Biktarvy 聯合藥丸可能是愛滋病毒和B型肝炎共病患者最有效的選擇
資料來源：Liz Highleyman / 2022 年 7 月 31 日 /aidsmap / 財團法人台灣紅絲帶基金會編譯
Anchalee Avihingsanon 博士在 2022 年愛滋病大會上。照片©Steve Forrest/Workers’ Photos/IAS
儘管兩種抗反轉錄病毒藥物方案被證明在抑制 HIV 方面同樣有效，但根據週五在蒙特婁舉行的第 24 屆國際愛滋病大會（AIDS 2022）上 preaidsmapsented 的研究，Biktarvy 組合藥丸［比克替拉韋(bictegravir)、恩曲他濱 (emtricitabine)、以及替諾福韋艾拉酚胺 ( tenofovir alafenamide) ］在抑制 HIV/HBV 合併感染者中的B型肝炎病毒 (HBV) 方面做得更好。
HIV-NAT 和泰國紅十字會愛滋病研究中心的 Anchalee Avihingsanon 博士報告說，更重要的是，Biktarvy 似乎對B型肝炎的功能性治愈產生了更深層次的反應。
HIV 和 HBV 的傳播途徑相似，許多人同時攜帶這兩種病毒。在全球範圍內，大約 8% 的 HIV 感染者也感染了 HBV，但在亞洲和非洲的部分地區，這一比例可能高達 25%。 Avihingsanon 指出，在B型肝炎高發地區新出現的 HIV 流行正在導致越來越多的 HIV/HBV 合併感染者。
數年或數十年，慢性B型肝炎會導致嚴重的肝病，包括肝硬化、肝癌和需要進行肝移植。與單獨感染B型肝炎的人相比，HIV 和 HBV 合併感染者的肝病進展平均更快，並且發生嚴重併發症的風險更高。
「這仍然是一個非常重要的問題，尤其是在亞洲，愛滋病毒感染者的B型肝炎臨床病程的特點是肝臟疾病進展加快」，國際愛滋病協會候任主席、在墨爾本的彼得.多爾蒂感染和免疫研究所的莎朗·萊溫教授於 2022 年愛滋病媒體簡報會上說。
某些用於治療 HIV 的抗反轉錄病毒藥物——拉米夫定 (lamivudine)、恩曲他濱 (emtricitabine)、富馬酸替諾福韋酯 (tenofovir disoproxil fumarate, TDF) 和丙酚替諾福韋酯 (tenofovir alafenamide , TAF)——也對 HBV 具有活性。它們是幾種廣泛使用的抗反轉錄病毒複合製劑的成分。治療指引建議 HIV 和 HBV 合併感染者應在其治療方案中加入此類雙重活性藥物。
B型肝炎的抗病毒治療可抑制 HBV 複製，從而減少肝臟炎症並使肝酶水平恢復正常。治療有時會導致B型肝炎抗原的喪失和抗體的產生（血清轉化），但這並不常見。B型肝炎表面抗原 (HBsAg) 的消失被認為是一種功能性治癒。
–
ALLIANCE 研究比較了：
• ［比克替拉韋(bictegravir)、恩曲他濱 (emtricitabine)、以及替諾福韋艾拉酚胺 ( tenofovir alafenamide) ］（簡稱B/FTC/TAF 或 Biktarvy），作為單一藥丸每天服用一次，對比
• 多替拉韋 (dolutegravir) 加上恩曲他濱/富馬酸替諾福韋二吡呋酯 (emtricitabine/tenofovir disoproxil fumarate)（簡稱FTC/TDF；Truvada 和仿製等效價藥物），每天一次，兩片。
因此，這兩個研究組在他們接受的整合酶抑製［比克替拉韋 (bictegravir) 或多替拉韋(dolutegravir) ］和他們接受的替諾福韋 (tenofovir) 版本（較新的 TAF 或較舊的 TDF）方面存在差異。
這項 III 期試驗招募了 243 名 HIV/HBV 合併感染者，大部分在泰國、中國或馬來西亞，他們以前沒有接受過 HIV 或B型肝炎治療。大多數是男性，約 90% 是亞洲人，中位年齡約為32 歲。約 80% 為B型肝炎‘e’抗原 (HBeAg) 陽性。
在研究開始時，他們的 HIV RNA 病毒載量為 500 或更高，HBV DNA 病毒載量至少為 2000。CD4 計數中位數非常低，約為 240，40% 低於 200。他們的 HIV 沒有對恩曲他濱 (emtricitabine) 或替諾福韋 (tenofovir) 具抗藥性，並且他們有足夠的腎功能（服用 TDF 的人的標準）。
參與者被隨機分配接受 B/FTC/TAF 或 dolutegravir 加 FTC/TDF。主要終點是 48 週時的 HIV 和 HBV 病毒抑制，治療持續至 96 週。
這兩種方案在抑制 HIV 方面都非常有效，正如之前對 HIV 感染者的研究中所看到的那樣。在 48 週時，95.0% 的服用 B/FTC/TAF 的人和 91.0% 的服用 dolutegravir 加 FTC/TDF 的人的 HIV 病毒載量低於 50。CD4 細胞增益分別為 200 和 175。
HBV 病毒抑制不太常見，B/FTC/TAF 被證明優於 dolutegravir 加 TDF/FTC：分別有 63.0% 和 43.4% 的 HBV DNA 低於 29，具有統計學意義的差異。兩組中HBV DNA下降的時間過程相似。
在基準線 HBeAg 陽性的參與者中，25.6% 的 B/FTC/TAF 組在 48 週時出現 HBeAg 消失，而dolutegravir加 FTC/TDF 組的這一比例為 14.4%。 B/FTC/TAF 組的 HBeAg 血清轉化率也更高，分別為 23.3% 和 11.3%。 Avihingsanon 報導，後一種差異在 48 週時具有統計學意義。
