Unexpected interactions between dolutegravir and folate: randomized trial evidence from South Africa.
Unexpected interactions between dolutegravir and folate: randomized trial evidence from South Africa.
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DOI：
10.1097/qad.0000000000002741
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发表时间：
2021-02-02
期刊：
影响因子：
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通讯作者：
Moorhouse MA
中科院分区：
文献类型：
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作者：
Chandiwana NC;Chersich M;Venter WDF;Akpomiemie G;Hill A;Simmons B;Lockman S;Serenata CM;Fairlie L;Moorhouse MA
怀孕时暴露于Dolutegravir与婴儿神经管缺陷风险增加的初步信号相关。由于母体叶酸水平低与神经管缺陷有关，我们旨在评估开始度鲁特韦治疗的妇女的血清叶酸浓度。我们分析了南非ADVANCE试验中登记的女性储存血浆中的血清叶酸浓度。我们比较了研究组间在第0、12和24周时平均血清叶酸的变化和低血清叶酸（<14.0 nmol/l）的发生率。 在ADVANCE中，1053例初治受试者随机接受替诺福韦-艾拉酚胺/恩曲他滨+度鲁特韦（TAF/FTC + DTG）、替诺福韦-富马酸二异丙酯（TDF）/FTC + DTG或TDF/FTC/依法韦仑（EFV）治疗。 分析包括406名女性，平均年龄31.5岁，基线CD 4+细胞计数356个细胞/μl。基线时，各治疗组的叶酸浓度相似。然而，TAF/FTC + DTG组的血清叶酸在12周内增加（+4.0 ± 8.1 nmol/l），而TDF/FTC + DTG组的叶酸浓度略有下降（−1.8 ± 8.9 nmol/l），TDF/FTC/EFV组下降（−5.9 ± 8.1 nmol/l）。 服用TDF/FTC/EFV的妇女在12周和24周时的叶酸浓度均低于其他组（P <0.001）。 在26名在研究第24周前怀孕的女性中，TAF/FTC+DTG组和TDF/FTC + DTG组的叶酸浓度在基线和第12周之间平均增加了2.4± 7.1 nmol/l， TDF/FTC + DTG组为2.3± 8.4 nmol/l，但TDF/FTC/EFV组下降了-3.3 ±8.1 nmol/l。出乎意料的是，在含度鲁特韦组中没有观察到下降，并且浓度显著高于EFV组。度鲁特韦可能阻断细胞摄取叶酸的可能性值得研究。
Dolutegravir exposure at conception was associated with a preliminary signal of increased infant neural tube defect risk. As low maternal folate levels are linked with neural tube defects, we aimed to assess serum folate concentrations in women starting dolutegravir. We analysed serum folate concentrations from stored plasma among women enrolled in the South African ADVANCE trial. We compared changes in mean serum folate and occurrence of low serum folate (<14.0 nmol/l) at weeks 0, 12 and 24 across study arms. In ADVANCE, 1053 treatment-naïve participants were randomized to initiate tenofovir–alafenamide/emtricitabine + dolutegravir (TAF/FTC + DTG), tenofovir–disoproxil–fumarate (TDF)/FTC + DTG or TDF/FTC/efavirenz (EFV). Analysis includes 406 females, mean age 31.5 years and baseline CD4+ cell count 356 cells/μl. At baseline, folate concentrations were similar across treatment arms. However, serum folate increased over 12 weeks in the TAF/FTC + DTG arm (+4.0 ± 8.1 nmol/l), while folate concentrations decreased slightly in the TDF/FTC + DTG arm (−1.8 ± 8.9 nmol/l) and decreased in the TDF/FTC/EFV arm (−5.9 ± 8.1 nmol/l). Women taking TDF/FTC/EFV had low folate concentrations at both 12 and 24 weeks compared with the other arms (P < 0.001). Of 26 women who became pregnant on study before week 24, folate concentrations increased between baseline and 12 weeks by a mean 2.4 ± 7.1 nmol/l in the TAF/FTC + DTG arm and 2.3 ± 8.4 nmol/l in the TDF/FTC + DTG arm, but decreased by −3.3 ± 8.1 with TDF/FTC/EFV arm. Unexpectedly, no declines were noted in the dolutegravir-containing arms, and concentrations were considerably higher than in the EFV arm. The possibility that dolutegravir may block cellular uptake of folate warrants investigation.