Clinical Effectiveness Group （British Association of Sexual Health and HIV）
Introduction and Methodology
The main objective is to reduce the number of sexually transmitted infections （STIs） and the complications that can arise in people either presenting with signs and symptoms of an STI, or undergoing investigation for possible infection.
This guideline offers recommendations on the diagnostic tests, treatment regimens and health promotion principles needed for the effective management of Hepatitis A, B and C. Covering, the management of the initial presentation, as well as how to prevent transmission and future infection.
It is aimed primarily at people aged 16 years or older （see specific guidelines for those under 16） presenting to health care professionals, working in genitourinary medicine departments within the United Kingdom. However, the principles of the recommendations could be adopted in other health care settings.
Stake holder involvement This is the third revision of a guideline first written in 1998. Previous versions of the guideline have been reviewed by the Health Advisers professional association （SHASTD）, the MSSVD, AGUM and Royal College of Physicians. All previous versions have also been on the MSSVD, AGUM and BASSH websites since 1998, were comments were invited from website visitors.
Rigour of development Search strategy
For each type of hepatitis, a medline search was performed for the years 1966 - 2004 （Feb.） for hepatitis types A and B and 1990-2004（Feb）for hepatitis C. From the MeSH terms“hepatitis A”, “hepatitis B”, and “hepatitis C”, the following sub-headings were used: Complications, Drug Therapy, Diagnosis, Epidemiology, Etiology, Mortality, Prevention and Control, Therapy, Transmission, Virology. The searches were limited to “human” for all searches. For Drug Therapy, Prevention & Control, and Therapy searches were limited initially to “randomized controlled trials” but in the absence of enough publications this was changed to “controlled clinical trials”, “clinical trials” or “reviews” in that order. For the sub-headings other than these three the search was limited to “reviews”. Textword searches for “hepatitis A”, hepatitis B”, and “hepatitis C” were combined, as appropriate, with textword searches for “ complication$”, “diagnosis”, “prevention”, “transmission”, “immunoglobulin”, “vaccine”, “non-response”, “non-responders”, “HIV”, “randomized controlled trial”, “lamivudine”, “famciclovir”, “ribavirin”
Criteria for inclusion:
- Evidence from RCTs was used were possible, and failing that the studies using other rigorous scientific method.
- Recommendations were based on RCT or other scientific evidence and graded accordingly.
- No harms are anticipated
Prior to publication the final draft of the guideline was placed on the BASHH website, and copies circulated to the BASHH branch chairs, GUNA and SHAS chairs for comment and peer review. After a period of three months any comments received were reviewed by the guideline authors, and acted on appropriately, before final authorisation by the CEG was given and publication was undertaken.
Timescale for next revision: 2 years
Hepatitis A virus infection
Aetiology
Caused by a picorna （RNA） virus. It is particularly common in areas of the world where sanitation is poor （developing countries） and largely affects children there. In the developed world it is less common （1381 cases reported in England and Wales, 2002） and causes disease in all age groups [1].
Transmission:
• Faeco-oral （via food, water, close personal contact） [2-7].
• Outbreaks have been reported in men who have sex with men , linked to oro-anal or digital-rectal contact, multiple sexual partners, anonymous partners, sex in public places and group sex [8-14]. However, several seroprevalence studies in the UK, Spain, USA and Italy show a similar rate of hepatitis A （IgG） antibodies in homosexual and heterosexual men [12,15,16].
• HIV positive patients are not at increased risk but may be more infectious [17].
• Outbreaks have also been reported amongst intravenous drug users [1,17-19], in institutions for people with learning difficulties, and in contaminated batches of factor VIII [20-22].
• Patients are infectious for approximately two weeks before and one week after the jaundice by the non-parenteral routes but virus can be found in the blood and stool until after the serum amino-transferase levels have peaked [23]. In HIV positive patients, Hepatitis A （HAV） viraemia may continue for over 90 days [17].
Clinical Features
Incubation Period: 15-45 days [2, 3, 24]
Symptoms [24]
Most children and up to half of adults are asymptomatic or have mild non-specific symptoms with little or no jaundice.
In the more ‘typical’ case there are two phases of symptoms -
▪ The prodromal illness: flu-like symptoms （malaise, myalgia, fatigue）, often with right upper abdominal pain. This phase lasts for 3-10 days. This is followed by -
▪ The icteric illness: jaundice （mixed hepatic and cholestatic） associated with anorexia, nausea and fatigue which usually lasts for 1-3 weeks. It can persist for 12 or more weeks in a minority of patients who have cholestatic symptoms （itching and deep jaundice） [25]. Fever is not found in this phase.
