A 49-year-old man comes to your office, requesting testing for hepatitis C. He recently attended his 25-year college reunion where an old friend he had "partied" with during experimentation with injectable drugs related that he has cirrhosis due to hepatitis C. The patient is otherwise healthy and denies any symptoms except for occasional fatigue after a long day at work. Physical examination of the patient is unremarkable. There are no stigmata of chronic liver disease.
Question 7.10.1 Which of the following is the most appropriate course of action?
A) Check a quantitative Hepatitis C virus (HCV) PCR ("viral load").
B) Order a recombinant immunoblot assay (RIBA).
C) Order HCV antibody test (enzyme immunoassay).
D) Order a qualitative HCV PCR.
Answer 7.10.1 The correct answer is "C." The sensitivity and specificity of the present-day HCV antibody test are excellent; thus, this is the best test to perform in this situation. Rarely, patients with immunologic impairment, such as HIV infection, have HCV viremia without detectable antibody, but this would not be a concern in this otherwise healthy patient. Quantitative HCV PCR is not a reliable means for diagnosing HCV infection because currently used methods are insensitive at low levels of viremia; thus, infection cannot be ruled out if the level of HCV viremia is below the lower limit of detection of the test. RIBA is an old test that is no longer used. Qualitative HCV PCR is the most sensitive test for the presence of HCV RNA, with a limit of detection that is lower than that of quantitative PCR. It is useful to establish the presence of viremia, but is more expensive than antibody testing and thus not a first-line test. Many patients with chronic HCV infection have normal liver enzymes and can still have progressive disease; therefore, in a high-risk patient, ALT and AST are not appropriate for screening for HCV.
The patient returns several weeks later to discuss his test results. His HCV antibody test is positive. A liver panel obtained that day shows an ALT of 48 IU/L (normal range, 0–20) and an AST of 39 IU/L (0–31). His albumin and total bilirubin are within normal limits. He is extremely anxious about his liver.
Question 7.10.2 To most accurately assess the degree of liver disease, your next step is to:
A) Obtain a liver–spleen scan to assess for evidence of cirrhosis.
B) Reassure the patient that his mild liver test abnormalities rule out cirrhosis.
C) Order a right upper quadrant ultrasound with Doppler to assess for evidence of cirrhosis.
D) Order elastography for evidence of cirrhosis.
E) Obtain an abdominal CT to assess for evidence of cirrhosis.
Answer 7.10.2 The correct answer is "D." Having established that the patient has hepatitis C with elevated liver enzymes, the next step is to determine the severity of his liver disease. Although his liver function tests are reassuring, this does not exclude the possibility of advanced fibrosis or even well-compensated cirrhosis. While biopsy has been the definitive test for liver fibrosis in the past (and you would not be wrong to order a biopsy if it were an option in this question), ultrasound elastography, a noninvasive technique of determining liver fibrosis, is being used more and more. The idea is that a fibrotic liver is a stiff liver. Don't worry about the details; just know that elastography (for example FibroScan) is a noninvasive and accurate method for determining the degree of hepatic fibrosis. The "F" score, discussed below, should allow you do make decisions about your hepatitis C patients. You would not be incorrect to order ultrasound imaging as well.
Fibrosis is scored from F0 to F4, with F0 representing no fibrosis and F4 representing cirrhosis. In addition to elastography, another noninvasive method of determining the degree of fibrosis is the AST/platelet ratio index, abbreviated APRI. This is calculated as follows:
APRI = [(patient AST - upper normal of lab AST) / platelet count] × 100.
Significant fibrosis (F2–F4) is present if the APRI is 0.7 or greater (77% sensitivity, specificity 72%) although some sources use 0.5 as the lower limit for "significant fibrosis." An APRI of 1 or greater represents cirrhosis. Finally, the FibroSure, Fibrotest, and ActiTest are proprietary methods of determining liver fibrosis—all of which have separate scoring systems for fibrosis. Note that a biopsy is not necessary for making a decision about who to treat: more on this below.
