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OUTCOME OF LAMIVUDINE THERAPY

  1. Top of page
  2. OUTCOME OF LAMIVUDINE THERAPY
  3. DURABILITY OF TREATMENT RESPONSE
  4. HBEAG-NEGATIVE DISEASE
  5. DECOMPENSATED CIRRHOSIS
  6. LAMIVUDINE SAFETY PROFILE
  7. SUMMARY
  8. REFERENCES

One-year study

In 1-year trials, lamivudine has shown promise for the treatment of chronic hepatitis B (CHB). A double-blind study of 358 Chinese CHB patients was designed to evaluate the outcome after 1 years of treatment.1 The patients consisted of males and females 16–70 years of age. All patients showed detectable hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) in serum at the time of screening and for at least the previous 6 months, serum hepatitis B virus DNA (HBV-DNA) levels of at least 5 pg/mL, and alanine aminotransferase (ALT) levels that were less than 10 times the upper limit of normal (ULN) at screening and for the previous 3 months. Patients were randomly assigned to receive 25 mg lamivudine (142 patients), 100 mg lamivudine (143 patients) or placebo (73 patients) orally once a day for a total of 12 months.1

Results from this study showed that after 1 year of treatment, the number of patients with HBeAg seroconversion – that is the loss of HBeAg and the development of anti-HBeAg – was 16% in the 100 mg lamivudine group and 13% in the 25 mg lamivudine group, compared with 4% in the placebo group. Viral levels fell rapidly in the 100 mg lamivudine group: at week 52, there was a 98% reduction in HBV-DNA, compared with 93% in the 25 mg group and 54% in the placebo group (P < 0.001 for both comparisons). In the 100 mg group, 96% had undetectable HBV-DNA on at least one occasion, compared with 73% of the 25 mg group and 23% for those taking placebo.1

At baseline, approximately 70% of patients had elevated ALT levels. In the 100 mg group, 72% of patients had a sustained ALT response (P < 0.0001 for either dose of lamivudine compared with placebo) after 52 weeks of treatment, compared with 65% in the 25 mg group and 24% in the placebo group.1

Both doses of lamivudine were more effective than placebo (intent-to-treat analysis). Improvements in necroinflammatory activity were seen in 56% of the 100 mg group, compared with 49% and 25% for the 25 mg group and placebo group, respectively (P < 0.001 for the comparison between 100 mg lamivudine group and the placebo group).1 The proportion of patients with worsening of fibrosis was lower in the 100 mg group (3%) than in the placebo group (15%).1 A worsening of histological findings was seen in 32% of the placebo group compared with 7% of those taking 100 mg lamivudine.1

During lamivudine therapy, the emergence of YMDD mutation was analyzed in serum samples taken from 335 patients at week 52. The incidence of YMDD was 14% in both lamivudine groups. YMDD appearance was not associated with decreased histological response.1

Long-term lamivudine therapy

From Lai's 1-year lamivudine study discussed above, a cohort of 58 HBeAg positive patients was treated with lamivudine 100 mg/day for up to five years.2 Of these 58 patients, 32 (55%) remained on lamivudine for 5 years. Before study end, 14 patients stopped treatment after achieving HBeAg seroconversion. At the end of the 5-year study period, 29 patients (50%) had achieved HBeAg seroconversion. Seroconversion rates increased in patients with elevated ALT levels; in those who had abnormal baseline ALT values, 26 of 41 (63%) achieved seroconversion and in those with baseline ALT > 2 × ULN, 20 of 26 (77%) achieved seroconversion (Fig. 1).

image

Figure 1. Hepatitis B early antigen seroconversion over 5 years of treatment in patients with elevated alanine aminotransferase (ALT). ULN, upper limit of normal.

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The appearance of YMDD-variant HBV occurred in 40 of 58 (69%) patients. Despite this, 38% still achieved seroconversion and 7 lost YMDD-variant HBV on subsequent testing.2 Median ALT value over the 5 years in 28 of the 40 YMDD-variant patients, who remained on lamivudine up to week 260, was 1.1, with a range of 0.2–18.9 × ULN.2

