Update, August 2013: The FDA approved Tivicay® (dolutegravir), manufactured by ViiV Healthcare, a GlaxoSmithKline company. Tivicay is an integrase strand transfer inhibitor that prevents the enzyme integrase from incorporating viral DNA into the host chromosome.
Original article: The human immunodeficiency virus (HIV) is a fleet-footed quarterback, sprinting past the body’s defenses. It mutates at an alarming rate and hides in the body’s reservoirs, evading even the most powerful immune system players. But during the drug discovery decade since 2003, nearly 20 new drugs have been developed to put the hurt on HIV.
The new drugs tackle HIV either before it enters cells or before it can reproduce in them. Fixed drug combination (FDC) pills now simplify a once-complicated regimen of numerous pills. New technologies are also making it feasible to create longer-acting drugs that are more powerful and less expensive. These discoveries should help expand the playbook for people with hemophilia who are strategically combating HIV.
To understand how the new drugs and classes of drugs work, it’s important to understand how HIV penetrates the body’s defensive line and blocks the workings of the immune system.
Backfield in Motion
Like other viruses, HIV needs a host to reproduce. It pursues CD4, or helper T, cells in the immune system, fusing to them so its contents can enter the host cell. CD4 cells coordinate the body’s defense against infection, including viruses. Once the HIV genetic material is integrated into the nucleus of a host cell, HIV takes on the role of “quarterback,” directing the CD4 cell to produce HIV strands of viral DNA. HIV then uses protease, another viral enzyme, to slice long proteins into smaller pieces that it needs to make new viral particles.
As the host cell manufactures new proteins, it inadvertently makes new copies of HIV as well. Initially, the immune system manufactures enough CD4 cells to replace the infected ones, keeping the virus in check. But eventually this defense collapses and HIV grows unabated. Once proviral DNA is integrated into the host cell, HIV becomes a chronic infection. The time span from infection until the proviral DNA is created can be as short as 72 hours.
Block That Pass
The goal of antiretroviral therapy (ART) is to reduce the viral load, the number of HIV copies in the bloodstream, to undetectable levels. Using today’s technology, that means fewer than 50 copies of HIV per milliliter (ml) of blood. This, in turn, helps the CD4 count rebound. A normal CD4 cell count is 600 to 1,200 cells per cubic ml of blood. ART typically begins when the CD4 count drops to 200 to 500 cells/cubic ml of blood.
But HIV is a formidable foe. It can suddenly mutate, or change, rendering drugs ineffective and causing viral loads to spike. That resistance can occur not only to one drug in a class, but the entire class. That’s why patients on ART must take a so-called “drug cocktail” of antiretroviral (ARV) drugs to block HIV, hitting it at various places in its life cycle.
Entry inhibitors work outside the cell. They block receptors on the CD4 cell’s surface that HIV needs to bind to and then gain entry. Fusion inhibitors use another strategy to hamstring HIV. They bind to a receptor on the host cell’s surface, stopping the virus and cell from fusing.
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Other ARV drugs act as defensive linemen inside the cell, preventing the action of three enzymes HIV needs to reproduce: reverse transcriptase, protease and integrase.Nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) block the action of reverse transcriptase, which is only found in human cells infected with HIV. NRTIs are similar to the nucleotide building blocks HIV needs to form chemical bonds but different enough that HIV can’t convert RNA into DNA. NNRTIs bind to reverse transcriptase, stopping HIV’s genetic material from being incorporated into the cell. Thus, new viruses can’t be produced. Without protease, HIV proteins can’t be broken into the smaller pieces the virus needs to infect new cells. Protease inhibitors (PIs) prevent immature noninfectious virus particles from becoming mature infectious particles. Integrase inhibitors, in contrast, thwart HIV from transferring a viral strand it needs to replicate inside the host cell’s DNA.
