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Dr Ed Wilkins

3 rd Annual Conference of the Children’s HIV Association ‘ Young People and HIV: Back to the Future’. Dr Ed Wilkins. North Manchester General Hospital. Friday 15 May, The Bridgewater Hall, Manchester. Second and third line HAART.

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Dr Ed Wilkins

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  1. 3rd Annual Conference of the Children’s HIV Association ‘Young People and HIV: Back to the Future’ Dr Ed Wilkins North Manchester General Hospital Friday 15 May, The Bridgewater Hall, Manchester

  2. Second and third line HAART Dr Wilkins has received educational grants and speakers honoraria from several pharmaceutical companies

  3. Kids grow up

  4. Care slowly transfers Age distribution* of children in follow-up in 2007 in UK & Ireland PAEDIATRICIAN SHARED CARE ADULT

  5. HIV prognosis in children is improving Age at Death by Year of Deathfor Infected Children Age at death PACTG 219 3,553 children Median f/u 5.3 yrs 298 deaths 22 20 HAART 18 16 14 12 Median Age at Death (IQR) 10 8 6 4 Mean age at death 1994: 8.9 years Mean age at death 2006: 18.2 years 2 0 1994 1996 1998 2000 2002 2004 2006 Year

  6. As it is in adults: Patient survival if CD4 Counts ≥ 500 cells/mm3 Standardized Mortality Ratio = Mortality in HIV-infected patients / Mortality in General Population Lewden C, et al. J Acquir Immune Defic Syndr. 2007;46:72–77.

  7. What happens in childhood determines ARV success when an adult Many older children had sequential mono & dual therapy prior to starting HAART & may have had periods of inadequate adherence Leads to the development of multi-drug resistant virus Limits choices for effective therapy Necessitates more complex regimens • However • Newer drugs used for salvage in adults often less available in children • Lag in trial data and development of paediatric formulations Adapted from Carlo Giaquinto

  8. A small proportion of older children have 3-class failure/resistance Antiretroviral drug experience N=1110 children with follow-up since January 2006

  9. Many guidelines still informed by adult trial data

  10. Data on new drugs in ‘old’ classes 1 2 3 Fusion Inhibitor viral proteins cellmembrane 8 PIs NRTIs double strandedDNA viralmRNA genomicRNA genomicRNA 7 5 NNRTIs 4 proviral RNA 6 cell nucleus

  11. And new drugs in ‘new’ classes Entry inhibitors 1 2 3 Maturation inhibitors viral proteins Integrase inhibitors cellmembrane 8 double strandedDNA 7 viralmRNA genomicRNA genomicRNA 5 4 proviral RNA 6 cell nucleus

  12. Hence, many drugs are now available for adults Integ. Is Entry Is NRTIs NNRTIs PIs RTG T 20 AZT NVP SQV/r EFV MVC ddI RTV ETR ddC IDV d4T NFV 3TC APV ABC LPV/r ATV/r TDF FPV/r FTC DRV/r

  13. More drugs are becoming available for children Integ. Is Entry Is NRTIs NNRTIs PIs RTG T 20 AZT NVP SQV/r EFV MVC ddI RTV ETR IDV FTC d4T NFV 3TC DRV/r ABC LPV/r ATV/r TDF FPV/r

  14. NO ART Incidence 1.3/100 pt/yr HAART, no PI Incidence 1.4/100 pt/yr ART but not HAART Incidence 2.8/100 pt-yr HAART including PI Incidence 4.1/100 pt-yr Baseline ART useno ARTART, no HAARTHAART, no PIHAART + PI Censor783362371194 Count44213219 Total823782501413 Median–––– Toxicity issues have become more important Raised cholesterol in children on HAART 1.0 Cholesterol >5.69mmol/L: Entry: 13% of 2123 children Follow-up: additional 13% (median f/u 50.4 mos) Incidence 3.4/100 pt-yr 0.9 0.8 Proportion remaining With a normal cholesterol 0.7 0 6 12 18 24 30 36 42 48 54 60 Months to consecutive CHOL 220+ or censoring Tassiopoulos K et al. JAIDS 2008

