格斯‧凱恩斯 / 2024 年 4 月 22 日 / 愛滋病地圖
丹麥的一項研究繪製了在開始PrEP 之前和之後到性健康診所就診的人中三種細菌性傳播感染（衣原體、淋病和梅毒）的年發生率，結果發現，他們的感染率是其兩倍多（多出115%）。
然而，它也發現診斷數量的增加很大程度上是由於檢測的增加。雖然在開始 PrEP 之前一段時間，人們的平均 STI 檢測率約為每 100 人年 50 次檢測（即每兩年一次檢測），但 PrEP 族群每年進行 3 到 4 次檢測，每當三個月內進行PrEP 檢查時檢測達到高峰。。
考慮到這一點，PrEP 族群中任何細菌性 STI 的診斷率僅比 PrEP 前高出 35%，而梅毒則沒有顯著增加。
然而，調查人員還發現，測試數量的增加在人們實際開始 PrEP 之前約 10-20 週開始，在此期間從每 100 人年約 200 次測試增加到 500 次測試，即使 PrEP 啟動時測試的大幅增加己被打了折扣。
哥本哈根大學醫院的 Sebastian von Schreeb 博士及其同事表示，他們的研究對抗了 PrEP 直接導致「風險補償」這一觀點的證據。這是一些行為科學家提出的理論，如果人們因為採取一種保護性行為而感到不那麼焦慮，他們往往會增加相關的危險行為——例如，因為繫了安全帶而開得更快。在 PrEP 和 U=U 的早期，一些研究人員擔心這會導致保險套使用量大幅下降，這可能會消除生物醫學預防的部分或全部益處。
作者表示，他們的研究顯示，PrEP 和性傳染感染的情況並非如此：「如果風險補償有效，我們預計當人們感到受到保護免受愛滋病毒感染時，性傳播感染的發生率可能會在 PrEP 開始後立即發生，也可能隨著時間的推移逐漸發生，因為他們變得更加放心。。
「由於沒有看到這種增加，另一種解釋是……性冒險行為的變化導致人們進行 PrEP」。
有關該研究的更多信息
要證明 PrEP 是否會帶來風險補償，需要在人們在開始 PrEP 之前獲得有關性傳播感染的發生率之數據，而這可能很難確定。這是因為研究人員通常只能獲得PrEP 使用者的性傳播染感染診斷數據，而且因為PrEP 的使用通常涉及更多的性傳播感染檢測，這將診斷出更多的感染，尤其是無症狀感染（據估計，85% 的直腸披衣菌和淋病感染來自PrEP 使用者）。 其他一些研究發現，在同性戀和雙性戀男性開始PrEP 之前，而不是之後，性傳播感染診斷或性傳播感染風險行為即有所增加，但其他研究則發現，在開始PrEP 後，性傳播感染診斷或性傳播感染風險行為的比例較高－如愛滋病地圖關於PrEP 和性傳染感染的證據簡介所述。
由於丹麥進行了徹底的醫療保健監測，這項新研究的數據特別可靠。每個公民都會獲得一個獨特的民事登記號碼，該號碼可以連結到微生物測試結果的綜合資料庫。因此，結果不太可能在系統中遺失。
丹麥公共衛生系統於 2018 年開始提供 PrEP，所有開始 PrEP 的人都參加了一項全國性前瞻性世代研究 DanPrEPD，並且即使停止 PrEP，也將繼續作為參與者。所有在 2019 年 1 月至 2022 年 6 月期間啟動 PrEP 且居住在丹麥首都地區（佔該國人口 30%）的順性別男同性戀和跨性別男女均被納入其中。
參與者總數為1326人，其中變性人10人。他們的平均年齡為 35 歲（範圍：16 歲至 78 歲）。除八名參與者外，所有參與者均開始每日 PrEP 治療。 147 名參與者(11%) 在2019 年1 月之前已接受PrEP，並被排除在PrEP 之前/期間的比較之外，還有237 名在研究期間停止PrEP 的人（這並不意味著有384 人被排除，因為有些被排除在外的人可能同屬於這兩個組）。
其餘參與者在研究期間開始PrEP 並在研究結束時仍在繼續，在PrEP 之前和之後觀察的時間大致相同：在PrEP 開始之前有2155 人年的可用數據，在PrEP 開始之後有2351 人年的可用數據。在一項為期 42 個月的研究中，進入研究和開始 PrEP 之間的平均間隔為 22 個月，所以大約已經過了一半。
在開始 PrEP 之前，有 708 例患者診斷出性傳播感染，而在開始 PrEP 後，有 1849 例患者被診斷出性傳染感染。這意味著 PrEP 前未調整的年發生率為每 100 人年 35 例，之後為每 100 人年 81 例（正如其他研究顯示的那樣，這並不意味著所有參與者在 PrEP 期間都有 81% 的機會感染性傳播感染：有些人可能沒有患過性傳播感染，而有些人可能有過反覆發作。
