Dual Therapy for Chronic Hepatitis B Virus

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1 Dual Therapy for Chronic Hepatitis B Virus Hussien Elsiesy, MD, and Douglas Dieterich, MD Corresponding author Douglas Dieterich, MD Division of Liver Diseases, Mount Sinai School of Medicine, One Gustave L Levy Place, Box 1123, New York, NY 10029, USA. Douglas.dieterich@mountsinai.org Current Hepatitis Reports 2008, 7:33 39 Current Medicine Group LLC ISSN Copyright 2008 by Current Medicine Group LLC Chronic hepatitis B virus infection is a leading cause of morbidity and mortality throughout the world. Antiviral therapy should target patients who are at a substantial risk of developing liver disease because the response to treatment is often suboptimal and long-term monotherapy is invariably associated with the development of resistance. Currently, there are six agents approved for the treatment of chronic hepatitis B: interferon alfa-2b, peginterferon alfa-2a, lamivudine, adefovir, entecavir, and telbivudine. The currently available monotherapy regimens have limited efficacy and result in suboptimal responses in many patients with chronic hepatitis B. Various studies have evaluated different combination regimens for the treatment of chronic hepatitis B, but no combined regimen has been proven superior to monotherapy in achieving sustained off-treatment viral suppression. Combination therapy has the advantage of a reduced rate of antiviral drug resistance, but this relative benefit over drugs with a low risk of antiviral drug resistance when used as monotherapy requires further comparative study. Introduction Chronic hepatitis B virus (HBV) infection is the most common cause of cirrhosis and hepatocellular carcinoma (HCC) worldwide. It is clear that high viral replication is a major risk factor for the development of cirrhosis and HCC. Outcome is improved by successful treatment leading to suppression of serum HBV DNA and seroconversion of hepatitis B e antigen (HBeAg) to antibody to HBeAg (anti-hbe) in HBeAg-positive patients with normalization of alanine aminotransferase (ALT) levels. Results from the available therapy for chronic hepatitis B (CHB) are suboptimal compared with those of chronic hepatitis C treatment, which may result in a sustained virologic response or cure. The potential advantage of combination therapy for CHB is a diminished or delayed rate of resistance. The disadvantages are added cost, potential for increased toxicity, and possible drug interactions. In this review, we discuss the role of combination therapy in compensated CHB in special populations such as those with HIV/HBV coinfection or cirrhosis, and following liver transplantation. Standard Interferon and Lamivudine Several trials evaluating the efficacy of combination therapy with lamivudine and standard interferon (IFN) compared with lamivudine monotherapy or IFN monotherapy have yielded different results [1 9]. HBeAg-positive chronic hepatitis B The first randomized controlled trial evaluated 230 treatment-naïve, predominantly Caucasian patients with CHB and detectable HBeAg and serum HBV DNA [1]. Patients were randomly assigned to receive combination therapy with lamivudine 100 mg daily and IFN-alfa 10 MU three times weekly for 16 weeks after pretreatment with lamivudine for 8 weeks (n = 75); interferon-alfa 10 MU three times weekly for 16 weeks (n = 69); or lamivudine 100 mg daily for 52 weeks (n = 82). The HBeAg seroconversion rate at week 52 was 29% for the combination therapy, 19% for the IFN monotherapy, and 18% for the lamivudine monotherapy group (P = 0.12 and P = 0.10, respectively, for comparison of combination therapy with IFN or lamivudine monotherapy). The HBeAg seroconversion rates at week 52 for combination therapy and lamivudine monotherapy were significantly different in the per protocol analysis: 36% (20 of 56) versus 19% (13 of 70), respectively (P = 0.02). The effect of combining lamivudine and IFN appeared to be most useful in patients with moderately elevated ALT levels at baseline. The author concluded that the lamivudine and IFN combination appeared to increase the HBeAg seroconversion rate, particularly in patients with moderately elevated baseline ALT levels. Another trial compared combination therapy with INF alfa-2b and lamivudine for 24 weeks (n = 76) with

