Updates on Islatravir: Western European Perspectives
Islatravir Updates From CROI 2023: Perspectives From Western Europe

Released: March 17, 2023

Expiration: March 15, 2024

Laura Waters
Laura Waters, FRCP, MD

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Key Takeaways
  • Dose-dependent effects of ISL on total lymphocyte and CD4+ counts led to the discontinuation of monthly ISL development for PrEP, but development has resumed for HIV treatment using lower oral doses.
  • Switch to DOR/ISL was noninferior to continued baseline 2- or 3-drug ART or to continued baseline BIC/FTC/TAF for maintaining virologic suppression in 2 phase III studies.

Islatravir (ISL) is a nucleoside reverse-transcriptase translocation inhibitor currently under investigation for HIV treatment and prevention. Its mechanism of action is similar to that of nucleos(t)ide reverse-transcriptase inhibitors (NRTIs), but ISL has an additional mechanistic component that enhances its barrier to resistance, allowing it to remain active in the presence of several important NRTI mutations.

In this commentary, I share my take on key ISL updates from CROI 2023.

ISL Safety Updates
Concerns about the impact of ISL on total lymphocyte counts led to cessation of its development at the end of 2021.

At CROI 2023, investigators presented summative safety data on ISL in HIV treatment and prevention studies. The results suggest that the effects of ISL on total lymphocyte and CD4+ counts are dose dependent, and lower doses do not have a significant impact on these white blood cell counts. Of note, in the dose-ranging phase IIb P011 study comparing various ISL doses plus doravirine (DOR) once daily vs DOR/lamivudine (3TC)/tenofovir disoproxil fumarate (TDF) once daily, exposure-related decreases in total lymphocyte counts through Week 72 were observed in the ISL 0.75-mg and 2.25-mg groups, whereas total lymphocyte count changes were comparable for the ISL 0.25-mg group and the DOR/3TC/TDF comparator group. Regarding CD4+ cell counts through Week 72, similar mean increases from baseline were observed in the ISL 0.25-mg and DOR/3TC/TDF treatment groups. By contrast, mean increases from baseline were smaller in the ISL 0.75-mg and 2.25-mg groups. Furthermore, after ISL discontinuation in the monthly ISL PrEP studies, total lymphocyte counts returned to ranges similar to those in the control groups. Based on these findings, research on lower doses of oral ISL (0.25 mg daily and 2 mg weekly) for HIV treatment will be continued, and higher-dosed monthly ISL for HIV PrEP will no longer be pursued.

DOR/ISL: Phase III Efficacy and Safety Results
Data from 2 randomized, noninferiority antiretroviral therapy (ART) phase III switch studiesan open-label trial and a blinded trial—also were shared at CROI 2023. In both trials, the safety and efficacy of DOR/ISL 100/0.75 mg daily were evaluated as a switch regimen for virologically suppressed individuals receiving stable ART. In the open-label study, participants (N = 672) were receiving 2- or 3-drug ART at baseline (51.8% integrase strand transfer inhibitor [INSTI] based, 34.5% nonnucleoside reverse-transcriptase inhibitor [NNRTI] based, 13.7% protease inhibitor [PI] based), and in the blinded study, participants (N = 641) were receiving bictegravir (BIC)/emtricitabine (FTC)/tenofovir alafenamide (TAF) at baseline. Eligible participants had no known DOR resistance and did not have active hepatitis B virus infection.

At Week 48, the switch to DOR/ISL was found to be noninferior to continued baseline ART in maintaining virologic suppression (by FDA snapshot) in both studies. In the study comparing the switch with continued BIC/FTC/TAF, only 1 case of virologic failure (confirmed HIV-1 RNA >200 copies/mL) occurred in the DOR/ISL arm, but no drug resistance was detected, and ISL was not detected in plasma samples at Week 12. In the other study, 3 participants who continued their baseline ART regimens (1 INSTI based, 2 NNRTI based) experienced virologic failure and developed emergent resistance to at least 1 drug in their regimen compared with 0 participants on the DOR/ISL arm.

Safety data were similar in both studies. In the open-label study, slightly higher rates of adverse events (AEs) were observed in the DOR/ISL arm compared with baseline 2- or 3-drug ART regimens. It is important to note that it is common to observe higher AE rates in the switch arm vs the continuation arm of switch studies, as patients adjust to the change from a stable ART regimen to a new regimen. No major AEs were reported in either study. Rates of drug discontinuation for drug-related AEs were low among all groups.

In both studies, a modest decrease in CD4+ and total lymphocyte counts occurred in the DOR/ISL arms, whereas a slight increase in CD4+ and total lymphocyte counts was observed among participants who continued their baseline ART. These differences were not deemed to be clinically relevant, as most individuals had high CD4+ counts at baseline.

Results from these 2 phase III trials demonstrate that DOR/ISL 100/0.75 mg is a virologically effective ART switch option for people with viral suppression, albeit with the now-expected lowering of total lymphocyte and CD4+ counts with 0.75-mg daily dosing of ISL.

Next Steps
The key question moving forward is if the ISL 0.25-mg dose is going to be as effective as the 0.75-mg dose; preliminary modeling data suggest that it will be. Both doses were predicted to be effective not only against wild-type virus, but also against virus harboring the M184V/I mutation, a common emergent NRTI mutation. It will be interesting to see whether the planned ISL dose reduction for the next wave of phase III studies will yield the same results.

The data on the dose-dependent effects of ISL echo previous research on rilpivirine (RPV), which initially was earmarked to be administered at a dose of 75 mg daily but, due to safety concerns related to QT prolongation, subsequently was developed for use at a 25-mg daily dose. Although data support the efficacy of RPV 25 mg, it has a relatively low barrier to drug resistance, thus requiring high levels of adherence and underperforming at higher viral loads.

Predicted Use in Western Europe
A key challenge that we have in Western Europe—and likely many other regions of the world—is our growing aging population. Our older population with HIV is often treatment experienced, and much of this population has probable or proven M184V/I mutation, which limits treatment options, particularly for 2-drug ART regimens such as dolutegravir/3TC. A 2-drug regimen such as DOR/ISL that does not include an NRTI could be a potential option in this scenario if future data pan out.

Other considerations in this special population include polypharmacy and multimorbidity, increasing the risk for drug‒drug interactions. In this regard, ISL has a favorable drug‒drug interaction profile, providing another potential advantage, especially as a PI- and INSTI-sparing ART regimen.

More data are needed to determine if ISL may offer metabolic benefits. Favorable lipid profiles have been observed with DOR, but we still are waiting for results on DOR/ISL, including its effects on weight. These data are expected to be presented at the International AIDS Society meeting later this year.

Your Thoughts?
What are your thoughts on how ISL may fit into the HIV treatment armamentarium if it becomes available in the future? Join the discussion by posting a comment.