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Viral Hepatitis


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Management and Treatment of Hepatitis C Viral Infection: Pretreatment Assessments

for Health Care Providers

Pretreatment Assessments

The 2002 National Institutes of Health Consensus Development Conference recommends antiviral treatment for patients with chronic HCV who are at greatest risk for progression to cirrhosis (6) . These are patients with detectable serum HCV RNA and liver histology showing more than portal fibrosis.

Because of limitations in efficacy and the potential for toxicity, each patient needs to be carefully assessed for the relative risks and benefits of beginning therapy immediately, delaying therapy, or deferring treatment indefinitely. Pretreatment assessments and contraindications to antiviral therapy are summarized in Tables 2 and 3.

Table 2. Pretreatment Assessments in Patients with Chronic HCV Infection


  • Medical history, including complications of liver disease, presence of significant extrahepatic disease, and symptoms of chronic HCV that may diminish quality of life
  • Psychiatric history, including past or ongoing psychiatric and substance use disorders
  • Screening for depression and alcohol use
  • Biochemical markers of liver injury and assessment of hepatic function, including ALT, albumin, bilirubin (particularly direct bilirubin), and prothrombin time
  • White blood cell counts with differential, hemoglobin, hematocrit, and platelets
  • Thyroid function tests
  • Serum creatinine
  • Serum glucose or glycosylated hemoglobin (HbA1c) in diabetics
  • Pregnancy test (in women of childbearing age)
  • HIV serology
  • Serum HBsAg, anti-HBc, anti-HBs, anti-HAV (total)
  • Quantitative HCV RNA measurement
  • HCV genotype
  • Previous antiviral therapies and response
  • Electrocardiogram in preexisting cardiac disease


  • Liver biopsy to stage severity of liver disease (especially in HCV genotype 1 infection)
  • Eye exam for retinopathy in patients with diabetes or hypertension
  • Serum ferritin, iron saturation and serum ANA
  • Urine toxicology screen for opiates, cocaine, and amphetamines
ALT = alanine aminotransferase; HBsAg = hepatitis B surface antigen; anti-HBc = antibodies to hepatitis B core antigens; anti-HBs = antibodies to hepatitis B surface antigens; anti-HAV = antibodies to hepatitis A virus; ANA = antinuclear antibodies.

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Table 3. Contraindications to HCV Therapy

  • Life-determining extrahepatic disease (malignancy, unstable angina, severe chronic obstructive pulmonary disease)
  • Clinically decompensated liver disease*
  • Uncontrolled autoimmune disorders
  • Pregnancy or planned pregnancy in a patient or the patient's sexual partner or unwillingness to use adequate birth control
  • Documented nonadherence to prior medical treatment or failure to complete HCV disease evaluation appointments and procedures
  • Inability to self-administer or to arrange appropriate administration of parenteral medication
  • Severe uncontrolled psychiatric disease, particularly depression with current suicidal risk
  • Ongoing injection drug use
  • Ongoing alcohol abuse
*Select patients with clinically decompensated liver disease may be candidates for treatment.
NIH Consensus 2000 Statement concluded, "Continued alcohol use during therapy adversely affects response to treatment, and alcohol abstinence is strongly recommended before and during antiviral therapy."

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Laboratory Testing

Treatment should be undertaken only in patients with preserved hepatic function (serum bilirubin <1.5 mg/dL, INR <1.5, albumin >3.4 g/dL, and no evidence of hepatic encephalopathy or ascites) along with sufficient hematological and biochemical parameters to tolerate therapy (Table 4).

