|Year : 2022 | Volume
| Issue : 5 | Page : 77-81
Expert group opinion for diagnosis and management viral hepatitis in solid organ transplant recipients in South Asia
Neeraj Saraf1, Swapnil Dhampalwar1, Vivek Kute2, Shyam Bihari Bansal3
1 Department of Transplant Hepatology, Medanta-Medicity, Gurgaon, Haryana, India
2 Institute of Kidney Diseases and Research Center and Dr. H L Trivedi Institute of Transplantation Sciences, Ahmedabad, Gujarat, India
3 Department of Nephrology and Renal Transplant Medicine, Medanta Kidney and Urology Institute, Medanta-Medicity, Sector 38, Gurugram, Haryana, India
|Date of Submission||13-Sep-2021|
|Date of Acceptance||14-Feb-2022|
|Date of Web Publication||18-Oct-2022|
Dr. Neeraj Saraf
Department of Transplant Hepatology, Medanta-Medicity, Gurgaon, Haryana
Source of Support: None, Conflict of Interest: None
Viral hepatitis is endemic in the South Asia region and is mainly caused by four hepatotropic viruses: hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatitis E virus (HEV). South Asia region consists of developing countries and HAV and HEV infections are common because of poor sanitary conditions and hygiene practices. HAV and HEV are transmitted person-to-person by fecal‒oral route. HBV and HCV are transmitted via permucosal or percutaneous exposure. It is important to know the impact of these viral infections in the setting of transplantation including evaluation and management in pre, peri, and posttransplant periods. This review summarizes the epidemiology, preventive practices, and advisory for travelers to these endemic regions. Furthermore, recommendations for screening donors and recipients in transplant settings are discussed.
Keywords: Solid organ transplant, South Asia, viral hepatitis
|How to cite this article:|
Saraf N, Dhampalwar S, Kute V, Bansal SB. Expert group opinion for diagnosis and management viral hepatitis in solid organ transplant recipients in South Asia. Indian J Transplant 2022;16, Suppl S1:77-81
|How to cite this URL:|
Saraf N, Dhampalwar S, Kute V, Bansal SB. Expert group opinion for diagnosis and management viral hepatitis in solid organ transplant recipients in South Asia. Indian J Transplant [serial online] 2022 [cited 2022 Dec 9];16, Suppl S1:77-81. Available from: https://www.ijtonline.in/text.asp?2022/16/5/77/358667
| Introduction|| |
Hepatitis means “inflammation of the liver.” It can be caused by drugs, toxins, and viruses. Viral hepatitis is commonly caused by one of five viral agents. These were denominated A, B, C, D, and E in order of their discovery. Viral hepatitis is endemic in the Southeast Asia region and is commonly caused by four hepatotropic viruses: hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatitis E virus (HEV). Viral hepatitis in a transplant candidate may have increased the morbidity as compared to the normal population. Even donors and transplant candidates who are asymptomatic are diagnosed with viral hepatitis when screened for transplantation. Hence, it is important to know the implications of viral hepatitis in transplant setting. This review summarizes the epidemiology of these hepatotropic viruses in South Asian countries and recommendations for the prevention of infection in solid organ transplant recipients and donors who are traveling to these areas.
| Hepatitis A Virus|| |
HAV infection is an acute, usually self-limited infection caused by a nonenveloped RNA virus of the picornavirus family. HAV is mainly transmitted person-to-person by the fecal‒oral route. Infection during early childhood is most often entirely asymptomatic. Infection during adolescence or adulthood is more likely to cause icteric illness; the risk of fulminant hepatitis and death is higher in these age groups. Patients with chronic liver disease and immunocompromised hosts are also at greater risk of acquiring HAV infection.
HAV infection occurs largely in developing countries with poor sanitary conditions and hygienic practices. Majority of children (85%) below the age of 2 years and around 50% aged between 2 and 5 years have nonspecific symptoms and are usually anicteric. However, HAV infection was reported to cause severe disease with increasing age of the patient and with the presence of underlying chronic liver disease. The case fatality rate has been mentioned to be the highest in patients over the age of 50 years (1.8%) when compared to younger adults (0.3%). In India, HAV infection is highly endemic. By 18 years of age, 90% of population is seropositive for HAV. Among children, HAV is the predominant cause of acute hepatitis. With changing sanitation practices and improvement in socioeconomic strata, there is a transition of seroprevalence of HAV from younger to older children (6–10-year group). In Pakistan, HAV accounts for 50%–60% of cases of acute viral hepatitis in children.
