Bypassing the oral lead-in period for Cabenuva in a clinical trial

When clinical trials of long-acting formulations of cabotegravir and rilpivirine began in 2014, researchers first gave participants oral formulations of these drugs for at least 20 weeks. The reason for this relatively long oral lead-in was so that researchers could find out more about the tolerability of oral cabotegravir in particular. At that time, cabotegravir was a new drug; rilpivirine had been in use for eight years so much was already known about it. Since that trial in 2014, oral and long-acting formulations of cabotegravir have been tested in combination with rilpivirine in at least 1,500 people with HIV. These drugs have been found to be generally safe and effective. The combination of the long-acting formulations of these two drugs is called Cabenuva and it is approved in Canada and other high-income countries.

As a result of the experience gained with Cabenuva in recent clinical trials, the oral lead-in was shortened to just four weeks once the drug was approved.

Since Cabenuva is well tolerated and has not been associated with dangerous side effects, some scientists have questioned the need for the oral lead-in period. The manufacturer of Cabenuva, ViiV Healthcare, has embarked on clinical trials to explore the impact of bypassing the oral lead-in period entirely.

In an ongoing clinical trial called Flair, researchers sought adult volunteers who had never previously used HIV treatment (ART). They were given oral formulations of the combination of dolutegravir + abacavir + 3TC for 20 consecutive weeks. Participants who achieved a suppressed viral load (less than 50 copies/mL) were then randomly assigned to do one of the following:

  • receive intramuscular injections of cabotegravir + rilpivirine once every four weeks
  • continue to take the oral regimen

After 96 weeks, participants who were on oral therapy could either switch to injectable treatment or withdraw from the study.

People who chose to receive injectable therapy could then choose to do one of the following:

  • have an oral lead-in with cabotegravir and rilpivirine pills (taken for four weeks)
  • after discussion and agreement with a study physician, skip the oral lead-in and go directly to injection of intramuscular formulations of cabotegravir + rilpivirine every four weeks (researchers called this choice “direct-to-injection”)

The vast majority of participants (92%; 232 out of 253 people) who had been taking oral ART for at least 96 weeks chose to subsequently initiate injectable therapy; the remainder left the study.

Among these people who chose injectable therapy, their distribution was as follows:

  • 52% (121 people) chose a four-week oral lead-in
  • 48% (111 people) decided to initiate direct-to-injection long-acting formulations

Researchers found that Cabenuva was safe whether or not an oral lead-in was used.

Assessment of blood samples of people who were using injectable treatment found that levels of cabotegravir and rilpivirine were similar whether or not participants had previously used an oral lead-in.

These favourable results have encouraged regulatory authorities in the European Union to make the oral lead-in (with pills of cabotegravir + rilpivirine) optional. What that means is that initiating injectable therapy is still restricted to people who have first suppressed HIV on an oral regimen. However, in the EU, the transition from a regimen of pills containing cabotegravir and rilpivirine before starting injectable therapy with long-acting formulations of these drugs is now optional.

Important to note

It is important for readers to note that people in Flair were all initially on a regimen of pills containing the drug dolutegravir (in combination with other oral drugs). Dolutegravir is similar in shape (or structure) to cabotegravir, so it is not surprising that cabotegravir was well tolerated. It is not clear if the results from Flair would be similar if people on different oral regimens subsequently initiated direct-to-injection with long-acting formulations of cabotegravir and rilpivirine. That is, would people on these other oral regimens also have minimal side effects? Clinical trials are planned or underway to explore this issue and confirm the safety of skipping the oral lead-in with more participants.

Study details

Flair took place in the following countries:

  • Canada
  • France
  • Germany
  • Italy
  • Japan
  • The Netherlands
  • Russia
  • South Africa
  • Spain
  • U.K.
  • U.S.

