HCV Basics

HCV is a single-stranded RNA virus that was discovered in 1989. Before then, we knew there was an infectious pathogen in the nation’s the blood supply, which was recognized because some people developed jaundice and liver inflammation after blood transfusions; this was referred to as non-A/non-B hepatitis. Now we know this as HCV. Globally, an estimated 71 million people are living with HCV infection, and it’s a major cause of liver disease including liver failure, hepatocellular cancer, and death. However, HCV is an RNA virus and it does not have a latent phase or reservoir, unlike HIV or HBV. And unlike those infectious pathogens, HCV infection can be cured.

HCV does, however, establish chronic infection. This is in part because of heterogeneity with HCV existing as different strains or genotypes. In the US, the most common strains are HCV genotypes 1, 2, and 3. Within an individual, HCV exists as a collection of closely related variants called quasispecies. This viral diversity is one reasons why HCV can escape the immune response and why HCV vaccines are not currently available. HCV is not an easy infection to prevent by vaccine, but some effort is underway to develop such a vaccine.

As a blood-borne pathogen, HCV is transmitted through routes of blood exposure.² In the early years before screening tests were available for HCV, transfusions were the predominant mode of transmission for this virus. Clearly, with the introduction of antibody testing and screening in the blood supply for HCV, the incidence of transfusion-related hepatitis has dropped dramatically since the early 1990s.

Currently, the predominant mode of transmission currently is continued injection drug use with the sharing of needles, syringes, or other paraphernalia used to prepare or inject those drugs.

Other modes of transmission are less frequent and less efficient. These include sexual exposure, particularly among those with high-risk sexual exposures, those having multiple sexual partners or having rough sex, or men having sex with men (MSM); this is particularly true among those who are already HIV-infected.

Also, uncommon but possible is transmission of HCV from a mother to her infant. ³ This rate of transmission is very inefficient (6% percent in most chronically infected mothers). The one exception to that is the HIV-coinfected mother, whose rate of transmission approaches 20%.

Meet Gary

Gary - Part 1

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GARY: I’m 62 years old. I’ve got a few extra pounds, I’ve got some aches and pains, and I have diabetes, but even with that, I still consider myself to be pretty healthy, especially compared to some of my friends my age. I have friends who have had serious illnesses, friends my age who have had heart attacks, strokes, even cancer, all sorts of things. But me, I don’t know, I never had any of that. All I have or thought I had is diabetes. And it’s not the kind where I have to give myself shots, I just take a metformin pill every day.

That all changed a couple of months ago. My wife and I retired and moved to Ft. Myers. New home, new place, new city, I have to find a new primary care doctor. I go online, I talk to some of my new friends in the neighborhood, and I identify a new doctor. I make an appointment with her, and I go into her office.

We go in, we sit down, we start chatting. She’s going through my file from my old doctor, and as we’re sitting there she’s asking me, “Gary, when was your last colonoscopy,” and “Have you ever had a cardiac stress test?” Those questions I expected her to ask me.

What I didn’t expect her to ask me, however, is “Have you been tested for hepatitis C?” I was shocked by that question. Do I look like a drug addict? I thought the only people who got hepatitis C are drug addicts and people in jail.

In the spirit of full disclosure, in college, I used needles once or twice with some friends. But that’s it. My new doctor didn’t ask me about that at all. Instead, she explained to me that all people my age, baby boomers, should be tested for hepatitis C.

“Okay, fine,” I said. “Great, let’s do the test. I thought that will be that. Except it wasn’t. A couple of days later, I get a call from my new doctor and she tells me I’ve tested positive for hepatitis C. There are antibodies, antibodies in my blood. Frankly, I went cold at that point, I don’t remember what else she said, but all I remember her saying is that I needed to go back to the lab and get another test. So, I did.”

Gary was screened for HCV by his primary care doctor as part of routine care. He was not asked about his particular risk factors for HCV. Gary was screened for HCV simply because he was born in the baby boomer years. Gary became infected many years earlier, but he was unaware of his infection for decades. What has happened in those intervening years? Just because Gary and the many others like him were unaware that they were infected with HCV does not mean that the virus is harmless.

Acute and Chronic Infection

When first confronted with the virus, the immune system responds. Antibodies generally appear within four to 12 weeks after exposure. For about 25% or 30% of people who become infected, the immune response is effective at completely clearing the virus, typically within six to 12 months after acquiring the infection. Unfortunately, however, most people go on to develop chronic HCV infection.

