Professor Chloe Orkin presents at HIV Glasgow 2020.
A combination of two long-acting injectable antiretrovirals taken once monthly maintained viral suppression with a very low rate of virologic failure, according to results from two phase III trials presented at the virtual Glasgow HIV conference .
Double injections of cabotegravir, ViiV Healthcare’s experimental integrase inhibitor, and the non-nucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine (currently available in pill form as Edurant ), suppressed HIV in more than 90% of treatment -naive people and in nearly all people who switched from another regimen with an undetectable viral load.
What's more, among people new to treatment, the injectable combination was effective regardless of whether study participants started injections right away or started on oral versions of the drugs for four weeks before switching to injections.
FLAIR study
Professor Chloe Orkin from Queen Mary University of London presented the latest results from the FLAIR study, which tested the injectables in people starting HIV treatment for the first time.
Study participants were initially started on a daily oral induction regimen of dolutegravir/abacavir/lamivudine ( Triumeq ) for 20 weeks to reduce virus levels. They were then randomly assigned to remain on this regimen or switch to injectable cabotegravir plus rilpivirine, starting with oral formulations of these drugs for the first month. Cabotegravir and rilpivirine were administered as two separate intramuscular injections given by a healthcare provider once monthly, with the buttocks being the preferred injection site.
As Orkin reported at the 2019 Conference on Retroviruses and Opportunistic Infections (CROI), 93.6% of those who switched to injectables had an undetectable viral load (below 50 copies/mL) at week 48, as did 93.3% of those who remained on the oral regimen. At this year’s CROI, she reported that 86.6% and 89.4%, respectively, maintained viral suppression at week 96.
At the Glasgow meeting, she presented findings from the study's extension switch phase, in which people originally assigned to stay on the oral regimen for the first 96 weeks switched to injectables, either receiving the jabs immediately (111 people) or after a lead-in of four weeks on oral cabotegravir and rilpivirine (121 people).
The rationale for oral introduction was to ensure that the drugs are well tolerated, since long-acting injectables cannot be phased out if they cause problems. However, Orkin said there were no safety concerns seen in the earlier part of the study that suggest people should start on oral medications. Other long-acting injected medications, such as psychiatric medications, do not require oral introduction, he noted.
Participants and their physicians chose their preferred option. Because they were not randomized, researchers were unable to make a formal statistical comparison between oral introduction (OLI) and direct injection (DTI) approaches.
However, the groups choosing each method were fairly comparable. In both the OLI and DTI arms, median age was similar (39 vs. 38 years), 14% were older than 50 years, and 22% were women. Body mass index (25 vs. 26) and baseline CD4 count (718 vs. 752) were also similar. Those choosing oral introduction were somewhat more likely to be white than those opting for immediate injections (78% vs. 69%), while the opposite was true for blacks (17% vs. 21%).
At week 124 of the study, or 24 weeks after switching from oral drugs, 93.4% of those in the OLI group and 99.1% of those in the DTI group had an undetectable viral load. One participant in each group (less than 1%) had no virologic response. Only one person in the DTI group met the study definition of confirmed virologic failure, and this person had no apparent integrase or NNRTI resistance mutations.
A pharmacokinetic analysis found that body concentrations of cabotegravir and rilpivirine did not differ depending on whether oral administration was used or not.
The treatment was generally safe and well tolerated. About one in five people in each group experienced drug-related adverse events, but there was only one serious event in the DTI arm (Hodgkin lymphoma, later deemed unrelated to treatment). This individual discontinued treatment, as did one person in the OLI arm because of weight gain, which has been linked to other integrase inhibitors . Orkin said details about the weight gain in the study will be reported in an upcoming journal article.
The most common side effect was injection site reactions, mainly pain. These were mostly mild and decreased in frequency over time. Only one person discontinued treatment due to injection reactions.
Long-acting cabotegravir plus rilpivirine, administered with or without an oral introduction, “was found to be a well-tolerated, safe and effective maintenance regimen,” the researchers concluded. They added that switching directly to injectables “was comparable in terms of safety and tolerability” to treatment with an oral introduction.
ATLAS Study
Professor Susan Swindells of the University of Nebraska Medical Center presented follow-up results from the ATLAS trial, which evaluated the injectable regimen in people switching from a standard oral antiretroviral combination with an undetectable viral load.
ATLAS included 616 treatment-experienced patients taking a variety of oral regimens. One-third were women, two-thirds were white, about a quarter were black, the mean age was 42 years, and the mean CD4 count was about 650 cells/ mm3 .
