Hepatitis C Virus
Authors: Steven K. Herrine, MD, Raymond T. Chung, M.D.
VIROLOGY
The discovery of hepatitis C virus (HCV) as the major cause of non-A, non-B hepatitis in 1989 was accomplished through incisive use of the modern tools of molecular biology (21). Despite this technological breakthrough progress on understanding the virology and pathophysiology of HCV has been hampered by the lack of suitable laboratory models. The HCV replicon system has been the standard tool used to investigate HCV replication and inhibition (14,74), while HCV functional pseudoparticles and other modeling systems have been employed to further investigate the virus (9, 57). Based on these, and other, methods, HCV has been classified as a Flavivirus, Hepacivirus genus. Similar viruses include yellow fever virus, dengue virus and bovine viral diarrhea virus. Molecularly, HCV contains a 9.6 kb plus-strand RNA genome composed of a 5' noncoding region, a long open reading frame encoding a polyprotein precursor of about 3000 amino acids, and a 3' NCR. The structural proteins include the core protein, thought to represent the viral nucleocapsid and the envelope glycoproteins E1 and E2. The envelope proteins form a non-covalent complex, the function of which is not fully understood.
Based on genetic sequencing, HCV is divided into six genotypes, named 1 through 6 which are further subdivided in to over 50 subtypes which are named alphabetically. The viral sequence can vary by up to 35% between genotypes highlighting its genetic diversity. Within a subtype the sequence may vary by about 2%, resulting in a heterogenous virus population in each chronically infected person known as quasispecies. There is some evidence to suggest that the presence or emergence of quasispecies may result in poorer response to therapy in certain infected individuals (36, 133).
EPIDEMIOLOGY
Hepatitis C virus infection is a leading cause of global hepatic morbidity and mortality. Although the prevalence of chronic HCV infection varies geographically, it has recently been estimated that global prevalence is about 2%, or some 123 million persons (97). The existence of and quality of seroprevalence data varies widely across the globe. Most experts concur that the infection is most prevalent in Africa and Asia, with lower seroprevalence rates in the industrialized countries such as those of the Americas, Europe and Australia. Some of the highest reported seroprevalence rates are from Egypt (22%), Pakistan (4%), and China (3.2%). The lowest reported rates are from Germany (0.6%), Australia (1.1%), France (1.1%), India (0.9%) and Canada (0.8%). Somewhat higher rates are reported in the US (1.8%), Japan (15-2.3%) and Italy (2.2%) (11). Peak incidence of HCV infections appears to have taken place during the decade of the 1980s, with significantly lower incidence in subsequent years. This decreased incidence is thought to be a result of lower transmission rates among those persons injecting drugs, rather than screening of the blood supply. Because of the prolonged latency of HCV infectious complications, prevalence and impact of chronic infection is estimated to in increase over the next two decades before going into slow decline (27).
The leading modes of transmission of HCV infection, like prevalence rates, vary globally, but the majority can be attributed to intravenous drug use, blood transfusion and unsafe therapeutic injection practices. Other parenteral exposure risks such as medical procedures, tattooing, body piercing, scarification practices, and sexual transmission are less important modes of transmission. In the US, Europe and Australia, intravenous drug use has been the leading mode of HCV transmission since the discovery of the virus. Rates of such transmission are clearly diminishing due not to improvement in blood supply, but in large part to safer injection practices. In the developing world, unsafe therapeutic injection has emerged as a major source of new HCV infections, accounting for an estimated 2 million new HCV infections in 2000 (45). It has become clear that the household reusable syringes in common use throughout the world are a common reservoir for ongoing HCV infection. An important example of this type of risk as part of a public health initiative is Egypt’s schistosomiasis eradication campaign using reusable glass syringes, which has resulted in the world’s highest seroprevalance of HCV (39). Other important data regarding this transmission mode is available from Pakistan (75) and Taiwan (72).
Despite the rarity of blood transfusion-related HCV transmission in the industrialized nations, such transfusion is like to significantly contribute to HCV incidence in the developing world. Transfusion-related infection has virtually disappeared from the US, Europe and Australia, largely to the adoption of all-volunteer system, but further aided by blood product screening for ALT, anti-HCV antibody, and HCV RNA (112). Many countries around the world continue to use paid blood donors (31, 10 2). Furthermore, the WHO estimated than only some 42% of blood products are screened for infectious agents (130). Sexual transmission is thought to exist as a risk factor for HCV acquisition, but is considered to be inefficient and relatively unimportant from a public health standpoint (122, 126). The CDC recommends no change in sexual practices for monogamous couples in which one is chronically infected with HCV. Vertical transmission rates have been estimated at between 2.7% and 8.4% and appear to be increased in mother co-infected with HCV and HIV (38, 131).