這意味著 PrEP 後 STI 診斷的頻率（(the Incidence Rate Ratio發生率比值或 IRR）比之前高 2.15 倍，無論是所有 STI 還是單一 STI。
然而，在開始 PrEP 後，人們進行的 STI 檢測數量是先前的三倍：PrEP 前總共進行了 7,936 次性傳播感染檢測，而之後進行了 23,654 次性傳播感染檢測。就個體性傳播感染而言，PrEP 後人們接受的淋病和披衣菌檢測比之前多了 2.6 倍，但梅毒檢測多了 4.4 倍；這似乎反映了梅毒檢測，這是一種對血液進行的抗體檢測，與其他兩種疾病的拭子檢測一樣已成為常規檢測，而在 PrEP 之前的期間則只進行了一半的數量。
當考慮到更高的檢測頻率而對 PrEP 前 STI 診斷的 IRR 進行調整時，所有 STI 的 IRR 從 2.15 下降至 1.35，換句話說，從一倍以上增加至 35%。披衣菌從 2.25 下降到 1.23，淋病從 2.21 下降到 1.24，梅毒從 2.46 下降到 1.15，這不再具有統計意義，這意味著 PrEP 梅毒病例的增加可能是偶然的。
與直腸衣原體相比，喉嚨或尿道的披衣菌出現症狀的可能性較小；相反，在淋病中，85% 的直腸和喉嚨感染是無症狀的，但只有 10% 的尿道症狀有症狀。這意味著，如果在 PrEP 上診斷出更多無症狀感染者，則與 PrEP 前相比，PrEP 後直腸衣原體的 IRR 應高於咽喉或生殖器衣原體，而尿道淋病的 IRR 應遠低於咽喉衣原體或直腸。
這正是所看到的。直腸披衣菌經檢驗調整後的 IRR 為 1.26，而口腔和生殖器披衣菌的比率為 1.19 和 1.14，且失去統計意義。對於淋病，直腸和口腔淋病的調整後 IRR 分別為 1.12 和 1.16，無統計學意義；但尿道淋病的測試調整 IRR 為 0.66，具有統計意義。這意味著，在調整測試頻率後，在 PrEP 期間診斷出尿道淋病的可能性實際上比之前低 34%（與未調整的 IRR 1.66 相比）。研究人員指出，這並不意味著PrEP 期間的實際感染減少，只是在這種情況下，因為大多數尿道淋病感染甚至可能在PrEP 和之前測試增加之前就被檢測到，因此未經調整的IRFR 為1.66更貼切地反映現實。
因此，在開始 PrEP 的人中診斷出更多性傳播感染的原因之一是，在 PrEP 之前，人們可能只有在出現症狀時才來接受檢查。由於 PrEP 前 10-20 週的檢測率與 PrEP 後相同，因此在敏感性分析中，研究人員排除了 PrEP 開始前 26 週內進行的檢測。與 PrEP 前相比，這將 PrEP 後 STI 診斷的 IRR 從 1.35 提高到 1.91，顯示在開始 PrEP 後大部分 STI 診斷可能是無症狀感染。
如果 PrEP 前檢測發現了所有無症狀感染，那麼在 PrEP 期間和之前，所有有症狀和其他性傳播感染的真實發生率可能會接近 90%，而不是 35%。這是否重要，因為兩種情況可能不僅是無症狀，而且具有自限性（正如先前的荷蘭模型研究所探討的那樣），這是一個公共衛生爭論的問題。
作者說，這項研究「並不意味著 PrEP 會導致風險補償」。 「相反，它顯示在性傳播感染風險增加時（即最需要的時候）正在給予 PrEP」。他們補充說，「這使得 PrEP 計劃成為介入的關鍵點，因此提供一個安全和支持性的環境，包括全面的性健康諮詢是至關重要的」。
參考文獻：
Von Schreeb S et al. 質疑風險補償：2019 年至 2022 年丹麥首都地區男男性行為者的暴露前預防 (PrEP) 和性傳播感染。
Danish study finds that STI rates in gay men increase before they start PrEP, not after
Gus Cairns / 22 April 2024 / aidsmap
A Danish study which was able to chart the annual incidence of the three bacterial STIs, chlamydia, gonorrhoea and syphilis, in people attending sexual health clinics both before and after they started PrEP has found that they had more than twice as many (115% more) STI diagnoses while on PrEP than they had some time before starting it.
