"Viral Hepatitis: An Epidemic in the Making? New
Approaches to the Prevention, Diagnosis, and Treatment of Viral Hepatitis"
(Located at the American Gastroenterological Association website)
TYPE C VIRAL HEPATITIS
Virology
Hepatitis C virus is a spherical, enveloped, single-strand linearRNA genome similar in genetic and virologic makeup to the pestiviruses and flaviviruses that compose the family Flaviviridae. The 54 end of the virus encodes the structural capsid and envelope proteins. The nonstructural regions are at the 34 end of the genome and encode the viral proteases, RNA polymerase, and regulatory peptides.
Hepatitis C virus lacks proofreading ability and therefore undergoes genetic changes during replication. Thus, viral populations are extremely heterogeneous. Over the centuries, this diversity has evolved to such a degree that several distinct groupings of virus have formed and are now classified as six major HCV genotypes. Within each of these genotypes are several subtypes. While genotyping of HCV has been reported to be associated with severity of disease and risk of progression, these associations are controversial and by no means certain. However, it is clear that genotype influences the response to short courses of interferon therapy.64
The ability of HCV to change its genomic makeup over time also occurs within the infected individual and creates a family of closely related viruses with minor differences, called "quasispecies." These minor changes may explain the apparent ability of HCV to evade the host's immune surveillance and persist.65 Indeed, antibody produced to one quasispecies does not necessarily afford protection against another. This quasispecies variation, as well as the more significant differences seen with genotypes, will provide a challenge for researchers attempting to construct a polyvalent vaccine.
Epidemiology: Incidence, Transmission, Seroprevalence, and Risk Factors
It is currently estimated that 3.9 million people in the U.S. are infected with HCV. Fortunately, the CDC estimates that the number of new cases each year has fallen during the past decade, from close to 200,000 to 28,000. Most of these new cases are found in young adults between the ages of 20 and 45 (CDC: unpublished data). This population also has the highest seroprevalance of HCV infection. Notwithstanding the decline in new cases, there remains a large number of chronically infected Americans who may serve as a potential source of transmission and who are at risk of the serious sequelae of chronic infection.
Transmission patterns have changed in recent years. Prior to the discovery of HCV, there was a strong correlation found between hepatitis and a recent history of blood transfusion. Injection drug use, employment in health care, sexual/household exposure, promiscuous sexual behavior, and low socioeconomic status also were important risk factors. Although direct percutaneous exposure through a transfusion of blood or blood product remains an efficient means of transmission, currently most HCV infections are acquired outside the transfusion setting.66 Elimination of paid donors, initiation of donor unit testing using both surrogate and viral specific tests, viral inactivation of clotting factor concentrates, and other changes in transfusion practices since 1992 have nearly eliminated the risk of hepatitis C for the transfusion recipient. As a consequence, injection drug use has emerged as the most common cause of HCV infection. While the number of acute cases of infection among injection drug users also has declined since 1987, the risk in this population remains high, accounting for more than half of all new and chronic infections. Efficiency of transmission is high among injection drug users as well. More than 75 percent of all new injection-drug users become seropositive for HCV within one year after beginning drug use (CDC: unpublished data). While it is difficult to design effective prevention campaigns for this population, needle distribution and exchange programs may be useful.
Today, among patients with presumed acute hepatitis C, the most commonly identified risk factors are injection drug use; hemodialysis; sexual or household exposure to an infected contact, multiple sexual contacts, or perinatal exposure; and health care employment (CDC: unpublished data). In up to 40 percent of cases, individuals with acute infection deny having an exposure to a recognized risk factor in the six months prior to infection, and as many as 20 percent deny a contact during their lifetime. Nonetheless, more than 60 percent have participated in some high-risk behaviors at some point during their lives, including past drug use, a history of STDs, body piercing, tattoos, intranasal cocaine use, or a prison stay (CDC: unpublished data). Low socioeconomic status, which is a common risk factor for other percutaneously transmitted infections, also remains a risk factor for hepatitis C (Figure 9 [NOTE: not included]).
