RECORD STATUS:

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CITATION:

National Institute for Health and Clinical Excellence. Adefovir dipivoxil and peginterferon alfa-2a for the treatment of chronic hepatitis B. London: National Institute for Health and Clinical Excellence (NICE). Technology Appraisal Guidance 96. 2006

Adefovir dipivoxil (ADV) is an effective antiviral drug against hepatitis B virus. The renal tolerance of ADV at the currently approved dose of 10 mg daily for the treatment of chronic hepatitis B (CHB) remains controversial. The present meta-analysis was therefore performed to evaluate the renal safety of ADV treatment in patients with CHB. Two independent investigators searched MEDLINE, Embase and China National Knowledge Infrastructure databases for eligible studies published in English or Chinese until June 1, 2014. The Peto odds ratios (Peto ORs) or the rates of each study were analyzed. Seven randomized controlled trials (RCTs), four cohort studies and six single-arm studies were identified. ADV treatment was not associated with a higher incidence of nephrotoxicity in RCTs [Peto OR, 1.781; 95% confidence interval (CI), 0.637-4.979; P=0.271] but appeared to increase nephrotoxicity significantly in cohort studies (Peto OR, 2.682; 95% CI, 1.470-4.894; P=0.001); the significant increase was further observed in CHB patients receiving longterm ADV treatment in cohort studies (Peto OR, 2.275; 95% CI, 1.127-4.593; P=0.022). The analysis based on single-arm studies showed that the rate of renal dysfunction in the ADV-treated patients was 10.6% (95% CI, 0.059-0.185); the subgroup analysis with the standard of createnine levels showed a lower rate (6.9%, 95% CI, 0.013-0.298) than those in the overall studies. In conclusion, although current evidence indicated a positive link between treatment with ADV in CHB patients and an increased risk of renal dysfunction, optimally designed studies are required for definitive conclusions.

BACKGROUND:

Adefovir dipivoxil, a nucleotide analogue, demonstrated clinically significant antiviral activity in patients with chronic hepatitis B in phase 1 and 2 clinical trials.

METHODS:

We randomly assigned 185 patients with chronic hepatitis B who were negative for hepatitis B e antigen (HBeAg) to receive either 10 mg of adefovir dipivoxil or placebo once daily for 48 weeks in a 2:1 ratio and a double-blind manner. The primary end point was histologic improvement.

RESULTS:

At week 48, 64 percent of patients who had base-line liver-biopsy specimens available in the adefovir dipivoxil group had improvement in histologic liver abnormalities (77 of 121), as compared with 33 percent of patients in the placebo group (19 of 57, P<0.001). Serum hepatitis B virus (HBV) DNA levels were reduced to fewer than 400 copies per milliliter in 51 percent of patients in the adefovir dipivoxil group (63 of 123) and in 0 percent of those in the placebo group (0 of 61, P<0.001). The median decrease in log-transformed HBV DNA levels was greater with adefovir dipivoxil treatment than with placebo (3.91 vs. 1.35 log copies per milliliter, P<0.001). Alanine aminotransferase levels had normalized at week 48 in 72 percent of patients receiving adefovir dipivoxil (84 of 116), as compared with 29 percent of those receiving placebo (17 of 59, P<0.001). No HBV polymerase mutations associated with resistance to adefovir were identified. The safety profile of adefovir dipivoxil was similar to that of placebo.

CONCLUSIONS:

In patients with HBeAg-negative chronic hepatitis B, 48 weeks of adefovir dipivoxil treatment resulted in significant histologic, virologic, and biochemical improvement, with an adverse-event profile similar to that of placebo. There was no evidence of the emergence of adefovir-resistant HBV polymerase mutations.

BACKGROUND:

In preclinical and phase 2 studies, adefovir dipivoxil demonstrated potent activity against hepatitis B virus (HBV), including lamivudine-resistant strains.

METHODS:

We randomly assigned 515 patients with chronic hepatitis B who were positive for hepatitis B e antigen (HBeAg) to receive 10 mg of adefovir dipivoxil (172 patients), 30 mg of adefovir dipivoxil (173), or placebo (170) daily for 48 weeks. The primary end point was histologic improvement in the 10-mg group as compared with the placebo group.

