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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Background  The efficacy of long-term adefovir dipivoxil monotherapy or combination of adefovir and lamivudine in hepatitis B e antigen (HBe-Ag)-negative lamivudine-resistant chronic hepatitis B (CHB) patients is still under investigation.

Aim  To assess the safety and efficacy of the long-term adefovir treatment alone or in combination with lamivudine in HBe-Ag-negative CHB patients who had developed breakthrough because of lamivudine-resistant mutants.

Methods  Fifty-nine patients received combination therapy, while 23 switched to adefovir alone after a 3-month course of combination therapy.

Results  The median follow-up after adefovir’s onset was 31 (18–40) months. Baseline characteristics were similar between the two groups. At 12 and 24 months, 69% and 89% of patients receiving combination therapy and 73% and 82% of patients receiving adefovir monotherapy had serum HBV-DNA <104 copies/mL (P > 0.5). Normalization of alanine aminotransferase levels occurred in 81% and 79% of patients receiving combination vs. 61% and 53% receiving adefovir monotherapy at 12 and 24 months, respectively (P > 0.50). Virological breakthroughs because of adefovir-resistant mutants occurred in five patients under adefovir monotherapy and in none receiving combination therapy (P = 0.001). No one developed decompensated liver disease or hepatocellular carcinoma during follow-up. Re-introduction of lamivudine in adefovir-resistant patients achieved reduction in HBV-DNA and biochemical remission, but re-emergence of lamivudine mutants was observed in one patient after 7.5 months.

Conclusion  In HBe-Ag-negative CHB patients with lamivudine resistance, adding adefovir to continuing lamivudine therapy maximizes anti-viral efficacy because of absence of viral resistance.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) predominates in the Mediterranean area and Asia and has an increasing prevalence in Western Europe and North America.1–3 The HBeAg-negative CHB is characterized by intermittent periods of exacerbation and quiescence and often runs a more aggressive course resulting frequently in cirrhosis, liver failure and hepatocellular carcinoma (HCC).4, 5 The principal goal of therapy in patients with HBeAg-negative CHB is the sustained suppression of viral replication to arrest and reverse the progression of the liver injury.6

Current therapeutic approach of HBeAg-negative CHB includes treatment with interferon-alpha, lamivudine (LAM), adefovir dipivoxil (ADV), entecavir and telbivudine.7 The excellent safety and tolerability profile of LAM leads to long-term therapies which, however, have been associated with the emergence of viral resistance because of selection of resistant mutants. Clinical data showed that emergence of LAM-resistant mutations can be associated with hepatitis flares, hepatic decompensation and death.8, 9 ADV is active against not only wild, but also LAM-resistant HBV strains. In contrast to LAM, resistance to ADV seems to occur less frequently and later in the course of long-term treatment. Resistance to ADV is related mostly to the emergence of mutation at codon 236 (asparagine to threonine, rtN236T) or at codon 181 (alanine to valine, rtA181V) of the HBV polymerase gene. In naive patients receiving ADV, genotypic resistance is observed in 3% of patients at year 2, 11% at year 3, 18% at year 4 and 29% at year 5.10 Although in vitro susceptibility to ADV is reduced only by two- to 13-folds, ADV resistance can be associated with viral rebound and decompensation.11

Clinical studies have shown that virological and biochemical improvements are observed in LAM-resistant patients after the addition of ADV to ongoing LAM or with ADV monotherapy.12, 13 In a randomized-controlled trial in HBeAg-positive CHB, ADV alone and ADV plus LAM combination therapy were found to achieve similar reductions of serum HBV-DNA after 1 year of treatment.14 The efficacy of long-term ADV monotherapy or combination of ADV and LAM in HBeAg-negative CHB patients with LAM-resistant CHB is still under investigation.

When ADV was first available in an expanded access programme for patients with LAM resistance, two different strategies (adding vs. switching) were followed by the clinicians regarding the continuation of LAM. In this prospective nonrandomized study, we report the efficacy and safety of long-term LAM and ADV combination therapy compared with ADV monotherapy in HBeAg-negative CHB patients with LAM resistance. In addition, we determined the incidence and risk factors of resistance to ADV in this setting in clinical practice.

