Future of long-acting HIV prevention expected to take many forms in products and delivery
Presenters: Charles Flexner, MD, Johns Hopkins University, Baltimore; Nittaya Phanuphak, MD, PhD, Institute of HIV Research and Innovation, Bangkok, Thailand; Rachel Baggaley, MD, World Health Organization, Geneva, Switzerland
Long-acting technologies are an exciting addition to HIV treatment and prevention that may promote adherence and reduce HIV stigma. Current and future HIV prevention and long-acting treatment technologies and differentiated service delivery models were addressed in a recent satellite symposium at the 24th International AIDS (IAS) Congress.
Innovations in delivery of long-acting technologies include oral, implantable, subcutaneous, intravenous, and transdermal antiretrovirals (ARVs), said Charles Flexner, MD, professor of medicine, Johns Hopkins University, Baltimore, Maryland, who reviewed the ARV drug delivery pipeline.
Islatravir is a long-acting oral ARV (once weekly for treatment, once monthly for pre-exposure prophylaxis [PrEP]) that inhibits reverse transcriptase by preventing translocation. Despite promising efficacy in reducing viral load with single doses ranging from 0.5 to 30 mg, a clinical hold was placed on oral islatravir based on observations of decreases in total lymphocyte and CD4+ T-cell counts in some clinical trial participants.
Tenofovir alafenamide is a long-acting ARV subdermal implant with the potential to provide protection from HIV-1 for 6 months or longer, according to preclinical data. The potential advantage is dual activity against hepatitis B virus, an important consideration given high rates of HIV and hepatitis B virus coinfection, said Dr. Flexner. Local toxicity, including tissue necrosis, is a concern with a long-acting tenofovir alafenamide implant and is “related to the rate of release of the drug from the implant, so that tenofovir alafenamide implants that have a slower daily release rate actually produce little or no local toxicity.”
Lenacapavir, an HIV-1 capsid inhibitor, has been shown to reduce viral load significantly in the short term (14 days) in treatment-experienced people living with HIV who show resistance to other ARV drug classes. The eventual intent is to use lenacapavir as an oral lead-in followed by subcutaneous delivery every 6 months, as the subcutaneous formulation has an extremely long half-life that requires an oral loading dose.
Several broadly neutralizing monoclonal antibodies are in development as intravenous ARVs, including VRC07-523LS, which was tested in HIV-1-negative participants and had demonstrated neutralizing activity out to 24 weeks.
Microarray patches load nanoformulated drugs at high concentrations into aqueous gels that are cast into a mold onto which a border adhesive is attached; the nanoformulated drugs are deposited in viable skin layers for sustained release and absorption. A cabotegravir microarray patch releases concentrations of cabotegravir that exceed the antiviral threshold for longer than 1 month. “I think we’re going to see studies with these patches in healthy volunteers with ARVs in the next 2 to 3 years,” he said.
Nittaya Phanuphak, MD, PhD, executive director at the Institute of HIV Research and Innovation, Bangkok, Thailand, spoke about the importance of key population (KP)-led PrEP delivery in the implementation of long-actine products, pointing to success in Thailand, where 80% of PrEP users receive PrEP from KP-led providers in KP-led clinics absent of physicians and nurses. HIV blood test results are shared online with a physician who can approve a PrEP prescription online. KP-led health services fill service gaps by providing accessibility and need-based services to clients using staff trained and qualified in accordance with national standards.
One principle that guides implementation of KP-led PrEP service is demedicalization, which is to identify key elements of services that can be offered by lay providers. Another is simplification, or finding less complex ways to deliver care, promote increased access, and reduce cost while retaining efficacy and quality. The third principle is differentiation, “which is to think about the when, where, what, and who based on a client-centered approach,” she said. Although one concern with cabotegravir-LA integration of the KP-led PrEP service is the necessity for remedicalization for HIV testing and product administration, third or fourth generation rapid testing/self-testing and other forms of delivery may eventually enable shifting these tasks to a lay provider or the client.
Despite the challenges with KP-led PrEP, “I remain optimistic…things may not seem feasible until we do it; this time we want a better plan than we had for oral PrEP a decade ago,” she said.
Rachel Baggaley, MD, coordinator of Key Populations and Innovative Prevention within the HIV Program at the World Health Organization in Geneva, Switzerland, ended the session by presenting the updated guideline for long-acting injectable cabotegravir, which states that it may be offered as an additional prevention choice for people at substantial risk of HIV infection, as part of combination prevention approaches (conditional recommendation, moderate certainty of evidence).
Disclosures
Dr. Flexner reports serving as a consultant for Gilead Sciences, Merck, Janssen, and ViiV Healthcare, and serves on the Scientific Advisory Board for Navigen. He is also a co-inventor on two issued patents related to the development of long-acting formulations for delivery of antiretroviral drugs. Dr. Phanuphak reports research funding and speaker fees from Gilead Sciences, is on the Advisory Board at ViiV Healthcare, and is a consultant to MSD. Dr. Baggaley has nothing to disclose.
References
Schürmann D, Rudd DJ, Zhang S, et al. Safety, pharmacokinetics, and antiretroviral activity of islatravir (ISL, MK-8591), a novel nucleoside reverse transcriptase translocation inhibitor, following single-dose administration to treatment-naive adults infected with HIV-1: an open-label, phase 1b, consecutive-panel trial. Lancet HIV 2020; 7(3):e164-e172. doi:10.1016/S2352-3018(19)30372-8
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Gaudinski MR, Houser KV, Doria-Rose NA, et al. Safety and pharmacokinetics of broadly neutralising human monoclonal antibody VRC07-523LS in healthy adults: a phase 1 dose-escalation clinical trial. Lancet HIV 2019; 6(10):e667-e679. doi:10.1016/S2352-3018(19)30181-X