BHIVA Guidelines: coinfection with HIV and Chronic hepatitis B virus
BHIVA Hepatitis B and C Guidelines Subcommitte members: Dr Gary Brook, Dr Janice Main (Co-Chairs), Dr Richard Gilson, Mr Nigel Hughes, Dr Gayle Mathews, Dr Mark Nelson, Dr Caroline Sabin, Dr Ed Wilkins
†I=Meta-analysis or RCT, II=Other good quality trial, III=Observational studies/Case Reports, IV=Expert Opinion.
Dr MG Brook, Department of GU Medicine/HIV, Central Middlesex Hospital, Acton Lane, Park Royal, London NW10 FNS. E-mail: firstname.lastname@example.org
Key recommendations (I–IV levels of evidence)†
Assessment of all HIV+ patients
- 1All HIV-positive patients should have anti-HBc and/or anti-HBs tests within a month of diagnosis (II).
- 2All those negative for hepatitis B markers should be immunised, although response to vaccine may be reduced if the CD4 count is less than 500 cells/μL (I).
- 3Following successful immunisation, anti-HBs levels should be checked yearly and booster doses of vaccine should be given to those with an anti-HBs level < 100 iu/L (IV).
- 4Persons 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).
- 5All patients who are anti-HBc positive but HBsAg negative are at risk of reactivation. Re-check HBsAg (and HBV-DNA if the HBsAg is still not detectable) if the liver function tests (LFT; AST/ALT) become abnormal (II).
- 6All HIV-infected persons should be assessed for HBV status before ARV therapy is commenced and then reassessed periodically according to HBV risk and immune status. Decisions on appropriate antiretroviral therapy combinations can then be made (IV).
Assessment and management of HIV/HBV coinfected patients
- 7All 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 LFT, clotting studies and HBV serology (including HBV-DNA level if HBeAg negative with abnormal LFTs) (IV).
- 8Liver biopsy should be considered, unless contraindicated (e.g. haemophilia), for those with HBV replication (HBeAg positive or HBV-DNA >105 copies/mL) and any of:
• 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 <105 copies/mL and normal ALT, a liver biopsy is not necessary but regular clinical monitoring should be performed (III).
- 9Consider other causes of liver disease if LFT out of proportion to the HBV-disease (IV).
- 10All persons not immune to hepatitis A should receive 2 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/μL (III).
- 11Patients 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).
- 12Carriers should be counselled regarding prevention of transmission of HBV (I).
- 13Sexual and household contacts should be tested for HBV markers and receive HBV immunisation if susceptible (II).
- 14Newborns 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.
- 15Consider HCC screening in patients with established cirrhosis by 6-monthly α-FP and USS (III).
- 16There should be close liaison between the HIV physician and a local hepatology team with links to a transplant centre to ensure optimal care (IV).
Anti-HBV therapy in HIV/HBV coinfection
- 17The 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>105 copies/mL (I).
- 18Interferon or adefovir can be considered for patients not on antiretroviral therapy with a high CD4 count (I) although there is a theoretical risk that adefovir may induce tenofovir resistant-HIV.
- 19Treatments with antiretroviral activity (e.g. lamivudine and tenofovir) must only be given as part of, or in addition to, an effective antiretroviral regime (II).
- 20As both lamivudine and tenofovir are licensed for HIV therapy, and both have anti-HBV activity, there may be utility in using both drugs as part of the same antiretroviral therapy regimen in HIV/HBV coinfected patients although the best use of these agents in this situation remains to be evaluated and such patients are best entered into a clinical trial (III).
- 21If there is a need to change the antiretroviral therapy in coinfected patients on lamivudine and/or tenofovir who have shown an HBV response, these latter agents should be continued in addition to the new regimen irrespective of any resistant HIV (III).
- 22New therapies which normally should be used under clinical trial conditions include entecavir, emtricitabine, clevudine (L-FMAU), l-dT and pegylated interferon.
- 23There is no evidence supporting the use of antiviral therapy in acute HBV infection.
- 1All HIV+patients should be screened for HBV markers.
- 2All HBV nonimmune patients at continuing risk should be vaccinated.
- 3All 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.
- 4All patients should have their HBV status measured before commencement of antiretroviral therapy.
