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Hepatitis B experts met at the 61st annual meeting of the American Association for the Study of Liver Diseases in Boston recently to share the latest in hepatitis B treatment and research.  News about promising new treatments, and new information about the effectiveness of existing antiviral and interferon treatments was shared with physicians and researchers. Here are some of the studies unveiled at the conference.

 

Promising New Treatment

New drug clears infection completely within weeks: Canadian and Bangladeshi researchers have identified an experimental drug that resulted in the complete clearance of chronic hepatitis B infection in five of six patients treated with REP 9 AC.

Research suggests that the hepatitis B surface antigen (HBsAg), the protein that provides the “cover” of the hepatitis B virus (HBV), plays a role in suppressing the immune system, which results in chronic or long-term hepatitis B. Researchers administered REP 9AC, a DNA-based polymer that stops infected liver cells from producing HBsAg, in six hepatitis B “e” antigen (HBeAg)-positive patients who had high viral loads and fibrosis.

Five out of six patients treated cleared HBsAg and developed surface antibodies—an indication that the patient has completely cleared the infection. In some patients, this occurred just seven days after starting treatment. In others, this occurred within 15 weeks after receiving higher doses of the drug.

Three patients achieved a 3- to 7-fold reduction in HBV DNA after 7-13 weeks of treatment. Additionally, two other patients cleared HBV DNA, and developed surface antibodies and have stopped treatment and are now being monitored carefully. One of the patients remains HBV-free six months after stopping treatment.

“This rapid HBsAg seroclearance appears to allow the restoration of an effective immune response, as evidenced by substantial reductions in HBV DNA, seroconversion for HBsAg and HBeAg, and the achievement of a six-month sustained response in at least one patient to date,” researchers wrote.

·        482.  REP 9AC: A potent HBsAg release inhibitor that can rapidly restore immunocompetence in patients with chronic hepatitis B

 

Antiviral Treatment

Tenofovir and emtricitabine (FTC): European researchers tried this antiviral combination, which has been used extensively against HIV, in 82 patients and monitored them for its effectiveness and potential antiviral resistance over 15 months.

Six months after starting treatment, viral loads dropped nearly three-fold, and after 12 months 82% of patients had undetectable viral load. In a subgroup with HBeAg-positive hepatitis B, many of whom had significant fibrosis, all had undetectable viral load after 17 months of treatment.

·        403. Efficacy and tolerance of tenofovir disoproxil fumarate plus emtricitabine combination in patients with chronic hepatitis B – A European multicenter study (Updated October 31, 2010)

 

Long-tenofovir works well in HBeAg-negative and –positive patients: Researchers, in separate studies, report tenofovir is highly effective in HBeAg-positive and –negative patients, and causes no drug resistance even after four years of continuous treatment. It was equally effective in Asian and non-Asian populations. Even in HBeAg-positive patients with extremely high viral loads, tenofovir knocked down viral loads to undetectable in 95% of these patients.

·        476. Continued Efficacy and Safety Through 4 Years of Tenofovir Disoproxil Fumarate (TDF) Treatment in HBeAg-Negative Patients with Chronic Hepatitis B (Study 102): Preliminary Analysis

·        477. Long Term (4 Year) Efficacy and Safety of Tenofovir Disoproxil Fumarate (TDF) Treatment in HBeAg-Positive Patients (HBeAg+) with Chronic Hepatitis B (Study 103): Preliminary Analysis

·        481. Four Years Efficacy and Safety of Tenofovir Disoproxil Fumarate (TDF) in Asians with HBeAg-positive and HBeAg-negative Chronic Hepatitis B (CHB), Preliminary Analysis

 

Tenofovir boosts effectiveness of entecavir: California researchers studied how 42 Asian-Americans (HBeAg-positive) who did not respond well to entecavir fared when tenofovir or adefovir were added to ongoing entecavir treatment. They found that adding tenofovir resulted in a high percentage of patients achieving undetectable viral load, compared to adding adefovir or replacing entecavir with tenofovir.

·        433. Response to Alternative Therapies in Patients with Chronic Hepatitis B (CHB) and Entecavir (ETV) Partial Response (PR)

 

Entecavir proves superior to adefovir (Hepsera): Several studies found entecavir to be more effective than adefovir in patients who had never been treated. Entecavir proved to be more effective after 96 weeks of treatment in both HBeAg-positive and –negative patients.

·        464. Evaluation of the efficacy of entecavir versus adefovir in HBeAg-positive chronic hepatitis B patients therapy at 96 weeks

·        405. A prospective randomized comparison of 96 weeks treatment efficacy between entecavir and adefovir in treatment naïve patients with chronic hepatitis B: Association with Change in Serum Hepatitis B Surface Antigen Level

 

Entecavir effective: Spanish researchers treated 190 previously untreated patients (both HBeAg-positive and -negative). After 48 weeks, 83% had undetectable viral load (61% among HBeAg-positive patients and 92% among HBeAg-negative). About 82% who had elevated alanine aminotransferase (ALT) levels (which indicates liver cell damage) developed normal ALTs, 21% achieved HBeAg seroconversion, and two cleared HBsAg.

