Hepatitis B virus and dialysis patients

INTRODUCTION — Hepatitis B virus (HBV) infection can lead to acute or chronic hepatitis, cirrhosis, and/or hepatocellular carcinoma. Despite the availability of effective vaccines since 1982, HBV infection has remained endemic in many countries. The World Health Organization estimates that in 2019, approximately 296 million people were living with chronic hepatitis B infection worldwide. (See "Hepatitis B virus: Clinical manifestations and natural history" and "Epidemiology, transmission, and prevention of hepatitis B virus infection".)

Among patients on dialysis or who have undergone kidney transplantation, HBV infection presents a distinct clinical problem due to the immunosuppressive effect of kidney failure, increased susceptibility for de novo infection and nosocomial transmission, and the long-term implications of untreated HBV on morbidity and mortality. The natural history of HBV infection in patients on dialysis may also vary according to the timing of infection, genotype, and locality.

This topic will discuss HBV infection among patients with end-stage kidney disease on dialysis, with an emphasis on hemodialysis since it is associated with a higher risk of nosocomial HBV transmission compared with peritoneal dialysis. Details regarding HBV infection in patients with a kidney transplant and kidney diseases in patients with HBV are presented elsewhere.

●(See "Kidney transplantation in adults: Hepatitis B virus infection in kidney transplant recipients".)

●(See "Kidney disease associated with hepatitis B virus infection".)

EPIDEMIOLOGY AND RISK FACTORS

Incidence and prevalence — The incidence of HBV infection in patients on dialysis has significantly decreased over the past few decades. This is due to the following factors:

●Screening of blood products for hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc)

●Implementation of infection control measures (see 'Infection control measures in the dialysis unit' below)

●Reduced need for transfusion after the advent of erythropoiesis-stimulating agents

●Hepatitis B vaccination (see "Immunizations in patients with end-stage kidney disease")

In the United States, the incidence of HBV infection among patients on hemodialysis has declined by approximately 95 percent since the initiation of hepatitis B vaccination. The annual incidence rate of HBV among patients on hemodialysis decreased from 6.2 percent in 1974 to 0.06 percent in 1999 [1] and has been stable since 1995 (0.12 percent in 2002), with a prevalence rate (by HBsAg seropositivity) of 1 percent [2].

HBsAg positivity rates in patients on dialysis correlate with endemicity in the general population, as illustrated by the prevalence rates within Asia [3,4]. HBsAg prevalence rates in patients on dialysis have been reported as follows:

●1 percent in United States [2]

●5.9 percent in Italy [5]

●12 percent in Brazil [6]

●1.3 to 14.6 percent in the Asian Pacific region (lower rates in countries such as Australia, Japan, and New Zealand; higher rates in countries such as Mongolia, the Philippines, and China) [4]

Risk factors for HBV infection in dialysis units — Independent risk factors for HBV infection among patients on dialysis in nonendemic areas include the following [7,8]:

●Presence of HBsAg-positive patients within the same dialysis unit

●Lack of provision of dedicated hemodialysis machines for HBsAg-positive patients

●A lower than 50 percent prevalence rate of hepatitis B vaccination among patients on dialysis in the same unit

Nosocomial transmission is a well-recognized risk for HBV infection in patients on hemodialysis. The preparation of injectable medications on a cart or in a location within the hemodialysis treatment area is associated with a higher incidence rate for HBV infection compared with centers that prepared these medications in a dedicated medication room (2002 incidence rates of 0.27 and 0.06 percent, respectively) [2]. (See 'Infection control measures in the dialysis unit' below.)

