SemOpenAlex |

SemOpenAlex

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2051277974> ?p ?o ?g. }

Showing items 1 to 54 of 54 with 100 items per page.

W2051277974 endingPage "150" @default.
W2051277974 startingPage "146" @default.
W2051277974 abstract "1. Rationale for combination therapyAmong the approximately 350 million individuals with chronic hepatitis B infection in the world, up to 50% (175 million) may have chronic hepatitis B-related symptoms or signs; in comparison, the number of people infected with human immunodeficiency virus (HIV) is estimated to be 60 million. Nearly all clinical conditions – chronic hepatitis progressing to cirrhosis; cirrhosis with active hepatitis at risk for variceal bleeding, ascites, and hepatocellular carcinoma; chronic hepatitis with high viremia at risk for transmitting HBV; chronic hepatitis B with extrahepatic complications – require treatment. However, monotherapy with either a standard course of 16–26 weeks of interferon-α or 1 year of lamivudine is effective in only a minority of patients. So, current regimens are inadequate for 60–90% of patients with chronic hepatitis B in need of therapy. In view of the low efficacy in relation to costs, the pressure to massively implement antiviral therapy in chronic hepatitis B has been restrained. To reduce the morbidity and mortality of chronic hepatitis B, more effective therapies have to be developed.For most patients an effective response is based upon profound suppression of hepatitis B virus (HBV) DNA, followed by alanine aminotransferase (ALT) normalization, whereas a sustained response requires an additional induction of host immunity. Interferon has only mild to moderate virus-suppressive activity but can induce an effective host immune response in susceptible patients. In contrast, lamivudine has marked virus-suppressive activity in the majority of patients but has not been shown convincingly to have clinically relevant immunomodulatory effects; in addition the virus-suppressive activity of lamivudine is limited in time by the progressive emergence of drug-resistant mutants.It is therefore logical to explore the efficacy of combination therapy of lamivudine and interferon in the hope to increase the virus-suppressive activity, to prevent the emergence of lamivudine resistant mutants, and to induce host immunity in all treated patients. The goal of therapy is a sustained response: HBV DNA<105 and ALT normalization 6–12 months after stopping treatment.In small but clearly defined subgroups of patients with chronic hepatitis B, interferon therapy is unlikely to be effective because of one or another form of immunodeficiency (dialysis, HIV, transplants). In others, interferon therapy is contraindicated because of the risk for toxicity (advanced cirrhosis, autoimmune disease, history of depression). For these patients combination therapy of lamivudine and a second drug active against lamivudine-resistant HBV (adefovir, entecavir) might lead to strong virus suppression in nearly all patients and prevention of emergence of drug resistant mutants. The goal of therapy is persistence of the response (HBV DNA<105 and ALT normal) by maintenance treatment. A summary of therapeutic outcome is given in Table 1.Table 1Limitations of current monotherapies addressed by combination therapiesTreatmentAntiviral activityImmune activationIFN+++LAM++−LAM+IFN++++++LAM+ADV+++−IFN, interferon; LAM, lamivudine; ADV, adefovir. Open table in a new tab 2. Current results of combination therapies2.1 Lamivudine–interferon combinations2.1.1 Selection of studies for reviewWe aimed at including all published large randomized trials (24 or more patients per arm) in compensated, immunocompetent chronic hepatitis B patients comparing the combination of lamivudine and interferon with standard lamivudine monotherapy (>100 mg daily for 52 weeks), standard interferon therapy (10 million units (MU) t.i.w. or 5 MU daily for 16–26 weeks) or placebo. In addition to four selected studies [1Schalm S.W Heathcote J Cianciara J Farrell G Sherman M Willems B et al.Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: a randomised trial.Gut. 2000; 46: 562-568Crossref PubMed Scopus (512) Google Scholar, 2Barbaro G Zechini F Pellicelli A.M Francavilla R Scotto G Bacca D 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: 406-411Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 3Schiff E.R Dienstag J.L Karayalcin S Grimm I.S Perillo R.P Husa P 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: 818-826Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar, 4Sanantonio T Niro G.A Sinisi E Leandro G Insalata M Pastore G et al.Lamivudine/interferon combination therapy in anti-HBe positive chronic hepatitis B: a controlled pilot study.J Hepatol. 