ValGanciclovir Versus ValAcyclovir for Viral Prophylaxis in Kidney Transplantation

Phase 2

Completed

Conditions: Transplantation Infection
Epstein-Barr Virus Infections
Cytomegalovirus Infections

Interventions: Drug: Valacyclovir
Drug: Valganciclovir

Registration Number: NCT01972035

Lead Sponsor: University of Minnesota

Brief Summary: Our study will compare all kidney transplant recipients receiving valganciclovir vs. valacyclovir for one year following kidney transplant and compare:

1. the incidence, magnitude and duration of CMV and EBV viremia in the first year after transplant.

2. the side effects of the anti-viral drugs requiring dose reduction or cessation

In addition, we will test renal tissue obtained from any biopsies post-transplant (surveillance or clinically indicated biopsies) by both polymerase chain reaction (PCR) and fluorescence in situ hybridization to assess for latent CMV and/or EBV.

Detailed Description: Herpes viruses such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV) cause considerable morbidity and mortality post-kidney transplant. Even subclinical CMV and/or EBV viremia have been associated with deterioration in kidney transplant function. Currently, valganciclovir (valG) is the primary prophylactic agent against CMV in kidney transplant recipients but CMV viremia has been noted in 22% of pediatric post-kidney transplant recipients, and the incidence at the University of Minnesota (UMMC) in all kidney transplant recipients is as high as 17% despite valG prophylaxis. CMV disease post-kidney transplant can manifest as fever, leucopenia, or mild to severe organ involvement. While an effective anti-CMV drug, valG has a number of adverse effects including leucopenia, also a side effect of mycophenolate mofetil (MMF), one of the cornerstones of current anti-rejection regimens. Combined therapy with MMF and valG frequently results in leucopenia associated infection or leucopenia necessitating reduction in MMF doses, increasing the risk of rejection. In addition, valG is prohibitively expensive forcing many centers adopt a pre-emptive therapeutic approach whereby post-Ktx patients are screened for CMV, and at new onset viremia, valG is initiated. This approach has been associated with increased CMV infections and resistant viral strains. Therefore, there is need for an alternate, more cost-effective drug with a more benign side effect profile and equal effectiveness against CMV.

To date, the anti-EBV effect of valG is poorly defined and prevention of EBV infection is by close monitoring and immunosuppression reduction at the discovery of EBV viremia. EBV can present post-kidney transplants as infectious mononucleosis syndrome, hepatitis and, most importantly, can initiate potentially fatal lymphoproliferative disorders (PTLD). Between October 2003 and December 2009, EBV viremia occurred in 20% of adults and 50% of pediatric kidney transplant recipients (60/120) at UMMC, and, PTLD occurred in 6% (7/120) of pediatric recipients. Effective anti-EBV prophylaxis could substantially improve kidney transplant outcomes.

UMMC conducts surveillance biopsies at transplant and 3 and 12 months post-kidney transplant on all adult transplant recipients, providing an ideal opportunity to assess kidney tissue for EBV and CMV via molecular and immunological assays. Isolating the virus from infected recipient would be a pivotal step in our understanding of the mechanisms of CMV and EBV infection post-kidney transplant.

In summary, if valacyclovir and valganciclovir have equivalent efficacy in CMV prophylaxis, and valacyclovir has the anticipated effect on EBV prevention, the use of valacyclovir will result in a reduced risk of leucopenia-associated infection, and a lower incidence of rejection by allowing the use of standard MMF doses. Since valacyclovir is cheaper, it is plausible that universal prophylaxis will be a plausible and affordable option for all transplant recipients.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 137

Inclusion Criteria

All consenting kidney transplant recipients.

Exclusion Criteria

Non-consent.
Recipients with allergies to valacyclovir or valganciclovir
Recipients that are unable to independently understand the consent form and do not have a legally authorized representative.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
ValAcyclovir	Valacyclovir	Kidney recipients who give informed consent will be randomly assigned to receive ValA or ValG in a 1:1 ratio. Duration of therapy is 3-12 months depending on risk and age of recipient. Dosing is based on glomerular filtration rate.
ValGanciclovir	Valganciclovir	Kidney recipients who give informed consent will be randomly assigned to receive ValG or ValA in a 1:1 ratio. Duration of therapy is 3-12 months depending on risk and age of recipient. Dosing is based on glomerular filtration rate.

Primary Outcome Measures

Name	Time	Method
Compare Incidence, Duration and Magnitude of CMV and EBV Viremia in Kidney Transplant Recipients Receiving valA vs. valG.	First year post-kidney transplant	In infectious mononucleosis intervention trials, two weeks of valA therapy resulted in a statistically significant reduction in oral EBV shedding, accompanied by a clinical benefit, and valA is currently used for the therapy of severe cases of infectious mononucleosis in the community. ValA has also been shown to reduce the incidence and delay the onset of CMV disease in both CMV seronegative patients (P\<0.001) and CMV seropositive patients (P=0.03). Therefore we hypothesize that the anti-EBV and anti-CMV effects of valA will be equal to or more effective than valG in reducing post-kidney transplant EBV and CMV viremia.

Secondary Outcome Measures