Hepatitis C drugs offer new options

Internists should be excited about hepatitis C.

“There are not very many times during our lifetime we can see a disease identified in 1989, which we could test for in 1992, and then 20 years later, we can cure with a regimen that's highly effective and very well tolerated,” said Henry Masur, MD, MACP, an infectious disease specialist and chief of the Critical Care Medicine Department at the National Institutes of Health Clinical Center in Bethesda, Md.

The approval of multiple drugs in 2013 and 2014 that are able to cure hepatitis C without the use of interferon has dramatically changed the screening, treatment, and epidemiologic paradigms of the virus.

The changes are significant enough to affect not only the specialists and experts who have traditionally treated hepatitis but also the practice of general internists, who see the millions of Americans with diagnosed or undiagnosed hepatitis C. From expanding screening and advising the newly diagnosed to possibly even curing hepatitis C themselves, internists will soon be pulled into this rapidly changing area of health care, experts said.

“It is very, very doable for internists who are interested or motivated, desiring to treat hepatitis C patients in their own practice. There are huge benefits to their patient and to the system at large,” said Rena K. Fox, MD, FACP, an internist and professor of clinical medicine at the University of California San Francisco.

Just a few challenges stand in the way of patients and society collecting those benefits, including physicians learning how to prescribe the growing array of approved medications to the increasing population of diagnosed patients and insurers and pharmaceutical companies agreeing on the price of this project.

Thankfully, internists only have to tackle the first half.

Screening and testing

The first step in the effort to cure hepatitis C, and the one that most requires general internists' participation, is identifying everyone with chronic infection, a group representing about 1% of the U.S. population, according to an analysis in the March 4, 2014, Annals of Internal Medicine.

“Internists are the front lines, and they need to be the ones to find the roughly 900,000 people who have hepatitis C and don't know they have it,” said David L. Thomas, MD, MPH, director of the Division of Infectious Diseases at Johns Hopkins in Baltimore.

In 2012, the CDC recommended that everyone born between 1945 and 1965 be screened for hepatitis C, in addition to those at-risk groups previously targeted for screening, including injection drug users and recipients of blood transfusions before 1992. The agency estimated that baby boomers account for three-quarters of the chronic hepatitis C infections in the U.S.

The advent of the new drugs has increased the importance of screening asymptomatic patients, the experts noted. “Most patients, or at least the majority of patients, will likely be eligible for treatment, which is radically different from the past,” said Dr. Fox.

But before treatment is even discussed, there are several steps internists should take in response to a positive initial result. “Screening can detect positive or negative antibody tests, but that doesn't make a diagnosis of chronic hepatitis C,” said Dr. Fox. “The next step would be to check a hepatitis C RNA and then if that is positive, then they've made a diagnosis of chronic hepatitis C.”

Then, talk to the patient. “Counsel the person about the meaning of their positive test, which includes talking to them about the ways of reducing the risk of passing the virus on to other people and ... ways that they're not going to give it to other individuals. One of the most important things to do is to reassure individuals that they're not going to pass it to a grandkid or a niece through normal household contact,” said Dr. Thomas.

Patients also need advice on protecting their health as much as possible. “Counsel the patient about how to reduce the risk of additional damage to their liver, like minimizing alcohol intake and protecting against possible hepatitis A or B infection [with] vaccination,” said Dr. Fox. “Educate the patient about other things that would contribute to liver damage, for example, obesity, diabetes, hyperlipidemia.”

Internists should also check whether hepatitis C has already damaged the patient's liver. “Not every patient needs a liver biopsy,” noted Dr. Fox. Although biopsy is the gold standard for fibrosis diagnosis, several other tests can be helpful, including platelet counts.

“If the platelet count is less than 140,000 [cells/µL] in a patient with hepatitis C, it should be assumed this is due to cirrhosis unless another cause is definitively known,” said Dr. Fox. However, platelet counts and related scores, such as the APRI (aspartate aminotransferase-to-platelet ratio index) and FIB-4 (Fibrosis-4) score, lack sensitivity, so they can miss some cirrhosis cases.

Patients should also be tested for HIV, as well as to find out their hepatitis C genotype. Then, it's time to talk about treatment. “You tell them that cure is possible. Contrary to what their Uncle Harry might have told them, they can be cured without interferon and it doesn't make all their hair fall out or anything like that,” said Dr. Thomas.

New treatments

Almost every patient should be encouraged to pursue treatment, the experts said. “The guidelines are very clear that every patient can potentially benefit from therapy and the only exception to that is patients who are likely to die from some other cause in the next 12 months,” said Dr. Masur.

To begin treatment, the sickest patients should continue to be referred to a hepatitis C expert. “If the patient has decompensated cirrhosis—ascites, encephalopathy—then they should be seeing a specialist,” said Dr. Fox. Dr. Masur added a few more categories to the referral list, including patients with renal disease or patients with complicated metabolic disorders such as hepatitis C-related diabetes.

However, for the rest of the hepatitis C population, the new drugs have brought the possibility of treatment by other clinicians, including general internists. “One of the things that was always necessary and made life a little more complicated for those of us treating with the old regimens was that the patients had to be monitored very closely,” said Raymond Koff, MD, FACP, a hepatologist and professor of medicine at the University of Connecticut Medical School in Farmington, Conn. “We had nurses who were just dedicated to this.”

