Adefovir dipivoxil and pegylated interferon alfa-2a for the treatment of chronic hepatitis B: a systematic review and economic evaluation.
OBJECTIVE
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).


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


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 alanine aminotransferase (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 HBeAg seroconversion 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: 5994 pounds for IFN compared with best supportive care, 6119 pounds for PEG compared with IFN, 3685 pounds for LAM compared with best supportive care, and 16,569 pounds for ADV compared with LAM. Incremental cost per QALY estimates (HBeAg-positive patients only) were: 7936 pounds for IFN (24 weeks) compared with best supportive care, 16,166 pounds for PEG (48 weeks) compared with IFN (24 weeks), 3489 pounds for LAM compared with best supportive care, and 15,289 pounds for ADV compared with LAM. Incremental cost per QALY estimates (HBeAg-negative patients only) were: 3922 pounds for IFN (48 weeks) compared with best supportive care, 2162 pounds for PEG (48 weeks) compared with IFN (24 weeks), 4131 pounds for LAM compared with best supportive care, and 18,620 pounds for ADV compared with LAM. For the sequential treatment strategies, incremental cost per QALY estimates ranged from 3604 pounds (IFN followed by LAM versus IFN alone) to 11,402 pounds (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 10,000 pounds 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 5994 pounds and 16,569 pounds 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 30,000 pounds. 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.
Shepherd
J
J
Southampton Health Technology Assessments Centre, UK.
Jones
J
J
Takeda
A
A
Davidson
P
P
Price
A
A
D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000191:economics / Q000627:therapeutic use; D000998:Antiviral Agents / Q000008:administration & dosage / Q000191:economics* / Q000627:therapeutic use*; D003362:Cost-Benefit Analysis; D004337:Drug Carriers; D004359:Drug Therapy, Combination; D006296:Health Services / Q000706:statistics & numerical data; D019694:Hepatitis B, Chronic / Q000188:drug therapy*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000627:therapeutic use*; D063065:Organophosphonates / Q000008:administration & dosage / Q000191:economics* / Q000627:therapeutic use*; D018579:Patient Selection; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000627:therapeutic use*; D011788:Quality of Life; D019057:Quality-Adjusted Life Years; D016032:Randomized Controlled Trials as Topic; D011994:Recombinant Proteins
D000998:Antiviral Agents; D004337:Drug Carriers; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D063065:Organophosphonates; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D000225:Adenine; C100416:peginterferon alfa-2a; C106812:adefovir dipivoxil