.th No. Age in Yr

14. Result of HIV-RNA Tests (N= 5,925 specimens) (September 2008) www.nhso.go.th

15. Resistance is probably the cause of failure if the patient takes medicine Fact: Imperfect adherence hasten the time to failure Fact: Imperfect adherence hasten the time to failure

16. Resistance Development While on 2NRTI+NNRTI Regimens Very early failure: 3TC-R: M184V Early failure: 3TC-R: M184V NNRTI-R: e.g.K103N, Y181C/I, Y188L, G190A/S Other NRTI-R: minimal or none Late failure: 3TC-R: M184V NNRTI-R: e.g.K103N, Y181C/I, Y188L, G190A/S TAMs: M41L, D67N, K70R, L210W, T215Y, K219Q/E

17. Drug Resistance Mutations in Adults Who Failed FDC of d4T/3TC/NVP Sungkanuparph S. CID 2007;44:447-52.

18. Predictors of Long-Term Viral Failure Among Ugandan Children and Adults Treated With Antiretroviral Therapy Kamya MR. JAIDS 2007;46:187-93.. Genotype Mutations CD4 Count Patient No. (Age in Years) RegimenAt 6-12 Months 1 (27)NVP, 3TC, d4TM184V, K103N 2 (31)NVP, 3TC, d4TM184V, K103N, T215Y 3 (26)NVP, 3TC, d4TM184V, K103N, G190A 4 (32)NVP, 3TC, d4TV751, M184V, Y181C, T69N, V751, T215Y 5 (41)NVP, 3TC, d4TM184V, K103N 6 (13)NVP, 3TC, d4TM184V, L210D, G190A 7 (16)NVP, 3TC, d4TM184V, K103N 8 (10)EFV, 3TC, d4TT69S, M184V, Y188L

19. Class-Sparing Regimens for Initial Treatment of HIV-1 Infection Riddler SA. NEJM 2008;358:2095—2106. +2NRTI P <0.003 @wk 96 +2NRTI EFV + 2NRTI has lower chance of virologic failure than LPV/r + 2NRTI. EFV+LPV/r was equal to EFV+2NRTI, but more likely associated with drug resistance.

20. Gupta R. CID 2008;47:712-22. Emergence of Drug Resistance After Receipt of First-Line HAART A Systematic Review of Clinical Trials at 48 wks by ITT Virologic Failure @ 48 wk NNRTI = 4.9% (3.9-6.1%) bPI = 5.3% (4.4-6.4%)

21. Prevalence of NRTI Resistance Among 95 HIV-infected Children Who Had Received Dual NRTI For > 6 Months NAMs, 60% had <4 NAMs, and 40% had NAMs. Lolekha R. CID 2005;40:309-12.

22. Interpretation of Genotypic Resistance NRTIs: –Any TAM: resist to AZT –TAM I pathway: More resistance; TAM II: still can use ddI, TDF –M41L + T215F/Y: resist d4T –2-3 TAMS may be able to use ddI, TDF, ABC –>3 TAMs: resist all NRTI –M41L, L210W, T215Y pathway is more resistant than D67N, K70R, K219Q/E –69 insertion+ T215Y+ 2 of M41L, A62V, K70R, L210W : resist to all NRTI –Q151M complex: Q151M+F77L+(A62V, V75I, F116Y): resist to all NRTI except TDF –L74V, K65R: resist to ABC and ddI –K65R: resist to TDF, but still susceptible to AZT TAM I: M41L, L210W, T215Y TAM II: D67N, K70R, K219Q, K219E

23. Drug Options for Salvage Regimens NRTI –AZT if no bad TAMs –ddI, TDF, ABC if < 4 TAMs, and no K65R –(TDF should not be used for <18 yo, and ABC is expensive) –3TC may still use with M184V to reduce fitness NNRTI: once resist, no option left PI: –LPV/r is excellent esp. for PI naïve –ATV/r is expensive, use with dyslipidemia –SQV is expensive, and only pill available –IDV/r is less potent and renal toxic

24. Interpretation of Genotypic Resistance NNRT: Any single mutation cause high level resistance PI: need more than 3-4 mutations to confer resistance –2 UPAM (universal PI-asso mutation) at 82, 84, and 90 position will resist to RTV, IDV, SQV, APV

25. Options for a Second-Line Regimen For Adults Who Failed FDC of d4T/3TC/NVP Sungkanuparph S. CID 2007;44:447-52. NRTI resistance patternOptions for the second-line ART regimen PI-based regimenBackbone NRTIs in settings without NRTI limitation M184V alone(Boosted) PIAZT plus ddI or TDF M184V plus TAMsBoosted PIddI plus ABC or TDF M184 plus K65RBoosted PIAZT plus ABC or d4T plus ABC M184V plus Q151M(Double) boosted PITDF plus? Q151M alone(Double) boosted PITDF plus? K65R alone(Boosted) PI3TC plus either AZT, ABC, or d4T No NRTI resistance(Boosted) PI3TC plus either TDF, ddI, AZT, ABC, or d4T

