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Managing the Fruits of HCV Cure: How Much Care do the Cured Need?

The feature by Eric Lawitz, MD, very nicely encapsulates the revolutionary changes occurring within hepatitis C therapy over the past few years. As he explains, this extraordinary newfound ability to cure almost all patients with chronic HCV raises many questions about clinical outcomes.

We’ve felt strongly for years that it was unjust to deny therapy to patients who didn’t have “sufficiently advanced scarring of the liver to warrant treatment” — a cost-based position that was anathema to most clinicians and patients. Today, there’s a wealth of literature showing fibrosis progression stabilizes or reverses after achieving SVR. Even patients with cirrhosis may have regression of cirrhosis after SVR. But an additional dimension of HCV infection about which our knowledge has dramatically expanded is the potential for extrahepatic morbidity and mortality associated with HCV infection, and the opportunity to ameliorate or prevent such outcomes by effecting virologic cure — problems such as diabetes, atherosclerosis, renal disease, cryoglobulinemia, lymphoma and others.

All of this raises the question of how to manage cured patients.

Though treatment choice is still an important decision, practitioner focus now shifts from which regimen to use (as there are several of extraordinary efficacy that are all well tolerated, albeit with some nuances that differentiate them, such as duration of therapy, potential drug-drug interactions and regimen-dependent need for ribavirin in some subpopulations), to wondering with increasing frequency what to do with the patients once we cure them.

We became familiar with this topic in the interferon era but now that this occurs so much more frequently, it becomes a question that can arise multiple times daily in a busy HCV-oriented practice. It’s important for us to link data regarding clinical outcomes after cure with management decisions about patients who may still be at risk for complications

HCC Risk Management

Of all the complications of liver disease, one of the most dreaded is hepatocellular carcinoma. Just as we’ve been gratified to learn that SVR brings a marked reduction in the risk for HCC, so we have also come to recognize the risk is far from negligible in patients with cirrhosis who have been cured and, to a lesser extent, in patients with advanced fibrosis short of cirrhosis.

Because of the lingering risk for HCC in cirrhotic patients after cure of HCV infection, the general rule that has arisen is that you must screen such patients every 6 months with imaging and optional alpha-fetoprotein determinations indefinitely. Some clinicians have voiced uncertainty about whether indefinite surveillance is too much of a burden to impose on patients when their risk may become progressively smaller to the point where it might not be ‘cost effective’ to continue to screen. I have heard a few colleagues suggest that if cirrhosis is no longer present based on parameters such as tissue elastography (eg, Fibroscan [Echosens] or other modalities), then perhaps we can stop screening. I regard this at present as a potentially risky proposition. We don’t yet have sufficiently robust data to suggest we have an identifiable parameter that says that the patient who was cirrhotic before treatment is no longer at material risk for liver cancer.

Speaking for myself and many other colleagues, who as I perceive it comprise the great majority of the field, we still should be screening these patients indefinitely.

I’m hopeful the day will come when we can point to multi-thousand patient databases that pinpoint a certain degree of improvement in fibrosis or cirrhosis in an identifiable parameter like elastography or perhaps a serum marker as a benchmark for cancer risk. We would then need large numbers of patient-years of follow up to say that the risk for cancer regresses to a level comparable to that of the background population.

The question arises as to what degree of fibrosis prior to treatment obviates the need for further follow up. Most society guidelines state that if you have F0 to F2 fibrosis, you don’t have to be screened. By and large, I am comfortable with that, but there are sporadic case reports and large series from Japan suggesting that there is a small, but not negligible, risk for liver cancer, particularly in patients with F2 fibrosis. These series don’t always make it clear whether patients may have had concomitant causes of progressive liver disease, but they do occasionally report cases of patients who did not have cirrhosis at the time their HCC was discovered.

My own practice is to get an ultrasound within a year of finishing therapy for patients and, if there’s no pre-treatment evidence that patients had Metavir F3 or F4 fibrosis, to stop subsequent screening, hoping the day never comes when I must face a patient who had mild fibrosis who in fact develops HCC.

