Häggblom Amanda, Svedhem Veronica, Singh Kamalendra, Sönnerborg Anders, Neogi Ujjwal
Unit of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden; Department of Infectious Diseases, County Council of Gävleborg, Gävle, Sweden.
Unit of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
Lancet HIV. 2016 Apr;3(4):e166-74. doi: 10.1016/S2352-3018(16)00023-0. Epub 2016 Mar 14.
People with HIV-1 in low-income and middle-income countries increasingly need second-line regimens with boosted protease inhibitors. However, data are scarce for treatment response in patients with HIV-1 subtype C (HIV-1C), which is predominant in these regions. We aimed to examine factors associated with virological failure in patients in a standardised national health-care setting.
We analysed data for participants in InfCare HIV, a prospective national cohort that includes more than 99% of people with HIV in Sweden. We extracted data for the cohort from the InfCare HIV database on Jan 14, 2015. Baseline was initiation of antiretroviral therapy. We used logistic regression to assess factors associated with primary virological failure (failure to suppress HIV-1 within 9 months) in patients with HIV-1B and HIV-1C and calculated odds ratios (OR) for failure. We also used Cox regression models to calculate hazard ratios (HR) for time-to-secondary virological failure (detectable viral load after initial virological suppression). We did homology-based molecular modelling to assess docking.
We included 1077 patients with HIV-1B and 596 with HIV-1C. In multivariate regression analysis, pre-therapy higher viral load (OR 1·82, 95% CI 1·49-2·21; p<0·0001), subtype C infection (1·75, 1·06-2·88; p=0·028), and boosted protease inhibitor-based regimens (1·55, 1·45-2·11; p=0·004) were associated with increased risk of primary virological failure. Individuals with HIV-1C who were given therapy with boosted protease inhibitors had earlier time-to-secondary virological failure than did those with HIV-1B given similar regimens (adjusted HR 1·92, 95% CI 1·30-2·83; p=0·002). Molecular modelling suggested lower affinity for protease inhibitors to HIV-1C protease than to HIV-1B.
Our findings suggest an increased risk of virological failure in patients with HIV-1C, especially in those on boosted protease inhibitor-based regimens. Future studies should further dissect the biochemical and viral mechanisms of resistance to protease inhibitors in patients with non-B subtypes of HIV-1, including clinical studies to assess the efficacy of boosted protease inhibitor-based regimens in low-income and middle income countries.
Karolinska Institutet Research Foundation, Swedish Research Council, Stockholm County Council, Swedish Physicians against AIDS, US National Institutes of Health, University of Missouri.
在低收入和中等收入国家，感染人类免疫缺陷病毒1型（HIV-1）的人群越来越需要使用增效蛋白酶抑制剂的二线治疗方案。然而，在这些地区占主导地位的HIV-1 C亚型患者中，关于治疗反应的数据却很少。我们旨在研究在标准化国家医疗保健环境中，与病毒学失败相关的因素。
我们分析了InfCare HIV研究参与者的数据，这是一项全国性前瞻性队列研究，纳入了瑞典超过99%的HIV感染者。我们于2015年1月14日从InfCare HIV数据库中提取了该队列的数据。基线为开始抗逆转录病毒治疗。我们使用逻辑回归评估HIV-1 B型和HIV-1 C型患者中与原发性病毒学失败（9个月内未能抑制HIV-1）相关的因素，并计算失败的比值比（OR）。我们还使用Cox回归模型计算继发病毒学失败时间（初始病毒学抑制后可检测到病毒载量）的风险比（HR）。我们进行了基于同源性的分子建模以评估对接情况。
我们纳入了1077例HIV-1 B型患者和596例HIV-1 C型患者。在多变量回归分析中，治疗前较高的病毒载量（OR 1.82，95%CI 1.49 - 2.21；p<0.0001）、C亚型感染（1.75，1.06 - 2.88；p = 0.028）以及基于增效蛋白酶抑制剂的治疗方案（1.55，1.45 - 2.11；p = 0.004）与原发性病毒学失败风险增加相关。接受增效蛋白酶抑制剂治疗的HIV-1 C型个体继发病毒学失败的时间比接受类似方案的HIV-1 B型个体更早（调整后HR 1.92，95%CI 1.30 - 2.83；p = 0.002）。分子建模表明，蛋白酶抑制剂对HIV-1 C蛋白酶的亲和力低于对HIV-1 B蛋白酶的亲和力。
我们的研究结果表明，HIV-1 C型患者病毒学失败的风险增加，尤其是那些接受基于增效蛋白酶抑制剂方案治疗的患者。未来的研究应进一步剖析HIV-1非B亚型患者对蛋白酶抑制剂耐药的生化和病毒机制，包括评估基于增效蛋白酶抑制剂方案在低收入和中等收入国家疗效的临床研究。
卡罗琳斯卡学院研究基金会、瑞典研究理事会、斯德哥尔摩郡议会、瑞典医师防治艾滋病协会、美国国立卫生研究院、密苏里大学。
