頭24週隨機接受192週替諾福韋聯合或不聯合培格干擾素阿爾法

StephenW

Randomized trial of 192 weeks of tenofovir with or without peginterferon alfa for the first 24 weeks followed by protocolized withdrawal in adults with chronic hepatitis B

About 5% in Randomized Trial Lose HBsAg After Long-Term TDF Stops

AASLD The Liver Meeting Digital Experience, November 13-16, 2020

Mark Mascolini

After 240 weeks of follow-up, 4.5% of people with chronic HBV treated for 192 weeks with tenofovir disoproxil fumarate (TDF) alone lost hepatitis B surface antigen (HBsAg), compared with 5.7% who combined 192 weeks of TDF with 24 weeks of peginterferon alfa 2a (PegIFN), a nonsignificant difference [1]. The proportion who lost hepatitis B e antigen (HBeAg) was 41% with TDF alone versus 61% with combined therapy, a difference that stopped short of statistical significance (P = 0.06).

Researchers who conducted this randomized parallel-group trial [2] noted that loss of HBsAg, indicating functional cure of chronic HBV infection, has become a frequent goal of anti-HBV therapy. People who lose HBsAg run a low risk of HBV disease progression. Treatment with nucleos(t)ides like TDF is limited by the need for long-term use and a low rate of HBsAg loss, especially in HBeAg-negative people. (HBsAg indicates current HBV infection; HBeAg indicates replicating, transmissible HBV.)

This trial aimed to assess the safety and efficacy of 192 weeks of TDF alone or with 24 weeks of PegIFN followed by structured withdrawal of TDF in participants with immune-active chronic HBV infection. The trial focused on participants in the Hepatitis B Research Network (HBRN), which has 21 clinical sites in the United States and 1 in Canada. Participants had to be at least 18 years old and free from antiviral therapy for at least 24 weeks before entering the trial. They could be HBeAg-positive or negative but could not have HIV, HCV, or HDV infection.

Researchers randomized participants 1-to-1 to take TDF alone for 192 weeks or TDF for 192 weeks plus PegIFN for 24 weeks. At week 192 participants could stop TDF if their HBV DNA lay below 1000 IU/mL for the previous 24 weeks, if they were HBeAg-negative and anti-HBe positive, and if they did not have cirrhosis. During the withdrawal phase, participants had to restart TDF if certain signals of liver disease progression arose. Follow-up continued until week 240, when the primary outcome was HBsAg loss.

The study included 102 people randomized to TDF alone and 99 randomized to dual therapy. Of the 102 TDF-alone participants, 96 got evaluated for TDF withdrawal at week 96, 51 stopped TDF (53% of 96), and 96 completed the study to week 240. Of the 99 people in the dual-therapy group, 92 got evaluated for TDF withdrawal, 60 stopped TDF (65% of 92), and 92 completed the study. Among those eligible for TDF withdrawal, 30% in the TDF-alone group and 39% in the dual-therapy group met criteria for inactive chronic HBV infection, a nonsignificant difference (P = 0.39).

Median age stood at 41 in both treatment groups. The TDF-alone group had a slightly lower proportion of women (30% vs 40%) and a barely lower proportion of Asians (80% vs 86%). Similar proportions in the TDF-alone and dual-therapy groups tested positive for HBeAg at the initial study visit (53% and 49%), and initial HBV DNA levels were similar in the two groups (medians of 6.7 and 6.3 log IU/mL).

In an intention-to-treat analysis after 240 weeks, 4 people (4.5%) in the TDF-alone group and 5 (5.7%) in the dual-therapy group lost HBsAg, a small and nonsignificant difference (P = 0.74). Cumulative incidence of HBsAg loss over 240 weeks did not differ by treatment group (P = 0.92). At the 240-week point, a slightly lower proportion in the TDF-alone group than in the dual-therapy group lost HBeAg (41% vs 61%), though that difference fell shy of statistical significance (P = 0.06). The two treatment groups differed little at week 240 in proportions with a normal alanine aminotransferase (ALT) (61% and 64%), HBV DNA below 20 IU/mL (51% and 53%), and HBV DNA below 1000 IU/ml plus a normal ALT (45% and 49%).

Throughout the study, 11% taking TDF alone and 7% taking TDF plus PegIFN had a serious adverse event. The proportion of participants with an ALT flare was marginally lower in the TDF-alone group (24% vs 31%). Most flares in the TDF-alone group (70%) came when TDF stopped, and most in the dual-therapy group (58%) came during dual therapy (the first 24 weeks).

The researchers suggested these results can inform the long-term management of chronic HBV infection until more effective therapies become available.

