Background
Very early antiretroviral treatment (ART) with effective viral suppression can enable ART-free remission in infants with in utero HIV. However, many infants do not achieve sustained viral suppression. Anti-HIV broadly neutralizing antibodies (bNAbs), such as VRC01, added to ART may enhance viral suppression but infant PK and safety data for bNAbs are limited.
Methods
Infants in P1115 initiated raltegravir, nevirapine, and 2 nucleoside reverse transcriptase inhibitors within 48 hours (hr) of birth; a subset were given 40 mg/kg VRC01 by slow subcutaneous (SC) push (approximately 10 minutes) by 72 hr of birth. Infants with confirmed in utero HIV received 3 additional VRC01 doses at 2, 6, and 10 weeks (wk) of age. Safety and plasma HIV RNA were assessed throughout follow-up. Plasma VRC01 levels were assessed in a PK group at 1 wk and in infants with HIV at 2, 6, 10, 14, 18, 22, and 26 wk. Observed VRC01 levels, categorized by concurrent HIV RNA, and predicted VRC01 levels from modeling of IMPAACT P1112 data for infants HIV exposed but uninfected (HEU) were visualized.
Results
222 neonates received VRC01 (218 in Zimbabwe, 4 in Malawi); 98% of doses were given within 48 hr of birth. Among 11 infants with HIV, 10 received 3 additional VRC01 doses; one withdrew early and received only 1 additional dose. Local injection reactions were rare (1.1% [3/253] doses), mild, and transient. There were no systemic injection reactions. Median [25th, 75th %ile] VRC01 levels at 1 wk after the birth dose were similar for infants with HIV (121.6 [109.2, 132.1] mcg/mL; n=10) and without HIV (111.5 [97.5, 130.3] mcg/mL; n=59). For repeated doses for infants with HIV, median (25th, 75th %ile) pre-dose levels were 83.9 (76.2, 89.4), 77.8 (67.8, 101.4), and 84.0 (46.2, 97.2) mcg/mL at 2, 6, and 10 wks, exceeding the protocol target of 50 mcg/mL. After the second dose, levels were approximately 40% lower than modeling based on data from HEU (Figure). After 10 wk, observed VRC01 levels trended lower for infants with concurrent plasma HIV RNA ≥ 200 cp/mL than for those with HIV RNA < 200 cp/mL (Figure).
Conclusions
VRC01 given in infancy by SC injection was well tolerated with extensive absorption at 1 week. Infants with/without HIV had similar levels after the initial dose, but with repeated doses in the infants with HIV, VRC01 clearance was faster than predicted from data in HEU, and particularly with ongoing viremia. These data support consideration of HIV status and viremia for infant bNAb dosing.
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