改變遊戲規則的二線 HIV 治療研究
資料來源：www.thelancet.com/hiv Vol 9 June 2022 / 財團法人台灣紅絲帶基金會編譯
當一項隨機對照試驗具有相關的臨床和公共衛生影響，並將改變世衛組織在非洲和其他資源有限地區的二線抗反轉錄病毒治療 (ART) 指引時，它應該被稱為改變遊戲規則者，這是每個研究人員的夢想。
在《剌胳針愛滋病毒》中，Nicholas I Paton 及其同事報告了 96 週的隨機、非劣效性 NADIA 試驗數據，該試驗比較了第二線抗反轉錄病毒療法中以多替拉韋與以利托那韋增強的地瑞那韋相較 (dolutegravir versus ritonavir-boosted darunavir)和以齊多夫定與替諾福韋的比較 (zidovudine versus tenofovir)。該研究在提供治療的相關環境，並在肯亞、烏干達和辛巴威的七個地點進行。我們祝賀所有作者在資源有限的環境中進行高質量的科學研究。
研究人員在篩查前 6 個月內招募了 464 名 HIV 患者並接受了基於非核苷類反轉錄酶抑製劑 (NNRTI) 加兩種核苷類反轉錄酶抑製劑 (NRTIs) 的一線方案治療失敗，這反映了在 NNRTI 耐藥性頻繁傳播且沒有通用基因型檢測的國家其 HIV 治療失敗的高發生率。
儘管 453 名參與者中有 391 名（86%）患有 Met184Val 或 Met194Ile，226 名（50%）在基準線時有 Lys65Arg 或 Lys65Asn 耐藥突變，但療效出人意料地高：替諾福韋組 233 名參與者中有 188 名（81%）和 齊多夫定組 231 人的173 名（75%）HIV-1 RNA 在 96 週時低於 50 拷貝/mL。事實上，基準線時 Met184Val 或 Lys65Arg 的存在與於第 96 週時病毒學抑制率提高至低於 400 拷貝/mL 上有顯著相關，這一發現需要除了治療之不順從性外並進一步研究才能理解。與齊多夫定相比，替諾福韋在 96 週時的主要終點（HIV-1 RNA＜400 拷貝/mL）既有非劣效果又優於齊多夫定（百分點差異 7·0%，95% CI 1·2–12·8） ，在任何 3-4 級不良事件的發生率較低，而且出乎意料的是，可能與較低的多替拉韋 (dolutegravir) 耐藥率有關。
鑑於當前和以前的研究結果，很明顯基因型抗藥性測試並不能準確預測二線抗逆轉錄病毒治療中的 NRTI 活性。 Paton 及其同事此前曾建議，在低收入地區的 ART 項目中進行常規耐藥性測試以選擇二線核苷類反轉錄酶抑製劑 (NRTI) 並不是優先事項。如果在一線 ART 中使用替諾福韋，WHO 建議改用齊多夫定便不再有意義：當考慮到 NADIA 研究的 96 週數據。
作者選擇的主要結果是 48 週時血漿 HIV-1 RNA 濃度低於 400 拷貝/mL 的參與者比例。然而，非洲研究的 HIV-1 RNA 效力閾值不應高於 50 拷貝/mL。因為他們的主要成果，不再有技術實驗室問題阻止在非洲研究中使用每毫升 50 個拷貝的標準閾值；在所有關鍵研究中，每毫升超過 200 個拷貝的 HIV-1 RNA 樣本被認為是病毒學失敗的。因此，考慮在終點窗口處 HIV-1 RNA 濃度為 200-399 拷貝/mL 的參與者為具有成功的病毒學抑制可能會產生誤導。巧合的是，作者確實以每毫升 50 份的閾值提供了數據，從而可以更嚴格地解釋他們的結果。
2 × 2 因子設計允許對多替拉韋和利托那韋增強的地瑞那韋 (dolutegravir and ritonavir-boosted darunavir)進行比較，結果顯示其非劣效性。值得注意的是，據我所知，這項研究是第一個顯示在任何情況下地瑞那韋與多替拉韋 (darunavir versus dolutegravir) 的非劣效性。值得注意的是，在類似的一線治療失敗情況下進行的 DAWNING 研究顯示，當與兩種 NRTIs 一起給藥時，多替拉韋(dolutegravir)在 48 週時優於利托那韋增強的洛匹那韋 (ritonavir-boosted lopinavir) 。同樣地，利托那韋增強的地瑞那韋 (ritonavir-boosted darunavir) 在 ARTEMIS 研究ART第一線之治療中，較利托那韋增強的洛匹那韋( ritonavir-boosted lopinavir) 為優。
在 NADIA 研究中，地瑞那韋(darunavir) 組沒有參與者在 96 週時出現治療耐藥性。然而，多替拉韋 (dolutegravir) 組中的 9 名 (4%) 參與者發展出治療產生之 dolutegravir 耐藥性，包括高水平耐藥性。基準線後，僅在 HIV-1 RNA 濃度至少為 400 拷貝/mL 的樣本中進行基因型耐藥性測試，因此一些耐藥性可能未被注意到。在 NADIA 中發現的耐藥率是之前在相同情況下進行的 DAWNING和 ODDYSEY 研究中報告的 2% 的兩倍。DAWNING 中的優雅病毒學分析，將體外多替拉韋 (dolutegravir) 耐藥性表徵為降低複製能力超過了十倍的變化。 因此，當與兩種大多數無活性的 NRTI 一起給藥時，對多替拉韋耐藥的屏障並不是最佳的。急切期待在 NADIA 中對多替拉韋耐藥性的更加詳細的分析。