- 5All HBV infected patients should be vaccinated against hepatitis A if nonimmune.
- 6All 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.
- 7Case-notes should contain clear evidence of an attempt to contact household and sexual contacts and offer vaccination to those who are nonimmune.
- 8All 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 over 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 . There are no comprehensive data from the UK defining HIV/HBV coinfection rates.
- •A study in 631 HIV-positive people in London, most of whom were gay men, showed a dual HIV/HBV infection rate of 6% .
- •In many parts of Africa, HIV/HBV coinfection is common, as seen in Malawi (13%) or the Ivory Coast (10%) [5,6]. Recent immigrants from Africa represent the largest group of newly diagnosed HIV-positive people in the UK  and therefore high coinfection rates are to be expected. A recent survey of 165 consecutive HIV-positive patients of African origin showed a HBV carriage rate of 5.5% (M.G. Brook, 2002, unpublished data).
- •Very high rates of hepatitis B infection are seen in intravenous drug users and therefore HIV/HBV is common – one study in Germany found 8% of an HIV clinic cohort, over half of whom were IVDUs, were chronically infected with HBV .
- •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 [9,10]. 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 [9,10] and there is some evidence for an increased rate of progression to cirrhosis .
- •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 [11,12].
- •The natural history of HIV infection does not seem to be influenced by hepatitis B [3,9] although there is an increased rate of antiretroviral-related hepatoxicity and possibly a poorer immunological outcome [13,14].
- •HBV reactivation and reinfection 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 [15,16]. The risk of reactivation is higher in patients who are positive for anti-HBc antibody but negative for other markers of HBV infection. 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 .
- •There is also a reduction in the rate of natural clearance of HBeAg by about 60% in coinfected patients compared to HIV negative patients [9,18]. However, there are reports of patients clearing chronic HBV infection with recovery of CD4 count responses following antiretroviral therapy .
- •Hepatitis B is preventable by vaccination. However, HIV positive patients respond less well to the vaccine, especially if the CD4 count is below 500 cells/mL, and lose protective antibodies quickly .
- •All newly diagnosed HIV patients should have an anti-HBc test and additionally an anti-HBs test if they have previously been immunised. 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-HBs antibodies, ideally greater than 100 iu/L.
- •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 . Subsequently, anti-HBs levels should be checked yearly and booster doses given if the anti-HBs level falls below 100 iu/L .
- •Persons who fail to seroconvert to HBV vaccine  should have annual HBV markers performed (HBsAg and anti-HBc).
Delta Hepatitis (hepatitis D virus)
- •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 .
Assessment and investigations
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 .
- •History – should include enquiring about injection drug use (current and remote), past immunisation for hepatitis A/B, episodes of jaundice, travel abroad and potential risk activity there (blood transfusion, intravenous drug use, sexual), alcohol use (current and past), family history of HBV infection, liver disease or hepato- cellular carcinoma, 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), modes and prevention of transmission, and treatment options. The development of ESLD in HBV infection occurs at younger age in heavy drinkers .
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. HBV-DNA is useful in anti-HBe-positive patients with abnormal LFTs;
- •exclusion of other viral liver disease – anti-HCVAb and anti-HDV Ab if 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 (>105 copies/mL)] and likely ESLD, HDV or HCV (PCR-positive) coinfection, or with deranged LFTs of uncertain aetiology. For patients with HBV-DNA levels <105 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 there has been an episode of heamatemesis;
- •3TC resistance – may be useful for patients with 3TC exposure and detectable HBV-DNA but is not widely available and its utility remains to be determined;
- •HBV genotyping – the significance of genotype with regard to risk of progressive liver disease, development of HCC, and response to treatment is being explored. Currently, there is no indication to perform an HBV genotype;
- •autoimmune screen, sopper/caeruloplasmin and iron/ferritin if other features consistent with autoimmune hepatitis, Wilson's Disease or haemachromatosis (plus HFE gene test if subsequently indicated).
- •All persons should have regular full biochemical profile including bilirubin, albumin and liver enzymes; and full blood count performed a minimum of every 6 months. Repeat prothrombin time if clinical or biochemical evidence of progression.
