改用基於TAF的暴露前預防(PrEP) 藥物可以改善腎臟和骨

 

改用基於TAF的暴露前預防(PrEP)藥物可以改善腎臟和骨骼標記,但是會增加心血管疾病的風險嗎?

Liz Highleyman / 20191015 / aidsmap news / 財團法人台灣紅絲帶基金會編譯

Truvada(舒發泰,tenofovir disoproxil fumarate/emtricitabine)轉向較新的Descovytenofovir alafenamide/emtricitabine)進行暴露前預防(PrEP)的人,其腎功能和骨密度的測量指標得到了改善,但兩種組合配方藥物的不良臨床結果均很少見,研究人員於最近在美國華盛頓特區舉行的IDWeek 2019大會上報告了這種配方。

但是,另一項研究愛滋病毒治療的研究表明,從tenofovir disoproxil fumarateTDF)改用tenofovir alafenamideTAF)會導致體重增加和心血管風險評分惡化。

TDF是用於HIV治療的最廣泛使用的藥物之一,也是首個獲准用於暴露前預防(PrEP)的藥物,通常安全且耐受性良好,但它可能導致易感人群腎功能受損和骨質流失。建議患有腎病的患者不要使用TDF及其組合配方藥物治療或預防愛滋病毒。

TAF是一種較新的前驅藥物,可在T細胞中以較TDF小的劑量產生更高水平的活性藥物(tenofovir diphosphate),這意味著在血液中的濃度較低,並且腎臟,骨骼和其他器官的藥物暴露較少。

過去幾年的研究表明,包含TAF的抗反轉錄病毒療法(ART)對腎臟和骨骼健康的有害影響要小於包含TDF的療法,並且從TDF轉換為TAF可以改善腎臟和骨骼的生物標記。但是,兩種藥物之使用都不常見腎功能衰竭和骨折。同時生產這兩種藥物的吉利德科學公司(Gilead Sciences)已在其單片療法之BiktarvyGenvoyaOdefseySymtuza中用TAF代替TDF

本月,美國食品藥品管理局批准了Descovy作為第二種PrEP治療方案,適用於透過性行為感染HIV風險的人,但屬接受性陰道性行為者除外。批准的依據是DISCOVER試驗的結果,該結果表明TruvadaDescovy在與男性和跨性別女性發生性行為的男性中,對HIV之預防同樣有效,但是Descovy對腎臟功能和骨骼生物標誌物的有害影響較小。

IDWeek會議上,洛杉磯男性健康基金會的Anthony Mills博士介紹了DISCOVER試驗參與者對腎臟安全結果進行分析的結果,其中包括從Truvada轉到Descovy的一個子集。北卡羅來納大學教堂山分校的David Wohl博士介紹了有關骨安全性結果的相關分析。

DISCOVER招募了5,300多名與男男間性行為者的高危男性和少數跨性別女性,但不包括順性別女性和跨性別男性。參與者被隨機分配為每天服用一次DescovyTruvada,最多兩年。其中,已有905人在參加試驗前已經服用了舒發泰Truvada,其中465人被隨機分配到Descovy部門並更換藥物。

腎臟的結果

腎功能評估包括尿液分析,估計的腎小球濾過率(eGFR),尿蛋白與肌酐比率,近端腎小管功能標記和研究者報告的腎臟不良事件。

總體而言,在第48週時,與Truvada相比,DescovyeGFR的更有利變化和近端腎小管功能標記相關,蛋白尿(尿液中的蛋白)較少見(分別為24%和21%),根據Mills博士報導。

服用Descovy的參與者發生與藥物相關的腎臟不良事件較少(14 vs 26例),嚴重的腎臟事件(2 vs 3例),因此中止治療的可能性較小(2 vs 6例)。但是,所有這些結果在兩組中都不常見(1%或更少)。一位服用Truvada但未服用Descovy的人發生近端腎小管病變或范康尼氏症候群(Fanconi syndrome,註),這是一種嚴重的腎功能損害。

