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FEBRUARY 2006
Case Studies:
Hepatitis C Therapy
Douglas G. Fish, MD Assistant Professor of Medicine Head, Division of HIV Medicine Albany Medical College Disclosures Speaker's Bureau: Gilead Sciences and Roche Laboratories, Inc. Research grant: Roche Laboratories, Inc. Advisor: Tibotec Therapeutics and Trimeris, Inc. Case 1: Does this patient need HCV therapy? A 45 year-old male inmate is diagnosed with HCV infection after he is found to have an elevated AST and ALT of 69 and 75 IU/L, respectively, on routine admission screening. His bilirubin is normal, and his albumin is 4.2 gm/dL. He feels well. He reports that he injected heroin for several years in his early twenties. Question: How do we know whether or not this patient needs treatment for HCV? Discussion The first thing we should do is determine whether or not he has chronic HCV infection as 15-25% of people who are exposed and infected with HCV will clear the virus on their own. This is in contrast to hepatitis B virus (HBV) infection, where 90-95% of people will spontaneously clear hepatitis B DNA if infected as an adult. Chronic HCV infection is determined by ordering a viral load for HCV, known as an HCV RNA PCR. Given the patient's elevated transaminases and his history of injection drug use (IDU), his pre-test probability of having chronic HCV infection is high. His viral load returns at 600,000 IU/mL, confirming chronic infection. If the viral load result is undetectable, the test should be repeated in 3-6 months for verification, and the patient would be confirmed as NOT having chronic infection, with no treatment necessary. The next step in evaluation of a patient with HCV viremia - in addition to screening for other forms of hepatitis, including hepatitis A virus (HAV) infection, HBV infection, autoimmune liver disease, and HIV - would be an assessment of the genotype, or strain of HCV, and consideration of liver biopsy. It is important to remember that HCV-infected patients can have significant fibrosis and even cirrhosis, yet have normal transaminases (AST and ALT). The genotype helps determine the length of HCV therapy and the likelihood of treatment response. Patients with genotypes 2 or 3 are usually treated for 24 weeks, whereas patients with genotypes 1 or 4 are treated for 48 weeks. Most hepatitis specialists recommend a liver biopsy, though there are situations where a biopsy may not be needed, particularly if one plans to treat regardless of a biopsy result. Patients with genotypes 2 or 3 have such a favorable treatment response that the 2004 American Association for the Study of Liver Disease (AASLD) treatment guidelines state that a liver biopsy in such patients can be considered optional. A liver biopsy does carry bleeding risks and a small risk of death (1/10,000 deaths). Treatment responses are poorer in patients with genotype 1. A liver biopsy can help determine how much scarring, or fibrosis, there is in the patient's liver and this information can be useful to the patient and clinician before and during HCV therapy. There are different scoring systems pathologists used for measuring liver fibrosis, and a common one is the Metavir fibrosis score (see HCV 101). The score ranges from F0 to F4, with F0 meaning no fibrosis and F4 signifying cirrhosis. If there is no fibrosis (Metavir F0), the patient does not need treatment and can be followed with a repeat biopsy in 3 to 5 years to look for progression. This is true regardless of the amount of inflammation seen in the biopsy (Metavir "A" score). If on liver biopsy, the patient has a Metavir score of F1, some experts would recommend treatment and others would observe, with a repeat biopsy in three to five years. The 2002 National Institutes of Health (NIH) Consensus Panel on HCV recommended treatment for patients with Metavir scores of F1 or higher. Similar to the AASLD guidelines, if the patient's virus is genotypes 2 or 3, this panel felt that a liver biopsy would be optional and hence not critical to the evaluation. HCV genotypes 2 and 3 respond more favorablly than genotypes 1 and 4 and usually require a shorter course of treatment, unless HIV-co-infection is present. HIV-HCV co-infected patients have a higher relapse rate when treated for 24 weeks, so most experts recommend 48 weeks of treatment regardless of genotype for these patients. Liver biopsy results may also be helpful to patients during therapy. If adverse effects of HCV therapy emerge and threaten treatment discontinuation, patients with more severe pathology may feel motivated to preserve whereas those with relatively milder disease on biopsy can consider this when weighing the risks and benefits of continuing treatment. If the patient has a coagulopathy, such as prolonged prothrombin time (PT) or thrombocytopenia, a biopsy can by done by an interventional radiologist via the transjugular approach. In cases where the patient declines a biopsy due to fear of the test or