I. HEPATITIS C VIRUS INFECTION IN THE GENERAL
POPULATION
HCV, an RNA virus
Hepatitis C virus (HCV) is a small single-stranded RNA virus with a lipid envelope (E) containing glycoproteins (E1 and E2) and a core with a genome consisting of 9500 nucleotides. HCV components are both structural (core, E1, and E2) and nonstructural (NS; P7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B). The nonstructural genes encode various enzymes including a polymerase responsible for replication of HCV. HCV isolates are classified into six distinct genotypes depending on sequence homology.
In the absence of HCV cell cultures, until very recently, studies of infectivity have relied on the chimpanzee. Exposure of chimpanzees to HCV is followed by the appearance of HCV RNA in serum within 1–2 weeks, with increase of serum alanine aminotransferase (ALT) 3–6 weeks later and subsequent seroconversion with antibodies developing mainly against HCV core, NS3, and NS4. As for other RNA viruses, the genetic sequence of HCV is characterized by a high rate of spontaneous mutations, with major implications for escape from the human immune system and the development of an effective vaccine.
Testing for HCV
After the identification of the hepatitis B virus (HBV) in the 1960s, it soon became apparent that many cases of posttransfusional
hepatitis remained unexplained, including the socalled ‘non-A, non-B hepatitis.’ The causative agent remained unknown for more than 15 years until a group, after screening over one million clones of a library of cDNA complementary to total RNA extracted from a chimpanzee infected with serum from a patient with post-transfusional non-A, non-B hepatitis, identified a single reactive clone of a virus called HCV.1 This led to the first-generation enzyme immunoassay (EIA) that detected antibodies against a single nonstructural HCV protein (C100-3).2 It was already apparent at that time that the presence of antibodies coincided with the presence of viral RNA and that antibodies were thus not protective.
Subsequently, second- and third-generation immunoblots and EIAs were developed, which detect antibodies against multiple HCV nonstructural proteins as well as HCV core. Both sensitivity and specificity improved dramatically as the second-generation EIA became available, and slightly more so with the third-generation EIA. Overall, first-generation EIA tests are now considered obsolete and most countries rely exclusively on third-generation EIA. Given the good performance of third-generation EIA tests, immunoblot tests have also become obsolete in clinical practice.3 The increased sensitivity of the last generation of HCV assays has dramatically reduced the risk of HCV transmission by blood components and also reduced the detection time between acquisition of infection and the development of anti-HCV antibodies (the ‘serologic window’) from 82 days to 66 days.4,5 Fourth-generation tests, which will soon become available, would allow the simultaneous detection of HCV antibodies and HCV core protein. These tests should further reduce the serologic window. In some populations, with frequent polyclonal hypergammaglobulinemia, there may be discrepancies among third-generation EIA tests. Thus, in pregnant women in Cameroon, HCV positivity using only one thirdgeneration EIA test was 4.9%, but it decreased to 1.9% when two third-generation EIA tests were performed; HCV RNA was present in 75% of women having concomitantly two positive EIA tests and was 0% in those having only one positive EIA test.6
Nucleic acid testing (NAT) is based either on qualitative HCV RNA detection or on HCV RNA quantitation. Qualitative detection assays are based on the principle of target amplification using conventional polymerase chain reaction (PCR), real-time PCR, or transcription-mediated amplification (TMA). All commercially available assays can detect 50 IUml-1 of HCV RNA or less and have equal
sensitivity for the detection of all HCV genotypes.7 The lower limit of detection of the qualitative conventional PCR-based assays or their semiautomated version is 50 IU ml-1; that of real-time PCR assays (which are able to simultaneously qualify and quantify HCV RNA) is 10–30 IU ml-1; and that of the TMA-based assay is 10 IUml-1. Quantitative assays are based either on target amplification techniques (conventional PCR or real-time PCR) or on signal amplification techniques (branched DNA). Branched DNA and most quantitative conventional PCR-based assays have detection limits higher than those of qualitative detection assays.8