Crucial to preventing nosocomial transmission is the implementation of and adherence to:

●Standard or universal precautionary measures (see 'Infection control measures in the dialysis unit' below)

●Hemodialysis unit procedures for the prevention of bloodborne infections (see 'Infection control measures in the dialysis unit' below)

●Hepatitis B vaccination of nonimmune individuals (see 'Hepatitis B vaccination' below)

Outbreaks of HBV infection in dialysis units are most often related to nonadherence to universal precautions, omission of initial and/or periodic HBsAg screening, sharing of multidose vials or blood-contact equipment, or inadequate vaccination, with surface contamination by HBV of shared equipment being a major contributing factor [9]. HBV deoxyribonucleic acid (DNA) has been shown to traverse the dialyzer membrane during high-flux dialysis, but the degree of infectivity of dialysate and ultrafiltrate remains controversial [10-12].

Patients on peritoneal dialysis have a lower risk of acquiring HBV infection compared with those on long-term hemodialysis. There is a reported 19-fold difference in seroconversion rates [13].

ASSESSMENT OF HBV STATUS PRIOR TO INITIATING DIALYSIS — All patients starting hemodialysis should be evaluated for HBV infection prior to initiating dialysis. The following serologic testing should be performed: hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc; total or immunoglobulin G [IgG]) (table 1).

Subsequent management depends upon the results of serologic testing:

●Anti-HBs positive (immunity) – Patients who have an anti-HBs titer ≥10 milli-international units (mIU)/mL have immunity to HBV infection either through vaccination (anti-HBc negative) or through prior infection (anti-HBc positive). Patients with immunity due to vaccination should undergo monitoring of anti-HBs titers to check for waning immunity. Also, these patients should be routinely tested for HBV while on dialysis since seroconversion to HBsAg positive can occur due to waning immunity. (See 'Patients without chronic or occult HBV infection' below.)

●HBsAg negative, anti-HBc negative, anti-HBs negative (no prior exposure) – Individuals with no prior exposure to HBV are at risk for nosocomial transmission of HBV in the dialysis unit and should receive vaccination as soon as possible. Such patients should also be routinely tested for HBV while on dialysis. For those who refuse vaccination, additional monitoring may be indicated. (See 'Patients without chronic or occult HBV infection' below.)

●HBsAg positive (chronic HBV) – Patients who are HBsAg positive have acute or chronic HBV infection. Such patients should be dialyzed in an area that is segregated from the main dialysis unit and require special infection control measures to prevent the transmission of HBV to other patients and staff. It should be noted that not all dialysis units may have the resources to dialyze patients with chronic HBV infection. (See 'Infection control measures in the dialysis unit' below and 'Patients with chronic HBV infection' below.)

For patients newly diagnosed with chronic HBV, further testing includes an assessment of hepatitis B e antigen (HBeAg) status, the HBV DNA level, and the presence or absence of cirrhosis. (See "Hepatitis B virus: Overview of management", section on 'Initial evaluation'.)

●Isolated anti-HBc positive – Patients who are negative for both HBsAg and anti-HBs and positive for anti-HBc are referred to as isolated anti-HBc positive. In such patients, we measure a circulating HBV DNA level to better assess HBV status and infectivity. Those who are negative for HBsAg but have detectable HBV DNA are considered to have occult HBV infection, which often represents a low viral replicative state. Isolated anti-HBc positivity can also occur as a transient phenomenon in acute HBV infection, in which case the anti-HBc is of the immunoglobulin M (IgM) isotype. (See "Hepatitis B virus: Screening and diagnosis in adults", section on 'Occult HBV infection'.)

Occult hepatitis B is relatively uncommon among patients on hemodialysis, affecting fewer than 3 percent, and the incidence correlates with the local prevalence of HBV carriers. However, occult HBV infection presents a risk for nosocomial transmission; thus, it is recommended that HBsAg-negative, HBV DNA-positive patients be segregated during dialysis with those who are HBsAg-positive [14-17]. (See 'Infection control measures in the dialysis unit' below and 'Patients with occult HBV infection' below.)