2002; 36: 799-804Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar] cohort studies including 24 or more patients receiving lamivudine-interferon combination therapy were assessed [[5]Tatulli I Francavilla R Rizzo G.L Vinciguerra V Ierardi E Francavilla A et al.Lamivudine and alpha-interferon in combination for precore mutant chronic hepatitis B.J Hepatol. 2001; 35: 805-810Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar].Pre-treatment patient characteristics, especially virus levels and types, ALT levels and previous interferon therapy, have a major impact on treatment outcome. Therefore, different trials should only be compared after correction for baseline values.2.1.2 HBeAg-positive hepatitisThree large randomized controlled trials in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B have been carried out. In the first international study [[1]Schalm S.W Heathcote J Cianciara J Farrell G Sherman M Willems B et al.Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: a randomised trial.Gut. 2000; 46: 562-568Crossref PubMed Scopus (512) Google Scholar], 226 previously untreated patients were randomized to receive either combination therapy with lamivudine 100 mg daily and interferon-α 10 MU three times weekly for 16 weeks after pretreatment with lamivudine for 8 weeks (n=75), interferon-α 10 MU three times weekly for 16 weeks (n=69), or lamivudine 100 mg daily for 52 weeks (n=82). The primary efficacy endpoint was the HBeAg seroconversion rate at week 52 (loss of HBeAg, development of anti-HBe and undetectable HBV DNA).The HBeAg seroconversion rate at week 52 was 29% for combination therapy, 19% for interferon-α, and 18% for lamivudine monotherapy (P=0.10 and P=0.12, respectively, for comparison of combination therapy with interferon-α or lamivudine monotherapy, intention-to-treat analysis). The difference in the HBeAg seroconversion rate at week 52 between combination therapy and lamivudine monotherapy was statistically significant in the per-protocol analysis comprising 180 patients (36 vs. 19%, respectively; P=0.02). The authors concluded that the potential benefit of combining lamivudine with interferon should be investigated further in studies with different regimens of combination therapy.In the second published study Italian investigators [[2]Barbaro G Zechini F Pellicelli A.M Francavilla R Scotto G Bacca D 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: 406-411Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar] compared 24 weeks of interferon combination therapy with 52 weeks of lamivudine monotherapy in 151 patients with HBeAg positive chronic hepatitis B; 20 patients were non-responders to a previous course of interferon therapy. The study was completed by 94–96% of the patients, indicating an excellent tolerance of combination therapy. HBeAg seroconversion with undetectable levels of serum HBV DNA by hybridization testing was observed in 35% at the end of treatment for the combination therapy versus 19% for lamivudine monotherapy. Relapse of detectable HBeAg and HBV DNA was observed in 7% for combination therapy and 21% for lamivudine monotherapy. The sustained HBeAg seroconversion rate of 33% for combination therapy was – on an intention-to-treat basis – significantly better than that of lamivudine monotherapy (15%).Strong elements in the trial design are the longer duration of combination therapy (24 weeks), the assessment at the end of therapy (24 or 52 weeks) and at the end of follow-up (48 weeks later). The result from this trial further supports the concept of combining lamivudine and interferon for increasing the sustained response rate in HBeAg-positive chronic hepatitis B. However, the trial also reports findings which contrast with earlier observations. With lamivudine therapy the ALT normalization rate of 27% and the histological improvement in Knodell score also of 27% were remarkably lower than in other large studies. In addition, the overall sustained response rate was 33% and therefore not different from interferon alone. For treatment-naı̈ve patients further randomized controlled trials including interferon monotherapy are required before the clinical value of combining lamivudine and interferon can be assessed with confidence. One such a trial comparing 52 weeks