Kidney Toxicity Uncommon among People Taking Tenofovir for Hepatitis B

[Guest guest]

http://www.hivandhepatitis.com/2011_conference/easl2011/docs/0419_2010_b.html

HIV and Hepatitis.com Coverage of the

46th Annual Meeting of the European

Association for the Study of the Liver

March 30 - April 3, 2011, Berlin, Germany

Kidney Toxicity Uncommon among People Taking Tenofovir for Hepatitis B

SUMMARY: People taking tenofovir to treat chronic hepatitis B seldom experience

kidney impairment, and this population does not appear predisposed to bone

problems, researchers reported at EASL 2011.

By Liz Highleyman

Tenofovir (Viread, also in the Truvada and Atripla coformulations) is highly

effective in treating hepatitis B virus (HBV), but it can potentially cause

kidney problems in susceptible individuals and may lead to bone loss over time.

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

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., 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.

[Guest guest]

http://www.hivandhepatitis.com/2011_conference/easl2011/docs/0419_2010_b.html

HIV and Hepatitis.com Coverage of the

46th Annual Meeting of the European

Association for the Study of the Liver

March 30 - April 3, 2011, Berlin, Germany

Kidney Toxicity Uncommon among People Taking Tenofovir for Hepatitis B

SUMMARY: People taking tenofovir to treat chronic hepatitis B seldom experience

kidney impairment, and this population does not appear predisposed to bone

problems, researchers reported at EASL 2011.

By Liz Highleyman

Tenofovir (Viread, also in the Truvada and Atripla coformulations) is highly

effective in treating hepatitis B virus (HBV), but it can potentially cause

kidney problems in susceptible individuals and may lead to bone loss over time.

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

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., 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.