HCV-HIV Co-Infection
It is estimated that 25% to 30% of HIV-infected individuals are co-infected with HCV (1, 8). Injection drug use results in higher rates of co-infection, but rates attributable to sexual transmission are on the increase. The natural history and clinical course of HCV is also altered by HIV co-infection. Persons with HIV co-infection tend to have higher HCV viral loads and are less likely to clear the HCV spontaneously (25). Before the advent of highly active antiretroviral therapy (HAART), HCV did not appear to have any significant effect on progression of HIV disease or death in HIV infected patients. With the advent of HAART, there has been a sharp decline in overall mortality in patients with HIV infection, largely due to a decrease in opportunistic infection. At the same time, liver disease has become a leading cause of mortality in HIV infected patients (13, 104). While in 1991, only 11.5% of deaths in HIV infected persons were due to liver disease, 50% of the deaths in 1998-1999 were due to end stage liver disease. Among the liver disease related deaths in 1998-1999, 93.8% of the patients had antibodies to HCV (13). Person co-infected with HCV/HIV are more likely to develop cirrhosis, have lower virologic response rates to interferon-based therapy, and are more likely to experience HAART therapy-related hepatotoxicity (81, 12, 105).
Natural History of HCV Infection
HCV infection resolves spontaneously in an estimated 15% to 40% of acutely exposed persons, while the remainder develops chronic infection with detectable virus in the serum. A number of series now demonstrate that recognition of acute HCV infection and early treatment results in a very high rate of viral eradication (107). Of those with chronic infection, 60% to 70% will have intermittently or persistently abnormal serum ALT levels. When retrospective and prospective data are combined, it is estimated that 15% to 20% of persons with HCV infection progress to cirrhosis, while approximately 5% will develop hepatocellular carcinoma (71,124). In one study of blood-transfusion recipients, the mean times between exposure to HCV and the development of chronic HCV infection, cirrhosis, and hepatocellular carcinoma were 13.7, 20.6, and 28.3 years, respectively (124). Several factors are known to increase the risk for fibrotic progression, including more advanced age, alcohol consumption, and histologic fibrosis (119,129). Patients with persistently normal levels of serum ALT have a lower risk for fibrotic progression (80). The average time from infection to development of cirrhosis is between 20 to 30 years. The progression can be significantly accelerated by HIV co-infection and alcohol consumption. Patients with HIV co-infection progress to cirrhosis after about 7 years as compared with those with HCV infection alone in whom the average time for such progression is about 23 years (13,15,118). Male sex, older age at diagnosis, co-infection with HBV and active IDU also increase the risk of progression of disease (15).
CLINICAL MANIFESTATIONS
Acute Viral Hepatitis
The overwhelming majority of hepatitis C infections that are seen clinically are chronic in nature. It should be noted however, that there is a growing recognition of acute HCV infection, especially in the context of needle stick injury and intravenous drug use. The realization that acute infection, when treated early, has a very high therapeutic response rate, has led to increase vigilance and surveillance from such infections. Acute hepatitis C presents in a similar fashion to the other hepatotropic viruses. Many infections will be subclinical, others may present with classic symptoms such as nausea, vomiting, right upper quadrant pain and malaise. A smaller percentage of cases will present with jaundice. There have been very few reported cases of HCV presenting with fulminant hepatic failure. The acute symptoms are self-limited, but the duration and severity of symptoms give no indication of the probability of chronicity. The significant spontaneous clearance rate of acute HCV infection has led to specific treatment delay recommendations when taking a clinical approach to such patients.
Chronic Viral Hepatitis
Chronic HCV is the most common hepatotropic virus infection in the industrialized nations. The frequency with which the infection becomes chronic is in the range of 85% of exposed persons, explaining the high prevalence of chronic infection. Many cases of chronic HCV infection are asymptomatic or associated only with mild non-specific symptoms such as fatigue. Such non-specific symptoms can be disruptive or even disabling, with consistently lower quality of life scores in HCV patients compared to match controls. The most common presentation of chronic HCV is the incidental notation of mildly elevated serum aminotransferases. In such patients with a positive anti-HCV antibody, viremia can be detected in about 85%, denoting chronic infection. In those patients with detectable anti-HCV antibody but repeatedly undetectable virus, the difference between false-positive antibody and resolved infection can be delineated by the recombinant immunoblot assay (RIBA). Up to 30% of chronically infected patients with have persistently normal aminotransferases, so a high index of suspicion to potential infectious risk factors is necessary (98). Natural history studies have shown that some 20% of chronically infected patients will develop hepatic cirrhosis over a period estimated from 20-30 years. Although clinical evidence of cirrhosis may be suggested in some patients by physical examination, laboratory assessment or radiographic studies, most patients, even those with significant liver fibrosis, will not demonstrate such findings. Therapeutic decisions regarding antiviral therapy must incorporate the estimated rate of progression (50). Fibrotic progression is higher is male patients, those who drink larger amounts of alcohol, those with HIV co-infection, and in those who have evidence of fibrosis on a liver biopsy.
LABORATORY DIAGNOSIS
The most common clinical presentation of the individual infected with HCV is the incidentally noted elevation of serum chemistries. Abnormal serum alanine aminotransferase (ALT) levels, if confirmed on repeat testing, should prompt a search for HCV infection risk, as well as serologic testing for HCV antibody by enzyme immunoassay (EIA) (103). Because as many as 30% of patents with chronic HCV infection have persistently normal ALT levels, a high index of suspicion is necessary to identify those chronically infected (98). The sensitivity and specificity of currently utilized HCV enzyme immunoassays in high prevalence populations are in the range of 98% to 100% (23, 128). The HCV EIA assay, now in its third generation, is available in kit form from several manufacturers and provides highly reproducible results (23, 61).
