SEATTLE — Monthly injections of long-acting cabotegravir (ViiV Healthcare) and rilpivirine (Edurant, Janssen) can suppress HIV as well as daily oral antiretroviral treatment, according to results from the ATLAS (NCT02951052) and FLAIR (NCT02938520) trials.
These studies are a "landmark" in the treatment of HIV, said Tom Giordano, MD, from the Baylor College of Medicine in Houston, who was not involved in either study. "They demonstrate noninferiority with a totally new paradigm of treatment."
But it is not clear what role the injections — which are not yet approved by the US Food and Drug Administration — will play in ending the epidemic.
The FLAIR and ATLAS trials — both presented at the Conference on Retroviruses and Opportunistic Infections 2019 — were designed to determine whether the combination injections could suppress HIV in people new to treatment and in those already on treatment.
Two Switch Studies
In FLAIR, 629 treatment-naïve study participants started with the daily combination of dolutegravir, abacavir, and lamivudine (Triumeq, ViiV Healthcare). Those who achieved viral suppression at 20 weeks were randomized to continue with the oral regimen or to switch to injections. Participants in the switch group began with a 30-day lead-in regimen of daily oral cabotegravir 30 mg plus rilpivirine 900 mg and then switched to monthly intramuscular injections.
In ATLAS, 616 people on oral treatment with viral loads below 50 copies/mL, indicating viral suppression, were randomized to continue with their oral treatment or switch to the injections, with the same cabotegravir and rilpivirine lead-in as in FLAIR.
In FLAIR, viral suppression at 48 weeks was similar in the injection and oral groups (93.6% vs 93.3%). Six patients in the injection group discontinued therapy: two because viral loads rose above 50 copies/mL and four because of treatment failure. Seven patients in the oral group discontinued therapy: two because viral loads rose above 50 copies/mL, three because of treatment failure, and two were lost to follow-up.
ATLAS findings were remarkably similar. At 48 weeks, viral suppression was similar in the injection and oral groups (93% vs 95%), and five patients in the injection group and three in the oral group had viral loads above 50 copies/mL.
"Both studies were a big success," said Susan Swindells, MBBS, from the University of Nebraska Medical Center in Omaha, who presented the ATLAS data at the conference.
In addition, adverse events were mostly what you'd expect, she told Medscape Medical News. In both studies, there were more grade 3 or 4 adverse events in the injection group than in the oral group, largely owing to injection-site reactions. But most reactions "resolved in 7 days," she reported.
The most common adverse event not related to the injection site was headache in both studies.
"I have several patients at my site who seemed to be doing just fine on daily oral medicines but wanted to switch to monthly injections and just love it," said Swindells. "Even though they might be a bit sore from the injections for a day or two, they really don't complain much about that and just enjoy the freedom from having to take pills every day."
But there were some surprising findings. Because the studies were conducted at multiple sites in Europe, North America, and Russia, the researchers had a chance to test the treatment in people with a variety of HIV subtypes. Three participants in each trial developed treatment-resistant mutations to non-nucleoside reverse-transcriptase inhibitors (NNRTIs) and protease inhibitors. In FLAIR, the two women and one man were from Russia and had HIV subtype 1A.
An A1 Question
This is an issue that "warrants further investigation," said Chloe Orkin, MD, from Barts Health NHS Trust in London, who presented the FLAIR data.
The research team is looking at the mutagenesis of this virus but has yet to find a specific answer, she explained.
"It's notable that across the whole long-acting cabotegravir program" — in the ATLAS study, the FLAIR study, and the LATTE prevention study, which had one patient who developed treatment-resistant mutations — they were all "subtype A, A1, or AG," she reported.
"I'm sure this has piqued the interest of a lot of virologists in the audience," she said in response to murmuring from the crowd.
But both FLAIR and ATLAS are notable for who was left out, several people pointed out.
