BHIVA guidelines on HIV and chronic hepatitis: coinfection with HIV and hepatitis B virus infection (2005)

Levels of evidence: I=Meta-analysis or RCT II=Other good-quality trial III=Observational studies/case reports IV=Expert opinion All HIV-positive patients should have serum markers for hepatitis B checked (HBsAg, anti-HBc and/or anti-HBs) tests within a month of diagnosis [II]. All those negative for hepatitis B markers should be immunized and anti-HBs checked at 12 weeks. Patients failing to respond to a conventional course of 20 μg vaccine should received booster doses and/or a repeat vaccination cycle with the 40 μg dose. Response to vaccine may be reduced if the CD4 count is less than 500 cells/mm3 [I]. Those patients with a CD4 count<200 cells/mm3 not on ART should receive combination therapy first and with immune recovery, subsequent immunization. Following successful immunization, anti-HB levels should be checked yearly and booster doses of vaccine should be given to those with an anti-HB level<100 iμ/L [IV]. Persons who fail to seroconvert to HBV vaccine and are at continuing risk of HBV infection should have annual HBV markers performed (HBsAg and anti-HBc) [IV]. All patients who are anti-HBc positive but HBsAg negative are at risk of HBV reactivation. HBV markers including HBV-DNA should be rechecked annually or if the liver function tests (AST/ALT) become abnormal [II]. All HIV-infected persons should have serum markers for HBV checked before antiretroviral (ARV) therapy is commenced and then reassessed at least once a year. Decisions on appropriate ART combinations can then be made [IV]. All HIV/HBV coinfected patients should have an assessment of disease status and risk of progression which includes a clinical history, examination and blood tests including liver function test (LFT), clotting studies, full HBV profile (including HBV-DNA) and HCV status [IV]. Liver biopsy should be considered, unless contraindicated (e.g. haemophilia), for all those with HBV replication (HBeAg positive or HBV-DNA≥104 copies/mL) especially if: history or signs suggestive of cirrhosis or a history of decompensated liver disease, HDV or HCV (PCR-positive) coinfection, deranged LFTs of uncertain aetiology. For patients with HBV-DNA levels<104 copies/mL and normal ALT, a liver biopsy is not necessary but regular clinical monitoring should be performed [III]. Consider other causes of liver disease if LFT is out of proportion to the HBV disease [IV]. All persons without serum anti-HAV IgG should receive two doses of hepatitis A vaccine 6–12 months apart, although the response to vaccine may be reduced if the CD4 count is less than 500 cells/mm3 [III]. Patients should be counselled about the dangers of alcohol consumption. Abstinence or only limited use of alcohol is recommended for those with abnormal liver function tests [III]. Carriers should be counselled regarding prevention of transmission of HBV and acquisition of HCV/HDV [I]. Sexual and household contacts should be tested for HBV markers and receive HBV immunization if susceptible [II]. Newborns of coinfected mothers should receive HBIG and HBV vaccine at delivery, in addition to postnatal HIV prophylaxis, and complete the recommended vaccination programme [I]. This requires optimal liaison between hospital and community staff. Screening for hepatocellular carcinoma (HCC) should occur in patients with established cirrhosis by 6-monthly α-FP and USS scans [III]. There should be close liaison between the HIV physician and a local hepatology team with links to a transplant centre to ensure optimal care [IV]. The optimal time for initiating anti-HBV therapy in coinfected patients has not been established, but HBV-specific treatment should be considered for all patients who are HBeAg positive, or are HBeAg negative but with an abnormal LFT (ALT>1.5 × upper limit of normal) and HBV-DNA≥104 copies/mL [I]. Interferon is the preferred option for HbeAg-positive patients and adefovir in HbeAg-negative patients with an HBV-DNA≥104 copies/mL not on antiretroviral therapy with a high CD4 count [I]. Early results suggest that adefovir does not select resistance in HIV and therefore compromise future use of tenofovir. Pegylated interferon is likely to prove to be more effective than interferon in the future. Treatments with antiretroviral activity must only be given as part of, or in addition to, an effective antiretroviral regime [II]. Tenofovir can be given as the sole anti-HBV agent [II]. 