「真實世界」的注射型治療使患者的不滿減半，前六個月只有兩次病毒學失敗
確定預先存在的阻力可能對成功至關重要
資料來源：格斯凱恩斯/2022 年 11 月 1 日/aidsmap / 財團法人台灣紅絲帶基金會編譯
Celia Jonsson-Oldenbüttel 博士在 HIV Glasgow 2022 上發表演講。圖片來自 Alan Donaldson Photography。
德國早期的數據顯示，在一個示範項目中，患者對使用可注射型卡博特拉韋 (cabotegravir) 和利匹韋林 (rilpivirine)（CAB/RPV – 歐洲的 Vocabria/Rekambys，北美和澳大利亞的 Cabenuva）的數據顯示，經過六個月的經驗，患者對使用抗反轉錄病毒療法 (ART) 的不滿減半（涉及他們的前四次注射）。在此期間，89.5% 的參與者繼續接受治療，病毒載量低於 50 拷貝。
在 22 名未能繼續接受治療或保持病毒檢測不到的世代成員中，只有 2 人出現病毒學失敗，定義為在 6 個月時連續兩次病毒載量超過 200，另外只有 4 人的病毒載量超過 50 拷貝。其他六人因注射部位反應不耐受而停止。
兩個病毒學失敗的人中的一個永遠不應該參與這項研究，因為事後發現之前含有非核苷反轉錄酶抑制劑 (NNRTI) 藥物的方案失敗了，導致他對利匹韋林 (rilpivirine) 產生耐藥性。但另一個令人費解，因為他並沒有明顯的風險因素。
這些數據由慕尼黑歌德廣場社區健康中心的 Celia Jonsson-Oldenbüttel 博士代表 CARLOS 世代提供，該世代是在柏林、科隆和慕尼黑的六家診所接受 CAB/RPV 注射型藥物許可後世代中的 HIV 患者。 CARLOS 試驗得到 cabotegravir 製造商 ViiV 的支持。
在使用 CAB/RPV 之前，所有參與者都被其他抗反轉錄病毒藥物抑制。該分析是針對 6 個多月前開始 CAB/RPV 的第一組患者。
230 名患者中的大多數人口服了一個月的卡博特韋和利匹韋林藥片；然後前兩次注射間隔一個月，然後每兩個月繼續注射。 CARLOS 世代將持續三年，並將招募更多改用注射劑的患者。
92% 的人接受注射的原因是個人喜好。5%則由於先前的順從性差，醫生建議使用：其他 3% 是出於吞嚥困難或噁心等醫學原因。
95% 是男性——這反映了男性在德國 HIV 流行病中的主導地位——他們的平均年齡為 43 歲；沒有提供種族或國籍數據。他們平均接受 ART 八年，45% 的人之前至少接受過 3 種 ART 治療處方。
在病毒學失敗的預先存在的風險因素方面，只有 2% 的人為 HIV 的 A6 或 A1 亞型，12% 的人的 BMI 超過 30，顯示肥胖。最大的問題是缺乏抗藥性測試。由於 39% 的人在改用注射劑之前的過去幾年中沒有進行過耐藥性測試，因此很大一部分人可能感染了 HIV，並且已經存在對整合酶抑製劑(integrase inhibitors) 的耐藥性突變，或者更有可能是非核苷反轉錄酶抑制劑 (NNRTIs) 抗藥。如上所述，一個病毒學失敗的人確實具有 NNRTI 抗性。
缺乏耐藥性測試不是排除 CAB/RPV 治療的原因，但之前的 NNRTI 方案失敗別則是。從先前的治療方案轉換並且已經被病毒抑制的人不能對他們的病毒 RNA 進行定序以進行耐藥性測試。雖可以對原病毒DNA (proviral DNA) 進行定序，但這很昂貴，而且大多數診所都不這樣做。唯一的選擇是依靠臨床病史，這並不總是完全可用的。
在六個月大關時，只有兩名患者確認病毒學失敗。如上所述，一個具有 NNRTI抗藥，但另一個令人費解；他並沒有預先存在的風險因素，並且在正確的時間進行了所有注射，但治療仍然失敗，當治療失敗時，他們發現有大量的整合酶抗性突變。這是否是由於某些藥物吸收問題導致的真正突破，或者他們是否具有未被發現的預先存在的耐藥性，還有待進一步調查。
55 名患者 (27.5%) 在總共 866 次注射中出現 218 次注射部位反應，例如疼痛、發紅或壓痛。所有人都是輕度的（1 級或 2 級），但如前所述，有 6 人因此而退出。 21 名患者報告了 50 種其他與藥物相關的不良事件，最常見的是發燒、與注射部位無關的疼痛、頭痛、疲勞或睡眠障礙以及噁心。其中一些發生在口服導入期間。所有都是 1 級或 2 級。有一個 3 級不良事件，但這是預先存在的焦慮症的惡化。
91% 的注射發生在預定預約之前或之後的一周內：19% 發生在當天，43% 發生在前一周，29% 發生在後一周。有 6.5% 的人提前一周以上，2.8% 的人遲到了一周以上（其中一半遲到了兩週以上）。在預定日期後超過一周的所有情況下，人們都會接受一周的口服治療，以彌補藥物水平的低谷。一個人在接下來的兩次注射之間有一個月的間隔。
患者對其治療的滿意度是透過一份經過驗證的問卷來衡量的，該問卷詢問了 11 個問題，從零（完全不滿意）到六（完全滿意），最高可能得分為 66 分。基準線時的平均分數已經很高，為 55.3，但六個月後已升至 60.6，或者換句話說，不滿意分數從 10.7 減半至 5.4。
