When long-acting injectable antiretroviral treatment for HIV finally arrives in the U.S., it will be a safe, effective, and practical alternative to daily oral regimens—even in the midst of the COVID-19 pandemic, according to new research presented at IDWeek 2020, a medical conference that took place virtually from Oct. 21 to Oct. 25.
The POLAR Study: A Choice Between Long-Acting and Oral ART
Anthony Mills, M.D., the CEO and principal investigator at Men’s Health Foundation, presented 12-month results of the phase 2b rollover POLAR study, which is assessing the safety and effectiveness of two medications in development as long-acting (LA) agents for maintaining virologic suppression. The drugs—cabotegravir (CAB), an integrase strand transfer inhibitor (INSTI), and rilpivirine (RPV, Edurant), an NNRTI—were given as injections to participants every two months. The results were compared to an oral regimen of CAB plus RPV that participants had received in the phase 2b LATTE study.
POLAR is an open-label, multicenter, non-randomized rollover study funded by ViiV Healthcare and Janssen Pharmaceuticals. [Editor’s note: ViiV and Janssen are often ad sponsors on TheBodyPro, but this article—just like everything we publish—is created independently by our editorial team based on our assessment of its importance to our readers.] It involved 97 people who each completed more than 312 weeks of oral CAB (30 mg) plus RPV (25 mg) in the LATTE study.
The median age of the cohort was 41, and 20% were over the age of 50. There were two cisgender women and three transgender women. The racial breakdown was 69% white, 25% Black, and 6% who identified their racial identity as “other.”
Offered a choice between regimens at the start of the study, 90 of the 97 participants decided to switch to the LA injectable. Seven preferred to take an oral regimen of dolutegravir (Tivicay) plus rilpivirine. As a result, according to Mills, the tiny sample for the oral treatment made any data from that arm of the study not very useful. “What is significant is that greater than 90% chose injectable therapy regardless of gender or race,” he said.
Mills et al looked at the proportion of participants with HIV-1 RNA greater than 50 copies/mL. They also looked at the proportion of participants with plasma HIV-1 RNA less than 50 copies/mL, the incidence of protocol-defined confirmed virologic failure (CVF), the incidence and severity of adverse events, and the proportion of patients who discontinued treatment due to adverse events.
POLAR Results: Good Virologic Suppression, Minimal Adverse Events
Overall, 98% of participants in the CAB+RPV LA arm (and all seven of the participants in the oral therapy arm) maintained virologic suppression at 12 months—and no participant had an HIV viral load greater than 50 copies/mL in either treatment arm of the study. (Two participants dropped out of the LA arm—one due to treatment-related depression, and one who was lost to follow-up.) Through month 12, no participants met the CVF criterion in either arm.
Adverse reactions were extremely common—96% percent of people in CAB+RPV LA arm reported adverse events—though these were “primarily due to injection-site reactions,” Mills said, the vast majority of which were mild. (By comparison, 43% reported adverse events in the oral treatment arm.) Importantly, researchers saw no clinically relevant patterns in clinical laboratory results over 12 months. No patients withdrew because of injection-site reactions.
At month 12, 88% of CAB+RPV LA recipients said they preferred their long-acting injection treatment over the oral CAB+RPV regimen they had received in the LATTE study. The most commonly cited reasons included convenience (69%) and lower frequency of administration (57%).
“Taken together, results indicated that CAB+RPV given every [two] months was well-tolerated maintenance therapy and may be preferable to oral therapy,” Mills said.
Impact of the Ongoing COVID-19 Crisis on Injectable HIV Treatment Adherence
The hope for injectable LA-ART for HIV treatment lies in the infrequency of its dosing: Instead of taking pills 365 days a year, people could get injectable treatments 12 times a year (or even less). But injections require a visit to a health care professional, potentially making this method difficult for people with limited health care access.
Some have voiced a concern that the COVID-19 crisis—and the social isolation and restrictions on access to health care services that have stemmed from it—could make getting injectable treatment even more difficult, if LA-ART is approved in the U.S. while the pandemic still rages.
