The era of once-a-month HIV treatment has begun in the European Union—and it may soon commence in the U.S. as well. Long-acting pre-exposure prophylaxis (PrEP) is also on the horizon.
On Dec. 21, the European Commission authorized use of the long-acting injectable HIV treatment regimen of cabotegravir and rilpivirine (LA-CAB+RPV) for combination antiretroviral therapy in the European Union. These two drugs are the first long-acting injectable HIV treatments to enter clinical use. The authorization comes after the European Medicines Agency recommended authorization on Oct. 16.
Cabotegravir is an integrase strand transfer inhibitor (INSTI), and rilpivirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI). The combination regimen is administered by intramuscular injection monthly or every two months. It is indicated for maintenance treatment of adults with HIV who meet the following criteria:
- Undetectable viral load (HIV RNA less than 50 copies/mL) on current antiretroviral regimen.
- Virus that has not exhibited NNRTI or INSTI resistance.
- No history of virologic failure while on an NNRTI- or INSTI-containing regimen.
“I continue to be surprised by the level of enthusiasm by many of our patients for getting their medicines by monthly injection, or injections every two months,” said Susan Swindells, M.B.B.S., the lead investigator of the Antiretroviral Therapy as Long-Acting Suppression (ATLAS) study, which was pivotal in the drug regimen’s eventual approval in Europe. “Taking one pill once a day does not seem that difficult in theory, but for many patients it is a challenge—and, importantly, a daily reminder of the fact that they have HIV. Having this alternative to offer is a great benefit for interested patients.”
Next Likely Window for U.S. Approval Arrives in Early 2021
In the U.S., injectable LA-CAB+RPV continues winding its way to a widely anticipated approval by the Food and Drug Administration (FDA), but not without some bumps in the road.
In the EU, the two components of the new regimen, LA CAB injection and LA RPV injection, were authorized as individual agents to be used in combination. In the U.S., however, the regimen is formulated as a single fixed-dose combination under the brand name Cabenuva, marketed by ViiV Healthcare. (The CAB component was developed by ViiV, and the RPV component was developed by the Janssen division of Johnson & Johnson.)
Cabenuva was approved for use in Canada by regulatory authorities on March 18, 2020 (along with Vocabria, the oral tablet form of CAB). ViiV submitted Cabenuva to the FDA for review in April 2019, but in December 2019 the FDA deferred its approval—not because of safety or efficacy concerns, but rather due to concerns around what the FDA referred to as chemistry, manufacturing, and control (CMC).
The precise concerns that scuttled the regimen’s approval in 2019 have not been made public, but Simon Collins, an HIV treatment advocate and co-founder of the online information resource i-Base, previously reported that at a United Kingdom community advisory board meeting in January 2020, a representative from ViiV indicated that the CMC concerns were related to scale-up—a term used in the pharmaceutical industry to refer to the increase in the batch size of a product. This may relate to the fact that the LA RPV formulation requires storage between 2 and 8 degrees Celsius (between 35.6 and 46.4 degrees Fahrenheit). ViiV resubmitted Cabenuva to the FDA in July 2020, with a decision on approval expected in early 2021.
Clinicians Prepare to Incorporate Long-Acting HIV Treatment Into Practice
“Rolling out this new strategy will be a challenge on many levels,” noted Swindells. “First, on the patient level, with the amount of education that will be required; and for them to work out how to incorporate monthly injections into their schedules, and how to manage potential injection-site reactions.
“For clinic staff, training will be needed; scheduling will be a major issue, as well as allocating provider time,” Swindells added. “Keeping track of patients who miss appointments will need to be incorporated. And then there are the practical issues of inventory management, the cold chain requirements for rilpivirine, and whatever mountains of paperwork that will be required by insurance companies and pharmacy benefit managers.”
Swindells also cautioned clinicians to balance their (and their patients’) excitement around prescribing the regimen alongside an awareness of the limited populations in which LA-CAB+RPV has been studied. “At present, we have data for the safety and efficacy of this strategy only in patients that mirror those that were enrolled in the clinical trials,” she noted. “Briefly, these are nonpregnant adults with normal renal and hepatic function, and no viral hepatitis. Importantly, we do not know yet if this approach will be helpful for patients with adherence difficulties, a key population that we are all anxious to support the best way we can,” Swindells added.
