U = U的證據:為什麼可以忽略不計的風險是零風險

 

 

U = UUndetectable = Untransmittable)的證據:為什麼可以忽略不計的風險是零風險    2017101日,預防和傳播相關特別報告,Simon CollinsHIV i-Base

資料來源:Aidsmap news;財團法人台灣紅絲帶基金會編譯

 

注意:參見PARTNER2研究結果的後記,該研究為男同志社群提供了U = U的進一步證據。

 

病毒量測不到=不具傳染性

 

在過去一年中,包括美國疾病控制中心(CDC)在內的數百個愛滋組織支持這樣的聲明,亦即當投予抗反轉錄病毒療法(ART) 至病毒量測不到時,就無法構成HIV傳播。

 

儘管已經有很長一段時間了解到抗反轉錄病毒療法對於減少HIV傳播的巨大影響,但是談及ART完全阻止HIV傳播則是新的概念。

鑑於對愛滋感染者的偏見和歧視仍然普遍存在,這概念變化尤為重要。因此,雖然對於病毒量測不到的感染者,是否仍具有傳染性這一問題很容易得到其回答為「否」,但解釋其原因則更為複雜。

本文總結了20年來積累的證據所選擇的關鍵研究,這些證據應該直接挑戰仍然普遍存在的對HIV的偏見和恐懼。

 

U = U:病毒量測不到=不會傳播(或不具傳染性)

 

2016年推出的Undetectable = UntransmittableU = U)活動基於以下聲明:「當感染者無法檢測到其病毒量時,則不會將HIV傳染給他們的伴侶」。

該活動聲明得到了來自34個國家超過350個組織的支持,這些組織參加了U = U運動,其中包括國際愛滋病協會(IAS)、聯合國愛滋病規劃署(UNAIDS)和英國愛滋病協會(BHIVA)等領先的科學和醫療組織。

鑑於科學無法負面舉證明其為真­­­­即某些事情將不會發生,對此聲明的支持也是非常了不起的。

相反地,那些聲稱愛滋病毒在病毒載量不可檢測時仍可傳播的人,反應該受到挑戰來證明其論點。

 

20年積累的證據

 

理解世界的科學方法通常涉及三個階段。

1.觀察一些事情。

2.設定一個或多個可能解釋它的假設。

3.在合適的實驗中測試前述任何理論。

 

根據定義,這種方法的優勢在於,一項好的研究應該是可重複的。如果結果是真實且不是偶然的,那麼其他研究人員應該也能夠重複地研究並且每次都得到類似且一致的結果。

支持U = U的證據涵括不同類型的研究,包括觀察性研究、隨機試驗,系統性的評價和專家意見。參見表1

 

該時間表的關鍵階段包括:

1998年:三合一抗反轉錄病毒療法減少了傳播。

1998年:專家意見認為傳播風險將降低(包括基於回顧與此防護細節相關的證據)。

2000 - 2005年:前瞻性觀察研究和其他相關研究(Rakai世代和其他人)。

2008年:進一步的專家意見和證據審查(瑞士聲明)。

2011年:來自隨機分配臨床試驗的第一份證據(HPTN 052)。

2014 - 2017年:進一步的前瞻性觀察研究(PARTNEROpposites Attract - 首次提供有關男同志風險數據的研究。

2016 - 2017年:進一步的專家意見(U = U運動)。

上述這些的每一項研究現在更被詳細地解釋。

 

早期證據:母子垂直感染與烏干達異性戀伴侶研究

 

19987月的一份非凡報告,提供了在病毒量對HIV傳播影響證據中的第一項臨床證據。

在日內瓦舉行的IAS會議上,Karen Beckerman博士報告了舊金山一小群女性感染者,在懷孕期間使用三合一療法,發現三合一療法將傳播減少到接近零,結果不是在使用ART之前母子垂直感染率所報告的30%,或者在使用AZT單一療法中所觀察到的10%。