Signs [16]
▪ None specific in the prodromal phase.
▪ cteric phase - jaundice with pale stools and dark urine. Liver enlargement/tenderness and signs of dehydration are also common.
Complications
▪ Fulminant hepatitis complicates approximately 0.4% of cases, although 15% of patients may require hospital care, of whom a quarter will have severe hepatitis （Prothrombin time PT > 3 seconds prolonged or bilirubin >170μmoles/l） [26,27]. Fulminant hepatitis A is more common in patients already infected with chronic hepatitis B or C, although studies differ widely in measured rates [26, 28].
▪ Chronic infection （>6 months） has only been reported in a tiny number of case-reports [29].
▪ The overall mortality is < 0.1% [26, 27].
▪ Pregnancy - The infection does not have any teratogenic effects but there is an increased rate of miscarriage and premature labour, proportional to the severity of the illness [30, 31]. There have been case reports of possible vertical transmission [32, 33].
Diagnosis （See also: Sexually Transmitted Infection Screening Guidelines） （www.bashh.org）
Serology
▪ Confirmed by a positive serum Hepatitis A virus - specific IgM （HAV-IgM） which remains positive for six months or more [34, 35]. HAV-IgG does not distinguish between current or past infection and may remain positive for life [34, 36].
Other tests
▪ Serum/plasma amino-transferases （AST/ALT） 500-10,000iu/l. Bilirubin up to 500μmoles/l. Alkaline phosphatase levels < 2x the upper limit of normal, but higher if there is cholestasis [24, 26-28].
▪ Prothrombin time （PT） prolongation by more than 5 seconds suggests developing hepatic decompensation [24, 26].
Management
General Advice
▪ Patients should be advised to avoid food handling and unprotected sexual intercourse until they have become non-infectious （III,B） [2-4, 7, 37]
▪ Patients should be given a detailed explanation of their condition with particular emphasis on the long-term implications for the health of themselves and their partner（s）. This should be reinforced by giving them clear and accurate written information.
▪ Hepatitis A is a notifiable disease.
Further Investigations
Screen for other sexually transmitted infections in cases of sexually-acquired hepatitis or if otherwise appropriate.
Acute icteric hepatitis
▪ Mild/moderate （80%） - manage as an outpatient emphasising rest and oral hydration （III, B） [24].
▪ Severe attack with vomiting, dehydration or signs of hepatic decompensation （change in conscious level or personality） - admit to hospital （III, B） [26, 27].
Pregnancy and Breast Feeding
▪ Pregnant women should be advised of the increased risk of miscarriage/premature labour and the need to seek medical advice if this happens [31].
▪ Breast feeding can be continued but consider giving Human Normal Immunoglobulin （HNIG） 125mg i.m. to the baby, although most children will have mild or asymptomatic infection （IV, C） [38].
Sexual and Other Contacts
▪Partner notification should be performed for at-risk homosexual contacts （oro/anal, digital/rectal and penetrative anal sex） within the period two weeks before to one week after the onset of jaundice. This to be documented and the outcome documented at subsequent follow-up. Other people thought to be at risk （household contacts, those at risk from food/water contamination） to be contacted via the public health authorities （consultant in communicable control （CCDC） or equivalent）. The CCDC has a duty of confidentiality to the index patient.
▪ Hepatitis A vaccine may be given up to 7 days after exposure providing exposure was within the infectious period of the source case （during the prodromal illness or first week of jaundice） （IIa, B） [38-41].
▪ HNIG 250-500mg intramuscularly should also be considered for patients at higher risk of complication （concurrent chronic hepatitis B or C, chronic liver disease or age >50yr） or if there has been a delay of more than 7 days after exposure （Ib, A） [38, 39].
▪ HNIG works best if given in the first few days after first contact with an efficacy of 90% and is unlikely to give any protection more than two weeks after first exposure, but may reduce disease severity if given up to 28 days after exposure [39].
▪Patients are most infectious for two weeks before the jaundice （i.e. before the illness is recognised）.
▪ Hepatitis A vaccine schedule: doses at 0 and 6-12 months, 95% protection for at least five years （Ib, A） [42-45]. Current advice is to revaccinate after ten years （IIb, B） [42-6], however there is increasing evidence that vaccine-induced immunity may be >20 years and possibly lifelong, so no further booster doses may be needed after the primary course in immunocompetent patients [42, 43].
