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Lopinavir /ritonavir in children

A randomized study comparing low dose versus standard dose lopinavir /ritonavir among HIV-infected children with virological suppression .

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Lopinavir /ritonavir in children

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  1. A randomized study comparinglow dose versus standard dose lopinavir/ritonavir among HIV-infected children with virological suppression Puthanakit T1,2, Suntarattiwong P3,Sangkla P4,Kosalaraksa P5, Ngampiyaskul C6, Srisamang P7,Kanjanavanit S8,Wongsawat J9,Petdachai W10, Chatchomchuan W11, Lertpienthum N12, Sophonphan J1, Ananworanich J1,13 on behalf of the PEARL Study Group. Department of Pediatrics, Faculty of Medicine, Chulalongkorn University HIVNAT, Thai Red Cross AIDS Research Center Funded by The National Research University Project of Commission of Higher Education and the Ratchadapiseksomphot Endowment Fund (HR 1161A-55) and The Thai Government Pharmaceutical organizationandThe Thai National Health Security office

  2. Lopinavir/ritonavir in children • LPV/r is the most common used PIs in children • Recommended LPV Ctrough > 1 mg/dl in PI naïve children • LPV blood level among Thai children • 1Therapeutic drug monitoring (TDM): Standard dose LPV/r tablet Median (IQR) LPV Ctrough = 6.7 (5.0-9.9) mg/dl • 212-hour PK study: Low dose (70%) versus Standard dose Mean AUC0-12h LPV = 83.1 versus 93.8 and mg.h/L Low dose LPV/r (70% of standard dose) using heat stable tablet formulation has non-inferiority efficacy at week 48 among HIV-infected children with virological suppression 1Puthanakit T et al. Ped Infect Dis J 2010;29(1):79-82.2Klinklom A, Puthanakit T. et al. AntivirTher. 2012;17(2):283-9.

  3. Study objectives Primary objective • To compare proportion of children with HIV RNA < 50 c/ml at week 48 between low and standard dose LPV/r arms Secondary objectives • To describe LPV Ctrough in low and standard dose arms • To compare proportion of children with dyslipidemia at week 48 between low dose and standard dose LPV/r arm

  4. Study design HIV-infected children age < 18 yrs with VL < 50 copies/ml (n=200) Randomize 1:1 Stratify by research sites and body weight Standard dose of LPV/r (FDA recommended dose) Low dose of LPV/r (70% of standard dose) Sample size calculation: Rate of failure in standard arm 12%, Non-inferiority 95% CI within -12%, power 80%, alpha 0.05, one-sided

  5. Study population Inclusion criteria Exclusion criteria Evidence of PI resistance Receive drug that have interaction with lopinavir/r e.g. rifampin, nevirapine, efavirenz Receive double boosted protease inhibitors • HIV infection • age < 18 years old • BW 25-50 kg • Currently on PI regimens • HIV RNA viral load < 50 c/ml • Written informed consent

  6. Sites UdonthaniHospital PI: Wanida Chatchomchuan , MD. Srinagarind Hospital, Khon Kaen U PI: Pope Kosalaraksa, MD. Nakornping Hospital PI: Suparat Kanjanavanit, MD Sappasitthiprasong Hospital PI: Pramot Srisamang, MD. Buddhachinaraj Hospital PI: Narong Lertpienthum, MD Surin Hospital PI: Pakarat Sangkla , MD. Prapokklao, Chantaburi PI: Chaiwat Ngampiyasakul, MD Queen Sirikit National Institute of Child Health PI: Piyarat Santarattiwong , MD. Bamrasnaradura Institute PI: Jurai Wongsawat, MD. Phrachomklao Hospital, Petchaburi PI: Wittaya Pedachai, MD. HIV-NAT & Chulalongkorn U. PI:ThanyaweePuthanakit, MD

  7. Patient characteristics Loss to follow-up or withdraw = 7 (3.5%), 3 in standard arm and 4 in low dose arm

  8. Virological efficacy at week 48 • Intention to treat (ITT) analysis (missing = failure) • Per protocol (PP)analysis (missing = censored) At week 48; 8 patients had HIV HIV RNA > 400 copies/ml Factors related to virological failure Poor adherence (aOR =3.3) and Weight 35-50 kg (aOR 3.6)

