Clinical Guidelines for the Medical Management of Hepatitis C
F. Medical Management
A multidisciplinary team approach is recommended for HCV patients with active co-occurring alcohol, substance abuse disorders and/or psychiatric illnesses who are not ready for antiviral treatment.
Patients with Unstable Drug Use
Perform a comprehensive substance abuse assessment, including type(s) of substance(s), frequency, quantity, method of use, environment, and change in use over time. Identify whether injection drug users share syringes, cookers, cotton, or water; and where the equipment is obtained.
Assess patient's understanding of his/her substance abuse disorder, readiness for change, and willingness to engage in substance abuse treatment.
Educate patient on the requirements for initiating antiviral treatment. In particular, clarify that drug abstinence is not a requirement for antiviral treatment. Conversely, alcohol abstinence is recommended for patients with alcohol abuse and/or dependence as heavy alcohol use adversely affects treatment outcomes.
Encourage patient to seek substance abuse treatment or harm reduction program (i.e. syringe exchange program). Make appropriate referrals for patients interested in pursuing treatment, counseling, and/or supportive services. Collaborate with addiction specialist to reassess for antiviral treatment eligibility.
Assess stability of substance use and eligibility for antiviral treatment at periodic intervals.
Patients with Unstable Alcohol Use
Patients with HCV infection who use alcohol need to be educated regarding the effects of alcohol on the course of HCV infection.
Patients with alcohol abuse or dependence should be referred for chemical dependency treatment.
Patients with alcohol abuse or dependence should be encouraged to enroll in a rehabilitation program and establish abstinence prior to treatment.
Patients who consume light or moderate amounts of alcohol should be advised to abstain from alcohol during antiviral therapy, but a pretreatment period of abstinence is not necessary.
Patients with Unstable Psychiatric Illness
Refer patients to a mental health provider for treatment and stabilization. Collaborate with mental health provider to reassess for antiviral treatment eligibility.
Assessment for antiviral treatment readiness should include an assessment of the patient's supportive networks, both formal and informal. Family meetings may help clarify expectations for the initiation of antiviral treatment, and promote family support to the patient.
Patients with unstable psychiatric illness who refuse to engage in psychiatric treatment are not candidates for antiviral treatment.
Assess stability of psychiatric illness and eligibility for antiviral treatment at periodic intervals.
Patients not currently undergoing antiviral therapy should be reassessed periodically for eligibility and interest. Providers and patients should actively address substance abuse, psychiatric, and medical co-morbidities in order to prepare for antiviral treatment.
All patients may benefit from hepatitis C support groups and peer education, whether or not they are undergoing antiviral treatment.
The 2002 National Institutes of Health (NIH) Consensus Statement and the 2004 AASLD Practice Guidelines recognized that patients with co-occurring alcohol, substance use, and psychiatric illness may be effectively treated for HCV infection.22,23 Indeed, a growing number of studies provide preliminary support for the use of interferon-based therapy for patients with HCV infection who have active substance use disorders and psychiatric illnesses. In order for this to be successful, a multidisciplinary approach should be used.74 Multidisciplinary models may include providers skilled in HCV, HIV, psychiatric and addiction medicine, as well nurses, social workers, substance abuse counselors, and case managers. A multidisciplinary approach promotes stabilization of psychiatric illness and monitoring of addiction prior to and during antiviral treatment. This approach also allows for a better overall coordination of patient care through the sharing of pertinent medical information needed to ensure patients and providers are fully informed about the treatment plan, any drug interactions, and that the patient receives consistent counseling messages.
Although coordination of care among primary care, psychiatric, and addiction service providers may best serve HCV-infected patients with co-morbidities, many medical care systems are not currently equipped to provide this comprehensive multidisciplinary service. A multidisciplinary approach is also possible through off-site linkages. Additionally, healthcare providers should seek additional training in order to develop expertise in addiction, psychiatry and HCV-related care.
1. Management of Patients with Unstable Drug Use
Although the above guidelines endorse the treatment of HCV infected patients with active drug use and patients with psychiatric illnesses on an individualized basis, there are some patients with unstable substance use disorders and/or psychiatric illness in whom immediate antiviral therapy is not warranted. Decisions regarding stability of addiction and psychiatric illness should be made in collaboration with an addiction specialist and psychiatrist whenever feasible. For these unstable patients, the focus should be on stabilization of addiction and/or psychiatric illness.
It is important to note that decisions made about eligibility of active drug users for antiviral treatment should be individualized and not be based primarily on type of drug, route of use, quantity, and/or frequency, but rather on safety of drug use, stability of psychiatric illnesses, and ability to adhere to appointments and treatment. Patterns of drug use that may indicate that antiviral treatment should be delayed include:
- Drug seeking, drug use, and recovery from drug use that sufficiently disrupts the daily routine so that it prevents regular adherence with appointments and antiviral medications.
