Tenofovir Alone Versus Tenofovir With Emtricitabine to Treat Chronic Hepatitis B
| Status: | Terminated |
|---|---|
| Conditions: | Hepatitis |
| Therapuetic Areas: | Immunology / Infectious Diseases |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 10/8/2017 |
| Start Date: | August 29, 2007 |
| End Date: | February 16, 2017 |
Tenofovir Disoproxil Fumarate Alone Versus Its Combination With Emtricitabine for Treatment of Chronic Hepatitis B
This study will test whether the combination of two medications, tenofovir and emtricitabine,
are safer and more effective for treating chronic hepatitis B than tenofovir alone. Chronic
hepatitis B is a liver disease caused by infection with the hepatitis B virus. Several
medications, including standard and pegylated interferon and the anti-viral drugs lamivudine,
adefovir, entecavir and telbivudine, are currently used to treat the disease. Problems are
associated with all of these agents, however, including development of viral resistance with
long-term therapy of the anti-virals. Since many patients require long-term therapy to
prevent their disease from worsening, a major goal of new approaches to treatment is to
prevent the development of viral resistance. Combination treatment has been shown to be an
effective strategy in preventing this resistance.
Tenofovir is an anti-viral drug approved for use in patients with HIV infection. In small
studies in patients infected with both HIV and hepatitis B, tenofovir lowered the level of
hepatitis B virus in the blood, with no viral resistance reported when used for up to 5
years. Emtricitabine is an anti-viral drug similar to lamivudine and is effective at lowering
viral load and improving liver damage.
Patients 18 years of age and older with chronic hepatitis B may be eligible for this study.
Participants are admitted to the NIH Clinical Center for a complete medical history and
examination, including blood and urine tests, chest X-ray, electrocardiogram, abdominal
ultrasound, Fibroscan (ultrasound exam of the liver that measures the amount of scarring),
bone mineral density scan and liver biopsy. They are then randomly assigned to take
combination treatment with tenofovir plus emtricitabine or tenofovir alone for at least 48
weeks. During the treatment period, patients visit the Clinical Center for blood tests and a
physical examination every 2 weeks for the first month and then every 4 to 12 weeks. After 48
weeks, patients are readmitted to the Clinical Center for a complete evaluation that includes
all the tests done at the start of therapy, including a liver biopsy. Patients who seem to
have improved with treatment may continue therapy for up to 192 weeks, when they are again
admitted to the Clinical Center for a complete medical evaluation and liver biopsy. Patients
whose condition has not improved after 48 weeks of treatment have their treatment changed or
stopped and continue to have regular outpatient clinic visits for 24 more weeks.
are safer and more effective for treating chronic hepatitis B than tenofovir alone. Chronic
hepatitis B is a liver disease caused by infection with the hepatitis B virus. Several
medications, including standard and pegylated interferon and the anti-viral drugs lamivudine,
adefovir, entecavir and telbivudine, are currently used to treat the disease. Problems are
associated with all of these agents, however, including development of viral resistance with
long-term therapy of the anti-virals. Since many patients require long-term therapy to
prevent their disease from worsening, a major goal of new approaches to treatment is to
prevent the development of viral resistance. Combination treatment has been shown to be an
effective strategy in preventing this resistance.
Tenofovir is an anti-viral drug approved for use in patients with HIV infection. In small
studies in patients infected with both HIV and hepatitis B, tenofovir lowered the level of
hepatitis B virus in the blood, with no viral resistance reported when used for up to 5
years. Emtricitabine is an anti-viral drug similar to lamivudine and is effective at lowering
viral load and improving liver damage.
Patients 18 years of age and older with chronic hepatitis B may be eligible for this study.