2 34 Hepatitis B: Epidemiology, Natural History, Treatment, and Transplantation lamivudine monotherapy for 52 weeks (n = 75) in patients with CHB who were followed for 48 weeks after treatment [2]. In an intention-to-treat analysis, sustained HBeAg seroconversion with undetectable serum levels of HBV DNA was observed in 25 of 76 patients (33%) treated with combination therapy and in 11 of 75 patients (15%) treated with monotherapy (P = 0.014). The author concluded that 6 months of treatment with IFN alfa-2b and lamivudine in combination appeared to increase the rate of sustained HBeAg seroconversion compared with 1 year of lamivudine monotherapy. This study lacked an IFN monotherapy arm, and the overall sustained response in the combination therapy arm may not differ significantly from that of IFN monotherapy. In a small randomized study, no significant difference was found in rates of sustained viral suppression between a group of 33 patients who received lamivudine (100 mg/d) plus IFN alfa-2b (10 MU three times weekly) and a group of 16 patients who received IFN alfa-2b alone (10 MU three times weekly) for 12 months (P = 0.133) [8]. In a larger controlled trial, 238 HBeAg-positive patients with CHB who failed prior IFN therapy were randomly assigned to receive lamivudine alone for 52 weeks, lamivudine in combination with IFN for 16 weeks after 8 weeks of lamivudine, or placebo for 52 weeks [7]. The HBeAg seroconversion rate (loss of HBeAg, development of anti- HBe, and loss of HBV DNA) was 18% (n = 119), 12% (n = 63), and 13% (n = 56), respectively, with no added benefit of combination therapy in this subset of patients. Sarin et al. [9] randomly assigned 75 treatment-naïve HBeAg-positive CHB patients to receive lamivudine 100 mg/d (n = 37) for 52 weeks or sequential therapy (n = 38) with lamivudine for 52 weeks with IFN 5 miu/d for 16 weeks added after the first 8 weeks. This study differed from previous studies in that lamivudine was continued for 52 weeks in the sequential-therapy arm. HBeAg seroconversion (loss of HBeAg, development of anti-hbe, and loss of HBV DNA) was observed in 38.6% of patients (n = 14) in the sequential-therapy arm compared with 10.8% (n = 4) in the lamivudineonly arm (P = 0.026). The authors concluded that sequential therapy is superior to lamivudine monotherapy. However, this was a small study without an IFN monotherapy arm, which makes it difficult to draw firm conclusions. HBeAg-negative chronic hepatitis B In a randomized controlled trial, 50 patients with anti- HBe positive CHB were treated for 12 months with lamivudine at 100 mg/d (n = 26) or IFN 5 MU three times weekly plus lamivudine 100 mg/d (n = 24). All patients normalized ALT and cleared HBV DNA during treatment [5]. The response was maintained until the end of therapy in the lamivudine/ifn group, whereas in 5 of 26 initial responders treated with lamivudine alone, a virologic and biochemical breakthrough was observed after 6 to 10 months of follow-up, with development of lamivudine resistance. After discontinuation of therapy, most patients relapsed. The response rate after 6 months was 17% in the lamivudine/ifn group and 19% in the lamivudine group. In anti-hbe positive CHB, a 12- month course of lamivudine/ifn combination therapy was not superior to lamivudine monotherapy; however, the combination regimen appeared to prevent or delay the emergence of lamivudine-resistant variants. A prospective pilot study using lamivudine and IFN for 12 months yielded a sustained response of 14%, similar to that of the previous study [3]. Peginterferon and Lamivudine Two large multicenter randomized controlled trials assessed pegylated IFN (PEG-IFN), lamivudine, and the combination of