INTRODUCTION — Monotherapy with a single antiviral agent or interferon is unlikely to be sufficient for the eradication of hepatitis B virus (HBV) infection in the majority of patients who are chronically infected. With the availability of several medications, it is possible to contemplate combination therapy for hepatitis B [1]. Such an approach has proven to be beneficial in patients with HIV infection and those with chronic hepatitis C. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach" and "Overview of the management of chronic hepatitis C virus infection".)
Ideally, therapeutic agents used in combination therapy should have additive or synergistic activity against HBV, delay or prevent the development of drug resistance, have no added toxicity, and promote restoration of immune response to HBV. The question is which agents to combine: two nucleos(t)ide analogs or one nucleos(t)ide analog plus interferon? Early experience involves the addition of another agent to lamivudine. However, none of the combination approaches have been approved for routine use. This topic review will summarize experience with combination therapy for chronic HBV infection.
STANDARD INTERFERON PLUS LAMIVUDINE — The combination of lamivudine and interferon seems logical because monotherapy with each agent is effective, and lamivudine and interferon have different mechanisms of action. However, disparate results have been described in controlled trials.
Treatment-naïve patients — There are conflicting data on the outcome after combination therapy in treatment-naïve patients [2-4]. One trial included 230 patients from Europe, Canada, and Australia who were randomly assigned to one of three treatment arms [2]:
●Lamivudine (100 mg daily) for eight weeks followed by combination therapy with lamivudine plus interferon alfa-2b (10 MU SQ three times weekly) for 16 weeks
●Lamivudine (100 mg daily) for 52 weeks
●Placebo for eight weeks followed by combination therapy with placebo plus interferon alfa-2b (10 MU SQ three times weekly) for 16 weeks
Hepatitis B e antigen (HBeAg) seroconversion at week 52 was higher in patients receiving combination therapy with interferon plus lamivudine, although the results were not statistically significant (29 versus 18 and 19 percent, respectively). More patients in the lamivudine monotherapy group had histologic improvement at 52 weeks, possibly because of the timing of the repeat liver biopsies; repeat liver biopsies were performed while the patients in the lamivudine monotherapy group were still on treatment, compared to 28 weeks after cessation of treatment in the other two groups. (See "Histologic scoring systems for chronic liver disease".)
Different conclusions were reached in another study of 151 patients who were randomly assigned to combination therapy with interferon alfa-2b (9 MU SQ three times weekly) plus lamivudine (100 mg daily) for 24 weeks, or lamivudine alone for 52 weeks [3]. Sustained HBeAg seroconversion with undetectable serum levels of HBV DNA was observed significantly more often in the combination therapy group (33 versus 15 percent). A corresponding improvement in histology was also more common in the combination therapy group (46 versus 27 percent).
Interferon nonresponders — One of the largest trials focusing on interferon nonresponders involved 238 HBeAg-positive patients from 63 international centers who failed to respond to interferon monotherapy and were randomly assigned to the following treatment groups in a 2:1:1 ratio [5]:
●Lamivudine (100 mg PO once daily) for 52 weeks
●Lamivudine (100 mg PO once daily) for eight weeks followed by lamivudine (100 mg PO once daily) plus interferon alfa-2b (10 million units SQ three times weekly) for an additional 16 weeks
●Placebo
The data suggest that retreatment of interferon nonresponders with combination therapy of interferon plus lamivudine offers no advantage compared with retreatment with lamivudine monotherapy.
HBeAg-negative chronic hepatitis B — The efficacy of combination therapy in patients with HBeAg-negative chronic hepatitis B has been evaluated, but the studies included small numbers of patients. While no significant differences were observed in initial response rates or relapse rates following discontinuation of therapy, fewer patients in the combination group developed M204V/I mutations during therapy.
PEGINTERFERON IN COMBINATION WITH OTHER AGENTS
Lamivudine plus peginterferon — In most countries, peginterferon has replaced standard interferon (IFN). The attachment of polyethylene glycol to standard IFN (pegylation) reduces its rate of absorption following subcutaneous injection, reduces renal and cellular clearance, and decreases the immunogenicity of the protein. These effects enhance the half-life of peginterferon, allowing it to be dosed once a week. (See "Pegylated interferon for treatment of chronic hepatitis B virus infection".)
