| Abstract|| |
Nucleot(s)ide analogues are making milestones in the treatment of chronic hepatitis B (CHB). Lamivudine was approved by FDA for the treatment of chronic hepatitis B in adult patients n 1998 (ZeffixTM HeptodinTM HeptovirTM Epivir-HBVTM Glaxo Wellcome). Adefovir dipivoxil was approved by FDA in 2002 (Hepsera, Gilead). Both were licensed and available in many countries. A comparison of their efficacy in the treatment of various subgroups of CHB patients will facilitate management decision and choice between these two agents.
Lamivudine suppresses viral replication and reduces serum HBV DNA level by 3-4 log 10 after one year of therapy, associated with normalization of serum alanine aminotansferase and significant improvement in histologic activity index. In HBeAg positive CHB, HBeAg loss/seroconversion rate at the end of one year of therapy is 18-30%; higher pretreatment serum alanine aminotransferase (ALT) level is associated with higher HBeAg loss/ seroconversion. HBeAg loss/seroconversion increases on extended therapy. The durability of response off therapy declines with time. Clinical efficacy in HBeAg negative CHB is similar. However, the drawback of Lamivudine therapy is increasingly being recognized. The endpoint for therapy is difficult to define and viral response is often not durable. Long-term therapy runs the risk of emergence of lamivudine resistant mutants (YMDDm) at the rate of around 15-30% each year, with a cumulative 70% at the end of year 4. YMDDm viraemia is eventually associated with relapse of hepatitis and occasionally hepatic decompensation. In patients with maintained or sustained response, there was significant improvement in necroinflammatory activity. Reversion of fibrosis has also been observed. In patients with advanced fibrosis and cirrhosis, three years of Lamivudine therapy reduced disease progression and possibly reduced occurrence of hepatocellular carcinoma. Lamivudine has also established its role for patients with hepatic decompensation pending liver transplantation, HBsAg positive patients receiving chemotherapy or organ transplantation. Its role in CHB children and viraemic CHB pregnant mothers is less certain.
The clinical benefit of Adefovir dipivoxil was initially recognized in patients with Lamivudine resistant YMDD mutants. Subsequent pivotal phase 3 placebo-controlled trials showed significant antiviral activity against both wild type and HBeAg negative HBV. Adefovir dipivoxil 10 mg daily showed significant clinical benefit in normalization of serum ALT and histologic improvement in both HBeAg positive and HBeAg negative CHB. One important advantage of Adefovir dipivoxil over Lamivudine in long term therapy is the much lower rate of emergence of drug resistant mutants. No resistant mutation was detected at the end of first year of therapy and around 15% at the end of four years. It has good safety profile except for possible reversible renal toxicity which has been reported in isolated patients on the 10mg dosage. Data and clinical experience in other patient subgroups are pending.
|How to cite this article:|
Leung N. Comparison of lamividine and adefovir dipivoxil in the treatment of chronic hepatitis B. Hep B Annual 2005;2:93-126
| Introduction|| |
Chronic hepatitis B virus infection (CHB) continues to be an important cause of morbidity, mortality and source of potential new infections in many parts of the world. Persistent infection develops in 3-10% of people who become infected after the age of six years and in over 90% of congenitally infected children. The World Health Organization estimates 400 million individuals being chronically infected with HBV. HBV is the 10th leading cause of death worldwide. In China, Southeast Asia and subSaharan Africa, as many as 10% to 15% of the population are chronically infected. The rates are much lower, usually below 1%, in North America and Northern Europe and 1-5% in Southern Europe (e.g., Italy, Greece and Spain), parts of South and Central America, the Middle East and Japan. Epidemiology is changing as a result of universal HBV vaccination of newborn which is being enhanced in Asian countries aiming to prevent mother-to-child transmission. Improved socioeconomic situation will also promote better prevention programs. However, population movement with migrants from high endemicity regions may introduce infection among those in low endemicity regions. CHB will continue to be a healthcare burden in most countries globally. The outlook may not be so grave as therapeutic advances lower viral load in CHB patients and this has been shown to have significant impact on the incidence of liver-related morbidity and mortality. This chapter will discuss and compare the two nucleoside analogues approved for CHB therapy, namely lamivudine and adefovir. It is important to bear in mind that this is an indirect comparison since there is no head-to-head clinical trial and the study design, cohort characteristics and serum HBV DNA assays of wide range of sensitivity and dynamic ranges were different.
Pharmacology and pharmacokinetics of lamivudine and adefovir dipivoxil
Lamivudine is a dideoxy-thiacytidine analogue with potent antiviral property against hepatitis B virus (HBV). It is the first oral administered medication for HBV with around 87% bioavailability. It is mostly excreted unchanged by the kidneys. Dosage reduction is required if creatinine clearance is <50 ml/min. No dosage adjustment is needed in decompensated liver disease. It has no appreciable inhibition of DNA synthesis in intact mitochondria. There is no ethnic difference in pharmacokinetics and clinical efficacy between Asian and Caucasian patients with different HBV genotypes.
Adefovir dipivoxil is another oral nucleoside analogue with anti-HBV activity. It is absorbed and hydrolyzed to Adefovir by nonspecific esterases in the intestinal mucosa and blood. Adefovir is not significantly metabolized further prior to elimination in the kidneys by a combination of glomerular filtration and active tubular secretion. In patients with normal renal function, approximately 30-45% of an orally administered Adefovir dipivoxil 10 mg dose (equivalent to the amount absorbed) is recovered unchanged in urine within 24 hours. The elimination halflife from serum was approximately 5 to 7 hours. In patients with moderate and severe renal impairment and in hemodialysis patients, modified dosing regimens are necessary. Patients with moderate and severe hepatic impairment have similar pharmacokinetics compared to healthy volunteers. Adefovir does not interfere with the functions of major isoforms of cytochrome P450 responsible for phase I metabolism of most drugs. There is no reported difference in pharmacokinetics and clinical efficacy between Asian and Caucasian patients and with different HBV genotypes.
