Intravenous drug use is the most common cause of hepatitis C infection, which becomes chronic in the majority of infected people. Alcohol dependence, intranasal cocaine use and mental illness are also risk factors for hepatitis C. Consequently, chronic hepatitis C (CHC), substance use disorders and mental illness frequently coexist in people seeking treatment for substance use disorders or for CHC. Treatment of CHC based on interferon alpha (IFN), alone or in combination with ribavirin, is associated with both increased depression and with exacerbation of other pre-existing mental disorders. Treatment has become increasingly effective and is changing rapidly. In this symposium, information on the most current screening methods, treatment options and outcomes for CHC and for coexisting mental and addictive disorders was presented. A model of integrated treatment currently undergoing evaluation was described and included both practical advice and descriptions of newer techniques being developed.

Dr. Smith discussed the natural history, diagnosis and treatment of hepatitis C, and Dr. Willenbring addressed integrating psychiatric and addiction treatment and treatment for chronic hepatitis C.

Symposium Chair: Mark L. Willenbring, MD, Minneapolis VA Hepatitis C Resource Center, University of Minnesota, Minneapolis, MN

Hepatitis C virus was first described in 1989. It is an RNA virus, and there is a huge reservoir of infection worldwide. It is the major cause of post-transfusion hepatitis in people receiving blood transfusions prior to 1992, which is when sensitive testing for hepatitis C became available.

It is the major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma worldwide including the United States. It has now become the most common reason for liver transplantation in the United States and in most other western countries. The prevalence has been estimated to be almost 2% of the population. It is said to account for between 10,000 and 20,000 deaths per year. Without therapy, that number is expected to triple.

A huge increase in the number of patients diagnosed with this condition has been estimated to occur between 1990 and 2015. The virus belongs to the flaviviridae family and is a single-stranded RNA virus. For acute infection, the incubation period is about 7 weeks. We rarely see acute infection; it’s usually subclinical.

One of the important effects of hepatitis C, as with all RNA viruses, is that there is very little proofreading ability of the virus and so there is frequent mutation. This results in a number of variants of the virus. There is said to be approximately 28,000 new infections occurring in the United States per year, but there is a huge reservoir that is already there — 3.9 million people have been infected, and approximately 2.7 million people are probably still chronically infected. An important point to note is that one quarter to almost one third of the patients who are infected are asymptomatic.

There is a higher prevalence in Hispanics and African Americans compared with Caucasians. Hepatitis C now accounts for more than half the number of cases of chronic liver disease seen in this country. The most common genotype we see, accounting for about 75% of the population, is genotype 1. Genotypes 2 and 3 account for about 20% together, and then there is a small proportion of mixed genotypes. Genotypes 4, 5 and 6 are much more prevalent in other parts of the world.

Who gets hepatitis C? A lot of the patients who get hepatitis C will have problems that bring them into your domain. The most common risk factor for hepatitis C is injecting drug use. This is a very efficient way to transmit hepatitis C. It has been said that more than 85% of people who use injecting drugs on more than one occasion will have hepatitis C. Considering the number of people who have used injecting drugs on more than one occasion, that is a very large problem.

Also at risk are people who have received transfusions before 1992 or an organ transplant and clotting factors before 1987, which was when recombinant DNA technology was introduced into the manufacture of these products.

People who practice unsafe sex have a higher prevalence of hepatitis C. The only real explanation is that sexual spread of hepatitis C can occur but is extremely uncommon.

Hemodialysis is becoming less of a problem in this country because awareness and appropriate precautions are being taken. Immigration from high-risk areas is also a problem. Less common risk factors include more recent transfusions, tattoos, body piercing, intranasal cocaine use, perinatal transmission and occupational exposure. The two biggest risk factors are injecting drug use and transfusions prior to 1992.

Hepatitis C has a long latent period. The disease progresses slowly over 30 years or more. The first two decades of infection are benign, quite often without any symptoms at all. If there are any symptoms, there is moderate or no morbidity or mortality at all. During the third and fourth decades and beyond, some people may experience problems, but this doesn’t happen in everyone. About 20% of patients will progress to fibrosis and cirrhosis and other associations of liver failure. Some will progress to end-stage liver disease, and some patients who do have cirrhosis will progress to hepatocellular carcinoma. In fact, hepatocellular carcinoma is increasing rapidly in this country. Over the past 5 to 10 years, the number of cases reported has gone up dramatically.