References
1. Terrault N, Lok AS, Wahed A, et al. Randomized trial of 192 weeks of tenofovir with or without peginterferon alfa for the first 24 weeks followed by protocolized withdrawal in adults with chronic hepatitis B. AASLD The Liver Meeting Digital Experience, November 13-16, 2020. Abstract 19.
2. ClinicalTrials.gov. Combination therapy of pegylated interferon alfa-2a and tenofovir versus tenofovir monotherapy in chronic hepatitis B (HBRN). ClinicalTrials.gov identifier NCT01369212. https://clinicaltrials.gov/ct2/show/NCT01369212

StephenW

頭24週隨機接受192週替諾福韋聯合或不聯合培格干擾素阿爾法的試驗，隨後對慢性乙型肝炎患者按方案退出

長期TDF停止後，約有5％的隨機試驗中HBsAg丟失

AASLD肝臟會議數字體驗，2020年11月13日至16日

馬克·馬斯科利尼

經過240週的隨訪，僅使用替諾福韋二富馬酸富馬酸鹽（TDF）治療192週的慢性HBV患者中有4.5％的患者喪失了乙型肝炎表面抗原（HBsAg），而將192週的TDF與24週的聯合治療的患者中的5.7％聚乙二醇干擾素α2a（PegIFN），無顯著差異[1]。單獨使用TDF時，丟失乙型肝炎e抗原（HBeAg）的比例為41％，而聯合治療時為61％，這一差異沒有統計學意義（P = 0.06）。

進行這項隨機平行組試驗的研究人員[2]指出，HBsAg的丟失表明慢性HBV感染的功能性治愈，已成為抗HBV治療的常見目標。失去HBsAg的人患HBV疾病的風險較低。長期使用的需求和低HBsAg丟失率限制了使用像TDF這樣的核苷酸治療，特別是在HBeAg陰性人群中。 （HBsAg表示當前的HBV感染； HBeAg表示正在復制，傳播的HBV。）

該試驗旨在評估免疫活性慢性HBV感染者單獨服用192週TDF或聯合使用24週PegIFN的安全性和有效性，然後有組織地撤回TDF。該試驗的重點是乙肝研究網絡（HBRN）的參與者，該網絡在美國擁有21個臨床站點，在加拿大擁有1個臨床站點。參加試驗的參與者必須年滿18歲並且必須接受抗病毒治療至少24週。他們可能是HBeAg陽性或陰性，但不能感染HIV，HCV或HDV。

研究人員將參與者從1對1隨機分配為單獨服用TDF 192週或服用TDF 192週，再服用PegIFN 24週。如果在過去的24週內其HBV DNA低於1000 IU / mL，且HBeAg陰性和抗HBe陽性，以及沒有肝硬化，則在192週時，參與者可以停止TDF。在戒斷階段，如果出現某些肝臟疾病進展的信號，參與者必須重新啟動TDF。隨訪一直持續到第240週，當時主要的結果是HBsAg丟失。

這項研究包括102名隨機接受TDF治療的患者和99名隨機接受雙重治療的患者。在102名僅使用TDF的參與者中，有96名在第96週時評估了TDF的戒斷，51名停止了TDF（96％的53％），有96名完成了研究直至第240週。在雙重療法組的99人中，有92人獲得了TDF的戒斷。評估了TDF的撤回情況，停止了60例TDF（佔92％的65％），完成了研究92例。在有資格撤回TDF的人群中，僅TDF組和雙重療法組中的30％符合非活動性慢性HBV感染的標準，差異無統計學意義（P = 0.39）。

兩個治療組的中位年齡均為41歲。僅TDF組的女性比例略低（30％比40％），亞洲比例則略低（80％比86％）。 TDF單獨治療和雙重治療組在初次研究就診時檢測到的HBeAg陽性比例相似（53％和49％），兩組的初始HBV DNA水平相似（中位數分別為6.7和6.3 log IU / mL） ）。

在240週後的意向治療分析中，僅TDF組有4人（4.5％），雙重治療組中有5人（5.7％）丟失HBsAg，差異很小且無統計學意義（P = 0.74）。治療組在240週內HBsAg丟失的累積發生率無差異（P = 0.92）。在240週時，僅使用TDF的組比接受雙重治療的組丟失HBeAg的比例略低（41％比61％），儘管這一差異沒有統計學意義（P = 0.06）。兩個治療組在第240週時的比例差異不大，其中正常丙氨酸轉氨酶（ALT）（61％和64％），HBV DNA低於20 IU / mL（51％和53％）和HBV DNA低於1000 IU / ml加上正常的ALT（45％和49％）。

在整個研究中，有11％的患者單獨服用TDF，有7％的患者服用TDF加PegIFN具有嚴重的不良事件。僅TDF組中有ALT發作的參與者比例略低（24％比31％）。僅使用TDF的組中的大多數耀斑（70％）發生在TDF停止時，而使用雙重治療的組中的大多數（58％）發生在雙重治療期間（頭24週）。

研究人員認為，這些結果可以為慢性HBV感染的長期治療提供參考，直到可以使用更有效的療法為止。

參考文獻
1. Terrault N，Lok AS，Wahed A等。在頭24週隨機或連續進行192週替諾福韋聯合或不聯合使用peginterferon alfa的試驗，然後根據協議對患有慢性乙型肝炎的成年人進行戒斷。AASLD肝臟會議數字化體驗，2020年11月13日至16日。摘要19。
2. ClinicalTrials.gov。 聚乙二醇化干擾素α-2a和替諾福韋的聯合治療與替諾福韋單藥治療慢性乙型肝炎（HBRN）。 ClinicalTrials.gov標識符NCT01369212。 https://clinicaltrials.gov/ct2/show/NCT01369212