other concerns, treatment should not be withheld, regardless of genotype. Some laboratories offer a panel of blood tests used as non-invasive markers of fibrosis, which might be helpful for patients who decline or can't receive a biopsy. These tests, however, are not as helpful as a biopsy. Some data also suggest that the ratio of the platelet count and serum albumin can be used to gauge liver fibrosis. It is important to remember if the patient is not immune to HAV or HBV, vaccination for these should be offered so the patient does not acquire infection with another hepatitis-causing virus on top of the one he or she already has. Screening for treatment should also include assessing thyroid function, cardiac status, mental health, and overall medical history. A past history of depression or other mental illness should not necessarily preclude treatment; more important is an assessment of the patient's current mental health. The history and physical exam can also give important information. Historical elements that are important include the length of time since a patient first injected drugs, and alcohol consumption. Most patients are infected with hepatitis C early on, often in their first year of injection drug use. Alcohol is a clear risk factor for progression of fibrosis, and patients should be advised to avoid all alcohol on release. The physical exam can reveals stigmata of cirrhosis, such as palmar erythema, spider angiomas, splenomegaly, and asterixis. Laboratory clues to cirrhosis include thrombocytopenia, low albumin, hyperbilirubinemia, and prolonged prothrombin time. To summarize, if the patient has detectable viremia with HCV, obtain a genotype. If the genotype is 1 or 4, a biopsy is generally recommended, though not required, for treatment. If the patient has genotype 2 or 3, a biopsy is less critical as treatment duration is shorter and treatment responses are higher - advantages that favor treatment regardless of biopsy result. If on liver biopsy, the patient has more than portal fibrosis (Metavir F2 or higher) and does not have decompensated liver disease, treatment is indicated. The standard treatment is now pegylated interferon with ribavirin. Patients with genotype 1 or 4 are assessed after 12 weeks of combination therapy, and if they have a treatment response, designated as at least a 2-log10 decrease or an undetectable viral load, treatment should be continued for 36 more weeks, or 48 weeks total. For patients with genotypes 2 or 3, 24 weeks of combination therapy is recommended. A sustained virologic response (SVR) is determined when the patient's viral load remains undetectable 24 weeks after therapy is completed. In this patient, a liver biopsy was performed and revealed a Metavir score of F2. He was found to be HIV-uninfected and susceptible to HAV. His HBV surface antibody and core antibody were both positive, indicating prior and resolved infection with that virus. His HCV genotype was 1 and he elected to start HCV therapy with ribavirin and interferon. Case 2: HCV therapy in a patient with cirrhosis A 48 year-old woman with chronic HCV infection undergoes a liver biopsy and is found to have cirrhosis with a Metavir score of F4. She has been incarcerated for two years, and started injecting drugs when she was 19 years old. Question: Given that she has cirrhosis, can she be treated for her HCV? Discussion Cirrhosis can be broadly broken down into two categories, compensated and decompensated. Decompensated liver disease implies hepatic encephalopathy, uncontrolled ascites, bleeding varices, or any of the late-stage consequences of cirrhosis. Determination of the patient's Childs-Pugh Score is useful to determine whether a patient's cirrhosis is decompensated. (see HCV 101) Each element is scored and the points calculated, with the maximum being 15, the worst score. Child's class A is compensated (score 5 or 6), Child's Class B is early decompensated (score 7-9), and Child's Class C is decompensated (score of 10 or higher) cirrhosis. Decompensated cirrhosis can be worsened by treatment with interferon and ribavirin. Patients with compensated cirrhosis should only be treated with the input of a clinician experienced in the management of patients with HCV. Patients with compensated cirrhosis may be treated with interferon and ribavirin, though they will require closer follow-up and more frequent laboratory monitoring to avoid untoward complications of therapy. Again, therapy should be undertaken only in conjunction with a clinician experienced in the management of such patients. Consideration for transplant listing should also be undertaken, if appropriate. Sustained virologic response rates are lower in patients with cirrhosis than in patients without cirrhosis. Patients with compensated cirrhosis typically have had stable liver disease for years and usually do not present often to sick-call or require hospitalization. As mentioned above, it is important to recognize that a subset of