Chronic HCV infection is defined as active infection with HCV RNA detected in the blood for more than six months after its acquisition. In persons with chronic HCV infection, the immune system responds to the virus but cannot eliminate the infection. Chronic HCV infection generally persists with detectable HCV RNA in blood until curative treatment is delivered. Most people are not aware of the presence of this chronic infection.

Our patient Gary has asymptomatic infection and had been unaware of this infection that has been present in his liver for decades. This a common scenario, but while he was unaware of his infection, liver damage was accumulating. Chronic liver inflammation due to HCV or other causes of liver injury can lead the liver fibrosis or scarring, which can progress over time to cirrhosis. Cirrhosis is a term used to describe a liver that has extensive fibrosis and is a serious medical condition. People with cirrhosis are at high risk for life-threatening complications, including liver failure, hepatocellular carcinoma, and without liver transplant, death. Remarkably, people with cirrhosis can be asymptomatic until the liver begins to decompensate or fail. The goal of HCV treatment is to stop the chronic liver injury and prevent progression of liver disease.

This is a very important goal. HCV is a major killer. It is estimated that more than 20,000 people die from HCV each year in the US.

Screening for HCV

At least 3.2 million Americans are infected with HCV, and some estimates are as high as 5 million. ^{4 5 6 7},ivThe CDC notes that about half of those infected are unaware of their infection, even though screening based on risk factors has been recommended since 1998. People with infection can’t be linked to care, treated, or cured if their HCV is not diagnosed. However, several barriers must be overcome.

The CDC’s original screening recommendations were founded on the presence of risk factors. However, the case identification rate was dismal with risk-based screening. The barriers to risk factor-based screening relate in many ways to potential stigma on the part of the patient for admitting a history of risky behaviors. But another factor may simply be faulty memory about perhaps a one-time needle-sharing event many decades earlier.

Clinicians may also contribute to poor case identification. They may hesitate to bring up the sensitive topic of past use of injection drugs.

Given the failure of risk-based screening to identify prevalent HCV, the CDC recognized that it had to change its strategy for case identification, particularly with the emerging new, highly successful oral therapies for HCV.

In 2012, the CDC changed its recommendation to focus on the group of patients born between 1945 and 1965, the so-called baby boomers, who account for 75% of prevalent HCV infections. ⁸ Because of that high frequency of infection in that group and because that infection would have been of long duration and potentially likely to have caused complications such as progressive liver disease, the CDC determined that a single screening of all persons born between 1945 and 1965 would be a much more efficient practice.

To clarify, this new screening strategy, implemented in 2013, recommends screening of people born between 1945 and 1965 without prior ascertainment of risk. That is, there is no need for the physician to ask their patients if they had any risk factors or if they ever used in injection drugs.

However, injection drug use is not limited to baby boomers. After many years of decline in the rate of HCV infection, an increase in new infections is observed among younger people — specifically, those born after 1990. From about 2005 to 2016, according to the CDC, a steep increase was observed in the rate of newly reported acute HCV infection, and this rise, particularly in the last four years, is attributable to the rise in injection drug use and the opioid epidemic.⁹ Unlike characteristic of the past or unlike what is assumed about injection drug use, the current wave of the opioid epidemic has impacted mainly people under the age of 30, particularly in rural, suburban, and central parts of the United States.^{10 11}

In particular, the injection drug use pattern developed differently than it has in the past. Previously, people went directly to injectable heroin use. Now, young people are first introduced to pill forms of opioids and then progress steadily through snorting to injecting of oral opioids in a crushed form, and then moving onto injectable heroin. This rise in the progression toward injectable heroin has been associated with high-risk injection drug use, which is associated with transmission of HCV. Therefore, we are seeing a rise in the number of newly reported cases of HCV. Currently, in the United States, 30,000 to 40,000 new infections occur every year. ¹²

Screening is essential to diagnosing the virus and linking those people to care.

How we diagnose HCV in the PWID population is extremely important, not just for those who have infection but also because active injection drug use is associated with ongoing transmission. In this population, the most important factor is meeting populations where they are most likely to intersect with the health care system. One of the main concerns with people who inject drugs is that, because of their stigmatization and frequent incarceration, they are often not able to access “normal” health care in the ways that people who do not use drugs can. Often, there is less trust and less support. People who inject drugs often do not want to present to the health care system.

Therefore, screening should take place where people who inject drugs present, such as methadone facilities, buprenorphine programs, social service organizations, syringe and needle exchange programs, and homeless shelters.

Other high-risk populations are covered in the current CDC screening recommendations.

