Farmacologie op CROI 2019
Focus op zwangerschap & pediatrie
Post CROI meeting, Utrecht
2 april 2019
David Burger, ziekenhuisapotheker/klinisch [email protected]
Disclosures David Burger
• Research grants: Janssen, Merck, ViiV, Bristol-Myers Squibb, Gilead
• Advisory boards: Merck, ViiV
NB all payments have been invoiced by the financial department of Radboudumc
Inhoud
• Farmacologie van ART tijdens de zwangerschap
• Antiretrovirale therapie bij kinderen
• Overig farmacologisch nieuws
Inhoud
• Farmacologie van ART tijdens de zwangerschap
• Antiretrovirale therapie bij kinderen
• Overig farmacologisch nieuws
Farmacologie van ART tijdens zwangerschap
Veiligheid voor het
kind
Effectiviteit & veiligheid
bij de a.s. moeder
Update on Antiretroviral Drugs
and Pregnancy Outcome
Including Birth Defects
Lynne M. Mofenson MD
Senior HIV Technical Advisor
Elizabeth Glaser Pediatric AIDS FoundationOpen spinal bifida
(Copp & Greene, 2016,
Encyclopedia of Life Sciences,
John Wiley)
http://www.croiwebcasts.org
Timing of In Utero ARV Exposure
and Fetal Risk
Ability to Rule-Out ↑ Birth Defect is Related to Prevalence Defect
and Number Observed Preconception/1st Trimester Exposures
200 exposures can rule out a 2-fold ↑ in overall birth defects
(prevalence 3%)
Watts DH. Curr HIV/AIDS Rep 2007;4:135-140
Overall defects
prevalence 3%RR 2.0
Drug-Specific Birth Defect Rates*Prevalence of Birth Defects (95% CI): 1 January 1989 – 31 July 2018
→ 20,064 exposures, 10,072 first trimester exposures
*For drug to be included for comparison with population rates, must
meet threshold of having ≥ 200 1st trimester exposed pregnancies
1 January 1989 through 31 July 2018
Texas Birth
Defects Registry
(4.2%)
Metropolitan Atlanta
Congenital Defects
Program
(2.7%)
2.7% (CI 2.4-3.1%)
MACDP: Metropolitan Atlanta Congenital Defects Program
TBDR: Texas Birth Defects Registry
However, to rule-out a 3-fold increase in a relatively rare event like
NTD (prevalence 0.1%), need about 2,000 preconception exposures
Watts DH. Curr HIV/AIDS Rep 2007;4:135-140
Neural tube defect
prevalence 0.1%
Overall defects
prevalence 3%
RR 3.0
RR 2.0
Ability to Rule-Out ↑ Birth Defect is Related to Prevalence Defect
and Number Observed Preconception/1st Trimester Exposures
NTD Prevalence Difference by Exposure: July 2018 Update
July 2018:
4/596
0.67%
July 2018 Update: 2 new NTD
• 1 HIV-uninfected
• 1 DTG start during pregnancy (8 wk GA)
May 2018
July 2018:
4/596
0.67%
(0.26%,
1.7%)
To Refute NTD Signal, How Many Preconception Exposures are Needed
to See Overlap of Lower 95% CI for NTD with Preconception DTG with
NTD Prevalence Observed with non-DTG Exposure?Schomaker M et al. Lancet Global Health 2018;6:e958-9
NTD Prevalence 0.1%
Non-DTG ART
No new defects 1 new defect 2 new defects
May 2018: 4/426,
lower 95% CI 0.37
Number of new
NTD diagnosis events
→If no new defects, after 1400
exposures, lower CI overlaps non-
DTG prevalence
→If 1 new defect, need 2000
exposures to see lower CI overlaps
non-DTG prevalence
→If 2 new defects, need 2500
exposures to see lower CI overlaps
non-DTG prevalence
To refute finding, how many
exposures are needed to see overlap
lower CI with non-DTG prevalence
How Do Tsepamo Study Findings
Compare to Prevalence of NTD in Sub-Saharan Africa?
0.23%
0.06%
African Region: Data from 8/47
WHO member countries,
represented by 11 studies; median
prevalence NTD was 0.12%
(11.7 per 10,000 births)
Zaganjor I et al. PLosOne 2016:11:e0151586
Birth Defect Surveillance Uganda Barlow-Mosha et al CROI 2019 Seattle Poster 743
▪ 4 hospital defect surveillance:
69,766 births (6,494 to HIV+
women, 80% on TDF-3TC-EFV
(no DTG used in country yet)
# HIV- HIV
+
NTD% births
HIV- women
NTD% births
HIV+ women
NT
D
71 66 5 0.11% (0.08-
0.13)
0.07% (0.03-
0.17)
HIV- women: 0.09% (95% 0.07-0.12%)
HIV+ EFV preconception: 0.05% (95% CI 0.02-0.15%)
Tsepamo NTD prevalence:
Earliest Trimester of Exposure – Prospective
Cases*
Periconception 1st Trimester 2nd/3rd Trimester
Overall birth defects Defects/live birth Defect/live birth Defects/live birth
Exposure to any
INSTI
16/604
(2.6%)
4/135
(3.0%)
17/452 (3.8%)
DTG* 6/174 (3.4%) 2/55 (3.6%) 4/137 (2.9%)
EVG 5/186 (2.7%) 0/27 (0%) 0/57 (0%)
RAL** 5/244 (2.0%) 4/68 (5.9%) 13/290 (4.5%)
Antiretroviral Pregnancy Registry
Prospective Cases of InSTI Exposure
1 Jan 1989 -
31 Jul 2019
Can be more than one organ system for a defect
No Neural Tube Defects
2 CNS: 1 (lissencephaly – neural migration disorder) with preconception DTG; 1
(ventriculmegaly with 2nd/3rd trimester DTG exposure.
