HCV at a Crossroads:The Pre- or Post-Transplant Treatment Debate

Hepatitis C virus infection is the leading indication for liver transplantation, with nearly half of registrants on the liver transplantation list infected with the virus. In today’s era, patients have the option to be treated for the infection before or after transplantation.

HCV Next spoke to several experts on liver transplantation and discussed the best time they believe to treat HCV is — before or after undergoing a liver transplant — and what providers should keep in mind when beginning therapy.

HCV Therapy Pre-Transplantation

David A. Sass, MD, FACP, FACG, AGAF, FAASLD, Associate Professor of Medicine at the Sidney Kimmel Medical College at Thomas Jefferson University in Philadelphia, recommends patients with HCV undergo and finish treatment before transplantation if at all possible (ie, they have stable renal function and their liver is not too decompensated).

“If patients undergo transplantation having hepatitis C viremia, recurrence is universal in liver transplant recipients, usually within the first 3 months of surgery,” Sass told HCV Next. “The natural history of post-transplant recurrent HCV is that there may be an accelerated progression in fibrosis along with very high hepatitis C viral loads with patients being on immunosuppressive drugs. Because of this, about 20% to 30% of patients may develop allograft cirrhosis within 5 years of the transplant.”

Sass also stated that patient and graft survival rates are markedly lower among HCV-infected patients who are undergoing transplant compared with patients undergoing transplant for other diseases, eg, cholestatic and alcohol-related liver disease.

“Because their outcomes are worse and recurrent hepatitis C is a big issue after transplant, my preference would always be to try and treat patients before the transplant and render them hepatitis C RNA-negative,” Sass said. “In those patients who develop recurrent hepatitis C after transplant, it may be associated with various extrahepatic manifestations of the disease (such as diabetes mellitus and renal impairment) and this can have a negative impact on the quality of life.”

HCV Next Editorial Board Member Stevan A. Gonzalez, MD, MS, medical director of liver transplantation at the Annette C. and Harold C. Simmons Transplant Institute, Baylor All Saints Medical Center, Fort Worth, Tex., also prefers treating HCV before transplantation due to the latest direct-acting antiviral regimens available.

“If there is any opportunity to treat before transplant, that would be ideal,” Gonzalez told HCV Next. “The fact that the new direct-acting antiviral therapy is now so much easier and well-tolerated, particularly in people with advanced liver disease, I think we will find we can do this more frequently.”

Gonzalez also stated that with new interferon-free regimens, more data is available to support pre-transplant treatment.

“A major challenge has been the tolerance of interferon-based therapy with patients with advanced liver disease, but now with the interferon-free regimens, there is more data to support pre-transplant therapy,” Gonzalez said.

In a study published in Hepatology, Gregory T. Everson, MD, of the University of Colorado in Denver, and colleagues, analyzed 59 patients undergoing treatment with dose-escalated pegylated interferon alfa-2b with ribavirin and 20 patients who did not undergo treatment before undergoing liver transplantation. Of 30 treated patients with HCV genotype 1, 4 or 6, transplant was performed in 23.

“Pre-transplant treatment prevented post-transplant recurrence of HCV infection in 25% of transplanted cases,” the researchers wrote. “Despite these potentially significant therapeutic benefits, PEG-IFN and [ribavirin] were poorly tolerated in these ‘difficult-to-treat’ and ‘difficult-to-cure’ patients. Future treatments incorporating direct-acting antivirals that accelerate and enhance virologic response should improve rates of post-transplant virologic response, but will require strategies to limit toxicity.”

“Prior to the advent of direct-acting antiviral therapy, several studies evaluated the potential role of IFN-based therapy in patients with advanced liver disease, including liver transplant candidates,” Gonzalez said, referring to the Everson study.

Gonzalez also referred to a study published in the Journal of Hepatology conducted by Jose A. Carrión, MD, of the Hospital del Mar in Spain, and colleagues, where 51 patients with HCV awaiting transplant underwent antiviral treatment with PEG-IFN-alfa-2a and ribavirin. Results showed that the antiviral therapy prevented hepatitis C recurrence in 20% of HCV-infected patients.

“These studies found that if HCV RNA clearance can be achieved immediately prior to undergoing liver transplantation, a post-transplant sustained virologic response can occur in 42% to 75% of patients,” Gonzalez said.

