Interactions Between Cytomegalovirus, Human Herpesvirus‐6, and the Recurrence of Hepatitis C After Liver Transplantation

Recurrence of hepatitis C (HCV) following liver transplantation is common. Herpesvirus reactivation following transplant may have an immunomodulatory effect resulting in increased HCV replication. We studied whether cytomegalovirus (CMV) and human herpesvirus‐6 (HHV‐6) may be associated with HCV recurrence and viral load after transplant. We prospectively followed 66 HCV liver‐transplant recipients with serial viral load testing for CMV and HHV‐6. Infection and viral load were correlated with the development of biopsy‐proven HCV recurrence and HCV viral loads. Histologic recurrence of HCV occurred in 41/66 (62.1%) patients. In the primary analysis, CMV infection and disease, and HHV‐6 infection were not associated with HCV recurrence. Peak CMV and HHV‐6 viral loads were not significantly different in patients with and without recurrence. No correlation was observed between HCV viral loads at 1 and 3 months post‐transplant and peak HHV‐6 or CMV viral loads. In a subgroup analysis, HHV‐6 infection was associated with the development of more severe recurrence (hepatitis and/or fibrosis score ≥ 2) (p = 0.01). Also, fibrosis scores at last follow up were higher in patients with CMV disease (1.67 vs. 0.56; p = 0.016) and in patients with HHV‐6 infection (1.18 vs. 0.55; p = 0.031). In conclusion, HHV‐6 and CMV infection and viral load were not associated with increased overall rates of HCV recurrence or HCV viral load after liver transplantation but may be associated with more severe forms of recurrence. Recurrence of hepatitis C (HCV) following liver transplantation is common. Herpesvirus reactivation following transplant may have an immunomodulatory effect resulting in increased HCV replication. We studied whether cytomegalovirus (CMV) and human herpesvirus‐6 (HHV‐6) may be associated with HCV recurrence and viral load after transplant. We prospectively followed 66 HCV liver‐transplant recipients with serial viral load testing for CMV and HHV‐6. Infection and viral load were correlated with the development of biopsy‐proven HCV recurrence and HCV viral loads. Histologic recurrence of HCV occurred in 41/66 (62.1%) patients. In the primary analysis, CMV infection and disease, and HHV‐6 infection were not associated with HCV recurrence. Peak CMV and HHV‐6 viral loads were not significantly different in patients with and without recurrence. No correlation was observed between HCV viral loads at 1 and 3 months post‐transplant and peak HHV‐6 or CMV viral loads. In a subgroup analysis, HHV‐6 infection was associated with the development of more severe recurrence (hepatitis and/or fibrosis score ≥ 2) (p = 0.01). Also, fibrosis scores at last follow up were higher in patients with CMV disease (1.67 vs. 0.56; p = 0.016) and in patients with HHV‐6 infection (1.18 vs. 0.55; p = 0.031). In conclusion, HHV‐6 and CMV infection and viral load were not associated with increased overall rates of HCV recurrence or HCV viral load after liver transplantation but may be associated with more severe forms of recurrence. Hepatitis C virus (HCV) related chronic liver disease has become one of the leading indications for liver transplantation. However, persistence of HCV is almost universal after transplantation. Biochemical and histologic evidence of recurrent HCV is common during the first year after transplantation, and increases further with longer follow up (1Gane JR Portmann BC Naoumov NV et al.Long‐term outcome of hepatitis C infection after liver transplantation.N Engl J Med. 1996; 334: 815-820Crossref PubMed Scopus (947) Google Scholar, 2Maschek H Tillmann HL Trautwein C et al.Long‐term outcome of hepatitis C virus infection after liver transplantation.Hepatology. 