Authors Waled Mohsen, Miriam T. Levy First
published: 11 April 2017
Viral hepatitis contributes to significant morbidity and mortality worldwide. While acute infection may be self-limiting, unrecognised chronic infection and under-utilisation of guideline-based approaches to therapy contribute to increasing rates of cirrhosis, hepatocellular carcinoma and death. Our aim was to review the current evidence for screening, diagnosis and treatment in hepatitis A to E. Evidence for this review was sourced from international and Australian guidelines and high-quality clinical trials. MEDLINE was searched using structured key word strategy and retrieved articles were reviewed methodically to inform a brief and up-to-date synopsis of hepatitis A to E. We share some of the recent developments in viral hepatitis, specifically the new therapies for hepatitis C. Direct-acting antiviral therapies are safe, well-tolerated and effective. Subsidies allow access for all Australians with most strains of hepatitis C. We outline evidence underpinning efficacy and safety of treatment for hepatitis B, while clarifying some of the nuances in the setting of pregnancy and immunosuppression. We provide a simplified concept to facilitate understanding of the five phases of hepatitis B; practical for real-world setting. Hepatitis A to E is a broad topic, not all aspects of these viruses can be covered in this short review. We provided suggestions for evidence based guidelines, which are a suitable supplement to this article.
Vaccination or previous exposure to hepatitis A gives long-term immunity. Post-exposure prophylaxis with immunoglobulin may be indicated when exposure was less than 14 days prior. Vaccine may also be effective. The time from exposure to clinical manifestations is approximately 30 days (range 15–50). Symptoms may be non-specific and include jaundice, anorexia, nausea, vomiting, abdominal pain and mild fever. Diagnosis is confirmed by identifying anti-HAV immunoglobulin class M (IgM) antibody, detectable 2 weeks after exposure and persisting for up to 14 weeks. The presence of IgG antibodies confirms lifelong immunity from the virus. Jaundice recovers after an average of 6 weeks (range 1–10 weeks).[4, 5]
Rarely, acute liver failure (characterised by jaundice, hepatic encephalopathy and coagulopathy) can result from acute hepatitis A infection. Patients with unrelated liver disease are at increased risk of developing acute liver failure from HAV and as such vaccination should be considered in these patients. A relapsing form of acute hepatitis with subsequent peaks of aminotransferase elevation is described in about 10% of patients with hepatitis A. A cholestatic form of hepatitis A with prolonged pruritus is also described.
Interpreting hepatitis B serology
|Acute hepatitis B||Positive||IgM positive||Negative|
|Chronic hepatitis B (≥6 months)||Positive||IgG positive||Negative|
|Resolved hepatitis B†||Negative||IgG positive||Positive|
Phase of infection: immune–virus interactionsThe HBV itself is not directly hepatotoxic, despite high viral levels in liver and blood. The clinical outcome is determined by the immunological response. The immune response is minimal in exposed infants after birth with correspondingly few symptoms and minimal biochemical hepatitis. Clearance of infection is rare and chronic hepatitis develops in greater than 90% of those infected at this time. In contrast, exposure to infection, later in life results in symptoms and biochemical hepatitis due to an effective immune response. Clearance usually occurs and chronic infection develops in less than 5% of cases.[5, 9]
Chronic hepatitis B
Simple information for patients about the phases of hepatitis B
|Phase: (traditional name)||1: Silent (immune tolerant)||2: Damage (immune clearance)||3: Control (immune control)||4: Escape (immune escape)||5: Clear (resolved)|
|What happens in this phase?||Your liver is not being damaged||The body is trying to clear the infection|
The liver is being damaged in the fight
|Liver damage stops but there may be damage from previous phases||Liver damage is occurring||Infection is gone, liver damage does not occur|
There may be damage from previous phases
|What should you do?||Your family doctor should monitor liver tests every 6 months|
No treatment required
|Review by a specialist may be required|
You may require treatment
|Monitor liver tests every 6–12 months|
Review to identify liver damage from previous phases
Regular ultrasounds monitoring for liver cancer might be required
|Is there any other reason your liver tests are abnormal?|
You need review by a specialist to plan best action
You might need some treatment
|The infection is gone and should not return|
Regular ultrasound to screen for liver cancer, especially if there is liver damage from previous phases
|What do your blood tests show?||Liver function tests (ALT) are normal|
Levels of virus are high (HBV DNA >20 000 IU/mL)
Hepatitis B sAg and eAg is positive
|Liver function tests (ALT) become abnormal|
Levels of virus are high (HBV DNA >20 000 IU/mL)
Hepatitis B sAg and eAg is positive
|Liver function tests return to normal (ALT)|
Levels of virus come under control (HBV DNA < 2000 IU/mL)
Hepatitis B eAg is negative/eAb positive
|Liver function tests (ALT) become abnormal|
Levels of virus rise again (HBV DNA > 2000 IU/mL)
Hepatitis B eAg is negative/eAb positive
|Liver function tests are normal|