HCV Therapy Post-Transplantation

Sammy Saab, MD, MPH, AGAF, FAASLD, professor of medicine and surgery in the division of digestive diseases and head of outcomes research in hepatology at David Geffen School of Medicine, University of California at Los Angeles, prefers to treat patients with HCV after transplantation.

“Unless there is a dire need of treatment before, I prefer treatment after transplantation, but there are exceptions,” Saab told HCV Next. “Treating HCV before transplant theoretically may delay transplantation because a patient becomes ineligible for positive hepatitis C graft or places a patient in a MELD limbo.”

Saab explained that if a patient has a highly abnormal liver test, they will be unable to receive locoregional therapy. Therefore, in those situations, pre-transplant treatment may be desirable.

“Most studies show the cure rate is over 90% after liver transplant,” Saab said, referring to a study presented at The Liver Meeting 2014 in Boston. “The major risk in waiting to treat HCV after transplantation is that the two most commonly used regimens include ribavirin. The use of ribavirin may increase the risk of hemolysis after transplantation.”

Parvez S. Mantry, MD, medical director of the Liver Institute Research and Hepatobiliary Tumor Program, Methodist Health System, Dallas, presented data from the CORAL-1 study at The Liver Meeting 2014, where he and colleagues looked at liver transplant recipients with HCV and Metavir F0-2 fibrosis who began treatment post-transplant. In the phase 2 study, liver transplant recipients with recurrent HCV genotype 1 infection and without cirrhosis received a combination of ombitasvir, paritaprevir, ritonavir and dasabuvir (Viekira Pak, AbbVie) for 24 weeks. All patients achieved a rapid virologic response and end of treatment response; 97.1% of patients achieved a sustained virologic response at 4 weeks, 97 achieved SVR12 and 93.3% achieved SVR24. No patients experienced breakthrough during treatment and one patient relapsed.

“They only looked at patients with F0 to F2 fibrosis [who] underwent a liver transplant at least 12 months prior and were hepatitis C treatment-naive since transplant. It was a very small study with only 34 study participants, but 33 of them had a sustained virologic response at 12 and 24 weeks post-treatment with an overall 97% SVR, which is an incredibly good number,” Sass said, referring to the Mantry study.

“This is exceptionally promising data showing that this particular regimen from AbbVie had a low rate of serious adverse events and a high rate of SVR among liver transplant recipients,” he said. “However, one has to keep in mind that there are some study limitations: the patient population were non-cirrhotic as this study selected patients with cases of HCV that have historically been easier to treat than those characterized by advanced fibrosis. Furthermore, patients underwent liver transplantation at least 12 months before study initiation, so the study excluded those with an early form of recurrent HCV (fibrosing cholestatic hepatitis) that could complicate treatment.”

Weighing the Patient’s Needs

Ibrahim A. Hanouneh, MD, hepatologist at Cleveland Clinic, discussed how he and other hepatologists at the Cleveland Clinic treat HCV in patients on the transplant wait list.

“HCV therapy can be done at any time, before or after liver transplant,” Hanouneh told HCV Next. “There are no definite guidelines to decide on when to do the treatment, but the approach at the Cleveland Clinic is that if the patient has low MELD score, they will have a longer wait time for a transplant, so HCV treatment will be completed because we have more time. Some people believe that if you treat hepatitis C, the liver will get better and they may not need a transplant altogether, but that has not been proven yet.”

According to Hanouneh, patients at the Cleveland Clinic with high MELD scores and cirrhosis will often be treated after transplant.

“We defer treatment until after transplant in patients with high MELD scores and cirrhosis because we don’t have time and because they are already sick. There is a chance they will end up in the hospital and treatment could be interrupted,” Hanouneh said. “Also, these patients could have such advanced disease that hepatitis C treatment wouldn’t make a difference beforehand.”

“I mostly treat post-transplant,” he continued. “It is highly effective and well-tolerated with minimal side effects. It is really changing the world with how we treat hepatitis C.”

Michael R. Charlton, MD, FRCP, professor of medicine and medical director of hepatology and liver transplantation at Intermountain Medical Center in Utah, believes the right time for HCV therapy depends on the patient’s needs.

“I think it depends on how much the patient needs liver transplantation,” Charlton told HCV Next. “If you have someone who’s barely meeting criteria for liver transplantation, say a lower MELD score and may have some reversibility of liver disease and a good quality of life when they become HCV RNA negative, those are the patients I think we should treat beforehand. We’ve seen in a series of studies the potential reversibility and decrease in portal hypertension and cancer with treatment. I think there is a benefit to treating people with early disease.”

