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Keywords:

  • entecavir;
  • genotypes;
  • hepatitis B virus;
  • PEG-Interferon;
  • sequential therapy

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Conflicts of interest
  8. Funding
  9. References
  10. Supporting Information

Complete eradication of hepatitis B virus (HBV) is rarely achieved. Treatment options include currently available nucleos(t)ide analogues and pegylated interferon. The aim of our exploratory study was to assess the effectiveness of sequential therapy for chronic hepatitis B (CHB) vs the current standard of care. We evaluated an association with entecavir and pegylated interferon alfa-2a (PEG-IFN) in 20 patients with hepatitis B, high HBV viremia and genotypes A, B, C and E. Patients received entecavir alone for 12 weeks, then entecavir and PEG-IFN for 12 weeks, lastly PEG-IFN alone for 36 weeks. The results were compared with 20 patients (control group) treated in the past with 48 weeks of PEG-IFN monotherapy. Our results show that complete sustained virological response (SVR) and partial SVR were, respectively, 60% and 80% in the study group and 10% and 30% in the control group; anti-HBe seroconversion rate were 76.9% vs 15%, and anti-HBs seroconversion were 20% vs 0%, respectively. We found a correlation among different genotypes and virological and serological outcomes – genotype C has a better virological response, while genotype A had a better serological response, and E genotype had a poor response. These results show that a sequential approach is a promising strategy of treatment in patients with CHB and high viremia in comparison with PEG-IFN monotherapy. The E genotype seems to have the worse rate of response and requires other treatment strategies.


Abbreviations
ALT

alanine aminotransferase

anti-HBe

antibody to hepatitis B e antigen

anti-HBs

antibody to hepatitis B surface antigen

cccDNA

closed circular DNA

CHB

chronic hepatitis B

cSVR

complete SVR

ETV

entecavir

HBeAg

hepatitis B e antigen

HbsAg

hepatitis B surface antigen

HBV

Hepatitis B virus

IFN

interferon

IQR

inter-quartile range

NA

nucleos(t)ide analogues

PEG-INF

pegylated interferon

pSVR

partial SVR

qHBsAg

quantitative hepatitis B surface antigen

SVR

sustained virological response

Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Conflicts of interest
  8. Funding
  9. References
  10. Supporting Information

Hepatitis B virus (HBV) infection globally affects around 350 million people and is a leading cause of end-stage liver disease, hepatocellular carcinoma and mortality. Progression of HBV-related liver disease to cirrhosis, hepatic decompensation and hepatocellular carcinoma is estimated to result in 0.5–1.2 million annual deaths [1].

The complete eradication of HBV is rarely achieved due to persistence of covalently closed circular DNA (cccDNA) in host hepatocytes [2], and the main goal of therapy is to prevent the development of cirrhosis, liver failure and hepatocellular carcinoma [3]. The most widely endpoints for assessing treatment response include HBV-DNA suppression (virological outcome), hepatitis B e antigen (HBeAg) loss with or without seroconversion, HBsAg loss with or without seroconversion (serological outcome), alanine aminotransferase (ALT) normalization (biochemical outcome) and improvement of liver histology (histological outcome) [4].

Treatment options include currently available nucleos(t)ide analogues (NA) with inhibition of the reverse transcription of the pregenomic RNA and direct antiviral effect, but without action on cccDNA and consequently on HBV eradication. The immunomodulatory agent interferon-alfa was the first drug used in the treatment of chronic hepatitis B (CHB), and its effect is the stimulation of T-cell cytotoxic for lysis of infected hepatocytes and the production of cytokines for control of viral replication [5]. Recent studies showed a relationship among interferon immunomodulatory action, turnover of infected hepatocytes and cccDNA clearance [6].

Both treatment strategies have different advantages and side effects [7]. The main baseline predictors of response to interferon therapy are as follows: younger age, lower HBV-DNA level, genotype A, B and C [8]. Young patients could have many advantage using interferon-based therapy. Indeed, the finite duration of treatment and increase rate of HBsAg loss compared with NA are the greatest favourable arguments. The role of HBV-DNA level is recently described in many studies [9, 10]. High viral load seems associated with a low T-cell activation and poor response to interferon treatment [9]. Interestingly, it has been recently reported that T-cell dysfunction in patients with CHB is directly correlated to level of HBV-DNA, and T-cell failure is associated with high replication level [10]. Many reports have demonstrated the role of HBV genotypes in the response to interferon therapy. Moreover, the HBV genotype D is associated with the worst response rate compared with A, B and C [11].

