- Lenacapavir injections have shown strong efficacy preventing HIV among cisgender women
- A new clinical trial included men who have sex with men, trans women and nonbinary people
- Fewer infections were seen among those who received the injection than those on oral PrEP
The drug lenacapavir is being studied for its ability to reduce the risk of HIV infection in different populations. It has already proven to be highly effective in a clinical trial with cisgender women and adolescent girls.
Researchers have recently published details from a randomized, double-blind, placebo-controlled trial of lenacapavir in 3,271 participants, the vast majority of whom were cisgender men who identified as gay, bisexual or other men who have sex with men (gbMSM). The prevention effects of lenacapavir every six months via injection were compared to those of daily oral Truvada. Use of lenacapavir was associated with a statistically significant reduction in the risk of HIV.
Study details
The study took place in the following countries:
- Argentina
- Brazil
- Mexico
- Peru
- South Africa
- Thailand
All participants were first screened for HIV with various assays (HIV antigen, antibody and, if positive, HIV RNA) and tested negative prior to the start of the study. They were also tested for HIV at regular intervals during the study.
Participants were then randomly assigned in a 2-to-1 ratio to receive either lenacapavir (one injection every six months) or oral daily Truvada, which is a pill containing the drugs FTC + TDF (tenofovir DF). The trial had a complicated design, with participants also receiving doses of fake drugs (placebos).
The distribution of participants and study drugs was as follows:
Lenacapavir
- 2,183 people – two subcutaneous (just under the skin) injections of lenacapavir in the abdomen on the first day of the study; on days 1 and 2, they also received two 300-mg tablets of lenacapavir to take orally. After this, no further oral formulations of lenacapavir were necessary unless they missed future injection appointments (every six months). This combination of injectable and oral lenacapavir is necessary to raise the dose of the drug to high (protective) levels quickly.
Participants who received lenacapavir also received pills designed to look like Truvada (these pills did not contain active drug; they were placebo).
Truvada
- 1,088 people – daily oral Truvada, which has been found to be highly effective when used as directed in previous clinical trials. Participants took two pills of Truvada on day 1, followed by one pill daily.
Participants who received Truvada also received injections containing fake lenacapavir and two additional tablets of fake lenacapavir, which acted as placebos.
All participants were regularly screened for HIV and common sexually transmitted infections and had fluid samples (blood and urine) analyzed for drug levels and potential toxicity.
The placebo-controlled part of the study lasted for one year. After this time, the trial was unblinded and study personnel told participants which drug they had been receiving. All participants who were HIV negative were then eligible to receive lenacapavir as prevention.
The average profile of participants upon study entry was as follows:
- age – 28 years (ranging from 17 to 74 years; nearly one-third were aged 16 to 25)
- gender identities: cisgender men – 78%; transgender women – 14%; gender nonbinary – 6%; transgender men – 1%
- sexual orientations: gay/bisexual – 90%; heterosexual – 7%; other – 3%
- major ethno-racial groups: Black – 37%; White – 33%; Indigenous – 16%; Asian – 12%
- 27% of participants had not been tested for HIV prior to the study
- among people who had been tested for HIV, their last test was an average of seven months prior to the study
- nearly one-quarter of participants had previously used HIV pre-exposure prophylaxis (PrEP)
- among people who had used PrEP, their last dose was about one year prior to the study
- 12% of participants used gender-affirming hormones
Results
A total of 11 new HIV infections occurred during the study, distributed as follows:
- lenacapavir – 2 people
- Truvada – 9 people
This difference was statistically significant; that is, not likely due to chance alone.
Focus on HIV and lenacapavir
Researchers analyzed blood samples from participants who became HIV positive during the study. In the two people who were taking lenacapavir, technicians found that the concentration of lenacapavir was in the expected range.
One participant was a transgender woman who was diagnosed with HIV at week 13 of the study. Her viral load was more than 900,000 copies/mL. The other participant was a cisgender gay man who was diagnosed with HIV at week 26 of the study. His viral load was just over 14,000 copies/mL.