Baby boomers, defined as those born between 1945 and 1965, represent the largest percentage of HCV infection in the United States; therefore, one-time testing of those people is recommended by the CDC. Other populations such as those who use injection drugs, the most common risk factor, should be tested. ¹³ Also, testing is recommended for people with noninjection drug use, particularly those who snort crack cocaine, pipes or straws may contain blood, which has a risk factor for transmission.

Sexual exposure is a known risk factor, particularly in the MSM population, although the exact transmission risk in heterosexual sexual exposure is unclear. However, we do know that HCV transmission among the MSM population, particularly HIV-infected MSM, is high and responsible for a number of acute HCV outbreaks.

Other risk factors are based on the roots of transmission, which center around blood exposure, so patients who have been on chronic hemodialysis, patients who in the 1970s through the 1980s received clotting factor concentrate transfusion of blood products, immunoglobulin, or organ and tissue transplantation are potentially at risk for HCV transmission. ¹⁴ Of course, perinatal transmission or mother-to-child transmission is a risk factor, which is why almost all pregnant women should be testified for HCV during their prenatal workup. ¹⁵

Finally, tattoos and piercings, because of the blood-related transmission of HCV, are a risk factor for acquiring HCV.¹⁶ The risk of acquiring HCV from a licensed, regulated tattoo professional is quite low; however, tattoo parties, tattoos done while incarcerated, and piercings of the like increase the risk for HCV acquisition.

Approximately one-quarter of people with HIV are coinfected with HCV, and the remaining three-quarters of the population are at risk for HCV acquisition compared to non-HIV infected people. Therefore, CDC guidelines and HIV guidelines recommend regular testing of HIV-infected people for HCV.

Screening is important, because many HCV patients will have no symptoms and they may have normal liver tests. These are people who are at risk — not those who are feeling poorly.

The HCV antibody test, which indicates if the patient has been exposed to HCV, is the first step in screening. A positive antibody test does not indicate current HCV, though, as 25% to 30% of people who are exposed spontaneously clear the virus. To confirm current infection, a HCV RNA test or viral load is done. ¹⁷ Some labs automatically “reflex” to these tests when the antibody test is positive. In other cases, the patient must be brought back for tor the confirmatory test of HCV RNA.

If the patient is HCV RNA-positive, the patient has active HCV. It is recommended that those patients have a brief screening for alcohol use. If the patient is abusing alcohol, treatment for this abuse is required in addition to treatment for HCV.

HCV testing should be completed annually for anybody who is injecting drugs or for HIV-infected men who have unprotected sex with men.

Gary’s HCV Is Diagnosed

Gary - Part 2

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GARY: When the results came back, my new doctor called and confirmed, in fact, I did have hepatitis C. Man, I felt like I got hit by a truck — mentally, obviously, not physically. How can I have hepatitis C? I mean look at me, I look healthy, right? I run, I play tennis, how can I do all that and still have gotten hepatitis C?

My new doctor explained that that’s just the thing: hepatitis C can hide in your body for decades. It can stay there for decades, and although you may feel fine, look fine, and have no symptoms, all the while the virus is there and it’s destroying your liver.

Then it hit me. If I’ve had this virus since college, that’s a long time ago, it’s decades, and if I was supposed to be tested before, then why wasn’t I? I saw my doctor for checkups and regular visits for my diabetes, so I just assumed that he knew the kind of tests I was supposed to have. I looked fine, I looked healthy, I’ve known him for years, but he didn’t test me.

My new doctor also explained that hepatitis C affects the liver and I have to stop drinking, so I quit drinking immediately. Frankly, I wish I would have known earlier. I could have easily skipped the wine.

In the spirit of full disclosure, in college, I used needles once or twice with some friends. But that’s it. My new doctor didn’t ask me about that at all. Instead, she explained to me that all people my age, baby boomers, should be tested for hepatitis C.

She also said that although hepatitis C is very serious, I’m going to be fine. She told me there are now new drugs that can cure hepatitis C. I don’t need a liver biopsy. I do not need shots. Now, it’s just pills I take once a day for two or three months, and the best part, she said most of her patients never complain about side effects.

Still, I’m worried. Have I been putting my family at risk the whole time? Did I give my wife HCV? How about my college friends? Am I supposed to track them down now and tell them that I have hepatitis C? How do I tell them? Honestly, I only injected drugs two times, maximum. Will they think I’m dirty somehow, or that I became a druggie?

