愛滋病毒和心血管疾病：確定未測量的風險
資料來源：刺胳針愛滋病毒醫學期刊；www.thelancet.com/hiv Vol 5 June 2018；財團法人台灣紅絲帶基金會編譯
心血管疾病在愛滋病毒感染者中更常發生，是已制定抗反轉錄病毒治療方案的國家的發病率和死亡率的主要原因，並且當人口中感染愛滋病毒者感染多年時可能會遍及全球都增加。當在愛滋病毒感染者觀察到心血管疾病發病率較高的情況無法單用傳統的危險因素去完全解釋時，從而導致一項假說即是所謂的愛滋病毒感染者尚未測量的心血管疾病風險。這種無法測量的風險在臨床上經由許多當代的心血管風險評估方法以及心血管疾病真正風險的方程式執行下，被轉化為對這個易感群體上的低估。
愛滋病特有的幾個因素可能有助於愛滋病毒感染者心血管疾病的發展，包括全身系統性炎症，膽固醇代謝的破壞，免疫功能障礙（特別是先天性免疫激活仍持續存在，儘管在有效的抗反轉錄病毒療法下），以及抗反轉錄病毒治療額外的特殊貢獻。藉由處於這一戳力最前沿已超過15年的抗反轉錄病毒藥物不良反應數據收集（the Data Collection on Adverse Effects of Antiretroviral Drugs，D：A：D）研究，大型的前瞻性世代研究已報告了接觸抗反轉錄病毒治療與心血管疾病之間的許多關聯。
Lene Ryom及其同事在他們發表於「剌胳針愛滋病毒」醫學期刊文章中報導了( D：A：D )研究的結果，該研究顯示使用常用的蛋白酶抑製劑，藥理學上由ritonavir來增強的darunavir（ritonavir-boosted darunavir），和伴隨心血管疾病事件之間的關聯（發生率的比率在使用5年以上者為1.59， 95％的信賴區間為1·33-1·91），並於許多相關業經調整之分析中持續存在。在2007年，D：A：D研究也報告了蛋白酶抑製劑的使用與心血管疾病之間的關聯，特別地顯示這種與蛋白酶抑製劑的關聯也引起了顯著的血脂異常。在2007年的分析中，校正後的脂質減少了，但重要的是，沒有完全消除使用先前的蛋白酶抑製劑和伴隨發生心血管疾病間其關聯的強度；這些觀察到的影響，無論如何，被假定在某種程度上反映了蛋白酶抑製劑誘導的血脂異常。
然而，在這項最新的分析中因幾個非常重要的原因，對這一假設提出了挑戰。首先，使用更新近的蛋白酶抑製劑與血脂異常的相關性較弱，並且與先前的D：A：D研究使用早期的蛋白酶抑製劑的分析一致，脂質的調整並未消除使用由ritonavir來增強的darunavir其與心血管疾病事件之間的關聯。此外，在使用另一種常用係由ritonavir來增強的atazanavir（ritonavirboosted atazanavir）的蛋白酶抑製劑後，並未觀察到與心血管疾病有相似的相關性，這顯示與心血管疾病的任何關聯不是蛋白酶抑製劑類別藥物的一個影響。這些發現提出了一些重要問題，被觀察的關聯是否準確？如果是這樣，什麼是潛在的發病機制？和可以做些什麼來減少或避免這種心血管疾病風險的增加？
對這些問題的明確答案仍然是難以捉摸的，並且極不可能進行有心血管疾病終點的隨機試驗來解決這些問題。但是，正在進行的研究確實提供了見解。頸動脈內膜中層厚度是亞臨床上心血管疾病的替代指標，在隨機研究中，愛滋病毒的感染者啟用增強的darunavir ( boosted darunavir )的和使用增強的atazanavir ( boosted atazanavir )相較之下增加得更多。在愛滋病毒感染者的多中心愛滋病世代研究中，由ritonavir來增強的darunavir其使用的持續時間更長與動脈粥樣硬化斑塊的特徵有關，例如增加了鈣化斑塊的盛行率和總斑塊評分（由電腦斷層冠狀動脈血管造影來確定），這是亞臨床上心血管疾病的替代性測量。心血管疾病替代指標的這些差異可能與脂質無關；由ritonavir來增強的darunavir與由ritonavir來增強的atazanavir相比，由ritonavir來增強的darunavir不會引起脂質或脂蛋白濃度的破壞性變化，因此可能不會在常規的心血管疾病風險評估中被報告。
觀察性的研究如D：A：D會有許多局限性，但它們仍然是臨床研究中有價值的方法。來自觀察性研究的數據不應被輕輕地解釋帶過，特別是如果它們已在若干研究中顯示。正如Ryom及其同事所指出的那樣，他們的觀察報告透過其他適當有力的分析的驗證有最佳的進步，以及經由具潛力的潛在機轉之確定抗反轉錄病毒藥物可以改變心血管疾病的風險。這種轉化方法讓其他抗反轉錄病毒藥物為何會增加心血管疾病的風險能夠有效地解釋，並可以為適當的隨機試驗設計提供信息，但這種方法往往依賴於個別研究者的驅動而非那些負責確保藥物安全的人。
大型前瞻性世代研究，如D：A：D研究，仍然是一個非常有價值的研究工具，可以增加我們對HIV感染長期後果的理解，並指出未測量的風險。由於許多新的抗反轉錄病毒藥物被引入到臨床實務中，D：A：D研究現在面臨著不確定的未來，使我們沒有較好的裝備去面對管理愛滋病毒感染者健康老化上的相關挑戰。由於心血管疾病已經成為愛滋病毒感染者整體死亡率上的重要因素，任何有可能改變危及生命的結果的藥物安全性信號，都必需在適當設計的研究下以及在負責確保藥物安全的人員的推動下堅實地進行探索。
HIV and cardiovascular disease: defining the unmeasured risk
Cardiovascular disease occurs more frequently in people living with HIV, is a leading cause of morbidity and mortality in countries with established antiretroviral treatment programmes. and will probably increase worldwide as the population of people with HIV ages. The higher incidence of cardiovascular disease that is observed in people with HIV cannot be fully explained by traditional risk factors alone, leading to a hypothesised socalled unmeasured risk of cardiovascular disease in people with HIV. This unmeasured risk translates clinically into an underestimation by many contemporary approaches to cardiovascular risk assessment and equations of the true risk of cardiovascular disease in this vulnerable population.