26. What Regimen to Change To (US) Guideline for the Use of Antiretroviral Agents in Pediatric HIV Infection Oct26, 2006 Initial RegimenRecommended Change 2 NRTIs+NNRTI- 2 NRTIs (based on resistance testing) plus PI 2 NRTIs+PI- 2 NRTIs (based on resistance testing) plus NNRTI - 2 NRTIs (based on resistance testing) plus alternative PI (with low-dose ritonavir boosting If possible, based on resistance testing) -NRTI(s) (based on resistance testing) plus NNRTI plus alternative PI (with low-dose ritonavir boosting if possible, based on resistnace testing) 3 NRTIs (recommended only in special circumstances) - 2 NRTIs (based on resistance testing) plus NNRTI or PI - NRTI(s) (based on resistance testing) plus NNRTI plus PI Failed regimens including NRTI, NNRTI, PI (recommended only in special circumstances) - >1 NRTI (based on resistance testing) plus a newer PI (with low-dose ritonavir, based on resistance testing)

27. RECOMMENDED SECOND-LINE REGIMENS IN INFANTS AND CHILDREN IN THE EVENT OF TREATMENT FAILURE OF FIRST-LINE REGIMENS First-line regimen at failure Preferred second-line regimen (A(II)) RTI components (NRTI/NNRTI) PI component 2 NRTI + 1 NNRTI AZT- or d4T- containing ABC + containing ddI + ABC ddI + AZT plus LPV/r Or SQV/r Or NFV Triple NRTI ddI + EFV or NVP WHO Guideline 2006

28. Nelfinavir Contamination with a carcinogen, ethyl methane sulfonate (EMS) during the production. Do Not Use

29. Problems of Drugs for Salvage Regimens for Children in Thailand ddI available in giant generic tablet to dissolve in water, unfriendly taste. ddI-EC is not available by NHSO, and not for young children. ABC is expensive and not available by NHSO TDF is available but can use only in adolescents and adults LPV/r available only in adult generic tablet (200/50), children need to cut the pill IDV is available, but the TDM is not feasible in routine SQV is expensive and not available by NHSO ATV is limited available, and only in adult tablet formulation

30. Lopinavir/ritonavir (Cap133/33, Tab 200/50, Tab 100/25) Heat stable tablet is easier Recommended dose using 200/50 mg tab: –15-25 kg 1 tab –25-35 kg1.5 tab –> 35 kg2 tab Study in 33 children (14 used 1.5 tab) at Siriraj, QSNICH, HIVNAT Mean Ctrough (SD) = 8.2 (5.7) using Abbott = 8.2 (5.4) mg/L using Matrix Abbott 133/33 mg Matrix 200/50 mg

31. Recommendation of Salvage Regimen in Thai Children Failing RegimensSalvage Regimens AZT/d4T+3TC +EFV/NVP - GPOvir S - GPOvir Z Preferred - ddI+3TC or ddI+ABC Plus LPV/r Use TDF(+AZT/3TC) if Tanner stage 4 or > 18 yo Alternative if > 3 (bad) TAMs esp. with high VL -Double boosted PI (e.g. LPV/r+SQV, LPV/r+IDV) +/-3TC Need good adherence, and close monitoring * TAM mutation = 41L, 215Y, 210W, 67N, 70R, 219Q/E

32. Salvage Regimen for The Patients Who Fail dual NRTIs Regimens If < 3 TAMs or good TAMs: –New 2NRTI + boosted PI If > 3 TAMs (esp” bad TAMs 41L, 210W, 215Y) : –NNRTI + boosted PI + 1-2NRTI Careful if to salvage with NRTIs + NNRTI Always check genotype if to continue NRTI

33. Advantages vs Drawbacks of Each PI AdvantagesDrawbacks LPV/r Highly effective High resistance threshold Liquid formulation available Need refrigerator Big size pill Expensive GI side effects, and dyslipidemia SQV/ r Good efficacy No dyslipidemia Dose only for >25 kg Big size, and many pills Expensive GI side effects IDV/r Effective Small and Less pill Kidney toxicity Need hydration Need blood level monitoring ATV/ r Highly effective No dyslipidemia Expensive May cause hyperbilirubinemia Use only for > 6 year-old

34. Efficacy of 2NRTI+lopinavir/ritonavir In 21 PI-naïve Children Who Failed 2NRTI+NNRTI Delaugerre, et al. J Acquir Immune Defic Syndr 2004;37 :1269-1275. 86 71 100 92

35. Factors Influencing Virologic Response (VL<400 copies/mL) In Children Receiving LPV/r Salvage Regimens ( Response in 56/67; 66%) Resino S. JAC2004;54:921-31. a Beginning of HAART protocol with LPV and other new drugs.