of combination therapy with 52 weeks of (pegylated) interferon has included 300 patients; its results will be available in 2003.The third large randomized controlled trial [[3]Schiff E.R Dienstag J.L Karayalcin S Grimm I.S Perillo R.P Husa P 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: 818-826Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar] was performed in 238 chronic HBeAg-positive hepatitis B patients who had not responded to a previous course of interferon therapy. The HBeAg seroconversion rate (loss of HBeAg, development of anti-HBe and loss of HBV DNA) at 12 months after start of therapy was not statistically different for placebo (13%, n=56), lamivudine (18%, n=119) and combination therapy for 16 weeks after pretreatment with lamivudine for 8 weeks (12%, n=63). Combination therapy for 16 weeks appears of no value for this patient category.2.1.3 Anti-HBe-positive hepatitisThe fourth randomized controlled trial on lamivudine-interferon combination therapy [[4]Sanantonio T Niro G.A Sinisi E Leandro G Insalata M Pastore G et al.Lamivudine/interferon combination therapy in anti-HBe positive chronic hepatitis B: a controlled pilot study.J Hepatol. 2002; 36: 799-804Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar] comprised 50 patients with anti-HBe-positive chronic hepatitis B that were treated for 12 months with lamivudine 100 mg daily (n=26) or with lamivudine 100 mg daily+interferon 5 MU t.i.w. (n=24). At baseline, all patients were positive for HBV DNA by molecular hybridization and had elevated ALT levels. Twenty-one patients had previously been treated with interferon. All patients normalized ALT and became HBV DNA-negative by hybridization during treatment. When assessed by quantitative polymerse chain reaction (PCR), HBV DNA levels declined more during lamivudine-interferon than during lamivudine therapy. The rate of undetectable viremia was 54 and 27% at 2 months, and 83 and 62% at 6 months in lamivudine–interferon and lamivudine monotherapy, respectively. The response was maintained until the end of therapy in patients on lamivudine-interferon combination therapy; in contrast, five of 26 (20%) of patients on lamivudine alone had a virological and biochemical breakthrough due to selection of YMDD mutant HBV. After discontinuation of therapy, most patients relapsed; the sustained response at 18 months was 17% for lamivudine-interferon combination and 19% for lamivudine alone. Thus, the combination regimen appears to prevent or delay the emergence of YMDD mutant HBV, but a 12-month course does not increase the sustained response rate observed for monotherapy in a clinically significant way.A prospective pilot study in 29 consecutive anti-HBe/HBV DNA positive patients by another Italian group [[5]Tatulli I Francavilla R Rizzo G.L Vinciguerra V Ierardi E Francavilla A et al.Lamivudine and alpha-interferon in combination for precore mutant chronic hepatitis B.J Hepatol. 2001; 35: 805-810Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar] confirmed that 12 months of combination of lamivudine with interferon 6 MU t.i.w. is highly effective in inducing and maintaining virological and biochemical remission (93%). No YMDD mutant HBV was detected during combination therapy. However, the sustained response at 24 months was only 14%. Patients that were naı̈ve to antiviral treatment (n=11) had a similar relapse rate than patients previously been treated with interferon (n=18).2.2 Nucleoside-analogue combinations2.2.1 Selection of studies for reviewIn view of absence of published randomized trials we looked for large studies (24 or more patients per arm) assessing combination of lamivudine and another nucleoside analogue in chronic hepatitis B patients, published or published in abstract and presented at a major meeting. No large study comparing combination of two nucleoside-analogues with monotherapy was found. Studies reviewed below report on the effects of adefovir add-on to lamivudine in patients with chronic hepatitis B and acquired resistance to lamivudine [6Benhamou Y Bochet M Thibault V Calvez V Katlama C Poynard T et al.Safety and efficacy of adefovir dipivoxil in patients co-infected with HIV-1 and lamivudine-resistant hepatitis B virus: an open-label pilot study.Lancet. 2001; 358: 718-723Abstract Full Text Full Text PDF PubMed Scopus (300) Google Scholar, 7Perrillo R Schiff E Hann H.W.L Buti M Strasse S Watkins K.M et al.The addition of adefovir dipivoxil to lamivudine in decompensated chronic hepatitis B with YMDD variant HBV and reduced response to lamivudine.Hepatology. 