Immunocompromised and nonvaccinated individuals are at high risk of acquisition of HAV infection while traveling to endemic areas. Infection occurs through ingestion of contaminated food or water. Men who have sex with men are also at risk of transmission. Maintaining sanitation and personal hygiene and food safety are paramount in preventing HAV infection. All transplant candidates >1 year who are at risk for HAV should be vaccinated prior to transplantation. solid organ transplant (SOT) recipients should receive the HAV vaccine series before traveling to moderate-to high-risk infection areas. Two doses of the monovalent vaccine or three doses of the combined hepatitis A and B vaccines can be taken. Ideally, seroconversion should be assessed before travel. Posttransplant HAV vaccine has lower mean antibodies titers and a shorter duration of protective immunity when compared with the healthy population. In case of incomplete or failure of vaccine, pooled immunoglobulins are recommended before travel. They are 85% to 90% effective for protecting against HAV infection in the short term.
Screening of donors and recipients
All transplant recipients should undergo serology for HAV (immunoglobulin M [IgM] anti-HAV). There are no reports of donor to recipient transmission of HAV in organ transplantation. Donors who have resolving hepatitis related to acute HAV can be accepted and these recipients do not need special treatment in perioperative period. Seropositive HAV recipients need to be managed conservatively.
| Hepatitis E Virus|| |
HEV is positive-stranded RNA virus belonging to the family hepeviridae.
HEV is primarily spread via the fecal–oral route and is an enterically transmitted pathogen like HAV. The incubation period of HEV infection is estimated to be around 2–6 weeks and during an epidemic of HEV, anicteric hepatitis is more common than icteric hepatitis and clinical hepatitis is seemingly more frequent in adults than in children aged <15 years. Chronic HEV infection although rare is classically described with HEV genotype 3 and can lead to cirrhosis in immunosuppressed patients and in patients undergoing a solid organ transplantation. Severe disease can occur in pregnant women with a mortality of 20%. In patients with preexisting liver disease, acute HEV infection might result in hepatic decompensation.
HEV is highly endemic in South Asian countries. In India, HEV infection is responsible for 30%–70% of cases of acute sporadic hepatitis and is the major cause of acute liver failure. In Pakistan, up to 20%–22% of adults and 2.4% of children were found to have acute hepatitis due to HEV. In Nepal, HEV accounts for 15%–50% of acute hepatitis cases.
Just like preventing HAV infection, improving the living standards and providing better sanitary conditions help in curtailing the spread of HEV in the community. Adequate sewage disposal and maintaining adequate personal hygiene are imperative to check the spread of the virus. Immunocompromised travelers to HEV endemic regions should take care of safe food handling, good hand washing practices, and water precautions. Unpurified drinking water including ice cubes, raw or inadequately cooked meat, inadequately washed raw salads, and unpeeled vegetables and fruits should be avoided. Boiling and chlorination of water will inactivate HEV, and it is safe to drink bottled water from reliable manufacturers. Travelers should take caution when buying food from street vendors. There is no commercially available vaccine for HEV.
Screening of donors and recipients
All transplant recipients should undergo serology for HEV (IgM anti-HEV). There are no reports of the donor to recipient transmission of HEV in organ transplantation. However, transfusion-transmitted HEV infections have been reported. Donor with acute infection is not accepted, however, patients with remote infections (e.g., HEV IgG positive) can be accepted as donors.
