治療:Vocabria 和 Rekambys 注射劑

 

Cabotegravir (Vocabria) rilpivirine (Rekambys) 注射劑

資料來源:Aidsmap /  Keith Alcorn / January 2021

VocabriaRekambys是經批准可組合使用的注射型抗反轉錄病毒產品。每種都是抗反轉錄病毒藥物的長效製劑,可每月或每兩個月一起給藥。

Vocabria是整合酶抑製劑,係Cabotegravir的可注射形式。 VocabriaViiV Healthcare公司銷售。

Rekambys是非核苷類反轉錄酶抑製劑,係rilpivirine的可注射形式。 RekambysJanssen公司銷售。

VocabriaRekambys2020年在歐盟和英國獲得批准,可用於已完全抑制病毒載量(<50拷貝/毫升)人群中的HIV治療。

兩種注射劑以Cabenuva命名的組合產品,分別於2020年在加拿大和2021年在美國獲得批准,可用於那些已完全抑制了病毒載量(<50拷貝/毫升)的人的HI V治療。

效用

Cabotegravirrilpivirine注射方案係基於三項臨床試驗的結果獲批准。

ATLAS研究針對616名在進入研究前至少已六個月病毒載量受到抑制的患者,進行了可注射之Cabotegravirrilpivirine並與採口服抗反轉錄病毒治療者進行比較。參與者隨機分派至接受注射治療者,則先服用Cabotegravirrilpivirine錠劑治療了一個月,然後才轉向注射。在第48週,接受長效治療的參與者中有92.5%的人和接受口服治療的參與者中有95.5%的人,其病毒載量低於50拷貝/毫升,兩者之差異無統計學上意義。

FLAIR研究則針對566位先前未接受治療的患者,比較了Cabotegravirrilpivirine注射型的藥物與DolutegravirAbacavirLamivudineTriumeq)藥物的療效。所有研究參與者均接受了DolutegravirAbacavirLamivudine20週誘導治療。在第16週,將病毒載量低於50拷貝/ ml的患者,隨機分派於繼續誘導方案,或在第20週切換至Cabotegravirrilpivirine的一個月誘導方案,然後每月注射Cabotegravirrilpivirine。在第48週,接受長效治療的患者中有93.6%和接受口服治療者有93.3%的病毒載量低於50拷貝/ ml。參與者改用長效治療後,治療滿意度提高;在第48週時,有91%的人選擇長效療法。

ATLAS-2M研究則比較了1,045名接受過治療且病毒載量受到抑制的成年人,採每月或每兩個月注射Cabotegravirrilpivirine 37%的參與者先前在ATLAS試驗中接受了為期四周的注射方案。在第48週時,接受2個月方案的參與者中有94.3%的人和接受每月方案的參與者有93.5%的人,持續具有不可檢測的病毒載量(少於50拷貝/ ml),顯示兩個月的給藥時間並不遜色於每月給藥。

在兩個月的治療組中,病毒學失敗率(HIV RNA超過50拷貝/ ml)為1.7%,而每月治療組為1.0%。兩個月一次的療程中有八人(1.5%)相較於一個月的療程中有兩個人(0.4%),經歷了確認的病毒學失敗,其定義為連續兩次的病毒載量超過200拷貝/ ml。十名證實病毒學失敗的人中有九人在改用完全積極的口服治療後恢復了病毒抑制。但是,使用兩個月一次治療方案的人更有可能發生耐藥性突變。

服用

開始注射長效治療方案的人們,將會從他們現有的抗反轉錄病毒治療方式轉化為每天服用一次cabotegravirrilpivirine錠劑持續一個月,然後再開始接受注射治療。導入治療旨在評估耐受性,並允許在長效治療開始之前停藥。

可以採每月或每兩個月注射一次;於回診時於臀部以分兩次肌肉注射的方式將Cabotegravirrilpivirine同時注射。如果錯過預定的注射時間超過一個星期,則應重新開始使用cabotegravirrilpivirine錠劑進行口服治療。含鈣或鎂的抗酸劑應在服用cabotegravir片劑至少兩個小時之前或至少四個小時之後服用。

