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AASLD 2012 Liver Meeting
HBV Coverage

by Christine M. Kukka

Hepatitis B experts from around the world, meeting at the 62nd annual American Association for the Study of Liver Diseases conference, shared the latest in hepatitis B treatment and research. Here are some of the highlights.

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New Treatments

Improving Patient Care

Treating Children and Teens

Combination Interferon and Antiviral Treatment

When can patients stop taking antivirals?

Side Effects from Antivirals

Entecavir vs. Tenofovir

Liver Cancer

HBV Transmission to Newborns

Preventing Hepatitis B Reactivation in Cancer Patients


New Treatments

Second-generation REP 9AC' clears HBsAg within weeks: Last year, researchers surprised the hepatitis B world when they debuted a new drug—REP 9AC—that stopped hepatitis B virus (HBV)-infected liver cells from manufacturing hepatitis B surface antigen (HBsAg) within weeks in more than half of patients treated. HBsAg is crucial for viral replication.

This year, a second-generation version called REP 9AC’ (nucleic acid-based amphipathic polymer—NAP) was combined with either pegylated interferon or Zadaxin (both drugs stimulate the immune system to fight infection) to assess the combined drugs' effectiveness.

The 12 patients in the study were HBsAg-positive with high viral loads (with HBV DNA exceeding 1 million copies/ml). Ten of 12 patients cleared HBsAg and developed surface antibodies after 20 to 30 weeks of treatment. Clearance of HBsAg reduced HBV DNA on average by between 250,000 to 1 million copies/ml.

"REP 9AC’ can rapidly and effectively clear HBsAg from the serum of infected patients and allow the restoration of an effective immune response, as evidenced by substantial reductions in serum HBV DNA," researchers wrote. Combination treatment with immune stimulants may leads to, "a permanent control of HBV infection."

  • 424. REP 9AC’: A second generation HBsAg release inhibitor with improved tolerability

New interferon causes fewer flu-like symptoms. A 24-week study comparing standard pegylated interferon with a new interferon, called pegylated interferon-Lambda, found Lambda was more potent and caused fewer side effects.

In this global study, 80 patients were treated with lambda and 83 with standard interferon. Most were male, Asian, with genotypes B and C and elevated ALT levels and high viral loads. Lambda-treated patients had significantly greater reduction in HBsAg levels and HBV DNA. HBeAg losses were similar in both groups. Two patients (both Lambda recipients) cleared HBsAg.

Patients treated with conventional interferon had higher rates of fever, hair loss, headache, muscle pain (76% vs 8%). These results match similar findings in hepatitis C patients treated with Lambda.

  • LB-14. Peginterferon Lambda, a New Potential Therapeutic Option for the Treatment of Chronic Hepatitis B: A Phase 2B Comparison with Peginterferon Alfa in Patients with HBeAg-Positive Disease

Improving Patient Care

Primary care providers fail to properly care for hepatitis B patients:  A study into the quality of care that 12,016 hepatitis B patients enrolled in a Northern California Kaiser Permanente Medical Care Program received between July 2009 and December 2010 found that while most specialists ordered the screenings required to monitor these patients' health properly, but primary care providers frequently failed to order lab test and liver cancer screenings recommended by medical guidelines.

  • 311. Chronic Hepatitis B Management in a California Integrated Care Population

New education tool helps patients learn about hepatitis B: Studies show the need to educate patients about hepatitis B in ways that make the complex infection understandable, especially if they have limited English proficiency (in the U.S.) or have limited knowledge about infection. One study found that having a health educator of a shared ethnicity was effective. In another one study, to simplify the complex stages of chronic hepatitis B infection, Australian physicians tried using an illustration of a bear, along with different terminology, to describe inactive, active and other phases of HBV infection.

They tried replacing current infection descriptors such as silent, damaging, controlled, escape and clear (for HBsAg loss) by using descriptions of a bear—hibernating, attacking, in a cage, breaking out of cage, and dead—to illustrate the infection.

Knowledge about hepatitis B increased among 30 patients who were given the new bear illustrations. Overall, 83% of patients reported the "bear" references were more effective in educating them about the phases of infection.

  • 334. The Hepatitis B Bear: Novel patient orientated information enhances patient understanding of the phases of Hepatitis B
  • 431. Disease and Treatment Perceptions Among Asian Americans Diagnosed with Chronic Hepatitis B Infection

Normal ALT levels can be misleading:  A U.S. study followed 40 Asian-American patients who initially had normal alanine transaminase (ALT) levels—showing no liver damage—after liver biopsies. Their ALT levels were tested every six weeks and 40% were found to have spikes in their ALT levels that indicated liver damage, underscoring the need to regularly test even patients with normal ALT levels and to treat as needed.