The currently standard approach for the treatment of CHB does not include the combination therapy of interferon-alfa and NA [4]. Some trials have examined the association therapy of interferon and lamivudine showing that the simultaneous combination failed to demonstrated a superiority to IFN monotherapy [12-14]. Combining interferon and NA could be a novel approach with synergic effect of immunomodulatory and antiviral action [15]. The problem is still debated [16] and seems to be encouraging a sequential combination therapy with NA before interferon administration. Sarin et al. [17] demonstrated that sequential therapy with lamivudine and interferon is superior to lamivudine monotherapy in achieving a sustained response. Serfaty et al. [18] have also showed that pretreatment with 20 weeks of lamivudine before interferon was associated with higher virological response. Sequential therapy is also used for the treatment of acute exacerbation of CHB with the induction of long-term remission both in HBeAg-positive and in HBeAg-negative patients [19]. Moreover, a recent study evidenced that sequential therapy with adefovir before pegylated interferon-alfa might be an interesting strategy in HBeAg-negative patients with higher viral loads [20].

Then, the aim of our exploratory study was to evaluate the effectiveness of sequential treatment, in a small group of patients with CHB and high viremia, in comparison with current standard treatment with PEG-IFN monotherapy in a control group of patients with the same baseline characteristics.

Patients and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Conflicts of interest
  8. Funding
  9. References
  10. Supporting Information

Patient population of the study

We have included 20 patients with the following inclusion criteria: documented CHB infection (HBsAg in serum for more than 6 months); age >18 years; HBV-DNA >106 log IU/mL; HBV genotype A, B, C and E; ALT levels >1.5 times the upper normal limit and naїve to treatment. The exclusion criteria were the following: co-infection with HIV, HCV, HDV; decompensated cyrrhosis; HBV-DNA genotype D; concurrent medical illnesses as malignancy, alcoholism and cardiopulmonary disease; women who were pregnant or nursing.

The study was conducted in compliance with the Declaration of Helsinki and in accordance with local regulations; all patients gave written informed consent according to standards of the local ethic committees.

Control group

We have included in the control group 20 patients treated in past for 48 weeks with PEG-IFN alfa-2a monotherapy (current standard of care of CHB), according to the same inclusion and exclusion criteria of the patient population of the study.

Study design

As showed in Fig. 1, patients were treated with entecavir 0.5 mg per day for 12 weeks (induction), then with both entecavir at the same dosage and PEG-IFN alfa-2a 180 μg per week for 12 weeks (association), followed by PEG-IFN alfa-2a at the same dosage alone for 36 weeks (maintenance).

image

Figure 1. The study design of treatment.

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We used a stopping rule after 12 weeks of PEG-IFN therapy (24 weeks of entecavir) combining a >0.5 log IU/mL decrease of qHBsAg with >2 log IU/mL HBV-DNA decrease. Patients who have not achieved these parameters have interrupted the PEG-IFN administration and they have continued with entecavir alone. We have followed patients for 48 weeks after the end of treatment.

We have evaluated ALT, HBV-DNA, qHBsAg monthly; anti-HBsAg was performed monthly in patients with qHBsAg reduction below 10 IU/mL; for patients with HBeAg+, we checked HBeAg/anti-HBeAg after 12, 24, 48 weeks of PEG-IFN, and 24, 48 weeks after treatment completion.

Study end points

We have studied the effectiveness of sequential therapy with entecavir and PEG-IFN through different end points: virological, serological and biochemical. We evaluated a complete sustained virological response (cSVR), defined as HBV-DNA <20 IU/mL (70 copies/mL) 24 weeks after treatment stopping, and partial virological response (inactive carrier) with HBV-DNA <2000 IU/mL (10 000 copies/mL) and ALT normalization 24 weeks after the end of therapy. We have used for ‘serological response’: HBeAg loss and anti-HBe appearance, HBsAg loss and anti-HBs appearance, qHBsAg decrease ≥1 log and qHBsAg <10 IU/mL at the end of treatment. The ‘biochemical response’ was defined as ALT normalization (ALT<37 IU/mL) 24 weeks after treatment completion.

