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.

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.

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

The investigators will consider all reasonable requests by health-care providers, investigators, and researchers to provide anonymised data to address specific scientific or clinical objectives. The investigators are committed to reviewing requests from researchers for access to clinical trial protocols, de-identified patient-level clinical trial data, and study-level clinical trial data. Data will be assigned a DOI through deposition in the University of Liverpool Research Data Catalogue (rdm@liverpool.ac.uk) and shared under a Data Transfer agreement (or equivalent e.g. as part of a research collaboration agreement or confidentiality disclosure agreement).

After study analysis has completed and manuscript is published for at least 5 years afterwards.

By reasonable request to the investigators.