Also Potentially Nearing Approval: Long-Acting PrEP
While the approval of LA-CAB+RPV for HIV treatment is eagerly awaited, perhaps even more hotly anticipated is the approval of LA-CAB as a single-agent injectable form of pre-exposure prophylaxis (PrEP).
In November 2020, the FDA granted breakthrough therapy designation to an LA-CAB injection for PrEP. The breakthrough therapy designation reduces hurdles facing the manufacturer in submitting the drug, and expedites review on the FDA side. The status is granted for drugs that address serious medical conditions and may provide a substantial improvement over currently available products. This is clearly the case in the PrEP arena, where Descovy (emtricitabine and tenofovir alafenamide, FTC/TAF) and Truvada (emtricitabine and tenofovir disoproxil fumarate, FTC/TDF) are currently the only approved options.
The FDA’s breakthrough designation was based on results from the HIV Prevention Trials Network (HPTN) 083 clinical trial that showed LA CAB injection to be superior to FTC/TDF for HIV prevention among men who have sex with men and transgender women who have sex with men. The application for FDA approval of Cabenuva for PrEP will be based on HPTN 083 as well as on HPTN 084, a study in sub-Saharan African women that was stopped in November 2020 on the recommendation of the data safety monitoring board after it was revealed that LA CAB injection was superior to oral FTC/TDF tablets.
The Research Behind Long-Acting Cabotegravir/Rilpivirine
The European Union authorization for LA-CAB+RPV was based on results from three clinical trials: ATLAS, ATLAS-2M, and the First Long-Acting Injectable Regimen (FLAIR) study, which among them included more than 1,200 participants from 16 countries.
ATLAS was a phase 3, open-label, multicenter, noninferiority trial including participants who had undetectable viral load for at least six months on their current ART regimen. Participants were randomly assigned either to continue their current oral regimen or to switch to monthly injections of LA CAB and LA RPV. At 48 weeks, HIV was detectable among 1.6% of those on LA injectable treatment, compared to 1.0% of those on standard oral treatment, satisfying the criterion for noninferiority. Both regimens were generally safe and well tolerated, although there were more adverse events in the LA CAB + LA RPV arm, mostly due to injection-site reactions. Nevertheless, those on LA injectable therapy were more satisfied with their treatment than those who remained on standard oral therapy and preferred their LA injectable regimen over their previous oral regimens.
ATLAS-2M was a rollover study from ATLAS in which participants from the original study who were undetectable for at least six months on either standard oral CAB + RPV or monthly injectable LA CAB + LA RPV were randomly assigned to injectable treatment either monthly or bimonthly. At 48 weeks, 2% of those on bimonthly treatment had detectable viral load, versus 1% of those on monthly dosing, satisfying the criterion for noninferiority. Safety and tolerability were similar between arms. Across all clinical trials, the most common side effects of the injectable regimen have been injection-site reactions, followed by headache, fever, nausea, fatigue, weakness, muscle aches, and dizziness.
FLAIR was a phase 3, randomized, open-label, noninferiority trial including adults living with HIV who had not previously been on ART. Participants went on treatment with Triumeq, a fixed-dose three-drug oral regimen including the INSTI dolutegravir (DTG) plus the nucleoside analog reverse transcriptase inhibitors (NRTIs) abacavir and lamivudine. After 16 weeks on Triumeq, those who had an undetectable viral load were randomly assigned (1:1) to continue on Triumeq or to switch to one month of oral CAB (Vocabria tablets) + oral RPV (Edurant) followed by monthly injections of LA CAB and LA RPV. At 48 weeks, 2.1% of those on LA injectable therapy had detectable viral load, versus 2.5% of those on oral medications, satisfying the criterion for noninferiority. As in ATLAS, there were more adverse events on injectable therapy than on oral therapy, but treatment satisfaction increased among those who switched to long-acting therapy, with 91% preferring long-acting therapy after 48 weeks.