Understanding Hepatitis C

There are at least 4 million cases of hepatitis C virus (HCV) infection in the United States (overall prevalence 1.8%, with many of these patients unaware of their infection) and 170 million worldwide. The consequences of this virus account for 10 000 deaths every year in the United States. HCV is the primary reason for liver transplantation in this country. Most new cases are now acquired through the use of illegal injection drugs (68%) or potentially sexual transmission (18%). Although the incidence of HCV infection has dropped sharply since the early 1990s because of improved blood-supply screening, the infections that were acquired from the 1960s to the 1980s are likely to dramatically increase the morbidity, mortality, and costs of HCV disease over the next 2 decades. A proportion of these individuals with long-term HCV infection will develop cirrhosis, decompensated liver disease, or hepatocellular carcinoma (HCC). These increases in HCV-related end-stage liver disease and HCC will have significant implications for clinicians and pharmacists in managed care settings. This article reviews the virology, serology, epidemiology, natural history, and the current and projected future disease burden of HCV in the United States.

(Am J Manag Care. 2004;10:S21-S29)

To understand the role of the hepatitis C virus (HCV) in progressive liver damage, cirrhosis, and hepatocellular carcinoma (HCC), it is helpful to review the virology and epidemiology of HCV as well as the serological response to HCV infection and the typical natural history, pathology, and time course of HCV disease progression. These varying perspectives on HCV infection provide the necessary broad base for subsequent exploration of current recommendations for managing this increasingly problematic disease. As will become clear in Dr Bacon‛s accompanying review of HCV therapy, many critical HCV treatment decisions will hinge on a clinician‛s or a patient‛s estimate of the likelihood of disease progression and treatment success. This article reviews the many factors that feed into the complex calculus for predicting HCV progression and therapy success–and that therefore may assist the clinician in recommending the best course of action for individual patients.

Much of the information in this article is adapted from the 2002 consensus statement from the National Institutes of Health (NIH) on Management of HCV.¹ Readers are referred to that full publication for more details. A downloadable copy of the formal published NIH conference proceedings is available at: http://consensus.nih.gov/cons/ 105/105_statement.pdf.

The Hepatitis C Virus

Hepatitis C is a small blood-borne ribonucleic acid (RNA) virus of the family Flaviviridae. This "non-A non-B" virus was first identified in 1989 by researchers in the San Francisco Bay area.^2,3 The RNA genome is 9600 kilobases in length and encodes a single large polyprotein that is cleaved posttranslationally into at least 4 structural proteins and 6 nonstructural proteins (Figure 1).⁴ The HCV replicates preferentially in hepatocytes but is not directly cytopathic.⁵ The virus mutates frequently as it replicates and spreads from cell to cell, a shifting that may explain the lack of a vigorous T-cell response to HCV infection as well as the historic difficulty in treating this infection. The virus is transmitted primarily through large or repeated direct exposure to blood.⁶

Six distinct genotypes of HCV are recognized, and within these major genotype categories there are more than 50 major subtypes and innumerable other genetic permutations (isolates or quasispecies). While the nucleotide sequence may vary by as much as 30% to 50% between the 6 major genotypes, all are capable of causing serious clinical disease. Genotypes of HCV are clinically relevant because genotype 1, which accounts for about 70% to 75% of infections in the United States, has a lower response rate to interferon-based therapy. Genotypes 2 and 3, which account for about 19% to 22% of US infections, are much more susceptible to current combination-therapy regimens. Response rates of the other genotypes are less certain because these are much less common in the United States (<5%).^1,5

Epidemiology

Hepatitis C is a global health problem, with 170 million carriers worldwide and 3 million to 4 million new cases per year.⁷ The distribution is heterogeneous, with an estimated 62 million chronic infections in the Western Pacific (ie, Far East and Asia), 32 million in Southeast Asia, 21 million in the Eastern Mediterranean, and 9 million in Western Europe. Overall, the global prevalence is 1% to 3% but hot spots of infection are seen in some cities and countries. In Egypt, for example, the legacy of parenteral treatment campaigns for schistosomiasis from the 1960s through the 1980s has left that population with a prevalence 10 times greater than that seen in the United States or Europe.^8,9 Similarly, a Japanese program of transfusions at the end of World War II has produced a substantial legacy of current HCV disease; in the 1990s the HCC death rate in Japan was 40 per 100 000 versus 7 per 100 000 in the United States.^10,11 Genotype distribution also varies considerably from country to country, with HCV genotype 3 most common in India and genotype 4 prevailing in Africa and the Middle East.⁵

