Forgotten History:The Hunt for Undiagnosed Patients with HCV

Millions of people are walking around the United States with undiagnosed hepatitis C infection, with estimates ranging from 3 million to 5 million or more. Amid the excitement of once-in-a-generation therapies — and all of the associated research and follow-up and observation of response rates and toxicities involved — the clinical community is also faced with the challenge of bringing those millions of patients into care and taking legitimate aim at eradicating the disease.

A critical area of focus is screening. Despite the expanded protocols for universal screening in the baby boomer cohort, there are myriad reasons why not everyone in this age group has been tested and why antibody and RNA assessments are administered inconsistently in other demographics.

Then there are patient factors, fueled largely by a lack of awareness of relevant information. Some undiagnosed individuals do not know that a single instance of injection drug use decades ago puts them at risk, while others have not kept up to speed with advances in therapy. Underlying all of that is the stigma of having a disease that has been associated with drug use and unprotected sexual behaviors.

Finally, there is the ever-present factor of cost. In this case, the issue is often that payers are unwilling to foot the bill for certain therapies or pre-existing agreements preclude coverage. Mountains of paperwork and wave after wave of emails and phone calls are sometimes required to get just one patient covered. Frequently, even after so much effort, the patient is refused coverage. All of this can lead to discouragement among both patients and clinicians.

But not all of the news is bad, according to Eugene R. Schiff, MD, professor of Medicine and director of the Schiff Center for Liver Diseases at the University of Miami Miller School of Medicine. “More and more people are coming in to get tested,” he said. “Education is helping.”

Schiff added that simple word of mouth may be even more effective than education. “People are now coming back who I haven’t seen for 30 years,” he said. “They want to get treatment because their friend or their relative is doing well on treatment, or they are seeing ads for these drugs on TV.”

Tracking Down High-Risk Populations

Phillip O. Coffin, MD, MIA, director of substance use research at the San Francisco Department of Public Health and assistant clinical professor in the division of HIV/AIDS at the University of California, San Francisco, and Andrew Reynolds, hepatitis C education manager at Project Inform, recently published a paper in Hepatic Medicine in which they estimated that only 49% to 75% of people with HCV are aware of their infection. “Any chance of addressing HCV in the U.S. is dependent upon screening to identify undiagnosed infections,” they wrote.

They called for “aggressive action” in finding and bringing these patients into care as a way of heading off downstream advanced liver disease. They zeroed in on active injection drug users as a key population to target, along with men having sex with men and prisoners, but the real focus of any hunt for the undiagnosed has to begin with baby boomers.

“During the Vietnam War era, a lot of people used drugs who were not necessarily addicts,” Schiff said. “They had no idea that when they shared needles they could get HCV. What happened is that that group was relatively asymptomatic. As they got older, many went off to college, got married, became blood donors and were unaware that they had HCV. This accounts for the majority of undiagnosed infections in the baby boomer cohort.”

Coffin described this common story as a “forgotten history” of drug use that may have consisted of only the occasional needle. “Identifying these patients is hard because they don’t recognize their own risk factors,” he said.

Compounding the problem is the upswing in injection drug use among young people, many of whom began with prescription pills from the cabinet and graduated to needles. “There are two distinct populations of current and former injection drug users,” Coffin said. “This makes for a moving target.”

There may also be room to broaden risk-based screening protocols, according to Reynolds. “The [U.S. Preventive Services Task Force] risk-based screening recommendations cover the right groups, although I would add the inclusion of people who smoke drugs,” he said. “The sharing of crack pipes, though less risky than injecting drugs, can still pose a risk for transmission.”

This varied population of drug users speaks to a larger epidemiological issue, according to Coffin. “The assumptions we are making about undiagnosed populations is based on risk factors of people who have been diagnosed,” he said. The implication is that there may be whole demographics of people at risk for HCV who have eluded experts and epidemiologists because they are simply not considered. For example, Reynolds added that much more focus should be placed on HIV-positive men who have sex with men.

Broadening the Search

Dawn A. Fishbein, MD, scientific director of viral hepatitis research for MedStar Health Research Institute and attending physician, infectious disease at MedStar Washington Hospital Center, offered practical solutions about how to find potential unknown populations.

“Medicare has approved testing in primary care, but we are still not testing in emergency departments and other hospital settings,” she said. “We’ve seen data that testing in EDs yields a high percentage of positive results. The problem is that if a patient comes in with a myocardial infarction, the insurance company won’t pay for an HCV test.”

