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Durability of serologic response after lamivudine treatment of chronic hepatitis B: 3 year follow-up
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Hepatology 2003;37:748-755. Jules Dienstag et al, Gastrointestinal Unit (Medical Services), Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Boston, MA
Successful treatment of chronic hepatitis B offers an opportunity for achieving durable therapeutic responses that result from prolonged suppression of viral
replication, especially when associated with hepatitis B e antigen (HBeAg) seroconversion. Loss of HBeAg during interferon therapy is associated with
persistent, multilog reductions in circulating hepatitis B virus (HBV) DNA levels, and such interferon-induced responses are associated with improvement in
survival and survival without complications.1 Because HBV DNA remains detectable in serum and hepatic tissue even after HBeAg loss/seroconversion, such HBeAg responses are associated with long-term clinical remission but not virologic "cure." Still, when levels of HBV replication fall below 10(3) to 10(40
virions/mL, a threshold is achieved below which infectivity falls dramatically and liver injury becomes negligible. In typical patients with chronic "wild-type"
HBV infection, suppression of HBV replication below this threshold often is reflected by loss of HBeAg.
Lamivudine (GlaxoSmithKline, Research Triangle Park, NC) is the first of a new generation of oral antiviral agents for the treatment of chronic hepatitis B.
Lamivudine therapy is associated with consistent, marked suppression of HBV replication, improvements in liver necrosis and inflammation, retardation of
hepatic fibrosis, and enhanced rates of HBeAg loss and seroconversion compared with placebo.
Short-term observations suggest that lamivudine-induced HBeAg responses are durable for months after successful therapy, but the question remains whether such HBeAg reponses can be maintained over extended periods. In this longitudinal study, we evaluated posttreatment durability for up to 3 years of serologic responses to lamivudine in patients who experienced HBeAg seroconversion in previous lamivudine studies.
Forty subjects with chronic hepatitis B and hepatitis B e antigen (HBeAg) seroconversion following lamivudine therapy in previous trials were monitored
after treatment to assess the durability of serologic responses. Patient follow-up began a median of 4.3 months after completion of therapy in previous
trials. At months 2, 4, 6, 9, and 12 of year 1, and every 6 months thereafter, we tested for HBeAg and hepatitis B surface antigen (HBsAg), hepatitis B
virus (HBV) DNA, and alanine aminotransferase (ALT). After a median (range) of 36.6 (4.8-45.6) months of follow-up monitoring, HBeAg seroconversion
was demonstrated at the last visit by 77% (30 of 39) of patients. In a post hoc analysis of a slightly different population of all 65 patients with HBeAg
seroconversion in previous trials, the 3-year durability of HBeAg seroconversion measured from the time immediately after discontinuing lamivudine
therapy was 64%. Nine (9 of 40, 23%) patients were HBsAg negative at the last assessment. Seventy-four percent (17 of 23) of patients with baseline
undetectable HBV DNA and normal ALT maintained these responses at the last visit. Eight patients (8 of 40, 20%) initiated retreatment for reappearance
of HBV markers, and 7 showed biochemical and/or virologic improvement (including regained HBeAg seroconversion in 2). No safety issues of concern
emerged. In conclusion, most HBeAg responses achieved during lamivudine therapy were durable, and most responders experienced prolonged clinical
benefit after HBeAg seroconversion and subsequent discontinuation of lamivudine. Lamivudine retreatment for reappearance of hepatitis B markers can achieve resumption of viral suppression.
Author Discussion
When we designed the protocol for this trial, patients who were derived from previous studies had durable HBeAg seroconversions for at least 12 to 16 weeks
after cessation of initial lamivudine therapy. In those "feeder" studies, durability of HBeAg seroconversion during the 3 to 4 post-treatment months was approximately 80%. Thus, those enrolled in this trial were selected to be more virologically durable. Furthermore, a proportion of qualified patients
declined or were unavailable for enrollment, introducing a potential selection bias. To address these issues, we conducted a post hoc "intent-to-treat" analysis that included durability on all 65 potential HBeAg seroconverters in the "feeder" trials measured from the time immediately after discontinuing lamivudine therapy. As described above, not all the protocol-defined cohort of 40 patients could be included in the post hoc cohort of 65 because some of the
protocol-defined 40 patients achieved HBeAg seroconversion in the months after discontinuation of therapy. Still, the post hoc analysis provides an estimate of the 3-year, long-term durability of HBeAg seroconversion, 64%, when the "clock starts" immediately after drug cessation.
In the present study, patients with reappearance of hepatitis B markers who were retreated with lamivudine experienced favorable clinical outcomes, including HBeAg seroconversion, ALT normalization, and HBV DNA loss. These findings and others suggest that, in immunocompetent patients with compensated liver disease, lamivudine can be discontinued following HBeAg seroconversion, and treatment can be reinitiated when required with resumption of clinical control of HBV infection. In immunosuppressed patients, however, such as those who have undergone liver transplantation, the need for long-term immunosuppression increases the risk of HBV reactivation, even in patients who have achieved HBeAg seroconversion. Studies to define treatment end-points in this population are in progress.
Our results in a predominantly western population indicate that the durability of HBeAg seroconversion in western patients with chronic hepatitis B is similar to the approximately 80% reported in Chinese patients. In contrast, Song et al.21 reported that lamivudine does not confer a high rate of posttreatment
durability of serologic response in Korean patients receiving 150 mg/d of lamivudine for 6 to 15 months, then discontinued 2 to 4 months after seroconversion. One- and 2-year durability of HBeAg responses were 62.5% and 50.8%, respectively. Factors that might explain the differences in posttreatment durability between the Korean patients and those in the Chinese and our studies include the unusually high 37% initial HBeAg seroconversion rate in the Korean study compared with 16% to 18% in the phase III studies and the fact that a substantial proportion (49%) of the Korean study patients were previous interferon nonresponders. The findings of Song et al were confirmed in another study in Korean patients treated with 100 mg/d of lamivudine for approximately 13 months; the 6-month durability of HBeAg seroconversion measured from cessation of therapy was only 43%, and posttreatment responses were sustained primarily in patients with HBV DNA suppression to <4.7 x 10(3) genomes/mL. Perhaps differences in the level of HBV DNA suppression account for the differences between the Korean studies and those done in China and the west; however, the bDNA assay that we used to measure HBV DNA did not identify any relation between durability of HBeAg seroconversion and degree of HBV DNA suppression. More sensitive HBV DNA assays will be required in future studies to address this issue definitively.
In conclusion, most patients with hepatitis B will experience a prolonged period of clinical benefit following HBeAg seroconversion and subsequent discontinuation of lamivudine therapy, and patients who experience reappearance of hepatitis B markers can be retreated to restore suppression of HBV replication. In a proportion of lamivudine-treated patients, long-term disease remission is attainable through a finite course of lamivudine monotherapy.
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