“To suppress the virus successfully, at least three active drugs must be used,” says Paul Sax, MD, director of the HIV program and Division of Infectious Diseases at Brigham and Women’s Hospital in Boston. He is also professor of medicine at Harvard Medical School. “It has turned out to be quite useful to use two drugs from the same class, NRTIs, plus a third key drug.” That additional drug could be a PI, an NNRTI or an integrase inhibitor. However, for people diagnosed with HIV years ago, including those with hemophilia, other combinations may be needed due to viral resistance, Sax says. For instance, a combination of an NRTI, PI and integrase inhibitor might be prescribed.
“The current HIV drugs are extraordinarily effective,” says Sax. “For people who are in care, the good news is that virologic suppression rates are now 80% or higher.” (See sidebar, “HIV Detection and Prevention.”) Treatment is much simpler, too. “When I saw two of my patients with hemophilia recently—and even though both have been infected for a long time—they were both taking three pills a day.”
Building a Championship Team
Despite these victories, new drugs are still needed. “We don’t have the perfect drug combination yet,” says Charles Flexner, MD, professor of medicine, pharmacology and molecular sciences, and international health in the School of Medicine and in the Bloomberg School of Public Health at Johns Hopkins University in Baltimore, Maryland. “We need better second- and third-line regimens for people who have been on treatment for perhaps 20 or more years and are looking or a regimen they can stay on for the rest of their lives,” he says. “All patients would like drugs that have essentially no side effects. That’s the next phase of activity.”
Sidelined by Side Effects
The side effects from HIV drugs range from nuisances to nephrotoxicity (kidney damage). The 2012 treatment recommendations of the International Antiviral Society–USA (IAS-USA), a nonprofit that provides guidance for physicians who treat patients with viral infections, were published in the Journal of the American Medical Association. They included side effects by drug class. The NRTI tenofovir can cause loss of bone mineral density in the hips and spine, leading to osteoporosis and fractures; it also can cause kidney damage. “If you look at populations, it’s clear that there is a very small, but significant, decline in kidney function over time,” Flexner says. Abacavir, another NRTI, has been linked to increased rates of acute heart attacks.
Although widely used, the NNRTI efavirenz causes abnormal dreams, dizziness and a persistent rash. “About 10% of people will drop off an FDC containing efavirenz in the first year because of side effects,” says Flexner. Protease inhibitors are notorious for causing everything from diarrhea and nausea to changes in the level of fats in the blood. They also disrupt electrical impulses in the heart. Integrase inhibitors are relatively safe, but the boosters added to them, particularly cobicistat, can cause drug interactions. Further, cobicistat causes an immediate small increase in serum creatinine, which can indicate kidney damage. “This could be a problem if you already have renal dysfunction,” says Margaret Ragni, MD, MPH, professor of medicine in the Department of Medicine, Division of Hematology/Oncology, at the University of Pittsburgh and director of the Hemophilia Center of Western Pennsylvania. Studies are lacking on patients who’ve been treated for HIV for years, she says. “Most of the new drugs are being tested on new, inexperienced patients.”
Patients managing hemophilia, HIV and hepatitis C have additional medication concerns. “People with hepatitis C are more likely to get liver toxicity from HIV drugs,” says Sax. Also, the drugs they take to treat separate viral conditions can clash. “The drug interactions between the new hepatitis C drugs and the HIV drugs are significant.” The IAS-USA recommends that patients with liver failure avoid protease inhibitors and some other ARVs.
For the immediate future, ARVs still need fitness training. “It would be nice to find an agent in every class that embodies a high threshold to resistance, a good acute tolerability and long-term safety,” Flexner says.
Coaches Make the Call on Substitutions
Switching products may be the antidote to bothersome side effects, but you need coaching from your team of physicians. “If a patient is on a winning regimen—his viral load is suppressed and he has no complaints—but he’s having side effects, one of the things we look at is switching him to a better-tolerated, simpler regimen,” says Ragni. That decision often involves a consultation with colleagues specializing in infectious diseases, she says. If a patient can’t tolerate one protease inhibitor, Ragni may substitute another one or switch to a combination product.
