Lopinavir Hair Concentrations Predict Virological Failure Among Asian Children

Transcription

1 Lopinavir Hair Concentrations Predict Virological Failure Among Asian Children Wasana Prasitsuebsai, Stephen J. Kerr, Truong Huu Khanh, Jintanat Ananworanich, Do Chau Viet, Nguyen Van Lam, Nia Kurniati, Pope Kosalaraksa, Virat Sirisanthana, Kulkanya Chokephaibulkit, Narukjaporn Thammajaruk, Thida Singtoroj, Sirinya Teeraananchai, Monica Gandhi, Annette H. Sohn for the TASER-P team 28 th June 2013 The 5th International Workshop on HIV Pediatrics Kuala Lumpur, Malaysia

2 Background Maintaining high levels of antiretroviral therapy adherence and identifying children at risk of treatment failure are major challenges. There are few pediatric second- and third-line antiretroviral (ARV) options available in resource-limited settings. Methods to assess long-term adherence in children are needed to complement existing approaches to clinical and laboratory monitoring. Protease inhibitor concentrations in hair are strongly associated with treatment outcomes in adults but have not been studied in Asian children. Gandhi M. AIDS 2009, CID 2011, JID Van Zyl GU. JAIDS Huang Y. Analytical and Bioanal Chem 2011.

3 Hair Concentrations Hair Concentrations Measure Extended-Exposure Plasma Hair levels average plasma levels Hair S M T W Th F S S M T W Th F S S M T W Th F S S M ARV levels in hair reflect drug uptake from the systemic circulation over the preceding months. T Day of week Modified from original slide: Gandhi M, 2012

4 Study Objectives To correlate ARV drug levels in plasma and hair samples To correlate hair ARV levels with virologic response and reported measures of adherence

5 Methods In 2011, the TREAT Asia pediatric HIV network initiated a study of HIV-infected children who had already been switched or were switching to secondline ART. There are eight participating clinical sites from referral hospitals and clinics in Indonesia (1), Vietnam (3) and Thailand (4). As of January 2013, 299 children were enrolled.

6 Assessments of Plasma and Hair ARV Levels Testing at week 24 Blood: viral load (VL) monitoring, plasma therapeutic drug monitoring (TDM) Adherence: 30-day visual analogue scale (VAS), pill count Lopinavir (LPV) concentrations in small hair samples TDM: high-performance liquid chromatography Testing at HIV-NAT, Bangkok Hair: liquid chromatography/tandem mass spectrometry Testing at the University of California, San Francisco (UCSF Drug Studies Unit Huang, Gandhi)

7 Hair Collection strands of hair are cut at the occiput from underneath the top layer of hair. Distal end of the strands are labeled. Hair is folded in aluminum foil and placed in a plastic bag with desiccants. Stored at room temperature. Modified from original slide: Gandhi M, 2012

8 Study Subjects 299 children enrolled 189 children with available week 24 visits and hair specimens 170 children on LPV/r-based regimens 149 children included in the analysis 19 on atazanavir 21 on LPV/r <24 wks

9 Characteristics of Children on LPV/r-based Regimens, N=149 Demographic data Results Female 70 (47%) Weight, kg (IQR) 25.7 ( ) Age, years (IQR) 10.3 ( ) CD4% (IQR) 26 ( ) Total CD4, cells/mm 3 (IQR) 754 (596-1,013) Daily LPV dose, mg/m 2 /day (IQR) 543 ( ) Duration of LPV-based ART, years (IQR) 2.9 ( )

10 LPV Plasma C trough vs. Hair Concentrations Pearson's rho = 0.20; P = from 149 children had blood samples for trough LPV levels. Median trough plasma LPV concentration was 6.7 ( ) mg/l.

11 LPV levels in hair (ng/mg) LPV Hair Concentrations Lower in Those with Virologic Failure VL <1000 VL >1000 (n=132) (n=17) VL <1000 c/ml Median LPV hair levels were 9.96 ( ) ng/mg of hair VL >1000 c/ml Median LPV hair levels were 5.43 ( ) ng/mg of hair

12 Adherence and Predictors of Virological Failure High levels of adherence >95% reported 135/148 (91%) children by 30-day VAS 129/145 (89%) children by pill count 30-day VAS and pill count <95% not associated with VL >1000 copies/ml Pill count <95%: OR 0.47 ( ); p= day VAS: OR 0.62 ( ); p=0.66 In univariate models, age, sex, body surface area, LPV plasma trough concentrations and adherence levels <95%, <90% or <80% were not associated with virologic failure.

13 Detectable VL vs. LPV Hair Concentration Quartiles LPV hair concentration quartiles (ng/mg of hair) 1 st quartile: 6.11 Number (%) of children with VL >1000 copies/ml OR (95% CI) for virological failure 10/38 (26%) 1 (reference) P value 2 nd quartile: rd quartile: /37 (8%) 2/37 (5%) 0.25 ( ) 0.16 ( ) P= th quartile: /37 (5%) 0.16 ( )

14 OR (95%CI) Detectable VL vs. LPV Hair Concentration Quartiles 1 OR 95%C 95%C 0, ( ) 0.16 ( ) 0.16 ( ) 0 1st Quartile 2nd Quartile 3rd Quartile 4th Quartile LPV hair concentration quartiles (ng/mg of hair)

15 Summary Low lopinavir hair concentrations in hair samples associated with virological failure. Measuring adherence using VAS or pill count was not a sensitive method to identify children with chronic poor adherence. Lopinavir hair levels were likely more predictive of adherence than VAS and pill counts As is virologic failure Plasma and hair LPV levels were not strongly correlated

16 Study Significance Given the limited number of second- and third-line options for children in resource-limited settings, early detection of those at risk for treatment failure is needed to better target adherence interventions. Testing ARV levels in hair is an innovative and noninvasive method which can reflect cumulative exposure. Correlation between hair levels (cumulative) and plasma levels (snapshot) is not expected. ARV levels in hair can serve as a surrogate marker of adherence and treatment failure.

17 Acknowledgements Study Sites Thailand HIV-NAT, The Thai Red Cross AIDS Research Centre, Bangkok Srinakarin Hospital, Khon Kaen University RIHES, Chiang Mai University Siriraj Hospital, Bangkok Indonesia Cipto Mangunkusumo Hospital, Jakarta Vietnam Children s Hospital 1, Ho Chi Minh City Children s Hospital 2, Ho Chi Minh City National Hospital of Pediatrics, Hanoi Hair testing University of California, San Francisco Yong Huang Alexander Louie Peter Bacchetti Funded by TREAT Asia/amfAR through an unrestricted grant from ViiV Healthcare s Paediatric Innovation Seed Fund For hair testing info: monica.gandhi@ucsf.edu