by George Taniwaki

The human cytomegalovirus (CMV), a member of the Herpesvirus genus, is highly contagious and quite widespread. It is estimated that over two-thirds of all adults have anti-CMV antibodies in their blood and the proportion of the population exposed increases with age.

CMV infection is usually quite mild. Most people who have it don’t even know it. However, it can cause serious illness and death to those who are immunocompromised such as infants, the elderly, patients with HIV infection, and patients who have received a bone marrow or organ transplant. An excellent primer on CMV and its impact on kidney transplants in provided in the J. Amer. Soc. Nephr. Apr 2001.

Because CMV is so common, it is impossible (both mathematically and ethically) to avoid using donor kidneys that are infected, even when transplanting into a patient who tests negative for CMV antibodies.

As can be seen in the table below, the infection risk is lower for patients who test negative for CMV antibodies (possibly because they have a natural immunity to the virus). It is also lower for patients who receive a kidney from a donor who tests negative (since the kidney is less likely to carry the virus). The percentages in each group assumes random distribution of CMV among donor and patient populations.

Level of risk and (% of population) Patient CMV-
Lower risk  (33%)
Patient CMV+
Higher risk (67%)
Donor CMV-
Lower risk (33%)
Lowest risk (11%) Low risk (22%)
Donor CMV+
Higher risk (67%)
High risk (22%) Highest risk (45%)

 

For solid organ transplant recipients, CMV is the most common serious viral infection. Medscape notes that, “CMV infection usually develops during the first few months after transplantation and is associated with clinical infectious disease (e.g., fever, pneumonia, GI ulcers, hepatitis) and acute and/or chronic graft injury and dysfunction.”

The standard procedure to prevent or treat CMV infection is to prescribe ganciclovir, sold under the trade names Cytovene and Cymevene (Roche). Like other antiviral drugs, ganciclovir disrupts the replication of viral DNA.

Unfortunately, this drug has several limitations. First, widespread use of the drug seems to be leading to increased incidence of ganciclovir-resistant CMV infection. Second, the drug can cause serious side effects including hematological (blood) effects such as granulocytopenia (low white blood count), neutropenia (low neutrophil count), anemia (low red blood count), and thrombocytopenia (low platelet count). Third, animal studies showed it to be a potential human carcinogen, teratogen, and mutagen.

image

Figure 1. Replication of long chain of viral DNA by CMV. Image from New Engl. J. Med.

New therapy option

A new drug to prevent or treat CMV called letermovir is currently under investigation. In the New Engl J. Med. May 2014 (subscription required), Roy Chemaly and his coauthors report that among patients receiving hematopoietic stem-cell transplants (bone marrow transplants), use of letermovir significantly reduced the incidence of CMV infection and the level of viral DNA fell as the dose increased. This means the new drug is quite effective. Just as important, it had an acceptable safety profile. Patient taking even the highest dosage  did not report greater side effects than those taking the placebo. Specifically, it showed no hematologic toxicity or nephrotoxicity (kidney damage). An excellent discussion of this breakthrough is provided in an accompanying editorial that appears in the same issue. The editorial also highlights the higher reliability and sensitivity of quantitative polymerase chain reaction (PCR) to measure viral load and predict the onset of symptoms.

Naturally, additional studies will need to be conducted to test letermovir with patients receiving a solid organ transplant. But the initial test results are promising and give hope that within this decade fewer kidney transplant patients will lose their graft or their life due to CMV infection.

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