Epidemiology

Hepatitis C is an RNA virus and a member of the family Flaviviridae and affects approximately 1.6% of the American population, with estimates at 3 to 4 million infected (Armstrong, 2006). Most commonly, the disease is transmitted by blood-to-blood to contact. Before the availability of the hepatitis C antibody test in the early 1990s, posttransfusion hepatitis C was a common means of contraction. However, the availability of reliable assays has led to a marked decrease in the incidence of posttransfusion hepatitis C (Alter, 1997). Currently, the risk of posttransfusion hepatitis C is approximately 1 in 2 million transfusions. The much more common means of contracting hepatitis C is by intravenous drug use. Other needle-stick exposures, such as with tattoos and occupational exposure, account for a much lower percentage of cases. Sexual transmission is likewise a low risk, particularly among monogamous partners. However, the prevalence of hepatitis C is much higher at sexually transmitted disease clinics, affecting nearly 10% of nonintravenous drug–using patients (Thomas et al, 1994), presumably related to sexual promiscuity and/or traumatic sex, with increased risk of blood to blood exposure. Inhalation of cocaine has been raised as a potential risk factor, based on the transmission via blood on straws used to snort the inhaled agent (Hepburn & Lawitz, 2004). This risk factor has been questioned, with the issue that inhaled cocaine may be associated with other high-risk behaviors that are, in fact, the modes of transmission.

Presentation

Patients with chronic hepatitis C are frequently asymptomatic, although many have nonspecific symptoms, usually related to fatigue, myalgias, arthralgias, and/or right upper quadrant discomfort. Most patients are only diagnosed when they seek medical care for other reasons or with the above symptoms and are found to have mild elevations of the transaminases. However, up to 30% of patients will have normal transaminases at any one time because transaminase levels may wax and wane over time (Piton et al, 1998). Thus a history of any of the risk factors outlined above should lead to serologic testing to rule out hepatitis C.

Diagnosis

The standard screening study for hepatitis C is an enzyme-linked immunosorbent assay (ELISA) for antibody to hepatitis C. This is the standard test used by blood banks around the country; it has a sensitivity and specificity in high-risk populations ranging from 98% to 100% (Vrielink et al, 1995). If a patient has a known risk factor and elevated transaminase levels, a positive hepatitis C antibody study by ELISA is consistent with the diagnosis of hepatitis C. The presence of hepatitis viremia is checked with a reverse transcriptase polymerase chain reaction (PCR). Unfortunately, the PCR may take days to a week to get results, depending on the frequency of testing at the local lab. Patients can have a positive antibody study without viremia if the acute infection spontaneously resolved, an event that occurs 15% to 40% of the time (Herrine, 2002). Antibody positivity frequently persists indefinitely, but it does not imply infection if viremia is absent, based on an undetectable viral load by PCR. Patients will have one of six genotypes, variants in the hepatitis C genome that mainly reflect responsiveness to antiviral therapy (McHutchison et al, 1998). If screening for hepatitis C, and background on a patient being considered for surgery is all that is needed, a genotype need not be checked. However, if antiviral therapy is being considered, a genotype will provide important information regarding the chance of a virologic response and the length of therapy. Genotype 1 is the most common genotype in the United States, accounting for 70% of cases. Genotype 2 accounts for 15% of cases, and genotype 3 accounts for another 10% (McHutchison et al, 1998). Genotype 4 is occasionally seen in the United States, although it is more commonly seen in the Middle East and northern and central Africa. Genotypes 5 and 6 are seen in the United States, although rarely; prevalence of each is higher in South Africa and Southeast Asia, respectively.

Natural History

The course of hepatitis C is quite variable and can be influenced by a number of factors. Progression of the disease is routinely measured over decades. One commonly quoted figure is that 20% of those with the disease for at least 20 years will have cirrhosis. It is important to keep in mind that this implies that 80% of those with the disease for 20 years do not have cirrhosis. Another important consideration in determining the extent of the disease at the time of surgical evaluation is knowledge of when the disease was contracted. For example, if the patient knows he or she received a blood transfusion at the time of a motor vehicle accident 35 years ago, the patient has probably had the disease for 35 years. Likewise, a patient with an extensive history of intravenous drug use as a young adult has likely had the disease for several decades by the sixth or seventh decade of life. The disease takes an accelerated course in patients who ingest excessive amounts of alcohol (Wiley et al, 1998), contract the disease at a later age, and are coinfected with HIV or hepatitis B (Ragni & Belle, 2001; Tsai et al, 1996).

