Rifabutin PK and Safety among HIV/TB Coinfected Children Receiving Lopinavir

Transcription

1 Rifabutin PK and Safety among HIV/TB Coinfected Children Receiving Lopinavir Holly Rawizza 1,2, Regina Oladokun 3, Emeka Ejeliogu 4, Stephen Oguche 4, Oche Agbaji 4, Georgina Odaibo 3, Godwin Imade 4, David Olaleye 3, Kristin Darin 5, Prosper Okonkwo 6, Phyllis Kanki 2, Kimberly Scarsi 7, Helen McIlleron 8 1 Brigham and Women's Hospital, Boston, Massachusetts, USA, 2 Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA, 3 University College Hospital, University of Ibadan, Ibadan, Nigeria, 4 Jos University Teaching Hospital, Jos, Nigeria, 5 Northwestern University School of Professional Studies, Chicago, Illinois, USA, 6 AIDS Prevention Initiative Nigeria (APIN), Ltd., Abuja, Nigeria, 7 University of Nebraska Medical Center, College of Pharmacy, Omaha, Nebraska, USA, 8 University of Cape Town, Cape Town, South Africa Funding: Harvard University Center for AIDS Research (HU CFAR) P30 AI H. Rawizza has no financial relationships with commercial entities to disclose. AIDS Prevention Initiative Nigeria

2 Background For HIV/TB coinfected children who require protease inhibitor (PI)-based antiretroviral therapy (ART), treatment options are lacking Rifampin is a potent inducer of the enzyme cytochrome P450 3A4 and p-glycoprotein, reducing lopinavir (LPV) exposure by approximately 75% when the drugs are given in combination 1 For coinfected children who require LPV/r-based ART, the WHO recommends 2 : (1) Triple nucleoside (3NRTI) regimen; or, (2) Super-boosted LPV/r (i.e. administration of additional ritonavir to provide a 1:1 LPV to ritonavir ratio versus the standard 4:1 LPV/r ratio) Both of these options are suboptimal 1. Bertz R et al. 5 th Int Congress In Drug Ther in HIV, 2000; Abst P WHO, Consolidated guidelines, 2 nd Ed.; Saavedra J et al. 41 st ICAAC, 2001.

3 Background (2) Rifabutin is the preferred rifamycin among adults who require PIs 1 Among children, a dosage of mg/kg daily is recommended for treatment of Mycobacterium avium complex (MAC) disease and TB 2 Only one study has evaluated rifabutin PK and safety among children receiving lopinavir/ritonavir-based ART 3 DSMB stopped study early after 2 of 6 children developed grade 4 neutropenia Among the 6 children in the study, all except one child had AUCs above the target (rifabutin dose: 5 mg/kg thrice weekly) 1. WHO, Consolidated guidelines, 2 nd Ed.; DHHS, Pediatric OI guidelines, 2018; p. U-9, V Moultrie et al. JAC 2014.

4 Methods: Study design and setting Since 2008, APIN began supporting rifabutin access for HIV/TB coinfected adults and children requiring PI-based ART. Rifabutin dosed 2.5 mg/kg daily Retrospective analysis of 42 children revealed favorable safety and efficacy outcomes 1 Prospective pharmacokinetic (PK) study to evaluate rifabutin concentrations and safety among 15 HIV/TB coinfected children 3-15 years of age who require concurrent LPV/rbased ART and rifabutin-containing TB treatment. Received 4-drug anti-tb treatment dosed according to WHO guidelines 1. Rawizza et al. CROI 2015; Abst 940.

5 Enrollment criteria Inclusion criteria: (1) ART-experienced HIV-infected children who are 3-15 years of age and require LPV/r-based ART due to first-line failure; (2) diagnosis of active TB; and, (3) willingness of the parent or legal guardian to provide consent, and child (7-15 years) to provide assent, for participation. Exclusion criteria: (1) baseline labs with evidence of grade 2 or higher abnormalities including alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels >2.5 times the upper limit of the normal (ULN) range for age, creatinine level greater than 2 times the ULN, or an absolute neutrophil count (ANC) less than 800 cells/mm 3 ; (2) receipt of a medication that has drug-drug interactions with LPV/r or rifabutin; or (3) suspected TB meningitis or those presenting with acute respiratory distress or decompensation.