In low-prevalence populations, such as asymptomatic blood donors, 40% of patients with anti-HCV by enzyme immunoassay represent false positives. Use of the recombinant immunoblot assay (RIBA) or HCV RNA can be helpful in this situation (5). In clinical practice, confirmatory testing is always undertaken, usually using HCV RNA testing, both to eliminate possibility of a false-positive antibody test and to provide prognostic information regarding the potential success of antiviral therapy. HCV RNA testing is based on a number of assays, including target amplification (RT-PCR), signal amplification (branched-chain DNA), or target-mediated amplification (TMA). Automated kits are available and are now used by many reference labs. In practice, qualitative detection assays detect 50 HCV RNA IU/mL or less, and have equal sensitivity for the detection of all HCV genotypes (20). Molecular assays are now capable of detecting HCV viremia at concentrations as low as 5 IU/ml (109). The diagnostic tests for HCV are summarized in Table 1.
Chronic HCV infection is characterized by positive HCV antibody and RNA. Patients with acute hepatitis C usually have a positive HCV RNA with a negative HCV antibody, although the HCV antibody may be present in acutely infected patients who have seroconverted. A positive HCV antibody in the setting of undetectable HCV RNA is indicative of cleared infection, false positivity, or of extremely low level viremia.
The quantification of HCV RNA is an important component of the management of patients chronically infected with HCV. There is no correlation between viral load and disease severity. The quantitative HCV PCR provides information to assist decision-making regarding success and duration of therapy, but not natural history of disease. Therefore, there is no need to order serial quantitative PCR in untreated patients. Quantitative HCV RNA testing is increasingly used to make treatment decisions during the administration of interferon-based anti-viral therapy. Because the failure to reduce viral load by at least 2 log -fold by 12 weeks of therapy is highly predictive of ultimate treatment non-response (high negative predictive value), therapy should be stopped in patients who fail to achieve this milestone (37,93). Analysis of interferon treatment data also suggests that the lack of virologic eradication by 24 weeks of therapy is strongly predictive of the lack of ultimate SVR (82). Therapy should therefore be stopped in patients who fail to meet this milestone as well. The investigation of even earlier predictive algorithms is underway (62). The achievement of an RVR may justify truncation of therapy in genotype 2 or 3-infected patients to 12-16 weeks (78, 127), although a recent large randomized trial in genotype 2 and 3-infected patients comparing 16 with 24 weeks of PEG-IFN and flat dose (800 mg/d) RBV therapy found a higher response rate in patients receiving 24 weeks (114).
There at least 6 major genotypes of HCV, with many subtypes (52, 91). This exceptional genetic heterogeneity may help to account for the resistance of HCV to therapy and vaccine development. Over 75% of patients in the US are infected with genotype 1, 15% with type 2 and 10% with genotype 3. There is no correlation between HCV genotype and severity of disease, but response rates to interferon-based regimens are significantly higher in those patients infected with genotypes 2 and 3 (28). Therefore, genotyping on a single occasion is recommended to provide information regarding expected response rates and duration of antiviral therapy. Commercial HCV genotyping kits rely on sequence analysis of the 5’ noncoding region (42,116,117 133).
Most hepatologists prefer to include an examination of liver histology in the management of patients with chronic hepatitis C. Random core biopsy reveals information about the inflammatory grade and fibrotic stage of chronic HCV. In patients with mild inflammation and no significant fibrotic change, treatment is less urgent because risk for progressive liver disease is lower. The presence of severe inflammation or bridging fibrosis should serve as an impetus for therapy. Histologic evaluation of the liver also aids in guiding the therapy of patients who do not respond to antiviral treatment. In persons with milder disease, further therapy can be deferred until more effective treatment regimens are developed. For patients whose biopsy reveals more advanced disease, further treatment should be considered. Liver biopsy has several limitations. It is attended by a serious adverse event rate of about 0.3% (predominantly bleeding) (100). Pain is not infrequent following the procedure. The potential for sampling error has also come under scrutiny (10). The general recommendation for repeat samples over time in untreated patients stems partially from this concern. In recent years, the development of non-invasive (serologic and elastography) assessment of hepatic fibrosis has provided a potential alternative (41, 58, 106). Although these tests have not yet entered the mainstream, it is reasonable to predict that their use will increase over the next decade.
PATHOGENESIS
Although important advances have been made in the understanding of the natural history, the diagnosis and the treatment of chronic HCV infection, details on the pathogenesis of the infection remain incomplete. HCV is an RNA virus that has been classified as a flavivirus. It is estimated that 10 trillion viral particles are produced per day. Multiple quasispecies of the virus exist within any given host simultaneously (90). In humans and primates in which virus has cleared spontaneously, virus-specific responses by cytotoxic T lymphocytes and helper T cells have been described (68, 120). The very high chronicity rates of the infection, which differs so radically from the other known hepatotropic viruses, suggests an ineffective immune response in most individuals. Studies have been hampered by the number of variables in the host and the virus. The current understanding of chronic HCV infection points to the host immune response as the primary etiology of hepatocellular injury. Both humoral and cellular immunity is involved in this complex reaction, yet neither is capable of clearing infection in the large majority of affected individuals. Direct viral cytopathicity has been described, but is thought to be of less importance than host immune-mediated injury (89).