RESULTS:

After 48 weeks of treatment, significantly more patients who received 10 mg or 30 mg of adefovir dipivoxil per day than who received placebo had histologic improvement (53 percent [P<0.001], 59 percent [P<0.001], and 25 percent, respectively), a reduction in serum HBV DNA levels (by a median of 3.52 [P<0.001], 4.76 [P<0.001], and 0.55 log copies per milliliter, respectively), undetectable levels (fewer than 400 copies per milliliter) of serum HBV DNA (21 percent [P<0.001], 39 percent [P<0.001], and 0 percent, respectively), normalization of alanine aminotransferase levels (48 percent [P<0.001], 55 percent [P<0.001], and 16 percent, respectively), and HBeAg seroconversion (12 percent [P=0.049], 14 percent [P=0.01], and 6 percent, respectively). No adefovir-associated resistance mutations were identified in the HBV DNA polymerase gene. The safety profile of the 10-mg dose of adefovir dipivoxil was similar to that of placebo; however, there was a higher frequency of adverse events and renal laboratory abnormalities in the group given 30 mg of adefovir dipivoxil per day.

CONCLUSIONS:

In patients with HBeAg-positive chronic hepatitis B, 48 weeks of 10 mg or 30 mg of adefovir dipivoxil per day resulted in histologic liver improvement, reduced serum HBV DNA and alanine aminotransferase levels, and increased the rates of HBeAg seroconversion. The 10-mg dose has a favorable risk-benefit profile for long-term treatment. No adefovir-associated resistance mutations were identified in the HBV DNA polymerase gene.

BACKGROUND:

Treatment with adefovir dipivoxil for 48 weeks resulted in histologic, virologic, and biochemical improvement in patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B. We evaluated the effect of continued therapy as compared with cessation of therapy.

METHODS:

One hundred eighty-five HBeAg-negative patients with chronic hepatitis B were assigned to receive 10 mg of adefovir dipivoxil or placebo once daily for 48 weeks (ratio, 2:1). After week 48, patients receiving adefovir dipivoxil were again randomly assigned either to receive an additional 48 weeks of the drug or to switch to placebo. Patients originally assigned to placebo were switched to adefovir dipivoxil. Patients treated with adefovir dipivoxil during weeks 49 through 96 were subsequently offered continued therapy. The primary end points were changes in hepatitis B virus (HBV) DNA and alanine aminotransferase levels.

RESULTS:

Treatment with adefovir dipivoxil resulted in a median decrease in serum HBV DNA of 3.47 log copies per milliliter (on a base-10 scale) at 96 weeks and 3.63 log copies per milliliter at 144 weeks. HBV DNA levels were less than 1000 copies per milliliter in 71 percent of patients at week 96 and 79 percent at week 144. In the majority of patients who were switched from adefovir dipivoxil to placebo, the benefit of treatment was lost (median change in HBV DNA levels from baseline, -1.09 log copies per milliliter; only 8 percent of patients had levels below 1000 copies per milliliter at week 96). Side effects during weeks 49 through 144 were similar to those during the initial 48 weeks. Resistance mutations rtN236T and rtA181V were identified in 5.9 percent of patients after 144 weeks.

CONCLUSIONS:

In patients with HBeAg-negative chronic hepatitis B, the benefits achieved from 48 weeks of adefovir dipivoxil were lost when treatment was discontinued. In patients treated for 144 weeks, benefits were maintained, with infrequent emergence of viral resistance.

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Standard treatments for chronic hepatitis B (CHB) include interferon-alpha (IFN-alpha) and lamivudine (LAM), but these are associated with adverse effects and viral resistance, respectively. The aim of this systematic review and economic evaluation was to assess the clinical effectiveness and cost-effectiveness of two alternative drugs for the treatment of adults with

CHB:

adefovir dipivoxil (ADV) and pegylated IFN-alpha-2a. We searched electronic databases, including Cochrane Systematic Reviews and Medline, for literature that met criteria defined in a research protocol. Retrieved articles were independently assessed for inclusion by two reviewers. We developed a Markov state transition model to estimate the cost-effectiveness (cost-utility) of pegylated IFN-alpha-2a and of ADV compared with nonpegylated IFN-alpha-2a, LAM and best supportive care. Seven randomized controlled trials and two systematic reviews met the inclusion criteria for our review of clinical effectiveness. ADV was significantly more effective than placebo or ongoing LAM in reducing levels of hepatitis B virus (HBV) DNA. Rates of hepatitis B e antigen (HBeAg) seroconversion were higher among patients receiving ADV than either placebo or ongoing LAM. Patients treated with pegylated IFN-alpha-2a, either as monotherapy or in combination with LAM, showed significantly reduced HBV DNA levels compared with patients treated with LAM monotherapy. HBeAg seroconversion rates at follow-up were significantly higher for pegylated IFN-alpha-2a patients than for those receiving LAM monotherapy. Results of our cost-effectiveness analysis demonstrate that incremental costs per quality adjusted life year (QALY) for a range of comparisons were between 5,994 and 16,569 British Pound, and within the range considered by NHS decision-makers to represent good value for money.