In a study by Schiff, 324 CHB patients who had remained HBeAg positive after taking part in three phase III lamivudine studies were enrolled to receive 100 mg lamivudine for a further 5 years.3 Two hundred and thirty-six patients completed 2 years of treatment and at the start of the follow-on study, 203 (89%) were HBeAg positive, median HBV-DNA was 692.5 Meq/mL and ALT was 1.8 × ULN. Paired liver biopsies were available from 128 (54%) patients. Before entry into phase III studies, baseline median necroinflammation and fibrosis histological activity index (HAI) scores were 5 and 3, respectively, and 17% of patients had cirrhosis. By year 2 of extended lamivudine treatment, 77/128 (60%) of patients exhibited a ≥ 2-point improvement in Knodell necroinflammatory score. A ≥ 2-point deterioration compared to baseline was seen in 12/128 (9%) of patients.3

Improvements in bridging fibrosis and cirrhosis were observed in 26/51 (51%) and 14/22 (64%) of patients, respectively. Only 4/106 (4%) of patients not cirrhotic at baseline progressed to cirrhosis and 7/55 (13%) demonstrated progression to bridging fibrosis.3

YMDD-variant HBV emerged in 142/236 (60%) of patients after 2 years of extended lamivudine therapy. Improvements in necroinflammatory score and bridging fibrosis were seen in 39/75 (52%) and 12/30 (40%) patients that developed YMDD-variant, respectively. Only 9/75 (12%) of those with YMDD-variant had worsening of liver inflammation and 6/31 (19%) showed progression to fibrosis.3

DURABILITY OF TREATMENT RESPONSE

  1. Top of page
  2. OUTCOME OF LAMIVUDINE THERAPY
  3. DURABILITY OF TREATMENT RESPONSE
  4. HBEAG-NEGATIVE DISEASE
  5. DECOMPENSATED CIRRHOSIS
  6. LAMIVUDINE SAFETY PROFILE
  7. SUMMARY
  8. REFERENCES

Following Lai and colleagues 1-year lamivudine study of 358 Chinese patients,1 36 patients who experienced HBeAg seroconversion during lamivudine treatment were followed to assess durability.4 Of these patients, 30 (83%) maintained a durable HBeAg response after a median follow-up of 19.6 months. Of these patients, 17 still remained HBeAg negative for 20–36 months follow-up, five of whom had YMDD-variant DNA.4

In a similar study where Caucasian patients from pre-vious  lamivudine trials were followed off-treatment, 37 of 43 (86%) showed durability of post-treatment HBeAg loss at 21 months median follow-up.5 Nine patients (21%) also experienced HBsAg seroconversion. Of these nine patients six had been HBsAg negative and HBsAb positive on entry to the follow-on study and a durable response was seen between 4 and 30 months.5

Results from a retrospective study in Korea, show that durability of response may be increased with continuation of lamivudine treatment for more than 6 months after HBeAg seroconversion. A total of 63 patients were initially positive for HBeAg and HBV-DNA. Treatment was stopped after HBeAg seroconversion and responders were those who had negative conversion  of  HBV-DNA  and  normalization  of  ALT. Of these, 68.3% were responders by the end of year 1. The HBeAg seroconversion rates were 30.2%, 38.8%, and 42.4% at years 1, 2, and 3, respectively. The cumulative durability of response was significantly higher in patients who received additional lamivudine for more than 6 months after HBeAg seroconversion, than for less than 6 months (90% showed stable response at 1 and 2 years).6

Durability of responses post-lamivudine is comparable to results found in the study by Korenman and colleagues with alpha-interferon (IFN-α) therapy.7 In this study, 64 CHB patients were treated with IFN-α between 1984 and 1986. Results showed that 23 of 64 (36%) patients responded to treatment and demonstrated loss of HBeAg and improvement in serum aminotransferases. These 23 responders were followed for 3–7 years (mean = 4.3 years). During this follow-up period, within 1 year of therapy, three of 23 patients relapsed with reappearance of HBeAg and abnormal serum aminotransferases. The remaining 20 patients continued to have no detectable serum HBeAg or HBV-DNA, although three patients did have minimal elevations in serum aminotranserases. Between 0.2 and 6 years (mean = 3 years) follow-up, 13 (65%) patients became negative for HBsAg after loss of HBeAg.7

HBEAG-NEGATIVE DISEASE

  1. Top of page
  2. OUTCOME OF LAMIVUDINE THERAPY
  3. DURABILITY OF TREATMENT RESPONSE
  4. HBEAG-NEGATIVE DISEASE
  5. DECOMPENSATED CIRRHOSIS
  6. LAMIVUDINE SAFETY PROFILE
  7. SUMMARY
  8. REFERENCES

The clinical benefit of extended lamivudine therapy has also been demonstrated in patients with HBeAg-negative CHB. It has been shown that response to lamivudine in these patients is similar to those patients with HBeAg-positive CHB in terms of liver histology, HBV-DNA suppression and ALT normalization.