Natural History
The clinical course of hepatitis C has been controversial, in large part because the onset of acute disease rarely is identified, and the evolution to cirrhosis and complications, if it occurs, usually requires decades. Moreover, many of the studies have investigated patients at different points in the course of disease, making comparisons difficult and further confounding the clinical picture. Nevertheless, despite the broad range of presentations and outcomes, and the lengthy history, there are a number of milestones and risk factors that help clarify the natural history of hepatitis C (Figure 10 [NOTE: Not included]).
The mean incubation period from infection to onset of acute hepatitis, as manifested by elevated serum ALT levels and detectable HCV RNA, is seven weeks, with a range of three to 20 weeks. Prospective studies beginning from recognized exposure have indicated that a third of infected patients become icteric and symptomatic. In contrast, among persons identified as HCV-positive through routine screening, as many as 90 percent do not recall an episode suggesting the onset of acute disease. When recognized, the acute illness typically lasts from two to 12 weeks. In up to 15 percent of cases, the disease is self-limiting; symptoms resolve, HCV RNA becomes undetectable, and ALT levels return to normal. At least two-thirds of all patients are asymptomatic. Jaundice is uncommon, and diagnosis during the acute illness is unusual. Unfortunately, more than 85 percent of patients with acute disease become chronically infected (HCV RNA+) and 65-85 percent develop chronic hepatitis (elevated ALT).66 Symptoms of chronic hepatitis usually are mild, intermittent, and nonspecific although they can affect quality of life. The most commonly reported are fatigue, abdominal pain, fever, and arthralgias. As a consequence, many patients do not present or are not tested for hepatitis until years after infection.
Approximately 30 percent of chronically infected patients have persistently normal ALT levels, and in some others, the ALT may be elevated only occasionally. On liver biopsy, these individuals usually have only mild histological changes. Generally, the prognosis is excellent in these patients, although the natural history has not been completely studied.
Chronic hepatitis C must be considered a progressive liver disease. However, disease progression usually evolves over decades and, in many patients, may be so slow that it does not result in increased morbidity or mortality (Figure 11 [NOTE: not included]).67 The rate of progression relates best to the degree of inflammation and fibrosis seen on liver biopsy68 (Figure 12 {NOTE: not included]) and to alcohol use.69 However, it is very difficult to predict accurately the course in individual patients.
There are several important extrahepatic manifestations of HCV infection, including essential mixed cryoglobulinemia (EMC), arthritis, membranoproliferative glomerulonephritis, keratoconjunctivitis sicca, lichen planus, and porphyria cutanea tarda. Hepatitis C is the most common cause of EMC, which is characterized by the presence of cryoglobulins in serum, hypocomplementemia, and symptoms such as fatigue, muscle and joint pain, arthritis, dermatitis, and neuropathy.
Approximately 20 percent of hepatitis C patients develop cirrhosis during the first two decades of disease, although in rare cases, cirrhosis can develop within the first two years.70 Symptoms usually become more noticeable in cirrhotic patients and may include severe fatigue, marked muscle soreness and neuralgia, fluid retention, jaundice, dark urine, upper intestinal hemorrhage, and itching. Many patients, however, will remain asymptomatic until a major complication, such as variceal hemorrhage or ascites, occurs (Figure13 [NOTE: not included]). The risk of developing cirrhosis appears to accelerate in patients over the age of 50-55 years and in the presence of alcohol intake.69 Thus, it is recommended that alcohol ingestion be strongly discouraged in all patients with hepatitis C.
Chronic hepatitis C, accompanied by cirrhosis and hepatic failure, is the leading indication for liver transplantation in adults in the U.S., accounting for 30-50 percent of cases at some large transplant centers.71 While nearly all recipients will remain positive for HCV RNA following transplantation, liver disease usually is mild and only slowly progressive. Five-year survival in these patients is similar to recipients transplanted for other disease.
