Kidney Toxicity Uncommon among People Taking Tenofovir for Hepatitis B

By Liz Highleyman

At the European Association for the Study of the Liver's International Liver Congress (EASL 2011) this month in Berlin, investigators presented findings from 2 studies of tenofovir side effects in people treated for hepatitis B.

Kidney Function

Patrick Marcellin and colleagues analyzed the effect of tenofovir on kidney function among 675 chronic hepatitis B patients in 3 large randomized clinical trials, Gilead's Study 102, 103, and 106. The first 2 studies compared tenofovir vs adefovir (Hepsera) for 48 weeks, then patients could continue open-label tenofovir through 8 years. Study 106 compared tenofovir alone vs tenofovir plus emtricitabine (Emtriva). These studies included only HIV negative people; another analysis presented at EASL looked at HIV/HBV coinfected patients.

Overall, about 75% of study participants were men, nearly 60% were white, about 30% were Asian, and less than 5% were black. The median age was 41 years and more than three-quarters were younger than 50. Just over 40% were hepatitis B "e" antigen (HBeAg) positive. Some patients had and some had not previously used adefovir, a related nucleotide analog that can also cause kidney toxicity.

With regard to other kidney risk factors, about 15% had a history of hypertension (high blood pressure) and about 5% had diabetes. At baseline, less than 1% had poor creatinine clearance (< 50 mL/min) and about 8% had somewhat impaired clearance (50-80 mL/min).

Researchers analyzed data collected through 144 weeks, evaluating kidney function based on serum creatinine and estimated glomerular filtration rate (eGFR) using the Cockcroft-Gault equation. Kidney events were defined as either a confirmed increase in serum creatinine by at least 0.5 mg/dL from baseline or confirmed eGFR < 50 mL/min.

Among 426 treatment-naive patients receiving tenofovir, there was a low incidence of kidney events through 144 weeks of treatment. No treatment-naive study participants had confirmed eGFR < 50 mL/min; 2 patients (0.5%) had at least a 0.5 mg/dL increase in creatinine. Results did not differ significantly between subgroups with and without hypertension or diabetes.

Among 249 adefovir-experienced study participants, 1 person (0.4%) had confirmed eGFR < 50 mL/min and 3 (1.2%) experienced at least a 0.5 mg/dL increase in creatinine. Again, results were similar for patients with and without hypertension or diabetes, though numbers were small.

Based on these findings, the researchers concluded, "Tenofovir monotherapy over 144 weeks was safe and well tolerated without clinically relevant changes in renal function across a broad range of patient populations including those with co-morbidities typically associated with renal impairment."

Overall, they continued, "few patients experienced a decline in renal function." Taken together, 5 of 675 patients (0.7%) had at least a 0.5 mg/mL increase in creatinine (including 3 with pre-existing hypertension and 1 with pre-existing diabetes). Just 1 patient (0.1%), who had pre-existing hypertension, had an eGFR decline to < 50mL/min.

The investigators noted, however, that the lack of a placebo group in these long-term studies -- as opposed to a control group that took a different potentially kidney-toxic drug -- "makes conclusions concerning the potential role of tenofovir in decreasing renal function more difficult to assess."

Bone Loss

As described in a related poster, an international team of investigators looked at prevalence of bone problems among chronic hepatitis B patients.

Metabolic bone disease is a known potential complication among people with chronic liver disease. Since tenofovir has been linked to bone loss, it would be useful to know how many people in the hepatitis B patient population might be especially prone to this side effect.

Gilead's Study GS-US-174-0121 randomly assigned 250 lamivudine (Epivir-HBV)-resistant chronic hepatitis B patients to receive either tenofovir alone or tenofovir plus emtricitabine. About 75% were men, the median age was 48 years, 60% were white, 35% were Asian, 48% were HBeAg positive, and the average body mass index was 25.1; less than 2% had thyroid disease or a history of past fractures.

Study participants underwent dual energy x-ray absorptiometry (DEXA) scans of the spine and hip prior to starting study drugs. The researchers found that more people had reduced bone mineral density according to baseline DEXA scans than had bone loss reported in their medical records; 6 had osteopenia, or low bone density, while 4 had more severe osteoporosis.

There was some indication that duration of chronic HBV infection and HBeAg status may contribute to greater risk of reduced bone density, but duration of treatment with lamivudine or adefovir did not appear to have an effect.

"In our study, baseline median Z- and T- scores [standard measures of bone density] suggest that males and Asians have greater reductions in bone mineral density compared to females and non-Asians," the researchers reported.

"Our data demonstrate a higher prevalence of baseline bone disease among patients with chronic HBV," they concluded. "Duration of chronic HBV but not duration of treatment appears to impact bone mineral density."

Investigator affiliations:

Marcellin et al: Hopital Beaujon, Clichy, France; Toronto Western Hospital, University of Toronto, Toronto, Canada; Universitätsklinik Leipzig, Leipzig, Germany; Gilead Sciences, Inc., Durham, NC; Gilead Sciences, Inc., Foster City, CA.

Fung et al: University Health Network, Toronto General Hospital, Toronto, Canada; Clinical Centre Vojvodina, Clinic of Infectious Diseases, Clinical Centre of Serbia, Novi Sad, Serbia; Toronto Western Hospital, University Health Network, Toronto, Canada; Uludag University Medical Faculty Hospital, Bursa, Turkey; Hepatitis Program, Vancouver Hospital, Vancouver, BC, Canada; Prof. Dr. Matei Bals Institute for Infectious Diseases, Bucharest, Romania; Faculty Hospital Brno and Faculty of Medicine, Masaryk University Brno, Brno, Czech Republic; Clinical Department of Infectious Diseases, Silesian Medical School, Chorzów, Poland; Clinic for Infectious and Tropical Diseases, Belgrade, Serbia; Auckland City Hospital, Auckland, New Zealand; Gilead Sciences Inc., Durham, NC.

4/19/11

References

P Marcellin, EJ Heathcote, T Berg, et al. Effects of tenofovir disoproxil fumarate on renal function in chronic HBV patients in three global randomized studies. 46th Annual Meeting of the European Association for the Study of the Liver (EASL 2011). Berlin. March 30-April 3. Abstract 616.

S Fung, M Fabri, F Wong, et al. Reduced bone mineral density derived from dual x-ray absorptiometry assessments in patients with chronic hepatitis B (CHB). 46th Annual Meeting of the European Association for the Study of the Liver (EASL 2011). Berlin. March 30-April 3. Abstract 175.