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Results of Lamivudine in Asian Trials

Yun-Fan Liaw, Liver Research Unit, Chang Gung Memorial Hospital and Chang Gung University, Taipei, Taiwan

Introduction

Chronic hepatitis B virus (HBV) infection is a serious clinical problem of Asia because over 75% of the 350 million chronically infected people in the world are from this area or of Asian ethnicity (1,2). The onset of chronic HBV infection in these people typically occurs perinatally or at early childhood (3). Early HBV infection induces immunological tolerance (4), thus the natural course of such chronic HBV infection can be divided into three phases: the “immune tolerant phase”, the “immune clearance phase” and the “residual phase” (5). Patients in immune tolerance phase usually have high HBV replication with normal or minimally elevated serum alanine aminotransferase (ALT) level. The immune clearance phase is characterized by a series of hepatitis flares and remissions. The hepatitis flares or exacerbations are the result of HLA-class I antigen restricted, cytotoxic T lymphocyte (CTL) mediated immune response against HBV antigen(s) and its downstream apoptotic mechanisms (6). These are eventually followed by hepatitis B e antigen (HBeAg) seroconversion to its antibody (anti-HBe) and/or HBV-DNA seroclearance (7). It has been shown that patients with ALT over 5 times upper limit of normal (ULN) have a spontaneous HBeAg seroconversion rate of 50% at 12 months and 60% at 18 months, in sharp contrast to 10% and 15% respectively in patients with ALT<5x ULN (8,9), suggesting that ALT levels reflect the magnitude of endogenous immune response against HBV (6-8). Although reactivation due to HBeAg reversion or evolution of precore mutant HBV may occur, spontaneous HBeAg seroconversion is usually followed by sustained clinical remission (10). The severity, extent, duration and frequency of the hepatic lobular alterations during hepatitis flares tend to determine the development of cirrhosis (11). Clearly, viral clearance with reduction or prevention of hepatic injury is the key to reduce or prevent disease progression.

Earlier trials have shown that HBV infected Asians often have long duration of infection and low serum ALT levels, both are predictors for a poor response to interferon-a therapy (12). Corticosteroid priming tends to enhance the efficacy of interferon therapy in patients with lower ALT levels (13,14) but has the risk of severe hepatitis upon withdrawal. Thymosin-a1 therapy in patients with ALT<5x ULN showed a response rate of 40% (vs. 9% in controls, P=0.004) but has not been firmly confirmed by other trials (15). The advent of lamivudine has provided opportunity to meet the need of Asian HBV patients for an effective and safe treatment.

The Asia Hepatitis Lamivudine Trial

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Study outline

A multinational, multicenter study initially involving 358 Asian patients with Chinese ethnicity was conducted between June 1994 and January 2001. This study comprised a 3 year randomized, double-blind, placebo-controlled phase, followed by a 2 year phase where all subjects received open-label lamivudine 100 mg once daily, after which subjects were eligible to enter a 6 month off-treatment follow-up observation (Figure 1). All patients were HBeAg positive and underwent liver biopsies before entering the study. Following-up liver biopsies were scheduled at the end of one year and optional at the end of 3 year treatment.

Results of randomized, double blind, placebo-controlled phase

One Year Results

The trial included 358 Chinese patients with chronic hepatitis B who were randomly assigned to receive 25 mg of lamivudine (142 patients), 100 mg of lamivudine (143 patients), or placebo (73 patients) orally once daily. Hepatic necroinflammatory activity improved (³2 points) in 56% of the patients receiving 100 mg, 49% of those receiving 25 mg, and 25% of those receiving placebo (P<0.001 and P=0.001, respectively vs. placebo). The 100 mg dose was associated with a reduced progression of fibrosis (P=0.01 vs. placebo) and with the highest rate of HBeAg seroconversion (16%), the greatest suppression of HBV-DNA (98% reduction) and the highest rate of sustained normalization of ALT level (72%). YMDD mutations occurred in 14% of the patients in both lamivudine groups (16). Higher pre-therapy ALT, HBV-DNA levels and a HBV-DNA level > 103 copies/ml after 6 months of lamivudine therapy were found to be factors for the emergence of YMDD mutations (17).

