*2.5.3 Preemptive therapy*

With quantitative monitoring of CMV DNA in plasma (viral load, viremia) once a week (sometimes twice a week), CMV viremia can be detected before the occurrence of symptomatic infection. However, the exact cutoff point of plasma CMV concentration to initiate preemptive treatment (from a few hundred to several thousand copies of CMV DNA in 1 ml of plasma) is not known. The decision to initiate preemptive treatment is therefore individual and depends mainly on the degree and duration of immunosuppression [40].

The benefits of this type of strategy are that fewer patients are exposed to antivirals and for a shorter period of time (fewer side effects, fewer interactions with other medicines, lower costs).

Intravenous ganciclovir (5 mg/kg every 12 h or a dose adjusted to creatinine clearance) is used for preemptive treatment in a patient with a high viral load (>50,000 copies of CMV DNA in 1 ml of plasma), in severe renal impairment, and in pediatric patients; otherwise, valganciclovir (900 mg every 12 h, or a dose adjusted to creatinine clearance) is recommended. If there is no CMV disease, the CMV viremia is checked for the first time after 7–10 days of preemptive treatment, afterward being monitored every 7–10 days. It is recommended to continue with

preemptive therapy until two negative results of quantitative plasma PCR CMV DNA tests performed in a space of 7 days [40].

### *2.5.3.1 Guiding of preemptive therapy by measurement of CMV-specific T lymphocytes*

The activity and concentration of CMV-specific lymphocytes in the blood have a decisive role in controlling CMV infection, especially in situations of increased risk of CMV reactivation or primary infection, such as after therapeutic use of antilymphocyte antibodies. The count of CMV-specific T lymphocytes allows a decision on preemptive treatment in a period when the viral load is still not critically increased.

Among the available methods, the most reliable predictor of viremia and disease is measurement of the blood concentration of T lymphocytes, which, after in vitro stimulation with CMV peptides, increasingly produce cytokines such as interferon gamma and interleukin 2. CMV-specific lymphocytes CD4 and CD8 are analyzed by the flow cytometry method (one of the most commonly used is a whole blood interferon gamma release assay QuantiFERON-CMV test marketed by an Australian company, Cellestis Inc., which measures the production of interferon gamma after stimulating the patient's lymphocytes with CMV peptides) [41].

#### **2.6 Treatment of CMV disease**

Treatment is always indicated in case of active CMV infection (CMV viral syndrome) or in the presence of tissue-invasive CMV disease [42].

Intravenous ganciclovir is a gold standard for the treatment of CMV disease. In mild to moderate cases of the disease, oral valganciclovir was found to be noninferior to intravenous ganciclovir. However, due to limited evidence, severe disease should be treated with intravenous ganciclovir. Acyclovir and valacyclovir are not indicated for treatment. The use of foscarnet as a first-line therapy is limited by its toxicity (mainly nephrotoxicity) (**Table 1**).

Drug resistance should be suspected in patients with persistent viral replication and/or clinical progression after 2–3 weeks of treatment. Ganciclovirresistant CMV infection has been observed in 1–2% of kidney transplant recipients and is a result of the widespread use of antiviral prophylaxis and preemptive therapy. Drug resistance typically develops in CMV D+/R− patients and is also associated with high viral load, prolonged antiviral therapy, high level of immunosuppression (i.e., use of antilymphocyte antibodies), and suboptimal serum drug concentrations. Genotypic tests reveal characteristic viral mutants (UL97) associated with resistance [43].

Drug-resistant or refractory CMV disease occasionally responds to an increased dose of ganciclovir. In cases of genotypic resistance of CMV to ganciclovir, it is necessary to introduce combined treatment with ganciclovir and foscarnet (half or standard doses) or treat with foscarnet only [44].

The treatment should be continuous until viral eradication is achieved in two assays after a minimum of 2 weeks of induction treatment. Initial treatment with intravenous ganciclovir can be later replaced with oral valganciclovir. During the course of treatment, renal function must be promptly monitored. In most cases (especially in high viremia, a moderate to severe clinical course, ganciclovir resistance), it is necessary to reduce immunosuppressive therapy (especially antimetabolites, i.e., azathioprine or mycophenolate). The same applies in cases of recurrent CMV infection/disease [35].

In the case of high-risk patients, some authors recommend secondary prophylaxis after completion of treatment, although no consensus has so far been achieved on this approach [35, 45].

