Chronic Hepatitis C: An Age Wave of Disease Burden

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There are at least 2.7 million individuals in the United States, most of them in their 40s and 50s, who are chronically infected with hepatitis C virus (HCV). As these infected individuals get older, about 20% will develop cirrhosis, and a significant fraction of those with cirrhosis (about 1 in 10) will then develop serious decompensated liver disease or hepatocellular carcinoma. Currently, HCV is the primary cause of death in 8000 to 12 000 people every year; the virus is also the primary reason for liver transplantation in the United States. Although the number of new cases of HCV infection has been dropping steadily since the introduction of improved blood-supply screening, the "age wave" of existing chronic HCV in baby boomers is expected to contribute to a substantial rise in morbidity, mortality, and costs over the next 2 decades. Although it is difficult to predict which HCV-infected patients will progress to serious liver disease, the availability of a combination drug regimen (peginterferon alfa plus ribavirin) that essentially "cures" the disease in more than half of treated patients now provides clinicians and pharmacists in managed care settings with the tools needed to diminish the impact of the anticipated wave of liver disease. This article reviews the epidemiology, natural history, clinical and economic burden, and screening and treatment options for HCV.

(Am J Manag Care. 2005;11:S286-

S295)

With the availability of effective interferon-based therapies, the fight against hepatitis C virus (HCV) has expanded from a public health-oriented focus on prevention and treatment of mainly the highest-risk ideal patient types to earlier diagnosis and drug therapy for a wider range of potentially difficult-to-treat patient types. This evolving treatment approach requires new strategies for patient risk assessment, cost-effectiveness analysis, and therapy initiation and monitoring. This article lays the groundwork for understanding these new strategies by reviewing the epidemiology, virology, burden, and therapy options of HCV.

Epidemiology

HCV is the most common long-term blood-borne infection in the United States.1 Based on a widely-cited population survey of anti-HCV antibody, the Centers for Disease Control and Prevention (CDC) estimate that 3.9 million (1.8%) Americans have been exposed to HCV; tests for viral ribonucleic acid (RNA) in the serum indicate that 2.7 million Americans have long-term infection.1-3 Because many high-risk populations–such as prisoners, intravenous drug users, and homeless people–are generally excluded from national surveys, such estimates of HCV prevalence are likely conservative.4 A recent study of 597 homeless veterans, for example, found an anti-HCV prevalence of 42%.5

Whatever the actual absolute number of chronically-infected individuals with HCV, the problem for clinicians and healthcare systems is compounded because these individuals often remain undiagnosed. Infection with HCV is usually clinically silent not just during the acute phase but for decades afterwards.6,7 As many as three quarters of all currently-infected patients have not been identified. Without knowing who is chronically infected, early risk reduction (eg, through counseling on alcohol and weight loss) and targeted drug treatment to avoid liver complications are not possible.

Who are these infected individuals? Most of the millions who are chronically infected with HCV are now in their fourth or fifth decade of life. As they move into their 60s and 70s, these individuals constitute an "age wave" of asymptomatic HCV infection that is headed toward clinical disease.3 Presumably, many of these baby boomers were infected in the 1960s and 1970s after experimentation with injection drug use. Administrators and clinicians in all socioeconomic settings should note that this category includes many individuals who used drugs only briefly many years ago.8 A recent retrospective population-based study done in a national managed care organization (MCO) confirms this peak prevalence of chronic HCV infection among those members who are 45 to 54 years of age (Figure 1).9 Rates of HCV infection are also generally higher among men and African Americans.10

This phenomenon of an aging generational cohort of HCV-infected patients is also a result of the rapidly declining incidence of new HCV infections over the past 25 years. The number of new infections per year has declined from an average of 240 000 in the 1980s to about 30 000 in 2003.11 Among 25- to 39-year-olds–historically the age group with the highest rate of infection–the incidence has declined by 86% from 1992 to 2002.1 These positive trends can be attributed to improved blood donor screening (available since June 1992) and the related reduction in transfusion-associated cases, but even more so to safer needle practices among injection drug users due to concern about infection with human immunodeficiency virus (HIV).1