Materials and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Study design and patient selection

Eighty-two consecutive adult patients with HBeAg-negative CHB, who started ADV because of virological breakthroughs (VBR) due to LAM-resistant mutants at four liver centres in Greece between November 2002 and June 2005, were included in this analysis. Participating institutions were: Department of Gastroenterology at Polyclinic General Hospital of Athens, 2nd Department of Internal Medicine at General Hospital of IKA Athens, 4th Academic Department of Internal Medicine at Hippokration Hospital of Thessaloniki and 1st Department of Internal Medicine at Naval Hospital of Athens.

Patients were required to have (i) hepatitis B surface antigen (HBsAg)-positive and HBeAg-negative for at least 6 months, (ii) VBR because of LAM-resistant HBV mutants defined as the reappearance of serum HBV-DNA by PCR during LAM monotherapy after initially undetectable HBV-DNA or as the increase in serum HBV-DNA at least 1 log10 compared with the on-treatment nadir. Patients were excluded from the study, if they had decompensated liver disease, detectable antibodies against hepatitis C, D or human immunodeficiency virus and serum creatinine levels >1.5 mg/dL. Additional criteria for exclusion were documented or suspected HCC, pregnancy, lactation and history of therapy with any anti-viral drug other than interferon-α.

Adefovir dipivoxil was given orally at the daily dose of 10 mg and LAM at the daily dose of 100 mg. ADV was added to an ongoing LAM therapy in 59 patients (group 1), while 23 patients (group 2) received combination of ADV plus LAM for only 3 months and thereafter switched to ADV monotherapy. Because of mild increases in alanine aminotransferase (ALT) levels in some patients when switching from LAM to ADV, we chose to offer a 3-month time period of combination therapy in all patients.14 The decision to switch to ADV or to use combination therapy was at the discretion of the investigator. The study was approved by the local ethics committees of the respective institutes. All patients gave written informed consent before starting ADV treatment and the study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki.

Follow-up

Follow-up at all four centres included clinical examination and laboratory tests for liver chemistry, serum amylase, creatinine, phosphorus, full blood count and prothrombin time at month 1 and then every 2 months thereafter, for the first year and every 3 months, thereafter. Serum HBV-DNA was evaluated at least every 6 months. Surveillance for HCC was conducted with repeated abdominal ultrasound and serum alpha-fetoprotein measurements every 6 months. Laboratory evaluations and adverse events were assessed at each clinic visit.

Laboratory investigation

Serum transaminase, albumin, bilirubin, amylase, prothrombin time were measured by standard laboratory procedures. HBsAg, HBeAg, anti-HBe, anti-HBs, anti-HBc, anti-HCV, anti-D and anti-HIV were measured by enzyme immunoassay. Quantitation of HBV-DNA was carried out using a commercially available quantitative PCR assay (AMPLICOR HBV MONITOR Assay; Roche Diagnostic Systems, New Jersey, USA). The sensitivity of the assay was approximately 400 copies/mL.15 HBV genotypes and LAM-resistant mutations were presented in 27 and 34 patients, respectively, from a previous published study.16 ADV-associated mutations were determined with a line probe assay for YMDD mutants (INNO-LiPA; Innogenetics NV, Gent, Belgium).

The histological lesions were evaluated according to Ishak classification system.17

Definitions

Virological breakthrough under anti-viral therapy was considered as the reappearance of serum HBV-DNA after initial undetectability or as the increase in serum HBV-DNA at least 1 log10 compared with the on-treatment nadir. Biochemical breakthrough (BBR) was defined as the reappearance of abnormal transaminase activity after a decline to normal during treatment in patients with VBR. Hepatic decompensation was defined as the development of Child–Turcotte–Pugh score >8 or the occurrence of one or more of the following events: ascites or portal hypertensive bleeding or hepatic encephalopathy.

