The burden of hepatitis C virus infection in Punjab, India: A population-based serosurvey.

INTRODUCTION: Hepatitis C virus (HCV) infection prevalence is believed to be elevated in Punjab, India; however, state-wide prevalence data are not available. An understanding of HCV prevalence, risk factors and genotype distribution can be used to plan control measures in Punjab. METHODS: A cross-sectional, state-wide, population-based serosurvey using a multi-stage stratified cluster sampling design was conducted October 2013 to April 2014. Children aged ≥5 years and adults were eligible to participate. Demographic and risk behavior data were collected, and serologic specimens were obtained and tested for anti-HCV antibody, HCV Ribonucleic acid (RNA) on anti-HCV positive samples, and HCV genotype. Prevalence estimates and adjusted odds ratios for risk factors were calculated from weighted data and stratified by urban/rural residence. RESULTS: 5,543 individuals participated in the study with an overall weighted anti-HCV prevalence of 3.6% (95% Confidence Interval [CI]: 3.0%-4.2%) and chronic infection (HCV Ribonucleic acid test positive) of 2.6% (95% CI: 2.0%-3.1%). Anti-HCV was associated with being male (adjusted odds ratio 1.52; 95% CI: 1.08-2.14), living in a rural area (adjusted odds ratio 2.53; 95% CI: 1.62-3.95) and was most strongly associated with those aged 40-49 (adjusted odds ratio 40-49 vs. 19-29-year-olds 3.41; 95% CI: 1.90-6.11). Anti-HCV prevalence increased with each blood transfusion received (adjusted odds ratio 1.36; 95% CI: 1.10-1.68) and decreased with increasing education, (adjusted odds ratio 0.37 for graduate-level vs. primary school/no education; 95% CI: 0.16-0.82). Genotype 3 (58%) was most common among infected individuals. DISCUSSION: The study findings, including the overall prevalence of chronic HCV infection, associated risk factors and demographic characteristics, and genotype distribution can guide prevention and control efforts, including treatment provision. In addition to high-risk populations, efforts targeting rural areas and adults aged ≥40 would be the most effective for identifying infected individuals.

An outbreak of hepatitis E in an urban area of Bangladesh.

We investigated an outbreak of jaundice in urban Bangladesh in 2010 to examine the cause and risk factors and assess the diagnostic utility of commercial assays. We classified municipal residents reporting jaundice during the preceding 4 weeks as probable hepatitis E cases and their neighbours without jaundice in the previous 6 months as probable controls. We tested the sera collected from probable cases and probable controls for IgM anti-hepatitis E virus (HEV), and the IgM-negative sera for IgG anti-HEV using a commercial assay locally. We retested the IgM-positive sera for both IgM and IgG anti-HEV using another assay at the Centre for Disease Control and Prevention (CDC), USA. Probable cases positive for IgM anti-HEV were confirmed cases; probable controls negative for both IgM and IgG anti-HEV were confirmed controls. We explored the local water supply and sanitation infrastructure and tested for bacterial concentration of water samples. Probable cases were more likely than probable controls to drink tap water (adjusted odds ratio: 3.4; 95% CI: 1.2-9.2). Fifty-eight percentage (36/62) of the case sera were IgM anti-HEV positive; and 75% of the IgM-positive samples were confirmed positive on retesting with another assay at CDC. Compared to confirmed controls, cases confirmed using either or both assays also identified drinking tap water as the risk factor. Two tap water samples had detectable thermotolerant coliforms. Research exploring decentralized water treatment technologies for sustainable safe water might prevent HEV transmission in resource-poor cities. Detection of serological markers in a majority of probable cases implied that available diagnostic assays could adequately identify HEV infection during outbreaks.

Variability of hepatitis E serologic assays in a pediatric liver transplant recipient: challenges to diagnosing hepatitis E virus infection in the United States.

Hepatitis E virus (HEV) is an emerging cause of viral hepatitis among immunocompromised individuals in developed countries. Yet the diagnosis of HEV infection in the United States remains challenging, because of the variable sensitivity and specificity of currently available tests, and the lack of a US Food and Drug Administration-approved test. We report a case of multiple discordant HEV serology results in a pediatric liver transplant recipient with idiopathic hepatitis, and review the challenges to diagnosis of HEV infection in the United States.

