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Management of HIV Drug Resistance in children

Management of HIV Drug Resistance in children . Jintanat Ananworanich, MD, PhD Deputy Director in Scientific Affairs, HIV-NAT Chief, SEARCH The Thai Red Cross AIDS Research Center Jintanat.a@hivnat.org ; Jintanat.a@SearchThailand.org. Outline. Diagnosis of treatment failure

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Management of HIV Drug Resistance in children

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  1. Management of HIV Drug Resistance in children Jintanat Ananworanich, MD, PhD Deputy Director in Scientific Affairs, HIV-NAT Chief, SEARCH The Thai Red Cross AIDS Research Center Jintanat.a@hivnat.org; Jintanat.a@SearchThailand.org

  2. Outline • Diagnosis of treatment failure • Assessment of patients with treatment failure • Interpretation of genotypic resistance testing • Available ARVs for children • Sequencing of regimens • Response to second-line regimens • Triple class failure and response to third-line regimens • Darunavir, Etravirine, Raltegravir, Maraviroc • What to do when there are no good options US Guidelines for the Use of ART in Pediatric HIV Infection (Nov 2012). http://aidsinfo.nih.gov/contentfiles/lvguidelines/pediatricguidelines.pdf. Update of the Drug Resistance Mutations in HIV-1: March 2013, Topics in Antiviral Medicine (www.iasusa.org)

  3. Virological failure Viral load > 50 copies/ml after 1 year of ART (< 1 year old) after 6 months of ART (≥ 1 year old) Immunological failure • Incomplete CD4 response after 1 year of ART • CD4 decrease Clinical failure • Growth, neurodevelopment failure • OI/more severe HIV-related illnesses Thai Guideline. Puthanakit T, Asian Biomedicine 2010

  4. Immunological failure • Incomplete CD4 response after 1 year of ART • CD4 increase < 5% (< 15% + < 5 years old before ART) • CD4 increase < 50 cells (< 200 cells/mm3+ ≥ 5 years old before ART) • CD4 decrease • Continued decrease > 5% (< 15% at baseline) • CD4 decrease > 30% in 6 months

  5. Q1: With the viral load results below, does this 6-year old child have virological failure? Yes B) No

  6. Viral Blips • Isolated episodes of plasma viral load < 1000 copies/ml followed by return to viral load < 50 copies/ml • Common • Generally not associated with virological failure • Repeated episodes with viral load > 1000 copies/ml is more likely associated with virological failure

  7. Q2: With the viral load results below, does this 6-year old child have virological failure? Yes B) No

  8. Q3: With the viral load results below, does this 6-year old child need to switch treatment? Yes B) No

  9. Incomplete virologic response to therapy • Detectable viral load < 200 copies/ml • Often will have virologic suppression < 50 copies/ml without regimen change1 • Ongoing non-suppression • If receiving protease inhibitor • May achieve viral suppression with improved adherence • If receiving NNRTI • May have increased risk of resistance 1Ribaudo HJ, 2009 CROI (Abstract 580)

  10. PENPACT-1: Randomized switch at viral load 1,000 vs. 30,000 copies/ml PENPACT-1, Lancet Infectious Diseases 2010

  11. Q4: What to do for this child? • An 8 year-old child with pre-ART CD4 of 1% and 10 cells/mm3 and CDC C. After 2 years of GPOvir Z, viral load is < 20 copies/ml. He is stunted but otherwise well. However CD4 is only 5%, 98 cells/mm3, how would you manage this child? A) Switch ART to a different regimen B) Keep the same ART regimen

  12. Poor immunologic response despite virologicsupression • In Thai children starting ART at CD4 of 5%, only 50% had CD4 > 25% after 2 years despite VL suppression1 • More common in children who started ART at very low CD4 • In adults • May be at higher risk for mortality (mostly cardiovascular events)2 • In children, long term outcome is unknown • Possible causes • Lab error • Normal age-related CD4 decline (around 5-6 years of age) • Low pre-ART CD4 count • AZT • Use of other drugs (steroids, chemo) • Other conditions (hep C, TB, malnutrition, autoimmune disease, syphilis) 1Puthanakit, Ananworanich, PIDJ 2009; 2van Lelyveld SFL, AIDS 2012

  13. Assessment of patients with virological failure • Pharmacokinetic factors • Children require higher weight-based dosing than adults • Failure to increase dosing in children with rapid growth • Impaired absorption due to gastrointestinal problems • Drug interactions • Herbal medication • Over the counter drugs • Adherence • Side effects • Number and size of pills, frequency, food requirements • Familial and social issues

