Pediatric Antiretroviral Resistance Challenges Thanyawee Puthanakit, MD The HIVNAT, Thai Red Cross AIDS research Center The Research Institute for Health Science, Chiang Mai University
Outline The burden of drug resistance in children The drug resistance mutations pattern in children failed NNRTI-based regimen Options for the second line therapy in children
HIV-infected children in Thai National AIDS program Gender Male Female Female 4,243; 54% Male 3,665; 46% Data as of Sep 2008, Slide collection: Dr. Sorakij
Thai National AIDS program HIV-infected children Age distribution Age distribution คน 1000 900 800 700 600 500 400 300 200 100 0 On ARV Total 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 ป Data as of Sep 2008, Slide collection: Dr. Sorakij
ARV regimen C 1% D 9% B 2% E 3% A,B,C: first-line D, E: second-line A 85% A B C D E Data as of Sep 2008, Slide collection: Dr. Sorakij
Result of viral load testing (5,925 tests) VL<2,000 VL=>2,000 VL=>2,000; 1,503; 25% VL<2,000; 4,422; 75% Data as of Sep 2008, Slide collection: Dr. Sorakij
The prevalence of virologic failure after first-line therapy Uganda Kamya MR. JAIDS 2007;46:187-93. 58/222 children (26%) had VL > 400 copies/ml at M12 Cambodia Janssens B. Pediatrics 2008;120:e1134-1140 15.5% had VL > 1,000 copies/ml at M12 3.7% had VL 400-1000 copies/ml at M12 Thailand Puthanakit T, Pediar Infect Dis 2007; 26: 953-6 18/107 (17%) had VL > 1,000 copies at M48 (include 10 had changed to PI-based regimen)
Risk factors of VL > 400 copies/ml at 12 Months in Cambodia Janssens B. Pediatrics 2008;120:e1134-1140.
Predictors of Long-Term Viral Failure Among Ugandan Children 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 Multivariate Analysis OR (95% CI) P OR (95% CI) P Male gender 1.48 (0.77to 2.83) 0.24 2.44 (1.20 to 4.93) 0.01 WHO stage -Stage III vs. stage I-II 0.93 (0.35 to 2.45) 0.88 2.68 (0.71 to 10.2) 0.15 -Stage IV vs. stage I-II 1.19 (0.041 to 3.43) 0.75 1.04 (0.16 to 6.72) 0.96 d4t-3tc-nvp vs. ZDV- 3TC-EFV Baseline CD4 <5% or <100 cell/mm3 (adults) 2.59 (1.20 to 5.59) 0.02 2.46 (1.23 to 4.90) 0.01 1.34 (0.74 to 2.40) 0.33 2.69 (1.28 to 5.63) 0.009 Kamya MR. JAIDS 2007;46:187-93.
NVP Resistance among Infants Failing Prophylaxis % with Resistance 100% 80% 60% 40% 20% SD NVP SD NVP, no maternal SD NVP AZT + SD NVP AZT + SD NVP, no maternal SD NVP 8% 13% 17% 20% 27% 33% 36% 53% 46% 42% 87% 0% Thai S Africa (NO mom NVP) Cote d'ivorie Thai Malawi (NVAZ NO mom NVP) Thai S Africa (with mom NVP) S Africa HIVNET 012 SAINT Malaw i (NVAZ with mom NVP) Clade: E,B C A E,B C E,B C C A,D C C CRF01, 06
Infants who exposed to NVP prophylaxis more likely to have Viral Failure with NVP-Based HAART Median age at start HAART 8.5 months Analysis after 6 months of HAART: 1/12 placebo group and 10/13 in SD NVP group had HIV RNA >400 copies/ml Lockman S, et al. NEJM 2007;356:135-47
Challenges: Optimal regimen A. Perform genotypic test and choose ARV depend on resistance pattern B. Use 2NRTI + boosted PI in all case who expose to NVP C. Use 2NRTI + NVP and perform viral load monitoring within 6 months D. Depend on severity of a child; - severe- use 2 NRTI + boosted PI, - mild/moderate- use 2NRTI + NVP
The drug resistance mutations pattern in children failed NNRTIbased regimen
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