Hepatitis B vaccination for healthcare personnel in American Samoa: pre-implementation survey for policy decision.

American Samoa does not have a hepatitis B vaccination policy for healthcare personnel (HCP). Consequently, hepatitis B has remained a health threat to HCP. In this study, we performed a cross-sectional study and examined demographic and risk information and hepatitis B vaccination, testing, and serostatus in hospital employees in American Samoa. Of 604 hospital employees, 231 (38·2%) participated, and of these, 158 (68·4%) were HCP. Of HCP participants, 1·9% had chronic hepatitis B infection, 36·1% were susceptible, and 60·8% were immune. Nearly half of HCP participants reported history of needlestick injury. Overall, participants' knowledge of their hepatitis B infection and vaccination status was low. These data support the adoption of a hepatitis B vaccination policy for HCP by American Samoa, as currently recommended by the World Health Organization and the US Centers for Disease Control and Prevention. Adherence to the policy could be monitored as a way to measure protection.

Hepatitis E virus infection in a liver transplant recipient in the United States: a case report.

BACKGROUND: Chronic infection with hepatitis E virus (HEV) has recently been recognized in immunocompromised or immunosuppressed individuals. CASE REPORT: We report a case of concurrent HEV and human herpes virus-6 (HHV-6) infection, documented by serum HEV RNA and HHV-6 DNA, in an orthotopic liver transplant (OLT) recipient in the United States, where HEV genotype 3 infection, although prevalent, is considered to be self-limited and almost always asymptomatic. The coinfection was accompanied by elevated serum aminotransaminases, liver biopsies demonstrating chronic hepatitis, and the presence of HEV RNA in the tissue. After lowering of immunosuppressive therapy and 2 courses of valganciclovir, sequential clearance of the viruses and normalization of the serum aminotransaminases were observed. CONCLUSIONS: HEV infection can lead to chronic hepatitis in OLT recipients, and evaluation of this virus should be considered in immunosuppressed individuals with unexplained liver test abnormalities.

Differences in variability of hypervariable region 1 of hepatitis C virus (HCV) between acute and chronic stages of HCV infection.

Distinguishing between acute and chronic HCV infections is clinically important given that early treatment of infected patients leads to high rates of sustained virological response. Analysis of 2179 clonal sequences derived from hypervariable region 1 (HVR1) of the HCV genome in samples obtained from patients with acute (n = 49) and chronic (n = 102) HCV infection showed that intra-host HVR1 diversity was 1.8 times higher in patients with chronic than acute infection. Significant differences in frequencies of 5 amino acids (positions 5, 7, 12, 16 and 18) and the average genetic distances among intra-host HVR1 variants were found using analysis of molecular variance. Differences were also observed in the polarity, volume and hydrophobicity of 10 amino acids (at positions 1, 4, 5, 12, 14, 15, 16, 21, 22 and 29). Based on these properties, a classification model could be constructed, which permitted HVR1 variants from acute and chronic cases to be discriminated with an accuracy of 88%. Progression from acute to chronic stage of HCV infection is accompanied by characteristic changes in amino acid composition of HVR1. Identifying these changes may permit diagnosis of recent HCV infection.

Clinical course and duration of viremia in vertically transmitted hepatitis E virus (HEV) infection in babies born to HEV-infected mothers.

Infection with the hepatitis E virus (HEV) causes a self-limiting acute hepatitis. However, prolonged viremia and chronic hepatitis has been reported in organ transplant recipients. Vertically transmitted HEV infection is known to cause acute hepatitis in newborn babies. The clinical course and duration of viremia in vertically transmitted HEV infection in neonates in not known. We studied 19 babies born to HEV infected mothers. Babies were studied at birth and on a monthly basis to evaluate clinical profile, pattern of antibody response and duration of viremia in those infected with HEV. Fifteen (78.9%) babies had evidence of vertically transmitted HEV infection at birth (IgM anti-HEV positive in 12 and HEV RNA reactive in 10) and three had short-lasting IgG anti-HEV positivity because of trans-placental antibody transmission. Seven HEV-infected babies had icteric hepatitis, five had anicteric hepatitis and three had high serum bilirubin with normal liver enzymes. Seven babies died in first week of birth (prematurity 1, icteric HEV 3, anicteric HEV 2 and hyperbilirubinemia 1). Nine babies survived and were followed up for clinical, biochemical, serological course and duration of viremia. Five of 9 babies who survived were HEV RNA positive. HEV RNA was not detectable by 4 weeks of birth in three babies, by 8 weeks in one and by 32 weeks in one. All surviving babies had self-limiting disease and none had prolonged viremia. Thus HEV infection is commonly transmitted from mother-to-foetus and causes high neonatal mortality. HEV infection in survivors is self-limiting with short lasting viremia.