B型肝炎表面抗原的下降不太常見：B/FTC/TAF 組 12.6% 和dolutegravir加 FTC/TDF 組 5.8% 在 48 週時實現 HBsAg 下降，分別有 8.4% 和 3.3% 經歷 HBsAg 血清轉換。儘管 B/F/TAF 組的 HBsAg 消失率和血清轉化率在數值上較高，但在 48 週時差異沒有達到統計學意義。
服用 B/FTC/TAF 的人比 dolutegravir 加 FTC/TDF 組的人（分別為 73.3% 和 55.3%）更有可能經歷 ALT 肝酶正常化，但在 48 週時差異也不顯著。分別有 7 名和 4 名參與者經歷了 ALT 突然發作、肝臟炎症爆發，這可能是 HBsAg 消失的前兆。
在 HIV 耐藥性方面，B/FTC/TAF 組中 3 名未實現 HIV 抑制的人和dolutegravir加 FTC/TDF 組中 4 名符合耐藥性檢測標準。後一組中的一個人具有 NRTI 耐藥性，但沒有人顯示出整合酶抑製劑耐藥性的證據。
Avihingsanon 說，治療通常是安全的並且耐受性良好。 B/FTC/TAF 組和dolutegravir加 FTC/TDF 組的藥物相關不良事件發生率相似（分別為 24% 對 27%），嚴重的實驗室異常也相似（34% 對 31%）。
兩組中最常見的藥物相關不良事件是體重增加，分別報告了 6% 和 7%。這是值得注意的，因為在先前的研究中，TAF 與體重增加有關，而 TDF 與體重減輕有關。總膽固醇和 LDL 膽固醇升高並不常見，但在 B/FTC/TAF 組中更常見。
兩組中嚴重的藥物相關不良事件均很少見，分別為 5% 和 1%。 B/FTC/TAF 組中只有一名肝癌患者因治療中出現的不良事件而停止治療。
基於這些結果，研究人員得出結論，在 HIV 抑制方面，使用 B/FTC/TAF 進行初始治療並不劣於 dolutegravir 加 FTC/TDF。 B/FTC/TAF 與更高的 HBeAg 血清學轉換率相關，在 HBeAg 消失、HBsAg 消失或血清學轉換和 ALT 正常化方面存在數值更高但無統計學意義的差異。
Avihingsanon 說，對於 HIV 和 HBV 合併感染的人來說，B/FTC/TAF 「是一種安全有效的治療方法」。
在評論這些發現時，Lewin 指出 HBeAg 血清轉換是B型肝炎治療成功的標誌之一。「這些發現不僅對 HIV 感染者而且對更普遍的B型肝炎管理而言都是重要的發現」。
參考文獻：
Avihingsanon A 等人。 Bictegravir/Emtricitabine/Tenofovir alafenamide (B/F/TAF) vs Dolutegravir + Emtricitabine/Tenofovir Disoproxil Fumarate (DTG+F/TDF) 作為 HIV/HBV 合併感染成人初始治療的第 3 期隨機對照試驗的第 48 週結果（聯盟）。第 24 屆國際愛滋病大會，蒙特婁，摘要 OALBX0105，2022 年。
Biktarvy combination pill may be most effective option for people with HIV and hepatitis B
Liz Highleyman / 31 July 2022 / aidsmap
Dr Anchalee Avihingsanon at AIDS 2022. Photo ©Steve Forrest/Workers’ Photos/IAS
Although two antiretroviral drug regimens proved about equally effective at suppressing HIV, the Biktarvy combination pill (bictegravir, emtricitabine and tenofovir alafenamide) did a better job suppressing hepatitis B virus (HBV) in people with HIV/HBV co-infection, according to research preaidsmapsented on Friday at the 24th International AIDS Conference (AIDS 2022) in Montreal.
What’s more, Biktarvy appeared to produce deeper responses associated with a functional cure for hepatitis B, Dr Anchalee Avihingsanon of HIV-NAT and the Thai Red Cross AIDS Research Centre reported.
HIV and HBV are transmitted by similar routes and many people carry both viruses. Worldwide, around 8% of people living with HIV also have HBV, but this can reach as high as 25% in parts of Asia and Africa. Avihingsanon noted that emerging HIV epidemics in areas with high hepatitis B rates are leading to an increasing number of people with HIV/HBV co-infection.
