Preventing and Treating Viral Hepatitis in End-Stage Renal Disease

Due to innate and adaptive immune alterations and the risk for nosocomial infection from exposure to potentially infected blood-borne sources, patients with end-stage renal disease (ESRD) have an elevated risk of contracting viral infections such as hepatitis B virus (HBV) and hepatitis C virus (HCV). An estimated 8% to 10% of ESRD patients in the United States have HCV infection compared with 1.6% of the general population, and HBV prevalence rates as high as 6.6% have been noted in dialysis centers across several countries.¹

HBV and HCV infection are associated with significant morbidity, mortality, and substantial treatment challenges in this patient group, including complications arising from concurrent hepatic and renal disease. “Cirrhosis can develop in untreated individuals and compound the already immense burden of disease in patients with ESRD, manifesting as encephalopathy, refractory ascites, coagulopathy, and variceal bleeding,” wrote nephrologist Vivek Soi, MD, and colleagues at Henry Ford Health System in Detroit, Michigan, in a 2019 review published in Advances in Chronic Kidney Disease.¹

In a 2016 study of 1,069 adult patients with ESRD initiating dialysis, researchers identified cirrhosis as an independent risk factor for mortality after adjustment for age, cardiovascular disease, diabetes, and other potentially confounding variables.² The cumulative survival rates of cirrhotic patients were 90%, 68%, and 48% at 1, 3, and 5 years, respectively, compared with 93%, 83%, and 73% in patients without cirrhosis.²

Another study published in 2016 compared 1,068 cirrhotic patients with ESRD to 10,680 randomly selected patients with cirrhosis without renal impairment. The results showed 1-year and 3-year mortality rates of 48.5% and 73.1% in the ESRD group vs 32.9% and 55.6% in the control group, respectively.³ In addition, patients cirrhotic and ESRD with recurrent complications demonstrated a nearly 2-fold increase in 3-year mortality (hazard ratio [HR], 1.98; P  <.001).

Such findings highlight the critical need for rigorous screening, prevention, and treatment strategies for HBV and HCV infection in patients with ESRD. To learn about best practices in this area, we interviewed Dr Soi and Helen C. Koenig, MD, MPH, associate professor of clinical medicine at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia and medical director of the MacGregor Infectious Diseases Practice at the Perelman Center for Advanced Medicine.

What are the recommended screening and prevention strategies for HBV and HCV in patients with end-stage renal disease?

Dr Soi: We recommend screening all patients for both HBV and HCV with serologic tests prior to starting dialysis. The following tests are ordered immediately prior to the patient’s first dialysis: hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), hepatitis B core antibody IgG (HBcAb-IgG) and hepatitis C antibody (HCV Ab). The HBsAg is repeated every 30 days, unless the patient has known immunity. HCV Ab is assessed between every 6 months to 1 year depending on the local prevalence of the disease in the community. Monthly liver function tests (aspartate transaminase and alanine transaminase) are also checked, and if an elevation in these enzymes is observed, repeat testing with the above serologic profile is performed.

Dr Koenig: For patients with HBV or HCV, the screening and prevention strategies are similar but have some important differences. Because the circulating load of HBV can be much higher than in other bloodborne infections, and HBV can survive on environmental surfaces, hemodialysis patients are at significant risk of HBV acquisition through nosocomial infection. Peritoneal dialysis patients are at a lower risk relative to hemodialysis patients, with a risk level closer to the general risk.

Prevention strategies include standard precautions (hand washing after coming into contact with potentially infectious surfaces; wearing gloves, mask, and gown with potential exposure to infectious fluids), as well as hemodialysis-specific measures (wearing gloves before contact with patients receiving hemodialysis or equipment; routine machine cleaning and disinfecting; no sharing of equipment or instruments between patients; no use of medication carts; and regular screening of hemodialysis patients for HBV with HBsAg, as well as HBV vaccination of both hemodialysis patients and staff).

For HBV, standard of care is to use dedicated hemodialysis machines for patients with positive HBsAg, and these dialyzers are to be excluded from reuse programs. With respect to vaccination, hemodialysis patients have lower response rates to HBV vaccines, but HBV vaccination was found to decrease the risk for HBV acquisition in these patients by 70%, so it remains a very effective prevention tool.⁴ Screening involves screening all patients new to hemodialysis and upon switching from one hemodialysis center to another; the recommended screening test is HBsAg. Screening should then be done annually, with extra screening if a patient’s titers rise or there is novel intercedent infection.

For HCV prevention, standard infection control practices and universal precautions are also recommended, and particular attention should be given to not sharing multidose heparin vials between patients with and without HCV and to changing gloves between patients while performing hemodialysis. However, patients with HCV do not require separate machines like patients with HBV, since the risk for HCV transmission through the internal pathways of the machine is very low.

Screening of patients with ESRD for HCV involves screening all patients upon hemodialysis initiation or transfer from another center, with concurrent HCV RNA and anti-HCV Ab at the time of initial screening (because the false negative rate of anti-HCV Ab screening alone has been found to be as high as 17.9% in hemodialysis patients⁵) and then anti-HCV Ab every 6 to 12 months thereafter. Patients who develop a new unexplained transaminitis or who have other risk factors for HCV (such as intravenous drug users and men who have sex with men) should be tested more often.

What are the optimal treatment approaches for patients with HBV or HCV and concurrent ESRD?

