Hepatitis C

Another virus that is a major cause for concern is hepatitis C. Hepatitis C is currently

the most common reason for liver transplantation, and recurrence of hepatitis C viral

replication after transplantation is universal.

83 Overimmunosuppression can have a

significant detrimental effect on this disease after transplantation. Survival rates are

significantly lower at 5 years after transplant compared with patients who received

liver transplants for non-hepatitis-C causes.

83 Recently, there have been dramatic

advances in the treatment of hepatitis C, with the advent of noninterferon-based

direct-acting antiviral (DAA) therapies. Preliminary studies have demonstrated

sustained virologic response rates of >70%, as compared to rates of 30% to 50%

with interferon-based therapies. In addition, the DAA therapies have a much

improved tolerability profile, with less cytopenias and limited constitutional

symptoms, thus substantially reducing the need to hold or discontinue therapy, as

compared to interferon and ribavirin.

84,85

Cytomegalovirus

CASE 34-10

QUESTION 1: A.A., a 58-year-old, 76-kg man with end-stage liver disease caused by alcoholic cirrhosis,

received an orthotopic liver transplant 4 months ago. He presents to the transplantation clinic with a 7-day

history of generalized malaise, fatigue, nausea, vomiting, diarrhea, low-grade fevers, and anorexia. At the time

of transplantation, the liver he received was positive for CMV antibody, but he had negative CMV serology

(CMV naïve). His postoperative immunosuppressant regimen included oral prednisone and tacrolimus 5 mg PO

BID, with adjustments made to his dose to maintain a 12-hour trough concentration between 6 and 12 ng/mL.

He was also given valganciclovir 450 mg PO daily for 3 months.

His postoperative course was complicated by an acute rejection episode on postoperative day 19, which was

treated successfully with a pulse and taper of steroids. At that time, MMF 1 g PO BID was added to his

immunosuppressant regimen. He was discharged from the hospital on postoperative day 24, with instructions to

return to the transplant clinic in 4 days. Since then, he has done fairly well with no complaints until now, 4

months later. On admission to the hospital, a physical examination was remarkable for an oral temperature of

38.8°C, a BP of 112/79 mm Hg, a heart rate of 104 beats/minute, a respiratory rate of 22 breaths/minute, and a

mild tremor. All other findings on his examination were benign. Pertinent laboratory findings include the

following:

WBC count, 3,400 cells/μL

Platelet count, 34,000 cells/μL

BUN, 29 mg/dL

SCr, 1.4 mg/dL

Total bilirubin, 2.2 mg/dL

AST, 62 IU/L

ALT, 126 IU/L

CMV PCR 184,000 copies/mL (normal <500 copies/mL)

12-hour tacrolimus concentration, 18.3 ng/dL

His current medications include tacrolimus 6 mg PO BID; MMF 750 mg PO BID; prednisone 10 mg PO

daily; TMP–SMX 80 mg PO Mondays, Wednesdays, and Fridays; calcium carbonate 1.25 g PO TID; vitamin

D 800 IU PO daily; enteric-coated aspirin 325 mg PO daily; and nizatidine 150 mg PO BID. What is the most

likely diagnosis for A.A.?

A major concern in A.A. at this time after transplantation is CMV infection, which

is commonly encountered within 1 to 6 months after solid organ and bone marrow

transplantation. It is a ubiquitous virus belonging to the herpes virus group. In healthy

immunocompetent adults, infection with the virus is usually asymptomatic, whereas

in immunocompromised patients, CMV can cause significant morbidity and mortality.

CMV can potentiate the risk for developing bacterial and fungal infections and induce

chronic injury to the transplanted organ (arteriosclerosis in the heart, obliterative

bronchiolitis in the lungs, vanishing bile duct syndrome in the liver, and chronic

arteriopathy in the kidneys).

86

ETIOLOGY

Cytomegalovirus infection in transplant recipients usually occurs when latent viruses

from a seropositive donor organ are reactivated owing to immunosuppression.