Virus is undetectable
Hepatitis B eAg is negative /eAb positive
Hepatitis B sAg is negative/sAb positive
TreatmentThere are currently two classes of drugs approved for the treatment of HBV infection: (i) direct antiviral agents, nucleos(t)ide analogues (NA), entecavir and tenofovir disoproxil fumarate (TDF); and (ii) pegylated interferon (PEG-IFN). PEG-IFN acts as an immunomodulator, with some weak direct antiviral activity. PEG-IFN has significant side effects, including flu-like symptoms, headache, fatigue, poor appetite, exacerbation of depression and other psychiatric disorders. Furthermore, it does not have a clear therapeutic advantage, so it remains a less popular alternative. Some evidence suggests that HBsAg seroconversion is more likely with PEG-IFN therapy, when compared with NA although a paucity of controlled trials, using matched populations convincingly demonstrate this.[11-13] Combination PEG-IFN and NA therapy has recently been shown in a controlled trial to increase the chance of HBsAg clearance from 2.8 to 9%, although these data are encouraging, it is a small difference, not reproduced in other similar studies, and has yet to influence clinical practice greatly.
The safety and durable potency of long-term NA therapy is well described, without appreciable emergence of viral resistance. Monitoring for toxicity is required, as nephrotoxicity and osteoporosis, although uncommon, may occur. A recent, real-world study using 53 500 subjects showed that NA do not increase the risk of renal and bone events, if appropriate toxicity monitoring and dose adjustments are made. A new prodrug formulation tenofovir alafenamide has been shown to have improved renal and bone safety parameters, resulting from targeted hepatocyte exposure with lower systemic drug levels. The long-term clinical relevance and cost effectiveness of this improved safety profile has yet to be proven.
While NA effectively suppress hepatitis B replication and reduce the risk of disease progression, they cannot clear the replication template of covalently closed circular DNA. HBsAg seroconversion rarely occurs. As a result, most patients require indefinite treatment. The reservoir of DNA template that remains in the liver cell nucleus including covalently closed circular DNA and integrated DNA is not impacted by current therapies . There are several potential therapies for hepatitis B, based on the greater understanding of the hepatitis B life cycle. These therapies aim to achieve a more durable off therapy control or even cure. A target of the sodium/taurocholate co-transporting polypeptide receptor, which inhibits viral entry, Myrcludex B, is an example of such research entering clinical trial phase with some promising very early results.[18, 19]
Decisions to commence therapy are based on the phase of infection, estimated accumulated liver injury and the risk of liver cancer. The primary goal of treatment is to improve patient survival by preventing or delaying the development of cirrhosis and HCC. Secondary goals include (i) HBV DNA suppression, (ii) biochemical and histological improvement and (iii) immunological control of the virus, particularly HbsAg loss and HBsAb development, although rarely achieved.[6, 8] Thus, guidelines recommend that treatment should not be terminated until there is durable HBeAg seroconversion with minimum of 6 months consolidation or in patients who are HBeAG negative, HBsAg clearance[8-10] (Table 3).
End point of hepatitis B therapy with nucleos(t)ide analogues
|Chronic hepatitis B treatment guidelines||European Association of the Study of the Liver EASL (2012)9||American Association of the Study of Liver Diseases AASLD (2016)6||Asian Pacific Association of the Study of the Liver APASL (Feb)10|
|HBeAg positive||Until HBeAg seroconversion followed by 12 months of consolidation||Until HBeAg seroconversion followed by 12 months of consolidation and undetectable DNA||Until HBeAg seroconversion followed by 12 months of consolidation + undetectable DNA|
|HBeAg negative||HBsAg clearance||HBsAg clearance†||Treatment for at least 2 years + DNA undetectable three times 6 months apart|
Hepatitis B infection and immunosuppressive therapy
Intense immunosuppression, such as with haemopotetic stem cell transplantation, or B-cell ablation with agents such as rituximab, can result in reactivation of resolved HBV infection (anti-HBcAb positive). While less likely, overall this large at risk population will get into trouble if ignored, as fulminant hepatitis and hepatitis-related mortality can occur. For example, HBV reactivation occurred in 17 out of 150 lymphoma patients with resolved HBV infection treated with R-CHOP (rituximab, cyclophosphamide, doxirubicin, vincristine and prednisone). Despite this evidence, universal HBV screening and initiation of treatment prior to immunosuppressive therapy is not routinely practised by all oncologists. A survey in 2011 showed that only 19% of oncologists practised universal screening. Guidelines recently reported by American Gastroenterological Association for most settings of immunosuppression report risk of reactivation with each HBV and immunosuppressive scenario. Where the risk is low (1%), such as in those with resolved HBV infection and treatment with biologic anti-biologic modifier therapies, the choice between monitoring and pre-emptive therapy is based on cost and patient preference.
