Gastroenterology Hepatology

Hepatitis C

How can I be sure that the patient has hepatitis C?

Generally, individuals with hepatitis C infection present with few characteristic signs and symptoms. Seventy-five percent of individuals who are infected with acute hepatitis C do not develop signs or symptoms of acute hepatitis (right upper quadrant [RUQ] pain, jaundice, nausea/vomiting) and thus fail to recognize the acute infection at the time of exposure. Those with chronic hepatitis C are typically asymptomatic ; however, fatigue and vague RUQ discomfort are common symptoms.

Typically, other symptoms associated with hepatitis C are associated with end-stage liver disease and advanced fibrosis, including the development of ascites (the most common complication of hepatitis C-related cirrhosis), fatigue, encephalopathy, pruritus, weight loss, and jaundice. Finally, hematemesis or coffee ground emesis in those with hepatitis C, cirrhosis, and variceal bleeding may be the presenting symptoms. (See Table I.)

Table I.

Symptoms of hepatitis C
Acute hepatitis C Chronic hepatitis C
Jaundice Fatigue
RUQ pain RUQ pain
Nausea/vomiting
Fever

A tabular or chart listing of features and signs and symptoms

There are no pathognomonic features of chronic hepatitis C. Acute hepatitis C may present with nausea, vomiting, diarrhea, RUQ pain, and jaundice. The differential diagnosis for hepatitis C includes other etiologies for elevated liver tests in the setting of nonspecific features, including fatigue and RUQ pain. These include the most common liver diseases in the United States, nonalcoholic fatty liver disease, alcoholic liver disease, alpha-1 antitrypsin, hereditary hemochromatosis, Wilson's disease, autoimmune hepatitis, chronic hepatitis B, or acute hepatitis B.

How can I confirm the diagnosis?

To make the diagnosis of hepatitis C, an anti-HCV antibody test (now third generation) should be ordered. This test now has high sensitivity and specificity to diagnose chronic hepatitis C, and may also be useful as a diagnosis of acute hepatitis C. After the anti-HCV antibody has been ordered and is positive, then determination must be made as to whether there is active viremia. This is typically done with a quantitative HCV RNA assay by PCR testing and an HCV genotype.

At least six genotypes have been reported. In the United States, the most common genotype is genotype I, which accounts for 70% of patients infected with hepatitis C. Genotypes II and III account for the other 30%, with rare genotypes in the United States, including genotype IV (primarily found in the Middle East), genotype V (South Africa), and genotype VI (typically Southeast Asia).

If the anti-HCV antibody is positive and PCR testing reveals no detectable HCV RNA, then it is possible that the patient was exposed to hepatitis C and cleared virus. Indeed, approximately 15% of patients who are infected with hepatitis C acutely will clear virus and, in fact, these patients are more likely to be those who possess the IL-28 CC genotype. A recombinant immunoblot assay (RIBA test) may be ordered to confirm that the anti-HCV antibody test was a true positive and that, indeed, a patient was exposed to the virus and cleared virus, although it is rarely required. Such patient would have no detectable HCV RNA and is unable to transmit the hepatitis C virus. (See Figure 1.)

Figure 1.

HCV testing algorithm.

A diagnostic algorithm would be as follows:

  • Clinical suspicion of hepatitis C with risk factors and/or elevated ALT level or those who meet criteria for screening (CDC birth cohort , born between 1945 and 1965): anti-HCV antibody.

  • If positive, order quantitative HCV RNA and hepatitis C genotype; refer for therapy if HCV RNA is detected.

  • If ALT is elevated and history of hepatitis C risk factors (intravenous drug use, blood transfusion, other high-risk behavior including tattoos, intranasal drug use, family member with hepatitis C, sexual promiscuity), order anti-HCV.

  • If anti-HCV antibody is undetected, begin evaluation for other etiologies of elevated ALT.

  • Finally, approximately one-fourth of individuals with hepatitis C will have normal ALT levels, and a normal ALT with risk factors should certainly also warrant evaluation with anti-HCV antibody.

What other diseases, conditions, or complications should I look for in patients with hepatitis C?

When evaluating patients with hepatitis C, it is important to look for other diseases that can commonly be associated with hepatitis C. In particular, adult onset diabetes, thyroid disease, and (less common) renal disease and cryoglobulinemia should all carefully be assessed for in the evaluation of a patient with chronic hepatitis C.

In addition, the main complications associated with hepatitis C arise from progression to advanced fibrosis (cirrhosis). (See Table II.) Those with hepatitis C can progress from mild disease to advanced fibrosis over many decades. The primary complications associated with hepatitis C relate to the development of cirrhosis, where patients will then be at risk to develop ascites (the most common complication of patients with hepatitis C and cirrhosis), variceal bleeding, hepatic encephalopathy, and jaundice. Moreover, with the development of cirrhosis, patients with hepatitis C are at increased risk for hepatocellular carcinoma. Indeed, the hepatitis C epidemic in the United States is primarily responsible for the marked increase in hepatocellular cancer seen in the United States. Those with cirrhosis and hepatitis C should be screened regularly for hepatocellular carcinoma with an ultrasound every 6 months.