Dr Soi: Infection control policies involving hand hygiene and universal precautions based on the United States Centers for Disease Control and Prevention guidelines are followed in in-center hemodialysis units.⁶ Chlorinated bleach or a compatible disinfectant is used to decontaminate machines that have been used by patients with HBV.

Ideally, patients should be immunized against HBV prior to initiating dialysis. When patients develop end-stage kidney disease, there is a tendency for humoral immunity to wane, and they may not develop immunity to the HBV vaccine. Most HBV immunization protocols reflect this by adding an additional dose of the vaccine and administer 4 doses instead of the typical 3 doses of either Engerix-B or Recombivax HB vaccines.

Patients with HBV should undergo hemodialysis in an isolation area that is separate from the general population of patients who do not have HBV, especially those who are not immune to HBV. Patients with HBV should be referred to a hepatologist for potential antiviral therapy. Although these medications do not offer a definitive cure, they can suppress viral replication and minimize morbidity.

There has been greater success with the use of direct-acting antiviral agents (DAAs) as treatment for HCV in patients with ESRD. Treatment protocols are based on the genotype of the virus involved.

Dr Koenig: For treatment of HBV in patients with HBV receiving hemodialysis, recommendations are for entecavir (renally adjusted, can range from 0.5 mg daily to 1 mg weekly depending on CrCl) or tenofovir alafenamide (TAF) 25 mg once daily dosed after hemodialysis. Patients with ESRD who are not yet receiving hemodialysis should be treated with renally adjusted entecavir, because TAF has only been studied once a patient below CrCl 15 is on hemodialysis. Dosing in peritoneal dialysis is a bit unclear for TAF as well; dosing of entecavir in these patients is 1 mg weekly.

For HCV, treatment choices are essentially the same as for patients with and without renal disease and depend on factors such as genotype, treatment history, other comorbidities. In general, glecaprevir-pibrentasvir and sofosbuvir-velpatasvir are first-line treatments, and they do not require renal adjustment. However, sofosbuvir is cleared by hemodialysis and thus should be administered after the session on hemodialysis days. Dosing among peritoneal dialysis patients is unclear.

What are some of the top challenges in treating these populations, and how might these issues be addressed in practice?

Dr Soi: DAAs for HCV have traditionally been very expensive and often involve prior authorization through associated insurance carriers, which can lead to challenges in obtaining treatment. There is controversy regarding the timing of treatment for HCV in patients who are nearing a kidney transplantation. In the past, many organs from donors with HCV have traditionally been discarded. Patients on the kidney transplant waiting list may undergo transplantation sooner if they receive a HCV-positive organ and undergo treatment with DAAs following the transplant. Collaborative care involving hepatology, the nephrology transplantation team, and infectious disease physicians can best individualize a treatment plan for these patients.

We recommend serial audits to help ensure that infection control protocols are being followed appropriately in the dialysis unit.

Dr Koenig: There are not too many challenges in patients with ESRD in particular, now that we have good screening tools and treatment choices that are safe in for this patient population (particularly those on hemodialysis). One big gap is that treatment recommendations in peritoneal patients. Another challenge is that, if patients acquire HBV while receiving hemodialysis, they are significantly more likely to end up with chronic infection.⁷ Thus, strategies to reduce new HBV acquisition are still very important, and new infections occasionally do sneak through – likely when the precautions above are not followed consistently.

What should be the focus of future research pertaining to this topic?

Dr Soi: Patient education on safe sex practices, including the avoidance of high-risk behaviors such as intravenous drug use, and early testing for these viral entities is of the utmost importance. Early identification and treatment prior to the onset of overt cirrhosis improves outcomes in terms of morbidity.

Further research on treatment with antiviral agents for HBV is still needed to help combat this disease. An entity known as occult HBV, where signs of HBV DNA are present in tissue without traditional serologic marker patterns, is also an area of potential future research in regards to patient significance and outcomes.

Dr Koenig: Treatment for peritoneal hemodialysis patients, as mentioned above, warrants further investigation. There is also a need for research regarding the role of fibroscan in hemodialysis patients, as we know it may not be as good as in patients with normal kidney function.

References

1. Soi V, Daifi C, Yee J, Adams E. Pathophysiology and treatment of hepatitis B and C infections in patients with end-stage renal disease. Adv Chronic Kidney Dis. 2019;26(1):41-50.
2. Kim AJ, Lim HJ, Ro H, et al. Liver cirrhosis leads to poorer survival in patients with end-stage renal disease. Korean J Intern Med. 2016;31(4):730-738.
3. Hung TH, Tsai CC, Tseng KC, et al. High mortality of cirrhotic patients with end-stage renal disease. Medicine (Baltimore). 2016;95(10):e3057.
4. Almueilo SH. Evaluation of response to hepatitis B vaccination in chronic hemodialysis patients. Saudi J Med Med Sci. 2017;5(3):218-223.
5. Moini M, Ziyaeyan M, Aghaei S, et al. Hepatitis C virus (HCV) infection rate among seronegative hemodialysis patients screened by two methods; HCV core antigen and polymerase chain reaction. Hepat Mon. 2013;13(6):e9147.
6. Centers for Disease Control and Prevention. Dialysis Safety. https://www.cdc.gov/dialysis/guidelines/index.html Accessed online May 8, 2020.
7. Bernieh B. Viral hepatitis in hemodialysis: An update. J Transl Int Med. 2015;3(3):93-05.