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Antiretroviral Therapy in Children With Drug Resistance Virus

Antiretroviral Therapy in Children With Drug Resistance Virus. By Kulkanya Chokephaibulkit, MD Department of Pediatrics Faculty of Medicine Siriraj Hospital Mahidol University. Recommended Drug Regimen to Start. USA (2008). EU (2004). WHO (2008). Preferred 2NRTIs+ LPV/r or ATV/r

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Antiretroviral Therapy in Children With Drug Resistance Virus

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

  2. Recommended Drug Regimen to Start USA (2008) EU (2004) WHO (2008) • 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 • First choice • 2NRTIs+ LPV/r or NFV or • 2NRTIs+EFV or NVP • 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) AIDSinfo.nih.gov Sharland M. HIV Med 2004 www.who.int

  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. 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 Janssens B. Pediatrics 2008;120:e1134-1140.

  6. Predictors of Long-Term Viral Failure Among Ugandan Children and Adults Treated With Antiretroviral Therapy Kamya MR. JAIDS 2007;46:187-93.

  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 <15%, persistent decline >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 Naive Experience NVP EFV NVP EFV - No. of failure needed to 1/38 2/34 9/23 10/44 switch from NNRTI (2.6%) (5.8%) (39%) (22.7%) - Median duration of Rx before switching (mo.) 24 24 24 18 All were switched to boosted PI or double boosted PI

  10. Virologic Criteria for Treatment Failure US Incomplete response to RX (VL decline < 1 log after 3 mo of Rx (>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) No. Age in Yr www.nhso.go.th

  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

  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..

  19. Class-Sparing Regimens for Initial Treatment of HIV-1 Infection 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. P <0.003 @wk 96 +2NRTI +2NRTI Riddler SA. NEJM 2008;358:2095—2106.

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

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

  22. Interpretation of Genotypic Resistance TAM I: M41L, L210W, T215Y TAM II: D67N, K70R, K219Q, K219E • 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

  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.

  26. What Regimen to Change To (US) Guideline for the Use of Antiretroviral Agents in Pediatric HIV Infection Oct26, 2006

  27. RECOMMENDED SECOND-LINE REGIMENS IN INFANTS AND CHILDREN IN THE EVENT OF TREATMENT FAILURE OF FIRST-LINE REGIMENS 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 kg 1.5 tab • > 35 kg 2 tab Abbott 133/33 mg Matrix 200/50 mg 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

  31. Recommendation of Salvage Regimen in Thai Children * 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

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

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

  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/mm3 http://www.aidsmap.com/en/news/80F577BE-9DFE-4796-B4A7-BC9E0CB33149.asp

  37. 100 Dosage Children Adults Adults Children IDV 220-300 mg/M2 600mg 400mg 400 mg/M2 RTV 100mg 400mg/M2100mg 100mg 125 mg/m2 10 IDV concentration, mg/L 1 .1 0.01 A B C D E Indinavir Plasma Levels at Different Dosage IDV can be used safely at 220-300 mg/M2 plus RTV 100 mg Level associate with toxicity Minimum target trough Bergshoeff AS. AAC 2004;48: 1904-7. Plipat N, et al. PIDJ 2007;26:86-8 Cressey TR, et al. JAC 2005;55:1041-4.,

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

  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! Check genotype for NVP-R to all infants exposed to SD-NVP

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

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

  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 = 300/75 mg/M2 (vs 230/57.5 mg/m@ 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 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) LPV/r-Based Versus NVP-Based HAART For Infants

  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 • 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

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