Epidemiology, management, and burden of cytomegalovirus in solid organ transplant recipients in selected countries outside of Europe and North America: A systematic review

Cytomegalovirus (CMV) is a frequent infectious complication following solid organ transplantation (SOT). Considering significant differences in healthcare systems, a systematic review was conducted to describe the epidemiology, management, and burden of CMV post‐SOT in selected countries outside of Europe and North America.


INTRODUCTION
Human cytomegalovirus (CMV) is one of the most common causes of viral complications in solid organ transplant (SOT) recipients. 1 Despite the use of various preventive strategies against CMV, infection develops in 50%-75% of patients receiving lung or simultaneous heart and lung transplantation and is also common in patients who undergo liver (22%-29%), kidney (8%-32%), and heart transplantation (9%-23%). 2 While CMV infection is generally asymptomatic in healthy individuals, the uncontrolled replication of the virus has a significant impact on morbidity and mortality in immunocompromised patients such as SOT recipients. 2 A primary CMV infection or reactivation from a latent stage may lead to CMV disease-whereby the direct cytopathic effect of the virus can cause pneumonitis, retinitis, colitis, or hepatitis. 2 CMV infection is defined as the presence of viral replication detected through antigenemia assay (i.e., positive pp65 antigenemia) or molecular tests such as polymerase chain reaction (PCR). CMV disease is evidenced by the presence of clinical signs and symptoms attributable to CMV in patients with CMV infection. 3 Well-known deleterious indirect effects of CMV disease in SOT recipients include graft dysfunction or rejection, increased risk of opportunistic infections, and acceleration of coronary artery atherosclerosis. 2,4 Universal prophylaxis and preemptive therapy represent two distinct approaches to preventing CMV infection in SOT recipients.
Prophylaxis is the administration of antiviral agents in at-risk patients without any evidence of CMV infection or reactivation, while preemptive therapy is triggered by the early detection of active CMV infection-early detection is achieved through periodic blood CMV surveillance using pp65 antigenemia or quantitative PCR assays. Treatment is initiated only when a positive antigenemia is detected or when the viral load exceeds a predefined threshold. Prophylaxis and preemptive therapy are both effective in preventing CMV disease in SOT recipients, and there is no agreed-upon preferred strategy. 5 However, across countries and centers, factors that may trigger the use of prophylaxis include a seronegative recipient for CMV who receives an allograft from a CMV-seropositive donor (D+/R-) or the use of Tlymphocyte depletion therapy with antithymocyte globulin (ATG) or alemtuzumab in CMV-seropositive recipients. [6][7][8][9] Intravenous ganciclovir (GCV) or its valyl prodrug oral valganciclovir are the conventional first-line treatments for the management of CMV in transplant recipients. 10 There are however unmet needs with currently available therapies due to resistance and hematological tox-icity, which may negatively impact their benefit-risk balance. Thus, for patients who are intolerant to first-line treatment or who show resistance to GCV, second-line agents such as foscarnet or cidofovir can be administered. These second-line drugs are however known to be nephrotoxic. 11 Therapeutic strategies may therefore vary across countries depending on local clinical practices, clinical guidelines, and drug coverage restrictions. Furthermore, standard definitions for resistant and refractory CMV in transplant recipients were issued only in 2019, which may contribute to the variability of estimates obtained during earlier and later years. 12   Society. Finally, the lists of references of retained sources were also hand searched (referred to as snowballing).

Study selection and data extraction
Study selection and data extraction were conducted independently by two assessors (with conflicts resolved by a third assessor). Eligibility criteria for the selection of relevant sources were based on the PICOTS and are listed in Table S6. At stage 1, literature search outputs were screened based on titles and abstracts, and percent agreement between assessors was determined. A review of full-text articles was conducted at stage 2 to confirm the eligibility of sources retained after screening. Reasons for exclusion of sources at this stage were documented. For each retained study, information on methods, populations, and results were recorded in a data extraction form that was piloted prior to the start of extraction. There was no attempt to contact study authors for Supplementary Data.

Methodological quality assessment
The methodological quality of retained studies published as full-text articles was assessed using the Joanna Briggs Institute critical appraisal tools for observational studies. 17

Synthesis of findings
Synthesis of findings was qualitative and there was no attempt to pool results through a meta-analysis. When available, data are reported according to type of organ transplanted.

