A Breakthrough For Folks Resistant To HIV Treatments

A Breakthrough in Resistance

Most people living with HIV who start treatment now may never have to deal with drug resistance. Modern antiretroviral drugs are less vulnerable to the development of resistance and have higher adherence rates.

Adherence, a critical element in preventing drug resistance, has increased over time due to medications becoming more tolerable (and now being available in easy-to-take, single-tablet regimens). As one 2016 meta analysis published in the journal of Infection, Genetics and Evolution reported, “Most ART regimens used for first-line therapy are sufficiently potent to completely block HIV-1 replication and have a genetic barrier to resistance high enough to maintain long-term virological suppression.”

The study also reveals that transmitted drug resistance may be as high as 12 to 24 percent of new diagnoses in the U.S. A small minority of others living with HIV (particularly long-term survivors) are resistant not to just one or two antiretrovirals, but three or more entire classes of drugs. For these folks, new treatment developments can literally spell the difference between life and death.

Fortunately, one innovative drug is offering a new way to fight the virus — and it may soon be on the market. Rather than interfering with binding, fusion, or entry of HIV into human T cells — the processes behind most ART therapies — fostemsavir’s strategy targets a different step of HIV’s lifecycle by attacking the virus itself (rather than targeting T cells).

Fostemsavir latches onto HIV’s gp 120 receptor, a protein that is exposed on the surface of the virus, and which plays an essential role in allowing HIV to hook onto T cells. By capping the receptors, fostemsavir essentially locks them closed, preventing HIV from being able to attach, and thereby blocking entrance into the immune system.

This new strategy, a first for HIV drugs, puts fostemsavir in a new class of HIV drugs known as attachment inhibitors. Because of its unique mechanism of action, those who have developed resistances to other classes of antiretrovirals are still unlikely to experience drug resistance to fostemsavir. That’s particularly good news for long-term survivors and others who’ve become resistant to multiple classes of antiretrovirals.

In fact, the 370 heavily treatment-experienced HIV-positive people who participated in fostemsavir’s phase 3 study (BRIGHTE) all had documented resistance, intolerability, or contraindication to all antiretroviral drugs in at least four of the six drug classes approved to treat HIV. In a statement to the press, John C. Pottage, Jr., MD, chief scientific and medical officer of ViiV Healthcare, described study participants as “failing on their current antiretroviral regimens and had few treatment options left available to them.”

Adding fostemsavir to their current failing regimens helped 54 percent of participants achieve virologic suppression. If that number seems low, keep in mind that participants were experiencing treatment failure prior to the study — so even having half reach undetectable viral loads after adding the new drug is still a remarkable breakthrough.

Fostemsavir’s success with HIV-positive people who have few treatment options helped it score a breakthrough therapy designation from the Food and Drug Administration. This important designation helps speed up the approval process for such medications.

In development by ViiV Healthcare and GlaxoSmithKline, fostemsavir will likely be approved for those experiencing multidrug resistance, to be used in combination with other HIV drugs. Forty-eight week results were presented at the HIV Drug Therapy Glasgow 2018 conference. Researchers showed that fostemsavir, in combination with optimized background treatment, maintained viral suppression from week 24 to week 48.

Not only do these results suggest that the drug suppresses viral loads much sooner than other antiretrovirals, but researchers say it appears to be reviving the immune system simultaneously. Those taking fostemsavir in trials are seeing their CD4 and T cells increase and strengthen, potential evidence of rebounding immune system health.

But, researchers caution it’s too early to make definitive declarations regarding the drug’s impact on immune system health, and what that might mean longer term.

“Every drug, every antiretroviral that you give to patients, shuts down the viral production because the virus is, if you leave it unchecked, producing almost millions of copies a day,” explains Max Lataillade, ViiV Healthcare’s head of clinical development. “Any drug that stops the viral production… [will] increase your CD4 count level.” But, he says the increase in this case seems particularly sizable and may point to an important (positive) side effect of fostemsavir.

Lataillade hypothesizes that as the fostemsavir is binding to gp 120 on the virus, it inadvertently “locks” the gp 120 into position. It’s being presented to the immune system for the first time in this locked position, and there’s something about that change that appears to make the immune response more effective.

“Binding to the virus is certainly innovative and I think would be a good thing for the immune system,” says Lataillade. “What we are seeing as well, in terms of the normal markers of recovery, is an increase in your CD4 and the CD4-CD8 ratio.”

Lataillade describes CD8 cells as the immune system’s killer cells. In other words, they are the cells that go out and kill invading pathogens. “If you think about the Marines, your CD8 would be like your SEALs,” he says. “They’re the ones who go by the action, but there’s one guy who’s always telling them where to go — that is the CD4. You always want your CD4 to CD8 ratio to be high. What we’re seeing in [trials] is that that CD4-CD8 [ratio] is steadily, steadily, steadily increasing.”

Another intriguing finding from the phase 3 study was “numerically higher rates of virologic response in patients [over] 50 years, females, or in patients who self-reported their race as ‘black’ or ‘African-American’ compared to their respective counterparts.” Although the researchers have not hypothesized the reasons for better success among women, black individuals, and those over 50, these are all groups facing unique hurdles in HIV treatment, and these findings may later become relevant.

If ViiV gains FDA approval for fostemsavir as it’s expected to, it would first go on the market as a drug reserved for heavily treatment-experienced people, i.e., those who’ve been on antiretroviral treatment for long periods (think long-term survivors) or those living with multiple co-morbidities. Because it’s not boosted, the drug also has an advantage in that it will not interfere with medications taken for diabetes, hypertension, or high cholesterol.

Researchers also plan to focus on smaller key studies in the future to better explain the immune recovery they are seeing.

“For example, does [fostemsavir] increase the CD4 count in people that even though they’re suppressed, their CD4 count doesn’t go up?” Lataillade ponders. “Is it better than a booster TI in certain situations? We’ll be focused on some key biomarkers to see whether some immune biomarkers are better with fostemsavir versus other drugs.”

Lataillade says ViiV’s long-term goal is to address people’s unmet needs, which includes long-acting therapies.

“What we are looking at is convenience,” he adds. “When you give a long-acting formulation to a patient, every month or every two months for example, the psychological effect is unbelievable. The patients say to me, ‘The fact that I’m not taking the pill every day is actually giving me relief psychologically that I have HIV.’ I think that that’s a powerful, powerful moment for me when a patient tells me something like that.”

Looking to the future, Lataillade boldly predicts brighter days for all people on treatment for HIV: “What’s going to happen is, if we can dose a patient once a month, once every two months — I’m going to say, why can’t we push it to every three months? We’re going to push for that.”

Additional reporting by Jacob Anderson-Minshall.

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