Advancing next generation integrase inhibitors for HIV

What is the current therapeutic landscape for integrase inhibitors and what are three key challenges hindering the field’s advancement?

Babafemi Taiwo (BT): Integrase strand transfer inhibitors (INSTIs) stop the HIV virus from inserting its genetic material into human cells. They are powerful against resistance, highly effective and well tolerated over the long term, contributing to a real promise of ending the epidemic. Core to ViiV Healthcare’s pipeline, they have transformed HIV care and are the gold standard in HIV treatment, eg, our oral INSTI, dolutegravir (DTG). We’ve developed the long-acting INSTI, cabotegravir, to make treatment and prevention easier, simpler and more effective, and are advancing it towards ultra long-acting (ULA), three times a year dosing.

Innovation in the INSTI space should be celebrated. The extraordinary success of agents like DTG has set an exceptionally high benchmark for efficacy and safety, making meaningful advancement increasingly rare and scientifically significant. The first challenge is that despite their success, current INSTIs saturate the active site of the integrase gene very well, making it challenging to make structural changes to new INSTIs that would improve overall efficacy.

Secondly, the way HIV becomes resistant to INSTIs forces the virus to give up part of its fitness, which makes it paradoxically more challenging to develop new integrase inhibitors with activity against such resistant strains. Looking ahead, VH184, an exciting addition to our portfolio, is the first third-generation INSTI in development, which may help address the evolving challenge of INSTI resistance. Although resistance remains uncommon, the large number of people using INSTIs means that even a small percentage can still affect many individuals.

That’s why continued innovation in this class remains important. At Conference on Retroviruses and Opportunistic Infections (CROI) 2026, in vitro data for VH184 showed improved potency and an enhanced resistance profile versus bictegravir in resistant HIV strains. It also retained activity against a broad range of resistant virus strains, including those with multiple INSTI-associated substitutions.

Finally, additional challenges come when developing ULA versions of INSTIs as there are limits to drug doses and injection volumes that would be considered acceptable in routine clinical use. With VH184, we believe we have pushed beyond these thresholds. We now see a path towards ULA INSTIs becoming the standard of care in the future, provided we work together to fully harness their potential in pursuit of ending the HIV epidemic.

What were the main findings from the interim analysis of the Phase IIb EMBRACE study of lotivibart (N6LS)?

BT: At CROI 2026, we shared positive 12-month data from the Phase IIb EMBRACE trial that support continued study of lotivibart (N6LS), a broadly neutralising antibody (bNAb), as part of a potential twice-yearly ULA HIV treatment regimen. These results build on our legacy of developing innovative long-acting options for HIV treatment that offer greater choice for people living with HIV.

In adults living with HIV on stable therapy, a regimen of lotivibart administered every four months, combined with monthly intramuscular (IM) long-acting cabotegravir (CAB LA), maintained viral suppression during 12 months of follow-up in 94 percent of participants receiving lotivibart intravenously and 82 percent subcutaneously, compared with 88 percent in the standard of care (SC) group. Lotivibart was generally well tolerated, with participants in both groups reporting high acceptability. Adverse events related to lotivibart were less common in the intraveneous group (24 percent) compared with the subcutaneous group (53 percent).

Based on these early data, we’re encouraged by the potential of ULA dosing intervals of four months and beyond. Part 2 of the EMBRACE study is now underway to evaluate twice-yearly intravenous dosing interval for lotivibart.

How do ViiV’s new ultra long‑acting integrase inhibitors differ from other long‑acting integrase inhibitors indicated for HIV?

BT: Currently, cabotegravir is the only approved long-acting INSTI for HIV treatment and prevention, and it has already shown what this class can deliver. A new cabotegravir formulation (CAB ULA) is the ULA version of cabotegravir being developed for dosing three times a year. VH184 is the first third-generation INSTI in development and it is best-in-class with the potential for ultra-long dosing intervals and an enhanced resistance profile.

When it comes to [ultra long-acting (ULAs)], a one-size-fits-all approach can inhibit progress”

When it comes to ULAs, a one-size-fits-all approach can inhibit progress. As the only pharmaceutical company 100 percent dedicated to preventing, treating and curing HIV, our R&D teams continue to work hard to bring novel and differentiated ULA options to the community. That’s why we are continuing to develop a differentiated pipeline of next-generation INSTIs and partner agents – like bNAbs, a capsid inhibitor, a non-nucleoside reverse transcriptase inhibitor (NNRTI) and a bispecific bNAb, that is guided by the needs of people impacted by HIV. VH184 is part of that evolution and is accelerating through early development, fuelled by robust clinical data, using advances in data and technology to progress as quickly as possible.