雖然這項研究報告了垂直感染而非性行為傳播,但它提供的臨床結果顯示,當無法檢測到病毒量時阻止了更高的傳播風險。

當年稍晚時候,於199812月美國DHHS更進一步更新其指引,將「可能降低病毒傳播的風險」包括於其中,作為開始提早抗病毒治療的另一個原因。

這些專家的指引,指出了缺乏支持此一陳述的直接證據,並強調即使在無法檢測到病毒量的情況下仍應使用保險套 - 而這項包含在由美國領先醫生所提出之百頁文件中這一點是非常重要。

下一個提供了將病毒量與HIV性傳播風險聯繫起來直接證據其中之一的重要研究,便是在烏干達拉凱的一項前瞻性觀察世代研究,針對415名異性戀相異伴侶,其中一名伴侶為HIV陽性,另一名為HIV陰性。Thomas Quinn及其同事的這項研究,於2000年在新英格蘭醫學雜誌上發表。在追蹤了平均22個月之後,HIV傳播的風險不僅與病毒量增加明顯相關。在HIV陽性伴侶病毒載量低於1500 copies/ mL51對夫婦中並無傳染給其陰性伴侶。

Rakai研究的一些細節很重要。這是在抗反轉錄病毒治療(ART) 可獲得前,且保險套的使用率很低情況下。研究發現,男性和女性的傳播率相似,其他性傳播感染並未影響愛滋病風險。它還報告了包皮環切術產生了非常顯著的影響 - 所有在研究期間變為陽性的男性都未曾接受過割包皮;這些結果是17年前的結果。

 

專家意見和證據審查:瑞士聲明

 

2000年到2008年,許多較小的研究報告在其他傳播途徑上傳播之減少,或透過其他支持性研究補充了觀察數據,例如報告ART對生殖器中體液之影響。

例如,在2005年,一個西班牙世代報告了近400對異性戀相異伴侶,其中陰性伴侶在1991年至2003年期間轉變成為HIV陽性;其結果分別呈現三個時期 - ART提供之前(1991-1993), ART早期-1996-1998)和晚期ART1999-2003- 並且當陽性伴侶參加了抗病毒治療時,結果報告了並沒有觀察到造成傳播之情形。

針對這些結果要留意的是,隨著時間的推移,其他相關之風險也隨著降低,例如保險套被廣泛使用,而且隨著年齡的增長,人們的性生活亦會減少,但零傳播仍然很顯著的。

2008年,Pietro Vernazza及其同事發表了第一篇眾所矚目的證據評論,結論是ART停止了HIV傳播。

本文以法文出版,但很快翻譯成英文,是對瑞士法律的回應,即感染者如果他們與陰性的伴侶發生性關係,即使在使用保險套或者是如果一對夫婦在完全同意的情況下想要懷孕時,HIV陽性者也將會被認定為犯罪行為。本文回顧了超過25項研究,並得出結論認為並沒有造成傳播。其估計風險為非常罕見的事件,機率並小於100,0000.001%)分之1 - 因此實際上為零。

瑞士聲明的重要考慮因素,包括HIV陽性者應堅持順從於有效之抗反轉錄病毒療法(無漏藥)且病毒量達無法檢測程度,同時沒有其他可能增加病毒量的性傳染疾病。

瑞士的聲明不僅被廣泛宣傳,而且還被廣泛地挑戰,產生了非常高的知名度。因此,它向其他醫生和研究人員提出了挑戰,要求報告任何反駁該聲明的案例。鑑於學術研究的競爭性,值得注意的是,在近十年之後,沒有任何案例反駁了瑞士聲明。

 

隨機分派研究之數據:HPTN 052

 

科學家在證明介入措施與結果之間的關聯時,是根據研究之設計對證據進行分級。對於許多問題,最好的證據來自隨機臨床試驗。將參與者隨機分配到兩個或多個僅限於介入措施不同的群體,是排除結果源自於機率的最佳方式。由於其他因素總有可能影響結果,因此隨機研究通常被認為是證據的黃金標準。

