In PK studies of parenteral islatravir in rodents, continuous duration of drug release (owing to the recycling of drug accomplished by translocation inhibition) was observed after 180 days (27)

In PK studies of parenteral islatravir in rodents, continuous duration of drug release (owing to the recycling of drug accomplished by translocation inhibition) was observed after 180 days (27). inhibitors began in 2003 (9), clinically relevant drugs did not reach demonstration in the public website until recently. Data for GS-CA1 was first presented in the conference on retroviruses and opportunistic infections (CROI) in 2017 as the first-in-class picomolar capsid inhibitor (10). GS-CA1 and GS-6207 (also known as GS-CA2, an analog of GS-CA1) bind to the linker connecting the N-terminal and C-terminal domains that form the capsid protein. The dual mechanism of action is similar to PF74, another capsid inhibitor first introduced in 2010 2010, although with higher affinity for the binding site (10). GS-CA1 showed promise in pre-clinical trials owing to its high potency, including against resistant HIV-1 strains (9, 11). However, five amino acid mutations at the GS-CA1 binding site were identified in resistance studies, raising concern about naturally-occurring polymorphisms potentially compromising activity (10, 12). In a cross-sectional, single-center study of 137 treatment na?ve PLWH, deep sequencing of the CA region was evaluated at baseline prior to treatment initiation. In 132 of the samples that were successfully sequenced, none of the amino acid substitutions identified in resistance studies were isolated (12), allaying concerns about naturally-occurring resistance. One of the main advantages of the CAI class, in addition to a high barrier to resistance, is the long-acting potential due to low predicted hepatic metabolic clearance based on cryopreserved hepatocyte models. The combination of prolonged half-life and aqueous solubility suggests the possibility of monthly subcutaneous dosing. Pharmacokinetic studies in rats and dogs demonstrated levels anticipated to be therapeutic at 12 weeks after administration of a single subcutaneous dose of GS-6207 (13). Currently, subcutaneous GS-6207 is being investigated in the Mollugin first phase Ib randomized controlled trial to evaluate antiviral activity in both treatment-na?ve and treatment-experienced PRKAR2 adults with HIV-1 (14). Preliminary data exhibited a mean 1.8 to 2.2 log10 decline in HIV-1 RNA at day 10 after a single subcutaneous dose, and there were no grade 3 or 4 4 adverse events requiring discontinuation (15). Maturation Inhibitors The virion maturation process plays an important role in the infectivity of HIV-1. Normally, HIV-1 protease cleaves the junction between the CA and spacer peptide 1 (SP1) of the Gag polyprotein, resulting in a mature virion (16). Bevirimat (also known as PA-457) was introduced in 2007 as the first maturation inhibitor (MI) to target the last step in the Gag cleavage process by binding to the CA-SP1 cleavage site, leading to the release of immature virions. Initially, bevirimat showed promise in phase I trials of treatment-na?ve adults with HIV-1 (17). However, a phase IIb study to assess the antiviral efficacy of bevirimat monotherapy Mollugin in treatment-experienced adults with HIV-1 found that 55% of the participants had 0.5 log10 viral load reduction after 15 days due to naturally-occurring Gag polymorphisms near the CA-SP1 site (18). Subsequent studies confirmed the presence of Gag polymorphisms conferring resistance (19), leading to the eventual discontinuation of bevirimat development. Data for GSK3532795 (formerly known as BMS-955176), a second-generation MI, was first presented publicly at CROI in 2015 (16). While structurally similar to bevirimat, GSK3532795 exhibited high potency against several HIV-1 clades (23). In a phase Mollugin I dose-escalation trial to evaluate GSK2838232, the half-life was observed to increase 100% to 34 hours when boosted with ritonavir, and achieved the target plasma exposure with higher doses of 200 mg daily compared to doses of 20, 50 and 100 mg (24). The results of a proof of concept, dose-ranging phase IIa trial to evaluate the safety, pharmacokinetics (PK) and antiviral activity of GSK2838232 boosted with cobicistat were recently presented publicly at CROI (23). In 33 treatment-na?ve adults, a dose proportional response.

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