Cytomegalovirus infection in solid organ transplant recipients

Cytomegalovirus infection in solid organ transplant recipients

REVIEW 10.1111/1469-0691.12594 Cytomegalovirus infection in solid organ transplant recipients C. Lumbreras1, O. Manuel2, O. Len3, I. J. M. ten Berge...

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REVIEW

10.1111/1469-0691.12594

Cytomegalovirus infection in solid organ transplant recipients C. Lumbreras1, O. Manuel2, O. Len3, I. J. M. ten Berge4, D. Sgarabotto5, H. H. Hirsch6,7 on behalf of the ESCMID Study Group of Infection in Compromised Hosts (ESGICH) 1) Infectious Diseases Unit, Hospital ‘12 de Octubre’, Instituto de Investigacion (i+12), Madrid, Spain, 2) Infectious Diseases Service and Transplantation Center, University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland, 3) Department of Infectious Diseases, Hospital Vall d0 Hebron, Barcelona, Spain, 4) Renal Transplant Unit, Department of Internal Medicine, Academic Medical Center, Amsterdam, the Netherlands, 5) Infectious and Tropical Diseases Division, Padova University Hospital, Padova, Italy, 6) Infectious Diseases and Hospital Epidemiology, University Hospital Basel and 7) Transplantation and Clinical Virology, Department of Biomedicine, University of Basel, Basel, Switzerland

Abstract Cytomegalovirus (CMV) is the most frequent infectious complication following solid organ transplantation (SOT). The virus, is responsible for both direct (viral syndrome, hepatitis, pneumonitis, colitis, etc.) and indirect effects (rejection, infections by other microorganisms and graft dysfunction). In this evidence-based guideline we deal with the most important aspects of CMV infection in SOT recipients, including pre- and post-transplant diagnosis assessment and risk factors, with special emphasis on the prevention and treatment of this viral infection. Overall, adequate management of CMV infection is a critical aspect of transplant patient care. Keywords: Cytomegalovirus, organ transplantation, prevention, risk factors, treatment Article published online: 17 February 2014 Clin Microbiol Infect 2014; 20 (Suppl. 7): 19–26

Corresponding author: C. Lumbreras, Infectious Diseases Unit, Hospital ‘12 de Octubre’, Avenida de C ordoba s/n. 28041, Madrid, Spain E-mail: [email protected]

Hot Topics

 Antiviral prophylaxis or preemptive therapy should be used





 

for the prevention of CMV replication and disease after solid organ transplantation (AII) Antiviral prophylaxis is preferred for patients at high risk of CMV disease (lung and intestinal transplant recipients, CMV D+/R patients, and patients receiving therapy with lymphocyte-depleting antibodies) (AII) The minimum duration of antiviral prophylaxis should be 6– 12 months for lung and intestinal transplantation and 3– 6 months for D+/R kidney, heart and liver transplantation (AII) Detecting CMV-specific cell-mediated immunity can identify patients at reduced risk of CMV replication and disease (BII) Valganciclovir or intravenous ganciclovir are recommended as first-line treatment (AI). Valganciclovir is preferred,

except in cases of life-threatening disease and in situations where oral intake may not be appropriate (AII). Sequential therapy (starting with i.v. ganciclovir followed by valganciclovir) may be an alternative strategy (BII)  Ganciclovir resistance should be suspected when persistence of or increase in viral load or clinical progression of CMV disease is detected despite adequate exposure to the drug after 3 weeks (AII)  Foscarnet is the empirical alternative antiviral treatment in the presence of serious CMV disease and suspected ganciclovir resistance provided no genotypic study is available (AII)  Genotypic determination of resistance is advisable to better guide treatment (AII) Human cytomegalovirus (CMV) is a b herpes virus, which infects about 30–80% of the general population in Europe [1]. Following primary infection, CMV persists as a latent, non-replicative infection in long-lived cells derived from the

