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Which Antiviral to Use First?

by Christine Kukka

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Today, there are four antiviral drugs approved by the U.S. Food and Drug Administration to treat people who are experiencing liver damage from hepatitis B – a vast improvement over the small arsenal that until recently was all that was available.
Despite the recent increase in antiviral drug options, there’s little consensus among experts about which antiviral should be used first. Use the wrong antiviral initially, and you can end up “resistant” to other antivirals, including those in the drug development pipeline. Bottom line, choosing the right antiviral is essential to long-term, successful treatment of hepatitis B virus (HBV) infection.
Currently, there are two types of drugs available to treat hepatitis B: interferons and antivirals.

  • Interferon is a substance that stimulates the immune system to fight infections. The newest interferon, pegylated interferon, is administered through a weekly injection and if you fit the “profile,” it may be the best first treatment. Interferon works best when your immune system is actively fighting the infection, usually indicated by high levels of alanine aminotransferase or ALT. Liver cells release ALT then they are damaged or die. When ALT levels rise, doctors assume your immune system is attacking the infected liver cells and could use an extra boost of interferon. But interferon is expensive, causes some hefty side effects, has a moderate success rate, and doesn’t work well unless ALT is elevated.
  • Antiviral medications, administered orally, interrupt important steps in the virus’s reproduction process by disabling DNA formation. Each antiviral disrupts a different “step” in HBV’s complicated reproduction cycle, but some antivirals work in similar ways and over time HBV can develop mutations and continue to reproduce despite the presence of one or more antivirals. HBV have a weak genetic blueprint, and with millions of HBV generated daily, some inevitably have mutations that allow them to “resist” an antiviral’s genetic roadblock.

To date, researchers have not developed a perfect antiviral or antiviral combination that works synergistically to disable all HBV at once to totally eradicate the infection. As a result, today’s sequence of antiviral treatment becomes very important for those who may require antivirals to keep their viral load in check for years or decades.
Here is a snapshot of available antivirals and the “resistance threat” each poses:

Approved in 1998, lamivudine (Epivir-HBV) was the only antiviral game in town for years, and today is the cheapest antiviral available. It works by inhibiting the reverse transcriptase, an enzyme that is essential to the HBV’s reproduction process. Lamivudine lowers viral load (HBV DNA) as it disables the virus’s replication process so there are fewer HBV infecting and damaging liver cells. But over time, lamivudine loses its effectiveness. It kills off the HBV without mutations, but the HBV with lamivudine-resistant mutations keep replicating and eventually become the dominant virus. Over time, viral load rebounds and ALT levels rise, signaling recurring liver damage.

On average, lamivudine-resistance occurs in 20% of patients after one year of treatment, and in 70% after four years. And there’s more bad news, once your HBV can resist lamivudine, they’re able to “resist” other antivirals that target the same enzyme and replication step. As a result, lamivudine has become a second-class citizen in the world of hepatitis B antiviral treatment.

“Few doctors who treat adults would use lamivudine as first line therapy today,” said Dr. Phil Rosenthal, medical director of the Pediatric Liver Transplant Program at University of California San Francisco. Dr. Rosenthal currently tries to avoid treating HBV-infected children with lamivudine, the only antiviral FDA has approved for children – or any antiviral unless absolutely necessary due to the looming threat of multiple-drug resistance that can develop over years of treatment. “I usually try interferon first,” said Dr. Rosenthal. Unfortunately, he can only use conventional interferon – the more effective pegylated interferon has not yet been approved by the FDA for children. Adefovir is currently the only new antiviral in pediatric clinical trial.

Adefovir (Hepsera), approved by FDA in 2002, was welcomed as the antiviral that could defeat all HBV, including lamivudine-resistant HBV. But similar to lamivudine, adefovir-resistant HBV can emerge, though at a much slower rate than lamivudine resistance. One report found adefovir resistance in 28 percent of HBeAg-negative patients after five years of treatment.

And, if patients have already developed lamivudine resistance, they will develop resistance to adefovir more rapidly. One study found that after just 48 weeks, 10 out of 57 lamivudine-resistant patients (18 percent) developed adefovir-resistance.

Today, once lamivudine resistance develops, many doctors add adefovir to the ongoing lamivudine treatment in an effort to vanquish the resistant HBV and make sure there is no sudden viral rebound and liver damage. If just adefovir is used in these lamivudine-resistant patients, about 20 percent will develop adefovir resistance within two years.

Entecavir (Baraclude), approved in 2005, is different than adefovir and lamivudine. It is a guanine analogue antiviral that inhibits three steps in the viral replication process and knocks down viral load and improves liver health faster than lamivudine or adefovir. A 0.5-mg daily pill is recommended if you have never been treated with an antiviral, and a 1-mg daily tablet is recommended for lamivudine-resistant patients.

Despite that good news, 10 percent of lamivudine-resistant patients develop resistance to entecavir after 96 weeks of treatment, and that resistance rate increases with time. Bottom line, if you’ve developed resistance to lamivudine, your HBV will be much less susceptible to entecavir.