Quantitative detection of hepatitis E virus RNA and dynamics of viral replication in experimental infection.

Hepatitis E virus (HEV) RNA has been detected in the stool and serum of patients with HEV infection and experimentally infected nonhuman primates. However, dynamics of HEV levels in the stool and serum during clinical and subclinical infections have not been determined. A real-time reverse transcription polymerase chain reaction assay, using SYBR Green I in a LightCycler, was developed and optimized to allow quantification of HEV RNA in the stool and serum of both genotype 1 and 2 isolates. The specificity of the assay was confirmed by testing known HEV-RNA-positive and -negative stool and serum specimens and the sensitivity was evaluated using a synthetic HEV RNA standard. Profiles of viraemia and faecal shedding in two chimpanzees inoculated with an isolate of HEV genotype 1 showed the appearance of virus in the stools on day 4 postinoculation (5.65-6.85 log copies/mg) and in the serum on day 7 postinoculation (6.0-6.93 log copies/mL). Peak HEV RNA levels in the stool and serum coincided with peak alanine aminotransferase (ALT) levels observed on day 22 postinoculation in the two chimpanzees. At the time of detection of IgG anti-HEV in serum, viral RNA was no longer detectable in the stool or serum and ALT values had returned to normal levels in both chimpanzees, suggesting the efficacy of the immune response in terminating viral replication. Quantitative evaluation of HEV RNA in humans may allow determining the role of virus levels in the pathogenesis and transmission of HEV.

Aetiology and prognostic factors in acute liver failure in India.

The early prognostic indicators for acute liver failure in endemic zones for hepatitis E virus have not been determined. All consecutive patients with acute liver failure from a geographically defined region endemic for hepatitis E virus were studied over the period April 1989-April 1996. Demographic, clinical and biochemical parameters were recorded at presentation and serum samples were analysed for known viral hepatitis (A-E) markers. Multiple parameters were compared in survivors and non-survivors in a univariate analysis. All significant factors on univariate analysis were entered into a stepwise logistic regression analysis to identify independent variables of prognosis. The sensitivity and specificity of significant prognostic factors was then assessed. A total of 180 [69 males and 111 females: age (mean +/- SD) 31.1 +/- 14.7 years] with acute liver failure were studied. Of these, 131 (72.8%) patients died. Hepatitis E virus was the aetiological cause in 79 (43.9%) patients, while hepatitis A virus, hepatitis B virus, hepatitis C virus and non-A, non-E agent/'s could be incriminated in four (2.1%), 25 (13.9%), 13 (7.2%) and 56 (31.1%) patients respectively. Of 83 women in childbearing age, 49 (59.0%) were pregnant, 33 (67.3%) of these were in the third trimester. Forty-seven (95.8%) pregnant women had HEV infection. Nine variables differed significantly between survivors and non-survivors on univariate analysis. Of these, four variables which predicted the adverse outcome on multivariate analysis were non-hepatitis-E aetiology, prothrombin time >30 s, grade of coma >2 and age >40 years in that order of significance. Pregnancy per se or duration of gestation did not adversely affect the prognosis. In endemic areas, hepatitis E virus is the commonest cause of acute liver failure. Acute liver failure occurs in a high proportion of pregnant women, mostly in third trimester. Early predictors of a poor outcome are non-E aetiology, prothrombin time >30 s, grade of coma >2 and age >40 years.

Aetiology, clinical course and outcome of sporadic acute viral hepatitis in pregnancy.

