美國食品藥物管理局(FDA)批准了基於TAF的暴露前預防藥物

 

美國食品藥物管理局(FDA)批准了基於TAF的暴露前預防藥物(PrEP)

用於許多有感染愛滋病毒風險者

Liz Highleyman / 2019107/ aidsmap news/財團法人台灣紅絲帶基金會編譯

美國食品藥品管理局(FDA)上週批准了tenofovir alafenamide/emtricitabine(商品名Descovy),這是一種包含tenofovir的更新版之組合藥,是許多人暴露前預防(PrEP)的第二種選擇藥物。但是,其適應症不包括那些透過陰道性行為而有感染愛滋病毒風險的人。

Descovy中,tenofovir alafenamideTAF)在HIV易感性免疫細胞中所產生的藥物活性水平高於tenofovir disoproxil fumarate (TDF)於先前批准的唯一PrEP方案,TDF/emtricitabine,後者以舒發泰(Truvada)的形式銷售,並且有越來越多地非品牌學名藥。這意味著可以用更低的劑量給予TAF,從而減少腎臟、骨骼和其他器官的藥物暴露。 DescovyTruvada均由吉利德公司(Gilead Sciences)製造。

TAF/emtricitabine 被批准用於體重至少35公斤且有透過性而感染HIV風險的成人和青少年,但有接受性陰道性行為風險的人除外。實際上,這意味著它適用於具有插入性肛交或陰道性交的順性別(非跨性別)男性,以及具有接受性肛交的順性別男性或跨性別的男性和女性。但是這種適應症並不適用於具有接受性陰道性行為(有時稱為正面性交)的順性別女性和跨性別男性。

FDA諮詢小組在八月份的聽證會上投票建議,由於缺乏對女性所作的試驗,建議批准TAF/emtricitabine PrEP用於男男間性行為者的男性和跨性別的女性,但不建議用於順性別之女性。最後,該機構係根據性活動的類型而不是性取向或性認同來確定其適應症。而TDF/emtricitabine PrEP沒有這樣的限制。

TAF/emtricitabine 預防愛滋病僅適用於在開始PrEP之前被確認為HIV陰性的人群。已經感染愛滋病毒的人必須將TAF/emtricitabine作為完整的抗反轉錄病毒治療方案中的一部分,因為單獨使用它可能會導致耐藥性。

TAF/emtricitabineB型肝炎病毒和HIV具有活性。因此,在停止服用PrEP時,應密切監測HIVB型肝炎合併感染的人,因為這可能導致肝病惡化。

TAF/emtricitabine PrEP的批准是基於DISCOVER試驗的結果,該試驗招募了具有風險的5300多名男男間性行為者和少數跨性別女性,但排除了順性別的女性和跨性別男性。他們被隨機分配為每天服用一次TAF/emtricitabineTDF/emtricitabine,持續兩年。

正如今年在反轉錄病毒和伺機性感染會議上所報導的那樣,兩種預防藥都被證明是非常有效的。經過一到兩年的追蹤,TAF/emtricitabine組中出現了7例新的HIV感染,而TDF / emtricitabine組中出現了15例,每100人年的發病率分別為0.160.34。經過血清陽轉的人中,有15個病例顯然是由於順從性差而引起的,而據認為有五個人在研究開始前不久就已經被發現有未被偵測到之愛滋病毒感染。

鑑於兩組的感染數量均很少,因此發病率的差異在統計學上並不顯著,這意味著可能是偶然發生的。因此,研究人員得出結論,TAF/emtricitabine不遜於TDF / emtricitabine,這意味著他們認為它同樣有效。

