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Viral Hepatitis Recommendations for Solid-Organ Transplant Recipients and Donors

Faria, Luciana Costa MD, PhD1; Terrabuio, Débora Raquel Benedita MD2; Leblebicioglu, Hakan MD3; Huprikar, Shirish MD4

doi: 10.1097/TP.0000000000002013
Reviews
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1 Department of Internal Medicine of Faculdade de Medicina da Universidade Federal de Minas Gerais. Gastroenterology Alfa Institute, Hospital das Clínicas da Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.

2 Department of Gastroenterology, University of São Paulo, Shcool of Medicine, Brazil.

3 Department of Infectious Diseases and Clinical Microbiology, Ondokuz Mayis University Medical School, Samsun, Turkey.

4 Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY USA.

Received 2 July 2017. Revision received 31 October 2017. Accepted 15 November 2017.

The authors declare no conflicts of interest.

Funded by a technical cooperation agreement between the Pan American Health organization (PAHO) and the Ministry of Health of Brazil.

This review is a chapter of Recommendations for Management of Endemic Diseases and Travel Medicine in Solid-Organ Transplant Recipients and Donors: Latin America supplement.

Correspondence: Luciana Costa Faria, MD, PhD, Departamento de Clínica Médica da Faculdade de Medicina da Universidade Federal de Minias Gerais - UFMG. Av. Prof. Alfredo Balena, 190. CEP 30130–100. Belo Horizonte, MG, Brazil. (lucostafaria@hotmail.com).

Travelers are at risk of acquiring viral hepatitis, which can lead to acute and chronic liver disease. Although some recommend that immunocompromised hosts should avoid travel during periods of intense immunosuppression such as the first year after solid-organ transplant (SOT) or during episodes of acute rejection,1,2 this may not be feasible in all situations. This review summarizes the epidemiology of hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV), and hepatitis E virus (HEV) in Latin America (LA) and recommendations for infection prevention in SOT donors, candidates, and recipients who travel. The risks of transmission by the donor and respective preventive measures will only be briefly mentioned.

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HEPATITIS A VIRUS INFECTION

Introduction and Epidemiology

HAV infection is an acute, usually self-limited disease caused by a nonenveloped RNA virus of picornavirus family. HAV is mainly transmitted person-to-person by the fecal-oral route.3,4 The risk of acute liver failure increases with age. Infection during early childhood is most often entirely asymptomatic. By contrast, infection during late childhood, adolescence, or adulthood is more likely to cause icteric illness; the risk of fulminant hepatitis and death is also higher in these age groups. Patients with chronic liver disease and immunocompromised hosts are also at greater risk.3,4 The World Health Organization estimates 1.4 million annual cases worldwide with 340 000 deaths.3 There is a higher incidence of HAV infection in developing countries with poor sanitary conditions and hygienic practices, and many children are infected by age 10. According to the World Health Organization, LA is a moderate- to high-risk area with intermediate seroprevalence in most countries.5 The highest rates in the region are in Andean, LA (96% in 2005).6 In Brazil, a decrease in seroprevalence has been observed, with a reported annual incidence of approximately 7.5 to 11 cases per 100 000 during 2000 to 2005.7 In 2010, a national prevalence survey of viral hepatitis performed on 26 102 people in all Brazilian capitals detected antibodies to HAV in 30.8% to 58.3% of the population.8

Travel to high-risk areas remains the highest risk for acquisition of HAV infection in nonvaccinated individuals, through ingestion of contaminated food or water. Men who have sex with men are also at risk of transmission. The improvement of basic sanitation, adequate personal hygiene practices, and food safety are fundamental for achieving disease control.3 HAV transmission via blood exposure is rare but documented.9 There are no reports of HAV transmitted via organ transplantation.

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Prevention

Ideally, all SOT recipients older than 1 year who are susceptible to HAV should be vaccinated before transplant.4 Vaccination after SOT is recommended starting 6 months after transplant1,2 but is associated with lower rates of seroconversion, lower mean antibodies titers, and shorter duration of protective immunity when compared with the healthy population.1,2,4 A recent survey of response to HAV vaccines across different studies reported antibody responses after the first and second vaccination of 37% and 82%.10 SOT recipients susceptible to HAV infection should receive the HAV vaccine series before travel to moderate- to high-risk infection areas. There are 2 options for preventing HAV, 2 doses of the monovalent vaccine or 3 doses of the combined hepatitis A&B vaccine. When feasible, seroconversion should be assessed before departure. If still seronegative, if the vaccination series is not completed or not feasible before travel (eg, insufficient time), pooled immunoglobulins are recommended before travel.1,2,11 They are 85% to 90% effective for protecting against HAV infection, but this effect is short term.12

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HEPATITIS B VIRUS INFECTION

Introduction and Epidemiology

Chronic HBV infection is globally distributed and causes acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma. There are approximately 11 million persons with chronic HBV infection in LA,13 and the majority of LA countries are considered low prevalence (<2%) regions. Intermediate prevalence regions in Central America are Guatemala, Belize, El Salvador, Honduras, Haiti, the Dominican Republic and Puerto Rico (2-8%) and in South America, include Ecuador, Venezuela, Guyana, Surinam, French Guyana and southern Brazil. High prevalence regions (>8%) include Peru, southern Colombia, northern Bolivia and northern Brazil14-16 (Figure 1).