▪ HIV-positive patients respond （antibody production） in 73-88% but titres are lower than in HIV-negative individuals （IIa, B） [45,46]. If patients with a low CD4 count （<300 cells/mm3） are vaccinated, they should be revaccinated if the CD4 count rises above 500/mm3 as a result of HAART [46, 47].
▪ There is a combined Hepatitis A+B vaccine given on the same schedule as the hepatitis B vaccine and has similar efficacy to the individual vaccines although early immunity to hepatitis B may be impaired （IIa, B） [48, 49].
▪ If an outbreak is suspected or if the index case is a food handler, notify the local CCDC/public health department by telephone （IV, C） [38, 39].
Follow-Up
▪ See at one or two weekly intervals until amino-transferase levels are normal （usually 4-12 weeks） （IV, C）.
▪ Immunity is usually lifelong [34, 36].
Primary Prevention
▪ Current evidence still suggests that most men who have sex with men are not at increased risk for hepatitis A infection [12, 15, 16] and therefore universal vaccination in this group cannot be firmly recommended （III, B）. However, many outbreaks have been reported amongst homosexual men in large cities and therefore clinics in these areas （eg central London） should offer vaccination, particularly when increased rates of infection have been recognised locally （III, B） [8-14, 38, 39].
▪ Intravenous drug users and patients with chronic hepatitis C infection should also be vaccinated （III, B） [17-19, 28, 38, 39].
▪Vaccination is also recommended for travellers to developing countries, people with haemophilia or chronic liver disease, those with occupational exposure and for people at risk in an outbreak （Ib, A） [1, 38, 39].
▪ Health/sex education should stress the routes of transmission and the higher incidence in developing countries （IV, C） [38].
Hepatitis B virus infection
Aetiology
Caused by a hepadna （DNA） virus. It is endemic world-wide, apart from isolated communities, with very high carriage rates （up to 20%） particularly in South and East Asia, but also in Southern Europe, Central and South America, Africa and Eastern Europe. In the UK carriage varies from 0.01-0.04% in blood donors to >1% in intravenous drug users and homosexual men [51]. In 2002 1072 cases were notified in England and Wales [52].
Transmission
▪ Sexual transmission occurs in unvaccinated or non-immune men who have sex with men and correlates with multiple partners, unprotected anal sex and also with oro-anal sex （“rimming”） [53-56]. Transmission also occurs after heterosexual contact eg 18% infection rates for regular partners of patients with acute hepatitis B [57-59]. Sex workers are also at higher risk [60, 61].
▪ Other routes are: parenteral （blood, blood products, drug-users sharing needles and syringes, needle-stick, acupuncture） and vertical （infected mother to infant） [53, 58, 62-65].
▪ Sporadic infection occurs in people without apparent risk factors, in institutions for learning difficulties and also in children in countries of high endemicity, but in these cases the means of transmission is poorly understood [66, 67].
Clinical Features
Incubation period 40-160 days.
Symptoms
▪ Virtually all infants and children have asymptomatic acute infection. Asymptomatic infection is also found in 10-50% of adults in the acute phase and is especially likely in those with HIV co-infection [24, 68-70].
▪ The prodromal and icteric phases are very similar to hepatitis A, but may be more severe and prolonged [24].
Signs
▪ As for hepatitis A in the acute phase.
▪ If chronic infection occurs there are often no physical signs. After many years of infection, depending on the severity and duration, there may be signs of chronic liver disease including spider naevi, finger clubbing, jaundice and hepato-splenomegaly, and in severe cases thin skin, bruising, ascites, liver flap and encephalopathy [54, 70-73].
Complications
▪ Fulminant hepatitis occurs in less than 1% of symptomatic cases but carries a worse prognosis than that caused by hepatitis A [26].
▪ Chronic infection （>6 months） occurs in 5-10% of symptomatic cases but the rate is higher in immuno-compromised patients with HIV infection, chronic renal failure or those receiving immuno-suppressive drugs [68, 70-72]. Immunosuppressive treatment can also reactivate hepatitis B [74]. A higher rate of chronic infection is also found in patients at institutions for learning disabilities [66]. Almost all （>90%） of infants born to infectious （HBeAg +ve） mothers will become chronic carriers unless immunised [62, 64].
