Aa
Is my understanding correct?
From the extract below from "Management of Chronic Hepatitis B"，Number 174，prepared by Minnesota Evidence-based Practice Center, Minneapolis, Minnesota for Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services, October 2008, is my understanding correct that despite the fact that IFN, antivirals, and their combinations thereof all may improve liver surrogates such as HBV DNA, HBeAg loss, HBeAg seroconversion, ALT normalization, histological improvement, combined virologic and biochemical outcomes, fundamentally, they do not reduce the chances for mortality, cirrhosis, hepatic decompensation, and hepatocellular carcinoma because they do not improve HBsAg clearance?
Question 2a. What is the efficacy (or effectiveness) of interferon therapy, oral therapy, and various combinations in treating hepatitis B with defined or continuous courses of treatment?
Clinical outcomes.
Mortality. Antiviral medications did not reduce mortality versus placebo, other antiviral medications, or in combination with corticosteroids, regardless of baseline HBeAg or cirrhosis status in 14 RCTs that were not designed to test long-term clinical outcomes.
Cirrhosis. A small trial failed to demonstrate that interferon alfa-2b prevented cirrhosis in HBeAg-positive patients. Another small RCT found no significant difference in histologically confirmed cirrhosis after interferon alfa-2b alone or with simultaneous prednisone. No data were available from RCTs for other antiviral drugs or longer followup.
Hepatic decompensation was not prevented by lamivudine compared to placebo or entecavir compared to lamivudine in three underpowered trials.
Hepatocellular carcinoma was not prevented in four studies with inadequate size and duration. In one RCT, analysis that adjusted for country, sex, baseline ALT level, Child-Pugh score, and Ishak fibrosis score and excluded five individuals who developed HCC within the first year of the study found a borderline significant effect of lamivudine. This study noted a nonsignificant increase in all cause mortality.
Intermediate outcomes. Evidence suggested drug effects on viral load or replication, liver enzymes, and histology at end-of-treatment and lasting from at least 6 months off treatment. No one treatment improved all examined outcomes and few assessed complete response or sustained outcomes (i.e., at >6 months off treatment).
HBV DNA clearance was assessed using assays with different sensitivities to detect HBV DNA. Adefovir and lamivudine increased HBV DNA clearance at end of treatment versus placebo. Entecavir increased clearance versus lamivudine with inconsistent effect size. Lamivudine was less effective than adefovir in lamivudine-resistant patients and less effective than telbivudine in HBeAg-positive patients. Limited evidence suggested that HBV DNA clearance was maintained at followup off therapy ranging from 18-24 weeks after interferon alfa-2b, lamivudine, or adefovir administration.
HBeAg loss was assessed in 35 trials. HBeAg clearance off treatment was demonstrated for interferon alfa- 2b. Lamivudine for 52 weeks versus placebo increased HBeAg loss at 16 weeks off therapy. HBeAg loss at 24 weeks post treatment was greater after peginterferon alfa-2a versus lamivudine.
HBeAg seroconversion was assessed in 36 studies. Lamivudine or adefovir increased HBeAg seroconversion versus placebo. Interferon alfa-2b64,83 increased post-treatment seroconversion. Lamivudine monotherapy failed to sustain seroconversion. Interferon alfa- 2b plus lamivudine demonstrated inconsistent effects on seroconversion at 6-28 weeks of followup with significant benefit in a pooled analysis from four RCTs using individual patient data. Telbivudine versus adefovir or peginterferon alfa-2a versus lamivudine increased post treatment HBeAg seroconversion. Peginterferon alfa-2a plus lamivudine increased HBeAg seroconversion versus lamivudine alone but not versus peginterferon alfa-2a alone.
HBsAg clearance. Nine studies compared active drugs with placebo or no treatment. Only one RCT of HBeAg-positive patients found a significant increase in HBsAg loss after interferon alfa-2b. Steroid pretreatment followed by interferon alfa-2b versus no antiviral drugs increased HBsAg loss at the end of treatments. Active treatments compared to each other did not demonstrate differences post-treatment HBsAg loss or combined outcomes that included loss HBsAg clearance.
ALT normalization was greater after adefovir versus placebo. Lamivudine increased rates of ALT normalization versus placebo at 24 weeks off treatment in HBeAg-negative patients. Interferon Alfa-2b at doses 35 million units (MU)/week compared to no antiviral treatment increased rates of ALT normalization at 8-24 weeks of followup. Sustained ALT 6 normalization at 24 weeks off treatment was greater after peginterferon alfa-2a compared to lamivudine and after combined therapy of peginterferon alfa-2a with lamivudine compared to lamivudine alone.
Histological improvement off treatment in necroinflammatory scores was reported in only one RCT95 after peginterferon alfa-2a compared to lamivudine in HBeAg-negative patients.
Combined virologic and biochemical outcomes. Low to moderate evidence suggested that some examined drugs or their combinations improved combined virologic and biochemical outcomes immediately after and post treatment.
Question 2a. What is the efficacy (or effectiveness) of interferon therapy, oral therapy, and various combinations in treating hepatitis B with defined or continuous courses of treatment?
Clinical outcomes.
Mortality. Antiviral medications did not reduce mortality versus placebo, other antiviral medications, or in combination with corticosteroids, regardless of baseline HBeAg or cirrhosis status in 14 RCTs that were not designed to test long-term clinical outcomes.
Cirrhosis. A small trial failed to demonstrate that interferon alfa-2b prevented cirrhosis in HBeAg-positive patients. Another small RCT found no significant difference in histologically confirmed cirrhosis after interferon alfa-2b alone or with simultaneous prednisone. No data were available from RCTs for other antiviral drugs or longer followup.