INFECTION CONTROL MEASURES IN THE DIALYSIS UNIT — In contrast to other bloodborne infections, the circulating load of HBV can be high in hepatitis B surface antigen (HBsAg)-positive individuals, and the virus can survive on environmental surfaces for a week or longer [18]. Consequently, patients on dialysis, in particular those on hemodialysis, are at risk for nosocomial HBV infection. Nosocomial HBV infection among hemodialysis patients has been related to inadequate infection control measures or technical breaks [19,20]. (See 'Risk factors for HBV infection in dialysis units' above.)

To prevent nosocomial transmission, standard precautionary measures must be rigorously followed [21]. These include barrier procedures to prevent exposure to bloodborne micro-organisms:

●Washing hands after contact with potentially infectious surface or material

●Wearing gloves when contacting potentially infectious surface or material

●Wearing a face mask and gown when exposure to blood or body fluids is expected

In addition to these standard precautions, measures specific to hemodialysis units are also important to prevent nosocomial HBV infection [22,23]. These include:

●Wearing gloves before contact with patients or dialysis equipment.

●Routine cleaning and disinfection procedures.

●Prohibition of sharing instruments or medications among patients.

●Preparing and distributing medications from a centralized area to avoid moving from patient to patient.

●Avoiding the use of medication supply carts.

●Regular screening of HBsAg status in nonimmune individuals. (See 'Surveillance' below.)

●Hepatitis B vaccination of patients and staff. (See 'Hepatitis B vaccination' below.)

●Healthcare workers handling the dialysis of patients with chronic HBV should not carry out clinical procedures for patients without HBV infection at the same session.

●Isolation of patients with chronic (HBsAg-positive) or occult HBV infection during dialysis.

●Regular auditing of infection control policies and practices to ensure adherence.

Treatment of HBV-infected patients on hemodialysis with antiviral therapy may also reduce the risk of other patients in the same hemodialysis center acquiring HBV infection [24]. This is consistent with the well-established association between the risk of nosocomial transmission and the prevalence of HBsAg-positive patients in a hemodialysis center.

Failure to segregate and use dedicated hemodialysis machines for HBsAg-positive patients is associated with an increased incidence of HBV infection, and machine segregation is now standard practice. On the other hand, the United States national surveillance in 1997 showed no difference in the incidence of HBV infection between centers that practiced segregation of dialysis rooms and those that did not [7,25]. Dialyzer reuse was also not associated with a higher risk of HBV infection both in patients and in staff. Nevertheless, the Centers for Disease Control recommended that dialyzers from HBsAg-positive patients be excluded from reuse programs [26].

DISEASE-SPECIFIC CONSIDERATIONS

Patients with chronic HBV infection — The clinical manifestations of chronic HBV infection or HBV-induced cirrhosis in patients on dialysis are identical to those in patients without kidney failure. (See "Hepatitis B virus: Clinical manifestations and natural history".)

Enhanced infection control precautions — Patients with chronic HBV infection should be dialyzed in an area that is isolated from the main dialysis unit. Other infection control measures are discussed in more detail above. (See 'Infection control measures in the dialysis unit' above.)

Routine monitoring — Patients with chronic HBV infection on dialysis should have regular monitoring of liver enzymes, serum albumin, and bilirubin concentration. Some UpToDate contributors measure these tests every 12 weeks in patients on dialysis since such patients are prone to various complications and exposed to multiple medications, whereas other experts may measure these tests less frequently (eg, every three to six months). Prothrombin time and international normalized ratio (INR) should also be measured when there is evidence of severe hepatitis or cirrhosis. Parenchymal liver enzymes are measured as a measure of hepatitic activity, while albumin, prothrombin time/INR, and bilirubin are useful indicators of liver function in patients with cirrhosis. We repeat hepatitis B surface antigen (HBsAg) testing annually and perform testing for HBV DNA, hepatitis B e antigen (HBeAg), and hepatitis B e antibody (anti-HBe) when clinically indicated. (See "Hepatitis B virus: Overview of management".)