Telbivudine (Tyzeka), approved in October 2006, also inhibits HBV replication and early reports indicate it lowers viral load and improves liver health faster than adefovir and lamivudine after one year. According to one report, telbivudine resistance occurred in 4.5 percent of patients after 48 weeks. How this antiviral will perform against lamivudine- and adefovir-resistant HBV is not yet clear.

Tenofovir has not yet been approved by the FDA for hepatitis B treatment, but this antiviral has been used safely for years to lower HIV viral load. It appears to be highly effective against lamivudine-resistant HBV and moderately effective against adefovir-resistant HBV. A recent study of 69 patients, who had never been treated with an antiviral before, showed consistent suppression of HBV DNA and no signs of viral resistance after five years of tenofovir treatment. HBeAg seroconversion was documented in 36 percent of the patients and HBsAg loss in 8 percent after two to three years. Some physicians are using this drug “off label,” even though it has not yet been approved by FDA, to treat hepatitis B patients who have developed resistance to lamivudine and adefovir.
Today, many doctors who treat adults use entecavir as first-line therapy because of the quick drop in HBV DNA and improvement in liver health it produces. However, many still use adefovir as a first treatment choice. How the recent FDA approval of telbivudine will affect their approach is unknown, said Rosenthal.
Patrick Marcellin, MD, head of the viral hepatitis research unit at Beaujon Hospital in Clichy, France, and a professor at the University of Paris, has researched antiviral resistance to hepatitis B drugs. With lamivudine out as a first-line therapy contender, “[t]here is no consensus about which antiviral to use first,” he said. “Personally, I’d choose either adefovir, telbivudine or entecavir as first choice,” in patients who tested positive or negative for the hepatitis B “e” antigen (HBeAg), and who had elevated ALT levels and a high viral load (HBV DNA).
“The virological response varies widely between patients and should be assessed after 24 weeks of therapy,” Marcellin added. “If HBV DNA remains detectable after 24 weeks, the drug needs to be changed.”

Stephen Locarnini, divisional Head of Research and Molecular Development at the Victorian Infectious Diseases Reference Laboratory in Melbourne, Australia, and an expert in antiviral resistance, has written research papers that encourage doctors to choose antivirals that have the “highest genetic barrier for resistance,” which will generate a low rate of resistance to other antivirals.
Locarnini writes that of all the antivirals either approved by FDA or in late clinical trials, entecavir and tenofovir have the highest rate of “genetic resistance.” Though the FDA has not yet approved tenofovir for hepatitis B, some physicians in the United States are prescribing tenofovir for patients who do not respond (and have probably developed resistance) to lamivudine and adefovir. Doctors are permitted to prescribe non-FDA approved drugs “off-label” if there is no adequate FDA-approved drug available.
Like Marcellin, Locarnini suggests that if an antiviral proves to be ineffective in lowering viral load and ALT levels after 24 weeks of treatment, then another antiviral that does not target the same HBV genetic material or reproduction step should be used. “Resistance will be prevented, or its emergence delayed, by using this approach,” he wrote in a recent report.
One patient, an Asian-American who has had hepatitis B since childhood and a family history of HBV-related liver cancer, is typical of patients who over time fail to respond to lamivudine treatment, followed by adefovir. “I had been on lamivudine for two years and then adefovir for 1.5 years, and my viral load dropped from 2.5 billion (copies/mL) to 90,000 copies (copies/mL),” she said. “For about six months, my viral load lingered at 90,000 and would not decrease despite the combination treatment of lamivudine and adefovir," she reported. “I began taking tenofovir one month ago in addition to a decreased dose of lamivudine (150 mg down to 100 mg). I had a blood test exactly four weeks after starting tenofovir and I just found out I have an undetectable viral load for the first time.”
Identifying viral resistance when it happens – usually indicated by a resurgence of HBV DNA and an increase in ALT – and preventing it for as long as possible is essential to long-term effective treatment. Studies show that infections with antiviral-resistant HBV are often more virulent and lead to liver damage faster than infection with non-resistant HBV.
According to Locarnini, if HBV DNA levels persist at greater than 1,000 copies/mL after six months of lamivudine or telbivudine therapy, there will probably be viral resistance after one year of treatment.
When adefovir is administered in HBeAg-negative patients, it was found that a viral load higher than 1,000 copies/mL after one year of therapy, “was associated with a significant risk of developing resistance by year five of treatment,” Locarnini noted.
Locarnini also urges doctors not to wait for clinical signs of drug resistance, such as elevated ALT, before changing their antiviral treatment regimen. Instead, HBV DNA should be closely monitored because a continued elevated viral load, or a surge in viral load, will be the first indicator of drug-resistant HBV.
Locarnini predicts that treatment strategies will eventually include a combination of antivirals that attack different parts of the HBV’s genetic material to prevent future cross-resistance. “A second strategy, based on a very early (drug) add-on regimen, would be to start with a drug having a very low rate of resistance and then add a second drug if (HBV DNA) levels do not decline below a threshold,” he wrote.
Given the potential for early HBV resistance, and future cross-resistance, patients should discuss their first and subsequent antiviral choices carefully with their doctors. Also, be prepared to challenge your health insurance or managed care plan if it tries to steer you towards the cheapest antiviral on the market, which is currently lamivudine.

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