Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Entry and Fusion Inhibitors

Ibalizumab

Drug Interactions

Additional information about drug interactions is available in the Adult and Adolescent Antiretroviral Guidelines and the HIV Drug Interaction Checker.

• Ibalizumab (IBA) is a humanized immunoglobulin G4 monoclonal antibody that blocks HIV entry into CD4 T lymphocyte (CD4) cells. Based on IBA’s mechanism of action and target-mediated drug disposition, drug–drug interactions are not expected. However, no drug interaction studies have been conducted.¹

Major Toxicities

• More common: Rash, diarrhea, headache, nausea, dizziness, depression^1,2
• Less common (more severe): Immune reconstitution inflammatory syndrome, hypersensitivity reaction¹

Resistance

HIV has shown reduced susceptibility to IBA, as defined by a decrease in maximum percent inhibition, when HIV loses N-linked glycosylation sites in the V5 loop of glycoprotein 120.^1-3

Phenotypic and genotypic test results showed no evidence of cross-resistance between IBA and any U.S. Food and Drug Administration (FDA)–approved classes of antiretroviral (ARV) drugs.⁴ IBA exhibits ARV activity against R5-tropic, X4-tropic, and dual-tropic HIV.⁴

Pediatric Use

Approval

IBA is not approved by the FDA for use in pediatric patients. IBA was approved by the FDA in 2018 for use in adults in combination with other ARV drugs, with approval limited to heavily treatment-experienced adults with multidrug-resistant HIV who are experiencing treatment failure on their current regimen.⁵ IBA has an orphan drug designation exempting the requirement for pediatric studies under the Pediatric Research Equity Act. The FDA requested that the company (i.e., Theratechnologies) create a registry to collect prospective data in individuals exposed to IBA during pregnancy to monitor maternal and pregnancy outcomes, including adverse effects on the developing fetus, neonate, and infant. Health care providers are encouraged to report these adverse events to Theratechnologies by calling 1‑833‑23‑THERA (1‑833‑23‑4372).

Efficacy in Clinical Trials

A TaiMed Biologics trial, TMB-301, was conducted in 40 adults aged 23 to 65 years who had body weights ranging from 50 kg to 130 kg, had resistance to ARV drugs from three classes, had been treated for at least 6 months on stable ARV regimens, had viral loads >1,000 copies/mL, and had viral sensitivity to at least one ARV drug.^3,5 Participants continued their current ARV regimens and received a 2,000-mg loading dose of IBA on Day 7 of the study. One week after the loading dose, participants optimized their ARV regimens. Participants received IBA 800 mg on Day 21 and every 2 weeks thereafter. At Week 25, 43% of participants achieved suppressed viral loads^1,3 of <50 copies/mL. At Week 48 of an open-label extension study, 24 participants were taking IBA and their optimized ARV regimen. Sixteen of 27 participants (59%) had viral loads <50 copies/mL at 48 weeks.^6,7

Mechanism of Action

IBA is a recombinant humanized monoclonal antibody that blocks HIV from infecting CD4 cells. It does this by binding to domain 2 of the CD4 receptor, which interferes with the post-attachment steps that allow HIV virus particles to enter host cells and prevent the viral transmission that occurs via cell–cell fusion.^1,7 IBA does not interfere with CD4-mediated immune functions because it binds to a conformational epitope located primarily in domain 2 of the extracellular portion of the CD4 receptor, away from major histocompatibility complex II molecule binding sites.

Embryo-Fetal Toxicity

In an enhanced prenatal and postnatal development study, pregnant cynomolgus monkeys were administered intravenous doses of IBA, and significant changes in infant monkey immune cell levels were found (CD4 T cell and B cell lymphocytopenia) that were attributed to in utero IBA exposure.¹ The lymphocyte changes correlated with infant monkey IBA serum concentrations and appeared to return to near-normal levels when IBA concentrations were nearly undetectable. One treatment-group infant monkey died from a systemic viral infection with secondary superficial bacterial infection that was acquired during the postnatal period. Despite the low incidence of death (1 of 20 infant monkeys), the death may be related to IBA-induced immunosuppression.¹

Based on these animal data, IBA may cause reversible immunosuppression (CD4 T cell and B cell lymphocytopenia) in infants born to human birthing parents who were treated with IBA during pregnancy. Immune phenotyping of the peripheral blood and expert consultation are recommended to provide guidance regarding monitoring and management of exposed infants based on the degree of immunosuppression observed. Furthermore, the safety of administering live or live-attenuated vaccines to infants with in utero IBA exposure and abnormal lymphocyte levels is unknown.

References

1. Ibalizumab-uiyk (Trogarzo) [package insert]. Food and Drug Administration. 2022. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761065s013lbl.pdf.
2. Iacob SA, Iacob DG. Ibalizumab targeting CD4 receptors, an emerging molecule in HIV therapy. Front Microbiol. 2017;8:2323. Available at: https://pubmed.ncbi.nlm.nih.gov/29230203.
3. Emu B, Fessel J, Schrader S, et al. Phase 3 study of ibalizumab for multidrug-resistant HIV-1. N Engl J Med. 2018;379(7):645-654. Available at: https://pubmed.ncbi.nlm.nih.gov/30110589.
4. Weinheimer S, Cohen Z, Marsolais C, Lewis S. Ibalizumab susceptibility in patient HIV isolates resistant to antiretrovirals. Abstract 561. Presented at: Conference on Retroviruses and Opportunistic Infections 2018. Boston, MA. Available at: http://www.croiconference.org/sessions/ibalizumab-susceptibility-patient-hiv-isolates-resistant-antiretrovirals.
5. Food and Drug Administration. FDA clinical pharmacology biopharmaceutics reviews. 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/TROGARZO_761065_TOC.cfm
6. Emu B, Fessel J, Schrader S, et al. Forty-eight-week safety and efficacy on-treatment analysis of ibalizumab in patients with multi-drug resistant HIV-1. Open Forum Infect Dis. 2017;4(Suppl 1):S38-S39. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5632088.
7. Gulick RM. Investigational antiretroviral drugs: what is coming down the pipeline. Top Antivir Med. 2018;25(4):127-132. Available at: https://pubmed.ncbi.nlm.nih.gov/29689540.