both in patients with HBeAg-negative and HBeAg-positive CHB [10,11 ]. Another trial compared PEG-IFN alone or in combination with lamivudine for HBeAg-positive CHB [12]. In the first trial, 537 patients with HBeAg-negative CHB were randomly assigned to receive PEG-IFN alfa- 2a (180 g once weekly) plus placebo (n = 177), PEG-IFN alfa-2a plus lamivudine 100 mg/d (n = 179), or lamivudine alone (n = 181) for 48 weeks [10 ]. After 24 weeks of follow-up, normalization of ALT or decrease of HBV DNA levels below 20,000 copies/ml was significantly higher with PEG-IFN monotherapy (59% and 43%, respectively) and PEG-IFN plus lamivudine (60% and 44%) compared with lamivudine monotherapy (44%, P = and P = 0.003, respectively; and 29%, P = and P = 0.003, respectively). Rates of sustained suppression of HBV DNA to below 400 copies/ml were 19% with PEG-IFN monotherapy, 20% with combination therapy, and 7% with lamivudine alone (P < for both comparisons with lamivudine alone). Loss of hepatitis B surface antigen (HBsAg) occurred in 12 patients in the PEG-IFN groups, as compared with none in the group given lamivudine alone. Patients with HBeAg-negative CHB had significantly higher rates of response, sustained for 24 weeks after the cessation of therapy with PEG-IFN, than with lamivudine. The addition of lamivudine to PEG-IFN did not improve the response rates. Higher baseline ALT, lower HBV DNA, younger age, female gender, and HBV genotype B and C compared with genotype D were predictors of response to treatment [13]. A larger study randomly assigned 814 patients with HBeAg-positive CHB to receive either PEG-IFN alfa-2a (180 g once weekly) plus oral placebo, PEG-IFN alfa- 2a plus lamivudine (100 mg/d), or lamivudine alone for 48 weeks, with follow-up for an additional 24 weeks [11 ]. The majority of patients in the study were Asian (87%), and most patients were infected with HBV geno-

3 Dual Therapy for Chronic HBV Elsiesy and Dieterich 35 type B or C. Significantly more patients who received PEG-IFN monotherapy or PEG-IFN plus lamivudine than received lamivudine monotherapy experienced HBeAg seroconversion (32% vs 19% [P < 0.001] and 27% vs 19% [P = 0.02], respectively) or HBV DNA levels below 100,000 copies/ml (32% vs 22% [P = 0.01] and 34% vs 22% [P = 0.003], respectively). Sixteen patients receiving PEG-IFN (alone or in combination) had HBsAg seroconversion, as compared with none in the group receiving lamivudine alone (P = 0.001). In patients with HBeAg-positive CHB, PEG-IFN offers superior efficacy over lamivudine based on HBeAg seroconversion, HBV DNA suppression, and HBsAg seroconversion. The addition of lamivudine to PEG-IFN did not improve post-therapy response rates. Janssen et al. [12] randomly assigned 307 HBeAg-positive patients with CHB to receive combination therapy with 100 g/wk PEG-IFN alfa-2b plus 100 mg/d lamivudine (n = 152) or 100 g/wk PEG-IFN alfa-2b plus placebo (n = 155) for 52 weeks. During weeks 32 to 52, the PEG- IFN dosage was 50 g/wk in both treatment groups. Based on the modified intention-to-treat analysis, 49 of 136 patients (36%) assigned to monotherapy and 46 of 130 (35%) assigned to combination therapy had lost HBeAg at the end of 26 weeks of follow-up (P = 0.91). More patients in the combination-therapy than in the monotherapy group had cleared HBeAg at the end of treatment (57 [44%] vs 40 [29%]; P = 0.01) but relapsed during follow-up. Response rates (HBeAg loss) varied by HBV genotype (P = 0.01): A, 42 patients (47%); B, 10 (44%); C, 11 (28%); and D, 26 (25%). The authors concluded that treatment with a combination of PEG-IFN and lamivudine is not superior to monotherapy and that HBV genotype is an important predictor of response to treatment. In a small study, Chan et al. [14] reported a higher response to combination therapy with PEG-IFN and lamivudine compared with lamivudine monotherapy; however, this study did not have a PEG-IFN monotherapy arm. All the aforementioned studies found that combination therapy produced higher on-treatment viral