Education After Diagnosis

The stigma that Gary talks about is not uncommon, and it stops many people from being tested. HCV is an infectious pathogen and human beings are afraid of infectious pathogens because of concerns about transmission. Some grandparents are not allowed to kiss their grandchildren because they have chronic HCV infection. This is not how the virus is transmitted and this is not acceptable. The other reason for stigma related to HCV it that one of the ways the virus can be transmitted is through the use of injection drugs, which also carries stigma.

Education is critical to overcoming the stigma that prevents people from getting testing and getting cured. HCV is primarily spread through exposure to contaminated blood and is not efficiently spread by sex. The CDC recommends screening sexual partners of persons with chronic infection. For persons in monogamous heterosexual relationships, the use of barrier methods such as condoms is not necessary because the risk of HCV infection through sexual exposure is very low, estimated to be in the range of one infection per 190,000 sexual exposures. For persons not in monogamous relationships, the CDC recommends using barrier methods to reduce the risk of transmission of other sexually transmitted pathogens, including HIV. Importantly, the rate of HCV sexual transmission is higher among men who have sex with men, particularly those with HIV infection. In this context, condom use is recommended as well as other harm-reduction strategies.

Another consideration is the risk that a pregnant woman with HCV can transmit HCV infection to her baby. Mother-to-child transmission occurs in approximately 3% of pregnancies.¹⁸ It is important to screen pregnant women for HCV infection and to discuss the possibilities that children of women living with HCV may have been infected years, even decades, earlier and be unaware of the infection.

Harm reduction is another important topic to address. To prevent hepatitis A and B virus infection, if the person is not immune, I recommend testing for anti-HAV, total (not IgM) and anti-HBs (surface). If these are negative, the person is not immune and should be vaccinated.

The other point of emphasis is alcohol consumption. The recommendation is that persons with active HCV infection should abstain from drinking alcohol. This is based on studies that demonstrate accelerated risk of liver disease progression in persons with HCV who also drink. We do not know if there is a safe amount of alcohol a person with HCV can consume; hence the recommendation for abstinence. ¹⁹ Persons with HCV should be screened for harmful drinking. Risky alcohol has been defined as more than four drinks on any day or 14 per week for men and more than three drinks on any day or seven per week for women. ²⁰ Of course, people with alcohol use disorders should be linked to treatment programs for this condition.

However, people who drink alcohol can and should be treated for HCV. Alcohol use is not a contraindication to curative HCV treatment, and HCV cure can reduce the risk of liver disease in persons who continue to drink.

Many people with HCV infection are concerned about their diets. There is no question that obesity can lead to nonalcoholic fatty liver disease, which can be a threat to the liver even after HCV is cured. People with HCV should achieve or maintain a normal BMI. The recommendations are to eat balanced meals, whole grains, fruits and vegetables, and adequate protein. People with HCV are longer advised to restrict protein, but they should restrict sugar and avoid dietary supplements.

Gary - Part 3

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GARY: Without question, I’m grateful that my new doctor tested me for hepatitis C. If she hadn’t, who knows how bad my liver would be by the time the infection was caught. I’m focused on staying healthy. I never smoked, and I quit drinking as soon as I learned I had hep C. Like I said, my liver is challenged because of this hepatitis C diagnosis, so I don’t want to push the limits by drinking alcohol. I’m doing everything I can to get my blood sugar under control. My new doctor explained that having diabetes makes it more difficult for the medication to get the virus under control, and conversely, my hepatitis can make my diabetes worse. Something about a fatty liver, so I have to be vigilant about taking my hep C medication and doing everything I can to get my blood sugar under control.

I am relieved that my HCV was diagnosed and I was able to start treatment before this infection led to more serious problems. My treatment will take a couple of months, then I’ll have blood tests every once in a while, and then I’ll be cured, and that is a huge relief.

Before Treatment

The key for a successful treatment program is understanding the patients that you should or should not be treating. The patient who has very advanced liver disease and needs a liver transplant is not a person who should be treated in primary care, but the stable patient who otherwise has compensated liver disease should do very well.

Before initiating treatment, certain assessments should be completed.

It is important to know the genotype of the patients, as it may affect the choice of drug. We have some drugs that are pangenotypic (ie, work in all of them), but we have others that only work in certain genotypes, so it is important to know.