Asymptomatic and acute hepatitis secondary to HEV infection in recipients needs to be managed conservatively and monitored closely. Chronic hepatitis E is diagnosed when recipients have evidence of viral replication in serum or stool beyond 3 months of acute infection. Transplant recipients have 60% chances of developing chronicity after acute hepatitis E infection which can be a mimicker of liver allograft dysfunction or rejection. These patients may have persistently elevated transaminases with persistent positive HEV IgM titers. However, a positive HEV RNA either in serum, stool, or liver tissue is required to confirm diagnosis of chronic hepatitis E. Liver biopsy is important to rule out other causes of allograft dysfunction and demonstration of HEV RNA in liver tissue is confirms the diagnosis of chronic HEV. Noninvasive tests which are helpful in determining the likelihood of chronic HEV are HEV serologies; fibroscan or AST/PLT ratio index scores may be falsely elevated as these are influenced by underlying inflammation and have no role in the diagnosis of chronic HEV. Recipients who have evidence of chronic Hepatitis E should be treated with reduced Calcineurin inhibitors dosage and addition of ribavirin.
| Hepatitis C Virus|| |
HCV is a single-stranded RNA virus belonging to the family Flaviviridae. HCV causes both acute and chronic infection, however, unlike HBV, HCV has a higher propensity to lead to chronic viremia and 25% of these patients can develop chronic hepatitis. HCV in South Asia is primarily spread from infected needles, blood transfusion, dental and surgical procedures, and unsafe tattoo practices. HCV has six major genotypes, with genotype 1 being the most prevalent genotype globally (46%), followed by genotype 3 in 22% and genotypes 2 and 4 in 13% each. HCV is one of the main causes of chronic liver disease, cirrhosis, and hepatocellular carcinoma worldwide. All-oral direct-acting antiviral agents are highly effective at treating HCV in SOT candidates and recipients.
In India, the estimated prevalence of HCV is about 0.5%–1.5%. Despite low prevalence, India accounts for a significant proportion of global HCV burden because of its large population of 1.2 billion. Approximately 12–18 million people are thought to be infected with HCV in the country. There is significant variation in prevalence across various geographical regions. Pakistan has 4%–5% prevalence of HCV. In Bangladesh and Nepal, the prevalence of HCV is <1%.,
Screening of donors and recipients
All transplant recipients should undergo serology for HCV (anti-HCV antibody) and HCV RNA qualitative polymerase chain reaction (PCR). For living donor kidney transplant, if testing for HCV antibody is negative, then nucleic acid testing (NAT) is not done. Anti-HCV antibody positivity implies either a treated infection or active infection or a false-positive result, in which case a quantitative NAT testing is performed, and if the HCV NAT is negative, then the donor can be accepted. In deceased donor kidney transplant, HCV NAT should be done as infection might be in the window period and HCV antibody and serocoversion take more than a month., For liver transplant, NAT testing is performed in all donors. Donor-to-recipient transmission of HCV has been reported in organ transplantation. Transplantation of HCV positive organs to HCV positive recipients is practiced in deceased donor transplant program, however, this is not widely accepted in living-donor transplant program.
In liver transplantation, recipients with HCV-related cirrhosis are treated with directly-acting antivirals (DAAs) in pretransplant period if model for end-stage liver diseases (MELD) score is <20. Recipients with MELD score of more than 20 are treated in the posttransplant period with DAAs for 12 weeks once graft function stabilizes (after 4 weeks). Recipients of HCV-positive organs should be treated with antivirals for HCV for 12 weeks once graft function stabilizes (after 4 weeks). Sustained virologic response (SVR) is assessed 12 weeks after completion of therapy by confirming a negative HCV RNA PCR. In case of SVR achievement, subsequent testing of HCV RNA is not done, unless clinically indicated.
There is no HCV vaccine, hence, prevention depends on education and avoidance of high-risk exposures. Travelers should be counseled on avoiding contact with nonsterile needles, syringes, cosmetic, tattoo procedures, or other risky behaviors. In case of exposure, HCV RNA should be done at week 2–6, and assessment for infection should be done.
| HBV Virus Infection|| |
HBV is a small DNA virus belonging to the family Hepadnaviridae. HBV is transmitted via permucosal or percutaneous exposure to infected body fluids or blood products and it replicates via an RNA intermediate that can integrate itself into the host genome. HBV risk factors include exposure to blood products and body fluids from injection, medical equipment, body piercing, sexual activity, dental treatment, cosmetic procedures, tattoo, acupuncture, and sharing of personal grooming items. Transmission of HBV via organ transplantation is well described. The spectrum of HBV infection varies from acute to chronic depending on the duration of persistence of HBV surface antigen (HBsAg) in the serum. Majority of patients with acute infection would remain asymptomatic and only 30% develop icteric hepatitis. The incidence of developing fulminant hepatic failure remains low (0.1%–0.5%). When HBsAg persists in the serum for over 6 months, the patient has chronic HBV infection. The likelihood to go on to chronicity varies with age, with the risk being ≥90% in neonates and <5% in adults.