With regard to screening for hepatocellular carcinoma, existing guidelines recommend surveillance ultrasonography every six months in HBV-infected patients with cirrhosis or at high risk of hepatocellular carcinoma, with or without additional measurement of serum alpha-fetoprotein; alpha-fetoprotein alone is not recommended, except in places where ultrasonography is not available, in view of its lower sensitivity, specificity, and diagnostic accuracy compared with ultrasonography [27]. Risk factors for hepatocellular carcinoma include the presence of cirrhosis, age over 40 years for Asian or Black males or over 50 years for Asian females, hepatocellular carcinoma in a first-degree relative, and coinfection with hepatitis delta virus. While kidney failure is associated with increased overall cancer risk, its impact on the incidence of hepatocellular carcinoma in HBV-endemic areas remains undefined [28,29]. In noncirrhotic patients without established risk factors for hepatocellular carcinoma, the need for monitoring is unclear. Some UpToDate contributors perform a liver ultrasound annually and measure a serum alpha-fetoprotein level every six months.

Laboratory testing during the acute or chronic phases of HBV infection can reveal elevations in the concentration of alanine and aspartate aminotransferase levels (ALT and AST). However, hypotransaminasemia is a well-recognized feature in patients on dialysis with or without liver disease [30]. Consequently, the normal range of transaminases should be adjusted downwards; otherwise, the incidence or severity of clinical liver disease might be underestimated. In this regard, levels of 24 and 17 units/L have been recommended as the upper limits of normal for AST and ALT, respectively, in patients on dialysis. (See "Serum enzymes in patients with kidney failure".)

Since the biochemical abnormalities (eg, transaminitis) do not always correlate with liver histology, a liver biopsy may be necessary in selected patients, with careful attention to minimize the risk of bleeding complications [31,32]. In this regard, transient elastography has increasingly replaced liver biopsy in the assessment of liver fibrosis due to viral hepatitis, especially since the optimal timing of liver biopsy in otherwise asymptomatic patients without clinical or biochemical abnormalities remains to be defined [33]. Data suggest that transient elastography should be performed postdialysis since fluid removal during dialysis decreases the value of liver stiffness measurement [34,35].

Treatment of chronic HBV — For patients with chronic HBV, the indications for treatment typically depend upon the HBV DNA level, the transaminase levels, and the presence of liver injury, including cirrhosis. In general, the indications for HBV treatment are the same for those with and without kidney failure. (See "Hepatitis B virus: Overview of management".)

However, certain patients on dialysis may be receiving immunosuppressive agents to treat their underlying condition. For such patients, treatment is typically indicated, regardless of the HBV DNA level or aminotransaminase levels given the risk of a flare of their HBV infection due to the immunosuppressive therapy. Similarly, when a kidney transplant with its associated use of immunosuppression can be anticipated in the near future, initiation of antiviral therapy may also be considered. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)

Patients requiring antiviral therapy should be treated with an agent that has a high barrier to resistance. For those on dialysis, tenofovir (tenofovir disoproxil fumarate or tenofovir alafenamide) or entecavir can be used. Dose adjustments are described in the table (table 2). Additional information on the use of these agents in patients with kidney failure can be found in the Lexicomp drug information topics within UpToDate. (See "Hepatitis B virus: Overview of management", section on 'Choice of initial agent'.)

Prognosis — Although early data suggested inferior clinical outcomes in HBV-infected patients on dialysis [36], the majority of more recent studies have not indicated significant differences in morbidity and mortality between HBsAg-positive and HBsAg-negative patients on dialysis, especially after the advent of antiviral therapies [37,38]. Fewer than 5 percent of these patients die from liver disease [37,38]. The adverse impact of HBV infection on the survival rate of patients on dialysis appears much lower compared with that of bacterial infections and vascular complications, which are the leading causes of death.

Cirrhosis of any cause is associated with a 35 percent increase in mortality rate among patients on dialysis; however, whether HBV infection alone contributes to this effect on patient survival remains controversial [37,39,40].