Esteban et al. reported a study of 76 HBeAg-negative CHB patients from a previous lamivudine trial; subsequently enrolled to receive further open-label lamivudine 100 mg daily until HBsAg seroconversion was achieved, or for a maximum of 5 years.8 The overall median age of the patients was 47 years and 82% were male. The median duration of participation in this study was 31.1 (12.4 to 44.4) months. Histological analyses were carried out on 49 patients with paired liver biopsies available at the start of the previous trial (baseline) and at month 24 of the extended therapy study. The median time between paired biopsies was 4.1 years (3.1–5.0 years). Interim analysis results showed that virological and biochemical responses were maintained in most patients at 2 years of therapy, despite the emergence of YMDD-variant HBV.8

Baseline median serum HBV-DNA and ALT were 30.7 Meq/mL and 3.1 × ULN, respectively. By month 2, median serum HBV-DNA had rapidly decreased to < 0.7 Meq/mL. At months 24 and 36, levels were maintained at 0.8 and < 0.7. By month 4, median ALT normalized to 0.8 × ULN. Levels were maintained between 0.8 and 1.2 × ULN up to month 36.8 Normalization of ALT and HBV-DNA was not sustained in all patients during 3 years lamivudine. The proportion of patients with normal ALT and negative HBV-DNA during 3 years’ extended lamivudine therapy was 51% at month 12, 34% at month 24, and 29% at month 36.8

The proportion of patients exhibiting YMDD HBV variant during 3 years lamivudine therapy in this study was 5% at study entry, 39% at month 12, 54% at month 24, and 57% at month 36. In these patients, median ALT at these time-points were 2.5, 2.1, 2.1, and 1.3 × ULN, respectively.8

None of the 43 patients without cirrhosis at baseline progressed to cirrhosis during the study period and only 4 of 25 (16%) patients without bridging fibrosis at baseline progressed to bridging fibrosis. Of the 42 patients without cirrhosis at baseline, 22 (52%) were YMDD-variant positive at month 24. For those without bridging fibrosis at baseline, 14 of 24 (58%) were YMDD-variant positive at month 24 and of these, 4 (29%) patients progressed to bridging fibrosis. All patients that progressed to bridging fibrosis or cirrhosis were in the YMDD-positive group.8

DECOMPENSATED CIRRHOSIS

  1. Top of page
  2. OUTCOME OF LAMIVUDINE THERAPY
  3. DURABILITY OF TREATMENT RESPONSE
  4. HBEAG-NEGATIVE DISEASE
  5. DECOMPENSATED CIRRHOSIS
  6. LAMIVUDINE SAFETY PROFILE
  7. SUMMARY
  8. REFERENCES

In decompensated cirrhosis resulting from chronic infection with HBV, the prognosis is poor. Furthermore, the side-effects associated with interferon treatment outweigh the benefits. Treatment with lamivudine has shown improvement of liver function in these patients.

Clinical outcome

In the study by Villeneuve et al., 35 patients with decompensated cirrhosis resulting from CHB received either 100 mg or 150 mg lamivudine orally once daily (Fig. 2).9 All patients presented HBsAg and HBV-DNA in serum for at least 12 months prior to study entry. They also had evidence of decompensated cirrhosis as shown by a Child–Pugh score of ≥ 8. During the study, Child–Pugh score was recorded at baseline and subsequently at 3 month intervals, along with serum ALT, AST, HBsAg and anti-HBs, HBeAg and anti-Hbe, and HBV-DNA.

image

Figure 2. Clinical outcome of lamivudine treatment in patients with decompensated cirrhosis resulting from chronic hepatitis B. HBV, hepatitis B virus; OLT, orthotopic liver transplantation; SBP, spontaneous bacterial peritonitis; HCC, hepatocellular carcinoma.