2011年,由Myron Cohen及其同事領導的美國研究人員於愛滋病預防治療網絡(HPTN)中報告了HPTN 052研究的早期結果。HPTN 052招募了超過1700對異性戀相異伴侶(主要是在南部非洲、拉丁美洲和東南亞。這些幾乎完全是異性戀伴侶,HIV陽性伴侶隨機接受立即開始抗病毒治療或等到他們的CD4計數降至350 cells/mm3(隨後WHO治療指引中所設定開始治療的閾值即為此)。

所有的伴侶均獲取有關減少HIV傳播風險的知識以及保險套,但很快就發現HIV傳播幾乎完全發生在等待抗反轉錄病毒治療的群體中。在39次傳播中,28次與HIV陽性伴侶有關。其中27/28的人正在等待抗反轉錄病毒治療。直接投予ART此組中唯一的傳播發生在開始治療的數週內,此時病毒量仍然很高且當然可以檢測得到。

這提供了非常高水平的證據顯示了抗反轉錄病毒治療(ART)與防止性傳播有直接相關,因此HPTN 052研究提前停止,因此所有HIV陽性參與者都可以立即接受抗反轉錄病毒治療。 HPTN的長期追蹤至少持續了四年,並證實了這些早期結果的持久性。

HPTN 052提供了證據,使HIV感染者能夠更早地獲得抗反轉錄病毒治療,以保護他們的伴侶 - 即是所謂「預防即治療」 TasP)。但該研究的局限性意味著它只能報告兩個研究組別之間的相對差異,而不是量化任何實際風險(即使風險是理論上的)。

同樣,這是一項異性戀研究,少有肛交行為的報告,且保險套使用率相對較高。這意味著雖然可以證明ART可以減少感染,但該研究無法估計這種風險的降低程度,或者不同類型性行為可能存在的風險。

 

大型世代觀察研究:伴侶(PARTNER)研究和感染情況相異對立但彼此吸引(Opposites Attract)研究

 

2009年,在HPTN 052結果出現前幾年,由健康、免疫和感染卓越中心(CHIP)的Jens Lundgren所領導的一組歐洲研究人員,啟動了前瞻性觀察之伴侶(PARTNER)研究。

PARTNER研究在招募血清狀態相異的伴侶上非常重要,因為HIV陽性的伴侶有接受抗反轉錄病毒治療,且伴侶倆者間也並不總是使用安全套(通常已多年)。

重要的是,近900對伴侶中大約有三分之一是男同志,該研究並包括了關於性活動的詳細調查問卷,以便根據實際暴露來估計風險。

與所有研究一樣,所有參與者都獲得有關減少愛滋病毒傳播的知識以及免費的保險套。然後隨著時間的推移追踪所有伴侶,試圖查看是否發生了傳染。

20142月的一次會議上所進行規畫中的早期分析,PARTNER報告了在超過44,000次暴露於沒有使用保險套且病毒量檢測不到(定義為低於200 copies/ mL)性行為之後,與傳播為零關聯(在伴侶間)。

PARTNER還為先前理論問題中的病毒量或其他性傳染病的感染提供了證明。在陽性伴侶有報告其他性病的91對伴侶中並沒有看到傳播發生(大約三分之一的男同志伴侶有開放式關係)。 20167月公佈的最終結果顯示,58,000次無保險套性行為後結果為零傳播。

PARTNER的結果在全球成為頭條新聞,但本研究中一個鮮為人知的方面是,突破性的結果卻需耗時近兩年的時間才公佈。這很可能與以保險套作為唯一預防的愛滋運動有關,而HIV傳播持續的高發率顯現以保險套做為唯一預防之成效的限制。

因為PARTNER研究的一個重要結果是量化理論風險範圍(95%信賴區間的上限),PARTNER 2研究繼續收集男同志伴侶的結果,以提供與異性戀數據相對平衡之證據。

最後,2017年在巴黎舉行的IAS會議上,來自澳大利亞、泰國和巴西的358名男同志伴侶的Opposites Attract研究結果也顯示,將近17,000次在未使用保險套的情況下之性行為後具關聯的傳播為零。再次地,性傳染病病感染並不罕見(約在1000次的事件中出現),惟並且沒有導致HIV傳播。

 

零到可以忽略不計:這一句話代表什麼?