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haematopoietic lineage [2]. Presumably, CMV has co-evolved with the human species and developed mechanisms to avoid its immunological elimination. CMV encodes proteins down-regulating human MHC class I molecules to decrease recognition and elimination by CD8+ T cells, and avoids lysis by NK cells through the expression of viral MHC class I homologue [3]. Although the human immune system cannot eliminate CMV infection, it is capable of controlling CMV replication and its pathological effects. Longitudinal studies in kidney transplant recipients revealed that CMV-specific T cells emerge early after the initial viral burst and acquire their stable phenotype in the months following primary infection [4,5]. CMV-specific CD8+ T cells differentiate into memory-effector cells as characterized by the successive loss of expression of CD45RA, CCR7, CD27 and CD28, followed by re-expression of CD45RA. In all stages, these CMV-specific T cells are able to lyse target cells in an antigen-specific manner, as indicated by the production of interferon-c (IFN-c) and presence of perforin. In asymptomatic patients, CMV-specific CD4+ T cells are the first to appear in the circulation, followed by CMV-specific CD8+ T cells and antibody responses. Actually, late emergence of circulating IFNc-producing CMV-specific CD4+ T cells appeared to be predictive for the development of CMV disease [4]. Latent infection is accompanied by a strong increase in the number of resting, effector-type CD4+ and CD8+ T cells with constitutive cytolytic activity in the circulation, but not in the lymph nodes [6]. A number of functional characteristics of these cells, specifically cytotoxicity, IFNc-production and migratory potential are already detectable during the primary expansion of this population, a process likely to be governed by the early and lasting changes in transcription factor expression [7]. The crucial role of T cells in the defence against the virus is illustrated by the occurrence of increasing viral replication leading to organ-invasive, even life-threatening disease, in solid-organ transplant (SOT) recipients during treatment with immunosuppressive drugs, in particular with anti-T-cell agents and/or antiproliferative drugs like mycophenolic acid derivatives [8]. In contrast, treatment with mTOR inhibitors seems to decrease the incidence of CMV replication or CMV disease, when compared with other immunosuppressive drug regimens [9]. The introduction of a CMV vaccine that protects against symptomatic CMV replication and disease, but does not induce the strong effector T-cell increase seen in natural CMV infection, might be an interesting option. However, the strong heterogeneity in CMV T-cell response at the clonal level [10] suggests that the design of a vaccine aimed at inducing a T-cell

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response able to completely suppress viral replication will be challenging.

Diagnostic Aspects Pre-transplant CMV assessment

CMV-specific antibody testing of donor and recipient is the key diagnostic assay pre-transplantation to enable risk stratification of CMV replication and disease post-transplantation. CMV-specific immunoglobulin-G (IgG) is measured using ELISA techniques, and values above the cut-off are considered as positive [11–13]. For CMV-IgG results below the cut-off, a negative CMV serostatus is assigned. Administration of intravenous immunoglobulin (IVIG) preparations can result in positive CMV serology results. Similarly, CMV antibody responses may be positive in children <18 months due to transplacental transfer of IgG from their mothers. In general, repeat serological testing should be considered when a CMV-negative IgG result has been obtained more than 2 months before transplantation. Similarly, repeat testing should be considered if CMV-specific IgG results are in the indeterminate zone of the assay, if there is the sole presence of CMV IgM, or if passive IgG transfer is suggested either transplacentally or post-infusion. If repeat testing is not possible, or if the same result is obtained, the donor or recipient should be assigned to the higher risk category and managed accordingly. Thus, the equivocal IgG result places a donor into the CMV-infected (CMV +) category, but a recipient into the CMV non-infected (CMV ) category, except when the donor is seronegative, in which case we should consider the recipient as seropositive. Measuring CMV-specific T cells in blood or testing for CMV DNA in blood or urine have been proposed as alternative tests for the pre-transplant assignment [14]. However, larger studies are lacking that specifically address this issue in clinical practice, and a negative result of these tests is unlikely to reliably rule out latent, persistent or de novo CMV infection in the respective donor or recipient. Post-transplantation detection of CMV replication

Recognition of post-transplantation ongoing viral replication could be achieved by nucleic acid amplification testing (NAT) in a quantitative format, by direct antigen detection (DAD) in blood (antigenaemia), in bronchoalveolar lavage (BAL) or tissue samples, or by virus isolation by culture (VIC), which is typically confirmed with in situ hybridization for CMV DNA or DAD for CMV pp72 antigen. All of these techniques may have some relevance in the diagnostic work-up of SOT patients post-transplant. In recent years, however, quantitative NAT in blood and immunohistochemistry for CMV antigens have emerged as key techniques for surveillance, diagnosis and

