Part 1: The Growing Burden of HCV infection in the US

Introduction

HOST: It’s the DKB Radio Hour. I’m Spencer Cannon. This episode is brought to you by an unrestricted educational grant from Gilead Sciences, Inc. and is accredited by the Postgraduate Institute for Medicin

Hepatitis C virus, or HCV, is a growing public health concern. Unlike mortality associated with other infectious diseases in the US, deaths from HCV infection are actually increasing, and a resurgence of injection drug use has created an expanding pool of newly infected, often young people who are not being tested or treated. ¹ These are your clients — you see them every day in your centers.

The good news is that safe and highly effective treatments for HCV are now available. For the first time, experts in HCV confidently use the word “cure” to describe the achievable endpoint of treatment. But many patients — as many as 50% — remain undiagnosed and untreated. ² Who are these patients, and how can we bring them into care?

Let’s begin by listening as Dr. Sulkowski, Professor of Medicine and Medical Director of the Viral Hepatitis Center at the Johns Hopkins University School of Medicine, puts a face on the epidemic, as he presented at the 2017 American Society of Addiction Medicine, or ASAM, conference in New Orleans. Here, he introduces a young woman named Theresa who contracted HCV infection through injection drug use.

Theresa – Part 1

DR. SULKOWSKI:Theresa was someone I saw a few months ago in our hepatitis clinic. I met her on a Monday morning — I see patients every Monday there — and there were a couple of things unique about her from the get-go. The first is when I called her back for her appointment she was with a baby, a child about 1-1/2 years old, and a male partner. The second thing that was unusual about her was she had driven 2-1/2 hours into Baltimore. I’m at Johns Hopkins in Baltimore, Maryland.

Sometimes patients’ stories really stick with you. Even years later there’s a patient you may have seen or client you talked to that resonates. And what really stuck with me about Theresa is her story. Maybe it’s not that atypical, but her story starts when she’s 16 years old in high school, and she had a boyfriend. She was a good student, Cs and Bs, and she started to use oral opioids. Her boyfriend got them from his parents’ medicine cabinet.

Then she injected heroin. And that went on, injecting narcotics for about a year and a half or so. She was able to break free of that, got herself into an addiction treatment program, took buprenorphine for a while, emerged from that, got back into some classes at a community college. Had a new boyfriend, a new partner, got pregnant, and had a baby. So, all is good, she’s got her life in a straight line now.

But after her baby was born, she had a pretty interesting postpartum experience. Her young son got a bit jaundiced. Not uncommon; a lot of kids get yellow, they stick them under the lights. That’s pretty typical for newborns. But they also ran some tests and found out that her young son had hepatitis C. He was antibody positive, which is hard to sort that out early after birth, but he was also virus positive.

That was devastating news. Here she is with a brand-new son who is hep C infected. But what was worse was that they told her, “We think you should be tested because you’re probably the source of your son’s hepatitis C.” She’d never been tested before. She was tested and was hepatitis C positive with the same strain of hepatitis C as her young son. That was a devastating moment for her, and one of the very first questions she asked me during our visit was, “how come I wasn’t tested earlier.”

Now, she never had jaundice, never got yellow, and never had textbook symptoms of liver disease. She really felt well. She went through a couple of rehab programs, had seen her family doctor, and no one had run a test for hepatitis C, although she certainly was known to have injected drugs, tried to be careful, and as far as she knew, her boyfriend at the time was hepatitis C negative; he said he was clean. (Turns out he’s got hepatitis C, too, but that’s a whole different story.)

So, the question she asked me and the one I haven’t been able to quite answer is, “Why wasn’t I tested? How come no one tested me? How come my OB didn’t test me? How come my family doctor didn’t test me? How come I learned of it this way?”

HCV Background

HOST: HCV was first discovered in the late 1980s as a cause of hepatitis in infected patients. ³ The liver is the main target of HCV. Let’s pick up with Dr. Sulkowski as he describes the impact of chronic HCV infection on the liver.

DR. SULKOWSKI: The human immune system has the ability to clear hepatitis C in 25% to 40% of people who get infected. ⁴ The remaining people, about 75%, go on to chronic infection. I think of this like a smoldering infection of the liver, they’re asymptomatic. Clinicians generally don’t pick it up, based on what they report, and it causes low level ALT and AST elevation, ⁵ the kind of thing that often gets ignored in a busy primary medical practice.

These infections often smolder for years or decades before diagnosis. Patients often say, “How could I possibly have had this since 1970?” The reality is, that’s the typical course of chronic hepatitis C infection.

The concern is that this smoldering infection of the liver over time can cause the liver to scar. Fibrosis is scar tissue that’s laid down very slowly and can lead to cirrhosis of the liver. ⁶ Cirrhosis is a condition where the liver is badly scarred. The liver looks nodular and a biopsy of the liver shows thick bands of scar. ⁷

A cirrhotic liver is a lot like a car with 140,000 miles on it. The cirrhotic liver can function quite well for some time but when things start to go bad, the clinical decline can be rapid. There’s liver decompensation, ascites, bleeding varices, encephalopathy, and liver cancer. ⁸ In fact, liver cancer is one of the only cancers still rising in incidence today, with rates that go up year after year being driven by hepatitis C. ⁹ So this can be a very deadly disease that can certainly lead to death in many people.

HOST: Keep in mind that there are actually multiple genotypes — or strains — of HCV. The prevalence of these genotypes varies geographically. In the US, genotype 1 accounts for about three quarters of cases; genotypes 2 and 3 are less common, while genotype 4 occurs even more rarely. ¹⁰

Although the US does not have the highest prevalence of HCV compared with other regions, we do see a significant and rising impact in terms of mortality. Dr. Sulkowski has now joined us on the phone. Dr. Sulkowski — why is that?