 

即使在沒有保險套和沒有抗反轉錄病毒治療情況下,HIV的傳播通常也是不常見的事。例如,估計每次暴露的平均風險範圍上限從接受性的肛交之0.014(千分之14)到接受性或插入性之陰道性行為的0.0011000分之一),其較低的範圍可能低許多倍。

然而,在感染後的前24週,當病毒載量可達數百萬 copies/ mL,且人們仍然認為他們是HIV陰性時,風險會更高。這導致許多健康運動(health campaigns)指出,若根據他們上一次HIV檢測而認為自己尚未感染的人,其相對風險高於任何病毒量測不到之HIV感染者

然而,零風險和可忽略之風險間的語義差異,即使當這種理論風險越來越小(與瑞士聲明一樣),卻也阻止了一些人說風險實際上是零。

U = U運動的推動下,去年最顯著的變化是,領導愛滋病毒科學家們現在宣稱,可忽略不計的理論風險實際上為零。

 

扭轉挑戰:現在去證明傳播是否可行

 

在理想情況下,大型前瞻性研究旨在發現病毒量檢測不到時的傳播病例,但仍未能做到這一點。

因此,2017年的證據缺口在現在仍缺乏任何證據去顯示當病毒量檢測不到時,HIV的傳播是可能的。

這逆轉了從「證明安全」到「證明風險」的科學挑戰。純粹的理論風險不再具充分的證據去維持恥辱和歧視,當然也不應是刑事定罪。

相反地,當沒有證據顯示當病毒量測不到時會發生HIV傳播,那些想要宣稱HIV或許可能傳播的人,現在則必須提供一定程度的證據。

 

結論

 

現在,全面的證據支持U = U聲明。這包括早期臨床和理論性研究、小型觀察性研究、隨機試驗和大型前瞻性世代研究。

此外,自瑞士聲明確定這一挑戰以來,已有九年多沒有報告HIV傳播病例。這些資料囊括男同志、有肛交行為的伴侶、甚或可能同時感染性病,延續期間為這些感染者維持在病毒量為低水平的時間。

實際上,即使實際風險為零,將生活中任何事物都視為無風險也是不健康的。即使在未來的某個時刻,在病毒量檢測不到的狀態下報告了一個不幸和罕見的傳播病例,U = U運動仍然適合於縮小「零」與「現實生活中實際含義為微不足道」間的差距。

本文源自於201771日在格拉斯哥舉行的感染者論壇演講,Simon CollinsPARTNER研究的指導委員會成員。

 

評論

 

20179月美國疾病預防控制中心的認可尤為重要。目前,美國許多州的愛滋刑事定罪法規已經過時且過於嚴格。結果導致數百名感染者多年來一直因未披露感染狀態而被監禁,而且往往並沒有造成實際傳播。

 

後記

 

自本文發表以來,已有更多之證據支持U = U 。在20187月,PARTNER 2研究的結果顯示,來自近1000名超過77,000次沒有使用保險套的男同志的性行為中,其造成HIV傳播之結果為零。

 

 

(備註:相異伴侶泛指愛滋感染情況相異伴侶,意即其中一位為陽性狀況,另一位為陰性。)

 

 

The evidence for U=U (Undetectable = Untransmittable): why negligible risk is zero risk

1 October 2017. Related: Special reportsPrevention and transmission.

 

Undetectable viral load = Untransmittable HIV

Note: See postscript for results from the PARTNER2 study that provided further evidence for U=U in gay men.

·Article translated into German.

·i-Base U=U resources

Simon Collins, HIV i-Base

Over the last year, hundreds of HIV organisations, including the US Center for Disease Control (CDC), have supported the statement that HIV transmission does not occur when viral load is undetectable on ART. 

And while the dramatic impact of ART on reducing HIV transmission has been known for a long time, saying ART stops this completely is new.

This change is especially important given that prejudice and discrimination against HIV positive people is still widespread.  So while it is easy to simply answer “no” to the question of whether someone with an undetectable viral load is still infectious, it is more complicated to explain why.

