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Association of Cytomegalovirus Infection and Disease With Recurrent Hepatitis C After Liver Transplantation

Bosch, Wendelyn1; Heckman, Michael G.2; Pungpapong, Surakit3; Diehl, Nancy N.2; Shalev, Jefree A.3; Hellinger, Walter C.1,4

doi: 10.1097/TP.0b013e3182472876
Clinical and Translational Research
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Background. Cytomegalovirus (CMV) has been inconsistently associated with recurrent hepatitis C virus (HCV) after liver transplant (LT).

Methods. A retrospective study of 347, donor or recipient CMV seropositive, first LT recipients transplanted for HCV was performed to evaluate the associations of CMV infection and disease occurring within 1-year of LT with the primary endpoints of allograft inflammation grade ≥2 and fibrosis stage ≥2. Associations were evaluated using multivariable Cox regression models.

Results. CMV infection and disease occurred in 111 (32%) and 24 (7%) patients, respectively. Hepatic allograft inflammation grade ≥2 and fibrosis stage ≥2 occurred in 221 (64%) and 140 (40%) patients, respectively. CMV infection was associated with increased risk of fibrosis stage ≥2 (relative risk [RR], 1.52; P=0.033). CMV disease was associated with increased risk of inflammation grade ≥2 (RR, 3.40; P<0.001), and although not significant, with fibrosis stage ≥2 (RR, 2.03; P=0.052). These associations did not differ significantly according to recipient CMV seropositivity.

Conclusions. Our results support an association between CMV infection and disease with recurrence of HCV after LT. Investigation of prevention of CMV infection and disease as a strategy to mitigate recurrent HCV in LT recipients is warranted.

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1Division of Infectious Diseases, Mayo Clinic in Florida, Jacksonville, FL.

2Division of Biostatistics, Mayo Clinic in Florida, Jacksonville, FL.

3Division of Transplant Medicine, Mayo Clinic in Florida, Jacksonville, FL.

The authors declare no funding or conflicts of interest.

Address correspondence to: Walter C. Hellinger, M.D., 4500 San Pablo Road, Jacksonville, FL 32224. E-mail: helling@mayo.edu

W.B., M.G.H., S.P., and W.C.H. participated in research design. W.B., M.G.H., S.P., and W.C.H. participated in the writing of manuscript. W.B., J.A.S., and W.C.H. participated in the performance of the research. W.B., M.G.H., N.N.D., and W.C.H. participated in data analysis.

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal's Web site (www.transplantjournal.com).

Received 15 August 2011. Revision requested 1 September 2011.

Accepted 16 December 2011.

In liver transplant (LT) recipients, organ-derived primary cytomegalovirus (CMV) infection or reactivation of the latent virus is associated with numerous detrimental effects (1, 2). CMV-directed prophylaxis or preemptive therapy during the first 3 months after solid organ transplant has significantly diminished the direct and indirect outcomes of CMV in transplant recipients (3, 4). Despite these preventive measures, the development of late-onset CMV disease in LT recipients remain associated with decreased patient and allograft survival (57). In patients who are transplanted for chronic hepatitis C virus (HCV) liver-related disease, universal recurrence of HCV in the allograft develops if it is not eradicated before LT. After hepatic allograft reperfusion, the histopathologic progression from acute HCV infection to chronic infection occurs at a much faster rate in LT recipients than in patients who are immunocompetent (8, 9). CMV has been implicated as a risk factor in the accelerated recurrence of HCV in the hepatic allograft. Studies investigating the recurrence of HCV after LT have demonstrated an association between CMV and increased graft loss, mortality, and the accelerated histopathologic recurrence of HCV demonstrated by increased allograft total Knodell score and fibrosis stage (1015). However, other studies have not identified associations between HCV and CMV (1618).

The primary aim of this retrospective cohort study of LT recipients transplanted for HCV liver-related disease was to evaluate whether associations exist between CMV infection or disease occurring during the first year after LT with the two histopathologic endpoints of hepatic allograft inflammation grade ≥2 and hepatic allograft fibrosis stage ≥ 2. As a secondary aim, we evaluated the associations of CMV infection and disease with the composite endpoint of graft loss or death, and examined whether the aforementioned associations differed according to recipient CMV seropositivity.