HCV-infected patients may have cirrhosis demonstrated by liver biopsy, yet have normal liver parameters, including normal transaminases and albumin. This is another reason many experts recommend a liver biopsy for patients with chronic HCV infection. This patient has cirrhosis but no evidence of decompensated disease and. As such, she is a candidate for HCV therapy. Case 3: Managing advanced liver disease A 55 year-old male with chronic HCV infection returns to your facility after being hospitalized for fever, ascites and a 25-pound weight gain over the preceding two months. He is on spironolactone 50 mg po bid and furosemide 40 mg po daily. He was treated for spontaneous bacterial peritonitis, and is now off antibiotics. He had an episode of confusion while hospitalized, and was found to have an ammonia level elevated at 50 Umol/L. He is now on lactulose 30 mL (20 gm) po bid. An upper endoscopy revealed moderate esophageal varices, and he was started on nadolol 20 mg po daily. He also has type 2 diabetes mellitus treated with an oral hypoglycemic, as well as chronic neuropathy pain, for which he had been on ibuprofen but for which he is now prescribed oxycodone. Question: How should this patient be managed, and what signs/symptoms should you expect? Discussion This patient will most likely come to your infirmary initially. His fluid balance may not yet be fully stabilized, so he will need monitoring of his weight several times per week, as well as close follow-up of his electrolytes. Adjustments may still need to be made in his diuretic therapy. A low-salt diet is best, and the patient may have been discharged on fluid restrictions. This patient has decompensated liver disease, and hence, is not a candidate for interferon/ribavirin therapy. In this type of patient, chronic acetaminophen therapy is contraindicated, as it may accumulate in his liver and cause additional problems. Furthermore, many such patients typically have thrombocytopenia and prolonged prothrombin times, increasing their bleeding risk. For patients with esophageal or gastric varices, aspirin and non-steroidal anti-inflammatory medications are also relatively contraindicated, so as to avoid bleeding complications. In addition, concomitant gastritis or duodenitis is common, and patients may require an H2-blocker or proton-pump inhibitor therapy. Oxycodone or low-dose morphine preparations, either short- or long-acting, may be appropriate analgesics to control chronic pain. Finally, these patients are at risk for renal failure (hepatorenal syndrome) and as they are often on diuretic therapy non-steroidal medications pose further risk. Hepatic encephalopathy is often managed with lactulose. The goal is to titrate the lactulose to soft/loose stools without severe diarrhea to help eliminate hepatic by-products. The level of serum ammonia elevation does not correlate well with the degree of encephalopathy. Once a patient has been diagnosed with hepatic encephalopathy, clinical monitoring will be more useful than following ammonia levels. Medications that depress central nervous system function, such as benzodiazepines, should be avoided as much as possible. Other medications that may be prescribed in patients to reduce the effects of hepatic encephalopathy include antibiotics such as neomycin, metronidazole, or rifaximin - a nonabsorbable derivative of rifampin. Patients with varices will often be prescribed a beta-blocker, as in this case, in an attempt to decrease portal pressure and reduce bleeding risks. Some clinicians may also recommend antibiotic prophylaxis for patients with ascites to prevent spontaneous bacterial peritonitis, particularly if the patient has had a previous episode of peritonitis. Antibiotic prophylaxis has not been shown to confer a survival advantage, however. This type of patient should be considered for orthotopic transplantation evaluation, if available. His clinicians must discuss with the patient the severity and life-threatening nature of his illness, as well as health care proxy and resuscitation wishes. Life expectancy will be greatly reduced and may be measured in months to years. References 1 CDC. Guidelines for Prevention and Control of Infections with Hepatitis Viruses in Correctional Settings. MMWR, 1/24/03 Vol. 52 (rr-1). 2Fried MW, Shiffman ML, Reddy R et al. Peginterferon alfa-2a plus ribavirin for chronic HCV virus infection. N Engl J Med 2002; 347:975-982. 3National Institutes of Health (NIH) Consensus Development Conference Statement - Management of Hepatitis C: 2002. Rockville (MD): June 10-12, 2002. www.health.nih.gov 4 Rimola A, Garcia-Tsao G, Navasa M et al. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. J Hepatology 2000;32:141-153. 5Riordan SM, Williams R. Treatment of Hepatic Encephalopathy N Engl J Med. 1997;337(7):473-479. 6 Strader DB, Wright T, Thomas DL, Seeff LB. Diagnosis, management and treatment of hepatitis C. Hepatology 2004;39:1147-71.
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