Seroprevalence of HAV Infection
There were 14 seroprevalence studies from India [11,12,13,14,15,16,17,18,19,20,21,22,23,24], 2 from Bangladesh [25, 26] and 1 from Pakistan , Sri Lanka  and Nepal  (Table 1, Table S1). The studies assessed seroprevalence of HAV antibodies (IgG and/or IgM) in healthy subjects and/or patients presenting with AVH symptoms.
In India, HAV was the most common etiology in adolescents and adults . In one of the studies it was also much more common than hepatitis E infection . A hospital-based study in jaundice patients (mean age 30 years) in Nepal found most of the cases were hepatitis E virus (HEV, 69.2%) and HAV (15.3%) induced . Surveillance data collected between 2014 and 2017 from across India found 12.6% of suspected viral hepatitis cases were due to HAV. Among children and adolescents, most cases (29.5% and 17.9%) were caused by HAV. The majority of the cases were in the southern region (22.4%), and higher HAV positivity rates were found during the monsoon season . The incidence of HAV-induced AVH increased significantly in children, adolescents and adults with time from 1999 to 2003 (Fig. 3) [11, 12]. Also, it was found that HAV-induced infections had decreased in < 5 years (75%) and increased in 6–15 years (70.8%) . The pattern of decreased HAV infection in children and increased infection in adolescents and/or adults was also found in Uttar Pradesh and Rajasthan [14, 17]. In a study from Pakistan, 25% of HAV-induced AVH cases were seen in > 12 years . HAV infection was the etiology in 31.2% of Indian adults with AVH or chronic or alcoholic liver disease . In a study of newly diagnosed cirrhotic patients who were not vaccinated (mean age: 55.8 years) from Sri Lanka, 58% were seronegative for anti-HAV IgG and therefore susceptible . In contrast, only one cross-sectional survey of healthy military trainees (mean age: 19.9 years, not vaccinated) from across India found high levels of immunity to HAV in which the majority (78.5%) of study participants were from rural areas .
Seroprevalence in Urban vs. Rural and Based on Socioeconomic Status
HAV exposure was also significantly different across the various study populations [urban vs. rural: 31.8% vs. 55.3%, p = 0.005; high/middle socioeconomic status (SES) vs. low SES: 33.3% vs. 53.9%, p = 0.022; family size 3–5 vs. ≥ 6: 31.6% vs. 59.1%, p < 0.001] . A study from Pune (N = 1065 serum samples) found that in high SES subjects, there was a significant increase in anti-HAV positivity, while in the lower middle SES group, a significant decrease (6–25 years, p < 0.0001) was recorded compared with 1998 data . Among healthy adult blood donors, HAV exposure was significantly lower for subjects with high vs. middle SES (89.0% vs. 95.9%, p < 0.01) . Furthermore, two large studies from Bangladesh also compared seroprevalence in urban and rural populations and by SES. The first study (N = 465) found significantly lower HAV seroprevalence in urban vs. rural populations (73.3% vs. 82.2%, p < 0.05) as well as in urban high SES vs. urban low SES populations (68.8 vs. 79.7%, p < 0.05). The 11–15-year urban high SES group had the lowest seroprevalence (72.3%) compared with the urban low SES (100%) and rural (90%) groups . The second study (N = 818) found similar trends: HAV exposure was highest in the rural lower-middle SES group (seroprevalence 96.5%) and lowest in the high SES group (49.8%); exposure among school children was lowest in urban high SES (43.0%) compared with urban low SES (76.2%) and rural (96.5%) schools (p < 0.01) .
Clinical Presentation and Complications of HAV Infection
Typical clinical presentation, including adolescent and adult cases, was reported in detail in five studies, from India [18, 30, 31], Pakistan  and Sri Lanka . All of these studies reported patients with jaundice (80–100%), abdominal pain (26–82%) and fever (45–91%). Other common symptoms included nausea/vomiting, dark urine, anorexia and fatigue. The studies in older age groups reported high rates of hepatomegaly (73–100%), and a high rate of splenomegaly was reported in a small subgroup of adolescents (86%) (Fig. 4).
In a prospective study of HAV IgM-positive subjects with jaundice, 62 had AVH (mean age: 22 years) and 7 had FHF (mean age: 29 years). More males than females had HAV infection . The duration of illness for HAV-induced AVH in the majority of patients (74.3%) was 1–4 weeks as seen from a study at a military hospital in Southern India .
Also, in a study of 221 HAV-induced AVH patients (mean age: 20.5 years), 96.3% of patients took 4–10 weeks from the onset of jaundice to recover, 18 patients (8.3%) developed ALF, of which 3 died, and the rest recovered within 16 weeks .
