fostemsavir
Sources réglementaires consultées
Indications approuvées
- Traitement combiné des adultes avec VIH-1 multirésistant sans autre schéma suppressif viable.
Contre-indications
Absolues
- Hypersensibilité au fostemsavir.
- Utilisation d’inducteurs puissants du CYP3A.
Mises en garde cliniques
- Il peut allonger le QT à forte exposition ; surveiller les patients cardiaques ou recevant des médicaments allongeant le QT. — CIMA/AEMPS, ficha técnica 1201518001
- Mise en garde majeure · Il peut provoquer une élévation des transaminases en coinfection VHB/VHC et un syndrome de restauration immunitaire. — CIMA/AEMPS, ficha técnica 1201518001
Interactions médicamenteuses
- ModéréeInducteurs puissants du CYP3A, notamment rifampicine, carbamazépine, phénytoïne, millepertuis, mitotane ou enzalutamide
Mécanisme: Ils réduisent le temsavir et peuvent entraîner une perte de réponse.
Recommandation: Ne pas associer.
CIMA/AEMPS, ficha técnica 1201518001
- SévèreÉthinylestradiol, elbasvir/grazoprevir, grazoprevir ou voxilaprevir
Mécanisme: Le fostemsavir peut augmenter l’exposition aux substrats OATP1B1/3 et le risque d’élévation des ALAT.
Recommandation: Limiter l’éthinylestradiol à 30 microgrammes/jour. Elbasvir/grazoprevir n’est pas recommandé ; appliquer la surveillance et les limites spécifiques avec grazoprevir ou voxilaprevir.
CIMA/AEMPS, ficha técnica 1201518001
Effets indésirables
Communs (≥1%)
Nausées, diarrhée, céphalées et douleur abdominale
Rares mais graves
Allongement du QT, hépatotoxicité et syndrome de restauration immunitaire
Grossesse et allaitement
Il est préférable d’éviter l’utilisation pendant la grossesse. Décider de l’allaitement après évaluation du bénéfice et du risque.
Bibliographie récente (PubMed)
Fostemsavir, a prodrug of temsavir, is indicated for heavily treatment-experienced adults with multidrug-resistant HIV-1 infection, antiretroviral (ARV) intolerance, or safety considerations. Understanding drug-drug interactions (DDIs) is important in individuals taking fostemsavir with hormonal contraceptives or menopausal or gender-affirming hormonal therapies. Effect of temsavir (active moiety) on the pharmacokinetics of ethinyl estradiol (EE) and norethindrone (NET) was evaluated in an open-label, single-sequence, four-cycle, four-treatment study in 26 healthy female participants (study 206279, NCT02480881). Relevant ARV-contraceptive interaction studies and guideline recommendations were reviewed; that information was then applied to other contraceptive methods and hormone-based therapies to predict the impact of fostemsavir co-administration. Temsavir increased EE concentrations by 40% and had no effect on NET concentrations. Fostemsavir co-administration with hormone therapy is not expected to impact hormone treatment efficacy. Fostemsavir did not impact progestin; therefore, progestin-only and non-hormonal contraceptives will not be impacted by fostemsavir. Recommendations for co-administration of fostemsavir and hormonal contraceptives or menopausal or gender-affirming hormone therapies are based upon known and predicted DDIs, ensuring adequate hormonal concentrations to maintain the target effect. Applying the results of Study 206279 and other relevant ARV-contraceptive studies, we recommend that when co-administering fostemsavir with combined oral contraceptives (COCs) and other oestrogen-based therapies, EE dose should not exceed 30 μg or equivalent, and caution is advised in the case of individuals with risk factors for thromboembolic events. Other oestrogen-based therapies may be co-administered with fostemsavir, with monitoring of oestrogen concentrations and appropriate dose adjustments. No impact of fostemsavir on COC efficacy is expected.
Fostemsavir is a recently Food and Drug Administration-approved HIV-1 attachment inhibitor that binds to HIV-1 gp120 and prevents viral attachment to the cellular CD4 receptor. Here, we review the pharmacology, efficacy, tolerability, and resistance profile of fostemsavir. Fostemsavir is well tolerated and maintains virologic activity in individuals harboring multidrug-resistant HIV-1. In conjunction with optimal background therapy, a majority of heavily treatment-experienced clinical trial participants treated with fostemsavir achieved virologic suppression. The approval of fostemsavir represents an important advance for individuals harboring multidrug resistant HIV-1 due to its novel mechanism of action and lack of cross-resistance to other antiretrovirals. Further study will better define the role of resistance testing for fostemsavir and fostemsavir's potential role outside of salvage therapy in heavily treatment-experienced individuals.
Fostemsavir, a prodrug of the first-in-class gp120-directed attachment inhibitor temsavir, is indicated in combination with other antiretrovirals for the treatment of multidrug-resistant HIV-1 in adults who are heavily treatment-experienced (HTE). Temsavir binds to HIV-1 gp120, close to the CD4 binding site, preventing the initial interaction of HIV-1 with CD4 on the host cell. Amino acid substitutions at four positions in gp120 have been identified as important determinants of viral susceptibility to temsavir (S375H/I/M/N/T/Y, M426L/P, M434I/K, M475I), with a fifth position (T202E) recently described. For most currently circulating group M HIV-1 subtypes, the prevalence of these resistance-associated polymorphisms (RAPs) is low. As with many other antiretrovirals, the impact of RAPs is modified by other changes in the target molecule. Different regions of gp120 interact to modify the temsavir binding pocket, with multiple amino acids playing a role in determining susceptibility. Extensive variability of HIV-1 gp120 means the susceptibility of clinical isolates to temsavir is also highly variable. Importantly, in vitro measurement of the susceptibility of clinical isolates to temsavir does not necessarily capture the range of susceptibilities of the heterogeneous mix of viruses generally present in each isolate. Due to these factors and limited phenotypic clinical data, thus far, no relevant phenotypic cutoff or genotypic algorithms have been derived that reliably predict response to fostemsavir-based therapy in individuals who are HTE; therefore, pre-treatment temsavir resistance testing may be of limited benefit. In the phase III BRIGHTE study, re-suppression after virologic failure was observed in some participants despite treatment-emergent genotypic and/or phenotypic evidence of reduced temsavir susceptibility, and substantial CD4+ T-cell count increases occurred even among participants with HIV-1 RNA ⩾40 copies/mL at Week 240. Clinical management of people who