- Category: HBV Treatment
- Published on Tuesday, 13 November 2012 00:00
- Written by Liz Highleyman
Tenofovir (Viread) continues to be safe and highly effective for treating chronic hepatitis B through 8 years of follow-up, researchers reported at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012) this week in Boston. Another study showed minimal bone loss among tenofovir-treated patients using the FRAX method.
Several nucleoside/nucleotide analogs are active against hepatitis B virus (HBV), but with long-term use HBV develops resistance to older drugs like lamivudine (Epivir-HBV), thereby compromising sustained effectiveness.
Tenofovir disoproxil fumarate -- which has potent activity against both HBV and HIV -- has a higher barrier to resistance. Gilead Study 102 and 103 showed that it maintains HBV DNA suppression, is well-tolerated, and shows no evidence of resistance through 6 years for previously untreated chronic hepatitis B patients.
Scott Fung from Toronto General Hospital and colleagues conducted a Phase 3b study of tenofovir for treatment-experienced hepatitis B patients. Participants were receiving lamivudine at study entry but had HBV viral load of 1000 IU/mL or more and documented lamivudine resistance (e.g., M204I/V or L180M mutations); some had also used adefovir (Hepsera) for no more than 48 weeks.
The analysis included 280 participants, about half of whom were hepatitis B "e" antigen (HBeAg) positive. Approximately two-thirds were enrolled in Europe and one-third in North America. They had been infected with HBV for 10 years on average and had been taking lamivudine for about 4 years.
About three-quarters of participants were men, about 60% were white, about 35% were Asian, and the average age was about 47 years. HBV genotype A was most common (22%), followed by B (14%), C (19%), and D (45%). At baseline the mean HBV DNA level was about 6.5 log copies/mL.
About 60% of participants had elevated alanine aminotransferase (ALT) at study entry. People with pre-existing kidney function impairment (creatinine clearance < 50 mL/min) were excluded, as were individuals with HIV or hepatitis C coinfection. At baseline about 30% of patients had evidence of low bone density (osteopenia or osteoporosis) on spine DEXA scans and about 20% had bone loss in hip scans.
Participants were randomly assigned to take tenofovir alone or coformulated tenofovir/emtricitabine (Truvada, approved for HIV treatment). Safety and efficacy were evaluated over 96 weeks.
Assessments included kidney biomarkers (serum creatinine, creatinine clearance, serum phosphorus) because tenofovir can cause kidney toxicity in susceptible individuals, and DEXA bone density scans because the drug has been linked to bone loss in people with HIV.
- About 90% of participants in both study arms completed 96 weeks of treatment.
- An intent-to-treat analysis at 96 weeks showed good -- and statistically equivalent -- efficacy in the tenofovir monotherapy and tenofovir/emtricitabine arms:
o Undetectable HBV DNA (< 400 copies/mL or < 69 IU/mL): 89% vs 86%, respectively;
o ALT normalization: 62% vs 63%, respectively;
o HBeAg loss: 15% vs 13%, respectively;
o HBeAg seroconversion: 11% vs 10%, respectively;
o Hepatitis B surface antigen (HBsAg) loss: 0 and 1 patients, respectively.
- No tenofovir resistance was detected in 18 tested participants through 96 weeks.
- Both treatments were generally well-tolerated.
- Only 1 patient experienced a serious adverse event.
- 3 people (1%) discontinued treatment due to adverse events.
- No participants had a confirmed serum creatinine increase of > 0.5 mg/dL from baseline, 1% had reduced serum phosphorus < 2 mg/dL, and 3% had creatinine clearance < 50 mL/min (most of whom had below normal kidney function at baseline).
- No clinically relevant bone loss was observed according to spine and hip bone mineral density T-scores and Z-scores, which compare bone density to population norms.
- 5 people experienced trauma-associated bone fractures, but no non-traumatic fractures -- those due to fragility in the absence of injury -- were reported.
Based on these findings the researchers concluded, "A high rate of HBV DNA suppression with no detectable [tenofovir] resistance was achieved with [tenofovir] in patients with documented lamivudine resistance through 96 weeks."
"Similar efficacy between the [monotherapy] and combination therapy arms supports the use of [tenofovir] monotherapy in this population," they continued. "[Tenofovir] was safe and well tolerated, with a low rate of renal events and no evidence of clinically relevant bone loss."
Since the 2 treatments were equally safe and effective, Fung said that tenofovir alone should be considered adequate.
In a related study, Upkar Gill from the Institute of Cell and Molecular Science in London and colleagues looked specifically at bone mineral density changes among chronic hepatitis B patients taking tenofovir.
The study was designed to show whether the World Health Organization's FRAX score is consistent with DEXA scans and bone-related biomarkers (e.g., serum alkaline phosphatase and calcium levels) for determining bone loss in this population, as the WHO method is less expensive and can be widely used in resource-limited settings.
FRAX is a web-based tool that combines several variables to calculate 10-year fracture risk, including sex, age, body mass index, individual and family history of fractures, smoking, and use of alcohol or steroids. The FRAX score may help determine which individuals could benefit from DEXA scans, ongoing monitoring, and lifestyle modification to reduce their risk.
The analysis included 122 hepatitis B patients who had used tenofovir for at least 48 weeks, and 48 individuals not exposed to the drug. About 70% were men, two-thirds were Asian, and the rest were about evenly split between black and white participants. The median age was 45 years in the tenofovir group and 36 in the control group. The tenofovir group had similar proportions of people with mild, moderate, and severe liver fibrosis, but in the control group nearly two-thirds had mild fibrosis. About 10% of participants were smokers and about 16% said they drank alcohol.
- Tenofovir recipients had a significantly lower average hip T-score than unexposed patients.
- T-scores for the lumbar spine and femoral neck (hip joint), however, did not differ significantly.
- Small changes in bone density were seen soon after starting tenofovir, but levels soon reached a plateau with no further bone loss progression.
- There was no correlation between duration of tenofovir use and bone loss at any site.
- There was no overall correlation between bone biochemistry and changes in bone mineral density.
- Tenofovir recipients had a tendency towards increased serum alkaline phosphatase, but the difference did not reach statistical significance.
- In a univariate analysis, older age, body mass index, smoking, and tenofovir use were all significant risk factors for bone loss.
- In a multivariate analysis controlling for other factors, however, the effect of tenofovir was no longer significant.
- Overall, 75% of tenofovir-exposed patients were determined to have a low risk of fractures according to pre-DEXA FRAX scores, and none required treatment for bone loss.
- FRAX score predicted major hip fractures as well as DEXA scans and did not miss any high-risk patients:
o Sensitivity: 100%;
o Specificity: 84%;
o Negative predictive value: 100%;
o Positive predictive value: 40%.
"We demonstrate the utility of FRAX as an alternative tool to assess fracture risk over time," the researchers concluded. "We recommend the use of FRAX to consolidate treatment decisions in chronic hepatitis B," reducing the need for costly DEXA scans, they added.
Using this method, Gill explained, people with low risk for bone fractures can be reassured, medium-risk patients can be monitored, and high-risk individuals can receive interventions.
S Fung, P Kwan, M Fabri, et al. Efficacy and Safety of Tenofovir DF (TDF) in Chronic Hepatitis B Virus Infected Patients with Documented Lamivudine Resistance (LAM-R). 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract 20.
U Gill, A Zissimopoulos, S Al-shamma, et al. FRAX score in the assessment of Bone Mineral Density changes in Tenofovir treated Chronic Hepatitis B patients: comparison with bone biochemistry and DEXA scanning. 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract 22.