In the United States, estimates extrapolated from 1988-1994 survey results indicate that 3.9 million individuals are likely infected with HCV and that, of this infected group, 2.7 million (74%) have chronic HCV infection.¹² This calculated national prevalence of 1.8% makes HCV infection the most common blood-borne infection in the United States.¹ The actual prevalence is likely even higher since the household survey on which this estimate is based excludes prisoners, homeless people, or those who are institutionalized–populations in whom injection drug use and HCV exposure are known to be high.^13,14 The national survey data showed that the prevalence of HCV infection was highest in those 30 to 49 years of age (Figure 2) and in those who were African American or Hispanic (Figure 3).¹² As many as two thirds to three fourths of all HCV-infected patients have not been identified.

Most current HCV infections were acquired from the 1960s to the 1980s. The Centers for Disease Control and Prevention (CDC) estimates that the incidence of new HCV infections between 1985 and 1989 was 242 000/year versus just 25 000/year in 2001.¹⁵ One major reason for the sharp decline in new infections starting in the early 1990s was the introduction of anti- HCV blood tests and the consequent virtual elimination of transmission via blood products and organ transplants. Since 1994, the risk of transfusion-associated HCV infection has been almost (but not completely) nonexistent. High-risk injection drug use is also less common today compared with the prehuman immunodeficiency virus (HIV) era of the 1960s and 1970s and this may also have contributed to declining HCV incidence. Specifically, anti-HIV educational programs aimed at promoting needle exchange and reducing use of shared needles appears to have had a "halo effect" on HCV incidence. ^16,17 Still, well over half of all new HCV cases are associated with the use of contaminated needles, syringes, or other drug paraphernalia (Figure 4).^15,18 Injection drug use remains a highly efficient form of HCV transmission –even more efficient than transmission of HIV (Table). More than 50% of individual users become HCV-positive within 5 years of using needles.¹⁵

Sexual transmission of HCV is rare between long-term steady partners but it is very much associated with multiple partners, early sex, non-use of condoms, other sexually transmitted diseases, and sex with trauma.¹⁵ Although rates of HCV infection are generally higher in men than in women, the rate of transmission in men having sex with men is not necessarily higher.^15,19 About 15% to 20% of acute and long-term HCV infections in the United States are probably sexually acquired. Occupational exposures including needle sticks in healthcare workers may account for about 4% of HCV infections, but the overall 1.5% prevalence among healthcare workers is actually lower than that seen in the general population. Extremely rare exposures associated with HCV infection in about 1% of cases include healthcare-related transmission (for example, chronic hemodialysis, nosocomial, unsafe injections) and perinatal transmission. The risk of transmission from an infected mother to a newborn is 6% (17% if coinfected with HIV) and there is no association with delivery method or breastfeeding. The source of HCV infection remains unknown in about 9% of all cases; potential risks of uncertain relevance include household transmission (for example, sharing of razors, toothbrushes), intranasal cocaine use, tattooing, body piercing, dental procedures, and acupuncture.^15,18

For many patients without obvious risk factors for HCV, determining the origin of the infection may be impossible. In some cases, patients may simply not remember a single exposure that explains the infection source. Establishing such single exposures can be extremely difficult even in cooperative patients. In other cases, the actual source of infection remains mysterious because of an individual&#8219;s or family&#8219;s obscure medical history. For example, a family that emigrated from Italy to the United States in the mid-1950s may have no records and minimal recollection of a series of immunizations administered by the local doctor. The fact that a brief use of unsterile needles by a foreign physician nearly half a century ago can explain an HCV infection manifesting as liver disease in US health clinics today illustrates how long and tortuous the true HCV transmission routes may be in patients who ask the apparently simple question: "How did I get it?"

Based on the main transmission routes of the past several decades, the prevalence of HCV infection in selected populations in the United States today is highest in those with past exposures to blood–especially injection drug users and persons with hemophilia who were treated with clotting factor concentrates produced before 1987, and recipients of transfusions from HCV-positive donors before 1992 (Figure 5). Patients undergoing long-term hemodialysis and those with high-risk sexual practices are in the next highest risk categories. It is based on such infection risk patterns that the CDC currently recommends screening for HCV infection in (1) anybody who ever injected illegal drugs, (2) recipients of clotting factors made before 1987, (3) recipients of blood or solid organs before July 1992, (4) hemodialysis patients, and (5) individuals with undiagnosed liver disease.¹⁵ Healthcare, emergency medical, and public safety workers do not need HCV testing unless they have a specific risk factor (for example, exposure to a needle stick or HCV-positive mucosa/blood). Because of the significant overlap between HIV and HCV infections, patients with documented HIV should also be screened for HCV infection.¹ The need for screening is less certain in several other populations, including recipients of transplanted tissues, users of intranasal cocaine, those with a history of tattooing or body piercing, and those with multiple sex partners.¹⁵

