Why we did this
Globally, 1.3 million people were newly diagnosed with HIV-1 in 2022. Although testing, treatment, pre-exposure prophylaxis (PrEP) have slowed the spread of HIV-1,1 many people remain at-risk. Passive immunization with broadly neutralizing monoclonal antibodies (mAbs) provides a novel approach as an additional potential HIV-1 prevention modality, alone or in combination with other existing prevention modalities. In the US, there were about 1.2 million persons with an indication for PrEP in 2020, of which 25% have received a prescription.2 Although the likelihood of an interaction between these two classes of drugs may be limited due to the distinct pathways regulating their metabolism, there have been reports of mAb-small molecule drug interactions.3 Therefore, it is important to investigate whether VRC01 pharmacokinetics (PK) in oral PrEP ([tenofovir disoproxil fumarate (TDF)-emtricitabine (FTC)], TDF-FTC) users differs from that in non-PrEP users, and if present, explore potential mechanisms of such interactions between PrEP and VRC01.
What we did
We used a cohort of 24 oral PrEP users (of TDF-FTC), and 24 non-PrEP users drawn from an efficacy trial of VRC01 in which participants were provided access to free oral PrEP, to compare PK features of VRC01 between PrEP and non-PrEP users. We measured participant serum concentrations of VRC01 after each of ten 8-weekly VRC01 infusions ~ every 4 weeks and applied population pharmacokinetics (popPK) models to analyze VRC01 concentrations over-time from both PrEP and non-PrEP users. We used the Targeted Maximum Likelihood Estimation (TMLE) approach to compare VRC01 PK features between PrEP and non-PrEP users. We estimated five individual-level PK features: clearance, volume of the peripherical compartment, distribution half-life, elimination half-life, and steady state dose-normalized area under the curve after adjusting for: age, body weight, race, baseline behavioral risk score,4 and creatinine clearance, and two inflammatory markers (IFN-γ and IL-10). We further explore potential molecular and physiologic mechanisms of the findings including an exploration of pro-inflammatory markers, liver and kidney function, and intestinal permeability.
What we found
We found two VRC01 PK features were significantly different between PrEP and non-PrEP users. Specifically, the mean clearance rate of VRC01 was 15% greater, and the mean area under the curve of VRC01 serum concentrations was 14% lower in PrEP users than in non-PrEP users.
These differences were not associated with serum inflammatory markers, liver, or kidney functions. We did; however, observe a significant increase in I-FABP levels, a marker of intestinal permeability, over time, among PrEP users, but not among non-PrEP users. I-FABP levels measured at about 4 weeks after PrEP use also positively correlated with the subsequent clearance rate of VRC01. We did not find evidence of an association with intestinal permeability via LBP, a marker of larger size than I-FABP, suggesting a selective leakage mechanism.
Why it matters
Given that oral PrEP has been licensed in several countries as an HIV-1 prevention tool, additional studies of mAbs for HIV prevention may include PrEP users. Understanding differential mAb PK measurements among PrEP users could ensure optimal dosing. The long duration of I-FABP upregulation may also be important to assess if the increased clearance rate of VRC01 also affects other populations taking anti-retrovirals, such as people living with HIV, who participate in treatment interruption trials using monoclonals.
Given the low to moderate influence on VRC01 clearance and area under the curve between PrEP and non-PrEP users, it is unlikely that dose adjustment would be needed for VRC01. However, it may be needed if verified for other HIV-1 mAbs entering the prophylaxis pipeline. Similarly, because the PK of VRC01resembles the PK of other IgG-based monoclonals, our investigation suggests that the PK of prophylactic or therapeutic antibodies for other diseases in PrEP users should be investigated to determine if optimal doses of immunotherapies are affected by PrEP.
If you want to know more, you can read the full text here: Adults on pre-exposure prophylaxis (tenofovir-emtricitabine) have faster clearance of anti-HIV monoclonal antibody VRC01 | Nature Communications
- Joint United Nations Programme on HIV/AIDS. IN DANGER: UNAIDS Global AIDS Update 2022. Licence: CC BY-NC-SA 3.0 IGO. 2022. https://www.unaids.org/sites/default/files/media_asset/2022-global-aids-update-summary_en.pdf
- Centers for Disease Control and Prevention. PrEP Coverage. Accessed May 30, 2023. https://www.cdc.gov/hiv/statistics/overview/in-us/prep-coverage.html
- Ferri N, Bellosta S, Baldessin L, Boccia D, Racagni G, Corsini A. Pharmacokinetics interactions of monoclonal antibodies. Pharmacological Research. 2016/09/01/ 2016;111:592-599. doi:https://doi.org/10.1016/j.phrs.2016.07.015
- Seaton KE, Yunda Huang P, Karuna S, et al. Pharmacokinetic serum concentrations of VRC01 correlate with prevention of HIV-1 acquisition. EBioMedicine. 2023;93:104590. doi:https://doi.org/10.1016/j.ebiom.2023.104590