PANNA study


The PANNA study is a study with the purpose of collecting pharmacokinetic data (PK curves) in pregnant HIV-infected women using newly developed antiretroviral agents.

The primary objective of this study is to describe the pharmacokinetics of antiretroviral agents during pregnancy for which no or only limited pharmacokinetic data during pregnancy are available. Pharmacokinetic curves will be collected in the 3rd trimester of pregnant HIV-infected women and at 4-6 weeks post-partum. In addition, the pharmacokinetics will be determined in the infant as well, in case of post-exposure prophylaxis with one of the agents tested.

The secondary objective of this study is to describe the safety of the antiretroviral agents during pregnancy and the efficacy in terms of viral load response of the mother and prevention of mother-to-child transmission.

Rationale

As the changes in pharmacokinetics during pregnancy are most prominent in the third trimester, a pharmacokinetic curve will be recorded in the third trimester after attaining steady state.

Antiretroviral agents under study

The following agents are being studied (open for inclusion):

  • Dolutegravir, Tivicay®, Triumeq®, DTG (integrase inhib)
  • Elvitegravir, Vitekta®, Stribild®, EVG (integrase inhib)
  • Cobicistat, in Stribild®, COBI (booster)
  • Rezolsta®, Darunavir/cobicistat FDC (PI)
  • Tenofovir alafenamide, Descovy®, Genvoya®, Odefsey® (NRTI)
  • Fosamprenavir, Telzir®, FPV (PI)
  • Tipranavir, Aptivus®, TPV (PI)
  • Indinavir, Crixivan® (PI)
  • Enfuvirtide, Fuzeon® (entry inhibitor)

The following arms have been closed because of sufficient inclusions:

  • Emtricitabine, Emtriva® or FTC (NRTI)
  • Tenofovir, Viread®, TDF (NtRTI)
  • Atazanavir, Reyataz® (PI)
  • Darunavir, Prezista® (PI)
  • Raltegravir, Isentress® (integrase inhib)
  • Abacavir, Ziagen® (NRTI)
  • Efavirenz, Stocrin®, EFV(NNRTI) (UK only)
  • Etravirine, Intelence®, TMC125 (NNRTI)
  • Maraviroc, Celsentri® (entry inhibitor)
  • Rilpivirine, Edurant®, TMC278 (NNRTI)

If new compounds are registered, they can be added to the list of compounds under study by an amendment. In that case, no new protocol has to be written.

Procedure pharmacokinetics

In the third trimester and at 4-6 weeks post partum blood samples (6 mL) will be taken for measurement of plasma drug concentration on T=0 (prior to dosing), and T= 0.5, 1, 2, 3, 4, 6, 8, 12 and 24h (24h sample only in case of QD regimen) post-dosing (9 or 10 samples per curve). The women will be admitted to the hospital during one day (12 hours admission). At delivery, a cord blood sample will be taken, if possible. In case the infant needs post-exposure prophylaxis with at least one of the agents, sparse PK sampling is optional.

Efficacy and safety

Viral load and CD4 count will be determined at screening and on the day of PK evaluation. The HIV status of the infant(s) will be collected. Biochemistry and haematology evaluation, urinalysis, at screening, and during the day of PK evaluation. Body weight at the day of PK evaluation. Adverse events will be collected from screening until last assessment.

Number of subjects planned

Per antiretroviral agent 16 subjects are planned.

Results presented/published

2017 

Oral presentation at 18th edition of the International Workshop on Clinical Pharmacology of Antiviral Therapy: A comparison of the pharmacokinetics of dolutegravir in pregnancy and postpartum (O_07)

Poster at CROI: Substantially lower rilpivirine plasma concentrations during pregnancy.

2016 

Publication in Front Pharmacol: Etravirine Pharmacokinetics in HIV-Infected Pregnant Women.

Publication in AIDS: Substantially lowered dolutegravir exposure in a treatment-experienced perinatally HIV-1-infected pregnant woman.

Publication in AIDS: First reported use of elvitegravir and cobicistat during pregnancy.

Publication in AIDS: The pharmacokinetics of abacavir 600 mg once daily in HIV-1-positive pregnant women.

One posters and one oral presentation at 17th edition of the International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy: Timing of the postpartum curve in pharmacokinetic studies in pregnancy should not be too early (O_3) and Is pregnancy a barrier to the proposed lower dose of efavirenz? P_26

One poster at CROI 2016: A Comparison of the Pharmacokinetics of Efavirenz During Pregnancy and Postpartum.

2015

Publication in Clinical Pharmacokinetics: Physiologically Based Modelling of Darunavir/Ritonavir Pharmacokinetics During Pregnancy.

Publication in CID: Maraviroc Pharmacokinetics in HIV-1-Infected Pregnant Women.

Publication in CID: Raltegravir in HIV-1-Infected Pregnant Women: Pharmacokinetics, Safety, and Efficacy.

Four posters at 16th edition of the International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy: Darunavir population pharmacokinetics in pregnancy; Ritonavir pharmacokinetics in pregnancy; Rilpivirine pharmacokinetics in pregnancy; Abacavir pharmacokinetics in pregnancy.

One poster at CROI 2015: Etravirine Pharmacokinetics During Pregnancy and Postpartum.

2014

Publication in JAC: Pharmacokinetics of total and unbound darunavir in HIV-1-infected pregnant women.

Publication in AVT: Atazanavir exposure is effective during pregnancy, regardless of tenofovir use.

Three posters were presented at CROI 2014: darunavir 800/100mg QD, raltegravir and atazanavir

Publication in AIDS: Pharmacokinetics, safety and transplacental passage of rilpivirine in pregnancy: two cases .

2013

Data on maraviroc were presented as a poster (collaboration with IMPAACT) at the 20th Conference on Retroviruses and Opportunistic Infections (CROI), Atlante, GA PANNA/IMPAACT poster maraviroc CROI 2013 .

Publication in AIDS: The pharmacokinetics, safety and efficacy of tenofovir and emtricitabine in HIV-1 infected pregnant women.

2012

Data on darunavir, atazanavir and ritonavir were presented as a poster at the 19th Conference on Retroviruses and Opportunistic Infections (CROI), Seattle, WA PANNA poster darunavir, atazanavir, ritonavir CROI 2012. Data on tenofovir were presented as a poster at the 13th International Workshop on Clinical Pharmacology of HIV Therapy, Barcelona PANNA poster PKworkshop 2012.

2011

Preliminary data raltegravir, poster presented at the 12th International Workshop on Clinical Pharmacology of HIV Therapy, Miami, FL raltegravir_poster_PKworkshop_2011.