▪ Concurrent hepatitis C infection can lead to fulminant hepatitis, more aggressive chronic hepatitis and increased risk of liver cancer [75-77]. Concurrent HIV infection increases the risk of progression to cirrhosis and death [78].
▪ Mortality is less than 1% for acute cases [26]. Between ten and fifty percent of chronic carriers will develop cirrhosis leading to premature death in approximately 50% [54, 68]. Ten percent or more of cirrhotic patients will progress to liver cancer [54, 68, 77].
▪ Pregnancy- increased rate of miscarriage/premature labour in acute infection [31]. Risk of vertical transmission （see above） [62, 64]
Diagnosis （see also Sexually Transmitted Infection Screening and Testing Guidelines - Hepatitis A, B and C）
Table 1 Hepatitis B serology [34, 54, 69]
|
Stage of infection |
Surface antigen （HBsAg） |
‘e’ antigen （HBeAg） |
IgM anti-core antibody |
IgG anti-core antibody |
Hepatitis B virus DNA |
Anti-HBe |
Anti-HBs |
|
Acute （early） |
+ |
+ |
+* |
+ |
+ |
- |
- |
|
Acute （resolving） |
+ |
- |
+ |
+ |
- |
+/- |
- |
|
Chronic （high activity） |
+ |
+/- |
- |
+ |
+ |
+/- |
- |
|
Chronic （low activity） |
+ |
- |
- |
+ |
- |
+/- |
- |
|
Resolved （immune） |
- |
- |
- |
+ |
- |
+/- |
+/- |
|
Successful vaccination |
- |
- |
- |
- |
- |
- |
+ |
* in very early infection the IgM anti-core can be negative and by definition so can the IgG
Other tests
▪ Acute infection - see hepatitis A
▪ Chronic infection - in most cases the only abnormality to be found will be mildly abnormal amino-transferase levels （usually <100iu/l） and in many the liver function tests （LFT） will be normal. Only in severe late stage liver disease does the LFT become grossly abnormal [54, 69-72]. Disease activity correlates with HBV-DNA levels and >105copies/ml is regarded as significant and meriting consideration of therapy.
Management
General Advice
▪ Patients should be advised to avoid unprotected sexual intercourse, including oro-anal and oro-genital contact until they have become non-infectious or their partners have been successfully vaccinated （see below） （III,B） [53, 54, 57 62, 79].
▪ Patients should be given a detailed explanation of their condition with particular emphasis on the long-term implications for the health of themselves and their partner（s）, routes of transmission of infection （see below） and advised not to donate blood （IV, C） [62].
▪ Hepatitis B is a notifiable disease
Further Investigations
▪ Screen for other sexually transmitted diseases in cases thought to have been sexually acquired or if otherwise appropriate （IIb, B） [52, 60].
▪ Other tests such as liver biopsy （for assessment of chronic disease） should be performed by specialists in this field （IV, C） [54, 69-72].
Acute icteric hepatitis
▪ As for hepatitis A.
Treatment of Chronic Infection
▪ Treatment should normally be given in collaboration with a hepatologist or physician experienced in the management of liver disease （IV, C）.
▪ Patients should be considered for therapy with lamivudine, adefovir or alpha interferon （Ib, A） [70-73, 80-83]. Additional promising treatments include pegylated interferons （III C）, entecavir （III C） and emtricitabine （FTC） （III,C） [86-88]. Treatment responders have long-term benefits in terms of reduced liver damage and decreased risk of liver cancer [80-90].
▪ Lamivudine, adefovir and tenofovir will suppress hepatitis B viral replication during therapy of immunocompromised patients, including those with HIV （see also the British HIV association guidelines on the treatment of HIV/HBV co-infection） [91-94], and may
delay liver damage （IIb, B） [92-94]. Cure is unusual in these patients, anti-viral resistance may develop after prolonged monotherapy and rebound hepatitis can occur if the agent is stopped or if resistance ensues （IIb） [92-4].
▪ Specific therapy is otherwise not indicated unless de-compensated liver disease ensues （IV, C） [54].
Pregnancy and Breastfeeding
▪ Vertical transmission （mother to infant） of infection occurs in ninety percent of pregnancies where the mother is hepatitis B e antigen positive and in about ten percent of surface antigen positive, e antigen negative mothers. Most （>90%） of infected infants become chronic carriers [64, 67, 95].
▪ Infants born to infectious mothers are vaccinated from birth, usually in combination with Hepatitis B specific Immunoglobulin 200iu im （Ia, A） [64, 95, 96]. This reduces vertical transmission by ninety percent.
