HN152 – PEARL Study

A randomized study comparing low 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 organization and The Thai National Health Security office

HN152 – PEARL Study

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

– 1 Therapeutic drug monitoring (TDM): Standard dose LPV/r tablet Median (IQR) LPV Ctrough = 6.7 (5.0-9.9) mg/dl – 2 12-hour PK study: Low dose (70%) versus Standard dose Mean AUC0-12h LPV = 83.1 versus 93.8 and mg.h/L

1Puthanakit T et al. Ped Infect Dis J 2010;29(1):79-82.2Klinklom A, Puthanakit T. et al. Antivir Ther. 2012;17(2):283-9.

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

HN152 – PEARL Study

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

HN152 – PEARL Study

Study design HIV-infected children age < 18 yrs with VL < 50 copies/ml

(n=200)

Standard dose of LPV/r (FDA recommended dose)

Low dose of LPV/r (70% of standard dose)

Randomize 1:1

Sample size calculation: Rate of failure in standard arm 12%, Non-inferiority 95% CI within -12%, power 80%, alpha 0.05, one-sided

Body weight Standard LPV/r Low dose LPV/r 25-35 kg 300/75 mg 200/50 mg 35-50 kg 400/100 mg 300/75 mg

Stratify by research sites and body weight

HN152 – PEARL Study

Study population

Inclusion criteria • HIV infection • age < 18 years old • BW 25-50 kg • Currently on PI regimens • HIV RNA viral load < 50 c/ml • Written informed consent

Exclusion criteria

• Evidence of PI resistance • Receive drug that have

interaction with lopinavir/r e.g. rifampin, nevirapine, efavirenz

• Receive double boosted protease inhibitors

HN152 – PEARL Study

Sites

6

Udonthani Hospital

PI: Wanida Chatchomchuan , MD.

Srinagarind Hospital, Khon Kaen U

PI: Pope Kosalaraksa, MD.

Sappasitthiprasong Hospital

PI: Pramot Srisamang, MD.

Surin Hospital

PI: Pakarat Sangkla , MD.

Phrachomklao Hospital, Petchaburi

PI: Wittaya Pedachai, MD. HIV-NAT & Chulalongkorn U.

PI: Thanyawee Puthanakit, MD

Bamrasnaradura Institute

PI: Jurai Wongsawat, MD.

Nakornping Hospital

PI: Suparat Kanjanavanit, MD

Prapokklao, Chantaburi PI: Chaiwat Ngampiyasakul, MD

Queen Sirikit National Institute of Child Health

PI: Piyarat Santarattiwong , MD.

Buddhachinaraj Hospital

PI: Narong Lertpienthum, MD

HN152 – PEARL Study

Patient characteristics Total

(n=199) Standard dose

(n=98) Low dose (n=101)

Age (years) 13.4(2.2) 13.6(2.0) 13.3 (2.5)

CD4 cell (cell/mm3) 786(305) 786(292.1) 787(319)

ARV regimen

LPV/r +AZT+3TC 93(47) 45(46) 48(47)

LPV/r +AZT+DDI 34(17) 16(16.3) 18(18)

LPV/r +3TC+TDF 32(16) 17(17.3) 15(15)

LPV/r + 3TC 23(12) 12(12.2) 11(11)

LPV/r +3TC+DDI 10(5) 3(3.1) 7(7)

Others 7(3) 5(5.1) 2(2)

LPV dose (mg/m2/dose) 284 (42) 210(32)

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

HN152 – PEARL Study

Virological efficacy at week 48

HIV-RNA Standard dose n/N(%)

Low dose n/N(%)

Difference ( 95%CI)

P- value

<50 copies/mL 90/98(91.8) 89/101(88.1) -3.7(-12.0 to 4.6) 0.38

<400 copies/mL 92/98(93.9) 93/101(92.1) -1.8(-8.9 to 5.4) 0.62

• Intention to treat (ITT) analysis (missing = failure)

• Per protocol (PP) analysis (missing = censored)