The virological and serological responses were also studied according to the role of different HBV genotypes.

In the control group, the values of qHBsAg were not present because the test was not yet available during their therapy.

Assays

Serum HBV-DNA levels were quantified with the real-time PCR COBAS AmpliPrep/COBAS TaqMan HBV Test 2.0 (Roche Molecular Systems, Branchburg, NJ, USA). HBV genotypes were determined with the INNOLIPA reverse hybridization assays (Innogenetics, Ghent, Belgium). HBsAg, HBeAg, anti-HBs, anti-HBe were detected by the Elecsys instrumental platform (Roche Diagnostics, Monza, Italy); qHBsAg was quantified with ARCHITECT HBsAg (Abbott Diagnostics, Dublin, Ireland). Fibrosis stage (F) was determined before treatment start with Fibroscan using the Metavir score.

Statistical analysis

For descriptive statistics, continuous variables were summarized as median (inter-quartile range: 25th to 75th percentiles). Categorical variables were described as frequency and percentage. All data were assessed for normality using a Shapiro–Wilk test, and categorical data were compared using a Mann–Whitney or Kruskal–Wallis statistical test. To investigate continuous data, a Spearman Rank correlation was utilized. The association was calculated using the chi-square-test. Statistical analyses were conducted by using SPSS software package ver. 18.0 (Chicago, IL, USA).

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Conflicts of interest
  8. Funding
  9. References
  10. Supporting Information

Baseline characteristics

Baseline characteristics (demographic, clinical, virological and biochemical) of the two groups of patients are reported in Table 1. We underline that the two populations of patients have the similar baseline characteristics.

Table 1. Baseline characteristics of the patients
CharacteristicAll patients sequential therapy (n = 20)All patients control group (monotherapy) (n = 20)
  1. ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; IQR, inter-quartile range.

Age (year) median [IQR]; (Range)33.5 [27.7–41.0]; (21–53)39.0 [31.5–46.5]; (25–57)
Male sex n (%)15 (75)17 (85)
Geographic origin n (%)
Italy2 (10)1 (5)
East Europe7 (35)7 (35)
China7 (35)8 (40)
Central Africa4 (20)4 (20)
Fibrosis score (stiffness KPa) median [IQR]; (Range)10.1 [9.4–12.3]; (9.1–18.4)10.7 [9.6–13.7]; (8.7–21.8)
HBeAg+ n (%)13 (65)11 (55)
HBV genotypes n (%)
A9 (45)8 (40)
B3 (15)4 (20)
C4 (20)4 (20)
E4 (20)4 (20)
HBV-DNA (Log IU/mL) median [IQR]; (Range)7.8 [6.5–8.2]; (6.1–8.2)6.8 [6.1–7.6]; (6.2–7.4)
qHBsAg (Log IU/mL) median [IQR]; (Range)4.3 [4.1–4.4]; (3.8–5)Not available
ALT (IU/mL) median [IQR]; Range114 [61.0–165.5]; (34–268)118 [63.4–155.3]; (54–311)

Virological and biochemical response

Data of virological and biochemical outcomes are showed in the Table 2.

Table 2. Virological and biochemical outcomes
 All patientsHBV genotypes
ABCE
Type of therapy: Sequential = ETV + PEG-IFN Monotherapy (control group) = PEG-IFN aloneSequentialMonotherapySequentialMonotherapySequentialMonotherapySequentialMonotherapySequentialMonotherapy
Number of patient and HBeAg statusN = 20N = 20N = 9N = 8N = 3N = 4N = 4N = 4N = 4N = 4
HBe+ = 13HBe+ = 11HBe+ = 5HBe+ = 4HBe+ = 3HBe+ = 2HBe+ = 2HBe+ = 2HBe+ = 3HBe+ = 3
HBe− = 7HBe− = 9HBe− = 4HBe− = 4HBe− = 0HBe− = 2HBe− = 2HBe− = 2HBe− = 1HBe− = 1
n % n % n % n % n % n % n % n % n % n %
  1. Nd, data not available; ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus.