▪ There is some evidence that treating the mother in the last month of pregnancy with lamivudine may further reduce the transmission rate if she is highly infectious （HBV-DNA > 1.2x109 geq/ml） （III, C）, but this needs to be further substantiated [97].
▪ Infected mothers should continue to breast feed as there is no additional risk of transmission （II, B） [98].
Sexual and Other Contacts
▪ Partner notification should be performed and documented and the outcome documented at subsequent follow-up. Contact tracing to include any sexual contact （penetrative vaginal or anal sex or oro/anal sex） or needle sharing partners during the period in which the index case is thought to have been infectious （IV,C） [37]. The infectious period is from two weeks before the onset of jaundice until the patient becomes surface antigen negative. In cases of chronic infection trace contacts as far back as any episode of jaundice or to the time when the infection is thought to have been acquired although this may be impractical for periods of longer than two or three years. Arrange screening for hepatitis B of children who have been born to infectious women if the child was not vaccinated at birth （IV, C） [62]. For screening of other non-sexual partners who may be at risk, discuss with the CCDC or equivalent.
▪ Specific hepatitis B immunoglobulin 500iu intramuscularly （HBIG） may be administered to a non-immune contact after a single unprotected sexual exposure or parenteral exposure/needle-stick injury if the donor is known to be infectious. This works best within 48 hours and is of no use after more than seven days （Ib, A） [62, 99].
▪ An accelerated course of recombinant vaccine should be offered to those given HBIG plus all sexual and household contacts （at 0, 7 and 21 days or 0, 1, 2 months with a booster at 12 months in either course） （Ib, A） [62, 63, 97, 98, 100, 101-105]. Vaccination theoretically will provide some protection from disease when started up to six weeks after exposure.
▪ Avoid sexual contact, especially unprotected penetrative sex, until vaccination has been successful （anti-HBs titres >10iu/l） （Ib, A） [62, 97, 98, 101-105].
▪ The ultra-rapid vaccination schedule （0, 7, 21 days） leads to an anti-HBs antibody response in only 80% of recipients 4-12 weeks after the third dose [101-105]. This rises to 95% just prior to the 12 month booster dose. It would be prudent to offer booster vaccinations of up to three further doses to the 20% of sexual or household contacts without detectable antibodies 4-12 weeks after the primary course （IV, C）, even though most would have eventually developed an antibody response.
Follow-up.
▪ Acute infection: as for hepatitis A. In view of the possibility of chronic infection, serology should be repeated after six months even if the LFT is normal [54, 68, 69].
▪ Chronic infection （HBeAg+ve or HBV-DNA >105iu/ml）: If untreated, patients should be regularly reviewed at intervals of one year or less, ideally by a physician with expertise in this disease （IV, C） [54, 68].
▪ Immunity after recovery from infection （surface antigen negative） is lifelong in over 90%.
Other tests
▪ Acute infection - see hepatitis A
▪ Chronic infection - in most cases the only abnormality to be found will be mildly abnormal amino-transferase levels （usually <100iu/l） and in many the liver function tests （LFT） will be normal. Only in severe late stage liver disease does the LFT become grossly abnormal [54, 69-72]. Disease activity correlates with HBV-DNA levels and >105copies/ml is regarded as significant and meriting consideration of therapy.
Management
General Advice
▪ Patients should be advised to avoid unprotected sexual intercourse, including oro-anal and oro-genital contact until they have become non-infectious or their partners have been successfully vaccinated （see below） （III,B） [53, 54, 57 62, 79].
▪ Patients should be given a detailed explanation of their condition with particular emphasis on the long-term implications for the health of themselves and their partner（s）, routes of transmission of infection （see below） and advised not to donate blood （IV, C） [62].
▪ Hepatitis B is a notifiable disease
Further Investigations
▪ Screen for other sexually transmitted diseases in cases thought to have been sexually acquired or if otherwise appropriate （IIb, B） [52, 60].
▪ Other tests such as liver biopsy （for assessment of chronic disease） should be performed by specialists in this field （IV, C） [54, 69-72].
Acute icteric hepatitis
▪ As for hepatitis A.
Treatment of Chronic Infection
▪ Treatment should normally be given in collaboration with a hepatologist or physician experienced in the management of liver disease （IV, C）.