Objective: To update and extend a 2006 report on the clinical effectiveness and cost-effectiveness of adefovir dipivoxil (ADV) and pegylated interferon alpha (PEG-α) for the treatment of chronic hepatitis B (CHB). Data sources: Thirteen bibliographic databases were searched including MEDLINE, EMBASE and the Cochrane Library. Searches were run from the beginning of 2005 to September 2007. Review methods: For the clinical effectiveness review, randomised controlled trials (RCTs) comparing ADV PEG-α-2a and PEG-α-2b with currently licensed treatments for CHB, including non-pegylated interferon alpha (IFN-α) and lamivudine (LAM), were included. Outcomes included biochemical, histological and virological response to treatment, drug resistance and adverse effects. A systematic review of economic evaluations of antiviral treatments for CHB was conducted. The economic Markov model used in the 2006 report was updated in terms of utility values, discount rates and costs. Results: Of the 82 papers retrieved for detailed screening, eight RCTs were included. Three evaluated ADV, four evaluated PEG-α-2b and one (from the original literature search) compared PEG-α-2b plus LAM with PEG-α-2b monotherapy. No RCTs of PEG-α-2a were identified. One ADV trial showed a statistically significant difference between ADV and placebo in terms of ALT response and HBV DNA levels, favouring ADV. Following withdrawal of ADV levels were similar to those in placebo patients. In the ADV versus ADV plus LAM trial, there was a statistically significant difference in favour of the combination treatment. In the PEG-α trials, there were statistically significant differences favouring PEG-α-2b plus LAM compared with either one of the drugs given as monotherapy. For the comparison between PEG-α-2b and IFN-α and the comparison between different staggered regimens of the commencement of PEG-α-2b and LAM, there were no statistically significant differences between groups. Four full economic evaluations were identified, in addition to one identified in the original report. Two assessed PEG-a-2a; the remainder assessed ADV. PEG-α-2a was associated with increased treatment costs and gains in quality-adjusted life expectancy. In a UK study, the incremental cost-effectiveness ratio (ICER) for PEG-α-2a was £10,444 per QALY gained compared with LAM. Evaluations of ADV found that LAM monotherapy was dominated; the ICER for ADV monotherapy compared with 'doing nothing' was $19,731. The results of the updated analysis were generally robust to changes in deterministic sensitivity analysis. In a probabilistic sensitivity analysis, the same sequence of treatments was identified as optimal. In a probabilistic sensitivity analysis, PEG-α-2b had a probability of being cost-effective of 79% at a willingness-to-pay threshold of £20,000 per QALY, and 86% at a willingness-to-pay threshold of £30,000 per QALY. Conclusions: Both ADV and PEG-α are beneficial for patients with CHB in terms of suppressing viral load, reducing liver damage-associated biochemical activity, inducing HBeAg seroconversion, and reducing liver fibrosis and necroinflammation. The effects of long-term treatment with ADV are generally durable, with relatively low rates of resistance. In most cases, cost-effectiveness estimates were within acceptable ranges. Further research should assess the clinical effectiveness and cost-effectiveness of newer antiviral agents in relation to existing drugs, including the role of initiating treatment with combination therapy. © 2009 Queen's Printer and Controller of HMSO. All rights reserved.

OBJECTIVES:

To assess the clinical effectiveness and cost-effectiveness of adefovirdipivoxil (ADV) and pegylated interferon alfa-2a (PEG) for the treatment of adults with chronic hepatitis B infection (CHB).

DATA SOURCES:

Electronic databases for the period from 1995-6 to April 2005. Websites of the relevant organisations.

