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 usedintravenous heroin until about 10 years ago-and sometimesshared needles. He also drank 6 or more beers a day for about 20 years, a practicehe 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 hasno history of hepatitis. Physical examination is unremarkable.THE RISK OF HEPATITIS C
This patient's history prompts consideration of infectionwith hepatitis C virus (HCV). HCV is a leading causeof chronic liver disease in the United States. Populationbasedstudies indicate that 50% of chronic liver disease inthis country is HCV-related. Between 8000 and 10,000deaths each year are attributed to HCV liver disease.¹ Anestimated 2.7 million Americans are chronically infectedwith HCV.²This patient's injection drug use is a known risk factorfor the infection and is one of the criteria establishedby the Centers for Disease Control and Prevention forHCV screening (Table 1). His history contains only thisone definite risk factor; however, tattooing and body piercingmay increase risk of HCV infection, although this hasnot been definitely established. Other behaviors in the lattercategory-and for which routine screening for HCVinfection 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 isinfected with HCV.

WHAT WOULD YOU DO NOW?

A.

Order an enzyme-linked immunosorbentassay (ELISA) to screen for the presence ofHCV antibodies and, if positive, follow with arecombinant immunoblot assay (RIBA) toconfirm the result.

B.

Order liver function tests (LFTs). If normal,recommend that the patient have these testsrepeated every 6 months.

C.

Order an ELISA to screen for HCV antibodies.There is no need for confirmatory testing, sincethe patient has a known risk factor for HCVinfection.

D.

Assume that hepatitis C is likely, since severalrisk factors are present; schedule biopsy of theliver to assess disease severity.

The best choice here is

C.

For all patients who meetthe criteria for screening, the ELISA is the most appropriatetest. The current third-generation ELISA detects antibodiesto recombinant HCV antigens from the core (C22)and nonstructural proteins (C33, C-100, 5-1-1, NS3, andNS5 antigens). It is easy to perform and highly reproducible.

³

The third-generation ELISA has a sensitivity of98% (except in patients unable to mount an antibody response-such as those with significant immunodeficiencyor cryoglobulinemia; consider measuring viral load insuch patients instead). Its specificity is 99% in patientswho have a known risk factor.

⁴

Note that the specificity of the ELISA is decreased inthose without known risk factors, with normal LFTs, orwith hypergammaglobulinemia (which is seen in autoimmunehepatitis); it may be as low as 45%, depending on thetest used.

⁵

Confirmatory testing using the more specificRIBA is recommended for any such patient who receivesa positive result on an ELISA.The RIBA tests a patient's serum against the sameHCV antigen bands that are used in the ELISA. However,the ELISA does not indicate how many or which bands areinvolved in a positive reaction, whereas the RIBA does.(RIBAs are not recommended as initialscreening tests because they are nomore sensitive than ELISAs and aretechnically more demanding.

³

)If a RIBA produces a positivereaction against 1 band, the result isconsidered indeterminate (however,if the single band is the C-100 orthe 5-1-1, this is usually a negativeresult). If there is a reaction against2 or more bands, the result is consideredpositive.

⁶

Patients with a positiveELISA and a negative RIBAdo not have HCV infection and donot need further testing for HCV.Conversely, up to 70% of patientswith an indeterminate RIBA (bandsother than C-100 or 5-1-1) have ongoingHCV infection.

³

In patients, such as the man inthis case history, with a known riskfactor for HCV infection, a positiveELISA can be considered a true positive.There is no need for confirmationwith a RIBA.LFTs are not used to screen forHCV infection because of their lack ofspecificity.Viral load measurements are technically complex,and their use is usually recommended only if initial testing(with an ELISA-and a RIBA, if clinical circumstanceswarrant) is positive.This patient's ELISA was positive.

WHAT WOULD YOU DO NOW?

A.

Prescribe interferon and ribavirin, if notcontraindicated.

B.

Check viral load using quantitativemethodology.

C.

Schedule a biopsy of the patient's liver.

D.

Check viral load and order LFTs.

The most appropriate choice is

D.