▪ Patients should be considered for therapy with lamivudine, adefovir or alpha interferon （Ib, A） [70-73, 80-83]. Additional promising treatments include pegylated interferons （III C）, entecavir （III C） and emtricitabine （FTC） （III,C） [86-88]. Treatment responders have long-term benefits in terms of reduced liver damage and decreased risk of liver cancer [80-90].
▪ Lamivudine, adefovir and tenofovir will suppress hepatitis B viral replication during therapy of immunocompromised patients, including those with HIV （see also the British HIV association guidelines on the treatment of HIV/HBV co-infection） [91-94], and may
delay liver damage （IIb, B） [92-94]. Cure is unusual in these patients, anti-viral resistance may develop after prolonged monotherapy and rebound hepatitis can occur if the agent is stopped or if resistance ensues （IIb） [92-4].
▪ Specific therapy is otherwise not indicated unless de-compensated liver disease ensues （IV, C） [54].
Pregnancy and Breastfeeding
▪ Vertical transmission （mother to infant） of infection occurs in ninety percent of pregnancies where the mother is hepatitis B e antigen positive and in about ten percent of surface antigen positive, e antigen negative mothers. Most （>90%） of infected infants become chronic carriers [64, 67, 95].
▪ Infants born to infectious mothers are vaccinated from birth, usually in combination with Hepatitis B specific Immunoglobulin 200iu im （Ia, A） [64, 95, 96]. This reduces vertical transmission by ninety percent.
▪ There is some evidence that treating the mother in the last month of pregnancy with lamivudine may further reduce the transmission rate if she is highly infectious （HBV-DNA > 1.2x109 geq/ml） （III, C）, but this needs to be further substantiated [97].
▪ Infected mothers should continue to breast feed as there is no additional risk of transmission （II, B） [98].
Sexual and Other Contacts
▪ Partner notification should be performed and documented and the outcome documented at subsequent follow-up. Contact tracing to include any sexual contact （penetrative vaginal or anal sex or oro/anal sex） or needle sharing partners during the period in which the index case is thought to have been infectious （IV,C） [37]. The infectious period is from two weeks before the onset of jaundice until the patient becomes surface antigen negative. In cases of chronic infection trace contacts as far back as any episode of jaundice or to the time when the infection is thought to have been acquired although this may be impractical for periods of longer than two or three years. Arrange screening for hepatitis B of children who have been born to infectious women if the child was not vaccinated at birth （IV, C） [62]. For screening of other non-sexual partners who may be at risk, discuss with the CCDC or equivalent.
▪ Specific hepatitis B immunoglobulin 500iu intramuscularly （HBIG） may be administered to a non-immune contact after a single unprotected sexual exposure or parenteral exposure/needle-stick injury if the donor is known to be infectious. This works best within 48 hours and is of no use after more than seven days （Ib, A） [62, 99].
▪ An accelerated course of recombinant vaccine should be offered to those given HBIG plus all sexual and household contacts （at 0, 7 and 21 days or 0, 1, 2 months with a booster at 12 months in either course） （Ib, A） [62, 63, 97, 98, 100, 101-105]. Vaccination theoretically will provide some protection from disease when started up to six weeks after exposure.
▪ Avoid sexual contact, especially unprotected penetrative sex, until vaccination has been successful （anti-HBs titres >10iu/l） （Ib, A） [62, 97, 98, 101-105].
▪ The ultra-rapid vaccination schedule （0, 7, 21 days） leads to an anti-HBs antibody response in only 80% of recipients 4-12 weeks after the third dose [101-105]. This rises to 95% just prior to the 12 month booster dose. It would be prudent to offer booster vaccinations of up to three further doses to the 20% of sexual or household contacts without detectable antibodies 4-12 weeks after the primary course （IV, C）, even though most would have eventually developed an antibody response.
Follow-up.
▪ Acute infection: as for hepatitis A. In view of the possibility of chronic infection, serology should be repeated after six months even if the LFT is normal [54, 68, 69].
▪ Chronic infection （HBeAg+ve or HBV-DNA >105iu/ml）: If untreated, patients should be regularly reviewed at intervals of one year or less, ideally by a physician with expertise in this disease （IV, C） [54, 68].
▪ Immunity after recovery from infection （surface antigen negative） is lifelong in over 90%.