Clinical efficacy of lamivudine and adefovir dipivoxil
Lamivudine and adefovir were evaluated in pivotal international multicenter phase III double-blinded randomized placebo-controlled trials prior to FDA approval. Inhibition of viral replication is demonstrated by a rapid decline in serum HBV DNA in all patients and is associated with normalization of serum alanine aminotransferase (ALT) and histological improvement in a significant proportion of the patients at the end of one year of therapy. Longer duration of therapy resulted in further clinical benefit in patients who maintained response. Although the inclusion and exclusion criteria for recruitment in these clinical trials are largely similar, subtle differences in baseline serum ALT levels above the upper limit of normal (ULN) and serum HBV DNA level are likely to have an impact on the reported overall response rates. The following sections attempt to make an analytical comparison of reported clinical efficacy of lamivudine and adefovir in both HBeAg positive and HBeAg negative CHB in different patient subgroups.
Clinical efficacy in compensated HBeAg positive CHB
a. Maintained virologic response on therapy
Lamivudine was evaluated in three pivotal international multicenter phase III double-blinded randomized placebo- or active-controlled trials prior approval.,, This included 291 patients randomised to lamivudine 100 mg daily for one year. Asian patients constituted 100%, 24% and 29% of these trials respectively. The baseline demography of the patients was: median age 30-40 years old, 71-86% male, median ALT levels 1.5-2.6 times ULN (66-95% had raised ALT above ULN); median serum HBV DNA was 74-136 pg/ml (Abbott's hybridization assay, equivalent to around 8 log 10 copies/mL) and Knodell histologic activity index (HAI) score between 4 and 10, 5-6% cirrhosis. None of these patients had received antiviral therapy in the past three to six months. Apart from these 3 pivotal clinical trials, the clinical efficacy of lamivudine 100 mg daily has been further assessed and compared as active control in double-blinded randomised clinical trials of new anti-viral agents too.
Adefovir 10 mg daily and 30 mg daily were evaluated in one pivotal phase III international multicenter randomized double-blinded placebo-controlled trial. 171 HBeAg positive patients were randomised to adefovir 10 mg daily for 48 weeks. About a quarter of the patients had previously received Interferon therapy. The baseline demography of the patients on adefovir 10 mg daily was comparable to the placebo group: median age 32 years, 76% male, median ALT 2.3 times ULN (98% of all patients had raised ALT), median serum HBV DNA 8.4 log 10 copies/mL (Roche Amplicor® Monitor™ PCR assay), median HAI score 8 (necroinflammatory score 7, fibrosis score 1).
Lamivudine inhibited viral replication and resulted in rapid decline in serum HBV DNA by around 3 log 10 copies/mL within the initial 8 weeks of therapy, followed by a slower decline to undetectable level by the end of the first year using Abbott's solution hybridization assay (lower limit of detection LOD 2.5 pg/ml or approximately 6 log 10 copies/mL). In later clinical trials using more sensitive HBV DNA assays with LOD 3 log 10 copies/mL, a median reduction of 5.5 log 10 copies/mL was demonstrated at the end of one year therapy. This is superior to median reduction of 3.52 log 10 copies/mL with adefovir dipivoxil. Serum HBV DNA was undetectable by polymerase chain reaction (PCR) assays in 28% Lamivudine treated and 21% adefovir treated patients. 16-18% of the lamivudine treated patients achieved HBeAg seroconversion, compared to 11% (22% HBeAg loss) among the adefovir treated patients. Both agents have significantly higher HBeAg seroconversion rate compared to 4-6% observed among the placebo group ( P <0.01). These data suggest that lamivudine is more potent and rapid in its antiviral activity. Both agents have few drug related side-effects. The main drawback of lamivudine therapy is drug resistant mutation. By the end of first year of therapy, 15-20% of the patients had detectable genotypic resistant mutations in the YMDD domain (see later section on drug resistance) leading to greatly reduced responsiveness to lamivudine. On the other hand, no adefovir resistant mutations were detected at the end of a year of adefovir therapy.
HBeAg seroconversion rate of both agents is disappointing. Selection of patients and decision to treat should be based on identifiable predictors of response. Stepwise logistic regression analysis in the Asian Lamivudine Study showed baseline serum ALT to be the only significant predictor of HBeAg seroconversion. 64% of the patients with ALT >5 x ULN seroconverted, compared to 26% with ALT 2-5 x ULN ( P =0.03) and 5% with ALT <2 x ULN ( P <0.01). Age, gender, HBV-DNA level, HAI score, presence of cirrhosis, body weight and body mass index could not predict HBeAg seroconversion. Integrated data analysis of the three phase III lamivudine trials showed no difference in HBeAg seroconversion between Asian and Caucasian patients when adjusted for baseline ALT. Adefovir therapy has not reported analysis on virological response based on baseline serum ALT except that patients with baseline fibrosis score of 3 or 4 (bridging fibrosis/cirrhosis) appeared to benefit more with numerically greater virological, biochemical and histological responses. 32% of patients with advanced fibrosis had HBV DNA reduced to <400 copies/ml compared to 17% among those with baseline fibrosis score of 0 or 1 ( P <0.001). However, the latter group had higher baseline serum HBV DNA level.
