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Evidence summaries

Cytomegalovirus Prophylaxis with Antiviral Agents for Solid Organ Transplantation

Prophylaxis with antiviral medications reduces cytomegalovirus (CMV) disease and CMV-associated mortality in solid organ transplant recipients. Level of evidence: "A"

A Cochrane review [Abstract] 1 included 37 studies with a total of 4 342 subjects. Prophylaxis with aciclovir, ganciclovir or valaciclovir compared with placebo or no treatment significantly reduced the risk for CMV disease (19 trials; RR 0.42, 95% CI 0.34 to 0.52), CMV infection (17 trials; RR 0.61, 95% CI 0.48 to 0.77), and all-cause mortality (17 trials; RR 0.63, 95% CI 0.43 to 0.92) primarily due to reduced mortality from CMV disease (7 trials; RR 0.26, 95% CI 0.08 to 0.78). Prophylaxis reduced the risk of herpes simplex and herpes zoster disease, and bacterial and protozoal infections. Prophylaxis did not reduce fungal infection, acute rejection or graft loss. There was no significant difference in the risk of CMV disease or all-cause mortality by organ transplanted or CMV serostatus.

Neurological dysfunction was more common with ganciclovir and valaciclovir compared with placebo/no treatment. In direct comparison trials, ganciclovir was more effective than aciclovir in preventing CMV disease (7 trials; RR 0.37, 95% Cl 0.23 to 0.60), and leucopenia was more common with aciclovir. Valganciclovir and intravenous ganciclovir were as effective as oral ganciclovir. The efficacy and adverse effects of valganciclovir/ganciclovir did not differ from valaciclovir in three small studies. Extended duration prophylaxis significantly reduced the risk of CMV disease compared with 3 months therapy (RR 0.20, 95% CI 0.12 to 0.35; 2 trials).

Several retrospective analyses compared low-dose versus high-dose valganciclovir (VGCV) for prevention of cytomegalovirus disease:

In a multicenter analysis 2 478 adult renal transplant recipients received VGCV 450 mg/day (n=398) or 900 mg/day (n=89) for 3 months. All VGCV was adjusted for renal function. All participiants received study-approved induction and maintenance immunosuppression regimens. The primary endpoint was incidence of CMV disease at 12 months and it was similar between the groups (3.5% vs 3.4%; P=1.000).

Another analysis 3 included 606 kidney transplant recipients induced with alemtuzumab. VGCV prophylaxis was stratified by recipient CMV risk status and low-dose (450mg) VGCV was given 3 times a week to low and moderate risk patients and daily to high risk individuals. Subject records were examined for recipient demographics, donor and recipient CMV serostatus, CMV viremia, and invasive infection.154 were defined as low risk for CMV infection (donor and recipient both negative, or D-/R-), 236 as moderate risk without mismatch (D+/R+), 122 as moderate risk with mismatch (D-/R+), and 94 as high risk (D+/R-). 29 individuals (4.8%) tested positive by PCR for CMV viremia and 10 (1.7%) patients developed invasive CMV disease, including colitis, esophagitis, enteritis, nephritis, and pneumonia (of which 5 were high risk and 4 moderate risk recipients). Overall rejection rate was 27%.CMV incidence was reduced compared to historically reported data by using low-dose (450mg) VGCV prophylaxis.

In a third study 4 VGCV was given for 6 months in CMV recipient seropositive (R+) lung transplantation recipients and given long-term in D+R- recipients. Of 137 recipients, 22 were D+R-, 49 D+R+, 43 D-R+, and 23 D-R-, with median follow up 4.1 years. CMV viremia at any time occurred in 44.5% of patients. CMV disease occurred in 6 (4.4%) recipients at an overall rate of 1.0 episode per 100 person-years (2 organ-specific disease, 4 CMV syndrome). One case of ganciclovir-resistant CMV was diagnosed. D+R+ and D+R- patients had higher viremia rates than the D-R+ group. Prophylaxis for 6 months in D+R+ and D-R+, and past 12 months in D+R- lung transplantation recipients, was effective at markedly reducing the incidence of CMV disease.

Yet another retrospective study 5 analyzed 364 liver transplantation recipients over a 4-year period. Adult first-time R+ recipients receiving low-dose VGCV prophylaxis were included (n=200). The primary endpoint was CMV disease at 1 year after transplant. Patients were compared with historical controls receiving high-dose VGCV prophylaxis. CMV disease occurred in only 9 (5%) patients, similar to rates in previous studies of patients receiving high-dose VGCV. Biopsy-proven rejection occurred in 18 (9%) patients. Patients received VGCV prophylaxis for a median of 3.4 months; 151 (76%) R+ LTRs receiving low-dose VGCV developed leukopenia. Premature VGCV discontinuation and granulocyte-colony stimulating factor use were infrequent and not significantly different between the 2 groups.

A retrospective analysis 6 on lung transplant recipients (n=103) assessed intermediate-risk patients that received either valganciclovir 450 mg per day (low) or 900 mg/day (high). All patients were followed for 1 year post-transplant for incidence of CMV viremia. In the low valganciclovir group, 16.4% developed CMV viremia compared to 8.3% in the high valganciclovir group (p=0.221) with no difference observed in adverse event rates between groups.

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    References

    • Hodson EM, Ladhani M, Webster AC et al. Antiviral medications for preventing cytomegalovirus disease in solid organ transplant recipients. Cochrane Database Syst Rev 2013;(2):CD003774. [PubMed]
    • Heldenbrand S, Li C, Cross RP et al. Multicenter evaluation of efficacy and safety of low-dose versus high-dose valganciclovir for prevention of cytomegalovirus disease in donor and recipient positive (D+/R+) renal transplant recipients. Transpl Infect Dis 2016;18(6):904-912. [PubMed]
    • Korneffel K, Mitro G, Buschor K et al. Low dose valganciclovir as cytomegalovirus prophylaxis in post-renal transplant recipients induced with alemtuzumab: A single-center study. Transpl Immunol 2019;56():101226. [PubMed]
    • Chang A, Musk M, Lavender M et al. Cytomegalovirus viremia in lung transplantation during and after prophylaxis. Transpl Infect Dis 2019;21(3):e13069. [PubMed]
    • Khan S, Sullivan T, Ali M et al. Low-dose valganciclovir for cytomegalovirus prophylaxis in intermediate-risk liver transplantation recipients. Liver Transpl 2018;24(5):616-622. [PubMed]
    • Hunt J, Chapple KM, Nasar A et al. Efficacy of low-dose valganciclovir in CMV R+ lung transplant recipients: a retrospective comparative analysis. Multidiscip Respir Med 2021;16(1):706.[PubMed]

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