Screening and Primary Prevention （see also Sexually Transmitted Infection Screening and Testing Guidelines - Hepatitis A, B and C）
▪ Hepatitis B testing in asymptomatic patients should be considered in men who have sex with men , sex workers （of either sex）, intravenous drug users, HIV-positive patients, sexual assault victims, people from countries where hepatitis B is common （outside of Western Europe, North America and Australasia）, needle-stick victims and sexual partners of positive or high-risk patients （IV, C） [61, 62, 79, 97, 98]. If non-immune, consider vaccination （see below） （Ib, A） [62, 63, 100-105]. If found to be chronic carriers consider referral for therapy （Ia, A） [70-73, 80-90].
▪ The simplest initial screening test in someone who is unvaccinated or is of unknown infection status is anti-HBc, with the addition of other tests as necessary （III, B） [106, 107]. Some also screen for HBsAg initially （IV, C） [79, 128]. Measure anti-HBs in those who have been vaccinated （1b, A） [101-117].
Flow chart for hepatitis B screening using serum anti-HBc ________________________Anti-HBc___________________
↓ ↓
Negative Positive
↓ ↓
No previous exposure to hepatitis B. Test for HBsAg Consider hepatitis B vaccination ____________________↓
（or anti-HBs test if previously ↓ ↓
vaccinated） Positive Negative Acute or Chronic Patient hepatitis B Carrier: naturally test for IgM anti-HBc immune to HBeAg/HBeAb hepatitis B （+/- HBV-DNA）
Flow chart for hepatitis B screening using serum HBsAg _________________________HBsAg____________________
↓ ↓
Negative Positive
↓ ↓
anti-HBc _________________________ Acute or Chronic
↓ ↓ hepatitis B Carrier:
Negative Positive test for IgM anti-
↓ ↓ HBc, HBeAg, HBeAb No previous exposure to Patient naturally （+/-HBV-DNA）
hepatitis B. Do anti-HBs immune to test if previously vaccinated hepatitis B ▪ Vaccination should be offered to non-immune patients in most of the above groups （Ib, A） [62, 63, 100, 101-105]. The main exception is people born in countries of high endemicity but not at continuing risk who are being screened primarily to detect chronic carriage （IV, C） [79].
▪ HIV positive patients show a reduced response rate to the vaccine （approximately 40%） and become anti-HBs negative more quickly, although double dose vaccine increases the response by 13% （IIb, B） [108-111]. Offer a repeat course of three doses of vaccine, which may be double dose, for HIV-positive vaccine non-responders （IIb, B）.
▪ The vaccination schedule for both the monovalent and the combined hepatitis A+B vaccines is outlined in Table 2. The ultra-rapid 0, 7, 21 day regimen offers the
advantage of a potentially higher uptake of the full course. Test for response （anti-HBs >10iu/l, ideally >100iu/l） 4-12 weeks after the last dose （Ib, A） [62, 63, 100, 101-105]. Only 80% of ultra-rapid vaccinees will have detectable anti-HBs antibodies at this stage （see ‘Sexual and other contacts’ above）. If someone is at high risk of acquiring infection, and are in the 20% without an early antibody response, consider further booster doses （IV, C）. They usually respond to further doses （up to three injections）, ideally as a repeat course （Ib, A） with response rates up to 100% （Ib, A） [112, 113]. Alternatively, for those at lower risk, offer a booster at 12 months by which time 95% would be anti-HBs-positive [101-105].
▪ New pre-S-containing vaccines （currently unlicensed） are effective （Ib, A） and may also be used for conventional-vaccine non-responders （IIa, B） [104-118].
Table 2 Vaccination Schedules for Hepatitis B using monovalent vaccine or combined A+B vaccine [62, 63, 100, 101-105].
▪ Hepatitis B testing in asymptomatic patients should be considered in men who have sex with men , sex workers （of either sex）, intravenous drug users, HIV-positive patients, sexual assault victims, people from countries where hepatitis B is common （outside of Western Europe, North America and Australasia）, needle-stick victims and sexual partners of positive or high-risk patients （IV, C） [61, 62, 79, 97, 98]. If non-immune, consider vaccination （see below） （Ib, A） [62, 63, 100-105]. If found to be chronic carriers consider referral for therapy （Ia, A） [70-73, 80-90].
▪ The simplest initial screening test in someone who is unvaccinated or is of unknown infection status is anti-HBc, with the addition of other tests as necessary （III, B） [106, 107]. Some also screen for HBsAg initially （IV, C） [79, 128]. Measure anti-HBs in those who have been vaccinated （1b, A） [101-117].