正如今年夏天在國際愛滋病學會會議上所描述的那樣,一些研究人員認為,TAF/emtricitabine組的血清陽轉率較低反映了療效的真正差異。這可能歸因於以下事實:TAF導致細胞中的藥物水平更高,與TDF相比,藥物水平更快地達到並且持續時間更長。對於那些奮鬥於順從每天服用PrEP的同性戀者和雙性戀男人以及那些於性交前後依需要使用或間歇性服用PrEP的同性戀者而言,這種「寬恕」可能很重要。TAF/emtricitabineTDF / emtricitabine均未獲批准用於間歇給藥,此新方案不建議用於順性別女性。)

鑑於他們被DISCOVER排除在外,因此尚未在臨床試驗中證明TAF/emtricitabine PrEP對陰道性行為的有效性。先前的研究顯示,與直腸組織相比,tenofovir在陰道和子宮頸組織中的含量較低,並且持續時間不長。吉利德(Gilead)敦促FDA從現有的藥物代謝動力學數據中推斷,該數據表明TAF可以在女性體內產生足夠的藥物水平,但該機構拒絕在沒有更多直接證據的情況下批准該族群使用Descovy

一些擁護者對這一決定表示讚賞,呼籲在女性和跨性別者中進行TAF/emtricitabine的臨床試驗,並認為在缺乏此類證據的情況下予以批准將開創一個不好的先例。然而,另一些人則擔心,女性現在的口服PrEP方案比男性少。儘管大多數DISCOVER參與者是男男間性行為者的順性別男性,但FDA審評人員仍將適應症擴展至異性戀男性。

105日致社區成員的信中,吉利德(Gilead)表示,該公司已與FDA達成協議,將進行一項研究,以評估Descovy在成年和青春期順性別女性中的PrEP使用。

談到安全性,在腎功能和骨質流失的生物標誌方面,TAF/emtricitabineTDF / emtricitabine具有更少的有害作用,儘管尚不清楚在骨折等臨床結果上這是否重要。另一方面,TAF/emtricitabine對有利於血脂水平的影響較小。因此,對於有腎臟或骨骼問題風險的人TAF/emtricitabine可能是一個較好的選擇,而對於那些有心血管疾病風險的人,TDF/emtricitabine可能是更值得被建議。

但是,對於絕大多數服用PrEP的人來說,TAF/emtricitabineTDF / emtricitabine可能都有很好的耐受性並且非常有效。一些倡導者認為,對於大多數人來說,安全性或功效的任何小幅的提高都不值得Descovy增加的成本,與通用TDF / emtricitabine學名藥相比,Descovy僅係為具有品牌的產品而已。

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

US FDA approves TAF-based PrEP for many people at risk for HIV

Liz Highleyman/ 7 October 2019/ aidsmap news

The US Food and Drug Administration (FDA) last week approved tenofovir alafenamide/emtricitabine (brand name Descovy), a combination pill containing an updated version of tenofovir, as a second pre-exposure prophylaxis (PrEP) option for many people. However, the indication does not include those at risk of acquiring HIV through vaginal sex.

The tenofovir alafenamide (TAF) in Descovy produces higher levels of the active drug in HIV-susceptible immune cells than the tenofovir disoproxil fumarate (TDF) in the only previously approved PrEP regimen, TDF/emtricitabine, which is marketed as Truvada and increasingly available as non-branded generics. This means TAF can be given at lower doses, resulting in less drug exposure for the kidneys, bones, and other organs. Both Descovy and Truvada are manufactured by Gilead Sciences.

TAF/emtricitabine was approved for adults and adolescents weighing at least 35kg who are at risk for sexually acquired HIV, with the exception of people at risk from receptive vaginal sex. In effect, this means it is indicated for cisgender (non-trans) men who have insertive anal or vaginal sex, as well as for cisgender or transgender men and women who have receptive anal sex. But the indication does not extend to cisgender women and trans men who have receptive vaginal sex (sometimes called frontal sex).

An FDA advisory panel voted at an August hearing to recommend approval of TAF/emtricitabine PrEP for men who have sex with men and for trans women, but not for cisgender women due to a lack of evidence from clinical trials. In the end, the agency based the indication on type of sexual activity rather than sexual orientation or gender identity. TDF/emtricitabine PrEP has no such limitations.

