歐洲研究發現，低水平的愛滋病毒和病毒載量信號是重要的警告信號
資料來源：Keith Alcorn / 2022 年 10 月 19 日 / aidsmap / 葉財團法人台灣紅絲帶基金會編譯
圖片來源：Jarun Ontakrai/Shutterstock.com
EuResist 研究報告的研究人員在臨床傳染病雜誌上報告說，超過 50 拷貝/ml 的病毒載量與後續治療失敗的風險增加有關，需要認真對待，作為服藥不順從性和新出現的耐藥性的信號。
但該研究還發現，絕大多數經歷過病毒性短暫或低水平病毒血症的人繼續抑制 HIV，並且沒有經歷病毒學失敗。
病毒載量高於檢測水平——通常是高於 50 拷貝/ml 的孤立測量值——是一種常見現象，但研究人員一直不確定其重要性。
一些研究顯示，它們代表病毒從潛伏感染細胞庫中的暫時釋放，而不是正在進行的病毒複製。
低水平病毒血症的連續測量——在高於 50 拷貝但低於 200 拷貝/毫升水平，通常用於定義高收入環境中的病毒學失敗——也難以解釋。一些研究發現，低水平病毒血症患者後續病毒學失敗的風險較高，兩項研究發現後續之死亡或臨床疾病進展之風險較高的趨勢。
但美國的一項研究發現，低於 200 拷貝/ml 的低水平病毒血症並不能預測人們在首次抗反轉錄病毒治療方案中的病毒學失敗。
EuResist 網絡是一個研究 HIV 耐藥性的歐洲研究合作組織，其研究人員調查了迄今為止在高收入環境中研究的最大人群中病毒短暫性突現和低水平病毒血症的影響。他們在德國、西班牙、意大利、盧森堡、比利時和葡萄牙的 HIV 診所確定了 22,532 名在 2005 年至 2015 年間開始治療，並在開始治療後至少進行了 12 個月的追蹤的人。
參與者分類如下：
• 持續病毒學抑制低於 50 拷貝/ml
• 病毒之光點般短暫突現：單個病毒載量高於 50 拷貝/ml
• 低水平病毒血症：數次的病毒載量在 51 到 199 拷貝/ml 之間，至少相隔 30 天
病毒學失敗，主要研究結果，定義為連續兩次病毒載量高於 200 拷貝/毫升或單個病毒載量高於 1000 拷貝/毫升。
在中位 2.8 年的追蹤中，發生了 1,424 例病毒學失敗，其中 72% 發生在先前有病毒學抑制的人中，15% 發生在經歷過病毒性短暫突現事件的人中，13% 發生在低水平病毒血症的人中。
在第一次檢測到病毒載量後，12% 的低水平病毒血症患者在兩年內繼續經歷病毒學失敗，相比之下，有 5% 的病毒光點般短暫突現之患者。
在調整了人口統計學和 HIV 相關因素（包括抗反轉錄病毒療法和治療經驗）後，低水平病毒血症被證明會使病毒學失敗的風險增加一倍（調整後的風險比 2.2，95% 信賴區間 1.6-3）。病毒性光點般短暫突現者適度地增加了病毒學失敗的風險（aHR 1.70, 95% CI 1.3-2.2）。
除了病毒性短暫突發事件和低水平病毒血症外，年齡較小、女性、CD4 計數較低、治療前病毒載量較高、治療經驗和注射吸毒史等均會增加病毒學失敗的風險，但影響較小而不是病毒對隨後的病毒學失敗風險的影響。
「12% 的低水平病毒血症患者在兩年內繼續經歷病毒學失敗，相比之下，只有5% 的病毒光點般短暫突現的感染者」。
當分析僅限於 2014 年之後開始治療的人時，病毒性光點短暫突現、低水平病毒血症和隨後的病毒學失敗風險之間的關係仍然顯著，但當分析僅限於初始治療方案包含整合酶抑製劑的人時，這種關係就停止且其結果是顯著的。然而，研究人員指出，此類病毒血症病例數量有限，這意味著應謹慎對待這一結果。
在低水平病毒血症發作期間，140 人在首次病毒載量測試後的 90 天內進行了耐藥性測試。 49 人至少有一個耐藥性突變；發現 16 個是在開始治療之前不存在的新突變。 16 名具有新突變的世代成員中有 7 名隨後出現病毒學失敗。低水平病毒血症中最常見的突變是與暴露於拉米夫定或恩曲他濱 (lamivudine or emtricitabine) 相關的 M184V 突變。
低水平病毒血症期間進行的耐藥性測試數量較少，因此難以判斷低水平病毒血症後病毒學失敗的程度是由低水平病毒血症期間早期出現耐藥性驅動的。但研究人員表示，他們在病毒載量低於 200 拷貝/ml 的人群中檢測到新的耐藥性突變這一事實，支持了歐洲愛滋病臨床協會關於在低水平病毒血症發作期間進行耐藥性檢測的建議，如果出現耐藥性，當抗藥性被檢測到時則應調整治療方案。
參考文獻：
Elvstam O et al. 抗反轉錄病毒治療期間低水平病毒血症和病毒性光點般突現後的病毒學失敗：來自歐洲多中心世代的結果。 《臨床傳染病》，2022 年 9 月 14 日在線上發表（開放獲取）。
DOI: 10.1093/cid/ciac762
Low-level HIV and viral load blips are important warning signals, European study finds
Keith Alcorn / 19 October 2022 aidsmap
Jarun Ontakrai/Shutterstock.com
Viral load blips above 50 copies/ml are associated with an increased risk of subsequent treatment failure and need to be taken seriously as signals of non-adherence and emerging drug resistance, investigators from the EuResist study report in the journal Clinical Infectious Diseases.