This article summarises selected key studies from 20 years of accumulating evidence that should directly challenge the prejudice and fear of HIV that is still widespread.

U=U: Undetectable = Untransmittable (or Uninfectious)

Launched in 2016, the Undetectable = Untransmittable (U=U) campaign is based on the following statement: “A person living with HIV who has undetectable viral load does not transmit HIV to their partners”. [1, 2]

The campaign statement has been endorsed by more than 350 from 34 countries HIV organisations who joined the U=U campaign, including by leading scientific and medical organisations such as the International AIDS Society (IAS), UNAIDS, and the British HIV Association (BHIVA).

The support for the statement is also remarkable given that science is not able to prove a negative – ie that something will not happen.

Instead, people who claim that HIV is transmittable when viral load is undetectable, should be challenged to prove it.

20 years of accumulating evidence

The scientific approach to understanding the world usually involves three stages.

  1. Observing something.
  2. Deciding on one or more hypotheses that might explain it.
  3. Testing any theory in a suitable experiment.

The strength of this approach is that a good study, by definition, should be repeatable. If the results are true and not by accident, other researchers should be able to repeat the study and get similar and consistent results each time.

The evidence supporting U=U includes different types of research spanning observational studies, randomised trials, systematic reviews and expert opinion. See Table 1.

Table 1: Key selected evidence supporting U=U

Key stages in this timeline include:

·1998: observations that triple therapy ART reduced transmission.

·1998: expert opinion that risk would be reduced (including based on reviewing evidence related to the details of this protection).

·2000 – 2005: prospective observational studies and related research (Rakai cohort and others).

·2008: further expert opinion and evidence review (Swiss Statement).

·2011: first evidence from a randomised clinical trial (HPTN 052).

·2014 – 2017: further prospective observational studies (PARTNER and Opposites Attract) – the first studies to provide data about risks for gay men.

·2016 – 2017: further expert opinion (U=U campaign).

Each of these studies is now explained in more detail.

Early evidence: mother-to-child and Ugandan heterosexual couples

A remarkable report in July 1998 provided some of the first clinical evidence for the impact of viral load on HIV transmission.

At the IAS conference held in Geneva, Dr Karen Beckerman reported on a small cohort of HIV positive women in San Francisco who had used triple therapy during pregnancy. Instead of the 30% mother-to-infant transmissions reported before ART, or the 10% seen with AZT monotherapy, triple therapy reduced transmissions to approaching zero. [3]

Although this study reported on vertical rather than sexual transmission it provided clinical results showing that an undetectable viral load stopped a much higher risk of transmission.

Then later that year, the December 1998 update to the US DHHS guidelines, included “possibly decreasing the risk of viral transmission” as an additional reason for starting early ART. [4]

These expert guidelines noted the lack of direct evidence supporting this statement and emphasised that condoms should still be used even with undetectable viral load – but this inclusion in the 100-page document from leading US doctors this was important.

One of the next key studies provided direct evidence linking viral load with risk of HIV sexual transmission. This was a prospective observational cohort study in 415 serodifferent heterosexual couples in Rakai, Uganda, where one partner was HIV positive and the other was HIV negative. The study, by Thomas Quinn and colleagues was published in the New England Journal of Medicine in 2000. [5]

After median follow-up of 22 months, the risk of HIV transmission was not only clearly linked to higher viral load. No transmissions were reported among the 51 couples where the HIV positive partner had viral load below 1500 copies/mL.

Several details of the Rakai study are important. It was before ART was available and condom use was low. It found that transmissions rates were similar for men and women and that other STIs didn’t affect HIV risk. It also reported highly significant impact from circumcision – all the men who became positive during the study were uncircumcised.

These results were 17 years ago.

Expert opinion and evidence review: the Swiss statement

From 2000 to 2008, many smaller studies reported reductions in other routes of transmission, or supplemented observational data with supportive research, such as reporting the impact of ART in genital fluids.