The optimum management post-partum is uncertain. High rates of post-partum flares are reported. Extended therapy post-partum beyond the indication of preventing mother to child transmission is not of proven benefit. At the present time, continuation to between 4 and 12 weeks post-partum is reasonable, unless another indication such as significant liver disease is present. The majority of post partum flares settle spontaneously within 6 months and extended therapy is not usually required in a large reported Australian cohort.
Screening and diagnosis
Evaluating for the presence of cirrhosis
Liver biopsy was once the gold standard for the diagnoses of cirrhosis now rarely performed due to pain, risk of serious adverse consequences and non-invasive alternatives. Transient elastography, or Fibroscan is a well-validated non-invasive tool to measure liver stiffness. Fibroscan is available in most metropolitan centres. A liver stiffness above 12.5 Kpa is a reliable threshold for identifying cirrhosis. The Fibroscan result, coupled with clinical examination, biochemical and radiological information are used synergistically to identify those with advanced fibrosis and cirrhosis. A reliable reading may be unachievable in 10% of patients, particularly those who are obese or with ascites. Reasonably accurate identification of cirrhosis is also possible with formulas incorporating serum biomarkers, such as the validated APRI score (aspartate aminotransferase (AST) to platelet ratio index). A systematic review including 172 studies conducted in patients with hepatitis C reported a median Area under Receiver Operator Characteristic (AUROC) of 0.77 and 0.84 for the APRI score, when used to identify patients with cirrhosis.
Direct-acting hepatitis C therapies according to sites of action
|Mechanism of action||Direct-acting anti-viral|
|NS3 protease inhibitor||Paritaprevir Grazoprevir|
|NS5B nucleotide inhibitor||Sofosbuvir|
|NS5B non-nucleotide inhibitor||Dasabuvir|
|NS5A inhibitor||Ledipasvir Ombitasvir Daclastavir Elbasvir|
|Genotype/subtype||Treatment naive||Treatment experienced|
|No cirrhosis||With cirrhosis||No cirrhosis||With cirrhosis|
|1a/b||Ledispasvir/sofosbuvir (12 weeks)†||Ledispasvir/sofosbuvir (12 weeks)||Ledispasvir/sofosbuvir (12 weeks)||Ledispasvir/sofosbuvir (24 weeks)|
|1a/b||Daclastavir and sofosbuvir (12 weeks)||Daclastavir and Sofosbuvir (24 weeks)|
Or 12 weeks with ribavirin‡
|Daclastavir and sofosbuvir (12 or 24 weeks)§||Daclastavir and Sofosbuvir (24 weeks)|
Or 12 weeks with ribavirin‡
|1a¶||Elbasvir/grazoprevir (12 weeks)||Elbasvir/grazoprevir (12 weeks)||Elbasvir/grazoprevir and ribavirin (16 weeks)||Elbasvir/grazoprevir and ribavirin (16 weeks)|
|1b¶||Elbasvir/grazoprevir (12 weeks)||Elbasvir/grazoprevir (12 weeks)||Elbasvir/grazoprevir (12 weeks)||Elbasvir/grazoprevir (12 weeks)|
|1a||Paritaprevir-ritonavir, ombitasvir, dasabuvir and ribavirin (12 weeks)||Paritaprevir-ritonavir, ombitasvir, dasabuvir and ribavirin (12 weeks)||Paritaprevir-ritonavir, ombitasvir, dasabuvir and ribavirin (12 weeks)||Paritaprevir-ritonavir, ombitasvir, dasabuvir and ribavirin (12 or 24 weeks)|
|1b||Paritaprevir-ritonavir, ombitasvir, dasabuvir (12 weeks)||Paritaprevir-ritonavir, ombitasvir, dasabuvir (12 weeks)||Paritaprevir-ritonavir, ombitasvir, dasabuvir (12 weeks)||Paritaprevir-ritonavir, ombitasvir, dasabuvir (12 weeks)|
|2||Sofosbuvir and ribavirin (12 weeks)||Sofosbuvir and ribavirin (12 weeks)||Sofosbuvir and ribavirin (12 weeks)||Sofosbuvir and ribavirin (12 weeks)|
|3||Daclastavir and sofosbuvir (12 weeks)||Daclastavir and sofosbuvir (24 weeks)||Daclastavir and sofosbuvir (12 weeks)||Daclastavir and sofosbuvir (24 weeks)|
|4¶||Elbasvir/grazoprevir (12 weeks)||Elbasvir/grazoprevir (12 weeks)||Elbasvir/grazoprevir and ribavirin (16 weeks)||Elbasvir/grazoprevir and ribavirin (16 weeks)|
|4||Sofosbuvir and peg-interferon alfa-2a/ribavirin (12 weeks)||Sofosbuvir and peg-interferon alfa-2a/ribavirin (12 weeks)||Sofosbuvir and peg-interferon alfa-2a/ribavirin (12 weeks)||Sofosbuvir and peg-interferon alfa-2a/ribavirin (12 weeks)|
|5 and 6||Sofosbuvir and peg-interferon alfa-2a/ribavirin (12 weeks)||Sofosbuvir and peg-interferon alfa-2a/ribavirin (12 weeks)||Sofosbuvir and peg-interferon alfa-2a/ribavirin (12 weeks)||Sofosbuvir and peg-interferon alfa-2a/ribavirin (12 weeks)|