Chronic HBV infection is globally distributed and causes acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Different geographic areas are divided into four groups as per the distribution of hepatitis B: areas of high endemicity >8%, high intermediate 5%–7%, low intermediate 2%–4%, and low endemicity <2%. As per the recent data, India and Nepal have low prevalence (<2%) of HBV infection., Pakistan and Bangladesh have intermediate endemicity (nearly 4%) of HBV infection [Figure 1].,
The preventive strategy of HBV infection should include vigilant screening of blood and blood products and routine testing of tissue and organ donors. A lot of emphasis needs to be laid on screening the high-risk group of patients which include those who receive blood transfusions (patients with thalassemia major), subjects actively involved in intravenous drug use (IVDU), tattooing, acupuncture, and health-care workers. Harm reduction advice needs to be given to subjects with IVDU and adequate education regarding the usage of barrier contraceptives (e.g., condoms) and safe sexual practices need to be provided.
Vaccination forms an imperative pillar in the preventive strategy framed for HBV infection and studies in the regions of high endemicity have shown a steady decline in the incidence of HBV infection among children to <2% with the institution of the effective vaccination protocol. Although the HBV vaccination series should ideally be given before transplantation, it is recommended for all unvaccinated SOT recipients, particularly before travel to highly endemic areas. When feasible, serologic testing of anti-HBs 1–2 months after completion of the vaccine series should be performed to confirm immunity. Revaccination should be considered for nonresponders (anti-HBs <10 mIU/mL) with the second series of vaccination or be evaluated for HBsAg positive status. In case of the second series of vaccination, a different brand of vaccine should be considered. Revaccinated persons should check their antibodies 1–2 months after the last dose of the series. If titers are still inadequate an accelerated series with potentially higher-dose HBV vaccine should be considered. Although HBV vaccination is typically administered over a 6-month period, travel may necessitate an accelerated series with variable efficacy.
Screening of donors and recipients
In kidney transplant candidates, HBsAg and core antibody testing are sufficient (IgG and IgM) for hepatitis B screening. However, for liver transplant candidates, HBV DNA PCR is also done routinely along with HBsAg and core antibody (IgG). Donors should undergo serology for HBsAg and core antibody (both IgM and IgG anti-Hbc). HBV DNA quantitative PCR should be done, if serology is positive. Donors with HBsAg and IgM anti-HBc positivity have acute hepatitis and excluded from donation, however, donors who are HBsAg negative and IgM anti-HBc positive might be in the window period and donation should be avoided. Donors who are HBsAg negative and IgG anti-HBc positive might be false positive or chronic carriers. In these donors, quantitative HBV NAT should be done and if it is negative, then nonliver organs can be used in recipients who are fully vaccinated with protective anti-HBsAb titers of >100 IU/ml or who were previously infected with HBV., Donor-to-recipient transmission of HBV has been reported in organ transplantation. Transplantation of HBV positive organs to HBV positive recipients is widely practiced in cadaveric transplant program. However, this is not widely accepted in living donor transplant program. Recipients of HBV-positive organs should be treated with antivirals for HBV for long term to prevent HBV reactivation. Recipients who have hepatitis B infection should be started on antiviral treatment with Nucleos (t) ide analogs, i.e., entecavir, tenofovir, preferably in the pretransplant period. In the era of nucleos (t) ide analogs with high barrier to resistance, adjuvant therapy with hepatitis B immunoglobulin along with antivirals can be considered in liver transplant recipients who have high HBV viral load (>105) to prevent posttransplant HBV recurrence.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Franco E, Meleleo C, Serino L, Sorbara D, Zaratti L. Hepatitis A: Epidemiology and prevention in developing countries. World J Hepatol 2012;4:68-73.