Search results
The flow of search results through the different stages of the selection process is presented in the PRISMA flow chart ( Figure 1). The litera-

Patient characteristics
The number of SOT recipients included across retained studies ranged between 18 in a single center study. 18 and 16 368 in a study conducted using health care databases. 19 The most frequent organ transplanted was the kidney (n = 34, 69.4%) and/or the liver (n = 10, 20.4%).
Most studies (n = 43, 87.8%) were conducted in adult patients, with a mean age between 24.0 and 57.2 years (26 studies) and a median age between 34 and 55 years (12 studies). In two studies conducted in pediatric patients, the median age at the time of kidney transplantation was 12 20 and 13 years. 6 In the 38 studies that reported the sex distribution of SOT recipients, males accounted for 43.3%-85.5% (Table   S9). Distribution of patients according to CMV serostatus was documented in less than half of the retained studies (n = 23 studies, 46.9%).

Prevention strategies for CMV infection and disease
In selected countries, there was no evidence of preference with regards to CMV preventive strategy. Prophylaxis was used in 45%-58. as acyclovir and its prodrug valacyclovir were also used to prevent the occurrence of CMV in Australia, 7 Brazil, 9 China, 49 Colombia, 43 Mexico, 20 and South Korea. 31 In adult and pediatric SOT recipients who developed CMV disease, intravenous GCV was found to be the preferred treatment, 21 and 24% 48 ). Data on the impact of these AEs on the management of patients were scarce. According to one study conducted in China, 11.1% of liver recipients who received GCV as prophylaxis discontinued treatment prematurely due to granulocytopenia. 49

Treatment of refractory and/or resistant CMV infection and CMV disease
Although a standardized definition of refractory and/or resistant CMV was published in 2019, 12 most studies included in the review were published in earlier years. Nevertheless, available data on refractory and/or resistant CMV were scarce. According to three studies conducted in Brazil, CMV resistance was reported in 0%, 33 3.1%, 22 and 4.4% 8 of adult (age ≥ 18 years) kidney recipients. The highest proportion (4.4%) was found in a cohort of high-risk patients (serostatus D+/R-). 8 For these patients, foscarnet or cidofovir was the preferred treatment. 59 However, owing to restricted access to these anti-CMV drugs in low to medium income countries, the use of high-dose GCV was also reported in Thailand. 18 The proportion of SOT recipients with refractory CMV in the countries covered by the review was not documented.

Burden of CMV infection and CMV disease in the SOT population
None of the studies included in the review examined the impact of CMV infection or disease on health-related quality of life and on longterm outcomes in SOT recipients-such as patient and graft survival, graft function and opportunistic infections. With regards to economic burden, the mean total health care costs in kidney transplant recipients who experienced CMV reactivation was significantly higher than costs in patients without CMV according to a study from Thailand (US$42 712 and US$34 614, respectively; p = .035). 52 Another study from Brazil was identified, although it was specific to high-risk liver transplant recipients with a D+/R-serostatus. This study reported total costs associated with preemptive monitoring of R$57 999 (corresponding to ∼USD$11 317). 41  studies). However, according to consensus guidelines, the advantage of either approach with regards to long-term outcomes (e.g., graft sur-vival or other CMV indirect effects) is not clearly established. 97 The salient heterogeneity of estimates, even within a given country, may be explained by the following factors. Although disease definitions are consistent, the methods of ascertainment of CMV infection and testing procedures differed across health care centers with regards to the type of specimen (e.g., whole blood or plasma) and diagnostic assay (antigenemia or PCR). Such differences in procedures are known to contribute to the variability in viral loads values and thus, the ability to detect CMV. 98 The lower rates of infection observed in China, Colombia, South Korea, and Turkey may also be explained by clinical practices that call for infrequent CMV monitoring or testing (e.g., access to testing facilities, delays for receiving results, costs of tests). Finally, other methodological differences relating to study design and populations (i.e., countries/regions, type of organ trans- Resistant CMV infection and disease was not well documented in the countries covered by the review but may occur in up to 4.4% of patients, according to a study from Brazil. 8 This result should however be interpreted with caution because it was found in a single center study including 89 high-risk kidney recipients (serostatus D+/R-). 8 In Europe and North America, a previous review found heterogeneous results with rates of resistant CMV ranging, respectively, from 0.7% to 8.4% and 0.6% to 13.8% of patients (Table S7)