Diagnosis
Serological tests are the primary screening tools for hepatitis C. The most important technique for detecting antibodies to HCV is the second-generation enzyme-linked immunoassay (EIA-2). The test is simple, automated, easily reproducible, and inexpensive. It is useful in both low- and high-risk settings; in populations with high-seroprevalence, such as injection drug users or patients with elevated serum ALT levels, the sensitivity and accuracy are both greater than 90 percent, and a positive test is sufficient for diagnosis.72 A more sensitive third generation assay, with sensitivity and specificity exceeding 95 percent, will be available soon.73
However, in low-seroprevalence populations, such as healthy blood donors with normal serum ALT levels, the EIA-2 assay may produce false positive results. To help resolve these findings, two supplemental assays, the radioimmunoblot assay-2 (RIBA-2) and qualitative reverse transcription-polymerase chain reaction (RT-PCR) assay for HCV RNA are most commonly employed. While the RT-PCR technique is more sensitive, it has been difficult to standardize; wide variation of results from different laboratories has lessened confidence in the reliability of the assay. In populations with low-seroprevalence, only 50 percent of individuals who are HCV EIA-2 positive are reactive with supplemental assays (i.e., are truly positive for hepatitis C). By comparison, in high seropositive populations, the positive predictive value of the screens is higher, nearly 90 percent.72 Supplementary testing for infection with HCV should always be performed on asymptomatic individuals from low-risk settings who are anti-HCV positive. Individuals in high-risk groups with positive EIA-2 results do not usually require supplementary testing to confirm the diagnosis. In the algorithm of diagnostic testing for individuals suspected of HCV infection, a negative EIA-2 test rules out infection in low-risk populations. A positive result would indicate a need for supplementary RIBA-2 testing. Indeterminate test results require HCV RNA testing by PT-PCR. For those with positive findings by both measures and persistently normal ALT, a liver biopsy is usually unnecessary unless antiviral therapy is a consideration.
For those with biochemical or clinical signs of liver disease, a positive EIA-2 finding will be sufficient to make the diagnosis. However, supplementary tests can be used to confirm if the clinician suspects that the test might be falsely positive, as in the patient with marked hyperglobulinemia. Disease activity and staging can be assessed only by liver biopsy.
As mentioned previously, serum ALT levels are elevated in the majority of patients with liver disease due to chronic hepatitis C. However, ALT levels do not correlate well with the histologic extent of the liver disease. Thus, only liver biopsy can provide information about the severity of liver disease, and is usually indicated to stage the disease, especially if treatment is being considered.
Management and Treatment
Currently, interferons are the only agents with proven efficacy in the treatment of HCV infection. In 1991, the U.S. Food and Drug Administration cleared the first alfa interferon, interferon alfa-2b (Intron.A), for the treatment of chronic hepatitis C.39 Five years later, the agency licensed a second drug, interferon alfa-2a (Roferon.-A).74 A third compound, interferon alfacon-1 (Infergen.), a synthetic consensus interferon, followed in 1997.75 Other interferons under investigation include a leucocyte interferon, a lymphoblastoid interferon, and an interferon beta.
The usual response to interferon treatment is lowering of the serum ALT level and reduction of serum HCV RNA. This occurs within the first few weeks and is usually maximal by the twelfth week of therapy. It is unusual for a response to occur after that time. Thus, it is currently recommended that treatment be stopped if the serum ALT has not returned to normal after the first 12 weeks of treatment. An exception may be the patient with non-detectable HCV RNA by RT-PCR and elevated ALT levels, in whom treatment may be continued. Response to interferon is defined as biochemical (normalization of serum ALT) and virologic (loss of detectable HCV RNA by RT-PCR), and is evaluated at the end of treatment (ETR) and at least six months following discontinuation of treatment (sustained response, or SR).76
A recent meta-analysis77 of all published randomized controlled clinical trials reported that the currently recommended regimen of 3 million units (MU) administered subcutaneously three times per week for at least 12 months resulted in a biochemical ETR in 50-54 percent of patients and a SR in 28-34 percent. These results compare to 44-53 percent and 14-22 percent, respectively, with the previously recommended therapeutic regimen of six months. Higher doses increased the ETR to 66-69 percent and SR to 46-49 percent when used for 12-18 months, but did not have an advantage if used for shorter durations. Higher doses are also associated with lower patient tolerance.