In the Asian Lamivudine study, patients were randomised to continue with Lamivudine or switched to placebo in a double-blinded manner at the end of the first and second year, followed by optional open-label Lamivudine for the fourth and fifth years.,,, Most patients had viral rebound shortly after switching to placebo, particular those who had not achieved HBeAg seroconversion. The efficacy of extending therapy beyond one year has been addressed for both agents. Viral suppression was maintained only among patients without lamivudine resistant YMDD mutants. After emergence of YMDD mutants, viral level remained low in some and viral breakthrough occurred in others. Relapse of hepatitis occurred eventually. Among the 58 Asian patients randomised to five years of continuous lamivudine therapy, incremental increase in HBeAg seroconversion at the end of each year were 22, 29, 40, 47 and 50% respectively [Figure - 1]. 77% (20/26) with baseline ALT > 2xULN achieved HBeAg seroconversion. YMDD mutants were detected in 69% (40/58) patients during the study. 15 of these 40 also achieved HBeAg seroconversion and 7 lost YMDDm on subsequent testing. Transient episodes of liver decompensation occurred in 2 patients (1 with confirmed YMDD mutant) who subsequently experienced stable HBeAg seroconversion. Similar results and experience were observed in other clinical trials.,
Adefovir trial also extended therapy beyond one year. A subset of 171 patients eligible to be randomised to continue open label Adefovir 10 mg was planned to be treated for 5 years. Unfortunately, misallocation at the beginning of year 2 resulted in only interim data on patients who had a short period of interruption in treatment. Data available at the end of 48 (n=65), 96 (n=29) and 144 (n=36) weeks showed HBeAg seroconversion 12, 29 and 43% respectively which is comparable if not slightly better than lamivudine by year three. Undetectable serum HBV DNA by PCR (<3 log 10 copies/mL) was 28, 45 and 56% respectively [Figure - 1]. No data on undetectable serum HBV DNA from Lamivudine trial was available for comparison. ALT normalization was 58, 73 and 81% respectively compared to 82, 70, 64% over three years of lamivduine, reflecting relapse of hepatitis with emergence of lamivudine resistant YMDDm. No adefovir resistant mutant was detected after 48 weeks of therapy. 2 patients (3.1%) were reported to have developed resistance through 144 weeks of adefovir therapy. Adefovir related severe adverse events were reported in 1% in year one and 0% in the group treated for three years. In particular, no patients had increase serum creatinine by >0.5 mg/dL above baseline.
There were sporadic HBsAg loss or seroconversion reported with lamivudine therapy but this was not observed among the Asian patients in the clinical trials. Adefovir therapy resulted in 2% HBsAg seroconversion at the end of first year therapy. Study on cccDNA during Adefovir therapy documented fall in hepatic level of HBV cccDNA by 0.8 log after 48 weeks of Adefovir therapy. 90% of patients maintained HBeAg seroconversion off therapy after follow up observation of less than one year. The reduction in hepatic cccDNA may be modest after 48 weeks of adefovir therapy but may be the crucial mechanism for potential viral eradication and durable viral response after longer term therapy.
b. Maintained biochemical and histologic response on therapy
As mentioned above, during anti-viral therapy, viral suppression was accompanied by normalization of ALT among those with raised baseline ALT. Transient ALT elevation was reported in the initial weeks of therapy in some patients treated with lamivudine, a result of rapid viral suppression and restoration of T cell responsiveness. This phenomenon has not been reported in adefovir therapy. During three years of lamivduine therapy, ALT normalization occurred in 82% at the end of year one, reducing to 70% and 64% at the end of year two and three respectively, reflecting relapse of hepatitis with emergence of lamivudine resistant YMDD mutants. With continued and maintained viral suppression with Adefovir and the much lower rate of emergence of adefovir resistance, ALT normalization increased with years, increasing from 63% at the end of year one to 73% and 80% respectively after two and three years of adefovir therapy.
Histologic improvement was used as the primary endpoint in both lamivudine and adefovir clinical trials. Paired liver biopsies before and after one year of therapy were assessed by central pathologists blinded to biopsy sequence and therapy regimen. One year of lamivudine improved total Knodell HAI score by >2 points in 62-70% of the patients, significantly better than 20-33% in the placebo group ( P <0.05).,, Comparable results were observed with one year adefovir therapy. 64% of patients treated with adefovir exhibited significant improvement in liver histology, compared with 33% of patients receiving placebo ( P =0.0002).
By ranked assessment, significant reduction in progression of fibrosis was demonstrated at the end of one year lamivudine therapy. In the Asian Lamivudine Study, fibrosis worsened in 15% of placebo as compared to 3% of Lamivudine treated group ( P <0.01). Integrated analysis revealed that there was reduced progression to cirrhosis in lamivudine-treated group compared to the placebo group.
Histologic response continued to improve among patients with continued viral suppression. However, with emergence of YMDD mutants, vireamia rebounded and hepatitis relapsed with deterioration in HAI when biopsies were taken at year three of therapy. The duration of harbouring YMDD mutants had a negative impact on the histologic response., In the North American Lamivudine Study, the histological impact of longer-term treatment was assessed with sets of 3 liver biopsies from 63 patients: before, after 1 year of randomized Lamivudine treatment and after 2 years of further open-label treatment. 57% improved HAI necroinflammatory score by > 2 points after one year of lamivudine, 38% remained unchanged and 5% worsened. Additional 2 years of lamivudine resulted in continued improvement in 19%, stable state in 60% and worsening in 21%. The overall impact of 3 years of lamivudine treatment was improvement in 56% of patients, no change in 33% and worsening in 11%. These results are not much different from year one and mainly due to the negative impact of YMDDm. Those without YMDD mutants were more likely to improve compared with those with YMDD mutants (77% vs. 44%) and less likely to deteriorate (5% vs. 15%). Duration of harbouring YMDD mutants has a direct association with deterioration, with those harbouring YMDD for over 2 years least likely to improve (36%). Bridging fibrosis improved in 63% and cirrhosis improved from score of 4 to < 3 in 8 of 11 patients. One of 52 patients showed progression to cirrhosis and 3 of 34 showed progression to bridging fibrosis. These four patients were all infected with YMDD mutants. Thus the emergence of YMDD mutants blunted the overall histologic benefit observed in some patients. Similar picture was observed in the year three results of the Asian Lamivudine Study.