36. FDA Approved ATV In Children March 2008 ATV capsule can be used from >6 yo. It should be used with RTV It should not be used in <3 mo. Safety: Cough 21%Jaundice 13% Fever 19%Diarrhea 8% Headache 7%Running nose 6% Increase bilirubin 49% Efficacy at 24 wk, VL <50 Rx-naïve : 59% Rx-exp : 24% Increase CD4 : 171 cell/mm 3 http://www.aidsmap.com/en/news/80F577BE-9DFE-4796-B4A7-BC9E0CB33149.asp

37. Indinavir Plasma Levels at Different Dosage IDV can be used safely at 220-300 mg/M2 plus RTV 100 mg Indinavir Plasma Levels at Different Dosage IDV can be used safely at 220-300 mg/M2 plus RTV 100 mg IDV concentration, mg/L A B C D E 100 10 1.1 0.01 Dosage Children Adults Adults Children IDV 220-300 mg/M2 600mg 400mg 400 mg/M2 RTV 100mg 400mg/M2 100mg 100mg 125 mg/m2 Level associate with toxicity Minimum target trough Cressey TR, et al. JAC 2005;55:1041-4., Bergshoeff AS. AAC 2004;48: 1904-7. Plipat N, et al. PIDJ 2007;26:86-8

38. National Access Program to ART (NHSO) (September 2008) www.nhso.go.th A= AZT/d4T+3TC+NVP/EFVB= AZT/d4T+3TC+IDV/r intolerance to A C= ddI/TDF+3TC+IDV/r or NNRTID= 2NRTI + LPV/r D = others

39. At least half of the infants exposed to perinatal single- dose NVP developed NVP resistance. Infants may need SECOND-LINE regimen from the start! At least half of the infants exposed to perinatal single- dose NVP developed NVP resistance. Infants may need SECOND-LINE regimen from the start! Check genotype for NVP-R to all infants exposed to SD-NVP

40. Frequency of Development of NVP Resistance in Infants Rate (%) 0 10 20 30 40 50 60 70 80 90 100 NVP- R A1= NVP - NVP A2= NVP - NVP/AZT B1= NO - NVP B2= NO - NVP/AZT 87 57 74 27 Mom - Baby NVP-R reduced by eliminate maternal NVP and use of neonatal NVP+AZT Eshleman SH. JID 2006;193:479-81.

41. P<0.001 P= 0.39 VL <400 at 6 mo Rx N = 60 N = 158 Time from SD-NVP/Pla 58 100 88 92 23 90 Response to NVP-based HAART After Exposure to Peripartum SD-NVP (MASHI) Lockman S. NEJM 2007;356;11:135-47. Mean age of Rx initiation = 8 mo.

42. We Should Test for Drug Resistance in All Infants Exposed to SD-NVP More incidence of NVP-R in adults recently High rate of NVP-R in infected infants (50%) after single dose perinatal exposure What if Genotyping is not available May try NVP regimen with close VL monitoring Infants who have a very rapid disease progression should not try NVP regimen, but should get LPV/r

43. A Cases Scenario A 3 week old infant, healthy, came for F/U The mother received AZT from 34 week and SD-NVP at labour The infant received AZT+3TC+SD-NVP The PCR at birth was positive Need to start HAART ASAP, and check if there is NVP-R Don’t forget to give AZT+3TC plus NVP (SD or 2 wks) in high risk cases (late Rx, poor compliance)

44. Antiretroviral Drugs for Neonates Exposed to HIV Drugs Dose Duration Syr. AZT 2 mg/kg Q 6 hr 1-6 wks or 4 mg/kg Q 12 hr 1-6 wks SD- NVP 2 mg/kg @ 48-72 hr- old once (or twice) NVP 2 mg/kg Q 24 hr x 7 d total 2 wk then 4 mg/kg Q24 hr x 7 d Syr 3TC 2 mg/kg Q 12 hr 1-4 wk Thai-MOPH SD-NVP 2 mg/kg @ birth or 48-72 hr. + Syr. AZT 2 mg/kg Q 6 hr x1 wk if maternal AZT >4 wks OR x 6 wks if maternal AZT <4 wks