Some of the factors that predict or seem to promote hepatitis C progression are heavy alcohol intake (certainly drinking more than three to five drinks per day has been associated with more rapid or more extensive progression of hepatitis C). Males progress more quickly than females, and those who acquire their infection at an older age are more likely to progress, particularly if contracted by a blood transfusion. Most people who acquire their infection over the age of 40 are less likely to have been drug users.

Other factors influencing rate of progression include coinfection with other viruses, in particular HIV and hepatitis B. Not surprisingly, given the mechanism of spread of hepatitis C, HIV and HBV, coinfection is not an uncommon event. The genotype, the viral load, the biochemistry and the mode of transmission have really not clearly been demonstrated to be associated with severity of infection.

It can be difficult to diagnose hepatitis C because patients may be asymptomatic. Two tests can be used. First, there is the antibody test, which is used for screening. The ELISA test indicates previous exposure to hepatitis C. By itself, it does not necessarily indicate ongoing infection. The majority of people who have a hepatitis C antibody positive test will be viremic. That’s when the test for viremia is used. This test actually measures HCV RNA. There is no relationship between the viral level and the severity of liver pathology. A high virus load doesn’t necessarily mean that this person is going to have bad liver disease, nor will he or she necessarily develop severe liver disease.

The HCV RNA test is both qualitative and quantitative. The quantitative test is important in guidance for therapy. One of the most important diagnostic tests is a liver biopsy. A liver biopsy will confirm the clinical diagnosis and will assess the severity of ongoing inflammation and fibrosis. Both of those are predictors of what is going to happen in the future. Those with minimal ongoing inflammation with a low grade of inflammation and those with a low stage of fibrosis are less likely to progress to severe liver disease in the immediate future. They might need to have another biopsy some years later to assess progression. We really have no way of assessing those other than by biopsy.

The primary goal of treatment is to get rid of hepatitis C. If that can’t be done, then the goal is to have the disease progress less rapidly. A number of treatment options are available. There is interferon alpha monotherapy. A number of varieties are available. However, for practical purposes, interferon monotherapy is not used anymore. Today, combination therapy with interferon and ribavirin is used. Interferon is usually administered by self-injection. The length of treatment is either 24 or 48 weeks. Ribavirin is taken by pill. It is usually taken in divided doses, and there is a lot of debate about the exact dose.

Who is likely to eradicate the virus? We can make some guesses. The most important predictor is the genotype. Non-1 genotypes are most likely to respond to treatment. Low viral load, younger people, females and those with less severe liver disease are also more likely to respond to treatment.

Interferon alone is not perfect. It is given three times a week, and there are side effects. When interferon is given, the blood level goes up, then it comes down. Obviously, those window phases allow the virus to replicate. The next step was pegylation. Pegylation is the addition of polyethylene glycol to interferons. It increases the extent and duration of activity. It may decrease the antigenicity. It also reduces the activity of the interferon, so the dose will need to be increased. There are now two pegylated interferons approved and on the market. Pegylated interferon with ribavirin can clear the virus in more than half of the cases. Genotypes 2 and 3 are getting up to 75% or 80% clearance. However, there is a cost to pay, and there are lots of side effects. Despite that, the rate of withdrawal from treatment is rather low. There is about a 10% withdrawal rate, and it is usually due to adverse events. Fewer than 2% to 3% of people will have to withdraw from treatment because their white cells or their platelets or their hemoglobin gets to levels that can’t be dealt with. Most withdrawals occur from adverse events, and most of those are in the neuropsychiatric area.

Psychiatric disorders are associated with hepatitis C. First, pre-existing psychiatric disorders occur commonly. This has become a frequent reason to deny therapy. It is often associated with an intolerance to therapy, and this is often due to exacerbation of psychiatric symptoms. The psychiatrist’s role is to help in evaluating and treating people before interferon therapy. Psychiatrists can also help when psychiatric symptoms develop in someone who is on interferon therapy. Most people with hepatitis C infection who are being considered for interferon treatment have well-compensated liver disease. These people can tolerate whatever medications or treatment modalities are thought appropriate.

The good news is that rapid advances in therapies have substantially increased response rates. More than half now respond with a sustained virological response. The bad news is that hardly anyone is getting treated. The role of the addiction psychiatrist is absolutely critical in increasing the proportion of patients who are able to receive this treatment.

The rates of exclusion for psychiatric disorders is in the range of 20%. The rates of exclusion for addictive disorders is in the range of 20%. Overall, about 70% to 80% of patients are commonly excluded. Having a mental or addictive disorder is the most common reason for exclusion. Only 8% to 10% of the total population of people with hepatitis C get a sustained virological response. It’s even lower when those who never come to the first appointment are included. No-show rates can be anywhere from 20% to 50%. The vast majority of patients are not being reached with this treatment.

