KHA-CARI guideline: Cytomegalovirus disease and kidney transplantationnep_

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1 Nephrology 16 (2011) Original Article KHA-CARI guideline: Cytomegalovirus disease and kidney transplantationnep_ HELEN PILMORE, 1 BRUCE PUSSELL 2 and DAVID GOODMAN 3 1 Department of Renal Medicine, Auckland Hospital, Auckland, New Zealand; 2 Department of Nephrology, Prince of Wales Hospital, Randwick, Sydney, New South Wales, Australia; and 3 Department of Nephrology, St Vincent s Hospital, Fitzroy, Victoria, Australia Correspondence: Dr Helen Pilmore, Department of Renal Medicine, Auckland Hospital, Park Road, Auckland 1000, New Zealand. hpilmore@adhb.govt.nz Accepted for publication 22 August Accepted manuscript online 13 September doi: /j x SUMMARY AT A GLANCE This paper summarises the updated guidelines for diagnostic tests, prophylaxis and treatment options for cytomegalovirus after transplantation. 1. DIAGNOSTIC TESTS FOR CYTOMEGALOVIRUS IN RENAL TRANSPLANTATION No recommendations possible based on Level I or II evidence.* Serology should be used pretransplant to define cytomegalovirus (CMV) serological status and thereby stratify the risk of CMV infection post-transplant. 1 Quantification of viral load may enable the prediction of likelihood of progression to disease based on absolute value and the rate of rise of viral load. Hence, a pp65 antigenaemia or a quantitative DNA test is preferred over a qualitative DNA test. The threshold levels for various tests at which to initiate pre-emptive therapy have not been critically defined in renal transplant and depend on the particular assay used. 2 There is marked variability in CMV DNA levels between different PCR assays. There is high inter-laboratory variability in CMV DNA levels. Some CMV PCR assays are unable to detect CMV at low viral loads. If treatment for CMV does not result in clinical improvement and a reduction in viral load, testing for ganciclovir resistance is recommended. Optimal cut-offs for both antigenaemia and quantitative PCR testing have been proposed; however, this is dependent on each laboratory and there is no consistency between different test assays. If pre-emptive treatment is to be used: Patients at risk of CMV infection should be monitored for evidence of infection by a validated and preferably standardized detection method. In practical terms, this currently means either the pp65 antigenaemia assay or a quantitative nucleic acid assay. Monitoring of patients not receiving prophylaxis should be regular, but there is no evidence to guide the frequency of testing based on outcome data or cost-effectiveness. Less than fortnightly testing is unlikely to be effective for preemptive treatment strategies. Nephrology 2011 Asian Pacific Society of Nephrology 683

2 H Pilmore et al. A variety of diagnostic tests for CMV are in common clinical use for the detection of CMV infection and disease following renal and other solid organ transplantation. The diagnosis of CMV infection can be made serologically, based on seroconversion or a fourfold rise in CMV-Ig G titre. More specifically, infection is diagnosed by the demonstration of viral replication directly by viral culture or indirectly, by the detection of viral antigen or nucleic acid. Infection may be asymptomatic or cause disease either the CMV syndrome or end-organ disease. A diagnosis of end-organ CMV disease can be confirmed by demonstrating tissue involvement by typical histological findings, or by the culture of CMV from tissue specimens. Culture-based techniques, both conventional and shell vial assay culture, have poor sensitivity. Although they remain the gold standard for the diagnosis of infection, they are no longer considered appropriate tests when there is a requirement for rapid and early detection to guide preemptive therapy. Antigen detection and qualitative PCR have enhanced sensitivity compared with culture techniques in the detection of infection and this also appears to be the case for quantitative PCR and the newer nucleic acid-based techniques. 