At least four controlled trials in hepatitis B e antigen (HBeAg)-negative and HBeAg-positive patients have evaluated the efficacy of combination therapy with peginterferon plus lamivudine [6-8]. Although combination therapy results in higher rate of virological and biochemical response at the end of therapy, sustained response assessed six months after treatment was similar compared to peginterferon alone.
HBeAg-positive chronic HBV — Several studies have evaluated peginterferon with and without lamivudine in the treatment of HBeAg-positive chronic HBV [6,8,9]. Considered together these data suggest that peginterferon is more effective than lamivudine in inducing HBeAg seroconversion when response is assessed six months after withdrawal of therapy and that combination therapy offers no advantage compared with peginterferon monotherapy. However, viral suppression occurred more rapidly in the groups that received lamivudine with or without peginterferon, and lamivudine-resistant mutation was less frequently detected in those who received combination of peginterferon and lamivudine compared to lamivudine monotherapy.
●A multinational study included a total of 814 patients who were randomly assigned to peginterferon alfa-2a (180 mcg once weekly) with either placebo or lamivudine (100 mg daily) or to lamivudine monotherapy [9]. Patients were treated for 48 weeks and assessed after 24 weeks of treatment-free follow-up. At week 72, all endpoints were significantly more likely in the groups receiving peginterferon compared with lamivudine monotherapy (HBeAg seroconversion 32 and 27 versus 19 percent), (HBV DNA <100,000 copies/mL (approximately 20,000 international units/mL) 32 and 34 versus 22 percent), (HBeAg loss 34 and 28 versus 21 percent), and (alanine transaminase [ALT] normalization 41 and 39 versus 28 percent) in the peginterferon monotherapy, combination therapy, or lamivudine monotherapy groups, respectively.
●Another trial included 307 patients who were randomly assigned to receive peginterferon alfa-2b with lamivudine (100 mg daily) or placebo for one year [6]. Patients were followed until six months after stopping therapy. The proportion of patients achieving loss of HBeAg at the end of follow-up was similar in the monotherapy and combination therapy groups (36 versus 35 percent). More patients in the combination therapy group had cleared HBeAg at the end of treatment (44 versus 29 percent), but there were more HBeAg seroreversions during follow-up. The response rates were similar when considering suppression of HBV DNA or changes in the serum aminotransferase levels. Response rates were higher in patients with HBV genotype A (47 percent) and B (44 percent) compared to genotype C (28 percent) and D (26 percent). The authors concluded that combination therapy was not superior to peginterferon monotherapy.
●Another trial included 100 Chinese patients with HBeAg-positive chronic hepatitis and moderately elevated ALT levels who were randomly assigned to either peginterferon-alfa-2b for 32 weeks plus lamivudine (100 mg daily) for 52 weeks or lamivudine monotherapy [8]. The rate of sustained virologic response (HBeAg seroconversion and HBV DNA <100,000 international units/mL) at least 24 weeks after the end of treatment was significantly higher in the combination therapy group (36 versus 14 percent). There were no significant differences in the proportion of patients with normalization of serum ALT or histologic improvement. Lamivudine-resistant mutations were detected more often in the monotherapy group compared with the combination therapy group (40 versus 21 percent).
Significance of ALT flares — Alanine transaminase (ALT) flares during interferon-based treatment are sometimes associated with HBeAg seroconversion. By contrast, ALT flares after discontinuation of nucleos(t)ide analogues are related to viral relapse.
In one study, ALT flares occurred in 38 (51 percent) patients who received peginterferon and lamivudine and in 37 (49 percent) patients who received peginterferon monotherapy [6]. Overall, flares were not more common in responders. However, host induced flares (flares followed by HBV DNA decrease) were significantly more likely to be associated with HBeAg loss than virus induced flares (flares following HBV DNA increase): 58 versus 20 percent [10]. Furthermore, hepatitis B surface antigen (HBsAg) loss was exclusively seen in patients who had a host-induced flare.