1997; 25: 203-210Google Scholar). Bridging fibrosis or cirrhosis develops in approximately 20–30% of patients with recurrent HCV by 5 years. A better understanding of factors favoring recurrence is important in developing strategies to improve outcomes. One of the factors promoting recurrence of HCV may be the reactivation of one or more of the herpesgroup viruses after transplantation. Cytomegalovirus (CMV) is the herpesvirus that most commonly results in symptomatic disease after transplant, but is also proposed to have an indirect immunomodulatory effect in transplant recipients. Cytomegalovirus infection has been associated with bacteremia (3Falagas ME Snydman DR Griffith J Werner BG Exposure to cytomegalovirus from the donated organ is a risk factor for bacteremia in orthotopic liver transplant recipients.Clin Infect Dis. 1996; 23: 468-474Crossref PubMed Scopus (93) Google Scholar), invasive fungal disease (4Griffith J Falagas ME Dougherty NN Rubin RH The independent role of cytomegalovirus as a risk factor for invasive fungal disease in orthotopic liver transplant recipients.Am J Med. 1997; 103: 106-113Abstract Full Text Full Text PDF Scopus (269) Google Scholar), Epstein–Barr virus‐related post‐transplant lymphoproliferative disease (5Wilson J Torre‐Cisneros J Kusne S et al.Posttransplant lymphoproliferative disease in primary Epstein‐Barr virus infection after liver transplantation: the role of cytomegalovirus disease.J Infect Dis. 1997; 176: 1462-1467Crossref Scopus (223) Google Scholar) as well as acute and chronic allograft injury (6Fishman JA Rubin RH Infection in organ transplant recipients.N Eng J Med. 1998; 338: 1741-1751Crossref PubMed Scopus (1358) Google Scholar). In addition, CMV replication may favor the recurrence of HCV through similar immunomodulatory effects (7Dhillon AP Emery VC Rolles K et al.The influence of cytomegalovirus viraemia on the outcome of recurrent hepatitis C after liver transplantation.Transplantation. 2000; 70: 1454-1458Crossref Scopus (44) Google Scholar, 8Gretch DR Flora KD Boudousquie A et al.Cytomegalovirus viremia: risk factor for allograft cirrhosis after liver transplantation for hepatitis C.Transplantation. 1997; 64: 721-726Crossref Scopus (136) Google Scholar). Another β‐herpesvirus, human herpesvirus‐6 (HHV‐6), also commonly reactivates following transplantation with HHV‐6 infection, as reported in 31–55% of solid‐organ transplant recipients (9Singh N Carrigan DR Human herpesvirus‐6 in transplantation: an emerging pathogen.Ann Intern Med. 1996; 124: 1065-1071Crossref PubMed Scopus (185) Google Scholar). Human herpesvirus‐6 has been implicated as a cause of febrile viral syndromes, hepatitis, pneumonitis, and encephalitis in this patient population (9Singh N Carrigan DR Human herpesvirus‐6 in transplantation: an emerging pathogen.Ann Intern Med. 1996; 124: 1065-1071Crossref PubMed Scopus (185) Google Scholar). This virus may also have an immunomodulatory role, and in‐vitro infection of T cells by HHV‐6 leads to a reduction of both IL‐2 synthesis and T‐cell proliferation (10Flamand L Gosselin J Stefanescu I Ablashi D Menezes J Immunosuppressive effect of human herpesvirus 6 on T‐cell functions: suppression of interleukin‐2 synthesis and cell proliferation.Blood. 1995; 85: 1263-1271Crossref PubMed Google Scholar). Human herpesvirus‐6 has been implicated as a risk factor for the development of CMV disease, graft dysfunction and other opportunistic infections (11Moussa G, Ashi‐Sulaiman A, Levy G, Mazzulli T. The clinical impact of human herpesvirus‐6 infection following liver transplantation. Transplantation; in press.Google Scholar, 12Kusne S Knox KK Gayowski T et al.Human herpesvirus‐6 in liver transplant recipients: role in pathogenesis of fungal infections, neurologic complications, and outcome.Transplantation. 2000; 69: 2566-2573Crossref PubMed Scopus (112) Google Scholar, 13Clark DA Quaglia A Davies SE et al.Human herpesviruses 6 and 7 as potential pathogens after liver transplant: Prospective comparison with the effect of cytomegalovirus.J Med Virol. 1999; 59: 496-501Crossref Scopus (132) Google Scholar). Given the evidence suggesting an immunomodulatory effect of HHV‐6 infection, this virus may also play a role in promoting HCV replication after transplant, although no studies have been published that specifically assess this hypothesis. In this study, we tested the hypothesis that CMV and HHV‐6 infection and viral load are associated with the histologic recurrence of HCV and HCV viral load after liver transplant. We employed molecular diagnostic tests to determine viral loads for all three viruses and liver biopsies to assess for recurrence of HCV. Adult patients undergoing liver transplantation for HCV were enrolled between June 1997 and March 2000. These patients were part of a larger trial