PrEP失敗(突破性感染)

PrEP失敗(突破性感染)

資料來源:安迪·卡斯滕斯 / 2022 年 5 月 / aidsmap / 財團法人台灣紅絲帶基金會編譯

 

圖片來源:非洲工作室 / Shutterstock.com

關鍵點

• 當人們按照規定服用PrEP時,幾乎可以100%地預防HIV感染。

• 全世界大約100萬服用PrEP的人中,科學期刊上報導的突破性病例不到20例。

• 服用PrEP時感染HIV的最高風險因素是服藥順從性低。

• 當報告了突破性感染時,通常發生在接受PrEP的人接觸到對PrEP中的藥物有抗藥性的愛滋病毒時。

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當人們定期服用PrEP時,幾乎可以100% 的預防HIV感染,因此暴露時體內的藥物水平很高。通常,當一個人在服用PrEP時感染HIV,是因為他們沒有定期服用,而且他們體內的藥物水平不足以保護他們。

很少有人在體內藥物水平足夠的服用PrEP時感染HIV - 這被稱為PrEP失敗或突破性感染,因為 HIV 以某種方式突破了PrEP通常提供的保護。為了說明突破性病例的罕見程度,請考慮在全球約 100 萬服用PrEP的人中,在科學期刊上報導的突破性感染還不到20例。 

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大約十個記錄在案的突破性病例發生在口服富馬酸替諾福韋二呲呋酯和恩曲他濱(TDF/ emtricitabine,有時也稱為Truvada)的人群中。到目前為止,還沒有一個涉及最近開發的口服 PrEP 製劑,該製劑結合了富馬酸丙酚替諾福韋和恩曲他濱(TAF/ emtricitabine,也稱為 Descovy)。這可能是因為使用這種較新配方的人要少得多,或者可能是因它在順從性不佳時提供了更好的保護。服用口服 PrEP 時發生的突破性病例數量是近似的,因為有幾個病例無法明確地證明這些感染 HIV 的人有足夠的藥物水平(亦即,他們仍有可能感染 HIV係因他們沒有很規律地服用 PrEP)。

在使用可注射型cabotegravir 的人群中報告7例突破性病例。更容易證明注射型 PrEP 的案例是真正的突破,因為注射係由醫療保健專業人員每兩個月進行一次。此外,它們係發生在一項臨床試驗期間,以評估該藥物在預防 HIV 感染方面的有效性。

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是什麼導致了突破性案例?

幾乎所有PrEP的突破性病例都被認為是透過同時與具有HIV可檢測水平且其HIV係對 PrEP 中的藥物產生耐藥性形式的人發生性關係而發生的。對於涉及口服PrEP的報告,除了一個突破性病例外,所有感染的 HIV 基因檢測都檢測到與對恩曲他濱(emtricitabine) 、替諾福韋( tenofovir)或兩者的耐藥性相關的突變。對於涉及可注射PrEP的報告,所有突破性病例均涉及對卡博特韋(cabotegravir)的耐藥性。

然而,當一個服用PrEP且服藥順從性不佳的人感染 HIV後雖沒有耐藥性但仍繼續服用PrEP時,也會產生耐藥性突變。感染後,因為PrEP中的藥物不能完全抑制病毒,HIV會產生耐藥性。且因耐藥性可能來自感染已經具抗藥性的 HIV,也可能來自感染 HIV 後發生的突變,因此有時很難評估哪個先出現。

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在某些情況下,當將病毒傳播給接受 PrEP 的人之傳播者是已知的,且還進行了基因檢測時。如果服用 PrEP 的人與將病毒傳播給他們的人係具有相同的突變,這就提供了更有力的證據顯示突破性感染是由耐藥菌株引起的(而不是感染後發生的突變)。但通常,這些信息並不可得。

此外,如果 PrEP 患者的耐藥性突變與 PrEP 中的藥物無關,而是與 PrEP 中未包含的抗反轉錄病毒藥物相關,這也可能是突破性案例的證據。

即使有這樣的證據,仍然很難確定人們在感染時是否有足夠的藥物水平,這使得很難評估感染是否真的是因為「突破」。儘管如此,口服 PrEP 不太可能預防已經對其成分藥物具有抗藥性的 HIV。這意味著對 PrEP 中的藥物具有抗藥性的 HIV 可能至少導致了一些口服 PrEP的突破性病例報告。

值得注意的是,有三個儘管口服了 PrEP 仍報告了突破性感染者(其中兩人患有具有耐藥性突變的 HIV)也同時患有直腸性病性淋巴肉芽腫 (lymphogranuloma venereum, LGV),這是一種衣原體。雖然沒有直接證據,但其中一個病例的臨床醫生假設直腸組織的炎症可能導致局部組織區域更容易受到 HIV 感染。 