在參加研究時從Truvada轉到Descovy的參與者最早在換藥後第4週就發現腎小球濾過率(eGFR)顯著增加,以及蛋白尿減少。

「在整個研究人群以及從Truvada轉向Descovy的那些人群中,這些重要腎臟健康指標的改善顯示,對於那些可能需要長期使用PrEP的愛滋病毒易感人群來說,Descovy有可能成為預防上選擇,包括以前使用過Truvada作為PrEP者」, Mills博士在Gilead新聞稿中說。

骨骼的結果

Wohl博士報告了來自383DISCOVER參與者的骨礦物質密度(BMD)子研究的結果。在這個小組中,有53名在加入研究時在Truvada組中,其中26名被隨機分配到Descovy

分配給Descovy組的人在48週時髖部和脊柱的骨密度略有增加,而Truvada則與這種下降有關,尤其是在年輕參與者中。與繼續使用Truvada的患者相比,從Truvada轉換為Descovy的參與者其脊柱特別是髖部骨質密度有明顯改善。

此外,Descovy的接受者不太可能出現脊柱骨質減少(骨變薄)或骨質疏鬆症(更嚴重的骨質流失),但在兩組中前述情況均很少見(低於1%)。兩組中骨折均不常見,發生頻率相似(53例,佔2%)。

體重和心血管的風險

儘管TAF對腎臟和骨骼的危害較小,但是TDF在涉及心血管風險方面可能具有優勢。Tenofovir可降低血脂水平,但由於TAF在血液中的濃度較低,因此它對TAF的作用不如對TDF的作用大。但是,TAF對其他心血管危險因素和預後的影響尚未得到很好的研究。

TDF轉換為TAF會導致體重增加和心血管風險評分惡化。」

費城傑弗遜藥學院的Jason Schafer介紹了對從TDF改用TAF而不改變其抗反轉錄病毒療法其他成分的HIV陽性人群的回顧性分析結果。

這項觀察性研究包括1104075歲的人,他們服用TDF至少一年並在轉用TAF之前保持了病毒抑制(低於200/毫升)。

大部分(80%)是男性,64%是非裔美國人,三分之一是白人。平均年齡為50歲;他們被診斷出愛滋病毒的中位數為12年,接受抗病毒治療的中位數為8年。 CD4中位數很高,為628個細胞 / 立方亳米。大約有一半服用整合酶抑製劑,其中29%服用非核苷酸反轉錄酶抑制劑,16%服用蛋白酶抑製劑。

TDF轉換為TAF之前和之後的一年,收集體重,身體質量指數(BMI),膽固醇水平和動脈粥樣硬化性心血管疾病風險評分。轉換前,有31%歸為正常體重,28%歸為超重,37%歸為肥胖,4%歸為體重不足。

TDF轉變為TAF的人在體重、BMI和膽固醇(總膽固醇,攜帶膽固醇的高密度脂蛋白HDL和攜帶膽固醇的低密度脂蛋白LDL)顯著增加後,儘管總膽固醇與HDL的比例沒有顯著改變。平均體重增加為1.36千克,或+ 9.2%。轉換後,心血管疾病風險中位數從6.9上升至8.1+ 1.9%)。

在調整了潛在的干擾因素後,研究人員計算出,從TDF轉換為TAF與平均心血管風險評分增加13%有關。這使得超過一半的參與者超過了美國心臟協會推薦使用他汀類藥物治療心血管風險的閾限值。

他們總結說:「我們觀察到的BMI改變不太可能代表『健康恢復』,因為患者長期存在HIV感染,在更換藥物之前一直由ART持續控制。」「身體質量指數(BMI)的變化是適度的,但可能與臨床相關,因為即使身體質量指數的微小變化,也會影響患者終生罹患糖尿病和動脈粥樣硬化性心血管疾病的風險。」

後續需要進行進一步的研究以確定在使用TAF進行PrEP的人群中是否也看到了這類變化,而這些人群往往是年輕人。

註:范康尼氏症候群(Fanconi syndrome):是一種腎臟近曲小管(Proximal convoluted tubule)的疾病, 病徵在於其中的葡萄糖,胺基酸,尿酸,磷酸鹽和碳酸氫鹽被傳遞到尿液,而不是被重新吸收。范康尼氏症候群影響腎單位的近曲小管,而近曲小管是用來處理流體通過腎小球過濾管部的第一部分。范康尼氏症候群可以由藥物或重金屬所產生或引起。

 

Switching to TAF-based PrEP improves kidney and bone markers – but does it raise cardiovascular risk?

