Abstract

American Journal of TransplantationVolume 7, Issue 9 p. 2106-2113 Free Access Oral Valganciclovir Is Noninferior to Intravenous Ganciclovir for the Treatment of Cytomegalovirus Disease in Solid Organ Transplant Recipients A. Åsberg, A. Åsberg Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway These authors contributed equally to this workSearch for more papers by this authorA. Humar, A. Humar University of Alberta, Edmonton, Canada These authors contributed equally to this workSearch for more papers by this authorH. Rollag, H. Rollag Institute of Microbiology, University of Oslo, NorwaySearch for more papers by this authorA. G. Jardine, A. G. Jardine Department of Medicine, University of Glasgow, Glasgow, UKSearch for more papers by this authorH. Mouas, H. Mouas Hoffmann-La Roche Ltd, Basel, SwitzerlandSearch for more papers by this authorM. D. Pescovitz, M. D. Pescovitz Department of Surgery, Indiana University,Indianapolis, INSearch for more papers by this authorD. Sgarabotto, D. Sgarabotto Department of Tropical and Infectious Diseases, Padua General and Teaching Hospital, Padua, ItalySearch for more papers by this authorM. Tuncer, M. Tuncer Department of Nephrology, Akdeniz University Medical Faculty, Antalya, TurkeySearch for more papers by this authorI. L. Noronha, I. L. Noronha Department of Nephrology, Hospital Beneficiencia Portuguesa, Sao Paulo, BrazilSearch for more papers by this authorA. Hartmann, Corresponding Author A. Hartmann Department of Medicine, Rikshospitalet-Radiumhospitalet Medical Centre, University of Oslo, Oslo, Norway * Corresponding author: Anders Hartmann, anders.hartmann@rikshospitalet.noSearch for more papers by this authoron behalf of the VICTOR Study Group, on behalf of the VICTOR Study Group Members of the study group are listed in the appendixSearch for more papers by this author A. Åsberg, A. Åsberg Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway These authors contributed equally to this workSearch for more papers by this authorA. Humar, A. Humar University of Alberta, Edmonton, Canada These authors contributed equally to this workSearch for more papers by this authorH. Rollag, H. Rollag Institute of Microbiology, University of Oslo, NorwaySearch for more papers by this authorA. G. Jardine, A. G. Jardine Department of Medicine, University of Glasgow, Glasgow, UKSearch for more papers by this authorH. Mouas, H. Mouas Hoffmann-La Roche Ltd, Basel, SwitzerlandSearch for more papers by this authorM. D. Pescovitz, M. D. Pescovitz Department of Surgery, Indiana University,Indianapolis, INSearch for more papers by this authorD. Sgarabotto, D. Sgarabotto Department of Tropical and Infectious Diseases, Padua General and Teaching Hospital, Padua, ItalySearch for more papers by this authorM. Tuncer, M. Tuncer Department of Nephrology, Akdeniz University Medical Faculty, Antalya, TurkeySearch for more papers by this authorI. L. Noronha, I. L. Noronha Department of Nephrology, Hospital Beneficiencia Portuguesa, Sao Paulo, BrazilSearch for more papers by this authorA. Hartmann, Corresponding Author A. Hartmann Department of Medicine, Rikshospitalet-Radiumhospitalet Medical Centre, University of Oslo, Oslo, Norway * Corresponding author: Anders Hartmann, anders.hartmann@rikshospitalet.noSearch for more papers by this authoron behalf of the VICTOR Study Group, on behalf of the VICTOR Study Group Members of the study group are listed in the appendixSearch for more papers by this author First published: 09 August 2007 https://doi.org/10.1111/j.1600-6143.2007.01910.xCitations: 311 AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract Intravenous ganciclovir is the standard treatment for cytomegalovirus disease in solid organ transplant recipients. Oral valganciclovir is a more convenient alternative. In a randomized, international trial, recipients with cytomegalovirus disease were treated with either 900 mg oral valganciclovir or 5 mg/kg i.v. ganciclovir twice daily for 21 days, followed by 900 mg daily valganciclovir for 28 days. A total of 321 patients were evaluated (valganciclovir [n = 164]; i.v. ganciclovir [n = 157]). The success rate of viremia eradication at Day 21 was 45.1% for valganciclovir and 48.4% for ganciclovir (95% CI –14.0% to +8.0%), and at Day 49; 67.1% and 70.1%, respectively (p = NS). Treatment success, as assessed by investigators, was 77.4% versus 80.3% at Day 21 and 85.4% versus 84.1% at Day 49 (p = NS). Baseline viral loads were not different between groups and decreased exponentially with similar half-lives and median time to eradication (21 vs. 19 days, p = 0.076). Side-effects and discontinuations of assigned treatment (18 of 321 patients) were comparable. Oral valganciclovir shows comparable safety and is not inferior to i.v. ganciclovir for treatment of cytomegalovirus disease in organ transplant recipients and provides a simpler treatment strategy, but care should be taken in extrapolating to organ transplant recipients not properly represented in the present study. Introduction Cytomegalovirus (CMV) is a significant viral pathogen affecting solid organ transplant recipients and is responsible for substantial morbidity. The clinical manifestations of CMV include an acute viral syndrome and tissue invasive disease, such as pneumonitis, hepatitis and gastrointestinal disease (1). In addition, CMV is associated with indirect immunomodulatory effects including opportunistic infections and acute and chronic allograft injury and rejection (1). Given the clinical consequences of CMV, many transplant centers have adopted prevention strategies. Although prophylaxis is effective in decreasing both the incidence and severity of CMV disease, it remains a common problem and both simple and efficient treatment options are needed (2). Intravenous ganciclovir, currently the recommended standard treatment for CMV disease in solid organ transplant recipients, requires frequent hospitalizations, long-term i.v. catheter access, and is expensive and inconvenient for patients (3-5). A safe and effective oral therapy would significantly improve and simplify the management of posttransplant CMV disease. Valganciclovir, an oral prodrug of ganciclovir, is absorbed and rapidly metabolized to ganciclovir in the intestinal wall and liver (6). The bioavailability of ganciclovir from valganciclovir is approximately 60%, and the systemic exposure from 900 mg valganciclovir once daily provides similar systemic exposure to that of 5 mg/kg/day i.v. ganciclovir (7-9). While valganciclovir is effective for treatment of CMV retinitis in patients with AIDS (10, 11) and for CMV prophylaxis in solid organ transplant recipients, its safety and efficacy for the treatment of posttransplant CMV disease has yet to be assessed in an adequately powered study. Material and Methods Study design A randomized, open-label, parallel-group, active drug-controlled, multi-center noninferiority trial in adult solid organ transplant recipients with CMV disease (ClinicalTrials.gov NCT00431353) was conducted in accordance with the Declaration of Helsinki, good clinical practice guidelines and applicable local regulatory requirements. The trial protocol was approved by local institutional review board at the 42 centers: 25 in Europe, six in Brazil, four in India, two in Canada, two in Venezuela, one in Mexico, one in Australia, and one in New Zealand. Written informed consent was obtained from each patient by the local investigator prior to randomization. Adult solid organ transplant recipients with both virological and clinical evidence of CMV disease, (regardless of donor or recipient CMV serostatus) were eligible for enrollment. Patients were ineligible if their CMV disease was considered life-threatening by the investigator, had a history of significant adverse reaction to ganciclovir, valganciclovir, acyclovir or valacyclovir, had proven ganciclovir resistance, had received an investigational new drug within the last 30 days or had a calculated creatinine clearance of 600 copies/mL (valganciclovir, n = 133; ganciclovir, n = 126). The intention-to-treat and per-protocol analyses showed consistent results (Table 2A and 2B). Detailed viral kinetic analyses were only performed on the per-protocol population. Median baseline viral loads were not different between the groups (Table 2B). Viral clearance (<600 copies/mL) at Day 21 was achieved in 74 of 133 patients (55.6%) in the valganciclovir group and 76 of 126 patients in the ganciclovir group (60.3%; p = NS), and increased to 110 of 133 patients (82.7%) and 110 of 126 patients (87.3%), respectively, at Day 49 (p = NS). Table 2. Analysis of efficacy Response Valganciclovir Ganciclovir Difference (95% CI) (A) Intention-to-treat population n = 164 n = 157 viremia eradication at Day 21 74 (45.1%) 76 (48.4%) −14% to +8% viremia eradication at Day 49 110 (67.1%) 110 (70.1%) −13% to +7% Clinical resolution of CMV disease at Day 21 127 (77.4%) 126 (80.3%) −12% to +6% Clinical resolution of CMV disease at Day 49 140 (85.4%) 132 (84.1%) −7% to +9% (B) Per-protocol population Valganciclovir (n = 133) Ganciclovir (n = 126) Median baseline viral load1 (copies/mL) 19 750 (3470–84 500) 16 675 (3520–83 500) Time to viral eradication (≤600 copies) (days) 21 (95% CI: 19.3–22.7) 19 (95% CI: 16.8–21.2) Time to viral eradication (≤200 copies) (days) 21 (95% CI: 17.1–24.9) 21 (95% CI: 17.2–24.8) Calculated decay slope (log copies/day)2 –0.060 (–0.084 to –0.042) –0.067 (–0.088 to –0.048) Calculated viral load half-life (days)2 11.5 (8.3–16.5) 10.4 (7.9–14.5) 1Inter-quartile range is shown in parentheses. 2Range is shown in parentheses. Viral loads decreased following approximate first-order kinetics, and decay curves were almost identical in both treatment arms (Figure 2). In most of the patients there was a lag-time before the reduction of viral load was seen. The mean time to a clinically relevant drop in viral load (≥0.3 natural log units) was 6.1 ± 4.5 days (n = 120) for valganciclovir and 6.6 ± 4.7 days (n = 116) for ganciclovir (p = NS). Median times to viral eradication (Kaplan–Meier estimates) using either the 600 copies or 200 copies cutoff were similar in both arms and are shown in Table 2B (per-protocol population). Figure 2Open in figure viewerPowerPoint Reduction in CMV viral load with time in patients treated with oral valganciclovir or i.v. ganciclovir. There was no difference in viral load reduction rate between the treatment groups (200 copies/mL as assay cutoff; per-protocol population). The median viral load half-life was 11.5 days (8.3–16.5 days) and 10.4 days (7.9–14.5 days) for valganciclovir- (n = 113) and ganciclovir- (n = 112) treated patients, respectively (p = 0.932). The median slope of viral load decay (kdecay) was comparable in both arms (Table 2B). Adverse events During the first 21 days, treatment was discontinued in 11 (6.7%) valganciclovir versus 7 (4.5%) ganciclovir patients, respectively (p = NS). The most frequent adverse events are listed in Table 3. There were no major differences in the frequencies of adverse events between the treatment groups. A total of 44 of 321 patients (13.7%) reported at least one serious adverse event during the induction phase of treatment (valganciclovir: 25 of 164 patients, 15.2%, and ganciclovir: 19 of 157 patients, 12.1%; p = 0.107). Leucopenia occurred in 11.8% of patients (valganciclovir, 11.6%; ganciclovir, 12.1%). Three patients treated with valganciclovir and seven patients treated with ganciclovir developed subsequent opportunistic infections (p = 0.484). Overall, 47 of 164 valganciclovir-treated patients reported at least one potentially treatment-related adverse event during induction therapy, compared to 40 of 157 i.v. ganciclovir-treated patients during induction treatment (relative risk 1.08; 95% CI 0.86–1.36; p = 0.514). Table 3. Distribution of main reported adverse events by treatment group (number of patients with at least 1 episode) Adverse event Valganciclovir Ganciclovir p-Value (Cochran-Mantel-Haenszel) Leucopenia 19 (11.6%) 19 (12.1%) 0.886 Diarrhea 12 (7.3%) 20 (12.7%) 0.109 Urinary tract infection 15 (9.1%) 17 (10.8%) 0.616 Anemia 20 (12.2%) 11 (7.0%) 0.120 Respiratory disorders 14 (8.5%) 9 (5.7%) 0.333 Cough 8 (4.9%) 7 (4.5%) 0.859 Abdominal pain 5 (3.0%) 9 (5.7%) 0.247 Nausea/vomiting 7 (4.3%) 7 (4.5%) 0.933 Diabetes 4 (2.4%) 4 (2.5%) 0.950 Sore throat 6 (3.7%) – 0.0151 Dyspepsia 4 (2.4%) 3 (1.9%) 0.747 Flu-like symptoms 2 (1.2%) 2 (1.3%) 0.965 Tremors 2 (1.2%) 2 (1.3%) 0.965 Neutropenia 2 (1.2%) – 0.4991 Any other event 92 (56.1%) 78 (49.7%) 0.260 Total patients with events 115 (70.1%) 100 (63.7%) 0.221 1Fisher's exact test. Overall, 22 patients had 25 episodes of acute graft rejection either at the start of treatment (n = 1) or during the study period (n = 24). The incidence of acute rejection was comparable in both arms. No episodes of graft loss were noted during the treatment and study periods, but two patients in each arm died due to septicemia and one valganciclovir treated patient died of fungal infection during the 49 days of treatment. None of these were treatment-attributable deaths. Potential factors affecting outcome Factors potentially related to treatment success/failure at Day 21 were assessed. Donor or recipient CMV pretransplant serostatus or serostatus at randomization, the presence of tissue invasive disease, previous anti-CMV therapy and type of organs transplanted or number of HLA-A or HLA-B locus mismatches had no significant influence on treatment success. The only factor predictive of viral eradication was the baseline viral load (Figure 3). Patients with a baseline viral load of <10 000 copies/mL had a univariate relative chance for eradication of viremia (cutoff: 600 copies/mL) at Day 21 of 6.41 (95% CI 3.61–11.36; p < 0.001) and at Day 49 of 2.56 (95% CI 1.29–5.08; p = 0.001), compared to those with a viral load of ≥10 000 copies/mL. Figure 3Open in figure viewerPowerPoint Kaplan–Meier curves showing the influence of three different baseline viral load levels on efficacy of treatment (viral eradication with cutoff level of 600 copies/mL plasma; per-protocol population) (p < 0.001, log-rank test). Discussion This is the first randomized controlled trial comparing oral valganciclovir to i.v. ganciclovir for the treatment of CMV disease in solid organ transplant recipients. The current American Society of Transplantation recommendation for the treatment of CMV disease is i.v. ganciclovir and this was the chosen comparator (5). The results of this trial show that 900 mg of oral valganciclovir twice daily is noninferior to 5 mg/kg of i.v. ganciclovir twice daily for the treatment of CMV disease. This was confirmed by both intention-to-treat and per-protocol analyses at Day 21 and Day 49. In the per-protocol population viral clearance by Day 21 was almost 60%, increasing to about 85% at the end of treatment (Day 49). Viral clearance kinetics based on plotting best-fit decay curves for each patient was almost identical in the two arms. In addition, clinical parameters such as resolution of fever and clinical resolution of CMV disease (as assessed by the investigator) were the same in both arms, with very high clinical success rates observed by Day 49 (valganciclovir, 85.4%; ganciclovir, 84.1%). Thus, both clinical and viral parameters were equivalent for valganciclovir- and ganciclovir-treated patients at all time points until Day 49. Several studies have demonstrated the importance of CMV viral load in the pathogenesis of CMV disease in transplant recipients (13-16) and the clinical utility of monitoring CMV viral load in transplant recipients is well established (13-17). In our study up to 12 viral load measurements were performed during the treatment period, enabling us to perform a detailed and sensitive analysis of viral kinetics, such as half-life and slope of decay. Median half-lives appear longer than those reported in smaller observational studies using the same therapies (14, 18). Reasons for these differences may include sample size, the frequency of viral load measurements, and differences in immunologic parameters, such as CMV specific T-cell responses in different populations (19). However, the viral load reductions of 1.06% and 1.07% copies/mL/day for the valganciclovir and ganciclovir groups, respectively, are similar to those achieved in allogenic stem cell transplantation (20). A median initial lag phase of approximately 6 days was commonly observed before a sustained reduction in viral load was achieved, especially in patients with high initial viral loads. This novel observation may be secondary to a true delay in viral clearance in heavily immunosuppressed patients, or potentially due to release of nonviable viral DNA from cells into the plasma component after the initiation of anti-viral therapy. Symptomatic CMV disease is generally treated with a 2–4 week course of i.v. ganciclovir (3, 5, 21). We chose a treatment length of 21 days followed by a maintenance period of 28 days. In transplant recipients treated for CMV disease, the risk of recurrent CMV disease after treatment is estimated to be 25–30% (22, 23). The most important predictor of disease recurrence after treatment of CMV disease is persistent viremia at the end of anti-viral therapy (14, 24). Therefore, current guidelines recommend treatment until eradication of CMV viremia (3, 5). Based on our study, it is apparent that viral eradication is only achieved in approximately 58% of patients with 21 days of therapy despite the resolution of symptoms in a significantly larger fraction of patients. Prolongation of therapy is therefore warranted for a substantial number of patients and should likely be individualized based on serial viral load measurements. We also analyzed predictors of viral eradication. Amongst the factors analyzed, only the baseline viral load was a significant predictor of viral eradication. Low baseline viral loads increased the likelihood of viral eradication several-fold. Therefore, viral load is clearly an important prognostic indicator for length of treatment. However, the absolute treatment length cannot be adequately predicted without viral monitoring. The pretransplant donor seropositive/recipient seronegative sub-group of patients is well known to be at higher risk of CMV disease. Interestingly, we found that these patients responded just as well to treatment as CMV seropositive patients. This finding cannot be explained by differences in baseline viral loads (multivariate logistic regression) and further substantiates that response to anti-viral therapy is likely dependent on a complex interaction between the virus and the host (25, 26). Both valganciclovir and ganciclovir were well tolerated, compliance was high and similar, and there was no difference in the adverse event profile, including leucopenia and neutropenia, between treatment arms. One of the limitations of this study was that treatment allocation was not blinded. It was felt that the use of i.v. placebo would be dif