Without prophylaxis, transmission of CMV from a positive donor to a negative

recipient leads to an 80% to 100% infection rate and a 40% to 50% disease rate; a

positive donor to a positive recipient leads to a 40% to 60% reactivation rate and a

20% to 30% disease rate; and a negative donor to a negative recipient leads to a 0%

to 5% infection rate. Transplant recipients at highest risk for developing the disease

are (a) those who are or have serologically positive donor and negative recipient

(D+/R−) at the time of transplant, (b) elderly, (c) those who received antilymphocyte

antibodies, (d) those who received a retransplantation because of acute rejection, and

(e) those who received larger amounts of immunosuppressive agents.

86 A.A. is at

high risk of CMV infection and disease because his CMV serology is D+/R−, he was

treated for rejection, and his immunosuppression regimen is fairly intense for a liver

transplant recipient.

DIAGNOSIS

Diagnosis of CMV is based on both clinical and laboratory findings. CMV may be

detected by culturing body fluids, such as bronchoalveolar lavage, urine, blood, and

tissue biopsies. CMV is contained within the host’s leukocytes, which appear to have

large intranuclear inclusion bodies. CMV PCR is now readily available with rapid

turnaround in most centers for measuring viral loads in the patient’s serum.

Documented viral shedding alone is not, however, diagnostic for active disease

without clinical signs and symptoms.

87 A.A. has laboratory findings consistent with

CMV infection: viral shedding, as indicated by the CMV PCR of 184,000 copies/mL,

leukopenia, thrombocytopenia, and clinical symptoms consistent with CMV infection,

including malaise, fatigue, nausea, vomiting, diarrhea, and anorexia.

CLINICAL MANIFESTATIONS

In healthy immunocompetent adults, the CMV-infected individual is usually

asymptomatic but may present with mild complaints of malaise, fever, and myalgias,

as well as abnormal liver enzymes and lymphocytosis. More severe reactions are

rare.

86,87 CMV may, however, be life-threatening in the immunocompromised.

Evidence indicates that CMV infection is associated with graft

p. 741

p. 742

rejection and that graft rejection in the setting of immunosuppression further

exacerbates CMV infection. It often is unclear which comes first. The actual CMV

course may be limited to fever and mononucleosis, or it may extend to organs

presenting as pneumonitis, hepatitis, gastroenteritis, colitis, disseminated infection,

encephalopathy, or leukopenia.

A.A.’s clinical presentation meets the criteria for CMV disease: viremia with

clinical signs and symptoms. At this time, it is unclear whether or not A.A. has any

end-organ involvement/disease. His liver enzyme concentrations are elevated, and he

is having numerous GI symptoms (nausea, vomiting, diarrhea, and anorexia), which

may be indicative of CMV hepatitis, CMV gastroenteritis, or CMV colitis,

respectively. Alternatively, the increased total bilirubin and serum transaminases

may be caused by acute rejection, and his GI problems and leukopenia may be a side

effect he is experiencing from his medications (e.g., MMF). To fully differentiate

among CMV hepatitis, CMV gastroenteritis, CMV colitis, acute rejection, and

medication side effects, tissue biopsies should be obtained.

CASE 34-10, QUESTION 2: What are the treatment options for A.A.’s diagnosed CMV disease? What

doses should be used, and how should the effects of these drugs be monitored?

Ganciclovir

Before ganciclovir was available, CMV infection was “treated” by reducing the

level of immunosuppression. This may be one of the explanations for an increased

prevalence of rejection associated with CMV infections. Graft loss in kidney

recipients is undesirable; yet, it is not immediately life-threatening because a patient

may return to dialysis. Reducing immunosuppression in liver recipients, however,

could result in the patient’s death owing to graft loss. Treatment has been largely

unsuccessful with acyclovir, adenine arabinoside, and immune globulin. Ganciclovir

is the first-line agent for the treatment of CMV disease in solid organ transplant

recipients. Although ganciclovir is highly efficacious, there is still a potential 20%

relapse rate of CMV after ganciclovir therapy in liver transplant recipients.

Ganciclovir, a virostatic agent, is a nucleoside analog that is phosphorylated in

infected cells to its active form and is then incorporated into replicating viral DNA.

