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Effect of Lowering HBV DNA Levels by Initial Antiviral Therapy Before Adding Immunomodulator Peginterferon on Treatment of Chronic Hepatitis B
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The American Journal of Gastroenterology
Volume 102 Issue 1 Page 96 - January 2007
Shiv Kumar Sarin, M.B.B.S., M.D., D.M.11Department of Gastroenterology and Hepatology, G.B. Pant Hospital, New Delhi, et al.
1Department of Gastroenterology and Hepatology, G.B. Pant Hospital, New Delhi;
"....Low HBV DNA levels have been shown to increase the response rates to immunomodulators.....The results of the present study support the contention that reduction in HBV DNA levels prior to starting immunomodulatory therapy results in higher frequency of sustained viral response. Furthermore, the patients who achieved a sustained response had greater log decline in HBV DNA levels at week 4.... his strategy was more effective than that of using immunomodulator from the start of therapy..... Simultaneous combination therapies using lamivudine and peg-IFN have not been found superior to monotherapy with either drug given alone.... Therefore, the strategy of using an antiviral initially to decrease HBV DNA levels before adding an immunomodulator leads to improved sustained responses as compared with using the immunomodulator from the start. The results of the present study clearly show that the strategy of using a potent antiviral such as lamivudine before adding an immunomodulator is a novel approach for improving the efficacy of the treatment of CHB. This approach, besides giving a better response compared with peg-IFN alone, would also reduce the frequency of antiviral resistance associated with the use of long-term antivirals."
Abstract
BACKGROUND: Lower hepatitis B virus DNA (HBV DNA) levels are associated with better responses in chronic hepatitis B (CHB). It is unclear whether an initial phase of antiviral treatment to lower HBV DNA levels before adding immunomodulator therapy is more effective than the strategy of using immunomodulators from the beginning.
AIM: The aim of the study was to compare the efficacy of lamivudine followed by pegylated-interferon (peg-IFN) therapy with placebo followed by peg-IFN therapy in HBeAg-positive CHB patients.
PATIENTS AND METHODS: Sixty-three treatment-naive HBeAg-positive patients with histologically proven CHB and alanine aminotransferase (ALT) > 1.2 ~ upper limit of normal (ULN) received placebo for 4 wk followed by peg-IFN 1.0 μg/kg/wk for next 24 wk (group A, N = 27; age 32 ± 11yr; M:F = 25:2) or lamivudine 100 mg per day for 4 wk followed by peg-IFN 1.0 μg/kg/wk for next 24 wk (group B, N = 36; age 32.5 ± 10.5 yr; M:F = 31:5). Patients were followed for next 24 wk after completion of treatment. Biochemical and virologic responses were assessed at weeks 4, 28, and 52 and analysis was done on intention-to-treat basis.
RESULTS:
At wk 4, mean ± SD of log change in DNA from baseline was 0.2594 ± 1.7873 in group A and 1.2186 ± 1.6347 in group B, respectively (P = 0.032).
At week 28, undetectable HBV DNA was seen in eight (29.6%) and 16 (44.4%) patients in groups A and B, respectively (P = 0.298).
At week 28, HBeAg loss occurred in eight (29.6%) in group A and 15 (41.7%) in group B (P = 0.43).
Six months posttherapy, at week 52, undetectable HBV DNA was seen in four (14.8%) and 18 (50%) in groups A and B, respectively (P = 0.028) and HBeAg loss was maintained in four (14.8%) and 14 (38.9%) (P = 0.05) patients.
Normal ALT was seen in five (18.5%) and 10 (27.8%) at week 28 (P = 0.552) and five (18.5%) and 13 (36.1%) at week 52 (P = 0.159) in groups A and B, respectively.
There was a significant correlation among achievement of HBeAg loss, anti-HBe appearance, and undetectable HBV DNA levels at week 28 (P = 0.008) and 52 (P < 0.001) and HBV DNA levels at week 4.
CONCLUSIONS: The strategy of using an antiviral initially to decrease HBV DNA levels before adding an immunomodulatory agent leads to improved sustained virological response as compared with using immunomodulator from the start.