DR. SULKOWSKI: If you look at 60 infectious pathogens, including HIV, TB, MRSA, and Zika, hepatitis C is the number-one killer of Americans. ¹¹ It kills more people than all these other pathogens together, about 20,000 Americans per year. Since 2007, more Americans have died of hepatitis C than of HIV. ¹² The number of HIV deaths is 6,000 to 7,000, ¹³ still too many, but hep C is 20,000 or more. ¹² Why is that? Well, HIV deaths are coming down because of a lot of public health effort to screen, link to care, and treat with highly effective antiretroviral therapy.

With hepatitis C, we haven’t done much of any of that, no public health effort and until recently very little treatment.

HOST: But many of these deaths can be prevented by identifying and treating chronically infected patients with the highly effective new drug regimens — and many of these people are being seen in addiction centers.

Think about that for a moment. Many of your clients, whom you work with daily, have undiagnosed HCV infection that, if left untreated, can make them ill and lead to their death. And that sickness and mortality will be caused not by their addiction, but by an infection that is curable.

Of the five million or so Americans with chronic HCV infection, only about half know they are infected. ¹² Not knowing they have HCV leaves these people at risk for liver damage and early death, and it also allows for potential transmission of HCV infection to others.

This leads to some major questions. For example, who is most at risk for HCV infection? Why are they not being tested? And how can we improve screening and linkage to care?

Let’s listen as Dr. Alain Litwin, Clinical Professor of Medicine at the University of South Carolina School of Medicine Greenville, describes the epidemiology of HCV infection in the US

Epidemiology of HCV

DR. LITWIN: So, the majority of Americans who are infected with hepatitis C, about three-quarters, 76%, 77%, are in the baby boomer generation. ¹⁴ These are people who were born between 1945 and 1965. For many years, this is where the core of the hepatitis C epidemic lay.

More recently, we’re seeing an increase in hepatitis C infection, now related to injection drug use among young people who inject drugs, specifically those who are 30 years of age and under, and this is happening in urban settings, as well as nonurban, specifically suburban and rural settings. ¹⁵ This has been fueled by the change in the heroin epidemic.

In the 1960s, a typical heroin user was maybe 17 to 19 years old and male; today they’re a little older and much more likely to be female. In the past, 45% of heroin users were nonwhite, and now it’s 10% nonwhite, and 90% of new heroin users are Caucasian. ¹⁶

In the ‘60s and ‘70s, people, when they started using opioids, they started with heroin, and now because of the prescription opioid epidemic and the increased availability of prescription opioids everywhere, many young people have experimented with opioids and started with using pills. They became dependent on opioids as supply has gone down and there’s been more control making it more difficult to obtain opioids, they transitioned to cheaper heroin and began injecting it. ¹⁶ And with that prescription opioid epidemic, we’re seeing a rapid increase in hepatitis C among young people, a three- or four-fold increase in the last several years throughout the country. ¹⁵

HOST: These data tell us where to look for HCV infection. But how does this epidemic play out in communities? To find out, we turned again to Dr. Litwin.

DR. LITWIN: Let me speak more specifically of what we’re seeing in many rural communities. Scott County, Indiana is a perfect case study. Several years ago, in 2011, we had discovered a cluster of hepatitis C cases in southeast Indiana that was linked to the prescription opioid epidemic. People were predominantly young and Caucasian, both males and females, and cases of hepatitis C were skyrocketing. ¹⁷

This was in a setting where there is very little access to kind of public health services, so there was inadequate HIV and hepatitis C testing, inadequate access to syringes; in fact, it was illegal for physicians to prescribe syringes. Syringe exchanges were illegal, so it was a perfect environment where if HIV were introduced into this network, it would take off.

And that’s precisely what happened in 2015 or so when they found a cluster of about 11 cases of HIV. After further investigation and the CDC coming in and other public officials in Indiana found that 169 cases of HIV were diagnosed in six months. More than 80% of these patients were coinfected with hepatitis C. Most likely these hepatitis C infections preceded the HIV infections by several years.

I think the overall lesson here is that when we see these cases of hepatitis C in these communities, and even before that, when we know that overdoses are happening and that people are using drugs, we need to immediately institute a number of public health interventions. The interventions can range from offering free testing programs for HIV and hepatitis C and vaccines for hepatitis B. Testing for HIV and hep C is important but not sufficient.

Obviously, we need to be able to link people to care. In many of these communities there are no places that provide care, and so we need to be able to train primary care providers, whether they are physicians, or nurse practitioners, or physician’s assistants, how to treat hepatitis C and HIV so we can decrease the community viral load. Then we need to make sure there’s ample access to syringes for people who are using drugs. If they don’t have access to clean syringes and other equipment, over time they will become infected with various viruses, specifically HIV and hepatitis C.

In addition, it’s very important that we offer evidence-based drug treatment intervention, specifically for the opioid epidemic. Methadone or buprenorphine are very effective at decreasing drug use and decreasing transmission of HIV, ^{17 18} and more recently we’ve seen this with hepatitis C. ¹⁹

HOST: Scott County demonstrates how this disease can spread among people who inject drugs and share needles. And our patient Theresa shows that vertical transmission, from mother to child, is another real concern that is not being addressed. Here’s Dr. Sulkowski from the ASAM meeting.

HCV Screening

DR. SULKOWSKI: In Philadelphia, they looked at nearly 568 hep C-positive women who gave birth and asked how many of their children were tested. ^{19 20} Only 84, 5%, of those children are likely infected, so there’s a lot of children out there who were never tested. Unfortunately, the OB recommendations are not to test women during pregnancy. So, the diagnosis of hepatitis C is easily missed in these children and mothers.

