Meeting NewsPerspective

Monthly injectable HIV treatment noninferior to daily oral therapy

SEATTLE — A monthly injectable two-drug regimen of cabotegravir and rilpivirine is noninferior to a daily three-drug oral regimen for the treatment of HIV and is overwhelmingly preferred by patients, according to data from two phase 3 trials presented at CROI.

The investigational injectable regimen was developed by ViiV Healthcare and Janssen Pharmaceuticals and studied in the ATLAS and FLAIR trials “with the hypothesis being that the long-acting injectable would be equally efficacious at maintaining viral suppression as daily, oral dosing, which is the standard of care today,” said Brian Woodfall, MD, vice president and global head of late development for Janssen.

“In fact, both of the studies met their primary endpoint, showing that they were noninferior [and] the safety and tolerability was very similar between the two regimens,” Woodfall told Infectious Disease News.

FLAIR

In the FLAIR trial, ART-naive participants received induction therapy with oral dolutegravir/abacavir/lamivudine for 20 weeks — “a short induction period,” Chloe Orkin, FRCP, clinical professor at Queen Mary University of London, noted in a news conference.

At 16 weeks, those with a viral load of less than 50 copies/mL (n = 566) were randomly assigned at a 1:1 ratio to continue with the oral regimen or switch to the long-acting injectable. To assess their tolerance for the injectable regimen, participants in that arm received an oral lead-in of cabotegravir 30 mg and rilpivirine 25 mg once daily for 4 weeks.

The primary endpoint was the proportion of patients with a viral load equal to or greater than 50 copies/mL at week 48. Safety, tolerability and confirmed virologic failure were secondary endpoints, according to Orkin and colleagues. The median age of participants was 34 years, 22% were female and 74% were white.

At week 48, 2.1% of participants in the long-acting injectable arm had a viral load equal to or greater than 50 copies/mL compared with 2.5% of participants in the oral regimen arm, falling within the noninferior margin of 6%. Further, 93.6% of participants who switched to the injectable regimen achieved viral suppression compared with 93.3% who remained on the oral regimen.

Orkin and colleagues identified confirmed virologic failure in 1.4% of participants in the long-acting injectable arm — a total of four participants. Serious adverse events or adverse events leading to withdrawal were “infrequent” in both study arms, the researchers said, with the most common drug-related adverse event being injection site reaction.

“But those injection site reactions were generally mild to moderate and did not require treatment discontinuation, and generally they decreased over time,” Woodfall said.

The researchers said 99% of patients preferred the monthly injectable regimen over the daily oral treatment.

“It is a big paradigm shift in our thinking in terms of how we can offer treatment, but I think it is important to note that there are other conditions with more patients than us that use this method,” Orkin said. “It can be done, we just haven’t done it yet.”

Woodfall noted the importance of giving patients more treatment options.

“It is important that we try to have treatments that fit to a patient’s lifestyle as opposed to trying to have a patient fit their lifestyle to a treatment,” he said. “We know that is not a recipe for great success, particularly for long-term chronic illnesses.”

ATLAS

For the ATLAS trial, Susan Swindells, MBBS, professor of medicine at the University of Nebraska, and colleagues enrolled 616 participants with virologic suppression for at least 6 months and who did not have prior virologic failure on oral regimens composed of two nucleoside reverse-transcriptase inhibitors plus one integrase strand transfer inhibitor, non-nucleoside reverse-transcriptase inhibitor, or a protease inhibitor.

Participants were randomly assigned to either continue current ART or switch to the long-acting injectable. For safety monitoring purposes, those in the injectable arm received oral cabotegravir 30 mg and rilpivirine 25 mg for 4 weeks, followed by single 3-mL loading doses of cabotegravir 600 mg (200 mg/mL) and rilpivirine 900 mg (300 mg/mL) via intramuscular (IM) injection. Finally, they received monthly 2-mL IM injections of cabotegravir 400 mg and rilpivirine 600 mg every month. As in FLAIR, the primary endpoint was the proportion of patients with a viral load equal to or greater than 50 copies/mL at week 48, according to the abstract.

