By Brezo Boerner
Headache was the most common adverse event (AE) experienced by people over 72 weeks of taking the investigational two-drug HIV treatment once daily, islatravir (ISL; Merck) plus doravirine (DOR; Merck), and those AEs were short-lived and mild, according to a safety analysis presented at the 2021 International AIDS Society (IAS) Conference.
That finding, combined with other data showing little change in metabolic markers, is potentially good news for people living with HIV, as two-drug regimens generally have fewer side effects than traditional three- or four-drug regimens, said Jean-Michel Molina, MD, PhD, of Saint-Louis and Lariboisière Hospitals, Paris, France, who previously presented efficacy data on the combination at the Glasgow 2020 HIV Virtual Conference.
"At this point, it's encouraging," Molina told Medscape Medical News . "The safety is good, the efficacy appears good. But the data is limited, and it's too early to say."
If it reaches the clinic, IS/DOR would be the fourth two-drug regimen approved for the treatment of HIV, following the U.S. Food and Drug Administration's approval of dolutegravir/lamivudine (Dovato), dolutegravir/rilpivirine (Juluca), and long-acting injectable cabotegravir/long-acting rilpivirine (Cabenuva).
DOR, un inhibidor de la transcriptasa inversa no nucleósido (NNRTI), está actualmente aprobado y es parte del régimen Delstrigo de tres medicamentos en una sola pastilla (doravirina / lamivudina / tenofovir disoproxil fumarato, DOR / 3TC / TDF, Merck). ISL todavía está en desarrollo para el tratamiento y la prevención . Molina había presentado previamente datos que mostraban que el 81,1% de las personas que vivían con el VIH mantenían cargas virales indetectables (definidas como <50 copias / ml) en comparación con el 80,6% de las personas que continuaban el tratamiento con DOR / 3TC / TDF. Los datos sobre ISL / DOR frente a DOR / 3TC / TDF para personas nuevas en el tratamiento del VIH se publicaron en The Lancet HIV en mayo.
The ISL/DOR trial was designed to evaluate the safety of three doses of ISL with 100 mg of DOR (0.25 mg, 0.75 mg, and 2.25 mg) as daily treatment. Researchers randomly assigned 29, 30, and 31 participants, respectively, to each of the dual-therapy arms and 31 participants to the DOR/3TC/TDF arm after an initial 24-week course of DOR/3TC/TDF. At week 60, all participants in the two-drug arms received 0.75 mg of ISL with DOR.
At HIV Glasgow, Molina did not present details on the safety profile of the two-drug combination. Douglas Cunningham, DO, a primary care provider with Pueblo Family Physicians in Phoenix, Arizona, presented such data at IAS 2021. He showed that during the first 96 weeks of the trial, there were a total of 118 adverse events (AEs) among the 90 participants in the ISL plus DOR arms and 42 of the 31 participants in the three-drug regimen arm, but there were only seven drug-related AEs for those in the ISL plus DOR arm, and all of them occurred during the first 48 weeks. There were none between weeks 48 and 96.
Overall, there were no serious drug-related adverse events (AEs) for ISL/DOR; there was one in the DOR/3TC/TDF arm. The most common AE was headache, which occurred in a total of 10 participants in the ISL/DOR arms. There were nine cases of vitamin D deficiency, eight cases of nausea, seven cases of arthralgia, diarrhea, sinus pain, and vomiting, and six cases of anxiety and rash. Four people experienced limb pain.
In the three-drug combination arm, side effects were much less frequent: only 18 occurred in at least 10% of participants. The most common adverse event among those taking the three-drug combination was diarrhea, which occurred in six participants. Nausea occurred in three; vomiting and headache in two; and there was one case each of vitamin D deficiency, arthralgia, sinus pain, rash, and limb pain.
"Most of these events were mild, transient, and unrelated to the study drug," Cunningham said.
Three ISL/DOR participants experienced an increase in fasting triglyceride levels of >500–1,000 mg/dL, and six patients experienced grade 4 changes in creatine kinase levels of ≥20 IU/L. Cunningham said that all but one of the cases of increased creatine levels resulted from the participants' physical exertion, and all of these changes were found to resolve at subsequent visits. The conclusion is that the two-drug combination was safe.
“In the islatravir and doravirine group, there were no serious drug-related adverse events (AEs) or discontinuations due to drug-related AEs from week 48 through week 96,” Cunningham said. “Islatravir in combination with doravirine was generally well tolerated through week 96 with few drug-related AEs.”
Even so, the value of this combination is unclear to Laura Waters, MD, consultant physician for HIV and sexual health at Central and Northwest London NHS Trust. She noted that the data are preliminary and that islatravir has not yet been shown to reduce the chances of developing treatment-resistant mutations, a major problem for two-drug regimens, as early attempts using only two drugs resulted in incomplete viral suppression and resistance. Merck is planning a study of the combination in previously treated individuals.
Merck presented data at the IAS on another investigational NNRTI, MK-8507, in combination with islatravir. MK-8507 has the potential to be used weekly instead of daily. Waters said he suspects this trial is just a proof-of-concept for islatravir in combination with an NNRTI. Merck has signed an agreement with Gilead Sciences to co-develop islatravir with the long-acting lenacapravir. Additionally, the two-drug combination of dolutegravir and lamivudine has been very successful.
"I would be surprised if they developed islatravir/doravirine as a usable combination," he said. "It's too early to say. My personal opinion is that people are being overly optimistic about it."
International AIDS Society (IAS) Conference 2021: Summary 2498.