My opinion is to keep screening your patients who had advanced fibrosis prior to their course of curative therapy. We are not there yet in determining a stopping point.

Stability vs. Regression

Patients familiar with Fibroscan frequently request the procedure after they’re cured before I even bring it up. I’m struck by how important it is for virologically cured patients to not only feel that their fibrosis has stabilized, which is a concept that I emphasize, but are understandably very attuned to getting the “fringe benefit” of fibrosis reversal.

I do tell patients that if their Fibroscan proves to be unchanged, not to stop exulting over the fact that they have eliminated their HCV infection. It does virtually ensure, in the absence of another liver disease, that they won’t progress to decompensation, and their risks for coming to harm are still greatly diminished even as they continue to need HCC screening.

Esophageal Varices

The other issue that arises is whether to continue screening patients for esophageal varices if they presented with cirrhosis. We have been gratified to find over the years that it’s quite unusual to have patients have a variceal bleed after they’ve had an SVR, but it can occur.

We continue to need to be on guard against the dreaded complication of variceal bleeding. In my practice, if patients have had no varices previously, I usually do another endoscopy within 1 to 2 years following SVR. If they still have no varices, which is generally the case, we can cease and desist from further endoscopic evaluation unless they have a concomitant liver disease manifested by an elevated alanine aminotransferase or other evidence of ongoing liver injury. In my experience, the most common cause for ongoing liver disease in patients cured of HCV infection is fatty liver disease. For varices too small to consider primary prophylaxis previously, endoscopic surveillance should continue.

If patients have varices that needed to be medically managed previously with beta blockers and/or variceal band ligation, that management must continue until and unless the varices have been shown to regress over repeated examinations. Recent evidence points to potential for portal hypertension to regress, but there is no assurance in any individual case that it will occur. Certainly, for patients who have had a variceal bleed, they continue to need the combination of periodic endoscopy with band ligation and beta blockade if they can tolerate beta blocker therapy.

We need more data on the long-term outcome of varices and portal hypertension in general. Quantitative data on the rate of variceal regression can better inform our decision about when we can stop performing endoscopic surveillance or in these patients.

Alcohol Consumption

Many patients ask about alcohol consumption after being cured. For most hepatologists, any alcohol consumption with preexisting cirrhosis is forbidden, but I think we can relax our previous restrictions if patients had demonstrable mild or even moderate liver disease. This is predicated on the assumption we’ve gotten to know the patient sufficiently well to be confident they are representing to us accurately their degree of alcohol intake.

For patients who have had problems with excessive drinking in the past, you can strongly recommend that complete abstention remains the rule.

These comments are a combination of subjective opinion based on practice and experience along with literature as we are just starting to see robust data sets emerging from large multisystem studies quantifying the degree of decreased hepatic and extrahepatic morbidity and mortality achieved due to SVR. These types of studies have been illustrated at the AASLD meeting where we’re beginning to see large data sets of clinical outcomes patients after DAA therapy that amplify greatly upon the data that we developed in the age of interferon.

We look forward to further studies as clinical researchers shift gears from the development of new drugs to important global issues like access and cost, but also to clinical outcomes studies. With the emerging information about these critical issues that will likely predominate at academic meetings and in the literature in the near future, we can optimally inform our decision-making about how to manage cured patients.

Ira M. Jacobson, MD

HCV Next

Co-Chief Medical Editor

• References:
• Jacobson IM, et al. Gastroenterology.2017;doi:10.1053/j.gastro.2017.03.018.

Disclosures: Jacobson reports consulting for AbbVie, Achillion, Bristol-Myers Squibb, Gilead, Intercept, Janssen, Merck and Trek; receiving grant or research support from AbbVie, Bristol-Myers Squibb, Gilead, Janssen and Merck; and speaking and teaching for AbbVie, Bristol-Myers Squibb, Gilead and Janssen.