assessing the clinical impact of HHV‐6 infection following liver transplantation (11Moussa G, Ashi‐Sulaiman A, Levy G, Mazzulli T. The clinical impact of human herpesvirus‐6 infection following liver transplantation. Transplantation; in press.Google Scholar). The study was approved by the institutional review board. After informed consent was obtained, blood samples for CMV and HHV‐6 viral load were collected at baseline and 1–2 weekly intervals until 12 weeks post‐transplant. The only antiviral prophylaxis was in patients who were donor (D) seropositive and recipient (R) seronegative (D+/R–) for CMV. These patients received 12 weeks' ganciclovir, and then samples were collected for an additional 8 weeks. Blood was collected for HCV viral load at 1 and 3 months post‐transplant. The treating physician was blinded to the test results, and therefore patients did not receive pre‐emptive antiviral therapy based on the results. All laboratory testing was done by technologists blinded to the patients' clinical status. Human herpesvirus‐6 PCR. DNA was extracted from peripheral blood leukocytes using Puregene DNA Isolation kits (Gentra Systems, Minneapolis, MN). For quantitation and standardization, an HHV‐6 DNA control (Advanced Biotechnologies Inc., Columbia, MD) with a known copy number was used. Polymerase chain reaction (PCR) was carried out using a HHV‐6 Custom Probe/Primer set (Digene Inc., Silver Spring, MD, which uses primers directed against the U1102 region of HHV‐6 variant A and the Z29 region of HHV‐6 variant B. Primer sequences(5′ to 3′) were GTT CCA GGC GGC ATG AAT TC and Biotin‐ACA CGG CCT CTC TAC ATC AC. Amplified DNA was detected and quantitated using the SHARP SignalTM System (Digene Inc., Silver Spring, MD), which is a colorimetric absorbance assay. Quantitation of HHV‐6 DNA was calculated by using known dilutions of the HHV‐6 DNA control to generate a standard curve, plotting the positive sample signals on this curve and extrapolating the copy number. Results were reported as log10 copies/µg input DNA. Quantitative CMV and HCV‐PCR were performed on plasma samples according to manufacturer's instructions using the Cobas Amplicor Monitor Test (Roche Diagnostic Systems, Inc., Branchburg, NJ). Results were recorded as the number of viral copies/mL plasma. For CMV, the lower limit of detection was 400 copies/mL and for HCV was 1000 copies/mL. Cytomegalovirus infection and disease. Cytomegalovirus infection was defined as any patient with a positive plasma PCR regardless of symptoms. Active CMV disease was diagnosed based on biopsy evidence of tissue invasion or in patients with fever, a positive plasma PCR or antigenemia assay, plus either leukopenia (WBC < 3.5 × 109/L), thrombocytopenia (platelet count < 100 × 109/L), or new onset arthralgias, myalgias and malaise (CMV viral syndrome) (11Moussa G, Ashi‐Sulaiman A, Levy G, Mazzulli T. The clinical impact of human herpesvirus‐6 infection following liver transplantation. Transplantation; in press.Google Scholar). In an attempt to distinguish active from latent viral infections, HHV‐6 viral load results were analyzed for samples taken between 0 and 7 days post‐transplant in a larger cohort of 200 liver‐transplant patients (11Moussa G, Ashi‐Sulaiman A, Levy G, Mazzulli T. The clinical impact of human herpesvirus‐6 infection following liver transplantation. Transplantation; in press.Google Scholar). These results are described in detail elsewhere (11Moussa G, Ashi‐Sulaiman A, Levy G, Mazzulli T. The clinical impact of human herpesvirus‐6 infection following liver transplantation. Transplantation; in press.Google Scholar), but all patients who had a positive result from day 0–7 had viral loads < 2‐log10 copies/µg input DNA (median 1.4 log10). Therefore, active HHV‐6 infection was defined as a viral load ≥ 2‐log10 copies/µg input DNA. Although somewhat arbitrary, this cut‐off was chosen as a conservative estimate of patients likely to have viral reactivation. However, as this may underestimate the rate of HHV‐6 infection, any positive PCR result (including < 2‐log10 copies) was also analyzed as a continuous variable (i.e. HHV‐6 viral load) for its with HCV recurrence. biopsies were performed patients with histologic evidence of hepatitis in the of or evidence of hepatitis virus infection were diagnosed as