THE FUTURE OF HIV DRUGS DRUGS IN DEVELOPMENT TAKE A VARIETY OF APPROACHES TO FIGHTING HIV, AND PRIORITIES INCLUDE LONG-ACTING TREATMENTS AND REPLACING FAILED REGIMENS. BY TRUDY RING
Scientists developing HIV drugs are taking diverse approaches to attacking the virus, such as targeting certain proteins on cells or keeping HIV from maturing. Some seek to eliminate the reservoir of latent HIV that remains even when the virus has become undetectable. Others are focused on treating HIV in patients who have developed resistance to other drugs. Longlasting treatments and preventive drugs (some injectable) for people who find it troublesome to take a pill every day are another priority. Several drugs in the pipeline have potential to be used in both treatment and prevention. Here’s a look at what could be on the way in the near future.
VYROLOGIX (LERONLIMAB-PRO 140): CytoDyn’s viral-entry inhibitor is a monoclonal antibody that would be the first self-injectable subcutaneous HIV drug. It works by masking CCR5, a protein on the surface of white blood cells, thus inhibiting HIV’s ability to enter healthy T cells. There have been nine clinical trials indicating it could significantly reduce or control viral load. For instance, a Phase III trial involving treatment-experienced patients showed that in combination with other antiretroviral drugs, it helped 81 percent of participants achieve significant viral suppression (less than 50 copies per mL). This summer, CytoDyn plans to submit its application for Food and Drug Administration approval of Vyrologix for use in combination therapy. It is also being studied as a single therapy for HIV; for use as pre-exposure prophylaxis; and as a treatment for 34
COVID-19, metastatic cancer, stroke, and nonalcoholic steatohepatitis, a chronic liver disease. However, the FDA has said studies of its use for COVID did not show significant benefits to patients. PGT121: A small study showed that an experimental monoclonal antibody called PGT121 led to viral suppression that lasted for up to six months in HIV-positive people who started with a low viral load. Being developed by a collaboration that includes the International AIDS Vaccine Initiative, the Bill & Melinda Gates Foundation, the Scripps Institute, and Theraclone Sciences, the recombinant monoclonal antibody targets the V3 glycan site on the outer envelope of HIV. At the 2019 Conference on Retroviruses and Opportunistic Infections, researchers reported that two participants with low viral loads experienced treatment-free viral suppression, which for one lasted over five months and for the other was still ongoing at six months. Then a study published in 2021 reported that PGT121, in combination with other drugs, delayed rebound of simian HIV in monkeys whose antiretroviral treatment had been interrupted. PGT121 could eventually become a very long-acting HIV medication or a functional cure that maintains viral suppression after antiretroviral therapy has ended. UB-421: In a Phase II trial, this broadly neutralizing antibody targeted domain 1 of CD4, and was shown to maintain viral suppression after treatment ended. Weekly or biweekly intravenous infusions of UB-421 kept the viral loads of all 29 participants suppressed after they stopped taking oral HIV meds. Research is continuing into the antibody’s potential as a functional cure as well as its efficacy in patients with multidrug-resistant HIV. LENCAPAVIR (GS-6207): Developed by Gilead Sciences, this first-in-class long-acting capsid inhibitor interferes with the transport of the viral genetic material and replication of HIV’s genetic blueprint into a host cell’s nucleus. It is given subcutaneously. At the 2021 Conference on Retroviruses and Opportunistic Infections, researchers reported that lenacapavir administered subcutaneously every six months helped patients maintain high rates of viral suppression through 26 weeks. The early trials show the drug has potential as a long-acting treatment for HIV, including for people who have developed resistance to multiple drug classes and those who are unable to take a daily pill. ISLATRAVIR (MK-8591): This Merck drug is the first nucleoside reverse transcriptase translocation inhibitor (NRTTI). In Phase IIb trials of treatmentnaive adults receiving islatravir as part of a combination antiretroviral regimen, it was shown to have less of a (negative) impact on bone mineral density, making it a potential replacement for those with poor bone health. The drug uses a variety of methods to block the HIV enzyme known as reverse transcriptase, and researchers say it may be effective against HIV strains that are resistant to other drugs. A Phase Ib trial, results of which were published in The Lancet in 2020, found a single oral dose of islatravir in treatment-naive patients significantly suppressed HIV; the drug was also well-tolerated. Interim results from a Phase IIb study, published in 2021, indicated that islatravir plus doravirine (brand name Pifeltro) made an effective and well-tolerated regimen, and researchers recommended further study of this combination. Islatravir is also being studied for HIV prevention, both as an oral med and as an implant. LENCAPAVIR AND ISLATRAVIR: Gilead and Merck recently announced an agreement to join in developing treatments that combine these two drugs. The initial focus will be on long-acting formulations, both oral and injectable, but other formulations may be added. The first clinical studies of the oral combination are expected to begin in the second half of 2021. LEFITOLIMOD (MGN1703): Lefitolimod is a type of latency-reversing agent called a toll-like receptor 9 agonist — toll-like receptors, or TLRs, are proteins that help the immune system recognize dangers, and agonists are used to enhance this activity. Researchers believe lefitolimod may improve the body’s immune response to HIV in addition to its effect on latent virus cells. Researchers in Denmark tested lefitolimod in the TEACH study, which showed it to be safe in early-phase trials. A Phase IIa study, TITAN, began in 2019 at Denmark’s Aarhaus University, in which patients on antiretroviral treatment are being given Lefitolimod along with virus-neutralizing antibodies developed by Rockefeller University to see if the therapy can reduce the viral reservoir. Lefitolimod was
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