Hepatitis E causes large-scale epidemics in endemic areas. The disease, during epidemics, has increased incidence and severity in pregnant women. Sporadic acute viral hepatitis (AVH) is common in endemic areas. The relationship of sporadic AVH and pregnancy has not been well studied. Over a 3-year period we prospectively studied 76 pregnant women and 337 non-pregnant women of childbearing age with sporadic acute viral hepatitis for aetiology, clinical course and outcome of disease. The aetiology in sporadic AVH was hepatitis A virus (HAV) in six (1.5%), hepatitis B virus (HBV) in 62 (15%), hepatitis C virus (HCV) in seven (1.7%), hepatitis D virus (HDV) co-infection in six (1.5%), hepatitis E virus (HEV) in 205 (49.6%), and hepatitis non-A-to-E (HNAE) in 127 (30.7%). Sixty-five (85.5%) pregnant women and 140 (41.5%) nonpregnant women had hepatitis E. The proportion of pregnant women was 31.7% in HEV group and 5.3% in non-HEV group [P < 0.001; OR=8.3 (95%C1 4.2-16.3)]. The prevalence of HEV in pregnant women in first trimester (76.9%), second trimester (88.9%), third trimester (83.8%) and puerperium (100%) did not differ significantly (P=0.09). Forty-seven (61.8%) of the 76 pregnant women developed fulminant hepatic failure (FHF), 69.2% in HEV group and 10% in non-HEV group (P < 0.001). Thirty-four (10.1%) nonpregnant women developed fulminant hepatic failure, 10% in HEV group and 9.7% in non-HEV group (P=0.86). FHF had occurred in four (40%) of 10 patients with HE in first trimester as against 41 (74.5%) of 55 patients in second trimester and beyond (P=0.015). Amongst the major complications of fulminant hepatic failure, cerebral oedema (53.2%) and disseminated intravascular coagulation (21.3%) occurred more often in pregnant women than in nonpregnant women (29.4% and 2.8%; P=0.03 and 0.016, respectively) while infections occurred more often in nonpregnant women (36.1%) than in pregnant women (10.6%; P=0.003). Fifty (61.7%) patients with FHF died [25 (53.2%) pregnant women and 25 (69.5%) nonpregnant women (P=0.06)]. Cerebral oedema and HEV aetiology were independent variables of survival in patients with FHF. Patients with cerebral oedema had worse prognosis and patients with HEV aetiology had best chances of survival. Hence HEV was the most common cause of sporadic AVH in this endemic area. High proportion of pregnant women and increased severity of disease in pregnancy were limited to patients with hepatitis E. Sporadic AVH caused by agents other than HEV did not show any special predilection to or increased severity in pregnancy. FHF in pregnant women caused by HEV was an explosive disease with short pre- encephalopathy period, rapid development of cerebral oedema and high occurrence of disseminated intravascular coagulation and may represent a severe manifestation of a Schwartzmann-like phenomenon.

Experimental studies on subclinical hepatitis E virus infection in cynomolgus macaques.

Serial subclinical transmission among susceptible humans may serve as a reservoir of hepatitis E virus (HEV) in areas in which HEV is endemic. This hypothesis was investigated in an experimental primate model. Four groups of 4 cynomolgus macaques each were inoculated intravenously with 10(4)-10(5) (group 1), 10-100 (group 2), and 1-10 (group 3) cynomolgus macaque HEV infectious doses. All 4 animals in group 1 had clinical disease marked by alanine aminotransferase (ALT) elevation, fecal virus excretion, viremia, and seroconversion. Of the animals in groups 2 and 3, only 1 had evidence of biochemical hepatitis, although most had virus excretion and viremia (3 animals each in groups 2 and 3), and evidence of seroconversion (1 animal in group 2 and 3 animals in group 3). Viral genomic titers in stool specimens of animals with or without ALT elevation were similar. Infectivity studies confirmed the viability and transmission potential of the virus excreted by animals without ALT elevation. These data suggest that subclinical HEV infection may represent an HEV reservoir.

Global epidemiology and medical aspects of hepatitis E.