1 5 The comparison of different techniques between centres is made difficult by the heterogeneity of populations studied and the non-standardization of methodology for similar tests. Currently, there remain many unresolved issues regarding the most appropriate application of available diagnostic tests for CMV in renal and other transplant settings. The current clinical applications of available tests include: evaluation of serostatus pretransplant diagnosis of established disease detection of CMV infection quantification of viral replication (viral load) to predict progression to disease and allow selection of individuals who should receive pre-emptive therapy, and quantification of viral replication (viral load) during treatment of CMV disease to monitor response and determine treatment duration. To achieve the latter three goals, a test for CMV should be sensitive and specific with high negative predictive value for infection and a high positive predictive value for progression to disease. It should also have the capacity to be quantified, have a short turnaround time and a high degree of reproducibility. The purpose of the following section has been to review the literature on diagnostic tests for CMV in solid organ transplantation with an emphasis on renal transplantation. The outcome sought was the production of guidelines for the use of currently available tests for CMV in the setting of renal transplantation. In particular, the questions considered were: Which test should be recommended for the detection of CMV infection following renal transplantation? What is the optimal viral load level at which accurate pre-emptive diagnosis of CMV can be made? Which quantitative assay is the most accurate for the rapid diagnosis of CMV? No systematic reviews or randomized controlled trials are available on this topic. The evidence is largely comprised of cohort studies which are variable in methodology and participant characteristics. Most are small, single-centre studies. Also, a number of diagnostic test accuracy studies comparing antigenaemia and quantitative PCR testing are available. 1. Greanya ED, Partovi N, Yoshida EM et al. The role of the cytomegalovirus antigenemia assay in the detection and prevention of cytomegalovirus syndrome and disease in solid organ transplant recipients: A review of the British Columbia experience. Can. J. Infect. Dis. Med. Microbiol. 2005; 16: Humar A, Paya C, Pescovitz MD et al. Clinical utility of cytomegalovirus viral load testing for predicting CMV disease in d+/r- solid organ transplant recipients. Am. J. Transplant. 2004; 4: Gouarin S, Vabret A, Gault E et al. Quantitative analysis of HCMV DNA load in whole blood of renal transplant patients using real-time PCR assay. J. Clin. Virol. 2004; 29: Gentile G, Picardi A, Capobianchi A et al. A prospective study comparing quantitative cytomegalovirus (CMV) polymerase chain reaction in plasma and pp65 antigenemia assay in monitoring patients after allogeneic stem cell transplantation. BMC Infect. Dis. 2006; 6: Sanghavi SK, Abu-Elmagd K, Keightley MC et al. Relationship of cytomegalovirus load assessed by real-time PCR to pp65 antigenemia in organ transplant recipients. J. Clin. Virol. 2008; 42: PROPHYLAXIS FOR CYTOMEGALOVIRUS INFECTION IN PATIENTS FOLLOWING RENAL TRANSPLANTATION 1 Prophylactic treatment for CMV is recommended in solid organ transplantation as it is associated with a significant decrease in CMV disease and infection compared with placebo or no treatment (approximately a 50% and 40% decrease in relative risk, respectively) (Level I evidence). 2 The use of the antiviral agents, oral valganciclovir, oral valaciclovir and intravenous (IV) ganciclovir, is recommended (Level II evidence). The addition of anti-cmv immunoglobulin to these agents is not recommended as there is no additional benefit (Level I evidence). 3 On the pretransplant CMV antibody assay, prophylaxis for CMV disease is indicated for the following donor/recipient subgroups: 684 Nephrology 2011 Asian Pacific Society of Nephrology

3 CMV disease and kidney transplantation D+ and R+ D+ and R- D-/R+ but not when Donor and Recipient are both negative. 4 In high-risk, D+/R- recipients, it is recommended that the duration of prophylaxis be extended from 3 to 6 months as it significantly reduces CMV disease and viraemia. 1 Cost-effectiveness: In D+/R- recipients, 6-month compared with 3-month prophylaxis was cost-effective in reducing CMV infection and disease. 2 There is no indication for the use of immunoglobulin in prophylaxis of CMV disease in solid organ transplant recipients. 3 Dosing: In the reported studies, total daily doses of antiviral agents used were as follows and were reduced for impaired renal function: oral valaciclovir 3200 mg oral valganciclovir 900 mg, and IV ganciclovir 5 10 mg/kg for an average of 14 days. Note: Oral ganciclovir is no longer available in Australia. 