- Drug use which impairs patient's ability to engage appropriately with the physician.
It has been shown that linking all of a substance user's needs is beneficial for both the active user and the various providers involved in his/her care.75 The medical management of HCV infection in complex patients may necessitate integration of interferon-based treatment into healthcare settings that care for substance using and psychiatrically ill patients. Such settings may include methadone clinics, prisons, mental health clinics, psychiatric hospitals, and enhanced walk-in clinics.58 Successful on-site primary medical services have been developed in some drug treatment programs in response to the HIV epidemic, and there is preliminary evidence that on-site HCV care may be feasible in drug treatment programs as well.76,77 Providers should have a basic understanding of substance use treatments that are available and the activities that can be expected in each setting. This information can help providers better understand what patients may experience and better assist patients in choosing treatment settings that fit with their needs.78 In addition, providers should explore whether or not the patient believes that the drug use is a problem, and if so what his/her goals are. Some may have a goal of abstinence whereas others may wish for decreased drug use, or safer drug use.
Options for treatment include pharmacotherapy for opioid addiction with opioid replacement therapies such as methadone or buprenorphine. Detoxifications (alcohol, heroin, or benzodiazepine) and short-term inpatient rehabilitation programs may also be useful when coupled with a comprehensive aftercare plan. Long-term residential treatment may be appropriate for persons who are interested but unable to achieve abstinence in the community setting. Patients should be informed of twelve-step programs such as Alcoholics Anonymous (AA) and Narcotics Anonymous (NA), but there is insufficient evidence to insist that patients take part in them if they are not self-motivated to do so.
Harm reduction is central to drug treatment, and is an approach that puts the well being of the user and society above the goal of abstinence. Harm reduction recognizes that while abstinence is one means of reducing drug-related harm, a drug user's major concern may not be cessation of drug use. Some keys to harm reduction in opioid addiction are syringe access, overdose prevention, and vaccination. Education is the backbone of harm reduction. When drug users are educated about the risks involved in drug use and are offered tools to reduce these risks, many alter their behavior. The provider should discuss how the patient obtains the injection equipment (syringe exchange program, expanded access pharmacy program, etc.), and the patient should agree to discuss ongoing drug use and high-risk behaviors.78 Drug users motivated to receive antiviral treatment are encouraged to abstain from the use of drugs and enroll in a substance abuse treatment program or harm reduction program. Individuals are not required to achieve abstinence prior to initiation of antiviral therapy, but ideally receive antiviral treatment and substance abuse treatment services concurrently.79 The clinician should make clear what the expectations are for initiating antiviral treatment. A clinician should reassess for stability of drug use and eligibility for antiviral treatment at periodic intervals.
2. Management of Patients with Alcohol Use
Numerous studies indicate that patients infected with HCV and heavy alcohol intake have increased progression of hepatic fibrosis and increased risks of cirrhosis, hepatocellular carcinoma, and death.80,91 While some studies suggest that light to moderate consumption may contribute to progression, this has not been clearly shown.82 All patients with HCV infection who use alcohol need to be educated regarding the effects of alcohol on the course of HCV infection. Abstinence in heavy drinkers infected with HCV is associated with improvement in chemical markers as well as a decrease in HCV RNA levels.83,84 Patients with alcohol abuse or dependence should be referred for chemical dependency treatment. There are limited data on patients with ongoing alcohol use during antiviral treatment. One study found a inverse correlation between rates of response to interferon treatment and levels of alcohol intake during therapy.85 Furthermore, there are reports of acute alcoholic hepatitis in several individuals consuming alcohol during interferon treatment.86 Individuals with alcohol abuse or dependence should be encouraged to enroll in a rehabilitation program and establish abstinence prior to treatment. Patients who consume light or moderate amounts of alcohol should be advised to abstain from alcohol during antiviral therapy, but a pretreatment period of abstinence is not necessary.79
3. Management of Patients with Unstable Psychiatric Illness
Patients who are not currently eligible for antiviral treatment due to unstable psychiatric co-morbidities should be referred to a mental health provider who has an awareness of HCV treatment risks and who can collaborate during the period of antiviral treatment. Mental health providers are uniquely positioned to assist patients to undergo HCV evaluations and procedures, adhere to difficult treatment regimens, and monitor and treat neuro-psychiatric adverse events.87 Ideally, patients should have 3 to 6 months of symptom reduction to a socially stable level for anxiety, depression, and psychotic symptoms.88 However, the decision regarding when to initiate treatment must be made on an individualized basis without arbitrary time limits.
