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Lenacapavir highly effective at preventing HIV in women

Researchers in South Africa and Uganda conducted a study on pre-exposure prophylaxis (PrEP) called Purpose 1 with 5,338 adolescent girls and young women, all of whom were cisgender. At the start of the study, all participants were HIV negative.

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Researchers randomly assigned participants to receive one of the following PrEP interventions:

  • lenacapavir– ultimately given by subcutaneous (just under the skin) injection every six months
  • Truvada – taken as a pill once daily
  • Descovy – taken as a pill once daily

The trial had a rigorous but complicated design—it was double blind and placebo controlled. In this case, that meant that all participants received a placebo (fake drug). So, everyone who was taking Truvada or Descovy also received injections of fake lenacapavir every six months. And those who were receiving real lenacapavir also received fake Truvada or fake Descovy (placebos) in pill form meant for daily use. Placebo pills and solution were made to look like the real drugs. Most personnel involved in the study were not aware which participants received which drugs until the trial was unblinded.

Researchers randomly assigned people to receive the study drugs in a 2:2:1 ratio (lenacapavir: Truvada: Descovy). 

Regular monitoring, visits to study clinics and consistent counselling about adherence were features of this study. Participants received condoms and lubricants, and they underwent regular screening for HIV and other sexually transmitted infections (STIs). 

Women and girls who became pregnant while in the study were given additional informed consent documents to read. If they signed the documents, they could remain in the study.

The lenacapavir regimen

Participants who were assigned to receive lenacapavir (the lenacapavir group) received two subcutaneous (just under the skin) injections in the abdomen on day 1. They also took an oral form of the drug on days 1 and 2. Participants were told to return to the study clinics within 26 to 28 weeks after their last injection. If they missed this window period and wanted to resume lenacapavir, they first had to undergo HIV testing (viral load and HIV antigen). If these tests were negative, they re-initiated oral lenacapavir for two consecutive days followed by injections.

Tenofovir-based regimens

Adherence to Truvada and Descovy was assessed in a randomly selected group of people—about 10% of participants. Researchers analysed a small amount of blood from each person for this purpose. 

Participants

At the start of the study, on average, participants were generally healthy, aged 21 (only 2% were younger than 18) and most (85%) were from South Africa. 

Results

The current analysis largely focuses on the first year of the study. In July 2024, the study was unblinded and researchers began to tell participants which active drug they received. Researchers then offered all participants the option to either initiate lenacapavir or continue to receive the drug. 

The numbers of new HIV infections were distributed as follows:

  • lenacapavir – 0 infections among 2,134 participants
  • Truvada – 39 infections among 2,136 participants
  • Descovy – 16 infections among 1,068 participants

Lenacapavir was associated with a significantly reduced risk of getting HIV. This drug also reduced the risk of HIV infection compared to tenofovir-based regimens. Most participants who became infected had low levels of tenofovir in their blood; this strongly suggests poor adherence.

According to researchers, the difference in the level of HIV risk reduction between Truvada and Descovy was not “meaningful.”

STI screening every 26 weeks uncovered high rates of chlamydia, gonorrhea and syphilis regardless of the PrEP drug used.

Remaining in the study

It is normal in all clinical trials for any condition for some people to prematurely withdraw for a variety of reasons. 

In the present study, the proportions of people who remained in the study at different time points were as follows:

  • week 26 – 97% remained
  • week 52 – 93% remained
  • week 104 – 91% remained

Retention in the study was similar regardless of the drug taken (lenacapavir, Truvada or Descovy).

Safety

The term adverse events is used to describe unfortunate events that occur in a clinical trial. Some adverse events may be caused by the study drugs, others by an underlying disease process, and still others may have nothing to do with the study (such as accidents).

A common adverse event was mild-to-moderate headache, distributed as follows:

  • lenacapavir – 13%
  • Truvada – 15%
  • Descovy – 17%

In general, adverse events were similar across the study drugs, except for nausea and vomiting, which were more common in people who received tenofovir-based regimens.

Lenacapavir 

  • nausea – 7%
  • vomiting – 6%

Truvada

  • nausea – 13%
  • vomiting – 10%

Descovy

  • nausea – 11%
  • vomiting – 11%

As mentioned, most adverse events were mild to moderate. However, some participants had more severe symptoms, distributed as follows:

  • lenacapavir – 4%
  • Truvada – 5%
  • Descovy – 4%

The proportions of people who prematurely left the study due to adverse events were as follows:

  • lenacapavir – 0.2%
  • Truvada – 0
  • Descovy – 0.1%

Injection site reactions

Injection site reactions were more common in people who received lenacapavir than in those who received a tenofovir-containing regimen (with injections of fake lenacapavir). However, these reactions in people who received lenacapavir were generally mild to moderate and diminished with repeated injections in the future. 

The distribution of injection site reactions was as follows:

  • lenacapavir – 69%
  • Truvada – 35%
  • Descovy – 35%

Many people who had injection site reactions developed lumps that the researchers called “nodules.” These nodules occurred in 64% of people who received lenacapavir and 17% of people who received placebo injections. The nodules generally shrunk over time. There was a reduced risk of nodules with subsequent doses of lenacapavir. 

Most of the injection site reactions were mild to moderate. However, four people who developed such reactions on lenacapavir prematurely left the study.  No one who received placebo injections prematurely left the study due to injection site reactions.

Abnormal lab test results

At some point in the study, researchers found that 91% of participants developed an abnormal lab test result when their blood was analyzed. However, these abnormalities were generally mild to moderate. No one appeared to experience any permanent injury from more serious lab abnormalities; such abnormalities were extremely rare.

Deaths

Six people died during the study—all were taking Descovy. Three died from violence and the remainder from complications due to the following:

  • traffic accident
  • cardiovascular disease (confirmed with autopsy)
  • ovarian cancer

None of these deaths were related to Descovy.

Pregnancy and birth defects

During the study there was a total of 510 pregnancies, distributed as follows:

  • lenacapavir – 193 people
  • Truvada – 98 people
  • Descovy – 219 people

At the time data were analysed, limited information was available on the outcome of those pregnancies, as follows:

  • 121 births 
  • 66 miscarriages
  • 90 abortions

Although lenacapavir is approved for the treatment of HIV in high-income countries, so far it has been rarely used. It is reserved for the treatment of people with multidrug-resistant HIV. As a result, doctors have little experience with it outside of clinical trials. Its effect on the fetus and during pregnancy is poorly understood.

The present study is the first to have a large data set on many women with long-term use of lenacapavir and in pregnancy. Further analysis of this data is needed.

One woman who used lenacapavir gave birth to an infant with an extra finger or toe. However, this woman had relatives who also had this condition (and they had not used lenacapavir), so investigators ruled that the extra digit was likely due to a preexisting genetic issue and not lenacapavir. 

Bear in mind

The current study in cisgender women and girls has produced exciting results. Lenacapavir taken every six months via subcutaneous injection is associated with a high degree of protection from HIV, much greater than that from daily Truvada or Descovy. According to the researchers, this difference in protection is due to “poor adherence” in people who used oral PrEP.

The researchers stated that the factors that drove poor adherence to oral PrEP may have been related to “stigma, dislike or lack of experience with daily pill-taking, and inaccurate perception of the likelihood of the acquisition of HIV infection.”

Lenacapavir given twice a year may help many women experiencing these issues.

—Sean R. Hosein

REFERENCE:

Bekker LG, Das M, Abdool Karim Q, et al. Twice-yearly lenacapavir or daily F/TAF for HIV prevention in cisgender women. New England Journal of Medicine. 2024; in press.