INTRODUCTION
Hepatitis B virus (HBV)-related hepatitis is a necroinflammatory liver disease of variable severity. Chronic HBV infection is characterized by an inefficient T helper (Th) cell response to hepatitis B surface antigen (HBsAg) and by a variable Th cell response to the HBV-related antigens such as hepatitis core antigen and hepatitis e antigen (1). Agents currently approved for the treatment of chronic HBV infection are divided into two main groups: the immunomodulators, e.g., interferons (IFNs), and the antivirals. IFN was the first drug found to be useful in the treatment of chronic hepatitis B (CHB). The immunomodulators act by promoting cytotoxic T-cell activity for lysis of infected hepatocytes and by stimulating cytokine production for control of viral replication. IFN has both immunomodulatory and antiviral effects (2). In HBeAg-positive patients, IFN monotherapy (5 mU daily or 10 mU thrice weekly) administered subcutaneously for 16-26 wk induces seroconversion to HBeAb in 20-40% and loss of HBsAg in approximately 8% of patients (3). More recently, pegylated-IFN (peg-IFN), given once a week, has been shown to induce seroconversion in 27% of patients and is associated with a greater reduction in HBV DNA than standard IFN (4, 5).
Lamivudine (a nucleoside analog) targets the viral polymerase causing termination of DNA strand synthesis (6). Seroconversion from HBeAg to HBeAb occurs in 15-30% of patients following a 50-100 wk course of oral lamivudine (100 mg once daily) (7-9), however, the response is less durable than with IFN, with relapse rates ranging from 20% to 50% (10). The rates of viral resistance because of the emergence of mutations in the tyrosine-methionine-aspartate-aspartate (YMDD) motif within the HBV polymerase gene approach 74% within 5 yr of commencing treatment (11, 12).
In view of the limited efficacy of monotherapies, use of drug combinations with different modes of actions was tried. Trials examining use of standard IFN and lamivudine in simultaneous combination in treatment-nave HbeAg-positive patients (13-15) failed to demonstrate superiority to monotherapy.
The simultaneous combination of lamivudine and peg-IFN also offered no advantage over peg-IFN alone. The rate of HBeAg loss at 78 wk in the study by Janssen et al. was 35% (16), which was similar to that observed by Lau et al. (28%) using 48 wk of peg-IFN alpha-2a plus lamivudine (17) and by Chan et al. (36%) using a 32-wk course of peg-IFN alpha-2a combined with 52 wk of lamivudine (18).
A high viral load is associated in CHB with a reduced T-cell response and poor response to IFN treatment (19, 20). Sequential combination therapy (reduction of serum HBV DNA by nucleoside analogs followed by combination therapy with IFN-alpha) may increase the chance of HBV clearance, as recently reported in a few trials of HBeAg-positive CHB (21, 22).
The combination therapies seem to reduce the rates of viral resistance. Lau et al. found that 27% of those receiving a 48-wk course of lamivudine monotherapy had detectable YMDD mutations versus 4% of those on both peg-IFN alpha-2a plus lamivudine (17). Janssen et al. (16) found that 6% of patients receiving combination therapy who entered the trial without a preexisting YMDD mutant developed such a mutation by the end of the 48-wk treatment period. This is substantially lower than the 15-32% rates of viral resistance at 1 yr observed in patients receiving lamivudine monotherapy (8, 9).
Because simultaneous combination therapies had not shown any added advantage in viral clearance, it seems logical to first reduce the virus and then to add an immunomodulator. In the previous trial of sequential therapy, we had continued the antiviral agent after the reduction in HBV DNA levels. While the overall HBeAg and HBV DNA loss was observed in 44.6% patients, the risk of emergence of lamivudine resistant mutants was seen in 15% subjects receiving sequential treatment (22). We therefore investigated in the current study the possibility of using an initial phase of antiviral treatment to lower HBV DNA levels using lamivudine (and then stopping the drug) before adding immunomodulator therapy using peg-IFN in the treatment of HBeAg-positive patients with CHB. This was compared with treating with peg-IFN from the beginning. This issue has not been addressed in any of the trials until now.
Furthermore, in this study a 6-month therapy regimen of peg-IFN for HBeAg-positive patients was utilized.
PATIENTS AND METHODS
Patients
Patients with CHB were included in the study if they fulfilled the following inclusion criteria: (a) adult men and women 16 to 70 yr old, (b) HBsAg positive, HBeAg positive, and anti-HBe antibody negative at the time of screening and for at least the previous 6 months, (c) quantifiable serum HBV DNA levels of >105 copies per milliliter, (d) alanine aminotransferase (ALT) levels greater than 1.2 times the upper limit of normal and less than 10 times the upper limit of normal at screening and for at least the previous 3 months, and (e) treatment nave.