Liz Highleyman

15 October 2019

People who switched from Truvada (tenofovir disoproxil fumarate/emtricitabine) to the newer Descovy (tenofovir alafenamide/emtricitabine) for pre-exposure prophylaxis (PrEP) experienced improvements in measures of kidney function and bone density, but adverse clinical outcomes were rare with either co-formulation, researchers reported at the recent IDWeek 2019 conference in Washington, DC.

However, another study looking at HIV treatment showed that switching from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) led to weight gain and worsening cardiovascular risk scores.

TDF, one of the most widely used medications for HIV treatment and the first drug approved for PrEP, is generally safe and well tolerated, but it can cause kidney impairment and bone loss in susceptible individuals. Those with pre-existing kidney problems are advised not to use TDF and its co-formulations for HIV treatment or prevention.

TAF is a newer prodrug that produces higher levels of the active drug (tenofovir diphosphate) in T-cells with smaller doses than TDF, which means lower concentrations in the blood and less drug exposure for the kidneys, bones and other organs.

Studies in the past few years have shown that antiretroviral therapy (ART) containing TAF has less detrimental effects on kidney and bone health than regimens containing TDF, and that switching from TDF to TAF leads to improvement in renal and bone biomarkers. However, kidney failure and fractures are uncommon with either medication. Gilead Sciences, which manufactures both drugs, has replaced TDF with TAF in its single-tablet regimens BiktarvyGenvoyaOdefsey and Symtuza.

This month the US Food and Drug Administration approved Descovy as a second PrEP option for people at risk for sexually acquired HIV, with the exception of those who have receptive vaginal sex. Approval was based on findings from the DISCOVER trial, which showed that Truvada and Descovy were equally effective for HIV prevention in men who have sex with men and transgender women, but Descovy had less detrimental effects on kidney function and bone biomarkers.

At IDWeek, Dr Anthony Mills of the Men’s Health Foundation in Los Angeles presented findings from an analysis of kidney safety outcomes among DISCOVER participants, including a subset who switched from Truvada to Descovy. Dr David Wohl of the University of North Carolina at Chapel Hill presented a related analysis of bone safety outcomes.

DISCOVER enrolled more than 5300 at-risk men who have sex with men and a small number of trans women, but excluded cisgender women and trans men. Participants were randomly assigned to take Descovy or Truvada once daily for up to two years. Of these, 905 people were already taking Truvada before joining the trial, including 465 who were randomised to the Descovy arm and switched drugs.

Kidney outcomes

Kidney function assessments included urinalysis, estimated glomerular filtration rate (eGFR), urine protein-to-creatinine ratio, markers of proximal tubular function and investigator-reported renal adverse events. 

Overall, at 48 weeks, Descovy was associated with more favourable changes in eGFR and markers of proximal tubular function compared with Truvada, and proteinuria (protein in the urine) was less common (24% vs 21%, respectively), Dr Mills reported.

Participants taking Descovy had fewer drug-related renal adverse events (14 vs 26 cases), serious renal events (2 vs 3 cases) and were less likely to discontinue treatment for this reason (2 vs 6 cases). However, all these outcomes were uncommon in both groups (1% or less). One person taking Truvada but none taking Descovy developed proximal renal tubulopathy, or Fanconi syndrome, which is a type of serious kidney function impairment.

Participants who switched from Truvada to Descovy at study entry saw significant increases in eGFR as early as week 4 after changing drugs, as well as decreased proteinuria.