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RESULTS

Patient baseline characteristics, operative, donor, and post-LT information for the cohort of 347 LT recipients are summarized in Table 1. The median length of follow-up time from LT was 40 months (range, 0.1–87 months), whereas the median length of time from LT to the last hepatic allograft biopsy was 23 months (range, 0.1–85 months). Valganciclovir prophylaxis was used in 94% of CMV donor seropositive/recipient seronegative (D+/R−) patients.

TABLE 1

TABLE 1

CMV infection occurred in 111 patients (32%) during the first year after LT: 38% CMV D+/R−, 37% CMV D+/recipient seropositive (R+), and 16% CMV donor seronegative(D−)/R+. CMV disease developed in 24 patients (7%) during the first year after LT: 18% CMV D+/R−, 5% CMV D+/R+, and 1% CMV D−/R+. Table 2 displays the overall cumulative incidence of CMV infection and CMV disease after LT, whereas these outcomes are shown according to CMV donor/recipient seromatch in Figure 1(a and b). CMV disease experienced among the cohort included CMV syndrome (62.5%), hepatitis (17%), gastroenteritis (12.5%), and pneumonitis (8%); all were treated except for one patient of CMV D+/R+ seromatch who was diagnosed with CMV disease immediately before death. A total of 63 LT recipients (57%) who developed CMV infection had documented treatment with intravenous (IV) ganciclovir or valganciclovir. Those who were treated included 25 of 30 (83%) CMV D+/R−, 31 of 67 (46%) CMV D+/R+, and 7 of 14 (50%) CMV D−/R+. CMV infection was not treated in five patients of the CMV D+/R− group because of low viral burden.

TABLE 2

TABLE 2

FIGURE 1

FIGURE 1

Within the first 3 months after LT, 8 patients of CMV D+/R− seromatch developed CMV infection without disease. Six patients were on appropriate CMV prophylaxis, including one patient receiving oral ganciclovir. Two patients discontinued prophylaxis with valganciclovir due to profound leukopenia or continued an adjusted dose of prophylaxis for renal insufficiency after normalization of renal function.

Hepatic allograft biopsies revealed 221 patients (64%) who developed allograft inflammation grade ≥2, 140 patients (40%) who developed fibrosis stage ≥2, and 12 patients (3%) developed cirrhosis. Ninety-four patients (27%) experienced the composite endpoint of graft loss or death. The estimated cumulative incidence after LT for the outcomes of allograft inflammation grade ≥2, fibrosis stage ≥2, cirrhosis, and the combined endpoint of graft loss or death are summarized in Table 2.

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Association of CMV Infection and CMV Disease With the Outcomes of Interest

An evaluation of the associations of CMV infection occurring within the first year after LT with the endpoints of hepatic allograft inflammation grade ≥2, fibrosis stage ≥2, and the combined secondary endpoint of graft loss or death is displayed in Table 3. In single-variable analysis, there was no statistically significant evidence of an association between CMV infection and allograft inflammation grade ≥2 (relative risk [RR], 1.28; P=0.12). However, there was evidence of an increased risk of allograft fibrosis stage ≥2 (RR, 1.49; P=0.027) and graft loss or death (RR, 1.68; P=0.023). In multivariable analysis, we adjusted for those variables that were most associated with the given endpoint, in addition to adjusting for donor/recipient CMV seromatch. Associations of individual variables with each of the three endpoints are shown in the Supplemental Table (see SDC 1,http://links.lww.com/TP/A627) including donor risk index, allograft rejection, basiliximab use, renal replacement therapy on or after LT, and human leukocyte antigen mismatch. The variables human deficiency virus infection and treatment with antithymocyte globulin were not included in the association analysis presented in the Supplemental Table (see SDC 1,http://links.lww.com/TP/A627) due to their rare occurrence. In multivariable analysis (see Table 3 footnote for a description of variables adjusted for in all multivariable analysis), the lack of association between CMV infection and allograft inflammation grade ≥2 remained (RR, 1.12; 95% confidence interval [CI], 0.80–1.58; P=0.50), and the association with graft loss or death weakened and was no longer significant (RR, 1.46; 95% CI, 0.90–2.37; P=0.13). However, CMV infection remained associated with an increased risk of allograft fibrosis stage ≥2 (RR, 1.52; 95% CI, 1.03–2.24; P=0.033).