Serological Response to HCV Infection

Knowledge of the typical serological course of HCV infection is valuable since tests for antibody and viral RNA are often used to guide diagnosis and monitor therapy. After initial exposure, HCV RNA can be detected in the serum of most patients within 1 to 2 weeks and this will continue to rise for several more weeks.⁵ The levels of serum alanine aminotransferase (ALT) rise within 4 to 12 weeks, indicating liver cell injury. Only about one third of patients develop symptoms of acute infection such as malaise, weakness, and jaundice ⁶ ; these symptoms usually peak and subside along with ALT levels over a course of about 4 to 12 weeks. Antibodies to HCV are detectable by enzyme immunoassay (EIA) only in about half of infected patients at the onset of symptoms, but in more than 90% of patients after 3 months. The EIA is currently recommended as the initial screening test for atrisk populations with clinical liver disease.⁷ However, because anti-HCV antibody is not always measurable when the symptomatic patient presents, serum ALT and HCV RNA tests are also sometimes employed to detect acute HCV infection.²⁰

The levels of HCV RNA and ALT are thought to fluctuate markedly in the evolution from acute to chronic HCV infection.⁵ This is why repeat testing is required to confirm the absence of chronic infection. Once chronic infection is established after about 6 to 12 months, the RNA levels tend to stabilize and spontaneous resolution is rare. Antibody levels to HCV also tend to stabilize at this point. Serum ALT is less consistently elevated in long-term disease. In fact, approximately 30% of patients with longterm HCV infection have normal ALT levels and another 40% have ALT levels less than 2 times the upper limit of normal.¹ These lower or normal ALT levels may correlate with mild or nonprogressive disease or with antiviral treatment response.⁵ Several quantitative RNA assays for HCV are now available to monitor the viral load in response to therapy. While the viral load is not considered an accurate indicator of disease severity or progression, serial HCV RNA measurements, while on therapy, with the same assay can provide useful clinical information on the likelihood of response to antiviral therapy.¹

Progression to Chronic Infection and Cirrhosis

HCV infection evolves at different rates and in different ways for different patients. The major branch points in these potential natural histories of HCV include progression from acute infection to long-term infection, from long-term disease to cirrhosis, and from cirrhosis to decompensation or HCC (Figure 6).¹² Prospective studies show that about 75% to 85% of HCV-infected individuals develop long-term infection, defined as the persistence of HCV RNA in the blood beyond 6 months.^1,6,21 In 15% or more of patients, the natural immune system is able to "clear" the acute infection spontaneously. Women and young individuals have a greater chance of clearing the virus naturally, while African American men and those with asymptomatic acute courses are more prone to develop long-term infection.^5,21

The long-term phase of HCV infection usually remains asymptomatic for decades and may even remain so, at least initially, in the 10% to 15% of long-term infected individuals who go on to develop progressive liver fibrosis and cirrhosis. The factors thought to increase the risk of progressive liver disease include older age at time of infection, male gender, Caucasian race (relative to African American race), HIV coinfection, concurrent hepatitis B or schistosomal infection, high levels of alcohol use, iron overload, and nonalcoholic liver disease. These host and environmental factors seem to play a larger role than viral load or genotype in determining which patients with long-term infection will progress. Unfortunately, there is no simple risk algorithm for predicting which patients with long-term HCV infection will progress based on patient characteristics or history.

While long-term HCV infection remains silent in the majority of patients, the prognosis for patients who develop advanced cirrhosis is poor. The first clinical signs of cirrhosis may include fatigue, right upper quadrant discomfort or tenderness, nausea, poor appetite, and muscle and joint pain; these early symptoms are often mild and intermittent. ²⁰ As liver damage progresses, the signs and symptoms become more prominent and include muscle weakness, weight loss, itch- ing, dark urine, fluid retention, and abdominal swelling. Physical examination may reveal an enlarged liver and spleen, jaundice, excoriations, ascites, and ankle swelling. The differential diagnosis includes autoimmune hepatitis, long-term hepatitis B and D, alcoholic hepatitis, nonalcoholic steatohepatitis, sclerosing cholangitis, Wilson&#8219;s disease, alpha- 1-antitrypsin-deficiency—related liver disease, and drug-induced liver disease. The diagnosis of long-term HCV is usually made when anti-HCV antibody is present and serum aminotransferase levels remain elevated for more than 6 months. Testing for HCV RNA confirms the diagnosis.¹⁸

