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A Matter of Compensation: HCV and Cirrhosis

Issue: February 2015

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A quick glance through the abstract book for any of the major meetings attended by hepatologists in 2014 — the European Association for the Study of the Liver, The Liver Meeting or Digestive Diseases Week — will reveal an undeniable trend: Data sets are showing that 12-week sustained virologic response rates among cirrhotic patients with hepatitis C virus are competing with those seen in non-cirrhotics. Moreover, response rates observed in decompensated cirrhotics are not far behind.

But they are still behind. And despite a great deal of enthusiasm within the clinical community, some questions about cirrhosis in HCV remain. One question surrounds the optimal duration of treatment in this patient population. Another involves the mechanism of action of cirrhosis. Still, other questions concern the way novel direct-acting antiviral therapies penetrate the liver on the cellular level and the drugs in the pipeline that may be more effective in this regard. Finally, there is the issue of toxicity and whether there is a point at which the risks of therapy may outweigh the benefits.

Several experts, including Robert S. Brown Jr., MD, MPH, Frank Cardile professor of medicine and medical director of the transplantation initiative at Columbia University College of Physicians and Surgeons in New York, addressed these questions with HCV Next. “Now that SVR12 rates in HIV look similar to those we have seen in standard patients, it is clear that cirrhosis is the last, most difficult, frontier in HCV,” he said. “Decompensated cirrhotics are the most difficult of that group. They are also the patients who need therapy the most. We still have to figure this out.”

Robert S. Brown Jr.

Several studies have addressed compensated or decompensated cirrhosis directly or indirectly, and just making sense of those numbers has posed a challenge for experts.

Compensated Cirrhosis

Some of the most up-to-date findings for HCV and cirrhosis were presented at The Liver Meeting in November. Many of these data sets confirm Brown’s point that the clinical challenges posed by compensated cirrhosis may be disappearing.

A study conducted by Bourliere and colleagues included 154 cirrhotic patients with genotype 1 disease who had previously failed pegylated interferon-containing regimens. Seventy-seven patients treated with an all-oral formulation of ledipasvir/sofosbuvir (Harvoni, Gilead) plus ribavirin for 12 weeks reached an SVR12 rate of 96%. The SVR12 rate for 77 patients treated with just ledipasvir/sofosbuvir for 24 weeks was 97%.

Other novel DAA regimens are showing similar results in compensated cirrhotics. Fried and colleagues found that ritonavir-boosted triple therapy with paritaprevir, ombitasvir and dasabuvir (Viekira Pak, AbbVie), known as the “3D” regimen, plus ribavirin yielded a 91.6% SVR12 rate among cirrhotics with genotype 1a disease. The SVR12 rate for the genotype 1b cohort treated with this regimen was 99.2%. The researchers added, however, that genotype 1a disease, along with prior null response to PEG-IFN and ribavirin and IL28B TT genotype, was associated with poorer outcomes.

Poordad and colleagues investigated the 3D regimen in a cohort of Child-Pugh-Turcotte class A HCV patients and published the results in The New England Journal of Medicine. The overall SVR12 rate among 208 patients who were treated for 12 weeks was 91.8%. SVR12 was 95.9% (97.5% CI, 92.6-99.3) among 172 patients treated for 24 weeks.

“Results are starting to look good for a number of regimens in compensated cirrhosis,” Brown said. “But we have to make sure these results are durable.”

Muir and colleagues investigated all-oral regimens of daclatasvir, asunaprevir and beclabuvir (Bristol-Myers Squibb) with or without ribavirin in treatment-naive and treatment-experienced compensated cirrhotics as part of the UNITY-2 study. Results indicated SVR12 rates of 93% among 57 naive patients treated without ribavirin, 98% among 55 naive patients treated with ribavirin, 87% among 45 experienced patients treated without ribavirin and 93% among 45 experienced patients treated with ribavirin.

