HIV
Conditions
Keywords
Pregnancy
Brief summary
A randomised, open label, controlled PK standard of care vs doravirine plus 2 nucleoside reverse transcriptase inhibitors backbone in pregnant women initiating combination antiretroviral therapy in the second trimester of pregnancy.
Detailed description
Women diagnosed HIV positive in the second trimester of pregnancy in South Africa will be enrolled and randomised 1:1 to receive standard of care or doravirine plus 2 NRTI backbone. Participants will receive study treatment until delivery and up to 28 weeks postpartum, with a maximum total of 14 months of study treatment. Given the high prevalence of NNRTI resistance, alternative ARV treatment options are essential. Doravirine is licenced for the treatment of HIV-1 in adults in North America and Europe. Whilst the efficacy and safety of doravirine has been established in non-pregnant adults, there are no adequate human data available to establish whether DOR poses a risk to pregnancy outcomes. It is important to have data on the safety and pharmacokinetics of the drug during pregnancy and in particularly the third trimester of pregnancy in order to support its use. The hypothesis for this study is that pregnancy influences the pharmacokinetics of doravirine when initiated in the second trimester.
Interventions
DRUGDoravirine
Fixed dose combination of doravirine, lamivudine and tenofovir disoproxil
DRUGDolutegravir
Fixed dose combination of dolutegravir, lamivudine and tenofovir disoproxil
Sponsors
University of Liverpool
Liverpool School of Tropical Medicine
Desmond Tutu Health Foundation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Women ≥ 18 years old * Ability to give informed consent prior to participation * Willing and able to comply with all study requirements * HIV positive * Pregnant (initiating cART ≥ 12 weeks and \< 26 weeks gestation) * Intention to breastfeed postpartum
Exclusion criteria
* Received any cART in preceding 6 months * Chronic hepatitis B (HBV) infection with clinical evidence of transaminitis * Elevations in serum levels of alanine aminotransferase (ALT) \> 5 times the upper limit of normal (ULN) or ALT \> 3xULN and bilirubin \>2xULN (with \> 35 % direct bilirubin) * Previous documented failure of an NNRTI-containing cART regimen * Previous history of hypersensitivity to any ARV * Concomitant medication which are inducers of SoC and DOR metabolism (e.g. rifampicin, anti-epileptic agents, rifabutin, St John's Wort, mitotane, enzalutamide, lumacaftor). Contraindicated medications can be found on Liverpool Drug Interactions website (hiv-druginteractions.org) * Participants with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption cannot take DOR as the tablet contains lactose monohydrate * Clinical depression or clinical judgment suggests increased risk of suicidality
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC of doravirine in pregnant women | 24 to 28 weeks gestation, 32 to 36 weeks gestation, 6 weeks postpartum | Pharmacokinetic parameters of doravirine in pregnancy - AUC |
| Cmax of doravirine in pregnant women | 24 to 28 weeks gestation, 32 to 36 weeks gestation, 6 weeks postpartum | Pharmacokinetic parameters of doravirine in pregnancy - Cmax |
| Cmin of doravirine in pregnant women | 24 to 28 weeks gestation, 32 to 36 weeks gestation, 6 weeks postpartum | Pharmacokinetic parameters of doravirine in pregnancy - Cmin |
| CL/F of doravirine in pregnant women | 24 to 28 weeks gestation, 32 to 36 weeks gestation, 6 weeks postpartum | Pharmacokinetic parameters of doravirine in pregnancy - CL/F |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To assess the number of treatment related adverse events by DAIDS v2.1 | Until study completion, a maximum of 13 months | Safety and tolerability of doravirine in mothers and neonates |
| To determine the concentration of doravirine in breastmilk, in breastfed infants, in genital tract, cord blood | 24 to 28 weeks gestation, 32 to 36 weeks gestation, 6 weeks postpartum | Pharmacokinetics of doravirine in various compartments |
| To assess maternal viral load responses | Delivery and 6 months postpartum | Viral load assessment |
| To determine infant transmissions in the first 6 months of life using HIV viral load | Delivery until 6 months postpartum | Assessment of perinatal transmission using HIV viral load |
| To assess the prevalence or emergence of HIV drug resistance by determining HIV mutations | Until study completion, a maximum of 13 months | Assessment of drug resistance tests |
Countries
South Africa
Contacts
CONTACTHelen Reynolds
PRINCIPAL_INVESTIGATORSaye Khoo
University of Liverpool
Outcome results
None listed