Another study found similar rates of inflammation and fibrosis among HBeAg-positive patients even if their ALT levels were normal or slightly elevated. Just under one-third of these patients with normal or moderately-elevated ALTs were found to have fibrosis. Both groups had similar HBV DNA levels.

  • 457. Clinical Course and Outcomes of Asian Patients with Chronic Hepatitis B (CHB), Normal ALT, and Live Biopsy (LB) Report of Mild Liver Injury
  • 354. Significant fibrosis in liver biopsies from HBeAg-positive chronic hepatitis B patients with low ALT

Treating Children and Teens

Pegylated interferon and tenofovir highly effective: Two studies found that two treatments—to date approved only for adults—appear highly effective in children. Thirty-one children, ages 2-16, treated with a weekly dose of pegylated interferon for up to 104 weeks, achieved undetectable HBV DNA. Additionally:

  • 41.2% cleared HBsAg and 35.3% developed surface antibodies and cleared the infection.
  • 41.2% of older children and 47.1% of younger children lost HBeAg and developed "e" antibodies. None of the children experienced any relapses up to 12 weeks after treatment ended.

A study into the effectiveness of the antiviral tenofovir (Viread) in adolescents, compared to a placebo-treated group, showed that after 72 weeks of treatment, 96% of patients who had high ALTs achieved undetectable HBV DNA, 75% had normal ALTs, and 31% lost HBeAg. Among those with moderately-elevated ALTs at the start of the study, 79% achieved undetectable HBV DNA and 71% had normal ALT levels—showing the antiviral worked well in both groups.

  • 387. The efficacy and safety of peginterferon treatment in children with chronic hepatitis B
  • 371. Tenofovir treatment results in high rates of virologic suppression and ALT response in adolescents with chronic active hepatitis B regardless of baseline ALT levels

Combination Interferon and Antiviral Treatment

Pegylated interferon plus an antiviral show promise:  Several studies examined whether sequential treatment with interferon and antiviral could result in higher rates of viral clearance.

One study administered pegylated interferon to patients who had already achieved undetectable HBV DNA through antiviral treatment to see if the 48 weeks of interferon would strengthen the patients' immune systems enough to clear the infection.

Half of 16 patients receiving the combination treatment lost HBsAg (all were HBeAg-negative when starting treatment), and five of them ultimately developed surface antibodies and cleared the infection. Two of five HBeAg-positive patients lost HBeAg during combination treatment.

Another study found 18% of patients treated with entecavir and interferon lost HBeAg, compared to 8% who received just the antiviral. Slightly more patients treated with both drugs achieved undetectable HBV DNA and HBsAg loss. One of 84 patients receiving both entecavir and interferon lost HBsAg. Adding 24 weeks of interferon to ongoing antiviral treatment, "increases HBsAg decline and clearance of HBeAg and may therefore improve the chances of finite treatment in HBeAg-positive patients..." researchers wrote.

  • 430. Improvement of HBsAg Loss by additional PEG IFN in Nucleosides Analogs treated Chronic Hepatitis B Patients
  • 19. Adding peginterferon alfa-2a to entecavir increases HBsAg decline and HBeAg clearance - first results from a global randomized trial (ARES study)
  • 485. Quasispecies analysis of HBV strains isolated from chronic hepatitis B patients treated with Peg-interferon+Tenofovir therapy

When can patients stop taking antivirals?

After clearing HBsAg: Several studies explored when it was safe for patients to stop taking antivirals. Physicians had hoped they could wean patients off antivirals after they lost HBeAg and/or had several months of undetectable HBV DNA and healthy ALT levels. Unfortunately, those endpoints have not been successful and many of these patients have experienced resurgences in infection after stopping treatment.

During this conference, researchers reported that once patients achieve undetectable viral load and lose HBsAg, they may be able to stop antiviral treatment. One study followed 58 patients (47% HBeAg-positive at start of treatment) who cleared HBsAg after nearly four years of lamivudine or entecavir treatment. Twenty months after treatment stopped, two redeveloped HBsAg, but their HBV DNA remained undetectable. Twelve of the 58 developed detectable HBV DNA, but none ever had high viral loads or had "flares" in their ALT. "HBsAg seroclearance following (antiviral) therapy is rare, but durable in most patients ... after treatment discontinuation," they wrote. "Therefore, HBsAg seroclearance would be an ideal treatment endpoint during (antiviral) therapy."