For example, in 2005, a Spanish cohort reported on almost 400 heterosexual serodifferent couples where the negative partner became HIV positive during the period 1991 to 2003. The results were presented for three time periods – pre-ART (1991–1993), early-ART (1996–1998) and late-ART (1999–2003) – and reported no transmissions when the positive partner was on ART. [6]

Cautions for these results were that other risks reduced over time, such as condoms being more widely used and people having less sex as they grew older, but zero transmissions was still significant.

In 2008, Pietro Vernazza and colleagues published the first high profile evidence review that concluded that ART stopped transmission. [7]

This paper, published in French but quickly translated into English, was a response to the laws in Switzerland that criminalised an HIV positive person if they had sex with a negative partner, even if condoms were used or if a couple wanted to conceive with full consent. This paper reviewed more than 25 studies and concluded that transmission did not occur. The estimated risk as a very rare event was less than 1 in 100,000 (0.001%) – and therefore effectively zero.

Important considerations for the Swiss Statement included that the HIV positive person should be adherent on effective ART (not missing doses), have an undetectable viral load, and not have sexual infections that might increase viral load.

The Swiss statement was not only widely publicised but it was also widely cricitised, generating a very high profile. As such, it set a challenge to other doctors and researchers to report any cases that disproved the statement. Given the competitive nature of academic research, it is notable that after almost ten years no cases have been published that refute the Swiss statement.

Randomised data: HPTN 052

Scientists grade evidence based on the design of studies to be able to prove a link between and intervention and outcome. For many questions, the best quality of evidence comes from a randomised clinical trial. The process of randomly assigning participants to two or more groups where only the intervention is different, is the best way to rule out the results having been due to chance.

Because there is always the potential for other factors to affect outcomes, randomised studies are usually credited as the gold standard for evidence.

In 2011, US researchers, led by Myron Cohen and colleagues at the HIV Prevention Treatment Network (HPTN) reported early results from the HPTN 052 study. [8]

HPTN 052 recruited more than 1700 serodifferent couples (mainly in southern Africa, Latin America and South-East Asia. These were almost entirely heterosexual couples, and the HIV positive partners were randomised to either start ART immediately or wait until their CD4 count dropped to 350 cells/mm3 (the then threshold in WHO guidelines for starting treatment).

All couples were supported with condoms and information on reducing the risk of HIV transmission, but it soon became clear that HIV transmissions were almost exclusively occurring in the group waiting for ART. Of the 39 transmissions, 28 were linked to HIV positive partner. Of these, 27/28 were in group waiting for ART. The single transmission in the immediate ART group occurred within weeks of starting treatment, when viral load would have still been high and certainly detectable.

This provided a very high level of evidence that ART was directly linked to protection against sexual transmission and as a result the HPTN 052 study was stopped early so that all HIV positive participants could receive immediate ART. Longer follow-up of HPTN continued for at least another four years and confirmed the durability of these early results. [9]

HPTN 052 produced evidence to enable HIV positive people to access ART earlier in order to protect their partners – called Treatment as Prevention (TasP). But limitations of the study meant that it could only report relative differences between the two study groups, rather than quantify any actual risk (even if the risk was theoretical).

Again, this was a heterosexual study, anal sex was rarely reported and condom use was relatively high. This meant that while ART could be proved to reduce infection, the study couldn’t estimate how low this risk became, or the likely risk for different types of sex.

Large observational cohorts: PARTNER study and Opposites Attract

In 2009, several years before the results from HPTN 052, a group of European researchers led by Jens Lundgren from the Centre of Excellence for Health, Immunity and Infections (CHIP) launched the prospective observational PARTNER study. [10, 11]

The PARTNER study was important for enrolling serodifferent couples where the HIV positive partner was on ART and where the couples were already not always using condoms (often for many years).

Importantly, approximately one-third of the almost 900 couples were gay men and the study included detailed questionnaires on sexual activity to estimate risk based on actual exposure.

As with all studies, information about reducing HIV transmission, including free condoms, were included for all participants. All couples were then followed over time, trying to see whether transmissions occurred.

