We identified 93 relevant articles representing RCTs of interferon alfa-2b37-68
, peginterferon alfa-2a69-73
, peginterferon alfa-2b86-97
, or telbivudine85,104,120,121
. We also reviewed one recently published study of tenofovir122
. The studies enrolled predominately HBeAg-positive individuals. We excluded eleven reports that described outcomes in HBeAg-negative patients47,50,52,55,57,67,69,71,74-76,119
. We identified 16 RCTs (4431 patients) that analyzed the effects of antiviral drugs on clinical outcomes and concluded that drug treatments did not improve clinical outcomes of chronic hepatitis B infection. Clinical outcomes were rarely reported, and the trials were underpowered to detect differences in mortality, liver cancer or cirrchosis2,4
. The results of meta-analyses with pooled relative risk, absolute risk differences, and weights from random effects models are presented in Online Appendix 1
We summarized the results of the RCTs into an evidence map (Table ). No one treatment improved all outcomes, and there was limited evidence on comparative effects.
Absolute Risk Difference in Tested Intermediate Outcomes After Antiviral Drugs for Chronic Hepatitis B in Adults
Only interferon therapies resulted in HBsAg loss, which is one of the criteria of resolved hepatitis B. One RCT demonstrated a significant increase in HBsAg loss at the end of administration of interferon alfa-2b60
and after interferon alfa-2b with corticosteroid. Pooled analysis of two RCTs that compared steroid pretreatment followed by interferon alfa-2b to no antiviral drugs found a significant increase in HBsAg loss at the end of treatment46,60
. Combined therapy of interferon alfa-2b with lamivudine resulted in HBsAg loss and HBV DNA clearance in one RCT43
. Peginterferon alfa-2b combined with lamivudine when compared to lamivudine alone increased HBV DNA clearance and HBsAg seroconversion95
. All treatments failed to increase rates of post-treatment HBsAg loss at follow up off drug administration (range 8-48 weeks off treatment)37,43,59,63,67,113,116
Monotherapy with oral antiviral drugs resulted in HBV DNA clearance and HBeAg seroconversion compared to placebo. For instance, lamivudine at the end of monotherapy compared to placebo increased the rates of HBeAg loss40,43,113,117
and HBeAg seroconversion,40,43,113,117,118,123
but it also increased rate of YMDD mutations (mutation in amino acid sequence tyrosine, methionine, aspartate, aspartate)43,109
. Adefovir improved fibrosis and necroinflammatory scores74,75,77
, and HBeAg loss77,78
Evidence on the comparative effectiveness of antiviral drugs was limited. Some antiviral drugs demonstrated superior effects on intermediate markers when compared to each other but no one regime demonstrated superior benefits on all biomarkers. For instance, lamivudine compared to peginterferon alfa-2a improved HBV DNA clearance72
but reduced HBeAg loss72
. Entecavir compared to lamivudine improved necroinflammation in three studies98,99,102
with no differences on fibrosis scores in two studies that examined this biomarker99,102
. Entecavir compared to lamivudine also increased the rates of HBV DNA clearance98-100,103
, with no differences in HBsAg99,103
and HBeAg loss99,100,102
, or HBsAg103
seroconversion. Low levels of evidence suggested greater effects of telbivudine on HBV DNA clearance when compared to lamivudine104
, or to adefovir85
with no differences in other outcomes. Moderate evidence from two RCTs suggested better effects from combined therapy with adefovir plus lamivudine on HBeAg loss82,84
and ALT normalization82,84
when compared to lamivudine alone, but not adefovir alone. Limited evidence from one recently published RCT122
suggested superior effects from tenofovir compared to adefovir on viral suppression, normalized ALT levels and loss of HBsAg at the end of 48 weeks of treatment.
Evidence about the comparative effectiveness of combined therapies is very limited. We found only one study that demonstrated peginterferon alfa-2a combined with lamivudine, compared to monotherapy with either lamivudine or peginterferon alfa-2a improved HBV DNA clearance72
Few of the drugs evaluated demonstrated sustained benefits superior to placebo. Interferon alfa-2b improved sustained HBV DNA and HBeAg clearance40,59,63
, and ALT normalization60,63
. Adefovir improved sustained ALT normalization75,78
and HBV DNA clearance75
.Pegylated interferon alfa-2a demonstrated superior sustained effects when compared to lamivudine. Pegylated interferon alfa-2a vs. lamivudine improved sustained HBV DNA72
and HBeAg clearance72
, and ALT normalization71,72
. Pegylated interferon alfa-2a plus lamivudine improved sustained HBV DNA72
and HBeAg seroconversion72
and ALT normalization71,72
compared to lamivudine, but not pegylated interferon alfa-2 monotherapy.
Number Needed to Treat
The number needed to treat to achieve one event of improved biomarker was fewer than ten for most of the treatments (Table ). Examining how many patients should be treated to improve liver histology (diagnostic markers of liver cirrhosis), we found that effectiveness is comparable among antiviral drugs. For instance, monotherapy with interferon alfa-2b was needed in four patients to achieve reduction in liver histological scores in one of them67
. We would need to treat two patients with combined therapy of interferon alfa-2b and lamivudine to achieve improvement in histological scores in one of them44
. Adefovir administration in four74,75,77
or entecavir in seven patients98,99,102
would result in reduced necroinflammation in one patient. Peginterferon alfa-2a administered in eight patients would result in sustained depression of necroinflammation in one patient when compared to lamivudine71
. Adefovir is the only drug that reduced fibrosis scores; administration to four patients would result in reduction of fibrosis scores in one patient74,77
Sustained HBV DNA clearance was associated with favorable clinical outcomes in observational studies18,19,124
. According to our analysis, sustained HBV DNA clearance in one patient would be possible if two were treated with interferon alfa-2b or adefovir or 13 with lamivudine. Sustained HBeAg loss in one patient would be achieved if four were treated with interferon alfa-2b. We would need to treat eight patients with interferon alfa-2b to have one case of sustained HBeAg seroconversion. Sustained ALT normalization could be seen in one patient when three were treated with interferon alfa-2b or four with adefovir. Viral resistant YMDD mutations would be detected in one from two treated with lamivudine patients.