Approval of the new drugs, which included sofosbuvir (Solvaldi), simeprevir (Olysio), and combined sofosbuvir and ledipasvir (Harvoni) at press time and possibly a few others by early 2015, changed management regimens.

“For the newer therapies, monitoring for early response seems to be unnecessary,” said Dr. Koff. “The response rates are extraordinary, approaching 100% for a number of patients ... a regimen that is very well tolerated with few adverse events, with the treatment duration being 12 weeks in most cases. In some cases, it'll probably be as short as 8 weeks.”

The short duration of therapy and fewer side effects should also make adherence to hepatitis C therapy much less of an issue than it has been, experts said.

Combine the decrease in the complexity of treatment with the increase in the eligible population, and it's not surprising that the hepatitis C field might look to primary care for help. Dr. Masur and colleagues wrote an article in the Sept. 16, 2014, Annals of Internal Medicine titled “Treatment of Hepatitis C Virus Infection: Is It Time for the Internist to Take the Reins?”

Dr. Masur and other experts say yes. “If our goal is to eradicate as much hepatitis C as possible, then we cannot ask all patients to be treated by a hepatologist, because there are not enough hepatologists in this country,” said Dr. Fox. The ranks of gastroenterologists and infectious disease specialists will also be insufficient to take on the potential deluge of patients, added Dr. Koff.

“Internists ought to be eager to have this challenge,” said Dr. Masur. “With a few hours of CME and the availability of the guidelines, internists should be able to treat patients who have early disease.”

The American Association for the Study of Liver Diseases (AALSD) and the Infectious Diseases Society of America (IDSA) have put out guidelines that include some of the new drugs. Since additional therapies are being approved, those guidelines are likely to be modified early and often, but the authors have a solution to that.

“These guidelines are a little different in that they're not going to be in a print version. They're going to be online, because this is a field that's going to be changing,” said Dr. Masur. The AASLD/IDSA guidelines, which were developed with the International Antiviral Society-USA as a collaborating partner, are available online.

“The guidelines are quite clear as to what drugs, doses, and durations are indicated for each stage of liver disease and each serotype ... We have a regimen that's good for almost every serotype and stage of disease now, but the armamentarium will expand as more drugs are approved,” Dr. Masur said.

All of the drugs will be similar in effectiveness, the experts predicted, but there will be differences in drug interactions and duration of therapy, and some may be better suited to certain patient groups.

“There's definitely still clinical decision making and judgment that goes into the choice of regimen, but it's far more uniform compared to how it's been in the past,” said Dr. Fox.

The problem

Of course, there's one more factor that will be an important determinant in use of the drugs: cost. The approved regimens are currently in the range of $100,000 for a course of therapy, and the coming options aren't expected to be dramatically cheaper.

“If these drugs cost $10 a course, there wouldn't be any debate about who should be treated or when we should treat, they'd all be treated now,” said Dr. Masur.

Instead, there is a lot of debate. The cost of the drugs and the size of the potential population make treating everyone a very expensive proposition. “People try to compare this to cancer, but I think it's not a good analogy, because you don't have 3 million untreated cancer patients on day 1. With expensive oncology drugs, you have a fairly predictable number of patients per year who would become eligible for that drug,” said Dr. Fox.

In response, payers have put some limits on coverage of the drugs. “The insurance companies, at the moment, some of them are saying they'll only support treatment of patients with advanced disease, meaning a biopsy that shows stage 3 or 4 fibrosis. If you have a patient that's stage 1 or 2, you have to wait until they get sicker, and that doesn't make any sense,” said Dr. Koff.

Coverage restrictions may also limit internists' ability to provide hepatitis C treatment. “Payers are at least currently using their authorization criteria to restrict prescriptions to specialists or hepatitis C experts,” said Dr. Fox. “Some of them say that the patient must have seen a specialist and had this regimen recommended. Different payers are just heterogeneous, but this is a very common part of the authorization criteria.”

The drugs' cost and appropriate use are issues for not just individual prescribers but a society facing the potential to eradicate hepatitis C, some experts said. “On a societal level, we should be asking questions about why the treatments are so expensive,” said Michael S. Saag, MD, an infectious disease specialist and director of the Center for AIDS Research at the University of Alabama at Birmingham.

So far, however, that hasn't happened. “It's a societal debate, but unfortunately, society is not engaged in it, so it ends up at the door of the doctor who has to fight with the insurance company. That's just kind of where we are today,” said Dr. Thomas.

As the therapeutic advances in hepatitis C continue to settle out, competition between drug companies may lower costs, or evidence of cost-effectiveness may convince payers to open their wallets.

At that point, experts hope a group of internists will be ready to jump into the field. “There are certainly internists who are very capable of doing this, and other internists will opt to become trained in seminars and other ways, and yet others will say I have enough to do,” said Dr. Thomas.

Dr. Saag encourages the first 2 groups. “Patients with hepatitis C are in [internists'] practices. If they are enough of them, I'd say 20 to 30, then it becomes worthwhile to learn about hepatitis C and treat them,” he said. “It's very doable and very rewarding. Once they get involved, I think they'll find it to be a great decision.”