The life cycle of HCV is incompletely understood, but the following model has been proposed: HCV binding to an cell surface receptor, internalization into the host cell, cytoplasmic release and uncoating of the viral RNA genome, IRES-mediated translation and polyprotein processing by cellular and viral proteases, RNA replication, packaging and assembly, and virion maturation and release from the host cell (83). Although a number of receptor candidates for HCV infection are being investigated, the details of this process are not understood (8). A number of non-structural proteins have been identified and characterized, providing potential strategies for therapeutic intervention. For example, the NS3 serine protease (66) and the NS5B RNA dependent RNA polymerase (70) have emerged as potential targets for antiviral therapies.
SUSCEPTIBILITY IN VITRO AND IN VIVO
Until recently, the advancement of our understanding of the mechanisms underlying HCV replication and persistence and the development of new antiviral therapeutics had been hampered by the lack of cell culture model systems capable of robust viral replication (33). Furthermore, a truly tractable small animal model does not yet exist for HCV, as HCV infects only humans and chimpanzees.
The recent development of both subgenomic and genomic replicon cell culture models capable of high-level autonomous HCV RNA replication has greatly facilitated the evaluation of antiviral activities of new drug candidates as well as the study of viral RNA replication and persistence (6,7). Although they have proven very useful, the main drawback of HCV replicons is that they do not produce infectious viral particles. The recent development of a successful infectious cell culture system has enhanced the ability to validate prospective compounds. Indeed, a number of anti-HCV compounds currently in development have moved directly from replicon or tissue culture models to man. These model systems have also permitted evaluation of selection for drug resistance, with a reasonable correlation with isolates identified in vivo. We can anticipate accelerated development of assays to assess both genotypic and phenotypic resistance as the pace of small molecule antiviral drug development accelerates.
ANTIVIRAL THERAPY
Drug of Choice
The choice of whether or not to offer antiviral treatment to an individual infected with HCV is complex and must be individualized (Table 2). Anti-viral therapy for HCV infection reached maturity with the development of interferon/ribavirin combination therapy (17). The treatment of choice and the current standard of care for treatment of HCV infected persons is the combination of pegylated interferon and ribavirin (Table 3).
When given for 48 weeks, this combination results in sustained virologic response (SVR) in about 54% of treated patients (29, 40, 46, 55, 73, 76, 82, 101). Treatment response is strongly dependent on HCV genotype. Patients with genotype 2 or 3 can expect SVR rates in the 76-84% range, while those with genotype 1 achieve SVR in about 42-52%. Patients infected with genotype 2 or 3 achieve similar sustained virologic response rates whether treated with pegylated interferon or the standard interferon (both in combination with ribavirin), and whether they are treated for 24 or 48 weeks (44, 46, 73, 76). In those infected with genotypes 2 or 3 and exhibiting early response, even shorter courses of therapy may be effective (78). There is some evidence that genotypes 2 and 3 should be approached differently, especially patients with genotype 3 infection with high viral load, who may require higher doses of therapy for longer duration (132). The generally agreed upon current recommendations are a treatment duration of 48 weeks for those infected with genotypes 1 and 4, and 24 weeks for those infected with genotypes 2 and 3.
Two peginterferon formulations are approved: peginterferon alfa-2a is dosed at 180 mcg weekly and peginterferon alfa-2b given at 1.5 mcg/kg weekly (Table 3).
The dose of ribavirin should be based on patient weight in those infected with genotype 1 (1000 mg or 1200 mg per day, for body weight less than or greater than 75 kg, respectively), but current recommendations state that patients with genotype 2 or 3 infection may be treated with a lower dose (800 mg per day) (44).
Assessing Response to Treatment
The primary end point in assessing treatment response is the sustained virologic response (SVR), defined as the absence of HCV RNA 24 weeks after any course of treatment. End of treatment response (ETR) is defined as the absence of HCV RNA at the end of a course of treatment. The reappearance of HCV RNA prior to the 24 week followup is defined as a relapse. With achievement of an SVR, late relapses are extremely rare. Biochemical response is defined as normalization of liver enzymes, and a histological response is defined as a measurable improvement in liver histology on a post-treatment liver biopsy specimen.
The goal of treatment of HCV is eradication of HCV RNA, which is associated with reduction in hepatic necroinflammation, which in turn can lead to a regression in fibrosis and a delay in progression of cirrhosis to clinical complications, including variceal bleeding and hepatocellular carcinoma (Table 4).
Treatment recommendations for HCV depend upon the genotype (Figure 1). All patients, regardless of genotype, should have persistent HCV viremia to be considered for treatment.
Genotype 1-infected patients should have their extent of liver injury assessed by a liver biopsy or indirectly by persistently elevated serum alanine and aspartate aminotransferases, in view of their relatively limited chance of achieving SVR. It is generally recommended to defer treatment for infected persons with no histologic abnormalities, since the rate of progression is likely to be very slow in these persons. Continued monitoring with serum biochemical markers and periodic liver biopsy (every 3 – 5 years) is recommended to monitor progression and to limit the effects of histologic sampling error (95).