HIV-RNA Standard dose n/N(%)

Low dose n/N(%)

Difference ( 95%CI)

P- value

<50 copies/mL 89/95(93.7) 89/97(91.8) -1.9(-9.4 to 5.5 ) 0.61

<400 copies/mL 91/95(95.8) 93/97(95.9) -0.1(-5.6 to 5.8) 0.98

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)

HN152 – PEARL Study

Lopinavir Ctrough at week 12, 48

05

1015

20Lo

pinav

ir pla

sma

conc

entra

tion

(mg/

L)

Week 12 Week 48Low dose Standard dose Low dose Standard dose

Target Ctrough > 1 mg/dl for PI-naïve

Median LPV C trough (min-max)

4.7 (0.5-14.6)

7.6 (1.6-17.0)

5.2 (0.2-11.8)

6.9 (0.3-20.4)

% with LPV < 1 mg/dl 4 1 10 4

HN152 – PEARL Study

Prevalence of dyslipidemia

Mean 185 vs 176 174 vs 141 97 vs 88 47 vs 49 (mg/dl)

34.4

60.4

13.5

30.2

20.6

44.3

7.2

20.6

0

10

20

30

40

50

60

70

Tholesterol > 200 mg/dL Triglyceride > 150 mg/dl LDL > 130 mg/dl HDL ≤ 40 mg/dL

Perc

enta

ge (%

)

Standard dose Low dose

P=0.03

P=0.03

P=0.15

P=0.13

HN152 – PEARL Study

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

HN152 – PEARL Study

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 2 Marlolas J et al. JAIDS 2009 : 51:29-36

HN152 – PEARL Study

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

HN152 – PEARL Study

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, Nonthaburi Jurai Wongsawat, Jarurnsook Ausavapipit, Supeda Thongyen Savita Issaard, Sumonmal Uttayamakul, Thaniya Chiewcharn Site 04: Department of Pediatrics, Faculty of Medicine, Khon Kaen University, Khon Kaen Pope Kosalaraksa, Pagakrong Lumbiganon,

Chanasda Sopharak, Piangjit Tharnprisan, Thanitta Udompanit Site 07: Nakornping Hospital, Chiang Mai Suparat Kanjanavanit, Siripim Khampangkome, Chanannat Chanrin, Duangrat Chutima Site 12: Prapokklao Hospital, Chantaburi Chaiwat Ngampiyasakul, Wanna Chamjamrat, Bhensiri Charoenvikkai, Pisut Greetanukroh,

Pathanee Teirsonsern Site 17: Queen Sirikit National Institute of Child Health, Bangkok Piyarat Suntarattiwong, Pugpen Sirikutt, Pimsiri Leowsrisook,

Naruemon Sassungnurn, Saranya Winyawong, Juree Uthaichalanont, Ruedeerampa Tannapai, Amornwadee Chudaeng, Site 23: Surin Hospital, Surin, Thailand Pakarat Sangkla, Jurairat Ruthaiwat, Suparat Phenphat, Natchakorn Yodsao, Santi Mungsanti,

Suparerk Siritawee, Ratchanok Sithichotiwong, Aekjittra Buathong Site 24: Sappasitthiprasong Hospital, Ubonratchathani Pramote Srisamang, Chareeya Thanee, Nipa Kraisawekwisai, Nitaya

Theerawathanachareansuk, Monchaya Siriangkhawut Site 25: Udonthani Hospital, Udonthani Wanida Chatchomchuan, Sukunya Tawmali, Vilaipun Aurchit, Prapaporn Kijwattanachai,

Kulladda Palakul, Arun Butsri Site number 26: Buddhachinaraj Hospital, Phitsanulok Narong Lertpienthum, Saiphon Kuanvaibud, Panadda Sangthong, Kamonnate Jirapraphusak, Thatchapong Buaprachum Site number 27: Phrachomklao Hospital, Phetchaburi Wittaya Petdachai, Paweena Kaewdang, Manee Yentung, Aroonwan Wattanapongchat, Kanjana Sonjai