rate of premature labour and miscarriage proportional to severity of illness. Vertical transmission rarely reported.Viral hepatitis is responsible for over 1.34 million deaths worldwide; this is comparable to the number of deaths caused by HIV and TB. The majority of deaths arise from chronic infection with HCV or HBV, leading to end-stage liver disease or hepatocellular carcinoma.
The risk of sexual transmission of viruses causing hepatitis is very variable. In general, transmission is more likely through anal sex, traumatic sex, or with concommitent STI. Many of the viruses involved may cause little or no symptoms during seroconversion.
A highly infectious RNA picornavirus. Identified in 1972, but condition had been known for a long time as epidemic jaundice, yellow jaundice, or infectious hepatitis.
Humans are the only known natural reservoir. Common in developing countries (poor sanitation) and with close personal contact. 1.4 million symptomatic cases/year. Seroprevalence in USA and western Europe 10–33% (90% in developing world). Transmission usually faeco-oral (contaminated food/water). Associated with urine contamination and contact with infected urine (e.g. urophilia). Most commonly affects children, but outbreaks reported in MSM (faecal contact), people who inject drugs (PWIDs), and institutions. Patients are infectious for 2 weeks before and 1 week after the onset of jaundice. After infection, immunity is life-long.
Usually 2–6 weeks.
Most children and up to 50% of all adults are either asymptomatic or have mild non-specific symptoms with no obvious jaundice. An icteric illness with jaundice, anorexia, nausea, diarrhoea and fatigue usually lasting 1–3 weeks (up to 12 weeks) is preceded by prodromal, flu-like symptoms (malaise, myalgia, fatigue, nausea) often with right upper abdominal pain lasting 3–10 days. Pyrexia usually disappears at the beginning of the icteric phase with symptomatic improvement at onset of jaundice.
Jaundice (hepatic and/or homeostatic), often with pale stools and dark urine. Liver tenderness and dehydration may occur.
Fulminant hepatitis in 0.4% (more common in those with hepatitis C). Up to 15% of symptomatic patients may require hospitalization with 25% having severe hepatitis. HAV-associated mortality very low (<0.2%). Chronic infection does not usually occur.
Associated with rate of premature labour and miscarriage proportional to severity of illness. Vertical transmission rarely reported.
• HAV-IgM: positive within 5 days of illness (up to 6 months).
• HAV-IgG: indicates past exposure or response to vaccination.
• Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) and bilirubin can to 10,000 IU/L and 500 µmol/L, respectively.
• Alkaline phosphatase (ALP) modestly, but higher with cholestasis.
• Prothrombin time prolongation of >5 seconds suggests decompensation.
• Screen for other hepatotropic infections and STIs if appropriate.
Provision of information and advice (avoid alcohol, food handling, and unprotected sexual intercourse until non-infectious). Most cases managed on an outpatient basis. Follow-up only necessary for patients whose ALT or bilirubin does not settle within 4–8 weeks.
HAV infection is a notifiable disease with contacts requiring follow-up by public health authorities including PN for sexual partners. Human normal immunoglobulin (HNIG) or early HAV vaccine may be considered for non-immune close contacts including neonates. Breastfeeding can be continued.
Active vaccination recommended for travellers to endemic countries, and in outbreak situations (e.g. amongst MSM), chronic liver disease, PWIDs, and those with HIV infection.
Schedule: 2 doses at 0 and 6–12 months giving 95% protection for 5–10 years. Vaccination provides protection for up to 25 years. Combination vaccine with hepatitis B follows same schedule as hepatitis B vaccination. HAV vaccine response may be lower in HIV or immunocompromised patients.