TABLE 3

TABLE 3

When examining the associations of CMV disease with the outcomes, single-variable analysis revealed an increased risk of allograft inflammation grade ≥2 (RR, 2.17; P=0.007) and graft loss or death (RR, 2.69; P=0.005). CMV disease was not significantly associated with allograft fibrosis stage ≥2 in single-variable analysis (RR, 1.52; P=0.23). In multivariable analysis, CMV disease remained associated with an increased risk of allograft inflammation grade ≥2 (RR, 3.40; 95% CI, 1.83–6.30; P<0.001), and although not significant, was associated with increased risk of allograft fibrosis stage ≥2 (RR, 2.03; 95% CI, 0.99–4.14; P=0.052) and graft loss or death (RR, 1.91; 95% CI, 0.91–4.03; P=0.087).

It was of interest to examine whether associations of CMV infection and disease with the primary and secondary endpoints are consistent between CMV D+/R− seromatch patients and the CMV R+ patients (CMV D+/R+ and CMV D−/R+). The results of this analysis are presented in Figure 2. There was no statistically significant evidence of an interaction of CMV infection or disease with recipient CMV seropositivity for any of the endpoints (all interaction P≥0.084), indicating that the associations of CMV infection and CMV disease with allograft inflammation grade ≥2, fibrosis stage ≥2, and graft loss or death are consistent between the two groups of patients. Of note, all estimated RR were above 1.0 and there was substantial overlap in 95% CI between both groups.

FIGURE 2

FIGURE 2

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DISCUSSION

In the largest retrospective cohort study of first LT recipients transplanted for HCV liver-related disease, we provide evidence that there is an independent association between the development of CMV infection or CMV disease within the first year of transplantation and an increased risk of severe histopathologic recurrence of HCV in the hepatic allograft on long-term follow-up. These findings were consistent between the CMV D+/R− patients who received targeted CMV prophylaxis and the CMV R+ patients who are at lower risk for developing CMV disease and did not receive CMV prophylaxis during the first 100 days after LT.

In previous studies, CMV infection and disease have been associated with severe recurrent HCV in LT recipients (1015). A cohort of 92 LT recipients with HCV demonstrated that asymptomatic or symptomatic CMV infection was associated with decreased patient and allograft survival during a median follow-up of 2 years. The development of CMV infection was associated with higher fibrosis stage on the 4-month allograft biopsy, but not at 1 year (11). Similar results were also demonstrated in a cohort of 93 LT recipients with HCV which showed an association between the development of CMV infection with increased allograft failure on long-term follow-up and fibrosis stage ≥2 at the 4-month allograft biopsy (12). Chopra et al. (13) performed a prospective study of 58 LT recipients with HCV and found that CMV infection was independently associated with a higher fibrosis progression rate. Our findings confirm the association of CMV infection and disease with accelerated hepatic allograft injury from recurrent HCV infection. Trends toward association of CMV infection and disease with increased risk of graft loss or death were also observed, however these findings were not statistically significant. These nonsignificant trends for graft loss, and also regarding the association between CMV disease and fibrosis stage ≥2, highlight the importance of considering the possibility of Type II error, especially when interpreting results involving associations with CMV disease, where power is lower due to its less frequent occurrence.

Exploration of the effect of CMV antiviral prophylaxis of CMV R+ LT recipients and extension of CMV prophylaxis of CMV D+/R− LT recipients on histologic injury of the allograft from recurrent HCV after LT is warranted. Examination of Figure 1(a and b) suggests a potential benefit from extending CMV prophylaxis in CMV D+/R− recipients to 6 months and provision of universal CMV prophylaxis in CMV R+ recipients for 4 months after LT. Studies of extension of CMV prophylaxis for CMV D+/R− kidney transplant recipients from 100 to 200 days and for CMV D+ or R+ lung transplant recipients from 3 months to 12 months have demonstrated reductions in frequencies of CMV infection and disease, reductions that are sustained during and after prophylaxis administration (19, 20).