45. LPV/r in Infants Younger than 6 Month Slightly higher clearance than older children At 24 weeks, 53% had VL < 400 cp/mL Poor adherence is the problem of virologic failure Suggested dose in 6 mo) PACTG 1030: After 24 wks of LPV/r-HAART initiate before 6 mo, 70% had VL<50 cp/mL Chadwick EG. AIDS 2008; 11;22(2):249-55 Persaud D. JID 2007;195:1402-10

46. LPV/r-Based Versus NVP-Based HAART For Infants LPV/r Advantages: –Highly effective –Better immunologic response –Liquid formulation available –No pre-existing resistance –High resistance barrier Disadvantages: –Expensive –Not good taste –Should be refrigerated –Less experience in < 6 mo. (not approved) NVP Advantages: –Cheap, affordable in all settings –Better taste –Liquid formulation available –May be less effective –FDC available Disadvantages: –May have pre-existing resistance esp. from perinatal NVP use –Low resistance barrier –Potential A/E in 15-20% (hepatitis, rash)

47. Management of Some Adverse Events From ARV Switch ARV: –Anemia -> change AZT –Lipodystrophy -> change d4T –Rash, hepatitis-> change NVP (sometimes EFV) Dyslipidemia: start intervention when Cholesterol > 200 mg% LDL > 130 mg% Triglyceride > 200 mg% –Start with diet control, exercise –If not improve, consider switch to ATV (now approve from 5 yo.)

48. Prevalence of Dyslipidemia from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Fontas E. JID 2004;189:1056-74.

49. Rash from Nevirapine Rash from Nevirapine Found in 15-20% mostly within 2-4 wks (up to 12 wks) may associated with hepatitis Can’t be prevented by steroid Rx: stop NVP, antihistamine (+steroid)

50. Lipodystrophy Associated with Stavudine Mostly found in older children getting into puberty 1/3 improved after stopping d4T and with growth spurt Lipodystrophy Associated with Stavudine Mostly found in older children getting into puberty 1/3 improved after stopping d4T and with growth spurt

51. Phillips AN. The Lancet 2007;370:1923-8. Cumulative risk of extensive triple-class virological failure Cumulative risk of virological failure of for individual drug classes according to years from start of that class PI/r=ritonavir-boosted protease inhibitor. Risk of Extensive Virological Failure to The Three Antiretroviral Drug Classes An Observational cohort study

52. Lower Risk of AIDS If Stay On Failing Regimens French cohort 2000-2005 in patients with CD4 6 months Stay on Falling Regimen (> 1 drug) VL >500 Interrupt Rx VL >500 On HAART VL <50 N = 8783N = 2399N =4351 New AIDS event (per pt-yr.) 14.518.54.5 - New AIDS event associated with CD4 30,000 - Interrupt Rx had highest risk of AIDS Kousignian I. CID 2007;46:296-304

53. What need to investigate next in children? Double boosted vs single boosted PI in PI-naïve patients –From initiation of salvage –After successful viral suppression What to use after first-line PI resistance –New PI: Darunavir –New class: Integrase inhibitor, receptor antagonist

54. Second-line regimen in children Retrospective cohort: 8 centers from Thailand 241 children failed NNRTI-based regimen Puthanakit and Ananworanich, et al.-in preparation Single-boosted (n=104) Double boosted PI (n=137) Age8.9(6.1-11.1)9.4 (7.6-11.2) CD4%17 (7-24)6 (2-12) Plasma HIV RNA4.5 (3.9-5.1)4.9 (4.5-5.4) Multi NRTI resistance11/89 (12.4)69/114 (60.5) HIV RNA <400 copies ml49/59 (83.1)42/50 (84.0) CD4% gain (n=147)7 (2-12)10 (6-15)

55. Changes in Risk of Death After HIV Seroconversion Compared With Mortality in the General Population Bhaskaran K. JAMA 2008;300:51-9. 40.8 31.4 11.9 9.5 8.5 6.1 Excess Mortality (/1000 person year)

56. Adjusted Life Expectancy On CART In High-Income Countries An analysis of 14 cohort studies by year of F/U and baseline CD4 The average number of years remaining to be lived at age 20 years was about 2/3 of that in the general population in these countries. The Lancet 2008;372:293-9. 1996-92000-22003-51996-2005 CD4 <100 CD4100-199CD4 >200 At exact age 20 years 36.141.249.443.132.442.050.4 At exact age 35 years 25.030.137.331.727.030.437.2 % surviving from 20- 44 yr 75.5%79.5%85.7%81.1%59.8%80.6%89.9%

58. Next Challenging Issues For The Grown-Up HIV-Infected Children Disclosure: children need to know their diagnosis and get positive attitude before becoming adolescent Lifelong adherence Being a teenager –Sex issues –Peer’s acceptance –High risk behaviors Future education and career Making own family

59. Treatment Supportive Specific Palliative Care Givers & Family Care Provider Team

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