非洲二線抗反轉錄病毒治療 (ART) 的未接受過整合酶治療的患者 (integrase-naive patients) 出現多替拉韋耐藥令人擔憂，需要緊急關注，特別是考慮到在利托那韋增強的地瑞那韋(ritonavir-boosted darunavir) 組中沒有參與者產生治療耐藥性這一事實。在一線和二線抗反轉錄病毒治療中過渡到多替拉韋是世衛組織的優先事項，將挽救許多生命，透過防止整合酶耐藥性的傳播來保持藥物的活性至關重要。非洲對愛滋病毒藥物的耐藥性日益增加，正在威脅全球抗擊病毒的進展，特別是必須解決整合酶耐藥性問題。因此，需要進一步研究來微調二線治療方案的活性，並減輕低收入國家的整合酶耐藥性選擇。同時，利托那韋增強的地瑞那韋 (ritonavir-boosted darunavir) 值得考慮在非洲公共衛生方法中擴大二線抗病毒治療的作用。
JML 在這個相關的評論之外，本人或演講者辦公室已收到來自 Janssen-Cilag、Gilead Sciences 和 ViiV Healthcare 的講座、演講的付款或酬金。Josep M Llibre jmllibre@flsida.org
Fight AIDS and Infectious Diseases Foundation, Infectious Diseases Division, University Hospital Germans Trias, Badalona 08916, Spain
Game-changing study of second-line HIV treatment
www.thelancet.com/hiv Vol 9 June 2022
When a randomised controlled trial has relevant clinical and public health implications and is going to change WHO’s guidelines on second-line antiretroviral therapy (ART) in Africa and other resource-limited settings, it deserves to be called game-changing. It is the dream of every researcher.
In The Lancet HIV, Nicholas I Paton and colleagues report the 96-week data of the randomised, noninferiority NADIA trial comparing dolutegravir versus ritonavir-boosted darunavir and zidovudine versus tenofovir in second-line ART. The study was designed to be relevant to the settings in which treatment is delivered and was done at seven sites in Kenya, Uganda, and Zimbabwe. I congratulate all authors for performing high-quality science in a resource-limited setting.
The researchers enrolled 464 patients with HIV and treatment failure within 6 months before screening to rst-line regimens based on a non-nucleoside reverse transcriptase inhibitor (NNRTI) plus two nucleoside reverse transcriptase inhibitors (NRTIs), reflecting the high rates of HIV treatment failure in countries with frequent transmission of NNRTI resistance and no universal genotypic testing.