But the study also found that the vast majority of people who experienced a viral blip or low-level viraemia went on re-suppress HIV and did not experience virologic failure.
Viral load blips above the level of detection – typically an isolated measurement above 50 copies/ml – are a common phenomenon but researchers have been uncertain about their significance.
Some studies have suggested that they represent temporary releases of virus from the reservoir of latently infected cells, not ongoing virus replication.
Successive measures of low-level viraemia – above 50 copies but below the 200 copies/ml level often used to define virologic failure in high-income settings – are also difficult to interpret. Some studies have found a higher risk of subsequent virologic failure in people with low-level viraemia and two studies have found a trend towards a higher risk of subsequent death or clinical disease progression.
But a US study found that low-level viraemia below 200 copies/ml did not predict virologic failure in people on their first antiretroviral regimen.
Researchers in the EuResist network, a European research collaboration that studies HIV drug resistance, investigated the impact of viral blips and low-level viraemia in the largest population studied to date in a high-income setting. They identified 22,532 people who started treatment between 2005 and 2015 and had at least 12 months of follow-up after starting treatment, at HIV clinics in Germany, Spain, Italy, Luxembourg, Belgium and Portugal.
Participants were classified as follows:
•Persistent virologic suppression below 50 copies/ml
•Viral blips: a single viral load above 50 copies/ml
•Low-level viraemia: several viral loads between 51 and 199 copies/ml, at least 30 days apart
Virologic failure, the primary study outcome, was defined as two consecutive viral loads above 200 copies/ml or a single viral load above 1000 copies/ml.
During a median of 2.8 years of follow-up, 1,424 virologic failures occurred, 72% in people with previous virologic suppression, 15% in people who had experienced a viral blip and 13% in people with low-level viraemia.
After the first detectable viral load, 12% of those with low-level viraemia went on to experience virologic failure within two years, compared to 5% of those with viral blips.
After adjusting for demographic and HIV-related factors (including antiretroviral regimen and treatment experience), low-level viraemia was shown to double the risk of virologic failure (adjusted hazard ratio 2.2, 95% confidence interval 1.6-3). Viral blips modestly increased the risk of virologic failure (aHR 1.70, 95% CI 1.3-2.2).
As well as viral blips and low-level viraemia, younger age, female sex, lower CD4 count, higher pre-treatment viral load, treatment experience and a history of injecting drug use each increased the risk of virologic failure, although each had less impact than viral blips on the subsequent risk of virologic failure.
“12% of those with low-level viraemia went on to experience virologic failure within two years, compared to 5% of those with viral blips.”
The relationship between viral blips, low-level viraemia and subsequent risk of virologic failure remained significant when the analysis was restricted to people who started treatment after 2014, but when the analysis was restricted to people whose first regimen contained an integrase inhibitor, the relationship ceased to be significant. However, the investigators note that the limited number of cases of viraemia in this category means that this result should be treated with caution.
One hundred and forty people had resistance tests within 90 days of their first viral load test during an episode of low-level viraemia. Forty-nine had at least one drug resistance mutation; 16 were found to be new mutations not present before starting treatment. Seven of the 16 cohort members with new mutations subsequently developed virologic failure. The most common mutation to emerge during low-level viraemia was the M184V mutation associated with exposure to lamivudine or emtricitabine.
The low number of resistance tests carried out during low-level viraemia make it difficult to judge to what extent virologic failure after low-level viraemia is driven by the early emergence of drug resistance during low-level viraemia. But the investigators say that the fact they detected new drug resistance mutations in people with viral load below 200 copies/ml lends support to the European AIDS Clinical Society’s recommendation of resistance testing during episodes of low-level viraemia, with adjustment of the regimen if resistance is detected.
References
Elvstam O et al. Virologic failure following low-level viremia and viral blips during antiretroviral therapy: results from a European multicenter cohort. Clinical Infectious Diseases, published online 14 September 2022 (open access).
DOI: 10.1093/cid/ciac762