The 60^th American Association for the Study of Liver Disease (AASLD) convened in Boston in early November to review the latest global research into the prevention and treatment of liver diseases, including hepatitis B virus (HBV) infection. Below is an overview of recent clinical trials and other hepatitis B-related research.

· A Turkish study that followed 230 patients for five years after 48 weeks of pegylated interferon treatment ended found that 17% achieved inactive hepatitis B (low viral load and no signs of liver damage) and 12% cleared the hepatitis B surface antigen (HBsAg), which indicates a near clearance of the virus. Patients who benefited most started treatment had elevated alanine aminotransferase (ALT) levels, which indicates liver cell damage, and low HBsAg levels. Patients with low HBsAg six months into treatment had higher chances of clearing the infection.

· Chinese researchers compared the effectiveness of 48 weeks of pegylated interferon treatment against 72 weeks of the antiviral adefovir (Hepsera) in hepatitis B “e” antigen (HBeAg)-positive patients who had developed viral resistance to the antiviral lamivudine. They found HBeAg seroconversion (loss of HBeAg and development of the “e” antibody) to be much higher in patients treated with interferon (11.6%) versus adefovir (3.8%). The rate of HBeAg seroconversion six months after treatment ended was twice as high in those treated with interferon. Researchers concluded that interferon is an excellent strategy for difficult-to-treat patients with lamivudine resistance.

· Another Chinese study found extending interferon treatment from the currently recommended 48 weeks to 72 weeks produced a higher rate of HBeAg seroconversion and HBsAg clearance. In one study, 67 HBeAg-positive patients with elevated ALT levels received either interferon or entecavir for 72 weeks. Half of the interferon patients seroconverted compared to 33% of the entecavir patients. A second Chinese study also found that extending interferon treatment markedly improved HBeAg clearance and decreased HBsAg levels.

· Greek researchers compared HBsAg loss in untreated patients against HBeAg-negative patients treated with interferon. Untreated patients spontaneously cleared HBsAg at an annual rate of 1.79%, those treated with interferon experienced an 11% clearance rate, and those treated with adefovir over five years had a 33% clearance rate.

· Chinese researchers assessed outcomes among 113 patients treated with either interferon alone, a combination of interferon and adefovir, or adefovir alone for 48 weeks followed by a 48-week follow-up period. Viral load declined more than three-fold in 42% treated with just interferon, 63% treated with the combination, and 23% of those treated with only adefovir. HBsAg clearance and development of surface antibodies at week 96 occurred in 3% of the interferon and adefovir group. None of the patients treated with just adefovir cleared HBsAg.

Interferon and Antiviral Combinations

Combination treatments employing both pegylated interferon and antivirals, which disrupt the viral reproduction process, has yielded inconclusive results to date.

· Chinese researchers followed 113 HBeAg-positive patients treated with either interferon only, adefovir only, or a combination of the two, to see which group cleared HBeAg and gained the "e" antibody at week 24, 48, and 96. HBeAg clearance was significantly higher at all time points in the two groups treated with interferon. At week 96, 42% of interferon-only, 49% of interferon and adefovir, and 15% pf adefovir-only treated patients, respectively, cleared HBeAg. Similarly, there was a significantly greater rate of HBeAg seroconversion at week 96 in the combination group than in the adefovir-only group, and similarly those receiving interferon experienced the highest decline in viral load (HBV DNA). HBsAg clearance and HBsAg seroconversion at week 96 were achieved by 3% of the interferon and adefovir-treated patients, compared with none of the adefovir patients. One year after treatment, the combination group largely sustained their response and low viral load, which was encouraging.

Tenofovir (Viread):

Tenofovir continues to do very well in long-term studies worldwide.

· One European study of 175 patients who had resistance to other antivirals found 92% of them achieved undetectable HBV DNA after 24 months of treatment, and HBeAg and HBsAg loss was observed in 24 patients (19%) and 5 patients (3%) respectively after an average treatment length of nine and 14 months respectively. No patients experienced a viral rebound due to the development of antiviral resistance, and no kidney problems resulted from the treatment. “Tenofovir therapy was well tolerated and induced a potent and long lasting antiviral response in (antiviral)-experienced patients with previous treatment failure,” researchers wrote.