However it also found that much of this increase in diagnoses was due to increased testing. While the average STI testing rate in people some time before starting PrEP was in the region of 50 tests per 100 person years (i.e. a test every two years), it was three to four tests per year in people on PrEP, with tests peaking each three months due to PrEP checkups.
When this was taken into account, the diagnosis rate of any of the bacterial STIs in people on PrEP was only 35% higher than it was before PrEP, and in the case of syphilis there was no significant increase.
The investigators also found, however, that the increase in tests started some 10-20 weeks before people actually started PrEP, increasing in this period from about 200 to 500 tests per 100 person-years in that period, even when the large spike in tests at PrEP initiation was discounted.
Dr Sebastian von Schreeb and colleagues at Copenhagen University Hospital say that their study is evidence against the idea that PrEP leads directly to “risk compensation”. This is the theory put forward by some behavioural scientists that if people feel less anxious because they adopt one protective behaviour, they will tend to increase a related risky behaviour – driving faster because they wear a seat belt, for instance. In the early days of PrEP and U=U some researchers were concerned that this would lead to condom use dropping by such an extent that it might wipe out some or all of the benefits of biomedical prevention.
The authors say that their study shows that this is not the case with PrEP and STIs: “If risk compensation was valid, we would expect STI incidence to increase when people feel protected against HIV [and that it] could occur immediately following the initiation of PrEP or gradually over time, as they became more assured.
“As no such increase was seen, an alternative explanation is that…changes in sexual risk-taking lead people to PrEP.”
More about the study
Demonstrating whether PrEP leads to risk compensation requires data about people’s STI incidence before they start PrEP, and this can be difficult to establish. This is because researchers often only have access to STI diagnosis data in PrEP users, and also because PrEP use usually involves more STI tests, which will diagnose more infections – especially asymptomatic ones (it is estimated that 85% of rectal chlamydia and gonorrhoea infections in gay men are asymptomatic). A couple of other studies have found that STI diagnoses or STI risk behaviour increased before, rather than after, gay and bisexual men started PrEP, but others have found higher rates after the start of PrEP – as described in aidsmap’s evidence brief on PrEP and STIs.
The new study’s data are particularly robust because of Denmark’s thorough healthcare surveillance. Each citizen is given a unique civil registration number which can be linked to comprehensive databases of microbiological test results. Results are thus less likely to get lost in the system.
PrEP became available through the Danish public health system in 2018 and all people starting PrEP are enrolled in a nationwide prospective cohort study, DanPrEPD, and continue as participants even if they stop PrEP. All cisgender gay men and trans men and women who initiated PrEP between January 2019 and June 2022 and who lived in the Capital Region of Denmark, which includes 30% of the country’s population, were included.
The total number of participants was 1326, of which 10 were transgender. Their average age was 35 (range: 16 to 78). All but eight participants started on a daily PrEP regimen. One hundred and forty-seven participants (11%) were already on PrEP before January 2019 and were excluded from the before/during PrEP comparison, as were 237 people who stopped PrEP during the study (this doesn’t mean 384 exclusions, as some could belong to both groups).
The rest of the participants, who started PrEP during the study and were still on it at the end, were observed for roughly equal times before and after PrEP: there were 2155 person-years of data available before the start of PrEP and 2351 after it. The average gap between entering the study and starting PrEP was 22 months in a 42-month study, so roughly halfway through.
