Aucune remarque pour cette diapositive
Comme le montre ce graphique, la classe d ’âge la plus représentée dans le réseau sentinelles est celle des 20-29 ans
Real-time PCR techniques, with their high sensitivity and dynamic range of HBV DNA quantification, provide a more accurate assessment of the virological response to antiviral therapy.
This slide shows several quantitative HBV DNA assays available for monitoring response to antiviral therapy. As we can see from the figure, the dynamic ranges of quantification of the available HBV DNA assays vary considerably. Most of the assay do not cover the full range of HBV DNA values that can be observed in untreated and treated patients with chronic hepatitis B. Some recent real-time PCR assays however, have a greater dynamic range. Abbott Molecular cover a wide range from 1 to 9.5 log IU/mL. The Artus and the Roche Cobas Taqman 48 HBV assays are the first standardised real-time PCR assays with dynamic ranges from 30 IU/mL to 8 log IU/mL.
This describes the pathophysiologic cascade of the chronic HBV infection.
The early phase of CHB is characterized by the presence of hepatitis B e antigen (HBeAg) and high serum levels of HBV DNA (referred to as HBeAg-positive CHB). Following infection, the immune system attempts to clear the HBV by destroying infected hepatocytes.
This leads to increasing circulatory blood levels of alanine aminotransferase (ALT). However, the majority of patients will clear HBeAg (and produce anti-HBe antibodies) and achieve a state of nonreplicative infection, characterized by low or undetectable serum levels of HBV DNA and normal ALT levels.
High HBV DNA and ALT levels may persist in some anti-HBe-positive patients (referred to as HBeAg-negative CHB) because of the presence of an HBV variant that is unable to produce HBeAg (HBeAg-negative variant, also called HBV precore stop codon mutant).
This slide depicts the findings of two trials that studied actuarial survival in end stage liver disease.
In a US study, Weissberg et al studied survival data from 379 patients with chronic HBV, including 130 patients with cirrhosis.1 The study found that the estimated 5-year survival rate for patients with cirrhosis was 55% compared with 86% for patients with chronic active hepatitis and 97% for patients with chronic persistent hepatitis.
In a European study, De Jongh et al studied survival data from 98 patients with HBsAg positive cirrhosis, including 21 with hepatic decompensation, which was defined as the presence of ascites, jaundice, encephalopathy, and/or a history of variceal bleeding at entry into the study.2 Within 3 years of the start of the study, 14 of these patients had died, with the remaining 7 patients still alive after 0.8 to 5.9 years of follow-up. Overall, the 5-year survival rate for the decompensated group was 14% compared with 84% for patients with compensated cirrhosis.
1.Weissberg JI, Andres LL, Smith CI, et al. Survival in chronic hepatitis B. An analysis of 379 patients. Ann Intern Med. 1984;101:613-616.
2.De Jongh FE, Janssen HLA, De Man RA, et al. Survival and prognostic indicators in hepatitis B surface antigen-positive cirrhosis of the liver. Gastroenterology. 1992;103:1630-1635.
This compares the cumulative hepatocellular carcinoma incidence at the end of the 13th year of follow-up derived from the stepwise analyses of different baseline viral levels. Approximately 15% of all participants with serum HBV DNA levels of 1 million copies/mL or greater at study entry developed hepatocellular carcinoma by the 13th year of follow-up compared with 1.3% of participants with undetectable levels of HBV DNA.The biological gradient of cumulative hepatocellular carcinoma incidence by serum HBV DNA level remained prominent in all stepwise analyses. Among the 2925 participants seronegative for HBeAg with a normal ALT level and no liver cirrhosis, the cumulative hepatocellular carcinoma incidence was 13.5% for HBV DNA levels of 1 million copies/mL or greater and 0.7% for those with undetectable levels of HBV DNA. Serum hepatitis B virus (HBV) DNA level is a marker of viral replication and efficacy of antiviral treatment in individuals with chronic hepatitis B.