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Of the 35 patients taking part in the study, seven underwent liver transplantation within the first 6 months of lamivudine treatment and, of these patients, three died in the postoperative period and four were  alive  and  free  of  HBV  recurrence  with lamivudine treatment at 21-month follow-up. Five of the 35  patients  died  within  the  first  6  months  of  therapy, all had Child–Pugh class C liver disease, four died as a result of liver failure and one as a result of hepatocellular carcinoma.9

The remaining 23 patients went on to receive lamivudine therapy for ≥ 6 months. Of these patients, all but one showed clinical improvement; defined as a decrease in the Child–Pugh score of at least 2 points. The one patient who did not improve, although loss of serum HBV-DNA was observed, underwent liver transplantation at month 16, but died of cyclosporinee-related progressive leucoencephalopathy 4 months later. Of the 22 patients that had shown improvement, two later died during follow-up at months 17 (spontaneous bacterial peritonitis) and 31 (hepatocellular carcinoma), respectively, and 20 patients were alive at their last follow-up visit at 17–21 months.

Thirteen of the 23 patients, who received lamivudine for 6 months or more, were HBeAg-positive at baseline. Of these, six patients achieved seroconversion from HBeAg-positive to HBeAg-negative/anti-HBe-positive during treatment and one also lost HBsAg. Two of the 23 patients had exhibited anti-HDV at baseline; during treatment they both achieved seroconversion from HBeAg-positive to anti-HBe-positive and showed normalized liver enzymes. Clinical improvement was significant and sustained during the follow-up period. No significant side-effects or flare of hepatitis in association with lamivudine was seen in any patient.9

Child–Pugh scores

In this study, among patients who received lamivudine for at least 6 months, all eight patients who had initial Child–Pugh class B status improved and those with initial Child–Pugh class C status improved (14 of 15 patients) to become either class B (n = 9) or A (n = 5).9

YMDD-variant

The emergence of YMDD-variant HBV following long-term lamivudine therapy results in reduced treatment response in some decompensated CHB patients. In order to improve the treatment response, Perrillo and colleagues conducted a 52-week study investigating the safety and efficacy of adding adefovir dipivoxil 10 mg to lamivudine 100 mg/day in 40 decompensated CHB patients with YMDD-variant HBV and a reduced response to lamivudine.10 At entry into this study the median treatment duration of previous lamivudine was 31.3 months and 74% (29 of 39) of patients were HBeAg positive. Eligibility criteria included serum HBV-DNA levels of ≥ 106 copies/mL and abnormal serum ALT values of > 1.3 × ULN.10

Preliminary 24-week results showed that 13% (4 of 31) of patients achieved a serum HBV-DNA level below the limit of detection (< 200 copies/mL). Of those patients that were HBeAg positive on entry into the study, 5% (1 of 21) achieved HBeAg seroconversion. A median reduction of 3.9 Log10 copies/mL was observed for HBV-DNA; approximately 60% of patients had a 3–4 Log10 copies/mL decline in HBV-DNA 4 and 13% had a 5 or 6 Log10 decline at week 24. Of those patients with abnormal ALT values at baseline, 41% (12 of 29) achieved ALT normalization, and 62% (8 of 13) and 40% (6 of 15) of patients achieved bilirubin and albumin normalization, respectively.10

LAMIVUDINE SAFETY PROFILE

  1. Top of page
  2. OUTCOME OF LAMIVUDINE THERAPY
  3. DURABILITY OF TREATMENT RESPONSE
  4. HBEAG-NEGATIVE DISEASE
  5. DECOMPENSATED CIRRHOSIS
  6. LAMIVUDINE SAFETY PROFILE
  7. SUMMARY
  8. REFERENCES

In the study by Guan and colleagues of lamivudine therapy in Chinese CHB patients for up to 5 years, lamivudine was well tolerated with little change in type or frequency of adverse events.2 Episodes of liver decompensation were seen in two patients, one of whom displayed YMDD-variant. However, both patients subsequently experienced stable HBeAg seroconversion.2

An integrated analysis of Phase 3 data by Lai et al. in which CHB patients were treated with either placebo or lamivudine 100 mg for up to 4 years, reported that a higher percentage of patients were seen with serious adverse events (SAEs) in year 1 in the placebo group, than in patients in the lamivudine group in years 1, 2, 3, and 4 (Fig. 3).11 It could be concluded that patients treated with placebo were twice as likely to experience SAEs than those treated with lamivudine.11 For patients with YMDD-variant the incidence of SAE's did not increase in successive years of lamivudine therapy.11

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Figure 3. Patients with serious adverse events in each year.