Neuropsychiatric symptoms occur in people who have hepatitis C at a higher rate than the general population even before they get interferon. People frequently complain of malaise and fatigue. In addition, cognitive changes can occur in the context of hepatitis C: impaired concentration, decreased alertness, verbal memory problems and mental slowing. People can be quite impaired with this illness.

Mental and addictive disorders are very common in chronic hepatitis C. Interferon alpha treatment is associated with a variety of neuropsychiatric symptoms such as cognitive changes, affective symptoms and behavioral problems, fatigue, irritability, insomnia, depression and anxiety. Mania and psychosis have both been reported, although they are not common. About 30% of people who are not depressed at baseline go on to develop significant depression during the treatment with interferon. This can become severe, and suicides have been reported.

Psychiatrists can offer the kind of support and comanagement that’s required for these patients throughout treatment, and thus make the hepatologist a lot more secure and therefore willing to go ahead and treat. The depression typically occurs in the early months of treatment — usually between 1 and 3 months. It has been reported as late as up to 24 weeks, but most of it starts in the first 3 months of treatment.

In terms of screening, four instruments have been shown to work well in this population: the Beck Depression Inventory, the CES-D, the Montgomery-Asperg Depression Rating Scale and the Zung self-rating scale. Any of these can work. It is important to select one and become familiar with its use in this particular population. Typically, a BDI score in the upper range of normal, which is between 6 and 10, is a predictor for an increased risk of needing treatment for depression during therapy. A family history of depression and a history of two or more psychiatric diagnoses have been identified as predicting depression. Also, the absence of a substance use disorder history was a predictor for the development of depression during interferon treatment.

There is inconsistent evidence regarding light to moderate drinking and its effect on hepatitis C. Abstinence in someone who has hepatitis C is the most prudent advice. Clearly, heavy drinking is associated with a substantially increased risk of fibrosis and cirrhosis, and the risk for hepatocellular carcinoma is particularly high. Most practice guidelines today recommend that you not treat anybody who is not abstinent from alcohol. However, more and more data are emerging that even people who are drinking at times heavily throughout treatment can and do respond with a sustained virological response.

Intravenous drug use is the most common cause of new infection. Hepatitis C infection typically occurs in the first 5 years of IV drug use. It is associated with having a mentor. All parts of the equipment are associated, not just syringes. Infection is also associated with frontloading, which is drawing blood into the syringe prior to injection. Unfortunately, 90% or more of IV drug users are positive for HCV after 5 years, so people need to be caught early. Routine screening for HCV is necessary in substance use disorders treatment programs. Substance use disorder is a risk in and of itself.

Screening for heavy drinking has to be routine. It has to include quantity and frequency. It is particularly important to pick up on heavy nondependent drinkers in the context of hepatitis C. The Audit or the Audit-C is recommended. The Audit-C is the first three items of the Audit, which functions almost as well as the entire 10-item Audit. These are items that have quantity/frequency indicators, so that both nondependent heavy drinking and dependent drinking can be picked up.

The cutoff for abuse and dependence likelihood is 6 or more. It has good reliability and validity, but a cutoff of 4 is recommended in the context of hepatitis C infection for the Audit-C in order to pick up even the moderate drinkers. In terms of screening for drug use disorders, it is very important to ask about specific drugs and use patterns. Ask what drugs they have used in their lifetime and what drugs they have used more than five times in their lifetime.

Urine toxicology screening should be routine. It is very important to check for the synthetic opioids, which are not tested on most typical urine drug screens. The number one element of management is a close relationship between hepatitis C staff and mental health and addictive disorder treatment staff. It requires active comanagement. It is important to have protocols in place in both places for screening, referral and management. Routine prophylaxis is recommended for people with BDIs above 10, even though they are not clinically depressed at baseline. People above 15 are getting symptomatic and should receive treatment. People between 6 and 10 should be told that they are at higher risk for developing depression, and they should be told about the risks and benefits of prophylactic treatment versus waiting and doing symptom-triggered treatment.

When treating heavy drinkers, it is important to determine whether it is hazardous use or whether they 

actually meet criteria for an alcohol use disorder. People with dependence need to go to a rehab program. It is unclear at this point what to do with those refusing referral. People who are dependent on opioids should be referred to an opiate agonist therapy program. For other drugs, refer to substance use disorder treatment. Again, it is unclear what to do with refusers.