Virological outcomes
HBV-DNA <2000 IU/mL at end of treatment16807359100562.5310012541001250000
HBV-DNA <20 IU/mL at end of treatment1260210666112.52660041001250000
HBV-DNA <2000 IU/mL at 24 weeks of follow-up16806309100450310012541001250000
HBV-DNA <20 IU/mL at 24 weeks of follow-up1260210666112.52660041001250000
HBV-DNA <2000 IU/mL at 48 weeks of follow-up1680525910045031001254100000000
HBV-DNA <20 IU/mL at 48 weeks of follow-up1260210666112.52660041001250000
Serological otucomes
HBeAg seroconversion1076.93155100125310012521001250000
HBsAg loss52500444001330000000000
HBsAg seroconversion at the end of treatment31500222001330000000000
HBsAg seroconversion at 24 weeks of follow-up42000333001330000000000
HBsAg seroconversion at 48 weeks of follow-up42000333001330000000000
qHBsAg <10 IU/mL at the end of treatment735ndnd9100ndnd266ndnd00ndnd00ndnd
[DOWNWARDS ARROW]qHBsAg >1 log IU/mL at the end of treatment1680ndnd9100ndnd3100ndnd4100ndnd00ndnd
Biochemical outcome
ALT normalization at 48 weeks of follow-up15758409100562.5310025041001250000

Time of achievement the undetectable HBV-DNA

We have found a correlation between viral genotypes and the time of achievement the undetectable HBV-DNA (= 0.012); HBV genotype C has showed the fastest response (median 4.5 months): C vs A (= 0.027); C vs B (= 0.032); C vs E (= 0.019); HBV genotype E has showed the longest time to achieve HBV-DNA undetectability (Fig. S1).

Serological response

The data of serological outcomes are showed in the Table 2.

Timing of serological outcomes

We have observed that nine patients have reached the HBeAg seroconversion between 12 and 24 weeks of treatment and only one between 24 and 48 weeks. Four patients have achieved the HBsAg seroconversion: only one between 12 and 24 weeks of therapy, two between 24 and 48 weeks and the last one during the first 6 months of follow-up.

Serum HBV-DNA and qHBsAg kinetics related to different genotypes

We have observed a different course of virological and serological response among HBV genotypes. We have found a significant correlation between viral genotypes and the reduction of HBV-DNA after 12 weeks of entecavir (Pearson = 0.772; = 0.028) and the decrease of qHBsAg after 12 weeks of PEG-IFN therapy (Pearson = 0.792; = 0.019). HBV genotype A has seemed to show the best serological response (qHBsAg reduction after 12 weeks of PEG-IFN therapy: 1.1 Log) in comparison with the others: A vs B (= 0.711, not significant); A vs C (= 0.030); A vs E (= 0.005). The virological response was similar to C genotype (= 0.439), but higher than B (= 0.012) and E (= 0.005). HBV genotype C has showed the best virological response (4.3 log reduction after 12 weeks of entecavir): C vs B (= 0.032); C vs E (= 0.021). HBV genotype B has had intermediate values of virological and serological response, while HBV genotype E has showed the worst virological and serological response (0.2 log qHBsAg and 1.9 log HBV-DNA reduction) from baseline.

Correlations of serological and virological outcomes

We have noticed a correlation between the logarithmic reduction of qHBsAg (ΔqHBsAg) after 12 weeks of therapy with PEG-IFN and HBsAg loss (= 0.012), qHBsAg <10 IU/mL (= 0.001), HBV-DNA undetectable (= 0.002) and HBV-DNA <2000 IU/mL (= 0.002) at the end of treatment. We have also found a correlation between ΔqHBsAg and ALT normalization at the end of therapy (P = 0.002).

The logarithmic reduction of HBV-DNA after 12 weeks of therapy with entecavir (Δ HBV-DNA) has showed, in our data, a significant correlation with ΔqHBsAg after 12 weeks of PEG-IFN (P = 0.005), HBeAg clearance (P = 0.023) and HBV-DNA undetectability at the end of therapy (= 0.010).

Comparison of results between the study population and the control group

We have noticed that all the results of sequential therapy were better of the monotherapy with PEG-IFN alone (Table 2). We have observed for all genotypes a cSVR of 60% with combination treatment vs 10% with monotherapy. The HbeAg seroconversion rate was 75% (sequential) vs 40% (monotherapy). It is worthy of note that any HbsAg seroconversion or HbsAg loss have been observed in the control group (Fig. S2).