HOST: What does this evidence add up to? In other words, exactly which patients should we be testing for HCV? Is there a right way of screening for HCV? And what do we do when patients test positive? Here’s Dr. Sulkowski again.

DR. SULKOWSKI: The US Preventive Services Task Force (USPSTF) recommendations are to screen every single baby boomer born between ’45 and ’65. ^{20 21} Don’t ask about risk factors, just look at the birthday: if it’s between 1945 and 1965, the patient should be offered a hep C antibody test. Why? Because nearly 5% of the adults in that cohort are hep C positive. Any past or present injection drug use, even once, warrants being screened. Hepatitis C is very contagious. A single needle exposure is thought to be a 3% risk if that needle is contaminated, 10 times more contagious by needles than HIV. ²² That’s why in Scott County of 500 with hep C and only 188 also had HIV.

The UPSTF also recommends testing for persons who have had sex with an injection drug user: ²³ While sexual transmission is relatively uncommon, it can occur, particularly among HIV-infected men who have sex with men, among whom HCV is clearly a sexually transmitted infection.

Any blood transfused before ’92: anyone with hemophilia who got factors before 1990.

Dialysis: outbreaks are occurring patients on dialysis in the United States even as we speak.

Children born to hep C positive mothers: they should be tested. Incarcerated individuals: they should be tested.

Intranasal drug use: there is some concern that that may spread hepatitis C, or it may be a marker for injection practices that aren’t reported.

Unregulated tattoos: I tell my kids not to get tattoos because of hepatitis C. The reality is, we don’t know how many people actually acquired hepatitis C through a tattoo, but the needles and even the inkwells can become contaminated and transmit hepatitis C.

Needle sticks on the job: health care workers, and then surgery before universal precautions. ²³ A lot of the baby boomers I see say, but doc, I didn’t inject drugs, why am I hep C infected? Well, think about it. Before AIDS in the 1980s, universal precautions as we know them today did not exist. And many people got hepatitis C through surgical procedures, through seeing a doctor. In fact, that’s how hepatitis C is spread in many countries.

HOST: So now we know who we should be screening, but how do we actually diagnose HCV? Dr. Sulkowski explains.

Diagnosing HCV

Dr. Sulkowski: The diagnostic process is pretty straightforward, it’s an antibody test that’s highly specific, highly sensitive. This can be done via routine phlebotomy or even by a point-of-care finger stick tests, with the result in 20 minutes. ²⁴ If they’re negative, they are hep C uninfected unless you think it’s an new or acute HCV infection or other special circumstances, in which the antibodies are not found. However, these scenarios are rare. If they’re positive — this is the next step — check for evidence of an active HCV infection with a blood test for HCV RNA. It’s important to understand that following acute HCV infection, around 25% of people will spontaneously clear infection; these individuals are HCV RNA negative and HCV antibody positive. ²⁵

I saw a man a month ago who thought he had hepatitis C for a decade, but no one had checked the RNA. I checked the RNA, it turns out he doesn’t have chronic hepatitis C. He spent 10 years thinking he was chronically infected, but he was not. So, test for the antibody, and follow with RNA. If RNA is positive they have hepatitis C infection and they should be referred for evaluation and consideration of treatment.

What else should happen? They should be assessed for alcohol use. CDC says everyone should get a screening and brief alcohol intervention, ²⁵ and in my opinion there is no safe amount of alcohol in people who are hepatitis C infected. If hepatitis C is like a smoldering fire in the liver, alcohol is like pouring gasoline on the fire. How much is too much, we don’t know, in part because when we try to do surveys for alcohol, people often under-report or underestimate their alcohol intake.

People should be educated about transmission and harm reduction, ²⁵ and in my view the treatment of addiction goes hand in hand with an assessment in treatment of hepatitis C.

One important point I want you to leave here with is that liver biopsy is not performed anymore. ²⁵ Your patient and any patient I see will not have a liver biopsy. That’s not the standard practice any longer.

We use blood tests. I like the FIB-4. It’s an equation based on age, ALT, AST, and platelet count. If you Google the term FIB, F-I-B-4, a website for an online calculator will come up, you just plug the numbers in and you’ll get a score. If it’s above 3.25, they are likely to have significant liver fibrosis whereas if the score is less than 1.45, the liver is likely to have minimal fibrosis. I do this when I first meet people so I can assess where their liver stands.

In our office, we also have the ability to measure liver stiffness using a machine called liver elastography or FibroScan. These modalities, blood tests and liver elastography, have replaced biopsy.

What are the next steps? The next steps for persons with active hepatitis C infection are to screen for hepatitis A and B immunity. ²⁵ If they’re negative for protective immunity, vaccinate them.

And then all patients should be considered for treatment and they should be referred. ²⁵ I would encourage everyone to find someone or a group of providers in your community with whom you can partner to get your patients treated and cured. They must be willing to work to overcome barriers to HCV care.

HOST: Linkage to care is a critical next step after someone has the diagnosis. But in daily clinical practice, and especially in addiction medicine settings, things don’t always go as planned.

To illustrate, let’s turn back to Theresa’s story from the New Orleans presentation.

Theresa – Part 2

DR. SULKOWSKI: So, she was in the office, as you recall, drove about 2-1/2 hours into Baltimore, there with her 1-1/2-year-old son — and I’ve got to tell you, there’s a reason why I’m not a pediatrician, and that’s because 1-1/2 year olds in the office are not always that much fun — but she was there because she wanted to be evaluated and treated for hepatitis C.

She wanted to be free of hepatitis C so she could think about planning a family and moving on with her life. And curing hepatitis C is a very powerful step forward.