A retrospective analysis on data from year one trial using stepwise modeling revealed that HBeAg seroconversion correlated highly with pretherapy ALT (P<0.001) but only marginally with baseline HBV-DNA (P=0.071) and cirrhosis (P=0.066) for lamivudine 100 mg and placebo comparison. Categorical analysis revealed that HBeAg seroconversion occurred earlier and the cumulative rate was highest in 100 mg lamivudine-treated patients with ALT levels greater than 5x ULN (64%) compared with patients with ALT 2-5x ULN (26%, P=0.03); and ALT <2x ULN, (5%, P<0.001), suggesting that lamivudine is more effective in patients who have mounted an ongoing immune response against HBV (18).

Two year results

A total of 334 patients with chronic hepatitis B from year one study were randomized to receive either lamivudine (100 or 25mg) or placebo for another year. ALT levels increased 8-12 weeks after switching from lamivudine to placebo, but returned to normal once lamivudine treatment was resumed. A significantly greater proportion of patients achieved sustained HBV-DNA suppression (52% vs. 5%; P<0.001) and ALT normalization (50% vs. 5%; P<0.001) with 100mg lamivudine daily for 2 years compared with lamivudine for 1 year followed by placebo for the second year. HBeAg seroconversion increased from 17% at week 52 to 27% at week 104, and increased significantly (P<0.001) with increasing pretherapy ALT levels (Figure 2). YMDD mutant emerged in 38% of the patients (19).

Results of 3-5 years of therapy

Fifty-eight patients from 1-year study were randomly assigned to receive 3 years of continuous treatment with lamivudine 100mg daily and subsequent open label therapy for additional 2 years. HBeAg seroconversion rate and incidence of YMDD mutations continued to increase over 5 years lamivudine therapy (20-22), as compared in Figure 3. HBeAg seroconversion rate also increases significantly with increasing pretherapy ALT levels (Figure 2).

Impact of YMDD mutants

Throughout 5 years lamivudine therapy, patients with YMDD mutations maintained lower median serum HBV-DNA and ALT levels than their baseline values and continued to achieve HBeAg seroconversion (16,19-22). However, a weekly or biweekly follow-up study during 8-164 (median 62) months after emergence of YMDD mutation in 32 patients showed that 30 (94%) had abnormal ALT, 13 (41%) experienced rise of HBV-DNA and exacerbation (ALT>5x ULN) between 4-94 (median 24) weeks, and 3 developed hepatic decompensation. The exacerbations were followed by high rate of HBeAg seroconversion and HBV and/or YMDD mutant clearance (23). Deterioration of histology was demonstrated in patients with YMDD mutation (20,23). Distinct lamivudine-resistant mutants could emerge and replace the original YMDD mutants as the cause of continuing hepatitis during prolonged lamivudine therapy (24). Mutagenesis experiments further indicate that there is a phenomenum of lamivudine dependent replication, which may explain high HBV-DNA levels, in some patients with YMDD mutations (24).

Safety

The incidence of liver disease-related serious adverse events (SAEs) was 0.7% in lamivudine-treated patients and 2% in those receiving placebo after one year’s treatment. Incidence did not increase in successive years of lamivudine therapy (2%, 1.9%, 1.4%). Over 4 years, the incidences of SAEs was 7.6% (liver disease related SAE: 4.1%; hepatitis decompenastion: 1.4% and YMDD mutants with hepatic decompensation: 0.8%) (21,22,25).

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Other Asian Trials

Trial in China

A randomized, double blind study is ongoing in 429 Chinese patients with chronic hepatitis B to compare the efficacy of lamivudine 100 mg daily (n=322) with placebo (n=107) for 12 weeks then open label lamivudine for a further 144 weeks. Of the 304 patients who have completed 3 years of treatment, HBeAg seroconversion rate increased from 14% at 52 wk to 22% at 104 wk and 34% at 156 wk in patients with ALT>2x ULN. In contrast, YMDD mutations emerged in 71% of the patients, however, 87% had HBV-DNA levels and 74% had ALT levels less than their baseline values and 9% achieved HBeAg seroconversion (26).