suppression and off-treatment response compared with lamivudine alone but no difference in sustained offtreatment response compared with IFN or PEG-IFN alone. Combination therapy was associated with a lower rate of lamivudine resistance compared with lamivudine alone; a low rate of lamivudine resistance was encountered compared with none in patients who received IFN or PEG-IFN alone [15]. Combination therapy with IFN and lamivudine is not more effective than lamivudine in retreatment of IFN nonresponders [7]. Future studies may consider peginterferon therapy followed by nucleoside/nucleotide analogue maintenance treatments. PEG-IFN improves liver histology in patients with HBeAg-positive CHB, with no added benefit from combination with lamivudine [16]. Lamivudine and Adefovir Nucleoside-naïve patients One trial randomly assigned 115 patients with CHB to receive a combination of adefovir and lamivudine (n = 55) or lamivudine alone (n = 57) for 104 weeks. There was no difference between the two groups in HBV viral suppression, ALT normalization, or HBeAg loss at week 52 [17]. The results were comparable in both groups at 104 weeks. Lamivudine-resistant HBV A small multicenter trial in patients with lamivudine resistance and compensated liver disease showed that the combination of adefovir and lamivudine was not superior to adefovir alone in decreasing serum HBV DNA levels [18]. Fifty-nine patients with HBeAg-positive CHB and genotypic evidence of lamivudine-resistant HBV, a serum ALT level greater than or equal to 1.2 times the upper limit of normal (ULN), and a serum HBV DNA level greater than or equal to 6 log 10 copies/ml despite ongoing treatment with lamivudine were randomly assigned to adefovir dipivoxil 10 mg/d, lamivudine 100 mg/d, or addition of adefovir dipivoxil to ongoing lamivudine. The primary end point was the time-weighted average change from baseline in serum HBV DNA level up to week 16. Rapid reduction in serum HBV DNA levels was seen by 4 weeks in all recipients of adefovir dipivoxil. ALT levels normalized in 10 of 19 (53%) and 9 of 18 (47%) recipients of adefovir dipivoxil/lamivudine and adefovir dipivoxil, respectively, compared with 1 of 19 (5%) recipients of lamivudine. Three patients receiving adefovir dipivoxil or adefovir dipivoxil/lamivudine and none receiving lamivudine monotherapy were HBeAg negative at week 48, and one became HBsAg negative. These data, limited to patients with compensated liver disease, indicate that adefovir dipivoxil alone or in combination with ongoing lamivudine therapy provides effective antiviral therapy in patients with lamivudine-resistant HBV. Another trial evaluated the efficacy and safety of adding adefovir dipivoxil to lamivudine in 135 patients with CHB and lamivudine-resistant HBV [19]. Ninety-five patients with compensated CHB (group A) were randomly assigned to adefovir 10 mg/d (n = 46) or placebo (n = 49) for 52 weeks while continuing treatment with lamivudine. Forty patients with decompensated hepatitis B or post liver transplantation (group B) received adefovir and lamivudine. The primary end point was a decline in serum HBV DNA level to 10 5 copies/ml or a greater than 2 log 10 reduction from baseline at weeks 48 and 52. Serum HBV DNA response occurred in 85% of patients (39 of 46) in group A given combined therapy versus 11% (5 of 46) receiving lamivudine alone (P < 0.001), with a significant change in HBV DNA level from baseline (P < 0.001) between treatment groups (median, 4.6 vs +0.3 log 10 copies/ml, respectively). Normalization of ALT levels occurred in 31% of patients (14 of 45)

