Apparently Healthy Man With History of Injection Drug Use: The Initial Approach

A 45-year-old man comes to see you for a routine physical. He has no complaints and no significant medical history. However, while questioning him you discover that he used intravenous heroin until about 10 years ago-and sometimes shared needles. He also drank 6 or more beers a day for about 20 years, a practice he stopped at the same time that he quit using illicit drugs. He has multiple tattoos, which were done at commercial parlors. He is married but has no children. His wife has no history of hepatitis. Physical examination is unremarkable. THE RISK OF HEPATITIS C
This patient's history prompts consideration of infection with hepatitis C virus (HCV). HCV is a leading cause of chronic liver disease in the United States. Populationbased studies indicate that 50% of chronic liver disease in this country is HCV-related. Between 8000 and 10,000 deaths each year are attributed to HCV liver disease.¹ An estimated 2.7 million Americans are chronically infected with HCV.² This patient's injection drug use is a known risk factor for the infection and is one of the criteria established by the Centers for Disease Control and Prevention for HCV screening (Table 1). His history contains only this one definite risk factor; however, tattooing and body piercing may increase risk of HCV infection, although this has not been definitely established. Other behaviors in the latter category-and for which routine screening for HCV infection is of uncertain value-include:

• Noninjection drug use.
• history of multiple sex partners.
• A history of sexually transmitted diseases.
• Long-term sexual relationship with a partner who is infected with HCV.

WHAT WOULD YOU DO NOW?
A. Order an enzyme-linked immunosorbent assay (ELISA) to screen for the presence of HCV antibodies and, if positive, follow with a recombinant immunoblot assay (RIBA) to confirm the result.
B. Order liver function tests (LFTs). If normal, recommend that the patient have these tests repeated every 6 months.
C. Order an ELISA to screen for HCV antibodies. There is no need for confirmatory testing, since the patient has a known risk factor for HCV infection.
D. Assume that hepatitis C is likely, since several risk factors are present; schedule biopsy of the liver to assess disease severity.

The best choice here is C. For all patients who meet the criteria for screening, the ELISA is the most appropriate test. The current third-generation ELISA detects antibodies to recombinant HCV antigens from the core (C22) and nonstructural proteins (C33, C-100, 5-1-1, NS3, and NS5 antigens). It is easy to perform and highly reproducible. ³ The third-generation ELISA has a sensitivity of 98% (except in patients unable to mount an antibody response- such as those with significant immunodeficiency or cryoglobulinemia; consider measuring viral load in such patients instead). Its specificity is 99% in patients who have a known risk factor.⁴ Note that the specificity of the ELISA is decreased in those without known risk factors, with normal LFTs, or with hypergammaglobulinemia (which is seen in autoimmune hepatitis); it may be as low as 45%, depending on the test used.⁵ Confirmatory testing using the more specific RIBA is recommended for any such patient who receives a positive result on an ELISA. The RIBA tests a patient's serum against the same HCV antigen bands that are used in the ELISA. However, the ELISA does not indicate how many or which bands are involved in a positive reaction, whereas the RIBA does. (RIBAs are not recommended as initial screening tests because they are no more sensitive than ELISAs and are technically more demanding.³) If a RIBA produces a positive reaction against 1 band, the result is considered indeterminate (however, if the single band is the C-100 or the 5-1-1, this is usually a negative result). If there is a reaction against 2 or more bands, the result is considered positive.⁶ Patients with a positive ELISA and a negative RIBA do not have HCV infection and do not need further testing for HCV. Conversely, up to 70% of patients with an indeterminate RIBA (bands other than C-100 or 5-1-1) have ongoing HCV infection.³ In patients, such as the man in this case history, with a known risk factor for HCV infection, a positive ELISA can be considered a true positive. There is no need for confirmation with a RIBA. LFTs are not used to screen for HCV infection because of their lack of specificity. Viral load measurements are technically complex, and their use is usually recommended only if initial testing (with an ELISA-and a RIBA, if clinical circumstances warrant) is positive. This patient's ELISA was positive. WHAT WOULD YOU DO NOW?
A. Prescribe interferon and ribavirin(, if not contraindicated.
B. Check viral load using quantitative methodology.
C. Schedule a biopsy of the patient's liver.
D. Check viral load and order LFTs.

