Viral Hepatitis

HAV  is  the  RNA  virus  from  piconaviridae  family  under  genus  hepatovirus.  It  primarily  infects  the  liver. The disease occurs sporadically or in epidemics and has an incubation period of 14 - 28 days.  The group most affected is aged between 5-14 years and adults are often infected by spread from  children.  

Clinical presentation 

Mild flu-like symptoms of anorexia, nausea and vomiting, fatigue, malaise, low-grade fever (usually <  39.5°C), myalgia, and mild headache. Dark urine appears first (bilirubinuria); pale stool soon follows. Jaundice occurs in most adults. Abdominal pain, itching (pruritus), arthralgias and skin rash (less  frequent than the above symptoms). 

Investigations 

Specific diagnosis involves serological detection of Hepatitis A specific immunoglobulins IgM or IgG antibodies in blood for acute and resolved infection respectively. Viral RNA detection through PCR is definitive and  confirmatory  specialized  laboratory  test.  Other  tests  include  FBP,  LFT,  RFT  and  tests for other viral hepatitis viruses (HBV±HDV, HCV, and HEV). 

Treatment 

• Supportive  management  such  as  hydration,  adequate  feeding  and avoiding concomitant use of hepatotoxic medications, including herbals, is all that is required in mild  infections. The disease resolves spontaneously in several weeks or months. 
• Hospitalization  is  necessary  in  settings  of  acute  liver  failure.  Therapy  is  aimed  at maintaining  fluid  replacement,  balanced  nutritional  feeding,  relief  of  pains  and  fever including specific management for liver failure.

New-onset hepatitis B infection that may or may not be icteric or symptomatic. Diagnosis is based on detection of hepatitis B surface antigen (HBsAg) and IgM antibodies to hepatitis B core antigen (anti-HBc). Recovery  is  accompanied by clearance  of  HBsAg  with  seroconversion  to  anti-HBs  (antibodies to hepatitis B surface antigen), usually within 3 months. 

Clinical presentation 

• Fever, anorexia, malaise, jaundice and abdominal pain
• Enlarged and tender liver
• Altered consciousness, coma (hepatic  encephalopathy), and  bleeding stigmata (in fulminant cases)

Investigations 

• Serological evidence of specific viral antigen/ core antibody tests (HBc IgM or HBc IgG), and
• Biochemical alteration of liver transaminases (ALT, AST)

Treatment of Acute Viral Hepatitis B 

• No specific antiviral treatment is required
• Offer supportive management and counselling
• Offer a follow up plan at 4 or 6 weeks’ intervals for a clinical and laboratory reassessment for evidence of symptoms recovery and biochemical remission
• Re-test at 6 months to assess seroconversion status or progression to chronicity

Hepatitis C virus (HCV) is a small enveloped RNA virus and a member of the family Flaviviridae.  HCV comprises six genotypes and hundreds of subtypes with variable geographical distribution and bears significance in determining the rate of liver disease progression, development of HCC and specific therapeutic responses. 

Clinical presentation 

• Initial  symptoms  of  HCV  are  often extrahepatic, most commonly involving  the  joints, muscle, and skin
• Arthralgias
• Paresthesias
• Myalgias
• Pruritus
• Sicca syndrome
• Sensory neuropathy

Symptoms  characteristic  of  complications  from  advanced  or  decompensated  liver  disease  are  related to synthetic dysfunction and portal hypertension, such as the following: 

• Mental status changes (hepatic encephalopathy), ankle edema and abdominal distension (ascites), hematemesis or melena (variceal bleeding)

Signs in patients with decompensated liver disease include the following: 

• Hand signs: Palmar erythema, Dupuytren contracture, asterixis, leukonychia, clubbing
• Head signs: Icteric sclera, temporal muscle wasting, enlarged parotid gland, cyanosis
• Fetor hepaticus, gynecomastia, small testes
• Abdominal signs: Paraumbilical hernia, ascites, caput medusae, hepatosplenomegaly, abdominal bruit
• Ankle edema, scant body hair
• Skin signs: Spider nevi, petechiae, excoriations due to pruritus

Other common extrahepatic manifestations include the following: 

• Cryoglobulinemia, Membranoproliferative glomerulonephritis, Idiopathic thrombocytopenic purpura, Lichen planus, Keratoconjunctivitis sicca, Raynaud syndrome, Sjögren syndrome
• Porphyria cutanea tarda, Necrotizing cutaneous vasculitis