Despite 391 (86%) of 453 participants having Met184Val or Met194Ile and 226 (50%) having Lys65Arg or Lys65Asn resistance mutations at baseline, efficacy was surprisingly high: 188 (81%) of 233 in the tenofovir group and 173 (75%) of 231 in the zidovudine group had HIV-1 RNA less than 50 copies per mL at 96 weeks. Indeed, the presence of either Met184Val or Lys65Arg at baseline was associated with significantly higher rates of virological suppression to less than 400 copies per mL at week 96, a finding that will need further research beyond treatment non-adherence to be understood. Compared with zidovudine, tenofovir was both non-inferior and superior for the primary endpoint (HIV-1 RNA＜400 copies per mL) at 96 weeks (percentage point difference 7·0%, 95% CI 1·2–12·8), had a lower rate of any grade 3–4 adverse event, and, quite unexpectedly, was possibly associated with lower rates of dolutegravir resistance.
In view of the current and previous study results, it is quite clear that genotypic resistance testing does not accurately predict NRTI activity in second-line ART. Paton and colleagues have previously suggested that routine resistance testing in ART programmes in lowincome settings for the purpose of selecting secondline NRTIs was not a priority.3 WHO’s recommendation of switching to zidovudine if tenofovir is used in firstline ART no longer makes sense when considering the 96-week data of the NADIA study.1
The authors’ chosen primary outcome was proportion of participants with a plasma HIV-1 RNA concentration of less than 400 copies per mL at 48 weeks.4 However, African studies should not have HIV-1 RNA efficacy thresholds higher than 50 copies per mL as their primary outcomes. There are no longer technical laboratory issues that prevent the use of the standard threshold of 50 copies per mL in African studies, and samples with HIV-1 RNA of more than 200 copies per mL are considered virological failures in all pivotal studies. Therefore, considering participants with HIV-1 RNA concentrations of 200–399 copies per mL at the endpoint window as having successful virological suppression could be misleading. Opportunely, the authors do present data at the 50 copies per mL threshold, allowing a stricter interpretation of their results.
The 2 × 2 factorial design allowed a comparison between dolutegravir and ritonavir-boosted darunavir, which showed non-inferiority. Remarkably, to my knowledge, this study is the first to show noninferiority of darunavir versus dolutegravir in any scenario. Of note, the DAWNING study, which was done in a similar setting of first-line treatment failure, showed that dolutegravir was superior to ritonavirboosted lopinavir at 48 weeks when administered with two NRTIs.5 Similarly, ritonavir-boosted darunavir was superior in first-line ART to ritonavir-boosted lopinavir in the ARTEMIS study.6
No participants in the darunavir group in the NADIA study developed treatment resistance at 96 weeks.1 However, nine (4%) participants in the dolutegravir group developed treatment-emergent dolutegravir resistance, including high-level resistance. After baseline, genotypic resistance testing was done only in samples with HIV-1 RNA concentrations of at least 400 copies per mL, so some resistance might have gone unnoticed. The resistance rate found in NADIA is double the rate of 2% previously reported in both the DAWNING7 and the ODDYSEY8 studies, which were done in the same scenario. An elegant virological analysis in DAWNING characterised in vitro dolutegravir resistance as a change of more than ten-fold with reduced replication capacity.7 Therefore, the barrier against resistance to dolutegravir when administered with two mostly inactive NRTIs is not optimal. A more detailed analysis of dolutegravir resistance in NADIA is eagerly awaited.
Emergence of dolutegravir resistance in integrase-naive patients on second-line ART in Africa is of concern and needs urgent attention, especially when considering the fact that no participants developed treatment resistance in the ritonavir-boosted darunavir group. Transitioning to dolutegravir in both first-line and second-line ART is a WHO priority and will save many lives, and preserving activity of the drug by preventing the spread of integrase resistance is of paramount importance.9 Growing resistance to HIV drugs in Africa is threatening progress made in the global fight against the virus, and integrase resistance in particular must be tackled. Therefore, further studies are needed to fine-tune the activity of secondline regimens and mitigate integrase resistance selection in low-income countries. Meanwhile, ritonavir-boosted darunavir merits consideration for an expanded role in second-line ART in the public health approach in Africa.
JML has received payments or honoraria for lectures, presentations, or speaker’s bureaus from Janssen-Cilag, Gilead Sciences, and ViiV Healthcare, outside of this linked Commen.
Josep M Llibre jmllibre@flsida.org Fight AIDS and Infectious Diseases Foundation, Infectious Diseases Division, University Hospital Germans Trias, Badalona 08916, Spain