The Drug Therapy Committee, with input from the Infectious Disease Division, has added oral valganciclovir (ValcytÒ ) to the MGH and Partners Formulary. Oral ganciclovir will be removed effective March 1, 2002. Intravenous ganciclovir will remain on Formulary. Valganciclovir has a superior bioavailability profile. Sixty-one percent of valganciclovir is readily available from the GI tract as compared to 5% for ganciclovir in individuals with normal gastrointestinal function. Peak serum concentrations are attained 15 minutes after an oral dose. Valganciclovir is rapidly metabolized to ganciclovir with a total half-life of about 4 hours. Both the parent compound and the active metabolite are excreted renally. The average wholesale price of a valganciclovir 450 mg tablet is $29.25.

Below are guidelines for drug prophylaxis and therapy of cytomegalovirus infections developed by Dr. Fishman with input from the staff of the Infectious Disease Division. Specific questions may be directed to a member of the ID staff or a pharmacist.

Cytomegalovirus (CMV) is a common cause of infection. After infection, infection is life-long as indicated by seropositivity. Many asymptomatic individuals secrete CMV in urine and sputum in the absence of invasive infection. Clinical CMV disease presents most often in immunocompromised hosts with fever, neutropenia, lymphopenia (CMV syndrome), pneumonitis, retinitis, hepatitis, or colitis (if documented, CMV disease). The risk for infection is correlated with CMV viral loads. Some microbiological assays including the CMV antigenemia assay and quantitative polymerase chain reaction (PCR) assays may be negative despite significant disease involving the GI tract or central nervous system. Otherwise, the PCR, hybrid capture, and antigenemia assays, tissue histopathology or cultures of sterile sites (not urine or sputum) provide useful diagnostic data. CMV infection contributes to the risk for other opportunistic infections, graft-vs-host disease (GvHD), and allograft rejection.

Individuals at greatest risk for invasive CMV disease include:

• HIV/AIDS patients with CD4 lymphocyte counts generally < 200/mm³ or unresponsive to HAART therapy (high viral load).
• Solid organ transplant recipients who are seronegative for CMV (R-) and receive a CMV graft from a seropositive donor (D+) OR who are seropositive (R+) and receive intensive immune suppression including antilymphocyte antibodies (e.g., for rejection).
• Bone marrow transplant (BMT) recipients who are seropositive and receive marrow or stem cells from a seronegative individual (CMV pneumonitis) or with active GvHD.
• Individuals with prolonged neutropenia after chemotherapy or radiation therapy.
• Any of the above after other acute inflammatory events including other infections, graft rejection, GvHD, transfusion reactions.

Systemic antiviral agents approved for the treatment of CMV infection include ganciclovir (po/iv), foscarnet (iv), cidofovir (po/iv), valganciclovir (po). CMV hyperimmune globulin is used as an adjunct to antiviral agents in some individuals.

Prophylaxis of High-Risk Patients: Prophylaxis is achieved with 50% of the therapeutic dose of ganciclovir or valganciclovir (corrected for renal function). This is generally initiated as intravenous ganciclovir while hospitalized and oral valganciclovir after discharge. Reduction in the dose administered (e.g., for toxicity) may risk emergence of viral resistance. Significant toxicity may reflect diminished renal function and formal creatinine clearance data may be useful to guide therapy. The main side effects of these agents include neutropenia and, uncommonly, renal dysfunction. Certain subgroups merit routine prophylaxis. These include:

• Solid organ transplant recipients who are naïve (seronegative, R-) and receive an organ from a seropositive donor (D+/R-).
• Solid organ transplant recipients who are seropositive (R+) who receive antilymphocyte antibodies or other intensive immune suppression (e.g., for graft rejection); D+ or R+ lung transplant recipients.
• BMT patients with graft-vs-host disease and a history of active CMV disease.

Treatment of Symptomatic CMV Disease: The standard of care for tissue-invasive CMV disease is a minimum of 2-3 weeks of intravenous ganciclovir at 5 mg/kg twice daily (dosage adjusted for renal dysfunction). The end point of intravenous therapy is the documented clearance of virus from the blood as demonstrated by CMV antigenemia assay (or quantitative PCR assay). The risk of subsequent relapse can be reduced following intravenous therapy with oral valganciclovir for 2-3 months. To prevent relapse in seronegative or hypogammaglobulinemic patients, CMV hyperimmune globulin (at a dose of 150 mg/kg iv x 1 and 100 mg/kg iv q month x 3-6) may be administered with ganciclovir therapy. Patients without pneumonia, gastrointestinal disease, hepatitis, pancreatitis or other evidence of tissue invasive disease may be treated with oral valganciclovir after loading with intravenous ganciclovir.

Ganciclovir iv: Dosing Nomogram for Treatment of CMV Infection

Serum Creatinine (mg/dl)	Intravenous Dose (mg/kg)	Frequency
<2.0	5	Q12h
2-3	5	Daily
3-5	1.25	Daily
>5.0	*1.25	QOD
Hemodialysis	5	Post- Dialysis
Peritoneal Dialysis	*2.5	Daily

Valganciclovir Conversions: With the availability of oral valganciclovir (450 mg tabs only), many patients can be converted to oral therapy. It may be preferable to load intravenously to obtain higher peak serum levels. At present, this agent is FDA-approved only in therapy of CMV retinitis. Studies in other patient groups are underway. It should be noted that hematopoietic suppression is more common with valganciclovir due to increased bioavailability. Renal function and leukocyte counts should be monitored.

Conversion to Valganciclovir
iv Ganciclovir	Valganciclovir
5 mg/kg QD	900 mg (2 x 450 mg) QD
5 mg/kg bid	900 mg (2 x 450 mg) bid

*Hemodialysis Patients: There are no data on dosing for HD patients at present.