Table 4. Monitoring Parameters for Interferon-Based Therapies With or Without Ribavirin
ALT = alanine aminotransferase; ANC = absolute neutrophil counts; EVR = early virologic response; Hb = hemoglobin; Hct = hematocrit; WBC = white blood cell count.
WBC with differential, Hb, Hct, platelets, serum creatinineBefore treatment, week 1 or 2, week 4, then monthly or bimonthly during therapy or more frequently as indicated.Prior to therapy, acceptable hematological and biochemical indices: Hb ≥12 g/dL for men and ≥11 g/dL for women; ANC >1.5 k/mm3; platelets >70 k/mm3; serum creatinine <1.5 mg/dL; creatinine clearance >50 mL/min. See Table 8 and Table 9 for dose modifications.
Serum ALTBefore treatment, month 1, then every 1-2 monthsMonitor when performing other tests.
Pregnancy testBefore treatment, monthly during therapy and for 6 months after completing therapyPatients and their partners should use two forms of contraception throughout therapy and for 6 months afterwards; if pregnancy occurs, therapy should be discontinued and the pregnancy monitored closely.
Thyroid-stimulating hormone (TSH)Before treatment and at least every 12 wk during therapyIf TSH becomes elevated, confirm result and check a free thyroxine (T4) level; consider thyroid replacement therapy if indicated.
Blood glucoseBefore treatment and at least every 12 wk during therapyIf blood glucose is elevated, confirm result by checking glycosylated Hb. If elevated, consider starting insulin sensitizer.
HCV RNA by quantitative and/or qualitative assayBefore treatment, 4, 12, and 24 wk during therapy, at end-of-therapy, and 6 months following the completion of therapyConsider discontinuing treatment at 12 wk if <2 log10 reduction in pretreatment HCV RNA. If EVR is not achieved and treatment is continued, discontinue treatment if HCV RNA is detectable at 24 wk if the goal is viral eradication.

An assay with a minimum lower detection limit of HCV RNA <50 IU/mL should be used at 24 wk, end-of-therapy, and 6 months following completion of therapy.
Assess for adverse effects and adherenceAt each routine visitNonadherence impairs response.
Depression screenAt baseline and each routine visitFor patients screening positive, consider antidepressant therapy and/ or referral to mental health specialist.
Substance use assessment (history of alcohol, cocaine, opiate, heroin, or amphetamine use)At baseline and each routine visitIf positive, refer to addiction specialist.

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HCV genotype should be determined, as genotype can influence treatment duration. Prior to antiviral therapy, a baseline viral load must be measured using a quantitative HCV RNA assay. For patients in whom HCV RNA levels are reported above a cut-off value (e.g., >500,000 IU/mL), the sample should be retested after dilution to provide absolute baseline values. Treatment response may be assessed using both quantitative and qualitative assays. Quantitative assays are used to measure changes in HCV RNA levels from baseline. For consistency, the same quantitative assay should be used prior to and throughout therapy. (7) Sensitive qualitative assays using technology such as transcription mediated amplification (TMA) or polymerase chain reaction (PCR) have traditionally been used to detect low levels of HCV RNA at intervals during therapy and in follow-up. (7) Newer quantitative assays have detection limits similar to those of qualitative PCR, and many laboratories have eliminated qualitative PCR assays.

Liver Biopsy

Liver biopsy is the best method for staging the degree of fibrosis (typically staged from 0-IV with the METAVIR and 0-VI with the Ishak scoring system) and grading inflammation (typically graded from 0-IV). (3, 7) In most cases, patients treated for HCV should have more than portal fibrosis (more than stage I; see "Patients with Minimal Histologic Evidence of Liver Disease"). Because treatment response in HCV genotype 2 or 3 infection is high, biopsy may not be necessary prior to antiviral therapy (7) .

Psychiatric Assessment

All patients should be evaluated for psychiatric disorders, particularly for depression and suicide risk. Uncontrolled psychiatric disorders are an absolute contraindication to interferon-based therapies (Table 3). Patients with psychiatric disorders in remission or stabilized may receive antiviral therapy. Standardized depression instruments such as the Beck's Depression Inventory (BDI) are helpful to use at baseline and during treatment. For example, a patient with a BDI score of >10 should be evaluated for major depressive disorder and started on antidepressants if criteria are met (8, 9) . Patients with a BDI score >18 or who meet diagnostic criteria for psychiatric conditions should be referred to a mental health specialist for management prior to initiating antiviral treatment (9) .

For additional information, refer to the VA/DoD Clinical Practice Guideline on the Management of Major Depressive Disorder in Adults.