4 Prophylaxis is also indicated when using T cell-depleting antibody separate to routine prophylaxis as described above. Cytomegalovirus is the most frequent viral infection following renal transplantation with evidence of infection found in at least two-thirds of patients. Cytomegalovirus belongs to the group of herpesviruses and is a common infection in the community, with about 80% of adults showing seropositivity to the virus. 1 The major determinants of infection are evidence of virus in the donor, the presence of latency (seropositivity) in the recipient, and the type of immunosuppressive regimen administered. It is usual to make a distinction between infection and disease where disease is characterized by evidence of organ damage and infection is by detection of virus, with or without disease. Cytomegalovirus disease is associated with increased morbidity and mortality, whereas infection alone may be associated with an increased risk of transplant rejection and bacterial and fungal infection. 2 4 These consequences have led to interventions for prophylaxis, early diagnosis and treatment. 5 8 The objectives of this guideline are to provide evidence to support/identify: the use of CMV prophylaxis in preventing primary infection or reactivation of latent infection the best agents to reduce infection and disease the duration of therapy the cost-effectiveness of therapy, and the effect of prophylaxis on acute rejection. Please refer to the evidence tables for this subtopic see the CARI (Caring for Australians with Renal Impairment) website under CMV Disease and Kidney Transplantation. 1. Flechner SM, Avery RK, Fisher R et al. A randomised, prospective, controlled trial of oral acyclovir versus oral ganciclovir for cytomegalovirus prophylaxis in high-risk kidney transplant recipients. Transplantation 1998; 66: Hibberd PL, Tolkoff-Rubin NE, Conti D et al. Preemptive ganciclovir therapy to prevent cytomegalovirus disease in cytomegalovirus antibody-positive renal transplant recipients: A randomized controlled trial. Ann. Intern. Med. 1995; 123: Lowance D, Neumayer HH, Legendre CM et al. Valacyclovir for the prevention of cytomegalovirus disease after renal transplantation. International Valacyclovir Cytomegalovirus Prophylaxis Transplantation Study Group. N. Engl. J. Med. 1999; 340: Paya C, Humar A, Dominguez E et al. Efficacy and safety of valganciclovir vs. oral ganciclovir for prevention of cytomegalovirus disease in solid organ transplant recipients. Am. J. Transplant. 2004; 4: Reischig T, Opatrny K Jr, Bouda M et al. A randomized prospective controlled trial of oral ganciclovir versus oral valacyclovir for prophylaxis of cytomegalovirus disease after renal transplantation. Transpl. Int. 2002; 15: Rubin RH, Kemmerly SA, Conti D et al. Prevention of primary cytomegalovirus disease in organ transplant recipients with oral ganciclovir or oral acyclovir prophylaxis. Transpl. Infect. Dis. 2000; 2: Snydman DR, Werner BG, Heinze-Lacey B et al. Use of cytomegalovirus immune globulin to prevent cytomegalovirus disease in renal transplant recipients. N. Engl. J. Med. 1987; 317: Winston DJ, Busuttil RW. Randomized controlled trial of oral ganciclovir versus oral acyclovir after induction with intravenous ganciclovir for long-term prophylaxis of cytomegalovirus disease in cytomegalovirus-seropositive liver transplant recipients. Transplantation 2003; 75: PRE-EMPTIVE TREATMENT OF CYTOMEGALOVIRUS Pre-emptive treatment of CMV infection significantly reduces the risk of CMV disease compared with placebo (Level I) evidence. Valganciclovir is equally efficacious in preventing CMV disease when used as prophylaxis or as pre-emptive treatment (Level II evidence but not designed for this outcome). 1 Pre-emptive treatment of CMV infection results in significantly less leucopenia than prophylaxis; however, there is no difference in other adverse events. Nephrology 2011 Asian Pacific Society of Nephrology 685