Patients receiving interferon therapy should have regular monitoring, including complete blood count, ALT and thyroid stimulating hormone levels, and viral load. At three months, serum ALT and HCV RNA levels should be determined. Patients who show no response at this time should discontinue treatment, because the likelihood of future response is negligible.
Side effects of interferon therapy include flu-like symptoms, such as fever, chills, headache, tachycardia, myalgia, and arthralgia. These tend to diminish over the first few days of treatment. Bone marrow suppression, neuropsychiatric problems (depression, cognitive impairment, and irritability), and fatigue may occur later in treatment. Side-effects can sometimes be ameliorated by nocturnal administration of interferon and, in the case of early-phase flu syndrome, by pre-treatment with acetaminophen or non-steroidal anti-inflammatory drugs. Nearly 10 percent of patients require dose reduction because of adverse events; as many as five percent must discontinue therapy. Fewer than two percent of patients suffer more serious side effects, including thyroid disorders or severe depression. Rare adverse events, including seizure disorder, acute cardiac and renal failure, hearing impairment, sepsis, interstitial pulmonary fibrosis, and retinopathy, have been reported.39, 74, 75
The recent panel at the National Institutes of Health Consensus Development Conference on the Management of Hepatitis C76 concluded that the indications for interferon treatment were unequivocal in patients with moderate-to-severe inflammation or fibrosis on liver biopsy, as they have the highest risk for progression to cirrhosis. It further recommended that the need for treatment be considered on an individual basis in patients with histologically less severe disease and those with cirrhosis (Figure 14). The NIH consensus panel recommended that patients with decompensated cirrhosis not be treated, but rather be considered for liver transplantation. In addition, the panel recommended that patients with normal serum ALT levels should not be treated, as there is no evidence of lasting benefit and some patients may develop elevated liver enzymes on treatment. The role of interferon therapy in immunosuppressed patients, such as those with HIV/HCV co-infection or transplant recipients is unclear and requires further study.
Interferon also is effective in the treatment of acute HCV infection. In the aforementioned meta-analysis, a three-month course of treatment was associated with a sustained virological response (absence of HCV RNA 12 months after treatment) of 41 percent compared to four percent in untreated controls.77 Unfortunately, it is uncommon for patients to present during acute infection. In view of the high response rate to interferon therapy, efforts should be made to identify these patients.
Other agents hold promise for the treatment of hepatitis C. Ribavirin is a nucleoside analogue that has in vitro antiviral activity against several viruses. As monotherapy, ribavirin lowers serum ALT levels in many patients with chronic hepatitis C, but has no effect on serum HCV RNA levels. However, when used in combination with interferon, it reduces post-treatment relapse.78,79 Several controlled studies are underway to confirm these results. Newer agents that are in development and will eventually require clinical consideration include viral enzyme inhibitors such as protease and HCV RNA polymerase inhibitors, oligopeptides including ribozymes and antisense oligonucleotides, therapeutic vaccines, and other immunomodulators. Studies of corticosteroids, ursodeoxycholic acid, iron reduction therapy, and alpha thymosin either have shown no effect or are inconclusive.
Regardless of other treatment considerations, all patients with hepatitis C should be vaccinated against hepatitis A and hepatitis B as these infections may cause significant morbidity and mortality when superimposed on pre-existing liver disease. In addition, chronic hepatitis C patients with cirrhosis should be monitored for the development of hepatocellular carcinoma by annual alpha fetoprotein determination and ultrasound.
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