Assessments for Substance Use Disorders

Patients with substance use disorders who have been stabilized can often be treated safely and effectively with HCV therapy. These patients require close monitoring, and care should be coordinated with addiction specialists. All patients should be evaluated for current substance use. The presence of current heavy alcohol use (>14 drinks/wk or >4 drinks/day for men, >7 drinks/wk or >3 drinks/day for women), binge alcohol use (>4 drinks per occasion at least once a month), or active current injection drug use requires referral to an addiction specialist prior to treatment initiation (10) . Urine toxicology screens for opiates, cocaine, or amphetamines may be used to supplement patient self-report.


The importance of treatment adherence should be discussed with patients considering antiviral therapy. Evidence of prior nonadherence to medical, psychiatric, or addiction therapies may predict nonadherence to HCV therapies. When necessary, treatment initiation should be deferred and attempts made to improve adherence.

Autoimmune Disorders

Treatment with interferon may exacerbate underlying autoimmune disorders. Patients with stable autoimmune thyroid disease or diabetes can usually be safely treated with HCV therapy. Patients with severe autoimmune diseases (e.g., psoriasis, Crohn's disease, or rheumatoid arthritis) should not receive HCV therapy unless the autoimmune disorder is controlled and underlying HCV disease is advanced. Decisions to treat patients with these disorders should be undertaken only in close collaboration with a medical specialist in these diseases, and patients should be monitored closely for any worsening of symptoms.

Hepatitis A and B and Other Liver Diseases

Patients should be tested for hepatitis B surface antigen, antibodies to hepatitis B surface and core antigens, and antibodies to the hepatitis A virus to evaluate for active hepatitis B infection and the need for hepatitis A and/or B immunization. See current recommendations and vaccine dosing schedules.

If serum ferritin or transferrin saturation is significantly elevated or there is clinical concern for hemochromatosis, consider evaluating the liver tissue for quantitative iron and/or testing the peripheral blood for hemochromatosis gene mutations. For additional information, refer to the AASLD Practice Guidelines on the Diagnosis and Management of Hemochromatosis.


A pregnancy test should be obtained from women of childbearing age prior to the initiation of HCV treatment. If a woman is pregnant or attempting to conceive, HCV treatment should not be started because ribavirin is teratogenic. Pregnancy must also be avoided in the partner of an HCV-infected male patient receiving treatment. Contraception for both partners is required and should include at least one barrier method of contraception during and for 6 months after HCV treatment (11, 12) . In the event that pregnancy occurs either in the patient or in the partner receiving ribavirin, ribavirin should be immediately discontinued and the pregnancy should be reported to the Ribavirin Pregnancy Registry at 1-800-593-2214 or www.ribavirinpregnancyregistry.comLink will take you outside the VA website. VA is not responsible for the content of the linked site..

Ocular Evaluation

In patients without risk factors for retinal disease, a pretreatment ocular examination is preferable and serves as a baseline evaluation of existing retinal abnormalities. The ocular examination can be repeated while on therapy in the event that retinopathy occurs or worsens while on therapy.

In patients with risk factors for retinal disease (e.g., hypertension, diabetes), an ophthalmic examination should be performed prior to and while on treatment as indicated to identify any worsening disease while on interferon.

Extrahepatic Manifestations of Hepatitis C

HCV infection is associated with a variety of extrahepatic manifestations including leukocytoclastic vasculitis, membranoproliferative glomerulonephritis, and porphyria cutanea tarda. In patients being considered for treatment of these extrahepatic manifestations, baseline serum cryoglobulins, urinalysis, 24-h creatinine clearance, and 24-h urinary protein should be measured.

Evaluation for Human Immunodeficiency Virus Coinfection

Human immunodeficiency virus (HIV) coinfection increases the risk of HCV-related liver damage, may influence the duration of HCV therapy, and appears to lower SVR. All patients with chronic HCV infection considering HCV therapy should be offered a voluntary HIV test if HIV status has not been previously established.


2. Patients should undergo pretreatment assessments as summarized in Table 2 (III).

3. Patients with more than portal fibrosis, including those with compensated cirrhosis, who lack contraindications, should be offered antiviral treatment (III).

4. Patients with contraindications summarized in Table 3 should not begin HCV antiviral therapy (III).

5. Patients should be counseled on their likelihood of achieving SVR prior to initiating therapy (III).