"The improvements observed in these important markers of kidney health in the overall study population and in those who switched from Truvada to Descovy point to the potential for Descovy to be a preventive option for appropriate people at risk for HIV who may require longer-term PrEP use, including those who have previously taken Truvada for PrEP," Dr Mills said in a Gilead press release.

Bone outcomes

Dr Wohl reported results from a bone mineral density (BMD) sub-study that included 383 DISCOVER participants. Within this group, 53 were on Truvada at study entry, 26 of whom were randomized to switch to Descovy.

People assigned to the Descovy arm experienced small increases in bone density at the hip and spine at 48 weeks, while Truvada was associated with declines – especially among younger participants. Those who switched from Truvada to Descovy had significant improvements in spine and especially hip BMD compared with those who continued on Truvada.

Further, Descovy recipients were less likely to develop osteopenia (bone thinning) or osteoporosis (more severe bone loss) of the spine, but these were rare in both groups (under 1%). Fractures were uncommon and occurred with similar frequency in both groups (53 cases, or 2%).

Weight and cardiovascular risk

While TAF is less harmful to the kidneys and bones, TDF may have the advantage when it comes to cardiovascular risk. Tenofovir is known to lower blood lipid levels, but this effect is not as great with TAF as it is with TDF because of TAF's lower concentration in the blood. However, TAF's impact on other cardiovascular risk factors and outcomes has been less well studied.

“Switching from TDF to TAF led to weight gain and worsening cardiovascular risk scores."witching from TDF to TAF led to weight gain and worsening cardiovascular risk Jason Schafer of Jefferson College of Pharmacy in Philadelphia presented findings from a retrospective analysis of HIV-positive people who switched from TDF to TAF without changing any other components of their combination antiretroviral regimen.

This observational study included 110 people age 40 to 75 years who had been taking TDF for at least a year and maintained viral suppression (below 200 copies/ml) before switching to TAF.

Most (80%) were men, 64% were African American and a third were white. The average age was 50 years; they had been diagnosed with HIV for a median of 12 years and on ART for a median of 8 years. The median CD4 count was high, at 628 cells/mm3. About half were taking integrase inhibitors, 29% were on NNRTIs and 16% were on protease inhibitors.

Weight, body mass index (BMI), cholesterol levels and atherosclerotic cardiovascular risk scores were collected for the year prior to and following the switch from TDF to TAF. Before switching, 31% were classified as normal weight, 28% as overweight, 37% as obese and 4% as underweight.

People who switched from TDF to TAF experienced significant increases in weight, BMI and cholesterol (total, LDL and HDL) after the change, although the total-to-HDL ratio did not change significantly. The median weight gain was 1.36kg, or +9.2%. The median cardiovascular risk score rose from 6.9 to 8.1 (+1.9%) after the switch.

After adjusting for potential confounding factors, the researchers calculated that switching from TDF to TAF was associated with a 13% increase in the average cardiovascular risk score. This shifted more than half of the participants above the American Heart Association threshold for recommending statins to manage cardiovascular risk.

"It is unlikely that the BMI changes we observed represent a 'return to health' since patients had longstanding HIV infection that was persistently controlled by ART prior to switching," they concluded. "BMI changes were modest, but could be clinically relevant as even small changes in BMI can influence a patient's lifetime risk for developing diabetes and atherosclerotic cardiovascular disease."

Further research is needed to determine if these kinds of changes are also seen in people taking TAF for PrEP, which tends to be a younger population.

References

Mills A et al. Renal outcomes for participants taking F/TAF versus F/TDF for HIV PrEP prep in the DISCOVER trial. IDWeek, Washington, DC, abstract 1962, 2019.

Wohl DA et al. Bone safety outcomes with F/TAF vs. F/TDF for PrEP in the DISCOVER trial. IDWeek, Washington, DC, abstract 1288, 2019.

Schafer J et al. BMI and ASCVD risk score changes in virologically suppressed patients with HIV switching from TDF to TAF containing ART. IDWeek, Washington, DC, abstract 979, 2019.