病毒抑制史較短的人是否有更大的多替拉韋/拉米夫定(dolutegravir/lamivudine)治療失敗之風險？

資料來源：基思·奧爾康 / 2022 年 10 月 6 日 /aidsmap / 財團法人台灣紅絲帶基金會編譯

圖片來源：Kateryna Kon/Shutterstock.com

法國研究人員在《全球抗菌素耐藥性》雜誌上報告說，導致對拉米夫定和恩曲他濱 (lamivudine and emtricitabine) 耐藥的突變的存在並未增加絕大多數 HIV 感染者的病毒反彈風險，他們在病毒受到抑制後改用多替拉韋/拉米夫定(dolutegravir/lamivudine) 兩種藥物方案。

但研究人員表示，他們擔心部分對拉米夫定或恩曲他濱耐藥的人出現病毒反彈的風險——這些人在改用含有拉米夫定的兩種藥物治療之前僅在短時間內受到病毒抑制。

當轉換到含有拉米夫定 (3TC) 或恩曲他濱 (FTC) 的兩種藥物治療是否安全的問題與許多 HIV 感染者相關，他們經歷了包含這些廣泛使用的抗反轉錄病毒藥物之一的治療方案失敗。當包含這兩種藥物的治療方案失敗時，出現的第一個耐藥突變通常是 M184V 突變，這會導致對拉米夫定和恩曲他濱的高度耐藥。

當存在 M184V 突變時，含有整合酶抑製劑（dolutegravir 或 bictegravir）的三藥治療足以抑制 HIV，即使該方案含有拉米夫定或恩曲他濱。

放棄第三種藥物可能很有吸引力，因為它可以最大限度地降低與第三種藥物相關的任何長期副作用的風險，通常是阿巴卡韋（abacavir，心血管疾病）、富馬酸替諾福韋酯（tenofovir disoproxil fumarate，骨質變薄或腎功能下降）或替諾福韋艾拉酚胺（tenofovir alafenamide，體重增加）。

但有人擔心在治療方案中放棄第三種藥物並改用多替拉韋/拉米夫定（Dovato）的風險。一些研究人員認為，在存在 M184V 突變的情況下，拉米夫定可能無法發揮足夠的抗病毒作用，從而有效地使人們使用多替拉韋進行單藥治療，並且治療失敗的風險更高。具有重大耐藥相關突變的人被排除在導致多替拉韋/拉米夫定許可的臨床試驗之外。

為了調查這個問題，研究人員進行了 LAMRES 研究，該研究觀察了有或沒有 M184V 突變的人在改用多替拉韋和拉米夫定後病毒反彈的風險。

該研究分析了在病毒載量完全抑制的情況下改用多替拉韋/拉米夫定且在治療轉換前至少接受過一次耐藥性測試的人的病毒學結果。在法國、意大利和西班牙的診所接受治療的 712 人符合納入回顧性分析的條件。

研究參與者主要是男性（77%），接受抗反轉錄病毒治療的時間中位數為 7 年，52% 的人被病毒學抑制至少 5 年。幾乎所有人（712 人中有 707 人）之前服用過拉米夫定或恩曲他濱，30% 服用過多替拉韋。

60 名 (8.4%) 的 M184V 突變在至少一項先前的抗性測試中可檢測到。在 11 例中，突變僅在 HIV DNA 中檢測到，而在複制病毒中檢測不到。

具有 M184V 突變的參與者更有可能有 CD4 計數低於 200 的病史（晚期 HIV）（58% 對 30% 沒有 M184V）、更長的治療史（20 年對 7 年沒有）、更多的治療失敗事件（3 vs 0）和更多先前的治療方案（10 vs 3）（所有p<0.001）。