The median age of patients was 42 years, 33% were female and 68% were white. At week 48, Swindells and colleagues reported that 1.6% of participants who switched to the injectable had a viral load of more than 50 copies/mL compared with 1% who remained on the oral regimen, meeting the 6% noninferiority criteria. Additionally, 93% of participants in the injectable arm achieved viral suppression compared with 95% in the oral regimen arm. The researchers reported confirmed virologic failure for three participants in the injectable arm and four participants who remained on the oral regimen.

According to the abstract, 231 participants in the LA arm reported injection site pain, but only 1% withdrew because of these events. The incidence of adverse events was similar in both arms, and one death was reported among the participants who remained on the oral regimen.

In ATLAS, 98% of patients who switched to the injectable regimen preferred it compared with the daily oral treatment, according to the researchers.

“Patients liked not having to worry about taking their pills every day. All they have to do is come every month, get their injection, and they are good to go,” Swindells said during the news conference.

“There’s a number of unmet needs that a treatment like this could certainly address,” Woodfall said. “We think that there is certainly a potential for good adherence to this type of therapy.” – by Marley Ghizzone

References:

Orkin C, et al. Abstract 140LB. Presented at: Conference on Retroviruses and Opportunistic Infections; March 4-7, 2019; Seattle.

Swindells S, et al. Abstract 139. Presented at: Conference on Retroviruses and Opportunistic Infections; March 4-7, 2019; Seattle.

Disclosures: Orkin reports numerous ties to industry. Swindells reports receiving a research grant and has a grant pending from ViiV Healthcare and Merck. Woodfall is an employee of Janssen.

SEATTLE — A monthly injectable two-drug regimen of cabotegravir and rilpivirine is noninferior to a daily three-drug oral regimen for the treatment of HIV and is overwhelmingly preferred by patients, according to data from two phase 3 trials presented at CROI.

The investigational injectable regimen was developed by ViiV Healthcare and Janssen Pharmaceuticals and studied in the ATLAS and FLAIR trials “with the hypothesis being that the long-acting injectable would be equally efficacious at maintaining viral suppression as daily, oral dosing, which is the standard of care today,” said Brian Woodfall, MD, vice president and global head of late development for Janssen.

“In fact, both of the studies met their primary endpoint, showing that they were noninferior [and] the safety and tolerability was very similar between the two regimens,” Woodfall told Infectious Disease News.

FLAIR

In the FLAIR trial, ART-naive participants received induction therapy with oral dolutegravir/abacavir/lamivudine for 20 weeks — “a short induction period,” Chloe Orkin, FRCP, clinical professor at Queen Mary University of London, noted in a news conference.

At 16 weeks, those with a viral load of less than 50 copies/mL (n = 566) were randomly assigned at a 1:1 ratio to continue with the oral regimen or switch to the long-acting injectable. To assess their tolerance for the injectable regimen, participants in that arm received an oral lead-in of cabotegravir 30 mg and rilpivirine 25 mg once daily for 4 weeks.

The primary endpoint was the proportion of patients with a viral load equal to or greater than 50 copies/mL at week 48. Safety, tolerability and confirmed virologic failure were secondary endpoints, according to Orkin and colleagues. The median age of participants was 34 years, 22% were female and 74% were white.

At week 48, 2.1% of participants in the long-acting injectable arm had a viral load equal to or greater than 50 copies/mL compared with 2.5% of participants in the oral regimen arm, falling within the noninferior margin of 6%. Further, 93.6% of participants who switched to the injectable regimen achieved viral suppression compared with 93.3% who remained on the oral regimen.

Orkin and colleagues identified confirmed virologic failure in 1.4% of participants in the long-acting injectable arm — a total of four participants. Serious adverse events or adverse events leading to withdrawal were “infrequent” in both study arms, the researchers said, with the most common drug-related adverse event being injection site reaction.

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“But those injection site reactions were generally mild to moderate and did not require treatment discontinuation, and generally they decreased over time,” Woodfall said.

The researchers said 99% of patients preferred the monthly injectable regimen over the daily oral treatment.

“It is a big paradigm shift in our thinking in terms of how we can offer treatment, but I think it is important to note that there are other conditions with more patients than us that use this method,” Orkin said. “It can be done, we just haven’t done it yet.”

Woodfall noted the importance of giving patients more treatment options.

“It is important that we try to have treatments that fit to a patient’s lifestyle as opposed to trying to have a patient fit their lifestyle to a treatment,” he said. “We know that is not a recipe for great success, particularly for long-term chronic illnesses.”

