Sebastião Cruz S, Bathy Jamila, Nhampossa Tacilta, Santos André, Miranda Mafalda, Manhiça Neusa Magode, Bila Rubão, Vubil Delfino, Seabra Sofia, O Martins Maria Rosário, Giovanetti Marta, Gomes Perpetua, Pingarilho Marta, Abecasis Ana B, Pimentel Victor
Global Health and Tropical Medicine (GHTM), Associate Laboratory in Translation and Innovation Towards Global Health (LA-REAL), Instituto de Higiene e Medicina Tropical (IHMT), Universidade NOVA de Lisboa (UNL), Lisboa, Portugal.
Centro Nacional de Investigação Científica (CNIC), Luanda, Angola.
J Med Virol. 2025 Mar;97(3):e70317. doi: 10.1002/jmv.70317.
Multidrug-resistant HIV patients have limited ART options. Lenacapavir (LEN) is a capsid inhibitor that exhibits substantial antiviral activity in patients with therapeutic failure but is also proposed for PrEP. Herein, we assessed LEN susceptibility among ART-naive HIV patients with drug resistance in Mozambique. In this study, 63 patients with DRM against PIs, NRTIs, NNRTIs, and INSTIs were included. The gag (p24) and env fragments were amplified with a low-cost in-house protocol and sequenced with nanopore. HIVDR database from Stanford University was used to assess LEN resistance and geno2pheno to assess viral tropism and protease/maturation inhibitor-associated mutations. A total of 59 patients were successfully sequenced. About 29% had DRMs to PIs, 5% to NRTI, 83% to NNRTI, and 2% to INSTI. No DRMs to LEN were detected. Additionally, 42% of the sequences presented protease/maturation inhibitor-associated mutations. A relationship was observed between the E138A/G mutation and protease/maturation inhibitors (p = 0.004). We identified changes at the first codon position of position 56 of the p24 gag gene, which represents a key site for resistance to LEN. Also, codon 66 was highly conserved. Our results support the potential effectiveness of lenacapavir as a PrEP regimen or rescue therapy for patients with at least one drug-resistance mutation.
多重耐药的HIV患者的抗逆转录病毒治疗（ART）选择有限。来那卡韦（LEN）是一种衣壳抑制剂，在治疗失败的患者中表现出显著的抗病毒活性，同时也被提议用于暴露前预防（PrEP）。在此，我们评估了莫桑比克未接受过ART治疗但具有耐药性的HIV患者对来那卡韦的敏感性。在这项研究中，纳入了63例对蛋白酶抑制剂（PIs）、核苷类逆转录酶抑制剂（NRTIs）、非核苷类逆转录酶抑制剂（NNRTIs）和整合酶链转移抑制剂（INSTIs）具有耐药相关突变（DRM）的患者。通过一种低成本的内部方案扩增gag（p24）和env片段，并使用纳米孔进行测序。使用斯坦福大学的HIVDR数据库评估来那卡韦耐药性，使用geno2pheno评估病毒嗜性和蛋白酶/成熟抑制剂相关突变。共有59例患者成功测序。约29%的患者对PIs有DRM，5%对NRTI有DRM，83%对NNRTI有DRM，2%对INSTI有DRM。未检测到来那卡韦的DRM。此外，42%的序列存在蛋白酶/成熟抑制剂相关突变。观察到E138A/G突变与蛋白酶/成熟抑制剂之间存在关联（p = 0.004）。我们在p24 gag基因第56位的第一个密码子位置发现了变化，这是对来那卡韦耐药的关键位点。此外，第66位密码子高度保守。我们的结果支持来那卡韦作为PrEP方案或对至少有一种耐药突变患者的挽救治疗的潜在有效性。
