SEARCH

SEARCH BY CITATION

Keywords:

  • HIV;
  • hepatitis B;
  • hepatitis C;
  • guidelines;
  • treatment

Table of Contents

Level of evidence

Audit standards

1.0 Introduction

2.0 Methodology

3.0 General section: Prevention of viral hepatitis and management principles for patients with viral hepatitis

 3.1 Screening of HIV-positive patients for hepatitis B and hepatitis C

  3.1.1 Recommendations

   3.1.1.1 Screening for hepatitis in new HIV-positive patients

   3.1.1.2 Ongoing hepatitis testing in known HIV-positive patients

 3.2 Prevention and immunization

  3.2.1 Condoms and safer sex

  3.2.2 Harm reduction in injecting drug users

  3.2.3 Recommendations for prevention

  3.2.4 Immunization

  3.2.5 Recommendations for immunization

 3.3 General management/care pathways

  3.3.1 Assessment of liver disease

  3.3.2 Investigations for liver disease

  3.3.3 Role of liver biopsy, hepatic elastography and other noninvasive markers of liver fibrosis

  3.3.4 Recommendations

 3.4 Antiretroviral therapy and hepatotoxicity

  3.4.1 Recommendations

 3.5 End-stage liver disease and its complications

  3.5.1 Recommendations

 3.6 The role of clinical networks

4.0 Coinfection with HIV and hepatitis B virus

 4.1 Background

  4.1.1 Prevalence

  4.1.2 Natural history

   4.1.2.1 The influence of HBV on HIV infection

   4.1.2.2 The influence of HIV on HBV infection

   4.1.2.3 Chronic hepatitis B: classification

 4.2 Assessment and investigations

  4.2.1 Diagnosis of HBV infection in HIV-infected individuals

  4.2.2 Molecular and serological tests in HBV infection

   4.2.2.1 The use of serum HBV DNA

   4.2.2.2 Measuring HBV serology during and after therapy

   4.2.2.3 HBV resistance testing

   4.2.2.4 HBV genotyping

  4.2.3 Screening for hepatocellular carcinoma (see 3.5 General section)

 4.3 Therapy

  4.3.1 Who to treat?

   4.3.1.1 Recommendations

  4.3.2 What to treat with?

   4.3.2.1 HIV therapy not indicated

   4.3.2.2 HIV therapy indicated

   4.3.2.3 Recommendations for patients with a CD4 ≥500 cells/μL

   4.3.2.4 Recommendations for patients with a CD4 <500 cells/μL

   4.3.2.5 Goals of therapy

   4.3.2.6 Clevudine (L-FMAU)

 4.4 Acute hepatitis B

  4.4.1 Recommendations

 4.5 Hepatitis delta virus (HDV)

  4.5.1 Recommendations

5.0 Coinfection with HIV and hepatitis C virus

 5.1 Background

  5.1.1 Prevalence

  5.1.2 Natural history

   5.1.2.1 The influence of HCV on HIV infection

   5.1.2.2 The influence of HIV on HCV infection

 5.2 Assessment and investigations

  5.2.1 Diagnosis of HCV infection in HIV-infected individuals

 5.3 Therapy

  5.3.1 The coadministration of anti-HCV and anti-HIV treatment agents

  5.3.2 Recommendations

  5.3.3 General principles of anti-HCV therapy

  5.3.4 Treatment options

   5.3.4.1 Peginterferon

   5.3.4.2 Ribavirin

   5.3.4.3 Monitoring

   5.3.4.4 Treatment duration

   5.3.4.5 ‘Easier-to-treat’ genotypes

   5.3.4.6 ‘Harder-to-treat’ genotypes

   5.3.4.7 Recommendations

  5.3.5 Nonresponders and relapsers

  5.3.6 New therapies for hepatitis C

 5.4 Acute hepatitis C

  5.4.1 Epidemiology

  5.4.2 Clinical picture and natural history

  5.4.3 Diagnosis of acute HCV infection

  5.4.4 Management

  5.4.5 Recommendations

Audit standards

  1. Top of page
  2. Level of evidence
  3. Audit standards
  4. 1.0 Introduction
  5. 2.0 Methodology
  6. 3.0 General section: Prevention of viral hepatitis and management principles for patients with viral hepatitis
  7. 4.0 Coinfection with HIV and hepatitis B virus
  8. 5.0 Coinfection with HIV and hepatitis C virus
  9. Conflicts of interest
  10. Appendices
  • 1
    All new HIV-positive patients should be screened for hepatitis B virus (HBV) and hepatitis C virus (HCV) markers.
  • 2
    All HBV nonimmune patients should be vaccinated.
  • 3
    All HIV-positive patients should have their HBV and HCV status tests repeated before commencement of antiretroviral therapy.
  • 4
    All HBV- and HCV-infected patients should be vaccinated against hepatitis A if nonimmune.
  • 5
    All HBV- and HCV-infected patients should have documented evidence in their case notes of a discussion on alcohol avoidance and how to reduce the risks of transmission.