The average profile of participants in Flair was as follows:

  • age – 37 years; 14% were 50 and older
  • 82% men, 12% women
  • major ethno-racial groups: White – 74%; Black – 19%
  • CD4+ count – 735 cells/mm3


As mentioned earlier, people who took oral treatment for at least 96 weeks subsequently chose one of the following courses of action:

  • 52% (121 people) chose a four-week oral lead-in followed by injections of long-acting formulations
  • 48% (111 people) decided to initiate direct-to-injection long-acting formulations

The proportions of participants with an undetectable viral load 24 weeks after entering one of the above dose regimens was as follows:

  • oral lead-in followed by injectable therapy – 93%
  • direct-to-injection – 99%

The reason that the proportion of people with viral suppression was lower in the above group with the oral lead-in was that more people left that group (and the study), so there were fewer people with data. The reasons that they left were as follows:

  • injection site pain – one person
  • excessive weight gain (8 kg) – one person

These reasons were related to the study medicine. However, five other people from the oral lead-in group also left the group and study due to other reasons, including:

  • finding travel to the study clinic burdensome
  • having to take a medicine that was not allowed in the study
  • moving residence
  • finding the study procedures difficult
  • pregnancy

Among people who began long-acting treatment earlier in the course of the study, 80% had an undetectable viral load after 126 weeks of Cabenuva. Four people out of 283 (2%) eventually had virological failure, all before week 48 of injectable treatment. Eight other people left the study because of “lack of efficacy,” but this was not further explained and is considered different from virological failure.

The reason that other people in this group did not have a detectable viral load (or any blood samples for analysis at the end of the study) was that there was no data. The reasons for the lack of data were related to premature departure from the study, mostly due to adverse events (some of which are explained later in this report) and some for reasons that were not specified and were listed as “other reasons.”

One person developed virological failure after week 48. He had HIV that was classified as subtype A6. This subtype is relatively common in countries of the former Soviet Union. As explained earlier in this issue of TreatmentUpdate, subtype A6 is associated with an increased risk of virological failure in people on Cabenuva. This person did not have resistance to cabotegravir or rilpivirine at the start of the study. At the time Cabenuva began to fail, his viral load was 887 copies/mL, and a subsequent blood test shortly after found that it went up to 1,112 copies/mL. Analysis of his blood samples when his viral load was detectable found that his HIV had acquired a very high level of resistance to cabotegravir and rilpivirine. This resistance occurred despite the man having relatively high concentrations of both drugs in his blood.

People who developed resistance to treatment while in the study were successfully transitioned to other (oral) regimens and subsequently were able to resuppress HIV.

Adverse events

Common adverse events while on injectable therapy included the following:

  • injection site pain – as in previous studies of Cabenuva, this pain was temporary, generally mild to moderate and resolved in the vast majority of people within a few days

Injection site reactions were more common among people who engaged in direct-to-injection. For instance, after the first injection, rates of injection site reactions were distributed as follows:

  • direct-to-injection – 71%
  • oral lead in – 56%

The discomfort/pain/swelling associated with injection site reactions were similar whether or not people had an oral lead-in.

Over the course of the study, participants reported reduced intensity of injection site reactions (mostly reduced pain) regardless of whether or not they had an oral lead-in.

Other adverse events

Over the course of the study, four people had elevated liver enzyme levels, three of which resolved without intervention. In the fourth person, study researchers decided to temporarily stop administering Cabenuva while his condition was investigated. Subsequently he was diagnosed with liver inflammation caused by syphilis. Treatment with penicillin resulted in his liver enzyme levels returning to normal and he then restarted Cabenuva.

Among the direct-to-injection group, only one of the participants prematurely left the study because of a serious adverse event. He developed a case of Hodgkin lymphoma. The study physician could not rule out that Cabenuva might have been related to this. The study sponsors—the pharmaceutical companies ViiV Healthcare and Janssen—dispute this. Readers should note that since 1996 when potent combination HIV treatment became available, there has never been any evidence that ART somehow causes cancer. Previous research has linked HIV itself (along with the herpes virus Epstein-Barr virus) to an increased risk for lymphomas.        

No one developed a hypersensitivity reaction to the study medicines.

For the future

Some patients and their doctors may find that skipping the oral lead-in period is convenient. Other patients and their doctors may find a four-week oral lead-in to be a reassuring step prior to initiating injectable treatment.

In the European Union, the oral lead-in is optional. Regulatory agencies in North America are reviewing data from Flair about the adverse events that occur with and without an oral lead-in and it is possible that they too will make the oral lead-in optional for some patients.

Other clinical trials assessing the impact of skipping the oral lead-in for Cabenuva are underway. Hopefully, future trials will have participants that are more diverse.

—Sean R. Hosein


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