The long-acting HIV treatment era is just beginning

Keith Alcorn, reporting from HIV Glasgow, 19 November 2024

The pipeline for HIV treatment is increasingly dominated by long-acting antiretrovirals, Professor José Arribas, Research Director of HIV and Infectious Diseases at La Paz Hospital, Madrid, told the HIV Drug Therapy Glasgow conference last week.

If the story of antiretroviral therapy until now has been the quest for greater potency, more profound viral suppression and a higher barrier to drug resistance, future development will focus on prolonging drug activity and increasing the interval between doses, Professor Arribas explained. The quest is driven by a desire to reduce the stressful burden of adherence. “If you ask a person with HIV, [on] how many days will I have to worry about taking my medication in the next six months? If you are taking daily pills, the answer is 181 days, if you are taking pills every week, you have to worry on 26 days. If you are taking drugs every four months, you worry two days.”

A US study carried out in 2018 asked people with HIV about their preferences regarding dosing intervals. Two-thirds (66%) were very interested in a once-weekly oral regimen, compared to 39% who were very interested in a two-monthly injectable regimen and only 18% who expressed strong interest in a 6-monthly antiretroviral implant. Another survey carried out in the US in 2023, found a strong preference for long-acting oral treatment with no pain, a dosing frequency of less than once a month, and the ability to take the medication at home.

As pharmaceutical companies shift towards developing long-acting products, the drug pipeline is dominated by integrase inhibitors, capsid inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs) and nucleoside reverse transcriptase translocation inhibitors (NRTtIs). However, nucleoside reverse transcriptase inhibitors (NRTIs) have disappeared from the pipeline because none are suitable for long-acting formulations. The disappearance of NRTIs means no hepatitis B coverage, Arribas warned. “We have to make a big effort to guarantee the safety of all the participants in these trials,” he said, alluding to a case of acute hepatitis B infection that occurred in an unvaccinated participant in the phase 2b study of weekly islatravir and lenacapavir presented at HIV Glasgow 2024. Only two drug combinations for daily dosing are still in development, islatravir 0.25mg plus doravirine (developed by Merck) and lenacapavir 25mg or 50mg plus bictegravir.

Results of the first trial of a once-weekly oral combination were presented at HIV Glasgow, showing that islatravir 2mg and lenacapavir 300mg were safe and effective in maintaining virological suppression in people switching from bictegravir / emtricitabine / tenofovir alafenamide. A second once-weekly combination under development by Merck pairs islatravir with a new NNRTI, ulonivirine (MK-8507), which is active against common NNRTI-resistant viruses.

As well as lenacapavir, Gilead is developing three agents for once-weekly dosing: GS-4182, the better-absorbed prodrug of the oral capsid inhibitor lenacapavir; bavtavirine (GS-1720), an oral integrase inhibitor that is active against common integrase inhibitor-resistant viruses and GS-5894, an oral NNRTI. GS-4182 and GS-1720 are being tested in a phase 2 study, WONDERS, in people virologically suppressed on bictegravir / emtricitabine / tenofovir alafenamide.

For dosing every two months, ViiV Healthcare is developing VH499, a capsid inhibitor, to be combined with a long-acting integrase inhibitor. VH499 can be self-administered, making it more convenient for users and requiring less clinic time. During HIV Glasgow 2024, Arribas and other speakers noted that clinic resources were already stretched by providing bimonthly injections of cabotegravir and rilpivirine to a minority of patients.

“That is one of the limits of long-acting therapies right now, we don’t have any that can be self-administered,” he pointed out. For longer dosing intervals, Gilead is developing GS-1614, a pro-drug of islatravir that may allow three-monthly dosing, and GS-6212, an integrase inhibitor suitable for three-monthly subcutaneous injection. Both agents are being evaluated in a phase 1b safety study in people with HIV. ViiV Healthcare is developing an ultra-long-acting formulation of cabotegravir that will permit intramuscular dosing three times a year.

The six-monthly dosing pipeline is dominated by integrase inhibitors and broadly neutralising antibodies. ViiV is developing VH-184 and VH-310, a prodrug of cabotegravir, while Gilead is developing GS-1219 and GS-3242. All these agents are integrase inhibitors; only VH-184 has reached human studies.

At HIV Glasgow 2024, Gilead presented data from a phase 1b study of six-monthly treatment with lenacapavir and two broadly neutralising antibodies, teropavimab (GS-5423) and zinlirvimab (GS-2872), showing that the combination maintained viral suppression at the higher zinlirvimab dose in all who switched to it.

ViiV is developing two broadly neutralising antibodies for six-monthly dosing, N6LS (VH-109) and VH-079. VH-109 has been tested in the phase 2 BANNER study while human studies of VH-079 are awaited.

But apart from the usual challenges of drug development, this pipeline faces a major reality check by 2029: the end of the last patents on dolutegravir. This means that the price of the world’s most-used antiretroviral combination, tenofovir disoproxil, lamivudine and dolutegravir (TLD) will fall to around 50 euros a year.

In a recent article in Clinical Infectious Diseases, Dr Andrew Hill of Liverpool University and colleagues at Berlin’s Institute of Tropical Medicine and International Health set out eight benchmarks that new combinations will have to meet to compete globally with TLD: superior efficacy; a high genetic barrier to resistance; safety in hepatitis B coinfection; favourable drug interaction profiles; efficacy against HIV-2; safety in pregnancy, availability in long-acting formulations and affordable pricing. Superiority studies such as LATITUDE, which evaluated injectable cabotegravir and rilpivirine against standard-of-care treatment in people with adherence challenges, will be needed to convince funders that long-acting treatments deliver benefits worth paying for, Arribas predicted. “We need the evidence that we provide enough value to compensate for the premium that we will have to pay for these new combinations,” he concluded. “We have to focus on patient-centric innovation, public health benefits and the health system impact.”
 
Reference
Arribas J. New treatments and future combinations. HIV Glasgow 2024.
Congress delegates can view the presentation here.
Fairhead C, Levi J, Hill A. Challenges for novel antiretroviral development in an era of widespread tenofovir-disoproxil/lamivudine (or emtricitabine)/dolutegravir availability (TLD) availability. Clinical Infectious Diseases, published online 11 July 2024.
 
Reporting from HIV Glasgow 2024 by Keith Alcorn, Gus Cairns and Roger Pebody has been financially supported by the Congress. The writers are editorially independent of the Congress and the presenting speakers.

Photo credit: Alan Donaldson Photography