Currently, the main risk factor for HCV transmission is injection drug use involving shared, unsterilized, or poorly sterilized needles and syringes (Figure 2).10,12,13 Anyone who has ever injected illicit drugs should be tested.14 Sexual transmission is the next largest cause of HCV infection. Although patients and spouses should be reassured that the risk of transmission in a stable monogamous relationship is less than 5%,8 they should also recognize that people with high-risk sexual behavior, multiple partners, and sexually transmitted disease are at increased risk for HCV infection.8,10,13,14 Although the current prevalence among persons with hemophilia is extraordinarily high due to exposure to clotting factor concentrates produced before 1987 and/or blood transfusions before 1992, the number of new cases attributable to tainted blood products is vanishingly low. Other minor categories of risk include pre-1992 blood transfusions for any purpose, current exposure to blood products (eg, transplant patients, chronic renal failure), infants born to HCV-infected mothers (overall risk of maternal-infant transmission is 5%), and needle-stick accidents among health workers. Some studies have suggested risk of HCV transmission with percutaneous exposures, such as acupuncture, body piercing, and tattooing, but these risks are considered low.14

Overall, HCV prevalence ranges from very high (~90%) in groups such as injection drug users and persons with hemophilia, to moderate (~10%) in recipients of blood transfusions before 1992, and to low (2%-5%) in those exposed by needle stick and sexual partners of HCV-infected persons. The current CDC guideline on who should be routinely tested for HCV infection (Table 1)10 reflects this overall understanding of HCV transmission risk and prevalence.13,14

Natural History

HCV is a small single-stranded RNA virus (family Flaviviridae) with a preference for hepatocytes. Its propensity for frequent mutations allows the virus to evade a vigorous cell-mediated immune response to the initial infection. This weak early response of T cells appears to set the stage for long-term infection.4 There are 6 major strains or genotypes of HCV and at least 50 subtypes. These genotypes have different geographic distributions, with types 1a and 1b being the most common in the United States (accounting for about 75% of cases) and genotypes 2 and 3 present in about 10% to 20% of patients.8 These subtypes are clinically relevant–and now routinely determined in testing–because genotypes 2 and 3 are very susceptible to current combination therapy regimens whereas genotype 1 has a lower response rate to interferon-based therapies.

Most patients have no signs or symptoms of acute HCV infection. In those rare patients where acute symptoms can be tracked (eg, a hospital worker with a needle stick injury who is being closely monitored), symptoms appearing a few weeks after exposure may include jaundice, fatigue, anorexia, weakness, dark urine, or abdominal pain.1 Even if such symptoms are present, they are frequently mild, nonspecific, or intermittent. After initial exposure, blood tests typically reveal HCV RNA within 1 to 3 weeks and elevated serum alanine aminotransferase (ALT), which indicates liver injury, within 4 to 12 weeks; at least 90% of patients will have a positive antibody test 3 months after HCV exposure.4

Currently, the enzyme immunoassay for anti-HCV antibody is performed at the initial screening test and then, in most cases, the HCV RNA test is performed to confirm viremia. These RNA tests using the polymerase chain reaction technique are extremely sensitive and almost all patients with chronic HCV will test positive. Both the quantitative HCV RNA test and the ALT may be useful in monitoring disease severity or progression and, even more practical, in gauging response to antiviral therapy with serial measurements.4

Progression from acute to chronic infection occurs in 50% to 85% of cases.15,16 The 15% or more of patients who are able to "clear" the virus spontaneously are of great interest to researchers. Understanding the mechanisms of this natural immunity to HCV may eventually lead to creation of an effective preventive or therapeutic vaccine. Chronic infections are often defined not by symptomology (they are also usually clinically silent) but by the persistence of HCV RNA in the blood for 6 months or longer.4,13 This asymptomatic long-term phase lingers over a period of decades and, in many cases, over a lifetime.