Approximately 6% of patients with cirrhosis eventually develop decompensated liver disease and become potential candidates for liver transplantation.²² In compensated cirrhosis the 5-year survival is 90%, and the 10-year survival is 80%.²³ However, there is a 30% risk of hepatic decompensation over 10 years.²⁴ Technically, all of these patients are potential candidates for liver transplantation. Up to 3% or 4% of patients with established cirrhosis develop HCC every year,^1,22 with the exact cancer progression rate varying from region to region.^6,24 The less common extrahepatic manifestations of chronic HCV infection that may become clinically significant include mixed cryoglobulinemia, B-cell non-Hodgkin&#8219;s lymphoma, glomerulonephritis, seronegative arthritis, keratoconjunctivitis sicca, lichen planus, various neuropathies and cognitive disorders, and porphyria cutanea tarda.⁵

Although liver decompensation and cancer linked to chronic HCV and cirrhosis rightfully attract most clinician concern in treatment decisions, recent studies have shed light on the subtle symptoms of liver disease that may also diminish patient quality of life. Up to 20% or 30% of patients with HCV infection, for example, may have psychological disorders including depression.¹ Fatigue has been reported in up to 67% of individuals with long-term HCV infection.²⁵ These symptoms and others, such as reduced vitality and diminished social functioning, are increasingly being recognized in HCV-positive patients with less advanced histologic liver disease.^26,27

Morbidity and Mortality of HCV Infection: Looking Ahead

HCV is estimated to cause 10 000 to 12 000 deaths annually in the United States.^15,20 In one analysis of CDC data, the overall number of HCV-related deaths increased 6-fold between 1982 and 1999 with a corresponding increase in the age-adjusted death rate from 0.4 to 1.8 deaths per 100 000 persons per year.²⁸ Although the bulk of this increase is because of the maturing of HCV infections acquired 20 to 30 years ago, part of the increase may also be attributable to a recent shift in what epidemiologists call the "competing mortality" of HIV. Patients with HIV and HCV coinfections are known to have accelerated rates of liver fibrosis, ²⁹ and as anti-HIV retroviral treatment regimens have improved over the past decade, these patients with HIV are living longer–but dying more frequently from HCV-related endstage liver disease.³⁰ Patients with long-term HCV who develop HCC have an especially poor prognosis, with survival rates as low as 1% at 2 years after HCC diagnosis in symptomatic and untreated patients.^24,31 As with HCV cirrhosis- related deaths, the incidence of HCC age-adjusted deaths has also increased dramatically in all parts of the world including the United States, where it went from 1.4 per 100 000 population for the period 1976-1980 and from 2.3 to 2.4 per 100 000 population from 1991-1995.¹¹

Based on projections of growth in populations with long-term HCV and cirrhosis, mortality from cirrhosis and HCC is expected to double or triple over the next 2 decades.^16,28 An estimated 165 900 deaths from HCV-related long-term liver disease and 27 200 deaths from HCV-caused HCC will occur from 2010-2019.³²

In terms of morbidity, the current toll of long-term HCV infection is also apparent– although sometimes difficult to measure precisely because of overlapping diagnoses. In 1998, there were an estimated 317 000 outpatient visits for HCV treatment.³³ That same year, an estimated 140 000 hospital discharges listed an HCV diagnosis and 1517 patients with HCV infection required a liver transplant.²⁸ In fact, more than half of all liver transplants are now the result of HCV cirrhosis, and the demand for transplants related to HCV infection has grown steadily over the past 5 years while the number of available cadaveric livers has remained steady at about 4000 to 5000 per year.

Looking ahead, the burden of HCV infection and cirrhosis as reflected in hospitalizations and need for transplantation is likely to accelerate. Although the overall prevalence of HCV infection is now thought to be declining –the near-term payoff for the rapid decline in incidence in the 1990s–the number of persons infected for more than 20 years could increase substantially before peaking in the year 2015 (Figure 7).¹⁶ This "bulge" of patients infected from the 1960s to the 1980s will have maturing HCV infection over the next 20 years and produce a parallel increase in clinical liver disease. This phenomenon of aging HCV infections, or "HCV gero-seropositivity," explains why even as the overall prevalence of HCV infection declines over the next several decades, the rate of HCV cirrhosis is projected to rise (Figure 8).³⁴ In other words, although the absolute number of patients with HCV infection will drop gradually, the percentage of these patients with ongoing long-term infections will increase and, hence, so will the relative rate of progressive cirrhosis in this population.