The positive resulton the ELISA is evidence of an antibody response to thevirus and only indicates that, at some time in the past, thepatient was infected with HCV. He may or may not be currentlyinfected. Of persons who have an acute HCV infection,15% clear the infection; in the remainder, the infectionbecomes chronic. Further testing is needed to determinewhether this patient currently has HCV infection andwhether treatment is warranted.Liver biopsy remains the definitive test for thestaging of liver disease, but this procedure is not necessaryto confirm current HCV infection. Confirmation ofongoing infection requires the detection of viremia.Either qualitative reverse transcription polymerase chainreaction (PCR) or branched-chain DNA (bDNA) assaysmay be used for this purpose. Although bDNA assaysare technically simpler and less susceptible to cross-contamination,PCR assays are preferred because of theirgreater sensitivity. These tests, which rely on nucleicacid amplification, can detect levels of RNA as low as100 copies/mL.

⁷

bDNA assays, which rely on hybridizationof existing nucleic acid to specific probes, can onlydetect levels of 200,000 genomic equivalents/mL orhigher.

³

Between 10% and 30% of patients with an undetectableviral load based on bDNA testing are found tobe viremic when a PCR assay is used.

⁸

The initial viral load is also useful in predictingresponse to therapy. Individuals with higher initialHCV RNA levels (2 million copies/mL or greater) havebeen shown to have a lower response rate than thosewith lower levels.

⁹

Use the same assay to follow responseto therapy as that used to measure the initial viral load.In addition to checking viral load, it is also advisableto check LFTs. These results provide clues to theprogression of the disease. Although patients whoare viremic-and even cirrhotic-may have persistentlynormal LFTs, LFT results may correlate, albeit loosely,with biopsy findings and may thus obviate the need forthat procedure in certain cases. Approximately 22% ofpatients with normal LFTs have significant abnormalitieson biopsy; however, in those with abnormal LFTs,60% have significant abnormalities on biopsy.

¹⁰

Anotherreason for conservative management in those with normalLFTs is the relatively benign prognosis usually seenin these patients.

¹¹

In patients whose LFTs are normal, check LFTstwice yearly rather than proceeding to biopsy. However,if a patient has physical examination findings consistentwith chronic liver disease-or laboratory abnormalitiesthat include hypoalbuminemia, an elevated prothrombintime, or thrombocytopenia-you may wish to refer forbiopsy despite normal LFTs.INTERPRETING TEST RESULTS
The patient's alanine aminotransferase (ALT) levelwas 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 withliver function abnormalities. Liver biopsy would likely revealongoing inflammation and possibly fibrosis, giventhe probability that he developed his infection over adecade ago while he was injecting illicit drugs. His normalalbumin level and international normalized ratio (Table 2)do not exclude the possibility of advanced fibrosis andeven cirrhosis on biopsy.

¹²

WHAT WOULD YOU DO NOW?

A.

Counsel the patient to abstain from alcoholand from sharing toothbrushes or razors withothers; schedule liver biopsy.

B.

Initiate treatment with interferon and ribavirinafter discussing possible side effects with thepatient.

C.

Counsel the patient to abstain from sexualintercourse without a condom; order an ELISAfor his wife.

D.

Counsel the patient to abstain from alcoholand from sharing toothbrushes or razors withothers; have him repeat LFTs in 3 months.
The optimal choice here is

A

. Inform the patientthat he has persistent infection with HCV and is potentiallya candidate for treatment. The 3 criteria used to identifyclear candidates for treatment of HCV infection are:

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

Patients who meet all 3 criteria have a 60% to 70%10-year risk of cirrhosis, even in the absence of alcoholabuse, HIV infection, or other viral hepatitis infection.

^6,13

This patient meets the first criterion. His LFTs wereinitially abnormal, but repeat testing is not recommended.Because LFT results can fluctuate during the course ofHCV infection and because levels only loosely correlatewith liver histology, repeated determinations are not helpfulin guiding therapy.Rather, if a patient has no contraindications and wishesto undergo treatment-which was the case with thispatient-liver biopsy is the recommended next step. Liverbiopsy provides useful information on the stage and prognosisof disease.

¹⁴

Subclinical cirrhosis, if discovered, mayaffect decisions to screen for varices or hepatocellularcarcinoma.

