By: Bisma Sekhery, PharmD Candidate c/o 2021
Fostemsavir (Rukobia) is a new Food and Drug Administration (FDA) approved antiretroviral agent for the treatment of Human Immunodeficiency Virus (HIV). It was approved in July 2020 for multidrug-resistant HIV-1. It is a pro-drug, metabolized to its active moiety, temsavir, which binds to the gp120 subunit within the HIV-1 envelope glycoprotein gp160, thereby inhibiting the interaction between the virus and cellular CD4 receptors. 2 This will prevent attachment and entry of the virus into the cells. The patients who benefit from this drug are treatment-experienced adults who have failed their current antiretroviral treatment due to drug resistance, tolerance, or safety concerns. 1
The overall efficacy of fostemsavir was studied in the BRIGHTE trial. 2 Two cohorts were utilized for this trial. The first cohort had two groups. Group 1 were patients who were failing their current antiretroviral regimen. Group 1 patients had the option of using at least 1 previously FDA-approved agent from another antiretroviral drug class, but no more than 2 drug classes, plus fostemsavir for 8 days. It was not specified in the trial which other antiretrovirals were administered to the patients. Group 2 was the control group. The placebo group received standard antiretrovirals. After 8 days, patients received open label fostemsavir with standard antiretrovirals along with it. Patients were randomized in a 3:1 ratio fostemsavir (N= 204) to control (N=68). The participants were all over the age of 18, had failed their current antiretroviral regimen and had no viable antiretroviral combination therapy options. The primary endpoint for this trial was mean change in log10 level of HIV-1 RNA to less than 40 copies per milliliter from baseline to week 24. At week 24, the intervention group had 57% of patients with HIV-1 RNA copies less than 40 copies per milliliter, while the placebo group had 45% of patients (p <0.001). The use of fostemsavir also improved CD4 T cell count even in the most immunocompromised patients.2
Currently, the only FDA-approved dosage is 600 mg extended release tablets and usually it is taken one tablet twice daily with or without food. 1 Although this drug is beneficial to many patients, some contraindications still exist. If a patient has a known hypersensitivity to the drug, it cannot be administered. Drugs that are strong CYP3A4 inducers may decrease the concentration of temsavir significantly. This drug carries a warning of causing Immune Reconstitution Syndrome as well. Patients with HIV develop this syndrome because when the immune system begins to recover after the use of antiretrovirals, the inflammatory response to infections is exaggerated, leading to worsening of the infection. 1
There are other warnings associated with this drug, however some adverse effects can be minimized. For instance, this drug is known to cause QT prolongation in doses of 4800 mg per day or more. 1 However, if the patient takes the drug as directed, which is one 600 mg tablet twice daily, this risk is minimized. Additionally, other medications that the patient is taking can be assessed to see if the patient is on other QT-prolongating drugs. Fostemsavir can also cause elevation in liver enzymes. Therefore, it may not be the best drug for patients who have liver failure or Hepatitis B or C infections. Like other antiretrovirals, when anti-hepatitis therapy is withdrawn, there is a risk for Hepatitis B reactivation. The most common adverse effect noted in the participants was diarrhea, nausea, upper respiratory tract infections, but this was manageable with appropriate medications.
Overall, this drug should not be used in pregnant women because there is no human data about the impact on this drug for pregnant women. 1 Instead there is data from rats, which showed increased embryonic death and maternal toxicity. In pregnant rats, temsavir was present in the breast milk. This is why the FDA suggests mothers to avoid breastfeeding their children while on this drug. FDA also recommends against breastfeeding for all HIV positive mothers to avoid the transmission of HIV to the neonate. 1
The novel mechanism of action, safety, efficacy, drug-drug interaction profile and lack of cross-resistance among the available antiretroviral drugs makes fostemsavir a great drug for patients who have failed almost all other drug options. The adverse effects are still concerning such as QT prolongation, hepatotoxicity, and Immune Reconstitution Syndrome, but these side effects are not common. Appropriate monitoring by clinicians can prevent these side effects from occurring. When fostemsavir is taken in combination with other antiretrovirals, it can be a viable option for treatment-experienced adults with multidrug-resistant HIV-1, who are failing their current antiretroviral regimen.
- Fostemsavir. Lexi-Drugs. Hudson, OH: Lexicomp, 2020. http://online.lexi.com Updated August 2020. Accessed August 20, 2020.
- Kozal M, Aberg J, Pialoux G, et al; BRIGHTE Trial Team. Fostemsavir in Adults with Multidrug-Resistant HIV-1 Infection. N Engl J Med. 2020; 382(13):1232-1243. doi: 10.1056/NEJMoa1902493. PMID: 32212519.