Based on Medicare and other government and private data sources, one researcher estimated US HCV costs in 1997 at $5.46 million.³⁴ One third of this national total went to direct health costs and two thirds went to indirect costs (for example, lost earnings); these estimates are considered conservative since costs related to diminished quality of life were not added. Approximately 92% of the total was spent on long-term liver disease while 8% was attributable to liver cancer. Separate calculations made for the year 1998 estimated HCV-related hospital costs at approximately $1 billion ²⁸ and anti- HCV drug costs at $530 million.³³

Based on the impending wave of HCV gero-seropositivity, the mortality, morbidity, and costs related to HCV are all expected to increase substantially over the next 10 to 20 years.^15,31 One economic model predicts that from 2010-2019, there will be $10.7 billion in HCV-related direct medical expenditures (Figure 9). The harder-to-measure indirect societal costs for years of decompensated liver disease or HCC and lost life could approach $75 billion.³²

Even allowing for the difficulties in capturing actual direct institutional HCV costs and for the inherent complexities of projecting future expenses based on current epidemiologic data, the trend is clear: managed care organizations will spend more money per member per year for HCV over the next 2 decades. The annual costs for HCV are already approaching those of other more widespread long-term diseases such as asthma ³⁵ and peptic ulcer disease.³³ Between now and 2020, as just reviewed, the costs of managing HCV will increase significantly. With the recent introduction of a combination-therapy regimen that effectively abolishes the risk of liver disease in more than half of those harboring the virus, increasing numbers of HCV-positive health plan members will become potential candidates for an expensive course of drug treatment. The safety, efficacy, and potential cost effectiveness of this treatment regimen will be outlined in the accompanying article.

Who to Treat?

As the inevitable wave of HCV disease burden approaches, clinicians and administrators will seek strategies to target screening, counseling, and provide therapy for those health plan members most at risk of cirrhosis and HCC. As made clear in this brief overview of the varying natural histories of HCV (Figure 6)–and notwithstanding the growing recognition of the psychological consequences of long-term hepatitis–only about 15 to 20 of every 100 individuals exposed to HCV will develop cirrhosis over 30 years of HCV infection, and the majority of those individuals with cirrhosis will remain stable over an extended period of 10 or more years, or compensated for the remainder of their lives. How can clinicians and healthcare systems target counseling and treatment on those patients most likely to develop decompensated liver disease and HCC?

Liver biopsy remains the traditional measure of predicting the risk of future progression. The degree of fibrosis as seen on biopsy is directly correlated with the subsequent rate of progression (Figure 10).³⁶ Although all patients with long-term HCV are potential candidates for antiviral therapy, treatment is generally recommended for those with an increased risk of developing cirrhosis. The current NIH guidelines define these high-risk patients as those with detectable HCV RNA levels higher than 50 IU/mL and a liver biopsy with portal or bridging fibrosis and at least moderate inflammation and necrosis.⁷ Thus, almost all patients receiving HCV combination therapy today have had a liver biopsy. Liver enzymes or symptoms are not considered adequate guides to initiating therapy. Since patients with HCV genotypes 2 or 3 have much higher chances of treatment success (80%), a liver biopsy in these patients may not always be necessary to make these initial treatment decisions.⁷

Of course, many other factors shape the decision to treat HCV infection. These include the likelihood of side effects and patient adherence, patient age, the extent of liver damage, and the presence of comorbidities, coinfections, and contraindications. These and other treatment-related considerations will be discussed in the accompanying article. In addition, clinicians and pharmacists need to realize that the treatment decision is no longer an all-or-nothing proposition. New "stopping rules" to determine when to abort therapy early in patients not likely to benefit are increasingly providing clinicians with a compromise approach that can avoid drug side effects and save money.

As clinicians weigh the potential for a permanent HCV cure against the risks of side effects and the substantial costs of therapy, clinical judgment and access to the evolving clinical evidence base will remain key. Ideally, fully informed patients make the final decision on whether or not to embark on a course of HCV therapy. In reality, the clinician and the health system remain responsible for shaping these decisions. Over the next 2 decades, the collective clinical and economic effects of these decisions –hundreds of thousands of them made one by one, patient by patient, in clinics and hospitals throughout the United States–will resonate widely.

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