In some individuals, however, chronic HCV infection sets the stage for progressive liver fibrosis and scarring. The factors that accelerate this steady attrition of functioning liver cells include alcohol use, nonalcoholic liver disease, coinfection with HIV or hepatitis B virus, and male sex. However, it is impossible to predict which patient with chronic HCV infection will progress rapidly to full-blown cirrhosis. Overall, about 20% of patients with chronic HCV infection will eventually develop cirrhosis, which may itself remain clinically silent until advanced disease or added risk factors produce overt hepatic decompensation. Alternatively, even without development of frank cirrhosis and liver complications, patients with chronic HCV infection may suffer from chronic fatigue or decreased quality of life.4,17,18

The first signs of decompensated liver disease are generally mild, nonspecific, and intermittent and include fatigue. Other symptoms include right upper quadrant discomfort and nausea. As the damage progresses, the symptoms become more prominent and include muscle weakness, weight loss, itching, dark urine, and fluid retention.4 Unfortunately, this late stage of disease progression is when many patients receive the initial diagnosis of HCV infection. Although a liver biopsy provides the definitive measure of hepatic fibrosis, physical findings of a firm liver or enlarged spleen provide further evidence of advanced liver disease.8 Every year, approximately 3% to 6% of patients with cirrhosis develop decompensated liver disease and thus become potential candidates for liver transplantation.15

Hepatocellular carcinoma (HCC) is another complication of chronic HCV infection. Up to 4% of patients with long-term HCV infection develop HCC every year.4,13,15 The virus seems to account for about one third of HCC cases in the United States.4 As with progression to cirrhosis, however, predicting which patients with HCV and cirrhosis will develop HCC is extremely difficult.

Indeed, the entire progression of HCV disease from stage to stage–from acute infection, to chronic hepatitis, to subclinical liver fibrosis, to cirrhosis that is mostly compensated, to decompensated liver disease and/or to liver cancer–is hard to predict. Studies that have evaluated this long-term natural history of HCV have produced varying results in terms of progression rates and risk factors, variations that are likely due to differences in the populations studied and the study definitions employed.16 Nonetheless, for clinicians and administrators seeking to develop policies for screening and treatment of HCV, the big picture should be clear: a significant proportion of patients infected with HCV will develop liver disease and its serious consequences. The summary flow-sheet in Figure 3 provides an overview of likely patient outcomes.15 Identification of HCV-infected patients earlier in this natural course of disease will allow earlier interventions in targeted high-risk groups.

Burden of HCV Will Grow From 2005 to 2020

The clinical and economic impact of chronic HCV infection in the United States will grow considerably in coming years. This projected increase in disease burden may seem paradoxical given the sharply decreased rates of new infections over the past 10 to 15 years. As just described, however, it is the smoldering 20-and 30-year-old infection that is most capable of causing permanent damage to the liver. Therefore, a large population of individuals who acquired HCV in the 1960s through the 1980s are at prime risk to develop clinical disease over the next decade. This coming increase in morbidity and mortality due to HCV cirrhosis in the face of declining overall prevalence of HCV infections is depicted in Figure 4.19 Davis et al have projected that as the duration of infection increases in the diminishing cohort of infected patients, the proportion with cirrhosis will increase from 16% to 32% by 2020 in an untreated population along with increases in complications, such as hepatic decompensation (up 106%), HCC (up 81%), and liver-related deaths (up 180%).19

HCV is already thought to account for at least 8000 to 12 000 deaths annually in the United States.4,8,10 Based on epidemiologic projections, mortality from HCV is expected to increase 2- to 4-fold over the next 2 decades.2,20,21 As the death rate from infection with HIV continues to decline, the effect of "competing mortality" may boost mortality due to HCV infections even further (ie, patients coinfected with HIV and HCV will live longer with HIV and therefore die from HCV rather than HIV/acquired immunodeficiency syndrome).4,22 Patients with HCC have an especially poor prognosis,23 and these cancer deaths have also been rising24 and will contribute to the increased HCV mortality in the years ahead. Overall, HCV-related liver disease is projected to cause 165 900 deaths from 2010 to 2019 plus an additional 27 200 deaths from HCV-related HCC.20

Morbidity attributable to HCV in terms of hospitalization and transplantation is also significant and growing. From 1992 to 1998, for example, hospitalizations in which HCV-related liver disease was the primary or secondary reason for admissions rose about 6-fold in one study based on a national database.2,25 Similarly, from 1990 to 2000, there was a 5-fold increase in the number of orthotopic liver transplantation recipients with HCV.2 Liver transplantation is the only treatment option for patients with fully decompensated cirrhosis, and HCV infection is now the primary reason for this complex and costly procedure. Reinfection with HCV after transplantation is common and often produces a rapidly progressive and hard-to-treat form of liver disease. These trends in increasing HCV morbidity are expected to continue.2,26 Recent data from one of our institutions, for example, indicate that HCV-related hospitalizations have been increasing by approximately 25% to 30% per year (J McHutchison, personal communication).

