Is HIV epidemic control by 2030 realistic?

Rates of new HIV acquisition remain unacceptably high in most populations in low-income, middle-income, and high-income settings despite advances in treatment and prevention strategies. Although biomedical advances in primary prevention of new infections exist, systematic scale-up of these interventions has not occurred at the pace required to end AIDS by 2030. Low population coverage, adherence to oral pre-exposure prophylaxis in settings with high rates of HIV acquisition, and the fact that a significant proportion of new HIV infections occurs in populations not identified as high risk and are hence not targeted for prevention approaches impedes current prevention strategies. Although long-acting injectables and monoclonal antibodies are promising approaches to help reduce incidence, high cost and the need for high coverage rates mean that a vaccine or vaccine-like intervention still remains the most likely scenario to produce a population-level impact on HIV incidence, especially in countries with generalised epidemics. Current global efforts are not sufficient to meet 2030 HIV epidemic goals; acknowledgment of this issue is required to ensure persistent advocacy for population-based control of the ongoing HIV pandemic.

Impact of LS Mutation on Pharmacokinetics of Preventive HIV Broadly Neutralizing Monoclonal Antibodies: A Cross-Protocol Analysis of 16 Clinical Trials in People without HIV.

Monoclonal antibodies are commonly engineered with an introduction of Met428Leu and Asn434Ser, known as the LS mutation, in the fragment crystallizable region to improve pharmacokinetic profiles. The LS mutation delays antibody clearance by enhancing binding affinity to the neonatal fragment crystallizable receptor found on endothelial cells. To characterize the LS mutation for monoclonal antibodies targeting HIV, we compared pharmacokinetic parameters between parental versus LS variants for five pairs of anti-HIV immunoglobin G1 monoclonal antibodies (VRC01/LS/VRC07-523LS, 3BNC117/LS, PGDM1400/LS PGT121/LS, 10-1074/LS), analyzing data from 16 clinical trials of 583 participants without HIV. We described serum concentrations of these monoclonal antibodies following intravenous or subcutaneous administration by an open two-compartment disposition, with first-order elimination from the central compartment using non-linear mixed effects pharmacokinetic models. We compared estimated pharmacokinetic parameters using the targeted maximum likelihood estimation method, accounting for participant differences. We observed lower clearance rate, central volume, and peripheral volume of distribution for all LS variants compared to parental monoclonal antibodies. LS monoclonal antibodies showed several improvements in pharmacokinetic parameters, including increases in the elimination half-life by 2.7- to 4.1-fold, the dose-normalized area-under-the-curve by 4.1- to 9.5-fold, and the predicted concentration at 4 weeks post-administration by 3.4- to 7.6-fold. Results suggest a favorable pharmacokinetic profile of LS variants regardless of HIV epitope specificity. Insights support lower dosages and/or less frequent dosing of LS variants to achieve similar levels of antibody exposure in future clinical applications.