4 36 Hepatitis B: Epidemiology, Natural History, Treatment, and Transplantation receiving combined therapy versus 6% (3 of 48) receiving lamivudine alone (P = 0.002). Ninety-two percent of patients (36 of 39) in group B had an HBV DNA response (median change of 4.6 log 10 copies/ml) and improved liver chemistries (P 0.001). The addition of adefovir dipivoxil to lamivudine in patients with CHB with compensated or decompensated liver disease due to lamivudine-resistant HBV is associated with virologic and biochemical improvement during 52 weeks of treatment and is well tolerated. Although adefovir alone is as effective as a combination of lamivudine and adefovir, an overlap rather than a switch is beneficial in decompensated liver disease to prevent flare of hepatitis B. In a small study, 30 patients underwent 48-week adefovir treatment (10 mg/d) for exacerbation of hepatitis B associated with lamivudine-resistant mutants [20]. Nineteen patients (63.3%) had baseline evidence of hepatic decompensation. Lamivudine was added to adefovir for 1 month or less in 8 (group I), 2 to 5 months in 10 (group II), and 6 months or more in 12 patients (group III). Serum ALT became normalized in 20 (66.7%) and HBV DNA decreased to less than or equal to 100 copies/ml in 8 patients (26.7%) at the end of the 48-week treatment. The log 10 reduction of serum HBV DNA was significantly smaller in group I patients compared with group II and III patients at weeks 24 and 48 of treatment (median [range]: 3.0 [ ] vs 4.5 [ ], P = 0.032; and 3.4 [ ] vs 5.2 [ ], P = 0.008, respectively). In contrast, the virologic responses at the end of the 48-week therapy were similar between groups II and III. These findings suggest that an overlap of lamivudine for 2 months or longer might lead to better virologic but not biochemical outcomes in patients receiving adefovir for lamivudineresistant HBV. However, the sample size was small, and the study was not randomly controlled. Recent data suggest that continuing lamivudine with adefovir in lamivudine-resistant HBV reduces the adefovir resistance rate [21,22]. Of 145 patients receiving adefovir plus lamivudine for 3 years, only 1 patient (0.7%) developed adefovir resistance (rta181t mutation) [23 ]. Development of adefovir resistance may be associated with hepatic decompensation and death [24]. Therefore, increasing evidence supports adding adefovir instead of switching to adefovir monotherapy for patients with lamivudine-resistant HBV. In summary, the combination of lamivudine and adefovir is an effective strategy, particularly to avoid resistance, based on the combination of anti-hbv drugs with nonoverlapping resistance profiles. Lamivudine and Telbivudine As with lamivudine and adefovir, the combination of lamivudine and telbivudine is not superior to telbivudine alone. A randomized double-blind multicenter trial evaluated the efficacy and safety of telbivudine 400 or 600 mg/d and telbivudine 400 or 600 mg/d plus lamivudine 100 mg/d (Comb400 and Comb600) compared with lamivudine 100 mg/d in HBeAg-positive adults with compensated CHB [25]. In this study, 104 patients were randomized 1:1:1:1:1 among the five groups. Median reductions in serum HBV DNA levels (log 10 copies/ml) at week 52 were as follows: lamivudine, 4.66; telbivudine 400 mg, 6.43; telbivudine 600 mg, 6.09; Comb400, 6.40; and Comb600, At week 52, telbivudine monotherapy showed significantly greater mean reduction in HBV DNA levels (6.01 vs 4.57 log 10 copies/ml; P < 0.05), clearance of polymerase chain reaction detectable HBV DNA (61% vs 32%; P < 0.05), and normalization of ALT levels (86% vs 63%; P < 0.05) compared with lamivudine monotherapy, with proportionally greater HBeAg seroconversion (31% vs 22%) and less viral breakthrough (4.5% vs 15.8%; P = not significant for both). Combination treatment was not superior to telbivudine alone. In retrospect, this was because the resistance mutations for lamivudine and telbivudine (at the 204 locus) are at the same place in the HBV genome. Clinical efficacy at 1 year appeared to be related to a reduction in HBV DNA levels in the first 6 months of treatment. Patients with CHB treated with telbivudine exhibited significantly greater virologic and biochemical responses compared with those treated with lamivudine, but the responses in patients treated with combination regimens were similar to those obtained with telbivudine alone. Combination Therapy in HIV HBV