There were 708 STI diagnoses in people before they started PrEP and 1849 after it. This implies an unadjusted annual incidence rate of 35 per 100 person-years before PrEP and 81 per 100 afterwards (as other studies have shown, this does not mean that all participants had an 81% chance of acquiring an STI while on PrEP: some may have had no STIs and others may have had repeated episodes.)
This means that the frequency of STI diagnoses (the Incidence Rate Ratio or IRR) was 2.15 times greater after PrEP than before, both for all STIs and for each individual STI.
However, people took three times as many STI tests after starting PrEP than before: in total, 7936 before PrEP but 23,654 after it. In terms of individual STIs people took 2.6 times more tests for gonorrhoea and chlamydia after PrEP than before, but 4.4 times more tests for syphilis; this appears to reflect the test for syphilis, which is an antibody test done on blood, becoming as routine as the swab tests done for the other two diseases, whereas it was only done half the time before PrEP.
When the IRR of post- compared to pre-PrEP STI diagnoses was adjusted to take account of greater test frequency, the IRR for all STIs fell from 2.15 to 1.35, or in other words from more than doubling to a 35% increase. In chlamydia it fell from 2.25 to 1.23, for gonorrhoea from 2.21 to 1.24, and in syphilis from 2.46 to 1.15, which was no longer statistically significant, meaning that the increase seen in syphilis cases on PrEP might have been due to chance.
Chlamydia in the throat or urethra is less likely to be symptomatic than rectal chlamydia; conversely, in gonorrhoea, while 85% or rectal and throat infections are asymptomatic, only 10% of urethral symptoms are. This implies that if more asymptomatic infections are being diagnosed on PrEP, the IRR of post- compared to pre-PrEP rectal chlamydia should be higher than that seen for throat or genital chlamydia, and the IRR for urethral gonorrhoea should be considerably lower than for throat or rectal.
This is exactly what was seen. The test-adjusted IRR for rectal chlamydia was 1.26 while the rates for oral and genital were 1.19 and 1.14, and lost statistical significance. With gonorrhoea, the adjusted IRRs for rectal and oral gonorrhoea were 1.12 and 1.16 and were not statistically significant; but the tested-adjusted IRR for urethral gonorrhoea was 0.66 and was statistically significant. This means that, adjusting for test frequency, urethral gonorrhoea was actually 34% less likely to be diagnosed while on PrEP than before it (compared with an unadjusted IRR of 1.66). The researchers point out that this does not mean that actual infections decreased on PrEP, merely that in this one case, because most urethral gonorrhoea infections were likely to be detected even before the test increase on and just before PrEP, the unadjusted IRFR of 1.66 may more closely reflect reality.
So one reason more STIs were diagnosed in people starting PrEP was because prior to PrEP, people might only have come for tests if they had symptoms. Because the testing rate in the 10-20 weeks before PrEP was the same as after PrEP, in a sensitivity analysis the researchers excluded the tests taken in the 26 weeks before PrEP initiation. This raised the IRR of post- compared to pre-PrEP STI diagnoses from 1.35 to 1.91, showing that a large proportion of the STI diagnoses after starting PrEP probably were of asymptomatic infections.
If pre-PrEP testing had picked up all asymptomatic infections, the true increase in the rate of all STIs, symptomatic and otherwise, during and immediately before PrEP, might be nearer 90% than 35%. Whether this matters, with two conditions that may not only be asymptomatic but also self-limiting (as a previous Dutch modelling study has explored) is a matter of public health debate.
The study “does not imply that PrEP causes risk compensation,” say the authors. “Rather, it indicates that PrEP is being given when the risk of STIs is increased, i.e. when it is most needed.” They add that “this makes PrEP programmes a critical point of intervention [in which] it is crucial so provide a safe and supportive environment that includes comprehensive sexual health consultation.”
References Von Schreeb S et al. Questioning risk compensation: pre-exposure prophylaxis (PrEP) and sexually transmitted infections among men who have sex with men, capital region of Denmark, 2019 to 2022. Eurosurveillance 29(13): 27-35, 2024 (open access).