Q.686. Comment briefly on CMV infection in R.Tx.?
KIDNEY TRANSPLANT
 |
Allograft |
INFECTION (CONTIN.)
Q.685. What are the treatment options
for those patients?
A. Ptns. without
R. dis., giving [Interferon
alfa (IFNa) + ribavirin] 🠞approved for both initial ttt & ttt
of relapse of ch. hepatitis C. However, clearance of ribavirin is impaired
in R.I. and drug & its metabolites are not removed by
HDX. Thus, ribavirin is not
recommended é Cr. Cl. < 50 mL/min.
IFNa after Tx.: A Mj. block to IFNa use 🠞Ac.
Rj.. In addition to antiviral
activety, IFNa hs pleiotropic effects incl.[anti-proliferative & immunomodulatory
properties].
IFNa also 🠞cytokine gene expression, 🠝cell surface expression of
HLA Ag. & 🠝function
of natural killer cells, cytotoxic T cells &
monocytes.These immunostimulant effects 🠞enhanced allog.
Rj.
when IFNa is used in Tx. recip. é CMV or hepatitis C. Use of IFNa as
Prox. agnst CMV disease has been associated é a high incidence of steroid-resistant
allog. Rj.🠞graft loss. Most
studies 🠞🠝risk of Ac. Rj. (40-100%) in recip. ttted é IFNa for ch. HCV hepatitis. However, there’re some life-threatening
complications of HCV infec. in wch benefits of treating outweigh
the risk of allograft loss due to INFa therapy. The 2008 KDIGO
guidelines for HCV infection in CKD. recommend: monothpy é standard INFa only be
considered in kidney Tx. recip. é HCV infection
resulting in fibrosing cholestatic hepatitis or life-threatening vasculitis. Ptn. shd be clearly informed of risks
prior to therapy. Pegylated
IFNa: use late after Tx. was repient in 8 recipient ttted after a mean delay between
R.Tx. & antiviral ttt of 198 m.. No Rj. occ. dur. or after ttt. One ptn dev. HUS🠞graft loss.
Recommendations: The high cost, limited
efficacy incr. risk of Ac. Rj. & significant S.E. ass. é IFNa hv dampened 😐enthusiasm for
its use
in [R.Tx. + ch. HCV]. Consistent é this view is NIH
Consensus Statement on management of hepatitis C tht currently lists R.Tx.
as C.I. to ttt é interferon . However, there’re
some life-threatening
complications of HCV infc. in which benefits of ttt may justify the risk of
possible loss of R. allograft é INFa thpy. KDIGO 2008 G.L. for
HCV in C.K.D. recommend:Monothpy é standard INFa only be considered in kid.
Tx. recip. é HCV infc. resulting in “fibrosing cholestatic hepatitis” or “life-threatening
vasculitis”
& ptn. shd be clearly informed
of the risks prior to initiating
thpy.
Ribavirin
alone after Tx.: Less data
available on efficacy of ribavirin alone in ptn cannot be
ttted é IFNa. In 2 histologic
studies, ttt é ribavirin alone was ass. é improvement in
histologic parameters
in one study , but not another. Possible explanations for this disparity
are that, in the study showing improvement, initial histologic injection was more
severe, duration & dose of ribavirin were
higher & the report failed to incl. a control group. Tolerance to
ribavirin varied, é some ptns needs signif. amounts of Epo, while ag. hd to
be discontinued in others.
IFNa before Tx.: Safer but less cost-effective strategy
might be to treat ch. hepatitis C in DX. ptn., who’re considered Tx.
candidates, prior to Tx.. IFNa thpy of HCV-infected ptn undergoing HDX.
seems to have a beneficial effect on course of
liver disease following R.Tx., regardless of virological resp.. In addition to high
rates of sustained biochemical & virological resp. é this regimen, neither
recurrence of liver dis. nor an incr. risk of Rj. after subsequent Tx.
is a mj problem.