REVIEW METHODS:

Searches were made for studies of clinical effectiveness, cost-effectiveness, quality of life, resource use/costs and epidemiology/natural history. Randomised controlled trials (RCTs) were included that compared PEG and ADV with currently licensed treatments for CHB, including non-pegylated ('standard') interferon alfa (IFN), lamivudine (LAM), and best supportive care. The trials were reviewed in a narrative synthesis but meta-analysis was not undertaken owing to heterogeneity in the interventions and comparators evaluated. A model was developed to estimate the cost-effectiveness (cost--utility) of PEG and of ADV compared with IFN, LAM and best supportive care in a UK cohort of adults with CHB. The perspective of the cost-effectiveness analysis was that of the NHS and personal social services. A Markov state transition model was constructed, informed by a systematic search of the literature to identify source material on the natural history, epidemiology and treatment of CHB. Interventions were evaluated against their closest comparator (for PEG this is IFN, and for ADV this is LAM). In addition, the cost-effectiveness of sequential treatment scenarios was modelled.

RESULTS:

A total of 1086 references to clinical effectiveness studies were identified, of which seven fully published RCTs and one systematic review met the inclusion criteria. Four of the RCTs evaluated the effectiveness of ADV and three reported results for PEG. In addition, a conference abstract was included reporting interim results from an on-going Phase II RCT of ADV in combination with LAM. The published trials were of good quality, although details of randomisation and allocation of concealment were poorly reported. ADV was significantly more effective than placebo. Response rates were in the range 21-51% compared with 0%, respectively. For patients resistant to LAM, response rates were significantly higher for those treated with ADV in addition to on-going LAM (35-85%) than those who continued on LAM with placebo (0-11%). Significant alanineaminotransferase (ALT) reductions to normal levels were observed in all studies. For treatment-naive patients, seroconversion rates were 12-14% for ADV compared with 6% for placebo (statistically significant), rates were higher for LAM-resistant patients who received ADV in addition to on-going LAM (8%) than those who continued on LAM with placebo (2%) (no significance value was reported), and rates were higher for LAM-resistant patients who switched to ADV than those who continued on LAM with placebo (11 versus 0%, respectively; not statistically significant). HBsAg loss or seroconversion was observed in less than 5% of patients taking ADV. Two ADV studies reported changes in liver histology. In general, histological improvement and necroinflammatory activity/fibrosis scores were significantly better in ADV groups than in placebo groups. Dose discontinuations for safety reasons were low for patients receiving ADV. With the exception of headache, the most commonly reported adverse events were often seen in the placebo groups in similar proportions to the ADV groups, with different trials reporting conflicting results. PEG/LAM dual therapy and PEG monotherapy were similar in effect on HBV DNA and ALT levels, and both were significantly superior to LAM monotherapy. Response rates were higher for HBeAg-negative patients than for HBeAg-positive patients. HBeAg seroconversion rates at follow-up were significantly higher for PEG monotherapy patients than for those receiving either a combination of PEG and LAM or LAM monotherapy (32, 27 and 19%, respectively). For the comparison between PEG and IFN-2a, there was a significant difference in the combined outcome of ALT normalisation, HBV DNA response and HBeAgseroconversion at follow-up (24 versus 12%, respectively). Changes in liver histology were reported by two studies. There was no statistically significant difference in histological improvement between the PEG monotherapy groups, the LAM monotherapy groups and the dual therapy groups. Two PEG trials reported small percentages (up to 5%) of HBsAg loss or seroconversion among patients receiving PEG either as monotherapy or in combination with LAM, but no HBsAg loss or seroconversion was reported in those receiving LAM monotherapy. Health-related quality of life (HRQoL) scores, as measured by the Short Form with 36 Items, decreased during treatment, but returned to at least baseline levels at follow-up (based on unpublished data). For HBeAg-positive patients, there were no significant differences in scores between treatment groups. Dose discontinuations for safety reasons were significantly higher for patients receiving PEG than for patients receiving LAM monotherapy. The most commonly reported adverse events in the PEG studies were headache, pyrexia, fatigue, myalgia and alopecia. Only one fully published economic evaluation was identified, reporting a US cost-effectiveness study of ADV as salvage therapy for chronic hepatitis B with LAM resistance. A Markov model was used to estimate cost-effectiveness of interferon alfa (6-12 months), LAM and LAM followed by ADV when resistance occurs. ADV generated the most (undiscounted) life-years, but at highest costs, with an incremental cost-effectiveness ratio (ICER) of US$14,204 per life-year gained. Using our model, incremental cost per QALY estimates (baseline cohort of all patients) were: pound5994 for IFN compared with best supportive care, pound6119 for PEG compared with IFN, pound3685 for LAM compared with best supportive care, and pound16,569 for ADV compared with LAM. Incremental cost per QALY estimates (HBeAg-positive patients only) were: pound7936 for IFN (24 weeks) compared with best supportive care, pound16,166 for PEG (48 weeks) compared with IFN (24 weeks), pound3489 for LAM compared with best supportive care, and pound15,289 for ADV compared with LAM. Incremental cost per QALY estimates (HBeAg-negative patients only) were: pound3922 for IFN (48 weeks) compared with best supportive care, pound2162 for PEG (48 weeks) compared with IFN (24 weeks), pound4131 for LAM compared with best supportive care, and pound18,620 for ADV compared with LAM. For the sequential treatment strategies, incremental cost per QALY estimates ranged from pound3604 (IFN followed by LAM versus IFN alone) to pound11,402 (IFN followed by LAM with adefovir salvage versus IFN followed by LAM). In all of these cases, the ICERs are well within the range that would conventionally be regarded as being cost-effective. The probabilistic sensitivity analysis found that LAM is a cost-effective option at lower willingness-to-pay thresholds for health outcomes, but as the threshold is increased adefovir is increasingly likely to be the optimal intervention. Where a willingness-to-pay threshold of above pound10,000 per QALY is employed, PEG is highly likely to be the optimal intervention compared with IFN (based on a cohort of HBeAg-positive and -negative patients). Interferon alfa (non-pegylated or pegylated) followed by LAM would be the optimal strategy at lower willingness-to-pay thresholds. As the threshold increases, the sequential treatment strategy of PEG followed by LAM with adefovir added as salvage therapy is increasingly likely to be the optimal intervention.

