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Novel Combination for ART Simplification
 A Novel 2-Drug Combination Therapy for ART Simplification

Released: April 15, 2026

Chloe Orkin
Chloe Orkin, MBChB, FRCP, MD
Activity Information

Activity

Key Takeaways

•    Regimen simplification while prioritizing maintenance of viral suppression is a central goal of HIV management, but so far, not everyone has been able to benefit from simplification.
•    Individuals with multidrug-resistant HIV often require complex ART regimens with asynchronous dosing schedules and multiple pills, accompanied by increased potential for adverse effects and drug–drug interactions.
•    In the ARTISTRY-1 and -2 trials, switching to BIC/LEN was noninferior to continuing either complex ART or BIC/FTC/TAF in terms of efficacy and safety, suggesting that this regimen could be an option for people living with multidrug-resistant HIV whose virus is susceptible to BIC and LEN and who wish to simplify their ART. 


Contemporary HIV care requires us to balance durable viral suppression with long-term tolerability and simplicity for maintaining adherence and quality of life. Since the 1980s, individualizing antiretroviral therapy (ART) for people living with HIV has evolved from a standardized, drug class–based approach to a tailored strategy, grounded in science and person-centered care. The US Department of Health and Human Services (DHHS) HIV treatment guidelines emphasize that any regimen switch must maintain virologic suppression without compromising future options.

Key drivers of ART selection include the resistance profile of the virus, the drug’s barrier to resistance, coexisting medical conditions, drug–drug interactions, adherence, and personal preference. This modern paradigm prioritizes once-daily, single-table regimens when feasible, but increasingly accommodates newer strategies, such as long-acting injectables and 2-drug regimens.

However, for individuals with multidrug-resistant (MDR) HIV, the choice of ART regimen is more complex. These individuals often have HIV with resistance across multiple drug classes. Accumulated resistance mutations constrain our options for constructing regimens with at least 2, ideally 3, fully active agents. This often necessitates using multiple agents with differing dosing schedules. And the use of older or salvage agents, although sometimes unavoidable for maintaining viral suppression, may be accompanied by less favorable safety and tolerability profiles and higher liability for drug interactions. Complex regimens also may increase the risk of virologic failure.

Thus, although regimen simplification is a central goal of HIV management, simplified, potent regimens remain limited for highly treatment-experienced people living with HIV. Simplification strategies include reducing pill burden and transitioning to long-acting injectable therapy. Two-drug regimens have also emerged as a key strategy. Approved and widely studied options include dolutegravir/lamivudine and dolutegravir/rilpivirine. These regimens reduce cumulative drug exposure while maintaining virologic suppression in appropriate candidates. 

The DHHS guidelines recommend the following core criteria for switching to a 2-drug regimen: sustained HIV-1 RNA <50 copies/mL for at least 3 months, no history of virologic failure, no known resistance to either component of the 2-drug regimen, and no active hepatitis B virus infection. Motivations for ART simplification include minimizing toxicity, improving adherence, and enhancing quality of life.

Investigating 1 Potential 2-Drug Option
The combination of bictegravir (BIC), an integrase inhibitor with a high barrier to resistance, and lenacapavir (LEN), a capsid inhibitor, was proposed to help meet these goals for people with HIV who are ineligible for current single-tablet regimens. BIC/LEN, the smallest single tablet regimen, was evaluated in 2 phase III clinical trials for people with virologically suppressed HIV: ARTISTRY-1 (in people mostly receiving complex ART) and ARTISTRY-2 (in people receiving the simple regimen of BIC/FTC/TAF). The most recent results from these studies were presented at CROI 2026.

ARTISTRY-1, an open-label switch study, included a unique participant population of people with no resistance to INSTIs or prior LEN exposure. Enrolled participants had a median age of 60 years, multiple coexisting cardiovascular conditions, and had been on HIV therapy for a median of 28 years. Due to these factors, this population has been effectively left behind by HIV drug development thus far.

Most participants were taking complex ART consisting of 3 tablets daily, but this ranged up to 11 pills per day. Approximately 40% of participants were taking regimens requiring twice-daily dosing, and more than 50% were on at least 2 drugs to treat other preexisting conditions. Most were on complex ART regimens due to drug resistance, ranging across protease inhibitors, non-nucleoside reverse transcriptase inhibitors, and nucleoside reverse transcriptase inhibitors. In fact, 77% were taking a protease inhibitor (PI)-based regimen.

Despite these potentially complicating factors, BIC/LEN was noninferior to continuing the complex ART regimen, according to the FDA snapshot algorithm at Week 48. Only 3 people exhibited HIV-1 RNA ≥50 copies/mL within the snapshot window, all of whom resuppressed or had low-level viremia while persisting on BIC/LEN.

And what about resistance? To enter the study, participants had to be naive to LEN and have no preexisting resistance to BIC. At Week 48, no resistance to BIC/LEN emerged.

Tolerability of BIC/LEN was good, with similar serious adverse events, adverse event–related lab events, and discontinuations in both groups. Of importance, lipids improved with BIC/LEN, a major benefit in this population with significant cardiovascular risk. This was largely driven by removing the boosted PI. Discontinuing the PI also reduces the risk of harmful drug interactions with a strong CYP3A4 inhibitor, such as cobicistat or ritonavir.

Switch to this simpler regimen was also associated with an improvement in treatment satisfaction as measured by the HIVTSQ status questionnaire, which improved by 7 points at all study time points. This increase was highly significant, indicating that a once daily single tablet regimen like this has the potential to greatly improve quality of life for a previously overlooked population of people living with HIV.

ARTISTRY-2 similarly compared BIC/LEN to continuing on one’s current ART, though this study was double-blinded and only enrolled participants taking BIC/FTC/TAF prior to switching—this was a population already taking a simple, modern regimen. Compared to ARTISTRY-1, participants had a younger median age (49 years) and relatively fewer comorbidities, although, like ARTISTRY-1, this study allowed people with cardiovascular comorbidities. 

In terms of efficacy in this trial, switching to BIC/LEN was noninferior to maintaining BIC/FTC/TAF at Week 48. One participant discontinued due to confirmed viral failure with emergent resistance—a R263K INSTI mutation, which maintained susceptibility to BIC. This participant had received prior raltegravir and dolutegravir. They were resuppressed when switched to a 3-drug regimen.

Tolerability was excellent, and there was no difference in drug-related adverse events. Of note, trends in weight were very similar, and there was no benefit in weight observed after switching from BIC/FTC/TAF.

My Take
In summary, BIC/LEN may represent an important future option for treatment-experienced people with multidrug-resistant HIV on complex regimens who have not historically been able to benefit from ART simplification. Approval of this regimen could provide this population the opportunity to increase adherence, minimize potential drug toxicity and drug–drug interactions, and improve their overall quality of life.

More generally, for all people living with HIV, BIC/LEN may add another option: a 2-drug single-tablet regimen containing a capsid inhibitor together with an INSTI.

Your Thoughts
What further questions would you have before you feel comfortable implementing BIC/LEN into your practice? Leave a comment to join the discussion!