Epidemiology of HCV infection in the general population
Hepatitis C virus is a blood-borne pathogen that appears to be endemic in most parts of the world. There are, however, substantial geographic and temporal variations in the incidence and prevalence of HCV infection, largely due to differences in regional risk factors for the transmission of HCV. The World Health Organization (WHO) estimates that the global prevalence of HCV infection averages 3%, or around 170 million infected persons worldwide. However, population-based surveys are not available for most parts of the world, and prevalence estimates are based on testing of selected populations such as blood donors. Prevalence of confirmed EIA positivity in blood donors ranges from less than 0.1% in Northern Europe to 0.1–0.5% in Western Europe, North America, parts of Central and South America, Australia, and a few regions of Africa. Intermediate rates (1–5%) have been reported from Brazil, Eastern Europe, the Mediterranean area, the Indian subcontinent, and parts of Africa and Asia.9 The highest prevalence of HCV has been found in Egypt (17–26%).9 A few population-based studies such as the Third National Health and Nutrition Survey (NHANES III) in the United States and similar small-sized studies from other countries, such as France and Italy, have clearly shown that prevalence estimates based on blood donors underestimate the actual prevalence of HCV in the general population by up to threefold.10–12
Globally, the major risk factors for HCV infection are blood transfusions from unscreened donors and intravenous drug use. However, exposure to HCV-infected blood from other health-care-related procedures and regional cultural practices are increasingly recognized as having an important function in HCV transmission in some parts of the world. Since the introduction and improvement in the 1990s of the screening of blood donors, HCV transmission by blood transfusions is now exceedingly rare (around or less than one per million) in developed countries.13,14 Unfortunately, the screening of blood donors for HCV is not yet routinely performed by some blood banks in developing countries.15 Most new cases in developed countries are related to intravenous drug use. Health-care-related procedures leading to nosocomial HCV transmission are not restricted to hemodialysis facilities. Several reports from Western countries have clearly documented nosocomial transmission of HCV through inadvertent sharing of multidose vials or unsterilized instruments, among others.16,17 Similar nosocomial transmission of HCV outside dialysis units is certainly not less likely to occur in developing countries but has not been reported until now. Additional risk factors for HCV transmission include occupational exposure, especially by accidental needlestick, as well as perinatal transmission (about 6%), whereas the transmission of HCV by sexual activity appears relatively inefficient.9,18
Natural history of HCV in the general population
Acute HCV infection is often mild and frequently does not prompt medical consultation, resulting in diagnostic delay. Unfortunately, HCV infection frequently becomes chronic, defined as the continued presence of HCV RNA for 6 months or longer after the estimated onset. Subsequent spontaneous loss of virus is unusual. Chronicity rates range from 50 to 90%, with somewhat lower rates in children and young healthy women (50–60%) and higher rates in older individuals and African Americans.19,20 Despite several studies, the natural history of chronic HCV infection remains poorly defined. The major long-term complications of chronic HCV infection are liver fibrosis and cirrhosis, portal hypertension and liver failure, and a high risk for hepatocellular carcinoma. The development of cirrhosis in published studies in the general population has ranged from 2 to 42%.21,22 In this regard, it should be noted that available studies do not yet extend beyond the first two decades after infection. Factors associated with an increased risk of progressive fibrosis include older age, male gender, white race, coinfection with human immunodeficiency virus (HIV) or HBV, chronic alcoholism, and coexistence of other comorbid conditions such as obesity and diabetes.
