研究還顯示，doxyPEP 對衣原體和梅毒有效，但只能阻止三分之一的淋病格斯‧凱恩斯 / 2024 年 3 月 4 日 / aidsmap
一年前，DoxyVAC 研究的中期結果帶來了希望，即透過將抗生素多西環素（「doxyPEP」）的暴露後預防與淋病候選疫苗相結合，可以在所有同性戀和雙性戀男性中大幅減少三種最重要的細菌性傳播感染的病例。
然而，巴黎聖路易斯醫院的Jean-Michel Molina 教授在今年的反轉錄病毒和伺機性感染會議(CROI 2024) 上發表的這項研究的最終分析發現，doxyPEP 和疫苗接種者對淋病的療效均較低，感染淋病的 PEP 使用者對多西環素的抗藥性增加。 這似乎限制了這些淋病預防措施的有效性。
DoxyVAC 研究的隨機階段在 DoxyPEP 研究結果公佈後於 2022 年 9 月初停止。 這項美國研究報告稱，多西環素 PEP 對所有三種性傳染感染（衣原體、梅毒和淋病）的整體療效為 66%，這一標題數字經常被引用為多西環素 PEP 的整體療效。
這是一種誤導； 事實上，它對 HIV 陰性男性的衣原體和梅毒的功效分別為 88% 和 87%（對 HIV 陽性的男性略低一些），但對淋病的功效僅為 55%。 不過，人們認為，預防一半的細菌感染是值得追求的，因為這種細菌（在極少數情況下）可能會導致關節炎、心臟缺陷和不孕症等嚴重後果。
然而，法國早期的一項研究發現多西環素PEP對淋病的療效為零，這顯然是因為法國對多西環素抗藥性的淋病細菌比例較高。
因此，對於DoxyVAC 研究，Molina 教授及其同事補充說，除了在每次可能的接觸後72 小時內服用多西環素藥丸外，還應在參與研究後的前兩個月內注射兩次B 型腦膜炎疫苗4CMenB 或Bexsero。淋病細菌與引起腦膜炎雙球菌性腦膜炎的細菌密切相關，先前的研究顯示，其對抗淋病的功效可能為 33-40%。
中期分析考察了 502 名試驗參與者三種性傳播感染的發生率。 它沒有研究 doxyPEP 與疫苗在接受兩種介入措施的參與者中的綜合療效。 部分原因是研究人員預期 doxyPEP 不會對淋病有顯著功效，部分原因是他們想單獨考慮疫苗的功效。 因此，針對淋病的結果作為兩個單獨的比較發布——doxyPEP 與無 doxyPEP，以及接受疫苗與無接受疫苗。
出乎意料的是，在中期分析中，doxyPEP 確實對淋病具有顯著功效，疫苗也是如此，因此人們謹慎樂觀地認為這兩種介入措施結合起來可能會提供針對淋病的有效保護。
然而，今天在 CROI 2024 上公佈的更大規模的最終分析結果在很大程度上破滅了這些希望。 儘管 doxyPEP 對衣原體和梅毒的功效已得到證實，但 doxyPEP 和疫苗對淋病的功效均低於最初所認為的效果。
在準備最終分析時，研究人員發現與中期結果相比存在一些差異— 一些淋病感染被忽略了。 此外，最終分析包括 545 名研究參與者（而不是 502 名），但更重要的是，他們擁有長達 21 個月的追蹤數據，而不是中期分析的 12 個月。 這意味著研究後期獲得的感染對結果產生了影響。
在這項分析中，研究族群的組成幾乎沒有變化：他們主要是同性戀，大部分是法國國籍，平均年齡在 40 歲之前。他們必須已經在接受 HIV PrEP，平均接受 PrEP 的時間接近三年。 參與者加入研究前一年的性傳染感染率很高，其中 68% 患有淋病，49% 患有披衣菌，21% 患有梅毒。 在加入研究前一個月，他們平均每週進行一次無套肛交行為，並且在過去三個月內平均有 10 個伴侶。 百分之二十二的人在上次性行為時使用過性愛的藥物。
doxyPEP對披衣菌和梅毒的功效最終分析變化不大。 未服用 doxyPEP 的參與者中衣原體的年發病率為 42%，服用 doxyPEP 的參與者中衣原體的年發病率為 6%，顯示有效率 86%，而中期分析發現有效率 89%。 對於梅毒，中期和最終分析的療效相同，均為 79%。 換句話說，doxyPEP 阻止了五個中的四個本來會發生的梅毒感染，以及幾乎十分之九的披衣菌感染。
doxyPEP 對抗淋病的功效在最終分析雖然還是降低。 於中期分析時發現，未接受 doxyPEP 治療的參與者的淋病年發生率為 41%，而 doxyPEP 組的淋病年發生率為 20.5%，相當於 51% 的有效率； 僅透過 doxyPEP 將淋病感染率減少一半看起來非常有用。
然而，歸根結底，由於追蹤時間相當長，對後來的淋病感染產生了影響。 雖然兩組之間的發生率在研究的前六個月有所不同，但之後它們基本上是相同的——顯示此點之後累積感染的圖表顯示了兩條平行線。 最終，非 PEP 組的淋病發生率為 68%，PEP 組的淋病發生率為 45.5%，這意味著有效率為 33%。 這仍然具有統計意義（p = 0.003），但顯然臨床相關性較低。
最終分析中疫苗的功效遠低於中期分析的疫苗功效，這使情況更加複雜。 在中期分析中，無疫苗組有 54 人感染，疫苗組有 36 人感染。 當比較疫苗與非疫苗參與者時，扣除 PEP 的任何影響，淋病的年發生率為 33%——已經處於預期功效的下限，但仍然有用。
但在最終分析時顯示，接種疫苗的參與者中有 103 例感染，未接種疫苗的參與者有 122 例感染，年發生率分別為 58% 和 77%。 這相當於只有 22% 的功效，在統計上不顯著 (p = 0.061)。 doxyPEP 和疫苗的效果之間沒有交互作用； 換句話說，接受 doxyPEP 和疫苗的男性罹患淋病的可能性並不比接受 doxyPEP 但未接種疫苗的男性低，反之亦然。
在研討會的問與答的過程中，莫利納教授指出，研究人員所選擇的是淋病的感染（透過 PCR 檢測確定）作為他們判斷疫苗有效性的結果。 疫苗在降低淋病的嚴重程度方面上更有效，這仍然是合理的，如果研究結果是針對有症狀的感染，那麼結果可能會更積極。
在中期分析發現，基準線時患有淋病的患者的所有少數細菌樣本都對多西環素具有低水平的抗藥性，但這不足以阻止藥物發揮作用。 然而，在整個研究期間從doxyPEP 使用者採集的31 個樣本和從非doxyPEP 使用者採集的40 個樣本中，他們在研究期間感染了淋病，其中35.5% 的服用PEP 的人具有可能影響療效的高水平抗藥性（中期分析為33%）。未採取 PEP 的人有12.5% 的人具有高水平抗藥性（中期分析為 19%）。 在衣原體樣本中則沒有發現明顯的抗藥性，儘管只從接受 doxyPEP 的一小部分人身上採集（因為感染人數要少得多）。