  14. Assessment of patients with virological failure • Drug resistance testing should be done when • Viral load is above 1000 copies/ml • Patient is taking the failing regimen or within 4 weeks of stopping the regimen Viral load every 6 months in the 2013 Thai guideline

  15. Q5: What to expect? A 14 year-old teenager has been on first-line GPOvir Z for 5 years with viral load < 50 copies/ml. She gives a history of perfect adherence but the last two viral loads over 6 months have been 19,200 and 54,000 copies/ml. You send a resistance testing today, what do you expect? A) M184V (3TC resistance mutation) B) Y181C, G190A (NNRTI resistance mutations) C) D67N, L210W, T215Y (NRTI resistance mutations) D) All above are correct E) No mutations

  16. Multi-NRTI Mutations • 69 insertion complex + TAMs at 41, 210 or 215 • 151 complex (Q151M+others, TDF not resistant) • Multi-NRTI resistance (≥ 4 thymidine analog mutations) Johnson VA, Topics in Antiviral medicine, March 2013

  17. NRTI mutations • K65R = tenofovir resistance (mainly selected by TDF, d4T) • AZT prevents K65R when used with TDF • M184V = 3TC, FTC resistance (delays TAMs) • TAMs = M41L, D67N, K70R, L210W, T215Y/F, K219Q/E

  18. NNRTI mutations • Resistance to NVP and EFV = require 1 major mutation • Universal cross resistance between NVP and EFV • Resistance to etravirine = require > 1 major mutation • K103N = no resistance to etravirine

  19. Q6: What is your next regimen? Your 14 year-old patient is failing GPOvir Z because of poor adherence. The family is going through bankruptcy. Her resistance testing shows • M184V (3TC resistance mutation) • Y181C, G190A (NNRTI resistance mutations) • D67N, L210W, T215Y (NRTI resistance mutations) She is willing to take second-line therapy. What is your next regimen? A) TDF + AZT + PI/r B) TDF + 3TC + PI/r C) ABC + ddI + PI/r D) ABC + 3TC + PI/r E) Other regimen

  20. Q7: What is the best regimen for this child? • A 12-year old girl failing first-line GPOvirZ with viral load 54300 copies/ml is here with her millionaire parents. You are consulted at a private hospital. Her resistance testing shows • M184V (3TC resistance mutation) • Y181C, G190A (NNRTI resistance mutations) • D67N, L210W, T215Y (NRTI resistance mutations) What is your next regimen? A) Raltegravir + PI/r B) 2NRTI + PI/r

  21. SECOND-LINE Study % patients with VL<200 c/ml Patients failed NNRTI-regimens RAL/LPV/r N= 270 83% 81% N= 271 NRTIs/LPV/r HIV-STAR study in Thai patients failing NNRTI 83% had VL< 50 after one year of TDF/3TC/LPV/r (Bunupuradah T, AVT 2012) Boyd M, Lancet 2013

  22. Recycle NRTIs + boosted PI: HIV-NAT 086 Study (n=104) Puthanakit T, Ananworanich J, AIDS Res Ther 2012

  23. PI mutations • Multiple mutations required for reduced activity • ATV/r and LPV/r have different patterns of resistance • DRV = negative impact by I47V (LPV), I84V (ATV) • but positive impact by V82A (LPV)

  24. Q8: Darunavir resistance • In patients who are failing LPV/r- or ATV/r-based second-line regimen, high level darunavir resistance is common A) True B) False

  25. Resistance to darunavir • Require 3 or more major mutations for reduced antiviral activity • In a UK cohort of 177 children failing PI • 1% had ≥ 3 darunavir resistance mutations • 3% had intermediate resistance • All these children had been on multiple PI (LPV/r and either nelfinavir, amprenavir, indinavir, fosamprenavir etc) • 0% of children who were on LPV/r only had intermediate or higher darunavir resistance Donegan KL, Antiviral Therapy 2012

  26. Integrase inhibitor mutations • Cross resistance is common between raltegravir and elvitegravir • Common mutations: N155H (early) and Q148H+G140S (late failure) • Elvitegravir needs boosting with ritonavir or cobicistat • Dolutegravir is the most potent integrase inhibitor and has higher • genetic barrier to resistance than the other drugs