Number Need to Treat to Have One Additional Event After Antiviral Treatments of Chronic Hepatitis B infection; Results from Randomized Controlled Clinical Trials
Finite courses of interferon were more expensive than oral drugs. Among interferon formulations, the cost of pegylated interferon alfa-2b administration was lower when compared to interferon alfa-2b or pegylated interferon alfa-2a. We estimate an average cost per patient34
of about $16,176 for 48 weeks of pegylated interferon alfa-2b administration, versus $60,390 for 24 weeks of interferon alfa-2b administration, or $97,065 for 48 weeks of pegylated interferon alfa-2a administration. Treatments with oral antiviral drugs are less expensive, averaging around $17,302 for 96 weeks of adefovir administration, $1,565 for 52 weeks of lamivudine administration, $8,274 for 52 weeks of entecavir administration, and $7,644 for 52 weeks of telbivudine administration.Sustained HBeAg loss in one patient can cost $161,760 if treated with peginterferon alfa-2b, or $215,681 if treated with interferon alfa-2b, and treatment with peginterferon alfa-2a alone or combined with lamivudine will cost to three to four times more. Sustained HBeAg seroconversion in one patient would cost more than $500,000 with interferon alfa-2b and more than $770,000 with peginterferon alfa-2a combined with lamivudine. Actual costs may be less due to possible price discounts, but relative differences would remain the same.
Attributable Events The number of events that were attributable to treatment with antiviral drugs varied across treatments (Figs. , , , , ). Compared to placebo, interferon alfa-2b alone or combined with lamivudine resulted in greater improvement in histological scores and HBV DNA clearance (Fig. ). HBV DNA clearance was greater after adefovir treatment when compared to lamivudine and greater after telbivudine when compared to lamivudine or adefovir (Fig. ). Improvement in histological scores was attributable only to interferon alfa-2b combined with lamivudine therapy when compared to interferon monotherapy (Fig. ). One RCT demonstrated that 320 cases of resolved hepatitis B per 1000 treated would be attributable to combined administration of peginterferon alfa-2b with lamivudine vs. lamivudine alone. Sustained HBV DNA clearance in more than 400 per 1,000 treated was attributable to adefovir or interferon alfa-2b administration when compared to placebo (Fig. ). Sustained intermediate outcomes could be attributed to the examined treatments when compared to active control in less than 300 per 1,000 treated patients (Fig. ).
Results from randomized controlled clinical trials that compared active treatments to placebo at the end of the treatment.
Results from randomized controlled clinical trials that compared active mono-treatments at the end of the treatment.
Results from randomized controlled clinical trials that compared combined therapy vs. monotherapy at the end of the treatment.
Sustained results from randomized controlled clinical trials that compared active treatments to placebo at follow up off the treatment.
Sustained results from randomized controlled clinical trials that compared active treatments at follow up off the treatment.
Absolute Rates of the Outcomes
Physicians and patients make individual decisions based on known average probabilities of clinically important benefits and harms125
. Probabilities vary depending on individual patient characteristics that can influence the expected treatment effects126,127
. We have synthesized the probabilities of clinical and intermediate outcomes in HBeAg positive patients that participated in RCTs (Fig. ). We hesitated to use indirect statistical comparisons that have not been examined in head-to-head RCTs. For example, mortality has never been examined in placebo controlled RCTs of pegylated interferon alfa-2a; therefore, lower rates of death after active drug (0%) vs. placebo (7.1%) could not provide good evidence of better survival. However, the rates of patient outcomes after placebo could provide a reasonable estimation of baseline risk in adults with CHB. Published studies examined the effects of antiviral drugs only on selected outcomes; none of the RCTs reported all outcomes. Analyzing the rates of all outcomes from different RCTs can give a more complete estimation of drug effects. Combined treatments did not result in better outcomes when compared to monotherapy. Relapse and treatment failure were more common after active treatments than after placebo128,129
The most common adverse events during antiviral therapy included flu-like symptoms after interferon, fatigue, headache, abdominal pain, nausea, diarrhea, or laboratory abnormalities, which were reported in over 50% of patients2,4
. Absolute rates of adverse events (in >10% of the patients) after placebo and active treatments are presented in Online Appendix Table 2
. Direct comparisons in published RCTs reported non significant differences in serious adverse events and withdrawal rates when compared to placebo2
. Laboratory toxicity after adefovir restricted usage of the drug in patients with impaired renal function2
. Entecavir was better tolerated than lamivudine. Dose modifications due to neutropenia and thrombocytopenia were necessary in 50% of patients after interferon treatment4
. Withdrawal rates were 24% higher after interferon-alfa-2b than with no treatment4
. Pegylated interferon-alfa-2a combined with lamivudine resulted in greater discontinuation versus placebo or lamivudine alone4
. Patients had serious adverse events more often after combined therapy of lamivudine with interferon-alfa-2b or pegylated interferon-alfa-2a than after lamivudine alone4
. Long-term adverse drug events include reduced bone mineral density after tenofovir and moderate serum creatine phosphokinase elevations after telbivudine130
Rates (%) of clinical and intermediate outcomes in HBe antigen positive patients (pooled from randomized controlled clinical trials with random effects models).