Hepatic decompensation was not prevented by lamivudine compared to placebo or entecavir compared to lamivudine in three underpowered trials.
Hepatocellular carcinoma was not prevented in four studies with inadequate size and duration. In one RCT, analysis that adjusted for country, sex, baseline ALT level, Child-Pugh score, and Ishak fibrosis score and excluded five individuals who developed HCC within the first year of the study found a borderline significant effect of lamivudine. This study noted a nonsignificant increase in all cause mortality.
Intermediate outcomes. Evidence suggested drug effects on viral load or replication, liver enzymes, and histology at end-of-treatment and lasting from at least 6 months off treatment. No one treatment improved all examined outcomes and few assessed complete response or sustained outcomes (i.e., at >6 months off treatment).
HBV DNA clearance was assessed using assays with different sensitivities to detect HBV DNA. Adefovir and lamivudine increased HBV DNA clearance at end of treatment versus placebo. Entecavir increased clearance versus lamivudine with inconsistent effect size. Lamivudine was less effective than adefovir in lamivudine-resistant patients and less effective than telbivudine in HBeAg-positive patients. Limited evidence suggested that HBV DNA clearance was maintained at followup off therapy ranging from 18-24 weeks after interferon alfa-2b, lamivudine, or adefovir administration.
HBeAg loss was assessed in 35 trials. HBeAg clearance off treatment was demonstrated for interferon alfa- 2b. Lamivudine for 52 weeks versus placebo increased HBeAg loss at 16 weeks off therapy. HBeAg loss at 24 weeks post treatment was greater after peginterferon alfa-2a versus lamivudine.
HBeAg seroconversion was assessed in 36 studies. Lamivudine or adefovir increased HBeAg seroconversion versus placebo. Interferon alfa-2b64,83 increased post-treatment seroconversion. Lamivudine monotherapy failed to sustain seroconversion. Interferon alfa- 2b plus lamivudine demonstrated inconsistent effects on seroconversion at 6-28 weeks of followup with significant benefit in a pooled analysis from four RCTs using individual patient data. Telbivudine versus adefovir or peginterferon alfa-2a versus lamivudine increased post treatment HBeAg seroconversion. Peginterferon alfa-2a plus lamivudine increased HBeAg seroconversion versus lamivudine alone but not versus peginterferon alfa-2a alone.
HBsAg clearance. Nine studies compared active drugs with placebo or no treatment. Only one RCT of HBeAg-positive patients found a significant increase in HBsAg loss after interferon alfa-2b. Steroid pretreatment followed by interferon alfa-2b versus no antiviral drugs increased HBsAg loss at the end of treatments. Active treatments compared to each other did not demonstrate differences post-treatment HBsAg loss or combined outcomes that included loss HBsAg clearance.
ALT normalization was greater after adefovir versus placebo. Lamivudine increased rates of ALT normalization versus placebo at 24 weeks off treatment in HBeAg-negative patients. Interferon Alfa-2b at doses 35 million units (MU)/week compared to no antiviral treatment increased rates of ALT normalization at 8-24 weeks of followup. Sustained ALT 6 normalization at 24 weeks off treatment was greater after peginterferon alfa-2a compared to lamivudine and after combined therapy of peginterferon alfa-2a with lamivudine compared to lamivudine alone.
Histological improvement off treatment in necroinflammatory scores was reported in only one RCT95 after peginterferon alfa-2a compared to lamivudine in HBeAg-negative patients.
Combined virologic and biochemical outcomes. Low to moderate evidence suggested that some examined drugs or their combinations improved combined virologic and biochemical outcomes immediately after and post treatment.
Current antiviral regimen only offer short-term biological, virological, and in some cases histological benefits to HBC. Long-term predictions of outcomes require years (decade) of data. Currently, we do not have these needed historical data to make any predictions on clinical outcomes. Let look back 10 years ago, we do not even have these lists of antiviral drugs. I would think that we will have a better picture in the next 5 or 10 years regarding HBV treatment and management challenges. For now, please do the best you can to achieve UND.
You are right most studies and both the IFN and AVs make the assumption that control of surrogates means control of the outcomes. The reason there are not too many studies on the outcomes is obviously the length of time required. We HepBers want the inference to be true, of course.
Okay, I think I read something recently that fills in the blanks.
Studies needed to prove that antivirals or IFN lead to reduction in deaths from HBV related problems would have to be long term. Right now studies indicate that elevated DNA is associated with increased risk of complications. IFN and AVs have been shown to lower DNA. So, the inference is that if you decrease the DNA you decrease the risk of complications leading to death.
But, no, it hasn't been proven.
Studies needed to prove that antivirals or IFN lead to reduction in deaths from HBV related problems would have to be long term. Right now studies indicate that elevated DNA is associated with increased risk of complications. IFN and AVs have been shown to lower DNA. So, the inference is that if you decrease the DNA you decrease the risk of complications leading to death.
But, no, it hasn't been proven.
To bberry: Baraclude = Entecavir
To zellyf: The other part of the picture would be many comparison studies that show that liver surrogate improvements do in fact slow or stop the disease progression. For example, a study in which the study group has ALT controlled to stay in normal range while the control group has ALT monitored only without intervention. Our hope is the result that the study group is reduced in mortality, cirrhosis, hepatic decompensation, and hepatocellular carcinoma.
To zellyf: The other part of the picture would be many comparison studies that show that liver surrogate improvements do in fact slow or stop the disease progression. For example, a study in which the study group has ALT controlled to stay in normal range while the control group has ALT monitored only without intervention. Our hope is the result that the study group is reduced in mortality, cirrhosis, hepatic decompensation, and hepatocellular carcinoma.
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