After a few phone calls, you find that elastography is not available anywhere nearby. The patient agrees to a liver biopsy to diagnosis cirrhosis and you make the referral. He is still very concerned about his situation and asks what you think the chances are that he already has cirrhosis.
Question 7.10.3 Regarding the development of progressive liver disease in hepatitis C, all of the following are true EXCEPT:
A) Approximately 20% of patients with chronic HCV infection will develop serious liver disease.
B) Heavy alcohol use is a risk factor for development of serious liver disease.
C) Acquisition of HCV infection after the age of 40 is associated with increased risk of developing serious liver disease.
D) HCV genotype affects the probability of developing end-stage liver disease.
E) Males are more likely than females to develop serious liver disease.
Answer 7.10.3 The correct answer is "D." While only a minority of persons infected with HCV develop serious liver disease (20%), the likelihood of progression is difficult to predict in an individual patient. Nonetheless, male gender, heavy alcohol use, and acquisition of HCV infection after the age of 40 are associated with increased risk of progressive liver disease, while genotype is not. In addition, Japanese ancestry, smoking (both cigarettes and marijuana), and acquiring hepatitis C from a blood transfusion, have been associated with an increased risk of progression. The genotype of the hepatitis C certainly makes a difference when it comes to treatment but not with progression to cirrhosis.
Patients who have a persistently normal ALT, acquired hepatitis C before the age of 35, are female, do not drink alcohol, and have minimal or no fibrosis on liver biopsy are unlikely to progress to end-stage liver disease.
The USPSTF recommends hepatitis C screening once for all individuals born between 1945 and 1965. Other populations deserving of screening include those with HIV, dialysis patients, and incarcerated patients.
The patient is concerned that he may transmit the virus to his wife or children. They are tested and are found to be negative for HCV antibody. He is relieved but asks for advice to prevent infecting them.
Question 7.10.4 You advise all of the following EXCEPT:
A) No change in sexual practices is recommended for couples in a long-term monogamous relationship in which one partner is HCV+ and the other HCV–.
B) The use of condoms is recommended for couples in a long-term monogamous relationship in which one partner is HCV+ and the other HCV–.
C) Hepatitis C is not spread by hugging, sneezing, or sharing a drinking glass.
D) Household members of persons infected with HCV should not share items that might be contaminated with small amounts of blood such as razors or nail clippers.
E) Parenteral exposure to infected blood is a major route of transmission of HCV.
Answer 7.10.4 The correct answer is "B." HCV is spread by parenteral contact with infected blood. In contrast to hepatitis B, sexual transmission of HCV is inefficient and appears to be a minor route of spread. In addition, the efficacy of latex condoms in preventing disease is not known. The NIH and the US Public Health Service do not recommend condom use for patients in a stable, long-term, and monogamous relationship. That said, using condoms will likely reduce an already low risk even further.
The patient's liver biopsy shows mild-to-moderate inflammatory activity and portal and periportal fibrosis (stage 2). He is relieved to find out that he does not have cirrhosis, but remains very concerned about his hepatitis and wants to do everything possible to "get rid of" the hepatitis C. He asks about the treatment of his HCV.
Question 7.10.5 Which of the following is NOT an indication for the treatment of hepatitis C?
A) Elastography showing cirrhosis.
B) APRI of 0.25 (pre-cirrhosis).
C) Liver biopsy showing bridging fibrosis.
D) Ability to pay for the treatment.
Answer 7.10.5 The correct answer (and not an indication for hepatitis C treatment) is "B." The cutoff APRI for the treatment is 0.5 to 0.7, representing F2 fibrosis. F2 fibrosis diagnosed by any method, including biopsy or elastography (e.g., FibroSure), is an indication for the treatment. You may be wondering about "D." Starting in 2014, a wave of new and more tolerable hepatitis C treatments started to become commercially available. However, the cost of these new drugs—at least, in the United States—is immorally high, costing up to $100,000 for a complete 12-week treatment. Public and private insurers have been forced into outright rationing. (To become appropriately outraged, read this article: http://www.latimes.com/business/hiltzik/la-fi-hiltzik-20150621-column.html.) If the United States treated all of the approximately 3 million HCV infected persons with the new drugs, it would cost our country about $300 billion. Because of the pharmaceutical companies setting prices differently in different markets, at least one of these new HCV drugs costs about 1% of the U.S. price in Egypt. So … One option is to send your HCV patients to Egypt for the treatment and put them up in a nice hotel—it would be significantly cheaper.