InvestigationsGeneral baseline studies in patients with suspected HCV include the following: 

• FBP, LFT, RFT TSH, T3
• Screening tests for coinfection with HIV or HBV
• Screening for alcohol abuse, drug abuse, or depression
• Pregnancy testing

Tests for detecting HCV infection include the following: 

• Hepatitis C antibody testing
• Qualitative and quantitative assays for HCV RNA PCR
• HCV genotyping
• Serologic testing (essential mixed cryoglobulinemia is a common finding)

TreatmentUse pan-genotypic drugs which are efficacious, safe and cost-effective. 

Who to treat 

• Confirmed cases of Hepatitis C irrespective of clinical stage of the liver disease
• Patients with HCC who are eligible for liver transplant if feasible
• Liver transplant patients if MELD score is < 18 (pre-transplant) or >18 (post-transplant)

Who not to treat 

• HCC patients who are not eligible for liver transplant
• Patient with limited life expectancy due to ESLD (by MELD score or Child-Pugh), or non-hepatic related co-morbidities

Pharmacological Treatment 

All individuals diagnosed with HCV infection who are ≥ 12 years old are eligible for treatment. In children <12 years old, the treatment should be deferred until they reach that age. 

S: ledipasvir (PO) 90mg 24hourly for 12-24weeks 

AND  

S: sofosbuvir (PO) 400mg 24hourly for 12-24weeks 

AND 

S:  ribavirin  (PO)  given  in  two  divided  doses  *<75kg  of  Body  weight  =1g/day;  >75Kg  of Body  weight  =1.2g/day for 12 weeks  (in  treatment  naive  patients)  OR  for  24  weeks  (in  treatment experienced patients) for genotypes 1, 4, 5 & 6. 

OR 

S: sofosbuvir (PO) 400mg daily AND ledipasvir (PO) 90mg daily AND ribavirin if a patient has been previously exposed to other antivirals

Note: 

• Due to complexity and variability of HCV management, care and treatment should be done at the tertiary level facility
• Ribavirin is contraindicated in patients with anaemia (Hb<8.5g/dL), and the dose should be reduced if Hb<10g/dL 
• Sofosbuvir is contraindicated if eGFR < 30ml/min/1.73m2 

When to stop medications 

• Ribavirin regimen should be stopped if patient's Hb drops to < 8.5g/dL during follow up schedules
• If there is an adverse drug reaction
• When there are ALT flares or massively increased ALT (>10 X UNL)
• If there is evidence of drug-drug interactions,  consider switching to a medication with less interacting potential

Clinical monitoring and follow up

• Assess treatment adherence, tolerance and toxicity at 4 weeks after treatment initiation
• Treatment toxicity
• Stop Ribavirin if Hb drops to <8.5
• Stop all DAAs if ALT >10 X ULN and other causes have been ruled out
• Stop Sofosbuvir if eGFR drops to < 30ml/min/1.73m² 

Hepatitis D virus (HDV) is a defective RNA virus belonging to genus of delta virus that requires the  helper function of Hepatitis B (HBV) for virion assembly, release and transmission, and therefore the  infection does not occur in the absence of hepatitis B virus. The routes of HDV transmission are  similar for HBV the most important being sexually, percutaneous or   parenteral exposure to blood or  blood products. 

Investigations 

Serology assays for HDV immunoglobulin titres for IgM and IgG are diagnostic for acute and post  exposure/chronic infections respectively. Real time PCR for HDV RNA is confirmatory. 

Treatment 

There is no specific treatment for acute or chronic HDV infection. 

Note: The more risk population includes health care workers, transfusion recipients and haemophiliacs,  PWID,  and  immigrants  of  endemic  areas.    Nucleotide  sequences  of  HDV  obtained  worldwide  indicates  the  existence  of  eight  genotypes,  with  genotype  1  being  detected  worldwide.    HDV  antiviral nucleotide analogues for HBV have no or limited effect on HDV replication and Pegylated  interferon alpha is the only drug effective against HDV now and more than one year of therapy may  be necessary as most of patients relapses after discontinuation of therapy.