Although ATLAS drew praise because women made up 30% of the study cohort, only 22% of FLAIR participants were women. That's not good enough, said Annette Haberl, MD, from Frankfurt University in Germany.
In the CASTLE study of atazanavir and ritonavir, 30% of participants in both treatment groups were women, and that was more than 10 years ago (Lancet. 2008;372:646-655), she told Medscape Medical News.
"I'm getting tired of all these pseudo arguments that it is not feasible to include men and women equally because the percentage of women with HIV is lower in high-income countries," she said.
"Looking at the total number of participants, it should have been feasible in the ATLAS study to enroll about 300 women," said Haberl.
In addition, 78% of ATLAS participants and 74% of FLAIR participants were white. However, recent data show that only 36% of young black men in the United States were virally suppressed between 2009 and 2014 (J Acquir Immune Defic Syndr. Published online February 13, 2019), and black trans and nontrans women consistently have lower viral suppression rates and worse outcomes than their white counterparts.
This is particularly relevant because people who are in care but not virally suppressed accounted for 19.8% of HIV transmissions in 2016, according to newly released data, as reported by Medscape Medical News.
The Missing 15%
To demonstrate the noninferiority of the injections, only people who had achieved viral suppression — with long-term therapy or during the 20-week lead-in period — were enrolled in ATLAS and FLAIR.
This is "understandable" because a noninferiority study needs to show that it is noninferior to the best treatment, Giordano told Medscape Medical News. However, it is a concern because "the big hope in the field is that long-acting treatments will help those who are currently not doing well" on oral treatment because of adherence issues.
At the Thomas Street Health Center in Houston, where Giordano is medical director, the clients are primarily underinsured, uninsured, or publicly insured. The good news, like many clinics funded by the Ryan White Care Act, is that about 85% of these patients are virally suppressed, he reported.
But because Texas has not expanded Medicaid, the clinic uses the portion of its Ryan White funding that would go toward wrap-around services to support people staying in care or to provide primary care, he explained. This means that it is up to patients to make sure they stay certified for the AIDS Drug Assistance Program, which provides free medication to people living with HIV, Medicaid where they qualify, and the Ryan White program itself.
For those people, the struggle to stay in care often means that they are not taking any pills at all. This is the 15% of the HIV population that is not virally suppressed, he said, and those people were definitely not part of FLAIR or ATLAS.
He also referred to the "long tail" of cabotegravir, which has been demonstrated in prevention trials, as reported by Medscape Medical News. What happens when someone gets a shot and then misses a shot? And what happens, Giordano asked, if someone "totally stops meds because they've gone to jail for 3 months and they don't want to tell anyone that they're taking them?"
If the answer is that people have to go back on oral treatment, "that's fine," he said, "but that's what we're trying to avoid in people who have failed on orals."
What FLAIR and ATLAS were able to show is that the injection could be a good option for "people with reasonable access to care, who are motivated, who have access to the support provided in a clinical trial," and for whom "taking a daily pill is not a barrier."
"Is this a safe regimen for patients who are not undetectable on their current regimen and who may have a problem with access to care?" he asked. The answer is that we don't know.
In other words, Giordano added, these studies were not designed to determine whether the injections will "help end the HIV epidemic."
FLAIR and ATLAS were funded by ViiV Healthcare, Janssen, and GlaxoSmithKline. Giordano has disclosed no relevant financial relationships. Swindells reports that ViiV Healthcare and Merck have provided research grants to her institution. Orkin reports receiving honoraria and speaking fees from Janssen, Merck, ViiV Healthcare, and Gilead Sciences. Haberl reports receiving speakers' fees, honoraria for advisory boards, or travel grants from Gilead Sciences, Merck, and Janssen.
Conference on Retroviruses and Opportunistic Infections (CROI) 2019: Abstract OA O-10 139 and 140LB. Presented March 7, 2019.
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Cite this: Monthly Shots for HIV Within Reach - Medscape - Mar 19, 2019.