Data from two cases of rilpivirine use in pregnancy

1 February 2014. Related: Pregnancy.

Polly Clayden, HIV i-Base

There are currently no safety or pharmacokinetic (PK) data available to guide the use of rilpivirine in pregnancy.

The PANNA study was established to collect data on PK and transplacental passage of new antiretrovirals during pregnancy. [1] It is a non-randomised, open-label, multicentre phase IV study.

Angela Colbers and colleagues from the PANNA group described two cases of rilpivirine use in pregnancy from PANNA in a letter to the 14 January 2014 edition of AIDS. [2]

Rilpivirine is an NNRTI, given once daily and available as a single 25 mg tablet and coformulated with tenofovir and FTC in a fixed dose combination (FDC). Rilpivirine is indicated for treatment-naïve adults with a viral load of 100,000 copies/mL or less.

The first case presented was a 19-year-old black woman, diagnosed with HIV in 2011, when she started antiretroviral treatment with the rilpivirine/tenofovir/FTC FDC (Eviplera). She conceived after approximately 14 weeks on this regimen.

The regimen was stopped after pregnancy was confirmed, then restarted at week 25 (viral load 3500 copies/mL) and continued for the rest of the pregnancy and after delivery.

At week 32, the investigators performed a full PK analysis, which gave the following values: AUC-24 1.25 mg*h/L; Cmax 0.07; C0h 0.04mg/L and T1/2, 30 hr.

At 38 weeks of pregnancy, the mother was admitted to the hospital due to irregular contractions. This was reported as a serious adverse event not considered associated with Eviplera

The infant was delivered vaginally at 39 weeks and 5 days gestational age; the mother’s viral load was undetectable <50 copies/mL. The infant was a girl, had no congenital abnormalities and weighed 3620 g. The infant’s HIV DNA PCR test at two weeks after delivery was negative.

The cord blood/maternal blood ratio was 0.74 at delivery.

At 45 days after delivery, maternal postpartum PK values were: AUC0-24 1.79 mg*h/L; Cmax 0.11 mg/L; C0h 0.07 mg/L and T1/2 43 hr.

The second case was a 24-year-old white woman, who was diagnosed with HIV in 2010. She began ART in September 2011 with a regimen of atazanavir/ritonavir 300/100 mg once daily and AZT/3TC. She switched to Eviplera in August 2012 and had been taking it for 10 weeks when she conceived.

The PK analysis was performed at 32 weeks of pregnancy, with the following values: AUC0-24 1.42 mg*h/L; Cmax 0.14mg/L, C0h 0.04mg/L and T1/2 33hr.

The infant was delivered by emergency Caesarean at 38 weeks and five days gestational age. The mother’s viral load was 77 copies/mL two weeks before delivery but was undetectable again four weeks post partum. The infant was also a healthy girl, she weighed 2945 g and tested negative for HIV at one day and 18 days of age.

Postpartum maternal PK values were: AUC0-24 2.49 mg*h/L; Cmax 0.15 mg/L; C0h 0.07mg/L and T1/2, 48 hr.

The investigators noted that exposure was 30–43% lower during pregnancy. This compares to the decrease seen for protease inhibitors. Postpartum AUC0-24 in these two cases is in line with the mean steady-state AUC0-24 in adults previously described in the literature. They suggested that the lower exposure during pregnancy might be driven by a shorter rilpivirine half-life – but accurate measurement of this under steady-state conditions is difficult.

They explained that target rilpivirine trough concentration, derived from phase III studies is 0.04 mg/L. In both cases, the Ctrough concentrations in the third trimester and the maternal sample at delivery were 0.04mg/L or less, indicating subtherapeutic levels during pregnancy.

Despite the low concentration, no vertical transmission of HIV was reported, but this needs to be confirmed with longer follow up of the infants.

The investigators noted that a limitation with these case studies is that no unbound rilpivirine concentrations were determined. Lower protein binding during pregnancy can compensate for lower total concentrations. They did not report any major safety issues in these two cases.

They recommended therapeutic drug monitoring for rilpivirine during pregnancy.

References:

1. The PANNA (Pharmacokinetics of newly developed ANtiretroviral agents in HIV-infected pregNAnt women) Study.
   http://www.pannastudy.com/ClinicalTrials.gov NCT00825929.
2. Colbers A et al. Pharmacokinetics, safety and transplacental passage of rilpivirine in pregnancy: two cases. AIDS 2014, Vol 28 No 2 pp: 149-292. 14 January 2014.