副作用

FLAIRATLAS研究人群的綜合分析發現,83%的注射型接受者經歷了注射部位之反應。在治療的最初幾個月中,注射部位反應更為頻繁,並且在大多數參與者中(88%)在7天內得到緩解。高達1%的試驗參與者由於注射部位之反應而終止了注射治療。在ATLAS-2M中,有76%的參與者經歷了注射部位的反應。其他常見的副作用包括體溫升高,肌肉疼痛,疲倦,虛弱,抑鬱,暈眩,夢境異常,腹瀉,噁心,嘔吐,腹痛和皮疹。

在臨床試驗參與者中,白血球和紅血球細胞計數降低、總膽固醇和低密度膽固醇升高、甘油三酸酯升高和胰澱粉酶升高等是常見的。

臨床試驗中報告了在注射rilpivirine後出現少見的短暫性注射後反應的案例。態樣包括呼吸急促、躁動、腹部絞痛、潮紅、出汗、口腔麻痺和血壓變化。

在少數人當中已經有報導了與其他整合酶抑製劑有關的超敏反應。惟迄今為止,尚未有報告使用cabotegravir時發生這些反應。

在開始抗反轉錄病毒治療後體重增加已有報導,對臨床研究的分析顯示,以整合酶抑製劑為基礎開始治療的人體重增加更大。注射方案的臨床試驗顯示體重適度增加。在FLAIR研究中,在以前未接受治療的人群中,將含有整合酶抑製劑的注射治療與另一種基於整合酶抑製劑的治療方案進行了比較,歷經48週,在體重增加上(+ 1.3kg+ 1.5kg)並沒有顯著差異。在ATLAS研究中,於有治療經驗的人中將注射療法與口服療法進行了比較,注射組的體重增加更大(+ 1.8kg+ 0.3kg)。 ATLAS研究的參與者中有三分之一其基線藥物即服用了整合酶抑製劑。在對有治療經驗的患者繼續或轉換為可注射方案的ATLAS-2M研究中,則其體重增加適中(第48週時+ 1kg)。

藥物交互作用

下列藥物不能與cabotegravirrilpivirine注射劑同時使用:

•抗驚厥的藥物carbamazepine, oxcarbazepine, phenobarbital, phenytoin

•抗分枝桿菌(如結核病的用藥)rifabutin, rifampicin, rifapentine

•全身性糖皮質糖皮質類固醇dexamethasone,單劑量治療除外

•聖約翰草(Hypericum perforatum,貫葉連翹,又名貫葉金絲桃,金絲桃科金絲桃屬植物,是歐美的常用草藥,主要用於婦女調經,亦有寧神、平衡情緒的作用)。

抗藥性

在最後一次注射後,低濃度的Cabotegravir可能會存留在血液中長達12個月或更長時間,但這不足以維持HIV抑制作用。低濃度的rilpivirine可能持續長達四年。

如果在停止每月一次注射治療後一個月內或在停止每兩個月注射治療後兩個月內未開始新的抗反轉錄病毒治療,可能會產生病毒之耐藥性。

FLAIRATLAS研究的分析顯示,包涵至少兩個下列基本因素的組合狀態可能與病毒學失敗風險的增加有關:封存的rilpivirine抗藥性突變、HIV-1 A6 / A1亞型或BMI 30 kg /m2。在不確定治療史且尚無以前的耐藥性測試數據的地方,如果存在BMI 30 kg / m2HIV-1 A6 / A1亞型存在的情況,則應格外小心。

懷孕

由於缺乏數據,不建議在妊娠期間使用cabotegravirrilpivirine長效型治療。Rilpivirine水平於妊娠期可能降低,增加了病毒學失敗的風險。

兒童

Cabotegravirrilpivirine長效療法未獲准用於兒童。

 

 

 

 

 

 

 

 

 

 

Cabotegravir (Vocabria) & rilpivirine (Rekambys) injections

Aidsmap / Keith Alcorn / January 2021

Vocabria  and  Rekambys  are injectable antiretroviral products approved for use in combination. Each is a long-acting formulation of an antiretroviral drug, administered together every month or every two months.