therapy should be limited to HIV-coinfected patients who are at a high risk for the development of liver disease. Practice guidelines published by the American Association for the Study of Liver Diseases (AASLD) recommend that all HIV-coinfected patients who meet treatment criteria for CHB should be treated [15]. Thus, candidates for therapy are HIV-infected patients who test positive for HBsAg with active HBV replication and ALT levels more than twice the ULN after 3 to 6 months of observation. The threshold for treatment is an HBV DNA level higher than 20,000 IU/mL in an HBeAg-positive patient or 2000 IU/mL in an HBeAg-negative patient. Individuals who have fluctuating or mildly elevated ALT values (one to two times the ULN) and elevated HBV DNA levels (> 20,000 IU/mL for HBeAg-positive individuals or > 2000 IU/mL for HBeAg-negative individuals) should undergo liver biopsy. Evidence of necroinflammation or significant fibrosis on liver biopsy is an indication for treatment [15]. Treatment is not generally recommended for HIV-infected patients who are HBsAg positive and have normal ALT levels and undetectable HBV DNA. With the exception of lamivudine, often used as a component of highly active antiretroviral therapy (HAART), clinical experience with anti-hbv therapies

5 Dual Therapy for Chronic HBV Elsiesy and Dieterich 37 in the setting of HIV coinfection is limited. Oral nucleotide and nucleoside analogues such as lamivudine [26], tenofovir [27], emtricitabine [28], and entecavir [29] have been shown to be active against both HBV and HIV. The US Department of Health and Human Services recommends that all patients with HIV/HBV coinfection (in contrast to HBV monoinfection) receive dual therapy for HBV if they require treatment for both viruses [30]. The combination of tenofovir and emtricitabine or lamivudine is recommended. PEG-IFN, adefovir, or telbivudine should be used if patients are not receiving HAART. Although there is a theoretic concern about HIV resistance in patients receiving adefovir [30], most experts do not consider it a significant worry. The combination of telbivudine and adefovir is very appealing when no HIV treatment is desired. There are no overlapping resistance mutations, and both are potent HBV antiviral agents with no HIV activity. Combination therapy for HBV after liver transplantation In the past, an unacceptable HBV recurrence rate with a high rate of graft loss was noted after liver transplantation for CHB. The use of hepatitis B immune globulin (HBIG) has resulted in improved patient and graft survival rates. Adding the nucleoside analogue lamivudine to HBIG has improved survival to an even greater degree. However, prolonged use of lamivudine will almost invariably lead to the development of viral mutations resistant to the drug [31]. There are now several other nucleoside and nucleotide analogues (adefovir, entecavir, tenofovir, and tenofovir/emtricitabine) available for the clinician to use against these resistant strains. HBIG monotherapy for HBV prevention was associated with nearly 20% recurrence after liver transplantation [32,33]. Several studies evaluated lamivudine monotherapy for HBV prevention after liver transplantation [34,35]. Because of the high recurrence rate, there is no role for lamivudine monotherapy in this setting. The combination of HBIG and lamivudine was associated with a recurrence rate of less than 10% [36,37]. With a significant number of patients developing lamivudine-resistant HBV strains in the pretransplantation setting or primarily infected with a lamivudine-resistant HBV mutant, the use of lamivudine to prevent recurrent HBV in the posttransplantation setting is of limited value. Adefovir dipivoxil is a good alternative. In a large international multicenter clinical trial, 324 patients with recurrent HBV infection and evidence of lamivudine-resistant HBV who were awaiting or who had undergone liver transplantation received adefovir dipivoxil 10 mg once daily. In the post-transplantation cohort, 196 