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Q.686. Comment briefly on CMV infection in R.Tx.?



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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



900 mg twice daily


900 mg once daily



450 mg twice daily


450 mg once daily



450 mg once daily


450 mg every 2 days



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).