- •Patients who have an unexpected rise in ALT should be re-screened for HBV replication (HBeAg and HBV-DNA) and other causes of hepatitis [HAV, HCV, (HDV if at risk)].
- •Consider screening patients with cirrhosis for HCC with 6-monthly ultrasounds and α–FP. Physicians and patients need to be aware, however, that even with more frequent screening the chance of detecting a treatable HCC is small [26,27].
- •Abnormal LFTs indicate liver inflammation and/or dysfunction. In coinfected patients, they may result from several causes:
♦ reactivation of HBV related to worsening immune function;
♦ improved immune response directed against HBV as a result of HAART;
♦ hepatitis flare on withdrawal of 3TC as part of HAART associated with WT virus repopulation;
♦ hepatotoxicity as a result of ARV agents or other drugs. Coinfected patients have more ARV-related liver toxicity;
♦ inflammation as a result of other hepatotropic virus infections (HCV, HDV, HAV).
- •HBV-DNA is a reliable marker of active HBV replication.
♦ Detection and quantification can be achieved by signal amplification or target amplification methods. Units of measurement have now been defined. Minor variations (up to half a Log) exist between assays and as a result of the intrinsic variability of the test and can be ignored. It is advisable the same assay is used for patient monitoring. Sensitivity of assays is down to 200–400 copies/mL. Nested PCRs can increase sensitivity but there can be difficulties in accurate quantification [28,29].
♦ The HBV-DNA cut-off level in HIV-negative HBV-infected patients that is associated with progressive liver disease is unknown although a threshold of 105 copies/mL has been generally accepted. However, most patients with inactive liver disease (HBeAg negative, anti-HBeAb positive and normal ALT) have levels of 103–104 copies/mL and a lower cut-off of 3×104 has been proposed. In coinfected patients, however, HBV-DNA levels are higher and may change with immune function [30,31].
- •Histological examination of the liver remains the most sensitive tool for assessing the severity of liver disease and thereby establishing prognosis and the need or urgency for treatment. It also excludes other aetiologies of liver disease in a patient with HBV infection.
♦ Several numerical scoring systems exist (Ishak, METAVIR, Knodell) which grade the degree of necroinflammatory activity and stage/extent of fibrosis. Concordance between the different scoring systems is good [32–35].
♦ On the basis of histology (scored by Ishak), the liver damage can be categorised as mild when the necroinflammatory score is ≤3/18 and the fibrosis stage is ≤2/6. In these circumstances, treatment may not be indicated. Higher scores may indicate the need for treatment (see later).
- •Lamivudine resistance mutations can be identified by either direct sequencing or line probe assay although this is only a research tool at the moment .
♦ HIV/HBV coinfected patients treated with 3TC accumulate resistance mutations at 20–25% per year. This is conferred by a mutation in the YMDD motif in the HBV DNA polymerase gene [37,38].
♦ At present, laboratory testing for lamivudine resistance is unlikely to influence patient management. Any patient who has detectable (or rising after an initial fall) HBV-DNA levels can be assumed to have lamivudine resistance. The place of resistance testing is likely to become more important as newer agents are developed and therapeutic options increase.
- •There should be close liaison with the local hepatology team (gastroenterologist specialising in hepatology or hepatologist), virologist, and established contacts with the regional transplant centre. It is expected that in the developing HIV service networks, protocols detailing clear referral pathways will be developed so that all patients with HIV/HBV coinfection with have equity of access to specialist care by a team of doctors and Nurse Specialists, irrespective of their main site of HIV care.
Hepatitis A Vaccination
- •All persons not immune to hepatitis A should receive 2 doses of hepatitis A vaccine 6–12 months apart .
- •Carriers should be counselled regarding prevention of transmission of HBV in terms of safer sex, avoidance of transmission through blood, partner vaccination and neonatal vaccination as appropriate . Contacts of patients with chronic HBV at risk of infection, which includes sexual partners, household contacts and people at risk from parenteral exposure should be offered testing for HBV and vaccination if nonimmune.