Treatment in the general population
Interferon-a (IFN-α) was approved for the treatment of chronic hepatitis C in 1991. The rate of sustained virologic response (SVR), defined as the absence of HCV RNA in serum at least 6 months after IFN-α withdrawal, is unfortunately low, usually o20%. The subsequent inclusion of ribavirin in the therapeutic regimen has been shown to improve SVR rates to 40–45%.23–25 The long-acting pegylated IFNs were introduced more recently. Owing to their longer half-life, pegylated IFN can be given as a weekly dose. In large trials of pegylated IFN, either alfa-2a (Pegasys; Roche, Basel, Switzerland) or alfa-2b (PEG-Intron; Schering-Plough, Kenilworth, NJ, USA), the rate of SVR after a 48-week course of combined pegylated IFN and ribavirin was 54 and 56%, respectively, as compared with 44 and 47% with IFN and ribavirin, and only 29% with pegylated IFN alone.23,26,27 Response rates were higher in patients with HCV genotype 2 or 3 (75–80%) than genotype 1 (40–45%). Recently, it was shown that patients with genotype 2 or 3 could be treated with 800mg rather than 1000–1200mg ribavirin daily, and for 24 weeks rather than 48 weeks, without reducing SVR (about 80%) rates.28–30 Absolute contraindications to therapy with IFN or pegylated IFN and ribavirin include pregnancy and breastfeeding. Relative contraindications include decompensated liver disease, major neuropsychiatric disease, coronary or cerebrovascular disease, active substance or alcohol abuse, and a history of kidney or heart transplantation. The most common adverse effects of pegylated IFN are muscle aches and fatigue. Additional side effects include depression, anxiety, and sleep disturbances. The most common side effect of ribavirin is hemolysis with anemia, requiring dose reduction.
II. HCV IN CHRONIC KIDNEY DISEASE
Relevance of the topic in CKD patients
Soon after the discovery of HCV as the major cause of non-A non-B hepatitis, HCV was recognized as an important cause and consequence of chronic kidney disease (CKD). Indeed, HCV is a significant cause of some forms of glomerulonephritis (GN), especially membranoproliferative GN (MPGN). The initial recognition of this association came from case series of patients with MPGN, in which the prevalence of HCV infection appeared much higher than expected. Subsequent population-based studies have found an association between
HCV positivity and markers of CKD, such as albuminuria or proteinuria. This has been documented in the United States (NHANES III) and Taiwan.31 These studies obviously did not have data on kidney histology, so it is unclear whether the association is mainly due to MPGN or other factors.32 In addition, HCV infection is a frequent consequence of CKD. Blood transfusions (before effective screening of blood donors for HCV was instituted), nosocomial transmission in dialysis units, and transmission by kidney grafts all have contributed to the much higher prevalence of HCV infection in CKD Stage 5D and transplant patients than in the general population.
Epidemiology of HCV infection in the various stages of CKD
As in the general population, the prevalence of HCV in CKD Stage 5D patients varies worldwide, ranging from as low as 1% to as high as over 70% (see Table 1). Overall, the current prevalence of HCV is below 5% in most of Northern Europe, around 10% in most of Southern Europe and the US, between 10 to 50% and up to 70% in many parts of the developing world, including many Asian, Latin American, and North African countries (Table 1). It is important to emphasize that the prevalence of HCV is highly variable from unit to unit within the same country, with recent reports from some dialysis units in the US reporting prevalences above 20%.33
Consistent risk factors for the presence of anti-HCV antibodies and/or HCV RNA include blood transfusions given before efficient testing for HCVand the total time spent on dialysis. Additional risk factors include a history of kidney transplantation, intravenous drug use, and having been dialyzed in a high-prevalence region.
Some studies from various European countries showed a decrease of the prevalence of anti-HCV during the 1990s. In contrast, the prevalence of anti-HCV antibodies, as recorded by the voluntary registration program of the Centers for Disease Control and Prevention (CDC), has apparently not changed significantly over the last 10 years, remaining around 8–10%.34 The evolution of the epidemiology of HCV in CKD Stage 5D patients in other countries is poorly defined.
The reported incidence of newly acquired HCV infection, usually detected by seroconversion, was high in the early 1990s, ranging from 1.4% to more than 20% per year.35,36 Recent data show that the incidence of seroconversion for HCV has decreased to less than 1–2% in many developed countries.34,37,38
Not surprisingly, the prevalence of HCV infection in CKD transplant patients is also high. Consistent risk factors include the total time spent on dialysis and a history of and/or the number of blood transfusions. The prevalence in a given population of CKD transplant patients parallels the prevalence in the general population of the same country or region. Recent population-based estimates of the prevalence of HCV infection in CKD transplant patients are not available.
