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Solid Organ Transplantation: Little Research, Big Need for Patients with HCV
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Hellen Chiao
Catherine T. Frenette
The CDC estimates that more than 3.2 million Americans have hepatitis C virus, and 17,000 new cases are diagnosed each year. The prevalence of HCV is highest in the baby boomer population born between 1945 and 1965, with current estimates at 3.25%, or one in 30 baby boomers.
The topic of organ transplantation among HCV-infected patients became paramount when the baby boomers aged. Between the scarce pool of organs and patients needing solid organ transplants, research on organ transplantation among HCV-infected patients has become more important than ever. There are currently 121,983 patients listed in the United Network for Organ Sharing (UNOS) database waiting for major solid organ transplant, and many of them have HCV.
Slow Progression of HCV
The progression of HCV is slow and chronic. Of all acute infections, 85% become chronic and 15% resolve. Approximately 20% of patients who develop chronic HCV also develop cirrhosis over 20 years. Other coinfections such as HIV and hepatitis B virus, alcohol, and fatty liver disease can all accelerate the development of cirrhosis. Among patients with cirrhosis, there is a 6% risk for developing end-stage liver disease, 4% annual risk for hepatocellular carcinoma, and 3% to 4% risk for liver disease mortality before receiving a liver transplant (Figure 1).
Figure 1. Abbreviations: ESLD, end-stage liver disease; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; OLT, orthotopic liver transplant.
Source: Chiao H, Frenette CT
HCV and Heart Transplant
There are few data on HCV infection in cardiac transplant patients. Historically, perioperative HCV infection in open heart transplant before 1990 was 28%. Since then, this alarming rate has significantly decreased to 4% or lower due to system-wide screening.
In the limited literature, one small case series included 20 HCV-infected patients who underwent open heart transplant. Two patients had cirrhosis before the operation; one survived 148 months and the other 61 months after transplantation. During the study, HCV RNA levels increased fourfold to 100-fold after transplant, but the researchers found no correlation with disease severity.
In another study by Lake and colleagues, 5-year follow-up after heart transplant revealed no significant differences in patient or graft survival between HCV-positive and HCV-negative transplant recipients. Fagiuoli and colleagues conducted a 6-year follow-up study of 36 patients with HCV who were undergoing heart transplantation. Of those, 58% developed chronic liver disease (liver enzyme levels >1.5 times the upper limits of normal), and 28% had clinically significant cirrhosis. In the same study, three of six patients with cirrhosis who had de novo HCV infection died of end-stage liver disease an average of 6 years after the heart transplant. It is unclear whether contracting HCV infection in the perioperative period confers a more aggressive course. Similar results have also been observed in kidney transplant recipients. Furthermore, with longer follow-up, Fong and colleagues found a reduced survival rate in HCV-seropositive heart transplant recipients compared with HCV-negative recipients.
In addition, there are few data on HCV treatment in the heart transplant population. A small case series examined four open heart transplant recipients with chronic HCV infection who were treated with interferon. At 12-months follow-up, Fagiuoli and colleagues reported no major complications. In fact, three patients had sustained biochemical response within 3 months, although sustained virologic response (SVR) was not maintained at the end of treatment. Despite the good outcome of this very small study, there have been case reports of fatality with interferon/ribavirin treatment. One patient treated with interferon/ribavirin after heart transplant for ischemic cardiomyopathy ultimately succumbed to severe heart failure and cardiotoxicity from pegylated interferon alfa-2b, according to a study by Wang and colleagues.
Although interferon monotherapy might be effective for HCV treatment in heart transplant patients, more powerful studies are needed to evaluate treatment options. Currently, most medical societies do not recommend interferon-based therapy after open heart transplant, especially those with severe cardiac disease.
HCV and Lung Transplant
Similar to heart transplantation, there are limited data on HCV infection in lung transplant recipients. In reviewing the UNOS database, 72% of programs considered HCV-infected patients for lung transplants, while 55% accepted HCV-positive lung allografts, and 17% had transplanted lung allografts from seropositive donors into uninfected patients.
Studies on outcomes, however, are lacking. A small case series of three patients who acquired HCV after lung transplant had high viral load with genotype 1b HCV. All patients died within 1 year after transplant; two died of hepatic failure despite treatment and one died of hemoptysis from fungal infection.
Another small prospective study conducted by Douette and colleagues described the outcomes of five lung transplant recipients with HCV. Previously, severe pulmonary disease was considered a contraindication to interferon therapy. However, in this small population, all patients were treated with the standard HCV therapy: ribavirin plus interferon alfa-2b or pegylated interferon alfa-2b for 24 or 48 weeks, depending on the genotype. Not surprisingly, all patients experienced adverse effects related to the interferon and ribavirin. However, three patients had SVR, and one even underwent uncomplicated lung transplant with immunosuppression (cyclosporine, mycophenolate mofetil and prednisone). At 21 months after transplant, this particular patient continued to have excellent lung function while HCV RNA level remained undetectable; however, he finally relapsed after 6 months. This small study offers hope for lung transplant candidates.