The exclusion criteria were: (a) hepatitis C, D, or HIV infection; (b) decompensated liver disease (defined by a serum bilirubin level more than 2.5 times the upper limit of normal, a prothrombin time prolonged by more than 3 s, a serum albumin level lower than 2.5 g/dL, or a history of ascites, variceal hemorrhage, or hepatic encephalopathy); (c) evidence of liver disease because of other etiology; (d) serum creatinine more than 1.5 times the upper limit of normal, hemoglobin less than 10 g/dL, platelet count less than 70,000/mm3, and white cell count less than 3,000/mm3; (e) serious concurrent medical illnesses (like malignancy, severe cardiopulmonary disease, uncontrolled diabetes mellitus, alcoholism); (f) women who were pregnant or nursing; and (g) inability to give informed written consent.
The study protocol was approved by the institutional ethics committee.
The patients were randomly assigned using a computer-generated randomization chart to receive either of the following regimens (Fig. 1):
1. Group A: Placebo for 4 wk, followed by peg-IFN alpha-2b (1.0 μg/kg) given once a week subcutaneously for 24 wk.
2. Group B: Lamivudine 100 mg daily for 4 wk, followed by peg-IFN alpha-2b (1.0 μg/kg) given once a week subcutaneously for 24 wk.
Evaluation
After the first clinic visit (at baseline), patients returned at 4 wk, then at week 16, 28, 40, and 52. Serum was assayed for HBV DNA, HBeAg and antibody to HBeAg (anti-HBe), and HBsAg at each visit. At each clinic visit, laboratory tests were performed to determine the safety of the treatment and adverse events since the previous visit were documented.
End Points
The primary end point of the study was loss of HBeAg, loss of detectable HBV DNA, and appearance of anti-HBe.
Normalization of ALT was defined as ALT ≦40 IU/L.
Assays
Serum HBV DNA levels were quantified with the use of a Hybrid capture assay (Digene Labs, Gaithersburg, Maryland) that has a lower limit of detection of 4,700 copies/mL. HBsAg, HBeAg, anti-HBe, anti-HCV, anti-HDV, and HIV were detected by enzyme immunoassay.
Safety Assessments
Patients were monitored at each study visit for adverse events and laboratory-value abnormalities. Grade III and IV abnormalities were defined as follows (2): for ALT a value 3.1 to 10 times the baseline value and more than 10 times the baseline value, respectively; for albumin a value of 2.0-2.4 g/dL and less than 2.0 g/dL; for amylase a value 3.1 to 10 times the baseline value and more than 10 times the baseline value; for lipase a value 2.6 to five times the upper limit of normal and more than five times the upper limit of normal; for bilirubin a value 5.1 to 10 times the upper limit of normal and more than 10 times the upper limit of normal; for creatine kinase a value seven to 9.9 times the baseline value and at least 10 times the baseline value; for hemoglobin a value of 6.4-7.9 g/dL and less than 6.4 g/dL; for the neutrophil count a value of 500-740/mm3 and less than 500/mm3; for the platelet count a value of 20,000-49,000/mm3 and less than 20,000/mm3; for the white cell count, a value of 1,000-1,400/mm3 and less than 1,000/mm3.
Statistical Analysis
The rates of response were determined on an intention-to-treat basis. Continuous variables were analyzed using independent Student's t-test. Fischer's exact test and 2 test were used to analyze categorical data. P < 0.05 was taken as statistically significant. All the statistical calculations were done using SPSS 10.05 software.
RESULTS
Study Population
Sixty three consecutive patients with HBeAg-positive CHB who fulfilled the inclusion criteria were randomly assigned to either group A, N = 27 patients, or group B, N = 36 patients. The study was completed by 25 of the 27 patients in group A, and by 34 of 36 in group B. Four patients failed to return and were lost to follow-up (Fig. 2).
The demographic, clinical, biochemical, virological, and histological features of the two groups of patients at baseline are summarized in Table 1.
Virological Response
At week 4, there was a significantly greater decline in HBV DNA from baseline in group B as compared with group A. Mean ± SD of log change in DNA from baseline was 0.2594 ±1.7873 in group A and 1.2186 ± 1.6347 in group B, respectively (P = 0.032).
Five (18.5%) patients in group A and 13 (36.1%) in group B showed more than or equal to 2 log decline in HBV DNA levels at week 4 (P = 0.164).