She had seen a doctor 2-1/2 hours away from my office who told her that her liver was in great shape and she did not need treatment. Well, of course, her liver was in great shape; she was just infected three or four years ago and had not yet progressed. This is not a reason not to treat hepatitis C.

So, I told her that we will do some tests. We did an elastography, a FibroScan in the office. We did genotype testing, found out she had genotype 1, subtype A, the most common strain we see in the US. Her viral load was pretty low, only about 500,000, and in general, viral loads run in the million to 6 million, even 10 million range, and she’s a good candidate for potentially eight weeks of treatment.

So, I told her that we’ll get her moving forward with treatment. She was very excited about that, very anxious to move forward, which makes the next part of my story a little bit confusing.

So, we put the prescription in with the pharmacy — and if there is one thing I hate about hepatitis C, it’s trying to get prior authorization. I mean, come on, really, busy heath care practitioners can’t stay on hold for hours to talk to someone about approval. But we did get her prior authorization, the approval for treatment.

We have a nice system at my hospital with a specialty pharmacy that will help us link our patients to these medications and then we have nurses who will work closely with our patients to help them succeed with treatment. We called and left a message with Theresa to let her know that the medicine is ready. But we never get a call back. We call again, and this time the cell phone we’ve got in our computer system is not active. She had a follow-up appointment scheduled about six weeks after the first visit. No show.

Our team is really good and dedicated, so they track down some relatives. They eventually track down her aunt and they talk to her. It turned out that she had relapsed into using drugs. I suppose we shouldn’t be surprised, but I was. I was confident, based on my just 45-minute interaction with her that she was ready to move forward and that she had everything going straight. But, this was clearly not the case.

So, in any event, we lost her to follow-up and we were not able to give her treatment.

HOST: As you’ve heard, evidence and guidelines tell us whom to test and how to test. So, what’s the problem? Why are 50% of patients with HCV undiagnosed?

As usual in public health, the answers are complex. Barriers to screening are multifactorial and affect all stakeholders, including patients, providers, and the health care system itself.

Also joining Dr. Sulkowski in New Orleans was Dr. Kathleen Brady, Distinguished University Professor at the Medical University of South Carolina and Director of the South Carolina Clinical and Translational Research Institute. Let’s listen to Dr. Brady as she reviews patient barriers to screening in greater depth and presents strategies to overcome these barriers.

Patient Barriers

DR. BRADY: With patient level barriers, there is certainly stigma associated with HCV, as there is with HIV. ²⁶ Individuals with addictions are known for their denial. We all know this is pathognomonic of the disease, so if they think testing for something is going to increase the stigma that they already feel, they’re likely to just deny that that’s even a possibility.

In addition, there’s a lack of knowledge. I think many drug users are unaware of the prevalence of HCV and what are the risk factors for having acquired HCV. They are also unaware of the potential harm and mortality associated with it, and they are unaware of improved treatments. Because of that lack of knowledge, they have a lot of fear. Treatment of HCV, even five to ten years ago, was different than it is today. So, when addicts talk among themselves about HCV and what happens when you have it, they’re talking about things they’re fearful of. Liver biopsy, and long-term treatment with lots of side effects.

What can we do to overcome these patient level barriers? One of the things is to normalize HCV screening. For goodness sake, if HCV screening is recommended for every person born between 1945 and 1965, it’s going to be pretty standard practice and it should not be a stigmatized test.

It is particularly helpful if we can have onsite testing at addiction treatment settings. One of the ways we can encourage our patients to learn more about it and ask questions and talk to their providers about it is by providing posters and visual prompts and patient centered educational materials addressing risk factors, prevalence, and treatment.

The CDC website has a number of these tools that you could download to use in your own practice. I think the greater education these patients have about it, the more likely they are to initiate the conversation that needs to be had.

HOST: Providers can also get in the way of appropriate testing, whether because of discomfort with the topic, insufficient time, or lack of support. To discuss these issues, we turned back to Dr. Litwin.

Provider Barriers

DR. LITWIN: From a provider perspective, the same barriers, both primary care providers and specialists, may not have adequate knowledge, believe it or not, around hepatitis C. ^{27 28} They still may have perceptions that a person who is actively using drugs or injecting drugs is not a candidate for treatment. The guidelines said that many years ago, and they had not been changed for nearly 20 years, so because the guidelines originally said that and because of the stigma that sometimes people are “not worthy,” they are denied treatment, or you thought that you must first cure the addiction — which is not curable, but it’s treatable — before we can proceed with hep C treatment.

HOST: Now we know that HCV can be cured even in people who are still using drugs or on opioid-agonist therapy, ²⁹ but as Dr. Litwin just said, some providers still don’t know that the guidelines have changed and these people are eligible for care. But are still more obstacles getting in the way. Dr. Litwin?

DR. LITWIN: The systemic barriers — workforce issues that there are just not enough providers who know how to treat hepatitis C, ³⁰ even it’s become much simpler, one pill a day in many cases.

With the government barriers, there’s just not enough funds. There’s so much more funding for HIV than there is for hepatitis C. Health care systems are overburdened and fragmented, with primary care in one place, psychiatry in another place, substance abuse somewhere else, and the hep C provider in a fourth location. You can’t be everywhere at once, so we don’t have enough one-stop shopping models.

Another barrier is problems with reimbursement for treatments. Although treatments have been quite expensive, they’re coming down in cost quite a bit, and so there is no reason why they can’t be covered for every American.

Thankfully, we have many strategies to overcome these barriers. Many focus on education, whether it’s for the patient or provider, and then just general barriers with different models, like peer navigation and case management.