The objective of the REVEAL study was to evaluate the relationship between serum HBV DNA level and risk of hepatocellular carcinoma.This was a prospective cohort study of 3653 participants (aged 30-65 years), who were seropositive for the hepatitis B surface antigen and seronegative for antibodies against the hepatitis C virus, recruited to a community based cancer screening program in Taiwan between 1991 and 1992.The main outcome measure was the incidence of hepatocellular carcinoma during follow-up examination and by data linkage with the national cancer registry and the death certification systems.
164 incident cases of hepatocellular carcinoma and 346 deaths during a mean follow-up of 11.4 years and 41 779 person-years of follow-up were reported. The incidence of hepatocellular carcinoma increased with serum HBV DNA level at study entry in a dose-response relationship ranging from 108 per 100 000 person-years for an HBV DNA level of less than 300 copies/mL to 1152 per 100 000 person-years for an HBV DNA level of 1 million copies/mL or greater. The corresponding cumulative incidence rates of hepatocellular carcinoma were 1.3% and 14.9%, respectively. The biological gradient of hepatocellular carcinoma by serum HBV DNA levels remained significant (P.001) after adjustment for sex, age, cigarette smoking, alcohol consumption, serostatus for the hepatitis B e antigen (HBeAg), serum alanine aminotransferase level, and liver cirrhosis at study entry. The dose-response relationship was most prominent for participants who were seronegative for HBeAg with normal serum alanine aminotransferase levels and no liver cirrhosis at study entry. Participants with persistent elevation of serum HBV DNA level during follow-up had the highest hepatocellular carcinoma risk.
Elevated serum HBV DNA level (10 000 copies/mL) is a strong risk predictor of hepatocellular carcinoma independent of HBeAg, serum alanine aminotransferase level, and liver cirrhosis.
This describes the relationship between high baseline serum HBV DNA levels with increased risk of HCC mortality.
In a prospective cohort study with 11 years of follow-up, Evans and colleagues assessed the relationship between past HBV viral load and mortality.
They measured HBV viral load by real-time PCR on stored samples from cohort entry (1992–1993) in 2763 hepatitis B surface antigen (HBsAg)-positive adults from a prospective cohort in Haimen City, China. Follow-up was completed through 2003, with information on deaths occurring during this interval abstracted from death certificates. Major endpoints were death from HCC or chronic liver disease (CLD). There were 447 deaths in total.
Viral load was divided into three categories: undetected (&lt;1.6 × 103 copies/mL); low titer (&lt;105 copies/mL); high titer (≥105 copies/mL).
For HCC, there was a significant increase in mortality across viral load categories (p trend&lt;0.001).
Compared to the HBV undetected category, the relative risk (RR) for HCC mortality in the low viral load group was 1.7 (95% CI 0.5–5.7) and 11.2 (3.6–35.0) in the high viral load group.
The relative risk associated with high viral load did not change with increased follow-up time.
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A single change in the amino acid sequence can have a significant impact on drug resistance. Amino acid substitutions associated with drug resistance occur in the reverse transcriptase region of HBV polymerase.
This slide shows how amino acid substitutions can result in resistance to an antiviral drug – in this case lamivudine (LVD).
Mutations in the sequence of the HBV polymerase gene that result in drug resistance do so through amino acid substitutions in the reverse transcriptase (RT) region of the polymerase.
The figure on the top left of the slide shows a space-filling model of the wild-type RT region. [Build 1] In contrast, the figure on the top right-hand side of the slide shows the RT region from an LVD-resistant (LVDr) HBV variant. In this variant, the methionine at amino acid position 204 has been replaced with a valine (M204V) and the leucine at amino acid position 180 has been replaced with a methionine (L108M).
The M204V substitution reduces the size of the binding pocket of the RT enzyme, meaning that LVD triphosphate (LVD-TP) is unable to bind to enzyme due to steric hindrance. However, the mutated RT enzyme is still able to bind it’s natural substrates (nucleoside triphosphates), so the virus can continue to replicate.