Week 28: At week 28, undetectable HBV DNA was seen in eight (29.6%) and 16 (44.4%) in groups A and B, respectively (P = 0.298). HBeAg loss occurred in eight (29.6%) in group A and 15 (41.7%) in group B (P = 0.43). HBeAg loss, anti-HBe appearance, and undetectable DNA levels were seen in seven (25.9%) and 12 (33.3%) (P = 0.588), respectively (Fig. 3).
Week 52: Of the eight patients in group A who had undetectable HBV DNA levels at week 28, three (37.5%) maintained this until week 52 whereas 14 of 16 (87.5%) patients in group B maintained this end point until week 52 (P = 0.021). In other words, relapse as regards to HBV DNA levels was seen in five of eight (62.5%) patients in group A and two of 16 (12.5%) in group B (P = 0.021).
The number of additional patients who had not achieved undetectable HBV DNA levels at week 28, but had undetectable HBV DNA at week 52 was one in group A and four in group B (P = 0.381). Of the seven patients in group A who had achieved the primary end point (i.e., HBeAg loss, anti-HBe appearance, and undetectable HBV DNA levels at week 28), three (42.8%) maintained the end point until week 52 whereas 10 of 12 (83.3%) patients in group B maintained the end point until week 52 (P = -0.129). In other words, relapse was seen in four of seven (57.1%) patients in group A and two of 12 (16.7%) in group B (P = 0.129). The number of additional patients who had not achieved the primary end point at week 28 but had achieved the primary end point at week 52 was one in group A and three in group B.
Overall, at week 52, undetectable HBV DNA was seen in four (14.8%) and 18 (50%) in groups A and B, respectively (P = 0.028). HBeAg loss was seen in four (14.8%) and 14 (38.9%) (P = 0.05) and HBeAg loss, anti-HBe appearance, and undetectable HBV DNA levels in four (14.8%) and 13 (36.1%) in group A and group B, respectively (P = 0.086) (Table 2 and Fig. 3).
HBV DNA Reduction and Treatment Response
There was a significant correlation between achievement of HBeAg loss, anti-HBe appearance, and undetectable HBV DNA levels at week 28 and 52 and log decline in HBV DNA levels at week 4 (Spearman's correlation coefficient and 2-tailed significance of -0.333 and 0.008 for week 28 and -0.474 and <0.001 for week 52, respectively) (Table 3).
Figure 4 shows serial HBV DNA levels in both the groups of patients. Baseline HBV DNA levels were comparable in both the groups. At week 4, HBV DNA levels were significantly lower in group B as compared with group A (mean ±SD of 7.1864 ± 1.5347 log copies/mL in group A and 6.3502 ±1.4037 log copies/mL in group B) (P = 0.03). Thereafter, mean HBV DNA levels were comparable in both groups at weeks 16, 28, 40, and 52.
Figure 5 shows the serial log decline in HBV DNA levels in both groups. Mean log decline in HBV DNA from the baseline at week 4 was significantly greater in group B (mean ± SD of 1.2186 ± 1.6347) than group A (mean ± SD 0.2594 ± 1.7873 [0.032]). Thereafter, mean log decline in HBV DNA levels from baseline were comparable in both groups at weeks 16, 28, 40, and 52.
Figure 6 shows response in patients who had ≥2 log decline (group 1) at week 4 vs those who did not have ≥2 log decline (group 2) at week 4. Of the 59 patients who had completed follow-up, 18 patients had ≥2 log decline at week 4. Twelve of 18 (66.67%) patients who had ≥2 log decline at week 4 achieved HBeAg loss, anti-HBe appearance, and undetectable HBV DNA levels at 52 week as compared with only five of 41 (12.19%) patients who did not have ≥2 log decline at week 4 (P < 0.001).
Overall, 17 patients (four in group A and 13 in group B) achieved HBeAg loss, anti-HBe appearance, and undetectable HBV DNA levels at week 52. Table 4 shows HBV DNA parameters in both groups of patients. Though HBV DNA levels at baseline were significantly higher in patients achieving the end point at week 52, log decline in HBV DNA at week 4 was significantly higher in patients achieving the end point at week 52. Thereafter, HBV DNA levels were significantly lower and log decline in HBV DNA from baseline significantly higher in patients achieving the end point at week 52 as compared with patients who did not achieve the end point at week 52.