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使用可注射的 PrEP,更容易確定藥物順從性,因為係由醫療保健專業人員進行注射。在涉及可注射 型PrEP 的 7 例的突破性病例報告中,所有 7 例都對卡博特拉韋(cabotegravir)產生了耐藥性。然而,在這七人中,有兩人在第一次注射後藥物水平出乎意料地下降,這增加了在某些人中,cabotegravir 需要更長的時間才能到達藥物所能保護免受 HIV 感染的組織(例如直腸和陰道)的可能性。需要進行更多的研究來解釋藥物水平的差異並找出它們發生的頻率。儘管如此,臨床試驗結果顯示,在預防HIV感染方面,cabotegravir 比口服 PrEP 更有效——因為參與者錯過的劑量更少。

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抗藥性有多普遍?

接觸已經產生這種抗藥性的 HIV 很少見,尤其是考慮到無論他們是否感染了對 PrEP 中的藥物具有抗藥性的 HIV,在HIV 水平無法被檢測到的人並無法傳播病毒。因此要使突破性感染成為可能,一個人必須同時暴露於HIV可檢測的水平和對他們正在服用的 PrEP 形式中具有抗藥性的版本。

華盛頓大學的一項研究發現,在西雅圖約 4,000 名愛滋病毒感染者中,只有不到 0.3% 的可檢測到愛滋病毒者對恩曲他濱和替諾福韋耐藥。

 

根據世界衛生組織的一項調查,在全球南方的 30 個國家中,對替諾福韋和恩曲他濱耐藥的愛滋病毒盛行率分別為 1.6%及1.7%,儘管在少數國家高達 8%。在四個非洲國家進行的另一項研究發現,在接受口服 PrEP 的 104,000 人中,只有 229 人感染了 HIV(大多數是因為順從性差),只有 27 人感染了 HIV其基因檢測顯示耐藥性突變(儘管尚不清楚他們獲得愛滋病毒是由於感染到耐藥性突變株抑或是在感染後才形成突變)。

儘管在 cabotegravir 上並不存在類似的研究,因為它要來得更新許多,但這些結果證實了在良好順從性的情況下服用 PrEP 時感染 HIV 的可能性很低。

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結論

很難證明在服用口服 PrEP 的人中是否在其系統中有足夠水平的 PrEP 藥物卻感染了HIV,因為需要在發生感染非常接近的時間進行測量。在大多數涉及口服 PrEP 的突破性案例中,可能永遠都不知道它們發生的原因。

對於可注射型的PrEP,需要進行更多的研究來解釋為什麼某些人的藥物水平會意外下降以及這種情況發生的頻率。對於口服和注射PrEP,突破性感染最可能的原因是暴露於HIV係處於可檢測的水平,而HIV也對 PrEP 中的藥物產生了耐藥性。

服用 PrEP 時感染 HIV 的最大風險因素是不順從遵守所推薦的服藥頻率,導致體內藥物水平不足。如果藥物水平足夠,PrEP 可以預防近 100% 的HIV感染。

 

 

 

 

PrEP failures (breakthrough infections)

Andy Carstens / May 2022 / aidsmap

 

Africa Studio/Shutterstock.com

Key points

•When people take PrEP as it’s prescribed, it prevents almost 100% of HIV infections.

•Fewer than 20 breakthrough cases have been reported in scientific journals, out of about one million people taking PrEP worldwide.

•The highest risk factor of acquiring HIV while taking PrEP is poor adherence.

•When breakthrough infections have been reported, they have typically occurred when people on PrEP have been exposed to HIV that has resistance to the drugs in PrEP.

PrEP prevents almost 100% of HIV infections when people take it regularly so that there are high drug levels in the body at the time of exposure. Usually, when a person acquires HIV while taking PrEP, it’s because they haven’t taken it regularly, and drug levels in their bodies were insufficient to protect them.

Rarely, someone can acquire HIV while taking PrEP with adequate drug levels in their bodies – this is called a PrEP failure or a breakthrough infection, because HIV somehow breaks through the protection that PrEP ordinarily provides. To illustrate how rare breakthrough cases are, consider that out of about one million people taking PrEP worldwide, fewer than 20 breakthroughs have been reported in scientific journals.

About ten of the documented breakthrough cases occurred in people taking oral tenofovir disoproxil fumarate and emtricitabine (TDF/emtricitabine, sometimes also known as Truvada). So far, none have involved the more recently developed formulation of oral PrEP, which combines tenofovir alafenamide and emtricitabine (TAF/emtricitabine, also known as Descovy). This could be because far fewer people use this more recent formulation, or because it may provide better protection with suboptimal adherence. The number of breakthrough cases that occurred when taking oral PrEP is approximate because several cases could not definitively prove the person who acquired HIV had adequate drug levels (i.e. it remains possible that they acquired HIV because they didn’t take PrEP regularly enough).