I think we need to sensitize providers at all levels, from medical school to senior, seasoned physicians, to help providers understand substance abuse and the related comorbidities such as hepatitis C and to understand it as a chronic disease and not as a moral issue.

A number of actions can help prevent both HIV and hepatitis C outbreaks among people who inject drugs. Physicians should screen all patients for both substance use disorders and mental health disorders; that is often not done in primary care settings. We need to test patients, and equally important, their sexual and drug injection partners for HIV, hep C, and other sexually transmitted infections.

For people who test positive for both HIV and hepatitis C, we need to offer immediate linkage to care and treatment. If we can just provide hepatitis B vaccines, even one dose can be effective.

We need to offer immediate referrals to substance use treatment programs that provide opiate-agonist therapy, whether it’s buprenorphine or methadone.

We must also support screening referral to free or affordable treatment for substance use disorders as well as infectious complications. And we need to be able to monitor state HIV and hepatitis C epidemiologic testing data to identify and respond to outbreaks early. If we can do this ahead of time we can prevent these outbreaks.

HOST: In part 1 of this series on HCV, we discussed the recommendations for screening, the importance of early diagnosis of HCV, and barriers to achieving these goals, thanks to Dr. Sulkowski, Dr. Litwin, and Dr. Brady.

Part 2 – Reversing the Tide by Curing HCV

Introduction

HOST: It’s the DKB Radio Hour. I’m Spencer Cannon. This episode is brought to you by an educational grant from Gilead Sciences, Inc. and is accredited by the Postgraduate Institute for Medicine.

Welcome to Part 2 of our series on the diagnosis and treatment of hepatitis C. In Part 1, we talked with experts about the growing burden of HCV infection in the US, especially among people who inject drugs. Dr. Mark Sulkowski, Professor of Medicine and Medical Director of the Viral Hepatitis Center at the Johns Hopkins University School of Medicine and Dr. Kathleen Brady, Distinguished University Professor at the Medical University of South Carolina and Director of the South Carolina Clinical and Translational Research Institute, speaking from the 2017 American Society of Addiction Medicine, or ASAM, conference in New Orleans, highlighted the importance of screening for HCV and the barriers that often prevent clinicians from screening at-risk people and linking chronically infected patients to care.

In Part 2, we will discuss the imperative of early treatment for these chronically infected patients and the game-changing efficacy of the newly available therapies.

HOST: It’s no exaggeration to say that recently approved novel therapies for HCV are game changers. Previously, the treatment of HCV was frankly medieval. It involved long courses of treatment with interferon-based therapies, which made most patients horribly ill and cured only a fraction. Here’s Dr. Sulkowski, from ASAM, describing his experience.

Treatment Options

SULKOWSKI: Until 2014, we used interferon. I’ve spent the last couple of years trying to forget the days of interferon because it made my life miserable; it made my patients miserable with side effects; treatment lasted nearly a year, 48 weeks; and it made everyone feel lousy. Patients came to me feeling well, then I gave them a liver biopsy and gave them interferon and made them sick for a year. Not good times in the hepatitis C therapeutic arena.

HOST: “Not good times” is an understatement. Research showed that response to interferon is genetically determined and varied dramatically by individual and HCV genotype. ³¹ As a result, only a minority of people responded to treatment, and even fewer achieved sustained viral suppression. For this slim chance at cure, patients suffered from side effects for nearly a year. This all changed with the introduction of interferon-free regimens that are effective across patient populations and genotypes.

These regimens use combinations of direct-acting antivirals, or DAAs, which target specific proteins in HCV and inhibit its replication. Combinations of DAAs are required, because the virus rapidly becomes resistant to individual agents. ³²

We called Dr. Raymond Chung, Director of Hepatology and Liver Center at Massachusetts General Hospital, to tell us more about these new combination regimens and their efficacy across hepatitis C genotypes.

DR CHUNG: The original treatment regimens are combination therapies of direct-acting antivirals, or DAAs. They were mainly directed against the dominant genotype worldwide, genotype 1 infection.

With the success of treating genotype 1, we found ourselves with a lagging performance of persons with chronic hepatitis C that was attributable to genotypes 2 and 3 infection. With the introduction of agents that had more so-called pangenotypic activity — molecules that worked effectively against each of the six major genotypes of hepatitis C — we found ourselves increasingly moving toward a one-size-fits-all approach for treatment with small-molecule, direct-acting antiviral combinations.

With the pangenotypic regimens that have included sofosbuvir in conjunction with velpatasvir as one example and the most recently approved glecaprevir and pibrentasvir as another, we are now again seeing 95% to 100% rates of sustained response for genotypes 1 through 6, including genotypes 2 and 3, which had historically become more difficult to treat compared to the success we’ve just seen with genotype 1. ^{33 34}

It should also be noted that not only is success possible with durations ranging from eight to 12 weeks, ³⁵ these regimens are extremely well tolerated with very low premature discontinuation rates owing to intolerance, described in both clinical trials and in the real-world experience thus far.

We are now seeing, by virtue of both efficacy as well as tolerability, the delivery of cure to many more patients than we could have imagined using the old interferon-centered strategy.

HOST: As Dr. Chung described, multiple highly effective regimens are now available. These regimens require shorter courses of treatment and are far more tolerable and effective than previous interferon-based therapies. They also work across HCV genotypes, further simplifying treatment.

This is one of those rare and exciting times in medicine when something that was once very difficult to treat and caused suffering and death is now rapidly curable for almost all affected patients.

Let’s bring the discussion back to your practices and how treatment plays out in the addiction medicine setting. In Part 1 of this series, Dr. Sulkowski introduced Theresa, a young woman with a history of opioid addiction who discovered she had HCV when her baby boy presented with jaundice. From ASAM, Dr. Sulkowski continues Theresa’s story.