HBeAg-negative chronic HBV — One trial included a total of 537 patients with HBeAg-negative chronic HBV infection who were randomly assigned to one of three groups [7]:
●Peginterferon alfa-2a (180 mcg weekly) plus placebo for 48 weeks
●Peginterferon alfa-2a plus lamivudine (100 mg daily) for 48 weeks
●Lamivudine for 48 weeks
After 24 weeks of follow-up, the percentage of patients with normalization of serum ALT levels or HBV DNA levels below 20,000 copies/mL (approximately 5000 international units/mL) was significantly higher with peginterferon monotherapy (59 and 43 percent, respectively) or combination therapy (60 and 44 percent, respectively) compared with lamivudine monotherapy (44 and 29 percent, respectively). Rates of sustained suppression of HBV DNA to below 400 copies/mL (approximately 80 international units/mL) were also significantly higher in the peginterferon monotherapy or combination therapy groups compared with lamivudine monotherapy (19 and 20 versus 7 percent, respectively). Loss of HBsAg occurred in 12 patients in the peginterferon groups compared with 0 patients in the lamivudine groups.
A subsequent report described follow-up for up to three years [11]. The proportion of patients with a normal ALT was significantly higher with peginterferon monotherapy or combination therapy group compared with lamivudine alone (31 and 31 versus 18 percent, respectively). HBV DNA levels ≤10,000 copies/mL (approximately 2000 international units/mL) were also more likely in those who received peginterferon monotherapy or combination therapy compared with lamivudine (28 and 25 versus 15 percent, respectively). Of those who received peginterferon, 9 percent cleared HBsAg. These data indicate that 25 to 30 percent of patients with HBeAg-negative chronic hepatitis B had sustained biochemical/clinical remission after a one-year course of peginterferon. However, only 59 percent of patients entered the long-term follow-up study.
Extension of peginterferon from 48 to 96 weeks with or without the addition of lamivudine has also been evaluated. In a randomized controlled trial, 128 patients with HBeAg negative chronic HBV genotype D were randomly assigned to one of three treatment arms: peginterferon alfa-2a (180 mcg weekly) for 48 weeks, peginterferon alfa-2a (180 mcg weekly) for 48 weeks followed by 135 mcg weekly for an additional 48 weeks, or combination treatment of peginterferon alfa-2a (180 mcg weekly) and lamivudine (100 mg/day) for 48 weeks followed by peginterferon alfa-2a (135 mcg weekly) for 48 weeks [12]. At 48-week post-treatment follow-up, treatment with peginterferon alfa-2a alone for 96 weeks as compared with 48 weeks resulted in a higher proportion of patients achieving a virological response (HBV DNA <2000 int. units/mL: 29 versus 12 percent). Combination treatment was not associated with a higher virological response as compared with peginterferon alfa-2a alone, regardless of duration. However, only 13 patients in the combination treatment group completed follow-up. Given the costs and potential for more adverse events, the clinical benefits of extended therapy with peginterferon alfa-2a need to be validated in larger studies. (See "Clinical significance of hepatitis B virus genotypes", section on 'Responses to interferon'.)
Entecavir plus peginterferon — There is no clear benefit of combination therapy with entecavir plus pegylated interferon among HBeAg-positive patients with chronic HBV infection.
●In one randomized, open-label study of 218 treatment-naïve patients from China, patients received 48 weeks of pegylated interferon alfa-2a alone, or with 24 weeks of entecavir administered prior to or after peginterferon was initiated [13]. Rates of HBeAg seroconversion 24 weeks post-treatment were similar in all three groups: 33 percent in the monotherapy group, 25 percent in the entecavir add-on group, and 26 percent in the entecavir pretreatment group.
●In another randomized, open-label study, 175 HBeAg-positive patients received entecavir monotherapy or entecavir plus pegylated interferon alfa-2a added on between weeks 24 and 48 [14]. There was a non-significant increase in response to therapy (defined as HBeAg loss and HBV DNA <200 IU/mL) at week 48 in the add-on compared with the monotherapy group (19 versus 10 percent, respectively).
Tenofovir plus peginterferon — The combination of pegylated interferon and tenofovir disoproxil fumarate may enhance the rate of HBsAg loss, but the benefit is mainly observed in patients infected with HBV genotype A [15]. Data evaluating this combination are discussed in detail elsewhere. (See "Pegylated interferon for treatment of chronic hepatitis B virus infection", section on 'Combination with other nucleos(t)ide analogues'.)
Adefovir plus peginterferon — An initial report of combination therapy with peginterferon plus adefovir found a marked decrease in HBV DNA. This trial involved 24 patients who were treated with 48 weeks of combination therapy followed by 96 weeks of adefovir monotherapy [16,17]. At week 144, 12 of 15 patients who were HBeAg positive had lost HBeAg, while ALT levels normalized in 23 patients (96 percent). Histologic improvement was noted in 11 of 16 patients who had a follow-up biopsy. Two patients developed adefovir resistance. These promising results need to be confirmed in larger studies.
