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Analogs and fibrosis regression in hepatitis BAnalogues et régression de la fibrose dans l’hépatite B

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Summary

Nucleoside or nucleotide analogs (NUCs) are a major step forward in the treatment of hepatitis B virus (HBV) infection. Apart from their proven antiviral efficacy, these drugs have proved able to significantly improve liver fibrosis as short-term treatment. Using different definitions of fibrosis regression, after 1 year of treatment, improvement in liver fibrosis was observed among HBe antigen (HBeAg)-positive naive patients: 35–61% with lamivudine; 41% with adefovir; 68% with telbivudine; 39% with entecavir; and 74% with tenofovir. Among HBeAg-negative patients, after 1 year of treatment, improvement in liver fibrosis was seen in: 36–46% with lamivudine; 48% with adefovir; 56% with telbivudine; 36% with entecavir; and 71% with tenofovir. Long-term treatment is often required with NUCs; the response continue to improve over time, reaching up to 63% of patients with lamivudine and 71% of patients with adefovir, although the development of antiviral drug resistance can blunt any histological improvement. Also, there is now growing evidence that non-invasive methods of fibrosis diagnosis, such as surrogate markers, are likely to become as important as liver biopsy for taking the initial decision to biopsy and for treatment, and in the follow-up of treated chronic HBV patients.

Résumé

Les analogues nucléosidiques ou nucléotidiques sont un progrès majeur dans le traitement des hépatites chroniques B. En dehors de leur efficacité antivirale prouvée, ces molécules ont montré une amélioration significative de la fibrose chez les patients traités. En utilisant des définitions différentes de régression de la fibrose, un traitement d’un an entraîne une amélioration de la fibrose chez les patients antigène HBe positif naïfs de traitement chez 35 à 61 % des patients traités par lamivudine, 41 % des patients traités par adéfovir, 68 % des patients traités par telbivudine, 39 % des patients traités par entécavir et 74 % des patients traités par ténofovir. Chez les patients antigène HBe négatif, à un an, une régression de la fibrose est observée chez 36 à 46 % des patients traités par lamivudine, 48 % des patients traités par adéfovir, 56 % des patients traités par telbivudine, 36 % des patients traités par entecavir et 71 % des patients traités par ténofovir. Un traitement prolongé est très souvent nécessaire avec les analogues et l’amélioration de la fibrose se poursuit avec le temps atteignant 63 % des patients traités par lamivudine et 71 % des patients traités par adéfovir. Cependant, la survenue de mutations de résistance réduit l’amélioration histologique. Il existe de plus en plus de données suggérant que les marqueurs non invasifs de fibrose ont une place importante à la fois pour l’évaluation préthérapeutique de la fibrose, mais aussi dans le suivi des patients traités.

Introduction

The goal of therapy for hepatitis B is to improve survival and quality of life by preventing progression of the disease to severe fibrosis, cirrhosis, decompensated cirrhosis, end-stage liver disease, hepatocellular carcinoma and death. This goal can be achieved if hepatitis B virus (HBV) replication can be suppressed in a sustained manner, as this results in reductions in both histological necroinflammatory activity and the fibrosis of chronic hepatitis. This, in turn, will lower the risk of cirrhosis as well as the risk of hepatocellular carcinoma in non-cirrhotic patients and probably — albeit to a lesser extent — in cirrhotic patients as well [1].

Two different types of drugs can be used in the treatment of chronic hepatitis B: interferon and nucleoside/nucleotide analogs. Analog therapies against HBV belong to three classes:

  • l-nucleosides (lamivudine, telbivudine and emtricitabine);

  • deoxyguanosine analogs (entecavir);

  • acyclic nucleoside phosphonates (adefovir and tenofovir).