Histologic data on long term Adefovir therapy is not available for comparison. With only around 5% adefovir resistance mutants emergence by the end of three years therapy, continued improvement or stable histology is expected.
c. Durability of response off therapy
The traditional concept of CHB therapy is treatment for a defined duration to achieve the desired response that is long lasting after the treatment is stopped. The pivotal phase 3 clinical trials were designed to address this issue.
During lamivudine therapy, serum HBV DNA was rapidly suppressed to undetectable level as assayed with hybridization assay. In the absence of HBeAg seroconversion, stopping lamivudine therapy would result in virological rebound and would often be associated with ALT elevation. Fatality has been reported among patients with ALT flare. The durability of HBeAg loss/seroconversion was initially reported to be around 80% to 90% 6 to 12 months after stopping lamivudine., Unfortunately, the post marketing experience of lamivudine showed that HBeAg reversion accumulates with time.,,, Recommendation to continue lamivudine for at least six months after HBeAg loss or seroconversion has been made. This recommended duration of additional therapy may need to be increased. In the Asian Lamivudine Study, 83% patients with durable response had 19.6 months (range 3.5 to 35.5 months) lamivudine post HBeAg seroconversion, compared to 9.0 months (range 3.8 to 30.9 months) among those who had HBeAg reversion. Other studies reported variable level of durability, ranging from 50% to 77% after 3 years follow-up. In a report from Korea, 61 patients stopped lamivudine 24 months after documentation of persistent HBV DNA and HBeAg negativity. HBV DNA rebound gradually and after 2 years, 31% became viraemic again and HBeAg reappeared in 16%. In addition to duration of therapy after response, older patients over 36 years of age, presence of precore mutants, high pretreatment ALT and HBV DNA levels and possibly genotype C may be predictors of reversion. Prompt resumption of lamivudine therapy averted relapse of hepatits and ALT flares.
Limited data is available on the durability of Adefovir induced viral response. 92% of 76 patients with HBeAg seroconversion maintained this status after a median 55 weeks off therapy (range 5-114 weeks). Those who maintained seroconversion had a median of 48 weeks post-seroconversion adefovir (range 5-136 weeks). Durable response was associated with serum HBV DNA <1,000 copies/ml and normal ALT.
Clinical efficacy in compensated HBeAg negative CHB
a. Maintained virologic response on therapy and durability of response
The efficacy of 24 weeks of Lamivudine 100mg daily in 60 patients with HBeAg-negative / HBV DNA positive (precore mutant) CHB was evaluated in a pivotal International Multicentre Phase III double blinded placebo-controlled clinical trial. The patients had baseline median age of 42 years, 83% were males; median ALT 3.2 times ULN (97% with elevated ALT); serum HBV DNA 255.0 pg/ml; HAI necroinflamatory score of 5 and 14% had cirrhosis. At 24 weeks of therapy, a significantly higher proportion of patients on lamivudine achieved combined response of undetectable serum HBV DNA (Abbott's hybridization assay, LOD 2.5 pg/ml or approximately 7 log 10 copies/mL) and normalization of ALT compared to placebo group (63% vs 6% respectively; P <0.001). 53 patients who had serum HBV DNA <2.5 pg/ml continued treatment up to 52 weeks. Viral response decreased by week 52 because 27% had YMDD mutants.
Pivotal International Multicentre Phase III double-blinded placebo-controlled clinical trial of adefovir dipivoxil evaluated adefovir 10 mg in HBeAg negative/anti-HBeAg positive (presumed pre-core mutant) CHB. 185 patients had baseline demography as follows: median age 46 years, 83% male, 67% white and 29% Asian, median ALT 2.3 times ULN (94% raised ALT), median HBV DNA 7.1 log 10 copies/mL, median HAI 10 (necroinflammation 8, fibrosis 1 and cirrhosis 11%). 39% had prior therapy (interferon 39%, lamivudine 8% and famiciclovir 6%). 51% of patients in adefovir group had undetectable serum HBV DNA (less than 400 copies/mL) at 48 weeks. None of the patients on placebo had undetectable serum HBV DNA ( P <0.001). The median reduction of serum HBV DNA was 3.91 vs 1.35 log copies/ml respectively ( P <0.001).
Clinical efficacy, safety and resistance profile of long-term lamivudine therapy are far from satisfactory., In a study on 50 Chinese-Canadian patients with genotype B and C, undetectable HBV DNA by PCR declined with time at 6, 12 and 24 months (100%, 92% and 86% in genotype B and 94%, 88% and 74% in genotype C patients respectively) [Figure - 2]. The cumulative genotypic YMDD mutation was 15% at year one and 25% at year 2. Four patients with YMDDm experienced hepatitic flare. After stopping therapy, virological relapse was 30%, 50% and 50% at 6, 12 and 24 months respectively. Relapse responded to reinstitution of Lamivudine promptly. In another retrospective study from Italy, 656 patients (mean age 49.1 years), 54% with chronic hepatitis, 30% Child's A cirrhosis and 16% Child's B/C cirrhosis were treated with Lamivudine. Maintained virological response was only 39% after 4 years. 7.2% patients underwent liver transplantation and 4.7% of the patients had worsening of liver disease. Hepatocellular carcinoma (HCC) developed in 4.7% and 3.6% died of liver disease-related causes. Multivariate analysis revealed that the presence of cirrhosis and viral breakthrough were independently related to mortality and development of HCC.