For those genotype 1 patients with more advanced liver injury who do require treatment, the HCV RNA level should be quantitated at baseline and at 12 weeks of therapy. If there is a 2-log decline or clearance of HCV RNA compared to baseline (early virologic response (EVR)), treatment should be continued. If HCV RNA is undetectable by a qualitative assay (lower level of detection < 50 IU/mL) at 24 weeks, then therapy should continue for the full 48 weeks, as there is a high likelihood of achieving SVR. Therapy should be stopped for those patients who fail to meet the criteria for continuing therapy at 12 and 24 weeks, as the chances for achieving SVR are extremely low in these patients. HCV RNA should be measured at end of treatment, then 24 weeks after treatment to determine if SVR is achieved (20, 95). (Figure 1A)
For genotype 2 and 3 patients, who have a very high likelihood of SVR, treatment can be recommended regardless of the severity of liver disease and an empiric course administered without a liver biopsy. Again, kinetic determinations of EVR, ETR and SVR apply (20, 95) (Figure 1B).
Investigations of whether shorter courses of therapy for genotype 2 and 3 disease have been undertaken, but the result of these studies has been mixed. While 2 randomized controlled trials have indicated that 12 or 16 weeks of therapy produce SVR rates equivalent to those observed for 24 weeks in genotype 2 or 3 HCV (77, 78), a recent large trial indicated that the full 24-week course is associated with higher overall rates of sustained virological response compared to 16 weeks (114).
The treatment of genotype 4, 5, and 6 HCV has not been as extensively studied as that for genotypes 1, 2, and 3. It is therefore recommended that genotypes 4, 5, and 6 be treated for a total of 48 weeks with the interferon and ribavirin dosages appropriate for genotype 1. It is reasonable to apply similar stopping rules for these genotypes (20, 95).
Treatment is less successful in persons with already established cirrhosis, but if stable these persons do benefit from treatment (47). However, treatment is currently not recommended for persons with decompensated liver disease. While many providers treat persons with chronic HCV and normal serum aminotransferases, the benefit of such treatment is not fully established. While many such patients have abnormal liver histology, the rate of progression of liver fibrosis is thought to be slower when compared with those with elevated serum aminotransferases (80, 69,104). An added important potential benefit of treatment is a reduction in the rate of hepatocellular carcinoma. For example, a 2001 meta-analysis showed that hepatocellular carcinoma was less frequent in patients treated with interferon than untreated patients (8.2% vs. 21.5%) (92).
Management of Side Effects
Commonly reported adverse events of interferon alfa-2 (both standard and pegylated formulations) include influenza-like symptoms, anorexia, psychiatric symptoms (especially depression), and neutropenia. Ribavirin causes dose-dependent hemolytic anemia and is teratogenic (76). Ribavirin is absolutely contraindicated in pregnancy and in patients and their partners who may conceive while on therapy and up to six months after stopping therapy (Table 5). The use of acetaminophen or nonsteroidal anti-inflammatory drugs after the initial interferon injections can abrogate influenza-like symptoms (88). Management of hematologic side effects of interferon therapy, primarily neutropenia and thrombocytopenia, may require dose reduction or discontinuation. Granulocyte-colony stimulating factor has been used to stimulate neutrophil counts, but this intervention has not been shown to improve outcome of therapy. Ribavirin-induced hemolysis is also treated by dose reduction. Erythropoietin is effective is raising hemoglobin levels on treatment and maintaining higher ribavirin dose, and improving quality of life, but effect on SVR has not yet been demonstrated (3). Neuropsychiatric side effects of antiviral therapy are common and can lead to poor compliance with treatment or treatment discontinuations. Antidepressants, especially SSRIs, have been shown to be effective in ameliorating some of these effects (64, 110) but do require time to work.
Treatment in Special Populations
Patients with HCV-HIV Co-infection
HCV-HIV co-infected persons pose a special treatment challenge. In these patients, SVR rates are lower than those seen in HCV mono-infected patients. In controlled trials, patients with HIV co-infection achieved SVR rates between 27% and 40% (22,63,67,87,125). Four major clinical trials in the HIV co-infected persons published in 2004 established peginterferon and ribavirin as the best therapy for these patients (19, 22, 65, 123, 125).
In the AIDS Clinical Trials Group study ACTG5071, subjects were treated with 180 micrograms of peginterferon alfa-2a weekly for 48 weeks or 6 million IU of standard interferon alfa-2a three times weekly for 12 weeks followed by 3 million IU three times weekly for 36 weeks. Both groups received ribavirin according to a dose-escalation schedule. The overall SVR was higher in the pegylated interferon group (27% vs. 12%), though this is substantially lower than what has been reported for HCV mono-infected persons. Pegylated interferon plus ribavirin treatment led to a SVR of 14% in subjects with HCV genotype 1 infection compared with 73% SVR in those with genotype non-1. A significant improved in liver histology was seen in those who responded to treatment as well as 35% of non-responders (22).
In an international study of HCV-HIV co-infected persons (APRICOT), subjects were assigned to receive peginterferon alfa-2a (180 mg per week) plus ribavirin (800 mg per day), pegylated interferon alfa-2a plus placebo, or interferon alfa-2a (3 million IU three times a week) plus ribavirin. The SVR was substantially higher in the pegylated interferon alfa-2a plus ribavirin group (40%) when compared with interferon alfa-2a plus ribavirin (12%), or pegylated interferon alfa-2a plus placebo (20%). The SVR was 29% in those with genotype 1 infection in the pegylated interferon plus ribavirin group, and 62% in those with genotype 2 or 3 infection (125).