6 Clinical visit schedule Clinical visits and laboratory monitoring occurred 12 times during the study Labs consisted of total WBC count (WBC), calculated absolute neutrophil count (ANC), hemoglobin, platelet count, creatinine, and alanine aminotransferase (ALT) HIV monitoring labs included CD4+ cell count/cd4% and viral load at baseline, then 6- and 12-months Intensive PK study visits occurred 2, 4, and 8 weeks after rifabutin initiation At each of these time points, serial steady-state rifabutin concentrations were measured at pre-dose (0), 2, 4, 8, 12, and 24 hours after the observed dose.

7 Outcomes Efficacy Immunologic and virologic response through 48 weeks TB outcomes through 48 weeks Safety Adverse events (AE) graded based on DAIDS Tables for grading the severity of adult and pediatric AEs (version 2.0; 2014) AEs during rifabutin were at least one grade higher in severity than baseline value PK outcomes Noncompartmental methods were utilized to determine the area under the curve (AUC 0-24 ) for rifabutin and 25-O-desacetyl rifabutin Primary comparator: adults receiving rifabutin 300 mg daily without ART (mean 3.8 g h/ml) 1,2,3 1. Naiker et al. BMC Pharmacol Toxicol 2014;15: Lan et al. PLoS One 2014; 9(1):e Boulanger et al. CID 2009;49:1305.

8 Patient demographics

9 Clinical outcomes

10 Safety summary

11 Individual Laboratory Adverse Events by Severity Grade 3 neutropenia occurred on 3 occasions (4.4%) and resolved despite continuation of rifabutin in all cases Anemia was the most common AE No Grade 3 or 4 abnormalities in platelet count, ALT, Cr No grade 3 or 4 clinical toxicities reported and no discontinuations due to ART or TB medications occurred

12 Rifabutin concentration-time curves: 20 PK visits among 8 patients

13 Rifabutin PK parameters

14 Comparison of rifabutin PK parameters across studies

15 No association between rifabutin AUC-24h and absolute neutrophil count (ANC) Spearman s rho = p= No association between AUC 0-24 and gender, age, weight (kg), body mass index (kg/m 2 ), rifabutin dosage (mg), rifabutin dosage in mg/kg, or PK visit week

16 Summary In children, rifabutin 2.5 mg/kg daily achieved AUC 0-24 comparable to adults. Median rifabutin AUC 0-24 of 4.77 mcg h/ml 3 instances of low rifabutin AUC 0-24, in all cases the values were appropriate at the 4- and 8-week PK visits Favorable HIV and TB outcomes were observed. Overall patients are clinically doing well, with 6 of 7 achieving virologic suppression to <1000 cpm and resolution of TB symptoms at 6 months Rare SAEs Of 407 follow-up laboratory results, Grade 3/4 abnormalities occurred in 11 (3%) and 2 (0.5%) instances, respectively Neutropenia was rare, mild, and improved with ongoing rifabutin therapy

17 Conclusions These data support the use of rifabutin for HIV/TB coinfected children who require LPV/r given the paucity of options for this vulnerable population. Data are limited by age range of patients Future directions Enrollment now complete Additional study underway in young children months

18 Acknowledgements H. McIlleron K. Scarsi R. Oladokun G. Olawoye G. Odaibo D. Olaleye P. Okonkwo All our colleagues at the APIN PEPFAR sites in Nigeria. Most of all, our patients and their caregivers. P. Kanki K. Darin E. Ejeliogu S. Oguche O. Agbaji G. Imade Funding support by HU CFAR P30 AI and HRSA under the terms of Cooperative Agreement #U51HA The contents are solely the responsibility of the authors and do not necessarily represent the official views of the funding institution.