Participants are admitted to the NIH Clinical Center for a complete medical history and
examination, including blood and urine tests, chest X-ray, electrocardiogram, abdominal
ultrasound, Fibroscan (ultrasound exam of the liver that measures the amount of scarring),
bone mineral density scan and liver biopsy. They are then randomly assigned to take
combination treatment with tenofovir plus emtricitabine or tenofovir alone for at least 48
weeks. During the treatment period, patients visit the Clinical Center for blood tests and a
physical examination every 2 weeks for the first month and then every 4 to 12 weeks. After 48
weeks, patients are readmitted to the Clinical Center for a complete evaluation that includes
all the tests done at the start of therapy, including a liver biopsy. Patients who seem to
have improved with treatment may continue therapy for up to 192 weeks, when they are again
admitted to the Clinical Center for a complete medical evaluation and liver biopsy. Patients
whose condition has not improved after 48 weeks of treatment have their treatment changed or
stopped and continue to have regular outpatient clinic visits for 24 more weeks.
Chronic hepatitis B is a major cause of cirrhosis, end-stage liver disease and hepatocellular
carcinoma and affects approximately 1.25 million Americans. Six medications have been
licensed for use in chronic hepatitis B in the United States, but their relative benefit and
long-term efficacy remain unclear. In previous studies, we have shown that maintained
suppression of HBV DNA can be achieved with nucleoside analogues and that suppression is
associated with marked improvements in disease. In this randomized study, we propose to
evaluate long-term therapy with tenofovir alone or in combination with emtricitabine (FTC).
Forty treatment-naive patients with chronic hepatitis B will be enrolled in the primary
study. After medical evaluation and liver biopsy, patients will be stratified by hepatitis B
e antigen (HBeAg) status and randomized to receive either tenofovir alone or in combination
with FTC. Treatment will be continued long-term (at least four years) and patients will be
carefully monitored for side effects, serum aminotransferase and HBV DNA levels. Patients
will undergo repeat liver biopsy and assessment of antiviral resistance at 1 and 4 years. The
primary endpoint of therapy will be the maintained suppression of HBV DNA to below 10(2)
copies/ml (lower limit of detection of current assays). The study will assess the relative
efficacy and safety of combination versus mono-therapy. A separate group of 60 previously
treated patients will also be enrolled and randomized to mono- or combination-therapy to
assess the safety profile of these agents. The primary analysis will be conducted on the
entire study cohort.
carcinoma and affects approximately 1.25 million Americans. Six medications have been
licensed for use in chronic hepatitis B in the United States, but their relative benefit and
long-term efficacy remain unclear. In previous studies, we have shown that maintained
suppression of HBV DNA can be achieved with nucleoside analogues and that suppression is
associated with marked improvements in disease. In this randomized study, we propose to
evaluate long-term therapy with tenofovir alone or in combination with emtricitabine (FTC).
Forty treatment-naive patients with chronic hepatitis B will be enrolled in the primary
study. After medical evaluation and liver biopsy, patients will be stratified by hepatitis B
e antigen (HBeAg) status and randomized to receive either tenofovir alone or in combination
with FTC. Treatment will be continued long-term (at least four years) and patients will be
carefully monitored for side effects, serum aminotransferase and HBV DNA levels. Patients
will undergo repeat liver biopsy and assessment of antiviral resistance at 1 and 4 years. The
primary endpoint of therapy will be the maintained suppression of HBV DNA to below 10(2)
copies/ml (lower limit of detection of current assays). The study will assess the relative
efficacy and safety of combination versus mono-therapy. A separate group of 60 previously
treated patients will also be enrolled and randomized to mono- or combination-therapy to
assess the safety profile of these agents. The primary analysis will be conducted on the
entire study cohort.
- INCLUSION CRITERIA (nucleoside analogue-naive subjects):
- Age greater than 18 years and older, male or female.
- Known serum HBsAg positivity for 24 weeks.
- Detectable HBV DNA greater than 10(4) IU/ml. For patients with cirrhosis HBV DNA
greater than 10(3) IU/ml
- Serum ALT or AST levels 1.5 times the upper limit of normal (for ALT: greater than or
equal to 62 U/L and for AST greater than or equal to 46 U/L) based on at least two
determinations taken at least one month apart during the 24 weeks before study entry;
no ALT requirement for patients with cirrhosis.
- Liver biopsy within 2 years of entry that is consistent with chronic hepatitis and
with a histology activity index (HAI) score of 4 or more (scores range from 0-18) and
an Ishak fibrosis score of at least 1 (scores range from 0-6). For patients who have
had a liver biopsy at another institution, slides must be obtained for reading and
scoring at the NIH.