Fibrosis should be evaluated with blood tests like FibroTest or calculations like the APRI score or the Fib-4 score that use our standard blood test to help us understand fibrosis. Biopsies are no longer required. The degree of fibrosis may guide the length of treatment and also helps us follow the patient over time.²¹

Kidney function should also be assessed, as some of the drugs have some renal clearance. It is also important to know if the patient is coinfected with HIV. HIV would have to be under good control before beginning HCV treatment, and there may be drug-drug interactions. Patients should also be tested for hepatitis B, and if necessary, treated for hepatitis B, as it can flare in the setting of HCV treatment.

Treatment

Current HCV medications, which are administered once daily, are well tolerated. Remember that the aim is to cure these people, which is possible in more than 95% of those who use these drugs.

The drugs in the table above are first-line agents, effective in >95%, and well tolerated. Occasionally, a patient may not do well with the current treatment, but several agents can be used as second line for the patients in whom first-line treatment failed. Glecaprevir-pibrentasvir can also be used in a second-line role, as can sofosbuvir-velpatasvir-voxilaprevir.

For many patients, offering treatment in a primary care situation is very reasonable, as long as the clinician has some training in managing HCV. As data accumulate in the aftermath of direct antiviral therapy and even the aftermath of older interferon-based regimens, we have learned that cure or sustained biologic response with these regimens is associated with very favorable outcomes. The benefits in the liver include prevention of cirrhosis and development of liver failure — and even a reduction in the frequency of hepatocellular carcinoma. However, the benefits extend to reductions in outcomes outside of the liver, including but not limited to cardiovascular disease, renal disease, and even the reduction of certain cancers outside of the liver.

Given these findings and the potential benefit for all who have chronic HCV, the AASLD IDSA guidance recommend that all patients who do not have a limited life expectancy measuring 12 months or less should be offered treatment for HCV given the potential health benefits for those patients. ²²

With the new pangenotypic medications, treatment is simple and straightforward, but barriers to accessing curative HCV treatment remain. Many are not medically justified and serve as artificial barriers to HCV cure. For example, provider or clinician training remains a barrier. HCV treatment can be effectively delivered by the primary care provider, and the prescription of HCV therapy need not be limited to clinicians with specialty training in gastroenterology or infectious diseases. Another example is the restriction of treatment to persons with advanced liver disease. The HCV treatment guidelines recommend treatment for all persons with HCV infection, including those with minimal liver damage.²³ HCV cure for those with minimal liver disease can prevent future risk of progression, as well as remove the risk of HCV transmission to others. Similarly, persons who are using drugs or alcohol should be treated for HCV and linked to programs to treat opiate or alcohol use disorders.

The success of HCV treatment in primary care was demonstrated in a paper in the Annals of Internal Medicine, which showed very high response rates with care given in the primary care setting. ²⁴ Patients should be treated in their medical homes. In Baltimore, we set up a program to train clinicians who work in federally qualified health centers to treat HCV; this has been a highly successful and rewarding program.

Some patients with HCV infection do need to be referred to specialty care, such as people with advanced cirrhosis who may need a liver transplant, those with HIV coinfection, or those whose first-line HCV treatment was not effective.

Clinicians treating people with HCV should understand that adherence is critical. ²⁵ Patients should be told that a cure is 99% likely if they take the medicine every day for 84 days (for 12-week treatment) or 56 days (for eight-week treatment). Not all people are good at taking medications. Some may require more intensive treatment support, such as frequent visits or phone calls; whereas others need very little support.

After Treatment

Recommendations for follow up are based on the degree of liver disease that was present before cure. Patients with minimal liver damage do not need further liver follow-up. Patients should be educated about the risks of HCV reinfection and harm-reduction strategies for those with ongoing risk. They should also be advised that they will remain HCV antibody-positive and that this test should not be repeated. Those with more significant liver disease before cure (cirrhosis) remain at risk for liver complications, including liver cancer. I recommend screening for hepatocellular cancer with liver ultrasound every six months with or without concurrent AFP testing. For persons at risk for reinfection, I recommend HCV RNA testing every six to 12 months to identify active HCV infection. If the person did not achieve HCV cure, we evaluate the person very carefully and we now have an FDA-approved rescue therapy that is highly effective.

Conclusion

In summary, HCV is a major cause of morbidity and mortality. In the United States, we currently have two HCV epidemics. The first is in baby boomers with prevalent disease acquired in the 60s, 70s, and 80s and are now at risk for cirrhosis, cancer, and death. The second is young people who inject drugs, have new infection, and are at risk of death from overdose. Getting people who inject drugs into an HCV care program as well as drug treatment program may be a pathway to recovery and may also prevent transmission to others. Most important, clinicians and patients need to know that HCV can be cured.