CONCLUSIONS:

ADV and PEG are associated with significant improvements in a number of biochemical, virological and histological outcomes in both HBeAg-positive and -negative patients. For a small proportion of patients this is associated with resolution of infection. For another proportion it leads to remission and a reduced risk of progressing to cirrhosis, hepatocellular carcinoma, liver transplant and death. For others who do not respond or who relapse, retreatment with another agent is necessary. The results of our cost-effectiveness analysis demonstrate that incremental costs per QALY for a range of comparisons were between pound5994 and pound16,569 and within the range considered by NHS decision-makers to represent good value for money. When subjected to sensitivity analysis, most costs per QALY estimates remained under pound30,000. Further RCT evidence of the effectiveness of anti-viral treatment is required, particularly for subgroups of patients with different genotypes, patients with cirrhosis, patients from different ethnic groups, patients with co-infections (e.g. HIV, HCV) and co-morbidities, liver transplant patients and children and adolescents. Executive summary and full-text available for free by visiting the document URL listed with this record

Background & Aims: Adefovir dipivoxil possesses potent in vitro and in vivo antiviral activity in wild-type hepatitis B. This study assessed the safety and efficacy of adefovir dipivoxil alone and in combination with lamivudine compared with ongoing lamivudine therapy in patients with chronic hepatitis B with compensated liver disease and lamivudine-resistant hepatitis B virus (HBV). Methods: Fifty-nine hepatitis B e antigen (HBeAg)-positive patients with genotypic evidence of lamivudine-resistant HBV, serum alanine aminotransferase (ALT) level ≥1.2 times the upper limit of normal, and serum HBV DNA level ≥6 log10 copies/mL despite ongoing treatment with lamivudine were randomized to adefovir dipivoxil 10 mg, lamivudine 100 mg, or addition of adefovir dipivoxil to ongoing lamivudine daily. The primary end point was the time-weighted average change from baseline in serum HBV DNA level (DAVG) up to week 16. Results: Rapid reductions in serum HBV DNA level were seen by 4 weeks in all recipients of adefovir dipivoxil; DAVG16 was -0.07 in the lamivudine group compared with -2.45 and -2.46 log10 copies/mL in the adefovir dipivoxil/lamivudine and adefovir dipivoxil monotherapy groups, respectively (P < 0.001). Median change from baseline in serum HBV DNA level at week 48 was 0.0, -3.59, and -4.04 log10 copies/mL in the lamivudine, adefovir dipivoxil/lamivudine, and adefovir dipivoxil groups, respectively. ALT level 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 hepatitis B surface antigen negative. Conclusions: 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.