A French group (RIBAVIC) also studied the effects of 48 weeks of interferon-alfa-2b plus ribavirin (800 mg per day) in HCV-HIV co-infected patients, with an overall SVR of 27%, with genotype 1 and 4 patients achieving a 17% SVR rate and other genotypes achieving a 44% SVR (19). A Spanish group also examined the effects of 48 weeks of peginterferon-alfa-2b plus ribavirin on HCV-HIV co-infected patients, with genotype 1 and 4 patients achieving a 38% SVR rate and other genotypes achieving a 53% SVR rate (65). The lower SVR rates in the RIBAVIC and ACTG studies may be attributable to the fact that the severity of baseline liver disease was high in each of these studies (123). Moreover, the ACTG study also had a high proportion of African-American patients with genotype 1 infection, a group with known decreased SVR rates (see below).
These trials have generally included only patients with relatively intact immune function as measured by the CD4 counts (usually > 400 cells/mm3). CD4 counts in HCV-HIV co-infected patients consistently drop by an average of 100 cells/mm3 on peginterferon-based therapy, although CD4% actually increases. More importantly, no significant AIDS-defining illnesses have been reported on treatment. Patients with HIV are also more likely to have concurrent medical, psychiatric and substance abuse problems making them less than ideal candidates for HCV treatment. While patients in care in the Veterans Healthcare System are also more likely to have similar issues than the HIV infected patients (16, 54, 84), there is no data to suggest that treatment response in veterans is poorer than the non-veterans.
For non-responders to a prior course of standard interferon and ribavirin, re-treatment with peginterferon plus ribavirin is associated with low rates of SVR (86). There are currently no recommended treatments for peginterferon and ribavirin non-responders. Several clinical trials employing higher dose peginterferon, alternative interferon formulations, or maintenance peginterferon are being conducted in this population.
African American Patients
African American patients have a higher prevalence of HCV infection than white patients, with a predominance of genotype 1 infection (2). The rate of hepatocellular carcinoma is higher compared to non-Hispanic whites and is growing at a faster rate (26). Even after adjusting for other factors, African American patients with genotype 1 infection have a poorer response to treatment than white Americans. Conclusions on actual rates and the reasons for diminished response have been limited by under representation in drug registration trials. Retrospective analysis suggests that interferon response rates vary by ethnicity (49) and in a prospective trial, the SVR in African American patients using combined peginterferon and ribavirin was 28% compared with 52% in white patients (60). The reasons for this disparity in response are not known. In a recent multicenter treatment trial, African American patients with chronic genotype 1 HCV had a lower SVR to peginterferon and ribavirin than Caucasian Americans (28% vs. 52%). These differences were not explained by disease characteristics, baseline viral levels, or amount of medication taken (24).
Patients with Renal Disease
Patients with advanced renal disease also pose a special challenge because ribavirin is contraindicated in these patients. In patients with renal failure, the elimination of ribavirin is significantly impaired leading to a prolonged plasma half life and accentuated hemolytic anemia. Available data in these patients supports the (14, 18) use of pegylated interferon alfa-2a monotherapy at 135 mcg weekly (4, 99, 115). Ribavirin should not be administered unless serum levels of ribavirin can be readily performed and monitored and dose of ribavirin modified according to the levels and hematocrit. These patients should generally be referred for clinical trials.
Patients with Decompensated Cirrhosis
Patients with decompensated liver disease, manifested by variceal bleeding, encephalopathy, prolonged prothrombin time, or other manifestations of portal hypertension of hepatic synthetic dysfunction are high risk candidates for treatment because of a significant chance of further decompensation and life threatening adverse events. Despite these risks, clinicians and investigators have evaluated such treatment given the growing problem of recurrent HCV following liver transplantation. Peginterferon/ribavirin therapy appears to have efficacy in cirrhotic patients, rivaling that in those without fibrosis, but cytopenias and physical side effects are limiting factors (79). Tolerability can be increased by use of a low accelerating dose regimen, even in patients with significant hepatic synthetic dysfunction (35). Because of the inherent risk of decompensation, this regimen should only be undertaken at transplant centers, and preferably after a patient has already been listed.
Pediatric Patients
Treatment of children with chronic hepatitis is attractive in theory, because these patients face such long time periods of chronic inflammation and are likely to tolerate therapies well. Currently, unmodified interferon in combination with ribavirin is approved by the US Food and Drug Administration for treatment of children over age 3 with chronic hepatitis C (30). Pediatric SVR rates compare quite favorably with those seen in adults (43). No data in yet available regarding the use of peginterferon products in the pediatric population.
Patients with Acute Hepatitis C
The overwhelming majority of cases of HCV infection are discovered in the chronic phase, usually years to decades after transmission. In those infrequent cases when acute infection is identified, often in the setting of needlestick injury or injection drug use, response rates to antiviral therapy are very high. Because of the paucity of such cases compared to chronic infection, randomized prospective trials are small and underpowered. A meta-analysis of interferon monotherapy trials, published in 2002, reported an SVR rate of 32%. A more recent prospective single-center trial using high dose interferon monotherapy achieved a remarkable 98% SVR (59). Smaller series employing peginterferon were associated with similarly high rates of sustained virologic response (111). Most authorities recommend a 12 week waiting period after the acute infection to allow for spontaneous clearance of virus, which appears to take place in as may as half the cases (108).
Alternative Therapy
Currently, peginterferon and ribavirin is the standard of care for anti-HCV therapy. There is no data to support the use of complementary or alternative medications.