總的來說，注射療法在這項研究中很受歡迎，至少在病毒學上與口服療法一樣有效，並且耐受性很好——只有 3% 的人由於注射部位反應而退出，而另外 2% 的人則因為對引入的口服藥丸不耐受反應而退出。。
最大的問題似乎是難以確定人們是否有先前的抗藥性：正如 HIV Glasgow 的另一項研究所證實的那樣，儘管一個單一的風險因素不一定會使人們失去使用注射劑型的資格，但兩種或多種風險因素（抗藥性、A6/A1 亞型和肥胖）的組合與更高的病毒失敗有關。
參考文獻：
Borch J 等人（由 Jonsson-Oldenbüttel C 提供）：真實世界環境中每 2 個月長效卡博特拉韋和利匹韋林的六個月結果：德國卡洛斯世代愛滋感染者注射型治療的有效性、依從性和患者報告的結果。 HIV 感染藥物治療國際大會（HIV 格拉斯哥），摘要 O43，2022 年 10 月。
‘Real world’ injectable treatment halves patient dissatisfaction, with only two viral failures in first six months
Ascertaining pre-existing resistance may be crucial for success
Gus Cairns / 1 November 2022 / aidsmap
Dr Celia Jonsson-Oldenbüttel presenting at HIV Glasgow 2022. Image by Alan Donaldson Photography.
Early German data from patients taking injectable cabotegravir and rilpivirine (CAB/RPV – Vocabria/Rekambys in Europe, Cabenuva in North America and Australia) in a demonstration project, shows that patient dissatisfaction with taking antiretroviral therapy (ART) halved after six months’ experience (involving their first four injections). During this time, 89.5% of participants remained on the therapy and with a viral load below 50 copies.
Out of 22 cohort members who did not stay on the therapy or maintain viral undetectability, only two had virological failure, defined as two consecutive viral loads over 200, at the six-month mark and only four others had a viral load above 50 copies. Six others stopped due to intolerance of injection site reactions.
One of the two with virological failure should have never been in the study, because it was found afterwards that a previous regimen containing NNRTI drugs had failed, leading them to develop resistance to rilpivirine. But the other is puzzling, as they had no apparent risk factors.
The data were presented by Dr Celia Jonsson-Oldenbüttel of the Goetheplatz Community Health Centre in Munich, on behalf of the CARLOS cohort, a post-licensing cohort of HIV patients taking CAB/RPV injections at six clinics in Berlin, Cologne and Munich. CARLOS is supported by ViiV, the manufacturers of cabotegravir.