Recommendations: The 2008
KDIGO G.L. for HCV infection in CKD. sugg.: HCV-infected kid.
Tx. candidates be considered
for ttt é INFa before Tx..
Clearance of ribavirin is impaired in R.F. & is not
removed by HDX.. Similar concerns
apply to pegylated
interferon
because
of its long half-life. Thus, ribavirin should not be used in R.F. and, until data
demonstrate efficacy & safety are available, pegylated interferon
is not recommended in such
patients.
Q.686. Comment briefly on CMV infection in R.Tx.?
A. CMV
incr. é age, more than 2/3rds of recipient have Ig. G
+ve, .. Sources:
Reactivation of latent virus. or,
Iry infection é donor-derived virus é allogaft or blood
products. or,
Reactivation
of latent donor virus.
-
CMV. disease 🠞= [Infection + Sm.s or tissue invasion].
-
Risk is
highest é : 🠞+D/-R then,
+D/+R then, -D/+R then, –D/-R.
- OKT3 & thymoglobulin 🠞🠝risk of subsequent disease arises 1-6 m. post Tx., but Retina & G.I. 🠞
🠝6 m.
-
C. P.🠞[fever- malaise-leukopenia]. (see Q.
22).
-
Detection of CMV é blood, tissue fluid, best achieved by specific Ag. assay, PCR, and in tissue by immunohistochemistry.
-
* ttt.: (1) Reduce im/m. dose.
(2) I.V. Gancyclovir/2-4 w, foll. by oral
antiviral/2-3
m. – Valgancyclovir: 🠞much better absorbed (P.O) than gancyclovir.
* Prox.
: P.O. Valgancyclovir & Gancyclovir.
“CMV Terminology”.
CMV infection:
{Isolation of CMV virus or detection of viral proteins or nucleic
a. in any body fluid or tissue specimen}.
Viremia: [CMV isolation by
culture by using standard or shell
vial techniques].
Antigenemia:
[Detection of CMV pp 65 in leukocytes].
Primary CMV
infection: [Detection of CMV infc. in previously CMV
sero -ve].
Recurrent infc.:
[New detection of CMV
infection in previously documented infc. ptn.
who has not hd virus detected for interval of at least 4 w. e active surveillance].
Reinfection: [Detection
of a CMV strain tht is distinct from the strain tht ws the cause of the
patient’s original infection].
CMV GI. disease:[Combination of Sms
from upper/lower GIT, findings of macroscopic mucosal lesions
on endoscopy & demonstration of CMV infection (Culture,
histopath. testing, immunohistochemical analysis, or in situ hybridization) in a GI biopsy].
CMV hepatitis: {Increased
bilirubin and/or enzymes
e LFT., é abs. of any other
doc-umented cause of hepatitis & detection of CMV infection. (by culture,
histopathologic testing, immunohistochemical analysis, or321)`zin situ
hybridization) in liver biopsy}.
Resistance to
ttt.: The viral isolate UL97 mutation,
accounts for > 90 % of
ganciclovir-resistant CMV isolates. Point mutations in UL97
protein kinase gene lead to changes tht prevent
phosphorrylation of ganciclovir. This finding necessities a change to 2nd
-line therapy: foscarnet,
60 mg/kg/8
h.. After 2 wk. of full-dose, maintenance-dose (90-120 mg/kg
daily) of IV foscarnet shd be started. Recommendations for managing CMV
resistance are to incr. the dose of ganciclovir for mild/moderate dis. or switch to foscarnet
for more severe dis., with or without continued use of ganciclovir. (Medscape).
Preemptive therapy: is initiated to prevent the progression of CMV dis. when {Viral load reaches a predetermined threshold level in an a.Sm.tic ptn. who hs bn screened frequently for viral replication}.
Adv. :[Selective
use (vs universal) of antiviral agents & dcr. drug cost, fewer drug-associated
toxicities, and dcr. risk for late-onset CMV infc.]. Disadv. incl.: {High cost & logistical difficulties ass. é frequent
monitoring of CMV viral load, and the potential for aggressive dis. and
indirect effects of CMV infc e allograft while ptn. is being monitored}. (Medscape).