The most appropriate choice is D. The positive result on the ELISA is evidence of an antibody response to the virus and only indicates that, at some time in the past, the patient was infected with HCV. He may or may not be currently infected. Of persons who have an acute HCV infection, 15% clear the infection; in the remainder, the infection becomes chronic. Further testing is needed to determine whether this patient currently has HCV infection and whether treatment is warranted. Liver biopsy remains the definitive test for the staging of liver disease, but this procedure is not necessary to confirm current HCV infection. Confirmation of ongoing infection requires the detection of viremia. Either qualitative reverse transcription polymerase chain reaction (PCR) or branched-chain DNA (bDNA) assays may be used for this purpose. Although bDNA assays are technically simpler and less susceptible to cross-contamination, PCR assays are preferred because of their greater sensitivity. These tests, which rely on nucleic acid amplification, can detect levels of RNA as low as 100 copies/mL.⁷ bDNA assays, which rely on hybridization of existing nucleic acid to specific probes, can only detect levels of 200,000 genomic equivalents/mL or higher.³ Between 10% and 30% of patients with an undetectable viral load based on bDNA testing are found to be viremic when a PCR assay is used.⁸ The initial viral load is also useful in predicting response to therapy. Individuals with higher initial HCV RNA levels (2 million copies/mL or greater) have been shown to have a lower response rate than those with lower levels.⁹ Use the same assay to follow response to therapy as that used to measure the initial viral load. In addition to checking viral load, it is also advisable to check LFTs. These results provide clues to the progression of the disease. Although patients who are viremic-and even cirrhotic-may have persistently normal LFTs, LFT results may correlate, albeit loosely, with biopsy findings and may thus obviate the need for that procedure in certain cases. Approximately 22% of patients with normal LFTs have significant abnormalities on biopsy; however, in those with abnormal LFTs, 60% have significant abnormalities on biopsy.¹⁰ Another reason for conservative management in those with normal LFTs is the relatively benign prognosis usually seen in these patients.¹¹ In patients whose LFTs are normal, check LFTs twice yearly rather than proceeding to biopsy. However, if a patient has physical examination findings consistent with chronic liver disease-or laboratory abnormalities that include hypoalbuminemia, an elevated prothrombin time, or thrombocytopenia-you may wish to refer for biopsy despite normal LFTs. INTERPRETING TEST RESULTS
The patient's alanine aminotransferase (ALT) level was 79 U/L, and his aspartate aminotransferase level, 52 U/L. HCV RNA PCR assay showed 835,000 copies/mL. These results indicate that the patient was viremic with liver function abnormalities. Liver biopsy would likely reveal ongoing inflammation and possibly fibrosis, given the probability that he developed his infection over a decade ago while he was injecting illicit drugs. His normal albumin level and international normalized ratio (Table 2) do not exclude the possibility of advanced fibrosis and even cirrhosis on biopsy.¹² WHAT WOULD YOU DO NOW?
A. Counsel the patient to abstain from alcohol( and from sharing toothbrushes or razors with others; schedule liver biopsy.
B. Initiate treatment with interferon and ribavirin after discussing possible side effects with the patient.
C. Counsel the patient to abstain from sexual intercourse without a condom; order an ELISA for his wife.
D. Counsel the patient to abstain from alcohol and from sharing toothbrushes or razors with others; have him repeat LFTs in 3 months.
The optimal choice here is A. Inform the patient that he has persistent infection with HCV and is potentially a candidate for treatment. The 3 criteria used to identify clear candidates for treatment of HCV infection are:

• Detectable levels of HCV RNA.
• Persistently elevated ALT levels.
• Fibrosis and/or moderate inflammation and necrosis on biopsy.