Statistical analysis

All analyses were performed using the stata 8.0 program (Stata Corporation, College Station, TX, USA). The clinical, biochemical and virological data are presented as median with range. Serum HBV-DNA concentrations below the detection limit (<400 copies/mL) were imputed to 399 copies/mL for the analysis. All HBV-DNA values were log-transformed for normality. Continuous variables were compared using the Wilcoxon’s rank sum or Mann–Whitney U-tests and categorical variables were compared using chi-squared or Fisher’s exact tests as appropriate.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Table 1 summarizes the baseline characteristics of patients in both groups. At ADV initiation, the demographic, clinical and virological characteristics did not significantly differ between two groups, except for a trend towards higher serum HBV-DNA and fibrosis levels in group 1. Seven (9%) patients had transaminase levels within normal ranges before starting ADV. Two patients were lost to follow-up during the second and third year. Both patients were receiving combination therapy and had undetectable serum HBV-DNA at the last visit. One patient receiving ADV monotherapy withdrew consent during the second year.

Table 1.   Baseline characteristics of 82 patients with HBeAg-negative chronic hepatitis B and lamivudine resistance treated with adefovir plus lamivudine combination therapy or with lamivudine monotherapy
 Adefovir + lamivudine combination therapy (n = 59) Adefovir monotherapy (n = 23) P-value
  1. Continuous data are presented as median (range) values.

  2. AST, aspartate aminotransferase; ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen.

  3. * Liver biopsy was performed before the initiation of lamivudine treatment; † HBV genotypes were determined in 27 patients; ‡ Lamivudine-resistant YMDD mutations were detected in 29 of the 34 patients.

Males (%) 45 (76)21 (91)0.12
Age (years)59 (33–79)57 (25–71)0.51
AST (IU/L)90 (24–481) 69 (19–453)0.31
ALT (IU/L)123 (35–935) 125 (47–514)0.62
Serum HBV-DNA (copies/mL) 34 700 000 (44 300–1 040 000 000)1 497 000 (1460–74 400 000)0.07
Necroinflammatory activity*9 (0–12)9.5 (7–14)0.22
Fibrosis stage*4 (1–6)2 (0–5)0.06
Genotype D† (%)14/1412/130.7
YMDD mutations‡18/1911/150.14
Follow-up (months)32 (18–40)30 (18–40)0.31

No serious adverse effects were considered attributable to either study drug by the investigators in either group. No patient required a dose reduction.

At the time of this analysis, the median total duration of ADV treatment was 31 (range: 18–40) months. Prior to initiation of ADV, the median time of LAM monotherapy was 21 (range: 6–48) months.

Virological response

At the initiation of ADV, serum HBV-DNA was >4 log10 copies/mL in 81 (99%), >5 log10 copies/mL in 80 (98%) and >6 log10 copies/mL in 53 (65%) of the 82 patients. Serum HBV-DNA concentrations did not differ between two groups at the end of the 3-month common treatment period (6.0 vs. 5.6 log10 copies/mL, P = 0.31). In the ADV and LAM combination group, median HBV-DNA reduction at 6 months was 2.9 log10 copies/mL (range: 0.34–5.59), at 12 months 3.2 (range: 0.86–6.15), at 18 months 4.2 (range: 1.6–6.4), at 24 months 4.6 (range: 1.9–6.4) and at 30 months 4.9 (range: 2–6). The proportion of patients with >4 log10 reduction of HBV-DNA at 12 and 24 months of therapy was 19 of 59 (32%) and 27 of 44 (61%), respectively. In the adefovir monotherapy group, median HBV-DNA reduction at 6 months was 2.5 log10 copies/mL (range: 0.56–4.6), at 12 months 3.2 (range: 0.56–5), at 18 months 3.4 (range: 0.17–4.9), at 24 months 3.1 (range: 0.56–5) and at 30 months 3.4 (range: 2.9–4.8). The proportion of patients with >4 log10 reduction of HBV-DNA at 12 and 24 months of therapy was three of 23 (13%) and four of 17 (24%), respectively. The effect of different treatment scheme on median serum HBV-DNA reduction became statistically significant at 18, 24 and 30 months (P = 0.01, P = 0.002, P = 0.03, respectively; Figure 1).

image

Figure 1.  Median values of serum HBV-DNA in 82 patients with hepatitis B e antigen-negative chronic hepatitis B and lamivudine resistance during treatment with adefovir plus lamivudine combination therapy (n = 59) or with adefovir monotherapy (n = 23). The median follow-up after the onset of adefovir was 31 (18–40) months. No significant difference between the two groups was observed. However, the effect of different treatment scheme on median serum HBV-DNA reduction became statistically significant at 18, 24 and 30 months (P = 0.01, P = 0.002, P = 0.03, respectively).