In the pivotal Phase III clinical trial of adefovir dipivoxil, 70 patients were treated with open label adefovir 10 mg daily for up to 192 weeks (just under 4 years). Serum HBV DNA was maintained below 1,000 copies/ml in 63, 77, 77 and 79% respectively at the end of week 48, 96, 144 and 192 respectively [Figure - 2]. There was infrequent and delayed emergence of adefovir resistant mutation (0/123, 4/134, 10/124 and 5/67 or 0, 3, 11 and 18% respectively. There is limited data on the durability of response off adefovir therapy.
b. Maintained biochemical and histologic response on therapy
In the pivotal Phase III Lamivudine clinical trial, the median baseline ALT was 3.2 times ULN (97% with elevated ALT) and ALT normalized within 12 weeks of Lamivudine therapy. At week 52, ALT was maintained or just slight above ULN in the majority of patients with YMDD mutants. There were two patients who had raised ALT 5 and 10 times ULN after one year Lamivudine. 42 of 60 patients had evaluable paired liver biopsies pre- and post-therapy which showed improved HAI necroinflammation in 60%, unchanged picture in 29% and worsening in 12%. In a ranked assessment of fibrosis score, 11% had improved, 86% remained unchanged and 2% worsened. There was no prospective or retrospective study on the impact of extended Lamivudine therapy on biochemistory and histology.
In the pivotal Phase III adefovir clinical trial, normalization of serum ALT increased over the years of therapy at 73, 83, 88 and 91% respectively.,, This was associated with a median reduction of Knodell HAI necroinflammatory score by 4 and 5 points respectively by the end of year 1 and 2. Ranked assessment of fibrosis score showed improvement in 63% and 74% respectively. Among the 70 patients randomized to 3 years Adefovir therapy, > 1 point improvement in Ishak fibrosis score from baseline increased from 35% to 63% by the end of year 1 and year 3 respectively.
Drug resistant mutants
HBV replication occurs at a tremendously rapid rate facilitated by HBV DNA polymerase. This polymerase is the molecular target of anti-viral nucleoside analogues. Due to poor fidelity in proofreading of HBV replication, quasispecies occur constantly during HBV replication. This creates opportunity for drug resistant mutants to emerge during therapy if viral suppression of the antiviral agent cannot rapidly eradicate all HBV forms completely. Under selection pressure, HBV variants with reduced sensitivity or resistance to the anti-viral agents emerge.
During lamivudine therapy, lamivudine resistant mutants start emerging from the sixth month of treatment. The mutants had two point mutations at Domain B and C of the polymerase YMDD loci. rtM204I/V (substitution of the methionine by valine or isoleucine) and rtL180M are now well recognized to be associated with lamivudine resistance with increase in IC50 of lamivudine by >10,000-fold. 14-30% of the patients harbor these mutants after one year of lamivudine. On extended therapy, YMDD mutants continue to emerge. The Asian Lamivudine Study showed 17, 40, 55, 67 and 69% of the treated patients had YMDD mutants at the end of each successive year of therapy [Figure - 3]. Integrated analysis from studies worldwide showed a very similar trend. YMDD mutants initially appear to be less competent in replication. However, viral breakthrough and elevation of serum ALT occurs eventually in the majority of patients. 13 (40.6%) of patients with YMDD mutants experienced acute exacerbation 4 to 94 weeks after its emergence was reported. Three patients deteriorated and developed hepatic decompensation. With continuation of lamivudine therapy, HBeAg seroconversion may occur in some patients after relapse of hepatitis. In clinical studies, it has been demonstrated that a proportion of patients had worsening liver histology after 3 years., Progression of liver disease and development of HCC occurred more frequently among patients harboring YMDD mutants., The high cumulative rate of YMDD mutant emergence after 5 years of therapy necessitates identification of predictive factors. With exploratory regression analyses, high liver HAI score was found to be significantly associated with YMDD mutant detection at the end of first year of therapy in the Asian Lamivudine Study. High baseline body weight, body mass index and HBV-DNA level have also been reported to be predictive of YMDD mutant emergence. Most studies on long-term therapy showed a high chance of eventual YMDD mutant emergence if serum HBV DNA is detectable by PCR assays at 24 months of lamivudine. The possibility of encountering ALT elevation and hepatitis flare increases with the duration of harboring of YMDD mutants.
Discontinuation of lamivudine when it is no longer effective may be a logical appraoch and has been shown to be a possible clinical strategy especially if ALT has not relapsed., A comparative study from Taiwan followed the clinical courses of 66 patients who continued and 68 patients who discontinued lamivudine therapy. In the 12 months follow-up, hepatitis flares occurred in 67% and 54% respectively in patients who continued and discontinued lamivudine therapy. Hepatic decompensation occurred in 11% and 7% respectively ( P <0.05). HBeAg seroconversion rate was 19% in continued group and 35% in discontinued group ( P =0.08). As expected, serum HBV DNA increased in 73% of the continued group with median level increasing from 46 pg/ml upon first detection of mutation to 330 pg/ml at the end of 12 months of continued therapy P <0.001). In contrast, in the discontinued group, serum HBV DNA level increased in 33% of patients only and the median level decreased from 172 to 55 pg/ml at the end of 12 months after stopping Lamivudine. With the approval of adefovir and entecavir, both effective in suppressing YMDD mutants, the management options have increasing. Adding or simply switching from adefovir to lamivudine have been shown to be effective both in patients with compensated CHB and in those pre- and post liver transplantation.,,,,, Suppression of YMDD mutants was associated with biochemical remission. There are case reports of Lamivudine resistant mutants reverting to Wild type HBV while on adefovir monotherapy, followed by rt236 adefovir resistance.