·        437. Outcomes of Treatment For Chronic Hepatitis B with Entecavir Therapy

 

Benefits from Antiviral Treatment

Reduced fibrosis: A Japanese study showed antivirals were highly effective in reducing fibrosis, which results in liver stiffness, in patients. Untreated, fibrosis can develop into cirrhosis and cancer. This study found that antiviral treatment significantly reduced liver stiffness, while untreated patients had increased liver stiffness and fibrosis.

·        367. Reduction of liver stiffness of chronic hepatitis B patients by antiviral therapy

 

Reducing cancer risk:  Antiviral treatment reduced the 5-year risk of liver cancer by 9% to 41%, according to a Japanese study. Researchers followed 613 HBeAg-positive patients who were screened for liver cancer over 5.5 years, and compared their outcomes to those of 197 patients who had been treated with antivirals for several years.

Interestingly, many of the untreated patients who later developed liver cancer had normal or moderate ALT levels—and therefore did not qualify for treatment under current guidelines. The 5-year cancer rate in the untreated group was 12%.

“The current treatment guidelines for chronic hepatitis B excluded a significant proportion of patients at high risk for liver cancer,” researchers wrote. If doctors use age, platelet counts, viral load, and presence of core promoter mutations as criteria, they would identify more than 90% of patients who are at high risk of liver cancer and should be treated. Antiviral treatment, they noted, “significantly reduced the incidence of liver cancer among these high risk patients.”

·        412. Nucleotide analogues may prolong survival time without recurrence and overall survival time for HBV-related liver diseases after curative treatment of hepatocellular carcinoma.

·        368. Identification of patients at risk for the development of hepatocellular carcinoma in chronic hepatitis B and assessment of the impact of nucleoside analogue therapy on risk reduction: Evaluation of the current treatment guidelines and proposal of novel criteria by data mining analysis

·        440. Long-term effect of lamivudine treatment on the incidence of hepatocellular carcinoma in patients with hepatitis B virus

 

Antivirals effective against cirrhosis: U.S. researchers reviewed numerous studies involving patients with cirrhosis and decompensated hepatitis, which means the liver can no longer function normally. They found that antivirals are effective and safe for treating decompensated cirrhosis. Lamivudine (Epivir-HBV) and entecavir should be avoided if patients have been treated with antivirals previously. Researchers urged more testing of entecavir and tenofovir in these patients, to determine which was more effective.

·        375. A systematic review of oral antiviral agents in decompensated HBV cirrhosis.

 

Side Effects from Antivirals:

Antivirals reduce bone density: Italian researchers followed 319 patients (76% males, average age 63, 57% with cirrhosis) treated with tenofovir, adefovir, and lamivudine either alone or in combination for three to four years to see what impact antiviral treatment had on their reduced bone density.

They found reduced density, which results in osteoporosis and other weak bone conditions, in 68% of the patients. The rate was higher (78%) among female patients. The doctors recommended that patients have a bone mineral assessment performed prior to starting treatment in order to prevent and treat the condition should it occur.

·        414. High prevalence of reduced bone mineral density in patients with chronic hepatitis B under nucleos(t)ides analogues treatment

 

Pegylated Interferon

More patients should be treated with interferon: Current guidelines recommend that patients with elevated ALT levels, low viral load, and genotypes A or B have an increased chance of responding to interferon. U.S. researchers examined 257 patients who received treatment between 2001-2009 to see what percentage of patients who qualified for interferon actually received it. Some patients opt not to take interferon because it is costly, has side effects, and requires injections.

Of the patients in the study, about half could have qualified for interferon, but only 19% received it. These patients were likely to be about age 45, male and Caucasian. Among the 12 with ideal characteristics for interferon, along with genotypes A or B, 42% percent remained in remission after received interferon treatment. Researchers noted that interferon, “is underutilized in the population predicted to have the best response.”

·        396. Interferon is Underutilized in Heptitis B (HBV) Patients Most Likely to Have Favorable Outcomes (Updated October 31, 2010)

·        399. Peginterferon alfa-2b induced HBsAg decline is durable through long-term follow-up in HBeAg-positive patients

·        451. Physician Preference Drives Choice of Oral Hepatitis B Therapy

 

Extended interferon treatment effective in HBeAg-negative patients with genotype D: Increasing the duration of pegylated interferon treatment from 48 to 96 weeks in genotype D patients improved response. Italian researchers compared the two dose lengths in 103 patients and found that 12 months after treatment ended, 11.8% of those treated for 48 weeks had HBV DNA under less than 2,000 IU/mL, and 28.8% of those treated for 96 weeks achieved that outcome.  The current 48-week course of interferon treatment is not recommended for patients with genotype D.