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At 6 months, serum HBV-DNA was <10 000 copies/mL in 27 of 55 patients of group 1 and nine of 22 of group 2, while undetectable levels of serum HBV-DNA were reported in 15 and seven of the above patients, respectively. At 12 months, 40 of 58 patients of group 1 and 16 of 22 of group 2 had HBV-DNA <10 000 copies/mL, of whom undetectable levels of serum HBV-DNA were reported in 24 and 12 cases, respectively. At 24 months, 39 of 44 patients in group 1 and 14 of 17 in group 2 had HBV-DNA <10 000 copies/mL, of whom undetectable levels of serum HBV-DNA were reported in 33 and 12 of group 1 and 2, respectively (Table 2). Finally, 26 of 28 patients who continued combination therapy until month 30 had undetectable serum HBV-DNA. All patients with undetectable viraemia at 3, 6, 12, 18, 24 and 30 months of therapy had serum HBV-DNA ≤5 log10 copies/mL prior ADV initiation.

Table 2.   Serum HBV-DNA levels at 3, 6, 12, 24 and 30 months of treatment with combination of adefovir plus lamivudine (n = 59) or with adefovir monotherapy (n = 23)
 Undetectable<10copies/mL >10copies/mL Total
  1. No significant differences between the two groups were observed.

Adefovir + lamivudine combination therapy (n = 59; serum HBV-DNA)
 3 months9163257
 6 months15122855
 12 months28121858
 24 months336544
 30 months261128
Adefovir monotherapy (n = 23; serum HBV-DNA)
 3 months441523
 6 months721322
 12 months124622
 24 months122317
 30 months7029

Biochemical response

Serum ALT levels declined in both treatment groups, with median ALT decreasing from 123 IU/L at baseline to 32.5, 26 and 28.5 IU/L at 6, 12 and 24 months in group 1 and from 125 IU/L at baseline to 33, 29 and 22.5 IU/L in group 2, respectively. At 6, 12 and 24 months, normal ALT was achieved in 41 of 59 (70%), 48 of 59 (81%) and 42 of 52 (79%) patients of group 1 and in 18 of 23 (78%), 14 of 23 (61%) and nine of 17 (53%) patients of group 2, respectively (Figure 2). ALT levels remained within normal levels in 27 of the 28 patients who continued combination therapy to month 30.

image

Figure 2.  Percentage of patients with normal alanine aminotransferase levels during treatment with combination of adefovir plus lamivudine (n = 59) or with adefovir monotherapy (n = 23).

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Virological and biochemical breakthrough – Salvage therapy

Virological breakthrough after the onset of ADV developed in five patients (22%) of group 2 and in none of patients in group 1 (P = 0.001). The median time to VBR development was 15 (range: 12–33) months after ADV treatment was initiated. VBR were persistent in all patients during a median follow-up of 6 (0–12) months. At the onset of VBR, median ALT and serum HBV-DNA concentrations were 48 IU/L (28–162) and 1 726 000 copies/mL (25 000–26 535 468), respectively. All five patients who experienced VBR were men. There was no significant difference in age, gender, ALT levels and duration of LAM resistance period between group 2 patients with and without VBR (Table 3). However, patients in group 2 who developed VBR had significantly higher baseline HBV-DNA levels [40 000 000 (35 000 000–74 400 000) vs. 1 000 000 (1460–65 200 000), P = 0.005]. In addition, all patients with VBR had serum HBV-DNA >104 copies/mL at 6 months under ADV (median 4.9 log10, range: 4.7–5.6), while the reduction in HBV-DNA compared to baseline levels was <2.5 log10 in four of five patients. At the onset of VBR, specific ADV-resistant mutations were confirmed in all five patients. N236T was detected in three and A181V in two patients. Furthermore, no LAM-resistant strains were observed. The cumulative probability of ADV resistance was 9%, 13% and 17% at 12, 18 and 24 months of ADV therapy (Figure 3). VBR was followed by a rise in ALT in two of the five patients at a median of 3 months (range: 0–6) after onset of VBR. ALT levels increased by >3 times the upper limit of normal in one patient. No patient developed decompensated liver disease, while bilirubin levels increased to 4 mg/dL in one patient.