Other studies followed patients for one year who stopped antivirals after 18 months of undetectable HBV DNA—but not undetectable HBsAg. A resurgence in viral load developed in 22 (48.9%) and 33 (73.3%) patients at 6 months and 12 months after therapy. Other studies underscored the risk posed by prematurely stopping antivirals, especially in HBeAg-negative patients, even if they have had undetectable HBV DNA for extended periods.

  • 313. Is HBsAg seroclearance following nucleoside analogue therapy durable in patients with chronic hepatitis B?
  • 362. Nucleos(t)ide analogues can be safely discontinued in chronic hepatitis B patients achieving HBsAg seroclearance
  • 336. Durability after discontinuation of nucleos(t)ide therapy in hepatitis e antigen negative chronic hepatitis B patients
  • 447. High relapse rates in HBeAg negative chronic hepatitis B patients after discontinuation of nucleos(t)ide analogues

Side Effects from Antivirals

As more patients are treated for longer periods with antivirals, doctors are identifying side effects that include mild kidney damage and bone density loss.

Impact on kidneys: One study followed 528 patients (180 taking adefovir (Hepsera), 128 tenofovir, and 220 entecavir (Baraclude) for three to five years. They found adefovir-treated patients had higher creatinine levels in their bloodstream, indicating reduced kidney function, compared to tenofovir- and entecavir-treated patients after one year. Eleven adefovir patients had to change to another antiviral due to kidney impairment.

Another study of 124 patients taking either entecavir or tenofovir found only mild impact on kidney function, and another study found that patients who had kidney problems with adefovir regained normal kidney function after switching to tenofovir.

However, a French study found that HBV-infected patients already had reduced kidney function even before starting antiviral treatment. They found kidney abnormalities in one-third of patients screened, and chronic kidney disease in one-quarter of HBsAg-positive patients, regardless of disease state. They recommended that all patients have renal evaluations before and during antiviral treatment in order to monitor kidney health and adjust antiviral dosing as needed.

Impact on bone density: Researchers measured bone mineral density (BMD) loss in patients treated with tenofovir for 12 months or more. They found BMD loss in 43% of the patients.

  • 385. Renal Abnormality in Chronic Hepatitis B Patients Treated with Oral Nucleos(t)ide Analogs
  • 443. Do tenofovir and entecavir affect renal function in patients with chronic hepatitis B (CHB)? A two-year observational study from a single Australian centre
  • 921. HARPE study: prevalence of renal abnormalities in chronic HBV infection
  • 406. Switching to tenofovir is safe in most chronic hepatitis B patients with a reduced glomerular filtration rate due to previous exposure to adefovir dipivoxil
  • 22.FRAX score in the assessment of Bone Mineral Density changes in Tenofovir treated Chronic Hepatitis B patients: comparison with bone biochemistry and DEXA scanning

Tenofovir Continues to be highly effective, even with multi-drug resistance: Several studies, including a six-year, multinational study following 466 patients, found this antiviral to be highly effective in suppressing HBV DNA, with no signs of tenofovir-resistance developing. The long-term study also found low rates of kidney problems and no evidence of "clinically-relevant" bone loss.

Even when drug resistance to both lamivudine (Epivir-HBV) and adefovir have developed, one study found four years of tenofovir treatment continued to keep HBV DNA at low or undetectable levels, with no signs of tenofovir-resistance.

  • 374. Six years of treatment with tenofovir DF for chronic hepatitis B virus infection is safe and well tolerated and associated with sustained virological, biochemical and serological responses with no detectable resistance
  • 361. Tenofovir rescue therapy achieves long-term suppression of HBV replication in patients with multi-drug resistant HBV: 4-year follow-up of the TDF109 cohort

Entecavir Research shows continued effectiveness: Studies find this antiviral to continue to be highly effective, with 49.88% achieving normal ALTs after six months, 54.42% at one year and 57.97% after four years. HBeAg seroconversion rates were 10.26% after six months, 16.54% after one year and 24.39% after four years.

Usage was also found to decrease liver cancer risk due to lowered viral load, and other studies showed the drug was effective in reducing recurrence of liver cancer and also lesions on the liver.

One study showed a small rate of antiviral resistance in entecavir in patients who failed to achieve undetectable viral load after 48 weeks. Three years into treatment, 1.6% of those who initially responded had a resurgence in viral load, and 5.9% of those who did not completely respond in the first 48 weeks of treatment had viral breakthrough.