4 H Pilmore et al. Pre-emptive treatment with 1/2 dose ganciclovir and 1/2 dose foscarnet results in increased drug toxicity compared with full-dose ganciclovir alone. The cost of both prophylaxis and pre-emptive treatment is substantial and depends on the costing of the diagnostic test and medications in individual units. Pre-emptive treatment depends on an accurate diagnostic test. Both CMV PCR testing and pp65 antigenaemia testing appear efficacious in the detection of CMV infection when used in trials of pre-emptive therapy. All studies have used CMV testing at weekly or fortnightly intervals in patients treated with pre-emptive therapy. Cytomegalovirus infection and disease are important causes of morbidity and mortality among renal transplant recipients. It has long been recognized that this is the most common opportunistic pathogen in renal transplant patients. CMV may manifest as a non-specific illness characterized by fever, mononucleosis, leucopenia and thrombocytopenia, or as a variety of clinical syndromes including pneumonitis, hepatitis, encephalitis and focal gastrointestinal disease. A number of strategies have been developed to prevent CMV disease. One of these is prophylaxis, which can be performed universally on all transplant recipients irrespective of the risk of CMV disease or can be targeted to subsets of patients, depending on risk stratification determined by the CMV zero-status of both the donor and recipient. Pre-emptive therapy, however, involves directing prophylaxis towards only those recipients in whom diagnostic tests have indicated early replication of CMV is occurring. This is an attempt to prevent the progression of asymptomatic infection into CMV disease. Since the initial CARI guideline, published in 2004, there have been a number of new trials and three meta-analyses examining the efficacy of pre-emptive therapy to prevent CMV disease in solid organ transplant recipients. This review has undertaken to assess the following factors: Is pre-emptive therapy effective in preventing CMV disease? Is there any difference between the efficacy of preemptive treatment and prophylaxis in preventing CMV disease? Which medications are efficacious in the pre-emptive treatment of CMV infection? What are the adverse effects associated with pre-emptive therapy?, and Is there any cost difference between pre-emptive treatment and prophylaxis? There are still only a small number of studies examining pre-emptive therapy in CMV. However, since the last CARI guideline, there have been a number of new trials and three meta-analyses. It is clear that pre-emptive treatment of CMV results in a lower incidence of CMV disease. Treatment with IV or oral ganciclovir and oral valganciclovir is effective and there is insufficient evidence to suggest that any of these medications is superior in efficacy to the others. 1 3 Similarly, current evidence is conflicting regarding the incidence of CMV disease with pre-emptive treatment or prophylaxis; however, there may be cost differences, depending on the individual costs in different institutions. In addition, there is one study that showed improved 4-year graft survival in patients treated with prophylaxis compared with those randomized to pre-emptive treatment. If this is confirmed, clear recommendations for prophylaxis compared with pre-emptive treatment may be able to be made in the future. 1. Khoury JA, Storch GA, Bohl DL et al. Prophylactic versus preemptive oral valganciclovir for the management of cytomegalovirus infection in adult renal transplant recipients. Am. J. Transplant. 2006; 6: Reischig T, Jindra P, Hes O et al. Valacyclovir prophylaxis versus pre-emptive valganciclovir therapy to prevent cytomegalovirus disease after renal transplantation. Am. J. Transplant. 2008; 8: Strippoli GFM, Hodson EM, Jones CA et al. Pre-emptive treatment for cytomegalovirus viraemia to prevent cytomegalovirus disease in solid organ transplant recipients. Cochrane Database Syst. Rev. 2006, Issue 1. Art. No.: CD DOI: / CD pub2. 4. TREATMENT OF CYTOMEGALOVIRUS DISEASE IN RENAL TRANSPLANT RECIPIENTS No recommendations possible based on Level I or II evidence. We suggest ganciclovir by IV administration be the treatment of choice for moderate severe CMV disease and patients with gastrointestinal involvement where drug absorption may be impaired. Mild CMV disease in adults may be treated with either oral valganciclovir or IV ganciclovir (Level II evidence, single study). 1 Drug dose should be reduced in patients with renal impairment. 686 Nephrology 2011 Asian Pacific Society of Nephrology