All of these drugs (except emtricitabine) have been approved in Europe for HBV treatment. Their efficacy in reducing HBV replication has been demonstrated in randomized controlled trials lasting 1 year (2 years for telbivudine). Longer-term results (up to 5 years) are available for lamivudine, adefovir, entecavir and telbivudine in patient subgroups [2]. The objective of this report is to review fibrosis regression in these studies in relation to viral suppression and the occurrence of resistance mutation.

Section snippets

Lamivudine and fibrosis regression

Lamivudine results in a rapid decrease in serum HBV DNA concentrations. Using different HBV DNA assays, undetectable HBV DNA was achieved in 1 year in up to 98% with the first-generation assay, and in 36–40% with the more sensitive polymerase chain reaction (PCR) assays in HBe antigen (HBeAg)-positive patients and around 72% with PCR assays in HBeAg-negative patients [2], [3], [4], [5]. Loss of HBeAg was found in 17–33% of patients after 1 year and HBeAg seroconversion was observed in 16–21%.

Adefovir dipivoxil and fibrosis regression

Adefovir dipivoxyl has proved effective against HBeAg-positive and HBeAg-negative chronic hepatitis B in randomized controlled trials [11], [12]. In HBeAg-positive patients, adefovir treatment led to undetectable HBV DNA with PCR assays in 21% of patients after 1 year, while 24% showed HBeAg loss and 12% had seroconversion to HBe antibodies [11]. In a small subset of patients who took adefovir for 5 years, undetectable HBV DNA was observed in 39% of patients, 58% showed HBeAg loss, 48% had

Telbivudine and fibrosis regression

Telbivudine proved effective in patients with HBeAg-positive and HBeAg-negative chronic hepatitis B in a large phase-III, randomized, controlled trial [6]. After 1 year of telbivudine, HBV DNA was undetectable by PCR assay (lowest limit of quantification is 300 copies/mL) in 60% of HBeAg-positive patients and 88% of HBeAg-negative patients, proportions that were significantly larger than seen with lamivudine (40 and 71%, respectively). In addition, 26% of patients had HBeAg loss and 22% had

Entecavir and fibrosis regression

Entecavir has proved effective against HBeAg-positive and HBeAg-negative chronic hepatitis B, with a good resistance profile in randomized controlled trials [7], [8]. In lamivudine-refractory patients, entecavir has been shown to be effective after 1 year, although extended duration of treatment led to a high rate of resistance mutation that, in turn, led to virological rebound [19].

In naive patients, 1 year of entecavir led to undetectable HBV DNA on PCR assays (< 300 copies/mL) in 67% of

Tenofovir disoproxil fumarate and fibrosis regression

Tenofovir has also been shown to be effective against HBeAg-positive and HBeAg-negative chronic hepatitis B, with an excellent resistance profile in randomized controlled trials [14]. In fact, no resistance mutation has been described so far.

In naive patients, 1 year of tenofovir resulted in undetectable HBV DNA on PCR assays (< 400 copies/mL) in 76% of HBeAg-positive and 93% of HBeAg-negative patients, percentages significantly higher than seen in the adefovir group (13 and 63%, respectively).

Assessment of liver fibrosis

Liver biopsy is still recommended for determining the degree of necroinflammation and fibrosis in the pretherapeutic assessment of hepatitis B [2]. However, the size of the needle biopsy needs to be large enough to precisely determine the degree of liver injury and fibrosis, and the technique is invasive, costly, and subject to sampling error and poor intra- and interobserver concordance [21], [22], [23], [24], [25], [26], [27]. Yet, although liver biopsy remains the primary endpoint tool for

Conclusion

There is considerable evidence that HBV treatment with analogs improves liver fibrosis and histological activity. Despite the use of different definitions of fibrosis regression across studies, no significant differences in fibrosis improvement were found after 1 year of treatment with the five approved drugs currently available in Europe. Despite a higher rate of undetectable HBV DNA among HBeAg-negative, compared with HBeAg-positive, naive patients, there was no major difference in improvement

Conflicts of interest

M. Bourlière, A. Kahloun and G. Gascou-Tessonier have no conflicts of interest.

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