Vocabria  is the injectable form of the integrase inhibitor cabotegravir. Vocabria is marketed by ViiV Healthcare.

Rekambys  is the injectable form of the non-nucleoside reverse transcriptase inhibitor  rilpivirine .  Rekambys is marketed by Janssen.

Vocabria  and  Rekambys  were approved in the European Union and United Kingdom in 2020 for use in combination to treat HIV in people with fully suppressed viral load (< 50 copies/ml).

The two injectable agents were approved in Canada in 2020 and the United States in 2021 as a combined product with the name  Cabenuva  to treat HIV in people with fully suppressed viral load (< 50 copies/ml).

Effectiveness

The cabotegravir and rilpivirine injectable regimen was approved based on the results of three clinical trials.

The  ATLAS study  compared injectable cabotegravir and rilpivirine to oral antiretroviral treatment in 616 people with suppressed viral load for at least six months prior to study entry. Participants randomised to injectable treatment took cabotegravir and rilpivirine pills for a month before switching to injections. 92.5% of participants receiving long-acting therapy and 95.5% of those receiving oral therapy had a viral load below 50 copies/ml at week 48, a non-significant difference.

The  FLAIR study compared injectable cabotegravir and rilpivirine to dolutegravir, abacavir and lamivudine (Triumeq) in 566 previously untreated people. All study participants received 20 weeks of induction treatment with dolutegravir, abacavir and lamivudine. At week 16, people with viral load below 50 copies/ml were randomised to continue the induction regimen or switch at week 20 to a one-month induction regimen of cabotegravir and rilpivirine tablets followed by monthly injections of cabotegravir and rilpivirine. At week 48, 93.6% of those who received long-acting therapy and 93.3% who received oral therapy had a viral load below 50 copies/ml. Treatment satisfaction increased after participants switched to long-acting therapy; 91% preferred long-acting therapy at week 48. (Orkin)

The  ATLAS-2M study  compared monthly or two-monthly injections of cabotegravir and rilpivirine in 1045 treatment-experienced adults with suppressed viral load. Thirty-seven per cent of participants had previously received the four-week injectable regimen in the ATLAS trial. At week 48, 94.3% of participants taking the two-monthly regimen and 93.5% of those taking the monthly regimen continued to have undetectable viral load (less than 50 copies/ml), showing that the two-monthly schedule was non-inferior to monthly administration.

Rates of virological failure (HIV RNA over 50 copies/ml) were 1.7% in the two-monthly group versus 1.0% in the monthly treatment group. Eight people (1.5%) on the two-monthly regimen and two people (0.4%) on the monthly regimen experienced confirmed virological failure, defined as two consecutive viral loads above 200 copies/ml. Nine of the ten people with confirmed virological failure regained viral suppression when switched to a fully active oral regimen. However, those using the two-monthly regimen were more likely to have drug resistance mutations. (Overton)

Taking it

People starting the injectable long-acting regimen will switch from their existing antiretroviral treatment to take cabotegravir and rilpivirine tablets once daily for a month before beginning injectable treatment. Lead-in treatment is designed to assess tolerability and allows discontinuation before long-acting treatment begins.

Injectable treatment can be given monthly or two-monthly.

Cabotegravir and rilpivirine are administered as two intramuscular injections in the buttocks at the same appointment.

If scheduled injections are missed by more than one week, oral treatment with cabotegravir and rilpivirine tablets should be resumed.

Antacids containing magnesium or calcium should be taken at least two hours before or four hours after cabotegravir tablets.