Theresa – Part 3

DR. SULKOWSKI: Let me pick up again and tell you where we left off with Theresa. The last point of the story was that she missed her appointment to start treatment and fell out of care; at least, care for hepatitis.

I mentioned earlier that sometimes patients’ stories stick with you. It really bothered me that she didn’t start treatment. That’s why I was surprised and happy when about six months later her name showed up on my Monday afternoon schedule. And I thought, well, maybe she’ll come, but then again, she missed the last several appointments so I’m not so confident. But, you know, I have a lot of charts to update and some notes to do, so I’ll just work in the office and maybe she’ll come.

Well, she showed up. She drove 2-1/2 hours into Hopkins, brought her child who is now about 2 years old and the same partner with her. Like you might expect, she had a story to tell. Her story was in part that she had untreated or inadequately treated depression and anxiety and wanted to get off her buprenorphine program too quickly. And that led to her relapsing into using narcotics again.

But to her credit, she is back on track. This time she is taking methadone. She is also taking antidepressant medication, back in school, and committed again. She updated me on a story related to her son, and that’s that while she was at Hopkins, she had seen our pediatric hepatologist. There’s not many of them but we have someone who specializes in liver disease in children. She brought her 2-year-old there, and she was a bit devastated because they told her that there are now treatments for kids who are 12 and older but we don’t treat younger children because the medications have not yet been formulated and approved for young kids. The pediatrician reassured her that her son would be fine but she is devastated about that but back on track for her own treatment.

HOST: Like many people who struggle with addiction, Theresa had some setbacks and challenges as she tried to stay off opioids and on track for HCV treatment.

In the past, clinicians debated if patients like Theresa were good candidates for therapy. We wondered how patients like her should be managed now, in the era of direct-acting antivirals. To answer this question, let’s go back to Dr. Chung. What do evidence and guidelines tell us about which patients should now be treated for HCV? Dr. Chung?

Evidence and Guidelines

DR. CHUNG: When and who should be treated, with the resounding success and tolerability of these direct-acting antiviral combination regimens, there is now a view that every patient with chronic hepatitis C should be offered therapy for their chronic hepatitis C.

There are very few reasons to not treat patients with chronic hepatitis C because of the success of therapy, and because of the long-term complications that can develop not just with advanced fibrosis, but also some increasingly extrahepatic complications of hepatitis C that can develop even in persons with early-stage disease. Kidney disease or cryoglobulinemia are two examples. It is incumbent on us to recognize any chronically infected person and to treat and eliminate their infection and, in so doing, to arrest and effectively reverse the natural history of that disease.

So, the only people for whom treatment is not recommended at this juncture would be those who have short life expectancies that cannot be remediated by treating the hepatitis C, by transplanting their livers, or by other directed treatments. ³⁶

Given the extraordinary tolerability and efficacy of these regimens, the AASLD and IDSA have broadly liberalized their recommendations of persons who should be treated.

An important corollary of this universal treatment recommendation is that persons who inject drugs, either currently or who have recently injected drugs, should not be viewed as ineligible for treatment. A number of studies have now demonstrated comparable success rates in producing sustained biologic response among people who inject drugs. ³⁷

HOST: The AASLD guidelines are clear: nearly all patients with HCV should be treated without delay. This guidance aligns with clinical trial evidence showing high cure rates across patient populations. Furthermore, studies from real-world clinical settings also report cure rates of 95% or more across populations, including patients with HIV coinfection or cirrhosis.

Here’s Dr. Sulkowski from ASAM, talking about treating patients in the addiction medicine setting.

Treating in the Addiction Medicine Setting

DR. SULKOWSKI: What about persons in opioid-agonist therapy settings, people in addiction treatment programs? A very important study, C-EDGE COSTAR, used elbasvir and grazoprevir, a one-tablet, once-a-day regimen for 12 weeks. ³⁷ I mentioned that there was no requirement for clean time or clean urines, and in this study, they allowed people who were actively using illicit drugs and gave them one pill a day for 12 weeks. We’ll get to some of the data in a minute.

So, the first question is, what was their adherence? More than 95% of people took 96% or more of the dose, so the adherence was great. All these people were in opioid-agonist therapy and many of them were in drug treatment settings. At 12 weeks, 91.5% of those who began treatment immediately achieved a sustained viral response.

There is one issue here, which I’ll come back to: reinfection. Some people, only five, in this clinical trial were proven to be cured, but then had a new strain of hepatitis C during the follow-up. ³⁷ Three were at one center in Thailand, suggesting that perhaps the harm-reduction strategies were not quite up to par at that particular setting. I can’t say that for sure, but in the other settings, only two patients out of more than nearly 200 were reinfected. I’m going to come back to that point in a minute.

But I mentioned active drug use. This is an atypical figure for a hep C paper, these are positive urine tox screens. ³⁷ This is during the immediate and then there was a delayed treatment phase. Sixty percent tested positive for one of these substances. You can see cocaine around 10%; opiates somewhere around 20%; benzos, cannabinoids, amphetamines. People not only had positive urine tox at entry, they used drugs for the entire 12 weeks and still achieved very high sustained virologic response rates. So as long as your patient can adhere to the treatment, he or she may be a very good candidate for treatment.

HOST: This all might sound too good to be true: new therapies that safely cure almost all patients with a life-threatening disease, regardless of substance use or most comorbidities. As our experts have described, the new HCV regimens are effective — so long as patients adhere to therapy. And this is where the rubber meets the road, especially in addiction medicine. To discuss the importance of adherence and strategies to help, here’s Dr. Kathleen Brady from ASAM, discussing this important issue

DR. BRADY: Suboptimal exposure can be associated with decreased sustained virologic rates, and the threshold for not having that happen is greater than 85% adherence. ³⁸ So we need to make sure that people are taking their medications in the way they’re prescribed, and this must be emphasized by their health care providers.