Treatment

Hepatitis C treatment is centered around the use of pegylated interferon and ribavirin. Routinely, the patient with chronic hepatitis C is started on therapy for one of several reasons; without question, the presence of hepatitis C viremia is the primary consideration for therapy, but careful consideration is also given to genotype, histologic changes, and potential relative and absolute contraindications. For example, patients with genotype 1 have a 45% to 50% chance of achieving a sustained virologic response, or “cure,” if they can complete a course of therapy. However, the profound fatigue and flulike symptoms commonly associated with antiviral therapy often lead to a decision to delay therapy if histologic changes are mild. For example, if a patient has genotype 1 with a high viral load, the most common demographic in American patients, a liver biopsy showing low-grade inflammation and fibrosis often leads to a period of observation that often lasts for years, or until therapeutic breakthroughs occur. If additional comorbidities associated with a poor response are added to this scenario, such as obesity (Charlton et al, 2006) and/or insulin resistance (D’Souza et al, 2005), and the patient is African American (Jeffers et al, 2004), the potential for successful treatment can drop to 20% to 25%, usually leading clinicians to delay therapy until factors that can be modified are changed. In the face of a disease that potentially may not lead to cirrhosis for 20 to 30 years, if ever, the wisdom of such an approach becomes obvious. Genotype 2 and 3 patients, however, respond in the range of 70% to 80% of the time, routinely requiring only 24 weeks of therapy versus the 48 recommended for genotype 1 patients. This higher response rate can be affected by the same cofactors outlined above.

Absolute contraindications to antiviral therapy include anemia, neutropenia, and severe thrombocytopenia. Because of a type of hemolytic anemia that can be induced by ribavirin, patients with a baseline hemoglobin less than 10 to 12 g/dL must be carefully evaluated if treatment is considered. A 2- to 3-g drop of hemoglobin is expected in the face of ribavirin; thus severe anemia is possible if the baseline hemoglobin level is low. Although reduced doses of ribavirin can be given with the hope of minimizing the anemia, reduced doses also lead to lower response rates; thus most experienced clinicians avoid dose reductions and use erythropoietin to increase hemoglobin levels. Neutropenia and thrombocytopenia are due to pegylated interferon and may improve with dose reduction, although similar lower levels of response can be expected. Granulocyte colony-stimulating factor or filgrastim can maintain neutrophil levels and obviate the need for dose reduction. Eltrombopag, a nonpeptide thrombopoietin receptor agonist, has been approved for patients with thrombocytopenia secondary to immune thrombocytopenic purpura and is under study for the treatment of thrombocytopenia secondary to pegylated interferon treatment. This will potentially allow thrombocytopenic patients to receive antiviral therapy.

Other potential contraindications to antiviral therapy include uncontrolled psychiatric illness, renal insufficiency, severe cardiopulmonary disease, and alcohol or substance abuse. Pegylated interferon and ribavirin can induce and exacerbate depression (Renault et al, 1987); thus recent suicidal ideation is an absolute contraindication to therapy. Well-controlled psychiatric disease can be successfully treated with careful follow-up. Renal insufficiency is a relative contraindication because of renal excretion of both interferon and ribavirin (Bino et al, 1982; Glue, 1999). The ribavirin dose must be decreased to avoid severe hemolytic anemia. Unfortunately, strict guidelines are not available, so dosing is often started at a low level, then increased based on patient tolerance. The anemia induced by ribavirin can exacerbate cardiac and pulmonary disease; these patients must therefore be carefully assessed before starting therapy. For example, a patient with congestive heart failure and a left ventricular ejection fraction of 40% may decompensate in the face of a drop in hemoglobin from 14 to 7 g/dL. Finally, patients with a history of alcohol or substance abuse are usually not treated until a period of abstinence can be maintained. Studies have shown a decreased response rate in patients with ongoing alcohol abuse (Pessione et al, 1998). Whether alcohol has a direct effect on drug pharmacokinetics and/or efficacy is unclear; however, the potential effect on compliance is obvious.