FIGURE 1

FIGURE 1

Higher prevalence of HBV infection is found in persons with lower socioeconomic status. In LA, sexual transmission and household transmission seem to be more prevalent than vertical transmission.14,18,19 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.20,21 Transmission of HBV via organ transplantation is well described, and consensus guidelines for prevention were recently published.22

HBV is among the most important transfusion-transmitted infections worldwide.23 Screening tests for hepatitis B surface antigens (HBsAg) and anti-hepatitis B core (anti-HBc) detect HBV transmissible blood and prevent recipient infection. Implementation of HBV nucleic acid testing (NAT) has revealed occult HBV infection in blood donors, and reduced the residual risk of HBV transmission.24-26 Nevertheless, it is costly and not always easily accessible in developing countries.27 Few data about occult HBV infection in blood donors are available in LA and prevalence ranges from 0% to 6.4%.28-33

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Prevention

Pretravel counseling about HBV infection prevention is essential and should include recommendations to avoiding exposures with emphasis on condom use and vaccination.19,20 Although the HBV vaccination series should ideally be given before transplantation,34,35 it is recommended for all unvaccinated SOT recipients, particularly before travel to highly endemic areas. When feasible, serologic testing of anti-HBs 1 to 2 months after completion of the vaccine series should be performed to confirm immunity. Revaccination should be considered if antibody response is suboptimal (anti-Hbs <10 mIU/mL),1 potentially with higher-dose HBV vaccine. Although HBV vaccination is typically administered over a 6-month period, travel may necessitate an accelerated series with variable efficacy.12,36 Potential donors with positive anti-HBc and negative HBsAg testing are appropriate for organ donation in most settings. Donor NAT testing for HBV DNA should be performed if available.22 When anti-HBc positive donors are used for liver transplantation, there is a risk of HBV transmission, and recipient prophylaxis with oral antiviral medication is recommended.22

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HEPATITIS C VIRUS INFECTION

Introduction and Epidemiology

HCV is one of the main causes of chronic liver disease, cirrhosis, and hepatocellular carcinoma worldwide.37 Between 6.8 and 8.9 million adults are estimated to be HCV seropositive in LA (Figure 2).39 The estimated HCV infection prevalence in adults is 2% to 2.5% in Brazil and Argentina, 1.4% in Mexico and Venezuela, 2% to 2.9% in Peru, and 2.3% in Puerto Rico.39,40

FIGURE 2

FIGURE 2

In general, the risk factors for HCV are like HBV. HCV transmission risk in travelers is thought to be low, but there is a paucity of data regarding travel-associated HCV acquisition.41-43 The magnitude of the risk will depend on the prevalence of HCV in the destination country and the presence of risky behaviors, which are more common during travel.44 LA has been proactive in screening the blood supply and minimizing the risk of transfusion transmission. Because Intravenous drug use (IDU) is less common in LA compared with the United States and Europe, other risk factors play a major role in HCV transmission. The suspected risk factors are nosocomial infections, non-IDU injections, such as vitamin shots, inadequate needle disposal, dental procedures, tattooing and other procedures, that involve contact with infected blood (eg, cosmetic procedures).39 Transmission of HCV from a viremic donor is almost universal.45 There is frequently an option to allocate organs from an HCV positive donor to an HCV-positive recipient. All-oral direct-acting antiviral agents are highly effective at treating HCV in SOT candidates and recipients. Use of organs from HCV viremic donors to HCV-negative recipients is now a consideration with the availability of these highly effective treatments, thus potentially expanding the donor pool.46,47

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Prevention

Because there is no HCV vaccine, prevention relies on education and avoidance of high-risk exposures. Travelers should be counseled on avoiding contact with nonsterile needles, syringes, cosmetic and tattoo procedures, or other risky behaviors.12 Potential donors who test positive for HCV antibody with negative NAT testing may be appropriate for donation. “Eclipse phase” (preceding appearance of detectable viremia) and “window period” transmissions (viremia before development of serologic response) still exist.47,48