Although most patients have the option to treat HCV pre- or post-transplant, some subpatient populations are more suitable for one or the other, based on the severity of their disease.

“Not everybody is necessarily a suitable patient to undergo hepatitis C therapy prior to transplant,” Sass said. “In the decompensated cirrhotic patients (advanced Child’s B or C patients), particularly those with impaired renal function (GFR < 30) and especially those on dialysis, they are not suitable candidates for sofosbuvir-based therapy.”

Patients with hepatocellular carcinoma may also be more suited for post-transplant HCV therapy, according to Charlton.

“There are patients who will need transplant whatever you do, such as those with liver cancer,” Charlton said. “Donors who have HCV positivity make up 4% of the donor pool so it wouldn’t be the best use of resources to spend that $100,000 or more on therapy before transplant in these patients and then using a hepatitis C-positive donor and ending up with infection again. [For] those with liver cancer who need liver transplantation, we are frequently not recommending treatment until after transplant.”

Undetectable Viral Load

In a Phase 2, open-label study published in Gastroenterology in January 2015, researchers, including Michael Curry, MD, from Beth Israel Deaconess Medical Center in Boston, studied the safety and efficacy of sofosbuvir (Sovaldi, Gilead Sciences) and ribavirin in patients on the liver transplant waiting list. They showed that 70% of patients with HCV RNA levels less than 25 IU/mL at the time of liver transplant achieved a post-transplant virologic response at 12 weeks. “This tells us that the strongest predictor of post-transplant virologic response at 12 weeks was the number of consecutive days of undetectable viral loads of HCV before transplant. If they had more than 30 days of hepatitis C RNA undetectability, they had a 95% chance of achieving a 12-week viral load that was undetectable, so a high predictor,” Sass said.

He explained that in high MELD score patients where the liver transplant wait-list time is expected to be less than 60 days, pre-transplant treatment of their HCV is unlikely to result in undetectable HCV loads for more than 30 days.

“If they don’t have undetectable hepatitis C viral loads for more than 30 days on treatment before their transplant, the Curry et al study demonstrated that patients have a post-transplant HCV recurrence rate of more than 60%,” Sass said.

K. Rajender Reddy, MD, from the Perelman School of Medicine at University of Pennsylvania, also presented data at The Liver Meeting 2014 from the SOLAR-1 study that focused on treating HCV post-transplant with ledipasvir/sofosbuvir (Harvoni, Gilead Sciences).

The prospective, multicenter study included 223 patients with HCV genotype 1 and 4 infection who had a liver transplant. The analysis included both treatment-naive and treatment-experienced patients with or without cirrhosis. All received treatment with ledipasvir/sofosbuvir plus ribavirin for 12 (n = 112) or 24 weeks (n = 111). The primary endpoint was SVR 12 weeks after completion of study treatment.

“In this particular study, 50% of patients that were treated were cirrhotic and these patients tolerated the ledipasvir/sofosbuvir therapy very well,” Sass said. “Reddy et al proved excellent safety and tolerability with SVR 4 showing high efficacy in patients getting ledipasvir/sofosbuvir with ribavirin with early data showing no apparent difference between 12 and 24 weeks of treatment.”

Saab called Reddy’s findings a “major breakthrough” for treating HCV in transplant recipients.

“Reddy used Harvoni in post-transplant recipients and the cure was over 90%,” Saab said. “This is a major breakthrough. The study had a high cure rate, no drug interaction [and] looked at people with all liver severity, not just liver disease. Those are big deals.”

Drug-Drug Interactions

Another factor to keep in mind if a patient will undergo HCV treatment post-transplant is the risk of different drugs interacting. Common drugs patients could take post-transplant include cyclosporine A (Neoral/Sandimmune, Novartis), tacrolimus (Prograf, Astellas) and prednisone (Deltasone, Pharmacia and Upjohn; Meticorten, Schering).

“In my opinion, hepatitis C treatment is safe and quite effective,” Hanouneh said. “After transplant, however, we have to be careful because hepatitis C medicine could interfere or interact with immunosuppression medicine and may need to be adjusted accordingly. In terms of treatment pre-transplant, if the patient has advanced liver disease, I wouldn’t worry about the treatment itself, but if the patient is in the hospital often or develops renal insufficiencies, the treatment of hepatitis C becomes a little bit complicated.