4. Role of Support Groups and Peer Educators
The documented successes of support groups and peers educators in HIV-infected individuals may inform the development of similar programs for HCV-infected individuals. Participation in a HIV support group has been shown to have a positive impact on depression, anxiety, high-risk behavior, plasma viral load, CD4 cell count, and survival in HIV-infected individuals.88-90 Similarly, peer education and role-modeling of positive behaviors in HIV-infected individuals have been proven to improve knowledge, attitudes, and behaviors; decrease psychological distress; increase quality of life; increase service utilization in target populations; and promote sustained behavior change.91-95
HCV support groups can focus on the basic steps of treatment, allow group members to share their experiences with evaluation and treatment, and engage in advocacy projects which promote sense of community.77,96 The role of peer educators in promoting HCV evaluation and treatment should be further investigated.
In conclusion, the possibility of a cure from CHC may provide motivation for some patients to focus on the treatment of their other chronic diseases. Providers and patients must actively address substance abuse, psychiatric, and medical co-morbidities in order to prepare for antiviral treatment. These efforts may include becoming engaged in substance abuse care, adherence with psychiatric appointments and psychotropic medication, and renewed commitment to the long-term treatment of conditions such as diabetes, hypertension, and HIV disease. A treatment contract may be useful in order to set goals and expectations prior to antiviral treatment initiation.
5. Frequency of Viral Load Testing
Serial HCV viral loads should not be routinely performed for patients who are not receiving antiviral treatment.
If there has been a significant lapse in time between the initial quantification of viral load and the initiation of antiviral treatment, the clinician may reassess the viral load again to establish an accurate baseline. If there is a history of excessive alcohol intake, the clinician may reassess the viral load prior to initiation antiviral treatment, as alcohol is known to increase viral load.97,98
6. Frequency of Liver Biopsy
Liver biopsies every 4-5 years may be considered for those patients in whom treatment is deferred because of mild fibrosis (Metavir score <2 or Ishak score <3) if progression of disease affects the decision to treat.22
Although there is no strong evidence to support more frequent biopsies, the clinician may choose to repeat liver biopsy sooner in patients with HIV/HCV co-infection. In patients with HIV/HCV co-infection, liver disease advances more rapidly, and there is a two-fold higher risk of cirrhosis.99
7. Management of Patients with Decompensated Liver Disease
An HCV-infected patient with decompensated liver disease should always be managed by, or in conjunction with, an expert in liver diseases.
Inflammation, necrosis and fibrosis due to chronic, active infection with HCV can lead to cirrhosis and decompensated liver disease. Decompensated liver disease in patients with cirrhosis is defined as the development of at least one of the following conditions: variceal hemorrhage, encephalopathy, reduced hepatic synthetic function (low serum albumin, elevated INR), or ascites.22 Up to 20% of HCV-infected patients will develop cirrhosis after 20 to 30 years, of whom one-third will progress to decompensated liver disease and 1% to 2% will develop hepatocellular carcinoma.22,23,100 Risk factors for progression to cirrhosis include: older age, obesity (and associated hepatic steatosis), male gender, HIV co-infection, and alcohol consumption (>50 grams/day).101-103 End stage liver disease due to CHC infection is the most common reason for liver transplantation in the U.S.
8. Timing of Referral for Liver Transplant in Patients with HCV-associated Cirrhosis
All attempts should be made to treat HCV infection pre-transplant even in patients with decompensated liver disease.
Any patient with decompensated liver should be evaluated by a liver transplant specialist.
Indications for referral for liver transplant are based on the development of conditions that are known to shorten survival (anticipated survival of less than one year), thereby justifying the risk of the procedure. Referral should be made as soon as the patient has developed decompensated liver disease due to the long projected waiting time for transplantation. Patients should be referred to a liver transplant center for the following reasons:104
- Development of ascites (especially ascites that is refractory to medical therapy).
- Spontaneous bacterial peritonitis.
- Hepatorenal syndrome defined as renal failure due to vasoconstriction of renal vasculature and renal hypoperfusion (Acute [Type 1], and stable/slowly progressive [Type 2]).105
- Hepatic encephalopathy.