^15,16

In addition, biopsy may establish the presenceof other liver diseases.

¹⁷

Finally, patients with relatively mild inflammation orfibrosis on liver biopsy may not be candidates for therapy.Although some authors have recommended that viremicpatients with abnormal LFTs may be treated without priorbiopsy,

¹⁸

biopsy is a prudent and useful step, especially inlight of the potential toxicity of available therapy.

SUPPORTIVE AND PREVENTIVE MEASURES

Meanwhile, it is crucial to counsel the patient aboutspecific measures and practices he can begin immediatelythat will limit the harm the infection can do to the liver-andthat will minimize the risk of transmission of HCV to others.Advise all patients with HCV infection to abstainfrom alcohol. In those who ingest more than 50 g/d, theincidence of fibrosis is twice that of patients who abstain,and the incidence of cirrhosis in the second decade of infectionis 10% to 15% higher.

^19-21

Significant alcohol intakealso increases the HCV viral load and impairs the responseto interferon treatment.This patient, like all patients with newly diagnosedHCV infection, should be screened for immunity to hepatitisA and B viruses (HAV, HBV). (To screen, use hepatitisB surface antigen, antibody to the hepatitis B surface antigen,and IgG antibody to core.

^22,23

) Patients infected withHCV have a high risk-40%-of fulminant disease withHAV superinfection.

²²

Although the risk of concurrent infectionwith HAV is low, it is usually recommended thatpatients who are HAV-naive be vaccinated against hepatitisA. HBV acts synergistically in the progression of HCVinfection, increasing the risk of cirrhosis and hepatocellularcarcinoma. As with HAV, it is prudent to vaccinatethose patients who are not immune.

Coinfection with HIV can also hasten disease progressionin patients with HCV infection; it can augment HCVviral 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 patientswho have clinical or laboratory evidence of chronic liverdisease with both pneumococcal and influenza vaccines.Although the guidelines indicate that rates of pneumococcaldisease are raised specifically in those with cirrhosis oralcoholism, all patients with chronic liver disease may havesubclinical immune defects that render them more susceptibleto invasive disease.

²⁶

The polysaccharide vaccine is safe and effective.

²⁶

The influenza vaccine is also safe andmay prevent morbidity in both healthy individuals and inthose with chronic disease.

²⁷

Patients with HCV infection frequently turn to herbalremedies.

²⁸

Some of these are potentially hepatotoxic (Table3), and it is prudent to caution patients against their use.In addition to measures that can help limit the damagethe infection will cause to the patient, it is important to reducethe risk of transmission. Hepatitis C is typically spreadthrough either percutaneous or permucosal contact withblood or body fluids containing blood. Advise the patientnot to share razors or toothbrushes with others and not todonate blood, organs, tissue, or semen. Tell him to avoidsexual 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 ismore complex. Currently, the seroprevalence of HCV infectionin long-term sexual partners of persons who areHCV-positive is 1.5%; this is similar to the rate of infectionin the general population.

²⁹

Thus, the risk of infection bymeans of ordinary sexual intercourse appears to be quitesmall. The use of condoms may decrease the risk still further(although this has not been proved). However, couplesmay reasonably opt against the regular use of condoms.

References:

REFERENCES:

1.

2000 Connecticut Infectious Disease Society meeting; September 12, 2000;Southbury, Conn. Abstract.

2.

Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of hepatitis Cvirus infection in the United States, 1988-1994. N Engl J Med. 1999;341:556-562.

3.

Lok AS, Gunaratnam NT. Diagnosis of hepatitis C. Hepatology. 1997;26(suppl 1):48S-56S.

4.

Catalina G, Navarro V. Hepatitis C: a challenge for the generalist. Hosp Pract(Off Ed). 2000;35:97-108.

5.

Hsu HH, Gonzalez M, Foung SK, et al. Antibodies to hepatitis C virus in lowriskblood donors: implications for counseling positive donors. Gastroenterology.1991;101:1724-1727.

6.

Gross JB Jr. Clinician’s guide to hepatitis C. Mayo Clin Proc. 1998;73:355-361.

7.

Moyer LA, Mast EE, Alter MJ. Hepatitis C, part I: routine serologic testingand diagnosis. Am Fam Physician. 1999;59:79-88.