· The Antiretroviral Pregnancy Registry, which reports birth defects worldwide, followed 942 births to HIV- and HBV-infected women who have been treated with tenofovir between 1989 and 2008. No increase in prevalence of birth defects was reported by the international registry.

· A U.S. study followed 43 patients with resistance to one or more antivirals who were then treated with tenofovir. All patients achieved normal ALT levels and undetectable viral load within six months.

· British and U.S. researchers followed 92 patients, 60 of whom were treated with tenofovir, to see what impact the antiviral had on bone loss. They reported that a higher percentage of tenofovir-treated patients (77%) had low vitamin D levels, which leads to bone loss. Doctors were encouraged to recommend vitamin D and calcium supplements, with frequent monitoring, to prevent bone loss and reduce side effects.

· U.S. researchers followed 364 patients treated with tenofovir over a three-year period to see what, if any, antiviral resistance occurred in these patients. They found no viral resistance to patients. A viral rebound occurred only in patients who did not take the antiviral dose as recommended.

Entecavir (Baraclude):

· An international team treated 354 patients with either lamivudine or entecavir to see how many cleared HBsAg after 120 weeks of treatment. They also tracked which genotype responded best to antiviral treatment. Patients with HBV strain or genotype A or D had a higher rate of clearing HBsAg (7.7% and 8.1% respectively) than patients with genotypes E or C in both treatment groups. Among those treated with entecavir, 18 or 5.1% lost HBsAg. Only 2.8% of lamivudine-treated patients lost HBsAg. This is among the first studies that explore which HBV genotypes respond best to antivirals.

· A U.S. study found that patients who had never been treated with antivirals fared best when treated with entecavir. The study of 109 primarily Asian-American patients in their 50s found that the response (normal ALT and undetectable viral load) was highest in those who were HBeAg-negative and had a moderate viral load when beginning treatment. After 12 months of treatment, 59% of HBeAg-positive patients responded compared to 90% of HBeAg-negative patients.

· A separate U.S. study followed 153 patients treated with entecavir over a three-year period. The average age was 51, most patients were of Asian descent, and most had elevated ALT levels. The rates of lowered viral load were 78%, 92%, and 98% at 12, 24 and 36 months in patients with elevated ALT, and 69%, 75%, and 86% in patients with moderate viral load. The response rates were highest in patients who had never been treated beforehand, and response rates among HBeAg-positive patients over 12, 24, and 36 months were 59%, 80%, and 90% and among HBeAg-negative patients they were 90%, 96%, and 100%. Researchers concluded that entecavir was most effective patients who were HBeAg-negative and who had never been treated.

· An Italian study of 376 mostly HBeAg-negative patients who were treated with entecavir for 72 weeks responded well to the antiviral with no signs of antiviral resistance. However, one fourth of high-viral-load patients showed only a partial response to the drug.

· Meanwhile, a South Korean study found that treating lamivudine- and adefovir-resistant patients with entecavir was ineffective. Most of the patients in the study were male and HBeAg-positive. Only 13% of these patients maintained undetectable viral load after 12 months of treatment.

· German researchers report that a high percentage of patients treated with entecavir develop a side effect called lactic acidosis, which occurs when antivirals prevent mitochondria from using oxygen to effectively convert food into glucose. When this occurs, lactic acid builds up in the bloodstream. The researchers followed 16 patients with liver cirrhosis who were treated with entecavir. Five out of the patients developed lactic acidosis. All patients with lactic acidosis had impaired liver function. Lactic acidosis was lethal in one patient but resolved in the other cases after drug usage stopped. “Our data indicate that lactic acidosis may be observed in patients with chronic hepatitis B and impaired liver function during treatment with entecavir,” they reported. “Thus, entecavir should be applied cautiously in patients with high MELD-Scores (indicating severe liver damage).”

Adefovir (Hepsera)

Increasingly, researchers are finding that long-term adefovir treatment can cause kidney damage. Japanese researchers who followed 37 patients treated with adefovir after they developed lamivudine resistance found that 11% of them had kidney problems. They encouraged doctors to track renal function carefully during treatment in order to identify if reducing adefovir dosing was necessary to prevent kidney damage.