Side effects

A combined analysis of the FLAIR and ATLAS study populations found that 83% of injectable recipients experienced injection site reactions. Injection site reactions were more frequent during the first months of treatment and resolved within seven days in most participants (88%). Up to 1% of trial participants discontinued injectable treatment because of injection site reactions. (Rizzardini)

In ATLAS-2M, 76% of participants experienced injection site reactions. (Overton)

Other common side effects were raised temperature, muscle pain, tiredness, weakness, depression, dizziness, abnormal dreams, diarrhoea, nausea, vomiting, abdominal pain and rash.

Lowered white and red blood cell count, raised total and LDL cholesterol, raised triglycerides and raised pancreatic amylase were common in clinical trial participants.

Rare cases of transient post-injection reactions after the rilpivirine injection were reported in clinical trials. Features included shortness of breath, agitation, abdominal cramping, flushing, sweating, oral numbness and changes in blood pressure.

Hypersensitivity reactions have been reported with other integrase inhibitors in a small number of people. These reactions have not been reported to date with cabotegravir use.

Weight gain has been reported after starting antiretroviral treatment and analysis of clinical studies shows that weight gain is greater in people starting integrase inhibitor-based treatment. Clinical trials of the injectable regimen show modest increases in weight. In the FLAIR study, which compared injectable treatment containing an integrase inhibitor to another integrase inhibitor-based regimen in previously untreated people, there was no significant difference in weight gain (+1.3kg vs +1.5kg) over 48 weeks. In the ATLAS study, which compared injectable treatment to oral treatment in treatment-experienced people, weight gain was greater in the injectable group (+1.8kg vs +0.3kg). One-third of participants in the ATLAS study were taking an integrase inhibitor at baseline. In the ATLAS-2M study in treatment-experienced patients continuing or switching to the injectable regimen, weight gain was modest (+1kg at week 48). (Orkin; Swindells; Overton)

Drug interactions

The following medicines should not be used at the same time as cabotegravir and rilpivirine injectable treatment:

·        the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin

·        the antimycobacterials rifabutin, rifampicin, rifapentine

·        the systemic glucocorticoid dexamethasone, except as a single-dose treatment

·        St John’s wort (Hypericum perforatum).

Resistance

Low concentrations of cabotegravir may remain in the bloodstream for up to 12 months or more after the last injection but these are not enough to maintain suppression of HIV. Low concentrations of rilpivirine may persist for up to four years.

Viral resistance may develop if a new antiretroviral regimen is not started one month after stopping monthly dosing of the injectable regimen or within two months after stopping two-monthly dosing of the injectable regimen.

Analysis of the FLAIR and ATLAS studies shows that a combination of at least two of the following baseline factors may be associated with an increased risk of virological failure: archived rilpivirine resistance mutations, HIV-1 subtype A6/A1, or BMI 30 kg/m2.Where treatment history is uncertain and previous resistance testing data is unavailable, caution is warranted in the presence of either BMI 30 kg/m2 or HIV-1 A6/A1 subtype.

Pregnancy

Cabotegravir and rilpivirine long-acting treatment is not recommended during pregnancy due to lack of data. Rilpivirine levels may be reduced during pregnancy, increasing the risk of virological failure.

Children

Cabotegravir and rilpivirine long-acting treatment is not approved for use in children.

References

Swindells S et al. Long-acting cabotegravir and rilpivirine for maintenance of HIV-1 suppression. New England Journal of Medicine, 382: 1112-1123, 2020.

Orkin C et al. Long-acting cabotegravir and rilpivirine after oral Induction for HIV-1 infection. New England Journal of Medicine, 382: 1124-1135, 2020.

Overton S et al. Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 48-week results: a randomised, multicentre, open-label, phase 3b, non-inferiority study. Lancet, 396: 1994-2005, 2020.

Rizzardini G et al. Long-acting injectable cabotegravir + rilpivirine for HIV maintenance therapy: Week 48 pooled analysis of phase 3 ATLAS and FLAIR trialsJournal of Acquired Immune Deficiency Syndromes, 85: 498-506, 2020.

This page was last reviewed in January 2021. It is due for revew in January 2024.