ADJUNCTIVE THERAPY
Perhaps the most important aspect of treatment and prevention of progression to end stage liver disease is cessation of alcohol consumption. Even moderate amounts of alcohol can accelerate liver damage and decrease time of progression to cirrhosis (53). There is a growing body of evidence that fatty infiltration of the liver works in a synergistic way with chronic HCV infection to cause hepatic fibrosis (51, 85). Fatty change, which appears to be a consequence of insulin resistance, may also affect sustained virologic response rates in patients undergoing interferon-based treatment (94). Therefore, interventions aimed to reduce or eliminate drug and alcohol use, and to promote lean body habitus, control of lipids and glycemic control, should all be primary foci of treatment.
In addition to these lifestyle modifications, it is important to exclude coexistent hepatic disease processes, such as metabolic liver disease (hemachromatosis, Wilson’s disease, alpha-1-antitrypsin deficiency) or autoimmune hepatitis, particularly where clinical suspicion exists. HCV-infected patients should also be vaccinated against hepatitis A and hepatitis B if they have no evidence of prior immunity.
ENDPOINTS FOR MONITORING THERAPY
The primary end point in assessing treatment response is the SVR, defined as the absence of HCV RNA by a sensitive, qualitative assay 24 weeks after completion of a course of treatment. End of treatment response (ETR) is defined as the absence of HCV RNA by a qualitative assay at the end of a course of treatment. The reappearance of HCV RNA during the 24 week followup period after ETR is defined as a relapse. The frequency of late relapses after 24 weeks of followup is extremely rare.
For genotype 1-infected patients who require treatment, the HCV RNA level should be quantitated at baseline and at 12 weeks of therapy. If there is a 2-log decline or more in HCV RNA level at 12 weeks (EVR), treatment should be continued. If HCV RNA is undetectable at 24 weeks, then therapy should continue for the full 48 weeks, as there is a high likelihood of achieving SVR, particularly with achievement of HCV RNA clearance at 4 weeks (RVR). Therapy should be stopped for those patients who fail to meet the criteria for continuing therapy at 12 and 24 weeks, as the likelihood of accomplishing SVR is extremely low. HCV RNA should be measured 24 weeks after treatment to assess for SVR. (20, 95) (Figure 1A).
Other endpoints for monitoring therapy include biochemical or histologic response. Biochemical response is defined as normalization of serum ALT levels, but is not well correlated with end of treatment or sustained response. Histologic response is defined as an improvement in necroinflammatory activity, fibrosis or both in a post-treatment liver biopsy compared with pre-treatment. Even patients who do not achieve a sustained virologic response may experience a significant improvement in histology, or least a delay in progression of liver disease over a period of time (113). This premise underlies the design of so-called maintenance trials of IFN to slow liver fibrosis progression.
VACCINES
There are no vaccines currently available for HCV, and prospects for imminent development of a broadly protective vaccine are limited. Nonetheless, the existence of partially protective neutralizing antibodies, and the observed ability to spontaneously clear acute HCV infection offer plausibility to such an approach. In this regard, vaccine development is ongoing, and the efficacy of at least one protein-based vaccine is undergoing prospective evaluation in clinical trials (32, 56). The utility of vaccine-based approaches for management of chronically infected persons is also being studied. Due to the heterogeneity of HCV virus, newer approaches include the development of “multi-genotype” vaccines, which targets a number of specific genotypes and viral subtype, and “library” vaccines which target pooled HCV genetic information from pooled patient cohorts (34).
PREVENTION
Education about the risk factor for acquisition of HCV is critical to break the infection cycle. Unsafe needles, whether used by practitioners in resource poor countries, by IDU or used for body piercing or tattooing, unscreened blood products and unsafe sexual practices should be avoided.
Infection Control
Universal precautions should be practiced by all health care workers. Proper sterilization and disinfection techniques should be employed in hospitals, especially hemodialysis, endoscopic and surgical units. The risk of transmission of HCV from an infected surgeon to a patient is very low but not zero. It is difficult to make any recommendations at this time whether HCV infected surgeons should continue to perform surgical procedures with added precautions. It makes sense to limit them from performing any emergency procedures where the chances of a breach of sterile surgical technique may be higher than routine procedures (96). Sexual transmission of HCV is undoubtedly possible, but not efficient. The CDC currently recommends no change in sexual practice in monogamous couples in which one partner is HCV positive. HCV-infected individuals with multiple sexual partners should be advised to employ barrier methods to decrease transmission risk (122). Users of intravenous drugs should not share needles and should employ injection equipment sterilization techniques. Although data is mixed, tattooing and body piercing may connote HCV risk; the use of sterile instruments is essential in these settings (48).
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Table 1. A summary of diagnostic laboratory tests for HCV.
Test |
Indication / Use |
|---|---|
Anti-HCV Ab (EIA) |
Screening of patients for HCV infection |
HCV RIBA |
Exclusion of false positive screening results in patients with low prior probability of infection |
HCV RNA qualitative |
Confirmation of HCV viremia and clearance of infection |
HCV RNA quantitative |
Assessment of pre-treatment and on-treatment HCV RNA levels |
Table 2. Indications for treatment of HCV infection
Recommended |
Not recommended |
Unclear |
|---|---|---|
|
|
|
Table 3. Approved drugs and commonly used dosages for treatment of chronic HCV infection.
