841 – Viremia Accelerates VRC01 Clearance in Infants Living With HIV-1: Insights From IMPAACT 2008

Background

VRC01, a CD4 binding–site broadly neutralizing antibody (bNAb), was administered concomitantly during the initiation of early antiretroviral treatment (ART) in infants with HIV-1 in IMPAACT 2008. We characterized VRC01 population pharmacokinetics (PopPK) and explored clinical factors associated with VRC01 PopPK.

Methods

Twenty-nine infants (median age at entry 2.4 months, range 1.6-2.8 months) received VRC01 40mg/kg administered subcutaneously at Weeks 0, 2, 6 and 10 with standard-of-care ART and provided sparse plasma VRC01 concentrations (n=141) during the first 16 weeks on study.  PK samples were collected prior to each dose and at Weeks 14 and 16. PopPK analyses were performed in NONMEM v7.6 (FOCEI) using a two-compartment model with first-order absorption. Body weight (WT) was allometrically scaled a priori with fixed exponents to account for size and growth (CL/F ∝ WT^0.85; Vss/F ∝ WT^1.0). Between-subject variability (BSV) was estimated for CL/F. Univariate covariate screening and multivariate analyses were used to evaluate associations of CL/F with age at entry, dose number (DNUM), sex, study site, race, ART, HIV RNA (log10) at entry (HIVRNA_WK0), at WK6 (HIVRNA_WK6), change from WK0 to WK6 (HIVRNA_WK0-WK6) and HIV RNA at the time of PK collection (HIVRNA_t). Final model selection was determined by objective function, goodness-of-fit diagnostics and bootstrap analysis.

Results

In the univariate assessment DNUM, HIVRNA_WK0, HIVRNA_WK6 and HIVRNA_t were identified as potential covariates. DNUM and HIVRNA_t were retained in the final multivariate model. PopPK model parameter estimates are:

CL/F (L/h) = 0.0182 × (WT/70kg)^0.85 × (DNUM/2)^0.507 × (HIVRNA_t/3.31)^0.495  

Vss/F (L) = 17.67 × (WT/70kg)

Unexplained BSV for CL/F was 51.4% CV. The estimated CL/F was greater than previously reported in infants HIV-exposed but uninfected (IHEU) (P1112-J Li, CPT 2020).  At Weeks 14 and 16, VRC01 concentrations were 2-fold greater in infants with HIV RNA <200 (Week 16 median 66 mcg/mL) than ≥200 copies/mL (33 mcg/mL).

Figure- Scatter plot of observed VRC01 concentrations in infants with HIV by plasma RNA levels and predicted concentrations in IHEU.

Conclusions

Infants with HIV receiving VRC01 at ART initiation have increased VRC01 CL/F and thus lower levels than those modeled from studies of IHEU. Higher viremia predicted faster CL/F. These results extend prior infant bNAb PopPK findings and support consideration of early on-treatment virologic measures when dosing VRC01.

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