2001; 34 Suppl: 349AGoogle Scholar, 8Schiff E.R Neuhaus P Tillmann H Samuel D Terrault N Marcellin P et al.Safety and efficacy of adefovir dipivoxil for the treatment of lamivudine resistant HBV in patients post liver transplantation.Hepatology. 2001; 34 Suppl: 446AGoogle Scholar].2.2.2 Lamivudine-resistant hepatitisAddition of adefovir to lamivudine has been evaluated in lamivudine-resistant chronic hepatitis B and either HIV/HBV co-infection, decompensated cirrhosis or HBV recurrence after liver transplantation.In the study in HIV/HBV co-infection [[6]Benhamou Y Bochet M Thibault V Calvez V Katlama C Poynard T et al.Safety and efficacy of adefovir dipivoxil in patients co-infected with HIV-1 and lamivudine-resistant hepatitis B virus: an open-label pilot study.Lancet. 2001; 358: 718-723Abstract Full Text Full Text PDF PubMed Scopus (300) Google Scholar], 35 patients on lamivudine therapy (150 mg twice daily) as part of their antiretroviral regimen and a rebound of HBV DNA and ALT due to a documented HBV mutation in the YMDD motif received adefovir 10 mg once daily for 48 weeks. The existing anti-HIV therapy was maintained. Suppression of HBV replication was observed in all patients. Mean HBV DNA levels fell from 108 to 105 at week 24 and 104 at week 48. HBeAg-seroconversion was observed in two of 33 patients (6%). Adverse effects were mild. ALT levels increased from week 8 until week 20, and then declined until week 48; the variability of ALT levels between patients at each time point was high. Increases in serum creatinine of greater than 44 μmol/l above baseline were seen in two patients; serum creatinine returned to baseline after adjustment of either adefovir or antiretroviral medication.In the study in advanced cirrhosis due to chronic hepatitis B [[7]Perrillo R Schiff E Hann H.W.L Buti M Strasse S Watkins K.M et al.The addition of adefovir dipivoxil to lamivudine in decompensated chronic hepatitis B with YMDD variant HBV and reduced response to lamivudine.Hepatology. 2001; 34 Suppl: 349AGoogle Scholar], 39 patients on lamivudine therapy (100 mg daily) with a virologic breakthrough due to confirmed YMDD mutant HBV received add-on adefovir 10 mg once daily. Preliminary results at 24 weeks showed a fall in mean HBV DNA from 108 to 105. All patients had a 2 log drop in serum HBV DNA and 30% a 4 log drop; in 15% of patients serum HBV DNA became negative by PCR. HBeAg-seroconversion was observed in five of 29 patients (16%). In many patients the suppression in HBV DNA was associated with improvements of ALT and clinical status. The Child–Pugh score decreased from 6 (range 5–10) to 5 (range 5–10); the mean change from baseline (0.8 points) was statistically significant (P<0.001). In addition to ALT normalization in about 50% of patients, significant improvements were observed in serum bilirubin and albumin (Table 2) . Adverse effects were infrequent. No increase in serum creatinine of 0.5 mg/dl was seen; there was a fatal exacerbation of hepatitis B at week 16 and one patient had variceal bleeding.Table 2Adefovir add-on therapy associated improvement in biochemical outcome measuresLiver function parametersPercentage abnormal testsBaselineWeek 24Bilirubin3818Albumin5126Prothrombin time5141Alanine aminotransferase9549 Open table in a new tab In the third study [[8]Schiff E.R Neuhaus P Tillmann H Samuel D Terrault N Marcellin P et al.Safety and efficacy of adefovir dipivoxil for the treatment of lamivudine resistant HBV in patients post liver transplantation.Hepatology. 2001; 34 Suppl: 446AGoogle Scholar], 131 patients post orthotopic liver transplantation with chronic hepatitis B and clinical lamivudine resistance (HBV DNA>106 and elevated serum ALT) received adefovir 10 mg once daily added to the background therapy; the treatment period was indefinite. The dose of adefovir was adjusted to changes in creatinine clearance and immunosuppressant related nephrotoxicity. Results at 24 and 48 weeks on serum HBV DNA and liver function (Table 2) were very similar to those described in the two earlier studies and confirmed the efficacy of additional adefovir in immunosuppressed patients with lamivudine-resistant chronic hepatitis B.The beneficial effects were also observed in patients with significant co-morbidity like renal impairment, hepatic decompensation, inadequate hematologic function, or HDV, HCV, HIV co-infection. Adverse effects were mainly nephrotoxicity with 10–20% of patients showing a rise in serum