“We have good evidence indicating that HCV eradication substantially modifies the natural history of compensated HCV-related cirrhosis,” Juan Berenguer, MD, PhD, consultant physician in the infectious diseases unit and head of HIV clinical research group at the Hospital Gregorio Maranon in Madrid, said in an interview. “However, little is known about the effect of HCV eradication in patients with decompensated cirrhosis.”

Juan Berenguer

Decompensated Cirrhosis

The key data set for decompensated cirrhosis is the SOLAR-1 study. Steven L. Flamm, MD, medical director of liver transplantation at Northwestern Memorial Hospital and professor of medicine and surgery at Northwestern University Feinberg School of Medicine, presented the findings at The Liver Meeting. SOLAR-1 included 108 patients with genotype 1 or 4 disease and decompensated cirrhosis. Participants received ledipasvir/sofosbuvir for 12 or 24 weeks. “This group of patients has not previously been included in clinical treatment trials,” Flamm told HCV Next.

The overall SVR12 rate was 87% in the 12-week group and 89% for the 24-week group. Patients with Child-Pugh-Turcotte class B cirrhosis achieved SVR12 rates of 87% for 12 weeks of treatment and 89% for 24 weeks. In the Child-Pugh-Turcotte class C group, 12 weeks of therapy yielded an 86% SVR12 rate vs. 90% for 24 weeks.

Successful intervention also was associated with improved liver function. The researchers reported decreases in bilirubin levels and increases in albumin blood protein levels from baseline to assessment at 4 weeks after treatment. Thirty-three patients also experienced decreased Child-Pugh-Turcotte status, and most patients in the class B and C groups showed improvements in MELD score.

Jordan J. Feld

“This study not only shows that the all-oral regimen of sofosbuvir, ledipasvir and ribavirin is efficacious and tolerable in a population of HCV patients with end-stage liver disease, but it also indicates that eradication of HCV has beneficial outcomes including improvement in bilirubin and albumin levels,” Flamm said. “Further, MELD score, a predictive measure of 90-day mortality, also improved in the majority of patients, suggesting a clinically significant favorable clinical outcome.”

“Frankly, it is astounding that markers of decompensation improved,” Douglas T. Dieterich, MD, professor of medicine in the divisions of liver disease, gastroenterology and infectious diseases at Mount Sinai School of Medicine, told HCV Next. “Albumin went up; bilirubin went down; platelets went up. They saw clinical improvements, as well. This is a huge advance in HCV among decompensated cirrhotics.”

Jordan J. Feld, MD, MPH, assistant professor of medicine and research director of gastroenterology at Toronto Western Hospital Liver Center and HCV Next Editorial Board member, said the data from SOLAR-1 are similar to those reported in Child-Pugh-Turcotte class A cirrhotics and non-cirrhotics. “It is likely that there will always be a slight drop off in SVR in the decompensated patients, if for no other reason than some patients will deteriorate independent of treatment but during treatment, thus preventing them from completing treatment and reaching SVR,” Feld said.

For Feld, the issue is not whether these patients will reach SVR12, but whether SVR12 will lead to clinical improvement. “The SOLAR-1 study showed that patients had initial improvement in liver function, but whether this will translate into improved clinical outcomes — such as avoidance of transplant — is yet to be seen,” he said. “It is likely that some will improve and some will not and, hopefully, we will be able to identify the point of no return at which attaining SVR is of little benefit. For such patients, treatment after transplant may be simpler.”

At the moment, sofosbuvir (Sovaldi, Gilead) with simeprevir (Olysio, Janssen) and sofosbuvir and daclatasvir with or without ribavirin are the preferred regimens for treating decompensated HCV-related cirrhosis, according to Berenguer. “Ledipasvir and sofosbuvir, with or without ribavirin, will be available as well,” he said.