3TC/FTC should not be used without also giving tenofovir because of the likelihood of the development of resistance in HBV [III]. In HbsAg-positive patients who have HBV-DNA levels<104 copies/mL, and who need antiretroviral therapy, inclusion of tenofovir and 3TC/FTC in the ART regimen may be considered in order to prevent HBV relapse but there is no evidence for the value of such therapy [IV]. If there is a need to change the ART in coinfected patients on FTC/lamivudine and/or tenofovir who have shown an HBV response, these agents should be continued in addition to the new regimen irrespective of any resistant HIV with the exception of a switch from 3TC/FTC to tenofovir [III]. New therapies can be considered, which normally should only be used under clinical trial conditions, including entecavir, clevudine (L-FMAU), LdT and pegylated interferon [IV]. There is no evidence supporting the use of antiviral therapy in acute HBV infection [III]. All HIV+patients should be screened for HBV markers. All HBV nonimmune patients at continuing risk should be vaccinated. All patients with abnormal ALT/AST levels who are anti-HBc-positive should have a serum HBV-DNA level measured irrespective of the HBsAg/HBeAg status. All patients should have their HBV status measured before commencement of antiretroviral therapy. All HBV-infected patients should be vaccinated against hepatitis A if non-immune. All HBV-infected patients should have documented evidence in their case notes of a discussion on alcohol avoidance and how to reduce the risks of transmission. Case notes should contain clear evidence of an attempt to contact household and sexual contacts and offer vaccination to those who are non-immune. All patients who are HBsAg-positive with abnormal LFTs should have a clear management plan written in their notes. There are approximately 350 million hepatitis B carriers and almost 40 million HIV-infected people worldwide [1,2]. As the routes of transmission for these infections are similar, there is a significant rate of coinfection in patients. Underlying HIV infection increases the chance of HBV chronicity [3]. There are no comprehensive data from the UK defining HIV/HBV coinfection rates. However, data from the Eurosida study [4] showed a 9% prevalence of HBsAg coinfection in participating centres. A study in 631 HIV-positive people, most of whom were gay men, in London showed a dual HIV/HBV infection rate of 6% [5]. In many parts of Africa, HIV/HBV coinfection is common, as seen in Malawi (13%) or the Ivory Coast (10%) [6,7]. Recent immigrants from Africa represent the largest group of newly diagnosed HIV-positive people in the UK [8] and therefore high coinfection rates are to be expected. A survey of 165 consecutive HIV-positive patients of African origin showed a HBV carriage rate of 5.5% (MG Brook, 2002, unpublished data). Very high rates of hepatitis B infection are seen in intravenous drug users (IVDUs) and therefore HIV/HBV is common; one study in Germany found that 8% of an HIV clinic cohort, over half of whom were IVDUs, were chronically infected with HBV [9]. Hepatitis B virus is immunopathic (the immune response to the virus causes most of the liver damage) and, therefore, in HIV infection there is often a decrease in the serum aminotransferase values and a decrease in the histological inflammatory indices [10,11]. However, at very high levels of viral replication the virus may have a direct cytopathic effect. Coinfection with HIV is generally accompanied by an increase in HBV replication [10,11] and there is evidence for an increased rate of progression to cirrhosis and death [4,11]. Since the introduction of combination antiretroviral therapy and the dramatic improvement in the prognosis of people with HIV, liver disease due to chronic viral hepatitis has become an important cause of morbidity and mortality in coinfected patients [4,12,13]. The natural history of HIV infection does not seem to be influenced by hepatitis B [3,4,10], although there is an increased rate of antiretroviral-related hepatoxicity and possibly a poorer immunological outcome [14,15]. HBV re-activation and re-infection can also occur, and patients who appeared to have cleared HBV infection can present with a further episode of acute or, more commonly, be found to have abnormal liver function tests and chronic hepatitis [16,17]. The risk of reactivation is higher in patients who are positive for anti-HBc antibody but negative for other markers of HBV infection (including HBV-DNA). In one long-term follow-up study of anti-HBc-antibody-positive, HIV-positive patients, transient HBsAg-positivity developed in 24%, HBV-DNA became positive in 60% and about a third of these had active liver disease [18]. There is also a reduction in the rate of natural clearance of HBeAg by about 60% in coinfected patients compared to HIV-negative patients [10,19]. However, there are reports of patients clearing chronic