Flow chart for hepatitis B screening using serum anti-HBc ________________________Anti-HBc___________________
↓ ↓
Negative Positive
↓ ↓
No previous exposure to hepatitis B. Test for HBsAg Consider hepatitis B vaccination ____________________↓
（or anti-HBs test if previously ↓ ↓
vaccinated） Positive Negative Acute or Chronic Patient hepatitis B Carrier: naturally test for IgM anti-HBc immune to HBeAg/HBeAb hepatitis B （+/- HBV-DNA）
Flow chart for hepatitis B screening using serum HBsAg _________________________HBsAg____________________
↓ ↓
Negative Positive
↓ ↓
anti-HBc _________________________ Acute or Chronic
↓ ↓ hepatitis B Carrier:
Negative Positive test for IgM anti-
↓ ↓ HBc, HBeAg, HBeAb No previous exposure to Patient naturally （+/-HBV-DNA）
hepatitis B. Do anti-HBs immune to test if previously vaccinated hepatitis B ▪ Vaccination should be offered to non-immune patients in most of the above groups （Ib, A） [62, 63, 100, 101-105]. The main exception is people born in countries of high endemicity but not at continuing risk who are being screened primarily to detect chronic carriage （IV, C） [79].
▪ HIV positive patients show a reduced response rate to the vaccine （approximately 40%） and become anti-HBs negative more quickly, although double dose vaccine increases the response by 13% （IIb, B） [108-111]. Offer a repeat course of three doses of vaccine, which may be double dose, for HIV-positive vaccine non-responders （IIb, B）.
▪ The vaccination schedule for both the monovalent and the combined hepatitis A+B vaccines is outlined in Table 2. The ultra-rapid 0, 7, 21 day regimen offers the
advantage of a potentially higher uptake of the full course. Test for response （anti-HBs >10iu/l, ideally >100iu/l） 4-12 weeks after the last dose （Ib, A） [62, 63, 100, 101-105]. Only 80% of ultra-rapid vaccinees will have detectable anti-HBs antibodies at this stage （see ‘Sexual and other contacts’ above）. If someone is at high risk of acquiring infection, and are in the 20% without an early antibody response, consider further booster doses （IV, C）. They usually respond to further doses （up to three injections）, ideally as a repeat course （Ib, A） with response rates up to 100% （Ib, A） [112, 113]. Alternatively, for those at lower risk, offer a booster at 12 months by which time 95% would be anti-HBs-positive [101-105].
▪ New pre-S-containing vaccines （currently unlicensed） are effective （Ib, A） and may also be used for conventional-vaccine non-responders （IIa, B） [104-118].
Table 2 Vaccination Schedules for Hepatitis B using monovalent vaccine or combined A+B vaccine [62, 63, 100, 101-105].
|
Vaccination Schedule |
Advantages |
Disadvantages |
|
0, 7, 21 days, 12 months |
- Rapid immunity, - Short duration, - High antibody titres at 12 and 13 months - Potential for better uptake |
- Little information on HIV or other immune-compromised patients - Low antibody titres in the first year （but current evidence suggests that protection is still adequate in the immune-competent） |
|
0, 1, 2, 12 months |
- Shorter time to early immunity than the 0, 1, 6 course - High antibody titres at 12 and 13 months |
- Antibody titres lower than the 0, 1, 6 regimen in the first year |
|
0, 1, 6 months |
- Higher antibody titres at 7 months than the other two regimens although this may not be clinically important - Long established regimen - Most researched in HIV |
- Poor uptake of the 6 month dose in the clinical setting |
▪ Evidence suggests that if vaccine courses are not completed in immunocompetent patients, the outstanding doses can be given four or more years later without the need to restart a three dose course （III, B） [ 123]. One or two doses of vaccine may provide immunity in 40% and over 90% of immunocompetent patients respectively [123, 124].
Hepatitis D （Delta virus infection, HDV）
This is an incomplete RNA virus that requires the hepatitis B virus outer coat. It is only found in patients with hepatitis B. It is largely an infection of intravenous drug users （IVDUs） and their sexual partners but also in female sex workers, and sporadically in other groups [125]. Suspect HDV in hepatitis B particularly if the acute hepatitis is severe, if chronic hepatitis B carriers get a further attack of acute hepatitis or if the liver disease in chronic HBV is rapidly progressive [24, 26, 54, 69]. There is a high rate of fulminant hepatitis and progression of chronic hepatitis to cirrhosis [24, 26, 54]. Diagnosis is confirmed by a positive anti-HDV antibody or HDV-RNA test [34, 69]. Response to anti-viral therapy is poor [126, 127].
