Declines in white blood cell counts in people taking the experimental HIV drug islatravir are not associated with higher rates of infections, and the combination of doravirine and islatravir is just as effective as existing treatment in maintaining viral suppression, researchers reported at the 30th Conference on Retroviruses and Opportunistic Infections (CROI 2023) in Seattle last week.
What is islatravir?
Islatravir is the first drug of a new class called nucleoside reverse transcriptase translocation inhibitors (NRTTIs). It is eliminated from the body slowly, potentially allowing for monthly dosing. However, clinical development was paused in November 2021 when the drug was associated with falls in white blood cells, including lymphocytes (such as CD4 cells) and B-cells (which generate antibody responses). These changes appeared to be dose-related and so subsequent studies have begun investigating the use of a lower dose of the drug, once daily. Islatravir is being developed as part of a once-daily combination with the non-nucleoside reverse transcriptase inhibitor doravirine.
Switching from suppressive antiretroviral treatment to doravirine/islatravir
A daily islatravir dose of 0.75mg was selected for phase 3 studies before development was put on hold. This dose was thought to be sufficient to achieve viral suppression in both previously untreated and heavily treatment-experienced people.
Professor Jean-Michel Molina of the University of Paris reported the 48-week results of a study in which people with suppressed virus and no history of treatment failure were randomised to continue with their existing treatment or switch to doravirine / islatravir. Treatment was given open-label in this study, so all participants and clinicians were aware of which treatment was being given.
The study recruited 672 people in 15 countries. The study population was just over one-third female (36%), approximately 26% of participants were Black or African-American, and the median time on the current antiretroviral regimen was 2.7 years. Less than 10% of participants had CD4 counts below 350.
The primary outcome analysis showed that switching to doravirine / islatravir was non-inferior to continuing the existing regimen at week 48; 95% of the doravirine / islatravir group and 94% of the non-switch group maintained a viral load below 50. There were no cases of viral rebound above 50 in the doravirine / islatravir group but three people experienced viral rebound on their existing regimen.
CD4 counts rose by an average of 30 in the non-switch group by week 48 but fell by an average of 38 in the doravirine / islatravir group. However, Molina said that this difference was not clinically meaningful as the mean CD4 count in the doravirine / islatravir group was 677 at week 48.
Total lymphocyte counts had fallen by 10% in the doravirine / islatravir arm by week 48 and remained stable in the non-switch group but an adverse events analysis showed that this resulted in no clinical difference in infections during the study. Thirty-three per cent in each arm developed an infection during the study and there was no difference in the rates of COVID-19 between study arms (5%).
One serious drug-related adverse event occurred in the doravirine / islatravir arm and five participants in this arm discontinued due to drug-related adverse events, compared to none in the non-switch arm.
Switching from Biktarvy to doravirine/islatravir
The second switch study was a placebo-controlled randomised comparison of bictegravir / tenofovir alafenamide / emtricitabine (Biktarvy) with doravirine / islatravir. The trial recruited 641 people with suppressed viral load and no history of treatment failure. Study participants were predominantly male, three-quarters were White, 18% were Black or African American and approximately 90% had CD4 counts above 350 at study entry. Participants had been taking Biktarvy for a median of 14 months.
The primary outcome analysis showed that switching to doravirine / islatravir was non-inferior to continuing the existing regimen; 93% of the doravirine / islatravir group and 94% of the non-switch group maintained a viral load below 50 at week 48. One participant in the doravirine / islatravir group experienced viral rebound above 200. No islatravir was detectable in blood samples collected at the time viral rebound was detected, suggesting non-adherence to treatment. Five per cent in each arm discontinued treatment due to adverse events, withdrew from the study or were lost to follow-up.
CD4 counts rose by an average of 40 in the non-switch group by week 48 but fell by an average of 19 in the doravirine / islatravir group. As in the study described previously, this difference was not clinically meaningful. At week 48, the mean CD4 count in the doravirine / islatravir group was 661.
Total lymphocyte counts remained stable in the non-switch arm but fell by 8% in the doravirine / islatravir arm. As in the other study, there was no difference in the rate of infections (31% vs 30%) or COVID-19 (6%) between the two study arms, suggesting that the change in total lymphocyte count was not clinically meaningful.
There was no difference in the rate of serious drug-related adverse events between study arms.
Lymphocyte changes during islatravir treatment: what do halted studies show?
Dr Kathleen Squires of Merck reported on lymphocyte changes in clinical trials of islatravir for treatment or prevention, involving approximately 2300 people. Islatravir triphosphate accumulates in lymphocytes and triggers cell death at very high drug concentrations. Islatravir PrEP studies tested monthly doses of 60mg or 120mg. Total lymphocyte counts fell by around 20% in these studies.
In studies testing a dose of 20mg once weekly for treatment, total lymphocyte counts fell by up to 30% by week 24. But in studies testing a dose of 0.75mg for treatment, total lymphocyte counts fell by 5-10% and tended to stabilise after 48 weeks of treatment, demonstrating the strong relationship between higher dose and the extent of decline in lymphocyte count.
Phase 2b dose-ranging studies showed that a dose of 0.25mg did not have a negative effect on lymphocyte or CD4 counts and was just as effective as higher doses. This dose is now being taken forward in combination with doravirine in phase 3 studies, developer Merck announced during CROI 2023. Two studies will evaluate switches from suppressive antiretroviral regimens to doravirine / islatravir and one study will evaluate the combination in previously untreated people. Another study will offer the new dosing regimen to people who received a 0.75mg dose of islatravir in previous studies.
Molina JM et al. Switch to DOR/ISL (100/0.75mg) qd: week 48 results from an open-label phase 3 trial. Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 196, 2023.
Mills AM et al. Switch to DOR/ISL (100/0.75mg) from B/F/TAF: week 48 results from a phase 3 trial. Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 197, 2023.
Squires KS et al. Effect of islatravir on total lymphocyte and lymphocyte subsets counts. Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 192, 2023.