  9. LopinavirCtrough at week 12, 48 Target Ctrough > 1 mg/dl for PI-naïve

  10. Prevalence of dyslipidemia P=0.03 P=0.03 P=0.13 P=0.15 Mean 185 vs 176 174 vs 141 97 vs 88 47 vs 49 (mg/dl)

  11. Discussions: Virological efficacy • Per protocol analysis 92% and 94% of children maintained virological suppression at week 48 • Adequate LPV Ctrough in low dose arm • 6 out of 7 children who had virologic failure and LPV Ctrough had lower than limit of detection of LPV level at week 48, which might be explained by poor adherence rather than too low LPV dosage

  12. Discussions:Dyslipidemia • Reduction in proportion of children with Chol > 200 mg/dl (34->21%) and TG > 150 mg/dl (60-44%) • Kaledose study1(LPV/r dose reduction 400 266 mg) • Dose reduction if LPV Ctrough > 5 mg/dl • Significant reduction in TG level (1.73 to 1.34 mmol/l) • ATAZIP study2(Switch to ATV/r versus continue LPV/r) • Week 48: Cholesterol -19 versus -4 mg/dl • Week 48: Triglyceride -53 versus -4 mg/dl 1 Meynard JL et al. JAC 2010: 125-8 2Marlolas J et al. JAIDS 2009 : 51:29-36

  13. Conclusions • This study demonstrated non-inferiority in virological efficacy of low dose compared to standard dose LPV/r tablet as maintenance therapy • This dosing regimen conferred adequate LPV blood level with reduce drug cost and potential long term complications such as dyslipidemia

  14. PEARL Study team Consultants: Kiat Ruxrungtham, David Burger DSMB member: Annette H. Sohn, Carlo Giaquinto, Tim R. Cressey, Kulkanya Chokephaibulkit, Matthew Law Site 01: HIV-NAT, Thai Red Cross AIDS Research Center, Bangkok Thanyawee Puthanakit, Jintanat Ananworanich, Torsak Burunupradah, Wasana Prasitsuebsai, Stephen Kerr, Jiratchaya Sophonphan, Sasiwimol Ubolyam, Naphassanant Laopraynak, Meena Gorowara, Tulathip Suwanlerk, Purivis Chart, Jintana Intasan, Chulalak Sriheara, Thongsuai Chuanjaroen, Theeradej Boonma-ngum, Chowalit Phadungphon, Chatsuda Auchieng, Kesdao Nanthapisal, Umaporn Methanggool Site 03: Bamrasnaradura Infectious Diseases Institute, NonthaburiJurai Wongsawat, JarurnsookAusavapipit, SupedaThongyen SavitaIssaard, SumonmalUttayamakul, Thaniya Chiewcharn Site 04: Department of Pediatrics, Faculty of Medicine, KhonKaen University, KhonKaenPope Kosalaraksa, Pagakrong Lumbiganon, Chanasda Sopharak, Piangjit Tharnprisan, Thanitta Udompanit Site 07: Nakornping Hospital, Chiang MaiSuparat Kanjanavanit, Siripim Khampangkome, Chanannat Chanrin, DuangratChutima Site 12: Prapokklao Hospital, ChantaburiChaiwat Ngampiyasakul, Wanna Chamjamrat, BhensiriCharoenvikkai, PisutGreetanukroh, Pathanee Teirsonsern Site 17: Queen Sirikit National Institute of Child Health, BangkokPiyarat Suntarattiwong, Pugpen Sirikutt, Pimsiri Leowsrisook, Naruemon Sassungnurn, Saranya Winyawong, JureeUthaichalanont, Ruedeerampa Tannapai, AmornwadeeChudaeng, Site 23: Surin Hospital, Surin, Thailand Pakarat Sangkla, Jurairat Ruthaiwat, Suparat Phenphat, NatchakornYodsao, SantiMungsanti, SuparerkSiritawee, RatchanokSithichotiwong, AekjittraBuathong Site 24: Sappasitthiprasong Hospital, UbonratchathaniPramoteSrisamang, Chareeya Thanee, NipaKraisawekwisai, NitayaTheerawathanachareansuk, MonchayaSiriangkhawut Site 25: Udonthani Hospital, UdonthaniWanida Chatchomchuan, SukunyaTawmali, VilaipunAurchit, PrapapornKijwattanachai, KulladdaPalakul, Arun Butsri Site number 26: Buddhachinaraj Hospital, PhitsanulokNarong Lertpienthum, SaiphonKuanvaibud, Panadda Sangthong, KamonnateJirapraphusak, ThatchapongBuaprachum Site number 27: Phrachomklao Hospital, PhetchaburiWittayaPetdachai, Paweena Kaewdang, ManeeYentung, AroonwanWattanapongchat, Kanjana Sonjai

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