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Treat Now or Wait

Issue: July/August 2014

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Complex debate on the decision to treat HCV with currently available therapies or wait for more options.

A conversation has developed in the hepatitis C virus community surrounding the necessity of treating certain patients with HCV right away or delaying treatment. In short, there is consensus that some patients require immediate intervention, whereas others can be monitored until further complications occur.

The clinical developments at the patient level include the development of fibrosis or more severe complications of HCV. The nonclinical developments at the market level will come in the form of greatly anticipated FDA approvals of new therapies that are currently moving through the pipeline. However, the nuances of the “treat-or-wait” discussion can become convoluted and warrant further investigation.

HCV Next Editorial Board members Mitchell L. Shiffman, MD, director of the Liver Institute of Virginia in the Bon Secours Health System, and Paul J. Pockros, MD, director of the Liver Disease Center of the division of gastroenterology/hepatology at Scripps Clinic and clinical director of research at the Scripps Clinic Liver Translational Science Institute, along with Rena K. Fox, MD, professor of clinical medicine in the division of general internal medicine at the University of California, San Francisco, provided their thoughts on whether to treat patients with HCV now using the available therapies or to wait until more options are available.

Issues of Cost, Manpower

At the heart of the issue is the cost of current therapies on the market today. The $84,000 price tag for a 12-week treatment course of sofosbuvir (Sovaldi, Gilead Sciences) and $66,000 for a course of simeprevir (Olysio, Janssen Therapeutics) has been a topic of debate in the discussion about choosing to delay treatment in some patients.

"If the new direct-acting antivirals were passed out to each patient with HCV today, the cost would exceed $300 billion", according to Shiffman. “We cannot afford that burden,” he said. “Indiscriminate use of resources is not good medicine. It is not good for society. We need to treat the patients at risk, and not everyone is at risk.”

“We would be having an entirely different discussion if the drugs were not so expensive,” Fox said. Instead, “we would be able to focus the decision-making on clinical evidence alone, without the same concerns about cost to individuals or the system.”

Rena K. Fox

The drug costs have been a focus of many meetings this year, including recent symposia such as the California Technology Assessment Forum. “This is very unusual in this country: To discuss both the clinical side and the cost perspective at the same time to try to determine how the drugs should be used, given their benefits as well as their costs,” Fox said.

It is difficult for clinicians to justify the high costs of new therapies to an insurance carrier when a patient has mild HCV and it is also difficult for the carrier to justify paying for treatment in this patient population, Shiffman added.

The good news, according to Pockros, is that a more competitive market is likely to emerge sooner than later. “We could be looking at multiple available regimens by sometime in 2015,” he said. “This should make prices more digestible.”

As more drugs are approved, clinical guidelines will need to evolve Fox said. Clinical practice guidelines can be helpful to clinicians to understand how to use new drugs, but they “usually leave aside the consideration of cost.” In addition, “payers may create their own approach in their own authorization criteria, which may or may not be consistent with  practice guidelines.”

The enormous public health problem of HCV, with an estimated 170 million people worldwide estimated to be infected, presents another issue.

Paul J. Pockros

“There is a huge number of patients who require HCV treatment. At the moment, there are simply not enough people to handle the work,” Pockros said.

For Fox, the cost of the new drugs has provided her an opportunity to reflect on the fundamental reasons for treating silent asymptomatic medical problems such as HCV. “It is important for us to remember that our aim is to reduce the risk of long-term outcomes such as cirrhosis and hepatocellular carcinoma,” she said.

Treat vs. Delay

The decision is based on patients with the most urgent need for treatment first.

“The patients we treat now are those with cirrhosis because they are at risk to decompensate. Patients with low platelets, low albumin and/or a prior complication of cirrhosis such as a variceal bleed, ascites or hepatic encephalopathy cannot tolerate pegylated interferon-containing regimens; they are at risk to develop decompensation during treatment,” Shiffman said. Further, patients with cryoglobulin and immune-driven extrahepatic manifestations of HCV also cannot tolerate pegylated interferon, he added.

“If these [aforementioned] patients have genotype 1, they should be treated with sofosbuvir and simeprevir for 12 weeks because this is far less costly and achieves a greater sustained virologic response than 24 weeks of sofosbuvir and ribavirin,” he said.

Although neither agent is approved by the FDA for use in patients with prior liver decompensation, “we feel comfortable inittiating treatment as long as the prior complications of cirrhosis have either resolved or are under control and the current CTP and MELD scores are under 10 and 20 respectively,” Shiffman said. “Although we are not certain that the success rate of this therapy is as high as it has been shown to be in patients with Child class A cirrhosis and no prior decompensation, achieving a sustained virologic response in this group may significantly reduce mortality and prevent the patient from requiring a liver transplant.”

