Nka Alex Durand, Bouba Yagai, Tsapi Lontsi Wilfried Rooker, Gouissi Anguechia Davy-Hyacinte, Teto Georges, Ka'e Aude Christelle, Semengue Ezechiel Ngoufack Jagni, Ambe Chenwi Collins, Takou Désiré, Forgwei Lum, Tekoh Tatiana Anim-Keng, Ngueko Aurelie Minelle Kengni, Fokou Bernadette Bomgning, Efakika Gabisa Jeremiah, Tchouaket Michel Carlos Tommo, TognaPabo Willy Leroi, Ayuk Ngwese Derrick Tambe, Njiki Bikoi Jacky, Armenia Daniele, Colizzi Vittorio, Yotebieng Marcel, Ndembi Nicaise, Santoro Maria-Mercedes, Ceccherini-Silberstein Francesca, Perno Carlo-Federico, Ndjolo Alexis, Fokam Joseph
Chantal BIYA International Reference Centre for Research on HIV/AIDS Prevention and Management, Yaoundé P.O. Box 3077, Cameroon.
Faculty of Medicine, UniCamillus-Saint Camillus International University of Health Sciences, 00131 Rome, Italy.
Viruses. 2025 Jan 6;17(1):69. doi: 10.3390/v17010069.
Islatravir (ISL) is a novel antiretroviral that inhibits HIV-1 reverse transcriptase translocation. The M184V mutation, known to reduce ISL's viral susceptibility in vitro, could arise from prolonged exposure to nucleoside reverse transcriptase inhibitors (NRTI) (3TC). This study evaluated the predictive efficacy of ISL and identified potentially active antiretrovirals in combination among treatment-experienced patients in Cameroon, where NRTIs (3TC) have been the backbone of ART for decades now. Although ISL is a long-acting antiretroviral, it will provide other therapeutic options in combination with other reverse transcriptase inhibitors that remain effective. We analyzed 1170 HIV-1 sequences from patients failing first-, second-, and third-line ART using the CIRCB Antiviral Resistance Evaluation (CIRCB-CARE) database. Drug resistance mutations (DRMs) were interpreted using Stanford HIVdb.v9, and covariation patterns between M184V and major NRTI/NNRTI DRMs were assessed. The study population, with a median age of 40 years, showed a high prevalence of resistance to NRTIs (77.4%) and NNRTIs (49.2%). The most frequent NRTI DRMs were M184V/I (83.3%), M41L (25.0%), and T215FY (36.8%), while common NNRTI DRMs included K103NS (53.3%), Y181CIV (27.7%), and G190ASE (22.2%). In first-line ART failure, M184V significantly covaried with K70R, L74I, and M41L for NRTIs and K103N and G190A for NNRTIs. In second-line failure, the covariation with M184V extended to T215Y, M41L, and D67N for NRTIs and G190A, K103N, and K103S for NNRTIs. No significant covariation with M184V was observed in third-line treatment failures. Based on these covariations and on the effect of these mutations on available anti-HIV drugs, TDF (partial efficacy) and Doravirine (fully active) were identified as potentially suitable candidates in combination with ISL among patients failing the first, second, and third lines, and could serve as a valuable therapeutic option in LMICs facing similar treatment challenges.
依斯拉曲韦（ISL）是一种新型抗逆转录病毒药物，可抑制HIV-1逆转录酶易位。已知M184V突变会在体外降低ISL对病毒的敏感性，它可能源于长期暴露于核苷类逆转录酶抑制剂（NRTI）（拉米夫定[3TC]）。本研究评估了ISL的预测疗效，并在喀麦隆接受过治疗的患者中确定了联合使用时可能具有活性的抗逆转录病毒药物，在喀麦隆，NRTI（3TC）几十年来一直是抗逆转录病毒治疗（ART）的主要药物。尽管ISL是一种长效抗逆转录病毒药物，但它与其他仍然有效的逆转录酶抑制剂联合使用时将提供其他治疗选择。我们使用CIRCB抗病毒耐药性评估（CIRCB-CARE）数据库分析了1170例一线、二线和三线ART治疗失败患者的HIV-1序列。使用斯坦福HIVdb.v9解释耐药性突变（DRM），并评估M184V与主要NRTI/非核苷类逆转录酶抑制剂（NNRTI）DRM之间的共变模式。研究人群的中位年龄为40岁，对NRTI（77.4%）和NNRTI（49.2%）的耐药率较高。最常见的NRTI DRM为M184V/I（83.3%）、M41L（25.0%）和T215FY（36.8%），而常见的NNRTI DRM包括K103NS（53.3%）、Y181CIV（27.7%）和G190ASE（22.2%）。在一线ART治疗失败中，M184V与NRTI的K70R、L74I和M41L以及NNRTI的K103N和G190A显著共变。在二线治疗失败中，与M184V的共变扩展到NRTI的T215Y、M41L和D67N以及NNRTI的G190A、K103N和K103S。在三线治疗失败中未观察到与M184V的显著共变。基于这些共变以及这些突变对现有抗HIV药物的影响，替诺福韦酯（部分疗效）和多拉韦林（完全活性）被确定为一线、二线和三线治疗失败患者中与ISL联合使用时可能合适的候选药物，并且可以作为面临类似治疗挑战的低收入和中等收入国家的一种有价值的治疗选择。