patients were treated for a median of 56.1 weeks. Among these patients, 34% of those who received 48 weeks of treatment achieved undetectable serum HBV DNA, with a median change in serum HBV DNA from baseline of 4.3 log 10 copies/ml. Serum ALT, albumin, bilirubin, and prothrombin time normalized in 49%, 76%, 75%, and 20% of the post-transplantation patients, respectively. No adefovir resistance mutations were identified in patients after 48 weeks of therapy. One-year survival was 93% for the post-transplantation patients. Treatment with adefovir resulted in significant improvements in virologic, biochemical, and clinical parameters in post-transplantation CHB patients with lamivudine-resistant HBV [38]. Another study described the use of prophylactic adefovir in 16 patients who had developed lamivudineresistant mutations while on the waiting list for a liver transplant [39 ]. Eleven patients received adefovir for a median of 20 days (range, days) before transplantation, whereas five patients started the drug at the time of transplantation. The median follow-up period after liver transplantation was 21.1 months (range, months). One patient died from a cause unrelated to HBV 12.2 months after transplantation. Fifteen patients (94%) were alive with the original graft. Pre-transplantation HBV DNA levels at the time of breakthrough were available in 15 patients and ranged from to copies/ml (median, copies/ml). Eight patients received HBIG (in addition to adefovir and lamivudine) for a median of 24 months, whereas the other eight patients received prophylaxis with adefovir and lamivudine alone. All 16 patients cleared HBV DNA and had no evidence of recurrence; furthermore, all remained HBeAg negative. The graft survival was 94% at a median follow-up of 21 months. The authors concluded that the combination of adefovir and lamivudine is preferable in patients with lamivudine resistance to avoid the emergence of multiresistant viral strains. Neff et al. [40] reported cost-effective prevention of HBV after liver transplantation in 10 patients who switched from HBIG and lamivudine to adefovir and lamivudine, with a mean follow-up of 21 months. It is expected that the development of adefovir mutations will similarly become a problem in the post-transplantation setting. If HBV recurrence occurs, adding another agent with nonoverlapping resistance mutations may result in viral suppression with improved clinical outcome. There are case reports demonstrating that the addition of adefovir to HBIG and lamivudine reversed fibrosing cholestatic hepatitis B after liver transplantation [41,42]. Conclusions CHB is a major cause of mortality and morbidity worldwide. Currently available therapy is suboptimal, in part because resistance develops with prolonged monotherapy. To improve treatment response, combination therapy for CHB using different regimens has been tested. The advantage of dual therapy is to decrease emergence of drug resistance. Dual therapy for CHB clearly has a role in decompensated cirrhosis, HIV coinfection, and the post liver transplantation setting. Its use in less severe

6 38 Hepatitis B: Epidemiology, Natural History, Treatment, and Transplantation CHB is uncertain and undergoing study. A general rule is to use one nucleoside analogue (lamivudine, entecavir, telbivudine, or emtricitabine) and one nucleotide analogue (adefovir or tenofovir). These two classes have different resistance mutation profiles. Long-term study of various combination regimens is needed. Disclosures No potential conflict of interest relevant to this article was reported. References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: Of importance Of major importance 1. Schalm SW, Heathcote J, Cianciara J, et al.: Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: a randomised trial. Gut 2000, 46: Barbaro G, Zechini F, Pellicelli AM, et al.: Long-term efficacy of interferon alpha-2b and lamivudine in combination compared to lamivudine monotherapy in patients with chronic hepatitis B. An Italian