Primary prevention
Prevention of primary cytomegalovirus (CMV) infection in pregnant women is encouraged through good hand hygiene methods. CDC: CMV and congenital CMV infection Opens in new window[30]
Vaccination is still in the investigational stage for the prevention of CMV disease. CMV-seronegative transplant recipients requiring blood transfusion should receive blood from CMV-seronegative donors. This is not logistically possible in all instances due to the scarcity of CMV-seronegative blood donors. If this is not available, use of leuko-reduced irradiated blood products is recommended. This reduces the incidence of CMV transmission to about 1%.[31]
In patients with HIV infection, use of antiretroviral therapy to keep the CD4+ cell count above 100 cells/microlitre is the recommended approach to prevent CMV end-organ disease.[2][32]
Secondary prevention
Antiviral prophylaxis:
This method entails the administration of oral antiviral drugs, such as valganciclovir or letermovir, to all patients at risk of cytomegalovirus (CMV) disease. Typically, this would include: all donor CMV-seropositive, recipient seronegative (CMV D+/R-) solid organ transplant recipients; CMV recipient seropositive (CMV R+) lung transplant recipients; and all transplant patients receiving lymphocyte-depleting agents for the treatment of rejection. Studies have demonstrated that antiviral prophylaxis reduces not only the incidence of CMV disease, but also all-cause mortality after organ transplantation.[78] It has also been used in CMV-seropositive AIDS patients with CD4 T-cell count of <50 cells/microlitre.[79][80] However, antiretroviral therapy (ART) is generally the preferred management option in order to improve CD4 count in patients with HIV who are severely immunocompromised.[2][32] Pill burden and additional medication side effects are important considerations when considering adding further prophylactic therapy for these patients.
Letermovir, an oral antiviral agent that targets the CMV DNA terminase complex has been adopted as the drug of choice for antiviral prophylaxis in haematopoietic stem cell transplant recipients at high risk for CMV replication, such as mismatched or unrelated donors, cord blood transplantation, or presence of graft-versus-host disease.[81] Letermovir is approved in the US and Europe for the prophylaxis of CMV infection/disease in adult CMV-seropositive recipients (CMV R+) of an allogeneic haematopoietic stem cell transplant. In a randomised controlled trial in haematopoietic stem cell transplant recipients, letermovir administered for 14 weeks significantly reduced the incidence of CMV infection at week 24 post-transplant, compared with placebo (37% vs. 61%, respectively; P <0.001).[81] Of note, CMV low level replication is common in HCT recipients receiving letermovir, although the clinical significance of this observation is not completely known.[82]
Letermovir is also approved in the US and Europe for the prophylaxis of CMV infection/disease in adult kidney transplant recipients who are at high risk (CMV D+/R-). In a randomised, double-masked trial comparing letermovir with valganciclovir in CMV-seronegative adults who received an organ from a CMV-seropositive kidney transplant donor, letermovir was non-inferior to valganciclovir for the prevention of CMV disease for 52 weeks after transplant (10.4% vs. 11.8%) and had a lower rate of leukopenia or neutropenia. Letermovir resulted in lower prophylaxis discontinuation rates due to adverse events (4.1% vs. 13.5% for valganciclovir), and there were no instances of drug resistance among those treated.[83] Because of the high cost of the drug, there is some debate on whether letermovir should be used as the preferred drug for prophylaxis in this population, or only in case of valganciclovir toxicity.
Prevention of congenital infection by treating pregnant women with CMV infection is an area of ongoing investigation.[30] One prospective, randomised, controlled trial found that valaciclovir reduced vertical transmission of CMV compared with placebo when given to pregnant women with primary CMV infection, particularly for CMV acquired in the first trimester; however, more studies are needed to determine the effect of the timing and duration of treatment.[84] Additionally, a meta-analysis of individual patient data indicates that valaciclovir significantly lowers vertical CMV transmission for infections acquired periconceptionally and during the first trimester, also reducing neonatal infections and pregnancy terminations due to CMV. Its effectiveness is enhanced by early treatment initiation, with a minimal rate of severe side effects.[85] One study evaluating the efficacy of hyperimmunoglobulin given to pregnant women with primary CMV infection found it did not significantly decrease the rate of vertical transmission compared with the placebo.[86] Another randomised controlled trial evaluating hyperimmunoglobulin for preventing congenital CMV infection was stopped early for futility.[87]
Pre-emptive therapy:
This method entails the administration of antiviral drugs, often valganciclovir or intravenous ganciclovir, only to people with laboratory markers of asymptomatic viral replication. A major component of this strategy is a highly predictive and sensitive method for detection of CMV in the blood, such as nucleic acid testing (NAT) or an antigenaemia assay.[88][89][90] The duration of antiviral drug administration in these patients is guided by the results of CMV surveillance with NAT or antigenaemia. Generally, it is administered until 2 weeks after negative CMV NAT or antigenaemia assay. Pre-emptive therapy appears to be effective at preventing CMV disease compared with placebo or standard care, but there are limited studies to determine its effect relative to that of prophylaxis in solid organ transplant recipients.[91] While both antiviral prophylaxis and pre-emptive therapy are recommended for prevention of CMV in solid organ transplant recipients, one study comparing the two approaches in donor CMV seropositive, recipient seronegative (D+/R-) CMV liver transplant recipients found that pre-emptive therapy resulted in a lower incidence of CMV disease over 12 months; more studies are needed.[92]
Screening:
Routine testing for congenital CMV infection in the first 21 days of life is recommended for infants with vertically transmitted HIV. CMV testing is also recommended for all infants exposed to HIV in utero, since their HIV status will be indeterminate during the first three weeks of life when congenital CMV infection can be diagnosed. Data indicates that the prevalence of congenital CMV may be higher among infants exposed to HIV compared with those unexposed to HIV, and that rates of congenital CMV and HIV co-transmission as well as symptomatic congenital CMV infection are high among infants exposed to HIV.[32]
CMV antibody testing is recommended at aged 1 year (or at baseline evaluation if aged >1 year at initial presentation) and then annually for CMV-seronegative infants and children with HIV who are immunosuppressed (i.e., CD4 cell count <100 cells/microlitre or CD4 percentage <10%).[32]
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