Background

Many countries are now replacing non-nucleoside reverse transcriptase inhibitor (NNRTI)-based first-line antiretroviral therapy (ART) with a regimen containing tenofovir disoproxil fumarate, lamivudine, and dolutegravir (TLD). Recognising laboratory limitations, Malawi opted to transition those on NNRTI-based first-line ART to TLD without viral load testing. We aimed to assess viral load and HIV drug resistance during 1 year following transition to TLD without previous viral load testing.

Methods

In this prospective cohort study, we monitored 1892 adults transitioning from NNRTI-based first-line ART to the TLD regimen in the Médecins Sans Frontières-supported decentralised HIV programme in Chiradzulu District, Malawi. Eligible adults were enrolled between Jan 17 and May 11, 2019, at Ndunde and Milepa health centres, and between March 8 and May 11, 2019, at the Boma clinic. Viral load at the start of the TLD regimen was assessed retrospectively and measured at month 3, 6, and 12, and additionally at month 18 for those ever viraemic (viral load ≥50 copies per mL). Dolutegravir minimal plasma concentrations (C_min) were determined for individuals with viraemia. Drug-resistance testing was done at the start of TLD regimen and at viral failure (viral load ≥50 copies per mL, followed by viral load ≥500 copies per mL; resistance defined as Stanford score ≥15).

Findings

Of 1892 participants who transitioned to the TLD regimen, 101 (5·3%) were viraemic at TLD start. 89 of 101 had drug-resistance testing with 31 participants (34·8%) with Lys65Arg mutation, 48 (53·9%) with Met184Val/Ile, and 42 (40·4%) with lamivudine and tenofovir disoproxil fumerate dual resistance. At month 12 (in the per-protocol population), 1725 (97·9% [95% CI 97·1–98·5]) of 1762 had viral loads of less than 50 copies per mL, including 83 (88·3% [80·0–94·0]) of 94 of those who were viraemic at baseline. At month 18, 35 (97·2% [85·5–99·9]) of 36 who were viraemic at TLD start with lamivudine and tenofovir disoproxil fumarate resistance and 27 (81·8% [64·5–93·0]) of 33 of those viraemic at baseline without resistance had viral load suppression. 14 of 1838 with at least two viral load tests upon transitioning had viral failure (all with at least one dolutegravir C_min value <640 ng/mL; active threshold), suggesting suboptimal adherence. High baseline viral load was associated with viral failure (adjusted odds ratio [aOR] 14·1 [2·3–87·4] for 1000 to <10 000 copies per mL; aOR 64·4 [19·3–215·4] for ≥10 000 copies per mL). Two people with viral failure had dolutegravir resistance at 6 months (Arg263Lys or Gly118Arg mutation), both were viraemic with lamivudine and tenofovir disoproxil fumarate resistance at baseline.

Interpretation

High viral load suppression 1 year after introduction of the TLD regimen supports the unconditional transition strategy in Malawi. However, high pre-transition viral load, ongoing adherence challenges, and possibly existing nucleoside reverse transcriptase inhibitor resistance can lead to rapid development of dolutegravir resistance in a few individuals. This finding highlights the importance of viral load monitoring and dolutegravir-resistance surveillance after mass transitioning to the TLD regimen.

Funding

Médecins Sans Frontières.

Translations

For the French and Portuguese translations of the abstract see Supplementary Materials section.

中文翻译：

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在马拉维实用过渡到多替拉韦一线治疗后 1 年的病毒抑制和 HIV-1 耐药性：一项前瞻性队列研究

背景

许多国家现在正在用包含富马酸替诺福韦二吡呋酯、拉米夫定和多替拉韦 (TLD) 的方案取代基于非核苷类逆转录酶抑制剂 (NNRTI) 的一线抗逆转录病毒治疗 (ART)。认识到实验室的局限性，马拉维选择将那些基于 NNRTI 的一线 ART 转换为 TLD，而无需进行病毒载量测试。我们的目标是评估过渡到 TLD 后 1 年内的病毒载量和 HIV 耐药性，而无需之前的病毒载量测试。

方法

在这项前瞻性队列研究中，我们在马拉维 Chiradzulu 区由 Médecins Sans Frontières 支持的分散 HIV 项目中监测了 1892 名从基于 NNRTI 的一线 ART 过渡到 TLD 方案的成年人。符合条件的成年人于 2019 年 1 月 17 日至 5 月 11 日在 Ndunde 和 Milepa 卫生中心以及 2019 年 3 月 8 日至 5 月 11 日在 Boma 诊所登记。回顾性评估 TLD 方案开始时的病毒载量，并在第 3、6 和 12 个月进行测量，对于曾经出现病毒血症的患者（病毒载量 ≥50 拷贝/mL）在第 18 个月进行测量。多替拉韦最低血浆浓度（C _min) 是针对患有病毒血症的个体确定的。在 TLD 方案开始和病毒失败时进行耐药性测试（病毒载量 ≥50 拷贝/mL，然后病毒载量 ≥500 拷贝/mL；耐药性定义为斯坦福评分 ≥15）。

发现

在过渡到 TLD 方案的 1892 名参与者中，101 名 (5·3%) 在 TLD 开始时出现病毒血症。101 人中有 89 人进行了耐药性测试，其中 31 名参与者 (34·8%) 有 Lys65Arg 突变，48 名 (53·9%) 有 Met184Val/Ile，42 名 (40·4%) 有拉米夫定和富马替诺福韦地索普西双重耐药性。在第 12 个月（在符合方案的人群中），1762 人中有 1725 人（97·9% [95% CI 97·1–98·5]）的病毒载量低于 50 拷贝/mL，其中 83 人（88·3 % [80·0–94·0]) 在基线时病毒血症的 94 人中。在第 18 个月，36 名 TLD 病毒血症患者中有 35 名 (97·2% [85·5–99·9]) 开始对拉米夫定和富马酸替诺福韦地索普西耐药，27 名 (81·8% [64·5–93·0 ]) 在基线时没有耐药性的病毒血症患者中，有 33 人具有病毒载量抑制。_最小值<640 ng/mL；主动阈值），表明依从性不佳。高基线病毒载量与病毒失败相关（调整优势比 [aOR] 14·1 [2·3–87·4] 1000 到 <10 000 拷贝/mL；aOR 64·4 [19·3–215·4 ] ≥10 000 份/mL）。两名病毒失败者在 6 个月时出现了多替拉韦耐药（Arg263Lys 或 Gly118Arg 突变），在基线时，两人都出现了对拉米夫定和富马酸替诺福韦二吡呋酯耐药的病毒血症。

解释

引入 TLD 方案 1 年后的高病毒载量抑制支持马拉维的无条件过渡策略。然而，高过渡前病毒载量、持续的依从性挑战以及可能存在的核苷类逆转录酶抑制剂耐药性可能导致少数个体快速发展为多替拉韦耐药性。这一发现强调了在大规模过渡到 TLD 方案后进行病毒载量监测和多替拉韦耐药监测的重要性。

资金

无国界医生组织。

翻译

对于摘要的法语和葡萄牙语翻译，请参阅补充材料部分。