multicenter, randomized trial. J Hepatol 2001, 35: Tatulli I, Francavilla R, Rizzo GL, et al.: Lamivudine and alpha-interferon in combination long term for precore mutant chronic hepatitis B. J Hepatol 2001, 35: van Nunen AB, Janssen HL, Wolters LM, et al.: Is combination therapy with lamivudine and interferon-alpha superior to monotherapy with either drug? Antiviral Res 2001, 52: Santantonio T, Niro GA, Sinisi E, et al.: Lamivudine/interferon combination therapy in anti-hbe positive chronic hepatitis B patients: a controlled pilot study. J Hepatol 2002, 36: Schalm SW: Combination therapy for chronic hepatitis B. J Hepatol 2003, 39(Suppl 1):S146 S Schiff ER, Dienstag JL, Karayalcin S, et al.: Lamivudine and 24 weeks of lamivudine/interferon combination therapy for hepatitis B e antigen-positive chronic hepatitis B in interferon nonresponders. J Hepatol 2003, 38: Yalcin K, Degertekin H, Yildiz F, Celik Y: Comparison of 12-month courses of interferon-alpha-2b-lamivudine combination therapy and interferon-alpha-2b monotherapy among patients with untreated chronic hepatitis B. Clin Infect Dis 2003, 36: Sarin SK, Kumar M, Kumar R, et al.: Higher efficacy of sequential therapy with interferon-alpha and lamivudine combination compared to lamivudine monotherapy in HBeAg positive chronic hepatitis B patients. Am J Gastroenterol 2005, 100: Marcellin P, Lau GK, Bonino F, et al.: Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2004, 351: This study defined the role of combination PEG-IFN and lamivudine in HBeAg-negative patients. 11. Lau GK, Piratvisuth T, Luo KX, et al.: Peginterferon alfa- 2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med 2005, 352: Another excellent article on the role of PEG-IFN and lamivudine combination therapy in HBeAg-negative patients. 12. Janssen HL, van Zonneveld M, Senturk H, et al.: Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet 2005, 365: Bonino F, Marcellin P, Lau GK, et al.: Predicting response to peginterferon alpha-2a, lamivudine and the two combined for HBeAg-negative chronic hepatitis B. Gut 2007, 56: Chan HL, Leung NW, Hui AY, et al.: A randomized, controlled trial of combination therapy for chronic hepatitis B: comparing pegylated interferon-alpha2b and lamivudine with lamivudine alone. Ann Intern Med 2005, 142: Lok AS, McMahon BJ: Chronic hepatitis B. Hepatology 2007, 45: van Zonneveld M, Zondervan PE, Cakaloglu Y, et al.: Peg-interferon improves liver histology in patients with HBeAg-positive chronic hepatitis B: no additional benefit of combination with lamivudine. Liver Int 2006, 26: Sung JJY: A randomized double-blind phase II study of lamivudine compared to lamivudine plus adefovir dipivoxil for treatment naive patients with chronic hepatitis B: week 52 analysis. J Hepatol 2003, 38: Peters MG, Hann HW, Martin P, et al.: Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology 2004, 126: Perrillo R, Hann HW, Mutimer D, et al.: Adefovir dipivoxil added to ongoing lamivudine in chronic hepatitis B with YMDD mutant hepatitis B virus. Gastroenterology 2004, 126: Liu CJ, Kao JH, Chen PJ, et al.: Overlap lamivudine treatment in patients with chronic hepatitis B receiving adefovir for lamivudine-resistant viral mutants. J Viral Hepat 2006, 13: Fung SK, Chae HB, Fontana RJ, et al.: Virologic response and resistance to adefovir in patients with chronic hepatitis B. J Hepatol 2006, 44: Snow A, Qi X, Zhu Y, et al.: Combination of adefovir (ADV) and lamivudine (LAM) prevented emergence of adefovir resistance mutations in chronic hepatitis B patients with lamivudine-resistant HBV [abstract]. Gastroenterology 2005, 128:M Lampertico P, Vigano M, Manenti E, et al.: 3 years of adefovir and lamivudine combination therapy minimize the risk of genotypic resistance to ADV in LAM resistant patients. J Hepatol 2007, 46(Suppl 1):S27. This study outlines the benefit of adefovir and lamivudine combination therapy in preventing adefovir resistance in lamivudine-resistant patients. 24. 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