ATLAS

For the ATLAS trial, Susan Swindells, MBBS, professor of medicine at the University of Nebraska, and colleagues enrolled 616 participants with virologic suppression for at least 6 months and who did not have prior virologic failure on oral regimens composed of two nucleoside reverse-transcriptase inhibitors plus one integrase strand transfer inhibitor, non-nucleoside reverse-transcriptase inhibitor, or a protease inhibitor.

Participants were randomly assigned to either continue current ART or switch to the long-acting injectable. For safety monitoring purposes, those in the injectable arm received oral cabotegravir 30 mg and rilpivirine 25 mg for 4 weeks, followed by single 3-mL loading doses of cabotegravir 600 mg (200 mg/mL) and rilpivirine 900 mg (300 mg/mL) via intramuscular (IM) injection. Finally, they received monthly 2-mL IM injections of cabotegravir 400 mg and rilpivirine 600 mg every month. As in FLAIR, the primary endpoint was the proportion of patients with a viral load equal to or greater than 50 copies/mL at week 48, according to the abstract.

The median age of patients was 42 years, 33% were female and 68% were white. At week 48, Swindells and colleagues reported that 1.6% of participants who switched to the injectable had a viral load of more than 50 copies/mL compared with 1% who remained on the oral regimen, meeting the 6% noninferiority criteria. Additionally, 93% of participants in the injectable arm achieved viral suppression compared with 95% in the oral regimen arm. The researchers reported confirmed virologic failure for three participants in the injectable arm and four participants who remained on the oral regimen.

PAGE BREAK

According to the abstract, 231 participants in the LA arm reported injection site pain, but only 1% withdrew because of these events. The incidence of adverse events was similar in both arms, and one death was reported among the participants who remained on the oral regimen.

In ATLAS, 98% of patients who switched to the injectable regimen preferred it compared with the daily oral treatment, according to the researchers.

“Patients liked not having to worry about taking their pills every day. All they have to do is come every month, get their injection, and they are good to go,” Swindells said during the news conference.

“There’s a number of unmet needs that a treatment like this could certainly address,” Woodfall said. “We think that there is certainly a potential for good adherence to this type of therapy.” – by Marley Ghizzone

References:

Orkin C, et al. Abstract 140LB. Presented at: Conference on Retroviruses and Opportunistic Infections; March 4-7, 2019; Seattle.

Swindells S, et al. Abstract 139. Presented at: Conference on Retroviruses and Opportunistic Infections; March 4-7, 2019; Seattle.

Disclosures: Orkin reports numerous ties to industry. Swindells reports receiving a research grant and has a grant pending from ViiV Healthcare and Merck. Woodfall is an employee of Janssen.

    Perspective
    Elizabeth Connick

    Elizabeth Connick

    These landmark studies of long-acting depot antiretroviral drugs represent the next generation of HIV therapies. For contraception, depot injections are more effective than oral medications due to enhanced adherence. Although there was no improvement in antiviral suppression in the IM cabotegravir/rilpivirine arms compared with conventional ART in these studies, levels of virologic suppression overall were close to 100% and substantially higher than what is seen in the community. It is essential to test this approach in real-world populations to determine if it improves clinical outcomes. A major concern with depot antiretroviral drug injections is the prolonged pharmacologic “tail” that occurs when individuals stop receiving injections. To prevent development of drug resistant virus, it is essential to replace t ART with an oral regimen while the depot drug decays. The consequence of nonadherence in this scenario is much more serious than for conventional ART and will present new challenges for adherence interventions. Further work on long-acting strategies is currently underway, including determining ways to extend the duration of drug delivery, as well as implantable drug-releasing devices that can be removed in the event of side effects and reduce the risk of the pharmacologic tail. Although monthly IM injections are not necessarily the best antiviral option for many individuals today, as further optimization of long-acting approaches occurs, they ultimately could become a preferred method of treatment and substantially contribute to elimination of the HIV epidemic.

    • Elizabeth Connick, MD
    • Professor of medicine
      Chief, division of infectious diseases
      University of Arizona College of Medicine – Tucson
      Member, Women’s Research Initiative on HIV/AIDS
      Infectious Disease News Editorial Board member

    Disclosures: Connick reports no relevant financial disclosures.

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