Calderon and colleagues conducted an anonymous prospective survey to a cohort of 2,078 patients visiting an ED and a pharmacy in New York City during 2010 and 2011.

Seventy-two percent of participants responded that they would be amenable to free HCV testing if it was made available. Among those individuals, 67% said that they would get tested for HCV or hepatitis B virus if it was offered in conjunction with HIV testing. Other findings indicated that previous hepatitis testing was associated with more understanding of HCV testing protocols.

“Most individuals would elect to be tested for hepatitis with HIV, which raises the possibility of integrated testing,” Calderon and colleagues concluded.

Fishbein suggested that as the clinical community moves forward with electronic medical records, there will be more prompts for HCV testing. Reynolds agreed, but with a qualification.

“It seems like having an automatic prompt in the electronic medical record works better, but that is dependent upon having a medical record and turning that prompt on,” he said.

It may also be helpful to look beyond the health care system to find undiagnosed patients, according to Fishbein.

“In urban settings, we see a lot of baby boomers who are not engaged in primary care,” she said. “They go to churches or community centers for a lot of their health care needs. We absolutely should be testing people in these places.”

Speaking more specifically, Fishbein noted that women in the baby boomer cohort are more likely to access primary care, but that men are more likely to be HCV positive. “We should be looking at data like this to inform our interventions,” she said.

Further afield, injection drug use in Appalachia and other rural areas is reaching epidemic proportions, and HCV rates are increasing accordingly. “We need to get to these places,” she said. These are opportunities to bring patients into the system.”

Don’t Ask/Don’t Tell

While many clinicians agree that more aggressive screening is necessary, how to achieve that goal remains a conundrum. In many cases, baseline testing protocols are still not being met, according to Margaret J. Koziel, MD, assistant vice provost for clinical and translational research, University of Massachusetts Center for Clinical and Translational Science and professor of medicine at the University of Massachusetts Medical School. “CDC guidelines are not in immediate recall for many clinicians,” she said. “People just don’t know to test baby boomers.”

She acknowledged, though, that increasing news about direct-acting antiviral therapies is changing awareness and attitudes; but, education cannot be effective without implementation.

One of the biggest hurdles to testing is something of a “don’t ask/don’t tell” culture surrounding injection drug use and other high-risk behaviors.

“Stigma and judgment reduces people to silence,” Reynolds said. “Medical providers need to be able to ask the questions in a non-judgmental manner, and patients need to feel safe to answer openly and honestly.”

For Koziel, developing a strong doctor-patient relationship can go a long way in making these conversations easier. “As an ID specialist, I am used to asking about these behaviors,” she said. “I can get the information I need without being invasive or asking for unnecessary details.”

The key is how the question is asked, Koziel said. “I tell them I am going to ask about HCV and let them know that it is a very treatable disease right now. I emphasize cure as opposed to a shaming factor.”

Reynolds highlighted the fact that models and training activities are available to help build this skill set. “But we have a long way to go,” he said.

Beyond shame, there is often a concrete financial reason for patients failing to disclose risk, according to Coffin. “If you mention injection drug use and it goes on a record, you might not be able to get life insurance,” he said. “This is a legitimate concern for many of our patients, so they just don’t admit their behaviors.”

Coffin suggested, though, that it may not just be an unwillingness to disclose behaviors. “Some people may simply have forgotten what they did 40 years ago,” he said.

But Coffin ultimately placed the responsibility on the clinician’s shoulders. “They need to know screening protocols and risk factors,” he said. “Doctors in general are not good exploring risk factors beyond what is immediately evident. So when they have a 60-year-old patient who refuses testing because he doesn’t believe he’s at risk, the clinician often says ok. It is not ok.”

Practical Barrier

Another obstacle to testing is the two-stage algorithm for diagnosing HCV, according to Coffin and Reynolds. They described it as “problematic and difficult for patients and providers to navigate.”

“If you take all of the people who have antibodies to HCV, up to 30% of them no longer have the virus, and on top of that there are many false positives,” Schiff said. “When the antibody test result comes back, you need to get them into the RNA test. It is only after you get the RNA test that HCV is confirmed. Many patients don’t make it through this process, let alone to treatment. It isn’t a matter of test and treat like HIV.”

