Farmacologie op CROI 2019 - Virology...

Farmacologie op CROI 2019

Focus op zwangerschap & pediatrie

Post CROI meeting, Utrecht

2 april 2019

David Burger, ziekenhuisapotheker/klinisch [email protected]

mailto:[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

Farmacologie van ART tijdens zwangerschap

Veiligheid voor het

kind

Effectiviteit & veiligheid

bij de a.s. moeder

http://upload.wikimedia.org/wikipedia/en/c/c7/Scales_Of_Justice.svg

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)


Veiligheid voor het

kind


bij de a.s. moeder

Door PK veranderingen tijdens zwangerschap kunnen spiegels van ART dalen



Veiligheid voor het

kind


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




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




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

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