Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Entry and Fusion Inhibitors

Fostemsavir

Drug Interactions

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

• Metabolism: Coadministration with strong cytochrome P450 3A inducers is contraindicated, because the plasma concentrations of the active metabolite, temsavir (TMR), are significantly reduced, which could result in loss of virologic efficacy.
• Cardiac toxicity: Caution is required when used in combination with drugs that are associated with prolongation of the QT corrected for heart rate (QTc) interval of the echocardiogram.
• Oral contraceptives and gender-affirming hormonal therapy: TMR may increase ethinyl estradiol concentrations and risk of thrombosis. Do not exceed 30 mcg ethinyl estradiol daily when fostemsavir is co-administered with estrogen-based therapies. For gender-affirming hormonal therapy, estrogen concentrations can be monitored with dose adjustments as needed.¹
• 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins): TMR may increase plasma concentrations of statins, including rosuvastatin, atorvastatin, fluvastatin, pitavastatin, and simvastatin. Use the lowest possible starting dose of statin and monitor for statin-associated adverse effects.
• Hepatitis C virus direct-acting antivirals: TMR may increase plasma concentrations of grazoprevir and voxilaprevir due to organic anion transporting polypeptide (OATP) 1B1/3 inhibition.
• Other antiretroviral agents: Drug interaction studies of fostemsavir (FTR) in combination with darunavir/cobicistat, darunavir/ritonavir, etravirine, and maraviroc have been conducted in healthy volunteers. FTR given in combination with these other ARVs was generally well tolerated, and no dose adjustments were required.^2,3

Major Toxicities

• More common: Nausea, fatigue, diarrhea (reported in ≥5% of patients)
• Less common: QTc prolongation with higher than recommended doses.⁴ Increased hepatic transaminases in patients with hepatitis B or hepatitis C coinfection.

Resistance

The International AIDS Society–USA maintains a list of HIV drug resistance mutations and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation.

TMR showed reduced antiviral activity against HIV subtype AE (the predominate subtype found in Southeast Asia but not commonly found elsewhere in the world). Treatment-emergent glycoprotein (gp120) genotypic substitutions at four key sites (S375, M434, M426, and M475) have been found in evaluable participants with virologic failure in clinical trials. However, overall frequency of polymorphisms previously associated with the potential to reduce susceptibility to TMR is low and should not be a barrier to its usage in patients with multidrug resistance.⁵

Pediatric Use

Fostemsavir (FTR) is an HIV-1 gp120-directed attachment inhibitor that is not approved for use in pediatric patients. FTR was approved by the U.S. Food and Drug Administration in 2020 for use in adults in combination with other antiretroviral (ARV) drugs, with approval limited to heavily treatment-experienced adults with multidrug-resistant HIV who are experiencing virologic failure on their current (ARV) regimen due to resistance, intolerance, or safety considerations.⁶ A pharmacokinetic, safety, acceptability, and swallowability study of FTR in children and adolescents weighing ≥20 kg is open to enrollment (PENTA Foundation: NCT04648280). The dose selection of FTR for children and adolescents weighing ≥20 kg utilized a population pharmacokinetic model–based approach to achieve similar adult TMR exposures following FTR 600 mg twice daily dosing that was demonstrated to be safe and effective in the BRIGHTE study in heavily treatment-experienced patients.⁷

Efficacy in Clinical Trials

The safety and efficacy of FTR in heavily treatment-experienced adults with HIV were evaluated in the BRIGHTE trial, a Phase 3, double-blind placebo-controlled trial. A total of 371 participants were enrolled into two cohorts (randomized and nonrandomized), depending on remaining treatment options. The randomized cohort included 272 participants, with at least one fully active drug in at least one but no more than two ARV classes that could be added to FTR. Participants received either FTR or a placebo twice daily for 8 days, in addition to their failing ARV regimen. On Day 8, participants treated with FTR had a significantly greater decrease in levels of HIV-RNA than those taking the placebo (0.79 versus 0.17 log₁₀ copies, respectively).⁸ After Day 8, all participants received FTR as part of an optimized regimen. In results reported through 48 weeks,⁸ 54% of participants had an HIV viral load of <40 copies/mL. At Week 96, 60% of participants^6,9 had HIV viral loads of <40 copies/mL and a mean increase in CD4 T lymphocyte (CD4) cell counts of 205 cells/mm³. In 51% (27 out of 53) of evaluable participants with virologic failure, treatment-emergent gp120 genotypic substitutions were detected at four key sites (S375, M434, M426, and M475). In the randomized cohort, virologic response rates increased over time, between the 24-week and 96-week analyses. Response rates were associated with better susceptibility scores for new optimized treatment regimens.¹⁰ Patients with the lowest CD4 counts at baseline were more likely to experience serious adverse events or death.¹⁰

An additional nonrandomized cohort of 99 patients who had no active drugs as treatment options but had FTR added to an optimized ARV regimen was studied. Of these, 38% achieved an HIV viral load of <40 copies/mL at 48 weeks.⁸ For this cohort, at 96 weeks,⁶ 37% of participants had HIV viral loads of <40 copies/mL, and the mean increase in CD4 counts was 119 cells/mm³.

