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Long-Acting Cabotegravir + Rilpivirine for Induction Then Maintenance Therapy

March/April 2016

As mentioned earlier in this issue of TreatmentUpdate, a long-acting formulation of the experimental integrase inhibitor cabotegravir is under development for pre-exposure prophylaxis (PrEP).

When long-acting cabotegravir is used together with another long-acting anti-HIV drug -- rilpivirine (a non-nuke) -- it is possible that this combination may be useful as a form of treatment. This works by first reducing and keeping a patient's viral load at the 50-copy/mL mark with a combination that includes oral formulations of cabotegravir and rilpivirine. Doctors can then consider switching the patient's treatment to a dual regimen of the long-acting (LA) agents alone. Note that long-acting agents must be injected deep into muscle (usually in the buttocks), where they are slowly released into circulation over a period of weeks.

In a study called Latte-2, researchers tested the safety and effectiveness of LA formulations of cabotegravir and rilpivirine. They found that the formulations work with high rates of virological success. The final regimen that will be chosen for phase III clinical trials -- injections every four or eight weeks -- is not yet clear.


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Study Details

Latte-2 had two parts, as follows:

Part 1

Participants received oral immediate-release cabotegravir at a dose of 30 mg once daily together with two other oral immediate-release anti-HIV drugs, abacavir + 3TC (both drugs are sold in one pill called Kivexa or Epzicom), also once daily. This oral regimen was taken for 20 consecutive weeks. In the final four weeks of this phase of the study, researchers added oral immediate-release rilpivirine, 25 mg once daily, to the regimens of participants.


Part 2

Participants were randomly assigned to one of three regimens, two of which featured long-acting formulations administered by injection. This phase of the study lasted for up to 96 weeks. The three regimens are as follows:

  • cabotegravir 400 mg + rilpivirine 600 mg, both drugs given by injection every four weeks -- 115 people
  • cabotegravir 600 mg + rilpivirine 900 mg, both drugs given by injection every eight weeks -- 115 people
  • continued oral drugs -- 56 people

The average profile of participants upon entering the study was as follows:

  • age -- 35 years
  • 92% men, 8% women
  • viral load -- 25,000 copies/mL
  • 18% of participants had a viral load of at least 100,000 copies/mL
  • CD4+ cell count -- 490 cells/mm3


Results

During the initial phase of the study about 95% of participants had a viral load less than 50 copies/mL

At the 32nd week of long-acting therapy, the following proportions of participants had a viral load less than 50 copies/mL:

  • long-acting therapy injected every four weeks -- 94% had a viral load less than 50 copies/mL
  • long-acting therapy injected every eight weeks -- 95% had a viral load less than 50 copies/mL
  • oral cabotegravir-based regimen -- 91% had a viral load less than 50 copies per mL


Discontinuations

Here is the distribution of the proportion of participants who left the study prematurely because of adverse events:

  • long-acting therapy injected every four weeks -- 3%
  • long-acting therapy injected every eight weeks -- 0%
  • oral regimen -- 2%

Adverse events responsible for these premature departures from the study were as follows:

  • HCV infection
  • rash
  • depression
  • psychosis


Focus on Side Effects

Side effects not related to injection site reactions were not common and were distributed by regimen as follows:

Fever

  • long-acting therapy injected every four weeks -- 4%
  • long-acting therapy injected every eight weeks -- 3%
  • oral regimen -- 0%

Unexpected lack of energy

  • long-acting therapy injected every four weeks -- 3%
  • long-acting therapy injected every eight weeks -- 2%
  • oral regimen -- 2%

Flu-like illness

  • long-acting therapy injected every four weeks -- 2%
  • long-acting therapy injected every eight weeks -- 3%
  • oral regimen -- 0%


Focus on Injection Site Reactions

Overall, the most common injection site reactions were pain (67%), swelling (7%) and nodules (6%).

Here is the distribution of the severity of injection site reactions:

Mild injection site reactions

  • long-acting therapy injected every four weeks -- 83%
  • long-acting therapy injected every eight weeks -- 80%

Moderate injection site reactions

  • long-acting therapy injected every four weeks -- 16%
  • long-acting therapy injected every eight weeks -- 18%

Severe injection site reactions

  • long-acting therapy injected every four weeks -- less than 1%
  • long-acting therapy injected every eight weeks -- 1%

In most cases (90%) these reactions subsided or resolved in one week or less.


Satisfaction

When asked about their preferences for type of therapy (immediate release or long acting), most participants (more than 96%) were highly satisfied with a long-acting regimen and 98% told researchers that they would like to continue on it.


Drug Levels

Analyses of blood samples showed that cabotegravir levels were elevated though not always as high as what was seen with the oral 30 mg/day dosing schedule.

Rilpivirine levels were lower than expected but gradually increased to what would have been seen if the drug had been taken orally.

Researchers are collecting further data and will later decide which dose of both long-acting medicines to use in phase III studies.

Bear in mind that much research lies ahead and even if all goes well in phase III trials, long-acting therapies are not likely to be approved in Canada for HIV treatment until at least 2019.


Reference

Margolis DA, González-Garcia J, Stellbrink H-J, et al. Cabotegravir + rilpivirine as long-acting maintenance therapy: LATTE-2 week 32 results. Conference on Retroviruses and Opportunistic Infections, 22-25 February 2016, Boston, MA. Abstract 31LB.


Related Stories

Long-Acting Cabotegravir -- Focus on Safety



This article was provided by Canadian AIDS Treatment Information Exchange. It is a part of the publication TreatmentUpdate. Visit CATIE's Web site to find out more about their activities, publications and services.
 

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