When prescribing hepatitis C therapy, potential drug interactions should be determined as some may cause adverse reactions, or altered efficacy of the medication or the DAA therapy. Internet-based resources such as University of Liverpool HEP drug interactions (http://www.hep-druginteractions.org) are useful. Assessing and managing anything that may affect adherence is also critical (see Table 6: Checklist prior to commencing DAA therapy for hepatitis C). Primary care doctors may prescribe DAA therapy, after consulting a gastroenterologist or infectious diseases physician or if they have sufficient experience in hepatitis C treatment (PBS requirement).
Monitoring after initiation of therapy with a DAA in a non-cirrhotic generally involves a blood test at week 4 of most DAA therapy (EUC, LFT and FBC) or week 8 if the patient is taking Zapatier (elbasvir/grazoprevir). Testing (HCV RNA, EUC, LFT, INR and FBC) 12 weeks after completing treatment to confirm complete eradication of the virus or sustained viral response is also important as some, although only a few, will fail and need a second-line therapy.
Checklist prior to commencing direct-acting anti-viral therapies for hepatitis C
Hepatologists and infectious diseases specialists will not have capacity to eradicate hepatitis C without help from community general practitioners, drug health and sexual health doctors. Novel telementoring programmes, such as Project ECHO (Extension for Community Healthcare Outcomes) has been demonstrated to expand expertise and are being tested in pilot form in South West Sydney Local Health District. Project ECHO uses video conference supported group-based learning to share knowledge between specialists and community doctors. It was developed in New Mexico and since its inception, has been validated and replicated in many countries including Ireland, Uruguay and India.[39, 40] Access to specialty knowledge for community doctors in rural or underserved areas may increase capacity by permitting patients with drug dependency and those from culturally or linguistically diverse communities to take up treatment with their local community or a drug health specialist. Building expertise will increase treatment numbers with the aim of eradication of HCV in Australia.
Hepatocellular carcinoma and chronic viral hepatitis
The risk of HCC in CHB infection is increased in patients who are male, elderly, have long duration of infection and have a family history of HCC. National hepatitis B vaccination programmes have dramatically reduced the prevalence of hepatitis B infection, and the incidence of HCC. Since the inception of a universal vaccination programme in Taiwan, the incidence of HCC in children between 6 and 14 years of age has fallen by 65–75%.
Screening utilising 6 monthly imaging by ultrasound has been recommended by the American Association of the Study of Liver Diseases (AASLD) (Table 7). Testing for alpha-fetoprotein (AFP) tumour marker at the same time is not recommended because of issues with false-positive results in the setting of liver inflammation. In practice, AFP in conjunction with a liver ultrasound is still used in many hepatology practices. Surveillance for HCC is often underutilised in patients with cirrhosis. In a study of 1873 patients diagnosed with HCC above the age of 65, in whom cirrhosis was recorded for 3 or more years, only 29% had received routine surveillance and a further 33% received inconsistent surveillance. Despite limited data from randomised clinical trials, early detection offers the best chance for curative treatment for patients with HCC, increasing the possibility for early curative treatment.[48-50]
American Association of the Study of Liver Diseases hepatocellular carcinoma screening guidelines
|Target population for liver ultrasound every 6 months|
|Non-cirrhotic hepatitis B carriers with a family history of hepatocellular carcinoma|
|Non-cirrhotic Africans and African Americans with hepatitis B|
|Non-cirrhotic Asian male hepatitis B carriers past the age of 40 years|
|Non-cirrhotic Asian female hepatitis B carriers past the age of 50 years|
Hepatitis deltaHepatitis D (delta) virus (HDV) is a small, defective RNA virus that requires HBsAg for transmission and packaging. HDV is considered to be a sub-viral satellite because it can propagate only in the presence of the HBV. The HDV genome consists of a single-stranded RNA, which is folded as a rod-like structure through internal base-pairing. Transmission of HDV can occur either via simultaneous infection with HBV (co-infection) or superimposed on CHB or hepatitis B carrier state (super-infection).