Improvements in patient-reported outcomes in health-related quality of life were observed among participants in both cohorts of the BRIGHTE trial at 48 weeks.¹¹

Mechanism of Action

FTR tromethamine is a prodrug of TMR, an HIV-1 gp120-directed attachment inhibitor. FTR is rapidly converted to TMR after oral administration. TMR binds directly to the HIV-1 gp120 and prevents viral attachment and subsequent entry of virus into host T cells. FTR has a novel mechanism of action and no in vitro cross-resistance with other ARVs, and it can be used regardless of HIV-1 tropism.⁵

Pharmacokinetics

FTR is pre-systemically metabolized to the active moiety TMR by alkaline phosphatase in the luminal surface of the small intestine, and then TMR is rapidly absorbed. In healthy adults, the estimated half-life is approximately 11 hours.¹²

References

1. Nwokolo N, Post E, Mageau AS, et al. Fostemsavir and ethinyl estradiol drug interaction: Clinical recommendations for co-administration. HIV Med. 2023;24(5):580-587. Available at: https://pubmed.ncbi.nlm.nih.gov/36372442.
2. Moore K, Thakkar N, Magee M, et al. Pharmacokinetics of temsavir, the active moiety of the HIV-1 attachment inhibitor prodrug, fostemsavir, coadministered with cobicistat, etravirine, darunavir/cobicistat, or darunavir/ritonavir with or without etravirine in healthy participants. Antimicrob Agents Chemother. 2022;66(4):e0225121. Available at: https://pubmed.ncbi.nlm.nih.gov/35315687.
3. Wire MB, Magee M, Ackerman P, et al. Evaluation of the pharmacokinetic drug-drug interaction between the antiretroviral agents fostemsavir and maraviroc: a single-sequence crossover study in healthy participants. HIV Res Clin Pract. 2021;23(1):1-8. Available at: https://pubmed.ncbi.nlm.nih.gov/35285786.
4. Lagishetty C, Moore K, Ackerman P, et al. Effects of temsavir, active moiety of antiretroviral agent fostemsavir, on QT interval: results from a Phase I study and an exposure-responses analysis. Clin Transl Sci. 2020;13(4):769-776. Available at: https://pubmed.ncbi.nlm.nih.gov/32027457.
5. Gartland M, Arnoult E, Foley BT, et al. Prevalence of gp160 polymorphisms known to be related to decreased susceptibility to temsavir in different subtypes of HIV-1 in the Los Alamos National Laboratory HIV Sequence Database. J Antimicrob Chemother. 2021;76(11):2958-2964. Available at: https://pubmed.ncbi.nlm.nih.gov/34297843.
6. Fostemsavir (Rukobia) [package insert]. Food and Drug Administration. 2024. Available at: https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Rukobia/pdf/RUKOBIA-PI-PIL.PDF.
7. Thakkar N, Magee M, Goyal N, et al. Model-based dose selection of fostemsavir for pediatric populations with multidrug-resistant HIV-1 and relative bioavailability assessment in healthy adults. Clin Pharmacol Drug Dev. 2023;12(10):991-1000. Available at: https://pubmed.ncbi.nlm.nih.gov/37329260.
8. Kozal M, Aberg J, Pialoux G, et al. Fostemsavir in adults with multidrug-resistant HIV-1 infection. N Engl J Med. 2020;382(13):1232-1243. Available at: https://pubmed.ncbi.nlm.nih.gov/32212519.
9. Gartland M, Cahn P, DeJesus E, et al. Week 96 genotypic and phenotypic results of the fostemsavir phase 3 BRIGHTE study in heavily treatment-experienced adults living with multidrug-resistant HIV-1. Antimicrob Agents Chemother. 2022;66(6):e0175121. Available at: https://pubmed.ncbi.nlm.nih.gov/35502922.
10. Ackerman P, Thompson M, Molina JM, et al. Long-term efficacy and safety of fostemsavir among subgroups of heavily treatment-experienced adults with HIV-1. AIDS. 2021;35(7):1061-1072. Available at: https://pubmed.ncbi.nlm.nih.gov/33946085.
11. Anderson SJ, Murray M, Cella D, et al. Patient-reported outcomes in the phase III BRIGHTE trial of the HIV-1 attachment inhibitor prodrug fostemsavir in heavily treatment-experienced individuals. Patient. 2021;15:131-143. Available at: https://pubmed.ncbi.nlm.nih.gov/34180035.
12. Magee M, Slater J, Mannino F, et al. Effect of renal and hepatic impairment on the pharmacokinetics of temsavir, the active moiety of fostemsavir. J Clin Pharmacol. 2021;61(7):939-953. Available at: https://pubmed.ncbi.nlm.nih.gov/33368327.