Editorial Board: Emmet B. Keeffe, MD (Chair); Anna Lok, MD; Brian McMahon, MD; Albert Min, MD; Myron Tong, MD; Naoky Tsai, MD; Bruce Tung, MD
HBV Watch^™
Timely Information for Practicing Physicians

December 2004

NUCLEIC ACID TESTING (NAT) FOR HBV INFECTION

NAT has been introduced in industrialized countries for the screening of HIV and HCV in pooled plasma samples and/or individual donations. Technical improvement and automation of all the steps of NAT including sample preparation have enabled high throughput performance of these assays, decreased the limits of detection to <10 IU/mL, and allowed multiplex assays to be performed in a single platform. The main purpose for adopting NAT for HBV screening of blood, tissue or organ donors is to diminish the window period between HBsAg and HBV DNA detection. This window may occur during the early phase of acute HBV infection, recovery from HBV infection, and the tail end of chronic HBV infection. The key questions regarding NAT for HBV are: (1) is it cost-effective, and (2) can NAT replace anti-HBc testing. Zou et al. estimated the probability of viremia undetected by HBsAg screening at the time of tissue donation. The prevalence of confirmed positive HBsAg test among 11,391 tissue donors in the U.S. was 0.229%. The probability that a donor is viremic at the time of donation was estimated to be 1 in 34,000 for HBV vs. 1 in 42,000 for HCV infection. The cost of eliminating one potentially infectious case of HBV was projected to be $2.6 million. Given the low risk of infectivity, the cost-effectiveness of additional NAT is unclear. However, the authors argued that tissues from a single donor may be used in an average of 50 patients, and the incremental cost of testing each tissue is only $5. In another article, Kuhns et al. examined whether NAT can replace HBsAg screening of blood donors. Samples from 200 HBsAg and anti-HBc positive donations were tested using 3 PCR assays. They found a poor correlation between HBsAg titer and serum HBV DNA levels. Only 64% of the samples had detectable HBV DNA using a commercially available PCR assay with detection limit of 400 copies/mL, 30% had detectable HBV DNA using an assay with detection limit of 65 copies/mL, 3% had detectable HBV DNA by an assay with detection limit of 1.3 copies/mL, while 3% had undetectable HBV DNA even with the most sensitive assays. The authors cautioned against dropping HBsAg from blood donor screening. (Zou S, et al. N Engl J Med 2004;351:751-759; Kuhns MC, et al. Transfusion 2004;44:1332-1339)

LAMIVUDINE

Patients with advanced liver disease. Yun-Fan Liaw and colleagues from the Cirrhosis Asian Lamivudine Multicentre Study Group randomized patients with chronic hepatitis B and advanced hepatic fibrosis or cirrhosis and compensated disease to receive lamivudine 100 mg daily (n = 436) or placebo (n = 215). Time to disease progression (i.e., hepatic decompensation, hepatocellular carcinoma, spontaneous bacterial peritonitis, variceal bleeding, or death related to liver disease) was the primary end point of the study. After a median duration of treatment of 32.4 months (range, 0-42 months), a significantly greater percentage of patients in the placebo group than in the lamivudine group had developed disease progression (17.7% vs. 7.8%; p = 0.001) and the study was terminated. The Child-Pugh score increased in only 3.4% of lamivudine-treated patients compared to 8.8% of placebo-treated patients (p = 0.02). Furthermore, hepatocellular carcinoma occurred in a lower percentage of patients in the lamivudine treatment group than in the placebo group (3.9% vs. 7.4%; p = 0.047). YMDD mutations developed in 49% of lamivudine-treated patients and the Child-Pugh score was more likely to increase in these patients than in other patients treated with lamivudine (7% vs. < 1%). These findings demonstrated that lamivudine treatment reduced the incidence of hepatic decompensation and hepatocellular carcinoma in patients with chronic HBV and advanced fibrosis or cirrhosis. (Liaw Y-F, et al. N Engl J Med 2004;351: 1521-1531)

Results of 2 years of treatment in patients with HBeAg-negative HBV infection. HBeAg-negative chronic hepatitis B (e-CHB) is characterized by the absence of HBeAg, detectable HBV DNA by non-PCR assays, and liver necroinflammation. Most e-CHB patients harbor variants of HBV that have mutations in the precore or core promoter regions of the HBV genome that abolish or down-regulate the production of HBeAg. Patients with e-CHB infection are most commonly seen in Mediterranean countries, the Middle East, and East Asia. Lamivudine has been shown to be effective therapy for both HBeAg-negative and HBeAg-positive chronic hepatitis B; HBV DNA is undetectable in the serum of 60% to 70% of patients at the end of 1 year of lamivudine treatment. However, within 6 months of the discontinuation of lamivudine, 90% of patients with e-CHB relapse with detectable levels of HBV DNA in serum and elevated ALT levels. In the current study, S. K. Fung and investigators from the University of Toronto and the University of Michigan report their treatment experience with 50 Chinese-Canadian patients with e-CHB infection treated with lamivudine 100 mg orally daily for 24 months. All patients had HBV genotype B or C infection. Patients were evaluated at monthly intervals for the first 3 months and at 3-monthly intervals thereafter. Lamivudine therapy was withdrawn in patients who had undetectable HBV DNA by PCR and normal ALT levels on ≥ 3 consecutive occasions during the second year of treatment and at month 24. These patients were then monitored for clinical and virological relapse. Patients who developed relapse were restarted on lamivudine 100 mg daily. During lamivudine treatment, biochemical response rates at months 6, 12, and 24 were 74%, 71%, and 66%, respectively. HBV DNA became undetectable by PCR assays in 94%, 88%, and 74% of patients at months 6, 12, and 24, respectively. The cumulative rates of genotypic resistance were 15% and 25% at the end of 1 and 2 years of treatment, respectively. The probability of virological relapse 6, 12, and 18 months after lamivudine withdrawal were 12%, 50%, and 50%, respectively. Restarting lamivudine resulted in prompt biochemical and virological responses. This study demonstrated that sustained virological responses can be achieved after a 2-year course of lamivudine treatment in 50% of patients with e-CHB. (Fung SK, et al. J Viral Hepat 2004;11:432-438)

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