Reynolds built on this point. “Test and treat early and the quality of life improves measurably,” he said. “The risk of cirrhosis and all the problems that follow virtually go away.”

Fishbein was more specific. “In community centers, you can’t really do an RNA test because it has to be a frozen sample, and it is just too expensive,” she said. “There are point of care tests of nucleic acid screening in development, but they are not approved yet.”

Clinicians at Medstar have been educating clinicians with the hope of more uptake, but poor testing rates remain a concern. “Even a rapid test in the community is expensive,” she added.

Stigmatized Disease

Many of the barriers to testing — such as patients being unwilling to disclose personal information — are a function of the stigma that still surrounds HCV. “Irritable bowl disease is a chronic disease with costly therapies but is not stigmatized in this way,” Fishbein said. “Cancer is not stigmatized in the same way.”

While stigma on the personal level is one thing, many aspects of the stigmas associated with HCV have larger consequences.

“Providers make judgments on who we should test,” Fishbein said. “When we started testing in our facility, even providers were shocked at those who were positive.”

Many experts believe that wider testing protocols could eliminate stigma and, consequently, draw more undiagnosed patients into care. “If everyone gets tested, then nobody feels like we are pointing a finger at them,” Fishbein said. “We can tell patients that we are just following the recommendations.”

But Koziel pointed out that more testing costs more money. “Testing everyone, period, is a debatable approach,” she said. “In the grand scheme of things, it is not incredibly costly. But resources are so limited right now that it might be difficult to justify.”

Stigma also impacts treatment. Coffin noted that payers have included restrictions on treating substance users. “There is no evidence to restrict treatment for active substance users,” he said. “But restriction is the policy for many payers.”

Again, though, Schiff was more optimistic. “Some payers are removing discriminatory restrictions on substance abusers,” he said.

Another restriction involves treating only patients with advanced fibrosis, which Schiff suggested may also have consequences related to finding the undiagnosed.

“Most of the people who are actively transmitting HCV are young injectors,” he said. “This group is very unlikely to have stage 3 or 4 fibrosis, so they often remain untreated, if not undiagnosed. We need to be reaching people at all stages of disease and allow for treatment of early stage disease, particularly in ongoing injection drug users. This is good for public health but bad for politics.”

For Koziel, it comes back to the doctor-patient relationship. “I tell them we have to wait until they develop cirrhosis, and they ask why,” she said.

Payers Not Paying

Schiff conducted an investigation of sofosbuvir (Sovaldi, Gilead Sciences) and sofosbuvir/ledipasvir (Harvoni, Gilead Sciences) in an attempt “to provide a factual basis for evaluating the claims regarding the benefits of Sovaldi relative to its costs.”

Schiff noted the significant resources required to prevent cirrhosis and transplantation costs, but that only a small ratio of patients with HCV become cirrhotics, and fewer need liver transplantation.

“The claim that treating all patients with HCV with Sovaldi would cost nearly as much as the current total U.S. expenditure on all prescription drugs, while factually correct, is not a realistic scenario,” he wrote. “Many patients with HCV will continue to go undiagnosed. In addition, the medical expense for those who are treated will be spread out over many years.”

The advent of the DAA era should be an alarm for the HCV community and public health experts alike, according to Schiff. “Sovaldi should act as a wake-up call for all health care stakeholders to engage in a meaningful, fact-based discussion about managing the cost of innovative new drugs to balance the needs of drug manufacturers, health plans, providers, and, above all, patients,” he wrote.

Reynolds put these issues in terms of screening. “There is a disincentive for both patients and providers,” he said. “Patients self-select themselves away from testing as they assume they won’t get treatment (this is also the case among people who use drugs). Providers may be unwilling to screen knowing that they can’t treat their patients.”

What all of this means is that potential patients don’t bother getting tested because they know they won’t be treated anyway. This translates into a whole population of individuals who more or less know they are at risk, but who remain undiagnosed.

For Schiff, it is a matter of hours in the day. “I know the system, I have been at it a long time and I’m highly motivated to help these patients, but even with all my efforts, I have a hard time getting approval to treat everyone,” he said. “The average doctor definitely does not have time to do all that is required.”

Clinicians as Advocates

Despite this lack of time, Fishbein said that if the problem of lack of coverage is to change, clinicians need to think beyond the clinic and beyond the individual patient. “As a clinician, I have to wear two hats,” she said. “I have to be fiscally responsible, but I also have to advocate for my patients.”

