Raltegravir in the prevention of mother-to-child transmission of HIV-1

HIV infection may be associated with an increased risk of preterm labour [1], and preterm neonates are at an increased risk of acquiring HIV congenitally [2]. Absorption of orally administered drugs in preterm neonates is unpredictable due to gastrointestinal tract immaturity, and parenteral antiretroviral options are also limited [3]. The HIV-1 integrase inhibitor, raltegravir (RGV), has rapid antiretroviral activity with shorter times to achieving virological suppression when used in combination treatments compared with conventional combination antiretroviral therapy (ART) [4,5]. RGV has a favourable pharmacokinetic profile with a terminal elimination half-life of between 7 and 12 h and a time to steady state of approximately 2 days [6]. It is eliminated by glucuronidation in the liver by human UGT1A1 [6] and much of the RGV glucuronide metabolite is eventually excreted in bile (approximately 50%) or in urine (31%) [6]. Although unlicensed in pregnancy, RGV has been used in patients who present late in pregnancy with high HIV-1 viral loads when it is critical to reduce the viral load to undetectable levels before delivery [7]. We have previously demonstrated effective RGV transplacental transfer and persistence of therapeutic drug concentrations in neonates for several days after delivery in mothers with HIV-1 resistant to protease, nucleoside/nucleotide and nonnucleoside inhibitors [8]. We describe three cases of preterm delivery in which RGV was used in the prevention of mother-to-child transmission (PMTCT) of HIV-1. Paired blood samples were taken from the mother and baby as close to delivery as possible and subsequently postpartum. RGV plasma concentrations (RPC) were measured using liquid chromatography with tandem mass spectrometric detection. Maternal HIV-1 viral load was monitored regularly until delivery and neonates were assessed for HIV-1 infection by HIV-1 DNA PCR at 0, 6 and 12 weeks (Roche Taqman 2.0 assay). Cases are summarized in Table 1. The mother in case 1 was a 24-year-old Rwandan lady who had been diagnosed with HIV-1 infection 10 years previously. She had a long history of poor adherence to ART and was known to have had K103N and M184V resistance mutations previously detected, as well as intolerance to ritonavir at pharmacoenhancing doses. This was her sixth unplanned pregnancy, and all her previous pregnancies had been obstetrically complicated. The mother in case 2 was 32 years old, from Ghana, and in her first pregnancy. She was newly diagnosed with HIV-1, having tested positive through routine antenatal screening, and was having difficulty accepting the diagnosis. She was poorly adherent to ART and her viral load never became undetectable. Her viral load was unknown when she presented at the time of delivery. The mother in case 3 was 32 years old, from Uganda and also in her first pregnancy. She had been diagnosed with HIV-1 3 years previously but had never previously received ART. She was started on combination ART in the second trimester of pregnancy and was fully adherent with a suppressed HIV viral load. All babies received 4 weeks of ART postpartum and have tested HIV negative by DNA PCR to date with no apparent adverse reactions.Table 1: Summary of cases.Therapeutic RPC (≥15 ng/ml) were achieved in all mothers and in all babies at both sampling times, despite RGV being initiated 22.5 and 14 h prior to delivery in two cases. RPC can remain at therapeutic levels for up to 5 days in preterm neonates, longer than babies born at term [8], probably reflecting immature UGT1A1-mediated glucuronidation. The use of RGV preloading in pregnancy for HIV PMTCT in preterm neonates may thus have added benefits above rapidly reducing maternal viral load by having a similar role to nevirapine [9] or double-dose tenofovir [10] for preloading preterm neonates who cannot take or absorb oral drugs poorly and for whom parenteral options are limited. In this small series, RGV levels in the mothers and neonates who commenced RGV with the aim of preloading the baby were much lower than in the mother who was on established treatment and had presumably reached steady state. The use of a dose of 800 mg should be explored for rapidly preloading premature infants. Larger studies are needed to further characterize the pharmacokinetics of RGV in pregnant women and neonates. Acknowledgements Conflicts of interest There are no conflicts of interest.