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follow-up of SOT recipients with asymptomatic or pre-symptomatic CMV replication, and the diagnosis of probable and proven CMV disease to mandate the administration of antiviral therapy. Because of poor inter-laboratory and limited intra-laboratory agreement, antigenaemia is no longer regarded as a preferred technique, while the use of quantitative NAT calibrated to an international WHO standard and expressed as international units (IU)/mL is strongly recommended [15,16]. This will allow for reproducible CMV load results in blood (CMV viraemia or DNAemia) across different transplant centres and laboratories, and permit better definition and clinical validation of generally accepted laboratory trigger points for beginning and ending antiviral treatment [17–20]. There are unresolved issues such as the use of plasma vs. whole blood, the use of BAL and tissue specimens with respect to thresholds, the identification of CMV disease, and the corresponding need for antiviral treatment. Diagnosis of post-transplant organ-invasive CMV disease

Immunohistochemistry is the key technique to diagnose organ-invasive CMV disease. The high specificity is complemented by a significant sensitivity in the case of CMV colitis if appropriate clinical biopsies are taken [21]. In fact, proven CMV colitis with undetectable CMV DNAemia is not infrequently encountered, but this issue needs to be re-evaluated using improved calibrated NAT assays. Detection of virus-specific T-cell responses

Measurement of CMV-specific T-cell responses is obtained by quantifying the number of cytokine-producing T cells after

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stimulation with specific viral epitopes using enzyme-linked immunospot assay or intracellular cytokine staining and flow cytometry [22–25]. Published studies suggest that the presence of CMV-specific T cells in the peripheral blood is associated with protection from viral replication and disease. Similar to the quantitative NAT, however, the comparison between different assays and antigens is limited, and a prospective clinical evaluation in an intervention trial is lacking.

Risk Factors The most important risk factor for the development of CMV disease in SOT recipients is mismatching CMV serology (positive donor and negative recipient), which confers more than 50% risk of developing CMV disease in the absence of antiviral prophylaxis or preemptive treatment strategies. Other risk factors for CMV disease in SOT recipients are related to the use of specific immunosuppressive therapy, the type of transplanted organ, or certain immunological characteristics of donors and recipients (Table 1) [26–39].

Prevention of CMV Disease Prevention of CMV disease is based on antiviral drugs administered as universal prophylaxis or preemptive therapy [40]. Preemptive therapy is uniquely exploited in the setting of CMV infection, with the aim of aborting the progression of asymptomatic infection into CMV disease.

TABLE 1. An evidence-based grading classification of risk factors for the development of CMV disease in solid organ transplant recipients Risk factor

Quality of evidence

D+/R

I

Use of OKT3/ATG

I

Acute graft rejection Use of MMF

I II

Alemtuzumab

II

Use of mTOR inhibitors Type of transplanted organ Viral co-infection (HHV-6) Hypogammaglobulinaemia TLR2 and TLR4 polymorphisms Low levels of MBL Mixed infections caused by different CMV-gB/gH genotypes Post-transplant serum Interferon c levels following ‘in vitro’ stimulation with CMV antigens

II II II II II II II II

Comments Increased risk of CMV replication and disease exceeds 50%. In D+/R+ and D/R+ situations without prophylaxis it is about 15–20%. In D/R combinations the risk of CMV replication and disease is very low Use associated with higher risk of CMV replication and disease. Targeted antiviral prophylaxis decreased the risk of CMV disease in patients who received these drugs Increased risk of CMV replication and disease due to proinflammatory cytokines and subsequent anti-rejection treatment Associated with higher risk when MMF dose >2 g/daily. MMF has been particularly linked to the development of CMV gastrointestinal disease in kidney transplant recipients Associated with higher risk when the drug is used for rejection treatment, but not when used for induction of immunosuppressive therapy Associated with a lower risk of CMV disease Decreasing risk according to small-bowel > lung > pancreas > heart > liver/kidney Increased risk of CMV disease in the early post-transplant period of liver and kidney transplant recipients Increased risk of CMV disease in heart and kidney transplant recipients Increased risk factors for Toll-like receptor polymorphisms for CMV disease in renal transplant patients Increased risk of MBL gene polymorphisms for CMV disease in kidney transplant recipients Increased CMV replication and CMV disease in SOT recipients when different gB/gH genotypes are co-detected Reduced risk of patients with detectable CMV-specific T-cell responses for CMV replication and disease as measured by interferon-c release assay or intracellular cytokine staining

