Cytomegalovirus infection medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aravind Kuchkuntla, M.B.B.S[2]

Overview

Antiviral therapy is the primary modality of treatment. Duration of therapy and the antiviral agents are selected based on the severity of the disease, location of the disease and the level of immunosuppression. Ganciclovir and valganciclovir are the commonly used antiviral drugs for the treatment of CMV infection.

Medical Therapy

Antiviral therapy is the primary modality of treatment. Duration of therapy and the antiviral agents are selected based on the severity of the disease, location of the disease and the level of immunosuppression.

CMV Retnitis

The choice of therapy is based on the location of the lesions and level of immunosuppression of the patient. Systemic antiviral therapy is preferred as infection rate of the contralateral eye is reduced.

• Initial Therapy for patients with immediate sight-threatening lesions (Adjacent to the optic nerve or fovea)
  • Preferred Regimen(1): Ganciclovir intraocular implant + valganciclovir 900 mg PO (BID for 14–21 days, then once daily) AND One dose of intravitreal ganciclovir may be administered immediately after diagnosis until ganciclovir implant can be placed
  • Alternate Regimen (1): Ganciclovir 5 mg/kg IV q12h for 14–21 days, then 5 mg/kg IV daily OR
  • Alternate Regimen (2): Ganciclovir 5 mg/kg IV q12h for 14–21 days, then valganciclovir 900 mg PO daily OR
  • Alternate Regimen (3): Foscarnet 60 mg/kg IV q8h or 90 mg/kg IV q12h for 14–21 days, then 90–120 mg/kg IV q24h OR
  • Alternate Regimen (4): Cidofovir 5 mg/kg/week IV for 2 weeks, then 5 mg/kg every other week with saline hydration before and after therapy and probenecid 2 g PO 3 hours before the dose followed by 1 g PO 2 hours after the dose, and 1 g PO 8 hours after the dose (total of 4 g)
    • Note(1): This regimen should be avoided in patients with sulfa allergy because of cross hypersensitivity with probenecid.
    • Note(2): If systemic anti-CMV treatment is not available, use sequential ganciclovir intravitreal injections until immune reconstitution in response to anti retroviral viral therapy is achieved.
• For Small Peripheral Lesions
  • Preferred Regimen: Valganciclovir 900 mg PO BID for 14–21 days, then 900 mg PO daily AND One dose of intravitreal ganciclovir may be administered immediately after diagnosis to deliver high local concentration until systemic ganciclovir concentration is reached.
• Chronic Maintenance Therapy (Secondary Prophylaxis) for CMV Retinitis
  • The drug of choice for chronic maintenance therapy and the preferred route (i.e., implant, intravitreal injection, IV, oral, or combination; and which drug) should be made in consultation with an ophthalmologist. Considerations should include the anatomic location of the retinal lesion, vision in the contralateral eye, the patient’s immunologic and virologic status and response to antiretroviral therapy.
  • Patients with sight-threatening retinitis will most benefit from ganciclovir implant to control retinitis progression, due to the delivery of high concentration of ganciclovir at the site of infection.
    • Preferred Regimen (1): Valganciclovir 900 mg PO daily + ganciclovir intraocular implant (for sight-threatening retinitis) OR
    • Preferred Regimen (2): Valganciclovir 900 mg PO daily (for small peripheral lesions) AND
    • Note(1): Ganciclovir intraocular implant should be replaced every 6–8 months until sustained immune recovery is documented.
    • Alternate Regimen (1): Ganciclovir 5 mg/kg IV 5–7 times weekly OR
    • Alternate Regimen (2): Foscarnet 90–120 mg/kg IV once daily OR
    • Alternate Regimen (3): Cidofovir 5 mg/kg IV every other week with saline hydration and probenecid as above.
• Immune Restoration Uveitis (IRU)
  • Preferred Regimen (1): Periocular corticosteroid or a short course of systemic steroid
• Stopping Chronic Maintenance Therapy for CMV Retinitis
  • CMV treatment for at least 3–6 months, with CD4 count >100 cells/mm3 for >3 to 6 months in response to ART.
  • Therapy should be discontinued only after consultation with an ophthalmologist, taking into account magnitude and duration of CD4 count increase, anatomic location of the lesions, vision in the contralateral eye, and the feasibility of regular ophthalmologic monitoring.
  • Routine (i.e., every 3 months) ophthalmologic follow-up is recommended for early detection of relapse or immune restoration uveitis, and then annually after immune reconstitution.
• Reinstituting Chronic Maintenance/Secondary Prophylaxis for CMV Retinitis
  • CD4+ count <100 cells/mm³