What are the barriers to adherence? One is the duration of treatment. As you’ll hear, currently treatments can be over in 12 weeks, or three months, which is maybe not that long, but when you are talking about somebody who is asymptomatic and taking a treatment for something that right now is not making them feel sick, that can be a long time. And in the past, treatment was longer and the duration of therapy was a problem.

Perceptions about complex medication regimens, as you will hear, most of the medication regimens that are used now are much simpler. That wasn’t always the case. Issues with side effects and adverse events, people worried about that. Cost, insurance coverage, lack of social support. It’s good if there are others in somebody’s life, people they live with, to talk to them about the importance of medication adherence.

Psychiatric disorders, in particular PTSD and depression, appear to be associated with poorer adherence, and in some cases an active substance use disorder can be problematic for adherence.

One analysis of 12 HCV adherence studies found fair evidence to support a couple of things. One was a systems-level intervention, which was directly observed therapy within substance use treatment facilities. ³⁹ Anybody who’s worked in a methadone treatment facility will know that that’s not an unusual concept. People come in and are observed taking their medications at least five days a week. Regimen related, if people are on complex pill regimens, packaging those pills with daily aliquots can be important

Patient-level interventions can include structured patient education and support systems like phone call reminders, case management, and that sort of thing.

The main things that can be helpful in addressing barriers to adherence are phone or email reminders. There may be phone apps or a number of those that can help people by giving — I heard somebody’s alarm go off in here — by setting an alarm that goes off at the time they’re supposed to take their medications. Case management, pill organizers. Again, information, and then aggressive management of side effects and directly observed therapy.

HOST: Good adherence is essential to achieving cure. Here’s Dr. Sulkowski again from ASAM, describing the role of adherence in Theresa’s case.

Adherence

DR. SULKOWSKI: You heard the issues of adherence and its importance on treatment, so one of the things I’m asking myself now is, “Is Theresa truly ready for treatment?” I felt I was a bit naïve the time before because I was convinced she was on the right track and ready for treatment, and she clearly wasn’t.

What we often do when we’re not sure if someone is ready is order some lab tests to update her viral load and scheduled her follow-up appointment for two weeks later. Part of the logic is that actions speak louder than words, so if she is ready for treatment, she’ll show up for that appointment. And, lo and behold, two weeks later, she’s there, and ready to start treatment

So, we went through the process, another prior authorization, and to be honest, I was a bit concerned, I might say, we did this once before for this person. But it went through. We were able to get her access to treatment.

In our system, we have developed a program to try to work well with patients to ensure adherence. We give our patients a color assignment: red, green, or yellow. The green patients are the ones who don’t need any help with treatment or adherence. They’re the ones who call us and say, “I was 30 minutes late on my dose of hep C therapy. Is that okay?” And you say, “Yes, it’s fine, stop calling. You could take the medication 30 minutes late.”

The yellow patients need some support. We often ask them to come in for teaching, go through their current meds and kind of get them on track. And the red patients…sometimes they come in once a week for a pillbox to fill.

Theresa lives far away so we couldn’t make her a red patient with the pillboxes, but we could contact her methadone program and talk to them about working with us and helping us commit to hepatitis C treatment. They were happy to do that. She ended up taking her medications at home on her own and she did great with it.

HOST: Let’s take a moment to reflect on what we’ve learned. We know that HCV is especially common among people who inject drugs, and we should screen all at-risk patients. For patients who are chronically infected, a variety of new treatments with extremely high cure rates are available, and guidelines support their use in almost every case, so long as patients can adhere to therapy. And our experts outlined some strategies to promote adherence, including communication and coordination between treatment clinics and addiction centers.

But this isn’t the end of the story. Even when patients are cured of HCV, they may still be at risk for reinfection. Here’s Dr. Sulkowski to discuss the risk for reinfection and strategies to mitigate this risk.

Reinfection

DR. SULKOWSKI: Reinfection is certainly possible, and I want every person I cure to know that if they’re re-exposed, they could be reinfected. But I want them also to understand that there are ways to prevent that. There’s needle exchange, the use of clean needles, clean equipment. There’s addiction treatment services, and clearly, we want to link people in to addiction treatment programs.

How many patients get reinfected? In a recent systematic review, if they were low risk, a baby boomer who might have injected during the Woodstock era but hasn’t used drugs in 30 years, reinfection doesn’t occur frequently and is really quite rare. ⁴⁰ In high-risk people who have recently injected drugs, the risk of reinfection may be as high as 10%. Among HIV-infected patients, this rate of reinfection reported in the medical literature is a bit higher, but here you also see higher rates of sexual transmission among HIV-positive men who have sex with men, many of whom are engaging in high-risk sex in the setting of well-controlled HIV infection.

There may be a publication bias in the published rates and we need to continue to collect data in the era of DAAs, but nonetheless, it’s important that patients know there is no HCV vaccine and there is no HCV immunity; they can be re-infected after achieving cure.

In addition to harm reduction, the idea of HCV treatment as prevention is being evaluation. The concept is that if we treat enough people with HCV who are using injection drugs together, we can stop the transmission of HCV. The concept is.social network–based treatment in which you don’t just treat the individual, you treat that individual and his or her injecting network. It’s a very novel strategy but I think it can work to prevent reinfection.

HOST: Because reinfection is possible, we need to be mindful of ways to limit this risk, such as the social network–based strategy described by Dr. Sulkowski. The potential for reinfection is not a reason not to treat in the first place; but it is an important reason to maintain close follow-up with patients after they complete therapy and achieve cure.

Let’s return to New Orleans to hear how Theresa did with treatment and follow up.

Theresa – Part 4

DR. SULKOWSKI: With hepatitis C, we have a visit three months after the last dose of treatment. She took a one-pill, once-a-day regimen for eight weeks. Three months later she comes back in, we check her viral load, we do that hepatitis C RNA test, and it’s not detected in the blood.

That means we’ve put out that smoldering fire in her liver, and she’s now achieved what we call a sustained virologic response or SVR. Now I’ve got to tell you, I hate that term, SVR. What does that really mean? It means a cure. I want you to leave here with the idea that hepatitis C can be cured and you should use the word cure in your conversations with people who are hep C infected. It’s a powerful word, and it’s something we do every day in our clinical practice: we cure patients.

At that three-month visit after treatment, I was able to tell her she’d been cured, but that’s not the end of the story. The care continuum or care cascade doesn’t end with cure because there is the risk that she could be reinfected. There is no vaccine for hepatitis C. There’s one for hepatitis A, there’s one for hepatitis B, but not for hepatitis C. There is no immunity; people can become infected again if they are exposed I want to make sure that patients understand that they can be reinfected if exposed. As we talked about, hepatitis C is very contagious from contaminated needles, equipment, or other works you use to inject drugs.

She’s on a methadone program and has access to clean needles in her community, but I want to talk to her quite frankly and honestly about the risk of reinfection so she understands that.

I schedule all my patients to come back and see me one year after they finish treatment so I can see how they’re doing. For my patients with cirrhosis, I want to be sure that they are engaged in liver ultrasound screening for liver cancer because the risk continues after cure. I also want to assess lifestyle issues, such as alcohol use and obesity, that may cause liver damage. These can cause fatty liver disease and could lead to more liver problems despite HCV cure.

For people like Theresa, I want to make sure she is still on the right track. Is she still doing well with her addiction? Has she been reinfected? And for a lot of these people we check a viral load every six to 12 months to make sure they’re still free of hepatitis C virus to try to intervene quickly if there’s a problem.

So, she came back in and was doing great. She got a job, was continuing to take classes at the community college, and probably the most exciting thing, she became pregnant again. What’s important is that she knows that when she delivers that baby, that baby will not be hepatitis C infected. So, I consider that a win/win/win. It’s a win for her because she doesn’t have to worry about liver disease, it’s a win for the community because she is not at risk to spread it to anybody else, and it’s a win for her children because they won’t be hepatitis C infected. And that’s one of the great things about hepatitis C these days: we win a lot.

HOST: Theresa is the type of patient you see every day who had significant challenges, including opioid addiction, but she still managed to complete treatment and achieve cure. And keep in mind that this outcome is possible for most of your clients who are HCV infected, with the right support and treatment.

You might wonder what all this recent success with HCV means for the broader population. Can effective treatment for HCV change the epidemic in your local center or region, or even across the US or the world?

The World Health Organization, or WHO, has set aggressive targets for HCV, which they call 90-90-90 by 2030. ⁴¹ They want 90% of those infected to be identified and diagnosed, 90% of eligible people to be treated, and 90% of those treated to be cured. With regard to addiction medicine, the WHO cites a goal of having 50% of people who inject drugs covered by harm reduction services.

If these goals are met, the WHO projects a 70% reduction in HCV incidence, with a 50% reduction by 2020. And the ultimate goal is a 60% reduction in HCV-related deaths. What’s it going to take to reach these goals? Dr. Sulkowski again, from ASAM.

Key Takeaways

DR. SULKOWSKI: We’ve got a lot of work to do. The WHO estimates that there were 71 million people with chronic HCV infection at the start of the DAA era; most of whom remain undiagnosed. To address HCV infection, we will to focus resources on testing and linkage of persons found to be HCV infected to treatment. We’ll also need simplified treatment algorithms that can be administered by non-specialists. Along with harm reduction interventions and medication assisted treatments, these efforts will need to focus on persons actively injecting drugs since these individuals are driving the spread of new HCV infection in the US and in many parts of the world. We will need to improve every single step of the HCV care continuum to achieve the WHO goal of HCV elimination.

HOST: As Dr. Sulkowski says, reducing the burden of HCV will require a multipronged approach, beginning with improved screening and linkage to care, early initiation of therapy — that is, before the onset of liver disease — and coordinated efforts by treatment clinics and addiction centers to ensure adherence and follow up.

The take-home message here is that engagement with multiple interventions by caregivers in addiction centers and treatment clinics can meaningfully impact a global epidemic — one that is now disproportionately affecting young Americans, many of whom struggle with addiction.

Here’s Dr. Sulkowski from the ASAM stage one last time.

DR. SULKOWSKI: On March 28, 2017 the National Academy of Medicine announced that in the US hepatitis C could be eliminated and 90,000 American deaths prevented by 2030 with better attention to prevention, screening and treatment, and with creative financing for medicines. ⁴² They also point out that viral hepatitis is simply not getting a sufficient priority in the United States.

Some take-homes. Hepatitis C treatment is recommended for nearly all patients. There are multiple regimens, and cure rates exceed 90%. Elimination may be possible but it will require prioritization along the entire care continuum, testing, links to care, access to treatment, and prevention of reinfection among those at risk.

HOST: We hope you’ve enjoyed this episode of the DKB Radio Hour. Thanks to Dr. Sulkowski, Dr. Chung, and Dr. Brady for joining us today. Please look for future episodes of the Radio Hour, when we discuss HIV and other topics.

I’m host Spencer Cannon, thanking you for your time.

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