8.

Gretch DR, dela Rosa C, Carithers RL Jr, et al. Assessment of hepatitis Cviremia using molecular amplification technologies: correlations and clinical implications.Ann Intern Med. 1995;123:321-329.

9.

Liang TJ, Rehermann B, Seeff LB, Hoofnagle JH. Pathogenesis, natural history,treatment, and prevention of hepatitis C. Ann Intern Med. 2000;132:296-305.

10.

Nutt AK, Hassan HA, Lindsey J, et al. Liver biopsy in the evaluation ofpatients with hepatitis C who have repeatedly normal or near-normal serumalanine aminotransferase levels. Am J Med. 2000;109:62-64.

11.

Van Thiel DH, Caraceni P, Molloy PJ, et al. Chronic hepatitis C in patientswith normal or near normal alanine aminotransferase levels: the role of interferonalpha 2b therapy. J Hepatol. 1995;23:503-508.

12.

New Haven County Liver Study, unpublished data.

13.

Liang TJ, Hoofnagle JH. Hepatitis C: Biomedical Research Reports. San Diego:Academic Press; 2000.

14.

Perrillo RP. The role of liver biopsy in hepatitis C. Hepatology. 1997;26(suppl 1):57S-61S.

15.

Galmiche JP. French consensus conference on hepatitis C: screening andtreatment. Gut. 1998;42:892-898.

16.

Collier J, Sherman M. Screening for hepatocellular carcinoma. Hepatology.1998;27:273-278.

17.

Cammell G, Easley K, Younossi Z, et al. Predicting cirrhosis without abiopsy. Gastroenterology. 1997;112:A1236.

18.

Wong JB, Bennett WG, Koff RS, Pauker SG. Pretreatment evaluation ofchronic hepatitis C: risks, benefits, and costs. JAMA. 1998;280:2088-2093.

19.

Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progressionin patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIRand DOSVIRC groups. Lancet. 1997;349:825-832.

20.

Wiley TE, McCarthy M, Breidi L, et al. Impact of alcohol on the histologicaland clinical progression of hepatitis C infection. Hepatology. 1998;28:805-809.

21.

Pessione F, Degos F, Marcellin P, et al. Effect of alcohol consumption onserum hepatitis C virus RNA and histological lesions in chronic hepatitis C.Hepatology. 1998;27:1717-1722.

22.

Vento S, Garofano T, Genzini C, et al. Fulminant hepatitis associated withhepatitis A virus superinfection in patients with chronic hepatitis C. N Engl JMed. 1998;338:286-290.

23.

Myers RP, Gregor JC, Marotta PJ. The cost-effectiveness of hepatitis A vaccinationin patients with chronic hepatitis C. Hepatology. 2000;31:834-839.

24.

Eyster ME, Fried MW, Di Bisciegle AM, et al. Increasing hepatitis C virusRNA levels in hemophiliacs: relationship to human immunodeficiency virus infectionand liver disease. Blood. 1994;84:1022-1023.

25.

Benhamou Y, Bochet M, DiMartino V, et al. Liver fibrosis progression inhuman immunodeficiency virus and hepatitis C virus coinfected patients.Hepatology. 1999;30:1054-1058.

26.

Prevention of pneumococcal disease; recommendations of the advisorycommittee on immunization practices (ACIP). MMWR. 1997;46(RR-08):1-24.

27.

Ahmed F, Singleton JA, Franks AL. Influenza vaccination in young adults.N Engl J Med. 2001;345:1543-1547.

28.

Flora KD, Rosen HR, Benner KG. The use of naturopathic remedies forchronic liver disease. Am J Gastroenterol. 1996;91:2654-2655.

29.

Recommendations for prevention and control of hepatitis C virus (HCV)infection and HCV-related chronic disease. MMWR. 1998;47(RR-19):1-39.

30.

Hadziyannis SJ. Skin diseases associated with hepatitis C virus infection.J Eur Acad Dermatol Venereol. 1998;10:12-21.

31.

What everyone should know before trying herbs. Available at:

http://www.liverdisease.com

. Accessed January 9, 2002.