Neither participant reported symptoms of HIV infection. Their infection was uncovered by testing, which underscores the importance of regular HIV screening after lenacapavir has been approved for prevention and is being used in the community.
Both participants had HIV that was resistant to lenacapavir.
Focus on HIV and Truvada
According to the researchers, “all nine participants who [received Truvada] who received a diagnosis of HIV infection had evidence of low or no adherence or had discontinued [Truvada] more than 10 days before diagnosis.”
Researchers were able to analyze levels of tenofovir (TDF, a component of Truvada) to infer adherence in eight people who became HIV positive. Two of the eight had low levels of tenofovir and the remaining six had undetectable levels of the drug. One participant had HIV that was resistant to FTC, the other component of Truvada.
Overall safety
In general, the study medicines were well tolerated. Rates of adverse events commonly reported in clinical trials of HIV medicines—diarrhea, headache, nausea—were relatively low and were distributed as follows:
Diarrhea
- lenacapavir – 7%
- Truvada – 7%
Headache
- lenacapavir – 6%
- Truvada – 7%
Nausea
- lenacapavir – 4%
- Truvada – 6%
These side effects were mild or moderate in severity and were generally temporary.
A very small proportion of participants left the study prematurely because of severe adverse effects, distributed as follows:
- lenacapavir – 0.3%
- Truvada – 0.6 %
Injection site reactions
Injection site reactions were the most common side effect, distributed as follows:
- lenacapavir – 83%
- Truvada – 70%
Most injection site reactions—temporary redness, pain and swelling—were mild or moderate. Roughly similar proportions of participants reported pain at the injection site (about 54%), whether they received lenacapavir or placebo injections.
More people who received lenacapavir (63%) than Truvada (39%) developed small bumps or nodules just under the skin at the injection site. According to the research team, these nodules have lenacapavir in them and they gradually resolve as the lenacapavir is released and enters circulation. The nodules from lenacapavir injections lasted an average of six months and varied in size. Larger nodules were on average about three centimetres in diameter. In other clinical trials with people with HIV where lenacapavir was used as part of combination treatment, scientists have reported that, in some cases, nodules contained an accumulation of cells of the immune system. This was not reported in the current trial, which enrolled HIV-negative people.
Among people who received Truvada and placebo injections, 39% developed nodules. These lasted on average just over two months. The larger nodules tended to be about two centimetres in diameter.
Researchers did not notice any scar formation among people who developed nodules, whether they received lenacapavir or placebo injections.
Over time, injection site reactions (including pain and the formation of nodules) became less common and less severe. This occurred whether participants received lenacapavir or injections of placebo.
A few people developed ulcers just under the skin where injections occurred. These likely developed because fluid was not injected sufficiently deep into the skin.
The proportion of participants who left the study because of bothersome injection site reactions was distributed as follows:
- lenacapavir – 1.2%
- Truvada – 0.3%
The researchers advanced the following possible reasons for the reduction in injection site reactions over the course of the study:
- Nurses became more skilled over time at injecting lenacapavir (and placebo), and participants received improved pre-injection counselling detailing what to expect.
- The use of ice or cold compresses placed on the injection site before and after injections was introduced during the study.
- “Participants may have become more accustomed to the injection experience and reported fewer concerns with subsequent injections.”
Lab test results
During the study, about 85% of participants developed an abnormal lab test result (of their blood or urine samples), regardless of the study drug received. According to the researchers, “most” of these lab test results were only mildly or moderately abnormal.
However, severe and very severely abnormal lab test results occurred in 11% of people taking lenacapavir and 14% who were taking Truvada. These changes were not associated with subsequent harm.
Kidney function declined modestly in people who were taking Truvada. This has been reported in many clinical trials of Truvada; it is an effect of TDF. In comparison, kidney function remained stable or improved slightly in people who took lenacapavir.
Sexually transmitted infections
Rates of common sexually transmitted infections were broadly similar in participants, regardless of which prevention regimen they received.
Deaths
Unfortunately, from time to time, some people pass away during a clinical trial. There were six deaths among people taking lenacapavir and two in people who received Truvada. Investigation revealed that none of these deaths were caused by the study drug.