Recompensation

Brown tempered the enthusiasm surrounding SOLAR-1. “We still have not seen data that these patients will recompensate,” he said. He noted that with interferon, even patients with mildly decompensated cirrhosis could decompensate after clearing the virus. “This may not all be an interferon effect. It is plausible that it could happen even with interferon-free therapies.”

That said, the clinical community should be working toward the goal of recompensation, according to Brown. “If we can get to recompensation, issues about efficacy and safety that exist in the decompensated patients will evaporate,” he said.

It may be helpful to move the discussion beyond the clinic, according to Berenguer. “From a research perspective, it is important to note that the availability of interferon-free regimens allows patients with decompensated cirrhosis to receive effective treatment against HCV,” he said. “This provides a unique opportunity to study the effect of HCV eradication on pathophysiological parameters and clinical events in patients with decompensated cirrhosis.”

Duration of Therapy

There are three main factors involved in the debate about whether it will ultimately be preferable to treat patients for longer durations or to treat patients with more drugs, according to Brown. “One is that we may not be getting drugs into every place we need to because of fibrosis or portosystemic shunting. The second is that there may be impaired immune function leading to viral persistence,” he said. “The third is that cirrhotics have had the disease longer. The first two argue for longer therapy and the last one argues for more drugs.”

Feld built on this point. “People with cirrhosis may also respond less well because of poor drug metabolism and impaired tolerability,” he said. “It may well vary from regimen to regimen, but on balance I would say that that longer duration will be more helpful in cirrhosis than more drugs.”

However, no data set has provided enough evidence to solidify the appropriate duration of therapy in patients with cirrhosis, according to Berenguer. Each clinician, then, must make individual clinical choices. “My preference is to treat for 24 weeks with sofosbuvir and daclatasvir,” he said. “With sofosbuvir and simeprevir, 12 weeks is acceptable for compensated cirrhosis. Twelve weeks of therapy with Harvoni could be acceptable for compensated cirrhosis if combined with ribavirin. The AbbVie 3D regimen will allow 12 weeks duration provided the patient is not infected with genotype 1a disease and is not a null responder.”

Some larger data looking more closely at duration are beginning to emerge. Bourliere and colleagues conducted a study investigating outcomes for ledipasvir/sofosbuvir with or without ribavirin for 12 or 24 weeks in a cohort of more than 500 patients with genotype 1 disease and compensated cirrhosis. The researchers used pooled data from a number of analyses, including LONESTAR, ELECTRON, ELECTRON-2, 337-0113, ION-1, ION-2 and SIRIUS. Results indicated an overall SVR12 rate of 96% for ledipasvir/sofosbuvir without ribavirin. The rates were 95% in the 12-week group and 98% in the 24-week group. Importantly, lower platelet count produced lower SVR rates in cirrhotics with treatment experience. Findings from a subgroup analysis indicated that the addition of ribavirin or the extension of treatment duration increased the SVR12 rate to 96% or better.

In a more targeted study (COSMOS cohort 2), Lawitz and colleagues reported 93% SVR12 in patients treated with simeprevir and sofosbuvir with or without ribavirin for 12 weeks. The rate was 100% for those treated for 24 weeks.

Despite these outcomes, Brown warned that treating patients for longer has the potential for added toxicity, which can lead to further decompensation. “The benefits may not outweigh the risks because we are still seeing lower response rates in decompensated cirrhotics,” he said.

Varied Drug Classes

The issue of drug classes is more complicated than the issue of duration, partly because the studies have not yet been conducted. “We actually do not have that much information in cirrhosis in terms of more drugs,” Dieterich said.

Douglas T. Dieterich

Experts, then, are left to speculate about whether more drug classes will be beneficial or not.

“As patients advance, the diversity of the virus becomes higher,” Brown said. “We see more resistant virus and differential distribution of the virus. With more drug classes, we may be more likely to get enough drugs into every compartment of the liver.”

Some members of the clinical community have voiced concerns about the development of resistance when treating patients with multiple drug classes. Brown offered a different opinion. “Resistance is caused by drug failure,” he said. “If we choose the right regimen and the right duration, this will likely not be an issue.”