[Build 2] The final figure on the bottom left-hand side of the slide shows the LVDr RT region binding entecavir triphosphate (ETV-TP). In this case, there is minimal steric clash between ETV-TP and the valine at amino acid position 204, accounting for why there is only partial cross-resistance between LVD and ETV.
Key message: The genetic barrier to resistance depends, in part, on the number of substitutions required for virologic breakthrough. Resistance to lamivudine and adefovir requires one substitution. Resistance to entecavir requires three substitutions (two lamivudine-resistance substitutions and at least one entecavir-resistance substitution.
When wild-type virus is treated with lamivudine or adefovir, it has only to acquire one mutation in order to escape the inhibitory effects of the drug (a change from methionine to either isoleucine or valine at position 204 for lamivudine; or either an asparagine to threonine mutation at position 236 or an alanine to valine or threonine at position 181 for adefovir).
In the absence of lamivudine refractory isolates, no resistant virus has yet been seen to emerge with up to 2 years of Baraclude treatment in nucleoside-naive patients. Evidence from in vitro studies and from lamivudine-refractory patients suggests that multiple mutations are required for the development of meaningful resistance to Baraclude. This represents a genetic barrier that may be more difficult for the virus to overcome, since the likelihood of two or three mutations arising simultaneously is much lower than for a single mutation.
Virus that has already developed resistance to lamivudine has a reduced sensitivity to entecavir in vitro and has a backbone of mutations on which to build entecavir resistance. This virus has to acquire at least one additional mutation at position 184, 202 or 250 in order to develop resistance to entecavir.
Archived covalently closed circular DNA (cccDNA) plays an important role in viral persistence.
This slide provides an overview of the archiving process. When HBV infects a hepatocyte in the liver, viral replication in the hepatocyte results in the formation of cccDNA within the cell. This cccDNA can serve as a template for the production of new virus, but can also remain within the hepatocyte, where it is said to be archived.
Archived cccDNA plays an important role in viral persistence and in the reactivation of viral replication after the cessation of antiviral therapy.
Viral variants with antiviral drug resistance may be archived in the form of cccDNA.
By drawing comparisons with animal models of HBV infection, it is believed that drug resistance may be archived in the form of cccDNA. In this slide, a viral variant with drug resistance (represented by the red circle) is formed via a point mutation during the replication of a sensitive variant (represented by the light blue circle). As described on the previous slide, during the normal course of replication cccDNA from this resistant variant may become archived in hepatocytes. Once archived in this way, drug resistance may persist for long periods in the absence of drug.
Archived cccDNA molecules in hepatocytes act mainly as a reservoir for future viral replication and are therefore not inhibited by nucleos(t)ide analogues, which inhibit replication when they are incorporated into nucleic acid molecules during replication.
Since cccDNA acts as a reservoir for future viral replication, the archiving of resistant variants may lead to the persistence and expansion of this population – as demonstrated on this slide where the number of resistant variants (red circles) has increased to become the majority population.
Genotypic resistance is the first manifestation of resistance. This may be followed by an increase in viral load (Virologic Breakthrough) which, in turn, may be followed by a rise in ALT (Biochemical Breakthrough)
There is a time lag between each of these events, the time may vary from patient to patient and from drug to drug
For practical reasons, viral load is normally used to monitor patients. ALT may also be used in certain regions.
This study showed a clear link between the magnitude of early viral suppression and the probability of achieving clinically important endpoints after 1 year
Significant relationships were seen between viral load at 6 months and efficacy outcomes at 1 year.
For HBeAg loss, a difference was evident even between those patients who were below 1000 copies/mL at 6 months but still PCR-positive (i.e. &gt;200 copies/mL), and those who were PCR-negative.
A similar, although less pronounced, relationship was seen with ALT normalization.
None of the patients who were below 1000 copies/mL at 6 months developed resistance at 1 year.
These results support the concept that maximizing early viral suppression is a key therapeutic objective in order to achieve the best possible efficacy outcomes.