莫利納教授評論道：「DoxyPEP 對淋病的效果較差，隨著時間的推移，對多西四環素的高水平抗藥性增加，顯示有效性可能會隨著時間的推移而減弱」。
至於疫苗：「雖然不能排除微小的好處，但其臨床意義似乎非常有限」。 仍需要一種更有效的疫苗，並且已經開始對不同候選疫苗的試驗。
參考文獻：Molina J-M et al. ANRS174 DOXYVAC 的最終結果：一項隨機試驗，旨在透過 PrEP 預防 MSM 中的性傳播感染。 第 31 屆反轉錄病毒和伺機性感染會議，丹佛，摘要 124，2024 年。
Full analysis of French STI study dashes hopes for a gonorrhoea vaccine
Full analysis of French STI study dashes hopes for a gonorrhoea vaccine
Gus Cairns / 4 March 2024 / aidsmap
A year ago, the DoxyVAC study’s interim results raised hopes that by combining post-exposure prophylaxis using the antibiotic doxycycline (‘doxyPEP’) with a candidate vaccine against gonorrhoea, cases of all three of the most important bacterial sexually transmitted infections could be substantially reduced in gay and bisexual men.
The final analysis of the study, however, presented at this year’s Conference on Retroviruses and Opportunistic Infections (CROI 2024) today by Professor Jean-Michel Molina of the Hôpital St Louis in Paris, found lower efficacy against gonorrhoea in both doxyPEP and vaccine recipients, and a rise in doxycyline resistance among PEP users who did catch gonorrhoea. This would seem to limit the usefulness of these preventative measures against gonorrhoea.
The randomised phase of the DoxyVAC study was stopped early in September 2022 after results from the DoxyPEP study were announced. This US study had reported an overall efficacy of 66% for doxycycline PEP against all three STIs – chlamydia, syphilis and gonorrhoea – and this headline figure is often quoted as doxyPEP’s overall efficacy.
This is misleading; in fact its efficacy against chlamydia and syphilis in HIV-negative men was 88% and 87%, respectively (in HIV-positive men it was a bit lower), but against gonorrhoea was only 55%. Preventing half of infections with a bacterium that (in a small minority of cases) can cause serious effects ranging from arthritis through heart defects to sterility was thought to be worth pursuing, though.
However, an earlier French study had found zero efficacy for doxyPEP against gonorrhoea, apparently because the proportion of gonorrhoea bacteria resistant to doxycycline was higher in France.
So, for the DoxyVAC study, Professor Molina and colleagues added, in addition to a doxycycline pill to be taken up to 72 hours after every possible exposure, a meningitis B vaccine, 4CMenB or Bexsero, given as two shots in the first two months after enrolment. The gonorrhoea bacterium is closely related to the one that causes meningococcal meningitis, and previous studies had indicated a possible efficacy against gonorrhoea of 33-40%.
