Review Article
Viral hepatitis in hemodialysis: An update Bassam Bernieh Consultant and Chief of Nephrology, Tawam Hospital in Affiliation with Johns Hopkins Medicine, Clinical Professor of Medicine, COMHS, UAE University, Al Ain, UAE
ABSTRACT Hepatitis outbreaks in hemodialysis (HD) patients and staff were reported in the late 1960s, and a number of hepatotropic viruses transmitted by blood and other body fluids have been identified. Hepatitis B virus (HBV) was the first significant hepatotropic virus to be identified in HD centers. HBV infection has been effectively controlled by active vaccination, screening of blood donors, the use of erythropoietin and segregation of HBV carriers. Hepatitis delta virus is a defective virus that can only infect HBV-positive individuals. Hepatitis C virus (HCV) is the most significant cause of non-A, non-B hepatitis and is mainly transmitted by blood transfusion. The introduction in 1990 of routine screening of blood donors for HCV contributed significantly to the control of HCV transmission. An effective HCV vaccine remains an unsolved challenge; however, pegylation of interferon-alfa has made it possible to treat HCV-positive dialysis patients. Unexplained sporadic outbreaks of hepatitis by the mid-1990s prompted the discovery of hepatitis G virus, hepatitis GB virus C and the TT virus. The vigilant observation of guidelines on universal precaution and regular virologic testing are the cornerstones of the effective control of chronic hepatitis in the setting of HD. Major recent advances in the viral diagnosis technology and the development of new oral, direct-acting antiviral agents allow early diagnosis and better therapeutic response. The current update will review the recent developments, controversies and new treatment of viral hepatitis in HD patients. Key words: DAAs, hemodialysis, hepatitis B, hepatitis C, occult HBV, viral hepatitis
INTRODUCTION
Address for Correspondence: Dr. Bassam Bernieh, Consultant and Chief of Nephrology, Tawam Hospital in Affiliation with Johns Hopkins Medicine, Clinical Professor of Medicine, COMHS, UAE University, Tawam Hospital, P.O.BOX: 15258, Al Ain - UAE. E-mail:
[email protected];
[email protected]
Access this article online Website: www.intern-med.com DOI: 10.1515/jtim-2015-0018 Quick Response Code:
It is well known that patients undergoing dialysis treatment, and in particular hemodialysis (HD), are at increased risk for contracting viral infections. This is due to their underlying impaired cellular immunity, which increases their susceptibility to infection. In addition, the process of HD requires blood exposure to infectious materials through the extracorporeal circulation for a prolonged period. Moreover, HD patients may require blood transfusion, frequent hospitalizations and surgery, which increase opportunities for nosocomial infection exposure.[1] The most frequent viral infections encountered in HD units are hepatitis B (HBV), hepatitis C (HCV) and, to a lesser extent, human immunodeficiency virus infection (HIV). After the identification of HCV in 1989 and HEV in 1990, there were still
unexplained cases of posttransfusion and “community-acquired” hepatitis, implying that cryptogenic hepatitis and cirrhosis may be related to viruses other than hepatitis A, B, C, D or E. By the mid-1990s, between 3% and 4% of anti-HCV-negative patients on chronic HD had elevated serum aminotransferase levels with no apparent etiology.[2,3] In 1995-1996, Simons et al.[4] and Linnen et al.,[5] both from the United States, independently reported a group of putative agents that accounted for the unexplained non-A to non-E hepatitis. These viruses were named GB virus C (GBV-C) and hepatitis G virus (HGV). HGV was identified by molecular cloning with plasma from a patient originally identified by the CDC as having NANBH.[5] Nucleotide sequence and amino acid sequence alignment revealed homology between HGV and GBV-C of 86% and 95%, respectively; thus, it is likely that they represent different genotypes of the same virus.[6] The clinical significance
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Bernieh: Viral hepatitis in hemodialysis
of GBV-C/HGV infection in humans remains to be established. Few data in patients on HD are available. After the identification of GBV-C/HGV in 1995-1996, it was thought that additional hepatotropic viruses might exist because GBV-C/HGV infection has not been consistently shown to induce liver disease.[7] In 1997, a novel virus associated with posttransfusion hepatitis was identified in three patients from Japan who developed serum aminotransferase elevation following transfusion and tested negative for all known hepatitis viruses.[8] The virus, referred to as TT virus (TTV) for the initials of the patient in whom it was originally isolated or mnemonically for “transfusiontransmitted virus,” exhibited hepatotropism as its titers in serum correlated with the rise in hepatic transaminase levels of affected subjects. The epidemiology of TTV in the HD population is not well characterized. A relationship between TTV infection and hepatitis or liver disease has not been established. Hence, the exact clinical significance of TTV in the HD population remains to be determined. In the current review, we will restrict our update to HBV and HCV only, and will discuss the most recent data of these viruses in HD.