Once a patient is deemed an appropriate candidate for therapy, one of two pegylated interferon products is started: pegylated interferon alfa-2a at 180 µg subcutaneously weekly or pegylated interferon alfa-2b at 1.5 µg/kg/week. Although no head-to-head studies have been performed, the agents appear to be equivalent in efficacy and side effects, although clinicians usually have a personal preference. Ribavirin is dosed at 13 mg/kg/day, given orally in divided doses. Because of the myalgias, arthralgias, fever, chills, and sweats that frequently occur after administration of pegylated interferon, patients frequently take an over-the-counter analgesic before the injection. Fatigue and flulike symptoms are usually at their worst in the 24 to 48 hours following the pegylated interferon injection, with milder symptoms for the remainder of the week, until the next scheduled injection. That said, many patients are affected by these symptoms on a nearly daily basis, but others have minimal discomfort. Most patients can maintain their usual activities with only scattered absences. However, a small percentage of patients are nearly disabled, requiring frequent absences from their usual responsibilities. Discontinuation of therapy as a result of intolerable side effects occurs in 5% to 10% of treated cases.

On treatment, laboratory work is followed at least monthly and more often if needed. Thyroid function is assessed quarterly because of the potential for development of hypothyroidism or hyperthyroidism (Marcellin et al, 1992). The addition of growth factors for cytopenias is often clinician dependent. Most clinicians start supplemental erythropoietin with a hemoglobin level less than 10 g/dL, although many clinicians start erythropoietin if a patient has severe fatigue in the face of a drop in hemoglobin of 25% to 40% (e.g., from 18 to 11 g/dL). Absolute neutrophil counts less than 500 mm³ usually lead to supplemental filgrastim, although many clinicians start filgrastim in response to an absolute neutrophil count of less than 1000 mm³. Drops in hemoglobin, absolute neutrophil counts, and platelet counts may lead to dose reduction of pegylated interferon and/or ribavirin, although the current standard of care is to attempt to maintain patients on standard doses unless all other measures fail.

Viral loads are monitored at 4, 12, and 24 weeks of therapy (Ghany et al, 2009). An undetectable viral load after 4 weeks of therapy is associated with an 85% to 90% response rate, if the patient can complete the course of therapy, regardless of genotype (Ferenci et al, 2005). Thus a response at 4 weeks should lead to maximal efforts to maintain a patient at standard doses and a full course of therapy. An undetectable viral load observed at 12 weeks drops the rate of a sustained virologic response to 67% to 80% (Davis et al, 2003), whereas patients with a “late” response at week 24 only respond approximately 18% to 30% of the time (Berg et al, 2006; Pearlman et al, 2007). In patients with the first undetectable viral load at 24 weeks, recent studies suggest that extending therapy for an additional 24 weeks may improve the rate of response by 20%, although patient tolerance for this extended therapy is poor (Berg et al, 2006; Pearlman et al, 2007).

If undetectable viremia is achieved during therapy, viral load is routinely checked 3 to 6 months following the end of therapy. An undetectable viral load at that point is consistent with a sustained virologic response. Long-term studies have shown this response is durable, with undetectable viral loads persisting indefinitely (Desmond et al, 2006), unless the patient is reinfected. Patients who do not respond to antiviral therapy do not benefit from another treatment trial unless specific circumstances resulted in underdosing. New classes of medicines are under study, and when used in combination with pegylated interferon and ribavirin, protease inhibitors appear to increase response rates.

Surgery in the Patient with Hepatitis C

In the noncirrhotic patient with hepatitis C undergoing hepatopancreatobiliary surgery, no special precautions need be taken. The risk of decompensation postoperatively is solely related to the presence of advanced fibrosis and is not related to the presence of the hepatitis C virus itself. If a patient is undergoing antiviral therapy at the time of surgery, the best advice is to ask a hepatologist to assess the situation. In the vast majority of cases, antiviral therapy need not be stopped in the face of surgery. Obviously, antiviral therapy can be stopped if more pressing issues require treatment. Stopping antiviral therapy for a period of weeks may necessitate starting over from the beginning.

Epidemiology

Hepatitis B is a DNA virus that represents the number one cause of chronic viral hepatitis worldwide, with more than 2 billion people infected at some point and more than 350 million infected chronically (World Health Organization, 2008). More than 45% of the world’s population lives in endemic areas, particularly in Asia and sub-Saharan Africa (Mahoney, 1999). More than 8% of the population in these areas is positive for hepatitis B surface antigen (HBsAg). The prevalence is much lower in North America, affecting less than 2% of the population overall. In the United States, approximately 73,000 new cases occur each year, with approximately 1.25 million patients infected chronically (McQuillan et al, 1999). However, because of the mobility of the world’s population, the possibility of acute or chronic hepatitis B must be considered in patients who have come to the United States. These changes in patterns of immigration will likely increase the prevalence of the disease by as much as a factor of two.