**47**

**Drug** Ganciclovir Valganciclovir

Foscarnet

90 mg/kg bw bd i.v. or 60 mg/kg

Inhibits activity to the viral

Nephrotoxicity, electrolyte disturbances,

neurotoxicity

DNA polymerase by binding

to the pyrophosphate binding

site and blocking cleavage of

pyrophosphate from the terminal

nucleoside triphosphate added to

the growing DNA chain

bw every 8 h; adjusted to eGF

900 mg bd p.o.; adjusted to eGF

Rapidly metabolized into active form (ganciclovir) in the intestinal wall and liver; same action as

ganciclovir

**Dosage** 5 mg/kg bw i.v.; adjusted to eGF

\* Oral preparation has low bioavailability

Competitive inhibition of DNA synthesis catalyzed by the viral DNA polymerase

**Action**

**Formulation**

**Common side effects**

Leukopenia, thrombocytopenia, diarrhea, long-term reproductive toxicity

*Viral Infections after Kidney Transplantation: CMV and BK*

Leukopenia, thrombocytopenia, anemia,

gastrointestinal toxicity

*DOI: http://dx.doi.org/10.5772/intechopen.86043*

#### *Viral Infections after Kidney Transplantation: CMV and BK DOI: http://dx.doi.org/10.5772/intechopen.86043*

*Perioperative Care for Organ Transplant Recipient*

DNA tests performed in a space of 7 days [40].

preemptive therapy until two negative results of quantitative plasma PCR CMV

*2.5.3.1 Guiding of preemptive therapy by measurement of CMV-specific T lymphocytes*

stimulating the patient's lymphocytes with CMV peptides) [41].

syndrome) or in the presence of tissue-invasive CMV disease [42].

Treatment is always indicated in case of active CMV infection (CMV viral

Intravenous ganciclovir is a gold standard for the treatment of CMV disease. In mild to moderate cases of the disease, oral valganciclovir was found to be noninferior to intravenous ganciclovir. However, due to limited evidence, severe disease should be treated with intravenous ganciclovir. Acyclovir and valacyclovir are not indicated for treatment. The use of foscarnet as a first-line therapy is limited by its

Drug resistance should be suspected in patients with persistent viral replication and/or clinical progression after 2–3 weeks of treatment. Ganciclovirresistant CMV infection has been observed in 1–2% of kidney transplant recipients and is a result of the widespread use of antiviral prophylaxis and preemptive therapy. Drug resistance typically develops in CMV D+/R− patients and is also associated with high viral load, prolonged antiviral therapy, high level of immunosuppression (i.e., use of antilymphocyte antibodies), and suboptimal serum drug concentrations. Genotypic tests reveal characteristic viral mutants

Drug-resistant or refractory CMV disease occasionally responds to an increased

The treatment should be continuous until viral eradication is achieved in two assays after a minimum of 2 weeks of induction treatment. Initial treatment with intravenous ganciclovir can be later replaced with oral valganciclovir. During the course of treatment, renal function must be promptly monitored. In most cases (especially in high viremia, a moderate to severe clinical course, ganciclovir resistance), it is necessary to reduce immunosuppressive therapy (especially antimetabolites, i.e., azathioprine or mycophenolate). The same applies in cases of recurrent

In the case of high-risk patients, some authors recommend secondary prophylaxis after completion of treatment, although no consensus has so far been achieved

dose of ganciclovir. In cases of genotypic resistance of CMV to ganciclovir, it is necessary to introduce combined treatment with ganciclovir and foscarnet (half or

**2.6 Treatment of CMV disease**

toxicity (mainly nephrotoxicity) (**Table 1**).

(UL97) associated with resistance [43].

CMV infection/disease [35].

on this approach [35, 45].

standard doses) or treat with foscarnet only [44].

The activity and concentration of CMV-specific lymphocytes in the blood have a decisive role in controlling CMV infection, especially in situations of increased risk of CMV reactivation or primary infection, such as after therapeutic use of antilymphocyte antibodies. The count of CMV-specific T lymphocytes allows a decision on preemptive treatment in a period when the viral load is still not critically increased. Among the available methods, the most reliable predictor of viremia and disease is measurement of the blood concentration of T lymphocytes, which, after in vitro stimulation with CMV peptides, increasingly produce cytokines such as interferon gamma and interleukin 2. CMV-specific lymphocytes CD4 and CD8 are analyzed by the flow cytometry method (one of the most commonly used is a whole blood interferon gamma release assay QuantiFERON-CMV test marketed by an Australian company, Cellestis Inc., which measures the production of interferon gamma after

**46**