Resistance to adefovir therapy was not reported in the two large scale 48 weeks clinical trials., Adefovir resistant mutant was first reported in a patient whose HBV DNA breakthrough to pretreatment level associated with marked increase in serum ALT and mild hepatic decompensation during a 96 weeks therapy. HBV DNA was PCR amplified and sequenced. A novel asparagine to threonine mutation at residue rt236 in domain D of HBV polymerase was identified with in vitro demonstration of markedly reduced susceptibility to adefovir. With addition of lamivudine, virologic and biochemical response were achieved. Characterization of this novel mutant showed its full susceptibility to lamivudine, entecavir and investigational drug L-dT with IC50 changes less than 2.4 folds. Adefovir resistance is associated with mutation at N236T or A181V alone, or there is a combination of N236T and A181V/T and a rise in HBV DNA by over 1 log 10 copies/mL. Emergence of resistance is sometimes associated with ALT flare. Addition of lamivudine to Adefovir resulted in decline of serum HBV DNA level. As mentioned before, long-term adefovir therapy for HBeAg negative CHB demonstrated slow emergence of adefovir resistant mutants at the end of week 48, 96, 144 and 192 in 0/123, 4/134, 10/124 and 5/67 (or 0%, 3%, 11% and 18%) respectively [Figure - 3]. The long-term clinical impact of adefovir resistant mutants remains to be defined.
Therapy for HB cirrhosis
One of the important therapeutic goals for CHB is the prevention of progression of disease and its complications, including the development of HCC. For patients already suffering from advanced fibrosis or cirrhosis, the effectiveness of antiviral therapy in this patient subgroup was demonstrated by the longterm lamivudine therapy study. 651 patients (98 percent Asian and 85 percent male) with histologically confirmed cirrhosis or advanced fibrosis were randomly assigned in a 2:1 ratio to receive lamivudine 100 mg daily or placebo for a maximum of five years. The study was terminated after a median duration of treatment of 32.4 months (range: 0 to 42 months) owing to a significant difference between treatment groups in the number of end points reached in an interim analyses of the data by an independent data and safety monitoring board. Primary end points (time to disease progression, defined by hepatic decompensation, hepatocellular carcinoma, spontaneous bacterial peritonitis, bleeding gastroesophageal varices, or death related to liver disease) were reached by 7.8 percent of the patients receiving lamivudine and 17.7 percent of those receiving placebo (hazard ratio for disease progression 0.45; P =0.001). The Child-Pugh score increased in 3.4 percent of the patients receiving lamivudine and 8.8 percent of those receiving placebo (hazard ratio, 0.45; P =0.02), whereas hepatocellular carcinoma occurred in 3.9 percent of those in the lamivudine group and 7.4 percent of those in the placebo group (hazard ratio 0.49; P =0.047). Genotypic resistance with YMDD mutations developed in 49 percent of the patients treated with lamivudine and the Child-Pugh score was more likely to increase in patients with these mutations than in the other patients treated with lamivudine (7 percent vs <1 percent). Overall, 12 percent of the patients in the lamivudine group and 18 percent of the patients in the placebo group reported serious adverse events. This study showed that continuous treatment with lamivudine delays clinical progression in patients with advanced fibrosis or cirrhosis by significantly reducing the incidence of hepatic decompensation and the risk of hepatocellular carcinoma. However, early termination for ethical reason left important questions unanswered: What will be the long term impact of YMDD mutants on 49% of these patients? What will be the consequence of rebound viraemia and relapse of hepatitis? Will more patients on long term lamivudine therapy develop YMDD mutants?
A 5 year prospective cohort study evaluated the long-term outcome of 44 HBeAg negative CHB patients with cirrhosis treated with lamivudine for 52 (5-84) months. The demography of the patients was: 89% men, 82% genotype D, 39% decompensated cirrhosis and 36% had oesophageal varies. Results showed 48% had undetectable serum HBV DNA (LLD <700,000 eq/ml, Bayer) and normal ALT. The 5 year cumulative probability of developing Lamivudine resistance was 63%. Clinical decompensation occurred more often among patients with YMDD mutants (0% vs 32%, P <0.001) whereas the rate of HCC development was similar in both groups (28% vs 41%). Survival was 74% which was similar among responders and those with lamivudine-resistant mutants. However, 5 of the 22 patients with YMDD mutants had rescue antiviral therapy.
A retrospective study to evaluate the safety and efficacy of adefovir therapy in cirrhotic and elderly (>65 years old) patients with lamivudine resistant HBV showed good clinical outcome. Patients achieving undetectable serum HBV (< 200 copies/ml) increased with time. At the end of median 11 (range 2.8-23.9) months of therapy showed 3.4 log drop in serum HBV DNA and 51-71% normalization of serum ALT. Only three serious adverse events were reported but were all not related to adefovir.