One of the greatest strengths of this study was the large sample size and the collection of substantial transplant-related information, which allowed for increased power compared with previous smaller studies, and adjustment of many of these variables in the multivariable analysis. Thus, the associations of CMV infection and disease with the poor outcomes identified are unlikely to be caused by confounding variables. Limitations of the study are related to its retrospective nature in a single transplant center, which potentially introduces bias to data collection and definition of clinical events. Caution should be drawn to the association between CMV infection and the outcomes examined. Asymptomatic CMV infection without disease in this and other similar studies was identified at arbitrary times after LT, times dictated by clinical protocols and usually during the first 4 months after LT. Whether and how CMV infection without disease appearing more than 4 months after LT is associated with increased risk of adverse outcomes remains to be determined. We also acknowledge that HCV treatment could have had a small effect on our results. However, this would only occur in the unlikely scenario that once HCV disease occurred, HCV treatment was given systematically less often to patients with CMV infection or CMV disease than to patients without these conditions.

In conclusion, in our large sample of 347 LT recipients transplanted for primary HCV-related disease, CMV infection or CMV disease was associated with increased severity of HCV recurrence in the hepatic allograft. This study provides further evidence of an association between the development of CMV infection or disease with an increased risk of adverse outcomes in HCV LT recipients. Additional study of the potential direct and indirect effects of CMV on the histopathologic recurrence of HCV infection in the hepatic allograft is needed. Investigation of universal CMV prophylaxis of HCV-infected CMV R+ LT recipients and extension of CMV prophylaxis of HCV-infected CMV D+/R− LT recipients, as strategies to mitigate allograft injury from recurrent HCV after LT, is warranted.

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MATERIALS AND METHODS

This retrospective cohort study evaluated 347 consecutive LT recipients who underwent first LT for HCV liver-related disease at Mayo Clinic in Florida between January 1, 2003, and December 31, 2008. Patients of CMV seromatch D+/R− [n=78], D+/R+ [n=180], and D−/R+ [n=89] were included in the study. Patients with combined organ transplants or evidence of eradication of HCV before LT were excluded.

CMV prevention strategies and treatment of CMV infection and CMV disease during the study period was consistent with the current American Society of Transplantation infectious disease guidelines for CMV at the time of the study (21). CMV infection was defined as the isolation of CMV by viral culture, CMV pp65 antigenemia or detection of CMV by nucleic acid amplification or immunostaining in any body fluid or tissue specimen in asymptomatic patients. CMV disease and syndrome were defined as per established criteria in transplant patients (22). CMV pp65 antigenemia assay or blood CMV quantitative polymerase chain reactions (PCRs) were performed weekly during the first 8 weeks, at 4 months, and at 12 months after LT. Liver biopsy and urine specimens were evaluated for evidence of CMV by PCR at 4 and 12 months after LT. Antiviral therapy of CMV infection or disease consisted of IV ganciclovir or oral valganciclovir.

LT recipients of CMV D+/R− seromatch received CMV prophylaxis with IV/oral ganciclovir or valganciclovir through day 100 after LT. Patients who developed CMV infection received antiviral treatment. For patients who were CMV R+, preemptive antiviral therapy was initiated for the development of CMV infection without disease if CMV pp65 antigen was more than 10 cells per 400,000 peripheral blood leukocytes, quantitative blood CMV PCR more than 5000 copies/mL (23), or if the quantitative CMV PCR showed rising viral copies on serial weekly follow-up measurements.

Immunosuppression consisted of tacrolimus, mycophenolate mofetil or azathioprine, and prednisone. Mycophenolate mofetil or azathioprine was discontinued by 4 months after LT or earlier in the setting of malignancy, infection, bone marrow suppression, or gastrointestinal side effects. Prednisone was tapered and discontinued by 4 months after LT unless there was graft rejection, inadequate primary immunosuppression, or conversion to a sirolimus-based regimen. Basiliximab induction was used in patients with renal insufficiency, defined by a serum creatinine greater than 1.5 mg/dL at the time of LT, to delay the initiation of tacrolimus.

