CMV Antiviral Prevention Strategies in D+R-Liver Transplants ("CAPSIL")

This is a prospective, randomized, multicenter trial of preemptive therapy vs. prophylaxis
for prevention of Cytomegalovirus (CMV) disease in seronegative recipient- seropositive donor
(R-D+) liver transplant patients.Subjects will be randomized within 10 days of transplant to
receive in an open label design, either antiviral prophylaxis with valganciclovir 900 mg
orally once daily or preemptive therapy for 100 days post-randomization with initiation of
oral valganciclovir 900mg orally twice daily at onset of CMV viremia (monitored weekly) and
continued until plasma PCR is negative on two consecutive weekly PCR tests. Study
participants will be followed during the intervention period (100 days post randomization)
and until 12 months post-transplant for CMV disease, toxicity, and clinical outcomes
(opportunistic infections, rejection, graft loss and mortality). Drug safety labs will be
assessed and recorded for the entire treatment period in both the prophylaxis and preemptive
group. Re-transplantation and all-cause mortality will also be assessed at study closure and
no longer than 5 years after enrollment. Additionally, the impact of the two CMV prevention
strategies on CMV-specific cellular and humoral immune responses will be evaluated at 100
days after randomization, and 6 and 12 months post-transplant. A minimum of 176 subjects will
be enrolled in the study. Allowing for over-enrollment to replace dropouts, up to 205
subjects may be enrolled to achieve the target enrollment of 176. Subjects will be randomized
into one of the two groups in 1:1 ratio. The study duration is 7 years. The primary objective
of this study is to compare prophylaxis versus preemptive therapy using valganciclovir for
the prevention of CMV disease in R-/D+ liver transplant recipients. The secondary objectives
are:1) to assess the two preventive strategies for clinical outcomes (major bacterial, fungal
and non-CMV viral infections, rejection, graft loss and mortality) at one year post
transplantation; 2) to assess the two preventive strategies for hematologic toxicity
(assessment of neutropenia and receipt of hematopoietic growth factor during study days
1-107).

Inclusion Criteria:

1. Be > / = 18 years of age.

2. Have negative Cytomegalovirus (CMV) serology (confirmed within 6 months of transplant)
and receive a liver from a donor with positive CMV serology (R-/D+).

3. Have received their first orthotopic liver transplant (the transplanted liver may be
deceased donor or live donor graft) within 10 days prior.

4. Have absolute neutrophil count > 1000/µL at randomization.

5. - If female, and not postmenopausal or surgically sterile, must have negative
pregnancy test (serum or urine) within 48 hours prior to randomization and must also
agree to use medically approved method of contraception. Acceptable methods include:
barrier method, intrauterine device (hormonal or non-hormonal), oral hormonal
contraceptives, abstinence for 100 days after randomization and 3 months after
valganciclovir cessation.

-- If male, and has not had a vasectomy, he must agree to practice barrier method of
contraception for 100 days after randomization and 3 months after valganciclovir
cessation.

6. Subject or legally authorized representative has provided written informed consent.

Exclusion Criteria:

1. Currently enrolled in any interventional trial of an investigational therapeutic agent
unless co-enrollment has been approved by study Principal Investigators (PIs) and the
DMID prior to enrollment.

2. Have hypersensitivity to acyclovir, ganciclovir or valganciclovir.

3. Be breast-feeding mother.

4. Have known Human immunodeficiency virus (HIV) infection (based on testing performed
during the transplant evaluation process).

5. Be undergoing multi organ transplant or have undergone prior organ transplant.

6. Have expected life expectancy of less than 72 hours.