Asociacion Civil Impacta Salud y Educacion, Lima, Peru.
Harvard T H Chan School of Public Health, Boston, MA, USA.
Lancet HIV. 2016 Jun;3(6):e247-58. doi: 10.1016/S2352-3018(16)30011-X. Epub 2016 Apr 18.
For second-line antiretroviral therapy, WHO recommends a boosted protease inhibitor plus nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs). However, concerns about toxicity and cross-resistance motivated a search for regimens that do not contain NRTIs. We aimed to assess whether boosted lopinavir plus raltegravir would be non-inferior to boosted lopinavir plus NRTIs for virological suppression in resource-limited settings.
A5273 was a randomised, open-label, phase 3, non-inferiority study at 15 AIDS Clinical Trials Group (ACTG) research sites in nine resource-limited countries (three sites each in India and South Africa, two each in Malawi and Peru, and one each in Brazil, Kenya, Tanzania, Thailand, and Zimbabwe). Adults with plasma HIV-1 RNA concentrations of at least 1000 copies per mL after at least 24 weeks on a regimen based on a non-NRTI inhibitor were randomly assigned (1:1) to receive oral ritonavir-boosted lopinavir (100 mg ritonavir, 400 mg lopinavir) plus 400 mg raltegravir twice a day (raltegravir group) or to ritonavir-boosted lopinavir plus two or three NRTIs selected from an algorithm (eg, zidovudine after failure with tenofovir and vice versa; NRTI group). Randomised group assignment was done with a computer algorithm concealed to site personnel, and stratified by HIV-1 RNA viral load, CD4 cell count, and intention to use zidovudine, with the groups balanced by each site. The primary endpoint was time to confirmed virological failure (two measurements of HIV-1 RNA viral load >400 copies per mL) at or after week 24 in the intention-to-treat population. Non-inferiority (10% margin) was assessed by comparing the cumulative probability of virological failure by 48 weeks. This trial was registered with ClinicalTrials.gov, NCT01352715.
Between March 13, 2012, and Oct 2, 2013, we randomly assigned 515 participants: 260 to the raltegravir group and 255 to the NRTI group; two participants in the raltegravir group and one in the NRTI group were excluded from analyses because of ineligibility. By the end of follow-up (October, 2014), 96 participants had virological failure (46 in the raltegravir group and 50 in the NRTI group). By 48 weeks, the cumulative probability of virological failure was 10·3% (95% CI 6·5-14·0) in the raltegravir group and 12·4% (8·3-16·5) in the NRTI group, with a weighted difference of -3·4% (-8·4 to 1·5), indicating that raltegravir was non-inferior, but not superior, to NRTIs. 62 (24%) participants in the raltegravir group and 81 (32%) in the NRTI group had grade 3 or higher adverse events; 19 (7%) and 29 (11%), respectively, had serious adverse events. Three participants in each group died, all from HIV-related causes.
In settings with extensive NRTI resistance but no available resistance testing, our data support WHO's recommendation for ritonavir-boosted lopinavir plus NRTI for second-line antiretroviral therapy. Ritonavir-boosted lopinavir plus raltegravir is an appropriate alternative, especially if NRTI use is limited by toxicity.
National Institutes of Health.
对于二线抗逆转录病毒治疗，世界卫生组织推荐使用增效蛋白酶抑制剂加核苷或核苷酸逆转录酶抑制剂（NRTIs）。然而，由于担心毒性和交叉耐药性，人们开始寻找不含 NRTIs 的方案。我们旨在评估在资源有限的环境中，强化洛匹那韦/利托那韦联合拉替拉韦是否与强化洛匹那韦/ NRTIs 相比在病毒抑制方面具有非劣效性。
A5273 是在 9 个资源有限国家的 15 个艾滋病临床试验组（ACTG）研究地点进行的一项随机、开放标签、3 期、非劣效性研究。在基于非核苷抑制剂的方案至少 24 周后，血浆 HIV-1 RNA 浓度至少为 1000 拷贝/ml 的成年人被随机分配（1:1）接受口服利托那韦增强洛匹那韦（利托那韦 100mg，洛匹那韦 400mg）加每日两次 400mg 拉替拉韦（拉替拉韦组）或利托那韦增强洛匹那韦加从算法中选择的两种或三种 NRTIs（例如，替诺福韦失败后用齐多夫定，反之亦然；NRTI 组）。随机分组是使用隐藏于站点人员的计算机算法进行的，并按 HIV-1 RNA 病毒载量、CD4 细胞计数以及使用齐多夫定的意图进行分层，每组由每个站点平衡。主要终点是意向治疗人群在第 24 周或之后确认病毒学失败（两次 HIV-1 RNA 病毒载量>400 拷贝/ml）的时间。通过在 48 周时比较病毒学失败的累积概率来评估非劣效性（10%的差距）。这项试验在 ClinicalTrials.gov 注册，NCT01352715。
在 2012 年 3 月 13 日至 2013 年 10 月 2 日期间，我们随机分配了 515 名参与者：260 名入拉替拉韦组，255 名入 NRTI 组；拉替拉韦组中有 2 名参与者和 NRTI 组中有 1 名参与者因不符合条件而被排除在分析之外。随访结束时（2014 年 10 月），96 名参与者发生病毒学失败（拉替拉韦组 46 名，NRTI 组 50 名）。到第 48 周时，拉替拉韦组病毒学失败的累积概率为 10.3%（95%CI 6.5-14.0），NRTI 组为 12.4%（8.3-16.5），加权差异为-3.4%（-8.4 至 1.5），表明拉替拉韦不劣于 NRTIs，但不优于 NRTIs。拉替拉韦组有 62 名（24%）参与者和 NRTI 组有 81 名（32%）参与者发生 3 级或更高级别的不良事件；分别有 19 名（7%）和 29 名（11%）参与者发生严重不良事件。两组各有 3 名参与者死亡，均死于与 HIV 相关的原因。
在存在广泛 NRTI 耐药但无耐药性检测的情况下，我们的数据支持世界卫生组织关于二线抗逆转录病毒治疗使用增效蛋白酶抑制剂加 NRTIs 的建议。洛匹那韦/利托那韦联合拉替拉韦是一种合适的替代方案，尤其是在 NRTI 的使用受到毒性限制的情况下。
美国国立卫生研究院。