All participants were virally suppressed on other antiretrovirals before taking CAB/RPV. This analysis is of the first group of patients who started CAB/RPV more than six months ago.
Most of the 230 patients took an oral ‘lead in’ of one month of cabotegravir and rilpivirine pills; the first two injections were then spaced a month apart, and then injections continued every two months. The CARLOS cohort will continue for three years and will enrol more patients who switch to the injectables.
Personal preference was the reason for 92% of people to take the injections. Doctors recommended them to 5% due to prior poor adherence and the other 3% for medical reasons such as swallowing difficulties or nausea.
Ninety-five per cent were men – reflecting the predominance of men in the German HIV epidemic – and their average age was 43; no ethnicity or nationality data were given. They had been on ART for an average of eight years and 45% had had at least three previous ART regimens.
In terms of pre-existing risk factors for virological failure, only 2% had the A6 or A1 subtypes of HIV and12% had a BMI of over 30, indicating obesity. The biggest problem was the lack of resistance testing. With 39% not having had a resistance test in the last few years prior to switching to injectables, a large minority could have had HIV with pre-existing resistance mutations to integrase inhibitors or, more likely, NNRTIs. As mentioned above, one person who failed virologically did turn out to have NNRTI resistance.
The lack of a resistance test was not a reason for exclusion for CAB/RPV treatment, but previous failure of an NNRTI regimen was. People who have switched from a previous regimen and are already virally suppressed cannot have their viral RNA sequenced for a resistance test. It is possible to sequence proviral DNA, but this is expensive, and most clinics don’t do it. The only alternative is to rely on clinical history and this will not always be fully available.
At the six-month mark, only two patients had confirmed virological failure. One, as mentioned above, had NNRTI resistance, but the other is puzzling; they had no pre-existing risk factors and had had all their injections at the right time, but nonetheless treatment failed, and when it did, they turned out to have a large number of integrase resistance mutations. Whether this was a genuine breakthrough due to some drug-absorption problem or whether they had had pre-existing resistance that had gone undetected is a matter for further investigation.
Fifty five patients (27.5%) had 218 injection site reactions such as pain, redness or tenderness in a total of 866 injections. All were mild (grade 1 or 2) but as mentioned, six people dropped out due to them. Fifty other drug-related adverse events were reported in 21 patients, the most common being fever, pain unrelated to injection site, headache, fatigue or sleep disorders, and nausea. Some of these happened during the oral lead-in. All were grade 1 or 2. There was one grade three adverse event, but this was an exacerbation of a pre-existing anxiety disorder.
Ninety-one per cent of injections took place within a week before or after the scheduled appointment: 19% on the exact day, 43% in the week before, and 29% in the week after. There were 6.5% which were more than a week early and 2.8% that were more than a week late (half of those were more than two weeks late). In all cases where more than a week had passed after the scheduled date, people were given a week’s worth of oral therapy to take to cover the trough in drug levels. One person had a one-month gap between their next two injections.
Patient satisfaction with their therapy was measured with a validated questionnaire which asked 11 questions scored from zero (totally unsatisfied) to six (totally satisfied), leading to a maximum possible score of 66 points. The average score at baseline was already high at 55.3 but after six months had risen to 60.6 – or, to put it another way, the dissatisfaction score had halved from 10.7 to 5.4.
In general, then, the injectable therapies were popular in those coming forward for this study, at least as virologically effective as oral therapies, and pretty well tolerated – only 3% dropped out due to injection site reactions, when another 2% dropped out due to intolerance of the lead-in oral pills.
The biggest issue would appear to be the difficulty of establishing if people have prior resistance: as another study at HIV Glasgow established, a combination of two or more risk factors (resistance, A6/A1 subtype and obesity) is associated with a higher risk of viral failure, though a single risk factor would not necessarily disqualify people from the injectables.
References
Borch J et al (presented by Jonsson-Oldenbüttel C): Six-month outcomes of every 2-months long-acting cabotegravir and rilpivirine in a real-world setting: effectiveness, adherence to injections and patient-reported outcomes from PLWHIV in the German CARLOS cohort. International Congress on Drug Therapy in HIV Infection (HIV Glasgow), abstract O43, October 2022.