Several researchers have attempted to gauge the economic burden of HCV disease. The national study of inpatient trends mentioned above estimated 1998 hospital charges for HCV infection in excess of $1 billion.2 Another study estimated the combined direct and indirect costs in 1997 to be approximately $5.5 billion,19 a level that already rivals the costs of more prevalent diseases, such as asthma.27 Only limited data are available for insurers or healthcare groups considering the "real-world" per-patient costs of care for members with chronic HCV infection. In a review of claims from 191 patients with chronic HCV, the total medical and pharmaceutical costs during 1995-1997 totaled $7.1 million.28 In another retrospective analysis of MCO claims, the median HCV-related costs in patients diagnosed with HCV and receiving interferon alfa were $2470 per patient per year.29 Practical studies of actual per-patient costs will be required to help MCOs evaluate the potential cost effectiveness of expensive therapies, such as peginterferon alfa and ribavirin, in various patient populations.30,31

Looking ahead, the cost burden of HCV is expected to grow parallel with the clinical burden. Economic models taking into account the projected increases in HCV morbidity and mortality indicate that the direct medical expenditures from 2010 to 2019 will be $10.7 billion.20 Over this same period, the societal costs attributable to the projected 720 000 years lost to decompensated cirrhosis and HCC are estimated to be $21.3 billion, while the indirect costs attributable to deaths in those younger than 65 years of age are expected to cost $54.2 billion.

Treatment Considerations

The ultimate goal of treatment is to prevent the complications of chronic HCV infection. This includes slowing disease progression, reducing hepatic inflammation and necrosis, and reducing the risk of HCC. Because these complications accrue, as just discussed, over an extremely long time frame, at different rates in different patients, and subclinically, the primary measurable goal of HCV therapy is to produce a sustained virologic response (SVR). The SVR is defined as the absence of HCV RNA in the serum at the end of treatment and 6 months later.14 The vast majority of patients–greater than 99%–who are still HCV-RNA negative 6 months after completing therapy will remain so indefinitely.32 SVR is considered, in practical terms, a signal of "cure" for chronic infection.

The options for HCV therapy have evolved over the past decade to produce steady gains in overall response rates (Figure 5).14 In the mid-1980s, monotherapy with interferon alfa for 6 months led to SVRs in only about 1 of every 10 patients. When this recombinant form of a natural host protein with antiviral properties was administered for 1 full year, the response rate doubled. With the addition of ribavirin, an oral agent with multiple nonspecific antiviral and immune properties, SVRs doubled again to the range of 34% to 42%. The most recent innovation in pharmaceutical design was to increase the half-life of the interferon molecule by attaching an inert polyethylene glycol moiety. When these long-acting forms of peginterferon are combined with ribavirin, more than half of the treated patients attain the virologic cure. The recommended dosing for agents approved by the US Food and Drug Administration for use in chronic HCV infection is listed in Table 2.14

Most of the trials supporting the efficacy of the combination regimen are based on the surrogate outcomes of SVR. Some evidence of treatment-related improved survival and/or reduction of liver fibrosis/cirrhosis or HCC is also available,33-38 but larger longer-term trials to document improved survival, prevention of end-stage liver disease, and reduction in rates of HCC are still required.39 In particular, data on long-term treatment outcomes in populations of asymptomatic HCV-infected patients, such as those who might be identified in screening, are lacking.40

Documentation of cost effectiveness of anti-HCV therapy–which can cost up to $20 000 or $30 000 per year per patient–is also still required. Despite these remaining questions, the evidence of efficacy with anti-HCV therapy is compelling and the National Institutes of Health (NIH) consensus committee considers pegylated interferon alfa plus ribavirin as the standard of care for chronic HCV infection.4,8 According to the NIH:

"All patients with chronic hepatitis C are potential candidates for antiviral therapy.