CMV &
Relapse:If the patient hs a typical pattern of
relapse after stopping preemptive therapy, the best ttt is to reinitiate oral valganciclovir
because no information is given that wd lead one to suspect antiviral
resistance that would be an indication for changing the drug. Either IV ganciclovir
(5 mg/kg twice daily) or oral ganciclovir (900 mg twice daily) are appropriate for ttt. of CMV dis., but IV ganciclovir is
generally used in children, when dis. is life-threatening, or when oral
medication is not tolerated or well absorbed. (Medscape).
Treatment of CMV Relapse: Until
recently, IV. ganciclovir
ws the gold-standard ttt of CMV dis.. Oral valganciclovir ws shown in VICTOR trial
to be noninferior to IV ganciclovir for ttt. of CMV in SOT
recipients e nonlife-threaten-ing dis.. It is important to give the appropriate
doses of valganciclovir or gan-ciclovir to dcr. the risk for dev.
of resistance & recurrence of CMV dis.. Twice daily dosing is
recomm. for ttt. of dis. in pt. e normal R. function e optimal duration of ttt.
is determined by monitoring viral load weekly & treating until 1 or 2
consecutive negative samples are obtained, but not for < 2
w.. (Medscape).
CMV Dis. & Rejection:The association between Ac. rejection & CMV dis.
is bid-irectional;
the im/m. drugs used to prevent & treat Rj increased risk for CMV dis.
and CMV disease increased the risk for Ac. rejection. (Medscape).
“Dosage*
Recommendations for Oral Valganciclovir in Adults”.
|
CrCl. (mL/min) |
|
Induction Dose |
|
Maintenance/Prevention Dose |
|
≥60 |
|
900 mg
twice daily |
|
900 mg
once daily |
|
40-59 |
|
450 mg
twice daily |
|
450 mg
once daily |
|
25-39 |
|
450 mg
once daily |
|
450 mg
every 2 days |
|
10-24 |
|
450 mg
every 2 days |
|
450 mg
twice weekly |
|
<10 (on HDX.) |
|
Not recommended |
|
Not recommended. |
*450-mg tablets, (Medscape).
Summary & Conclusions:
The
burden of CMV dis. after SOT is significant. Direct effects incl.
a clinical spectrum of dis. fr. aSm.tic viremia to life-threatening
tissue-invasive dis.. Indirect effects incl. allograft dysfunction & loss, incr.
risk for other opportunistic infections, lymphoproliferative diso. & death.
The best approach for CMV dis. in SOT is prevention, but it still debatable wch strategy: prophylaxis or preemptive thepy,
is optimal. Ganciclovir
& valganciclovir remain the best options for prevention &
ttt. of CMV dis. in SOT, but they‘re costly & ass. é toxicity. A boxed warning about hematologic
toxicity, carcinogenicity, teratogenicity & impairment of fertility is incl.
in prescribing information for both drugs. CMV disease after SOT
continues to be ass. é adverse outcomes; thus, new preventive strategies
are needed. N.B.:
CMV-seronegative ptn. are at highest risk for CMV posttransplant when the donor organ
is from CMV-sero+ve.
Type of organ Tx. is a risk f. for CMV infection after transplant.
{Lung, heart, small intestine, pancreas &
kidney-pancreas transplant} recipients are at greater risk for CMV infection than kidney & liver
Tx. recipients.
Universal Prox.: giving antiviral ttt to either all
ptns or to a select group to prevent CMV infection and dcr. the
direct & indirect effects of CMV infection.
The first-line empiric ttt. for CMV dis.is: IV ganciclovir 5 mg/kg twice
daily
The gold standard ttt for CMV
disease is IV ganciclovir,
5 mg/kg twice daily and should be adjusted based on the patient's renal function (Medscape).
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