Lamivudine in the treatment of chronic hepatitis B
    J. Reichen M.D.
    Lamivudine ([(-)2'-deoxy-3'-thiacytidine, 3TCâ, Zeffixâ] is well introduced as a treatment for HIV infection but has also activity in vitro against the replication of the hepatitis B virus by inhibiting HBV DNA polymerase. In addition to this effect it also restores T-cell responsiveness (1). Dose-finding studies (25, 100, 300 mg/d) determined 100 mg/d to be the lowest dose making HBV-DNA undetectable in all patients (2-4). This is the dose used thereafter in most trials. Liver disease does not affect disposition of lamivudine and therefore, no dose adjustment is necessary (5).
    Chronic hepatitis B: Lamivudine was first used in patients coinfected with HIV and HBV; in an open series of 40 patients, 96. 3 and 100 % of patients with high and low level replication lost HBV-DNA; among the former 11.3 still were positive by PCR whereas in the latter all became PCR negative (6). The results of two placebo-controlled trials (7, 8) are reported in table 1:

    Table 1
    Effects of lamivudine in two trials of HBe-antigen positive chronic hepatitis. Figures are given in %. Improvement in histology refers to an improvement of > 2 points on the Knodell score.

    Lamivudine  
    Placebo
    		  
     
    Lai
    Dienstag
    Lai
    Dienstag
    n
    143
    66
    73
    71
    Seroconversion HBe ® anti-HBe 
    16
    17
    4
    6
    Loss of HBV-DNA
    76
    44
    23
    16
    Normalization of ALT
    72
    41
    24
    7
    Improvement in Histology
    56
    52
    29
    23

    The results of the first trial can also be consulted on two slides. The first one shows design and response rates, the second one effect on liver histology. A follow-up study demonstrated that extending treatment to two years can induce HBe to anti-HBe seroconversion in an additional 10 % of patients (9). Newer studies are less enthusiastic: in a study from Korea, loss of HBe was initially observed in 35 % but relapse rates were close to 50 % after 2 years (32). Similar data were reported from Greece and the U.S. with only ~50 % patients remaining in remission, all others having developped resistance (33,34). Two recommendations from a recent editorial by Dr. Richman should be taken to heart, therefore (35):
     


    Cirrhosis: Lamivudin has been successfully used in patients with decompensated cirrhosis (36). Given the potential for resistance development and flare-up, this should only be done in cooperation with a transplant center.
    Transplantation: In renal transplantation, lamivudine has been shown to effective against fibrosing cholestatic hepatitis in case reports and small series (10,11). The same holds true for bone marrow transplantation (12). In OLT lamivudine has been effective in several case reports. In one of the first series, loss of DNA was associated with normal histology in all patients post-transplant (13). the small series by Andreone et al. (see table) 45 % of treated patients even lost HBsAG (14). In the largest study recently reported (30), ALT normalization was achieved in 71 % and a loss of HBV-DNA by solution hybridization occurred in 60 %.

    Liver transplantation

     
    Reference #
    N
    Response (DNA)
    Response (ALT)
    Resistance
    (15)
    12
    100 %
    90 %
    10 %
    (13)
    5
    100 %
     
    40 %
    (16)
    3
    100 %
    100 %
    0
    (14)
    12
    73 %
    73 %
    27 %
    (17)
    40
    82.5 %
     
     
    (30)
    52
    60 %
    71 %
    27 %

    Histology: In patients responding there is a marked improvement in the Knodell index from 4.4 to 2.8 (18). In the large trial by Lai et al. 56 % of patients treated with 100 mg/d improved by two or more points as opposed to 25 % in the placebo group (7). Chronic hepatitis remained active in transplanted patients (14).
    Combination treatment: Combination with famciclovir is synergistic with lamivudine and induces viral clearance in a higher proportion of patients (19).
    In contrast to predictions based on restoration of T-cell responsiveness by lamivudine, combination with interferon does not provide additional benefits (20). For transplanted patients, combination of lamivudine with HBIG is effective (21).
    Side effects: Virtually nil. In particular, there is no mitochondrial toxicity (22). Two cases of transient hepatic decompensation during a breakthrough have been described in one of the dose-finding studies (4).
    Resistance: Two patterns have been described, incomplete response and breakthrough, both together with an actuarial incidence of 30 % (23). Resistance relies in the YMDD motif of the HBV-DNA polymerase (24). In a large database, two substutions in this locus conferring resistance with a 105-fold increase in IC50 has been reported (25). Resistance is transitory since the wild-type takes over again after cessation of treatment (26-28); some of these patients will respond to retreatment (27) but this response appears to be temporariliy limited (29). In the large Asian study mutations in the YMDD region occurred in 14 % but were not assciated with a decreased histological response (7). Resistance occurs 20x more often in the subtype adw (31).
     

    Reference List

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March 10th 1999
Last revision August 13th 2001