Hepatitis B (HBV) was initially known as the Australia antigen, the virus was discovered in 1965 by Dr Blumberg and colleagues. HBV is a hepadnavirus and is a small partially double-stranded DNA virus. Structurally, a lipoprotein coat containing HBV surface antigen (HBsAg) surrounds a nucleocapsid made up of hepatitis B core antigen within which the HBV genome and DNA polymerase reside. Replication occurs within hepatocyte nuclei where HBV DNA is converted into covalently closed circular DNA (cccDNA). This is responsible for viral persistence and in patients with chronic infection is resistant to clearance by antivirals. Nuclear cccDNA results in infective virus particles and large amounts of non-infective HBsAg, both of which may be found in the serum of chronically infected patients
There are 6 genotypes A–F.
About 257 million people or 5% of the world’s population are HBsAg +ve and, therefore, have chronic HBV infection. The rate of carriage varies in the population from 0.1% in northern European countries to over 6% in the western Pacific and African regions; rates can be as high as 20%.
The main mode of transmission varies depending on rates of infection in the population. In areas of high endemicity vertical transmission is common, risk reducing through vaccination from 4.7% to 1.3% of new infection seen in under 5 years. In areas of low endemicity sexual transmission and blood-borne transmission more common.
Transmission occurs in 40% of non-immune heterosexual partners of patients with chronic HBV. In the UK, the incidence of acute HBV is 0.83 per 100,000 (2/3 men). Risk in MSM, >7 sexual partners, PWID.
Incubation 30–180 days.
• Infants and children usually have asymptomatic acute infection.
• 10–50% of adults are asymptomatic.
• Symptoms more likely if seroconversion.
• Chronic: usually no physical signs. After many years, signs of chronic liver disease may emerge including spider naevi, finger clubbing, gynaecomastia, palmer erythema, and in end stage, disease jaundice, ascites, liver flap, and encephalopathy.
• Acute infection: mortality is <1% due to fulminant hepatitis.
• Chronic infection: defined as >6 months of HBsAg-positivity. In immunocompetent adults <5% develop chronic infection. Generally, asymptomatic. More common in HIV infection, chronic renal failure, the immunosuppressed, and >90% of vertically infected children. May progress to cirrhosis (8–20% with active disease over 5 years) with attendant clinical features and the annual risk of hepatocellular carcinoma (HCC) is 2–5%. Decompensated liver disease occurs in 20% of those with cirrhosis over 5 years. Immunosuppression can also lead to HBV reactivation. Concurrent infection with HCV can lead to more progressive chronic liver disease. Co-infection with hepatitis D (Delta agent), usually seen in PWID, may lead to rapid deterioration and poor treatment response
• HCC may develop without cirrhosis. Risk of development of HCC is increased in patients with cirrhosis/necro-inflammation of liver, males, older age, African origin, smokers, diabetes/metabolic syndrome, alcohol excess, family history, high HBV/HBsAg levels, genotype C infection.
• If suspected, check hepatitis B core antibody (HBcAb) and HBsAg. If HBsAg +ve in acute infection check HBeAg and hepatitis B IgM should be positive. HBV viral load will be high >1 million IU/mL. Acute hepatitis with ALT, bilirubin and alkaline phosphatase. If prothrombin time significantly, consider fulminant hepatitis. Clearance is suggested with loss of HBeAg and HBsAg at 6 months and development of eAb.
• There are 4 phases of chronic infection (see Table 25.1).
• Patients should have fibrosis blood test or Fibroscan® (<6 kPa mild disease, >12 kPa severe disease/cirrhosis) to assess fibrosis. Fibroscan score with ALT>5ULN (upper limit of normal), food, steatosis, alcohol may artificially. Serum biomarkers may be helpful in addition. FIB-4 (platelets, AST and ALT) commonly used.
• Patients should have HCV, HIV, HDV tested. ALT, AST,
Table 25.1 Phases of chronic HBV infection
• Information and advice, including avoiding unprotected sexual intercourse until non-infectious or partner successfully vaccinated.
• Stop or 
alcohol consumption.
• Refer to specialist unit if acute deteriorating liver disease.
• Notifiable disease: PN and screening of close family contacts are important with public health involvement for non-sexual contacts.