在這項研究中，病毒反彈定義為連續兩次病毒載量測量值高於 50 拷貝/ml。有 M184V 突變的人與沒有突變的人在改用兩種藥物治療後 1 年、2 年或 3 年之間病毒反彈的風險沒有統計學上的顯著差異。在轉換後三年，M184V 患者的病毒反彈概率為 11.9%，而沒有 M184V 的患者為 6.3% (p=.206)。當研究人員使用更嚴格的病毒反彈定義（超過 200 拷貝/ml 或 1,000 拷貝/ml）時，他們仍然發現 M184V 與更高的病毒反彈風險之間沒有關聯。

當研究人員根據 M184V 突變的存在以及從檢測到 M184V 突變到轉換為雙重治療之間的病毒抑制持續時間對參與者進行分層時，他們發現具有 M184V 突變的人被病毒抑制的時間少於和三年半與具 M184V 突變和病毒抑制持續時間較長的患者相比，轉換後三年內經歷病毒反彈的可能性顯著更高（22.7% 對 7.8%，p = 0.007）。

但是，在對單變量分析中顯著的變量（HIV 暴露類別、國籍、種族、峰值病毒載量、先前整合酶抑製劑失效）進行調整後，轉換前病毒載量抑制的持續時間不再顯著，並且唯一與反彈是峰值病毒載量超過 100,000 拷貝/毫升和 HIV 暴露類別（異性戀或注射吸毒者）。然而，研究人員表示，他們不能排除基於吸毒等特徵而給予個人的治療類型的偏見。他們指出，其他三項研究觀察到，在轉換為雙重治療之前較短的抑制時間與較高的病毒反彈風險相關。

病毒反彈後，39 人中有 18 人在不改變治療的情況下抑制了 HIV。在大多數情況下，病毒反彈非常小，以至於基因型耐藥性檢測不可行，只有 8 人在反彈後接受了耐藥性檢測。只有一份樣品顯示出 M184V 突變，一份顯示出整合酶抑製劑抗性。

研究人員總結說：「先前對 M184V 患者進行短期病毒學抑制的效果仍然令人不安，需要特別的臨床試驗來證實」。他們推測，在轉換為雙聯治療之前，較短的病毒抑制期可能無法讓HIV 感染細胞貯存庫病毒中池攜帶 M184V 突變病毒在治療下減少。具有 M184V 突變的大量病毒可能會增加病毒反彈的風險。

參考文獻：

Santoro MM 等人。在有或沒有過去 M184V 的抑制 HIV-1 患者的回顧性觀察世代中切換到 DTG 加 3TC 的病毒學療效：LAMRES 研究。《全球抗菌素耐藥性雜誌》，31：52-62，2022 年。

DOI：https://doi.org/10.1016/j.jgar.2022.07.022

Are people with a shorter history of viral suppression at greater risk of failure of dolutegravir/lamivudine?

Keith Alcorn / 6 October 2022 / aidsmap

Kateryna Kon/Shutterstock.com

The presence of a mutation that causes resistance to lamivudine and emtricitabine did not increase the risk of viral rebound in the vast majority of people with HIV who switched to a two-drug regimen of dolutegravir/lamivudine when virally suppressed, French researchers report in the Journal of Global Antimicrobial Resistance.

But the researchers say that they are concerned about the risk of viral rebound in a subset of people with lamivudine or emtricitabine resistance – those who had only been virally suppressed for a short time before switching to two-drug treatment containing lamivudine.

The question of whether it is safe to switch to two-drug treatment that contains lamivudine (3TC) or emtricitabine (FTC) is relevant for many people with HIV who have experienced the failure of a regimen that contained one of these widely used antiretrovirals. When regimens containing either of these drugs fail, the first resistance mutation to appear is usually the M184V mutation, which causes high-level resistance to lamivudine and emtricitabine.

Three-drug treatment containing an integrase inhibitor (dolutegravir or bictegravir) is powerful enough to suppress HIV when the M184V mutation is present, even if the regimen contains lamivudine or emtricitabine.

Dropping a third drug may be attractive, as it could minimise the risk of any long-term side-effects associated with the third drug, typically abacavir (cardiovascular disease), tenofovir disoproxil fumarate (bone thinning or declining kidney function) or tenofovir alafenamide (weight gain).