Bear in mind
The present study found that twice-yearly injections of lenacapavir were highly effective at reducing the risk of participants acquiring HIV. What’s more, lenacapavir was more effective than daily Truvada at preventing HIV infection, likely because of reduced burden of adherence. In a previous study, lenacapavir was found highly effective at reducing the risk of HIV in women and adolescent girls.
Although two HIV infections occurred in participants who were taking lenacapavir, note that more than 99% of participants who received lenacapavir were protected from infection. Researchers noted that this overall high level of protection occurred despite “high levels of sexual exposure [to HIV], use of drugs in conjunction with sex (“chemsex”), and sexually transmitted infections.”
Steps toward access
Lenacapavir’ s twice-yearly dosing for HIV prevention will likely help simplify adherence; if it becomes widely accessible, it will also help reduce the spread of HIV. The use of lenacapavir for reducing the risk of HIV will probably be approved in Canada and the European Union in 2026. In the U.S., it will probably be approved in 2025. After approval in Canada, it will take several months for lenacapavir to be covered by private insurance companies. Once lenacapavir has been approved for prevention, its manufacturer, Gilead Sciences, will negotiate with provincial and territorial ministries of health to hopefully find a price that is affordable for Canada’s provinces and territories so that they can subsidize the drug and make it accessible.
For the future
In this CATIE News bulletin, we have focused on a clinical trial where injectable lenacapavir was given twice a year. In 2025, Gilead will begin testing once-yearly dosing of lenacapavir to find out if it can also significantly reduce the risk of HIV infection. If this trial is successful, it has the potential to be another milestone in the history of the HIV pandemic, as once-yearly dosing will greatly simplify adherence and likely people’s willingness to use and stick to PrEP.
However, for lenacapavir to reach its full potential in changing the trajectory of the HIV pandemic, many additional steps are needed in Canada (and likely other countries), including at least the following:
- responsible pricing by the manufacturer
- provincial and territorial ministries of health subsidizing lenacapavir
- broader access to healthcare providers – currently it is mostly general practitioners, infectious disease specialists and some nurse practitioners who prescribe and administer PrEP and associated laboratory monitoring. In Canada, researchers estimate that tens of thousands of people who are at risk for HIV are not on PrEP, in part because they do not have a primary care practitioner. (Note that millions of Canadians do not have access to a primary care provider.) In the future, if access to lenacapavir is to reach a broad swathe of vulnerable populations, health systems need to envisage a wide variety of care providers administering the drug, including pharmacists and nurses at sexual health and public health clinics. Additional specialties, such as obstetrics and gynecology and addiction medicine, could also be considered for lenacapavir prescribing.
- a national de-stigmatization campaign around HIV in general, and testing and prevention in particular – the broader use of lenacapavir (and other forms of PrEP) will require this in order to help make HIV testing and prevention (and treatment when necessary) seen as routine and a regular part of healthy living.
All these efforts will need to take place over the long term and will require additional financing.
Lenacapavir and other forms of PrEP have the potential to help end HIV as a public health issue. However, until political will and money are firmly behind trying to bring about an end to the HIV pandemic, this potential will not be realized.
—Sean R. Hosein
Resource
Lenacapavir highly effective at preventing HIV in women – TreatmentUpdate 254
REFERENCES:
- Kelley CF, Acevedo-Quiñones M, Agwu AL, et al. Twice-yearly lenacapavir for HIV prevention in men and gender-diverse persons. New England Journal of Medicine. 2024; in press.
- Shahaed H, Glazier RH, Anderson M, et al. Primary care for all: lessons for Canada from peer countries with high primary care attachment. CMAJ. 2023 Dec 3;195(47):E1628-E1636.
- Cohen J. The long shot. Science. 2024 Dec 13;386(6727):1208-1209.
- Thorp HH. The great work continues. Science. 2024 Dec 13;386(6727):1193.
- Editorial. Lenacapavir licenses will not deliver on all opportunities. Lancet HIV. 2024 Nov;11(11):e717.