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Conflicts of interest
  8. Funding
  9. References
  10. Supporting Information

We introduce an explorative study about a novel approach of treatment of CHB: the patients included in our study, and in the control group, shared the same clinical and virological characteristics as high HBV-DNA levels, young age, Metavir score >F1, ALT levels >twofold upper normal level and infection from HBV genotypes A, B, C or E. We have not included patients infected by HBV genotype D for two reasons: first, all our patients with D genotype, and not previously treated, present low HBV-DNA levels (below 105 IU/mL); second, all data available from literature show that genotype D has the lowest response with PEG-IFN and requires other strategies of therapy [21].

The choice to administer PEG-IFN or NAs therapy depends on some factors: genotypes non-D have a favourable response to PEG-IFN therapy and in the young patients, it is preferable a finite-duration treatment with interferon, because these patients have the best chance of a sustained response after therapy. Moreover, females can have child after antiviral therapy. The main obstacle to the PEG-IFN monotherapy in these patients is the elevated viremia of HBV, that is, associated with a low T-cell response and efficacy of therapy [22].

As previously stated, current guidelines [23] do not consider the association of PEG-IFN and NAs, but some studies showed encouraging results with sequential combination therapy [16]. In our study, the combined approach was determined by the peculiar characteristics of our populations. Indeed, all patients must have been treated, but the choice of therapy was very difficult, because monotherapy with PEG-IFN has a high risk of failure and long-term treatment with NAs has indefinite duration, lower rate of seroconversion and elevated risk of drug resistance. In our study, we chose entecavir for the high antiviral power without significant side effects, and we have started first with entecavir monotherapy for reducing HBV-DNA, then we added PEG-IFN due to the immunomodulatory effect of the molecule. Three different phases could be designed in our schedule: initial treatment with entecavir alone for 12 weeks as the ‘induction phase’, where the main goal was a reduction of HBV-DNA before the PEG-IFN administration to start immunomodulatory therapy with interferon at lower levels of HBV-DNA results that is known to result in a better response; a second phase characterized by the ‘association’ of entecavir with PEG-IFN for 12 weeks; a third phase of ‘maintenance’, that is, a monotherapy with PEG-IFN for 36 weeks similar to the standard of care for CHB.

For the evaluation of antiviral response during the treatment, we used serum HBV-DNA and qHBsAg (data not available in the control study) according to recently published studies [24] showing the usefulness of qHBsAg as a predictive marker for the treatment response. These studies led to the observation that on-treatment qHBsAg decrease >1 log IU/mL and qHBsAg levels below 10 IU/mL at the end of therapy were strongly associated with sustained HBsAg clearance 3 years after treatment completion [25]. The reduction of at least 0.5 log and 1 log IU/mL at weeks 12 and 24 of treatment with PEG-IFN had negative predictive values of 92% and 97%, respectively, for SVR [26]. A better value (negative predictive value = 100%) was obtained with association of qHBsAg and HBV-DNA decrease (>2 log IU/mL at week 12 of treatment) [27].

In our study, we used a stopping rule after 12 weeks of PEG-IFN therapy (24 weeks of entecavir) combining a >0.5 log IU/mL decrease of qHBsAg with >2 log IU/mL HBV-DNA decrease. Only the four patients with E genotype did not reach these criteria, then PEG-IFN was stopped and they continued long-term treatment with entecavir, whereas all the other patients completed 48 weeks of treatment with PEG-IFN.

HBeAg clearance was observed in 76.9% of patients and only three patients with E genotype did not obtained anti-HBe seroconversion. Our rate of seroconversion is high in comparison with those described in previous studies (27–30%) [23, 28]. It is of note that nine patient lost the HBeAg during the combination therapy and only one during the maintenance phase.

HBsAg clearance was observed in 15% of patients at the end of treatment and in 20% after 24 and 48 weeks of follow-up. These data are very encouraging, considering that in previous studies, the values of HBsAg loss/seroconversion varied between 2% and 3% [23, 28].

Because 16 patient (80%) achieved a reduction of qHBsAg >1 log at the end of therapy, we may postulate other seroconversions in following years.

