Fostemsavir in treatment-experienced people

HIV-positive people who doctors described as “heavily treatment-experienced” were enrolled in a study on fostemsavir called Brighte. Most participants had strains of HIV that were resistant to multiple classes of drugs and their pre-study regimens were failing.

When used as part of combination HIV treatment, fostemsavir can be highly effective against HIV. As is generally the case with other anti-HIV drugs, the more active drugs in a regimen, the more effective the regimen. In Brighte, fostemsavir was able to stabilize and/or improve the health of many participants.

Study details

People enrolled in Brighte were initially divided into the following two groups:

Randomized group

In this group, participants were randomly assigned to receive one of the following regimens:

• fostemsavir 600 mg twice daily + their pre-study regimen for eight consecutive days – 203 people
• placebo + pre-study regimen for eight consecutive days – 69 people

After this initial period in the study, all of the above participants received fostemsavir + an optimized background regimen (OBR). To determine each participant’s OBR, doctors used the results of HIV resistance testing to try and find drugs to which HIV was fully susceptible.

Non-randomized group

These 99 participants enrolled in the study had pre-study regimens that were failing; laboratory analysis revealed that their HIV was resistant to all approved HIV treatments. They received fostemsavir at 600 mg twice daily + an optimized background regimen. However, in their case, due to previous extensive drug resistance by HIV, this OBR was only partially effective against HIV. The study scientists hoped that even low-level anti-HIV activity from some drugs in the OBR, combined with fostemsavir, could extend the survival of some of these participants.

The average profile of all participants who entered the study was as follows:

• age – 50 years
• 78% men, 22% women
• major ethno-racial groups: white – 70%; black – 22%
• viral load – 4.6 log (about 30,000 copies/mL)
• CD4+ count – 80 cells/mm³

Commonly used anti-HIV drugs in the OBR:

• dolutegravir (Tivicay and in Triumeq)
• darunavir
• tenofovir DF

Results

The proportions of participants in the randomized group with a suppressed viral load (in this study it was set at 40 copies/mL) at different time points were as follows:

• week 24 – 53%
• week 48 – 54%
• week 96 – 60%

The proportions of participants in the non-randomized group with a viral load less than 40 copies/mL at different time points were as follows:

• week 24 – 37%
• week 48 – 38%
• week 96 – 37%

CD4+ cell counts

The CD4+ cell count is generally used to assess the health of the immune system.

Increases in CD4+ cell counts were generally steady over the course of the study, with the average increases as follows:

• randomized group – 205 additional CD4+ cells/mm³
• non-randomized group – 119 additional CD4+ cells/mm³

As people in the non-randomized group were generally sicker and had fewer treatment options, their increases in CD4+ cell counts were less than those in the randomized group.

Among 71 people who entered the study with less than 50 CD4+ cells (in the randomized group), 56% had a CD4+ count of at least 200 cells/mm³ by week 96.

Another way to assess the immunological health of people is to examine the ratio of CD4/CD8 cells. A ratio less than 1.0 suggests immunological dysfunction and weakness.

Among participants randomized to receive fostemsavir, the ratio was initially 0.2. However, by week 96 it had increased to 0.443, suggesting some improvement in immunological health.

No CD4/CD8 ratios were released by the researchers for the non-randomized group of people.

Safety

The proportions of participants who developed drug-related side effects that were at least of moderate severity were as follows:

• randomized group – 21%
• non-randomized group – 22%

Common drug-related side effects of moderate to severe intensity were distributed as follows:

Diarrhea

• randomized group – 2%
• non-randomized group – 3%

Headache

• randomized group – 2%
• non-randomized group – 1%

Nausea

• randomized group – 3%
• non-randomized group – 5%

Weakness

• randomized group – less than 1%
• non-randomized group – 2%

Serious drug-related side effects were distributed as follows:

• randomized group – 3%
• non-randomized group – 3%

There was a total of 16 serious side effects related to fostemsavir and/or other medicines. These serious side effects were distributed among 12 participants, as follows:

• kidney stones – 2 people
• acute kidney injury – 1 person
• kidney impairment – 1 person
• higher-than-normal levels of blood sugar – 1 person
• higher-than-normal levels of potassium in the blood – 1 person
• immune reconstitution inflammatory syndrome (IRIS) – 3 people
• loss of consciousness – 1 person
• inflammation of the heart – 1 person
• liver injury – 1 person
• muscle weakness – 1 person
• a fetus stopped growing – 1 person
• disorientation – 1 person
• rash – 1 person

The following numbers of people left the study because of adverse events:

Abdominal pain

• randomized group – 2 people
• non-randomized group – 0 people

Chest pain unrelated to the heart

• randomized group – 1 person
• non-randomized group – 1 person

Liver failure

• randomized group – 0 people
• non-randomized group – 2 people

Bear in mind that the population enrolled in Brighte was generally unwell. Since the average CD4+ count upon study entry was around 80 cells/mm³, it is likely that many participants would have had symptoms related to uncontrolled HIV and some participants would likely have had low-level (smouldering) AIDS-related infections and tumours. Furthermore, people with low CD4+ cell counts tend to be more susceptible to drug-related side effects.

Fostemsavir helped many people in the study get better. However, for some participants, fostemsavir was the only drug in their regimen that was fully active against HIV. In effect, these people would have been taking fostemsavir monotherapy (equivalent to taking fostemsavir alone). It was therefore inevitable for HIV to develop resistance to fostemsavir in such cases. Once HIV overcame fostemsavir, these participants would have had no future options for treatment and their health would have significantly deteriorated. It should not be surprising then that 29 people died during the study, distributed as follows:

• randomized group – 12 people (4%)
• non-randomized group – 17 people (17%)

A majority of deaths (62%) in the study were due to AIDS-related infections and cancers.

Key points

• When used as part of an optimized background treatment, fostemsavir had good antiviral activity against HIV.
• CD4+ counts and CD4/CD8 ratios improved over the course of the study.
• Fostemsavir was generally safe but because many people in the study were weak and ill, side effects were common. However, serious side effects were not common.

—Sean R. Hosein

REFERENCE:

Lataillade M, Lalezari J, Aberg J, et al. Week 96 safety and efficacy of the novel
HIV-1 attachment inhibitor prodrug fostemsavir in heavily treatment-experienced participants infected with multi-drug–resistant HIV-1 (BRIGHTE Study). In: Program and abstracts of the 10^th IAS Conference on Science, 21-24 July 2019, Mexico City. Abstract MOAB0102.