“It shouldn’t be a provider problem, but it is becoming a provider problem,” Fishbein continued. “Many of our patients are underserved and underinsured, and they can’t advocate for themselves. We need to step up and do it for them.”

Koziel was less ambiguous: “Insurance companies know that a 32-year-old will likely change jobs. They know he’ll be insured by someone else later, so they wait and push it to the next person to treat them when they have cirrhosis,” she said. “Insurance companies are kicking the can down the road. At the systems level, we have to take the long-term cue to treat people before they become cirrhotic or need a liver transplantation. It’s enormously frustrating to try to explain all of this to a patient.”

Fishbein is optimistic that as awareness of therapies and cure rates increases, patients will become more empowered. Schiff agreed.

“Organizations like [National AIDs Treatment Advocacy Project] [which advocated for more government payment for HIV drugs] can serve as a model,” Schiff said. “The VA treats veterans for HCV across the board, and they are treating milder and milder disease. Private companies vary in terms of coverage, but Medicare part D is offering coverage.”

Schiff suggested that these steps, along with an increasing number of lawsuits against the big payers, will lead to increasing numbers of patients being diagnosed and brought into care. “I hate to see these lawsuits happen, but I also don’t like to have to explain to my patients about the deterrents to treatment,” he said. “The industry is getting some bad publicity over the cost of these therapies, and so Medicaid, Medicare and some of the big payers are starting to pay for these drugs.”

With these advances, all facets of HCV care are likely to improve, including the number of undiagnosed patients, according to Schiff. “As it improves, a snowballing effect will occur, where more people are cured and more people talk about it,” he said. “This will lead to more people getting tested. Eventually, we would like to be able to tell our patients: Test, and you’ll be treated. We can’t say that right now, but that day may be coming soon.”

For Reynolds, it all comes back to the doctor-patient relationship. “Medical providers need to be able to practice medicine,” he said. “If their clinical judgment calls for an HCV test, it should get covered. If they decide that a person should be treated — regardless of stage of liver disease or substance use — treatment should get covered. Let them do their work. Doctors, nurse practitioners and physician assistants know what’s best for their patients.” – by Rob Volansky

• References:
• Calderon Y, et al. Prev Med. 2014;doi:10.1016/j.ypmed.2013.12.026.
• Coffin PO, et al. Hepat Med. 2014;doi:10.2147/HMER.S40940.
• Schiff L. Clin Ther. 2015;doi:10.1016/j.clinthera. 2015.02.009.
• Wong VW, et al. J Gastroenterol Hepatol. 2014;doi:10.1111/jgh.12355.

• For more information:
• Phillip O. Coffin, MD, MIA, can be reached at 25 Van Ness Ave Suite 500, San Francisco, CA 94102; email: phillip.coffin@ucsf.edu.
• Dawn A. Fishbein, MD, can be reached at 110 Irving Street NW, Ste. 2A56, Washington, DC 20010; email: Dawn.A.Fishbein@medstar.net.
• Margaret J. Koziel, MD, can be reached at 55 Lake Ave North, S1-868, Worcester, MA 01655; email: margaret.koziel@umassmed.edu.
• Andrew Reynolds can be reached at 273 Ninth St., San Francisco, CA, 94103; email: areynolds@projectinform.org.
• Eugene R. Schiff, MD, can be reached at Jackson Medical Towers, 1500 NW 12 Ave., Suite 1101 ET, Miami, FL 33136; email: lworley2@med.miami.edu.

Disclosures: Coffin reports no relevant financial disclosures. Fishbein reports being on the advisory boards of Bristol-Myers Squibb and Gilead Sciences; receiving research funding from the Gilead FOCUS program; and stock ownership in Abbvie and Gilead. Koziel and Reynolds report no relevant financial disclosures. Schiff reports being a consultant with Acorda; being on the advisory board of Bristol-Myers Squibb, Gilead, Merck and Janssen; being on the data monitoring board of Arrowhead, Bristol-Myers Squibb, Pfizer and Salix; receiving grant support from Abbott, Beckman Coulter, Bristol-Myers Squibb, Conatus, Discovery Life Sciences, Gilead, Janssen, MedMira, Merck, Orasure Technologies, Roche Molecular and Siemens.