- Written informed consent.
INCLUSION CRITERIA SALVAGE STUDY (nucleoside analogue experienced subjects):
- Age >18 years and older, male or female
- Known serum HBsAg positivity for 6 months
- Detectable HBV DNA >10(2) IU/ml.
- Liver biopsy within 5 years of entry that is consistent with chronic hepatitis
- Written informed consent
INCLUSION CRITERIA: SALVAGE STUDY (relapsers)
- Age greater than 18 years and older, male or female.
- Known serum HBsAg positivity for 6 months.
- Detectable HBV DNA greater than 10(3) IU per milliliter.
- Liver biopsy within 5 years of entry that is consistent with chronic hepatitis.
- Written informed consent.
Serum ALT or AST levels 1.5 times the ULN (for ALT: greater than 62 U/L and for AST:
greater than 46 U/L) based on at least two determinations taken at least 2 weeks apart.
EXCLUSION CRITERIA:
- Previous or current treatment with tenofovir or emtricitabine.
- Co-infection with HDV as defined by the presence of anti-HDV in serum and/or HDV
antigen in the liver.
- Co-infection with HCV as defined by the presence of HCV RNA in serum.
- Co-infection with HIV as defined by the presence of anti-HIV in serum.
- Decompensated liver disease as defined by serum bilirubin greater than 2.5 milligram
per deciliter (with direct bilirubin greater than 0.5 milligram per deciliter),
prothrombin time of greater than 2 seconds prolonged, a serum albumin of less than 3
grams per deciliter, or a history of ascites, variceal bleeding or hepatic
encephalopathy.
- Presence of other causes of liver disease (i.e. hemochromatosis, Wilson disease,
alcoholic liver disease, nonalcoholic steatohepatitis, alpha-1anti-trypsin
deficiency).
- A history of organ transplantation or in the absence of organ transplantation, any
immunosuppressive therapy requiring the use of more than 5 milligrams of prednisone
(or its equivalent) daily.
- Significant systemic illness other than liver diseases including congestive heart
failure, renal failure, chronic pancreatitis, diabetes mellitus with poor control that
in the opinion of the investigator may interfere with therapy.
- Pregnancy or inability to practice contraception in patients capable of bearing or
fathering children and lactating women.
- Hepatocellular carcinoma (HCC), or the presence of a mass on imaging studies of the
liver that is suggest of HCc, or an alpha-fetoprotein level of greater than 500ng/mL.
- History of clinically apparent pancreatitis or evidence of subclinical pancreatitis as
shown by serum amylase values twice the upper limits of the normal range and
abnormalities of the pancreas on CT or other imaging studies of the abdomen.
- Sensory or motor neuropathy apparent from medical history and physical examination.
- Creatinine clearance less than 50 ml/min, serum creatinine greater than 1.3 mg/dl or
urine protein greater than 1 gram/24 hours; creatinine clearance will be determined on
the average of two 24 hour urine specimens. Accuracy of collection will be ensured by
documenting appropriate total creatinine excretion in the 24 hour urine specimen
(15mg/kg) and correcting for the patient's age, gender and body surface area.
- Concurrent use of nephrotoxic agents (e.g. aminoglycosides, amphotericin B,
vancomycin, foscarnet, cis-platinum, pentamidine, nonsteroidal anti-inflammatory
agents) or competitors of renal tubular excretion (e.g. probenecid) within 2 months
prior to study screening or the expectation that the subject will receive these during
the course of the study.
- History of hypersensitivity to nucleoside analogues.
- Active ethanol/drug abuse/psychiatric problems such as major depression,
schizophrenia, bipolar illness, obsessive-compulsive disorder, severe anxiety,
personality disorder that, in the investigator's opinion, might interfere with
participation in the study.
- History of renal tubular acidosis.
- History of malignancy or treatment for a malignancy within the past 5 years.
- Presence of conditions that, in the opinion of the investigators, would not allow the
patient to be followed in the current study for at least 5 years.
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
Phone: 800-411-1222
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