Complications and Deaths
Complications following hepatitis A infection seen in the literature are acute renal injury, FHF, ALF, relapsing hepatitis A, gall bladder wall thickening, acute-on-chronic liver failure (ACLF), gastrointestinal bleeding, intracerebral bleeding, hypoglycemia, encephalopathy, acute liver cell failure, prolonged cholestasis, coagulopathy, ascites, thrombocytopenia, pleural effusion, congestive heart failure, higher creatinine levels, increased hospital stay and mortality.
In a prospective study (N = 224 AVH, mean age: 22.5 years) of 74 cases of HAV-induced AVH, there was 1 patient with ALF, 4 patients with relapsing hepatitis A and 2 patients with gall bladder wall thickening . Data collected over the 1999–2004 period in a tertiary care hospital in Northern India showed that HAV-induced ALF in adults increased when compared with earlier studies (22.2% vs. 4–6%) . In a retrospective study of patients > 12 years, 14.5% (n = 33/228) had complications: most common was acute renal injury (n = 17) and FHF (n = 4). Patients with complications had significantly higher mean creatinine values (3.28 vs. 1.12) and mean international normalized ratios (2.46 vs. 1.43) than patients with no complications (p < 0.05). Mortality (21.2%, n = 7) occurred only among patients aged 20–40 years . Another study of AVH in children ≤ 15 years (N = 138) found only the 10–15-year group (5.8%, n = 8/22) had complications [gastrointestinal bleeding, intracerebral bleeding and hypoglycemia in one child each, grade I encephalopathy in two children, acute liver cell failure in four children and prolonged cholestasis (> 12 weeks) in three children] . A study from Eastern India reported the following complications in adolescents (n = 10 aged 10–14 years): coagulopathy (n = 4), ascites (n = 3), two cases each of thrombocytopenia, gall bladder wall thickening and pleural effusion, and one case of congestive heart failure . In a study conducted in Pakistan including 185 acute hepatitis A patients (26% > 16 years), FHF occurred in a comparable number of < 15 and > 15 year olds (2% vs. 3%, respectively) and required longer hospital stays (9 days compared with 2.9 without FHF; mean length of stay). The hospitalization rate was significantly higher for > 15 year olds (45% vs. 24% in < 15 years, p < 0.006) .
Acute hepatitis A is also known to cause severe complications such as ACLF in patients with cirrhosis. In a study of 3220 cirrhosis patients (mean age: 36.3 years), 121 cases of ACLF were reported of which 27.2% were HAV induced. ACLF was also associated with a high 3-month mortality rate (44.6%) .
Several HAV outbreaks were reported across India between 2004 and 2017 [4, 31, 38,39,40,41,42,43] as well as one in Sri Lanka in 2009–2010 [33, 44] (Table S2). It was noted that men were more affected as were adolescents and young adults (16–30 years, 142 cases) [42, 43]. The highest attack rate was found among 15–24 year olds followed by 5–14 year olds . Most of these outbreaks were caused by water contamination or food contamination from a hotel.
In an outbreak in Pune due to HAV in a susceptible population from the middle SES group, the overall attack rate was 55.8%. This was highest among 5–10-year-old (65.8%) children, higher than for children < 5 years (44.5%; p < 0.001) and comparable to the 11–15-year-old group (p = 0.064) . In the same year, another outbreak due to water contamination was reported in adults in Kerala, Southern India. Of the 540 cases in a medical college hospital area, HAV infection was confirmed in 87% (n = 248/285) of patients and 39% (n = 52/132) of medical staff and students for whom serum samples were available. HAV was predominant among 18–20 year olds (42.5%) followed by 21–25 year olds (41.4%), 36–52 year olds (25.0%) and 26–35 year olds (20.0%). Two deaths were also reported among adults . Many more HAV outbreaks were reported in Kerala between 2012 and 2016: in total, 84 outbreaks of which 2 involved > 100 people, 13 involved > 50 people and 49 involved > 20 people, with 22 deaths reported in 2015–2016 [43, 45]. In Kashmir, India, 23 outbreaks were reported between 2015 and 2017, of which 12 were due to HAV . In Punjab, India, in 2011, there was an outbreak due to hepatitis E (primarily), in which nine cases were due to HAV and five to HAV and HEV co-infection. Half of the patients with HAV infection were > 20 years old compared with 17.5% of those with HEV infection . A large outbreak of HAV infection (N = 13,477 cases) was reported in Sri Lanka in 2009, primarily in the Northern Province following civil war, which included the community and a displaced persons camp (n = 5245) and armed forces in the area (n = 6622) .
Economic Burden of Hepatitis A Infection
Following multiple outbreaks in Kerala, and with an average 8268 suspected cases per year, mostly affecting 15–35 year olds, one study assessed the out-of-pocket cost of hepatitis A to households in 2015 . Of the 95 patients with confirmed hepatitis A interviewed, 83.2% were admitted to the hospital for 7.6 days on average and lost a median of 60 working days (range 21–180 days). The total estimated mean cost for the household due to one person with hepatitis A was 24,775 rupees (95% confidence interval: 19,426–30,123) (364 US dollars) .