Efavirenz: History, Development and Future

Abstract

Efavirenz (Sustiva®) is a first-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) used to treat human immunodeficiency virus (HIV) type 1 infection or to prevent the spread of HIV. In 1998, the FDA authorized efavirenz for the treatment of HIV-1 infection. Patients formerly required three 200 mg efavirenz capsules daily, which was rapidly updated to a 600 mg tablet that only required one tablet per day. However, when given 600 mg once daily, plasma efavirenz concentrations were linked not only to poor HIV suppression but also to toxicity. Clinical data suggested that the standard dose of efavirenz could be reduced without compromising its effectiveness, resulting in a reduction in side effects and making the drug more affordable. Therefore, ENCORE1 was performed to compare the efficiency and safeness of a reduced dose of efavirenz (400 mg) with the standard dose (600 mg) plus two NRTI in antiretroviral-naïve HIV-infected individuals. Nowadays, due to the emergence of integrase strand transfer inhibitors (INSTIs), some consider that it is time to stop using efavirenz as a first-line treatment on a global scale, in the parts of the world where that is possible. Efavirenz has been a primary first-line antiviral drug for more than 15 years. However, at this moment, the best use for efavirenz could be for pre-exposure prophylaxis (PrEP) and repurposing in medicine.

Proposal of pharmacophore model for HIV reverse transcriptase inhibitors: Combined mutational effect analysis, molecular dynamics, molecular docking and pharmacophore modeling study

“…Docking between the six first-line ARVs (ZDV, FTC, 3TC, ABC, NVP and EFV) and their target, the viral reverse transcriptase enzyme, was performed and resulted in a binding energy varying between −5.1 and −3.9, whose EFV presented the low score. Based on what has been reported and on several articles in the literature 7 , 73 – 75 that confirmed the resistance to EFV and subsequently its ineffectiveness, through our study, we tried to propose in silico EFV analogues that can substitute EFV later.…”

In vitro antibacterial activity of antiretroviral drugs on key commensal bacteria from the human microbiota

“…However, EFV accumulation in cervicovaginal secretions has been reported to be minimal (0.25-0.34 ratio compared to blood plasma concentrations) ( Else et al., 2011 ; Neely et al., 2015 ), thus according to our results, female genital concentrations of EFV would not reach antibacterial activity against G. vaginalis . Efavirenz has been a first-line ARV for more than 15 years and it is still used in low-and-middle income countries due to cost and availability although it is no longer recommended as a first-line treatment in high-income countries ( Costa and Vale, 2022 ). Thus, EFV direct effect on gut microbiota composition could have an important impact in a great number of PLWH worldwide, as is the case of AZT, as mentioned before.…”

Repurposing efavirenz, the HIV antiretroviral drug for Chikungunya virus infection

“…Among these shortlisted compounds, jervine and tomatidine are natural steroidal alkaloids derived from Veratrum californicum (Bailly et al, 2016) and unripe green tomatoes (Troost et al, 2020), respectively. Dehydrocholic acid, on the other hand, is a synthetic bile acid (Soloway et al, 1973), and efavirenz is a non-nucleoside inhibitor of HIV reverse transcriptase, used for treating HIV type 1 infection and or to prevent the spread of HIV (Costa & Vale, 2023). To evaluate their binding affinity to the CP, we employed the highly sensitive SPR technique and successfully determined the binding of efavirenz and dehydrocholic acid to CP within a concentration range of 1 to 200 µM.…”