·        135. Safety and tolerability of extended (96 weeks) treatment with peginterferon alfa-2a [40KD] in genotype D patients with HBeAg-negative chronic hepatitis B

 

Combination Treatment

Extended treatment with antivirals and interferon combo effective: Forty-one HBeAg-positive patients with genotypes B or C received pegylated interferon with either lamivudine or adefovir for 96 weeks (previously the recommended course was 48 weeks).

·        After 48 weeks, 96% of patients achieved undetectable HBV DNA, but after 96 weeks of treatment 100% had responded.

·        HBeAg seroconversion: After 48 weeks, 50% of patients treated with interferon and lamivudine achieved HBeAg seroconversion, after 96 weeks 75% did. Forty-four percent of the interferon-adefovir group achieved seroconversion after 48 weeks, but 71% did after 96 weeks.

·        HBsAg clearance: In the interferon-lamivudine group, HBsAg seroconversion rates were 8% after 48 weeks of treatment and 30% after 96 weeks. In the interferon-adefovir group, HBsAg seroconversion was 4% after 48 weeks and 24% after 96 weeks.

No additional side effects were reported in those who received the longer treatment.

·        377. Treatment of HBeAg-positive CHB infection with peginterferon alfa-2a [40KD] plus lamivudine or adefovir for 96 weeks results in high rates of HBsAg clearance/ seroconversion

 

Customizing interferon and antiviral treatment effective: Chinese researchers treated 92 HBeAg-positive patients with pegylated interferon, and then measured their HBV DNA at week 12 in order to try individualized treatment approaches for 76 patients who did not respond. These options included the conventional 48-week course of interferon, a combination of interferon with either adefovir or entecavir for 48 weeks, or extended interferon treatment up to 72 weeks. Patients were then followed for 24 weeks after treatment ended.

The rate of sustained response (lowered viral load, normalized ALT levels) was 78.3% in the group receiving extended interferon and 83.3% and 85.7% in the combination groups receiving entecavir and adefovir respectively. The response rate was 38.1% in the conventional group that received only 48 weeks of pegylated interferon.

 

Treating Antiviral Resistance

Antiviral combinations effective: A study of 109 patients treated with antiviral combinations after they developed drug resistance showed the treatment was highly effective and resulted in a rapid decline in viral load. Most of the Asian-American patients (77%) achieved undetectable viral load within six months of starting combinations of entecavir and tenofovir, tenofovir and lamivudine (Epivir-HBV), entecavir and adefovir, and adefovir and lamivudine.

·        440. Long-term effect of lamivudine treatment on the incidence of hepatocellular carcinoma in patients with hepatitis B virus

 

Safe to switch from adefovir to entecavir: U.S. doctors followed 106 patients who had responded—or partially responded—to adefovir and were switched to entecavir. Most were male, in their 40s, and were still HBeAg-positive. Those who had responded to adefovir continued to respond well to entecavir with normal ALTs and low viral load. Eight-two percent of patients who had only partially responded to adefovir eventually responded robustly to entecavir after 24 months of treatment.

·        383. Complete viral suppression (CVS) by entecavir (ETV) in patients previously treated with adefovir (ADV): Interim report for a multicenter study (Updated October 31, 2010)

 

Pregnancy and HBV

Researchers are examining the safety and effectiveness of treating HBV-infected pregnant women with antivirals. Antivirals are used to lower viral load to prevent transmission of infection to newborns and to treat women who are experiencing liver damage, indicated by elevated ALT levels. Even when infants are immediately immunized and treated with HBIG, many born to women with high viral loads still become infected.

Telbivudine (Tyzeka)

Telbivudine proved safe in two studies: Chinese researchers treated 53 pregnant women, in their second and third trimesters of pregnancy, with telbivudine (600 mg daily). Their HBeAg status, ALT levels, viral load, and the health of their infants were evaluated in the study.

At time of delivery, 53% of treated patients had undetectable viral loads and 62% had achieved undetectable viral load four weeks after delivery. Only 4% of infants tested positive for the hepatitis B surface antigen (HBsAg), which indicates infection, compared to 23% of the newborns born to women in an untreated, control group. All infants born to women treated with the antiviral during pregnancy were healthy, and the treatment caused no problems during pregnancy and delivery.

·        364. A Prospective Open-label Study to Evaluate the Efficacy, Safety and Tolerability of Telbivudine (Ltd) in HBeAg + Chronic Hepatitis B (CHB) Pregnant Women

In another Chinese study, 94 HBeAg-positive, pregnant women were treated with telbivudine during their third trimester. At birth, 6.32% of newborns born to treated mothers were HBsAg-positive, compared to 30.43% in an untreated control group. Twenty-eight weeks later, 2.11% of infants born to treated mothers were HBsAg-positive, compared to 13.04% in the control group.