Our data concerning the virological response seem to confirm the superiority of sequential approach therapy over monotherapy with PEG-IFN. Sixty percentage of patients were HBV-DNA undetectable at the end of therapy, 80% showed HBV-DNA below 2000 IU/mL (partial SVR) and 60% achieved the cSVR. Moreover, all patients who obtained HBV-DNA undetectability at the end of therapy maintained the virological response after 24 and 48 weeks. Only patients affected by E genotype were ‘non-responders’ and they continued antiviral therapy with entecavir alone.

About biochemical response, ALT normalization was found in 60% of patients at treatment completion and in 75% after 48 weeks of follow-up.

Moreover, we have confirmed the good results of our study through the outcome comparison to a control group with the same sample size. All the virological, serological and biochemical outcomes showed to be better in the patients treated with sequential treatment (Table 2 and Fig. S2).

An interesting finding in our study was the different serological and virological outcome among HBV genotypes. We know that viral genotype is an important predictor of response to treatment with PEG-IFN [23, 29]. Genotypes A, B and C have the much greater rate of response than genotype D [23, 30], while data are uncertain concerning the virological response with NAs. No report is so far published at our knowledge about the response of E genotype, and our study is the first one showing the lack of response of genotype E to the combination of PEG-IFN and entecavir (Figs 2-4 and Fig. S1).

image

Figure 2. The reduction of hepatitis B virus (HBV)-DNA after 12 weeks of ETV and qHBaAg after 12 weeks of PEG-INF, according to HBV genotype.

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image

Figure 3. Hepatitis B virus (HBV)-DNA kinetics among HBV genotypes during the treatment.

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image

Figure 4. qHBsAg kinetics among hepatitis B virus (HBV) genotypes during the treatment.

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We observed that qHBsAg and HBV-DNA kinetics were genotype dependent. HBV genotypes A and B showed the highest qHBsAg decrease during PEG-IFN therapy and the best serological response after treatment cessation. HBV C genotype seemed to have the better virological response to entecavir. These findings are confirmed by the evaluation of the time to the achievement of the virological response (Fig. 3 and Fig. S1). Genotype C was the only one that reached HBV-DNA undetectability after a mean of 4.5 months of treatment with entecavir and approximately after 1 months with PEG-IFN. We could therefore assume a major response to entecavir for this genotype.

Then, the main observation in our study could be the virological response of genotype E that seems to be a ‘difficult to treat genotype’, because these patients showed only a dismal virological and serological response and required a much longer suppressive therapy with NAs. The reason of this finding is unclear, but we assume a possible role of viral genetic diversity related to the recent appearance of this genotype into the general African population [31] (our all E genotype were from central Africa).

Nevertheless, this study has some limits: first, this is an explorative study of a novel proposal of treatment in a special population of patient affected by CHB, which explains the small number of subjects enrolled. Second, we have proposed a comparison with a historical control group of patients, with the similar baseline characteristic but not entirely homogeneous: the median age was older in the control group with more frequently anti-HBe+ (45% vs 35%): these findings could have influenced the poor efficacy of the PEG-IFN monotherapy. Third, the data on the response to entecavir in the C genotype should be accepted with caution for the small number of patients.

In conclusion, we would like underline that were not available data of effectiveness of treatment in patients with HBV-DNA levels >106 IU/mL, condition that requires in our opinion a different therapy strategy: our results suggest that the approach with sequential therapy based on entecavir administration followed by the combination with PEG-IFN might be a novel strategy for special population of patients with CHB, with a high viral load and HBV genotype other than D. These patients with a optimized PEG-IFN therapy associated with entecavir pretreatment achieved a global high rate of SVR. Patients infected by genotype E should be treated with more potent analogues (entecavir or tenofovir) because their response to interferon is very poor.

Finally, further studies, with a larger sample size, are required to explore this approach also for the patient with D genotype and low-viral load who require PEG-IFN treatment.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Conflicts of interest
  8. Funding
  9. References
  10. Supporting Information

Supporting Information

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Conflicts of interest
  8. Funding
  9. References
  10. Supporting Information
FilenameFormatSizeDescription
jvh12018-sup-0001-FigS1.tifimage/tif916KFig. S1: Time (months) to HBV-DNA undetectability according to different HBV genotypes.
jvh12018-sup-0002-FigS2.tifimage/tif5727KFig. S2: Results of the treatment in the two groups of patients.

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