Table 3.   HBeAg-negative chronic hepatitis B patients with lamivudine resistance treated with adefovir monotherapy
 ADV-RNo ADV-RP-value
  1. Comparisons between patients with and without subsequent adefovir resistance (ADV-R). Patients who developed virological breakthrough had higher HBV-DNA levels at the initiation of ADV.

  2. Continuous data are reported as median (range) values.

  3. ALT, alanine aminotransferase; ADV-R, adefovir resistance; LAM, lamivudine; HBeAg, hepatitis B e antigen.

Males5/516/180.4
Age (years)54 (39–71)57.5 (25–68)0.9
Duration of LAM resistance11 (8–14)69 (10–48)0.1
ALT (IU/L)198 (47–287)108 (54–714)0.4
Baseline serum HBV-DNA (copies/mL) 40 000 000 (35 000 000–74 440 000)1 000 000 (1460–65 200 000) 0.005
image

Figure 3.  Cumulative probability of virological breakthrough in 82 patients with hepatitis B e antigen-negative chronic hepatitis B and lamivudine resistance treated with adefovir plus lamivudine combination therapy (n = 59, solid line) or with adefovir monotherapy (n = 23, dashed line) (P = 0.001). Numbers at risk at the beginning of each interval time are displayed.

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Salvage LAM therapy was initiated in four patients at a median of 6 (0–12) months after the diagnosis of VBR. We did not offer salvage treatment in only one patient with VBR (A181V mutation) who had no evidence of baseline cirrhosis, because of persistently normal levels of ALT and a stabilized serum HBV-DNA at or around 104 copies/mL. Two (one with A181V) patients were followed up for ≥6 months after salvage treatment. After a median follow-up of 7.5 months, combination of LAM plus ADV resulted in a >2.5 log10 reduction in serum HBV-DNA and normalization of transaminase levels in both patients. Sequencing analysis at the last visit revealed the re-emergence of the LAM-resistant mutant in one patient (L180M + M204V), while the second patient remained with the A181V ADV-resistant mutant strain.

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Lamivudine is an effective and well-tolerated treatment for patients with CHB, but has the major limitation of the development of drug-resistant mutants occurring at a rate of 16–32% during the first year of treatment and increasing by 15% with each year of additional treatment. Resistance development is equivalent to treatment failure.18 Therefore, it is clear that an alternative treatment with an agent without cross-resistance to LAM, such as ADV, is necessary to maintain anti-viral efficacy against wild, precore and YMDD mutant strains of HBV. The role, however, of continuing LAM treatment in patients with LAM-resistant HBV who are started ADV is a matter of controversy. A previous study by Peters et al. suggested that there may be no benefit of ADV plus LAM combination therapy compared to ADV monotherapy regarding ALT flares and viral suppression after 1 year in patients with HBeAg-positive CHB.14 In contrast to the above study, we have shown that in HBeAg-negative CHB patients with LAM resistance, adding on ADV is superior to adefovir monotherapy, as it is associated with no evidence of viral resistance and VBR up to 40 months. According to our data, VBR as a result of ADV-resistant mutants were observed in 22% of patients on ADV monotherapy arm compared to none of those receiving combination therapy. In accordance with our results, two recent studies from Italy and Greece reported that in HBeAg-negative patients who developed LAM resistance, ADV monotherapy is associated with a higher risk of ADV-resistant mutant strains development and ADV-related treatment failure.19, 20 The Italian study involving 588 patients from 31 centres reported ADV-related mutations in 5% in the ADV monotherapy group, while Rapti et al. involving 42 patients in a randomized study found a higher rate (21%) of ADV-related treatment failure because of development of ADV resistance mutations. The enhanced anti-viral efficacy of LAM plus ADV combination therapy in LAM-resistant patients may be explained by the fact that LAM hampers the emergence of ADV-resistant strains.