Patients who meet all 3 criteria have a 60% to 70% 10-year risk of cirrhosis, even in the absence of alcohol abuse, HIV infection, or other viral hepatitis infection.^6,13 This patient meets the first criterion. His LFTs were initially abnormal, but repeat testing is not recommended. Because LFT results can fluctuate during the course of HCV infection and because levels only loosely correlate with liver histology, repeated determinations are not helpful in guiding therapy. Rather, if a patient has no contraindications and wishes to undergo treatment-which was the case with this patient-liver biopsy is the recommended next step. Liver biopsy provides useful information on the stage and prognosis of disease.¹⁴ Subclinical cirrhosis, if discovered, may affect decisions to screen for varices or hepatocellular carcinoma.^15,16 In addition, biopsy may establish the presence of other liver diseases.¹⁷ Finally, patients with relatively mild inflammation or fibrosis on liver biopsy may not be candidates for therapy. Although some authors have recommended that viremic patients with abnormal LFTs may be treated without prior biopsy,¹⁸ biopsy is a prudent and useful step, especially in light of the potential toxicity of available therapy. SUPPORTIVE AND PREVENTIVE MEASURES Meanwhile, it is crucial to counsel the patient about specific measures and practices he can begin immediately that will limit the harm the infection can do to the liver-and that will minimize the risk of transmission of HCV to others. Advise all patients with HCV infection to abstain from alcohol. In those who ingest more than 50 g/d, the incidence of fibrosis is twice that of patients who abstain, and the incidence of cirrhosis in the second decade of infection is 10% to 15% higher.^19-21 Significant alcohol intake also increases the HCV viral load and impairs the response to interferon treatment. This patient, like all patients with newly diagnosed HCV infection, should be screened for immunity to hepatitis A and B viruses (HAV, HBV). (To screen, use hepatitis B surface antigen, antibody to the hepatitis B surface antigen, and IgG antibody to core.^22,23) Patients infected with HCV have a high risk-40%-of fulminant disease with HAV superinfection.²² Although the risk of concurrent infection with HAV is low, it is usually recommended that patients who are HAV-naive be vaccinated against hepatitis A. HBV acts synergistically in the progression of HCV infection, increasing the risk of cirrhosis and hepatocellular carcinoma. As with HAV, it is prudent to vaccinate those patients who are not immune.

Coinfection with HIV can also hasten disease progression in patients with HCV infection; it can augment HCV viral load and speed up HCV-related liver deterioration. Moreover, the rate of HIV/HCV coinfection is high. Thus, HIV testing would also be recommended for this patient.^24,25 It is also prudent to inoculate HCV-infected patients who have clinical or laboratory evidence of chronic liver disease with both pneumococcal and influenza vaccines. Although the guidelines indicate that rates of pneumococcal disease are raised specifically in those with cirrhosis or alcoholism, all patients with chronic liver disease may have subclinical immune defects that render them more susceptible to invasive disease.²⁶ The polysaccharide vaccine is safe and effective.²⁶ The influenza vaccine is also safe and may prevent morbidity in both healthy individuals and in those with chronic disease.²⁷ Patients with HCV infection frequently turn to herbal remedies.²⁸ Some of these are potentially hepatotoxic (Table 3), and it is prudent to caution patients against their use. In addition to measures that can help limit the damage the infection will cause to the patient, it is important to reduce the risk of transmission. Hepatitis C is typically spread through either percutaneous or permucosal contact with blood or body fluids containing blood. Advise the patient not to share razors or toothbrushes with others and not to donate blood, organs, tissue, or semen. Tell him to avoid sexual intercourse without a condom when his wife is menstruating, or in the presence of open genital lesions. The issue of regular use of barrier contraception is more complex. Currently, the seroprevalence of HCV infection in long-term sexual partners of persons who are HCV-positive is 1.5%; this is similar to the rate of infection in the general population.²⁹ Thus, the risk of infection by means of ordinary sexual intercourse appears to be quite small. The use of condoms may decrease the risk still further (although this has not been proved). However, couples may reasonably opt against the regular use of condoms.