Over years or decades, chronic hepatitis B can lead to severe liver disease, including cirrhosis, liver cancer and the need for a liver transplant. People with HIV and HBV co-infection experience more rapid liver disease progression, on average, and are at increased risk for serious complications compared to those with hepatitis B alone.
“This is still a very important problem, particularly in Asia, and the clinical course of hepatitis B in people living with HIV is marked by accelerated liver disease progression,” International AIDS Society president-elect Professor Sharon Lewin of the Peter Doherty Institute for Infection and Immunity in Melbourne said at an AIDS 2022 media briefing.
Certain antiretrovirals used to treat HIV – lamivudine, emtricitabine, tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) – are also active against HBV. They are components of several widely used antiretroviral co-formulations. Treatment guidelines recommend that people with HIV and HBV co-infection should include such dually active drugs in their regimen.
Antiviral treatment for hepatitis B suppresses HBV replication, which can reduce liver inflammation and bring liver enzyme levels back to normal. Treatment can sometimes lead to loss of hepatitis B antigens and production of antibodies (seroconversion), but this is much less common. Hepatitis B surface antigen (HBsAg) loss is considered a functional cure.
The ALLIANCE study compared:
•bictegravir, emtricitabine and tenofovir alafenamide (B/FTC/TAF or Biktarvy), taken as a single pill once daily, versus
•dolutegravir plus emtricitabine/tenofovir disoproxil fumarate (FTC/TDF; Truvada and generic equivalents), taken as two pills once daily.
The two study arms therefore differed in the integrase inhibitors they received (bictegravir or dolutegravir) and in the version of tenofovir they received (the newer TAF or the older TDF).
More news from South and South-east Asia
This phase III trial enrolled 243 people with HIV/HBV co-infection, mostly in Thailand, China or Malaysia, who had not previously been treated for HIV or hepatitis B. Most were men, about 90% were Asian and the median age was about 32 years. About 80% were hepatitis B ‘e’ antigen (HBeAg) positive.
At study entry, they had an HIV RNA viral load of 500 or higher and an HBV DNA viral load of at least 2000. The median CD4 count was quite low, at approximately 240, and 40% fell below 200. Their HIV was not resistant to emtricitabine or tenofovir, and they had adequate kidney function (a criteria for people taking TDF).