Treatment options include directly acting antivirals (DAA); TDF, tenofovir alafenamide (TAF) or entecavir (ETV) or interferon; pegylated interferon alfa α (PegIFNα). Lamivudine, adefovir and telbivudine are not recommended.
No treatment, but warn patient to inform doctor if going to be immunosupressed as reactivation possible and treatment with DAA may be required.
Treatment not recommended, as can risk of chronic infection, consider DAA if life threatening.
See Table 25.2.
Treatment should be considered for all severe liver disease, HCC, or cirrhotic, HBV DNA >2000 IU/mL and ALT >ULN and moderate fibrosis on liver Bx or Fibroscan (consider strongly if ALT normal and liver Bx moderate), HBV >20,000 IU/mL and ALT >2ULN can start treatment without biopsy.
Table 25.2 HBV treatment options
Treatment with DAA vs PegIFNα depends on genotype (A>D/E with PegIFNα), age, severity of disease (PegIFNα contraindicated in decompensated liver disease), co-morbidities (PegIFNα use with caution in diabetics, vascular disease, or significant mental health problems).
In those not considering treatment monitor with ALT, HBV VL, HBsAg/eAg/eAb in those with eAg +ve <30 years monitor 3–6-monthly; HBeAg –ve, HBV VL <2000 IU/mL monitor every 6–12 months; HBeAg –ve HBV VL >2000 IU/mL monitor every 3 months for 1 year then 6-monthly.
If not vaccinated or HBsAb post-vaccination <10 IU/mL consider specific HBV immunoglobulin 500 U IM (ideally ≤48 hours or within 1 week) and rapid vaccination of recent sexual contacts.
Treat mother if HBV VL >200,000 IU/mL. Vaccination (rapid schedule) in all born to HBV +ve mothers and HBV specific immunoglobulin 200 U IM (all born to mothers HBeAg +ve, sAg +ve if eAb –ve, or HBV VL >106) vertical transmission by 90%. Breastfeeding can continue.
Apart from contacts, including household contacts, vaccination should be considered for those at risk, e.g. MSM, sex workers, association with endemic areas, prisoners, PWIDs, those sexually assaulted, occupational/needlestick risk, severe renal/liver disease. Protection of vaccinated patients is assessed by HBsAb level >100 mIU/mL is ideal, but levels >10 mIU/mL may be adequate, subsequent HBV infection is very rare. It has been suggested that memory cells provide protection as immunity appears to be maintained, even if HBsAb provided there has been a good initial response.
Engerix B®, HBvaxPRO® and Fendrix® are used. HBvaxPRO 40® is used in dialysis patients; may offer immunogenicity in immunocompromised as can Fendrix®. Twinrix® is combined HAV/HBV vaccines.
Havrix monodose®: adult dose 1 mL with the deltoid region the preferred site (subcutaneous may be used in those with bleeding disorders).
Engerix B®, HBvaxPRO®, HBvaxPRO40®, Fendrix®: adult dose—1 mL (0.5 mL Fendrix®) with the deltoid region the preferred site (subcutaneous may be used in those with bleeding disorders). Should not be injected into the buttocks (efficacy reduced).
Twinrix®: inactivated HAV and recombinant HBV surface antigen
Adult dose—1 mL with the deltoid region the preferred site (subcutaneous may be used in those with bleeding disorders, although immune response may be reduced). Should not be injected into the buttocks (efficacy reduced).
• Ultra-rapid course: of recombinant vaccine schedule (Engerix B®): 3 doses and booster at 0, 7, 21/28 days plus 12-month booster.
• Rapid course schedule for post-exposure: 3 doses and booster at 0, 1, 2 months plus 12-month booster.
Note these schedules are not licensed for neonates.
• Standard schedule: 3 doses—0, 1, 6 months, booster dose at 12 months if protective antibody level <100 IU/mL.
Further 5-year booster recommended no need to recheck HBsAb level.
