Introduction

Tenofovir disoproxil fumarate is approved for use in chronic hepatitis B and decompensated liver disease; however, it is associated with worsening renal function. In hepatitis patients with renal disease or on hemodialysis, dose adjustment and careful monitoring are required. Phase 3 studies have shown tenofovir alafenamide to have non-inferior efficacy to tenofovir disoproxil fumarate, with improved renal and bone safety.

Aim

To evaluate the safety and efficacy of switching to tenofovir alafenamide in patients with virologically controlled chronic hepatitis B and renal or hepatic impairment.

Patient Profile

• 124 chronic hepatitis B patients who were virally suppressed on nucleoside or nucleotide analogues
• The study consisted of two parts: part A included patients with renal impairment (moderate to severe impairment in cohort 1 [estimated glomerular filtration rate (eGFR) 15–59 mL/min] or end-stage renal disease [eGFR <15 mL/min] on haemodialysis in cohort 2) and part B included moderate or severe hepatic impairment including decompensation (Child–Turcotte–Pugh score 7–12)

  Method

  Study Design

• Open-label, multicentre, phase 2 study
• Participants switched to 25 mg of tenofovir alafenamide given orally once daily for 96 weeks

Endpoints

• Primary efficacy endpoint: proportion of participants with virological response (HBV DNA <20 IU/mL) at week 24
• Secondary efficacy endpoints at weeks 24, 48, and 96: proportion of individuals with virological response (only at weeks 48 & 96); proportion of individuals with virological response and target detected/not detected; proportions of participants with normal serum alanine aminotransferase (ALT) concentrations and normalised ALT concentrations; proportion of participants with loss of HBsAg or loss of HBeAg and seroconversion; change in fibrosis; and change from baseline in CPT and MELD scores in participants with hepatic impairment (part B)
• Primary safety endpoint: incidence of graded adverse events and graded laboratory abnormalities at week 24
• Secondary safety endpoint: incidence of graded adverse events and graded laboratory abnormalities at weeks 48 and 96
• Additional secondary safety endpoints: percentage change from baseline to weeks 24, 48, and 96 in part A and B in hip and spine bone mineral density and in eGFR in part A, cohort 1 and in part B
• Prespecified exploratory safety endpoints: change from baseline to weeks 24, 48, and 96 in renal function measures and quantitative markers of proximal renal tubular function in part A, cohort 1 or part B and serum biomarkers of bone turnover
• Post-hoc endpoints: ALT change at each visit; log₁₀ quantitative HBsAg change at weeks 24, 48, and 96; change in fasting lipids at weeks 24, 48, 72, and 96; shifts from baseline in chronic kidney disease stage in cohort 1 and part B participants; and bodyweight

Results

Efficacy

• Tenofovir alafenamide achieved the primary endpoint of virological response (HBV DNA <20 IU/mL) in 97.8% of individuals in part A and 100% participants in part B at week 24
• The secondary efficacy endpoints are summarized in Table 1

   

  Table 1: Primary, secondary, and post-hoc efficacy responses at weeks 24, 48, and 96

  	Part A (renal impairment)	Part B (hepatic impairment)
  HBV DNA <20 IU/mL at week 24 Target not detected Target detected	97.8% 73.1% 24.7%	100% 77.4% 22.6%
  HBV DNA <20 IU/mL at week 48 Target not detected Target detected	92.5% 65.6% 26.9%	100% 74·2% 25·8%
  HBV DNA <20 IU/mL at week 96 Target not detected Target detected	83.9% 68.8% 15.1%	77·4% 77·4% 0.0%
  Normal aminotransferase Week 24 Week 48 Week 96	88·2% 86·0% 76·3%	80.6% 80.6% 58.1%
  HbeAg loss Week 24 Week 48 Week 96	0.0% 0.0% 6.3%	0.0% 0.0% 0.0%
  HbsAg loss Week 24 Week 48 Week 96	0.0% 1.1% 0.0%	0.0% 3.3% 6.7%
  HbsAg change, log10 IU/mL Week 24 Week 48 Week 96	0.12 0.14 0.23	0.13 0.14 0.17
  Change in Fibro Test Score Week 24 Week 48 Week 96	0.09 0.10 0.11	0.11 0.10 0.12
  Change in CTP Score Week 24 Week 48 Week 96	- - -	1.1 1.1 1.2
  Change in MELD Score Week 24 Week 48 Week 96	- - -	1.9 2.4 1.6

   

  Safety 

• Adverse events occurred in 78.5% and 77.4%, grade 3/4 severity adverse event in 19.4% and 25.8%, and serious adverse event in 22% and 32% in part A and B groups, respectively; none were related to treatment
• Grade 3/4 laboratory abnormalities occurred in 25.8% in part A and 4.8% in Part B
• By week 96, the most common adverse event was upper respiratory tract infection, which occurred in 15% participants in part A and in 19% participants in part B
• No treatment-related deaths occurred
• When assessed over 96 weeks, parameters of kidney function and measures of bone mineral density were stable or improved slightly across both parts of the study: median change in eGFR (Cockcroft– Gault formula) was 1.0 mL/min in cohort 1 and −2.4 mL/min in part B; similar results were seen by the CKD-EPI creatinine formula; after early decrease, quantitative markers of proximal renal tubular function remained stable thereafter; small changes in spine and hip bone mineral density were seen (1.02% & 0.20% in part A and −0.25% & 0.28% in part B) and small decreases occurred in serum biomarkers of bone turnover
• Small to modest median increases in total cholesterol, HDL cholesterol, and triglycerides occurred during treatment in part A and median fasting lipid parameters increased by <10 mg/dL at week 96 in part B, with little change in total cholesterol to HDL ratio from baseline
• Shifts in chronic kidney disease stage indicating worsening renal function occurred in one patient in part A and in two patients in part B
• After 96 weeks, a median increase in bodyweight was observed in part A (1 kg) and B (2.4 kg) participants after 96 weeks of tenofovir alafenamide treatment

Conclusion

• The virological response was maintained upon switching from tenofovir disoproxil fumarate or other antivirals to tenofovir alafenamide for 96 weeks in chronic hepatitis B patients with virological suppression and moderate-to-severe renal impairment, end-stage renal disease, or hepatic impairment
• Tenofovir alafenamide was safe and well tolerated, with no treatment-related grade 3 or grade 4 or serious adverse events; key measures of kidney function and bone density remained stable or improved
• Tenofovir alafenamide exhibited a positive benefit–risk profile in these two populations with chronic hepatitis B
• This study supports the EASL and AASLD guideline recommendations that switching to tenofovir alafenamide can be a suitable option for patients with chronic hepatitis B and renal impairment

Lancet Gastroenterol Hepatol 2024; 9: 718-33