Resistance drug mutation patterns in children with early virologic failure after NNRTI-based HAART 202 HIV-infected children, Aug 2002- Oct 2006 Monitor CD4, viral load q 6 month Genotypic resistance testing if plasma viral load > 1,000 copies/ml The average age of 7.1 yr, CD4 baseline 6.7% 61% NVP-based, 39% EFV-based Median follow-up time 209 weeks 40/202 (20%) had VL failure > 1,000 copies
The probability of non-virological failure in HIV-infected children received NNRTI-based first-line therapy
The pattern of NRTI mutation 100 89% 84% Percentage of children 80 60 40 20 18% 11% 5% 3% 0 Any NRTI M184V/I Any TAM K65R Q151M complex NRTI mutaions 3 TAMs
The pattern of NNRTI mutation 100 97% 80 60 40 20 0 58% 34% 18% 13% 5% 5% 5% 0% 0% 0% Any NNRTI L100I K103N V106A/M K108I Y181C/I Y188C/L/H G190S/A P225H M230L P236L Percentage of chilren NNRTI mutations
Options for the second line therapy in children
NRTI NNRTI PI Others Stavudine Nevirapine Lopinavir/r CCR5 inhibitor (Maraviroc) Didanosine Efavirenz Indinavir Integrase inhibitor (Raltegravir) Zidovudine TMC125 Saquinavir Antigp41 (Enfurvirtide) Lamivudine TMC278 Ritonavir Emtricitabine Abacavir Tenofovir Atazanavir (> 6 yr) Nelfinavir Fosamprenavir Darunavir Tipranavir DHHS guidelines, February 28, 2008. www.aidsinfo.nih.gov
WHO Recommended Second Line Regimen
New LPV/r pediatric tablet The mean (SD) C trough of LPV 8.2(5.7) and 8.2(5.4) mg/l Film-coated tablet of LPV/r 100/25 mg, 200/50 mg No need for refrigeration Take with or without food Need to swallow whole tablet Recommended dose 15-25 kg 2 tab 25-35 kg 3 tab > 35 kg 4 tab From the slide collection of Dr. Thanyawee Puthanakit
Early Failure: Efficacy of 2NRTI + lopinavir/ritonavir in 21 PI-naïve children (Failed 2NRTI+NNRTI) 15 of 21 were pre-treated with NRTI/NNRTI (median 3 TAMs) 100 90 80 70 60 50 40 30 20 10 0 86 71 100 92 6 months 12 months Viral load < 400 Viral load < 50 Delaugerre, et al. J Acquir Immune Defic Syndr 2004;37:1269 1275 Larru B, et al. J Antimicrobial Chemotherapy 2008: 61(1):183-90 4 years data on 69 PI-exp children
Tenofovir Most used NRTI in second line regimen in adults Retains some antiviral activity even when there is NRTI mutations Not approved for age < 18 years Potential toxicities in children Renal tubular diseases (Papaleo A, PIDJ 2007:26(10):949-51) Bone problems Investigational dose in children 2-8 years: 8 mg/kg once daily >8 years: 210 mg/m 2 once daily Maximum 300mg once daily Currently should be restricted to Older children (preferably tanner stage 4 and up) Children with multi-nrti/multiclass resistance and no other good options Need to monitor for growth, kidney and bone toxicity
Second-line regimen in children Retrospective cohort: 8 centers from Thailand 241 children failed NNRTI-based regimen Single-boosted (n=104) Double boosted PI (n=137) Age 8.9 (6.1-11.1) 9.4 (7.6-11.2) CD4% 17 (7-24) 6 (2-12) Plasma HIV RNA 4.5 (3.9-5.1) 4.9 (4.5-5.4) Multi NRTI resistance 11/89 (12.4) 69/114 (60.5) HIV RNA < 400 copies/ml 49/59 (83.1) 42/50 (84.0) CD4% gain (n=147) 7 (2-12) 10 (6-15) (Puthanakit and Ananworanich, et al. in preparation)
Pediatric Antiretroviral Resistance Challenges Strategies to maintain the success of firstline regimen Early detection of treatment failure to preserve second-line option ( VL monitoring) The availability of drug that is safe and easy to use in children for second-line drug
Acknowledgement Assoc. Prof. Kulkanya Chokephaibulkit Prof. Virat Sirisanthana RIHES, Chiang Mai University HIVNAT, Thai Red Cross Research Center Pediatric centers in Thailand for 086 study