By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The Food and Drug Administration has approved the first-in-class human immunodeficiency virus-1 (HIV-1) attachment inhibitor. This drug should be used to treat HIV-1 infections in patients with multidrug-resistant HIV-1 who have failed their current antiretroviral regimen. Fostemsavir is a prodrug. Temsavir attaches to glycoprotein 120 (gp120) on the outer surface of HIV-1, interfering with binding to CD4 receptors, thereby blocking entry and infection of immune cells.1,2 Fostemsavir received fast track, priority review, and breakthrough therapy designations. It is marketed as Rukobia.
Fostemsavir is indicated, with other antiretrovirals, to treat HIV-1 infections in heavily treatment-experienced adults with multidrug-resistant HIV-1 infections who are failing current regimens.1 Failure may be because of resistance, safety, or intolerance.
The recommended dose is one tablet taken orally twice daily without regard to food.1 Fostemsavir is available as extended-release tablets, each containing 600 mg of fostemsavir (725 mg of fostemsavir tromethamine).
Fostemsavir provides a new mechanism of action against HIV-1 and is effective in significantly reducing HIV-1 viral load in treatment-experienced patients with multidrug-resistant HIV-1 infections.1,3 It is the first orally administered agent approved for this indication. Both enfuvirtide and ibalizumab, with similar indications, require administration by injection. In vitro data indicate there is no cross-resistance between fostemsavir and other HIV-1 entry inhibitors (e.g., enfuvirtide, ibalizumab).2
Fostemsavir may increase QTc intervals in susceptible patients, such as those with a history of QTc prolongation or those taking a drug with a known risk of causing arrhythmias (e.g., Torsade de Pointes).1 Temsavir is a substrate of CYP3A isoenzyme; coadministration with a strong CYP3A inducer is contraindicated.1 As with other antiretroviral therapies (ART), initial treatment may cause immune reconstitution syndrome. Patients with hepatitis B and/or C coinfection may experience elevation of hepatic transaminases.1
The efficacy of fostemsavir was evaluated in a partly randomized, double-blind, placebo-controlled, 96-week trial.1,3,4 Subjects were enrolled in a randomized or nonrandomized cohort. In the randomized cohort, subjects were required to have at least one, but no more than two, fully active and available antiretroviral agent(s) at screening. Subjects were randomized to fostemsavir (n = 203) or placebo (n = 69) in addition to their failing regimen (i.e., functional monotherapy) for eight days. After day 8, subjects received open-label fostemsavir and with investigators-selected optimized background therapy (OBT). In the nonrandomized cohort (n = 99), subjects had no fully active ART available at screening. All subjects took open-label fostemsavir plus OBT. The overall study population was male (78%), white (70%), median age 49 years, median baseline HIV-1 RNA was 4.6 log10 copies/mL, 86% had history of AIDS, 71% were treated for > 15 years, and 85% had exposure to ≥ 5 different HIV treatment regimens. The primary endpoint was mean decline in HIV-1 RNA from day 1 to day 8 compared to placebo.
At day 8 in the randomized cohort, fostemsavir achieved a mean decrease of 0.79 log10 copies/mL compared to a reduction of 0.17 log10 copies/mL for the placebo group, with 46% achieving > 1 log10 copies/mL decrease vs. 10% for the placebo group. Subjects with baseline viral load of > 1,000 copies/mL showed a reduction of 0.86 log10 (vs. -20 log10 for the placebo group). For those with baseline ≤ 1,000 copies/mL, the reduction was 0.22 log10 (+0.10 log10 for placebo).
At week 96, 60% of the subjects had HIV-1 RNA < 40 copies/mL. In the nonrandomized cohort, 37% had HIV-1 RNA < 40 copies/mL. Median increase in CD4+ was 205 cells/mm3 (baseline 99 cells/mm3) in the randomized cohort and +119 cells/mm3 (baseline 41 cells/mm3) for the nonrandomized cohort. The proportion of subjects who discontinued treatment because of adverse events at week 96 was 5% in the randomized cohort and 12% in the nonrandomized cohort.1
Fostemsavir represents the eighth class of HIV-1 antiviral agents and the third agent approved for salvage therapy. While all three are HIV-1 entry inhibitors, each has a different molecular target. Enfuvirtide is a gp41 fusion inhibitor and ibalizumab is a CD4 direct post-attachment inhibitor. Fostemsavir offers the first orally effective agent in this group. In patients with first regimen virologic failure, the new regimen options are based on the type of failing regimen.5
With second regimen failure, the new regimen is based on past and current genotypic ± phenotypic resistance testing and ART history using at least two (preferably three) fully active agents.5 In heavily treated patients with multidrug-resistant HIV-1 infections with unsuppressed virus and limited options, treatment options include enfuvirtide, ibalizumab, and now fostemsavir. The latter offers a new mechanism of action and the convenience of oral dosing vs. twice-daily or every-two-weeks injections for enfuvirtide and ibalizumab, respectively. Fostemsavir also appears to lack cross-resistance to the other two entry inhibitors.2 The cost for fostemsavir is $7,650 for a 30-day supply.
- ViiV Healthcare. Rukobia prescribing information. July 2020.
- Li Z, Zhou N, Sun Y, et al. Activity of the HIV-1 attachment inhibitor BMS-626529, the active component of the prodrug BMS-663068, against CD4-independent viruses and HIV-1 envelopes resistant to other entry inhibitors. Antimicrob Agents Chemother 2013;57:4172-4180.
- Kozal M, Aberg J, Pialoux G, et al. Fostemsavir in adults with multidrug-resistant HIV-1 infection. N Engl J Med 2020;382:1232-1243.
- ClinicalTrials.gov. Attachment inhibitor comparison in heavily treatment experienced patients.
- Department of Health and Human Services. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Last reviewed Dec. 18, 2019.