recurrent HCV T for the for the of in chronic hepatitis 1996; PubMed Google Scholar). were by a blinded to the results of CMV, and HCV viral load A score for the of hepatitis based on the of and and = 1 = = 3 = was T for the for the of in chronic hepatitis 1996; PubMed Google Scholar). In this and hepatitis is based on the of and For a biopsy with either or be at as et this score T for the for the of in chronic hepatitis 1996; PubMed Google Scholar). A score was for the fibrosis = 1 = = and fibrosis without 3 = = of chronic and PubMed Scopus Google Scholar). All was performed using The of factors with the recurrence of HCV was using the or test for and the for continuous were to determine the of between a number of and the to HCV recurrence. patients undergoing liver transplant for HCV infection were followed prospectively of or and = or plus and either = or = or other = was in patients for were followed for a of 1 year or until follow up was days patients during the study of which patients of recurrent HCV. recurrent HCV occurred in 41/66 patients to recurrence was days the of the hepatitis score was 1 in patients in patients and 3 in three patients 1 fibrosis was in in three and 3 in three patients. HCV to chronic active hepatitis or fibrosis ≥ in a of days post‐transplant HCV viral load at 1 post‐transplant was log10 copies/mL log10 and at 3 months post‐transplant was copies/mL log10 recurrence (i.e. a positive plasma HCV occurred in patients by 3 months post‐transplant and was universal by 6 months post‐transplant. The HCV viral load at 1 was of biopsy‐proven recurrence with a risk of a log10 copies/mL in viral load p = However, HCV viral load at 3 months was not of recurrent disease = p = The of was not associated with a higher recurrence rate in this cohort Recurrence was not associated with the of and specifically the of The number of of was in patients with recurrence vs. in patients without recurrence (p = was in patients without recurrence vs. in patients with recurrence (p = vs. had no influence on recurrence (p = of cytomegalovirus and human herpesvirus‐6 infections between patients with and without histologic hepatitis C recurrence < loads in log10 = = recurrence = CMV HHV‐6 at 1 at 3 = human = = viral = hepatitis C = in a new of cytomegalovirus and human herpesvirus‐6 infections between patients with and without severe histologic hepatitis C recurrence or hepatitis ≥ < are loads in log10 = severe = = CMV HHV‐6 at 1 at 3 = human = = viral = hepatitis C = in a new = human herpesvirus CMV = cytomegalovirus = viral loads HCV = hepatitis C virus = = human herpesvirus CMV = cytomegalovirus = viral loads HCV = hepatitis C virus = Cytomegalovirus donor (D) and recipient was as = = = and = Cytomegalovirus prophylaxis of was in only patients Cytomegalovirus infection occurred in patients CMV disease occurred in patients and was as CMV viral = CMV = and CMV hepatitis = Peak CMV viral load in patients with CMV infection occurred at a of days post‐transplant peak CMV viral load was not different in patients with and without recurrence (median = in both vs. log10 p = The number of biopsies in patients with and without CMV disease and infection was the in patients with CMV disease vs. in and vs. in patients with CMV infection vs. p = for both The of between transplant and last biopsy was the in patients with and without CMV (p = Cytomegalovirus infection, disease and viral load were in patients with and without histologic HCV recurrence Cytomegalovirus infection occurred in of patients without recurrence vs. of patients with HCV recurrence (p = Cytomegalovirus disease occurred of patients without recurrence vs. of patients with HCV recurrence (p = The risk of recurrent HCV did not with CMV viral loads = for copies/mL in peak CMV viral p = Cytomegalovirus viral infection and disease were not associated with increased HCV viral loads at 1 and 3 months C viral loads at 1 and 3 months post‐transplant in patients with and without cytomegalovirus or human herpesvirus‐6 loads in log10 copies/mL = viral load at 1 viral load at 3 months HHV‐6 CMV CMV = human = = hepatitis C virus in a new = human herpesvirus CMV = cytomegalovirus HCV = hepatitis C virus Human herpesvirus‐6 PCR was positive in patients at during post‐transplant No patient that were to infection with