But concerns have been voiced about the risk of dropping a third drug in the regimen and switching to dolutegravir/lamivudine (Dovato). Some researchers have argued that in the presence of the M184V mutation, lamivudine may not contribute enough antiviral effect, effectively leaving people on single-drug therapy with dolutegravir and at higher risk of treatment failure. People with major resistance-associated mutations were excluded from the clinical trials which led to the licensing of dolutegravir/lamivudine.

To investigate this question, researchers carried out the LAMRES study, which looked at the risk of viral rebound after switching to dolutegravir and lamivudine in people with or without the M184V mutation.

The study analysed virological outcomes in people who had switched to dolutegravir/lamivudine with a fully suppressed viral load and who had undergone at least one resistance test prior to the treatment switch. 712 people receiving treatment at clinics in France, Italy and Spain were eligible for inclusion in the retrospective analysis.

Study participants were predominantly male (77%), had been taking antiretroviral therapy for a median of seven years and 52% had been virologically suppressed for at least five years. Almost all (707 out of 712) had taken lamivudine or emtricitabine previously and 30% had taken dolutegravir.

Sixty (8.4%) had the M184V mutation detectable in at least one previous resistance test. In eleven the mutation was detectable only in HIV DNA and not in replicating virus.

Participants with the M184V mutation were more likely to have a history of a CD4 count below 200 (advanced HIV) (58% vs 30% without M184V), a longer treatment history (20 years vs 7 years without), more episodes of treatment failure (3 vs 0) and more previous treatment regimens (10 vs 3) (all p< 0.001).

In this study, viral rebound was defined as two consecutive viral load measurements above 50 copies/ml. There was no statistically significant difference in the risk of viral rebound between people with the M184V mutation and those without one, two or three years after switching to two-drug treatment. At three years post-switch, the probability of viral rebound was 11.9% in those with M184V compared to 6.3% in those without (p=.206). When the researchers used more stringent definitions of viral rebound (above 200 copies/ml or 1,000 copies/ml), they still found no association between M184V and a higher risk of viral rebound.

When the researchers stratified participants by presence of the M184V mutation and the duration of viral suppression between detection of the M184V mutation and switching to dual therapy, they found that people with the M184V mutation who were virally suppressed for less than three-and-a-half years prior to switching were significantly more likely than those with M184V and a longer duration of viral suppression to experience viral rebound within three years of switching (22.7% vs 7.8%, p =0.007).

But, after adjusting for variables that were significant in univariate analysis (HIV exposure category, nationality, ethnicity, peak viral load, prior integrase inhibitor failure), the duration of viral load suppression prior to switching ceased to be significant and the only factors associated with rebound were peak viral load above 100,000 copies/ml and HIV exposure category (heterosexual or injecting drug use). However, the researchers say that they can’t rule out biases in the type of treatment given to individuals on the basis of characteristics such as drug use. They note that three other studies have observed that a shorter period of suppression prior to a switch to dual therapy is associated with a higher risk of viral rebound.

After viral rebound, 18 out of 39 people resuppressed HIV without changing treatment. In most cases, viral rebound was so small that genotypic resistance testing was not feasible and only eight people underwent resistance testing after rebound. Only one sample showed the M184V mutation and one showed integrase inhibitor resistance.

“The effect of a short duration of previous virological suppression in individuals with M184V remains troubling and needs ad hoc clinical trials to be confirmed,” the researchers conclude. They speculate that a shorter period of viral suppression prior to a switch to dual therapy may not allow time for the pool of viruses carrying the M184V mutation in the reservoir of HIV-infected cells to diminish under treatment. A larger pool of viruses with the M184V mutation might raise the risk of viral rebound.

References

Santoro MM et al. Virological efficacy of switch to DTG plus 3TC in a retrospective observational cohort of suppressed HIV-1 patients with or without past M184V: the LAMRES study. Journal of Global Antimicrobial Resistance, 31: 52-62, 2022.

DOI: https://doi.org/10.1016/j.jgar.2022.07.022