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Unsuccessful rescue therapy with adefovir dipivoxil for lamivudine resistant HBV in a patient with liver failure
  1. D Thabut1,
  2. V Ratziu1,
  3. B Bernard-Chabert1,
  4. T Poynard1,
  5. Y Benhamou1,
  6. V Thibault2
  1. 1Service d’Hépato-Gastroentérologie, Groupe Hospitalier Pitié-Salpêtriére, Paris, France
  2. 2Service de Virologie, Groupe Hospitalier Pitié-Salpêtriére, Paris, France
  1. Correspondance to:
    D Thabut, Service d’Hépato-Gastroentérologie, 47-83 Bld de l’Hôpital, 75013 Paris, France;
    dthabut{at}libertysurf.fr

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Adefovir dipivoxil is a new nucleoside analogue which is active against lamivudine resistant hepatitis B virus (HBV). A 48 week course of adefovir in human immunodeficiency virus type 1 infected patients with lamivudine resistant HBV induces a rapid and major decrease in serum HBV DNA levels with improvement in liver inflammation.1 Although reassuring, this efficacy of adefovir may be influenced by the timing of its initiation after the emergence of lamivudine resistant HBV. We report here the case of a cirrhotic patient treated with lamivudine for four years who died of liver failure due to the emergence of lamivudine resistant HBV, despite the introduction of adefovir.

Observation

A 55 year old woman was diagnosed with decompensated cirrhosis due to HBV infection in December 1996. Serum HBV DNA level, as assessed by molecular hybridisation (Murex), was 1695 pg/ml and hepatitis B e antigen (HBeAg) was positive. Lamivudine 100 mg daily was started and resulted in rapid clinical and biological improvement and undetectable HBV DNA by polymerase chain reaction (PCR) (Monitor Roche, positive threshold 1000 copies/ml) in April 1997. HBV replication remained undetectable by PCR during follow up for almost four years. By 21 February 2001, PCR HBV became positive (48 000 copies/ml) while alanine aminotransferase (ALT) levels remained normal until four months later when they increased to five times the upper limit of normal (ULN). One month later, jaundice, ascites, and encephalopathy developed, prompting hospitalisation on 14 July. HBeAg remained positive. The patient never discontinued lamivudine or consumed alcohol. There was no evidence of sepsis, gastrointestinal haemorrhage, renal failure, or hepatocellular carcinoma. ALT was 20 ULN, bilirubin 337 μmol/l, and prothrombin time 19 seconds above normal. Viral load was high (>40 000 000 copies/ml) and HBV polymerase gene sequencing demonstrated substitution of Met to Val at position 550 in the YMDD motif (M550V). Adefovir 10 mg daily was added to lamivudine on 18 July. Ten days later, serum HBV DNA decreased to 4 062 000 copies/ml but encephalopathy and liver failure worsened. The patient died on 5 August.

Discussion

Data from pivotal clinical trials of lamivudine have shown frequent emergence of YMDD variants with long term therapy (67% after four years)2,3 but without a major clinical impact on the course of HBV infection. Indeed, the increase in ALT level remains below pretreatment values while anti-HBe seroconversion and histological improvement can still be achieved.4 However, most of these patients have mild liver damage. In cirrhotic patients, isolated reports of severe5–9 or fatal10 breakthrough related to YMDD variants have been reported. Adefovir is effective and now available for the treatment of lamivudine resistant HBV, but the timing of its initiation is still unknown. In this case, although adefovir induced a potent and rapid suppression of HBV replication, death from liver failure could not be avoided. HBV replication usually precedes the occurrence of symptomatic hepatitis by several months, which in cirrhotic patients can precipitate serious liver injury. Therefore, we suggest that adefovir should be promptly introduced in cirrhotic patients after significant viral relapse is documented (that is, increase of sensitive HBV DNA above 10 000 copies/ml), without waiting for changes in transaminases. This could avoid death from cirrhosis decompensation.

References

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