Antivirals for CMV

Twenty five years ago cytomegalovirus (CMV) infection was the most serious pathogen in transplant recipients. CMV pneumonia was common and led to graft dysfunction and death. Antivirals for CMV together with sensitive viral assays have allowed much better control of CMV infection.

Although these drugs will be initiated in specialist centres, it is important to understand the nature of CMV infection, the rationale for use of the drugs and of shared care protocols.

CMV is a member of the Herpesviridae subfamily and has similarities with other members of the Herpes family of viruses including the ability to cause latent and persistent infections. CMV infection is ubiquitous in populations worldwide with prevalence rates for CMV infection ranging from 40-100%. Rates of infection rise with age.

In immunocompetent hosts CMV infection is usually asymptomatic but can produce mild flu-like symptoms. It can produce a Glandular Fever (Infectious Mononucleosis) like illness. Mortality in these circumstances is negligible.

It is best recognised for causing disease in immunocompromised hosts (most commonly in patients with deficient cell mediated immunity) with the rise of HIV infection, AIDS and the increased use of immunosuppressive medications. Latent CMV infection may reactivate when the host is immunocompromised from the effect of:

• Drugs (For example immunosuppressive drugs used in transplant surgery). Infection most commonly arises in donor positive/ recipient negative infections¹ except in the case of bone marrow transplantation where it is equally common in either circumstance. CMV pneumonia can occur after transplantation. It is more common after bone marrow transplantation than after solid organ transplantation. Before ganciclovir mortality was over 85%.
• Infection (for example HIV). CMV disease can then affect almost every organ. Mortality in these circumstances can be very high depending on type of infection and treatment. Retinitis is the most common manifestation of CMV infection in HIV positive patients. The incidence of CMV retinitis has dropped with use of antiretroviral therapy.

CMV infection in pregnancy

CMV infection in pregnancy can affect the placenta causing intrauterine infection and in 10% of cases this may cause cytomegalic inclusion disease in the child and/or foetus with a poor prognosis. CMV is the most common cause of congenital infections in humans and the sequelae include deafness and mental retardation.² As there are different strains of CMV, previous infection does not exclude the possibility of infection with a new strain followed by intrauterine infection.

• Treatment of CMV infection in immunocompromised patients
• Prevention of CMV infection in immunocompromised patients.

Ganciclovir

• It is related to aciclovir but both more active against CMV and more toxic.
• It is used mainly orally for prophylaxis of CMV disease in transplant patients. Usually it is given for 3 months. Resistance can occur when given over a long period.
• It is used with immunoglobulin for CMV pneumonia.
• It is used intravenously to give higher serum levels for initial treatment of CMV retinitis in AIDS patients.
• It can be used locally (i.e. implanted into the vitreous) for treatment of CMV retinitis.
• Other uses include treatment of gastrointestinal and CNS CMV disease.
• Handling caution: personnel should be adequately protected (for example by wearing double layer gloves) during handling and administration as the drug is toxic. Wash off immediately with soap and water if the solution comes into contact with skin or mucosa.³

Valganciclovir

• It is an ester of ganciclovir.
• It too is used in CMV retinitis both for initial induction (at higher dose) usually for 21 days and then for maintenance at half the dose.
• It is used for prophylaxis of CMV disease in solid organ transplant patients, usually where the donor is CMV positive.
• Handling caution: protect hands with gloves when handling tablets as the drug has carcinogenic and teratogenic potential. Wash off with soap and water immediately if contact with skin or mucosa.³

Foscarnet

• It is more toxic and usually a second line drug.
• It is used intravenously for CMV retinitis (and also for mucocutaneous herpes simplex not responding to first line drugs in the immunocompromised).