Therapy for decompensated CHB
Exacerbation of chronic HBV infection can lead to decompensated liver disease. Rapid deterioration may occur and mortality is high. Efficacy of lamivudine in reducing mortality has been reported.,, Lamivudine therapy has to be instituted early before there is clinical jaundice. Immediate mortality rate was significantly reduced among those with total serum bilirubin level <20 mg/dl (0% lamivudine treated vs 25% control, P =0.013, Odds ratio 2.667; 95% confidence interval 1.787-3.979). Virologic response (HBeAg loss/seroconversion and undetectable serum HBV DNA) often occurred when CHB patients are treated during acute exacerbation. However, the response appears less durable in this subgroup of patients and long-term therapy may be required. Lamivudine also benefits patients with endstage decompensated liver disease pending liver transplantation. Before lamivudine was approved by FDA, it was available on compassionate ground for patients with endstage decompensated liver disease pending liver transplantation. Many patients had significant improvement after at least 6 months of therapy. There was reduction in bilirubin level, improvement in prothrombin time and albumin level. The overall Child's Pugh score improved to the extent that many no longer require transplantation. YMDD mutants emerged in around 20% of the treated patients and may need additional therapy for suppression. In 30 consecutive cirrhotic patients with decompensated HBeAg-negative/HBV-DNA CHB treated with lamivudine, significant clinical improvement defined as a reduction of at least two points in Child-Pugh score was observed in 23 of the 30 treated patients (76.6%) versus none of the 30 patients in the control group ( P < 0.0001) after a mean follow-up of 20.6 + 12.1( + SD) months. There were 10 deaths in the treated group versus 24 in the control group ( P = 0.07). Liver-related deaths occurred in five of the eight patients soon after the development of biochemical breakthrough. Patients with clinical improvement had better survival than patients with no improvement ( P = 0.04) or those who developed biochemical breakthrough due to YMDD mutants ( P = 0.001). There are few reports on the clinical efficacy of adefovir therapy for clinical spontaneous acute exacerbation since its mode of action is regarded as slower than lamivudine. In patients with decompensation secondary to lamivudine resistant acute exacerbation, adefovir has been shown to have beneficial role in uncontrolled studies.
Role in liver transplantation for CHB
In the late 1980s, risk of HBV recurrence and mortality after liver transplantation was unacceptably high. A fatal form of fibrosing cholestatic hepatitis related to high level of viral replication was recognized. Lamivudine monotherapy reduced HBV recurrent rate to 10 to 30% in the first year and 40 to 50% in the third year. Prophylactic combination therapy with HBIG has greatly improved the prospect and has become the standard regimen. The suggested strategy is:
(1) patients with native replicative HBV should be treated with HBIg and lamivudine peri-operatively, followed by tapering of HBIg and longterm lamivudine.
(2) patients without native replicative HBV may be treated with HBIg and lamivudine peri-operatively only.
(3) patients with lamivudine resistant mutants should be treated with HBIg and adefovir.,,,,
This strategy is adopted in most liver transplantation centers and thus there is very little data on the comparison of efficacy of lamivudine and adefovir in the same clinical setting.
Lamivudine also increases the opportunity of liver transplantation by allowing the use of donor livers who have markers of past HBV infection (anti-HBs and / or anti-HBc positive). Use of these donor organs has definite risk of reactivation of HBV infection and loss of grafts and recipient patients. Prophylaxis with HBIG and lamivudine has open a new era that allows the use of grafts from anti-HBc positive donors even if they are PCR HBV-DNA positive.
Management of CHB during immune suppression
CHB patients undergoing immunosuppressive therapy for organ transplantation and systemic disease or chemotherapy for malignancy often risk acute exacerbation of CHB. This is associated with high morbidity and mortality. Lamivudine has been used as a rescue therapy., Early institution of therapy suppresses viral replication and normalizes ALT gradually. If therapy is started late when jaundice and liver failure have set in, the clinical benefit is not assured. Clinical experience indicates that HBV reactivation usually follows 2 or 3 cycles of chemotherapy. Prophylactic suppression of HBV covering the entire course of chemotherapy has demonstrated efficacy in prevention of ALT flares., This approach has been shown to be cost-effective in prospective studies. For post organ transplanation patients, long-term viral suppression with Lamivudine therapy may be required. These patients need to be monitored for lamivudine resistant YMDD mutants and treated with adefovir dipivoxil. The role of Lamivudine for the treatment of hepatitis B virus-related liver disease after renal transplantation has been well established with benefit demonstrated in meta-analysis of 14 clinical trials including 184 patients. Increased duration of lamivudine therapy was positively associated with the frequency of HBeAg loss (r =0.51, P =0.039) and lamivudine resistance (r =0.620, P =0.019). There is little data on adefovir in this clinical situation.
Therapy for CHB children
The disease course and prognosis of childhood HBeAg positive and negative CHB is very variable. The estimated 40% lifetime poor outcome is alarming and distressing to most parents. CHB children mostly have high viral load and high infective potential. Therapy for children with chronic hepatitis B infection is important not only for the child but also vis-a-vis public health. Interferon therapy only benefited a limited proportion of children with moderately raised serum alanine aminotransferase level. It has significant side-effects and this makes it particularly difficult to administer. The pivotal randomized placebo controlled clinical trial of lamivudine was conducted on 288 children with CHB. Recruitment criteria included HBeAg positive, measurable serum HBV DNA by branched-chain DNA assay, serum ALT >1.3 times the upper limit of normal (but <500 IU/L) and histologic evidence of inflammation. Dosage used was 3 mg/Kg body weight; maximum 100 mg daily. After one year of lamivudine therapy, higher maintained virologic response (HBeAg loss and undetectable serum HBV DNA) was achieved with lamivudine than placebo (23% vs 13%; P =0.04). HBeAg seroconversion and ALT normalization was also higher. Histologic response was not addressed. Safety profile and tolerability was good. However lamivudine therapy in children is also overshadowed by the problem of optimal duration of therapy given that drug resistant YMDD mutants occurred in 19% of the children by the end of year one. The same therapeutic dilemma occurs in children as in the adult CHB patients.
Follow-up data on two cohorts on extended therapy showed paradoxically lower virologic response after 3 years compared to 2 years therapy. HBV DNA undetectable rate was 48% after 2 years and 28% after 3 years of therapy. HBeAg seroconversion was 34% and 26% respectively. Therefore the overall virologic response was 33% and 21% respectively. No data was given on YMDD mutation rate and the management strategy for the non-responders. In another study of 20 children in Israel, only one child lost HBeAg and it is a matter of concern that YMDD mutants were detected in 11 of 17 (65%) children. Prognostic indicators to select children for lamivudine therapy such as ALT levels, histology grading and staging for sustained response to therapy need to be clarified.