Mackinney-Novelo I, Barahona-Garrido J, Castillo-Albarran F, Santiago-Hernández JJ, Méndez-Sánchez N, Uribe M, et al.
Clinical course and management of acute hepatitis A infection in adults. Ann Hepatol 2012;11:652-7.
Carrion AF, Martin P. Viral hepatitis in the elderly. Am J Gastroenterol 2012;107:691-7.
Acharya SK, Madan K, Dattagupta S, Panda SK. Viral hepatitis in India. Natl Med J India 2006;19:203-17.
Arankalle V, Mitra M, Bhave S, Ghosh A, Balasubramanian S, Chatterjee S, et al
. Changing epidemiology of hepatitis A virus in Indian children. Vaccine Dev Ther 2014;4:7-13.
Butt AS. Epidemiology of viral hepatitis and liver diseases in Pakistan. Euroasian J Hepatogastroenterol 2015;5:43-8.
Kotton CN, Hibberd PL; AST Infectious Diseases Community of Practice. Travel medicine and transplant tourism in solid organ transplantation. Am J Transplant 2013;13 Suppl 4:337-47.
Purdy MA, Harrison TJ, Jameel S, Meng XJ, Okamoto H, Van der Poel WH, et al.
ICTV virus taxonomy profile: Hepeviridae. J Gen Virol 2017;98:2645-6.
Goel A, Aggarwal R. Advances in hepatitis E – II: Epidemiology, clinical manifestations, treatment and prevention. Expert Rev Gastroenterol Hepatol 2016;10:1065-74.
Kamar N, Garrouste C, Haagsma EB, Garrigue V, Pischke S, Chauvet C, et al.
Factors associated with chronic hepatitis in patients with hepatitis E virus infection who have received solid organ transplants. Gastroenterology 2011;140:1481-9.
Khuroo MS, Teli MR, Skidmore S, Sofi MA, Khuroo MI. Incidence and severity of viral hepatitis in pregnancy. Am J Med 1981;70:252-5.
Shrestha A. Epidemiology of viral hepatitis and liver diseases in Nepal. Euroasian J Hepatogastroenterol 2015;5:40-2.
Robertson B, Myers G, Howard C, Brettin T, Bukh J, Gaschen B, et al.
Classification, nomenclature, and database development for hepatitis C virus (HCV) and related viruses: Proposals for standardization. International committee on virus taxonomy. Arch Virol 1998;143:2493-503.
Polaris Observatory HCV Collaborators. Global prevalence and genotype distribution of hepatitis C virus infection in 2015: A modelling study. Lancet Gastroenterol Hepatol 2017;2:161-76.
Al-Mahtab M. Past, present, and future of viral hepatitis in Bangladesh. Euroasian J Hepatogastroenterol 2016;6:43-4.
Malinis M, Boucher HW; AST Infectious Diseases Community of Practice. Screening of donor and candidate prior to solid organ transplantation – Guidelines from the American society of transplantation infectious diseases community of practice. Clin Transplant 2019;33:e13548.
White SL, Rawlinson W, Boan P, Sheppeard V, Wong G, Waller K, et al.
Infectious disease transmission in solid organ transplantation: Donor evaluation, recipient risk, and outcomes of transmission. Transplant Direct 2019;5:e416.
McMahon BJ. Epidemiology and natural history of hepatitis B. Semin Liver Dis 2005;25 Suppl 1:3-8.
Lee WM. Etiologies of acute liver failure. Semin Liver Dis 2008;28:142-52.
Madayag RM, Johnson LB, Bartlett ST, Schweitzer EJ, Constantine NT, McCarter RJ Jr, et al.
Use of renal allografts from donors positive for hepatitis B core antibody confers minimal risk for subsequent development of clinical hepatitis B virus disease. Transplantation 1997;64:1781-6.
Dodson SF, Bonham CA, Geller DA, Cacciarelli TV, Rakela J, Fung JJ. Prevention of de novo hepatitis B infection in recipients of hepatic allografts from anti-HBc positive donors. Transplantation 1999;68:1058-61.
Pilmore HL, Gane EJ. Hepatitis B-positive donors in renal transplantation: Increasing the deceased donor pool. Transplantation 2012;94:205-10.