University of Pittsburgh, Pittsburgh, Pennsylvania.
VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania.
JAMA. 2020 Apr 14;323(14):1378-1387. doi: 10.1001/jama.2020.3138.
Despite the use of a cytomegalovirus (CMV) prevention strategy of antiviral prophylaxis for high-risk CMV-seronegative liver transplant recipients with seropositive donors, high rates of delayed-onset postprophylaxis CMV disease occur. An alternate approach, preemptive therapy (initiation of antiviral therapy for early asymptomatic CMV viremia detected by surveillance testing), has not previously been directly compared with antiviral prophylaxis in these patients.
To compare preemptive therapy with antiviral prophylaxis in CMV-seronegative liver transplant recipients with seropositive donors for the prevention of CMV disease.
DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial of preemptive therapy vs antiviral prophylaxis in 205 CMV-seronegative liver transplant recipients with seropositive donors aged older than 18 years. The trial was conducted at 6 academic transplant centers in the United States between October 2012 and June 2017, with last follow-up in June 2018.
Patients were randomized 1:1 to receive either preemptive therapy (valganciclovir, 900 mg, twice daily until 2 consecutive negative tests a week apart) for viremia detected by weekly plasma CMV polymerase chain reaction for 100 days (n = 100) or valganciclovir, 900 mg, daily for 100 days as antiviral prophylaxis (n = 105).
The primary outcome was incidence of CMV disease by 12 months, defined as CMV syndrome (CMV viremia and clinical or laboratory findings) or end-organ disease. Secondary outcomes included acute allograft rejection, opportunistic infections, graft and patient survival, and neutropenia.
Among 205 patients who were randomized (mean age, 55 years; 62 women [30%]), all 205 (100%) completed the trial. The incidence of CMV disease was significantly lower with preemptive therapy than antiviral prophylaxis (9% [9/100] vs 19% [20/105]; difference, 10% [95% CI, 0.5% to 19.6%]; P = .04]). The incidence of allograft rejection (28% vs 25%; difference, 3% [95% CI, -9% to 15%]), opportunistic infections (25% vs 27%; difference, 2% [95% CI, -14% to 10%]), graft loss (2% vs 2%; difference, <1% [95% CI, -4% to 4%]), and neutropenia (13% vs 10%; difference, 3% [95% CI, -5% to 12%]) did not differ significantly for the preemptive therapy vs antiviral prophylaxis group, respectively. All-cause mortality at last follow-up was 15% in the preemptive therapy vs 19% in the antiviral prophylaxis group (difference, 4% [95% CI, -14% to 6%]; P = .46).
Among CMV-seronegative liver transplant recipients with seropositive donors, the use of preemptive therapy, compared with antiviral prophylaxis, resulted in a lower incidence of CMV disease over 12 months. Further research is needed to replicate these findings and assess long-term outcomes.
ClinicalTrials.gov Identifier: NCT01552369.
尽管采用了抗病毒预防策略来预防高风险 CMV 血清阴性的肝移植受者与 CMV 血清阳性供体发生 CMV 疾病，但仍会发生高比率的延迟发作的预防后 CMV 疾病。另一种方法是抢先治疗（在通过监测检测到早期无症状 CMV 病毒血症时开始抗病毒治疗），但以前并未在这些患者中直接与抗病毒预防进行比较。
比较抢先治疗与抗病毒预防在 CMV 血清阴性的肝移植受者与 CMV 血清阳性供体中的应用，以预防 CMV 疾病。
设计、地点和参与者：在 2012 年 10 月至 2017 年 6 月期间，在美国 6 个学术移植中心进行了一项关于抢先治疗与抗病毒预防的 205 例 CMV 血清阴性的肝移植受者与 CMV 血清阳性供体的随机临床试验，最后一次随访时间为 2018 年 6 月。
患者被随机分为 1:1 接受抢先治疗（缬更昔洛韦，900mg，每日两次，直到每周间隔 2 次连续阴性检测）或抗病毒预防（缬更昔洛韦，900mg，每日一次）100 天。抢先治疗组（n=100）通过每周一次的血浆 CMV 聚合酶链反应检测病毒血症，100 天内进行抢先治疗；抗病毒预防组（n=105）。
主要结局是 12 个月内发生 CMV 疾病的发生率，定义为 CMV 综合征（CMV 病毒血症和临床或实验室发现）或终末器官疾病。次要结局包括急性移植物排斥反应、机会性感染、移植物和患者存活率以及中性粒细胞减少症。
在 205 例随机分组的患者中（平均年龄 55 岁；62 例女性[30%]），所有 205 例（100%）均完成了试验。抢先治疗组的 CMV 疾病发生率明显低于抗病毒预防组（9%[9/100]与 19%[20/105]；差异为 10%[95%CI，0.5%至 19.6%]；P=0.04]）。移植物排斥反应（28%与 25%；差异，3%[95%CI，-9%至 15%]）、机会性感染（25%与 27%；差异，2%[95%CI，-14%至 10%]）、移植物丢失（2%与 2%；差异，<1%[95%CI，-4%至 4%]）和中性粒细胞减少症（13%与 10%；差异，3%[95%CI，-5%至 12%]）在抢先治疗组与抗病毒预防组之间无显著差异。最后一次随访时的全因死亡率在抢先治疗组为 15%，在抗病毒预防组为 19%（差异为 4%[95%CI，-14%至 6%]；P=0.46）。
在 CMV 血清阴性的肝移植受者与 CMV 血清阳性供体中，与抗病毒预防相比，抢先治疗在 12 个月内导致 CMV 疾病的发生率降低。需要进一步研究来复制这些发现并评估长期结果。
ClinicalTrials.gov 标识符：NCT01552369。