Protective antibody level in 80–95% after full course of vaccination, but lower response rates if aged >40 years or immunocompromised, e.g. HIV infection particularly if CD4 < 200 cells/µL, but even <500 cells/µL. High-dose vaccine HBvaxPRO 40®, Engerix® double dose or Fendrix® are more immunogenic in immunocompromised. If HBsAb <10 IU/mL should be considered non-immune, alternative vaccine can be considered and/or higher dose.
RNA virus of the family Flaviviridae discovered in 1989. Six predominant genotypes. In the UK genotype 1 (G1) is most common (~50% of cases) followed by G3 (together 40–50%). G1 relatively more common in those infected through blood products and G3 in PWID.
HCV is a single strand +ve sense RNA virus. It exists as a lipo-viral particle in serum, thus escaping the immune system through association with apolipoprotein and multiple quasi-species. After entry into the liver cell via multiple receptors, replication occurs in cytoplasm. NS5B RNA dependent polymerase facilitates replication through synthesis of –ve strand RNA, which acts as a template for HCV polyprotein (cleaved by NS4A protease) and HCV +ve strand viral RNA to produce new virions.
Worldwide 2.5% infected with HCV (177.5 million). UK has prevalence of around 0.5% with a higher prevalence in PWIDs (20–50% PWIDs). High prevalence in Egypt (40% in some areas), Mongolia, Eastern Europe, and some areas of SE Asia.
Transmission, mainly parenteral through shared needles, syringes, or equipment. Found in up to 1% of GUM patients <2% infection are sexually acquired. Sexual transmission very rare in heterosexuals 1:380,000 per sexual contact. Outbreaks described in HIV +ve MSM and prevalence in ♀ sex workers. Vertical transmission occurs in 5–8%, with HIV co-infection, prematurity, HCV VL >106.
• Incubation period: 4–20 weeks.
• Symptoms: acute hepatitis occurs in 20% and is less likely to be followed by chronic infection.
• Signs: similar to HAV and HBV.
• Complications: acute fulminant hepatitis is rare, but can occur.
• >80% become chronically infected with HCV, most unaware.
• high alcohol intake, co-existing HBV, HIV, and other chronic liver diseases can lead to a more rapid progression to cirrhosis and liver cancer
• progression to cirrhosis in 10–20% after 20–30 years
• thereafter, annual rate of developing cancer 1–5% and developing decompensation 3–6%. ALT may be normal, despite severe liver disease.
Screening with HCV Ab should be offered to:
• all PWIDs (past and present)
• blood (prior to September 1991)
• regular sexual partners of those with HCV infection
• HCP exposure to blood/needlesticks
• those with HIV infection, particularly MSM
• people tattooed or with skin piercings, where poor infection control
• children of mothers with HCV infection.
Some groups with ongoing risk may need repeat screening. It may be advised for prisoners/ex-prisoners; those sexually assaulted or if outbreak identified.
• If HCV antibody (Ab) +ve confirmation by PCR test for viral RNA. Abs usually appear within 3 (rarely 6) months of infection. HCV Ab may be –ve in HIV or the immunocompromised.
• Genotype testing: influences choice of treatment.
• Liver function, clotting tests, and exclusion of other viral hepatotropic infections, HIV and liver-related diseases are helpful.
• FibroScan® can be used to assess for severe fibrosis (≥14 kPa cirrhosis, ≥9.6 kPa severe fibrosis) and APRI can help determine severe fibrosis.
• Abdominal ultrasound and α-fetoprotein recommended.
A notifiable infection with partner notification and public health implications:
• Provide information and advice (PWID risk of sharing, risks of sexual transmission).
• Stop (or ) alcohol consumption.
• If patient amenable to further management, refer to specialist.
Monitor if still +ve at 6 months consider treatment with anti HCV DAA.
• DAA act on HCV protease (NS3/4A inhibitor) HCV RNA dependent polymerase (NS5B), modulator of NS5B (NS5A) see Table 25.3.
