Efficacy and Safety of TAF in Patients With Suboptimal Response to Other Nucleos(t)Ides

Efficacy and Safety of Tenofovir Alafenamide in Chronic Hepatitis B Patients With Suboptimal Response Following Nucleos(t)Ide Therapy

Both tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are potent antiviral agents for hepatitis B virus (HBV) and recommended by the American Association for the Study of Liver Disease (AASLD) as well as the European Association for the Study of Liver (EASL) guidelines for the treatment of nucleos(t)ide therapy induced HBV resistance. However, it is not clear if chronic hepatitis B (CHB) patients with nucleos(t)ide treatment experience without genotypic mutations would be benefit from TAF therapy. Previous studies have observed that suboptimal response (SOR) following antiviral therapy with nucleos(t)ide treatment is associated with an increased risk of subsequent treatment failure and viral resistance. It remains unclear whether switching to TAF is a reasonable approach in patients with SOR to second-line antivirals Lamivudine (LAM)/ Telbivudine (LdT)/ Adefovir Dipivoxil (ADV) and its combinations with other second-line antivirals for 24 weeks, or SOR to the first-line antiviral Entecavir (ETV) or any antiviral combinations containing ETV for 48 weeks. This study is aimed to determine how the aforementioned patients with SOR to nucleos(t)ide treatment respond to TAF monotherapy. The investigator's study will provide evidence base for therapy selection in SOR patients, especially in China where the majority of patients with CHB are treated with nucleos(t)ide therapy.

This is a prospective, single-arm, multicenter cohort study evaluating the efficacy, safety, and tolerability of TAF monotherapy in in Asian CHB adults with SOR to the nucleos(t)ide therapy by assessing the HBV DNA suppression in 48 weeks. Approximately one hundred adults who received the aforementioned nucleos(t)ide therapy will be prospectively enrolled during the period from December 2019 to June 2021. Subjects will be enrolled by medical clinic in about 10 university centers in different regions in China. Approximately 10-15 consecutive eligible patients will be enrolled from each participating sites. This study will be conducted in accordance with the guidelines of Good Clinical Practices (GCPs) including Institutional Review Board (IRB) approval and consent will be applied. Patient identification (ID) will be de-identified for submitting to the central database for analyses from all study sites. Free TAF treatment will be provided to all enrolled patients for 48 weeks. Patients will be under the local standard of care upon the completion of the current study.

Patients aged 18-80 with CHB infection who had received nucleos(t)ide therapy over 24 weeks of LAM/LdT/ADV or 48 weeks of ETV with medication adherence, but failure to achieve the levels of HBV-DNA below 300 IU/mL will be eligible. Subjects will be excluded if they meet the following criteria: co-infected with HIV or other viral hepatitis; the serum levels of HBV DNA are too low (i.e. about 300 IU/mL) to be analyzed for the genotypic mutation(s); nucleos(t)ide resistant mutants have been detected at screening visit, patient is under a clinical research protocol of phase I-III development; unable to consent or unlikely to complete one year follow up after the enrollment; and other medical condition may affect the ability to participate the study.

Inclusion Criteria:

• Patients must be 18-80 years of age.

• Patients must have documented compensated and stable chronic hepatitis B defined by all of the following:

  • HBsAg persistently positive > 6 months.
  • Clinical history, physical findings, and test results are compatible with compensated chronic hepatitis B

• Patients must have received nucleos(t)ide therapy consisting of LAM/LdT/ADV and its combinations with other second-line antivirals for 24 weeks, or with the first-line antiviral ETV or any antiviral combinations containing ETV for 48 weeks with medication adherence.

• Although having undergone therapy, patients have had failure to achieve the levels of HBV-DNA below 300 IU/mL.

• Patient is willing and able to comply with the study drug regimen and all other study requirements.

• Patient must understand the risk, and be willing and able to provide written informed consent to participate in the study.

Exclusion Criteria:

• Pregnant women, and women who are breastfeeding or who believe they may wish to become pregnant during the course of the study.

• Males and females of reproductive potential who are not willing to use an effective method of contraception during the study. For males, condoms should be used and for females, a barrier contraception method should be used in combination with one other form of contraception.

• Unwilling and/or unable to provide written informed consent

• Patients with CHB but are also co-infected with HIV or other viral hepatitis

• Patients whose serum levels of HBV DNA are too low (i.e. about 300 IU/mL) to be analyzed for the genotypic mutation(s) at the onset of this trial, i.e. baseline

• At the screening visit, nucleos(t)ide resistant mutants have been detected in the strain of HBV of the patient

• The patient is under a clinical research protocol of phase I-III development; unable to consent or unlikely to complete one year follow up after the enrollment; and other medical condition may affect the ability to participate the study.

• Decompensated liver disease defined as direct (conjugated) bilirubin ≥ 1.2 Upper Limit of Normal (ULN); Prothrombin Time (PT) ≥ 1.2 ULN, platelets ≤ 150,000/mm3, or serum albumin ≤ 3.5 g/dL

• Prior history of clinical hepatic decompensation (e.g., ascites, jaundice, encephalopathy) or variceal hemorrhage

• Serum α-fetoprotein ≥ 50 ng/mL

• Evidence of hepatocellular carcinoma (HCC)

• History of significant renal disease (e.g., nephrotic syndrome, renal dysgenesis, polycystic kidney disease, congenital nephrosis, acute tubular necrosis, other renal disease)

• History of significant bone disease (e.g., osteomalacia, chronic osteomyelitis, osteogenesis imperfecta, osteochondrosis, multiple bone fractures)

• Significant cardiovascular, pulmonary or neurological disease

• Evidence of a gastrointestinal malabsorption syndrome that may interfere with absorption of orally administered medications

• History of solid organ or bone marrow transplantation

• Ongoing therapy with any of the following: Nephrotoxic agents

  • Parenteral aminoglycoside antibiotics (e.g., gentamicin, tobramycin, amikacin)
  • Cidofovir
  • Cisplatin
  • Foscarnet
  • IV amphotericin B
  • IV pentamidine
  • Oral or IV ganciclovir
  • Cyclosporine
  • Tacrolimus
  • IV vancomycin
  • Chronic daily non-steroidal anti-inflammatory drug therapy
  • Competitors of renal excretion (e.g., probenecid) Systemic chemotherapeutic agents
  • Systemic corticosteroids
  • Interleukin-2 (IL-2) and other immunomodulating agents

• Investigational agents (except with the expressed approval of the lead investigators)

Note: administration of any of the above medications must be discontinued at least 30 days prior to the Baseline Visit and for the duration of the study period.

• Known hypersensitivity to the study drugs, the metabolites or formulation excipients
• Any other condition (including alcohol or substance abuse) or prior therapy that, in the opinion of the Investigators, would make the subject unsuitable for the study or unable to comply with dosing requirements