Contraindications for liver transplant include uncured extrahepatic malignancy and other severe uncontrolled medical illness (e.g., end-stage cardiomyopathy or advanced chronic obstructive pulmonary disease). Although a period of abstinence from alcohol and active substance abuse is required by many centers, methadone patients have been found to be good candidates for transplant.106 HIV infection before the availability of highly active antiretroviral therapy (HAART) was often considered a contraindication for liver transplant, improved survival with HAART therapy has enabled consideration of patients.107,108
Once referred for liver transplant, patients are prioritized for surgery based on policies determined by the United Network for Organ Sharing (UNOS) according to their Model for End-Stage Liver Disease (MELD) score. Patients with fulminant liver failure with very short life expectancy receive the highest priority, but due to the constriction of time and the scarcity of donor organs many of these patients do not find a suitable donor. Priority for transplantation is based on the MELD score for prediction of short-term (3-6 month) mortality, defined as:109
- 3.8 log (bilirubin [mg/dl]) + 11.2 log10(INR) + 9.6 log10(creatinine [mg/dl]) + 6.4(etiology);
- Etiology = 0 if disease is due to cholestasis or alcohol;
- 1 for all other causes (including HCV).
Clinicians who manage patients with chronic liver disease may use the relatively easy-to-calculate Child-Turcotte-Pugh score to prognosticate and assess clinical/biochemical severity in conjunction with other relevant clinical information (see Table 3). Note, that the Child-Turcotte-Pugh score is not used as an assessment tool for liver transplantation. Virtually all patients with HCV who undergo liver transplantation will develop recurrence of HCV infection, often with a more rapid progression of disease in the transplanted organ.108,110 Therefore, all attempts should be made to treat HCV infection pre-transplant even in patients with decompensated liver disease.22 The risks and benefits of HCV treatment must be weighed carefully for the patient with decompensated liver disease due to the potential for lower response rates and higher toxicity including: leukopenia, anemia, thrombocytopenia, increased infection risk and possible acceleration of liver decompensation. Treatment of patients with end-stage liver disease from HCV infection should entail close monitoring for treatment related toxicity and judicious use of colony-stimulating growth factors and dosage modifications.22
|Encephalopathy*||Stage 0||Stage 1-2||Stage 3-4|
|Serum Bilirubin (mg/dL)||<2||2-3||>3|
|Serum Albumin (g/dL)||>3.5||2.8-3.5||<2.8|
|Score: Class A = 0-6 points; Class B = 7-9 points; Class C = 10 or more points
*Mental status in hepatic encephalopathy can be graded by use of the West Haven criteria
9. Liver Health
Providers should discuss the role played by alcohol in the progression of hepatitis C.
Providers should warn patients to be aware that over-the-counter medications can be hepatotoxic and that they should discuss medication use with a medical provider.
Patients should be made aware that no herbal products have yet been shown to delay progression of hepatitis C and that some herbs are hepatotoxic.
Heavy alcohol use (greater than or equal to 50 grams per day) is strongly associated with progression of hepatitis C. The effects of light to moderate use are not as well studied but have not been clearly associated with increased fibrosis.82 The National Institute on Alcohol Abuse and Alcoholism states that safe levels of alcohol use for healthy people are up to 2 drinks/ day for men and 1 drink per day for women and for persons over 65. One drink consists of 12 ounces of beer, 5 oz of wine or 1.5 ounces of liquor and contains 14 grams of alcohol. While heavy alcohol use is contraindicated in HCV patients, it is not clear that all patients must eliminate moderate use of alcohol.
Non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, have been have been associated with hepatitis C flares. There are no reports of adverse effects of acetaminophen when taken as directed and without alcohol.111 Many patients take herbal preparations for a variety of illnesses, including hepatitis C. The National Center for Complementary and Alternative Medicine has funded several clinical trials studying the effects of herbal preparations on hepatitis C progression including one of a widely used herb, silimarin, or milk thistle.112
Injection Drug Users
Injection drug users should be advised to stop injecting, and seek treatment if indicated.
If unable to stop, IDUs should be advised to obtain sterile syringes from pharmacies or syringe exchanges and to avoid sharing any injection equipment.
Risk Reduction and Partner Notification
Non-monogamous patients should use condoms and other barrier methods with sexual partners.
HCV-positive patients should be advised to avoid sharing items that may be contaminated with blood such as toothbrushes and razors; blood spills should be promptly cleaned.
Providers should be available to assist patients when they inform partners and family members about their HCV status to provide information on transmission, treatment and prognosis.
Numerous long-term studies find minimal risk of transmission among monogamous heterosexual couples; therefore, the CDC does not recommend condoms under this circumstances.113 However, some couples may choose to use them. There are no data regarding monogamous same sex partners but HCV is not substantially higher among homosexual men. There have been case reports of nonsexual household transmission, however such transmission is rare and routine testing of household members is not recommended.19 While HCV infection is a reportable disease, there are no regulations or guidelines regarding partner notification of people with HCV infection. However, patients with HCV infection are encouraged to notify their at-risk partners. Two useful public health strategies for notification are: (1) the patient may chose to notify sex and needle-sharing partners, or (2) the physician may notify partners with the patient's permission.