Q5. Safety: What is the clinical significance of the higher incidence of (in TAF vs TDF): (1) Hyperlipidemia (2) Increased amylase ?

Safety:
What is the clinical significance of the higher incidence of (in TAF vs TDF):
(1) Hyperlipidemia (2) Increased amylase ?

美國心臟醫學會（American Heart Association）指出，TC:HDL 比值是用來預測 10 年內發生心肌梗塞或中風風險的重要指標 ¹。試驗 108 與 110 顯示，使用 TAF 或從 TDF 轉換為 TAF 治療 240 週後，兩者的 TC:HDL 比值並無差異（Figure 1）²。
In Studies 108/110, there were no differences in TC to HDL ratio between TAF and TDF →OL TAF arms through week 240.2 According to the American Heart Association, TC:HDL is an important factor to predict 10-year risk for myocardial infarction (MI) or stroke.¹
- 先前研究已知 TDF 具有降低血脂參數的效果，包括TC、LDL、HDL 和 TG。而 TAF 對這些參數的影響則可忽略不計。
  TDF is known to have lipid lowering effects (LLE) based on the experience from various TDF clinical studies. TDF subjects had an overall reduction in TC, LDL, HDL and triglyceride. TAF has a negligible effect on these parameters.
- 換藥組的各項血脂參數在 TDF 治療期間內微幅降低，轉換為 TAF 之後則上升。
  In the TDF→OL TAF 3- and 2-year groups: modest decreases were seen in TC, HDL, LDL, and TG during DB TDF, consistent with the known LLE of TDF; increases in these parameters occurred when switched from TDF to TAF, consistent with removal of the TDF LLE.
- 在超過 5 年的治療期間內，無論是持續使用 TAF 或從 TDF 轉換為 TAF，TC:HDL 比值僅微幅增加（增加幅度為 0.4-0.5）。
  - In the TAF group: TC was stable over 5 years, HDL decreased slightly, TG increased slightly, and LDL increased modestly over 5 years.
  - TC:HDL ratio increased slightly over 5 years in all 3 groups (ranged from 0.4-0.5).
- TAF 治療組中需開始使用降血脂藥物的病人比例少於 5%。
  < 3% of patients started lipid-lowering agents during TAF DB compared with < 5% across the 3 groups during OL TAF.

在比較 TDF 和 TAF 的血脂參數時，試驗 4018 與 4035 也觀察到類似的趨勢變化（Figure 2,3） ^3-5 。
In Studies 4018 and 4035, we see a similar patterns regarding lipid changes when comparing TAF to TDF.^3-5

一篇真實世界的研究比較 CHB 病人使用 TDF 或 ETV 的血脂變化，結果發現在 TDF 治療後 ，TC、LDL、HDL 均明顯降低；而 ETV 則無明顯變化（Figure 4）⁶ ，另一篇真實世界的研究追蹤 CHB 病人使用 TAF 一年的血脂變化，結果發現在 TAF 治療後，TG、TC、LDL 均無明顯變化 ⁷。
Recently, a real-world study comparing lipid changes in CHB patients treated with either TDF or ETV was conducted. The results showed that after TDF treatment; TC, LDL and HDL all declined significantly, while those on ETV had little to no changes.⁶ These results are consistent with the differences noted between TDF and TAF.⁷

依據 VEMLIDY^® 仿單，在試驗 108/110 中，於第 96 週時，有 8 位使用 TAF 治療且有澱粉酶濃度升高現象的受試者出現相關的症狀，如噁心、下背痛、腹部觸痛或疼痛或脹氣、膽源性胰臟炎及胰臟炎。在這 8 位受試者中，有 2 位因澱粉酶及 / 或脂肪酶升高而停用 TAF；其中 1 位受試者在重新開始使用 TAF 之後再度發生不良事件。並無任何使用 TDF 治療的受試者出現相關的症狀或停止治療 ⁸。
In Studies 108/110, eight subjects treated with TAF with elevated amylase levels had associated symptoms, such as nausea, low back pain, abdominal tenderness, distension and pain, biliary pancreatitis, lipase elevation or diarrhea. Of these eight, two subjects discontinued TAF due to elevated amylase and/or lipase; one subject experienced recurrence of adverse events when TAF was restarted. No subject treated with tenofovir disoproxil fumarate had associated symptoms or discontinued treatment.⁹
從 96 週至 120 週期間，在開放性試驗階段繼續接受 TAF 治療的受試者中，新增 1 位受試者發生澱粉酶濃度升高並出現相關症狀；從 TDF 改為 TAF 的受試者中，則無新增澱粉酶濃度升高病例 ⁸。
From week 96 to week 120, one additional subject who continued open-label TAF and none of the subjects who switched from TDF to TAF had elevated amylase levels and associated symptoms.⁹
依據 GENVOYA^® (elvitegravir 150 mg / cobicistat 150 mg / emtricitabine 200 mg / TAF 10 mg) 美國 FDA 仿單，試驗 104/111 中，於第 96 週時，2% 使用 GENVOYA^® 的受試者（n = 866）出現第 3 – 4 級的澱粉酶異常；而使用 STRIBILD^® 的受試者（n = 867）則有 4% 出現第 3 – 4 級的澱粉酶異常 ¹⁰。
In GENVOYA studies (104/111), 2% of patients (n=866) in the GENVOYA arm had amylase lab abnormalities (Grade 3-4) compared to 4% (n=867) in the STRIBILD arm.¹⁰

CHB, chronic hepatitis B; CVD, cardiovascular disease; DB, double-blind; ESRD, end stage renal disease; ETV, entecavir; FDA, Food and Drug Administration; HDL, high-density lipoprotein; HI, hepatic impairment; LDL, low-density lipoprotein; LDL-C, LDL cholesterol; LLE, lipid lowering effects; MI, myocardial infarction; OAV, oral antiviral; OL, open-label; PSM, propensity score matching; Q, quartile; RI, renal impairment; TAF, tenofovir alafenamide; TC, total cholesterol; TDF, tenofovir disoproxil fumarate; TG, triglyceride; vs, versus; y, year.

References: 1. What your cholesterol levels means. American Heart Association. http://www.heart.org/HEARTORG/Conditions/Cholesterol/AboutCholesterol/What-Your-Cholesterol-Levels-Mean_UCM_305562_Article.jsp#.WEWYe0DCZcZ. 2020. Accessed October 25, 2021; 2. Chan HLY, et al. AASLD 2020. 803; 3. Lampertico P, et al. EASL 2020. O91; 4. Janssen H, et al. EASL 2020. SAT429; 5. Lim YS, et al. EASL 2020. SAT442; 6. Shaheen AA, et al. Aliment Pharmacol Ther. 2017;46:599-604; 7. Chen PL, et al. Exp Ther Med. 2021;22(5):1325. 8. 韋立得膜衣錠。中文仿單［TWN-NOV20-US-FEB20-（EU-NOV17）］; 9. VEMLIDY^® [prescribing information]. Foster City, CA: Gilead Sciences, Inc.; August 2020. 10. GENVOYA^® [prescribing information]. Foster City, CA: Gilead Sciences, Inc.; December 2016;

TW-VEM-0044