Drug |
Trade name (manufacturer) |
Commonly used dosages |
|---|---|---|
Interferon alfa-2a |
|
3 million units 3 times per week |
Interferon alfa-2b |
|
3 million units 3 times per week |
Interferon alfacon-1 |
|
9-15 mcg 3 times a week |
Ribavirin |
|
800 – 1200 mg per day |
Peginterferon alfa-2a |
|
1.5 mcg/kg weekly |
Peginterferon alfa-2b |
|
180 mcg weekly |
The dosages are provided for information purposes only. Health care providers are advised to familiarize themselves with these drugs usage,
dosages and adverse events, including dose-related toxicities, as provided in the package inserts of each drug.
Table 4. Goals of therapy for HCV infection
|
Table 5. Contraindications to treatment with Interferon alfa/Ribavirin.
|
Interferon alfa |
Ribavirin |
Combination Interferon alfa and Ribavirin |
Absolute |
Active suicidal behavior Autoimmune hepatitis Hypersensitivity to Interferon alfa |
Pregnancy |
Same as individual drugs |
Relative |
Active autoimmune disease (other than autoimmune hepatitis) Depression (stabilize before starting treatment) |
Anemia Renal failure |
Same as individual drugs Decompensated cirrhosis |
Figure 1 (A&B)
What's New
Klevens RM, et al. Evolving epidemiology of Hepatitis C virus in the United States. Clin Infect Dis 2012;55:Suppl S3-9.
Baccarani U, et al. Is liver transplantation feasible in patients coinfected with human immunodeficiency virus and hepatitis C virus? Liver Transpl 2012;18:744-745.
Tsui JI, et al. Hepatitis C virus infection is associated with painful symptoms in HIV-infected adults. AIDS Care 2012;24:820-827.
Deresinski, S. Genetic Determinants of Outcomes in Chronic Hepatits C Virus Infection. Clin Infect Dis 2010;50:iii.
Deresinski S. Hepatitis C Virus (HCV)-HIV Coinfection: 2b or Not 2b? Clin Infect Dis 2009;48:v-vi.
Schulze Zur Wiesch J, et al. Sustained Virological Response after Early Antiviral Treatment of Acute Hepatitis C Virus and HIV Coinfection. Clin Infect Dis 2009;49:466–472.
Thompson ND, et al. Nonhospital Health Care-associated Hepatitis B and C Virus Transmission: United States, 1998-2008.Ann Intern Med. 2009. Jan 6;150(1):33-9.
Van den Eynde E et al. Response-Guided Therapy for Chronic Hepatitis C Virus Infection in Patients Coinfected with HIV: A Pilot Trial. Clin Infect Dis. 2009 Mar 10.
McHutchinson JG, et al. Peginterferon Alfa-2b and Alfa-2a with Ribavirin for Treatment of Hepatitis C Infection. N Engl J Med 2009:361:580-593.
Dionne-Odom J, et al. Acute hepatitis C and HIV coinfection. Lancet 2009;9:775-783.
Berger S. Emergence of Infectious Diseases into the 21st Century, 2008.
Liu, et al. Pegylated Interferon-alpha-2a Plus Ribavirin for Treatment-naive Asian Patients with Hepatitis C Virus Genotype 1 Infection: A Multicenter, Randomized Controlled Trial. Clin Infect Dis.2008 Nov 15;47(10):1260-9.
FDA: FDA Approves First Nucleic Acid Test to Screen for Additional Types of HIV In Donated Blood and Tissues. December, 2008.
GUIDED MEDLINE SEARCH FOR
Reviews
Wray CM, et al. Screening for Hepatitis C. JAMA 2015;313:1855-1856.
Clinical Review & Education. From the Medical Letter on Drugs and Therapeutics. A 4-Drug Combination (Viekira Pak) for Hepatitis C. JAMA 2015;313:1857-1858.
Adhikari P, Mietzner T. Cell Mediated Immunity.
Liang TJ, et al. Current and future therapies for hepatitis C virus infection. N Engl J Med 2013;368:1907-1917.
Yu ML, et al. Treatment of chronic hepatitis C in Asia: when East meets West. J Gastroenterol Hepatol.2009 Mar;24(3):336-45.
Funk GA, et al. Viral dynamics in transplant patients: implications for disease. Lancet Infectious Diseases 2007;7:460-472.
Rockstroh JK, Spengler U. HIV and hepatitis C virus co-infection. Lancet Infect Dis. 2004 Jul;4(7):437-44.
GUIDED MEDLINE SEARCH FOR RECENT REVIEWS
History
Tice JA, et al. Comparative Clinical Effectiveness and Value of Novel Interferon-Free Combination Therapy for Hepatitis C Genotype 1: Summary of California Technology Assessment Forum Report. JAMA Intern Med 2015, Jul 13 doi: 10.1001/jamainternmed.2015.3348. [Epub ahead of print]
Berger S. Emergence of Infectious Diseases into the 21st Century, 2008.
GUIDED MEDLINE SEARCH FOR HISTORICAL ASPECTS
Table of Contents
- Virology
- Epidemiology
- Clinical Manifestations
- Laboratory Diagnosis
- Pathogenesis
- Susceptibility in Vitro and in Vivo
- Antiviral Therapy
- Adjunctive Therapy
- Endpoints for Monitoring Therapy
- Vaccines
- Prevention