The interim analysis looked at the incidence of the three STIs in 502 trial participants. It did not look at the combined efficacy of doxyPEP plus the vaccine in participants given both interventions. This was partly because the researchers did not expect doxyPEP to have significant efficacy against gonorrhoea and partly because they wanted to consider the vaccine’s efficacy in isolation. So the results against gonorrhoea were issued as two separate comparisons – doxyPEP versus no doxyPEP, and vaccine versus no vaccine.
Unexpectedly, doxyPEP did appear to have significant efficacy against gonorrhoea in the interim analysis, as did the vaccine, so there was cautious optimism that the two interventions together might provide useful protection against gonorrhoea.
However, the results of a larger final analysis presented today at CROI 2024 have largely dashed these hopes. Although the efficacy of doxyPEP against chlamydia and syphilis has been confirmed, the efficacy of both doxyPEP and the vaccine against gonorrhoea is lower than initially thought.
When preparing the final analysis, the researchers identified some discrepancies compared to their interim results – with a number of gonorrhoea infections having been omitted. In addition, the final analysis included 545 study participants (rather than 502), but more significantly they had up to 21 months of follow-up data rather than the 12 months in the interim analysis. This means that infections acquired later in the study have made a difference to the results.
The makeup of the study population is little changed in this analysis: they were largely gay and largely of French nationality with an average ago of 40. They had to be already taking HIV PrEP, with an average time on PrEP of nearly three years. There were high rates of STIs in the year before enrolment in participants, with 68% having had gonorrhoea, 49% chlamydia and 21% syphilis. In the month before joining the study, they averaged one act of condomless anal sex per week, and they had had an average of 10 partners in the last three months. Twenty-two per cent had used chemsex drugs at their last encounter.
The efficacy of doxyPEP against chlamydia and syphilis was little changed in the final analysis. The annual incidence of chlamydia was 42% in participants not on doxyPEP and 6% in people on doxyPEP, indicating 86% efficacy, where the interim analysis had found 89% efficacy. With syphilis, the efficacy was the same in interim and final analyses, at 79%. In other words, doxyPEP stopped four out of five syphilis infections that would otherwise have occurred and almost nine out of 10 chlamydia infections.
The efficacy of doxyPEP against gonorrhoea was, however, reduced in the final analysis. The interim analysis found 41% annual incidence of gonorrhoea in participants not on doxyPEP versus 20.5% in the doxyPEP arm, equating to an efficacy of 51%; this halving of gonorrhoea infections through doxyPEP alone looked very useful.
Because the follow-up period in the final analysis is considerably longer, however, later gonorrhoea infections made a difference. While the incidence rates between the two arms diverged in the first six months of the study, after that they were essentially the same – the graph showing cumulative infections after this point shows two parallel lines. Ultimately the incidence of gonorrhoea was 68% in the non-PEP arm and 45.5% in the PEP arm, implying an efficacy of 33%. This was still statistically significant (p = 0.003) but clearly of less clinical relevance.
This was compounded by the efficacy of the vaccine being considerably lower in the final analysis than in the interim analysis. In the interim analysis, 54 people were infected in the no-vaccine arm and 36 in the vaccine arm. The annual incidence of gonorrhoea, when vaccine versus non-vaccine participants were compared, discounting any effect of PEP, was 33% – already at the lower limit of expected efficacy, but still useful.
But in the final analysis there were 103 infections in participants receiving the vaccine versus 122 in ones who did not, for an annual incidence of 58% versus 77%. This equates to an efficacy of just 22%, which just fails to be statistically significant (p = 0.061). There was no interaction between the effects of doxyPEP and the vaccine; in other words, men who received doxyPEP and the vaccine were no less likely to acquire gonorrhoea than people who received doxyPEP but not the vaccine, and vice versa.
During questions and answers, Professor Molina noted that the researchers had chosen gonorrhoea infection (as identified on a PCR test) as the outcome that they would judge the effectiveness of the vaccine by. It remains plausible that the vaccine is more effective in reducing the severity of gonorrhoea disease, and if the study outcome had been symptomatic infection, the results may have been more positive.
The interim analysis had found that all of a small number of samples of bacteria from people presenting with incident gonorrhoea at baseline had low-level resistance to doxycycline, but that it was not sufficient to stop the drug working. However, in 31 samples taken from doxyPEP users and 40 from non-doxyPEP users who acquired gonorrhoea during the study, 35.5% of those taking PEP had high-level resistance that could impact on efficacy (33% in the interim analysis) and 12.5% of those not taking PEP (19% in the interim analysis). No significant resistance was found in chlamydia samples, though only a small number were taken from people on doxyPEP (as there were far fewer infections).
Professor Molina commented: “DoxyPEP is less effective against gonorrhoea, with increased rates of high level resistance to tetracyclines over time suggest effectiveness may wane over time”.
As for the vaccine: “Though a small benefit cannot be ruled out, its clinical relevance seems very limited.” A more effective vaccine is needed, and trials of a different candidate vaccine have begun.
ReferencesMolina J-M et al.Final results of ANRS174 DOXYVAC: a randomized trial to prevent prevent STIs in MSM on PrEP. 31st Conference on Retroviruses and Opportunistic Infections, Denver, abstract 124, 2024.