CASE 34-10, QUESTION 3: Is there any way to prevent CMV in high-risk patients such as A.A.?
Because of its significant consequences, efforts should be made to prevent CMV
disease. Many studies have tried to ascertain the easiest, most cost-effective regimen
These studies have focused on the combined use of different agents as well as IV
followed by oral therapies. Trials have also targeted high-risk patients and assessed
the use of CMV PCR monitoring, without the use of universal prophylaxis therapy
The use of both the IV and oral formulations of ganciclovir to prevent CMV
disease has been studied in liver and kidney recipients.
been conducted, and most of the data in the solid organ transplantation population are
from small uncontrolled trials. Another difficulty lies in that large discrepancies exist
widely used prophylactic agent.
In the United States, oral ganciclovir therapy has not been commercially available
for a number of years. Thus, most transplant centers are now solely using
valganciclovir therapy as their first-line agent. IV ganciclovir is still available and
can be used for short periods if the patient is not able to tolerate oral therapy.
Valganciclovir was developed because oral ganciclovir has a very low
bioavailability (<10%). Valganciclovir is the L-valyl ester of ganciclovir, which is a
prodrug that is rapidly and completely converted into ganciclovir by hepatic and
intestinal esterases once absorbed across the GI tract. The absolute bioavailability of
valganciclovir is approximately 60%, so that a 900-mg single PO dose given with
food is an AUC equivalent to a 5 mg/kg IV dose of ganciclovir. This is roughly twice
the AUC achieved by 1,000 mg of ganciclovir given orally TID. Valganciclovir is
currently FDA-approved for the treatment of HIV-associated CMV retinitis and to
prevent CMV disease in heart, kidney, and pancreas transplantation.
Valganciclovir is not FDA-approved for prevention of CMV disease in liver
transplantation, although it is often used in such cases. Several small studies have
demonstrated that valganciclovir is effective in treating CMV infection preemptively
and potentially preventing CMV disease.
Because valganciclovir is very expensive and has a high potential for causing
hematologic toxicities, several studies have been conducted using reduced dosing
strategies. Most use half the recommended dose of 900 mg PO daily in patients with
good renal function and have shown equivalent clinical outcomes with the potential
of reducing cost and toxicities. These studies were conducted in kidney transplant
patients, and the dosing of this agent is transplant center-specific based on
One published meta-analysis of 12 trials that included 1,574 patients evaluated
valacyclovir as a prophylactic agent in transplant recipients.
found to be more effective than acyclovir in preventing herpes viruses, including
CMV. Most transplantation centers, however, do not use valacyclovir for routine
prophylaxis of CMV, and still consider valganciclovir first line.
Cytomegalovirus Hyperimmune Globulin
The role of CMV hyperimmune globulin in preventing CMV disease is controversial.
Many studies have combined this agent with either oral acyclovir or ganciclovir, but
because of its high cost and IV route, its use as a prophylactic agent has decreased. In
addition, in patients who are D+/R−, results have been mixed.
A.A. has several risk factors that predispose him to developing CMV disease. At
the time of transplantation, A.A. was CMV D+/R−, which means that he has about an
80% chance of developing CMV infection and a 40% chance of developing CMV
disease. In addition, A.A. had an early acute rejection episode, which means he
received higher doses of immunosuppression, also putting him at higher risk for
developing CMV disease. Because of these risk factors, A.A. should have (and did)
receive CMV prophylaxis for at least 3 months after transplantation. Some centers
may extend prophylaxis to 6 months post-transplant in patients like A.A. A.A.
developed CMV disease and is being treated with ganciclovir 190 mg every 12 hours
IV. Once A.A. is tolerating oral medications, he can start receiving oral
valganciclovir at a dose of 900 mg twice daily with food. Because A.A. has renal
insufficiency, his oral valganciclovir dose will be adjusted to 450 mg daily.
Cytomegalovirus Resistance to Anti-viral Therapies
Although uncommon, CMV resistance to anti-viral therapies, as defined by continued
viral replication despite prolonged treatment, may be present in 5% to 12% of
patients that have a high-risk serostatus (D+/R−). There have been two primary gene
mutations associated with this resistance, one to the UL97 kinase and the other to the
UL54 DNA polymerase gene. The vast majority (90%) of resistant strains to
As illustrated by A.A.’s case, a patient who has received prophylactic therapy
does not preclude the development of CMV disease after the prophylaxis is
withdrawn or, in rare instances, during prophylactic therapy. The incidence of CMV
disease while receiving valganciclovir is significantly lower when compared to oral
ganciclovir, probably because drug exposure is approximately 2 times higher.
Because of recent advances in the laboratory tests used to identify and quantify CMV;
because prophylactic therapy is not always effective; and because it is often toxic
and very expensive, preemptive therapy has also been used to prevent CMV disease.
