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Lenacapavir and multidrug-resistant HIV

Lenacapavir is an experimental drug undergoing clinical trials in different populations, including the following:

  • people who have HIV that is partially or wholly resistant to other treatments
  • people without HIV who are using it to reduce their risk of getting HIV

Lenacapavir belongs to a new class of anti-HIV drugs called capsid inhibitors. For use in clinical trials, lenacapavir is available as tablets taken orally or as a liquid for injection just under the skin (subcutaneous injection). When a person initiates the use of lenacapavir, they begin with several doses of the oral formulation over the course of two weeks. After this time, they can switch to the injectable formulation. Lenacapavir is designed to be slowly broken down, so injections are required only every six months.

Limited treatment options

Researchers in the U.S. and other countries conducted a short placebo-controlled study of lenacapavir in 36 people whose HIV treatment regimens were failing. After 14 days, people who were on placebo and their failing regimen switched to lenacapavir and an optimized background regimen (their regimens were adjusted based on HIV resistance testing to try to maximize the antiviral activity of their treatments). At the end of the initial 14-day period, participants switched from oral to injectable lenacapavir. The remaining participants who initiated the study with oral lenacapavir and their failing regimen were also switched after 14 days to injectable lenacapavir and an optimized background regimen.

Researchers subsequently recruited 36 other people whose regimens were also failing and gave them a combination of oral lenacapavir and an optimized background regimen for two weeks. After this time, these people switched from oral to injectable lenacapavir.

Participants were monitored for one year.

In the placebo-controlled portion of the study, after two weeks HIV viral load fell by at least two thirds (half a log) in 88% of people on lenacapavir vs. 17% of people on placebo.

After six months, about 82% of all 72 participants had a suppressed viral load (less than 50 copies/mL) and CD4+ cell counts had increased by 75 to 104 cells/mm3.

Side effects during the first six months were usually mild to moderate and were resolved.

Results after one year are presented later in this report.

Study details

Researchers recruited 72 participants primarily from the U.S. and also Europe and Asia. Their average profile at the start of the study was as follows:

  • age – 52 years (ranging between 23 to 78 years)
  • 75% men, 25% women
  • major ethno-racial groups: White – 41%; Black – 38%; Asian – 21%
  • viral load – 15,000 copies/mL; 14 people had a viral load greater than 100,000 copies/mL
  • CD4+ count – 150 cells/mm3; 16 people had a CD4+ count below the 50 cell/mm3 mark, indicating severe immune deficiency

The four classes of drugs commonly used in background regimens were as follows:

  • nucleoside reverse transcriptase inhibitors (nukes)
  • non-nucleosides (non-nukes)
  • protease inhibitors
  • integrase inhibitors

The proportions of people with HIV that was resistant to two or more drugs in each class were as follows:

  • nukes – 99%
  • non-nukes – 97%
  • protease inhibitors – 81%
  • integrase inhibitors – 69%

A total of 33 people (46%) had HIV that was resistant to at least two drugs in all four classes. Indeed, the researchers stated that “many [participants] had exhausted both the integrase (54%) and protease inhibitor (42%) classes.”

The dosing of lenacapavir in this clinical trial was as follows:

  • day one – 600 mg orally (two 300-mg tablets)
  • day two – 600 mg orally
  • day eight – 300 mg orally
  • day 15 – two subcutaneous injections into the abdomen of 1.5 mL of the liquid formulation, for a total injected dose of 927 mg

Results – the first six months

Six months after entering the study, whether participants immediately initiated lenacapavir or placebo, the proportion that ultimately achieved a suppressed viral load was similar, about 82%. Also, after six months, CD4+ cell counts increased by at least 75 cells/mm3.

Focus on lenacapavir resistance

Blood samples from 19 participants were subsequently analysed for the presence of HIV that may have become resistant to lenacapavir. The reason for this was that not all participants achieved or maintained viral suppression and researchers wanted to better understand how lenacapavir fared in such circumstances, as it is a new drug. Eight of the 19 people developed HIV that was partially resistant to lenacapavir. Despite this finding, four of these eight people were able to suppress their viral load once again while continuing to use lenacapavir.

Among the four other people (out of the eight who developed partial resistance to lenacapavir), two remained in the study with detectable HIV. One person died at week 10 of the study (explained later) and the other person left the study at week four.

Among all eight participants with HIV that was partially resistant to lenacapavir, researchers found that the level of this drug in their blood was within the acceptable range. This finding suggested that lenacapavir was being released at expected rates from subcutaneous tissue.

The researchers noted that four of these eight people “had poor adherence to their background therapy.” This likely explained why their viral load became detectable during the study.

Among the remaining 11 participants whose blood samples were analysed—none of whom had any resistance to lenacapavir—seven were able to re-suppress their viral load while they continued in the study (and remained on lenacapavir).