  15. Numbers of children under care continues to increase 80 60 40 20 0

  16. 2nd and 3rd line HAART Evidence based Experience based

  17. Evidence based DRUG A ═ OUTCOME DRUGS B/C

  18. Experience based what works to begin with

  19. May not work forever

  20. CHIVA Guideline committee EVIDENCE-BASE and EXPERIENCE-BASE

  21. Second-line HAARTCHIVA guidelines 2008

  22. Additional information available • Past history of treatment and virological breakthrough • Daniel: presented aged 20m with severe chickenpox and failure to thrive

  23. Additional information available • Past history of treatment and virological breakthrough • Adherence assessment

  24. Additional information available • Past history of treatment and virological breakthrough • Adherence assessment • Forgiveness of particular combination Log concentration (ng/mL) Half-life: 24 hours Miss Dose Dose Dose Dose Dose MIC Day 1 Day 2 Day 3 Day 4 Day 5

  25. Additional information available • Past history of treatment and virological breakthrough • Adherence assessment • Forgiveness of particular combination • TDM • Trofile test

  26. Additional information available • Past history of treatment and virological breakthrough • Adherence assessment • Forgiveness of particular combination • TDM • Trofile test • Resistance test

  27. First HAART failure RESISTANCE TEST RESULT • No resistance • NRTI resistance only • NNRTI +/- NRTI resistant • PI +/- NRTI resistance • 3-class resistance ALL OPTIONS FEW OPTIONS

  28. First HAART failure LIMITED VIRAL LOAD FALL Poor adherence ANY COMBINATION ALL OPTIONS RESISTANCE TEST WILD TYPE VIRUS Likely no resistance FEW OPTIONS

  29. First HAART failure VIROLOGICAL BREAKTHROUGH Falling adherence NNRTI/2NRTI backbone ALL OPTIONS RESISTANCE TEST WILD TYPE VIRUS Possible NNRTI/3TC-FTC low-level minority resistance if on treatment at failure: depends on regimen forgiveness FEW OPTIONS

  30. Low- frequency NNRTI resistance increases risk of subsequent VF ACTG 5095 compared ZDV/3TC + ABC or EFV or ABC/EFV Sensitive assay performed for Y181C: (sensitivity: 0.03%) Reference: Y181C negative/Adherent 6.4 Standard GT resistant/Adherent Standard GT resistant/Non-adherent Standard GT sensitive but low level assay test resistant/Adherent Standard test GT sensitive but low level assay test resistant Y181C/Non-Adherent 7.1 3.6 6.1 20 1 2 5 HR for VF Sensitive = by bulk Y181C = by ASPC Paredes et al., Abstract 83, 15th CROI

  31. First HAART failure VIROLOGICAL BREAKTHROUGH Falling adherence PI/r/2NRTI backbone ALL OPTIONS RESISTANCE TEST WILD TYPE VIRUS PI resistance remote. Possible 3TC/FTC low-level minority resistance if on treatment at failure FEW OPTIONS

  32. First HAART failure VIROLOGICAL BREAKTHROUGH NNRTI/2NRTI backbone ALL OPTIONS RESISTANCE TEST >1 NRTI MUTATIONS Likely NNRTI low-level minority resistance if on treatment at failure FEW OPTIONS

  33. First HAART failure VIROLOGICAL BREAKTHROUGH PI/r/2NRTI backbone ALL OPTIONS RESISTANCE TEST >1 NRTI MUTATIONS Very low chance of PI resistance FEW OPTIONS

  34. First HAART failure VIROLOGICAL BREAKTHROUGH NNRTI/2NRTI backbone ALL OPTIONS RESISTANCE TEST NNRTI +/- >1 NRTI MUTATIONS FEW OPTIONS

  35. Fragility of Etravirine when NNRTI/NRTI mutations exist: comparison with boosted PI Woodfall et al, HIV8 2006

  36. Boosted PI’s after NNRTI/NRTI failure: Darunavir/r vs. Lopinavir/r (TITAN study) • Phase III randomised, controlled trial with primary analysis at Week 48 Treatment phase (96 weeks) Screening phase (4 weeks) DRV/r 600/100mg bid + OBR Treatment-experienced, LPV-naïve VL ≥1,000 copies/mL Stable HAART (≥12 wks) or STI (≥ 4 wks) LPV/r* 400/100mg bid + OBR 31% PI-naïve 77% NNRTI-experienced 785 screened, 595 patientsrandomised and treated • All patients received optimised background therapy • at least two or three ARVs from approved NRTI and/or NNRTI classes; enfuvirtide disallowed *LPV/r patients were allowed to switch to new formulation upon its approval by the regulatory authorities; VL = viral load; DRV/r = darunavir with low-dose ritonavir, LPV/r = lopinavir with low-dose ritonavir Valdez-Madruga J, et al. IAS 2007. Abstract TUAB101.