However, more powerful studies are still needed to validate the safety and efficacy of interferon-based HCV therapy in lung transplant recipients.
HCV and Kidney Transplant
The rate of HCV infection is much higher in kidney transplant candidates compared with transplantation of other solid organs. Before the identification of HCV, screening for non-A, non-B hepatitis was by liver enzymes (aspartate aminotransferase [AST] and alanine aminotransferase [ALT] levels). However, a normal aminotransferase did not indicate a disease-free liver, as we now know. In fact, transaminases are often normal in patients with HCV who have renal disease on hemodialysis.
The CDC recommends initial HCV screening with HCV antibody and ALT in all patients before starting hemodialysis. Monthly ALT and semiannual HCV antibody evaluation is also recommended while receiving hemodialysis. However, in patients undergoing hemodialysis, data have shown a high false-negative rate with HCV antibody alone, estimated to be as high as 17.9%. Thus, patients at high risk should be screened with HCV polymerase chain reaction assays, which remains as the gold standard.
Other studies have demonstrated that the impact of pre-transplant HCV infection appears to have no significant difference in patient or graft survival during short-term follow-up of less than 5 years. However, studies with longer-term follow-up have revealed decreased graft and patient survival in HCV-positive organ recipients. The etiology of decreased survival includes sepsis, HCV-related glomerulopathy, recurrent or cirrhotic liver disease, or development of post-transplant diabetes.
In two studies, Pereira and colleagues and Hanafusa and colleagues reported that HCV-positive recipients had a higher rate of post-transplant liver disease and poorer 20-year survival compared with their HCV-negative counterparts (64% vs. 88%). In a meta-analysis by Fabrizi and colleagues published in 2005, the presence of HCV antibody was an independent risk factor for death and graft failure. In addition, hepatocellular carcinoma and liver cirrhosis were common causes of mortality in HCV-positive recipients. Whether immunosuppression after renal transplant confers increased rates of progression of hepatic fibrosis is controversial.
Before renal transplant, HCV should ideally be eradicated. In one study of 15 HCV-positive patients treated with interferon alfa before transplant, 10 (67%) were able to achieve SVR before transplant. In addition, patients on hemodialysis who are being treated with interferon alfa appear to have a beneficial effect on the course of their liver disease after transplant. The current consensus is that interferon alfa treatment should be strongly considered in HCV-positive patients on hemodialysis awaiting renal transplant.
After kidney transplant, one must weigh risks against the benefits of HCV treatment. In patients with evidence of chronic liver injury with severe cholestatic hepatitis, recurrent and progressive HCV-associated glomerulopathy in the allograft should be considered for therapy. In post-transplant patients, amantadine or ribavirin monotherapy is not efficacious in clearing HCV. However, interferon alfa in the setting of post-transplant patients has been associated with acute graft rejection. In a small observational study, 63.6% (seven of 11) patients experienced acute deterioration of allograft function associated with interferon alfa therapy. Currently, the effects of combination therapy are not sufficiently clear. More powerful studies are needed to provide further recommendation.
HCV and Liver Transplant
HCV remains the most common indication for orthotopic liver transplant in the United States. However, recurrence of HCV infection after liver transplant is almost definite and rate of progression to fibrosis is accelerated compared with nontransplant patients. It is estimated that cirrhosis occurs in 30% of orthotopic liver transplant recipients by 5 years, and rapid liver decompensation is not uncommon. There is no clear relationship between pre-transplant HCV viral load and post-transplant recurrence, and, unfortunately, there is also no good strategy for prevention of HCV reinfection. Overall, patients with HCV have poorer survival compared with orthotopic liver transplant patients without HCV.
The first month after orthotopic liver transplant is an important period to determine long-term outcome. Significant necroinflammation with acute hepatitis, evidence of portal hypertension or fibrosis are all poor indicators for graft loss and decreased patient survival. Risk factors include old donor age, female gender, corticosteroid boluses, cytomegalovirus infection and biliary complications.
Recurrent HCV is characterized by inflammatory infiltration of the liver parenchyma, hepatocellular damage, and tissue remodeling leading to fibrosis and cirrhosis. Immunosuppression remains a challenge because it is a very fine balance between suppressing host immunity for graft survival against host response to HCV infection. Similar to renal transplant, eradication of HCV before orthotopic liver transplant is ideal in minimizing recurrence. Studies aimed at achieving SVR before orthotopic liver transplant with a short course (3-4 months) of triple therapy with protease inhibitors, pegylated interferon and ribavirin may be useful in treatment-naive patients or prior partial responders. Approximately 20% of patients were able to maintain long-term viral clearance after orthotopic liver transplant. Favorable factors include genotype 2 or 3 and CC polymorphism in interleukin-28B. Unfortunately, many patients were unable to tolerate therapy due to advanced liver disease, cytopenia or life-threatening coinfections. However, it may still be a reasonable option for patients with preserved liver function (MELD <18 or Child-Pugh <8) before orthotopic liver transplant. However, for patients with cirrhosis or prior nonresponders, SVR rates were less than 15%. The rates may be even lower for patients with more advanced cirrhosis. In addition, interferon has significant adverse effects that prevents its use in the advanced liver disease population. Moreover, direct-acting antiviral (DAA) agents may be frequently interrupted when patients cannot tolerate full doses of pegylated interferon and ribavirin.
