Q3. Safety: Is TAF safe and efficacious in patients with: (1) Renal impairment (2) ESRD on hemodialysis (HD) ?

Safety:
Is TAF safe and efficacious in patients with:
(1) Renal impairment (2) ESRD on hemodialysis (HD) ?

依據 VEMLIDY^® 仿單，對於腎功能不全（估計 CrCl ≥ 15 mL/min）或末期腎病（ESRD）且長期接受血液透析的病人，無須調整 TAF 劑量。血液透析當日，待血液透析治療完成後再投與 TAF ¹。
According to the VEMLIDY US PI, no dose adjustment is required in patients with mild, moderate, or severe renal impairment, or in patients with ESRD (estimated creatinine clearance < 15 mL/min) who are receiving chronic HD. On days of HD, administer VEMLIDY after completion of HD treatment.²
TAF 與下列藥物併用，並未發現任何具臨床意義的藥物交互作用（DDI）：ethinyl estradiol、midazolam、norgestimate、sertraline ¹。
TAF does not have clinically significant DDI with ethinyl estradiol, midazolam, norgestimate, and sertraline.⁴
與腎功能正常的病人相比，重度腎功能不全病人的 TAF 與 TFV 暴露量分別高出 1.9 倍與 5.7 倍（Figure 1）；在腎功能正常的病人，TFV 的暴露量介於 TDF 的暴露量範圍內或更低 ³。
Relative to subjects with normal renal function (estimated CrCl ≥90 mL/min), the TAF and TFV systemic exposures in subjects with severe renal impairment were 1.9-fold and 5.7-fold higher, respectively; the TFV exposure observed was in or below the range of that following administration of TDF in subjects with normal renal function.³

在健康族群與重度腎功能不全病人（估計 CrCl 15 ~ < 30 mL/min），TAF / TFV 的藥物動力學性質沒有臨床上的明顯差異 ^{4<.。
No
clinically relevant differences in TAF or TFV pharmacokinetics
have been
observed between healthy subjects and subjects with severe renal
impairment (estimated CrCl 15 to < 30 mL/min). ⁴}
由 Gilead 執行、探討 TAF 治療 HBV、HIV 或 HBV-HIV 合併感染的試驗中，沒有腎小管病變（renal tubulopathy）或 Fanconi 氏症候群的案例發生 ^5-7。
No cases of renal tubulopathy or Fanconi syndrome have been reported in any of Gilead’s trials evaluating TAF or TAF-based regimens for HBV, HIV, or HIV-HBV coinfection.^5-7
試驗 4035 針對 HBV 已受抑制且併有中至重度腎功能不全或 ESRD （有接受透析治療）的成年病人，評估從 TDF 轉換為 TAF 的療效與安全性 ^8,9。
Study 4035 evaluated the efficacy and safety of switching to TAF in virally suppressed CHB patients with moderate/severe renal insufficiency (eGFR 15 – < 60 mL/min) and ESRD maintained on HD (eGFR < 15 mL/min).^8,9
- 轉換成 TAF 治療 96 週，不僅可維持高比例的病毒抑制率與 ALT 恢復正常（Figure 2），也能維持或促進腎臟與骨骼安全性（Figure 3）⁹。
  Switching from TDF and/or other oral antivirals to TAF resulted in the persistence of high rates of viral suppression and normal ALT levels at week 96 as well as stable/improved renal and bone safety.
- TAF 的整體耐受性良好，不良事件或實驗室數值異常與病人自身的腎臟疾病一致。
  Overall TAF was well tolerated; AEs and laboratory abnormalities were consistent with those seen in patients with underlying renal disease.

對於接受肝臟移植且併有慢性腎臟病（CKD，中位數 eGFR 為 49-52 mL/min）的病人，一項第二期隨機分派臨床試驗中，比較 TAF 和 TDF 48 週的療效和安全性，並在 48 週將 TDF 轉換為 TAF，持續追蹤所有病人 192 週；試驗結果顯示 ^10,11：
A phase 2 study was conducted to evaluate the safety and efficacy of TAF (n=26) vs a TDF containing regimen (n=25) as prophylaxis for HBV in post liver transplant patients with CKD (median eGFR ranged from 49-52 mL/min).^10,11
- 使用 TAF 預防療法 48 週的病人，eGFR 高於持續使用 TDF 的病人（Figure 4）；在帶有特定腎臟風險因子的病人，例如老年、使用 calcineurin 抑制劑或 eGFR 較低，腎功能同樣呈現改善的趨勢。
  Median increases in eGFRCKD-EPI over 48 weeks were numerically greater in those who received TAF compared to patients who continued TDF. Additionally, patients with certain known renal risk factors (e.g., older age, calcineurin inhibitor use, lower eGFR) who switched to TAF showed a trend toward improved renal function.
- 使用 TAF 預防療法 192 週的病人，包含於試驗第 48 週將 TDF 改用 TAF 的病人，所有病人維持高病毒抑制率，且eGFR 依然高於原先使用 TDF 的病人；骨密度在不同腎功能的病人中也都有所改善（Figure 5）。沒有任何移植病人在使用 TAF 後發生與 TAF 相關的第 3-4 級或嚴重不良反應。
  TAF was deemed safe and well tolerated in liver transplant recipients and no patient discontinued treatment or died in the TAF arm.

日本、加拿大、義大利的真實世界數據皆顯示，CKD 病人在改用 TAF 後，腎功能均有所改善 ^12-14。
- In a real world switch study from TDF or ADV to TAF conducted in Japan, significant improvements in renal function and CKD stages in those with baseline renal impairment were observed.¹²
- RWD out of Canada reported eGFR improvements across all CKD stages after switching to TAF, especially for those with stage 2 CKD at baseline (P =0.05).¹³
- Loglio and colleagues reported that switch from TDF to TAF rapidly improved tubular function even in an elderly population with a long-term history of NUC exposure (median eGFR 68 mL/min at baseline). The use of specific tubular markers such as UBCR, better demonstrated the early positive impact of TAF on renal safety (as opposed to eGFR).¹⁴
有病例報告指出，曾因使用 ADV 和 / 或 TDF 而發生 Fanconi 氏症候群的病人，以 TAF 治療成功 ¹⁵。
There are case reports of using TAF containing regimens successfully in patients with a history of Fanconi syndrome on ADV and/or TDF.¹⁵

AASLD, American Association for the Study of Liver Diseases; AE, adverse event; ALT, alanine aminotransferase; AUC, area under the curve; BMD, bone mineral density; CG, Cockcroft-Gault formula; CHB, chronic hepatitis B; CPT, Child-Pugh-Turcotte score; CrCl, creatinine clearance rate; DNA, deoxynucleic acid; eGFR, estimated glomerular filtration rate; HI, hepatic impairment; hr, hour; IU, international unit; OAV, oral antiviral; PI, prescribing information; PK, pharmacokinetics; Q, quartile; SAE, serious adverse event; SD, standard deviation; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; TFV, tenofovir; US, United States.

References: 1. 韋立得膜衣錠。中文仿單［TWN-NOV20-US-FEB20-（EU-NOV17）］; 2. Custodio JM, et al. EASL 2016, Poster Fri-127; 3. VEMLIDY® [prescribing information]. Foster City, CA: Gilead Sciences, Inc.; August 2020; 4. Lim YS, et al. EASL 2021. #2338; 5. Lim YS, et al. EASL 2020. SAT442.

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