HEPATITIS B VIRUS (HBV) HBV infection is a substantial global health problem. It is estimated that more than two billion people worldwide have serological evidence of current or historical infection.[9] HBV is highly infectious compared with other bloodborne viruses: An untreated percutaneous exposure to an infected source carries a risk of seroconversion of up to 30%. By contrast, the risks for HCV and HIV are 1.8% and 0.31%, respectively.[10] Acute infection occasionally results in fulminant hepatitis, but more importantly can progress to a chronic state, where decompensation, cirrhosis and hepatocellular carcinoma (HCC) are all potential complications. HD, which requires access to the bloodstream, affords an opportunity for transmission of HBV between patients and between patients and staff. Viral hepatitis complicating HD has been recognized from the earliest days of this therapy. While the introduction of vaccination programs and stringent infection control measures have succeeded in limiting the spread of hepatitis infection within dialysis facilities, outbreaks continue to occur periodically and prevalence rates remain unacceptably high. As such, HBV infection remains an important issue in renal replacement therapy. Epidemiology of HBV Hepatitis B is a blood-borne virus. Modes of infection include perinatal and through percutaneous or mucosal exposure to infected blood or body fluids.[11] There are considered to be more than 350 million people worldwide 94
with chronic hepatitis B (CHB) infection.[12] More than 75% of these live in the Asia-Pacific region, with high numbers also residing in Africa and the Amazon basin. In areas of high endemicity, the lifetime infection rate is above 50%, and more than 8% of the population are chronic carriers.[13] Infection in such regions is typically acquired in childhood, either horizontally from other children or perinatally from maternal carriers. By contrast, parenteral transmission is common in Australia, and fewer than 2% of the population are chronic HBV carriers. HCC is the sixth most common cancer worldwide, and half of all cases are caused by HBV.[14] HBV is the second most important carcinogen after cigarette smoke. In dialysis units, both patient-to-patient and patient-tostaff transmission of the virus have been recognized since the 1960s. Before the advent of vaccination, some success in limiting the spread of HBV was achieved by dialyzing seropositive patients separately from those who were seronegative. This followed the publication in the UK of the Rosenheim Report in 1972,[15] which set out a code of practice for reducing transmission of hepatitis among dialysis patients. In 1977, guidelines were published in the USA to reduce HBV infection in dialysis units.[16] The incidence of new hepatitis B infections in US dialysis patients subsequently fell from 6.2% in 1974 to 1% by 1980.[17] Testing of a vaccine began in the 1970s, and this came into widespread clinical use from the early 1980s.[18,19] This further reduced the risk of HBV infection in the dialysis setting. Nevertheless, although rates of new infection are now low,[20] hepatitis B continues to exist in dialysis populations. Prevalence rates tend to be dependent on baseline population rates. An analysis of data from the Dialysis Outcomes and Practice Patterns Study showed an HBV prevalence of 0-6.6% across dialysis facilities in Western Europe, Japan and the USA.[21] In contrast, a registry study of Asia-Pacific countries found that the prevalence of hepatitis B surface antigen (HBsAg) positivity ranged between 1.3% and 14.6%.[22] Reports from much smaller cohorts elsewhere have indicated HBsAg positivity rates of 13.3% in Turkey and 2.4-10% in Brazil.[23-25] In the middle East, the prevalence of HBV was reported as 11.8% in Saudi patients, 3.7% in Bahrainis[26] and 2.2% in our HD unit in the UAE (no published data) In addition to being at increased risk of infection, it has been demonstrated that HD patients are more likely to become chronic carriers of HBV than members of the general population.[27] Occult hepatitis B Recently, with advanced HBV diagnostic tools, emerged the problem of occult HBV infection (OBI). OBI is defined
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Bernieh: Viral hepatitis in hemodialysis
as the presence of HBV-DNA without detectable HBsAg with or without hepatitis B core antibody (anti-HBc) or hepatitis B surface antibody (anti-HBs). Sensitivity and specificity improvement of polymerase chain reaction (PCR) methods with a detection limit of 1.5 times ULN therefore might prove too high and not sensitive enough for the identification of HBV-infected dialysis patients with significant hepatic inflammation who otherwise warrant anti-viral treatment. As such, it has been suggested that if a dialysis patient with chronic HBV infection has otherwise unexplained elevation in serum ALT level persistently above 30 IU/L or 0.75 times ULN, or if the serum ALT level does not reach that level but there is clinical evidence of progressive liver disease, significant hepatic inflammation should be suspected and liver biopsy should be considered.[84] Current treatment options for patients with CHB are interferons or antiviral therapy with nucleos(t)ide analogs (NAs) that target the viral polymerase.[85] The treatment of CHB in patients with CKD is based on nucleoside (lamivudine, telbivudine, entecavir) or nucleotide (adefovir, tenofovir) analogues (NAs). Entecavir and tenofovir represent the currently recommended first-line NAs for NA-naive CHB patients, while tenofovir is the NA of choice for CHB patients with resistance to nucleosides.[86] Table 1 and Figure 1 show the dose adjustment and the algorithm of use of NAs in CKD patients.[86]
HEPATITIS C (HCV) HCV Epidemiology Hepatitis C is a liver disease caused by the HCV, the virus that can cause both acute and chronic hepatitis infection
Figure 1: Mechanisms of action for direct-acting antivirals, currently in development. NNPI, nonnucleoside polymerase inhibitor (adapted from Reference 161)
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Bernieh: Viral hepatitis in hemodialysis Table 1: Dosage adjustments of nucleos(t)ide analogues according to creatinine clearance (CrCl) based on the approved special product characteristics (SPCs)
CrCl (mL/min)
Lamivudine
≥50 30–49 15–29 5–14 5
100 mg daily 100 mg loading dose – 50 mg daily 100 mg loading dose – 25 mg daily 35 mg loading dose – 15 mg daily