Question 7.10.6 You tell him which of the following?
A) Combination therapy with interferon and ribavirin results in sustained virologic responses (SVR) in 40% to 70% of patients treated.
B) Combination therapy with interferon and ribavirin can cause numerous side effects including cytopenias, flu-like symptoms, worsening of autoimmune conditions, depression, and hemolytic anemia.
C) The HCV genotype is a strong predictor of response to the treatment.
D) Newer treatment regimens including ledipasvir/sofosbuvir are much more effective than the tradition combination of interferon/ribavirin.
Answer 7.10.6 The correct answer is "E." Combination therapy with interferon and ribavirin is the traditional treatment of HCV and it is clearly not as effective at achieving a SVR as the newer drugs. The HCV genotype is a major factor determining the likelihood of achieving SVR, although not the likelihood of progression to end-stage liver disease. Genotype 1 is responsive to the newer drugs, such as the combination of ledipasvir/sofosbuvir (Harvoni); an entirely oral regimen with response rates of 93% or better for genotype 1. A second entirely oral treatment is ombitasvir/paritaprevir/ritonavir/dasabuvir (Viekira Pak [U.S.]). However, it must be combined with ribavirin for genotypes 1a and 1b if cirrhosis is present. Stage of fibrosis is also a factor, and patients with stages 3 and 4 (bridging fibrosis and cirrhosis) are less likely to achieve SVR. Higher baseline viral levels also tend to predict poorer response to the treatment. Combination therapy is expensive and is associated with significant toxicities. The major concerns with ribavirin are hemolytic anemia and teratogenicity, while the interferons (standard or the long-acting pegylated forms) have a long list of potential side effects, of which neuropsychiatric problems, such as depression and irritability, are often the most troublesome. Almost no treatment regimen still requires interferon.
OK, now the game changers. Here is a table (Table 7-5) for you to review the new hepatitis C drugs and the genotype treated. This is pretty basic. For a more complete summary, see http://www.hepatitis.va.gov/pdf/treatment-considerations-2015–07.pdf. Side effects of the newer drugs are headache, GI upset, etc., and generally much less problematic than previous generations of hepatitis C treatment. What happened to the protease inhibitors (telaprevir and boceprevir), you ask? They have gone the way of the dodo bird and are no more … too many side effects when used for hepatitis C.
TABLE 7-5REGIMENS FOR HEPATITIS Ca ||Download (.pdf) TABLE 7-5 REGIMENS FOR HEPATITIS Ca
|Primary Regimens ||Genotype and Primary Regimens ||Response Rate (%) ||Note 1 ||Notes |
|aAll Genotype 1 ||Harvoni (Ledipasvir/sofosbuvir) or Viekira Pak (ombitasvir/paritaprevir/ritonavir/ dasabuvir) ||95 ||Without cirrhosis || |
Duration of treatment differs based on cirrhosis vs. no cirrhosis, failure of prior treatment, etc.
Note the oral only regimens: Harvoni for all genotype 1 and genotype 4
|Genotype 1a and 1b ||Harvoni or Viekira Pak plus ribavirin ||95 ||With cirrhosis ||Viekira pack for genotype 1 without cirrhosis. |
|Genotype 2 ||Sofobufir (Sovaldi) plus ribavirin ||97 || || |
|Genotype 3 ||Harvoni plus ribavirin ||98 || || |
|Genotype 4 || |
Viekira Pak plus ribavirin
Sovaldi plus ribavirin
|95 || || |
Objectives: Did you learn to…
Evaluate a patient at risk for hepatitis C?
Understand the natural history of the disease process in hepatitis C?
Describe the transmission of hepatitis C?
Discuss the treatment issues for a patient with hepatitis C?