Patients with occult HBV infection — Similar to patients with chronic HBV infection, patients with occult HBV and measurable HBV DNA in serum should be dialyzed in an area that is isolated from the main dialysis unit, and they require special infection control measures to prevent the transmission of HBV to other patients and staff. Routine monitoring is similar to that for patients with chronic HBV, as described above. (See 'Infection control measures in the dialysis unit' above and 'Routine monitoring' above.)

Patients without chronic or occult HBV infection — Patients on dialysis who do not have evidence of chronic or occult HBV infection include those with HBV immunity through vaccination or prior infection, those with no prior HBV infection, and those who are hepatitis B core antibody (anti-HBc) positive and HBV DNA negative (table 1). Patients with no prior infection should be vaccinated to reduce the risk of acquiring HBV infection. However, since hepatitis B vaccination is less effective in those on dialysis, routine surveillance testing to detect new HBV infection or the need for a booster dose of the hepatitis B vaccine should be performed.

Hepatitis B vaccination — Individuals with no prior exposure to HBV are at risk for nosocomial transmission of HBV in the dialysis unit and should receive vaccination as soon as possible. Vaccination is important both to prevent susceptible patients from acquiring HBV and to reduce the pool of HBV-infected patients. In a case-control study, the risk of HBV infection in patients on hemodialysis was reduced by 70 percent after hepatitis B vaccination [41]. It is imperative that HBV vaccination be performed early in the course of kidney failure in nonimmune subjects since seroconversion response correlates with the level of kidney function and is significantly lower in patients on dialysis, who require higher doses of vaccine or other measures to increase the vaccination response [42]. A booster dose of vaccine can be given to patients who are isolated anti-HBc positive but HBV DNA negative to see if it stimulates the production of hepatitis B surface antibody (anti-HBs). Issues surrounding hepatitis B vaccination in patients on dialysis are discussed in detail separately. (See "Immunizations in patients with end-stage kidney disease", section on 'Hepatitis B virus vaccine' and "Hepatitis B virus immunization in adults", section on 'Patients on dialysis and immunocompromised hosts'.)

Surveillance

New HBV infection — All patients without chronic or occult HBV infection should be routinely monitored for the development of new HBV infection:

●Laboratory testing – Patients should undergo routine testing for HBsAg to detect new HBV infection. The frequency of testing depends upon the patient's HBV serology profile and may also vary among dialysis units. At our center, we perform HBsAg testing every three months. In certain patients, such as those with an anti-HBs titer >100 milli-international units (mIU)/mL, the frequency of testing can be extended to once every six months, but for ease of implementation, dialysis units may prefer to routinely check HBsAg every three months.

●Clinical monitoring for acute infection – Clinicians and patients should be alert to signs and symptoms of HBV infection since the manifestation of acute HBV infection in patients on dialysis is extremely variable. The majority of patients on dialysis with new HBV infection are either asymptomatic or have mild clinical symptoms [36]. Serum transaminase levels are either normal or only slightly elevated. This also relates to the lower values of the normal range in these patients. It is not uncommon that the diagnosis of HBV infection is made through regular surveillance testing. (See "Serum enzymes in patients with kidney failure", section on 'Aminotransferases'.)

The genetic variant of HBV may affect the severity of clinical manifestations. As an example, an outbreak of fulminant hepatitis resulting in four deaths in a dialysis center in Tokyo was attributed to infection by a precore mutant [43].

Acute hepatitis B in patients on dialysis is more likely to result in chronic infection compared with nonimmunosuppressed individuals. Up to 80 percent of acutely infected patients on dialysis may become chronic carriers [36].

Waning immunity — All patients with immunity to HBV should undergo routine testing for anti-HBs at least annually to detect waning immunity and determine the need for a booster dose of the hepatitis B vaccine. We administer a booster vaccine dose when the anti-HBs level drops below 10 mIU/mL. This is often given to those with immunity due to vaccination, especially when kidney transplantation in the near future is anticipated. Some experts also give a booster dose to those with waning immunity due to prior infection since there is a potential benefit and vaccination is well tolerated; however, there are limited data supporting this approach and vaccination of those with prior infection is not routinely done in all dialysis centers.  

