Northern Alberta researchers study Biktarvy and mutations in HIV

Resistance to anti-HIV drugs can be a concern for doctors treating some people with HIV, particularly people who have been taking HIV treatment (ART) for decades. In the early years of HIV, treatment was typically one drug used on its own (monotherapy). In the early 1990s, it became two drugs. The drugs in common use in that era were nucleoside analogues (nukes). By themselves or even in combination with other nukes, these drugs are unable to suppress HIV for long. As a result, some people developed strains of HIV that were partially or wholly resistant to other anti-HIV drugs (usually other nukes). It was not until about 1996 that regimens became more effective with the addition of other classes of drugs—particularly protease inhibitors and non-nucleosides (non-nukes). Today, HIV treatment regimens are much more robust than those that were used in the late 1990s or early 2000s. The robustness of these regimens is usually due to the presence of an integrase inhibitor. Examples of integrase inhibitors include bictegravir (in Biktarvy), dolutegravir (Tivicay and in Dovato, Juluca and Triumeq) and raltegravir (Isentress).

Back to nukes

Examples of nukes that are used today include the following:

• 3TC
• abacavir
• FTC
• tenofovir; this comes in two formulations – tenofovir DF and tenofovir alafenamide (TAF)

Nukes are sometimes combined into one pill (co-formulated):

• tenofovir DF + FTC – sold as Truvada and available in generic combinations
• TAF + FTC – sold as Descovy

However, as mentioned earlier, nukes on their own are insufficient to suppress HIV. Therefore, some nukes are coformulated with other more potent drugs—usually integrase inhibitors or non-nukes (such as doravirine or rilpivirine)—to form a complete regimen in one pill. Here are some examples of that:

• bictegravir + TAF + FTC — sold as Biktarvy
• dolutegravir + 3TC – sold as Dovato
• dolutegravir + 3TC + abacavir – sold as Triumeq
• doravirine + tenofovir DF + 3TC – sold as Delstrigo
• rilpivirine + TAF + FTC – sold as Odefsey

Northern Alberta

For their study on the potency of Biktarvy, researchers at the University of Alberta in Edmonton scoured medical records of HIV-positive people to find information about people who were taking Biktarvy. They found 779 records; 50 of these people had drug resistance testing done at some point in the past (prior to initiating Biktarvy) when their viral loads were detectable.

The Northern Alberta researchers focused on resistance testing that identified mutations, or changes, in HIV’s genetic material that were associated with resistance to nukes. None of the participants had HIV that was resistant to integrase inhibitors (Biktarvy contains the integrase inhibitor bictegravir). All 50 participants had at least one mutation associated with resistance to nukes. A total of 29 participants had just one such mutation. The remaining 21 participants had two or more mutations that were associated with resistance to nukes. Despite this finding, 48 out of 50 participants had a viral load less than 50 copies/mL an average of 18 months after initiating treatment with Biktarvy.

The Alberta study confirms the usefulness of triple therapy anchored by an integrase inhibitor—in this case, bictegravir.

Study details

Researchers collected health-related information between May 2020 and January 2022. Viral load testing could have been done at any time in the past when participants had a detectable viral load. In most cases, this was before they switched to another regimen, and well before they subsequently began to take Biktarvy.

The average profile of the 50 participants prior to initiating Biktarvy was as follows:

• age – 54 years
• 64% men, 36% women
• CD4+ count – 609 cells/mm³

Results

Shortly before initiating Biktarvy, four people had a detectable viral load, distributed as follows:

• two people who had never previously taken ART but had become infected with HIV that was resistant to some nukes – one of them had a viral load of almost 1,800 copies/mL, while the other had a viral load of 62,000 copies/mL
• two people who had previously used ART – one of them decided to stop ART two months before initiating Biktarvy. Their viral load was 68,000 copies/mL. This person had HIV with mutations that were associated with resistance to some nukes and protease inhibitors. The other person had a viral load close to 1,000 copies/mL and doctors suspected that he had problems with adherence.

Before the 50 people initiated Biktarvy, the most common regimen used was anchored by a boosted protease inhibitor.

Distribution of mutations associated with resistance to nukes

A total of 29 participants had just one mutation associated with resistance to nukes. The remaining 21 participants had two or more such mutations, distributed as follows:

• two nuke resistance mutations – nine people
• three nuke resistance mutations – three people
• four nuke resistance mutations – four people
• five nuke resistance mutations – two people
• six nuke resistance mutations – one person
• seven nuke resistance mutations – one person
• eight nuke resistance mutations – one person

Deaths

Two people died during the study period; both died 10 months after initiating Biktarvy. One person died from unspecified trauma and the other person died from complications caused by tumours that had spread from the liver. These deaths were unrelated to Biktarvy.

Regardless of previous treatment, the vast majority of participants (48 out of 50) had a viral load less than 50 copies/mL an average of 18 months after initiating Biktarvy. One person had a viral load that was greater than 50 copies but less than 100 copies/mL. The other person was not taking Biktarvy as directed.

Technical note

Researchers found that one particular mutation was common—M184V. This mutation is associated with resistance to the nukes 3TC and FTC and partial resistance to the nuke abacavir.

Bear in mind

Although the study relied on data that was collected in the past for one purpose and subsequently analyzed for another purpose, its findings are in line with larger studies.

The researchers stated: “We had limited numbers of patients with three or more [mutations associated with nucleoside resistance], which could be due to the low prevalence of such patients but could also be explained by patient selection bias.” That is, doctors may be reluctant to treat such patients with Biktarvy alone. Instead, doctors in northern Alberta may have given such patients more complex, multi-pill regimens.

The researchers reviewed key studies and stated that in many cases nuke resistance mutations “do not appear to impair the virological response to triple therapy with two [nukes] combined with a boosted protease inhibitor, or dolutegravir or bictegravir…provided that there is no resistance to the protease inhibitor, dolutegravir or bictegravir. Our study provides further evidence that this is true of [Biktarvy] specifically.”

—Sean R. Hosein

REFERENCES:

1. Shafran SD, Hughes CA. Bictegravir/emtricitabine/tenofovir alafenamide in patients with genotypic NRTI resistance. HIV Medicine. 2022; in press.
2. Wensing AM, Calvez V, Ceccherini-Silberstein F, et al. 2022 Update of the Drug Resistance Mutations in HIV-1. Topics in Antiviral Medicine. 2022;30(4). Available at: https://www.iasusa.org/resources/hiv-drug-resistance-mutations/