D+/R, donor CMV-seropositive, recipient CMV-seronegative; ATG, anti-thymocitic globulin; MMF, mofetil mycophenolate; TLR, Toll-like receptors; MBL, mannose-binding lectine; gB, glycoprotein B; gH, glycoprotein H. [26–39].

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There are few studies that have directly compared preemptive therapy with universal prophylaxis, so there is an open debate about the advantages and disadvantages of each approach. Results from several meta-analyses (including different transplant populations, antiviral drugs and immunosuppressive regimens) have basically shown that the incidence of CMV disease is significantly reduced (by c. 70%) with both approaches [44,45]. In one meta-analysis, both prophylaxis and the preemptive approach reduced the risk of rejection, although only universal prophylaxis significantly reduced the risk of bacterial and fungal infections and death [41]. Randomized controlled trials comparing both approaches generally have included a limited number of patients. Khoury et al. [42] did not observe differences in the incidence of CMV disease between the valganciclovir prophylaxis and the preemptive approach in 98 kidney transplant recipients, including the subgroup of patients at high risk. Kliem et al. [43] compared ganciclovir prophylaxis with intravenous ganciclovir preemptive therapy in 148 renal transplant recipients, noting an increased frequency of CMV infection and disease in the preemptive group. Of note, graft survival at 4 years was lower in the group that developed CMV infection and received preemptive therapy. Recently, an observational nationwide cohort study in Switzerland compared both strategies in more than 1200 SOT recipients [44]. While the incidence of CMV disease was similar in both groups, patients who received antiviral prophylaxis had better graft-failure-free survival, due to a better control of early-onset CMV viraemia. In summary, while both preventive approaches can effectively reduce the incidence of CMV disease after transplantation, universal prophylaxis has some advantages as it is easier to implement and may better prevent the occurrence of indirect effects, by reducing the burden of CMV viraemia. However, side-effects such as renal toxicity, bone marrow suppression and costs for patients who may never develop CMV replication and disease are the downsides of universal prophylaxis. Preemptive therapy can reduce the cost and toxicity of antiviral drugs, and may allow the development of specific cell-mediated immunity by preventing the development of late-onset CMV disease [45]. However, the preemptive approach depends on close monitoring of viral replication and adequate clinical interpretation and response, and therefore depends on the existence of adequate diagnostic and medical logistics in the transplant programme. Our recommendations support the use of a prophylactic approach for those patients at high risk of CMV disease, such as lung and intestinal transplant recipients, D+/R patients and patients who received lymphocyte-depleting antibodies, in whom any mistake in the essential surveillance for preemptive

