Fostemsavir, an HIV-1 attachment inhibitor, is a novel therapeutic option for multidrug-resistant HIV. It represents the first oral agent developed for this indication in over a decade and provides promise for patients with limited remaining treatment options.
Significant advancements in drug development have transformed the prognosis of HIV from a deadly disease to a chronic condition that can be easily managed with combination antiretroviral therapy (ART), often coformulated into a single tablet. Despite this progress, there are many reasons why virologic failure can still occur, including suboptimal adherence, poor tolerability, and drug-drug interactions (DDIs). In the presence of viremia, HIV drug resistance can emerge across multiple agents and classes. For individuals with multiclass drug resistance and few remaining treatment options, novel agents and mechanistic classes are needed to construct a fully suppressive regimen. In the United States alone, there are approximately 25,000 individuals with MDR HIV and 12,000 individuals in need of novel therapies to achieve virologic control.1 Without viable treatment options, there is a risk for disease progression, increased mortality, and increased rates of MDR HIV transmission.
Fostemsavir (Rukobia) is a first-in-class HIV-1 attachment inhibitor approved by the FDA in July 2020 for the treatment of MDR HIV-1 infection in heavily treatment-experienced (HTE) adults who are failing their current regimen due to resistance, safety, or intolerance.2 Fostemsavir (FTR) is available as a 600-mg extended-release tablet and is administered orally every 12 hours. This article will review its mechanism of action, pharmacokinetic properties, safety and efficacy data, and role in the treatment of MDR HIV-1 infection.
MECHANISM OF ACTION
FTR is an oral prodrug of temsavir (TMR), an HIV-1 envelope glycoprotein 120 (gp120) attachment inhibitor, which prevents viral attachment and entry into host CD4+ T cells. Once FTR is converted to the active moiety, TMR binds directly to the viral gp120 subunit near its CD4-binding site. This results in a conformational change that inhibits attachment to CD4+ T cell–surface receptors and subsequent viral replication.3
FTR is rapidly hydrolyzed to TMR upon oral administration. The half-life of TMR is 11 hours, and it can be administered without regard to meals. The extended-release tablets should not be split, crushed, or chewed, limiting use to those who are able to swallow tablets whole.2 The metabolism of TMR occurs primarily through esterase-mediated hydrolysis with minor contribution of cytochrome P450 (CYP) 3A4. TMR is also a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) and inhibits organic anion transporter (OATP) 1B1/3 and BCRP.4 Less than 2% of TMR is eliminated unchanged in the urine. There were no clinically relevant differences in the pharmacokinetics of TMR in individuals with mild to severe renal or hepatic dysfunction, and TMR is not significantly removed by hemodialysis. Consequently, dose adjustments are not required in renal or hepatic impairment.
FTR has a low potential for DDIs; however, there are a few notable exceptions. Coadministration with strong CYP3A4 inducers, such as rifampin, is contraindicated and may lead to virologic failure. In the setting of mycobacterial coinfection, rifabutin may be combined with FTR without dose adjustments. Additionally, CYP3A4 inhibitors can be combined with FTR without concern for toxicity.4,5 TMR may increase levels of grazoprevir and voxilaprevir, increasing the risk for ALT elevations; however, simultaneous use with glecaprevir is not anticipated to significantly alter glecaprevir concentrations.2 Concomitant use with HMG-CoA reductase inhibitors may result in significantly increased statin levels and potential for toxicity. For example, rosuvastatin maximum concentration (Cmax) and area under the curve were increased by 78% and 69%, respectively, when combined with TMR. TMR increased ethinyl estradiol Cmax by 40%; therefore, the dose of ethinyl estradiol should not exceed 30 mg when combined with FTR.4
PHASE 3 CLINICAL TRIALS
Investigators evaluated the safety and efficacy of FTR for the treatment of MDR HIV-1 in a partially randomized, multicenter, double-blind, placebo-controlled 96-week trial (BRIGHTE Study, NCT02362503),6 which enrolled 371 HTE adults with HIV-1 and documented failure of current ART (HIV-1 ribonucleic acid [RNA], ≥400 copies/mL). Patients were included if at least 3 ART classes were exhausted due to resistance, intolerability, contraindications, or patient refusal. Individuals with chronic untreated hepatitis B virus (HBV), decompensated cirrhosis, congestive heart failure, or congenital prolonged QT syndrome were excluded. Additionally, those with an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level greater than 7 times the upper limit of normal (ULN) or a bilirubin level at or greater than 1.5 times the ULN were also excluded. Participants with 1 to 2 fully active agents (FAAs) from 2 or fewer classes remaining (n = 272) were randomized 3:1 to receive blinded FTR 600 mg every 12 hours or placebo in addition to their failing regimen on days 1 to 8 (functional monotherapy), followed by open-label FTR plus optimized background therapy (OBT) after day 8. Participants with zero FAAs remaining were placed in a nonrandomized cohort (n = 99) and were initiated on FTR plus OBT on day 1. The primary outcome was mean change in log10 HIV-1 RNA from day 1 to 8 in the randomized cohort, and secondary outcomes included rates of virologic suppression (HIV-1 RNA, <40 copies/mL) for both cohorts at 24, 48, and 96 weeks.