Safety

Readers should note that people with relatively low CD4+ cell counts and detectable viral loads—which would have been the majority of participants when they entered the study—tend to have immune deficiency and high levels of inflammation and exposure to proteins from HIV in their blood. As a result, they are more susceptible to developing drug side effects, fatigue, low-level and even serious infections and, in some cases, cancer.

Some general adverse events experienced by participants over the course of the study were as follows:

  • nausea – 13%
  • constipation – 11%
  • diarrhea – 11%

Investigation suggested that these symptoms were unrelated to lenacapavir. Furthermore, such symptoms were mostly mild.

The person who died (as mentioned earlier) entered the study with an extreme degree of immune deficiency—a CD4+ count of just 7 cells/mm3. This person would likely have been physically weak. They had a history of non-Hodgkin’s lymphoma and died from complications related to an unspecified cancer in the 10th week of the study.

Injection site reactions

As is usual with injectable therapies, a majority of participants (63%) had some injection-site side effects, including the following:

  • pain – 31%
  • swelling – 31%
  • redness – 25%
  • formation of a nodule – 24%

Most of these reactions were mild and resolved in a few days.

One person left the study because a nodule formed 10 weeks after they received their second injection of lenacapavir.

Abnormal lab test results

In 28% of participants, lab analysis of blood and/or urine samples revealed serious abnormalities. However, these particularly abnormal measures of kidney health were temporary and, in most cases, quickly normalized without further intervention.

Some people also developed elevated levels of sugar in their blood and urine. These were usually temporary or linked to pre-existing diabetes.

Results – one year later

Researchers provided some results after one year for 35 people initially randomized to placebo or lenacapavir add-on therapy for 14 days at the start of the study. Safety data were provided for about 70 people.

Here are the virological results:

  • 30 people achieved a suppressed viral load
  • five people had virological failure

Analysis found a trend: the greater the number of fully active drugs (this means that HIV had no resistance to such drugs) in a background regimen at the end of the first year, the greater the likelihood that a person’s viral load would be suppressed. Here is the distribution of viral suppression by the number of active drugs in a background regimen:

  • no active drugs – four out of six people (67%) were undetectable
  • one active drug – 11 out of 14 people (79%) were undetectable
  • two or more active drugs – 15 out of 16 people (94%) were undetectable

The average CD4+ cell count stabilized by the 36th week of the study and then remained stable for the rest of the year. Participants gained an average of 83 more CD4+ cells/mm3 by the end of the year. The impact of lenacapavir was dramatic—after one year on lenacapavir and an optimized background regimen, 60% of participants had a CD4+ count of at least 200 cells/mm3.

Not everyone had such good results. Recall that many people entered the study with severe immune deficiency and few treatment options.

Initially there were eight people who entered the study with less than 50 CD4+ cells/mm3. By the 16th week of the study, all eight had more than 50 CD4+ cells/mm3. However, after one year in the study, one person’s CD4+ count fell below the 50-cell mark. This probably occurred because of increasing resistance by HIV to their regimen.

Injection site reactions

By the sixth month of the study participants received their second injection of lenacapavir. Researchers could then assess reactions to the second injection. For the most part, researchers found that injection site reactions were mild to moderate after the second injection. Here is the breakdown of injection site reactions after the second dose:

  • swelling – 13%; average duration – 12 days
  • redness – 11%; average duration – six days
  • pain – 21%; average duration – three days
  • nodule – 11%; average duration – 180 days
  • hardening of the skin – 10%; average duration – 118 days

Bear in mind

Lenacapavir has been shown to be very helpful for many people with few treatment options. Most people tolerated it.

For the future

If all goes well in this clinical trial, lenacapavir likely will be approved for use by people who have multidrug-resistant HIV in many high-income countries over the coming 24 months. Approval of lenacapavir for HIV prevention will take longer, as those clinical trials were interrupted because of the issue with the glass vials (mentioned in the previous report). Now that this issue has been resolved, those trials can now resume using injectable lenacapavir.

—Sean R. Hosein

REFERENCES:

  1. Segal-Maurer S, DeJesus E, Stellbrink HJ, et al. Capsid inhibition with lenacapavir in multidrug-resistant HIV-1 infection. New England Journal of Medicine. 2022 May 12;386(19):1793-1803.
  2. Marrazzo J. Lenacapavir for HIV-1 – Potential promise of a long-acting antiretroviral drug. New England Journal of Medicine. 2022 May 12;386(19):1848-1849. 
  3. Ogbuagu O, Segal-Maurer S, Brinson C, et al. Long-acting lenacapavir in people with multidrug resistant HIV-1: Week 52 results. Conference on Retroviruses and Opportunistic Infections, 12-16 February 2022.
  4. Gilead Sciences. FDA Lifts Clinical Hold on Investigational Lenacapavir for the Treatment and Prevention of HIV. Press release. 16 May 2022.