After orthotopic liver transplant, there are no solid data for an immunosuppressive regimen in the setting of HCV infection. Tacrolimus is the most widely used calcineurin inhibitor, and it has a lower reported rate of acute rejection compared with cyclosporine. Nevertheless, research has shown no clear significant difference in patient or graft survival between the two agents in the long term. Regarding antiviral therapy, some retrospective studies have suggested a positive outcome using ribavirin and interferon with cyclosporine. A systematic review of 19 studies and 600 patients with recurrent HCV were treated with pegylated interferon and ribavirin showed a SVR rate of 30%. However, this regimen was ultimately terminated in 27% of the patients due to adverse effects, and 73% of the patients required dose reduction due to anemia. Graft rejection occurred in less than 5% of cases. Early viral clearance is the most important predictor of successful treatment outcome in HCV orthotopic liver transplant. If treatment is ultimately unsuccessful, re-transplantation is a consideration, although survival rate after the second orthotopic liver transplant is much lower.
More Research Needed on Newer Therapies
In late 2013, two new DAAs were approved, sofosbuvir (Sovaldi, Gilead) and simeprevir (Olysio, Janssen Therapeutics). Both therapies were approved for use in patients with HCV genotype 1 in combination with pegylated interferon and ribavirin. Sofosbuvir was also approved for use without pegylated interferon, but with ribavirin for 24 weeks in those patients with genotype 1 who were ineligible to receive interferon. Sofosbuvir and ribavirin in combination have been approved for genotypes 2 and 3. Neither agent has been studied extensively nor approved in patients with solid organ transplantation.
There are no data on use of DAAs before or after heart, kidney and lung transplantation or in patients on hemodialysis. Simeprevir is approved for patients with severe renal disease and creatinine clearance <30, but not for patients on hemodialysis. Several ongoing studies are evaluating the new DAAs in patients with end-stage renal disease, and data should be forthcoming in the coming months.
Since HCV is the most common reason for liver transplantation, many patients are desperate for new therapies. Recently published HCV guidelines recommend sofosbuvir plus simeprevir, with or without ribavirin for 12 to 24 weeks, for treatment-naive patients with HCV genotype 1 after liver transplantation. This recommendation was based on the phase 2 COSMOS trial that showed SVR rates of more than 90% in nontransplant patients. For patients with genotypes 2 or 3, current guidelines recommend sofosbuvir plus ribavirin for 24 weeks.
There are some early data on the use of sofosbuvir after liver transplantation. A group of 40 post-transplant recipients received 24 weeks of sofosbuvir plus ribavirin, started at 600 mg daily, and the dose was increased as tolerated. Sixty-three percent of patients had cirrhosis upon study entry. After 24 weeks of treatment, all patients had undetectable HCV RNA, and 77% remained negative 4 weeks after completion of the treatment. The therapy was well tolerated in this group. Additional data were obtained via a sofosbuvir compassionate-use program for patients with severe, recurrent HCV after a liver transplant who were predicted to have less than a 6-month prognosis. This very ill patient population also demonstrated good response, with 56% achieving SVR.
Drug interactions have traditionally been a problem associated with HCV treatment after organ transplantation. Sofosbuvir and simeprevir appear to solve much of this problem, with minimal drug interactions with immunosuppressants including tacrolimus and cyclosporine. No dose modification is required when dosing sofosbuvir and tacrolimus or cyclosporine. There is a small amount of interaction between simeprevir and cyclosporine, but the combination of simeprevir and tacrolimus results in a small decrease in tacrolimus levels. Levels should be monitored and doses adjusted as needed. In clinical practice, the dose adjustment has not been difficult.
Because the DAAs seem safe in the post-transplant setting, there has been some discussion of clearing patients to proceed with solid-organ transplants despite active HCV viremia, with plans to treat the HCV after transplantation. More data are needed in all transplant patient populations.
What the Future Holds
In conclusion, patients under evaluation for solid-organ transplant should be screened for HCV, with HCV antibody and/or HCV RNA level, depending on the risk profile. Patients with HCV should have a hepatology consultant to help determine whether proceeding with organ transplant is safe, and whether treatment of HCV should be considered. Current treatment regimens are available, but remain difficult due to tolerance in the patient with end-organ diseases. In addition, the balance between immunosuppression and antiviral therapy continues to be a great challenge. Further studies are desperately needed in all solid-organ transplantation data to conclude well-validated regimens.
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For more information:
Hellen Chiao, MD, is from the department of medicine at Scripps Green Hospital. Catherine T. Frenette, MD, is from the department of organ transplant at Scripps Clinic and is a member of the HCV Next Editorial Board. Frenette can be reached at Scripps Green Hospital Center for Organ and Cell Transplantation, 10666 N. Torrey Pines Road N200, La Jolla, CA 92037; email: frenette.catherine@scrippshealth.org.Disclosure: The authors report no relevant financial disclosures.