Overall, 71% (262/371) of included participants were treated for HIV-1 infection for more than 15 years, 85% (316/371) had prior experience with 5 or more ARV regimens, and 86% (329/371) had a history of acquired immunodeficiency syndrome. In the randomized cohort, 52% (142/272) and 42% (114/272) had 1 or 2 FAAs in their initial OBT, respectively. The most common ARVs in the OBT in the randomized cohort included dolutegravir (84% [229/272]) administered twice daily in 75% (171/229) of individuals, and darunavir (49% [134/272]) administered twice daily in 74% (99/134) of individuals.7 Of the 99 nonrandomized participants, 82% (81/99) had no approved FAAs or investigational ARVs in their initial OBT, and 15 had investigational ibalizumab in their initial OBT.
In the randomized cohort, 8 days of functional monotherapy with FTR demonstrated superior efficacy to placebo with a mean decrease in HIV-1 RNA (log10 copies/mL) of 0.79 versus 0.17 in the FTR and placebo group, respectively (P < .001). At week 96, 60% (163/272) and 37% (37/99) of individuals in the randomized and nonrandomized cohort, respectively, achieved an HIV-1 RNA of less than 40 copies/mL.7 Rates of virologic suppression were similar across subgroups of age, sex, race, geographic region, and number of FAAs in initial OBT. In the randomized cohort, rates of virologic suppression were lower in those with a baseline CD4 count of less than 20 cells/mm3 (49% [39/80]) and an HIV viral load greater than 100,000 copies/mL (46% [33/72]).
ADVERSE REACTIONS, WARNINGS, AND PRECAUTIONS
Similar to other clinical trials with HTE patients, adverse effects occurred frequently (92%) in BRIGHTE Study patients, but very few led to treatment discontinuation in the randomized cohort (7%). The most common adverse effects experienced by those taking FTR plus OBT were nausea (10%), diarrhea (4%), and headache (4%). The OBT, which often contained a protease inhibitor, may have contributed to the incidence of gastrointestinal adverse effects, as the incidence was similar in both groups. Adverse effects leading to discontinuation were not commonly related to FTR and were largely due to infections. QTc prolongation is a rare adverse effect, which occurred in less than 2% of patients but did not require intervention or discontinuation. QTc prolongation (mean increase, 11.2 milliseconds) was observed in a phase 1 study only at supratherapeutic doses (2400 mg twice daily).8 Grade 3 or 4 elevations in hepatic laboratory parameters that were significantly higher than the placebo arm included increased direct bilirubin (14% vs 7%) and bilirubin (7% vs 4%) levels. Elevations in ALT and AST levels were more common in patients who were coinfected with viral hepatitis. However, a portion of those elevations were attributed to patients who had HBV reactivation as a result of their change in ART.6
Investigators observed virologic failure in 25% of patients in the randomized cohort and 51% in the nonrandomized cohort at week 96. As expected, higher rates of virologic failure occurred in the nonrandomized cohort. Approximately half of patients in the randomized cohort and three-fourths of those in the nonrandomized cohort who were experiencing virologic failure developed treatment-emergent resistance mutation(s) at the 4 key sites in the gp120 region. The 4 substitutions associated with significant changes in TMR effective concentrations were S375N, M426L/I, M434I/L, and M475I/L/V.9 There does not appear to be cross-resistance with other entry inhibitors, including ibalizumab and maraviroc; however, this conclusion is based on a small number of patients.3,10 Although investigators have observed reduced susceptibility to TMR in HIV subtype AE, it is uncommon in subtype B, which is the prevalent subtype in the Americas. Baseline resistance testing (including viral tropism) is not recommended.2
PLACE IN THERAPY
Fostemsavir is an exciting new addition to the limited repository of salvage therapy for MDR HIV. It represents the first orally administered novel class developed for this indication since the approval of maraviroc and raltegravir in 2007 and has low potential for cross-resistance to other agents and classes. Furthermore, clinical data have demonstrated that it is well tolerated, has minimal DDIs, and can be conveniently administered without renal or hepatic dose adjustments. Based on the available data, the patients most likely to derive clinical benefit from FTR are those with at least 1 additional remaining FAA. Although the twice daily dosing of fostemsavir may be difficult for some patients, it aligns well with twice daily administration of medications that are common components of salvage regimens, such as dolutegravir, darunavir/ritonavir, maraviroc, and etravirine. Unfortunately, the investigators studied fostemsavir in a limited number of patients, and long-term adverse effects are not yet known. Patients are also required to swallow the tablet whole, as crushing is not permitted due to the extended-release formulation. Resistance testing is not yet commercially available, and the implications of fostemsavir resistance are not yet well understood.
Amy L. Brotherton, PharmD, AAHIVP, BCIDP, is a clinical specialist in infectious diseases at The Miriam Hospital Infectious Diseases and Immunology Center in Providence, Rhode Island, and a member of the American College of Clinical Pharmacy HIV Practice and Research Network Advocacy Committee. She is also an active member of the Society of Infectious Diseases Pharmacists and Making a Difference in Infectious Diseases.
Rajeev Shah, PharmD, AAHIVP, BCIDP, is a clinical specialist in infectious diseases at The Miriam Hospital Infectious Diseases and Immunology Center in Providence and a member of the American College of Clinical Pharmacy HIV Practice and Research Network Newsletter Committee and the Society of Infectious Diseases Pharmacists Publications and Podcast Committee.