Federal University of São Paulo, São Paulo, Brazil.
Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
BMC Infect Dis. 2023 May 24;23(1):347. doi: 10.1186/s12879-023-08288-8.
BACKGROUND: Since January 2017, the recommended first-line antiretroviral regimen in Brazil is the fixed-dose combination of tenofovir plus lamivudine with dolutegravir (TL + D). According to the literature, integrase resistance-associated mutations (INRAMs) are rarely found upon virologic failure to first-line dolutegravir plus two nucleoside reverse transcriptase inhibitors. We evaluated the HIV antiretroviral genotypic resistance profile of patients referred for genotyping in the public health system who failed first-line TL + D after at least six months of therapy on or before December 31, 2018. METHODS: HIV Sanger sequences of the pol gene were generated from plasma of patients with confirmed virologic failure to first-line TL + D in the Brazilian public health system before December 31, 2018. RESULTS: One hundred thirteen individuals were included in the analysis. Major INRAMs were detected in seven patients (6.19%), four with R263K, one with G118R, one with E138A, and one with G140R. Four patients with major INRAMs also had the K70E and M184V mutations in the RT gene. Sixteen (14.2%) additional individuals presented minor INRAMs, and five (4,42%) patients had both major and minor INRAMS. Thirteen (11.5%) patients also presented mutations in the RT gene selected by tenofovir and lamivudine, including four with both the K70E and M184V mutations and four with only M184V. The integrase mutations L101I and T124A, which are in the in vitro pathway for integrase inhibitor resistance, were found in 48 and 19 patients, respectively. Mutations not related to TL + D, thus probable transmitted resistance mutations (TDR), were present in 28 patients (24.8%): 25 (22.1%) to nucleoside reverse transcriptase inhibitors, 19 (16.8%) to non-nucleoside reverse transcriptase inhibitors, and 6 (5.31%) to protease inhibitors. CONCLUSIONS: In marked contrast to previous reports, we report a relatively high frequency of INRAMs among selected patients failing first-line TL + D in the public health system in Brazil. Possible reasons for this discrepancy include delays in detecting virologic failure, patients inadvertently on dolutegravir monotherapy, TDR, and/or infecting subtype.
背景：自 2017 年 1 月以来，巴西推荐的一线抗逆转录病毒治疗方案是替诺福韦和拉米夫定加度鲁特韦的固定剂量组合（TL+D）。根据文献，在最初的一线多替拉韦加两种核苷逆转录酶抑制剂治疗失败后，很少发现整合酶耐药相关突变（INRAMs）。我们评估了在 2018 年 12 月 31 日或之前接受至少六个月治疗的公共卫生系统中，因一线 TL+D 治疗失败而转介进行基因分型的患者的 HIV 抗逆转录病毒基因耐药谱。
方法：从 2018 年 12 月 31 日之前在巴西公共卫生系统中因一线 TL+D 治疗失败而确诊的患者的血浆中生成 HIV Sanger 序列的 pol 基因。
结果：113 名患者纳入分析。在 7 名患者（6.19%）中检测到主要的 INRAMs，其中 4 名患者有 R263K，1 名患者有 G118R，1 名患者有 E138A，1 名患者有 G140R。4 名有主要 INRAMs 的患者在 RT 基因中也有 K70E 和 M184V 突变。另外 16 名（14.2%）患者出现了次要的 INRAMs，5 名（4.42%）患者同时存在主要和次要的 INRAMs。13 名（11.5%）患者还出现了替诺福韦和拉米夫定选择的 RT 基因的突变，其中 4 名患者同时存在 K70E 和 M184V 突变，4 名患者仅存在 M184V 突变。体外整合酶抑制剂耐药途径中的整合酶突变 L101I 和 T124A 分别在 48 名和 19 名患者中发现。与 TL+D 无关的突变，因此可能是传播耐药突变（TDR），在 28 名患者中存在（24.8%）：25 名（22.1%）对核苷逆转录酶抑制剂，19 名（16.8%）对非核苷逆转录酶抑制剂，6 名（5.31%）对蛋白酶抑制剂。
结论：与之前的报告相比，我们报告了在巴西公共卫生系统中，一线 TL+D 治疗失败的患者中 INRAMs 的相对较高频率。这种差异的可能原因包括检测病毒学失败的延迟、患者无意中接受多替拉韦单药治疗、TDR 和/或感染亚型。
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