HHV‐6. Peak viral load occurred a of days post‐transplant. peak HHV‐6 viral load was log10 copies/µg input DNA in patients with recurrence vs. log10 in patients with no recurrence (p = The risk of recurrent HCV was log10 copies/µg input DNA in peak HHV‐6 viral load p = Human herpesvirus‐6 infection defined as a viral load ≥ log10 copies/µg input DNA occurred in patients. Human herpesvirus‐6 infection occurred in of patients with HCV recurrence vs. of patients with no recurrence (p = Human herpesvirus‐6 viral load and infection were not associated with HCV viral loads at 1 and 3 months The number of biopsies in patients with and without HHV‐6 was the vs. p = The of between transplant and last biopsy was the in patients with and without CMV (p = fibrosis score at last follow up was vs. in patients with CMV disease vs. without (p = 0.016) and vs. in patients with CMV infection vs. without (p = The hepatitis score at last biopsy was not significantly score was vs. in patients with HHV‐6 infection vs. without (p = of a more severe recurrence of HCV (hepatitis or fibrosis score ≥ 2) occurred in patients. were analyzed for with severe recurrence was a CMV disease and the development of more severe recurrence vs. p = Human herpesvirus‐6 infection was associated with the development of severe recurrence vs. p = 0.01). In a the risk of severe HCV recurrence was in patients with HHV‐6 infection p = No was observed between peak HHV‐6 viral load in HHV‐6 copy p = and severe HCV recurrence or peak CMV viral load and severe HCV recurrence copies/mL in CMV viral p = Hepatitis C virus viral load at 1 was associated with severe recurrence copies/mL in HCV viral p = but HCV viral load at 3 months was The number of of was in patients with recurrence vs. in patients without recurrence (p = factors for the most severe fibrosis ≥ were also analyzed Cytomegalovirus disease was associated with severe fibrosis of patients with CMV disease had ≥ 3 fibrosis vs. in patients without CMV p = be that only patients the of fibrosis score ≥ a sample No with HHV‐6 and fibrosis score ≥ 3 was C fibrosis score at last liver biopsy in patients with and without cytomegalovirus or human herpesvirus‐6 C fibrosis score at last HHV‐6 CMV CMV = human = in a new = human herpesvirus CMV = cytomegalovirus This is the first study to prospectively assess CMV and HHV‐6 viral loads and with both histologic HCV recurrence and HCV viral loads post‐transplant. We no correlation between CMV and HCV viral loads and between HHV‐6 and HCV viral loads. In addition, viral loads were analyzed as a continuous peak CMV and HHV‐6 viral load were not associated with biopsy‐proven HCV recurrence. In the primary analysis, CMV infection, disease and HHV‐6 infection were also not associated with HCV recurrence. However, the fibrosis score at last biopsy was significantly higher in patients with CMV disease and with HHV‐6 In addition, the development of severe recurrence or hepatitis score ≥ 2) was significantly more common in patients with HHV‐6 This was not by in therapy no in the or of therapy was in the different are by which herpesviruses may with HCV. These viruses may an immunomodulatory effect resulting in For CMV has been to be a risk factor for the development of invasive fungal and infections (3Falagas ME Snydman DR Griffith J Werner BG Exposure to cytomegalovirus from the donated organ is a risk factor for bacteremia in orthotopic liver transplant recipients.Clin Infect Dis. 1996; 23: 468-474Crossref PubMed Scopus (93) Google Scholar, J Falagas ME Dougherty NN Rubin RH The independent role of cytomegalovirus as a risk factor for invasive fungal disease in orthotopic liver transplant recipients.Am J Med. 1997; 103: 106-113Abstract Full Text Full Text PDF Scopus (269) Google Scholar). in‐vitro studies have that HHV‐6 infection of T cells results in the of IL‐2 and and a reduction in resulting in a (10Flamand L Gosselin J Stefanescu I Ablashi D Menezes J Immunosuppressive effect of human herpesvirus 6 on T‐cell functions: suppression of interleukin‐2 synthesis and cell proliferation.Blood. 