  • 351. Entecavir monotherapy in NA naive chronic hepatitis B and cirrhosis patients: A retrospective and prospective cohort study over 4 years of treatment
  • 367.Entecavir treatment significantly reduces the risk of hepatocellular carcinoma recurrence in patients with chronic hepatitis B
  • 376. Long-term efficacy of continuous entecavir 0.5 mg monotherapy in naïve chronic hepatitis B patients with partial virological response at week 48

Entecavir vs. Tenofovir

Is one better than the other? Real world treatment data shows there is little difference in the effectiveness of these two antivirals, which are currently recommended as the top two antivirals for treating hepatitis B.

One study compared two years of data from 130 entecavir-treated patients and 121 tenofovir-treated patients—both groups had similar levels of infection and liver damage, and about one-third in each group were HBeAg-positive.

There was no significant difference in HBV DNA levels after one year of treatment, however, two years into treatment, more entecavir patients had lost HBeAg than those treated with tenofovir. But even those rates began evening out into the third year of treatment.

In patients with cirrhosis, entecavir and tenofovir also appeared to be equally effective.

  • 337. Entecavair [sic]versus tenofovir in treatment-naïve chronic Hepatitis B patients: Real-world data from the realist* study
  • 390. Long-term clinical outcomes of entecavir and tenofovir in hepatitis B cirrhosis

Liver Cancer

Antiviral treatment reduces liver cancer risk: A U.S. study following 2,463 patients found that those who were treated with antivirals were at lower risk of liver cancer. The incidence of liver cancer was 3.3 cases per 1,000 person-years among those treated with antivirals, and 5.3 cases per 1,000 person years among those who were not treated. Other risk factors for liver cancer included older age and male gender.

  • 318. Hepatitis B therapy and incidence of hepatocellular carcinoma in a U.S. population

Genotype D appears to carry higher risk of liver cancer, despite antiviral treatment: Even prolonged antiviral treatment does not appear to lessen liver cancer risk in older adults with hepatitis B genotype or strain D. Researchers in Italy followed 235 patients with HBV genotype D who had been treated with antivirals and discovered that 32 (13.2%) developed liver cancer over a seven-year period. Liver cancer occurrence was higher in these genotype D patients who had cirrhosis, were age 60 or older, and who had not completely responded to antiviral treatment.

  • 21. Impact of liver fibrosis in development of hepatocellular carcinoma in HBeAg negative genotype D patients with chronic hepatitis B treated with nucleos(t)ide analogues.

Past lamivudine use may raise liver cancer risk: In a unique study, researchers compared liver cancer risk in patients who had been successfully treated with antivirals. Despite achieving low viral loads, a small group of older patients developed liver cancer—many of whom had been treated with lamivudine. "The association with lamivudine exposure raises the possibility of drug-induced mutations associated with an increased risk of liver cancer development - this possibility is currently under investigation," they wrote.

  • 332.Hepatocellular carcinoma risk in chronic hepatitis B patients achieving viral suppression with antiviral therapy.

HBV Transmission to Newborns

Amniocentesis increases HBV risk to newborns: A joint U.S.-Chinese study found that performing amniocentesis on HBV-infected pregnant women increased the risk that their infants would become infected—especially if the women had high HBV DNA levels.

  • 904. Risk of hepatitis B virus (HBV) vertical transmission after amniocentesis in mothers with chronic hepatitis B

Preventing Hepatitis B Reactivation in Cancer Patients

Experts: Don't use lamivudine to prevent reactivation during chemotherapy: Two studies suggest the antiviral lamivudine should not be used in cancer patients who have inactive or resolved hepatitis B infections. Chemotherapy weakens the immune system and can contribute to life-threatening reactivation of hepatitis B. Because of this, physician often prescribe antivirals to prevent reactivations during cancer treatment.

One study described two men, both HBeAg-negative, who was treated with chemotherapy for lymphoma. They were both given lamivudine during treatment to suppress any HBV DNA resurgence. However, several months after chemotherapy ended, both died from liver failure despite their continued lamivudine treatment.

"Lamivudine should not be used for prophylaxis of patients with chronic hepatitis B with detectable HBV DNA undergoing chemotherapy with R-CHOP, even if they have never had exposure to lamivudine in the past," researchers wrote. "In this setting, lamivudine failure due to resistance can develop quickly leading to liver failure that cannot be salvaged with tenofovir."

In another study, researchers compared the effectiveness of lamivudine, telbivudine (Tyzeka) and entecavir in preventing HBV reactivation after chemotherapy for a variety of cancers. They found lamivudine to be the least effective.

  • 435.Death from liver failure despite lamivudine prophylaxis during R-CHOP chemotherapy due to rapid emergence M204 mutations
  • 906. Comparison of lamivudine, telbivudine, and entecavir as antiviral prophylaxis for patients with hepatitis B undergoing cytotoxic chemotherapy


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