By Liz Highleyman

Viread Tablet

Several nucleoside/nucleoside analogs have potent activity against hepatitis B virus (HBV), but their long-term effectiveness is limited by the emergence of drug-resistant virus. Due to cross-resistance, individuals who develop resistance to one or more agents in this class may not derive as much benefit from related drugs.

The nucleotide analog tenofovir (Viread, also a component of the Truvada and Atripla fixed-dose combination pills) is currently approved in the U.S. for the treatment of HIV, and is under study for hepatitis B. The European Union approved tenofovir for HBV last week.

Three studied presented at the 43rd annual meeting of the European Association for the Study of the Liver (EASL), held last week in Milan, looked at the efficacy of tenofovir in chronic hepatitis B patients previously treated with other nucleoside/nucleotide analogs.

Study 1

In the first study, an international researcher team looked at antiviral response to tenofovir among participants in Gilead studies 102 and 103 with or without prior lamivudine experience.

In these double-blind studies, HBV monoinfected subjects with hepatitis B "e" antigen (HBeAg) positive (Study 103) or HBeAg negative (Study 102) chronic hepatitis B were randomized in a 2:1 manner to receive tenofovir or adefovir (Hepsera) for 48 weeks. Adefovir, also a nucleotide analog, is approved in the U.S. for hepatitis B treatment.

Participants had compensated liver disease and baseline HBV DNA > 1,000,000 copies/mL (HBeAg positive) or > 100,000 copies/mL (HBeAg negative). Among this cohort, 70 had more than 12 weeks prior exposure to lamivudine (49 in the tenofovir arm, 21 in the adefovir arm) and 571 were lamivudine-naive (377 and 194, respectively). Most (61) of the lamivudine-experienced participants were HBeAg negative. Baseline demographics, mean baseline HBV DNA, and ALT were comparable in both treatment groups. Liver biopsies were performed prior to treatment and between weeks 44 and 48 of therapy.

Results

• Within the tenofovir treatment group, similar responses were observed for lamivudine experienced and lamivudine-naive subjects:

• 88% versus 86%, respectively, with HBV DNA < 400 copies/mL (69 IU/mL);

• 80% versus 72%, respectively, with histological improvement;

• 78% versus 74%, respectively, with ALT normalization.

• Consistent with the overall findings of these studies, a greater antiviral response and similar histological response were observed for tenofovir and adefovir in both the lamivudine-experienced and lamivudine-naive patients.

• Safety and tolerability were also comparable between the lamivudine-experienced and lamivudine-naive subjects and between the tenofovir and adefovir treatment arms.

• Renal (kidney) safety was described as "excellent," and no patients in the tenofovir arm had a confirmed 0.5 mg/dL creatinine increase or creatinine clearance value < 50 mL/min.

Medizinische Hochschule Hannover, Hannover, Germany; University Of Miami School Of Medicine, Miami, FL; University of Thessaly Medical School, Larissa, Greece; Medizinische Klinik Mit Schwerpunkt Hepatologie und Gastroenterologie, Charite Universitatsmedizin, Berlin, Germany; Hopital de Hotel Dieu, Lyon, France; Alfred Hospital, Department of Gastroenterology, Melbourne, Australia; Hospital La Fe, Servicio de Medicina Digestiva, Valencia, Spain; University of Torino, Dipartimento di Gastroenterologia, Turin, Italy; Gilead Sciences, Durham, NC.

Study 2

In the second study, investigators retrospectively analyzed response to tenofovir monotherapy among all 153 chronic hepatitis B patients treated at 15 centers in Germany and the Netherlands, most of whom had prior nucleoside/nucleoside experience.

Of this number, 26 patients were excluded due to undetectable HBV DNA, recently started therapy, or non-adherence. Of the remaining 127 subjects, most (99) were men, about half (75) were HBeAg positive, and 21 had liver cirrhosis. Only 6 patients were treatment-naive, the rest having prior exposure to lamivudine (16), adefovir (9), lamivudine followed by adefovir (72), lamivudine/adefovir combination therapy (21), entecavir (2), and lamivudine followed by entecavir (1).

Treatment lasted a median of 20 months. HBV DNA, ALT, and creatinine levels were measured at baseline and every 3 months. Screening for drug resistance mutations was performed at baseline.

Results

• At 12 months, 103 patients remained under observation and the mean reduction in HBV DNA was 4.1 log copies/mL.

• 88 patients (85%) achieved undetectable HBV DNA.

• Virologic breakthrough (HBV DNA >1 log from nadir) was not observed.