HBV infection with recovery of CD4 count responses following antiretroviral therapy [20]. Hepatitis B is preventable by vaccination. However, HIV-positive patients respond less well to the vaccine, and the response rate varies with the CD4 count with best response (approximately 80%) at >500 cells/mL and worse response (approximately 25%) with counts <200 cells/mL [21]. Protective antibodies are lost more quickly [22]. All newly diagnosed HIV patients should have an anti-HBc test and additionally an anti-HB test if they have previously been immunized. If negative for both, they should receive a course of vaccination and subsequent boosters up to a further three doses until they have detectable serum anti-HB antibodies, ideally greater than 100 iu/L [22]. It is not known if the ultra-rapid (0, 1, 3 week, 12 month) schedule is effective in HIV-positive patients but the 0,1,2,12 month schedule is effective [22]. Double-dose vaccine may improve response rates. Subsequently, anti-HB levels should be checked yearly and booster doses given if the anti-HB level falls below 100 iu/L [23]. Persons who fail to seroconvert to HBV vaccine [24] should have repeat vaccination courses once the CD4 count rises to >500 cells/mL or after significant immune recovery, and whilst non-immune should have annual HBV markers performed (HBsAg and anti-HBc). This virus can only replicate in the presence of HBV as it requires the HBV surface protein for its own structure. HDV is seen mainly in IVDUs and their sexual partners in the UK although it can be found in other HBV-positive patients. It is not clear if HIV coinfection influences the course of HBV/HDV disease but there is some evidence that it leads to a more rapidly progressive form of hepatitis and fulminant liver failure [25]. HBV-related liver disease is mostly confined to patients with evidence of ongoing viral replication, usually with HBeAg-positivity and high HBV-DNA levels detectable by PCR or a comparable nucleic acid amplification test. The initial evaluation should include history and clinical examination [26]. History should include enquiring about injection drug use (current and remote), past immunization for hepatitis A/B, episodes of jaundice, travel abroad and potential risk activity there (blood transfusion, IDU, sexual), alcohol use (current and past), family history of HBV infection, liver disease or HCC, and previous investigation for hepatitis. Clinical examination for evidence of chronic liver disease (peripheral stigmata, portal hypertension, decompensation). Patients should be counselled about the significance of coinfection, lifestyle modifications that may be necessary (alcohol, injection drug use and safer sex), modes and prevention of transmission, and treatment options. The development of ESLD in HBV infection occurs at a younger age in heavy drinkers [27]. Initial work-up for an HBsAg-positive individual should include tests for: liver disease–full biochemical profile including bilirubin, albumin and liver enzymes; prothrombin time and full blood count; HBV replication–HBeAg, anti-HBe and HBV-DNA; exclusion of other viral liver disease–anti-HCVAb and anti-HDV Ab if at particular risk; HAV immunity–anti-HAV IgG Ab. Additional tests may be indicated depending on these results: Liver biopsy: consider for those with HBV replication (HBeAg positive or HBV-DNA positive [≥104 copies/mL]) and likely ESLD, HDV or HCV (PCR-positive) coinfection, or with deranged LFTs of uncertain aetiology. For patients with HBV-DNA levels<104 and normal ALT, a liver biopsy is not necessary but regular monitoring should be performed. AFP and USS (USS on all HBeAg-positive patients and all anti-HBe-positive who have abnormal liver function tests), especially for patients with suspected advanced liver disease. An OGD to exclude varices is indicated if portal hypertension is suggested on USS or cirrhosis on liver biopsy or if there has been an episode of haematemesis. Autoimmune screen, copper/caeruloplasmin and iron/ferritin if other features consistent with autoimmune hepatitis, Wilson's Disease or haemachromatosis (plus HFE gene test if subsequently indicated). Lamivudine (3TC): resistance may be useful for patients with and detectable HBV-DNA but is not and its to be HBV the significance of with to risk of progressive liver disease, development of HCC, and response to treatment is there is no to an HBV All persons should have a regular full biochemical profile including bilirubin, albumin and liver and full blood count performed a of prothrombin time if clinical or biochemical evidence of Patients who have an in should be for HBV replication (HBeAg and HBV-DNA) and other causes of hepatitis HDV if at All patients