Recent data on the pharmacokinetic and safety of adefovir therapy among children and adolescents with CHB showed good tolerance. The dosage for children aged 2-6 years is 0.3 mg/kg, aged 7-11 years is 0.25 mg/kg and aged 12-17 years is 10 mg daily. More clinical data is required to assess the role of adefovir in this age group and no comparison can be made with lamivudine.
Role in peri-natal transmission of HBV infection
Vertical transmission of HBV can be prevented by active vaccination of the newborn. Addition of passive immunization (HBIg) at birth further enhances efficacy. Clinical impact of active-passive immunization program has been realized in many Asian countries who have high endemicity. Taiwan reported significant reduction of childhood hepatocellular carcinoma ten years after the introduction of the immunization program. However, certain issues need to be addressed. Firstly, a small percentage of offspring from highly viraemic mothers were still infected and chronicity developed. Secondly, rarely intra-uterine transmission is not prevented by active-passive immunization. Thirdly, HBIg is very expensive and not available in many endemic regions of low socio-economic status. The complementary role of antivirals in reducing viremia levels and vertical transmission has been explored.,, In a small cohort of eight highly viremic (HBV DNA > n1.2 x 10 9sub geq/mL) mothers, Lamivudine 150 mg daily was administered in the last 4 weeks of pregnancy in addition to active-passive immunization for their offspring. At 12 months, one of 8 (12.5%) children was HBsAg positive and 3 children had transient HBV DNA detection during the first year of monitoring. This compares favorably with historic controls where 7 of the 24 children (28%) who received active-passive immunization became chronically infected. Another study from China compared Lamivudine with 200IU HBIG monthly administration from 28 weeks gestation and showed similar effectiveness in reducing HBV intrauterine infection. The potential role of lamivudine in the prevention of vertical transmission has to be verified in a large-scale study.
Combination of lamivudine or adefovir with other nucleoside analogues or immune modulators seems to be theoretically more potent. Viral kinetic studies too suggested that lamivudine and famciclovir may have additive effect. However, clinical trials on lamivudine / telbivudine combination showed no additive or synergistic effect between these agents. Pivotal trial comparing lamivudine / interferon combination after lamivudine priming showed no significant difference., The maintained HBeAg seroconversion at the end of one year treatment was 29% for combination, 18% for lamivudine, 19% for Interferon and 4% for placebo. Preliminary results on combination therapy of lamivudine and pegylated interferon alfa 2b are promising, with sustained HBeAg loss and seroconversion around 35 to 40% among HBeAg positive patients. Ongoing studies on combination therapy of Lamivudine and pegylated interferon alfa 2a on both HBeAg positive and HBeAg negative patients have not revealed additive beneficial response from this combination. The result of combination of adefovir with lamivudine compared to adefovir with placebo is pending.
Safety and contraindications
Both lamivudine and adefovir have good safety profile in long-term therapy. No specific adverse events were reported apart from occasional ALT elevation during initial Lamivudine therapy and possible ALT flare on treatment withdrawal. Adefovir at dosage > 30 mg daily is associated with nephrotoxicity. In clinical trials using Adefovir 10 mg daily up to 4 years, increase in serum creatinine of greater than or equal to 0.5 mg/dL from baseline confirmed on two consecutive occasions was reported in three patients. These abnormalities resolved in one patient while on treatment and the other two patients after treatment was stopped.
Lamivudine and adefovir have no in vivo tetratogenicity concern but their use during early pregnancy is contraindicated. Accidental exposure of fetus to lamivudine has not reported to result in congenital abnormalities in these newborns.
| SUMMARY and CONCLUSION|| |
Recent advances in CHB therapy has improved the prognosis of patients. Interferon and Lamivudine have been the only approved agents for a while. The approval of Adefovir in 2002, Pegylated Interferons and Entecavir in 2005 opens up more choices and chances. Many professional bodies including AASLD, EASL and APASL, have reviewed available data and drawn up guidelines.,,, This chapter reviews and compares the clinical efficacy of lamivudine and adefovir. Both agents have demonstrated significant viral suppression in HBeAg positive and HBeAg negative CHB. Lamivudine is possibly more potent and acts more rapidly. They significantly facilitate HBeAg seroconversion in HBeAg positive patients with raised ALT and improve liver histology in one year as compared to placebo-controlled groups. The long term benefit evaluated in extended therapy up to 4 to 5 years showed maintained or further viral suppression in lamivudine and adefovir treated patients with increased HBeAg seroconversion. However, lamivudine has the disadvantage of high annual emergence rate of lamivudine resistant mutants associated with reversion of clinical benefit in some patients. Adefovir dipivoxil, on the other hand has a much lower annual emergence rate of resistant mutants and this increase in clinical benefit in long term therapy is promising. Besides, it is also effective against lamivudine resistant YMDD mutants. Reported nephrotoxicity, more common in dosages above 10mg daily used for treating CHB may still pose a clinical dilemma among patients with renal insufficiency. For CHB patients with compensated liver disease and normal renal function, weighing the pros and cons of long term efficacy and complexity of management protocols, adefovir may prove to be more advantageous. Furthermore, viral eradication may be potentially achievable after years of Adefovir therapy as suggested by hepatitc cccDNA studies. However, since adefovir has not been widely used, more data is needed to comment on its use as first line agent for all CHB patients. Data on its impact on reduction in liver disease related morbidity and mortality is lacking.
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Consultant Physician, Alice Ho Miu Ling Nethersole Hospital Adjunct Associate Professor, The Chinese University of Hong Kong, Hong Kong SAR
[Figure - 1], [Figure - 2], [Figure - 3]