Allograft biopsies were performed on day 7, 4 months, and once yearly after LT, and for the evaluation of hepatic decompensation. Acute cellular rejection was defined by histological assessment and classified as mild, moderate, or severe degree based on the International Banff Schema for Liver Allograft Rejection (24). Patients with moderate-to-severe acute cellular rejection were treated with IV methylprednisolone 1 to 3 g, divided into three alternate-day doses. Muromonab or antithymocyte globulin infusion was reserved for patients with acute cellular rejection resistant to methylprednisolone. Allograft biopsies were evaluated for the degree of recurrence of HCV using the METAVIR scoring system (25). The degree of lobular hepatic inflammation was classified as grade 0 to 4, whereas the degree of portal fibrosis was classified as stage 0 to 4. Treatment for recurrence of HCV after LT was at the discretion of the hepatologist and based on the degree of histopathologic recurrence of HCV, patient's tolerability of therapy, medical comorbidities, and psychosocial factors affecting treatment.

Information on patient and donor characteristics at LT, operative and postoperative variables which have been associated with CMV infection, CMV disease, recurrent HCV, graft loss or death were gathered from LT databases and medical records. If the patient received a second LT within the first year of the original transplant, data were only collected for the time period of the first LT. Collection of data demonstrating significant histopathologic recurrence of HCV included hepatic allograft biopsy results with evidence of inflammation grade ≥2, fibrosis stage ≥2, or cirrhosis. If the patient was not diagnosed with CMV infection before the development of CMV disease, they were then considered to have CMV infection and CMV disease simultaneously. Patients who experienced death were assumed to have graft loss simultaneously. The study was approved by the Institutional Review Board of the Mayo Foundation.

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Statistical Analysis

The Kaplan-Meier method was used to estimate the cumulative incidence of CMV infection, CMV disease, hepatic allograft inflammation grade ≥2, fibrosis stage ≥2, cirrhosis, and graft loss or death after LT, along with 95% CIs. The two primary endpoints of interest were allograft inflammation grade ≥2 and fibrosis stage ≥2, with the composite endpoint of graft loss or death considered as a secondary endpoint. Censoring occurred on the date of graft loss, death, or last allograft biopsy for inflammation grade ≥2 and fibrosis stage ≥2, and on the date of last follow-up for endpoint of graft loss or death.

The associations of CMV infection and CMV disease with the three endpoints were evaluated using Cox proportional hazards regression models. Cirrhosis was not considered as an outcome of interest in the association analysis due to the small number of patients who experienced this outcome. Single-variable Cox models were used in an exploratory analysis, and multivariable Cox models adjusting for potentially confounding variables in the primary analysis. In the multivariable analysis, we first adjusted for the a priori known potentially confounding variable of CMV donor/recipient seromatch. With that variable included in all models, we then adjusted for variables showing the strongest single variable associations with the given endpoint, allowing for no more than one variable in the model for every 10 patients who experienced the given endpoint (26). RRs and 95% CI were estimated. We also assessed the presence of interactions of recipient CMV seropositivity (CMV D+/R− vs. CMV D+/R+ or CMV D−/R+) with CMV infection and disease in association analysis involving the three endpoints using the previously described multivariable Cox regression models, substituting recipient CMV seropositivity as a covariate for CMV donor/recipient seromatch to avoid collinearity.

Posttransplant variables were considered as time-varying covariates in Cox regression analysis. Length of hospital stay (≤14 days, >14 days) was dichotomized for utilization in Cox regression analysis as a time-varying covariate. We did not consider HCV treatment as a potential time-varying covariate to adjust for in multivariable Cox regression models, because rather than acting as a potentially confounding variable, HCV treatment is a preliminary measure of HCV-related outcomes, and can equally be thought of as presence of HCV disease. The number of human leukocyte antigen donor/recipient mismatches was dichotomized as 0 or 1 vs. 2 owing to the small number of patients with 0 mismatches. P values less than or equal to 0.05 were considered statistically significant.

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Keywords:

Cytomegalovirus; Hepatitis C virus; Liver transplantation; Death; Graft loss

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