Table II.

Complications of hepatitis C
Cirrhosis 20% develop cirrhosis after 20 years
Hepatoma 3-5% after developing cirrhosis
Diabetes 2.2% associated with advanced fibrosis
Cryoglobulins up to 40% depends on assay
Arthralgias 23%
Thyroid dysfunction 3%

The risk factors for hepatitis C include injection drug use (the most common risk factor in the United States). Other high-risk behaviors include intranasal cocaine use, history of sexually transmitted diseases, history of being in prison, lower socioeconomic status, sex with multiple partners, blood transfusion, healthcare occupation, household contact, and high-risk tattoos and piercings. In 2012, the CDC added Guidelines for Age Cohort Screening—Those Born 1945-1965.) It should be noted that the CDC does not consider hepatitis C to be a heterosexually transmitted disease as sexual transmission is an inefficient means of transmission, though it can occur. Transmission rates are higher in male homosexuals and in HIV/hepatitis C coinfection, and men having sex with men is a well-recognized risk factor.

Extrahepatic manifestations of hepatitis C include diabetes, thyroiditis, sicca syndrome; hematologic disorders, including essential mixed cryoglobulinemia, B-cell non-Hodgkin's lymphoma, idiopathic thrombocytopenia; dermatologic conditions, including lichen planus, porphyria cutanea tarda, and cutaneous and necrotizing vasculitis. With the mixed cryoglobulinemia is associated renal disease. Complications from hepatitis C include those of end-stage liver disease, including ascites, variceal bleeding, hepatic encephalopathy, jaundice, and hepatocellular carcinoma.

What is the right therapy for the patient with hepatitis C?

We have now entered the era of multiple combinations of direct-acting antiviral agents for the treatment of hepatitis C and have eliminated in virtually all circumstances the previous backbone therapy, peginterferon. Given the ongoing rapidity of drug development and research, the IDSA and AASLD have specific guidelines for the care of patients with chronic hepatitis C, including specific treatment regimens. The decision for which drug regimen to choose is based on the HCV genotype, presence or absence of cirrhosis, prior treatment exposures, and, in some cases, specific testing for resistance-associated variants when appropriate.

For genotype 1, there are now multiple all-oral treatment options that allow the patient who is genotype 1 infected to achieve sustained response at high rates. These include combinations of the nucleotide polymerase inhibitor sofosbuvir (chain terminating), a potent nucleotide analog with antiviral activity against all known genotypes (1 through 6) with NS5A inhibitors and NS3 inhibitors. Currently, the approved therapies for hepatitis C genotype 1 include the combination of sofosbuvir with ledipasvir, elbasvir with grazoprevir, simeprevir with sofosbuvir, sofosbuvir with velpatasvir, and daclatasvir with sofosbuvir. A non-sofosbuvir-containing regimen that also leads to high-sustained response rates is the combination of the NS3 protease inhibitor paritaprevir and ombitasvir with twice-daily dasabuvir with ribavirin for genotype 1a infection. All combinations lead to high sustained response rates. In genotype 1b-infected individuals, the same four regimens demonstrate comparable efficacy, though ribavirin does not appear to be required for paritaprevir, ombitasvir, and dasabuvir.

In July 2016 the FDA approved a single tablet Viekira XR for treatment of genotype 1 hepatitis C.

For genotype 2 infection, daily sofosbuvir and velpatasvir for 12 weeks are recommended. An alternative regimen is sofosbuvir 400 mg and daclatasvir 60 mg for 12 weeks.

Genotype 3 hepatitis C remains the most difficult genotype to treat, as well as having an aggressive natural history with higher rates of progression to cirrhosis and hepatocellular carcinoma. The current recommended regimens include the NS5A inhibitor, daclatasvir 60 mg with sofosbuvir 400 mg for 12 weeks without cirrhosis or 24 weeks with cirrhosis with or without weight-based ribavirin. Another option is velpatasvir and sofosbuvir.

For genotype 4, there are three treatment options, and they include ledipasvir and sofosbuvir for 12 weeks, paritaprevir, ombitasvir, and weight-based ribavirin for 12 weeks or daily sofosbuvir velpatasvir for 12 weeks.

Finally, for genotypes 5 and 6, there are limited data, but the combination of ledipasvir and sofosbuvir or sofosbuvir/velpastasvir for 12 weeks achieves high-sustained response rates.