Participants were randomly assigned to remain on their current oral regimen or switch to injectable cabotegravir and rilpivirine administered once monthly after a four-week oral lead-in.
"The rationale for oral introduction was to ensure that the drugs are well tolerated, as long-acting injectables cannot be phased out if they cause problems."
Swindells reported 48-week results at last year's CROI, at which point 92.5% of those who switched to injectables and 95.5% of those who continued their oral regimen had an undetectable viral load.
At that point, those originally assigned to remain on their existing regimen could choose to switch to monthly injectable cabotegravir and rilpivirine, again after an oral lead-in. Another option was to transition to the ATLAS-2M study, which evaluated the injectable regimen given every other month. Most participants eventually crossed over to ATLAS-2M, leaving 52 people in the 96-week analysis of the monthly regimen.
At 96 weeks, 100% of the remaining 23 people who switched to the monthly injectable regimen at the start of the study and 96.6% of the 29 people who switched at week 52 still had HIV RNA below 50 copies/ml. Only one person in the latter group (3.2%) had virologic lack of response.
Again, the treatment was well tolerated. No one who switched to injectables early on experienced new drug-related adverse events between weeks 52 and 96. Four people who switched at week 52 had serious side effects (three injection site reactions and one case of elevated lipase). Among those who switched later, about 19% had injection site reactions. These were generally mild, but one person withdrew for this reason.
Participants continued to report a high level of satisfaction with the injectable regimen, as they did at the 48-week analysis. All those who switched at week 52 said they preferred the injectables to their previous oral regimen.
Additional analysis
Other presentations at the Glasgow meeting described the results of additional analyses of these two studies and ATLAS-2M.
At this year’s CROI, researchers presented data from ATLAS-2M showing that injectable cabotegravir and rilpivirine every two months suppressed viral load as well as monthly injections. At 48 weeks, 93.5% of those on the monthly regimen and 94.3% of those on the every-two-month regimen still had undetectable viral load.
At the Glasgow meeting, Dr Vasiliki Chounta of ViiV Healthcare reported results of an indirect analysis showing comparable efficacy and safety between people receiving the injectables every two months and those taking standard-of-care oral regimens in ATLAS, ATLAS-2M and FLAIR.
About a quarter of the participants in ATLAS-2M were women. A subgroup analysis of the 143 women who received the injectables once a month and the 137 women who received them every other month found that efficacy, safety and satisfaction were similar to these outcomes among men.
Finally, Dr. David Margolis, also from ViiV, presented an analysis of factors influencing virologic outcomes among ATLAS, ATLAS-2M, and FLAIR participants.
Four variables were associated with virologic failure: rilpivirine resistance mutations at baseline, HIV subtype A6/A1 (most commonly seen in Russia), body mass index (which can affect rilpivirine levels in the body), and rilpivirine concentration at week 8. Female sex and receiving injections every eight weeks rather than every four weeks were not risk factors.
No single factor was found to predict treatment failure, but among people with two or more factors, the virologic failure rate rose to 26%. However, the number of participants with more than one risk factor was small, and the efficacy of injectable cabotegravir and rilpivirine remained high overall.References
D'Amico R et al (presentation by Orkin C). Cabotegravir + long-acting rilpivirine as maintenance therapy: results from ATLAS week 48. HIV Glasgow 2020, abstract O414.
Swindells S et al. Cabotegravir + long-acting rilpivirine as HIV-1 maintenance therapy: results from ATLAS Week 96. HIV Glasgow 2020, abstract P006.
Chounta V et al. Comparability of efficacy and safety at 48 weeks of cabotegravir + long-acting rilpivirine every 8 weeks with standard of care in HIV-1-infected patients with suppressed therapy . HIV Glasgow 2020, abstract P011.
Benn P et al. Outcomes for women receiving long-acting cabotegravir + rilpivirine monthly and every 2 months: results from week 48 of the ATLAS-2M study. HIV Glasgow 2020, abstract P017.
Margolis D et al. A combination of viral and participant factors influences virologic outcome of long-acting cabotegravir and rilpivirine: analysis of multivariable and baseline factors in the phase III ATLAS, FLAIR, and ATLAS-2M studies . HIV Glasgow 2020, abstract O442.
At: https://www.aidsmap.com/news/oct-2020/long-acting-injectables-work-without-oral-lead-period