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

A clinical trial called HPTN 084 took place with cisgender women at high risk of HIV. These women were recruited from countries in Sub-Saharan Africa. This study had a similar design to the trial in men and transgender women (HPTN 083) discussed in the previous article.

In HPTN 084, participants were adults who were assigned female at birth (cisgender women). Participants were randomly assigned to receive either oral cabotegravir or oral tenofovir DF + FTC (sold as Truvada and available in generic forms; hereafter abbreviated to TDF + FTC). All pills were taken daily.

Cabotegravir was initially dispensed one pill (30 mg) taken daily for five consecutive weeks. After this time, participants were switched to the liquid long-acting formulation of cabotegravir (LA cab). This formulation was injected by healthcare personnel deep into the buttocks once monthly for two consecutive months (to raise and maintain high levels of cabotegravir in the blood). After this period, injections occurred every two months.

To add to the complexity of the study, participants did not know if they received cabotegravir or TDF + FTC, as participants who received cabotegravir injections were given fake TDF + FTC pills and participants who received TDF + FTC were given injections of fake LA cab.

Researchers enrolled 3,224 women—1,614 were assigned to receive cabotegravir and 1,610 were assigned to receive TDF + FTC.

Participants were an average of 25 years old when they enrolled in the study and were in the following seven countries:

  • Botswana
  • Eswatini
  • Kenya
  • Malawi
  • South Africa
  • Uganda
  • Zimbabwe

Results

A total of 40 new cases of HIV infection were detected during the study and distributed as follows:

  • cabotegravir – four women
  • TDF + FTC – 36 women

According to the study researchers, their findings showed that “although both [interventions] for HIV prevention were generally safe, well-tolerated, and effective, cabotegravir was superior to TDF+FTC in preventing HIV infection in women.

Focus on infections – cabotegravir

According to the researchers, two of the four women in the cabotegravir group who developed HIV infection “did not receive any cabotegravir injections.” What’s more, when researchers analysed blood samples from these participants, they did not have any detectable cabotegravir at the time their HIV was first detected.

In the third woman, HIV infection was first detected when she began cabotegravir injections. However, HIV was subsequently found in her blood samples that were taken around the time she enrolled in the study. It is possible that she had been infected a few days before enrolling in the study. In such cases, HIV testing at that time would not have detected the infection.

The fourth woman’s HIV infection occurred during the period when she had switched to cabotegravir injections. However, clinic records indicated that her injections were not given on time and that the amount of cabotegravir in her blood was below a protective level.

None of these four women had HIV that had significant resistance to integrase inhibitors, the class of drugs to which cabotegravir belongs. Other integrase inhibitors that are commonly used as part of HIV treatment include the following:

  • bictegravir (in a pill called Biktarvy)
  • dolutegravir (in a pill called Tivicay and co-formulated with other HIV drugs and sold under the brand names Dovato, Juluca and Triumeq)
  • raltegravir

Focus on infections – TDF + FTC

All 36 infections in women assigned to receive TDF + FTC occurred after participants entered the study. According to researchers, “none of these cases had [levels of TDF] consistent with six to seven doses/per week.” In other words, participants who developed HIV infection were not taking TDF + FTC as directed.

One participant who developed HIV infection had a history of poor adherence to TDF + FTC. She had HIV that was resistant to FTC and 3TC.

Adverse events

The term adverse events is used to describe unfortunate events that occur in clinical trials. 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.

In general, researchers found that the rate of moderate or more severe adverse events were similar whether participants received cabotegravir or TDF + FTC.

The researchers stated that “most” of the severe adverse events were due to temporarily abnormal lab test results and that these were “seldom clinically significant.”

Adverse events led to a very small proportion of participants leaving the study prematurely:

  • cabotegravir – 1.1%
  • TDF + FTC – 1.4%

Selected adverse events that were graded at least of moderate intensity included the following:

Nausea and/or diarrhea

  • cabotegravir – 21%
  • TDF + FTC – 23%

Abnormal uterine bleeding

  • cabotegravir – 19%
  • TDF + FTC – 19%

Headache

  • cabotegravir – 17%
  • TDF + FTC – 17%

Focus on injection site reactions

Injection site reactions were more commonly reported in women who received LA cab (38%) than in women who received TDF + FTC (11%). Recall that participants who received TDF + FTC also received injections of fake (placebo) LA cab.

Injection site reactions that were moderate or of greater severity occurred in 13% of women who received LA cab and 2% of women who received TDF + FTC.

Pain was the most common injection site reaction.

According to researchers, “most injection site reactions were reported at the first injection and diminished over time.” For instance, among women who received LA cab injections, 29% reported injection site reactions at their first injection. However, by the fourth injection, only 2% of participants reported such reactions. Other clinical trials have reported a decreased risk of injection site reactions with LA cab over time. None of the participants left the study because of injection site reactions.

Focus on pregnancy

At the start of the study, all participants were taking long-acting contraceptives. Despite this, there were 49 confirmed pregnancies during the study, distributed as follows:

  • cabotegravir – 29 pregnancies
  • TDF + FTC – 20 pregnancies

At the time the data were analysed, researchers had data on the results of 31 out of 49 pregnancies (the remaining women had not yet given birth). According to the researchers, “most pregnancies resulted in a live birth,” distributed as follows:

  • cabotegravir – 13 out of 18 pregnancies were live births
  • TDF + FTC – 10 out of 13 pregnancies were live births

According to researchers, the remaining women on whom they had data experienced miscarriages or terminated their pregnancies.

None of the infants were born with birth defects.

Serious side effects and deaths

The vast majority of adverse events were not graded as serious. Indeed, researchers only considered six adverse events to be serious, as follows:

  • cabotegravir – two women had serious adverse events; one was hospitalized for “fetal distress” and another for a “respiratory tract infection”
  • TDF + FTC – four women had serious adverse events; one had liver toxicity, two had liver injury and one had a seizure

There was a total of three deaths; all occurred in women assigned to receive cabotegravir. However, researchers judged that none of these deaths were caused by use of cabotegravir. Rather, according to the researchers, the deaths were due to high blood pressure and heart disease (one woman), a stroke (one woman), and “an unexplained headache that could not be further investigated.”

Focus on weight gain

On average, studies report that adults in the general public are gaining weight over time. Studies in people with HIV who are taking treatment indicate that some participants gain weight.

In the present study, researchers found that participants initially gained a small amount of weight (less than half a kilogram) but subsequently gained about 2 kg per year—2.4 kg in people who took cabotegravir and 2.1 kg in people who took TDF + FTC.

Note that a proportion of participants experienced what the researchers called “abnormal weight loss,” distributed as follows:

  • cabotegravir – 5%
  • TDF + FTC – 7%

For most participants experiencing this issue, the weight loss was of moderate intensity. However, a small proportion of women experienced more intense weight loss, distributed as follows:

  • cabotegravir – 1%
  • TDF + FTC – 2%

Bear in mind

Overall, the researchers found that LA cab provided “an adherence advantage over daily oral pill-taking. An injection every eight weeks is convenient and discreet, and might overcome the difficulties with pill-swallowing, HIV stigma, intimate partner violence, and discrimination.”

—Sean R. Hosein

REFERENCE:

Delany-Moretlwe S, Hughes JP, et al. Cabotegravir for the prevention of HIV-1 in women: results from HPTN 084, a phase 3, randomised clinical trial. Lancet. 2022 May 7;399(10337):1779-1789.