Hepatitis E virus (HEV) belongs is a RNA virus belonging from a family Hepadna viridae under  Genus Hepevirus and acute liver infection. The virus has at least 4 different types: genotypes 1, 2, 3  and 4. Genotypes 1 and 2 have been found only in humans. Genotype 3 and 4 viruses circulate in  several animals (including pigs, wild boars, and deer) without causing any disease, and occasionally infect humans.  

Clinical presentation 

Prodromal-phase symptoms include the following: 

• Myalgia, arthralgia, fever with mild temperature elevations
• Anorexia, nausea/vomiting, weight loss, dehydration, right upper quadrant pain 

Icteric-phase symptoms may last days to several weeks and include the following: 

• Jaundice, dark urine, light-colored stool, pruritus 

Other features include the following:

• Malaise (most common), arthritis, pancreatitis
• Aplastic anemia, thrombocytopenia
• Neurologic symptoms of polyradiculopathy, Guillain–Barré syndrome, Bell palsy, peripheral neuropathy, ataxia, and mental confusion
• Membranoproliferative glomerulonephritis and membranous glomerulonephritis

Investigations 

Serology assays for HEV immunoglobulin titres for IgM and IgG are diagnostic for acute and post  exposure/chronic infections respectively. Real time PCR for HEV RNA in serum and particularly in  stool is confirmatory. 

Treatment 

There is no specific treatment for cure or reversing the course of acute hepatitis E. The disease is  usually  self-limiting;  hospitalization  is  generally  not  required  except  for  patients  with  fulminant  hepatitis  or  for  symptomatic  pregnant  women  where  severity  of  infection  is  usually  high  and  associated with high rates of fetal loss and mortality especially in third trimester. 

Note: 

• The virus is shed in the stools of infected persons and enters the human body through the intestine. It is transmitted mainly through contaminated drinking water. Usually the infection is self-limiting and resolves within 2–6 weeks. Rarely the infection can lead to fulminant hepatitis with acute liver failure.
• The  virus  causes  sporadic  cases  and  major  epidemics  of  viral  hepatitis  and  occurs  in resource   poor population with unhygienic conditions and through    ingestion of contaminated water and food.

All  infants  and  neonates  should  have  mandatory  vaccination  according  to  the  recommended  National EPI schedule. Neonates born to mothers infected with HBV and HBeAg positive, should  receive at birth dose of hepatitis B immunoglobulin (HBIG) and HBV Vaccine, and then follow up  with  EPI  program  schedule  at  6weeks.  During  pregnancy,  prevention  of  HBV  transmission  from  mother  to  child should  follow  similar  protocols  as  per  adults  with  HBV  infection. HBsAg  positive  pregnant mothers with VL >200,000 IU/ml should receive TDF at 3^rd trimester until 6months post- natal period.  

Pharmacological Treatment 

• First dose for the infant: Hepatitis B vaccine born to HBsAg-negative mothers
• Medically stable infants weighing ≥2,000 grams: 0.5 mL (IM) within 24h of birth
• Preterm infants weighing <2,000 g: 0.5 mL (IM) 1 month after birth or at hospital discharge

First dose for the infant: Hepatitis B vaccine born to HBsAg-positive mothers 

B: hepatitis B vaccine (HBV) (IM) 0.5 mL within 12hours of birth 

AND

S: hepatitis B immune globulin (HBIG) (IM) 0.5 mL within 12hours of birth 

Note: Mother's HBsAg status unknown: 0.5 mL IM within 12 hour of birth AND HBIG 0.5mL (IM); if newborn wt <2 kg, determine mother's HBsAg status as soon as possible and, if she is HBsAg-positive, also administer HBIG for infants weighing 2 kg or more (no later than age 1 week)

For the HBV positive pregnant mother 

A: tenofovir (PO) 300mg 24hourly (from third trimester to 6 months post-delivery for the mother) 

Post exposure prophylaxis (PEP) 

HBIG and HBV vaccine should be given to individuals who are HBsAg negative exposed to HBsAg positive focus within 24hours followed by active standard schedule to complete 3 doses

S: hepatitis B immune globulin (HBIG) (IM) 0.06 mL/kg once 

AND 

B: hepatitis B vaccine (HBV) (IM) 1 mL (20 mcg) at 0, 1, and 6months 

Note: HBIG and HBV vaccine should be given at different intramuscular sites. PEP should be given in <24hours, may not be effective after 72hours of exposure.