To explore this concern, one presentation at IDWeek looked at the COVID-related impact on CAB + RPV LA dosing during ongoing clinical trials and examined whether restrictions on access to some clinical trial sites present challenges to the continuous delivery of the regimen during a pandemic. It found that the impacts were indeed real—but that in many cases they could be mitigated.
Maggie Czarnogorski, M.D., M.P.H., the head of innovation and implementation science at ViiV Healthcare, presented a descriptive analysis conducted using data from several ongoing CAB+RPV LA clinical trials (including ATLAS, ATLAS-2M, CUSTOMIZE, FLAIR, LATTE-2, and POLAR). The data were compiled through Sept. 15, 2020, and then aggregated, categorized, and summarized to show trends.
Czarnogorski and colleagues found that, as of Sept. 15, 129 (7.4%) of the 1,744 active participants in the LA studies had injection visits that were impacted by COVID-19. Of those 129 visits that were impacted, LA dosing was interrupted in:
- 54 (42%) due to clinic closure or staffing constraints.
- 18 (14%) for confirmed or suspected COVID-19 infection.
- 11 (9%) due to self-quarantine.
- 7 (5%) due to travel restrictions.
- 6 (5%) because the participant elected not to go to the clinic.
- 33 (26%) for other reasons.
Geographically, 72 (56%) of the impacted participants were from North America, 33 (26%) from Europe, 17 (13%) from South Africa, and 4 (3%) from Latin America.
Fortunately, there were mitigation strategies for those whose LA dosing was interrupted. These included short-term oral therapy with CAB+RPV (received by 94 of the participants), a short-term switch to a standard-of-care oral antiretroviral regimen (27 participants), and rescheduling of LA injections (7 participants). As of Oct. 19, 110 of the 121 study participants who had switched to an oral regimen had already resumed their LA regimen. Although viral load data collection is ongoing for those participants, no suspected or confirmed virologic failure was observed for any of the people who have been impacted by COVID-19 to date.
In an email interview, Czarnogorski said the results of the analysis showed that the COVID-19 pandemic did impact the ability of some participants to attend their injection appointments, mainly due to clinic closure, self-quarantine, or travel restrictions. “However, when missed visits occurred, they were manageable and successfully mitigated, primarily by switching patients onto short periods of daily oral therapy of cabotegravir and rilpivirine, with no resulting virologic failure or emerging resistance,” she said.
Czarnogorski commented that the findings show that, even in the midst of a global health crisis that has restricted access to some clinics and providers, “the injectable regimen of cabotegravir and rilpivirine can be adapted to meet the needs of people living with HIV and ensure the continuous delivery of treatment, even if they encounter disruptions to their clinic or provider visits.”
She added that, although the LA injectable regimen must currently be administered in a clinical setting, “we continue to research and explore additional ways to expand how it can be provided to people with HIV.”
When Will Injectable Long-Acting HIV Treatment Be Available in the U.S.?
Right now, a long-acting antiretroviral regimen is only an approved treatment option in Canada. Prior studies have shown LA injectable treatments to be just as effective as a daily pill, but there still are some hurdles to overcome. Last December, the U.S. Food and Drug Administration (FDA) declined to approve ViiV Healthcare and Janssen’s new drug application for LA CAB+RPV, citing manufacturing concerns—but not safety or efficacy problems.
ViiV spokesperson Melinda Stubbee told TheBodyPro that the regimen was resubmitted to the FDA earlier this year and is currently under review. Stubbee noted that the PDUFA date—i.e., the target date by which the FDA aims to complete its review of the application—was set for Jan. 28, 2021.
Meanwhile, in Europe, the European Medicines Agency recently issued a positive opinion in which it recommended marketing authorization for injectable LA CAB+RPV. The regimen still has additional bureaucratic hurdles to leap before being granted formal approval throughout the European Union, but the recommendation is an important step in that process.