CMV Colitis and Esophagitis

Duration of therapy: 21–42 days or until signs and symptoms have resolved

• Preferred Regimen (1): Ganciclovir 5 mg/kg IV q12h, may switch to valganciclovir 900 mg PO q12h once the patient can absorb and tolerate PO therapy.
• Alternate Regimen (1): Foscarnet 60 mg/kg IV q8h or 90 mg/kg IV q12h for patients with treatment limiting toxicities to ganciclovir or with ganciclovir resistance OR
• Alternate Regimen (2): Oral valganciclovir may be used if symptoms are not severe enough to interfere with oral absorption OR
• Alternate Regimen (3): For mild cases: If ART can be initiated or optimized without delay, withholding CMV therapy may be considered.
  • Note (1): Maintenance therapy is usually not necessary, but should be considered after relapses.

CMV Pneumonitis

• Doses are the same as for CMV retinitis.
• Treatment experience for CMV pneumonitis in HIV patients is limited. Use of IV ganciclovir or IV foscarnet is reasonable.
• The role of oral valganciclovir has not been established.
• The duration of therapy has not been established.

Neurologic Disease

• Doses are the same as for CMV retinitis.
• Treatment should be initiated promptly.
• Combination of ganciclovir IV + foscarnet IV to stabilize disease and maximize response; continue until symptomatic improvement
• Continue therapy until resolution of neurologic symptoms
• Optimize ART to achieve viral suppression and immune reconstitution

Solid Organ Transplant

Risk Assessment of CMV infection

• All donors and transplant candidates should be tested for CMV serology prior to transplantation in order to allow for risk stratification and guide prevention strategies.
• Serologic test that measures CMV-IgG is recommended. CMV IgM is measured only when clinical presentation is suspicious for a primary infection.
• In patients with borderline or indeterminate CMV serology results, the assignment of serostatus should assume the most conservative approach.
  • If a donor CMV serology is borderline or indeterminate, it should be considered as positive.
  • If the recipient CMV is borderline or indeterminate, the result should be considered in the context of donor serology to assign the most conservative designation. If the donor CMV serology is positive, the recipient will be considered seronegative (i.e. CMV D+/R– mismatch). If the donor CMV serology is negative, the recipient will be considered seropositive.
• Transplant recipients who receive treatment with lymphocyte depleting drugs, especially if given for the treatment of rejection, should be considered at high risk for CMV disease.

Laboratory diagnosis of CMV infection

The laboratory methods to confirm CMV infection are:

• Histopathology
• Culture
• Serology
• Antigenemia
• Molecular assays that detect and quantify CMV nucleic acid

Treatment options for CMV infection in patients with solid organ transplant patients:

• Universal prophylaxisgisiving antiviral medication at prophylaxis dose for a defined time.
• Preemptive therapy is defined as serial testing done weekly or biweekly for the first few months after transplant or after treatment of rejection, with treatment dose antiviral therapy initiated once a certain defined positive threshold is reached.

The following table contains the description of treatment options for CMV infection in patients with solid organ transplant:

Organ Transplant	Risk Category	Recommendations
Kidney	D+/R–	Antiviral prophylaxis is preferred Drugs: valganciclovir, oral ganciclovir, intravenous ganciclovir or valacyclovir Duration: 6 months Preemptive therapy is an option Weekly CMV PCR or pp65 antigenemia for 12 weeks after transplantation, and if a positive CMV threshold is reached, treat with (1) valganciclovir 900-mg 1p.o. BID, or (2) IV ganciclovir 5-mg/kg IV every 12 h until negative test
	R+	Antiviral prophylaxis Drugs: Valganciclovir, oral ganciclovir, intravenous ganciclovir or valacyclovir Duration: 3 months Preemptive therapy Weekly CMV PCR or pp65 antigenemia for 12 weeks after transplantation, and if a positive CMV threshold is reached, treat with (1) valganciclovir 900-mg1 p.o. BID, or (2) IV ganciclovir 5-mg/kg IV every 12 h until negative test
Pancreas and kidney/pancreas	D+/R–	Antiviral prophylaxis is preferred Drugs: valganciclovir, oral ganciclovir or intravenous ganciclovir Duration: 3–6 months Preemptive therapy is an option Weekly CMV PCR or pp65 antigenemia for 12 weeks after transplantation, and if a positive CMV threshold is reached, treat with (1) valganciclovir 900-mg 1p.o. BID, or (2) IV ganciclovir 5-mg/kg IV every 12 h until negative test
	R+	Antiviral prophylaxis Drugs: Valganciclovir, oral ganciclovir or intravenous ganciclovir Duration: 3 months Preemptive therapy Weekly CMV PCR or pp65 antigenemia for 12 weeks after transplantation, and if a positive CMV threshold is reached, treat with (1) valganciclovir 900-mg1p.o. BID, or (2) IV ganciclovir 5-mg/kg IV every 12 h until negative test
Liver	D+/R–	Antiviral prophylaxis is preferred Drugs: valganciclovir (note FDA caution2), oral ganciclovir or intravenous ganciclovir Duration: 3–6 months Preemptive therapy is an option Weekly CMV PCR or pp65 antigenemia for 12 weeks after transplantation, and if a positive CMV threshold is reached, treat with (1) valganciclovir 900-mg 1p.o. BID, or (2) IV ganciclovir 5-mg/kg IV every 12 h until negative test
	R+	Antiviral prophylaxis Drugs: Valganciclovir, oral ganciclovir or intravenous ganciclovir Duration: 3 months Preemptive therapy Weekly CMV PCR or pp65 antigenemia for 12 weeks after transplantation, and if a positive CMV threshold is reached, treat with (1) valganciclovir 900-mg1 p.o. BID, or (2) IV ganciclovir 5-mg/kg IV every 12 h until negative test
Heart	D+/R–	Antiviral prophylaxis is preferred Drugs: valganciclovir, oral ganciclovir or intravenous ganciclovir Some centers add adjunctive CMV immune globulin Duration: 3–6 months Preemptive therapy is an option Weekly CMV PCR or pp65 antigenemia for 12 weeks after transplantation, and if a positive CMV threshold is reached, treat with (1) valganciclovir 900-mg1 p.o. BID, or (2) IV ganciclovir 5-mg/kg IV every 12 h until negative test
	R+	Antiviral prophylaxis Drugs: Valganciclovir, oral ganciclovir or intravenous ganciclovir Some centers add adjunctive CMV immune globulin Duration: 3 months Preemptive therapy Weekly CMV PCR or pp65 antigenemia for 12 weeks after transplantation, and if a positive CMV threshold is reached, treat with (1) valganciclovir 900-mg1p.o. BID, or (2) IV ganciclovir 5-mg/kg IV every 12 h until negative test
Lung, heart–lung	D+/R–	Antiviral prophylaxis Drugs: valganciclovir or intravenous ganciclovir Duration: 12 months. Some centers prolong prophylaxis beyond 12 months Some centers add CMV immune globulin
	R+	Antiviral prophylaxis Drugs: valganciclovir or intravenous ganciclovir Duration: 6–12 months
Intestinal	D+/R–, R+	Antiviral prophylaxis Drugs: Valganciclovir or intravenous ganciclovir Duration: 3–6 months
Composite tissue allograft	D+/R–, R+	Antiviral prophylaxis Drugs: valganciclovir or intravenous ganciclovir Duration: 3–6 months

Note:
1.D+R–: Donor CMV seropositive and recipient CMV seronegative
2.R+: Recipient CMV seropositive
Table adopted from Cytomegalovirus in Solid Organ Transplantation and Updated International Consensus Guidelines on the Management of Cytomegalovirus in Solid-Organ Transplantation