Face, ear, face, neck: 2
Cleft lip/palate: 2
Respiratory: 1
Cardiac/circulatory: 11
Lower GI: 1
Renal: 4
Musculoskeletal: 8
Chromosome abnl: 2
Other organ systems: 1
Specified syndromes 1
See Poster 747
Albano et al.
▪ Poster 745: Merck review of database on pregnancies
with RAL exposure:
− Prospective: 456 periconception RAL: no NTD
▪ Glasgow HIV Conf Oct 2018: Gilead of database on
pregnancies with EVG or BIC exposure:
− Prospective: 155 periconception EVG, no NTD
18 periconception BIC exposures, no NTDSEE ALSO:
→ Poster 744, Sibiude et al
(French Perinatal Cohort)
→ Poster 747 Albano et al (APR)
→ Rasi V et al. JAIDS 2018 Nov 20 epub
(UK/Ireland NSHPC)
Farmacologie van ART tijdens zwangerschap
Veiligheid voor het
kind
Effectiviteit & veiligheid
bij de a.s. moeder
Door PK veranderingen tijdens zwangerschap kunnen spiegels van ART dalen
Farmacologie van ART tijdens zwangerschap
Veiligheid voor het
kind
Effectiviteit & veiligheid
bij de a.s. moeder
Door PK veranderingen tijdens zwangerschap kunnen spiegels van ART dalen
Geen cobicistatGeen rilpivirine
Colbers et al. CROI 2019; #758
Inhoud
• Farmacologie van ART tijdens de zwangerschap
• Antiretrovirale therapie bij kinderen
• Overig farmacologisch nieuws
Ruel et al. CROI 2019; #829
Bollen et al. CROI 2019; #830
“50mg film-coated tabletten kunnen gegeven worden vanaf 20 kg (in NL: + TDM)”
Subtherapeutische Cmin
TB/HIV: 61%HIV: 24%
Inhoud
• Farmacologie van ART tijdens de zwangerschap
• Antiretrovirale therapie bij kinderen
• Overig farmacologisch nieuws
Alle ART behandelingen
Alleen ART die zowel als STR als MTR beschikbaar is
CROI 2019; abstract # 511
Lymphoid Tissue Pharmacokinetics of Tenofovir-alafenamide vs. disoproxil fumarate
Courtney V. Fletcher, Ann Thorkelson, Campbell K, Lee Winchester, Timothy Mykris, Jon Weinhold, Jodi Anderson, Jacob Zulk, Puleng Moshele,
Siri Jorstad, Anthony Podany, Jason Baker and Timothy Schacker
University of Nebraska Medical Center and University of MinnesotaOmaha, NE and Minneapolis, MN
Presented at the 26th CROI, Seattle, WA, March 4-7, 2019
Results: Tenofovir-diphosphate Concentrations
MatrixTenofovir-diphosphate (fmol/106 cells)
Median (and Interquartile Range)TAF (n=13) TDF (n=45)
PBMC 497 (384, 639) 63 (44, 91)
LN 136 (88, 156) 22 (8, 27)
Ileum 82 (17, 250) 3056 (458, 5835)
Rectum 47 (31, 102) 441 (287, 985)
PHARMACOKINETICS AND SAFETY OF ADJUSTED DOSES OF DARUNAVIR/RITONAVIR WITH
RIFAMPIN IN PLWH
Ismaeel Ebrahim, Gary Maartens, Lubbe Wiesner, Catherine Orrell, Wynand Smythe, Helen McIlleron
Division of Clinical Pharmacology, University Of Cape Town
Background
DRV/r -better tolerated than LPV/r
Doubling LPV/r achieves therapeutic LPV concentrations when co-administered with rifampin (RIF) 1,2
• PLWH 2/21- asymptomatic ALT elevation2
• Healthy volunteers high rates symptomatic hepatitis3 (also adjusted dose ATV/r & SQV/r)
DRV/r with rifampin - contraindicated • Marked reduction in DRV exposures expected4
• Switching RIF to rifabutin recommended • Rifabutin not available in most LMIC
Physiologically based pharmacokinetic model• Doubling DRV/r to 800/100 mg BID or 1600/200 mg QD could
overcome RIF induction5
1. La Porte 2004; 2. Decloedt 2011; 3. Nijland 2008; 4. Goran 1998; 5. Siccardi 2015
Darunavir trough concentrations across dosing regimens
EC50
858
678
1595
211
300
0
200
400
600
800
1000
1200
1400
1600
ALT
(IU
/L)
Days on study
ALT in cohorts 1 & 2
All 5 participants with grade 3/4 ALT were symptomatic
RIF added RTV added
The Challenges of HIV Treatment in an Era of Polypharmacy
David Back
University of Liverpool
CROI – March 2019
http://www.croiwebcasts.org
Conclusies
• Net als in vorige jaren was er veel interessant farmacologisch nieuws bij de CROI
• Nog steeds veel te doen voor ons als “HIV farmacologen”:• PK in subgroepen (zwangeren, kinderen)• Interacties
Visit virology-education.com for more information
WORKSHOP CHAIRS
REGISTRATION IS OPEN
David Burger PharmD, PhDRadboud University Medical CenterThe Netherlands
Jennifer KiserPharmDUniversity of Colorado Skaggs School of PharmacyUnited States
ORGANIZED BY
14 – 16 MAY 2019 | NOORDWIJK, THE NETHERLANDS