5 CMV disease and kidney transplantation Consider reduction in immunosuppressive therapy. We suggest graft function be monitored closely as acute rejection may occur. Ganciclovir and valganciclovir may cause leucopenia and increase serum creatinine. We suggest treatment should continue for 2 3 weeks or until CMV-DNA is not detectable (Level III evidence). Persistence of CMV-DNA after 21 days is associated with disease recurrence. 2 Treatment failure may be due to inadequate treatment, super-infection or ganciclovir resistance (Level III evidence). Foscarnet and cidofovir remain second-line agents (Level III evidence). Cytomegalovirus disease is characterized by clinical symptoms and signs of disease coupled with microbiological evidence of CMV infection. Disease occurs in 8% of renal transplant recipients compared with liver or combined kidney pancreas (29%) and heart lung (39%) recipients. A large proportion of patients have CMV infection detected by blood testing such as PCR or CMV serology without any clinical symptoms or signs of disease. Patients at greatest risk of developing disease include D+/R- recipients and those who have been given methyl-prednisolone or antilymphocyte antibody (Atgam, ATG, OKT3, Thymoglobulin, Atgam: Pfizer, New York, NY, USA; ATG: Fresenius, Germany; OKT3: Janssen-Cilag, The Netherlands; Thymoglobulin: Genzyme, Cambridge, MA, USA). The diagnosis may be complicated by the fact that CMV infection is frequently associated with super-infection with other bacteria, fungi, protozoa and viruses. Ganciclovir is the treatment of choice for CMV disease and should be administered intravenously with the dose modified according to creatinine clearance. It is unlikely that a randomized controlled trial will ever be undertaken to confirm the efficacy of IV ganciclovir compared with placebo. Treatment should be continued for at least 2 weeks or until CMV-DNA is not detectable. While immunosuppressive therapy is frequently reduced in patients with CMV disease, this measure has not been subjected to a clinical trial. Several clinical studies using mtor inhibitors after renal transplantation have observed a reduced incidence of CMV disease and this warrants further study. Oral ganciclovir has been used successfully to treat mild to moderate CMV disease but is no longer available for clinical use. The recent introduction of valganciclovir, with 10 times the bioavailability of oral ganciclovir and kinetics comparable with IV ganciclovir, may provide an alternative to IV therapy. 1 4 Valganciclovir therapy in patients with milder forms of CMV disease has the potential to reduce hospital stay and the complications associated with prolonged IV access. Ganciclovir resistance remains an important issue and has been reported in up to 7% of solid organ transplants and may be treated with second-line agents such as foscarnet and cidofovir. Both of these agents are associated with significant nephrotoxicity and side effects. There is no evidence to support the use of acyclovir, valaciclovir and CMV-Ig in renal transplant recipients. Failure to respond to therapy may be due to inadequate treatment, ganciclovir resistance or super-infection. 1. Asberg A, Humar A, Rollag H et al. Oral valganciclovir is noninferior to intravenous ganciclovir for the treatment of cytomegalovirus disease in solid organ transplant recipients. Am. J. Transplant. 2007; 7: Asberg A, Humar A, Jardine A et al. Long-term outcomes of CMV disease treatment with valganciclovir versus IV ganciclovir in solid organ transplant recipients. Am. J. Transplant. 2009; 9: Humar A, Segal D, Moussa G et al. A prospective assessment of valganciclovir for the treatment of cytomegalovirus infection and disease in transplant recipients. J. Infect. Dis. 2005; 192: Len O, Gavalda J, Aguado J et al. Valganciclovir as treatment for cytomegalovirus disease in solid organ transplant recipients. Clin. Infect. Dis. 2008; 46: *EXPLANATION OF LEVELS OF EVIDENCE The levels of evidence used for the KHA-CARI guidelines are as follows: Level I: Evidence obtained from a systematic review of all relevant randomized controlled trials. Level II: Evidence obtained from at least one properly designed randomized controlled trial. Level III: Evidence obtained from comparative studies (e.g. cohort studies, case control studies and pseudo-randomized controlled trials). Level IV: Evidence obtained from case series (either posttest or pre-test/post-test). ACCESS TO THE FULL-TEXT VERSION For a full-text version of the guideline, readers need to go to the CARI website (go to the Guidelines Transplantation Guidelines section ( Nephrology 2011 Asian Pacific Society of Nephrology 687