  27. Current Available Antiretroviral Agents 2013in Adults (Available = 26) PI = 8 NRTI =7 NNRTI =4 Lopinavir/r (LPV/r) Atazanavir (ATV) Darunavir (DRV) Saquinavir(SQV) Indinavir(IDV) Nelfinavir(NFV) Fosamprenavir (fAPV) Tipranavir(TPV) Zidovudine(ZDV) Didanosine (ddI) Stavudine(d4T) Lamivudine(3TC) Abacavir(ABC) Emtricitabine(FTC) Tenofovir DF (TDF) Nevirapine(NVP) Efavirenz(EFV) Etravirine(ETR) Rilpivirine (RPV) Integraseinh =3 Entry inh =2 Boosters =2 Enfuvirtide(T-20) Maraviroc(MVC) Raltegravir(RAL) Dolutegravir(DTG)* Elvitegravir (EVG) Ritonavir(RTV) Cobicistat* (cobi) *In expanded access or submitted for regulatory approval Modified from the slide collection of Prof. Kiat Ruxrungtham

  28. Current Available Antiretroviral Agents 2013for Thai children (Available = 16) NRTI =7 NNRTI =3 PI = 4 Zidovudine(ZDV) Didanosine (ddI) Stavudine(d4T) Lamivudine(3TC) Abacavir(ABC) Emtricitabine(FTC) Tenofovir DF (TDF) Nevirapine(NVP) Efavirenz(EFV) Etravirine (ETR)* Lopinavir/r (LPV/r) Atazanavir (ATV) Darunavir (DRV)* Indinavir(IDV) Entry inh =0 Integraseinh =1 Booster =1 Raltegravir(RAL)* Ritonavir(RTV) *In expanded access program Modified from the slide collection of Prof. Kiat Ruxrungtham

  29. Antiretrovirals for children failing therapy

  30. Sequencing first-line to second-line regimen to third-line regimen Goal: 2-3 fully active drugs to achieve viral load < 50 copies/ml First-line Second-line Third-line AZT+3TC TDF+3TC* ≥1 NRTIs TDF+3TC AZT+3TC** PI/r (DRV/r) NVP LPV/r Integrase EFV ATV/r ETR DRV/r *TDF+AZT or ABC **ABC + 3TC Entry inh

  31. Sequencing first-line to second-line regimen to third-line regimen Goal: 2-3 fully active drugs to achieve viral load < 50 copies/ml First-line Second-line Third-line AZT+3TC TDF+3TC* ≥1 NRTIs TDF+3TC AZT+3TC** PI/r LPV/r NNRTI Integrase ATV/r Other PI/r ETR DRV/r Integrase *TDF+AZT or ABC **ABC + 3TC Entry inh

  32. Triple class failure • COHERE European cohort1 • Of 1007 children, 24% exposed to triple class and 10% had triple class failure • Risk of triple class failure at 5 years after ART is 12% (twice that in adults) • HIVNAT 113 Thai children2 • 44 children, majority failing LPV/r therapy (31% with > 6 LPV mutations. New regimen (mean 4.5 drugs) • All had darunavir/ritonavir, 20% had etravirine and 5% had raltegravir • At 7 months, 75% had viral load < 50 copies/ml • 10 (23%) had viral load > 1000 copies/ml due to poor adherence • French study of 12 triple class failing children3 • Median ART of 15 years. New regimen = Raltegravir + darunavir/ritonavir + etravirine • At 12 months, 92% viral load < 400 copies/ml, 50% viral load < 50 copies/ml 1COHERE, Lancet 2011; 2Ananworanich J, 2012 IAS; 3Thuret I, AIDS 2009

  33. Etravirine • Approved for ≥ 6 years old • Available in 25mg, 100mg, • 200mg tablets • Tablets can be dispersed • in water • In treatment-experienced settings, only use with boosted PI1,2 • Poor virologic response to ETR+2NRTI in first-line NNRTI failing • adults3 • Two scoring systems are used to assess level of resistance • (DUET and monogram weighted scores) 4 1Osterholzer D, HIV AIDS (Auckl). 2013 (review); 2Königs C, AIDS 2012; 3Ruxrungtham K, HIV Medicine 2008; Bunupuradah T, AVT 2011

  34. Using 100mg RTV with DRV resulted in appropriate PK ● 20-30kg, ■ 30-40kg, ▲ >40kg • All had Cmin > 0.55mg/L • Well tolerated Available in 75mg, 150mg, 300mg, 400mg, 600mg tablets Chokephaibulkit K, Ananworanich J, et al Antiviral Therapy 2012

