Clinical trial NCT04391608: TDF Dose Adjustment VS. Switching to TAF in TDF-experienced CHB Patients With Renal Impairment
Official title: Randomized Trial of Tenofovir Disoproxil Fumerate Dose Adjustment VS. Switching to Tenofovir Alafenamide in Tenofovir Disoproxil Fumarate-experienced Chronic Hepatitis B Patients With Renal Impairment
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Renal Insufficiency
Tenofovir
Keywords: Tenofovir
Tenofovir disoproxil fumarate
Tenofovir alafenamide
TDF
TAF
Renal
Impairment
Insufficiency
Lead sponsor: Mahidol University
Sponsor class: OTHER
First posted: 2020-05-18
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Tenofovir is a nucleotide analog drug that works against both Human immunodeficiency virus (HIV) and HBV. TDF and TAF are prodrug of Tenofovir. TAF has a higher plasma stability than TDF, which makes TDF require a higher dose to get the concentration of drugs in the liver equal to the amount of TAF.

Previous studies have shown the effects of TAF once daily and TDF once daily on kidney function and bone mass. The efficacy of TAF in virus suppression is comparable to TDF, but the effect on the kidneys and bone mass from TAF has less side effects than TDF. In addition, changing the medication from TDF to TAF shows that kidney function tends to improve.

Hepatitis B patients taking TDF have adjusted their dosage due to impair renal function, for example, from 1 time per day to every 48 hours or every 72 hours. This group of patients does not have a clear evidence-based recommendation for choosing a reduced dose of TDF or change to TAF. Therefore, the main objective of this study is to study patients with hepatitis B who have taken TDF and have renal function impairment that have been adjusted. Taking the same medicine with dose adjustment or changing the drug to TAF which treatment will more improve the kidney function.

Detailed description: Hepatitis B virus is a global public health problem. More than 250 million people are infected worldwide. These infections lead to chronic hepatitis, cirrhosis and liver cancer. According to past statistics, infection with hepatitis B virus is an important factor of death in 880,000 patients per year.

Patients who receiving natural immunity or receiving antiretroviral therapy that loss of hepatitis B surface antigen (HBsAg loss) reduce the risk of cirrhosis and hepatocellular carcinoma (HCC). HBsAg loss is now considered the target of treatment.

Nucleot(s)ide is an antiviral drug that can reduce the number of viruses, reduce the risk of HCC and death from Hepatitis B viral infection. The most widely used drugs are Lamivudine (LMV), Entecavir (ETV), Tenofovir disoproxil fumerate (TDF) and Tenofovir alafenamide (TAF). However, Nucleotide is unable to eliminate the Hepatitis B virus from the liver cells of the infected person due to covalently closed. circular DNA (cccDNA), which is a template for viral replication. Therefore, long-term Nucleotide therapy is necessary. As a result, patients may have side effects from the treatment when taking medication for a long time, such as viral resistance in Lamivudine, deterioration of kidney function and osteoporosis in Tenofovir.

Tenofovir is a nucleotide analog drug that works against both Human immunodeficiency virus (HIV) and HBV. TDF and TAF are prodrug of Tenofovir. TAF has a higher plasma stability than TDF, which makes TDF require a higher dose to get the concentration of drugs in the liver equal to the amount of TAF.

The side effects of Tenofovir treatment found on the kidneys and bones which are problems for long-term treatment. It is recommended to reduce the dose of TDF in patients with renal function reduced to less than 50 ml / min as shown in Table but do not have to adjust the dose of TAF except when the GFR value is less than 15 ml / min. it is recommended to stop taking TAF if severe renal impairment.

Previous studies have shown the effects of TAF once daily and TDF once daily on kidney function and bone mass. The efficacy of TAF in virus suppression is comparable to TDF, but the effect on the kidneys and bone mass from TAF has less side effects than TDF. In addition, changing the medication from TDF to TAF shows that kidney function tends to improve. Therefore, there is a recommendation in the practice guideline to change from TDF to TAF or ETV in patients who use TDF and there is a risk of kidney problems or thin bone mass based on history for LMV resistance (if LMV resistance, ETV should not be used because HBV is more resistant to ETV).

Hepatitis B patients taking TDF have adjusted their dosage due to impair renal function, for example, from 1 time per day to every 48 hours or every 72 hours. This group of patients does not have a clear evidence-based recommendation for choosing a reduced dose of TDF or change to TAF. Therefore, the main objective of this study is to study patients with hepatitis B who have taken TDF and have renal function impairment that have been adjusted. Taking the same medicine with dose adjustment or changing the drug to TAF which treatment will more improve the kidney function.

Eligibility criteria: Inclusion Criteria:

1. Age between 18 - 75 years old
2. Chronic hepatitis B virus infection
3. Reduced renal function and need to adjust the dose of TDF
4. Have an eGFR of \> 15 ml / min.
5. HBV DNA viral load levels \< 10 U/mL in the last 3 months before participating in the project
6. No HCC by Ultrasonography of the upper abdomen or CT 3-phase of liver or MRI liver in the 3 months before participating in the project.

Exclusion Criteria:

1. HIV infection or hepatitis C or hepatitis D co-infection
2. Decompensated cirrhosis, including variceal bleeding, ascites, hepatic encephalopathy
3. Active hepatocellular carcinoma or during the 3 years after treatment
4. Solid organ transplantation or Bone marrow transplantation
5. Chronic kidney disease caused by glomerulonephritis, tubulo-interstitial nephritis), Obstructive uropathy or autosomal dominant polycystic kidney, and Kidney disease from other causes
6. Diabetes with HbA1c\> 8 or uncontrollable hypertension
7. Active malignancy of cancer in other organs in the last 3 years
8. History of receiving non-steroidal anti-inflammatory drugs (NSAIDs) or other nephrotoxic drugs within the past 1 month (except tenofovir) (For patients receiving NSAIDS after participating in this study, patients were advised to stop taking NSAIDs but not exclude from the study)
9. Receive immunosuppressive drug
10. Pregnancy

Primary outcomes:
measure: Renal safety assessed by changes in eGFR
timeFrame: 48 weeks
Secondary outcomes:
measure: Renal safety assessed by changes in urine sugar (0 to 4+)
timeFrame: 48 weeks
measure: Renal safety assessed by changes in urine protein creatinine ratio
timeFrame: 48 weeks
measure: Renal safety assessed by changes in urine ß2-microglobulin (µg/mL)
timeFrame: 48 weeks
measure: Renal safety assessed by changes in urine phosphate (mg/dL)
timeFrame: 48 weeks
measure: Renal safety assessed by changes in urine neutrophil gelatinase-associated lipocalin (NGAL) (ng/mL)
timeFrame: 48 weeks
measure: Efficacy of viral suppression assessed by amount of hepatitis B (HBV DNA) (IU/mL)
timeFrame: 48 weeks
Other outcomes:
Locations:
city: Bangkok Noi
country: Thailand
facility: Faculty of Medicine Siriraj Hospital, Mahidol University
state: Bangkok
Study officials:
affiliation: Mahidol University
name: Watcharasak Chotiyaputta, Asso Prof
role: PRINCIPAL_INVESTIGATOR
References: