SEARCH

SEARCH BY CITATION

Keywords:

  • Cytomegalovirus;
  • lung transplant;
  • valganciclovir

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

We prospectively determined the safety and efficacy of valganciclovir for prevention of cytomegalovirus (CMV) in at-risk (donor positive/recipient negative [D+/R−] or R+) lung transplant recipients. We also determined the length of prophylaxis required to significantly decrease both CMV infection and disease. Consecutive lung transplant recipients surviving >30 days (n = 90) received combination prophylaxis with intravenous (i.v.) ganciclovir (GCV) 5 mg/kg/day and cytomegalovirus immune globulin (CMV-IVIG) followed by valganciclovir (450 mg twice-daily) to complete 180, 270 or 365 days of prophylaxis. This group was compared to a historical group (n = 140) who received high-dose oral acyclovir following i.v. GCV and CMV-IVIG. CMV disease was significantly lower in patients receiving valganciclovir compared to acyclovir (2.2% vs. 20%; p < 0.0001). Freedom from CMV infection and disease was significantly greater (p < 0.02) in patients receiving 180, 270 or 365 days of prophylaxis (90%, 95% and 90%, respectively) compared to those receiving 100–179 days (64%) or <100 days (59%). No patient receiving valganciclovir died during the study. Following prophylaxis with i.v. GCV and CMV-IVIG, valganciclovir is safe and effective for prevention of CMV infection and disease in at-risk lung transplant recipients. The required length of prophylaxis was at least 180 days.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Cytomegalovirus (CMV) remains the most important pathogen following lung transplantation and is a significant cause of direct morbidity and mortality in this patient population. In addition to its direct effects, CMV is also associated with a number of indirect effects. Through mechanisms of enhanced allorecognition, CMV is associated with, though not causally linked to, the development of acute rejection and bronchiolitis obliterans syndrome (BOS); the physiologic manifestation of chronic allograft rejection (1,2). BOS remains the major limiting factor to long-term survival following lung transplantation (3).

Many factors predispose to the development of CMV infection and disease in solid organ transplant (SOT) recipients. The greatest risk occurs when CMV seropositive donor lungs are transplanted into seronegative recipients (D+/R− (4). Lung transplantation involves the transfer of a high latent CMV viral load compared to other solid organs and consequently the risk of CMV infection may increase in this population (4). In at-risk patients (D+/R−D+/R+, or D−/R+) the incidence of CMV infection has been reported to be as high as 75% (5).

The success of antiviral agents in the prevention of CMV infection and disease in SOT recipients has been well documented (6). Several prophylactic regimens have been studied in lung transplant recipients, including i.v. and oral GCV alone or in combination with CMV hyperimmune globulin (CMV-IVIG) (7–12). However, the optimal prophylactic strategy in lung transplant recipients remains controversial; the appropriate regimen and duration of therapy remains unclear.

Limitations associated with GCV formulations [oral: low bioavailability, 6–10% (13,14) and i.v.: patient inconvenience, cost and catheter-related infections (15)] led to the development of valganciclovir, an ester prodrug of GCV and valine. Valganciclovir, administered as 900 mg/day, provides comparable plasma GCV exposures compared to those achieved with 5 mg/kg i.v. GCV (14). Its bioavailability (60%) is approximately 10-fold higher than that of oral GCV (14). Studies have demonstrated the safety and efficacy of valganciclovir in AIDS patients with CMV retinitis (16), and of CMV prophylaxis in solid organ transplant (SOT) patients excluding lung transplant recipients (17).

We and others (4,7) have previously shown that universal prophylaxis incorporating a combination therapy with i.v. GCV and CMV-IVIG followed by high-dose oral acyclovir on post-transplant day 180, decreases the incidence of CMV and delays its onset in lung transplant recipients. However, while decreased compared to the published literature, the overall incidence of CMV infection was still 35% and of CMV disease was 10–20% (4,7). The availability of a potent, oral antiviral agent allows prolonged exposure without the catheter-related complications associated with prolonged i.v. therapy. Therefore, we hypothesized, that following universal prophylaxis with i.v. GCV and CMV-IVIG, prolonged exposure to GCV with the use of valganciclovir would further decrease the incidence of CMV infection and disease in lung transplant recipients. The goal of the present study was to prospectively determine whether valganciclovir is safe and effective for the prevention of CMV following lung transplantation and to determine the length of prophylaxis required to significantly decrease the incidence of CMV infection and disease. Therefore, following universal prophylaxis with i.v. GCV and CMV-IVIG, we substituted valganciclovir for the high-dose oral acyclovir in our regimen, measured the occurrence of CMV infection and disease and compared it to our published historical control group of patients who had received acyclovir following i.v. GCV and CMV-IVIG.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Study design

Ninety consecutive adult lung transplant recipients at risk for CMV (D+/R− or any R+) who survived >30 days were included in this study. All patients received combination prophylaxis with i.v. GCV 5 mg/kg for 30 days and 3 doses of CMV-IVIG followed by valganciclovir as outlined in Figure 1A. D+/R− recipients received extended i.v. GCV for 90 days and 7 doses of CMV-IVIG followed by valganciclovir as outlined in Figure 1B. The first 11 patients in this study received valganciclovir 900 mg/day in a single dose. However, due to leucopenia (WBC < 3500 cells/mm3) or neutropenia (absolute neutrophil count <1500 cells/mm3) and concerns about their possible relationship to peak serum concentrations, the rest received valganciclovir 450 mg bid. To determine the length of therapy required to decrease the incidence of CMV infection and disease, consecutive patients were prescribed to receive valganciclovir to complete a total of 180, 275 or 365 days of prophylaxis (n = 30 at each time point) following the universal prophylaxis phase. Patients were followed for 180 days after valganciclovir cessation. Dosing adjustments were made according to renal function; valganciclovir was decreased to 450 mg/day for creatinine clearance <60 mL/min. Following prophylaxis with i.v. GCV and CMV-IVIG as outlined above, the historical control group (n = 140) received high-dose oral acyclovir 800 mg three times daily until day 180 instead of valganciclovir and then followed for 180 days following cessation of the high-dose acyclovir. The primary study endpoints were the development of CMV infection or disease and the time for onset of CMV. This study was approved by the Combined Multi-Institutional Review Board of the University of Colorado Health Sciences Center.

imageimage

Figure 1. Combination antiviral prophylaxis regimen consisting of i.v. GCV and cytomegalovirus (CMV) hyperimmune globulin (CMV-IVIG) followed by valganciclovir for (A) CMV seropositive recipients (R+), and (B) CMV seropositive donors and CMV seronegative recipients (D+/R−).

Monitoring for CMV infection

Following completion of the period utilizing i.v. GCV and CMV-IVIG prophylaxis, CMV infection was assessed by the hybrid capture assay (Digene, Gaithersburg, MD) as previously described by Bhorade et al. (18). Testing was performed each week to day 90, then every 2 weeks to day 180 and finally at regularly scheduled monthly clinic visits. Asymptomatic patients with <1000 viral copies/mL were considered negative and followed routinely. Patients with 1000–3000 copies/mL were tested weekly until progression or resolution occurred. Levels >3000 copies/mL prompted the institution of antiviral therapy. In symptomatic patients, >1000 copies/mL was considered positive and the patients were evaluated for tissue invasive disease. This treatment algorithm had been previously validated in our center (19).

Definitions

CMV infection was defined as a hybrid capture assay with >1000 viral copies/mL. In the historical control group, CMV infection was determined by the hybrid capture assay or qualitative or quantitative polymerase chain reaction (PCR) as previously described (19,20). CMV disease was defined as evidence of tissue invasive disease by transbronchial biopsy or tissue culture, a positive bronchoalveolar culture with or without chest X-ray infiltrates or a syndrome characterized by fever, leucopenia and a positive PCR or hybrid capture assay.

Treatment of CMV infection and disease

Asymptomatic patients with CMV infection above our treatment threshold (>3000 copies/mL) were treated with valganciclovir 900 mg bid for 3 weeks and a single dose of CMV-IVIG 150 mg/kg. If the infection persisted, as measured by a hybrid capture value of >1000 viral copies/mL after 2 weeks of therapy with valganciclovir, i.v. GCV (5 mg/kg bid) was administered for a minimum of 3 weeks or until 1 week after the hybrid capture became negative. CMV disease was treated with i.v. GCV (5 mg/kg bid) for 3 weeks and 4 doses of CMV-IVIG 100 mg/kg every 4 days. Intravenous ganciclovir was continued until 1 week after the hybrid capture eventually became negative. Patients with breakthrough viremia >1000 copies/mL while on prophylaxis were treated with 3 weeks of i.v. GCV and a single dose of CMV-IVIG.

Immunosuppressive regimen

All patients in the study and historical control groups received standard triple drug immunosuppressive therapy with cyclosporine, azathioprine and prednisone. Cyclosporine was dosed to attain levels of 400–450 ng/mL during the first post-transplant year. Seventy-two percent of the patients in the acyclovir group and 78% in the valganciclovir group were switched to tacrolimus following their first episode of moderate acute rejection (biopsy grade A2 or higher) usually within 2–3 months post-transplant or for manifestations of cyclosporine toxicity (neurotoxicity or renal insufficiency). Target blood levels for tacrolimus were 7–10 ng/mL during the first post-transplant year. Azathioprine was dosed to keep a white blood cell (WBC) count of 4000–6000 cells/mm3. Methylprednisolone 500 mg was given intra-operatively, then 125 mg bid for 6 doses followed by prednisone at 1 mg/kg/day in a divided dose and tapered weekly to a maintenance dose of 10–15 mg/day. Induction therapy is not utilized in our program. Mycophenolate mofetil is not used routinely (6% of patients) in our program during the first 1–2 years post-transplant.

Monitoring for antiviral resistance

Emergence of antiviral resistance was suspected in patients with tissue invasive disease who failed to respond to i.v. GCV therapy or who had persistent viremia after 2 weeks of therapy or recurrent viremia during or after GCV or valganciclovir therapy. Antiviral resistance was determined genotypically by PCR to detect mutations in specific regions of the human CMV DNA polymerase (UL54) and the human CMV phosphotransferase (UL97) genes. The analyses were performed in the Virology Laboratory at the University of Colorado Health Sciences Center as previously described by Weinberg et al. (21). Patients suspected of having GCV resistant isolates were treated with foscarnet pending results of the resistance testing. If found to have a resistant isolate, patients received foscarnet for 3–6 weeks directed by serial monitoring of their viral load.

Statistics

The incidence of CMV infection and disease was compared between groups by the Fischer's Exact Test. The time for onset of CMV between valganciclovir groups was compared using the Kaplan-Meier method and log-rank statistics. Significance was defined as a p value <0.05.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Demographic and clinical characteristics are presented in Tables 1 and 2. There were no significant differences between the valganciclovir and historical control groups with regard to gender, age, the indication for transplant or CMV donor/recipient matching. The incidence of acute rejection in the first year post-transplant was 67% in the historical and 71% in the study cohorts (p = NS). Steroid resistant acute rejection occurred in about 16% of the historical patients and 18% of the study patients. The frequency and type of lympholytic agents used for treatment of steroid resistant rejection were similar between the two cohorts with ATGAM followed by OKT3 used in the historical group and thymoglobulin followed by OKT3 in the study group. OKT3 was used in 5% of patients in each group. Ninety patients received valganciclovir for prolonged prophylaxis. Patients were enrolled consecutively and prescribed valganciclovir to complete 180, 270 or 365 days of prophylaxis. We originally planned to enroll 30 patients in each group; however, 32% (n = 29) were unable to attain their prescribed length of prophylaxis due to leucopenia (WBC < 3500 cells/mm3) or neutropenia (ANC [absolute neutrophil count] < 1500 cells/mm3) (n = 23), increased liver function tests (n = 3) and central nervous system symptoms consisting of headache or confusion (n = 2) or cost (n = 1). A similar percentage of patients discontinued valganciclovir in each group and were assigned to groups based on their total length of i.v. GCV and valganciclovir exposure. This resulted in five groups of patients: those receiving <100 days (n = 18), 100–179 days (n = 11), 180 (n = 21), 270 (n = 20) or 365 days (n = 20) of prophylaxis. There were no significant demographic differences including the percentage of D+/R− patients between the valganciclovir groups or the historical control group (Tables 1 and 2).

Table 1. Baseline demographic data for the valganciclovir study group and the historical acyclovir control group
 Valganciclovir group* (n = 90)Acyclovir group (n = 140)
  1. *No significance differences were noted in any variable between groups using the Fisher's Exact Test.

Age, mean (years)53.4 ± 4.754.0 ± 5.8
Gender: male/female50/4076/44
Indication for transplant, n (%)
 Chronic obstructive pulmonary disease45 (50)65 (46.5)
 Alpha-1-antitrypsin deficiency21 (23.3)32 (22.8)
 Idiopathic pulmonary fibrosis8 (8.9)20 (14.2)
 Cystic fibrosis12 (13.3)16 (11.4)
 Primary pulmonary hypertension4 (5.5)7 (6.1)
CMV donor/recipient serostatus, n (%)
 D+/R−18 (20)31 (22)
 D+/R+45 (50)66 (47)
 D−/R+27 (30)43 (31)
Acute Rejection 1 year post-transplant (%)7167
Steroid resistant acute rejection (%)1816
Patients switched to tacrolimus (%)7872
Patients receiving mycophenolate mofetil (%)66
Lympholytic therapy
 ATGAM (%)09
 OKT3 (%)55
 Thymoglobulin (%)132
Table 2. CMV serologic data for the valganciclovir study groups and acyclovir group
 Valganciclovir group*Acyclovir group (n = 140)
  1. *No significance differences were noted between groups using the Fisher's Exact Test.

Length of prophylaxis (days)<100 (n = 18)100–179 (n = 11)180 (n = 21)270 (n = 20)365 (n = 20) 
CMV donor/recipient serostatus
 D+/R((n [%])3 (17)2 (18)5 (24)5 (25)3 (15)31 (22)
 D+/R+ (n [%])8 (44)5 (46)11 (52)10 (50)11 (55)66 (47)
 D−/R+ (n [%])7 (39)4 (36)5 (24)5 (25)6 (30)43 (31)

Valganciclovir prophylaxis group

The incidence of CMV disease was significantly reduced in this population compared to the control group (2.2% vs. 20%; p < 0.0001; Table 3). Asymptomatic CMV infection occurred in 15.6% of patients receiving valganciclovir prophylaxis compared to 15% in the control group (Table 3). When compared to the control group, the overall incidence of CMV infection and disease was reduced by almost 50% in patients receiving valganciclovir (p < 0.005) (Table 3).

Table 3. Incidence of cytomegalovirus (CMV) infection and disease in lung transplant recipients while receiving prolonged valganciclovir prophylaxis to their prescribed courses of 180, 270 or 365 days
CMVValganciclovirAcyclovir
Overall (n = 90)Tolerated (n = 61)Discontinued (n = 29)Historical rates (n = 140)
  1. *p < 0.0001 vs. acyclovir; +p < 0.005 vs. acyclovir.

  2. Both valganciclovir and acyclovir groups had received prophylaxis with i.v. GCV and CMV-IVIG prior to starting either oral agent.

Asymptomatic infection (%)15.66.634.515
CMV disease (%)2.2*0*6.9*20
Total (%)17.8+6.6*41.435

Sixty-one patients tolerated valganciclovir for their prescribed length of prophylaxis for at least 180 days. While receiving the drug, there were no cases of CMV disease in this patient group compared to an incidence of 20% in the historical control group (p < 0.0001; Table 3). Breakthrough asymptomatic viremia occurred in 4 patients, none were GCV resistant and all responded to treatment of 3 weeks of i.v. GCV. Breakthrough viremia was not associated with a prior dose reduction from 900 mg/day to 450 mg/day for renal insufficiency.

Valganciclovir prophylaxis was discontinued prior to 180 days in 29 patients. The reasons for discontinuation of prophylaxis are outlined in Table 4. There was no correlation with patient age, indication for transplant, serum creatinine, the use of cyclosporine or tacrolimus and the reason for discontinuation. In the 29 patients who discontinued prophylaxis, 1 patient developed CMV gastritis, 1 CMV pneumonia and 10 patients developed asymptomatic CMV infection; 3 of whom showed GCV resistance (UL97) and responded to i.v. GCV.

Table 4. Indication for discontinuation of prophylaxis in lung transplant recipients receiving valganciclovir
IndicationNumber of patientsTime of onset (days)
Leucopenia (WBC < 3500 cells/mm3) or neutropenia (ANC < 1500 cells/mm3)2314–40
Elevated liver function test (>2 × normal)326–86
Central nervous system symptoms27 and 44
Cost1

Effect of varying the length of prophylaxis

To determine the length of valganciclovir prophylaxis required to decrease the incidence of CMV infection and disease, lung transplant recipients were given prolonged prophylaxis up to day 365 post-transplant. Patients were stratified by the duration of total prophylaxis received; those completing <100 days, 100–179 days, and 180, 270 or 365 days of prophylaxis. Following termination of prophylaxis, freedom from CMV infection and disease 180 days after valganciclovir cessation was significantly greater (p < 0.02) in patients receiving 180 (90%), 270 (95%) or 365 (90%) days of prophylaxis compared to those receiving prophylaxis for 100–179 days (64%) and <100 days (59%) (Figure 2). As a combined group, patients who received either 180, 270 or 365 days of prophylaxis, had an incidence of CMV disease that was significantly reduced when compared to the historical control group (1.6% vs. 20%; p = 0.0003; Table 4). Asymptomatic CMV infection was also reduced by 50% in this group compared to the historical control group (p = 0.11) (Table 5).

image

Figure 2. Percent of lung transplant recipients free from cytomegalovirus (CMV) infection and disease following prolonged prophylaxis with valganciclovir for <100 days (n = 18) ⋯⋯, 100–179 days (n = 11) ––– , and 180 (n = 21) ——, 270 (n = 20) ⋯⋯ or 365 (n = 20) days —— . p < 0.02 for 180, 270 or 365 days vs. either <100 days or 100–179 days group, respectively. p = NS for 180 vs. 270 vs. 365 days, respectively.

Download figure to PowerPoint

Table 5. Incidence of cytomegalovirus (CMV) infection and disease in lung transplant recipients receiving valganciclovir prophylaxis for various lengths of time
 ValganciclovirAcyclovir
  1. *p < 0.03 vs. acyclovir; +p < 0.005 vs. acyclovir; ++p < 0.04 vs. acyclovir.

Length of prophylaxis (days), n<100 (n = 18)100–179 (n = 11)180 (n = 21)270 (n = 20)365 (n = 20)180 (n = 140)
Asymptomatic infection (%)33279.55515
CMV disease (%)1100*0*520
Total (%)44279.5*5+10++35

Valganciclovir treatment group

Fourteen lung transplant recipients received treatment with valganciclovir 900 mg/kg bid for 3 weeks for asymptomatic CMV infection above the treatment threshold (>3000 viral copies/mL). Twelve patients cleared the CMV completely by week 3. Two patients remained CMV positive; however, the virus was cleared upon initiation of treatment with i.v. GCV for 3 weeks. Three patients discontinued valganciclovir treatment (leucopenia, n = 2; increased liver function tests, n = 1). CMV infection recurred in two of these patients but in none of the others by 6 months following valganciclovir therapy resulting in a recurrence rate of 14%.

Ganciclovir resistant mutations

The incidence of genotypically determined GCV resistance in patients who had received prolonged valganciclovir prophylaxis was 4.4% compared to an incidence of 4.8% in the acyclovir group. These occurred in 3 patients with asymptomatic viremia who were found to have GCV resistance (UL97) and cleared with 3 weeks of i.v. GCV. The fourth patient had received 365 days of valganciclovir and developed CMV pneumonia 170 days after valganciclovir cessation. Despite treatment with i.v. GCV and CMV-IVIG, his viral load remained elevated, resistance was suspected and treatment with foscarnet begun. Ganciclovir resistance (UL54) was confirmed and his symptoms and viremia cleared after 6 weeks of foscarnet therapy. CMV pneumonia recurred 4 months later, which required maintenance therapy with half-dose foscarnet and half-dose i.v. GCV due to the development of renal insufficiency.

Long-term outcomes

Overall survival was 96% at 18 months in the valganciclovir group versus 92% in the acyclovir group (p = NS). No patient receiving prolonged valganciclovir prophylaxis died due to CMV during the study period (18 months post-transplant) compared to 1.4% of patients in the control acyclovir group. The interval follow-up is too short to determine whether prolonged valganciclovir had an effect on BOS development.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

CMV infection and disease remains a serious concern and continues to limit long-term survival following lung transplantation (4). Given the potentially devastating impact of CMV, most transplant centers administer antiviral prophylaxis; however, the optimal strategy for the prevention of CMV infection and disease remains unknown. Several prophylactic strategies have been assessed in lung transplant recipients, including the efficacy of i.v. GCV for 28 (10), and 35 days (22). Brumble et al. (8) reported on the use of a unique 2-week delayed i.v. GCV prophylactic regimen. Shorter regimens may not prove effective (23) and although lengthier regimens have a greater impact on the incidence of CMV disease than shorter courses, they are expensive and still not completely effective (12). Many centers administer GCV alone (9,12,15), or in combination with CMV-IVIG (7,11) for ≥3 months. We recently introduced a prophylactic regimen employing valganciclovir following i.v. GCV and CMV-IVIG. In D+/R+, D−/R+ transplants, patients receive 30 days of i.v. GCV and three doses of CMV-IVIG followed by oral valganciclovir. CMV mismatched recipients (D+/R−) receive 90 days of i.v. GCV and 7 doses of CMV-IVIG followed by a shorter course of oral valganciclovir. In our study, we found that prophylaxis with valganciclovir significantly reduced the incidence of CMV disease compared to our published, historical acyclovir control group (2.2% vs. 20%; p < 0.0001). This is seen most clearly by direct comparison of the 180 day valganciclovir group to the acyclovir group (which received 180 days of therapy), which shows a significant reduction in the incidence of CMV infection and disease. There was no CMV disease reported in patients while receiving and tolerating valganciclovir prophylaxis. This low incidence of disease in the valganciclovir group is important as lung transplant recipients are at particularly high risk of developing CMV disease.

Valganciclovir has significantly enhanced bioavailability compared to oral GCV and has the convenience of a once-daily oral dosing regimen. Valganciclovir has proven efficacy in the treatment of AIDS patients with CMV retinitis (16) and for the prevention of CMV infection in SOT patients (excluding lung transplant recipients) (17); however, data on its use in lung transplant recipients are lacking.

Prophylactic and immunosuppressive regimens employed at different centers may vary considerably and the definitions of CMV disease differ across studies; consequently a meaningful comparison of the incidence of CMV disease between studies is difficult. However, the overall incidence of CMV disease (2.2%) in patients receiving any valganciclovir in our study compares very favorably to those previously reported in patients receiving prolonged prophylaxis in lung transplant patients. Weill et al. (7) and Gutiérrez et al. (11) reported an incidence of CMV disease of 7.8% and 12.8%, respectively, in patients receiving i.v. GCV for up to 12 weeks with CMV-IVIG. In addition, despite 100 days of i.v. GCV prophylaxis, Hertz et al. (15) found an incidence of CMV disease of 35% suggesting that a longer course of prophylaxis is required in lung transplant recipients. In an effort to determine the length of valganciclovir prophylaxis required to decrease the incidence of CMV infection and disease, patients in our study received prophylaxis for up to 365 days post-transplant. Stratification of patients by duration of prophylaxis indicates that prolongation of therapy is associated with a reduced incidence of CMV infection. The required length of prophylaxis was found to be at least 180 days of prophylaxis.

In this study we also used valganciclovir for the treatment of breakthrough asymptomatic CMV infection. Twelve of the fourteen patients receiving valganciclovir cleared CMV within 3 weeks, indicating the potential of valganciclovir for the treatment of CMV viremia. While it is unclear whether treatment of asymptomatic viremia is beneficial for lung transplant recipients, the association of CMV infection with BOS may warrant this practice. A randomized, controlled study to determine the effect of valganciclovir treatment of asymptomatic viremia in lung transplant recipients would be desirable. However, with the low rate of CMV infection and disease observed with current prophylactic strategies, enrollment of a very large number of patients would be required for future trials to show differences in outcomes, assuming patients in both arms were receiving effective antiviral management. It may also be unethical in any such trials not to treat patients or to give them placebo given the morbidity of CMV infection in lung transplantation.

We did find significant leucopenia and neutropenia in the valganciclovir group, which required discontinuation of the drug in 32% of our patients. This is higher than the reported incidence (8.2%) of neutropenia in the valganciclovir SOT prophylaxis study (17). The apparent increase in our lung transplant cohort compared to other SOT may be due to our more liberal definition of leucopenia or neutropenia but with increased experience with the drug our current discontinuation rate is 18% (unpublished data). Interestingly, we have only had to discontinue i.v. GCV in approximately 3% of our patients due to neutropenia, neurologic symptoms or elevations in serum creatinine. Severe neutropenia puts immunocompromised patients at risk for invasive fungal disease and this risk must be balanced by the potential benefit of CMV prophylaxis in lung transplant recipients. Given the association of CMV disease with BOS and the apparent efficacy of valganciclovir, prophylaxis with this agent appears justified although it does require regular monitoring of the WBC.

Another issue with prolonged CMV prophylaxis is the potential for the development of viral resistance. In our study, the incidence of genotypically determined resistance was 4.4% in patients receiving prolonged valganciclovir prophylaxis compared to 4.8% in the acyclovir control group. Boivin et al. (24) studied viral resistance in SOT recipients receiving valganciclovir prophylaxis for 100 days. In that study, no GCV-resistance mutations were detected in CMV isolates obtained from patients receiving valganciclovir. The discrepancy between these two studies is unexplained at present but our study involved lung rather than non-lung transplant recipients and our patients had received i.v. GCV prior to valganciclovir.

The main limitation of the current study is the comparison with a historical control group. However, we believe that the two cohorts are comparable with respect to their risk for CMV infection. First, there were no significant differences in demographics or the percentages of D+/R− patients between the groups as outlined in Tables 1 and 2. Survival during the study follow-up period, the incidence of acute rejection, steroid resistant rejection and the frequency and type of lymphocytic agents used were similar between groups. While some patients in the valganciclovir groups (270- and 365-day groups) were followed 15–18 months post-transplant compared to 12 months for the acyclovir group, the length of follow-up was 180 days following cessation of the oral prophylactic agent in both the valganciclovir or acyclovir groups. While this could account for differences in the incidence of CMV infection and disease, our patients are typically at their maintenance levels of immunosuppressive therapy by 6 months post-transplant. Our immunosuppressive regimen has remained relatively constant over the life of our program. We have never employed induction therapy and have continued to use cyclosporine, azathioprine and prednisone as our standard primary immunosuppressive regimen. Following the approval of tacrolimus, it has been our practice to switch patients from cyclosporine to tacrolimus after the development of their first episode of symptomatic acute rejection or cyclosporine toxicity. Therefore, the majority (72% and 78% in the acyclovir and valganciclovir groups, respectively) were receiving tacrolimus during the period of observation.

It also could be argued that since the two groups received different lengths of prophylaxis, this might account for the observed differences. However, comparison of the day 180 valganciclovir group to the acyclovir group (which received 180 days of therapy) shows a significant reduction in the incidence of CMV infection and disease. In addition, exposure to valganciclovir (270 or 365 days) did not result in a further decrease in incidence compared to the 180 day valganciclovir group. Similarly, our methods of monitoring CMV have evolved but have been based on molecular techniques (PCR or hybrid capture) since 1994. A recent study showed that while the COBAS Amplicor CMV Monitor test and the Hybrid Capture System CMV DNA test had similar test performance characteristics at lower concentrations of input CMV DNA, the latter had greater linearity at higher concentrations (25). A report from our center found that the sensitivity and specificity of hybrid capture using whole blood was similar to that of PCR using peripheral blood leucocytes in monitoring CMV infection in bone marrow transplant recipients (19). Therefore, despite the evolution of monitoring techniques in our center, the efficacy of PCR and the hybrid capture assay would appear to be comparable.

Finally, it could be argued that differences in monitoring frequencies could account for the apparent benefit of prolonged prophylaxis. Patients who did not tolerate the valganciclovir and discontinued prophylaxis prior to 180 days were indeed monitored every 2 weeks, while those completing at least 180 days were monitored every 4 weeks. While this could account for increased detection of asymptomatic CMV infection in patients receiving <180 days, it is unlikely to account for the observed differences in this study. Previous work from our center found that asymptomatic viremia required several weeks rather than days to resolve below the level of detection and should have been detected by our monthly monitoring algorithm (20). In addition, while the incidence of CMV infection may spike within 6 weeks following cessation of prophylaxis, the overall incidence has been shown to be less after the first 6 months post-transplant (15).

In conclusion, our study demonstrates that following combination prophylaxis with i.v. GCV and CMV-IVIG, valganciclovir is safe and effective for the prevention of CMV infection and disease and the prevention of recurrent CMV infection following treatment of asymptomatic viremia. Furthermore, the required length of prophylaxis was found to be at least 180 days. Future studies to determine the pharmacokinetic activity of valganciclovir in lung transplant recipients are required to determine optimal dosing in this patient population and the cost effectiveness of the combination regimen described here also needs to be assessed.

Acknowledgment

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

This work was presented at the 2003 American Transplant Congress, May 30–June 4, 2003, Washington DC.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References
  • 1
    Schulman LL, Weinberg AD, McGregor CC. Influence of donor and recipient HLA locus mismatching on development of obliterative bronchiolitis after lung transplantation. Am J Respir Crit Care Med 2001; 163: 437442.
  • 2
    Heng D, Sharples LD, McNeil K, Stewart S, Wreghitt T, Wallwork J. Bronchiolitis obliterans syndrome: Incidence, natural history, prognosis and risk factors. J Heart Lung Transplant 1998; 17: 12551263.
  • 3
    Sharples LD, McNeil K, Stewart S, Wallwork J. Risk factors for bronchiolitis obliterans: A systematic review of recent publications. J Heart Lung Transplant 2002; 21: 271281.
  • 4
    Zamora MR. Use of cytomegalovirus immune globulin and ganciclovir for the prevention of cytomegalovirus disease in lung transplantation. Transpl Infect Dis 2001; 3(Suppl 2): 4956.
  • 5
    Ettinger NA, Bailey TC, Trulock EP et al. Cytomegalovirus infection and pneumonitis. Impact after isolated lung transplantation. Am Rev Respir Dis 1993; 147: 10171023.
  • 6
    Couchoud C. Cytomegalovirus prophylaxis with antiviral agents for solid organ transplantation. Cochrane Database Syst Rev 2000; 2: CD001320.
  • 7
    Weill D, Lock BJ, Wewers DL et al. Combination prophylaxis with ganciclovir and cytomegalovirus (CMV) immune globulin after lung transplantation: Effective CMV prevention following daclizumab induction. Am J Transplant 2003; 3: 492496.
  • 8
    Brumble LM, Milstone AP, Loyd JE et al. Prevention of cytomegalovirus infection and disease after lung transplantation. Results using a unique regimen employing delayed ganciclovir. Chest 2002; 121: 407414.
  • 9
    Speich R, Thurnheer R, Gaspert A, Weder W, Boehler A. Efficacy and cost effectiveness of oral ganciclovir in the prevention of cytomegalovirus disease after lung transplantation. Transplantation 1999; 67: 315320.
  • 10
    Wreghitt TG, Abel SJ, McNeil K et al. Intravenous ganciclovir prophylaxis for cytomegalovirus in heart, heart-lung, and lung transplant recipients. Transpl Int 1999; 12: 254260.
  • 11
    Gutierrez CA, Chaparro C, Krajden M, Winton T, Kesten S. Cytomegalovirus viremia in lung transplant recipients receiving ganciclovir and immune globulin. Chest 1998; 113: 924932.
  • 12
    Duncan SR, Grgurich WF, Iacono AT et al. A comparison of ganciclovir and acyclovir to prevent cytomegalovirus after lung transplantation. Am J Respir Crit Care Med 1994; 150: 146152.
  • 13
    Pescovitz MD, Pruett TL, Gonwa T et al. Oral ganciclovir dosing in transplant recipients and dialysis patients based on renal function. Transplantation 1998; 66: 11041107.
  • 14
    Pescovitz MD, Rabkin J, Merion RM et al. Valganciclovir results in improved oral absorption of ganciclovir in liver transplant recipients. Antimicrob Agents Chemother 2000; 44: 28112815.
  • 15
    Hertz MI, Jordan C, Savik SK et al. Randomized trial of daily versus three-times-weekly prophylactic ganciclovir after lung and heart-lung transplantation. J Heart Lung Transplant 1998; 17: 913920.
  • 16
    Martin DF, Sierra-Madero J, Walmsley S et al. A controlled trial of valganciclovir as induction therapy for cytomegalovirus retinitis. N Engl J Med 2002; 346: 11191126.
  • 17
    Paya C, Humar A, Dominguez E et al. Efficacy and safety of valganciclovir vs. oral ganciclovir for prevention of CMV disease in solid organ transplant recipients. Am J Transplant 2004; 4: 611620.
  • 18
    Bhorade SM, Sandesara C, Gerrity ER et al. Quantification of cytomegalovirus (CMV) viral load by the hybrid capture assay allows for early detection of CMV disease in lung transplant recipients. J Heart Lung Transplant 2001; 20: 928934.
  • 19
    Weinberg A, Schissel D, Giller R. Molecular methods for cytomegalovirus surveillance in bone marrow transplant recipients. J Clin Microbiol 2002; 40: 42034206.
  • 20
    Weinberg A, Hodges TN, Li S, Cai G, Zamora MR. Comparison of PCR, antigenemia assay, and rapid blood culture for detection and prevention of cytomegalovirus disease after lung transplantation. J Clin Microbiol 2000; 38: 768772.
  • 21
    Weinberg A, Jabs DA, Chou S et al. Mutations conferring foscarnet resistance in a cohort of patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis. J Infect Dis 2003; 187: 777784.
  • 22
    Soghikian MV, Valentine VG, Berry GJ, Patel HR, Robbins RC, Theodore J. Impact of ganciclovir prophylaxis on heart-lung and lung transplant recipients. J Heart Lung Transplant 1996; 15: 881887.
  • 23
    Bailey TC, Trulock EP, Ettinger NA, Storch GA, Cooper JD, Powderly WG. Failure of prophylactic ganciclovir to prevent cytomegalovirus disease in recipients of lung transplants. J Infect Dis 1992; 165: 548552.
  • 24
    Boivin G, Goyette N, Gilbert C et al. Absence of CMV resistance mutations following valganciclovir prophylaxis in a prospective multicentric study in solid organ transplant recipients. J Infect Dis 2004; 189: 16151618.
  • 25
    Caliendo AM, Yen-Lieberman B, Baptista J et al. Comparison of molecular tests for detection and quantification of cell-associated cytomegalovirus DNA. J Clin Microbiol 2003; 41: 35093513.