Safety and Tolerability of Raltegravir in a Premature Neonate: A Case Report

To the Editors: Triple antiretroviral prophylaxis with zidovudine, lamivudine and either nevirapine or raltegravir is recommended for infants at high risk of perinatal HIV transmission.1 Raltegravir is recommended for neonatal prophylaxis because of its potent antiviral activity and favorable resistance profile. However, current approval is limited to use in term neonates with a birth weight of at least 2 kg and a gestational age of 37 weeks or greater.1 Data regarding the safety and dosing of raltegravir in premature infants remain scarce. We report the use of raltegravir-containing triple antiretroviral prophylaxis in a premature neonate at high risk of perinatal HIV transmission. The infant was born via normal spontaneous vaginal delivery to a 23-year-old woman living with HIV-1 infection who had not received regular antenatal care or antiretroviral therapy during pregnancy. Gestational age was estimated as 32 weeks based on Ballard scoring, and birth weight was 1800 g. She was referred to our hospital within 24 hours after birth, and oral zidovudine prophylaxis was initiated within the first 6 hours of life at the referring hospital. Oral lamivudine was added at 24 hours of age following transfer. As nevirapine was not available in our country, raltegravir was selected as the third antiretroviral agent. Raltegravir was initiated at a dose of 4 mg once daily (2.2 mg/kg/dose). Unconjugated bilirubin levels peaked on postnatal day 5 and subsequently declined without evidence of cholestasis or elevation in aminotransferase levels (Table 1). TABLE 1. - Laboratory Parameters of the Patient Day of Life Hemoglobin (g/L) Neutrophils (× 109/L) Bilirubin Unconjugated (µmol/L) Bilirubin Conjugated (µmol/L) ALT (U/L) AST (U/L) 2 127 6.5 82.8 6.8 <5 38 5 86 3.2 157.5 9.6 <5 21 8 121 2.9 133.6 7.2 <5 23 14 88 4.0 18.3 13.2 <5 17 21 111 1.9 3.8 9.9 9 18 23 106 10.6 5.5 8.4 15 19 36 69 1.6 8.0 8.4 13 20 44 123 3.0 7.2 8.7 7 18 63 87 2.2 2.6 3.2 17 28 ALT indicates alanine aminotransferase; AST, aspartate aminotransferase. On postnatal day 8, the raltegravir dose was increased to 8 mg twice daily (4.4 mg/kg/dose) in accordance with age-based neonatal dosing recommendations. HIV DNA polymerase chain reaction (PCR) tests performed on postnatal days 2 and 18 were negative. After confirmation of a second negative HIV DNA PCR on postnatal day 28, lamivudine and raltegravir were discontinued, while zidovudine prophylaxis was continued until 6 weeks of age. An additional HIV DNA PCR at 2 months of age was negative. Written informed consent was obtained from the patient’s parents. The IMPAACT P1110 study demonstrated that raltegravir can be safely administered to term neonates using a stepwise, age-dependent regimen.2 However, evidence supporting its use in premature infants is extremely limited. To date, only 2 published case reports have described raltegravir use in preterm neonates for prevention of perinatal HIV transmission, both employing therapeutic drug monitoring to guide intermittent dosing.3,4 In the present case, therapeutic drug monitoring was not available. Therefore, raltegravir was administered at the lowest available dose during the first week of life, followed by dose escalation.1 Reported adverse effects of raltegravir in neonates include anemia, neutropenia and hyperbilirubinemia.1 In our patient, no rash, neutropenia, significant liver enzyme elevation or hyperbilirubinemia requiring phototherapy was observed. Episodes of anemia were considered secondary to prematurity, low birth weight and neonatal intensive care unit hospitalization rather than drug-related toxicity. In conclusion, raltegravir was well tolerated in a premature infant. Nevertheless, additional real-world data and pharmacokinetic studies are needed to establish optimal dosing strategies and confirm the safety of raltegravir use in premature neonates.