with cirrhosis should be screened for with and and patients need to be that with more the chance of a is LFTs liver and/or In coinfected patients, they may from of HBV to immune immune response against HBV as a of Hepatitis on of or tenofovir as part of with virus as a of agents or other patients have more liver as a of other virus infections or HBV of 3TC/FTC resistance after initial HBeAg or HBsAg HBV-DNA is a of active HBV and can be by amplification or amplification of have been to half a between and as a of the of the test and can be It is that the is used for of is to can increase but there can be in The HBV-DNA level in HIV-negative HBV-infected patients that is with progressive liver disease is although a of copies/mL is generally patients with liver disease and normal have levels below In coinfected patients, HBV-DNA levels are higher and may change with immune function examination of the liver the most for the of liver disease and prognosis and the need or for It also other of liver disease in a with HBV that the of activity and of between the is the of by the liver can be as the and the In these treatment may not be may the need for treatment resistance can be by direct or although is only a at the HIV/HBV coinfected patients with resistance at year. This is by a in the in the HBV gene for resistance is to who has detectable after an initial HBV-DNA levels 3TC/FTC can be to have The of resistance is likely to become more important as agents are developed and There should be close liaison with the local hepatology team in hepatology or and established contacts with the transplant It is that in the HIV clear be developed that all patients with HIV/HBV coinfection with have of to care by a team of and irrespective of their of HIV All persons not immune to hepatitis A should receive two doses of hepatitis A vaccine 6–12 months However, response is approximately at cells/mL and to 8% at CD4 cells/mL vaccination should be once the CD4 has or 500 on Carriers should be counselled regarding prevention of transmission of HBV in of safer avoidance of transmission vaccination and vaccination as appropriate of patients with chronic HBV at risk of infection, which includes sexual household contacts and people at risk from should be for HBV and vaccination if non-immune. is at viral replication and liver If treatment is with HBeAg to anti-HBe there may be a treatment and HBV treatment may be This occurs in of HIV-negative patients, depending on the agent used and the of but is in HIV-positive patients. long-term treatment be in most patients. The to treatment on the following of HBV replication for treatment are usually HBeAg-positive The activity and of liver with normal or liver function tests are less likely to significant liver disease, and are less likely to respond to of HIV disease for those with advanced HIV disease, treatment of chronic hepatitis may not be a and a response is very to be but viral and improvement in liver function is in disease. HIV treatment status is on antiretroviral treatment the of HBV Patients with normal or liver function tests the upper limit of normal) and who are with an copies/mL are to have active liver disease or viral replication and should be monitoring should be continued to reactivation of viral replication accompanied by of or of liver disease in A liver biopsy may be to that the liver disease is not as of cirrhosis in with normal LFTs has been Patients who are HBeAg-positive have higher levels of viral replication and are at greater risk of progressive liver disease and are more are the for LFTs or more active on liver biopsy increase the of a treatment should be considered for patients with abnormal liver function tests and in whom other causes of the abnormal LFTs have been patients are likely to be infected with a virus that the of HBeAg but is replication viral a of viral replication but levels are than in HBeAg-positive patients. Recent evidence that in patients, HBV-DNA levels copies/mL copies/mL if they have decompensated should be the for therapy In some patients it may also be appropriate to in order to reduce at any HBV-DNA The treatment for chronic HBV infection are but HBV can be to or not they have activity as If they have they must be used in with an effective antiretroviral regimen in order to prevent the of with HBV activity may form part of an antiretroviral or be in patients have to change because of or of the anti-HBV should be continued from 3TC/FTC to if it is not part of the subsequent The optimal time to anti-HBV treatment in HIV coinfected patients is not Response rates may be higher with treatment given the CD4 count is well but the are limited and long-term antiviral treatment is