Safety and effectiveness of long-acting cabotegravir for prevention in men and transgender women

Clinical trials have found that long-acting cabotegravir (LA cab) is highly effective at reducing the risk of getting HIV. Furthermore, at least one randomized double-blind clinical trial (code-named HPTN 083) found that LA cab was statistically superior to daily oral tablets of tenofovir DF + FTC (sold as Truvada and available in generic formulations; hereafter abbreviated to TDF + FTC) at preventing HIV infection. About a year and a half into HPTN 083, this trial was unblinded, as statistical analysis found that LA cab was highly effective. When this trial was unblinded, participants were told which drug(s) they were receiving. At that point, participants could choose to receive either prevention option. In the report below, we detail findings from the unblinded part of the study. Examining results from the unblinded phase is important because this phase is more likely to resemble what will occur in clinics where participants will know which drug they are getting.

A total of 3,290 participants were in the unblinded phase of the study. During this phase, researchers found that the use of LA cab continued to provide a lower risk of HIV infection compared to daily oral TDF + FTC. Specifically, participants who received LA cab had about a twofold lower risk of getting HIV.

However, researchers unexpectedly found that some participants were less adherent to the study interventions in the unblinded phase of the study. In the case of LA cab (which is injected by a healthcare provider deep into the muscles of the buttocks), there were delays in some participants visiting study clinics for their injections, which are ultimately given every two months.

About the LA cab study – unblinded phase

In the present study, cabotegravir was initially given at a dose of one pill (containing 30 mg) taken orally for five consecutive weeks. If participants tolerated this and took the pills as directed, they could then switch to injectable LA cab (600 mg in 3 mL of liquid). Initially, LA cab was given as a single injection every four weeks for two consecutive months, and then every eight weeks thereafter.

Participants who were supposed to get injections every eight weeks but missed clinic visits (that is, they did not go to the clinic every eight weeks as scheduled) were temporarily switched to receive injections every four weeks for two consecutive months, after which time they could resume clinic visits for their injections every eight weeks. The reason for this schedule of injections is that levels of cabotegravir in the blood need to be relatively high and then maintained to suppress HIV should participants be exposed to the virus. Late appointments for injections result in less-than-desirable cabotegravir levels, so more frequent injections (every four weeks) were temporarily needed.

At those clinic visits, participants gave blood samples, some of which underwent HIV testing and other assessments. Other blood samples were stored for later testing and analysis (for example, measuring levels of cabotegravir).

If a test result was positive for HIV at the clinic, the blood sample was sent to a central laboratory for further analysis and measurement of cabotegravir levels (or, if they were on TDF + FTC, for TDF levels).

In the unblinded phase of the study, data from 1,663 people taking LA cab and 1,627 taking TDF + FTC were analysed. Participants were in the unblinded phase for almost one year.

A total of 87% of participants identified as gay, bisexual or other men who have sex with men (gbMSM). Most of the remaining people identified as transgender women who had sex with men. Four people did not disclose their sexual identity. The average age of participants was 26 years old.

Trial HPTN 083 took place in the following countries:

• Argentina
• Brazil
• Peru
• South Africa
• Thailand
• U.S.
• Vietnam

Results – HIV infections

During the unblinded phase of the study, HIV infections were distributed as follows:

• LA cab – 12 new infections
• TDF + FTC – 32 new infections

When researchers combined data from both the blinded and unblinded phases, the distribution of infections was as follows:

• LA cab – 25 new infections
• TDF + FTC – 73 new infections

During the unblinded phase, some infections occurred under the following circumstances in people taking LA cab:

• one person received their injections on time and had expected levels of cabotegravir in their blood for most periods
• one person received their injections on time but their levels of cabotegravir unexpectedly fell rapidly between injections; researchers did not find any drug interactions or problems with injections and were puzzled by their findings
• three people had at least one delay of more than 10 weeks between injections
• other HIV infections occurred in people more than six months after the last LA cab injection

As a result of infections occurring during the study, some participants developed HIV with a degree of resistance to integrase inhibitors—the class of drugs to which cabotegravir belongs.

As mentioned above, in the unblinded phase of the study, two people developed HIV infection despite getting injections of LA cab on time. In the blinded phase of the study, four other people developed HIV infection despite getting injections on time. Researchers noted that this occurred in six out of 2,282 people who were taking LA cab in the blinded and unblinded phases of the study, which represents 0.26% of participants. These six people were subsequently treated with a combination of drugs, including NNRTIs (non-nucleoside reverse transcriptase inhibitors) or protease inhibitors and nucleoside analogues. They were all able to achieve undetectable viral load levels.

These six people developed HIV that was at least somewhat resistant to integrase inhibitors because of exposure to cabotegravir. Researchers do not know if these people would have been able to suppress HIV if their treatment included the leading integrase inhibitors bictegravir (in Biktarvy) or dolutegravir (in Dovato, Juluca and Triumeq).

Adverse events

The term adverse events is used in clinical trials to describe all unfortunate events that occur. Some of these events are caused by the study intervention (in this case drugs). Others can be caused by an underlying illness or infection. Some adverse events may be caused by other issues unrelated to the study drug. Below are some selected adverse events experienced by participants in the present study and their distribution:

Increased blood pressure

• LA cab – 19 people
• TDF + FTC – two people

Increased cholesterol levels

• LA cab – 33 people
• TDF + FTC – 14 people

Increased levels of so-called bad cholesterol (LDL-C)

• LA cab – 41 people
• TDF + FTC – 23 people

Weight gain

• LA cab – 0.84 kg per year
• TDF + FTC – 0.80 kg per year

The above differences in weight gain between people taking different drugs were minor and not statistically significant.

Among people taking LA cab, 23% had injection site reactions (these tend to become less common over time). None of the people with such reactions quit the study.

Bear in mind

The increased cases of high blood pressure among LA cab users were unexpected and require further study. It is possible that such an increase occurred because cabotegravir belongs to a class of drugs called integrase inhibitors. In some people taking these drugs, there have been reports of an increased risk for high blood pressure, abnormal blood sugar levels and increased cardiovascular disease risk. However, bear in mind that only 19 of the 1,627 people who took LA cab in the unblinded phase developed high blood pressure; this represents about 2% of participants on the drug, which is low. This finding is encouraging. However, as LA cab gets used by more people in the future, some of whom may be older and may have pre-existing cardiovascular disease, doctors and nurses will need to monitor participants for this and other related issues.

Infections among daily oral PrEP users

According to the researchers, when adherence to daily TDF + FTC is high, new cases of HIV infections are rare. In the present study, the researchers stated that “almost all of the infections observed in the daily oral PrEP group…occurred in participants with poor adherence or no evidence of drug dosing [based on analysis of their blood samples].” These participants were subsequently offered treatment and were able to suppress HIV.

—Sean R. Hosein

REFERENCES:

1. Landovitz RJ, Hanscom BS, Clement ME, et al. Efficacy and safety of long-acting cabotegravir compared with daily oral tenofovir disoproxil fumarate plus emtricitabine to prevent HIV infection in cisgender men and transgender women who have sex with men 1 year after study unblinding: a secondary analysis of the phase 2b and 3 HPTN 083 randomised controlled trial. Lancet HIV. 2023 Dec;10(12):e767-e778. 
2. Landovitz RJ, Donnell D, Clement ME, et al Cabotegravir for HIV Prevention in Cisgender Men and Transgender Women. New England Journal of Medicine. 2021 Aug 12;385(7):595-608.