What makes ViiV’s pipeline assets, VH184 and VH499, potential next-generation treatments?

BT: At CROI 2026, we shared early data on VH184 and VH499, both of which have the potential to support twice-yearly dosing. That matters because longer-acting options can help simplify treatment, reduce the burden of therapy and, in some cases, make treatment a smaller part of people’s lives – which is something many people tell us they want from future HIV treatment options. VH184 is our third-generation INSTI candidate, which builds on the strength of earlier INSTIs.

In this early study, a single-dose injection maintained drug levels for up to six months, supporting its potential for twice-yearly dosing. The resistance data also suggest activity against a broader range of HIV INSTI-resistant strains. What these data tell us is that VH184 holds promise for unsurpassed potency coupled with an improved resistance profile while delivering extended dosing intervals, meaning it has the potential to play a vital role in future HIV care.

[Injectable VH499 has the potential] as an integral part of future treatment approaches. Data suggest a low potential for drug–drug interactions, which could be an important differentiator in future long-acting regimens”

VH499 is a capsid inhibitor being developed as part of our best-in-class agent pairing approach. In an ongoing Phase I study in adults without HIV, VH499 was given as a single intramuscular or subcutaneous injection between 100mg and 1,200mg. Data showed that both injection routes maintained stable drug levels for a prolonged period, indicating that injectable VH499 has the potential for twice-yearly dosing and promise as an integral part of future treatment approaches. Data suggest a low potential for drug–drug interactions, which could be an important differentiator in future long-acting regimens.

In the broader landscape, how can drug developers harness the potential of integrase inhibitors?

BT: INSTIs remain at the core of how we think about future HIV treatment and prevention options because of their potency, durability and generally well-tolerated profile. Looking ahead, we’re exploring the potential of pairing INSTIs with excellent partner agents to support more personalised options that can address specific needs. Across the HIV landscape we’re likely to see more of this kind of tailored approach in the years ahead.

We must also ensure that everyone can benefit from the latest development in INSTI innovation and we are committed to the broadest possible access to our innovative medicines. We updated our voluntary licensing agreement with the Medicines Patent Pool (MPP) in July 2025 for cabotegravir, to include patents relating to its use in a long-acting treatment regimen, in addition to prevention. The granting of generic licenses will enable the development, manufacture and supply to 133 additional countries worldwide.

And crucially, extending innovation to address longstanding treatment gaps for paediatric and adolescent populations remains important too. Collectively, we need to address individual needs for everyone living with HIV. Children under 15 years of age account for approximately three percent of people living with HIV, yet are often overlooked. Establishing viral control early is a priority, as the journey with this chronic disease is lifelong, and long-acting INSTIs could help support adherence and simplify treatment in the future.

At CROI 2026 we presented positive viral suppression results from the phase I/II IMPAACT 2017 study – the first trial to evaluate a complete injectable long-acting treatment regimen in adolescents living with HIV – alongside additional paediatric data from IMPAACT 2036 (CRAYON), the first study to provide pharmacokinetic and safety data on long-acting cabotegravir + rilpivirine in children as young as two years.

What primary factor will shape the future of integrase inhibitor development?

BT: Long-acting medicines are key to ending the HIV epidemic. The future of INSTI development will be about delivering longer or ULA options that offer more choice in meeting the varied needs of people impacted by HIV. New options can reduce the frequency of injections needed, may better suit a person’s life, have fewer side effects or be better for long-term health and outcomes.

Fundamentally, if we can continue to demonstrate the success of less frequent dosing through clinical trials and real-world evidence, we can offer a suite of ULA options that will give people with HIV, and those who could benefit from PrEP, greater choice over their regimens. Alongside this, we may start to see the introduction of alternative and novel delivery methods that will bring convenience from the lab to the clinic.

As we look ahead, these conversations will continue to define how we treat and prevent HIV. One day we hope HIV will disappear completely, because that will mean we have delivered a cure. Everything we learn from developing our next generation of therapies brings us closer to that goal. We’ve come a long way in the last 30 years when it comes to tackling HIV, but the race isn’t slowing down; it’s speeding up.