Even less is known of the prevalence of HCV in the various stages of CKD before dialysis or transplantation. It is, however, apparent from several case series—admittedly relatively small-sized—that patients with CKD Stages 3–5 have a disproportionately high prevalence of HCV infection compared with the general population.
Natural history of HCV infection in CKD
Multiple observational studies have shown an independent and significant association between HCV positivity and lower patient survival, despite adjustment for a number of comorbid conditions. The major complications of HCVrelated chronic liver disease (cirrhosis and hepatocellular carcinoma) have been implicated in the lower survival of anti-HCV-positive CKD Stage 5D patients. Similarly, HCVinfected
CKD transplant patients have lower long-term graft and patient survival than uninfected CKD transplant patients. In addition, the presence of HCV RNA in CKD transplant patients has been implicated in the development of post-transplant immune complex GN and a higher incidence of post-transplant diabetes mellitus. Very little is known of the natural history of chronic HCV infection and its prognostic impact in the earlier stages of CKD (see Guideline 2).
Liver biopsy in patients with CKD
Liver biopsy is not without risk and complications, especially hemorrhagic. In patients with CKD, hepatocellular dysfunction, drugs with antiplatelet activity, and uremic platelet dysfunction, all may contribute to this risk. The place of liver biopsy in the diagnostic strategy, the prevention of complications of the procedure, and the scoring of liver biopsies are discussed in Appendix 1.
Treatment of HCV infection in CKD
Treating chronic HCV infection in CKD patients is associated with a number of challenges. As glomerular filtration rate (GFR) decreases, the half-life of both IFNs and ribavirin increases, resulting in potentially poorer tolerance and the need for dosage adaptations in severe CKD. In kidney graft recipients, the use of IFNs and immunostimulating agents further entails a substantial risk of rejection. These issues are discussed extensively in Guideline 2.
HCV infection in children with CKD
Very little is known about HCV infection in infants and children with CKD. Only a few reports describe the basic epidemiologic characteristics of HCV infection in children with CKD Stage 5D and transplant recipients.51,52 This very limited information implies that the current guidelines do not apply directly and completely to this specific population. Pediatric nephrologists and other physicians in charge of caring for children with CKD should carefully evaluate the extent to which the current guidelines may be extrapolated to children.
Management of potential occupational exposure to HCV
Hepatitis C virus is not easily transmitted through occupational exposure to blood. The average incidence of anti-HCV seroconversion after accidental percutaneous exposure to an HCV-positive source is 1.5% (range 0–7%).53 Transmission rarely occurs from mucosal exposure to blood, and no transmission has been documented from intact or nonintact skin exposure to blood. Postexposure prophylaxis (unlike for HIV) is not recommended, either with immunoglobulins or with antiviral agents (IFNs or ribavirin).
In the absence of postexposure prophylaxis for HCV, recommendations for postexposure management aim at identifying early actual HCV infection. Cohort studies in the general population strongly suggest that early antiviral treatment (at the stage of acute hepatitis C) is associated with a very high (over 90%) rate of cure for hepatitis C.54 For HCV postexposure management, the HCV status of the source and the exposed health-care worker should be determined. For health-care workers exposed to an HCVpositive source, follow-up testing should be performed to determine if hepatitis C develops. The minimal recommendation is to perform tests for ALT and EIA (and/or NAT) monthly for 4 months after exposure.55 In the case of acute HCV infection, the health-care worker should be referred urgently to a specialist for appropriate management. This does not imply that the viral treatment will always be immediately started, as acute hepatitis C may resolve spontaneously in 15–20% of cases within 3 months,56 but close follow-up is essential.
III. FORMAT OF GUIDELINE STATEMENTS
Each listing of guideline statements is accompanied by a table that summarizes the interpretation of the three levels of recommendations used. Each statement strength is matched with specific wording and with a given basis for the strength. For further clarity in the lists of statements, Strong statements are in bold print, Moderate statements are in regular print, and Weak statements are in italics.