Treatment is recommended for patients with an increased risk of developing cirrhosis.

These patients are characterized by detectable HCV RNA levels higher than 50 IU/mL, a liver

biopsy with portal or bridging fibrosis, and at least moderate inflammation and necrosis.

The majority also have persistently elevated ALT values."

The practice guidelines of the American Association for the Study of Liver Diseases (AASLD) also consider peginterferon alfa plus ribavirin the treatment of choice for chronic HCV infection.14 As detailed in Figure 6,14 the need for biopsy confirmation as well as the choice of dose and duration of treatment depend on the genotype of the virus. In fact, both the NIH and AASLD guidelines emphasize the need to individualize therapy based on the likelihood of treatment response, the potential for side effects, the severity of liver disease, and the presence of comorbid conditions.4,14

P

Differences in treatment response based on such factors have been made clear in the major randomized clinical trials with peginterferon alfa plus ribavirin. In a study of 1530 patients with chronic infection, for example, SVR in patients with genotype 1 was 42% compared with an SVR of 54% in the patient population as a whole.41 In this same study, the incremental benefit of using pegylated interferon alfa-2b rather than nonpegylated interferon was +9% in the genotype 1 group (= .01) versus just +3% in the genotype 2 and 3 group. This study also showed that SVRs were higher in those patients who adhered more to therapy. Essentially identical results were found in the other major randomized trial with combination therapy (n = 1121), where the SVR in all patients receiving pegylated interferon alfa-2a plus ribavirin was 56% overall, and 76% in those with genotype 2 or 3.42

The range of side effects seen with interferon-based therapy in these and other trials was considerable although generally manageable; side effects included neutropenia, fever/nausea, and injection-site reactions (Table 3).8,41,42 The interferon side effects generally diminish after the first few weeks of therapy, and acetaminophen may be helpful for muscle aches and low-grade fever. Depression requires careful monitoring and may benefit from antidepressant therapy.8 The contraindications to interferon therapy include severe depression or other neuropsychiatric syndromes, active substance or alcohol abuse, autoimmune disease (eg, rheumatoid arthritis, lupus, psoriasis) that is not well controlled, bone marrow compromise, and an inability to practice birth control. The dose-related anemia associated with ribavirin can precipitate angina or myocardial infarction in susceptible people receiving combination therapy. This is why ribavirin is contraindicated in patients with marked anemia or coronary artery or cerebrovascular disease. Renal dysfunction and inability to practice birth control are other ribavirin contraindications.8

In summary, the major trials confirm that anti-HCV drug treatment is effective in more than 50% of all patients and in approximately 80% of those patients with genotype 2 or 3. Adherence to therapy is critical in obtaining the best results. A retrospective analysis has documented that patients who receive more than 80% of their total interferon doses and more than 80% of their ribavirin doses for more than 80% of the duration of therapy (ie, "80+80+80") had significantly higher SVRs compared with those with worse adherence (Figure 7).43 These results imply that patient selection, education, and monitoring are critical to successful treatment of patients with chronic HCV infection. Careful attention to these factors will help MCOs and health plans attain optimal results with the limited resources available.

Conclusion

MCOs now provide care for large cohorts of individuals with chronic HCV infections. Because many of these individuals are covered by employer-sponsored plans, the clinical and economic fallout of liver disease from these members with chronic hepatitis will be borne increasingly by MCOs and private insurers in the years ahead.9,44 To reduce this projected rise in the burden of HCV-related symptomatic liver disease, health plans will need to increase efforts at targeted HCV screening and treatment. Detection of chronic HCV before the onset of liver cirrhosis and decompensation will allow, in those individuals deemed at high risk for progression, counseling and institution of anti-HCV combination drug therapy that now essentially cures more than half of all infected patients. Adherence to therapy is critical in producing a greater SVR and, hence, in preventing advanced liver disease.

Drs Bacon and McHutchison wish to acknowledge Paul Courter's contribution to the writing and editing of this article.