  37. TITAN: Viral load <400 copies/mL to Week 96 (ITT-TLOVR) 100 80 60 40 20 0 67% 59% Patients with HIV-1 RNA <400 copies/mL (% [95% CI]) Estimated difference in response versus LPV/r for non-inferiority:* PP = 8.7% (95% CI: 0.7–16.8) p<0.001 Estimated difference in response versus LPV/r for superiority:* ITT = 8.7% (95% CI: 0.7–16.7) p=0.034 Darunavir/r (N=298) LPV/r (N=297) 0 12 24 36 48 60 72 84 96 Time (weeks) *Derived from a logistic regression model including use of an NNRTI in the OBR as factor and baseline log10 plasma viral load as covariate; PP = per protocol Bánhegyi D, et al. 9th ICDTHI 2008. Abstract P22

  38. First HAART failure VIROLOGICAL BREAKTHROUGH PI/r/2NRTI backbone ALL OPTIONS RESISTANCE TEST PI +/- >1 NRTI MUTATIONS * Dependent on initial PI/r **TIP/r may be substituted on basis of resistance test FEW OPTIONS

  39. First HAART failure VIROLOGICAL BREAKTHROUGH PI/r/NNRTI/NRTI backbone ALL OPTIONS RESISTANCE TEST PI/NNRTI/NRTI MUTATIONS FEW OPTIONS *TIP/r may be substituted on basis of resistance test

  40. Second HAART failure VIROLOGICAL BREAKTHROUGH PI/r/NNRTI/NRTI experience ALL OPTIONS RESISTANCE TEST PI/NNRTI/NRTI MUTATIONS FEW OPTIONS *TIP/r may be substituted on basis of resistance test

  41. With 3-class failure Resistance mutations Increasing viral load Decreasing CD4 Clinical progression & ↓ options Time (years)

  42. Daniel • Diagnosed February 1998 • Admitted with severe chickenpox, failure to thrive • Mother Nigerian, father UK, no siblings • CD4 525 cells/mm3, CD4% 13, viral load 1,526,000 c/ml • Started treatment Feb 1998 with ZDV, DDI, 3TC • CD4 count increased to 746 (21%) and viral load fell to 100,402 c/ml by June 1998 • Since then 9 different combinations • Now 12 years old: CD4 842 (32%), viral load 2120 c/ml

  43. Current choice guided by Assess availableactive agents Treatmenthistory Currentand past resistance testing Assess individual situation, potential interactions and co-morbidities Assess abilityto adhere to future treatment options Interpretation of resistance tests Except in extraordinary circumstances, adding only 1 drug shouldbe avoided Trofile test

  44. Issues with Daniel • Good swallowing tablets but problems if too many • Would like to take once daily • Issues with refrigeration at home • Aware of HIV diagnosis • Stable family relationship but mother poorly and father away a lot • Doing well at school, plenty of friends • Achieved undetectable viral load previously

  45. Current choice guided by Assess availableactive agents Treatmenthistory Currentand past resistance testing Assess individual situation, potential interactions and co-morbidities Assess abilityto adhere to future treatment options Interpretation of resistance tests Except in extraordinary circumstances, adding only 1 drug shouldbe avoided Trofile test

  46. Daniel’s treatment history

  47. All resistance tests

  48. Current choice guided by Assess availableactive agents Treatmenthistory Currentand past resistance testing Assess individual situation, potential interactions and co-morbidities Assess abilityto adhere to future treatment options Interpretation of resistance tests Except in extraordinary circumstances, adding only 1 drug shouldbe avoided Trofile test

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