General principles of hepatitis B therapy
Treatment is aimed at suppressing viral replication and improving liver histology. If treatment is associated with HBeAg to anti-HBe seroconversion there may be a durable treatment effect and HBV treatment may be withdrawn. This occurs in up 10–40% of HIV-negative patients, depending on the agent used and the type of patient treated, but is lower in HIV-positive patients. Once initiated, long-term suppressive treatment will be required in most patients. The approach to treatment depends on the following factors:
- •markers of HBV replication – candidates for treatment are usually HBeAg-positive (see below);
- •the activity and stage of liver disease – patients with normal, or near normal LFTs are less likely ever to develop clinically significant liver disease, and are less likely to respond to treatment;
- •stage of HIV disease – for those with advanced HIV disease, treatment of chronic hepatitis may not be a priority, and a sustained response is very unlikely to be achievable, but viral suppression, and improvement in liver function is achievable even in late stage disease;
- •HIV treatment status – whether someone is on antiretroviral treatment affects the choice of HBV treatments available (see below).
Who to treat
- •Patients with normal or near-normal LFTs (ALT/AST < 1.5 times the upper limit of normal) and who are HBeAg-negative are unlikely to have active liver disease or viral replication and should be treated conservatively. Regular monitoring should be continued to detect reactivation of viral replication (usually accompanied by reappearance of HBeAg) or of liver disease (rise in transaminase levels).
- •Patients who are HBeAg-positive have higher levels of viral replication and are at greater risk of progressive liver disease and are more infectious. They are the principal candidates for treatment. Higher LFTs or more active inflammation on liver biopsy increase the probability of a treatment response.
- •Treatment should be considered for HBeAg-negative patients with abnormal LFTs and in whom other possible causes of the abnormal LFTs have been excluded. These patients are likely to be infected with a precore mutant virus that prevents the translation of HBeAg but is still replication competent. Plasma viral load provides a measure of viral replication; levels are lower than in HBeAg-positive patients. In some patients it may be appropriate to treat in order to reduce infectivity.
When to start treatment
- •The treatment options for chronic HBV infection are limited, but improving. HBV treatments can be categorised according to whether or not they have anti-HIV activity as well. If they have anti-HIV activity they must be used in conjunction with an effective antiretroviral regimen in order to prevent the emergence of HIV drug resistance. Drugs with HBV activity may either form part of an antiretroviral regimen, or be in addition. When patients have to change anti-HIV treatments, because of intolerance or lack of efficacy, the anti-HBV component should be continued, even if it is not part of the subsequent anti-HIV regimen.
- •The optimal time to initiate anti-HBV treatment in HIV coinfected patients is not known. Response rates may be higher with treatment given earlier, when the CD4 count is well preserved, but the options are limited and long-term antiviral treatment is likely to be needed. There is insufficient evidence to conclude that anti-HBV therapy should always be included when antiretroviral therapy is initiated. If it is not, then HBV treatment should be delayed until HIV replication is controlled and the maximum CD4 count response obtained, or until there is evidence of liver disease progression.
Current treatment options
- •Interferon-α (IFN-α) can be used in patients with coinfection, whether or not they are on antiretroviral therapy; it has some anti-HIV effect but this is not clinically significant.
♦ Side effects (most commonly ‘flu-like symptoms, malaise, weight loss) are common, and the response rate for HBeAg to anti-HBe seroconversion is low. Interferon may lower CD4 counts. Few physicians therefore use IFN-α in this setting.
♦ In HIV-negative patients the HBeAg to anti-HBe seroconversion rate is 5–10%, but up to 40% in those with raised transaminase levels and low HBV-DNA levels. The data in HIV-positive patients is limited, with conflicting evidence suggesting either a lower response rate [41,42], or a similar response compared to HIV-negative patients .
♦ Treatment is not recommended in patients with cirrhosis or a history of decompensated liver disease because of the risk of further decompensation (excluding advanced liver disease is the strongest indication for liver biopsy in this setting).
- •Lamivudine is licensed for the treatment of chronic hepatitis B in patients who are HBeAg-positive with evidence of active liver disease. The effective dose for hepatitis B treatment is 100 mg daily, a dose at which it also has anti-HIV activity and should not be used except in combination with effective combination antiretroviral therapy.
♦ In both HIV-negative and coinfected patients, lamivudine treatment is associated with viral suppression and improvement in liver function tests [44–46], however, mutations in the polymerase YMDD motif, analogous to that in HIV, results in antiviral resistance in up 69% after 5 years' treatment . This develops more rapidly in coinfected patients with up to half of all patients showing resistance after 2 years [45,48,49]. With relapse of viral replication, liver disease activity increases [49,50].