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Combination of lamivudine and adefovir dipivoxil was well tolerated.10 In Perrillo's study no patients exhibited nephrotoxicity. Three patients (8%) reported SAEs, however, none were related to the study drug. One patient who was jaundiced and cirrhotic at screening with a Child-Pugh score of 11, experienced exacerbation of hepatitis B and respiratory distress at week 16 – this patient was withdrawn from the study.10

SUMMARY

  1. Top of page
  2. OUTCOME OF LAMIVUDINE THERAPY
  3. DURABILITY OF TREATMENT RESPONSE
  4. HBEAG-NEGATIVE DISEASE
  5. DECOMPENSATED CIRRHOSIS
  6. LAMIVUDINE SAFETY PROFILE
  7. SUMMARY
  8. REFERENCES

In conclusion, most patients with CHB have their disease controlled by lamivudine therapy, and those with elevated ALT respond well. The incidence of YMDD-variant increases with duration of treatment, although patients with YMDD still gain clinical benefit from continued lamivudine therapy and seroconversion can still be achieved. Lamivudine has shown efficacy in HBeAg-negative patients and those with decompensated cirrhosis. In long-term use, lamivudine has been found to be well tolerated. Even in patients with YMDD-variant HBV, no increase in hepatic serious adverse events was seen. In patients with decompensated CHB the combination of lamivudine and adefovir dipivoxil showed significant efficacy. After only 24 weeks, clinical improvements in liver function were seen.

REFERENCES

  1. Top of page
  2. OUTCOME OF LAMIVUDINE THERAPY
  3. DURABILITY OF TREATMENT RESPONSE
  4. HBEAG-NEGATIVE DISEASE
  5. DECOMPENSATED CIRRHOSIS
  6. LAMIVUDINE SAFETY PROFILE
  7. SUMMARY
  8. REFERENCES
  • 1
    Lai CL, Chien RN, Leung NW et al. A one-year trial of lamivudine for chronic hepatitis B. New Eng J. Med. 1998; 339: 618.
  • 2
    Guan R, Lai CL, Liaw YF, Lim SG, Lee CM. Efficacy and safety of 5 years lamivudine treatment of Chinese patients with chronic hepatitis B. J. Gastroenterol. Hepatol. 2001; 16 (Suppl.): A60.
  • 3
    Schiff ER, Heathcote J, Dienstag JL et al. Improvements in liver histology and cirrhosis with extended lamivudine therapy. Hepatology 2000; 32: 296A (Abstract 546).
  • 4
    Leung NW, Liaw YF, Chang TT et al. Durable HBeAg response in Chinese patients treated with lamivudine. Hepatology 2001; 34: 348A (Abstract 705).
  • 5
    Schiff ER, Cianciara J, Karavalein S et al. Durable HBeAg and HBsAg seroconversion after lamivudine for chronic hepatitis B (CHB). Hepatology 2000; 32: 99 (Abstract P/C06/12).
  • 6
    Hong SP, Han KH, Ahn SH et al. Additional lamivudine therapy after HBeAg seroconversion would prolong the durability of response in HBV endemic area. Hepatology 2001; 34: 322A (Abstract 600).
  • 7
    Korenman K, Baker B, Waggoner J, Everhart JE, Di Bisceglie AM, Hoofnagle JH. Long-term remission of chronic hepatitis B after alpha-interferon therapy. Ann. Intern. Med. 1991; 114: 62934.
  • 8
    Esteban R., Goldin RD, Tassopoulos NC et al. Clinical & histological outcome of extended lamivudine in patients with HBeAg-negative chronic hepatitis B. Hepatology 2001; 34: 446A (Abstract 1097).
  • 9
    Villeneuve JP, Condreay LD, Willems B et al. Lamivudine treatment for decompensated cirrhosis resulting from chronic hepatitis B. Hepatology 2000; 31: 20710.
  • 10
    Perrillo R., Schiff E, Hann H et al. The addition of adevofir dipivoxil to lamivudine in decompensated chronic hepatitis B patients with YMDD variant HBV and reduced response to lamivudine – preliminary 24 week results. Hepatology 2000; 34: 349A (Abstract 708.
  • 11
    Lai CL, Maddrey WC, Marr C, Woessner M, Atkins M. Long-term safety of lamivudine in patients with chronic hepatitis B. J. Gastroenterol. Hepatol. 2000; 15 (Suppl.): 1208 (Abstract P-H-70).