likely to be for HIV-positive patients with HBV infection and high CD4 count not HIV therapy. can be used in patients with coinfection, or not they are on antiretroviral it has some but is not are common, and the response rate for HBeAg to anti-HBe is interferon may CD4 use in In HIV-negative patients the HBeAg to anti-HBe rate is but up to in those with levels and HBV-DNA The data in HIV-positive patients are with most evidence a response rate is not recommended in patients with cirrhosis or a history of decompensated liver disease because of the risk of further advanced liver disease is the for liver biopsy in Recent evidence that pegylated interferon may prove to be more effective is for the treatment of chronic hepatitis B in patients who are HBeAg-positive with evidence of active liver disease. The effective for hepatitis B treatment is 100 a at which it also has activity but to select and should not be used in combination with effective combination antiretroviral therapy and then at a higher of or In HIV-negative and coinfected patients, treatment is with viral and improvement in liver function tests However, in the to that in HIV, results in antiviral resistance in up to after of treatment This more rapidly in coinfected patients with up to half of all patients resistance after relapse of viral replication, liver disease activity increases of may in an acute of hepatitis that may be to liver of in coinfected patients therefore, more be for those patients with evidence of progressive liver disease. The value of anti-HBe-positive carriers with normal liver function and or viral to prevent has not been In HIV-negative patients who are viral replication and but is not a is in the and a of once adefovir has been shown to HBV replication and improve in chronic HBV carriers who are HBeAg-positive and anti-HBe-positive has no significant antiretroviral at it does at higher and therefore be given to patients not on antiretroviral therapy there is a of HIV a study of coinfected patients for showed LFT in and no of HIV or HBV although all patients were ART with an viral also be used in patients antiretroviral therapy if tenofovir is not used is no for There is very limited clinical trial data in patients although they were in the first clinical trial in HBV carriers in whom viral in HIV-positive and HIV-negative patients. is active against of HBV In HIV-negative patients it has been shown that treatment can be from to adefovir in there is no in continuing the as well there is any of adefovir with is for or HIV-negative patients. Tenofovir is a to there are no in chronic hepatitis there is evidence that it HBV replication of and 20 coinfected patients, most of whom were showed a reduction in HBV-DNA viral in levels and of HBeAg of 40 coinfected patients on 60% of whom had showed with HBV-DNA at and had lost HBeAg can be used in combination for coinfected patients as part of, or in addition to an effective antiretroviral of the trial showed that patients had dual infection, of whom had received and received tenofovir and the patients tenofovir and had a greater in HBV-DNA compared to all patients on developed resistant which only in one of the on dual therapy. study also showed HBV-DNA in coinfected patients on at Patients should be to clinical Early significant and anti-HBV activity in HIV-negative patients. In evidence suggest that there be between and and, therefore, these agents should not be used should not be in the of HBV therapies are in clinical including entecavir, clevudine and which is the of the natural has anti-HBV activity in chronic hepatitis B are in In suggest that there be no with In HIV-negative patients, pegylated interferon is with an response rate compared with conventional as has been in chronic hepatitis agent may be used in HIV coinfection to be although it likely that it conventional interferon has anti-HBV activity but only at high doses and is not recommended treatment clinical in patients with infection is of no value therapies have and but there is no for these therapies of clinical In patients with a high CD4 count not HIV therapy, but HBV therapy, HBV therapy should be with agents that have no activity at the doses Interferon for months is in HBeAg-positive patients and an abnormal LFT or long-term adefovir in any Pegylated interferon may interferon in the future. In patients HIV therapy who are therapy normally include tenofovir or a combination of tenofovir with or as part of, or in addition to, their antiretroviral in HIV-positive patients, most of acute hepatitis B and without therapy has been shown to improve the outcome or reduce the risk of chronic is treatment may have to be if there is LFT on of the HIV Brook,