• Interferon no longer recommended.
Treatment combinations are outlined in Table 25.4. Drug interactions may be important (see Chapter 55, ‘HIV: management’, pp. 621–651).
Table 25.3 HCV Treatment classes
| NS3/4A inhibitors | NS5A inhibitors | NS5B inhibitors | |
| HCV drugs | Glecaprevir | Daclatasvir | Sofosbuvir |
| Grazoprevir | Elbasvir | Dasabuvir | |
| Paritaprevir | Ledipasvir | ||
| Voxilaprevir | Ombitasvir | ||
| Velpatasvir | |||
| Pibrentasvir |
Table 25.4 HCV treatment regimes
| HCV GT | Treatment regime | Treatment duration | ||
| Non-cirrhotic | Compensated cirrhosis | Treatment experienced to DAA | ||
| 1 or 4 | SOF/LDV | 8–12 weeks | 12 weeks | 12 weeks +RBV |
| SOF/VEL | 12 weeks | 12 weeks | 12 weeks +/- RBV | |
| SOF/VEL + VOX1 | 8 weeks | 12 weeks | 12 weeks if DAA experienced | |
| SOF/DCV | 12 weeks | 12 weeks + RBV | 12 weeks +RBV | |
| OMB/PAT/r + DSV (not GT4) | 1a–12 weeks with RBV 1b 12 weeks | 1a–12 weeks with RBV 1b 12 weeks | 24 weeks + RBV | |
| OMB/PAT/r + RBV (GT4) | 12 weeks + RBV | |||
| EBR/GZR | GT1a or GT4 treatment experienced; 12 week if VL ≤800 000 IU/mL, Add RBV 12 weeks of VL >800 000 IU/mL | |||
| GT1b or GT4 naïve; 12 weeks | ||||
| GLE/PIB | 8 weeks | 12 weeks | 12–16 weeks | |
| 2 | SOF/DCV | 12 weeks | ||
| SOF/VEL | 12 weeks | |||
| GLE/PIB | 8 weeks | 12 weeks | 8–12 weeks | |
| 3 | SOF /DCV | 12 weeks | 12 weeks + RBV | 24 weeks + RBV |
| SOF/VEL | 12 weeks | 12 weeks + RBV | ||
| SOF/VEL/VOX | 8 weeks | 12 weeks | ||
| GLE/PIB | 8 weeks | 12 weeks | 16 weeks | |
| 5 or 6 | SOF/LDV | 12 weeks | 12 weeks + RBV | |
| SOF/VEL | 12 weeks | |||
| SOF/VEL/VOX | 8 weeks | 12 weeks | 12 weeks + RBV | |
| SOF/DCV | 12 weeks | 12 weeks + RBV | ||
| GLE/PIB | 8 weeks | 12 weeks | 8 weeks | |
DCV, daclatasvir; DSV, dasabuvir; EBR, elbasvir; GLE, glecaprevir; GZR, grazoprevir; LDV, ledipasvir; OMB, ombitasvir; PIB, pibrentasvir; PTV/r, paritaprevir/ritonavir; RBV, ribavirin; SOF, sofosbuvir; VEL, velpatasvir; VOX, voxilaprevir.
NS5a RAS mutations may effectiveness of treatment, particularly G3 or G1a treatment experienced. Y93H is a key mutation. Testing should be considered in treatment experienced and, if +ve, add RBV/lengthen treatment. Consider in naïve G1a if using EBR/GZR or in 3a if using SOF/DCV, and adding RBV or using alternative agent.
No vaccine available. Currently, no treatment for needlestick injuries recommended.
For different tests, see Table 25.5.
Table 25.5 Serological, virological, and liver enzyme tests in different stages of viral hepatitis A, B, C
| HAV | HBV | HCV | |
| Acute infection | |||
| Chronic infection | Does not usually occur | ||
| Recovered infection | |||
| Successful vaccination | HAV IgG +ve | Not available |