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therapy could result in the development of CMV disease (Table 2). Despite significant improvements in the prevention of CMV disease, it is desirable to further reduce the burden of CMV infection with the aim of improving the long-term allograft outcomes. Two recent randomized controlled trials have shown that extending the duration of prophylaxis from the standard 3–6 months (D+/R kidney transplant recipients) and 12 months (all lung transplant recipients) [46,47] is associated with a much lower incidence of CMV disease. However, not all transplant programmes have accepted 6 months of prophylaxis as the standard of care, due to concerns regarding costs and toxicity [48]. The use of antiviral prophylaxis followed by screening for CMV replication may improve the detection of patients at risk of late-onset CMV disease [49]. However, there is little evidence for recommending its general use. Another approach is to measure the specific cell-mediated immunity against CMV in order to stratify patients according to the individual risk of subsequently developing late-onset CMV disease. An earlier study identified a threshold of 0.03% pp65-specific CD4+ T cells as protective against CMV replication in the following 8 weeks. A recent study showed that developing a positive CMV CD8+ T-cell response at the discontinuation of prophylaxis predicted protection against CMV disease [25]. Another study in CMV-seropositive SOT recipients found that patients without a detectable pre-transplant cell-mediated immunity had a higher incidence of post-transplant CMV replication [14]. However, the positive predictive value of detecting CMV-specific T cells for protection has been good, ranging from 70% to >90%, but the negative predictive value has been typically poor, being <50%. Moreover, the clinically relevant cut-offs have not been defined in prospective studies. Interventional studies are needed to identify the optimal time-point, cut-offs and assays before introducing the cell-mediated immunity assays into routine clinical practice. TABLE 2. Recommendations for prevention of CMV disease in solid organ transplant recipients Antiviral prophylaxis or preemptive therapy should be used for the prevention of CMV replication and disease after solid organ transplantation. Grade: AII Antiviral prophylaxis is preferred for patients at high risk of CMV disease, such as lung and intestinal transplant recipients, CMV D+/R patients, and SOT patients receiving induction or rejection therapy with lymphocyte-depleting antibodies. Grade: AII The minimum duration of antiviral prophylaxis should be 6–12 months for lung and intestinal transplantation and 3–6 months for D+/R kidney, heart and liver transplantation. Grade: AII When a preemptive approach is used, monitoring of CMV viral load in peripheral blood should be done every 1–2 weeks during the first 3 months post-transplant. AII. More frequent testing (i.e. twice weekly) may be considered in patients at high-risk (i.e. D+/R patients, early post-transplant and following use of lymphocyte-depleting antibodies). Grade: BII An approach based on antiviral prophylaxis followed by the preemptive strategy may e used in high-risk patients. Grade: BIII Detecting CMV-specific cell-mediated immunity can identify patients at reduced risk of CMV replication and disease. Grade: BII

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TABLE 3. Recommendations for the treatment of CMV disease in solid organ transplant recipients Valganciclovir or intravenous ganciclovir are recommended as first-line treatment. Grade: AI. Valganciclovir is preferred except in cases of life-threatening disease and in situations where oral intake may not be appropriate. Grade: AII. Sequential therapy (starting with IV ganciclovir followed by valganciclovir) may be an alternative strategy. Grade: BII. Antiviral dose adjustment should be performed based on renal function by Cockroft-Gault formula. Grade: AI. Dose reduction of valganciclovir and ganciclovir due to adverse events should be avoided due to risk of resistance. Grade: AIII. The addition of G-CSF should be considered before cessation of antiviral therapy in cases of severe leukopenia. Grade: BIII. Laboratory monitoring of CMV should be performed weekly during the treatment phase to monitor response. Grade: AII. Treatment should be continued until viral eradication is achieved at least on one assay after a minimum of 2 weeks. Grade: AII. Secondary prophylaxis is not routinely recommended. Grade: CIII. Dose reduction of immunosuppressive therapy should be considered in severe CMV disease, in non-responding patients, in patients with high viral loads and those with leukopenia. Grade: AIII. Intravenous immunoglobulin may be considered for severe forms of CMV disease such as pneumonitis. Grade: BII. Ganciclovir resistance should be suspected when persistence of or increase in viral load or clinical progression of CMV disease is detected despite adequate exposure to the drug after 3 weeks. Grade: AII. Foscarnet is the empirical alternative antiviral treatment in the presence of serious CMV disease and suspected ganciclovir resistance provided no genotypic study is available. Grade: AII. Genotypic determination of resistance is advisable to better guide treatment. Grade: AII.