Biochemical Response
Week 28: ALT normalization was seen in five (18.5%) and 10 (27.8%) patients at week 28 in group A and B, respectively (P = 0.552).
Week 52: ALT normalization was seen in five (18.5%) and 13 (36.1%) patients at week 52 (P = 0.159) in groups A and B, respectively.
Combined (Biochemical Response plus Virological Response)
Week 28: Combined response was seen in five (18.5%) and 10 (27.8%) patients at week 28 in group A and B, respectively (P = 0.552).
Week 52: Combined response was seen in four (14.8%) and 13 (36.1%) patients at week 52 (P = 0.086) in groups A and B, respectively.
Safety
The principal adverse clinical and laboratory events documented during treatment and follow-up are reported in Table 5. None of the patients in either group had grade III or IV abnormalities in serum bilirubin levels, hemoglobin levels, neutrophil counts, or white cell counts.
DISCUSSION
The results of the present study support the contention that reduction in HBV DNA levels prior to starting immunomodulatory therapy results in higher frequency of sustained viral response. Furthermore, the patients who achieved a sustained response had greater log decline in HBV DNA levels at week 4.
Simultaneous combination therapies using lamivudine and peg-IFN have not been found superior to monotherapy with either drug given alone. The combination of peg-IFN with lamivudine does not seem to result in significantly better viral kinetics during the first month of treatment than those associated with treatment with lamivudine alone (23). Moreover, in the long term, compared with monotherapy, this combination has been associated with only a modest increase in the mean decrease in HBV DNA levels and mean loss of HBeAg after 48 to 52 wk of treatment (24). On the other hand, after 24 wk of follow-up after a course of combination treatment, the mean decrease in HBV DNA and mean loss of HBeAg were similar to those associated with peg-IFN monotherapy (16, 24).
Sequential combination therapy (reduction of serum HBV DNA by nucleoside analog followed by combination therapy with IFN-alpha) may increase the chance of HBV clearance, as recently reported in a few trials of HBeAg-positive CHB (21, 22).
Superiority of sequential combination therapy over simultaneous combination therapy might be as a result of a low pretreatment serum HBV-DNA level, which is associated with a greater probability of response to IFN-alpha. The most important factor known to predict a favorable response to IFN-alpha is low baseline HBV DNA levels (25-29). In a randomized-controlled trial of IFN-alpha, with or without prednisone priming, Perrillo et al. (25) found that baseline serum HBV DNA level was the most important independent predictor of response (P = 0.003). A study investigating the posttreatment durability of HBeAg seroconversion following lamivudine, IFN monotherapy, or IFN-lamivudine combination therapy also identified pretreatment HBV DNA level as the major predictor of sustained response (29). Brook et al. (20) found that on stepwise logistic regression analysis, HBV DNA, aspartate aminotransferase (AST), and a history of acute hepatitis predicted response independently to IFN therapy (P < 0.05). Secondly, high viral load in CHB leads to impaired T-cell responsiveness to various HBV proteins. A short course of 4 wk lamivudine therapy probably restores the specific T-cell responsiveness by reducing the HBV load (19, 30)
The combination therapies seem to reduce the rates of viral resistance but still may have a risk for the development of nucleoside-resistant mutants.
The results of the present study showed that at week 4 there was a significantly greater decline in HBV DNA levels from baseline in the lamivudine pretreatment group compared with the placebo pretreatment group. This finding is similar to previous studies that show that during placebo treatment, a proportion of patients have unchanged HBV DNA levels, while another proportion shows extensive (1-5 log) oscillations in HBV DNA levels (31). However, during treatment with polymerase inhibitors practically all patients have an immediate rapid decline in viremia (32).
Though at week 28, undetectable HBV DNA was seen in a similar number of patients in the lamivudine pretreatment group as compared with the placebo pretreatment group (29.6% and 44.4%, respectively; P = 0.298), at week 52 undetectable HBV DNA was seen in a significantly higher number of patients in the lamivudine pretreatment group as compared with the placebo pretreatment group (14.8% and 50%, respectively; P = 0.028). Also, though HBeAg loss, anti-HBe appearance, and undetectable DNA levels were seen in similar numbers of patients in the lamivudine pretreatment group and placebo pretreatment group (25.9% and 33.3%, respectively; P = 0.588), at week 52 there was a trend toward significance, with undetectable HBV DNA being seen in a higher number of patients in the lamivudine pretreatment group as compared with the placebo pretreatment group (14.8% and 36.1%, respectively; P = 0.086). There was a significant correlation between achievement of HBeAg loss, anti-HBe appearance, and undetectable HBV DNA levels at week 28 and 52 and the HBV DNA levels at week 4.