Several factors specific to HIV might contribute to the development of cardiovascular disease in people with HIV, including systemic inflammation, disruptions to cholesterol metabolism, immune dysfunction (particularly innate immune activation that persists despite effective antiretroviral therapy), and additional specific contributions from antiretroviral therapy.
Many associations between exposure to antiretroviral therapy and cardiovascular disease have been reported from large, prospective cohort studies, with the Data Collection on Adverse Effects of Antiretroviral Drugs (D:A:D) study at the forefront of this endeavour for, more than 15 years.
In their Article in The Lancet HIV, Lene Ryom and colleagues report on findings from the D:A:D study that show associations between use of a commonly used protease inhibitor, darunavir that is pharmacologically boosted with ritonavir (ritonavir-boosted darunavir), and incident cardiovascular disease events (incidence rate ratio 1·59 over 5 years of use; 95% CI 1·33–1·91), which persisted in several relevant adjusted analyses. Associations between the use of protease inhibitors and cardiovascular disease was also reported in 2007 by the D:A:D study, specifically showing this association with protease inhibitors that also induced significant dyslipidaemia. In the 2007 analysis, correction for lipids reduced but, importantly, did not fully abrogate the strength of the association between use of the previous protease inhibitors and incident cardiovascular disease; the observed effects were, however, presumed to be in some way reflective of protease inhibitor-induced dyslipidaemia.
This latest analysis, however, challenges that assumption and is important for a couple of reasons. First, use of more recent protease inhibitors has a weaker association with dyslipidaemia and, consistent with the previous D:A:D analysis of earlier protease inhibitors, adjustment for lipids did not abrogate the association between use of ritonavirboosted darunavir and cardiovascular disease events. Additionally, similar associations with cardiovascular disease were not observed after use of ritonavirboosted atazanavir, another commonly used protease inhibitor, suggesting that any association with cardiovascular disease is not an effect of the protease inhibitor drug class. These findings raise important questions. Is the observed association accurate? If so, what is the underlying pathogenesis and what can be done to reduce or avoid this increased risk of cardiovascular disease?
Definite answers to these questions remain elusive and it is highly unlikely that a randomised trial with cardiovascular disease endpoints will be done to address these questions. However, ongoing research does provide insights. Carotid intima–media thickness, a surrogate of subclinical cardiovascular disease, increased significantly more in a randomised study of people with HIV initiating boosted darunavir compared with boosted atazanavir. Within the Multicenter AIDS Cohort Study of men with HIV, a longer duration of ritonavir-boosted darunavir use was associated with characteristics of atherosclerotic plaques, such as increased prevalence of calcified plaque and total plaque score (determined by CT coronary angiography), which is an alternative measure of subclinical cardiovascular disease. These differences in surrogate measures of cardiovascular disease might not be related to lipids; ritonavir-boosted darunavir does not induce damaging changes in either lipid or lipoprotein concentrations compared with ritonavir-boosted atazanavir and therefore might not be reported in routine cardiovascular disease risk assessments.
Observational studies such as D:A:D have many limitations, but they remain a valuable method in clinical research. Data derived from observational studies should not be lightly explained away, particularly if they have been shown in several studies. As Ryom and colleagues rightly note, the observations that they report are best advanced through validation in other, adequately powered analyses, and through determination of the potential underlying mechanisms by which antiretroviral medications could modify risk of cardiovascular disease. This translational approach has enabled valid explanations for how other antiretrovirals could increase risk of cardiovascular disease and can inform design of appropriate randomised trials, but this approach has tended to rely on the drive of individual investigators rather than those responsible for ensuring drug safety.
Large, prospective cohort studies, such as the D:A:D study, remain an incredibly valuable research tool to increase our understanding of the long-term consequences of HIV infection and to identify the unmeasured risks. As many new antiretrovirals are introduced into clinical practice, the D:A:D study now faces an uncertain future, leaving us less well equipped to face the challenges associated with managing healthy ageing in people with HIV. Because cardiovascular disease is already an important contributor to overall mortality in people with HIV, any drug safety signal that has the potential to modify life-threatening outcomes requires robust exploration in appropriately designed studies, driven by those responsible for ensuring drug safety.
www.thelancet.com/hiv Vol 5 June 2018