1995; 85: 1263-1271Crossref PubMed Google Scholar). factors as by herpesvirus reactivation may have effects on HCV recurrence. CMV and HHV‐6 infection have been associated with the of J Ablashi Menezes J Human herpesvirus 6 and factor but not in peripheral cell Virol. Scopus Google Scholar, J et al.Cytomegalovirus infection in transplant recipients. The role of Scopus Google Scholar, Cytomegalovirus cells by the of and virus by cell and during Infect Dis. 1998; PubMed Scopus Google Scholar). For HHV‐6 infection results in the of which is to play important role in the pathogenesis of HCV J Ablashi Menezes J Human herpesvirus 6 and factor but not in peripheral cell Virol. Scopus Google Scholar, J K S of factor with variable of hepatitis C recurrence after liver transplantation.Transplantation. 1999; Scholar). may be that the of HCV and the reactivation of herpesviruses may both be of an of Although in were not observed in study patients with and without more severe HCV is no standard for the of in a Therefore, as therapy was the this may impact on HCV viral load and Also, therapy for acute may both herpesvirus and HCV recurrence and potential studies of herpesviruses and HCV have on CMV. et (7Dhillon AP Emery VC Rolles K et al.The influence of cytomegalovirus viraemia on the outcome of recurrent hepatitis C after liver transplantation.Transplantation. 2000; 70: 1454-1458Crossref Scopus (44) Google Scholar) analyzed a cohort of HCV liver‐transplant recipients who had and that the of CMV did not influence HCV recurrence. However, as patients received pre‐emptive based on positive PCR is to potential between HCV and CMV in a not by antiviral et DR Flora KD Boudousquie A et al.Cytomegalovirus viremia: risk factor for allograft cirrhosis after liver transplantation for hepatitis C.Transplantation. 1997; 64: 721-726Crossref Scopus (136) Google Scholar) that the of cirrhosis was higher in HCV liver‐transplant recipients with CMV However, this study was by the number of patients with CMV = are no published studies assessing between HHV‐6 and HCV. However, as HHV‐6 has been associated with CMV disease, graft and other opportunistic infections in liver‐transplant recipients (11Moussa G, Ashi‐Sulaiman A, Levy G, Mazzulli T. The clinical impact of human herpesvirus‐6 infection following liver transplantation. Transplantation; in press.Google Scholar, 12Kusne S Knox KK Gayowski T et al.Human herpesvirus‐6 in liver transplant recipients: role in pathogenesis of fungal infections, neurologic complications, and outcome.Transplantation. 2000; 69: 2566-2573Crossref PubMed Scopus (112) Google Scholar, 13Clark DA Quaglia A Davies SE et al.Human herpesviruses 6 and 7 as potential pathogens after liver transplant: Prospective comparison with the effect of cytomegalovirus.J Med Virol. 1999; 59: 496-501Crossref Scopus (132) Google Scholar). risk factors for HCV recurrence in studies HCV viral and a score at the of transplant A of and organ transplantation on the and of hepatitis C virus Infect Dis. 2000; PubMed Scopus Google Scholar). study was not or to assess in to recurrent HCV. The of study was to assess herpesvirus reactivation and its potential with HCV. of study the of viral load testing to CMV, HHV‐6 and HCV. Also, the results of all testing was and patients did not receive pre‐emptive based on we did in patients who were for CMV. this only is to have the results A of study is that HCV testing was not although studies in recurrence have been A et al.The influence of hepatitis C virus on the outcome of liver 1998; Scopus Google Scholar, NN et between hepatitis C and of recurrent hepatitis C after liver transplantation.Transplantation. 1997; Scopus Google Scholar). Also, we had a sample and the positive may have by of the of However, study is the study to to specifically assess CMV and HHV‐6 with HCV molecular diagnostic we did not liver biopsies on which may to in the onset of HCV as may not with However, the of patients did have biopsies post‐transplant Also, as the follow up was only approximately is likely that more patients have to fibrosis follow up had been further We no overall between CMV, HHV‐6 infection or viral loads and HCV recurrence. However, viral reactivation may be associated with more severe forms of fibrosis or study the immunomodulatory effects of different viruses in a larger cohort of patients is to whether an studies also suppression of herpesvirus reactivation with antiviral therapy the of HCV infection post‐transplant.

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