Cidovir

• Even more toxic and usually third line after foscarnet for CMV retinitis.
• It is usually given with probenecid.
• It is particularly nephrotoxic.
• It can be used for local treatment of CMV retinitis.
• Handling caution: personnel should be adequately protected during handling and administration. If solution comes into contact with skin or mucosa wash off immediately with water.³

Cytomegalovirus infection after transplantation

The best approach to management is uncertain. Some centres with low prevalence of CMV disease may adopt a "watch-and-wait" policy, treating patients if they develop clinical evidence of CMV infection.⁴

Current opinion favours active management during the first few months after transplantation.^5,6 The 2 basic approaches to preventing CMV infection are universal prophylaxis (antiviral therapy for all patients after transplantation, usually 90 days) and pre-emptive therapy (monitoring of patients using viral assays every 1-2 weeks and giving a few weeks of treatment if tests are positive). The major controversy in the management of CMV infection after solid organ transplantation is which of these approaches is best. The former could lead to resistant organisms, but avoids the need for such frequent monitoring. The latter is cheaper and minimizes drug toxicity. A meta-analysis⁷ compares the two approaches and shows that both substantially reduce CMV disease and episodes of acute rejection.
Antiviral drugs are now more potent and with the newer prodrugs serum levels after oral administration are similar to levels after intravenous therapy.^8,9 More trials to establish optimal doses and duration of treatment are needed.¹⁰

Cytomegalovirus, HIV and AIDS

CMV is, after Pneumocystis carinii and Candida, the third most common pathogen in AIDS patients.

Cytomegalovirus retinitis

This is a common manifestation of CMV disease in HIV infection. Patients report loss of visual acuity, floaters and field defects starting on one side. Ganciclovir orally has been used to treat this, but may only slow progression. Foscarnet may be used. Ganciclovir implanted in the vitreous is also used, usually with systemic therapy.

Cytomegalovirus gastrointestinal disease

This was first described in the 1960s and CMV colitis is second most common CMV infection in AIDS patients (second to CMV retinitis). CMV infection occurs in steroid- dependent ulcerative colitis. This complicates both diseases and about 2/3 of patients with steroid- refractory ulcerative colitis have CMV colitis and a much worse prognosis results.

Cytomegalovirus pneumonia

This occurs most often in patients receiving bone marrow transplants but also occurs in HIV infection. It is difficult to treat even with new antivirals.

Congenital cytomegalovirus infection

There is as yet no generally accepted antiviral therapy for treatment of symptomatic congenital CMV infections. Valganciclovir has been tried.²

Initiation is in specialist centres and investigations are determined by the particular clinical scenario. Investigation may include:

• Diagnostic tests including sensitive viral assays
• Full blood count, platelets-some can cause neutropenia
• Renal function
• Pregnancy testing
• Ophthalmology assessment

These drugs are initiated in specialist centres but the use of shared care protocols is essential to assist monitoring of patients for complications of the disease and complications of treatment. Attention is drawn to the handling cautions with ganciclovir, cidofovir and valganciclovir. Generally administration in hospital is by doctors with suitable training and gloved skin protection.

See individual drugs, but consider
Caution in:

• Renal impairment
• Diabetes (hydration)
• Cytopenias

• Concomitant use of other nephrotoxic drugs
• Pregnancy. There are also important considerations with respect to conception in men and women. (For example with cidofovir avoid pregnancy during treatment and for 1 month after treatment. Men should avoid fathering children for 3 months after treatment).
• Breast feeding

See individual drugs, but consider:

• General effects (fatigue with all drugs)
• Gastrointestinal effects (nausea, vomiting, diarrhoea)
• Nephrotoxic effects
• Ocular disorders (cidofovir)
• Psychiatric effects ( particularly ganciclovir and its prodrug valganciclovir)
• Hepatic dysfunction
• Cardiovascular effects (particularly foscarnet)
• Marrow suppression
• Rashes
• Anaphylactic reactions

Any drugs which share toxic effects should be considered carefully. Zidovudine given with ganciclovir causes profound marrow suppression.

Explicit guidance for all physicians sharing the care of patients should be given detailing treatment plans, monitoring and protocols for management of common complications. The following is an example of an outline of the shared care protocol for a liver transplant patient similar to that used at King's College Hospital in London:

This should be included in shared care protocols.