That move is backed by research results. “I’ve recently seen data that you can switch patients from regimens of boosted protease inhibitors to the combination tenofovir/emtricitabine and rilpivirine, pretty safely,” Sax says. But the switch should only be made if there is no history of viral resistance, he says.
Adherence is the Adversary
Adherence, sticking to a drug regimen over time, can be problematic for people with chronic conditions like HIV. Forgotten doses, travel or sickness can all foul up the most regimented regimen. “If patients previously well-controlled on ART develop detectable viral load, then the question is: Was it because they were tired of it and missed doses, the side effects were getting them down, or they had to stop their medications for surgery or procedures?” says Ragni. So-called “pill fatigue” can occur in patients on lengthy drug treatments.
The stakes for nonadherence are high. HIV is an opportunist. Unhampered, it can crank out billions of copies of itself daily. The Strategies for Management of Antiretroviral Therapy (SMART) study, the largest international AIDS study, was discontinued in 2006 after patients in the interrupted ART arm developed AIDS-related illnesses at a significantly higher rate. “Most, if not all, HIV drug resistance that occurs after the start of therapy is the consequence of occasional nonadherence,” Flexner says. “One of the challenges now is to understand how to best promote long-term adherence in people who are going to wind up being on HIV therapy often for their entire life.”
Rookie Season for a Talented Player
To combat adherence issues, less is more. The fewer pills a patient takes, the greater the chance he will stick to the regimen. A rookie player that could be a real game-changer hit the field in August 2012. Stribild™, manufactured by Gilead Sciences, is the first quad therapy approved by the FDA. It’s a once-a-day pill with four ingredients—the NRTIs emtricitabine and tenofovir, and two new drugs—elvitegravir, an integrase inhibitor, and cobicistat, a pharmaco-enhancer. Unlike the other components, cobicistat has no antiviral activity. Instead, it boosts the other drug levels in the bloodstream. “Because it is more soluble, you can combine it with other drugs more easily,” Sax says. So far, he’s impressed with Stribild. “The combination is very potent and very well tolerated.”
However, Stribild is only approved for adults with HIV who have never been treated. Still, its introduction should benefit people with hemophilia and HIV. “I do think that at some point in the near future one pill once a day is going to become the standard of care for treatment-experienced patients as well as treatment-naive patients, but we’re just not there yet,” says Flexner.
Draft Pick Predictions
Strengthening the team that tackles HIV could mean bringing in new players. Flexner’s associates are using nanotechnology, ultrafine particles that slowly release a drug into the body, to create a long-acting drug given monthly or quarterly. “One could imagine a once-a-year injectable ARV combination, much like what we’re doing now for hormonal contraception,” he says.
Selective toxicity—for HIV and not the host—is another key trait for a new line of defensive drug players. When dolutegravir, a once daily integrase inhibitor, is approved by the FDA as a component of FDCs, many problems will be solved. It is low in toxicity and doesn’t require a boosting agent. “Along with elvitegravir, it will provide additional safer options for patients,” Sax says.
Another asset is a star player with a low-salary requirement. Gilead’s GS-7340, a prodrug or precursor of tenofovir, is potent. To achieve the same effect, you need about 40 times as much tenofovir, says Flexner. He’s a fan for two reasons. “The drug is likely to be very easy to coformulate, so that will give us a lot more options. And it’s much cheaper to synthesize a drug whose daily dose is 8 mg than a drug whose daily dose is 300 mg.”
The FDA now requires longer studies of HIV drugs—48 weeks’ worth of data. Everybody gains yards from that, says Flexner. “Treatment-experienced patients benefit from these kinds of studies because the drugs that now may be available to them as well will come to market with a better understanding of their safety. The bar has been raised.”
Scrimmaging Continues
Until HIV is cured, on-field scrimmaging between the virus and a patient’s immune system will continue. Although the current team of ARVs is unified and powerful, there are holes in its defense. “Our bleeding disorders patients should have the best options possible,” Ragni says. “We have to do what we can to make their quality of life better, reduce any side effects they have and help to ensure that they’re going to have fewer long-term problems as time goes on.”