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Tenofovir (Viread) Produces Long-term Response in Chronic Hepatitis B Patients with Prior Treatment Failure

SUMMARY: Tenofovir (Viread) monotherapy produced long-lasting response in HBeAg positive and negative chronic hepatitis B patients who had experienced treatment failure using other nucleoside/nucleotide analogs, according to a study reported in the January 2010 issue of Hepatology. Pre-existing resistance to lamivudine (3TC, Epivir-HBV) did not impair response to tenofovir, though adefovir (Hepsera) resistance reduced it by half. Tenofovir was well tolerated, with no serious adverse events.

By Liz Highleyman

Several nucleoside/nucleotide analog drugs (NAs) are active against hepatitis B virus (HBV), but the virus can mutate to develop resistance to these agents. Many people treated with lamivudine monotherapy -- the former standard of care -- experience HBV breakthrough as this resistance emerges.

Tenofovir, a nucleotide analog which has been used for a decade to treat HIV, was approved for the treatment of chronic hepatitis B in August 2008. Studies suggest that HBV may not develop resistance as readily to this tenofovir.

Florian van Bömmel and colleagues from Germany and the Netherlands performed a retrospective analysis to assess the long-term efficacy of tenofovir monotherapy in patients with prior treatment failure or resistance to other NAs.

The multicenter study included 131 participants. About 70% were men and the mean age was 42 years; 65% were hepatitis B "e" antigen (HBeAg) positive, the remainder HBeAg negative. At enrollment, patients had HBV viral load > 4.0 log copies/mL and had been taking tenofovir for at least 6 months. At the time of tenofovir initiation, the mean HBV DNA level was 7.6 log copies/mL.

Prior treatment consisted of lamivudine monotherapy (n = 18), adefovir monotherapy (n = 8), lamivudine followed by adefovir (n = 73), or lamivudine with adefovir subsequently added (n = 29); 3 patients had experienced treatment failure using the newer drug entecavir (Baraclude). Resistance analysis (done for 113 patients) revealed that 62% had lamivudine resistance mutations and 19% had adefovir resistance mutations.

All participants started tenofovir (300 mg/day), which they took as their sole anti-HBV drug. The mean treatment duration was 23 months (range 6-60 months).

Results

Overall, the cumulative proportion of patients achieving HBV DNA < 400 copies/mL was 79%.
Lamivudine resistance did not influence the antiviral efficacy of tenofovir.
However, patients with adefovir resistance were about half as likely as non-resistant patients to respond to tenofovir (52% vs 100%, respectively).
Nontheless, HBV virological breakthrough (HBV DNA increase after suppression < 400 copies/mL) did not occur in any patients during the observation period.
Factors including age, sex, presence of liver cirrhosis, and HBeAg status did not influence response to tenofovir.
24% of patients experienced HBeAg loss, after a median duration of 11 months.
3% experienced hepatitis B surface antigen (HBsAg) loss, after 9, 17, 23, and 25 months of tenofovir treatment.
65% of patients with elevated ALT at baseline experienced ALT normalization.
No significant adverse events were reported during tenofovir monotherapy.
No ALT flares (> 5 x upper limit of normal) were observed while taking tenofovir.
No significant increase in creatinine was observed (a marker of kidney function, assessed because tenofovir has been linked to kidney impairment in a small proportion of susceptible HIV patients).
Based on these findings, the investigators concluded, "[Tenofovir] monotherapy induced a potent and long

Based on these findings, the investigators concluded, "[Tenofovir] monotherapy induced a potent and long-lasting antiviral response in NA-experienced patients with previous treatment failure."
"Our data may have implications for current add-on strategies," they added.
Current practice guidelines recommend adding adefovir or tenofovir to ongoing lamivudine treatment after a patient develops resistance to lamivudine monotherapy, the authors elaborated in their discussion.

Although it is more difficult for HBV to develop resistance mutations to multiple drugs and still maintain its "fitness," patients with high viral load have a low likelihood of achieving HBV suppression even after adding adefovir.

This study, however, found that baseline HBV DNA level did not influence response to tenofovir; even people with high viral load had a good chance of achieving complete viral suppression after switching to tenofovir monotherapy.

"In conclusion, [tenofovir] 300 mg per day as monotherapy is an effective and well-tolerated treatment option for patients with HBV monoinfection and NA treatment failure either due to incomplete adefovir response or lamivudine resistance," the researchers wrote.

However, given the lower likelihood of response in patients with adefovir resistance, they added, "Optimal management of genotypic adefovir resistance and possible cross-resistance to [tenofovir] should be the subject of further studies."

Medizinische Klinik m. S. Hepatologie und Gastroenterologie Charité, Universitätsmedizin Berlin, Germany; Man Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands; Hannover Medical School, Hannover, Germany; University of Hamburg Eppendorf, Germany; Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universitätsklinik Düsseldorf, Germany; Gastroenterologische Schwerpunktpraxis Herne, Germany; Medizinische Klinik IV für Gastroenterologie und Infektiologie, Universitätsklinikum Heidelberg, Germany; Johann Wolfgang Goethe-University Hospital, Frankfurt, Germany; I. Medizinische Klinik und Poliklinik, Johannes Gutenberg-Universität Mainz, Germany; University of Bonn, Germany; University Hospital Aachen, Germany; Hepatologische Schwerpunktpraxis, Berlin, Germany; Abteilung für Gastroenterologie, St. Marien Hospital, Hamm, Germany; Laborgemeinschaft Hamburg, Germany.

1/15/10

Reference
F van Bömmel, RA de Man, H Wedemeyer, and others. Long-term efficacy of tenofovir monotherapy for hepatitis B virus-monoinfected patients after failure of nucleoside/nucleotide analogues. Hepatology 51(1): 73-80 (Abstract). January 2010.


 




 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

FDA-approved Therapies for Chronic HBV Infection
Baraclude  (entecavir)
Epivir-HBV
  (lamivudine; 3TC)
Hepsera
  (adefovir dipivoxil)
Intron A  (interferon alfa-2b)
Pegasys  (peginterferon alfa-2a)
Viread  (tenofovir)
Tyzeka   (telbivudine)


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