While antiretroviral therapy (ART) has been a lifesaver for many people with HIV, patients who experience drug resistance often have few if any choices in medication that can keep their viral levels suppressed; new drug options are urgently needed.
A prodrug called fostemsavir
was developed specifically for these patients, with the goal of adding it to their other HIV medications.
A team of investigators, led by infectious disease doctors at Yale School of Medicine and Icahn School of Medicine at Mt. Sinai in New York, recently reported the results of the phase 3 BRIGHTE clinical trial, which delved into the efficacy and safety of fostemsavir, in The New England Journal of Medicine.
In the BRIGHTE trial, 371 patients with multidrug-resistant HIV living in 23 countries were split into 2 cohorts.
The first cohort was comprised of 272 patients who were able to take at least 1 ART medication in 1 or 2 ART classes. This group was randomized in a 3:1 ratio to either add 600 mg of fostemsavir twice a day to their current therapies for 8 days, or to add a placebo to their current therapies for 8 days. Both groups then took open-label fostemsavir in addition to optimized background therapy.
The second cohort consisted of 99 patients who had run out of ART options; this group took open-label fostemsavir in addition to optimized background therapy for 8 days. The subjects then were followed for at least 48 weeks to track their HIV RNA levels.
On the eighth day of the study, the average HIV RNA level had decreased by 0.79 log10
copies per milliliter in the group that received 600 mg of fostemsavir twice a day versus 0.17 log10
copies per milliliter in the group that took the placebo.
The average reduction in viral load in the 241 subjects who had a baseline RNA level of at least 1,000 copies per milliliter at the study’s start was 0.86 log10
copies per milliliter in subjects who received 600 mg of fostemsavir twice a day and 0.20 log10
copies in the placebo group.
By week 48, 54% of subjects in the first cohort had achieved an HIV RNA level of less than 40 copies per milliliter, compared with the second cohort in which 38% had achieved an HIV RNA level below 40 copies per milliliter. CD4+ T-cell counts in the first cohort rose over time as well, by an average of 139 cells per cubic millimeter by week 48. The average CD4+ T-cell count rise in the second cohort was 64 cells per cubic millimeter by week 48.
“In this trial involving adults with multidrug-resistant HIV-1 infection with limited treatment options, fostemsavir had significantly better efficacy than placebo after 8 days of functional monotherapy,” the authors wrote. “All the patients in the trial had exhausted all approved agents in at least four classes of antiretroviral drugs and had a low CD4+ T-cell count.”
Noting that viral suppression held up over time, they added, “Efficacy was sustained through 48 weeks, which supports further development of fostemsavir as a therapeutic option for patients with multidrug-resistant HIV-1 infection and few remaining options for active therapy. Fostemsavir has a novel mechanism of action with no in vitro cross-resistance to currently available classes of antiretroviral drugs, has a favorable drug-drug interaction profile, and has shown both immunologic and virologic responses.”
Most of the subjects experienced adverse events during the trial, with 92% of them reporting at least 1 by week 48. Nearly half (47%) of participants in the second cohort endured significant or severe adverse events versus slightly more than a quarter (26%) in the first cohort, due to participants in the second cohort being sicker and likelier to have advanced AIDS.
The authors determined that the rates of adverse events were in line with those of prior studies. A total of 7% of participants dropped out of the trial due to adverse events. Several participants also died by week 48—11 subjects in the first cohort and 14 in the second cohort—mostly due to infections or complications of AIDS.
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