Concerns about lower lymphocyte levels in HIV with the once-daily oral drug islatravir in combination with doravirine changed the trajectory of clinical trial plans that are now back on track, according to investigators.
The nucleoside reverse transcriptase translocation inhibitor hit a roadblock in December 2021 when the US Food and Drug Administration put a hold on investigational new drug applications for both the oral and implant formulations of islatravir after some patients in clinical trials showed decreases in total lymphocyte and CD4+ cell counts.
A phase 3, double-blind, randomized, controlled trial was underway at the time of once-daily islatravir (0.75mg) in combination with 100mg doravirine compared with bictegravir, emtricitabine, tenofovir alafenamide (B/F/TAF) as initial therapy for HIV infection in treatment-naïve individuals. Recruitment was stopped, 83 participants short of the planned 680, but the trial could continue the full 48 weeks.
Jürgen Rockstroh, MD, professor of medicine and head of the HIV Outpatient Clinic at the University of Bonn, Bonn, Germany, presented the latest results from that trial of 597 patients at the International AIDS Society (IAS) 2023 Conference on HIV Science in Brisbane, Australia.
At week 48 after starting therapy, 88.9% of participants in the islatravir and doravirine arm and 88.3% of patients in the B/F/TAF arm achieved the primary outcome of HIV-1 RNA levels below 50 copies/mL.
One patient treated with islatravir and doravirine and four patients taking B/F/TAF experienced virologic failure.
Rockstroh told the conference the patient who developed viremia with the new islatravir combination had very high viral load at baseline but showed a rapid response to treatment, which reduced his viral load down to around 1200 copies/mL by week 4.
However, by week 24, his islatravir concentration had reduced below detectable levels, suggesting a problem with adherence. His viral load increased again, and three treatment-resistant mutations were detected.
While both arms of the study showed a significant increase in CD4+ T cell counts, Rockstroh pointed out that some individuals in the islatravir and doravirine arm had a lower absolute increase in lymphocyte counts at week 48.
Overall, the mean change in CD4+ T cell counts was 182 cells/mL in the islatravir and doravirine group compared with 234 cells/mL in the B/F/TAF group.
However, more patients in the islatravir combination arm discontinued treatment due to a decrease in CD4+ T cell or total lymphocyte counts — 5.4% compared with 2% in the B/F/TAF arm.
“These changes in lymphocyte counts did not lead to any difference in the amount of infection-related adverse events, which happened in both arms in relatively comparable percentages,” Rockstroh said at the conference.
New Lower Dose
Because of persistent concerns about the impact on CD4+ T cells and total lymphocytes, Rockstroh said another phase 3 trial is now underway using a lower 0.25 mg dose of islatravir, again combined with 100 mg doravirine, in people who are treatment-naïve and virologically suppressed.
The study also examined the impact of both treatments on weight gain and found the mean change in weight was similar between both arms — 3.45 kg gain in those on islatravir with doravirine and 3.32 kg gain in those on B/F/TAF, which was not significantly different.
There are several important reasons it is a good idea to have more treatment options available for people with HIV, Rockstroh told Medscape Medical News.
With integrase inhibitors potentially interfering with metabolic health, weight gain, hypertension, insulin resistance, and possible diabetes, “I think it’s wise that we at least have alternative strategies,” he said.
James McMahon, MD, PhD, an infectious diseases physician and head of the Infectious Diseases Clinical Research Unit at the Alfred Hospital and Monash University in Melbourne, Australia, said there is always a need for new HIV treatments, particularly ones that are more powerful.
“Whenever you get a drug that’s potent at low dose, it means you can have smaller pills, [and] you can then consider giving more of it in long-acting formulations,” McMahon said.
He pointed out that the study did not show any signal of increased infections with the lower CD4+ T cell counts in the islatravir and doravirine arm, “but that difference is enough to raise that concern that it’s not ideal and it should be moved forward with a lower dose, which is what they’ve done.”
International AIDS Society (IAS) 2023 Conference on HIV Science.
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