Of the 350 million individuals with chronic HBV infection, approximately 15 million have also been exposed to HDV. While HDV is relatively common in the Mediterranean basin, HDV is not common in Australia. There are approximately 30 cases reported per year. Acquiring HBV and HDV during the same exposure (co-infection) is associated with more severe acute hepatitis and higher mortality, when compared with acute HBV mono-infection. HDV super-infection in an HBV carrier can manifest as an acute hepatitis although usually results in chronic HDV infection. The progression to cirrhosis is faster in patients with chronic HDV, when compared with HBV mono-infection: 80% of patients with chronic HDV will progress to cirrhosis in 5–10 years.
The fate of HDV is determined by the host response to HBV, and HDV is cleared if HBV is cleared. HBV DNA is usually low or negative in chronic HDV infection, because HDV suppresses HBV replication. HDV IgM is positive in acute infection and can persist in chronic infection; if it does persist, it can be used as a surrogate marker for HDV replication. Qualitative HDV RNA is a marker of viral replication that is positive in chronic infection. HDV RNA is useful to monitor treatment response, but is not readily available. Furthermore, HBsAg is useful to monitor treatment response if quantitative HDV RNA is not available.
The mainstay of treatment for HDV infection is PEG-IFN-alpha for at least 48 weeks. Efficacy is disappointing, with control of infection estimated in only 20–25% of the patients, worse in those with cirrhosis.[55, 56] The oral nucleos(t)ides appear to have limited activity against HDV, because the virus uses host enzymes for replication and thus lacks enzyme targets. Nevertheless, control of HBV is always indicated and after long-term therapy, delta viral levels can decline. New targets, such as with Myrcludex B a first in class entry inhibitor inactivating the HBV and HDV receptor are promising but results are preliminary. Patients with HDV should be managed in a specialist centre.
HEV is not a common cause of liver disease in Australia. The first case of HEV was reported in 1993. Over the last 6 years, there have been approximately 30–40 cases of hepatitis E diagnosed every year, predominantly in returned travellers. However, a recent cluster of HEV infection linked to a single restaurant in Sydney in May 2014 was the first reported Australian outbreak of locally acquired HEV infection, and one of the largest linked with a restaurant reported anywhere. A total of seventeen cases were linked to consuming pork liver pâté at this restaurant during a 9-month period.
Clinically, acute HEV infection is similar to hepatitis A; however, a longer incubation period, a longer clinical course, a higher fatality among pregnant women, patients with pre-existing liver disease and patients with HIV and dialysis patients is also described . The clinical course of acute HEV infection is characterised by a 3–8-week incubation period, during which HEV RNA can be detected in the stool or serum. After 8 weeks, symptoms develop in some patients and are usually accompanied by a rise in ALT and the appearance of anti-HEV IgM. IgM persists for months and declines with the resolution of infection. Suspected HEV infection in immunocompromised patients should also be confirmed by HEV RNA testing. Chronic hepatitis does not usually develop after acute HEV infection, except in the transplant setting and possibly in other settings of immunosuppression. Patients with chronic hepatitis E infection may develop liver cirrhosis. Ribavirin has become the drug of choice for chronic HEV and its efficacy has been proven in larger studies. As hepatitis E is normally self-limiting, most patients do not require specific treatment, other than supportive care.
Two candidate vaccines against hepatitis E have undergone successful clinical testing. The first (56-kDa truncated ORF2 protein of HEV) achieved 100% seroconversion and protective efficacy of up to 95.5% during a 2-year follow up of 2000 patients. The second vaccine (ORF2 protein) showed a protective efficacy of 100% during a 13-month follow up. The use of this vaccine was approved in China in 2012. Unfortunately, this vaccine has not been licenced for marketing in other countries, due to lack of profitability. Currently, the best way to prevent hepatitis E is by the provision of safe drinking water, proper disposal of human faeces and education about personal hygiene.