在接受抗逆转录病毒治疗失败的儿童和青少年中，替诺福韦的交叉耐药性最小，这使他们有资格接受替诺福韦-拉米夫定-度鲁特韦治疗。

Minimal Cross-resistance to Tenofovir in Children and Adolescents Failing ART Makes Them Eligible for Tenofovir-Lamivudine-Dolutegravir Treatment.

机构信息

Department of Molecular Medicine and Haematology National Health Laboratory Services, Johannesburg, South Africa.

Department of Molecular Medicine and Haematology, University of the Witwatersrand, Johannesburg, South Africa.

出版信息

Pediatr Infect Dis J. 2022 Oct 1;41(10):827-834. doi: 10.1097/INF.0000000000003647. Epub 2022 Jul 20.

DOI:10.1097/INF.0000000000003647

PMID:35895893

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9508940/

Abstract

BACKGROUND

Fixed-dose combination of dolutegravir (DTG) with tenofovir disoproxil fumarate (TDF) and lamivudine (3TC) likely improves adherence and has a favorable resistance profile. We evaluated predicted efficacy of TLD (TDF-3TC-DTG) in children and adolescents failing abacavir (ABC), zidovudine (AZT), or TDF containing regimens.

METHODS

Drug resistance mutations were analyzed in a retrospective dataset of individuals <19 years of age, failing ABC (n = 293) AZT (n = 288) or TDF (n = 69) based treatment. Pol sequences were submitted to Stanford HIVdb v8.9. Genotypic susceptibility scores were calculated for various DTG-containing regimens.

RESULTS

Genotypes were assessed for 650 individuals with a median age of 14 years (IQR 10-17 years). More individuals failed a protease inhibitor (PI)-based (78.3%) than a non-nucleoside reverse transcriptase inhibitors (NNRTI)-based (21.7%) regimen. Most individuals in the AZT group (n = 288; 94.4%) failed a PI-based regimen, compared with 71.0% and 64.2% in the TDF (n = 69) and ABC group (n = 293). Genotypic sensitivity scores <2 to TLD were observed in 8.5% and 9.4% of ABC- and AZT-exposed individuals, compared with 23.2% in the TDF group. The M184V mutation was most often detected in the ABC group (70.6%) versus 60.0% and 52.4% in TDF and AZT groups. The presence of K65R was rare (n = 13, 2.0%) and reduced TLD susceptibility was commonly caused by accumulation of nucleoside reverse transcriptase inhibitor (NRTI) mutations.

CONCLUSIONS

Cross-resistance to TDF was limited, further reducing concerns about use of transition to TLD in children and adolescents. The NADIA trial has subsequently shown that patients failing a TDF/3TC/EFV regimen can safely be transitioned to a TLD regimen but we do not have data for patients failing an ABC/3TC/NNRTI or PI regimens. Frequent virological monitoring is recommended after switch to DTG, especially in children continuing ABC in the backbone. Clinical studies correlating predicted resistance with clinical outcomes, especially in settings without access to genotyping, are required.

摘要

背景

固定剂量组合的多替拉韦（DTG）与富马酸替诺福韦二吡呋酯（TDF）和拉米夫定（3TC）可能会提高依从性，并具有有利的耐药性特征。我们评估了 TLD（TDF-3TC-DTG）在失败于阿巴卡韦（ABC）、齐多夫定（AZT）或 TDF 方案的儿童和青少年中的预测疗效。

方法

对年龄<19 岁、失败于 ABC（n=293）、AZT（n=288）或 TDF（n=69）的个体的回顾性数据集进行了耐药突变分析。将 Pol 序列提交给斯坦福 HIVdb v8.9。计算了各种含 DTG 方案的基因型敏感性评分。

结果

评估了 650 名中位年龄为 14 岁（IQR 10-17 岁）的个体的基因型。失败于基于蛋白酶抑制剂（PI）的方案的个体比例高于基于非核苷类逆转录酶抑制剂（NNRTI）的方案（分别为 78.3%和 21.7%）。在 AZT 组（n=288；94.4%）中，大多数个体失败于基于 PI 的方案，而在 TDF（n=69）和 ABC 组（n=293）中，这一比例分别为 71.0%和 64.2%。在暴露于 ABC 和 AZT 的个体中，观察到对 TLD 的基因型敏感性评分<2 的比例分别为 8.5%和 9.4%，而在 TDF 组中为 23.2%。M184V 突变最常发生在 ABC 组（70.6%），而在 TDF 和 AZT 组中分别为 60.0%和 52.4%。K65R 的存在很少见（n=13，2.0%），且 TLD 敏感性降低通常是由于核苷逆转录酶抑制剂（NRTI）突变的积累引起的。

结论

对 TDF 的交叉耐药性有限，进一步降低了对儿童和青少年使用 TLD 过渡方案的担忧。随后的 NADIA 试验表明，失败于 TDF/3TC/EFV 方案的患者可以安全地转换为 TLD 方案，但我们没有失败于 ABC/3TC/NNRTI 或 PI 方案的患者的数据。建议在转换为 DTG 后进行频繁的病毒学监测，尤其是在继续使用 ABC 作为骨干药物的儿童中。需要进行临床研究，将预测的耐药性与临床结果相关联，特别是在没有基因分型的情况下。