Telbivudine (Tyzeka)

· Greek researchers followed 213 HBeAg-positive and 185 HBeAg-negative patients treated with telbivudine over four years. They found 79% of HBeAg-positive patients had undetectable viral load and 86% had normal ALT levels, with 55% losing HBeAg and 42% seroconverting over four years. Among the 185 HBeAg-negative patients, 84% had undetectable viral load and 91% had normal ALT levels. ALT flares occurred in 3% of patients.

· Chinese researchers found a similar high response to telbivudine among 213 HBeAg-positive patients. The rate of ALT normalization and undetectable HBV DNA at weeks 12, 24 and 48 were 91.2%, 95%, and 96% respectively. HBeAg loss and seroconversion at week 24 and 48 were 43.3% and 55.8%. “It was remarkable that after a four-week telbivudine treatment, HBV DNA decreased more than (3-fold) with corresponding HBeAg decline in about 70% of telbivudine-treated patients,” researchers wrote. The dramatic decline in HBeAg was probably linked to the high rate of HBeAg seroconversion, they suggested.

Development of Antiviral Resistance

· Chinese researchers followed one patient who was treated over 80 months with a succession of antivirals including lamivudine, adefovir, and entecavir. They identified the viral mutations that evolved with the administration of each successive antiviral. They concluded that the evolution of viral mutations that can resist antivirals is a stepwise, selective process and that doctors should be very careful when treating patients with antivirals.

· Japanese researchers made a similar finding when tracking patients treated with lamivudine and adefovir. They found the resulting viral mutations could also resist entecavir. “The risk of multiple drug-resistant strains with long-term therapy must be considered,” they wrote, especially in patients who do not completely attain undetectable viral load.

Treatment in Patients with Severe or Decompensated Liver Disease:

· A global team of researchers treated 112 people with decompensated liver disease with either tenofovir, the experimental antiviral emtricitabine combined with tenofovir, or entecavir to see if the antivirals were safe in this high-risk population. Through week 48, all treatments were generally well-tolerated with improvement in viral suppression and liver health.

Impact of HBV Strains or Genotypes:

· Spanish researchers followed 51 patients who lost HBeAg to see what impact HBV genotype had on the development of viral mutations and elevated viral load. They found that patients with detectable HBV DNA after HBeAg seroconversion were older, more often infected by HBV genotype D, and had precore and core promoter mutations.

Assessing When Treatment Will Work

To avoid costly treatment and severe side effects, researchers are searching for ways to determine whether interferon treatment will succeed as early in the treatment process as possible.

· One European study followed 133 HBeAg-negative patients treated with an antiviral and pegylated interferon. They found that reductions in viral load and HBsAg at week 12 indicated if a patient would benefit from continued treatment.

· A separate Dutch study similarly followed HBsAg levels and viral load in 28 HBeAg-positive patients treated with a combination of pegylated interferon and adefovir for 48 weeks. They found a strong decline in HBsAg levels during the first 24 weeks of treatment was associated with HBeAg loss and seroconversion, while high levels of HBsAg and HBV DNA at week 24 predict treatment failure.

Alternative Treatment

High caffeine consumption is associated with lower risk of liver inflammation in those with viral hepatitis.

· A Canadian study examined whether caffeine intake from caffeinated cola or tea produced the same beneficial results in 177 patients with viral hepatitis and other liver diseases. They reported that caffeine from two cups of coffee daily lowered the risk of fibrosis far more effectively than when caffeine was derived from other sources.

Quality of Care Faulted

· A U.S. study found that only 32% of primary care providers adequately treat Asian-American patients for hepatitis B. Fifty-eight percent of the doctors surveyed reported they recommended their HBV-infected patients be monitored three or more times a year, but only 39% of their patients returned for the recommended monitoring. About 62% of doctors were not familiar with current treatment guidelines. Researchers concluded that while most doctors consider hepatitis B to be a serious disease, only one-third adequately screen their Asian-American patients for the infection. More education among doctors about hepatitis B, disease progression, and treatment, is required.