Participants were evenly randomised to receive B/FTC/TAF or dolutegravir plus FTC/TDF. The primary endpoint was HIV and HBV viral suppression at 48 weeks, with treatment continuing through 96 weeks.
More news from AIDS 2022
Both regimens were highly effective at suppressing HIV, as seen in previous studies of people with HIV alone. At 48 weeks, 95.0% of people taking B/FTC/TAF and 91.0% of those taking dolutegravir plus FTC/TDF had an HIV viral load below 50. CD4 cell gains were 200 and 175, respectively.
HBV viral suppression was less common, and B/FTC/TAF proved superior to dolutegravir plus TDF/FTC: 63.0% and 43.4%, respectively, had HBV DNA below 29, a statistically significant difference. The time course of HBV DNA decline was similar in both groups.
Among participants who were HBeAg positive at baseline, 25.6% in the B/FTC/TAF arm experienced HBeAg loss at 48 weeks, compared with 14.4% in the dolutegravir plus FTC/TDF group. HBeAg seroconversion has also higher in the B/FTC/TAF group, 23.3% vs 11.3%, respectively. The latter difference was statistically significant at 48 weeks, Avihingsanon reported.
Declines in hepatitis B surface antigen were less common: 12.6% in the B/FTC/TAF arm and 5.8% in the dolutegravir plus FTC/TDF group achieved HBsAg loss at 48 weeks, and 8.4% vs 3.3%, respectively, experienced HBsAg seroconversion. Although the rates of HBsAg loss and seroconversion were numerically higher in the B/F/TAF arm, the differences did not reach statistical significance at 48 weeks.
People taking B/FTC/TAF were more likely than those in the dolutegravir plus FTC/TDF group (73.3% vs 55.3%, respectively) to experience ALT liver enzyme normalisation, but again the difference was not significant at 48 weeks. Seven and four participants, respectively, experienced ALT flares, bursts of liver inflammation that can be a precursor to HBsAg loss.
Looking at HIV drug resistance, three people who did not achieve HIV suppression in the B/FTC/TAF group and four in the dolutegravir plus FTC/TDF group met the criteria for resistance testing. One person in the latter group had NRTI resistance, but none showed evidence of integrase inhibitor resistance.
Treatment was generally safe and well tolerated, Avihingsanon said. The frequency of drug-related adverse events was similar in the B/FTC/TAF and dolutegravir plus FTC/TDF arms (24% vs 27%, respectively), as were severe laboratory abnormalities (34% vs 31%).
The most common drug-related adverse event in both groups was weight gain, reported by 6% and 7%, respectively. This is noteworthy because in prior studies TAF has been linked to weight gain and TDF to weight loss. Total and LDL cholesterol increases were uncommon, but seen more often in B/FTC/TAF group.
Severe drug-related adverse events were rare in both groups, 5% and 1%, respectively. Only one person with liver cancer in the B/FTC/TAF arm discontinued therapy due to treatment-emergent adverse events.
Based on these results, the researchers concluded that initial treatment with B/FTC/TAF was non-inferior to dolutegravir plus FTC/TDF when it came to HIV suppression. B/FTC/TAF was associated with a higher rate of HBeAg seroconversion, with numerically higher but not statistically significant differences in HBeAg loss, HBsAg loss or seroconversion and ALT normalisation.
B/FTC/TAF “is a safe and effective treatment” for people with HIV and HBV co-infection, Avihingsanon said.
Commenting on the findings, Lewin noted that HBeAg seroconversion is one marker of successful hepatitis B treatment. “These are important findings not just for people living with HIV but for hepatitis B management more generally.”
References
Avihingsanon A et al. Week 48 Results of a Phase 3 Randomized Controlled Trial of Bictegravir/Emtricitabine/Tenofovir alafenamide (B/F/TAF) vs Dolutegravir + Emtricitabine/Tenofovir Disoproxil Fumarate (DTG+F/TDF) as Initial Treatment in HIV/HBV-Coinfected Adults (ALLIANCE). 24th International AIDS Conference, Montreal, abstract OALBX0105, 2022.
View the abstract on the conference website.
Update: this article was corrected on the day of publication to remove an incorrect statement about pill burden.