It is known that therapies that give rise to larger decreases in HBV DNA (e.g., more potent enzyme inhibitors) do not usually result in a larger fraction of patients that lose HBeAg (33, 34). A potential hypothesis for the apparent discrepancy between the extent of the decrease in HBV DNA and the loss of HBeAg is that HBeAg is a marker of the number of infected cells. A more potent antiviral drug may block production of virions more effectively, thereby giving rise to lower viremia, but the same threshold number of infected cells, at the time of HBeAg loss. On the other hand, the immunogenic properties of IFN may result in a greater rate of decline of infected cells, and hence increase the loss of HBeAg.
Several studies have shown that the decrease in viral load induced by lamivudine therapy is associated with the subsequent restoration of the CD4 and then the CD8 cellular immune response against HBV (19, 35). Another recent study showed that the activation of the specific cellular immune response depends on a relatively low level of viral load (36).
There was no significant difference in the HBV DNA levels in both the groups at weeks 16, 28, 40, and 52. Also the log decline at weeks 16, 28, 40, and 52 was not significantly different in the two groups, although patients who had >2 log decline in HBV DNA at week 4 maintained the greater decline as compared with patients who did not achieve >2 log decline at week 4. It has been observed that when therapy with peg-IFN is initiated, a small proportion of patients undergo an immediate rapid decrease of HBV DNA but a substantial proportion has either a delayed response or no decrease in HBV DNA (23). The effectiveness of peg-IFN in blocking virion production is significantly lower than that of lamivudine (37, 38). Moreover, the administration of weekly injections of peg-IFN gives rise to a decrease in serum IFN levels at the end of each week because of the pharmacokinetic properties of peg-IFN. Sypsa et al. (37) reported that 50% of patients treated with peg-IFN-2b have an increase in the levels of HBV DNA at the end of each week. However, when extremely different individual patterns of HBV kinetics are observed for the same treatment, assessment of the mean viral kinetics is a mediocre approach to interpretation of the data (23). Patients who showed a ≥2 log decline in HBV DNA at week 4 maintained the decline until week 52. Though HBV DNA levels at baseline were significantly higher in patients achieving the end point at week 52, log decline in HBV DNA at week 4 was significantly higher in patients achieving the end point at week 52. Thereafter, HBV DNA levels were significantly lower and log decline in HBV DNA from baseline significantly higher in patients achieving the end point at week 52 as compared with patients who did not achieve the end point at week 52.
Duration of IFN therapy may be important for achieving a sustained virologic response. Manesis and Hadziyannis (39) had identified longer duration of IFN treatment as a significant factor for long-term response among treatment-naive patients. The effect of use of a longer duration, like 1 yr of peg-IFN therapy, in such a strategy remains to be seen. Also the effect of using a longer term antiviral during the initial phase remains to be seen.
As in many studies (33, 34), we observed that patients with undetectable DNA and those who achieved seroconversion at week 52 did not always correlate. One of the possible explanations could be that the method that was used in this study had a high HBV DNA detection limit of 4,700 copies/mL in comparison with polymerase chain reaction (PCR) (300-400 copies/mL). Therefore, it is possible that a number of patients without seroconversion had viral load higher than detectable by PCR and it is known that seroconversion is associated with profound and stable suppression of viral replication.
The concept of reduction in HBV load was also found useful in immunotolerant patients with chronic HBV infection. When HBV DNA was reduced by a short course of lamivudine followed by a treatment-free period, there was a rise in the ALT levels and restarting lamivudine therapy resulted in about 35% seroconversion at 24 months. This concept of lamivudine pulse therapy is especially useful for subjects with chronic HBV infection with normal ALT (40).
Therefore, the strategy of using an antiviral initially to decrease HBV DNA levels before adding an immunomodulator leads to improved sustained responses as compared with using the immunomodulator from the start. The results of the present study clearly show that the strategy of using a potent antiviral such as lamivudine before adding an immunomodulator is a novel approach for improving the efficacy of the treatment of CHB. This approach, besides giving a better response compared with peg-IFN alone, would also reduce the frequency of antiviral resistance associated with the use of long-term antivirals.
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