• HBeAg seroconversion was documented in 12 patients (16%) and HBsAg loss in 1 patient (1%).

• At baseline, 33% of subjects had normal ALT, compared to 70% at month 12.

• Baseline characteristics including age, sex, liver cirrhosis, HBeAg status, and lamivudine resistance had no observed influence on response to tenofovir.

• Patients with genotypic resistance to adefovir experienced a significantly slower decrease in HBV DNA.

• However, they achieved undetectable HBV DNA by the end of the total observation period if HBV DNA was < 7 log copies/mL at baseline.

• No side effects associated with tenofovir were observed.

Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Charité-Universitätsmedizin Berlin, Germany; Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, the Netherlands; Innere Medizin IV, Universitätsklinikum Heidelberg, Germany; Gastroenterologische Gemeinschaftspraxis, Herne, Germany; I. Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany; Medizinische Klinik I, Johan Wolfgang Goethe Universität, Frankfurt am Main, Germany; I. Medizinische Klinik und Poliklinik, Johannes Gutenberg Universität Mainz, Mainz, Germany; Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Germany; Zentrum Für Innere Medizin, Universitätsklinikum Bonn, Germany; Medizinische Klinik III, Universitätsklinikum Aachen; Klinik Für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Germany.

Study 3

Finally, a third study looked at treatment with tenofovir monotherapy or tenofovir plus emtricitabine in 105 chronic hepatitis B patients (76% men, 73% HBeAg positive) who continued to have detectable HBV DNA (1000 copies/mL or higher; mean 5.97 log10 copies/mL) despite being treated with adefovir for at least 6 months (mean 423 days, range 140-917 days).

Emtricitabine (Emtriva, also a component of Truvada and Atripla) is structurally similar to lamivudine (3TC; Epivir-HBV) -- a drug frequently used as first-line therapy for hepatitis B -- and cross-resistance between the 2 drugs is common.

Results

• Among subjects with available resistance data, approximately 11% harbored adefovir-associated resistance mutations at baseline.

• By week 24, the majority of subjects who were still viremic on adefovir experienced robust virological suppression after switching to a tenofovir-containing regimen.

• Through 24 weeks, in the tenofovir monotherapy and tenofovir/emtricitabine arms combined, 68% achieved HBV DNA < 400 copies/mL.

• This included 65% of HBeAg positive subjects and 79% of HBeAg negative patients.

• 58% achieved HBV DNA < 169 copies/mL.

• 66% experienced ALT normalization.

• Tenofovir-containing regimens were well-tolerated.

Medizinische Klinik Mit Schwerpunkt Hepatologie & Gastroenterologie, Charite-Universitatsmedizin Berlin, Berlin, Germany; Hepatologische Schwerpunktpraxis, Berlin, Germany; San Jose Gastroenterology, San Jose, CA; Private Practice, Flushing, NY; Service d'Hepatologie, Hopital Beaujon, Clichy, France; Hepatology Unit Digestive Department, Hospital Universitario de Valme, Seville, Spain; Gilead Sciences, Durham, NC.

Taken together, these studies indicate that tenofovir -- with or without emtricitabine -- is an effective therapy for chronic hepatitis B patients who have prior experience with other nucleoside/nucleotide analogs.

While tenofovir monotherapy has performed well in studies, many experts believe first-line combination therapy - rather than sequential therapy or adding a new drug after one fails - is the best way to prevent emergence of resistance.

4/29/08

References

M Manns, L Jeffers, G Dalekos, and others. The Antiviral Response to Tenofovir Disoproxil Fumarate (TDF) is Comparable in Lamivudine (LAM)-Naive and LAM-Experienced Subjects Treated for Chronic Hepatitis B (CHB). 43rd annual meeting of the European Association for the Study of the Liver (EASL 2008). Milan, Italy. April 23-27, 2008.

F van Bömmel, RA de Man, K Stein, and others. A Multicenter Analysis of Antiviral Response after One Year of Tenofovir Mono-Therapy in HBV-Monoinfected Patients with Prior Nucleos(t)Ide Analog Experience. 43rd annual meeting of the European Association for the Study of the Liver (EASL 2008). Milan, Italy. April 23-27, 2008.

T Berg, B Moller, H Trinh, and others. Tenofovir Disoproxil Fumarate (TDF) versus Emtricitabine plus TDF for Treatment of Chronic Hepatitis B (CHB) in Subjects with Persistent Viral Replication Receiving Adefovir Dipivoxil (ADV). 43rd annual meeting of the European Association for the Study of the Liver (EASL 2008). Milan, Italy. April 23-27, 2008.