creatinine of more than 0.5 mg/dl. The clinical improvement observed in these three studies has made the addition of adefovir to lamivudine the combination of choice for patients with serious liver disease and lamivudine failure.3. Novel developments3.1 Selection of studies for reviewFrom the Pub-Med file with key words lamivudine, interferon and hepatitis, pilot studies which pointed to potential novel developments were selected for assessment; to identify potential clinically important developments in nucleoside combination therapy we also looked for pilot studies published in abstract form and presented at a major hepatology meeting.3.2 Sequential lamivudine-interferon combinationIn a French pilot study [[9]Serfaty L Thabut D Zoulim F Andrean T Chazouillères O Carbonell N et al.Sequential treatment with lamivudine and interferon monotherapies in patients with chronic hepatitis B not responding to interferon alone: results of a pilot study.Hepatology. 2001; 34: 573-577Crossref PubMed Scopus (90) Google Scholar] in 14 HBV DNA-positive patients without a sustained response to interferon alone, lamivudine monotherapy 100 mg once daily for 20 weeks was combined with interferon 5 MU t.i.w. for 4 weeks, and followed by interferon monotherapy for 24 weeks. Sustained serum HBV DNA clearance 6 months after the end of sequential treatment was observed in 8/14 patients (56%), HBeAg to anti-HBe seroconversion in 5/11 patients (45%), and hepatitis B surface antigen (HBsAg) to anti-HBs seroconversion in 3/14 patients (21%). Since a similar Dutch study in 24 patients (van Nunen, unpublished observations) led to a sustained HBeAg response in only two of 20 patients that completed therapy (10%), further evaluation in clinical trials of adequate size should be undertaken.3.3 Lamivudine plus intradermal vaccine with or without interleukin-2 (IL-2)To evaluate therapeutic immunostimulation 14 chronic hepatitis B patients with HBV DNA detectable by hybridization received daily lamivudine in combination with six monthly intradermal vaccinations with HBsAg; five patients received in addition IL-2 daily for 3 months [[10]Dahmen A Herzog-Hauff S Bocher W.O Galle P.R Lohr H.F Clinical and immunological efficacy of intradermal vaccine plus lamivudine with or without interleukin-2 in patients with chronic hepatitis B.J Med Virol. 2002; 66: 452-460Crossref PubMed Scopus (62) Google Scholar]. After therapy was stopped, seven of nine lamivudine/vaccine recipients and two of five lamivudine/vaccine/IL-2 recipients did not have detectable HBV DNA. Four patients (28%) cleared the virus and had normalized ALT levels during follow-up. Compared to 11 control patients receiving lamivudine alone, patients receiving immunostimulation had a significant rise in hepaitis B core antigen (HBcAg)-specific proliferative T-helper cell response; however, the hepatitis B-specific T-helper cell induction failed to induce a sustained B-cell response as detected by ELISPOT.Combination of nucleoside analogues with vaccine should be evaluated for the established outcome measures at the end of treatment and end of 6–12 months of follow-up in controlled trials.3.4 Lamivudine–adefovir combination versus adefovir aloneA randomized trial is ongoing comparing adefovir 10 mg daily, adefovir 10 mg daily+lamivudine 100 mg daily, and lamivudine 100 mg daily in patients with lamivudine-resistant chronic hepatitis B. In a preliminary report [[11]Peters M Hann H.W Martin P Heathcote E Buggisch P Moorat A.E et al.Adefovir dipivoxil (ADV) alone and in combination with lamivudine (LAM) suppresses lam-resistant hepatitis B virus (HBV) replication: 16 week interim analysis.J Hepatol. 2002; 36 Suppl: 6-7Abstract Full Text PDF Google Scholar] on results at 16 weeks, adefovir-containing regimens show significant reductions in HBV DNA and ALT levels in contrast to no change in the lamivudine alone group. There appears also no difference in these outcome measures between adefovir alone and lamivudine-adefovir. This study points clearly to the need of further assessment of nucleoside-analogue combination therapy vs. monotherapy in chronic hepatitis B.4. Summary and recommendationsThe combination of lamivudine and interferon has now been proven to be significantly more effective than either treatment alone in naı̈ve, HBeAg-positive, immunocompetent patients with compensated chronic hepatitis B. Combination therapy leads to a higher percentage of viral, biochemical and histological remission and to a lower percentage of lamivudine resistance