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HEPATITIS D VIRUS INFECTION

Introduction and Epidemiology

HDV is a small, defective RNA virus that requires preexisting or concurrent infection with HBV because it uses HBsAg as its own virion coat. There are 8 genotypes of HDV with different geographical distribution and different degrees of liver disease.30 Coinfection is associated with a greater risk of acute liver failure but lower risk of chronic infection (1-3%). HDV superinfection is associated with a high risk of chronic HDV liver disease (70-80%).49-52

The distribution of HDV parallels HBV infection, although with different prevalence rates. LA is an area of intermediate HDV endemicity. There are some data on severe and fatal acute and chronic hepatitis D among indigenous people of Venezuela, Colombia, Brazil, and Peru, areas with high chronic HDV infection rates.51,53 In Brazil, 76.3% of 1812 cases of HDV recorded in 1999 to 2010 occurred in the northern region of the country, 69.5% of them in the age range 20 to 49 years.8 In this region, the proportion of anti-HDV in HBsAg carriers reaches 32%. In 4 Colombian areas, the prevalence of HBsAg was 5.66%, and 5.2% of the HBV carriers were positive for anti-HDV.52 Risk factors for HDV are like HBV. HDV infection should be considered in all HBsAg carriers with unexplained elevation in liver enzymes. Patients should be tested for HDV via anti-HDV (IgG or IgM) antibodies.4 Interferon-based therapies remain the only treatment option of the hepatitis delta. The beneficiary effects of the interferon-based therapies, however, stop frequently with termination of the given therapy, relapse rate is very high, and the efficiency does not exceed 30%. The main goal of the current treatments is clearance of HBsAg.54

Favorable patient and graft outcomes have been described in liver transplant recipients with HBV/HDV coinfection, when HBV reinfection is prevented by prophylaxis with HBIG and/or nucleos(t)ide analogues.53

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Prevention

The measures aimed at HBV prevention will also prevent HDV transmission in patients susceptible to HBV. However, HBV immunoglobulin and HBV vaccine do not protect HBV carriers from HDV infection, and avoiding high-risk exposures is essential.4

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HEPATITIS E VIRUS INFECTION

Introduction and Epidemiology

HEV is a RNA virus member of the Hepevirus genus of the Hepeviridae family.55 HEV genotype (GT) 1/2 is transmitted by the fecal-oral route through contaminated drinking water and may cause water-related outbreaks in developing countries with low standards of sanitation. Zoonotic transmission from animal reservoirs to humans has also been suggested. After an incubation period of 2 to 6 weeks, HEV generally causes an acute self-limiting viral hepatitis. Severe disease can occur in pregnant women with a mortality of 20%. In patients with a preexisting liver disease, acute HEV infection might result in hepatic decompensation.56

Human HEV outbreaks have been reported in LA, and specifically, twice in Mexico, when the GT 2 was identified.57 HEV has also been detected in pigs from Mexico and Costa Rica.58 Moreover, recent reports demonstrated that HEV circulates in Uruguay58 and central Argentina.59 Additionally, it is endemic in the Brazilian Amazon60 and is postulated to be present in Bolivia based on the detection of antibodies against HEV.61

HEV GT3 is transmitted by consumption of uncooked/undercooked pork, boar, and deer, and is endemic in Europe, United States, China, and Japan. It is known to cause chronic hepatitis in immunocompromised hosts.62,63 Chronic HEV infection develops in 66% of the SOT recipients,64 and there is an evidence of rapid fibrosis progression to cirrhosis in HIV-infected patients within 3 years.65 In a retrospective case series of SOT patients with HEV (n = 59), 78% had a sustained virologic response with ribavirin, which appears to be a promising treatment option.66

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Prevention

There is currently no commercially available HEV vaccine. A highly effective HEV vaccine has been developed, but is currently only available in China.67 Immunocompromised travelers to HEV endemic regions should be informed about 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. To date, there is no specific recommendation for screening organ donors.

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NONHEPATOTROPHIC VIRUSES

The liver may be infected after SOT by other viruses than the hepatotrophic ones, as cytomegalovirus,68-70 herpes simplex virus,71 varicella zoster virus,72 Epstein-Barr virus,73 human herpes virus 6 and 7,74,75 adenovirus.76,77 It may be an isolated site of clinical infection, or its involvement may be part of a systemic infectious process. Clinical evidence of liver infection may range from asymptomatic biochemical derangement of liver enzyme tests to fulminant hepatic failure.

The other viral infections occurring in LA that may affect the liver are the arboviruses dengue, chikungunya, zika, and yellow fever. Other articles of this supplement address this issue.

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ACKNOWLEDGMENTS

The authors thank Leah Casner for her assistance with formatting the article. The authors also thank Paulo Henrique Orlandi Mourão for creating the figures.

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