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Dialysis".)

SUMMARY AND RECOMMENDATIONS

●Assessment of HBV status prior to dialysis initiation – All patients starting hemodialysis should be evaluated for hepatitis B virus (HBV) infection prior to initiating dialysis with the following serologic testing: hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc; total or IgG) (table 1). Subsequent management depends upon the results of testing. (See 'Assessment of HBV status prior to initiating dialysis' above.)

●Infection control measures – Patients on hemodialysis are at risk for nosocomial HBV infection, usually related to inadequate infection control measures or technical breaks. To prevent nosocomial transmission, standard precautionary measures as well as measures specific to hemodialysis units must be rigorously followed. (See 'Infection control measures in the dialysis unit' above.)

●Management based on HBV serologic status

•Patients with chronic HBV – Patients with chronic HBV infection are HBsAg positive.

-Enhanced infection control precautions – Patients with chronic HBV infection should be dialyzed in an area that is isolated from the main dialysis unit. (See 'Enhanced infection control precautions' above.)

-Monitoring – Patients with chronic HBV should have regular monitoring of liver enzymes, serum albumin, and bilirubin, at least once every 12 weeks. Prothrombin time should also be measured when there is evidence of severe hepatitis or cirrhosis. We repeat HBsAg testing annually and perform testing for HBV DNA, hepatitis B e antigen (HBeAg), and hepatitis B e antibody (anti-HBe) when clinically indicated. With regard to screening for hepatocellular carcinoma, we perform a liver ultrasound every six months in patients with cirrhosis or other risk factors for hepatocellular carcinoma; in other patients, liver ultrasound is done annually, with serum alpha-fetoprotein level measured every six months. (See 'Routine monitoring' above.)

-Treatment – The indications for treatment typically depend upon the HBV DNA level, the transaminase levels, and the presence of cirrhosis. Patients requiring therapy should be treated with an agent that has a high barrier to resistance, such as tenofovir or entecavir. (See "Hepatitis B virus: Overview of management", section on 'Choice of initial agent'.)

•Patients with occult HBV – Patients who are negative for HBsAg, are positive for anti-HBc, and have detectable HBV DNA are considered to have occult HBV infection, which often represents a low viral replicative state. Similar to patients with chronic HBV, patients with occult HBV should be dialyzed in an area that is isolated from the main dialysis unit and require special infection control measures to prevent the transmission of HBV to other patients and staff. Routine monitoring is similar to that for patients with chronic HBV. (See 'Patients with occult HBV infection' above.)

•Patients without chronic or occult HBV – Patients on dialysis who do not have evidence of chronic or occult HBV infection include those with HBV immunity through vaccination or prior infection, those with no prior HBV infection, and those who are anti-HBc positive and HBV DNA-negative.

-HBV vaccination – Patients with no prior infection should be vaccinated to reduce the risk of acquiring HBV infection. However, hepatitis B vaccination is less effective in patients with kidney failure. (See 'Hepatitis B vaccination' above.)

A booster dose of vaccine is also reasonable for patients who are isolated anti-HBc positive but HBV DNA negative, to see if it stimulates the production of anti-HBs.

-Surveillance – All patients without chronic or occult HBV infection should be routinely monitored for the development of new HBV infection. The frequency of testing, ranging from every three to six months, depends upon the patient's HBV serology profile and may also vary among dialysis units. Clinicians and patients should be alert to signs and symptoms of HBV infection. All patients with immunity should undergo routine testing for anti-HBs at least annually to detect waning immunity and determine the need for a booster dose of the hepatitis B vaccine. We administer a booster vaccine dose when the anti-HBs level drops below 10 milli-international units (mIU)/mL. (See 'Surveillance' above.)