Tenofovir (Viread): New York doctors treated eight pregnant women with 300 mg daily of tenofovir during their third trimester of pregnancy. Three were treated due to ongoing liver damage (elevated ALTs) and four were treated in order to prevent infection of their newborns.

Tenofovir effectively lowered ALT levels up to four-fold during four weeks of treatment in all women. Women and newborns alike were all healthy. Three infants—the only ones for whom test results were available—tested negative for HBsAg nine months after birth.

·        372. Outcomes of Eight Chinese-Americans Pregnant Patients with Chronic Hepatitis B (CHB) Treated with Tenofovir DF (TDF) During Pregnancy (Updated October 31, 2010)

 

Caesarean delivery may reduce HBV infection: Chinese researchers monitored 569 infants born to HBeAg-positive mothers and found HBV infection in 5.94% who were delivered vaginally, 8.51% who were delivered by emergency Caeserean section, and 2.12% who were delivered by elective Caesarean section. The researchers suggest elective Caesarean delivery may be the preferred delivery choice to reduce infection risk.

·        235. A Retrospective Study for Clinical Outcome of Caesarean Section on Perinatal Transmission of Hepatitis B Virus in Infants Born to HBeAg Positive Mothers with Chronic Hepatitis B (CHB).

 

Vaccine alone effective in preventing mother-to-child HBV transmission: Currently, the medical practice is to administer both the first hepatitis B vaccine dose and HBIG immediately when an infant is born to an HBV-infected mother, followed by a second and third vaccine dose. HBIG is costly, and often not available in developing countries.

An Indian study found no added benefit from HBIG. They looked at 170 infants born to infected mothers over 18 weeks and found that equal numbers were infected in both groups. “Our study clearly documents that vaccine alone confers equal protection against HBV infection in newborns (born to) chronic HBV infected mothers,” they wrote. “However, in spite of this protection, a large number of babies in both the groups developed occult HBV infection, which may be due to intrauterine transmission of HBV infection. Trials using antivirals during pregnancy should be done to prevent this immunoprophylaxis failure.”

·        1431. Giving vaccine alone confers equal protection from chronic Hepatitis B infection to neonates born of HBsAg positive mothers as compared to vaccine plus HBIG: A large randomized controlled trial

 

When to Treat?

AFP test can indicate when treatment is needed: Many patients have liver damage, but current ALT tests fail to identify up to one-third of patients who have liver damage and could benefit from treatment. Taiwanese researchers assessed 152 HBeAg-negative patients who had never been treated and who had liver biopsies that showed concrete signs of liver damage. They found that alpha fetoprotein levels greater than 7 ng/mL indicate a patient has liver damage and requires treatment. The test improved accuracy for assessing treatment needs from 66.7% to 81%.

·        457. Application of Alpha-fetoprotein to Identify Patients Who Need Antiviral Treatment in HBeAg-negative Chronic Hepatitis B

 

Screening for HBV

Primary care providers ineffective in screening Asian-American patients for HBV. Asian-Americans, who are at high risk of hepatitis B, should be tested for HBV. A study of 5,143 Asian American patients cared for by primary care providers affiliated with the Mayo Clinic, revealed that only 31% were screened for HBV infection between 1994 and 2009. Of those screened, 8% were HBsAg-positive. Of the remaining 1,474, 70% were surface antibody positive (showing a resolved infection or immunization, and 30% showed no immunity against HBV.

Asian-Americans who were older tended to be screened more than those who were younger. One-third of HBsAg-positive patients had normal ALT levels, which shows that doctors should not depend on abnormal ALT tests as prompts to conduct HBV screening.

“…HBV screening has been grossly inadequate,” Mayo Clinic researchers wrote. “In those screened, the prevalence of HBV remained high. Despite publicity and awareness efforts, HBV remains one of the largest yet under-diagnosed health disparities in the U.S.”

·        787. Effectiveness of Hepatitis B Screening in Primary Care Setting

 

Knowledge of HBV low among Vietnamese-Americans: Researchers studied infection rates and knowledge of disease among 698 Vietnamese-Americans living in the San Francisco area. All were foreign-born and had lived in the U.S. for about 20 years.

They found that 95 (13.6%) were positive for HBsAg, with higher infection rates in men (16.4% in males vs. 11.3% in females), in those between 30-39, and the uninsured.

There was a significantly higher infection rates in those with a family history of HBV and those with prior occupational exposure to blood.

More education about disease prevention and treatment is needed, researchers noted, especially among the uninsured.

·        788. Prevalence, Risk Factors, and Disease Knowledge of Chronic Hepatitis B Infection in Vietnamese Americans in California: A Cross-Sectional Study