TAF/emtricitabine for HIV prevention should only be prescribed for people who are confirmed to be HIV negative immediately prior to starting PrEP. People who already have HIV must take TAF/emtricitabine as part of a complete antiretroviral treatment regimen, as using it alone could lead to drug resistance.

TAF/emtricitabine is active against hepatitis B virus as well as HIV. For this reason, people who have HIV and hepatitis B co-infection should be monitored closely when they stop taking PrEP, as this could lead to worsening liver disease.

Approval of TAF/emtricitabine PrEP was based on findings from the DISCOVER trial, which 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. They were randomly assigned to take TAF/emtricitabine or TDF/emtricitabine once daily for two years.

As reported at this year's Conference on Retroviruses and Opportunistic Infections, both prevention pills proved highly effective. After one to two years of follow-up, there were seven new HIV infections in the TAF/emtricitabine arm and 15 in the TDF/emtricitabine arm, yielding incidence rates of 0.16 and 0.34 per 100 person-years, respectively. Among those who seroconverted, 15 cases were apparently due to low adherence, while five people were thought to already have had undetected HIV acquired shortly before they started the study.

Given the small number of infections in both groups, the difference in the incidence rates was not statistically significant, meaning it could have happened by chance. Thus, the researchers concluded that TAF/emtricitabine is noninferior to TDF/emtricitabine, meaning they considered it equally effective.

As described at the International AIDS Society Conference this summer, some researchers have suggested that the lower seroconversion rate in the TAF/emtricitabine group reflects a real difference in efficacy. This may be attributable to the fact that TAF leads to higher drug levels in cells, which are reached more quickly and persist longer compared with TDF. This added 'forgiveness' could potentially be important for gay and bisexual men who struggle with adherence to daily PrEP and those using on-demand or intermittent PrEP before and after sex. (Neither TAF/emtricitabine nor TDF/emtricitabine has been approved for intermittent dosing, and this regimen is not recommended for cisgender women.)

Given their exclusion from DISCOVER, the effectiveness of TAF/emtricitabine PrEP for people who have vaginal sex has not yet been demonstrated in a clinical trial. Prior research has shown that tenofovir reaches lower levels and does not last as long in vaginal and cervical tissues compared with rectal tissue. Gilead urged the FDA to extrapolate from existing pharmacokinetic data showing that TAF produces adequate drug levels in women, but the agency declined to approve Descovy for this group without more direct evidence.

Some advocates applauded this decision, calling for clinical trials of TAF/emtricitabine in women and trans men, and arguing that approval in the absence of such evidence would set a bad precedent. Others, however, are concerned that women now have fewer oral PrEP options than men. Although most DISCOVER participants were cisgender men who have sex with men, the FDA reviewers nonetheless extended the indication to heterosexual men.

In a 5 October letter to community members, Gilead indicated that the company has agreed with the FDA to conduct a study evaluating Descovy for PrEP in adult and adolescent cisgender women.

Turning to safety, TAF/emtricitabine has less detrimental effects than TDF/emtricitabine on biomarkers of kidney function and bone loss, although it is not clear whether this matters in terms of clinical outcomes like fractures. On the other hand, TAF/emtricitabine has a less favorable effect on blood lipid levels. TAF/emtricitabine could therefore be a preferable option for individuals at risk for kidney or bone problems, while TDF/emtricitabine might be more advisable for those at risk for cardiovascular disease.

However, for the vast majority of people taking PrEP, TAF/emtricitabine and TDF/emtricitabine are likely to be both well tolerated and highly effective. Some advocates contend that for most people, any small improvements in safety or efficacy will not be worth the added cost of Descovy, which is only available as a branded product, compared with generic TDF/emtricitabine.

References

Food and Drug Administration. FDA approves second drug to prevent HIV infection as part of ongoing efforts to end the HIV epidemic. Press release. October 3, 2019.