In a planned early analysis, presented at a conference in February 2014, PARTNER reported zero linked (within-partner) transmissions after more than 44,000 times when condoms hadn’t been used and viral load was undetectable (defined as less than 200 copies/mL). [10]

PARTNER also provided reassurance for previous theoretical concerns from viral load blips or other STIs. No transmissions were seen in the 91 couples where the positive partner reported an STI (approximately one-third of gay couples had open relationships). The final results, presented and published in July 2016, reported zero transmissions after 58,000 times without condoms. [11]

The PARTNER results made headlines globally, but a less well-known aspect of this study was that the ground-breaking results took nearly two years to be published. This is likely linked to the implications the results would have on HIV prevention campaigns that were based on always using a condom, even when the limitation of condom-only prevention were clear from continued high rates of HIV transmission.

Because an important outcome of the PARTNER study is to quantify the theoretical range of risk (the upper limit of the 95% confidence interval), the PARTNER 2 study continued to collect results in gay couples to provide an equal balance of evidence compared to heterosexual data. [12]

Finally, at the IAS conference held in Paris in 2017, results from the Opposites Attract study in 358 gay male couples from Australia, Thailand and Brazil, also reported zero linked transmissions after almost 17,000 when condoms were not used. [13]

Again, STIs were not uncommon (present in around 1,000 of these occasions) and didn’t result in HIV transmission.

Zero to negligible: what is in a word?

HIV transmission, even without a condom and without ART, is generally an uncommon event.

For example, the average upper range of estimated per-exposure risk ranges from 0.014 for receptive anal sex (14 in 1000) to from 0.001 for receptive or insertive vaginal sex (1 in 1000) and the lower ranges are many fold lower. [14]

However, during the first 2 to 4 weeks after infection, when viral load can be millions of copies/mL and people still believe they are HIV negative, risk will be higher. This led to many health campaigns pointing out that someone who believes they are HIV negative based on their last HIV test is associated with a much higher relative risk than any HIV positive person with undetectable viral load on ART.

Nevertheless, the semantic difference between zero risk and negligible risk, even when this theoretical risk is increasingly tiny (as with the Swiss Statement), prevented some people saying that the risk was effectively zero.

The most significant change over the last year, driven by the U=U campaign, has been for leading HIV scientists to now assert that a negligible theoretical risk is effectively zero.

Reversing the challenge: to now prove whether transmission is possible

Under ideal circumstances, large prospective studies that were designed to find cases of transmission when viral load was undetectable have not been able to do so.

So the evidence gap in 2017 is now the lack of any proof showing that HIV transmission is possible when viral load is undetectable.

This reverses the scientific challenge from proving safety to proving risk. Purely theoretical risks are no longer a good enough level of evidence to sustain stigma and discrimination and certainly not criminalisation.

Instead, there is no evidence to show that HIV transmission occurs when viral load is undetectable. People who want to assert the theory that HIV transmission might be possible, now have to provide some level of proof.

Conclusion

A comprehensive body of evidence now supports the U=U statement. This ranges from early clinical and theoretical studies, through small observational studies, randomised trials and the large prospective cohorts.

In addition, no cases of HIV transmission have been reported, over nine years since the Swiss Statement set this challenge. This includes data for gay men, for couples that have anal sex, over periods when low-level viral blips are likely and even when STIs are present.

In reality, even if the actual risk is zero, it is not healthy to think about anything in life as being risk-free. Even if at some point in the future an unlucky and rare case of transmission is reported with undetectable viral load, the U=U campaign is still right for closing the gap between zero and the real-life meaning of negligible in real terms.

The article is based on a talk given to the Positive People’s Forum held in Glasgow on 1 July 2017. [15]

Simon Collins is on the Steering Committee for the PARTNER studies.

COMMENT

The US CDC endorsement in September 2017 is especially important. [16]

Currently, the HIV criminalisation laws in many US states are outdated and severe. As a result, hundreds of HIV positive people have been imprisoned for many years for non-disclosure and often in the absence of actual transmission.

POSTSCRIPT

Since this article was published further evidence has become available to support U=U. In July 2018, results from the PARTNER 2 study reported zero linked HIV transmissions from nearly 1000 gay couples who had sex more than 77,000 times without condoms. [17, 18]