Of note, in October 2015, the Food and Drug Administration required a change to the labeling of the Viekira Pak (ombitasvir/paritaprevir/ritonavir + dasabuvir) and Technivie (ombitasavir/paritaprevir/ritonavir) to reflect the risk of hepatic decompensation and liver failure in patients with underlying cirrhosis after reports of these complications were noted in some patients with advanced cirrhosis who were started on treatment. In this setting, AbbVie (the makers of Viekira Pak) have updated drug labels from "not recommended in Child Pugh B patients" to contraindicated in those with Child-Pugh B and C cirrhosis.

What is the most effective initial therapy?

See the above section on therapy of the patient with hepatitis C.

Listing of usual initial therapeutic options, including guidelines for use, along with expected result of therapy.

See above.

A listing of a subset of second-line therapies, including guidelines for choosing and using these salvage therapies

Simeprevir was approved in combination with peginterferon and ribavirin for naïve and previous peg interferon ribavirin treatment failure patients. The approval was based on the phase 3 Quest 1 and Quest 2 studies, which demonstrated high sustained virologic response of 80% compared to the control arm SVR rate of 50%. In addition, 88% of individuals treated were able to be treated for just 24 weeks with a high sustained virologic response rate. Complicating this was a lower sustained response rates in individuals with the pre-existing Q80K polymorphism at baseline. This polymorphism occurs predominantly in genotype 1a individuals (and is rare in genotype 1b). Sustained virologic response rates were lower (genotype 1a Q80K positive 58%, Q80K 1a negative 75%) compared to genotype 1b, where sustained virologic response rates were above 80%.

Listing of these, including any guidelines for monitoring side effects.

Compared to the prior treatment regimens that featured peginterferon and ribavirin, most of the new treatment regimens have a very favorable side effect profile. Prior regimens using peginterferon and ribavirin led to side effects including flu-like symptoms, hemolytic anemia, depression, insomnia, as well as GI side effects of nausea and vomiting. A common feature of many of the studies involving new regimens for hepatitis C included favorable side effect profiles with most side effects not requiring withdrawal from those studies.

Due to reports of hepatitis B reactivation, which in rare cases led to fulminant hepatic failure and death, the FDA issued a black box warning for HCV DAAs in 2017. Specifically, it is recommended that all patients be tested for evidence of HBV infection by measuring hepatitis B surface antigen and hepatitis B core antibody before starting treatment. If either of these are positive, it is recommended that these patients be followed closely for evidence of hepatitis B reactivation during treatment and in the post-treatment period. If indicated based on AASLD or other guidelines, treatment should be started for HBV infection.

How should I monitor the patient with hepatitis C?

In a patient who is not referred for therapy for hepatitis C, there are a variety of counseling measures that can be undertaken to help ameliorate the fibrosis rates in those who have chronic hepatitis C infection. Numerous studies were reported that alcohol consumption of more than 50 g per day is associated with a higher rate of fibrosis worsening. However, other reports have suggested that even lower levels of alcohol consumption may be associated with deleterious effects on the natural history of hepatitis C and, in general, abstinence is recommended.

The contribution of metabolic syndrome and nonalcoholic fatty liver disease to hepatitis C fibrosis has also emerged as an important factor that may adversely affect the natural history of hepatitis C. Therefore, those individuals who are overweight (BMI >25) should be counseled appropriately about weight loss. In addition, along with weight reduction, improvement in insulin resistance may also have the beneficial effect of improving response to hepatitis C therapy.

Patients who do not have protected antibodies to hepatitis A and B viruses should receive the appropriate vaccinations. Currently, there is no data that suggests that complimentary alternative medicines are effective and, indeed, complimentary alternative medicines can lead to acute hepatitis and other liver injuries. The most commonly used worldwide is silymarin (milk thistle) and, while data on efficacy is limited thus far, this particular complimentary alternative medicine (CAM) is associated with minimal side effects.

Fibrosis progression also is important in patients infected with hepatitis C virus. In the past, a liver biopsy would often be performed every 3 to 5 years to assess fibrosis progression in those who are not treated. However, there are now serum tests as well as fibrosis assessments that can be made from routine biochemical tests that can predict advanced fibrosis. Moreover, other technologies such as transient elastography (sound waves that are transmitted and measure liver stiffness) may also allow clinicians to detect the presence of advanced fibrosis without a liver biopsy.

Again, it is important to assess hepatitis C patients for disease progression because patients who progress to cirrhosis require additional measures. As mentioned earlier, in addition to being most in need of hepatitis C therapy, these patients should also be screened for hepatocellular carcinoma.

Patients with mild disease may be seen on an annual basis and should be considered for therapy to prevent the development of fibrosis. In fact, all patients with hepatitis C should be considered for therapy for hepatitis C. Those with more advanced fibrosis who cannot be treated should be followed closely at no less than 6-month intervals. Patients with advanced fibrosis should strongly be considered for therapy for hepatitis C. Patients with cirrhosis should be referred for treatment for hepatitis C, and should be screened for hepatocellular carcinoma. Those with hepatitis C and decompensation should be referred for orthotopic liver transplantation if appropriate.

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