Treatment of CMV Disease Intravenous (IV) ganciclovir has been the standard treatment for cytomegalovirus (CMV) in SOT recipients, for both adults and children (Table 3). An international, multicentre trial showed that oral valganciclovir was similar in efficacy and safety to IV ganciclovir in the treatment of CMV disease in a population of patients with SOT [50,51]. During long-term follow-up, clinical and virological recurrence was not significantly different between groups. However, this study had the following limitations. The majority of the patients were kidney transplant recipients, paediatric patients were not included and, generally, serious or life-threatening CMV disease was not included. Unfortunately, valganciclovir for treatment of CMV disease has not been validated by studies in children. Hence, the drugs recommended for first-line treatment of mild to moderate CMV disease are oral valganciclovir at doses of 900 mg/12 h or IV ganciclovir at doses of 5 mg/kg/12 h, dose-adjusted to renal function. In patients with severe, life-threatening disease and when oral valganciclovir is poorly tolerated or oral drug absorption may not be appropriate, intravenous ganciclovir should be used. Sequential therapy (starting treatment with IV ganciclovir followed by oral valganciclovir once improvement is initiated) is a potential therapeutic modality that has, however, not been extensively evaluated. This pragmatic approach provides an effective therapy with appropriate drug exposure, reduces treatment costs and avoids prolonged hospitalization [52].

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It is important to administer appropriate doses of both valganciclovir and ganciclovir. Suboptimal doses can cause lack of drug efficacy and promote the development of resistance [53], while supratherapeutic doses favour the appearance of adverse effects. Glomerular filtration rate should be estimated/ followed during antiviral treatment. The dose and timing of antiviral drugs should be adjusted according to the estimated creatinine clearance values as shown in Table 4. Should leukopenia occur, the differential diagnosis includes not only potentially myelotoxic drugs such as ganciclovir, valganciclovir, mycophenolic acid derivatives, mTOR inhibitors (sirolimus and everolimus), azathioprine and trimethoprim-sulphamethoxazole, but also the direct effects of significant CMV replication. Careful consideration of the potential myelotoxic drugs and the viral replication dynamics should lead to a judicious decision about lowering or discontinuing drugs without compromising antiviral treatment and increasing the risk of emergence of drug-resistant CMV. In severe leukopenia, especially if absolute neutrophil count is <1000/lL, the use of granulocyte colony stimulating factor (G-CSF) may be considered. The optimum duration of the treatment of CMV disease should be individualized based on clinical follow-up and viral load monitoring. Determinations should be performed weekly for antigenaemia or viral load by real-time quantitative PCR. Although both techniques have similar specificity, >90%, PCR is preferred in view of a better sensitivity (94% vs. 27%) [54]. Treatment should be maintained until a determination of antigenaemia or viral load becomes lower than the test’s lower limit of quantification or negative. In high-risk patients it is preferable to confirm two consecutive negative determinations with a 1-week interval between them to ensure the clearance of the virus. In any case, the minimum duration of treatment must never be <2 weeks [55]. A recent study has proved that patients with a pretreatment viral load lower than 18 200 IU/mL resolve CMV disease more rapidly than those

TABLE 4. Dosing of ganciclovir and valganciclovir for treatment of CMV disease in SOT recipients based on creatinine clearance. [11–13] Creatinine clearance (mL/min) >70 60–69 50–59 40–49 25–39 10–24 <10 a

IV ganciclovir

Valganciclovir

5 mg/kg/12 h 2.5 mg/kg/12 h 2.5 mg/kg/12 h 1.25 mg/kg/12 h 1.25 mg/kg/12 h 0.625 mg/kg/12 h 0.625 mg/kg 3 times per week (after haemodialysis)

900 mg/12 h 900 mg/12 h 450 mg/12 h 450 mg/12 h 450 mg/day 450 mg/48 h 200 mg 3 times per week (after haemodialysis)a

Using powder for oral suspension.

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with a higher viral load, and confirmed the direct association between viral suppression below the test’s lower limit of quantification and disease resolution [56]. With this therapeutic regimen, the risk of development of resistance and recurrence of CMV disease is very low. A concomitant reduction of immunosuppressive therapy should be considered in the presence of CMV disease. This decision should be individualized and particularly considered in the presence of severe CMV disease in neutropenic patients, in disease with high viral load and when there is a lack of clinical response to antiviral treatment. An adequate immunosuppressive treatment should be restored when clinical and virological response is achieved but, as far as possible, the level of immunosuppression should be lower because the return to previous values can lead to CMV disease recurrence. The role of immunoglobulins in the treatment of CMV disease is not well defined, but their use is deemed complementary in severe inflammatory forms of the disease such as pneumonitis. The association of ganciclovir and foscarnet, in the absence of demonstrated ganciclovir resistance, adds no advantages to monotherapy but greater toxicity [57].