Prednisolone priming : A pilot study in Taiwan

Thirty patients with ALT levels <5x ULN received 30 mg of prednisolone daily for 3 weeks, 15 mg daily for 1 week, no treatment for 2 weeks, and then lamivudine daily for 9 months. Clinical rebound with an ALT over 5x ULN was observed in 20 patients (67%), 12 (60%) showed complete response as compared with 1 (10%) of the 10 patients without significant ALT rebound (P<0.002). The responders showed Th1 dominant response to prednisolone priming. These results suggest that corticosteroid priming induced immune/ALT rebound greatly enhances response to lamivudine therapy (27).

Studies on the durability of HBeAg response

The durability of lamivudine-induced HBeAg seroconversion during the 5 year Asian hepatitis lamivudine trial was tested in 36 patients who stopped lamivudine after HBeAg seroconversion and had > 6 months follow-up data. After 6-36 (median 19) months follow-up, 30 (83%) patients maintained a durable HBeAg responses. The range of time on treatment after HBeAg seroconversion in the 30 durable patients (3.5-35.5 months) was similar to that of the 6 non-durable patients (3.8-30.9 months). However, four of six non-durable patients had £10 months lamivudine after HBeAg seroconversion, five of them became HBeAg positive from 3.7 to 12 months and the other after 18.7 months of stopping lamivudine (28).

Two retrospective analysis were conducted in Korea to examined the durability of lamivudine induced HBeAg seroconversion. One study included 67 Korean patients treated with lamivudine 150 mg daily for 6 months and had either 2 or 4 months of additional treatment following HBeAg seroconversion in 34 patients. Those receiving 4 months treatment after seroconversion had a lower relapse rate than those receiving 2 months treatment (74.3 vs. 31.7% at 2 years; P=0.014) (29). Another study involved 73 Korean patients who received lamivudine 100 mg daily for more than 12 months. The durability of response was 90% after 1 year and 2 years in patients receiving lamivudine for >6 months after HBeAg seroconversion. In contrast, durability of response was 40% after 1 year and only 20% after 2 years in those receiving lamivudine for <6 months after HBeAg seroconversion (30).

The relapse rate was also high in Taiwanese patients. To examine the determinants for sustained HBeAg response to lamivudine therapy, factors including age, gender, pretherapy ALT levels, pretherapy HBV-DNA levels, time to HBeAg seroconversion, additional treatment after HBeAg seroconversion, total duration of treatment, hepatitis activity index and HBV genotype were compared between 42 patients with sustained response and 43 patients whose response was not durable. All of these patients received a mean period of 16 months lamivudine therapy and had achieved HBeAg seroconversion/HBV-DNA seroclearance and normal ALT, and were follow-up for 12-60 months. Stepwise logistic regression analysis showed that genotype B was the only predictor (Odds Ratio, 7.793; 95% confidence interval, 2.061-29.468; P=0.002) for sustained response (31). Noteworthy is that genotype C is predominant in Korean patients.

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Summary and Conclusion

In summary, 100mg daily lamivudine therapy is safe and effective in Asian patients in terms of HBV suppression, ALT normalization and improvement in histology. The complete response rate after one year lamivudine therapy is only around 15% but increases with increasing duration of treatment and increasing pretherapy ALT levels. Similar results were observed in patients with HBeAg-negative chronic hepatitis but published data are limited. YMDD mutation may emergence after 9-10 months of lamivudine therapy and its incidence also increases with increasing duration of therapy. The emergence of YMDD mutations is associated with viral and biochemical breakthrough. Hepatitis flares, sometimes associated with hepatic decompensation, may develop after stopping lamivudine therapy and in patients with YMDD mutations during continuing lamivudine therapy. The benefit of long-term lamivudine therapy therefore must be weighted carefully against the concern about YMDD mutations and the durability of therapeutic response (32). The development of new strategies, including selection of patient and timing of therapy, and new drugs are needed to further improve the outcomes of treatment.

Acknowledgments

The author thanks Moult A and Tognarini D of GlaxoSmithKline for providing relevant information, and Miss Chu SC for excellent assistance.

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References:

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