Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Entry and Fusion Inhibitors

Maraviroc

Drug Interactions

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

• Absorption: Absorption of maraviroc (MVC) is slightly reduced with ingestion of a high-fat meal. Food restrictions were not part of either the adult trials (which used the tablet formulation) or the pediatric trial (which used both the tablet and oral solution formulations) that demonstrated the efficacy, antiviral activity, and safety of MVC. Therefore, MVC can be given with or without food.
• Metabolism: MVC is a cytochrome P450 (CYP) 3A and p-glycoprotein (P-gp) substrate and requires dose adjustments when administered with medications that modulate CYP3A or P-gp. A patient’s medication profile should be carefully reviewed for potential drug interactions before MVC is administered; recommended MVC doses are based on concomitant medications and their anticipated effect on MVC metabolism.

Major Toxicities

• More common: Cough, fever, upper respiratory tract infections, rash, musculoskeletal symptoms, abdominal pain, vomiting, diarrhea, and headache. Dizziness occurred in 12.2% of adults but only 3.2% of children when MVC was administered twice daily.
• Less common (more severe): Hepatotoxicity has been reported; some cases were preceded by evidence of a systemic allergic reaction (including pruritic rash, eosinophilia, or elevated levels of immunoglobulin). Serious adverse events (AEs) occurred in <2% of MVC-treated adult patients and included cardiovascular abnormalities (e.g., angina, heart failure, myocardial infarction), hepatic cirrhosis or failure, cholestatic jaundice, viral meningitis, pneumonia, myositis, osteonecrosis, and rhabdomyolysis.

Mechanism of Action

MVC is a CCR5 receptor antagonist that selectively binds to the human chemokine receptor CCR5 on the cell membrane, preventing interaction between HIV-1 gp120 and CCR5 tropic HIV-1, inhibiting viral entry into the cell.

Resistance

An HIV tropism assay should be performed before MVC is administered to a patient. Clinical failure may also represent the outgrowth of CXCR4-using (naturally resistant) HIV variants. However, in circumstances when MVC is needed for presumptive HIV therapy for full-term neonates at high risk of perinatal HIV transmission, initiation of MVC should not be deferred until assay results are available, and consultation with an HIV expert is recommended.

Pediatric Use

Approval

MVC is approved by the U.S. Food and Drug Administration (FDA) for treatment of CCR5-tropic HIV virus, when used in conjunction with other antiretroviral drugs, in full-term infants weighing ≥2 kg, as well as children, adolescents, and adults who have a CCR5-tropic HIV virus when used in conjunction with other antiretroviral drugs.^1,2

Pharmacokinetics and Efficacy

The International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT 2007) study evaluated the pharmacokinetics (PK) and safety of MVC added to a 6-week prophylactic antiretroviral regimen to prevent perinatal HIV transmission of HIV among infants born to mothers living with HIV.² Analyses were stratified by exposure to efavirenz (EFV), either in utero or through breastmilk, versus non-EFV exposure. The MVC exposure target was average plasma concentration (C_avg) ≥75 ng/mL, as determined by adult treatment studies. MVC oral solution was dosed at 8 mg/kg twice daily for the first 6 weeks of life. Among 25 infants with evaluable PK data, 12 of whom were EFV-exposed, 67% of the EFV-exposed infants achieved a C_avg ≥75 ng/mL at Week 1, whereas 77% of the EFV-unexposed infants had a C_avg ≥75 ng/mL. At Week 4, the proportion of infants achieving a C_avg ≥75 ng/mL declined to 42% among EFV-exposed infants and 31% among EFV-unexposed infants. No infants in the study met safety endpoints or discontinued MVC during the study and no infants acquired HIV. The FDA recommendation for MVC dosing among children >6 weeks of life but younger than 2 years of age is based on modeling using PK data from the IMPAACT 2007 study.  A population PK model, which included assessment of age and maturational changes, was developed from IMPAACT 2007 data to describe MVC disposition within the first 6 weeks of life.³ Simulations with FDA-approved weight-band dosing resulted in the majority of simulated patients (84.3%) achieving an average concentration of ≥75 ng/mL. When considering the use of MVC for neonates and infants, a pediatric HIV specialist should be consulted.

PK, safety, and efficacy of MVC for treatment-experienced children, ages 2 years to <18 years and weighing ≥10 kg, who had plasma HIV RNA >1,000 copies/mL, were examined in an international dose-finding and efficacy study (A4001031). Of the 103 children who participated in the study, 51% had HIV-1 subtype C, 25% had subtype B, and 23% had other subtypes.

In this trial, the MVC dose was based on body surface area and the composition of the patient’s optimized background therapy. Most participants (90 of 103 participants [87%]) received MVC in combination with potent CYP3A inhibitors; 10 participants received MVC with noninteracting medications; and only 3 participants received MVC with CYP3A inducers (without CYP3A inhibitors). The key pharmacologic target (geometric mean C_avg of >100 ng/mL) was achieved with both the tablet and oral solution formulation of MVC.⁴

From a mean baseline plasma HIV RNA concentration of 4.4 log₁₀ copies/mL, a decrease of ≥1.5 log₁₀ occurred in all four age-based cohorts. Only two participants discontinued the study due to AEs. The most common MVC-related AEs through 48 weeks were diarrhea (which occurred in 20.3% of participants), vomiting (19.8%), and upper respiratory infections (16.2%). At Week 48, 48% of participants had HIV RNA <48 copies/mL.⁴ The absolute CD4 T lymphocyte cell count and percentage increased in all four subgroups of the study, with overall median increases of 192 cells/mm³ (interquartile range [IQR] 92–352 cells/mm³) and 4% (IQR 1% to 8%), respectively.

References

1. Maraviroc (Selezentry) [package insert]. Food and Drug Administration. 2020. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/022128Orig1s019,208984Orig1s002lbl.pdf.
2. Rosebush JC, Best BM, Chadwick EG, et al. Pharmacokinetics and safety of maraviroc in neonates. AIDS. 2021;35(3):419-427. Available at: https://pubmed.ncbi.nlm.nih.gov/33252481.
3. Liyanage M, Nikanjam M, McFadyen L, et al. Maraviroc population pharmacokinetics within the first 6 weeks of life. Pediatr Infect Dis J. 2022;41(11):885-890. Available at: https://pubmed.ncbi.nlm.nih.gov/35980827.
4. Giaquinto C, Mawela MP, Chokephaibulkit K, et al. Pharmacokinetics, safety and efficacy of maraviroc in treatment-experienced pediatric patients infected with CCR5-tropic HIV-1. Pediatr Infect Dis J. 2018;37(5):459-465. Available at: https://pubmed.ncbi.nlm.nih.gov/29023357.