on treatment. Available evidence suggests that the effects of combination therapy on virological, biochemical and histological outcomes on treatment are similar in other subgroups of chronic hepatitis B like anti-HBe-positive chronic hepatitis B and in those not having responded to a previous course of antiviral therapy. However, the goal of combining a virus suppressant with an activator of host immunity is to increase the rate of sustained remission significantly; at present there is insufficient evidence that this goal has been reached. Therefore, at present the combination of lamivudine with interferon cannot be recommended outside of clinical trials.For both HBeAg-positive and anti-HBe-positive chronic hepatitis B the results of ongoing large trials assessing combination therapy of lamivudine with pegylated interferon for 6–12 months will be forthcoming in 2003.Further assessment of the combination of nucleoside analogues with pegylated interferon is recommended. Drug regimens should aim for induction of loss of HBV DNA negativity (by PCR) by week 26 and continuation of combination therapy for another 6 months. Discovery of a drug that significantly reduces the relapse rate would bring about the long-awaited improvement in sustained response rates in immunocompetent patients with compensated chronic hepatitis B.For lamivudine-resistant chronic hepatitis B, addition of adefovir to lamivudine is effective in suppressing viral replication and in reducing hepatitis activity, both in immunodeficient and decompensated chronic hepatitis B. It appears likely that the goal of therapy (persistence of the response with HBV DNA<105 and normal ALT) can be maintained long-term, because resistance to lamivudine-adefovir occurs only rarely according to current studies.However, there is no evidence that a combination of lamivudine and adefovir is superior to adefovir alone. Thus addition of adefovir to lamivudine is recommended for immunodeficient or decompensated chronic hepatitis B; for others, at present the combination of two nucleoside analogues cannot be recommended outside of clinical trials. 1. Rationale for combination therapyAmong the approximately 350 million individuals with chronic hepatitis B infection in the world, up to 50% (175 million) may have chronic hepatitis B-related symptoms or signs; in comparison, the number of people infected with human immunodeficiency virus (HIV) is estimated to be 60 million. Nearly all clinical conditions – chronic hepatitis progressing to cirrhosis; cirrhosis with active hepatitis at risk for variceal bleeding, ascites, and hepatocellular carcinoma; chronic hepatitis with high viremia at risk for transmitting HBV; chronic hepatitis B with extrahepatic complications – require treatment. However, monotherapy with either a standard course of 16–26 weeks of interferon-α or 1 year of lamivudine is effective in only a minority of patients. So, current regimens are inadequate for 60–90% of patients with chronic hepatitis B in need of therapy. In view of the low efficacy in relation to costs, the pressure to massively implement antiviral therapy in chronic hepatitis B has been restrained. To reduce the morbidity and mortality of chronic hepatitis B, more effective therapies have to be developed.For most patients an effective response is based upon profound suppression of hepatitis B virus (HBV) DNA, followed by alanine aminotransferase (ALT) normalization, whereas a sustained response requires an additional induction of host immunity. Interferon has only mild to moderate virus-suppressive activity but can induce an effective host immune response in susceptible patients. In contrast, lamivudine has marked virus-suppressive activity in the majority of patients but has not been shown convincingly to have clinically relevant immunomodulatory effects; in addition the virus-suppressive activity of lamivudine is limited in time by the progressive emergence of drug-resistant mutants.It is therefore logical to explore the efficacy of combination therapy of lamivudine and interferon in the hope to increase the virus-suppressive activity, to prevent the emergence of lamivudine resistant mutants, and to induce host immunity in all treated patients. The goal of therapy is a sustained response: HBV DNA<105 and ALT normalization 6–12 months after stopping treatment.In small but clearly defined subgroups of patients with chronic hepatitis B, interferon therapy is unlikely to be effective because of one or another form of immunodeficiency (dialysis, HIV, transplants). In others, interferon therapy is contraindicated because of the risk for toxicity (advanced cirrhosis, autoimmune disease, history of depression). For these patients combination therapy of lamivudine and a second drug active against lamivudine-resistant HBV (adefovir, entecavir) might lead to strong virus suppression in nearly all patients and prevention of emergence of drug resistant mutants. The goal of therapy is persistence of the response (HBV DNA<105 and ALT normal) by maintenance treatment. A summary of therapeutic outcome is given in Table 1.Table 1Limitations of current monotherapies addressed by combination therapiesTreatmentAntiviral activityImmune activationIFN+++LAM++−LAM+IFN++++++LAM+ADV+++−IFN, interferon; LAM, lamivudine; ADV, adefovir. Open table in a new tab Among the approximately 350 million individuals with chronic hepatitis B infection in the world, up to 50% (175 million) may have chronic hepatitis B-related symptoms or signs; in comparison, the number of people infected with human immunodeficiency virus (HIV) is estimated to be 60 million. Nearly all clinical conditions – chronic hepatitis progressing to cirrhosis; cirrhosis with active hepatitis at risk for variceal bleeding, ascites, and hepatocellular carcinoma; chronic hepatitis with high viremia at risk for transmitting HBV; chronic hepatitis B with extrahepatic complications – require treatment. However, monotherapy with either a standard course of 16–26 weeks of interferon-α or 1 year of lamivudine is effective in only a minority of patients. So, current regimens are inadequate for 60–90% of patients with chronic hepatitis B in need of therapy. In view of the low efficacy in relation to costs, the pressure to massively implement antiviral therapy in chronic hepatitis B has been restrained. To reduce the morbidity and mortality of chronic hepatitis B, more effective therapies have to be developed. For most patients an effective response is based upon profound suppression of hepatitis B virus (HBV) DNA, followed by alanine aminotransferase (ALT) normali" @default.
W2051277974 created "2016-06-24" @default.
W2051277974 creator A5034065954 @default.
W2051277974 date "2003-01-01" @default.
W2051277974 modified "2023-09-23" @default.
W2051277974 title "Combination therapy for chronic hepatitis B" @default.
W2051277974 cites W1980874631 @default.
W2051277974 cites W1994449949 @default.
W2051277974 cites W2056089018 @default.
W2051277974 cites W2069934268 @default.
W2051277974 cites W2112145547 @default.
W2051277974 cites W2146778260 @default.
W2051277974 cites W2147194699 @default.
W2051277974 cites W2149337924 @default.
W2051277974 cites W2149836081 @default.
W2051277974 doi "https://doi.org/10.1016/s0168-8278(03)00352-0" @default.
W2051277974 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/14708694" @default.
W2051277974 hasPublicationYear "2003" @default.
W2051277974 type Work @default.
W2051277974 sameAs 2051277974 @default.
W2051277974 citedByCount "17" @default.
W2051277974 countsByYear W20512779742016 @default.
W2051277974 crossrefType "journal-article" @default.
W2051277974 hasAuthorship W2051277974A5034065954 @default.
W2051277974 hasBestOaLocation W20512779741 @default.
W2051277974 hasConcept C159047783 @default.
W2051277974 hasConcept C2522874641 @default.
W2051277974 hasConcept C3020491458 @default.
W2051277974 hasConcept C71924100 @default.
W2051277974 hasConceptScore W2051277974C159047783 @default.
W2051277974 hasConceptScore W2051277974C2522874641 @default.
W2051277974 hasConceptScore W2051277974C3020491458 @default.
W2051277974 hasConceptScore W2051277974C71924100 @default.
W2051277974 hasLocation W20512779741 @default.
W2051277974 hasLocation W20512779742 @default.
W2051277974 hasOpenAccess W2051277974 @default.
W2051277974 hasPrimaryLocation W20512779741 @default.
W2051277974 hasRelatedWork W2359884894 @default.
W2051277974 hasRelatedWork W2366237216 @default.
W2051277974 hasRelatedWork W2418867336 @default.
W2051277974 hasRelatedWork W2463471700 @default.
W2051277974 hasRelatedWork W2622038044 @default.
W2051277974 hasRelatedWork W2971401778 @default.
W2051277974 hasRelatedWork W3047213975 @default.
W2051277974 hasRelatedWork W3207911508 @default.
W2051277974 hasRelatedWork W401483725 @default.
W2051277974 hasRelatedWork W4281762544 @default.
W2051277974 hasVolume "39" @default.
W2051277974 isParatext "false" @default.
W2051277974 isRetracted "false" @default.
W2051277974 magId "2051277974" @default.
W2051277974 workType "article" @default.