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Long-Acting Cabotegravir -- Focus on Safety

March/April 2016

Cabotegravir is an experimental integrase inhibitor that is being tested in both immediate-release and long-acting formulation. In a study code named Éclair, researchers tested long-acting cabotegravir given by injection every 12 weeks to HIV-negative men who were at low risk for HIV infection. The purpose of Éclair was to assess the safety of the drug and to measure changes in the concentration of cabotegravir in the blood over time. Overall, the drug did not cause serious long-term side effects, though like all long-acting therapies there were temporary side effects related to pain at the site of injection. Participants expressed satisfaction with long-acting therapy and said that they would prefer to receive it rather than oral immediate-release therapy. The best frequency of dosing for cabotegravir, were it to be used as part of a package of HIV prevention efforts, is not yet clear.


Study Details

Éclair had two parts as follows:

Part 1 -- Oral

In this oral lead-in phase, either cabotegravir (30 mg once daily) or placebo was taken for four consecutive weeks.

Part 2 -- Injection

Immediately following the oral phase, long-acting (LA) cabotegravir (800 mg) or placebo was administered by injection into muscle in the buttocks by study nurses. Specifically, a 2-mL solution of LA cabotegravir was injected into each buttock every 12 weeks over a period of 36 weeks. After the third injection, participants were monitored for an additional 40 weeks. One week after receiving each series of injections, participants returned to the study clinic for blood tests and other assessments.

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The average profile of participants upon entering Éclair was as follows:

  • age -- 31 years
  • HIV-negative and healthy men
  • major ethno-racial groups -- a majority of participants were white, the next largest group was black, followed by Latino

Researchers screened 205 participants. Out of these they selected 127 who were randomly assigned in a five-to-one ratio to the following interventions:

  • cabotegravir -- 105 men
  • placebo -- 21 men


Results -- Side Effects in the Oral Phase

Most reported side effects were of mild-to-moderate intensity; however, 19% of participants on placebo and 23% on oral cabotegravir developed side effects that were of moderate-to-serious intensity. In general, the latter side effects were usually only detected with laboratory testing of blood, such as the following:

  • Elevated levels of the enzyme creatine phosphokinase. This has been reported as a rare side effect from integrase inhibitors; it may be associated with muscle weakness.
  • Lower-than-normal levels of a group of white blood cells called neutrophils. However, this finding was not associated with any infection(s).
  • A moderate degree of tiredness and unexpected lack of energy.


Results -- Side Effects in the Injection Phase

Overall, 90% of participants on placebo developed a side effect, as did 98% of participants on cabotegravir.

The proportions of participants who experienced side effects of moderate, severe or serious intensity were as follows:

  • placebo -- 48%
  • cabotegravir -- 80%

These side effects were distributed as follows:

Pain at the injection site

  • placebo -- 5%
  • cabotegravir -- 59%

Fever

  • placebo -- 0%
  • cabotegravir -- 7%

Itchy skin at the injection site

  • placebo -- 0%
  • cabotegravir -- 6%

Swelling at the injection site

  • placebo -- 0%
  • cabotegravir -- 6%

One person who received placebo left the study because he developed a blood clot in his veins. One person taking cabotegravir developed an inflamed appendix.


Focus on Pain at the Site of Injection

In total, 27% of placebo and 92% of cabotegravir injections were associated with pain. The distribution of participants with different intensities of injection-site-related pain were as follows:

Mild pain

  • placebo -- 26%
  • cabotegravir -- 45%

Moderate pain

  • placebo -- 2%
  • cabotegravir -- 37%

Severe pain

  • placebo -- 0%
  • cabotegravir -- 10%

On average, among people who received injections of placebo, pain lasted for two days. Among people who received cabotegravir injections, pain lasted for over five days.


At the Injection Site

The part of the body that receives an injection can have a temporary reaction to the substance injected. Such reactions include swelling that is soft, the formation of a small hard swelling called a nodule or bump, or bruising. Here is the distribution of some of these side effects:

Nodule/bump

  • placebo -- 0%
  • cabotegravir -- 8%

Bruising

  • placebo -- 2%
  • cabotegravir -- 6%

Most of these side effects resolved after a few days. However, people who received injections of cabotegravir and who developed a nodule/bump had them for an average of 10 days.


Concentrations of Cabotegravir

Injections of LA cabotegravir led to high concentrations of the drug in the blood of participants. After an injection, the levels of this drug would rise swiftly, reaching high levels within just one day. In theory, if LA cabotegravir was used as PrEP, such high levels should provide a great degree of protection from infection with HIV. This estimation is based on the results of experiments with monkeys and the hybrid immune deficiency virus SHIV (simian-human immunodeficiency virus). In people who received cabotegravir, these high protective levels of the drug persisted for about eight weeks, sometimes a bit longer. However, in the present study there were some people, between 15% and 31% of participants, whose levels of cabotegravir in the blood were not always at the highly protective level.

All of this means that when it comes to protecting people from HIV infection (if LA cabotegravir were to be used as PrEP), a more frequent dosing interval will be required -- perhaps every eight weeks.


HIV Infections

The Éclair study was designed to assess the safety of cabotegravir as well as how much of the drug built up in the blood (and how long it took for the drug to leave people's bodies). It was not designed to assess protection from HIV.

Two cases of HIV infection occurred during the study as follows:

One participant who was on placebo during the injection phase became HIV positive. He was referred to an infectious disease specialist for care.

The second man tested negative for HIV and its genetic material on routine blood tests done at regular intervals as part of the study. His last negative test result occurred at week 41 and analysis of his blood sample from that time found very low levels of LA cabotegravir since his last injection would have been at week 21. He disclosed to researchers that he had "unprotected sex with a casual partner between [study clinic] visits at weeks 41 and 53."

At week 53, blood tests revealed that he had elevated levels of liver enzymes, suggestive of injury to this organ. His HIV viral load was 3.8 million copies/mL. He was referred to an infectious disease specialist for care and received a regimen of darunavir (Prezista) + ritonavir (Norvir) + Truvada (tenofovir + FTC).

Antibodies to HIV were not detected until a subsequent clinic visit at week 65.

Analysis of the strain of HIV with which he was infected did not detect any mutations or changes to the virus that would have allowed it to resist integrase inhibitors, including cabotegravir, or any other anti-HIV drug.


Satisfaction

Researchers interviewed a sub-set of participants and many (74%) told researchers that they would prefer to continue to receive injections of LA cabotegravir rather than oral formulations. This level of satisfaction puts into context reports of temporary pain that can arise from injections of LA cabotegravir. However, readers should bear in mind that there was likely a degree of unintended bias in these survey results. That is, participants who chose to enter this study very likely wanted to receive injections of LA medicines rather than take oral formulations. This may explain the very high levels of satisfaction expressed toward LA cabotegravir by participants.

Éclair illustrates the complexities of clinical trials of long-acting formulations of anti-HIV drugs. There are still at least several years of clinical trials ahead before researchers will know if LA cabotegravir can provide a high degree of protection from HIV or whether, when used in combination with LA rilpivirine, it can act as part of therapy for people with HIV. Our next report explores the preliminary testing of LA formulations for HIV treatment.


Reference

Markowtiz M, Frank I, Grant, R, et al. Éclair: phase 2A safety and PK study of cabotegravir LA in HIV-uninfected men. Conference on Retroviruses and Opportunistic Infections, 22-25 February 2016, Boston, MA. Abstract 106.


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Long-Acting Therapies -- Safety and Other Issues to Consider




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