The development of a new fusion inhibitor for the treatment of HIV

Abstract

Since the introduction of combination antiretroviral therapy (ART), there has been a dramatic improvement in the prognosis of people living with HIV. Indeed, data from numerous cohorts now show that for people commenced on ART at high CD4 counts and who are retained in care, life expectancy is similar to matched HIV-negative people. Consequently, the number of years an individual diagnosed with HIV can expect to be treated with ART is set to increase markedly.

With the emergence of an older population, polypharmacy and drug-drug interactions are now more prominent clinical problems in the management of HIV. Furthermore, as the number of years an individual spends on ART increases, treatment fatigue leading to suboptimal adherence and antiretroviral resistance are frequently observed. As such, the development of long-acting parenteral antiretroviral drugs with low propensity for drug-drug interactions, low toxicity and high genetic barriers to resistance is highly desirable.

Fusion inhibitors are a class of antiretroviral drugs which display limited systemic toxicities and few drug-drug interactions. They are rarely used, however, owing to injection site reactions associated with their delivery. C34-PEG4-Chol is a novel fusion inhibitor derived from the lead molecule, C34, but modified with the addition of polyethylene glycol (PEG) and cholesterol (Chol). With addition of cholesterol, potency of the drug is enhanced by concentrating it in cell membrane domains where viral fusion occurs. Moreover, the addition of cholesterol has been shown to markedly enhance its circulatory half-life in rodents such that it may potentially act as a long-acting antiretroviral drug in humans with infrequent subcutaneous injections.

In this thesis, I assess the antiretroviral resistance pattern of C34-PEG4-Chol in vitro. An adaptive clinical trial design was simulated to examine options of optimising the output of useful pharmacokinetic data after administration of single doses of C34-PEG4-Chol to HIV-positive men. Finally, I undertook a ‘first-in-man’ study to examine the pharmacokinetic profile of C34-PEG4-Chol and potential of this agent as a long-acting antiretroviral drug.

My work demonstrates the emergence of mutations to C34-PEG4-Chol via novel pathways within the heptad repeat (HR)-1 domains of gp41. Compensatory mutations were also observed within the HR-2 domain. The phenotypic effect of a HR-1 mutation was demonstrated following generation of mutant viral clones and assessing viral entry into cells in the presence of drug. An adaptive clinical trial design has shown, through simulations, to lead to more efficient allocation of trial participants across potentially therapeutic doses of the drug. Following a ‘first-in-man’ study, a promising pharmacokinetic profile was characterised which showed an extended drug half-life several fold above the 90% inhibitory concentration of the drug for over 4-days. This is the first time a cholesterol-endowed antiviral peptide has been entered into clinical trials in humans and has demonstrated the potential value of cholesterol-endowed peptides drugs in the field of various infectious diseases such as HIV, influenza and paraomyxoviruses.