Telbivudine plus peginterferon — Telbivudine plus peginterferon should not be administered together because of a high rate of peripheral neuropathy. A study evaluating the efficacy of this regimen was stopped early due to increased rates of peripheral neuropathy in those receiving combination therapy compared with those receiving monotherapy with telbivudine or peginterferon (14, 1, and 0 percent, respectively) [18].
TENOFOVIR DISOPROXIL PLUS ENTECAVIR — The use of tenofovir disoproxil plus entecavir does not offer any benefit compared with entecavir monotherapy for most treatment-naïve patients. However, the use of this combination may be effective in patients who have experienced treatment failure to sequential courses of nucleos(t)ide analogue therapy and/or have multi-drug resistant hepatitis B virus (HBV).
As examples:
●A trial of 379 previously untreated patients with chronic HBV (hepatitis B e antigen [HBeAg]-positive and HBeAg-negative) evaluated the use of combination therapy with entecavir and tenofovir. Individuals were randomly assigned to receive entecavir (0.5 mg daily) as monotherapy or in combination with tenofovir (300 mg daily) for 100 weeks [19]. At week 96, the proportion of patients achieving the primary endpoint (HBV DNA level <50 IU/mL) was similar in both groups. However, in a subgroup analysis, combination therapy was more effective (79 versus 62 percent) in HBeAg-positive patients who had baseline HBV DNA levels of ≥108 IU/mL. There was no evidence of antiviral resistance at the end of the study in either group. The rate of alanine aminotransferase (ALT) normalization was higher in the patients that received entecavir monotherapy as compared with combination therapy. There was no significant difference in the rates of HBeAg seroconversion and HBeAg loss.
●An open-labeled study of 57 treatment-experienced patients examined the efficacy of combination therapy with entecavir (0.5 mg daily for lamivudine naïve or 1.0 mg daily for lamivudine experienced patients) plus tenofovir (300 mg daily) [20]. Participants had evidence of antiviral drug-resistant HBV or an incomplete virologic response or failure to previous antiviral therapy regimens. Participants were previously treated with a median of three lines of therapy, and most had received a regimen that contained adefovir or lamivudine. HBV DNA became undetectable in 51 of the 57 patients (89 percent) after a median of six months on combination therapy. In addition, five patients lost HBeAg and one developed hepatitis B surface antigen seroconversion.
TENOFOVIR DISOPROXIL PLUS EMTRICITABINE — Combination therapy with tenofovir disoproxil plus emtricitabine is described separately. (See "Tenofovir and adefovir for the treatment of chronic HBV infection".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Management of hepatitis B".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Hepatitis B (The Basics)")
●Beyond the Basics topics (see "Patient education: Hepatitis B (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Combination therapy offers the potential to achieve three important goals in the treatment of hepatitis B virus (HBV): increasing the rate of hepatitis B e antigen (HBeAg) seroconversion or viral clearance, and (in those in whom this cannot be accomplished) achieving long-term viral suppression while avoiding drug resistance. Unfortunately, none of these goals has been achieved convincingly to an extent greater than with currently available monotherapies. This may be because all nucleos(t)ide analogs for HBV have the same viral target. Most studies on combination therapy have focused on lamivudine and the main advantage observed is a reduction in incidence of lamivudine resistance. Given the low rate of antiviral resistance associated with entecavir or tenofovir monotherapy, it would be difficult to demonstrate that combination therapy will provide additional benefit.
●Clinical trials comparing peginterferon and lamivudine to peginterferon alone suggest that while the initial response rate is higher in the combination therapy group, a sustained response after stopping treatment is not increased. Among patients receiving peginterferon with or without entecavir, no difference in the initial response was observed among those receiving combination therapy versus peginterferon or entecavir alone. (See 'Lamivudine plus peginterferon' above and 'Entecavir plus peginterferon' above.)
●One trial comparing combination of tenofovir disoproxil plus entecavir to entecavir monotherapy in treatment naïve patients found that overall responses were similar but combination therapy resulted in more rapid viral suppression in HBeAg-positive patients with high baseline HBV DNA. Whether this difference is clinically relevant is not clear. (See 'Tenofovir disoproxil plus entecavir' above.)