Although ganciclovir-resistant strains of CMV have been isolated, their occurrence is

far more common in patients with HIV; currently, ganciclovir-resistant CMV in solid

organ transplantation is not a large concern. A.A. should receive ganciclovir IV, or

oral valganciclovir for mild CMV disease; a recent study has demonstrated

equivalence between IV ganciclovir and oral valganciclovir. Because relapses of

CMV disease after treatment are of concern, some suggest that patients should be

placed on maintenance therapy with valganciclovir or oral acyclovir after the IV

course is completed.

88

Dosing

In patients with normal renal function, the usual dose of ganciclovir is 5

mg/kg/dose every 12 hours and the usual dose of valganciclovir is 900 mg PO BID,

both for 14 to 21 days. Dosage adjustment is necessary for patients with renal

dysfunction with either agent. Because A.A. has an estimated creatinine clearance of

60 mL/minute, he should receive 2.5 mg/kg/dose (190 mg) IV every 12 hours for 2 to

3 weeks, followed by maintenance valganciclovir 450 mg PO daily for 2 to 4 weeks.

The most common adverse effect associated with ganciclovir therapy is

neutropenia, occurring in up to 27% of patients.

87 Neutropenia is defined as an

absolute neutrophil count of less than 500 to 1,000 cells/μL. The neutropenia usually

resolves with a decrease in dosage or discontinuation of the drug, but colonystimulating factors increase the total white count.

88 Because CMV disease has a

propensity to cause neutropenia as well, it is often difficult to distinguish the cause. If

laboratory findings and clinical signs and symptoms of CMV disease are resolving

and the patient remains neutropenic, the most likely cause is ganciclovir.

Thrombocytopenia occurs in approximately 20% of ganciclovir recipients. Patients

with initial platelet counts less than 100,000/μL appear to be at greatest risk. Other

adverse effects include CNS effects, fever, rash, and abnormal LFT findings.

86,87

A.A.’s WBC with differential and platelet counts should be assessed every 3 to 4

days during therapy, and ganciclovir should be held if neutrophils fall to less than

500/μL or platelets fall to less than 25,000/μL. To monitor either the regression or

progression of A.A.’s CMV disease, a weekly serum CMV DNA PCR should be

obtained.

Immunoglobulins

The use of immunoglobulins to treat CMV disease in solid organ transplantation is

controversial. They are expensive and sometimes in short supply. Immunoglobulins

provide passive immunization by potentiating an antibody-dependent, cell-mediated

cytotoxic reaction. Basically, the immunoglobulins modify the immunologic response

that damages host tissue. Some evidence suggests that immunoglobulins may have

synergistic or additive effects with current antiviral drugs in the treatment of CMV

disease.

88 Both unselective immunoglobulins and CMV hyperimmune globulin have

been studied in combination with ganciclovir. CMV hyperimmune globulin is

prepared from high-titer pooled sera that have a fourfold to eightfold enrichment of

CMV titers compared with unscreened immunoglobulin.

Cytomegalovirus immunoglobulin may be given as 100 mg/kg/dose every other day

for 14 days. This is the dose recommended for treatment of CMV when used in

combination with ganciclovir. The most common adverse effects associated with the

administration of immunoglobulins are infusion related and include fever, chills,

headache, myalgia, light-headedness, and nausea and vomiting.

Foscarnet

Foscarnet is a virostatic pyrophosphate analog that inhibits DNA synthesis; however,

unlike ganciclovir, no phosphorylation is required for activation. Because this drug

has a high nephrotoxicity propensity and because most transplant recipients are

already receiving drugs that are nephrotoxic, experience with the use of foscarnet in

solid organ transplantation is limited. In most centers, foscarnet is a second-line or

third-line agent to be used only if intolerance or resistance develops with ganciclovir

therapy.

The usual dosage of foscarnet is 60 mg/kg/dose every 8 hours for 14 to 21 days.

The dosage should be reduced in patients with renal dysfunction. The most serious

adverse effect with foscarnet is nephrotoxicity, which occurs in up to 50% of patients

and is probably induced by acute tubular necrosis. Therefore, prehydration is

suggested to help minimize or avoid nephrotoxicity. GI effects, a decrease in

hemoglobin and hematocrit, an increase in LFTs, and alteration of serum electrolyte

concentrations are other side effects of foscarnet. All of these appear to be reversible

on discontinuation of the drug. SCr should be monitored daily during therapy.

87