The technique involves withholding prophylactic therapy and monitoring laboratory
tests to identify presymptomatic CMV viremia, usually by using serum CMV DNA
PCR. Once a patient develops viremia (CMV PCR viral load >2,000 copies/mL),
he/she receives treatment with IV ganciclovir or oral valganciclovir. This strategy
has been prospectively studied and is as effective as universal prophylaxis, with
some potential cost advantages. However, a few recent studies have demonstrated a
controversial, with many centers still using universal CMV prophylaxis in all solid
Post-transplantation Lymphoproliferative Disorder
therapy. She received tacrolimus and prednisone after transplantation and had MMF added to her
(4 weeks) for CMV infection. The donor was CMV-positive, and she is CMV-positive. Her EBV DNA PCR is
clinicalsigns and risk factors in A.L. are associated with lymphoma?
A.L. has developed a PTLD, one of many types of malignancies that have been
reported after solid organ transplantation. The exact etiology of this condition is
unclear and probably multifactorial. The presentation of PTLD varies significantly.
Patients can present asymptomatically, with mild mononucleosis-like symptoms or
with multiorgan failure. A.L. presents with fever, lymphadenopathy, malaise, and
lack of appetite. Although these symptoms are consistent with PTLD, they also are
consistent with infection. Because PTLD can involve various organ systems, patients
can present with organ-specific symptoms (e.g., acute abdominal pain, perforation,
obstruction, bleeding if a tumor is in the GI tract). Depending on its location, a tumor
can impinge on the function of other organs, as seen in A.L.
immunosuppression, two factors that have been strongly associated with PTLD are
the presence of EBV and the age of the patient. Children have a higher incidence of
97 A.L. developed EBV DNA viremia, indicating that she had been exposed to
this virus at the time of transplantation or afterward. EBV also can be transmitted
from the donor liver and/or blood products. Also, EBV-positive recipients at the
time of transplantation can experience reactivation of this virus as a result of
A.L. received a significant amount of immunosuppression. This could lead to an
inability to suppress an active viral infection by cytotoxic T cells and result in
uncontrolled B-cell proliferation and polyclonal and monoclonal expansion. In
addition to this T-cell defect, an imbalance or alteration in cytokine production in
primarily of B-cell origin. Small percentages are of T-cell origin, however, and are
96 The incidence and detection of PTLD has increased. Newer, more
potent immunosuppressive agents used in different combinations, increased numbers
of transplantation procedures, and closer monitoring contribute to this phenomenon.
When cyclosporine-based regimens were compared with azathioprine or
cyclophosphamide-based regimens, lymphomas made up 26% and 11% of all
cancers, respectively. The lymphomas occurred, on average, within 15 months after
compared with only 11% in the latter group.
The incidence of PTLD increases with rabbit antithymocyte globulin therapy and
appears to be related to a cumulative dose and multiple courses. PTLD is not caused
by any single agent but probably reflects the intensity of immunosuppression with
multiple agents. Chronic antigenic stimulation by foreign antigens, repeated
infections, genetic predisposition, and indirect or direct damage to DNA are other
variables that might affect the development of PTLD.
infection, which also could have contributed to this process.
As a percentage of all malignancies, PTLD occurs more commonly in thoracic than
in other types of solid organ transplants and is even more common in children.
Lymphomas develop in about 1% of kidney transplantations and 2% of liver
transplantations. These tumors often appear early and progress rapidly. The overall
prevalence of malignancies in the transplantation population averages about 6%, and
the risk of cancer increases with time after a transplantation. Major organ transplant
recipients are 100 times more likely to have cancer than the general population.
Furthermore, the most common types of cancer observed in transplant recipients
(e.g., lymphomas, cancer of the skin and lips) are uncommon in the general
population. The development of skin and lip cancers in the transplant population has
been attributed partially to exposure to sunlight and sensitization of skin to sunlight
by an azathioprine metabolite, methylnitrothioimidazole.
CASE 34-11, QUESTION 2: What are the therapeutic maneuvers and outcomes that would be expected in
Treatment of a PTLD depends on timing, presentation, symptoms, extent of
involvement, histologic type, and transplant type. Early experiences with PTLD
indicated that reduction or discontinuation of immunosuppression led to regression of
the cancer. Therefore, the first step in treating PTLD is to consider the
discontinuation of all immunosuppressives, with the potential exception of the
corticosteroids. This course of action is not feasible for A.L., however, because her
transplanted liver is essential for her life. Immunosuppressive drugs can be
discontinued in kidney recipients because dialysis can be reinstituted. A.L. will need
chemotherapy for her cancer. Therefore, her MMF probably should be discontinued
to minimize the potential for severe bone marrow toxicity. Additionally, A.L. will
likely have a small reduction in her tacrolimus doses, with the goal of achieving
trough concentrations on the lower end of her therapeutic range (4–6 ng/mL); her
prednisone should also be reduced to the lowest dose possible. If her
immunosuppressive drug therapy is diminished, she should be monitored closely for
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