Treatment CMV

against

Ganciclovir-Resistant

The emergence of ganciclovir-resistant CMV is a clinical challenge associated with high morbidity and mortality. Its incidence may be as high as 13% in lung and in combined kidney-pancreas transplant recipients [54]. Risk factors for development of resistance to ganciclovir are D+/R serostatus, pancreas and lung transplantation, serious invasive disease and/or high viral load, concomitant intense immunosuppressive treatment, exposure to suboptimal ganciclovir levels, and prolonged antiviral therapy [58]. In practice, ganciclovir resistance should be suspected when persistence of or increase in viral load or progression to clinical CMV disease is detected despite adequate exposure to the drug for 2 weeks. The antiviral treatment may be insufficient to suppress viral replication without phenotypic or genotypic virological resistance when certain host factors are present, such as severe concomitant immunosuppressive therapy or hypogammaglobulinaemia. There are no data from controlled clinical trials showing the best alternative to treat ganciclovir-resistant CMV disease. So, empirical alternative antiviral treatment in the presence of risk factors or serious CMV disease would consist of adding, or replacing ganciclovir with, foscarnet [59].

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Lastly, treatment decisions will be taken depending on the genotypic analysis of UL97 and UL54 genes. If genotypic resistance tests show a high mutation resistance in the UL97 gene (mutations M460V/I, A594V, L595S or C603W, which confer enhanced resistance to ganciclovir more than five times the IC50) or UL54 gene (which confers cross-resistance to ganciclovir and cidofovir) ganciclovir will be changed to foscarnet. Other mutations in the UL97 gene could be treated by increasing the dose of ganciclovir up to 10 mg/kg every 12 h. Cidofovir is not recommended unless the disease is not clinically severe and mutation in the UL54 gene is ruled out. No data are available regarding the development of ganciclovir resistance in children.

Other Antiviral Drugs Maribavir is an oral potent inhibitor of CMV UL97 kinase. Unlike ganciclovir, it produces no myelotoxicity and nephrotoxicity. A phase III trial is ongoing to show its efficacy in treating CMV infection compared with valganciclovir. An oral derivative of cidofovir (CMX-001) has proved recently its effectiveness in a phase II trial to prevent CMV disease in HSCT recipients [60]. It avoids the nephrotoxicity of cidofovir, with diarrhoea as the most frequent adverse event. Letermovir inhibits CMV UL56 terminase. Its antiviral effect was reported in a phase II trial of prophylaxis in HSCT recipients [61]. Sirolimus and everolimus are immunosuppressive drugs that act by blocking signal transduction of growth factors. Several studies with these drugs have shown a lower incidence of CMV disease [37]. Therefore, it has been proposed to convert immunosuppression from anticalcineurin inhibitors to mTOR inhibitors in cases of recurrent or ganciciclovir-resistant CMV disease. Some other drugs have been used as potentially effective agents against resistant or recurrent CMV such as leflunomide and artesunate. At present, data to justify the use of these drugs are scarce and anecdotal. Passive immunotherapy with anti-CMV-specific immune globulin has been employed in an attempt to improve the immune status of the host against this virus. Similarly, the adoptive transfer of T cells specific for CMV, obtained directly from immunized donors, or after extraction and ex vivo expansion, has been evaluated in the treatment of CMV disease. Clinical trials to evaluate the safety and efficacy of the transfer of specific T lymphocytes against CMV are currently active.

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Transparency Declaration CL has received funding for research from Astellas and payment for lectures from Roche, MSD and Pfizer. OM has received funding for research from Roche and payment for lectures from MSD. OL has received payment for lectures from MSD and Roche. IJMB does not have any relationships/ conditions/circumstances that present a potential conflict of interests. DS has received research grants from Astellas and MSD and patment for lectures from Astellas, Novartis, Pfizer and MSD. HHH reports receiving speaker honoraria, grant support or consultancy fees from Astellas, Chimerix, Novartis and Roche.

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