HepB Forum : Unofficial Research Thread (URT) Tx info

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Case 4:  62yo man of Greek origin presents with fatigue, otherwise healthy, by Anna S.F. Lok

A 62-year-old man presented to his primary care physician in June of 2000 with fatigue. He gave a history of two similar episodes of extreme fatigue in the past five years. During one of these episodes, elevated liver enzymes were found. He did not seek further attention at that time. An examination showed that he was otherwise healthy. He was not on medications, and he denied drinking. He had no known family history of liver disease. He had been born in Greece, and moved to the United States in 1980. Physical examination did not reveal any significant findings. There was no evidence of jaundice.

Laboratory Results:
AST: 349
ALT: 452
Total bilirubin: 0.9
Platelet count: 210k
HBsAg: positive
Anti-HCV: negative

The patient was referred to a gastroenterologist. By August of 2000, when he first saw the gastroenterologist, his symptoms had resolved. Repeat testing at this time showed the following:

Laboratory Results:
AST: 55
ALT: 68
Total bilirubin: 0.7
HBeAg: negative
Anti-HBe: positive
HBV DNA: 125,000 copies/mL

What is your diagnosis?
1. Acute antigen-negative hepatitis B
2. Chronic antigen-negative hepatitis B
3. Clinically resolved case of hepatitis B
Dr. Lok (OC): This is very classical of patients with E-antigen negative chronic Hepatitis, they tend to run a fluctuating course. The fact that he's E-antigen negative, does not mean that he does not have active virus replication, because we now know that there's a variant of Hepatitis B virus these patients can continue to have active HBV DNA level and active liver disease.

Which would you do?
1. Nothing; monitor patient
2. Begin anti-viral therapy
3. Order more tests
Dr. Lok (OC): Given the fact that we know that most patients with E-antigen negative chronic Hepatitis will require a very long duration of therapy. We want to have a much better understanding of the severity of his liver disease before committing him to this long course of therapy.

Which test(s) would you order?
1. Anti-HDV
2. Liver biopsy
3. Both
Dr. Lok: ....Because he came from Greece, it is possible that he actually acquired Hepatitis B way back in his childhood and therefore it is important to test him for the Delta virus.... We also did the liver biopsy on him because of the fact that by the time he came to see us, his liver enzymes were close to normal.

Subsequent test results showed the following:

Anti-HDV: negative
Liver biopsy: moderate inflammation, fibrosis

Adefovir was not available at this time. Which treatment would you choose?
1. Interferon
2. Lamivudine
Dr. Lok: Well in August in 2000, there're really two choices of therapy. One is interferon and the other is lamivudine. In fact, both choices were being discussed with the patient....The downside of interferon obviously is the side effects. And to some extent, cost because for patients of E-antigen negative chronic Hepatitis, one would have to give the patients at least a 12-month pulse and some studies would actually suggest that you should be giving 24 months treatment. The advantage of interferon is that you can stop treatment in some patients. And certainly with 12 months treatment about 15-20 percent of patients would have a sustained response with two years treatment... Whereas in patients treated with lamivudine we know that if we try to stop treatment after one year, the likelihood of relapse is more than 90 percent and most of these patients end up receiving very long durations of therapy, which then is associated with increasing risks of drug resistance.... If we had seen this patient now, we would have a third option which would be adefovir therapy.... The benefit of adefovir is that the risk of drug resistance is very low, so continuation of treatment is going to be associated with maintained response in majority of patients, but that's going to be a fairly expensive therapy if we keep going year after year.

The patient chose oral therapy. He began lamivudine 100 mg/d. He responded well. His virus level became barely detectable, his liver enzymes became normal, and he felt significantly better. Two years after starting lamivudine treatment, the laboratory reported the following:

Laboratory Results
AST: 42
ALT: 59
Total bilirubin: 0.8
HBV DNA: 6,500,000 copies/mL

Which would you do?
1. Stop lamivudine; do not treat with any anti-viral therapy; monitor patient
2. Continue lamivudine; do not add another anti-viral drug; monitor patient
3. Stop lamivudine, treat with adefovir
4. Continue lamivudine, add adefovir
The attending physician had the capability to test for mutation resistance. A sample from the patient tested positive for YMDD mutation. Although the patient's liver enzymes were still well controlled, the attending physician decided to initiate salvage therapy because of the marked increase in HBV DNA levels.

Dr. Lok (OC): There is indeed one study-granted on a very small number of patients, 19 patients in each arm-showing that in patients who've developed lamivudine resistance, you can stop lamivudine and just switch them over to adefovir therapy and it results in a similar rate of viral suppression. However, there is a small risk of Hepatitis flairs during the transition period. And we now know that by putting the patient on adefovir alone, instead of leaving them on combination of lamivudine and adefovir, there is perhaps some higher chance of resistance to adefovir over time.... Because the two drugs select for different resistance mutation, continuation of both drugs might minimize selection of adefovir resistant mutation.... That's the reason why we chose to leave this patient on lamivudine and just add adefovir.

Dr. Lok (OC to VO): Adefovir dipivoxil 10 milligram daily was started in January of 2003. He had a very slow drop in HBV DNA level but it kept coming down. And in May of 2004, his HBV DNA level was still detectable by PCRSA, but at extremely low levels.

[cajim]

Notes on “Hepatitis B Virus: Inactive carriers,” Yogesh Chwla, Virology Journal 2005, 2:82.

Inactive carriers forms the largest group in chronic HBV infected patients. Around 300 million people are inactive carriers The inactive HBsAg carrier state is diagnosed by absence of HBeAg and presence of anti-HBe, undetectable or low levels of HBV DNA in PCR-based assays, repeatedly normal ALT levels, and minimal or no necroinflammation, slight fibrosis, or even normal histology on biopsy. Inactive cirrhosis may be present in patients who had active liver disease during the replicative phase of infection. The prognosis of the inactive HBsAg carrier state is usually benign. Long-term follow- up (up to 18 years) of these carriers has indicated that the vast majority show sustained biochemical remission and very low risk of cirrhosis or hepatocellular carcinoma (HCC). Rarely, patients, even noncirrhotics, may develop liver cancer during the inactive HBsAg carrier state. In addition, approximately 20 to 30% of persons in the inactive HBsAg carrier state may undergo spontaneous reactivation of hepatitis B during follow-up. Multiple episodes of reactivation or sustained reactivation can cause progressive hepatic damage and even hepatic decompensation. Introduction

Hepatitis B virus (HBV) infection and its sequelae are major global health problems [1]. It is estimated that 400 million people worldwide are HBV carriers [2]. The natural history of hepatitis