“These are things we keep in mind, but overall, the treatment for HCV is safe pre- and post-transplant.”

Gonzalez stated: “If a patient can’t undergo treatment pre-transplant, they will get it post-transplant. There is now a greater level of tolerability post-transplant. However, with Viekira Pak, you do have to account for drug-drug interactions and adjust the doses of immunosuppressive therapy.”

Treating HCV Recurrence

Hepatitis C recurrence post-transplant is universal and inevitable, according to the experts, but how it recurs is a factor to be considered when planning to treat HCV post-transplant.

“In most scenarios, the recurrence will be slow and will lead to liver damage over many years; so you have plenty of time to make a decision about treatment,” Hanouneh said. “However, in 5% of patients, recurrence will be very aggressive. If we see evidence of [fibrosing cholestatic hepatitis] or fibrosis, we tend to treat right away because we know they will not do well and could die.”

“Overall, we wait until the patient recovers from surgery before beginning HCV therapy,” Hanouneh said. “However, in many cases, we do surveillance liver biopsies to see if hepatitis C recurrence has caused any scarring or damage to the liver, then we choose whether or not to defer treatment due to cost issues. The disease is slowly progressive and we have a protocol where we do liver biopsy at 6 months, then again at 1 year, then yearly after. If we see damage in the liver from hepatitis C, we treat, but if we see no damage, we defer treatment for cost-related reasons.”

“We ideally would like to treat all post-transplant patients who develop recurrent hepatitis C, but may be limited by the insurers and payers,” Sass said. “We are encountering circumstances where patients have minimal fibrosis so we aren’t necessarily receiving approvals for them to go on treatment. Generally speaking, we would wait several months after a patient’s transplant. In some centers like ours, we do allograft liver biopsies at 6 months and 1 year to see if there’s any progression in fibrosis to help make our determination on whether to treat them. The more rapid the progression of fibrosis, the more urgent the indication for treatment.”

“In most cases, we wait a period of time to treat HCV post-transplant and the reason is at this point, there isn’t a lot of data out there for immediate treatment post-transplant with the new direct-acting antivirals,” Gonzalez said. “A concern immediately postoperatively is patients can have complications where they would need to be hospitalized and other factors that could make it difficult to maintain the course of HCV treatment, even in an interferon-free setting.”

In the PHOENIX study, 115 liver transplant recipients with HCV were randomized to PEG-IFN a-2a/ribavirin treatment or observation 10 to 26 weeks post-transplant (prophylaxis arm, n = 55; observation arm, n = 60). Prophylaxis patients received PEG-IFN a-2a plus ribavirin. Overall, SVR was achieved by 22.2% of prophylaxis patients and by 21.4% of observation patients who switched to treatment.

“In the PHOENIX trial, patients were initiated on treatment within 6 months post-transplant,” Gonzalez said. “It was very difficult to enroll patients who could even be candidates as a large number did not meet inclusion criteria, mainly because of issues related to complications or persistent cytopenias post-transplant. I think there will be a time where we consider earlier [rather] than later treatment, but that has yet to be evaluated in a clinical trial setting.”

Charlton explained that the SOLAR study also showed that patients should be 6 months post-transplant to achieve a 96% SVR with all-oral therapy.

“The cure rates decline if patients are sicker. For instance, if you have cirrhosis or Child’s B or C cirrhosis, the cure rates fall significantly. I would say if you treat within 6 to 12 months, ideally after transplant, you get a lower likelihood of disease being severe enough that you don’t get the same good outcome. Don’t wait to begin HCV therapy until patients get too sick,” Charlton said.

AASLD HCV Treatment Recommendations

The American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America (IDSA) in collaboration with the International Antiviral Society-USA (IAS-USA) have developed web-based HCV guidelines. They provide multiple recommendations on how to treat post-transplant recurrent HCV stratified by various patient characteristics.

Some of the recommendations include:

“For those who have been working in the field, HCV has taken a terrible toll on patients before and after transplantation,” Charlton said. “To finally have safe and effective therapies that are well-tolerated … is a real game changer for patients and providers. It is a different era and it came very quickly; so, it is a welcomed thing.”

According to the published guidelines, liver transplant recipients are among the top patients in highest priority for immediate HCV treatment.

“The AASLD published guidelines in terms of who should get high priority for HCV therapy and liver transplant recipients are considered the highest priority for treatment,” Saab said. “This is great for us and we are delighted these patients have high preference.”