Seven breakthrough cases have been reported in people taking injectable cabotegravir. It’s easier to prove the cases for injectable PrEP were true breakthroughs because the injections are administered every two months by a healthcare professional. In addition, they occurred during a clinical trial to evaluate the drug’s effectiveness at preventing HIV infection.

What causes breakthrough cases?

Almost all breakthrough cases with PrEP are thought to have occurred through having sex with someone who has both detectable levels of HIV and a form of HIV that has developed resistance to the drugs in PrEP. For the reports involving oral PrEP, genetic testing of the HIV acquired in all but one breakthrough case detected mutations associated with resistance to emtricitabine, tenofovir, or both. For reports involving injectable PrEP, all of the breakthrough cases involved resistance to cabotegravir.

However, resistance mutations can also develop when a person taking PrEP with suboptimal adherence acquires HIV without resistance but continues to take PrEP. After the infection, HIV can develop resistance because the drugs in PrEP do not fully suppress the virus. Because resistance can come either from acquiring HIV that already has it or from developing mutations after acquiring HIV, it is sometimes difficult to evaluate which came first.

In some cases, the person who transmitted the virus to the person on PrEP is known and also has genetic testing. If the person who was taking PrEP has the same mutations as the person who transmitted the virus to them, that provides stronger evidence that the breakthrough infection resulted from a resistant strain (as opposed to the mutations developing after infection). But often, that information isn’t available.

Also, if the person on PrEP has drug resistance mutations that are not associated with the drugs in PrEP but instead with antiretroviral medications that aren’t included in PrEP, that could also be evidence of a breakthrough case.

Even with evidence like that, it can still be difficult to determine whether people had adequate drug levels at the time of infection, which makes it difficult to assess whether infections are truly because of ‘breakthrough’. Nonetheless, it’s less likely that oral PrEP would protect against HIV that is already resistant to its component drugs. That means that HIV with resistance to the drugs in PrEP has likely caused at least some of the breakthrough cases reported with oral PrEP.

It’s worth noting that three of the people with reported breakthrough infections despite oral PrEP (two of whom had HIV with resistance mutations) also had rectal lymphogranuloma venereum (LGV), which is a type of chlamydia. Though there’s no direct evidence, clinicians in one of the cases hypothesised that inflammation of rectal tissue may have created localised areas of tissue that were more vulnerable to HIV infection.

With injectable PrEP, adherence is easier to ascertain because a healthcare professional administers the injection. In the seven reported breakthrough cases involving injectable PrEP,  all seven had resistance to cabotegravir. However, in two of the seven people, drug levels dipped unexpectedly after the first injection, which raises the possibility that, in some people, cabotegravir takes longer to reach tissues (e.g. rectal and vaginal) where the drug protects against HIV infection. More research needs to be conducted to explain differences in drug levels and find out how often they occur. Despite this, the clinical trial results showed cabotegravir to be more effective than oral PrEP at preventing HIV infections – because participants missed fewer doses.

How common is resistance?

Being exposed to HIV that has already developed this type of resistance is rare, especially considering that someone with undetectable levels of HIV cannot transmit the virus, regardless of whether they have a form of HIV that’s resistant to the drugs in PrEP. For a breakthrough infection to be possible, a person has to be exposed both to detectable levels of HIV and a version that has resistance to the form of PrEP they’re taking.

A study at the University of Washington found that in about 4000 people with HIV in Seattle, less than 0.3% had detectable levels of HIV with resistance to emtricitabine and tenofovir.

According to a World Health Organization survey, out of 30 countries in the global South, the prevalence of HIV with drug resistance to tenofovir was 1.6% and to emtricitabine was 1.7%, although it was as high as 8% in a few countries. Another study that took place in four African countries found that out of 104,000 people on oral PrEP, just 229 people acquired HIV (most because of poor adherence), and just 27 people acquired HIV where genetic testing revealed resistance mutations (though it’s unclear whether they acquired HIV because of the mutations or whether the mutations formed after infection). 

Although no similar studies don’t exist for cabotegravir because it’s much newer, these results confirm the low likelihood of acquiring HIV while taking PrEP with good adherence.

Conclusion

It’s very difficult to prove whether someone taking oral PrEP acquired HIV with adequate levels of PrEP drugs in their system because measurements are needed very close to when the infection occurred. In most of the breakthrough cases involving oral PrEP, it may never be known why they occurred.

For injectable PrEP, more research needs to be conducted to explain why drug levels dip unexpectedly in certain people and how often it happens. For both oral and injectable PrEP, the mostly likely cause of breakthrough infections is being exposed to detectable levels of HIV that has also developed resistance to the drugs in PrEP.

The biggest risk factor to acquiring HIV while taking PrEP is not adhering to the recommended frequency, resulting in inadequate drug levels in the body. If drug levels are adequate, PrEP prevents nearly 100% of HIV infections.