♦ Withdrawal of lamivudine may result in an acute exacerbation of hepatitis that may be sufficient to precipitate liver decompensation [50,51]. Use of lamivudine in coinfected patients may therefore more appropriately be reserved for those patients with evidence of progressive liver disease.
♦ The value of treating anti-HBe-positive carriers with normal liver function and low or undetectable viral load pre-emptively, to prevent reactivation, has not been established.
♦ In HIV-negative patients who are anti-HBe/HBV-DNA-positive, lamivudine suppresses viral replication and improves LFTs, but this effect is not durable .
- •Adefovir, a nucleotide analogue, has recently been licensed in the US and Europe. At a dose of 10 mg once daily, adefovir has been shown to suppress HBV replication and improve histology both in chronic HBV carriers who are HBeAg-positive, and anti-HBe-positive [53,54].
♦ Adefovir has no significant antiretroviral effect at this dose (although it does at higher dose) and therefore could be given to HIV coinfected patients not on antiretroviral therapy . However, there remains a theoretical danger of inducing HIV resistance which needs further research.
♦ Adefovir could also be used in HIV coinfected patients receiving antiretroviral therapy if tenofovir is not being used (there is no rationale for combining them). There are very limited clinical trial data in HIV coinfected patients , although they were included in the first clinical trial in HBV carriers  in whom viral suppression was similar in both HIV-positive and HIV-negative patients.
♦ Adefovir is active against lamivudine-resistant strains of HBV [58,59]. In HIV-negative patients it has been shown that treatment can be switched from lamivudine to adefovir in lamivudine-resistant cases; there is no benefit in continuing the lamivudine as well .
♦ Whether there is any advantage of combining adefovir with lamivudine is unknown for either HIV-coinfected or HIV-negative patients.
- •Tenofovir is a nucleotide analogue similar to adefovir. Although there are no randomised trials in chronic hepatitis B, there is evidence that it suppresses HBV replication .
♦ Recent open-label studies of 6 and 20 tenofovir-treated coinfected patients, most of whom were lamivudine-experienced, showed a reduction in HBV-DNA viral load (of 4 log10), fall in ALT levels and loss of HBeAg (25%) [62,63].
♦ However, there is still insufficient evidence to confirm its long-term utility in coinfected patients. As with lamivudine, tenofovir should be continued if the patient has shown an HBV response (reduction in AST/ALT and HBV-DNA levels) even if there is a need to change the other components of antiretroviral regimen.
♦ Lamivudine/tenofovir can be used in combination for coinfected patients as part of, or in addition to an effective antiretroviral regimen but there is insufficient evidence to say whether this confers any advantage. Patients should be encouraged to join clinical trials.
Other treatment options
- •Other nucleoside reverse transcriptase inhibitors are currently in clinical trials including entecavir, emtricitabine, clevudine (L-FMAU) and l-dT, which is the beta-L configuration of the natural nucleoside, thymidine .
- •Entecavir (FTC) and emtricitabine have both anti-HIV and anti-HBV activity [65,66]. Phase III trials in chronic hepatitis B are in progress. In vitro studies suggest that there will be cross-resistance between lamivudine and emtricitabine , but not entecavir, a guanosine analogue .
- •A trial of pegylated interferon will investigate whether it is associated with an improved response rate compared with conventional interferon, as has been demonstrated in chronic hepatitis C. How this agent may be used in HIV coinfection remains to be determined although it seems likely that it will replace conventional interferon.
- •Famciclovir has anti-HBV activity but only at high doses and is not recommended treatment outside clinical trials. Adding famciclovir in patients with lamivudine resistant infection is of no value .
- •Other experimental therapies have included ribavirin and thymosin alpha but there is no place for these therapies outside of clinical trials.
Acute hepatitis B
Even in HIV-positive patients, most cases of acute hepatitis B resolve spontaneously and without complications. No specific therapy has been shown to improve the outcome or reduce the risk of developing chronic infection. Treatment is supportive. Antiretroviral treatment may have to be interrupted if there is marked LFT elevation.