Hepatitis E is a self-limited enterically transmitted acute viral hepatitis that occurs frequently in epidemic outbreaks and as sporadic hepatitis in the Indian sub-continent, Southeast and Central Asia, the Middle East, parts of Africa, and Mexico. Hepatitis E virus (HEV) is excreted in faeces and is transmitted predominantly by the faecal-oral route, usually through contaminated water. The reservoir of the virus during the inter-epidemic periods in disease-endemic countries may reside in the environment, in sub-clinically HEV-infected humans, and/or animals infected with an HEV-like virus. Chronic infection is unknown. Diagnosis of HEV infection is usually made by detection of anti-HEV antibodies or HEV-RNA in patients serum specimens. Clinical illness due to HEV infection is similar to other forms of viral hepatitis except in pregnant women, in whom the illness is particularly severe with a mortality as high as 25%. Asymptomatic and anicteric infections may occur. No specific treatment is available, and the most effective mode of preventing this disease is use of clean water and proper sanitation. Recombinant vaccines are being developed that may be particularly useful for travellers to the disease-endemic areas and for pregnant women.

Hepatitis E.

Hepatitis E, previously known as enterically transmitted non-A, non-B hepatitis, is an infectious viral disease with clinical and morphologic features of acute hepatitis. Its causative agent, hepatitis E virus, consists of small, 32- to 34-nm diameter, icosahedral, nonenveloped particles with a single-stranded, positive-sense, 7.5-kb RNA. The virus has two main geographically distinct strains, Asian and Mexican; recently, novel isolates from nonendemic areas and a genetically related swine HEV have been described. HEV is responsible for large epidemics of acute hepatitis and a proportion of sporadic hepatitis cases in the Indian subcontinent, southeast and central Asia, the Middle East, parts of Africa, and Mexico. The virus is excreted in feces and is transmitted predominantly by fecal-oral route, usually through contaminated water. Person-to-person transmission is uncommon. Clinical attack rates are the highest among young adults. Recent evidence suggests that humans with subclinical HEV infection and animals may represent reservoirs of HEV; however, further data are needed. Diagnosis of hepatitis E is usually made by detection of specific IgM antibody, which disappears rapidly over a few months; IgG anti-HEV persists for at least a few years. Clinical illness is similar to other forms of acute viral hepatitis except in pregnant women, in whom illness is particularly severe with a high mortality rate. Subclinical and unapparent infections may occur; however, chronic infection is unknown. No specific treatment is yet available. Use of clean drinking water and proper sanitation is currently the most effective method of prevention. Passive immunization has not been proved to be effective, and recombinant vaccines for travelers to disease-endemic areas and for pregnant women currently are being developed.

Vertical transmission of hepatitis E virus.

Little is known about vertical transmission of hepatitis E virus from infected mothers to their infants. We studied eight babies born to mothers infected with hepatitis E in third trimester. One baby was icteric at birth with elevated transaminases and four babies had anicteric hepatitis. Two babies were born with hypothermia and hypoglycaemia and died within 24 h; one had massive hepatic necrosis. Hepatitis E virus RNA was detected by PCR in cord or birth blood samples of five infants. Six infants had evidence of hepatitis E infection. We conclude that hepatitis E virus is commonly transmitted from infected mothers to their babies with significant perinatal morbidity and mortality.

Spectrum of hepatitis E virus infection in India.

A solid phase enzyme linked immunosorbent assay (ELISA) that detects IgM and IgG to hepatitis E virus (HEV) was used to study seroepidemiology in 40 healthy subjects and 227 consecutive patients with liver diseases in an endemic area. Fifty-two of the liver diseases patients (22.9 percent) had acute hepatitis E. In contrast, none of the 40 healthy subjects were positive for IgM anti-HEV, validating the ELISA assay. Twenty-three of 25 (92%) patients with epidemic non-A, non-B hepatitis were confirmed as having acute hepatitis E. Only 1 of the 10 patients with sporadic, fulminant hepatic failure of non-A, non-B, non-C etiology was positive for IgM anti-HEV. Five (31.2%) of the 16 patients with acute hepatitis in HBsAg carriers were positive for IgM anti-HEV. One patient with acute hepatitis B was coinfected with acute hepatitis E. Acute hepatitis was a disease of the adult population, with peak attack rates in the second and third decades of life. This disease was seen in only 4 (16%) of the 25 patients with acute viral hepatitis occurring below 14 years of age. Cholestasis was predominant in 25% of patients, enzyme elevation was monophasic, and all patients had clinical and biochemical recovery from the disease. The data suggest that the majority of patients with acute sporadic non-A, non-B, non-C hepatitis in India have hepatitis E. However, fulminant hepatic failure to sporadic nature is rarely from hepatitis E.