A recent study including 95 HBeAg-positive CHB patients showed that that ADV resistance is more common in patients with prior LAM resistance compared with naive patients after 48 weeks of therapy.21 We and others previously showed that clinical deterioration and death may occur very soon after development of BBR because of emergence of YMDD mutants under long-term LAM or ADV monotherapy in patients with HBV cirrhosis.8, 11 Furthermore, our data confirmed previous observations showing that salvage therapy with ADV, in patients with LAM resistance, achieves more rapid and higher rates of virological response, if ADV initiates at an early phase of LAM resistance with low levels of viral replication.9, 19, 22 Thus, close monitoring of serum HBV-DNA using a sensitive technique is crucial in patients under long-term anti-viral treatment to detect resistance and initiate salvage therapy promptly.

We found that combination of ADV and LAM was associated with a significantly higher reduction in serum HBV-DNA after 18 months of treatment, although the proportion of patients with undetectable HBV-DNA or viraemia <4 log did not differ between the two groups. The lower baseline serum HBV-DNA concentrations in group 2 compared with group 1 and the viral rebounds because of ADV-resistant mutations in group 2 might be responsible for the differences in the reduction in viraemia between the two groups.

Another important finding of this study is the association between baseline serum HBV-DNA, suboptimal response to ADV and breakthrough because of ADV-resistant mutations. Patients who developed VBR had higher HBV-DNA levels at the initiation of ADV and HBV-DNA >4 log10 copies/mL at 6 months of treatment; only one of them had serum HBV-DNA reduction of >2.5 log10 copies/mL during treatment. Previous retrospective analysis of patients with CHB receiving LAM or ADV have shown similar results indicating that high levels of viral replication may reduce the magnitude of HBV-DNA suppression and thus facilitate the emergence of drug resistance.10, 16 Therefore, an early initiation of additional therapy in patients at high risk of drug resistance could prevent resistance and may be a promising future therapeutic strategy.

Studies evaluating the treatment of patients who have developed resistance to ADV are lacking. In vivo and in vitro data have shown that LAM and entecavir may be promising drugs.23–25 According to our data, addition of LAM in patients who developed ADV-resistant mutants achieved biochemical response and reduction in viraemia. However, reintroduction of LAM was followed by re-emergence of LAM-resistant mutants in one patient after 7.5 months. Our results are compatible with the observations of Fung et al.11 stressing the problem in the treatment of patients who have acquired resistance to more than one nucleos(t)ide analogue. Although longer follow-up is required to establish the significance of our finding, in the era of newer anti-viral drugs, LAM may not be an optimal therapeutic option for LAM-experienced patients with ADV resistance.

In this study, our aim was to present the long-term efficacy of two different therapeutics strategies in patients with HBeAg-negative CHB and LAM resistance. However, it might be argued that as our study was not randomized, our results are prone to selection bias. The similarity, however, of the baseline characteristics of the patients between the two groups may overcome the weak points of this comparison. The fact that a trend towards higher baseline HBV-DNA levels was observed in patients under combination therapy could not feeble our results, because high HBV-DNA prior treatment is associated with higher risk of drug-induced mutations.16

In conclusion, our results clearly demonstrate that in HBeAg-negative CHB patients with LAM resistance, adding ADV to continuing LAM therapy maximizes anti-viral efficacy because of prevention of viral resistance. Baseline high viraemia levels and suboptimal response to ADV are associated with an increased risk of subsequent ADV resistance. Although our data suggest that combination of LAM plus ADV is the best therapeutic choice for HBeAg-negative CHB patients with LAM resistance, the optimal type and timing of combination therapy should be carefully assessed within well-designed studies, particularly in the forthcoming era of new stronger anti-viral agents.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Declaration of personal interests: S. Manolakopoulos has served on advisory boards for Bristol-Myers Squibb and Gilead Sciences and has received research grants from Schering-Plough and Hoffman La Roche. J. Goulis has served on advisory boards for Bristol-Myers Squibb and Gilead Sciences. G. Papatheodoridis has served on advisory boards for Bristol-Myers Squibb, Gilead Sciences, Hoffman La Roche, Idenix-Novartis and Wyeth Research, and has received research grants from Gilead Sciences and Idenix-Novartis. The remaining authors have nothing to declare. Declaration of funding interests: This study was partially supported by Gilead Sciences.

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  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
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