Brown said, however, that more drug classes, like longer duration of therapy, may also come with a tradeoff. “You can’t ignore the fact that many of the drugs are metabolized by the liver, which means higher toxicity and impaired renal function,” he said.

Feld remains firmly on the side of longer duration. “More drugs may also work but, arguably, whatever is preventing the fewer drugs from working effectively — shunting past the liver due to portal hypertension or impaired intrahepatocyte metabolism — will also be a problem with the additional agents,” he said. “Treating longer likely overcomes this because all of these processes are less efficient but not completely inoperative, which means they just take longer to suppress the virus.”

Mechanism of Decompensation

There are still questions about why cirrhotics respond to therapy more poorly than non-cirrhotics, according to Brown. “Until you understand the mechanism, it is hard to predict responses,” he said.

Dieterich discussed two important unknowns about the mechanism of decompensation. “One is that it is difficult to predict when it will happen,” he said. “The other is that people decompensate in different ways.”

But Dieterich added that decompensation is not a complete mystery. “We know there is a point at which the liver no longer can support its functions,” he said. “Once that happens, there is confusion, bleeding, ascites, edema, swelling in the feet, ankles and legs, and bleeding in esophageal varices.”

Clinicians must be aware of a number of factors that can lead to decompensation. Those include alcohol use, age of the patient and age at infection, obesity and the infecting genotype, among others. All of these variables may affect the efficacy of treatments.

“For patients with CPT-A cirrhosis with minimal or no portal hypertension, I suspect the liver is well penetrated,” Feld said. “That is why the results look very good with the same regimens as use in non-cirrhotics. In more advanced cirrhosis, shunting happens at a microscopic level in the sinusoids, which prevents drug delivery at a very local level and may happen at a larger more macroscopic level due to shunting around the liver entirely. These factors are hard to measure but, hopefully, tools in the future will give us enough information to predict which patients have a significant shunt and may require longer therapy.”

That said, Feld said he believes that it is unlikely that multiple comprehensive studies will be conducted on these mechanisms. “The focus will be on treating people before they have cirrhosis so that they do not progress,” he said. “Ideally, we would be able to identify patients who would never progress and therefore would not require treatment. However, no predictive factor is likely to be accurate enough that one would choose to withhold therapy because of a low probability of progression.”

Reasons for Optimism

Despite many of these unanswered questions, there is reason for optimism, according to Dieterich. “We saw at AASLD that failures on sofosbuvir and ribavirin were treated successfully with sofosbuvir and ledipasvir,” he said. “Resistance with sofosbuvir doesn’t seem to be an issue. Failures on previous protease inhibitor therapy got close to 100% SVR12. There are some really good data on the AbbVie combination in cirrhotics. I’d feel confident using Harvoni to treat these patients.”

Berenguer agreed. “There are many treatment options for compensated cirrhosis,” he said. “Decompensated cirrhosis can be treated with interferon-free regimens.”

Brown noted that the industry is likely to continue producing therapies, and Feld added that tools such as the HepQuant device will provide clinicians with more detailed information about the liver. In the meantime, the clinical community is anxiously awaiting further data from studies like SOLAR-1.

“Patients will be followed over the long-term to determine if patients with decompensated liver disease will improve enough that liver transplantation can be avoided,” Flamm said. “The final analysis of the data is awaited. However, the efficacy and safety of this combination in the decompensated population is potentially an important addition to the armamentarium for treatment of patients with HCV genotype 1.”

Dieterich was optimistic in growing that armamentarium for patients with decompensated cirrhosis.

“It is true that the drugs work the least in these patients that need it most,” Dieterich said. “But the good news is that we are able to treat them because we couldn’t treat them with interferon. We have jumped from a 0% cure rate to an 88% cure rate in some cases. That is huge, dramatic news.”– Rob Volansky