  35. Raltegravir • P1093 US study of treatment experienced children age 2 to 18 years1,2,3 • Viral load < 50 copies/ml in 57% at one year (n=96) • Ongoing follow up and including younger children • Spanish study of 19 highly treatment experienced children4 • Mean age 16 years, 9 years of ART, triple class failure • On 1.5 years of raltegravir-based treatment, 68% had viral load < 50 copies/ml 1Clinical Trials.gov NCT00485264; 2Nachman S, 2012 CROI; 3Spector S, 2012 CROI; 4Briz V, PIDJ 2012

  36. Raltegravir • Approved for ≥ 2 years old • Free expanded access for chewable tablets for • children 2-12 years old (global@idispharma.com)

  37. Maraviroc • Is CCR5 inhibitor a therapeutic option for children with treatment failure? • 51 children in France with 8 years of ART and 6 drugs1 • 70% still has CCR5-tropic virus • CXCR4 virus is associated with cumulative exposure to viral replication (high HIV DNA) • Dosing depends on concomitant ARV (approved for ≥ 16 years) • Dosing 300mg BID • Higher dosing with EFV and ETR (600mg BID) • Lower dosing with PIs (150mg BID) 1Frange P, AIDS 2012

  38. Q9: What to do when there is extensive resistance? A 14-year old child with exposure to multiple ARVs in the past is now failing her second-line therapy (TDF, 3TC, LPV/r) despite good adherence. Her viral load is 3,500 copies/ml and CD4 is 620 cells/mm3. Resistance testing showed multi-NRTI resistance, K65R, ETR resistance, > 6 LPV/r mutations and partial resistance to DRV/r. What is your management of this case? A) Switch her to third-line using DRV/r + NRTIs B) Keep her on the same regimen while waiting for new drugs to become available

  39. No fully active drugs • Options • Continue failing regimen • Discontinue failing regimen • Simplify failing regimen • Switch to new regimen • Goal of continuing incomplete suppressive until new drugs become available • Minimize HIV clinical and immunological deterioration • Proportion of children experiencing WHO grades 3 and 4 events at 2.5 years of follow up is 10% if viral load ≤ 5000 copies/ml vs. 25% if viral load > 5000 copies/ml1 • Risk • Accumulation of resistance mutations 1Oliveira R, Clin Infect Dis 2010

  40. Q10: What to do for teenagers with poor adherence to second-line regimen? A 16-year old boy is failing TDF, 3TC, LPV/r for the past 1 year because of poor adherence despite all efforts to help him by the health care team. His CD4 is 430 cells/mm3 and viral load is 67,000 copies/ml. He has some NRTI and PI mutations. What is your management? A) Interrupt all ART B) Partial interruption by continuing only 3TC C) Partial interruption by continuing TDF/3TC D) Continue failing regimen E) Switch to third-line regimen with DRV/r

  41. Lamivudine holding therapy in adults with M184V 3TC no 3TC 3TC no 3TC Castagna A, AIDS 2006

  42. Partial treatment interruption • 21 subjects with resistance to NRTIs + PI regimen • Age 7 years, CD4 27%, 712 cells/mm3, viral load 4 log • Interrupt PI for 48 weeks • Continued NRTIs – mostly AZT or d4T + 3TC • CD4% significantly declined • No change in viral load • No new CDC clinical events Abadi J, JAIDS 2006

  43. New drugs • Dolutegravir • Will be approved soon for adults failing raltegravir or elvitegravir • Superior virologic suppression compared to raltegravir1 • Ongoing studies in children • Elvitegravir available in QUAD pill • TDF, FTC, elvitegravir, cobicistat • Similar virological suppression compared to raltegravir2 • Approved for ≥ 18 years old • Rilpivarine • Poorer virological response than efavirenz when viral load > 100,000 copies/mlbut fewer side effects • Only recommended for use when viral load < 100,000 copies/ml 1Cahn P, Lancet. 2013; 2Elion R, , JAIDS 2013; 3Rimsky L, Antiviral Ther 2013

  44. Conclusion • It is important to monitor viral load for early detection of virological failure • Before switching treatment due to failure, always confirm with viral load testing and extensively discuss adherence • Delayed switch is associated with accumulation of resistance particularly if on NNRTI regimen • Recycle NRTIs + boosted PIs is effective in more than 70% of failing NRTI/NNRTI first-line patients • The regimen that will most likely be used in triple class failing patients is ≥ 1 NRTIs + DRV/r ± ETR ± RAL • Approved drugs for treating children with ART failure: TDF (≥2 yrs), ETR (≥6 yrs), DRV/r (≥3 yrs) RAL (≥2 yrs), MVC (≥16 yrs)

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