It is also reasonable to treat all patients with genotype 2 now with sofosbuvir and ribavirin, as “there is unlikely to be anything better for these patients in the future,” Shiffman said.

However, “patients with genotype 3 are problematic because they have the lowest SVR rates and require 24 weeks of therapy at twice the cost. This is especially true for patients with genotype 3 who have failed previous pegylated interferon therapy where the SVR rate is only 60% to 85%,” he said. Preliminary data have demonstrated that adding pegylated interferon to sofosbuvir and ribavirin can improve SVR to more than 90%. In Europe, this combination is approved for use in patients with genotype 3, and this may be an option for some patients in the United States.

“Patients with genotype 1 or 3 and mild disease should wait for cheaper and, in the case of genotype 3, more effective regimens,” he said.

Patients with normal liver function and adequate platelet counts do not require treatment right away, according to Shiffman.

For those patients deemed eligible for delaying treatment, Pockros said his facility is making use of the FibroScan machine on a daily basis to assess the extent of liver fibrosis. Non-cirrhotic patients or those with mild fibrosis are candidates for observation until further notice.

“If a patient is medically able to wait 6 months [for treatment], it will not make a difference in their long-term outcomes,” Shiffman said.

Patient Perspective

To a non-expert or a patient diagnosed with HCV who does not have cirrhosis, it may be difficult to understand why it is acceptable to delay treatment until more options are available. Thus, communication is important, according to Fox.

“An informative, respectful conversation can help each patient understand the rationale behind treating vs. not treating. Patients appreciate knowing what the evidence is and what the issues are that their physician considers,” she said. “Sometimes the general public and industry assume that patients will be outraged if they don’t get treated immediately — that hasn’t been my experience.”

Shiffman said if a patient with mild HCV asks for the interferon-free combination of sofosbuvir and simeprevir, he tells them that it is not FDA approved and it is unlikely that the insurance company will justify coverage for mild HCV. “They should wait until the end of this year when the Gilead fixed-dose tablet and the AbbVie 3-D regimens [are expected to be] available,” he said.

Although nonapproved use of the drugs occurs, Pockros noted insurance approvals, particularly for drugs being used off-label, are also labor-intensive. “So are appeals,” he said.

Fox suggested that clinicians think about the treat-or-wait decision broadly, in terms of practice guidelines and policy perspective, but also in terms of the individual patient. “For the last 20 years, we have been telling our patients who could not tolerate interferon therapy or were treatment failures with interferon that HCV is a variable disease in which only 20% get cirrhosis and the other 80% have no bad outcomes,” she said.

“Now, it seems that the whole discussion vanished once the new drugs were approved, and there is the urge to treat the entire population at once. Certainly we want to treat and cure every case of HCV and prevent any new cases. But, we can also remember that most patients will never develop cirrhosis or hepatocellular carcinoma,” Fox said.

Strength of Evidence

Recent data for sofosbuvir, simeprevir and forthcoming regimens have generated a great deal of enthusiasm in the clinical and research communities. These data hold a particular position in the treat-or-wait discussion.

“Now that we have a cure that is virtually 100%, regardless of disease severity, why do you have to treat everyone with mild disease since many will simply not develop cirrhosis or any clinical symptoms?” Shiffman said. “Do not get me wrong. I wish we could treat every single person with HCV and eradicate this virus from the planet. But can we really afford to do that?”

Mitchell L. Shiffman

Pockros noted that ongoing data continue to emerge that corroborate the clinical trial results that led to the approval of these drugs in the first place.

However, according to Fox, there should still be some concern in terms of where the clinical evidence is strong and also where it is not strong enough. “The evidence is rapidly changing,” she said.

“Whenever a new [treatment] comes out, there are a lot of reasons for enthusiasm, and these drugs are rightfully generating major excitement and use since they are changing the treatment and outcomes of HCV, which has had no good treatment up until now,” she said. “But, we need to remind ourselves that trial results are not always what we will see in the real world.”

For example, many trials were conducted in highly selected patient populations, she said. “In the real world, there are a lot of variables that don’t apply in trials. The reality is that even the best regimens do not always have the same results in real life in terms of success or side effects.”

In the end, the medical community remains enthusiastic about the future of HCV treatment, whether it involves treating immediately or waiting.

“In a medically non-urgent patient, there are reasons to hold off prescribing. In a medically urgent patient, it is a whole different story,” Fox said. — Rob Volansky