Early-treated HIV+ children may be ideal candidates for use of broadly neutralizing monoclonal antibodies (bNAbs) as an alternative to antiretroviral treatment (ART), but pediatric bNAb data to date has been limited to subcutaneous administration of VRC01/LS during infancy. In preparation for a trial of dual bNAb use as a treatment alternative, we evaluated the safety and pharmacokinetics (PK) of monthly VRC01LS or 10-1074 dosed intravenously among HIV+ children on suppressive ART.
The PK phase of the Tatelo Study in Botswana enrolled 12 children who had received ART continuously from < 7 days through at least 96 weeks of life, and had HIV-1 RNA < 40 copies/mL for at least 24 weeks prior to entry. While continuing ART, 6 participants received VRC01LS (30 mg/kg load at day 0, then 10mg/kg at days 28 and 56) and 6 participants received 10-1074 (30 mg/kg on days 0, 28 and 56). bNAb concentrations were tested 18 times over 12 weeks using murine anti-VRC01 and anti-10-1074 antibodies.
Among the 12 children enrolled, the median age was 38 months (range 26 to 50 months), 75% were female, the median CD4 cell count was 1211 cells/mm3 and CD4% was 34%. All children were receiving lopinavir/ritonavir, zidovudine, lamivudine (and one was also on abacavir). All but one infusion occurred on schedule and to completion, and infusions were well tolerated. No infusion reactions occurred, and no grade 3 or 4 events were related to either bNAb. For VRC01LS, median (range) first dose peak concentrations (Cmax) and Day 84 trough concentrations (C84D) were 726 (559-799) mcg/mL and 157 (126-201) mcg/mL respectively, both about half of predicted values based on PK in uninfected adults (Figure 1A). For 10-1074, median (range) first dose Cmax and C84D concentrations were 1633 (1174-1999) mcg/mL and 258 (122-467) mcg/mL respectively, both somewhat greater than predicted values from HIV-infected adults on suppressive ART (Figure 1B).
Intravenous VRC01LS and 10-1074 were safe and well tolerated among HIV+ children receiving ART.Pediatric PK of these two bNAbs differed from PK in adults. For VRC01LS, an increased maintenance dose of at least 15mg/kg may be needed to achieve concentrations similar to adults when dosed monthly. For 10-1074, predicted adult concentrations were slightly exceeded with 30mg/kg monthly.