· Another U.S. study found Asian-American physicians living in large cities also failed to adequately screen their Asian-American patients for hepatitis B. While 90% of the Asian-American physicians reported to screening some Asian-American patients for hepatitis B, fewer than half ported that they had screened more than 25% of their Asian-American patients for HBV.

HCV-HBV Coinfection

· A team of Taiwanese researchers followed 108 patients coinfected with HBV and the hepatitis C virus (HCV) who were treated with ribavirin and pegylated interferon, which is the standard of treatment for hepatitis C. Surprisingly, this treatment was effective against hepatitis B. Eighteen months after treatment ended, researchers found that 51 patients (47%) had undetectable HBV DNA, 91 (84%) had undetectable HCV RNA, and 38% of the coinfected patients had undetectable levels of both viruses. Researchers concluded that the current hepatitis C treatment appeared highly effective in patients coinfected with HCV and HBV, and, “The high rates of HBsAg clearance--the closest outcome to cure in chronic hepatitis B--coupled with the similar sustained virologic response rates in HCV-HBV coinfection ... suggests that (interferon and ribavirin) is an effective first-line treatment strategy for this patient group.”

Depression and Interferon Treatment

Hepatitis C patients report a higher rate of depression when treated with pegylated interferon and the antiviral ribavirin then hepatitis B patients treated with interferon and different antivirals.

· Taiwanese researchers compared rates of depression among 85 hepatitis B patients and 90 hepatitis C patients treated with interferon and antivirals. After 48 weeks, three hepatitis B patients and 13 hepatitis C patients reported depression. Researchers concluded that ribavirin may be the cause of increased depressive symptoms in hepatitis C patients.

Mother-to-Newborn (Perinatal) Infection

· Each year about 24,000 infants are born to women with chronic hepatitis B infection with a resulting in section rate of 1%. New York City doctors followed 45 babies were born to HBV-infected Chinese-American mothers, who had been immunized and treated with hepatitis B immunoglobulin (HBIG) at birth to prevent perinatal infection. Twelve of the mothers were HBeAg-positive, 24 were HBeAg-negative, and 9 were not tested. Thirty-eight infants developed immunity to HBV by 24 months of age, three infants tested negative for both HBsAg and surface antibodies. Four infants were HBsAg-positive and anti-HBs negative. None of the infected infants were breastfed or had infected siblings at home. Researchers concluded that the mother-to-child transmission rate was 8.9% in this population, despite the intervention at birth, far higher than previously reported in the U.S.

· Indian researchers followed 158 HBsAg-positive pregnant women and found a surprising number of newborns had “occult” HBV infection despite immediate immunization and injection with HBIG at birth. Occult infection occurs when patients test negative for HBsAg but have measurable HBV DNA in their bloodstream. Indian doctors found adequate surface antibody protection from HBV infection in 122 (78%) babies (some of whom did not receive HBIG), and only three tested positive for HBsAg. But HBV DNA was present in 51 babies, including some who tested positive for the surface antibody and negative for HBsAg. Researchers concluded that hepatitis B vaccination is effective in preventing mother-to-child infection in 94% of babies. But, nearly 70% of babies born to infected mothers may still have occult HBV infection despite the presence of surface antibodies. “The long-term significance of occult HBV infection and mutations in the HBV (viral) sequences in these babies need to be studied further,” they noted.

When can antiviral treatment be stopped?

· A team of Dutch in Chinese researchers followed 29 patients for 12 months after they stopped antiviral treatment following HBeAg seroconversion to see if this seroconversion represented a safe stopping point for antiviral treatment. There is no medical consensus about when it is safe to stop antiviral treatment. Eight patients had ongoing detectable viral load despite the seroconversion. Ultimately, a sustained response in absence of treatment occurred in only 2 of 9 patients who discontinued therapy after seroconversion. “HBeAg seroconversion induced by (antivirals) was not durable in a majority of cases. These findings may indicate that HBeAg seroconversion, in contrast to what current guidelines suggest, is an imperfect endpoint in assessing antiviral therapy. Treatment with antivirals should thus probably be continued indefinitely or until HBsAg seroconversion,” the researchers noted.