  • 6
    Case notes of new HBV-positive patients should contain evidence of an attempt to contact household and sexual contacts and offer vaccination if nonimmune.
  • 7
    Case notes of new HCV-positive patients should contain evidence of an attempt to notify parenteral and sexual contacts and offer them a test.
  • 8
    All patients who are HBV surface antigen (HBsAg) positive or HCV positive should have a clear antiviral treatment plan written in their notes at least once a year.
  • 9
    All HCV RNA-positive patients should have an HCV viral load and genotype determination performed.
  • 10
    All HBV-positive patients should have their ‘e’ status checked, an HBV DNA viral load measurement and an anti-hepatitis delta virus (HDV) antibody test.
  • 11
    All patients with chronic HBV or HCV should be offered an assessment of liver fibrosis by liver biopsy, hepatic elastography or other validated noninvasive fibrosis test.
  • 12
    All HBV-positive patients with an HBV DNA >2000 IU/mL and evidence of liver damage should be offered treatment.
  • 13
    All HCV RNA-positive patients should be considered for treatment unless there is a specific contraindication.
  • 14
    All patients with cirrhosis should be jointly treated by a hepatologist and have regular assessments for hepatocellular carcinoma (HCC) according to risk.
  • 15
    All patients with decompensated cirrhosis should be referred for liver transplantation assessment unless specifically contraindicated.

1.0 Introduction

  1. Top of page
  2. Level of evidence
  3. Audit standards
  4. 1.0 Introduction
  5. 2.0 Methodology
  6. 3.0 General section: Prevention of viral hepatitis and management principles for patients with viral hepatitis
  7. 4.0 Coinfection with HIV and hepatitis B virus
  8. 5.0 Coinfection with HIV and hepatitis C virus
  9. Conflicts of interest
  10. Appendices

The 2010 guidelines have been updated to incorporate all new relevant information that has become available since the previous versions were published in 2005. The 2005 versions came as separate hepatitis B and C guidelines but for 2010 we have decided to amalgamate them into a single document. This is to avoid duplication, as the general management of chronic liver disease is similar for both infections. The guidelines follow the methodology outlined below and all the peer-reviewed publications and important, potentially treatment-changing abstracts from the last 4 years have been reviewed.

The translation of data into clinical practice is often difficult, even with the best possible evidence, because of differences in factors such as trial design and inclusion criteria. The recommendations based upon expert opinion have the least good evidence but provide an important reason for writing the guidelines – to produce a consensual opinion about current practice. The Writing Group seeks to provide guidelines that optimize management, but such care needs to be individualized and we have not constructed a document that we would wish to see used as a ‘standard’ for litigation.

The major changes/amendments include the following:

  • increased discussion on hepatitis screening and prevention
  • clarification of the role of liver biopsy and noninvasive liver fibrosis assessment
  • more emphasis on screening for delta virus
  • increased discussion on end-stage liver disease management and HCC screening
  • molecular diagnostic tests used for the diagnosis and management of HBV and HCV infection
  • revised CD4-based guidance on the management of chronic HBV infection
  • management of acute HBV infection
  • revised guidance on the management of chronic HCV infection, including antiretroviral therapy (ART) interactions
  • management of acute HCV infection
  • management of treatment nonresponders and relapsers in both chronic HBV and chronic HCV infection.

2.0 Methodology

  1. Top of page
  2. Level of evidence
  3. Audit standards
  4. 1.0 Introduction
  5. 2.0 Methodology
  6. 3.0 General section: Prevention of viral hepatitis and management principles for patients with viral hepatitis
  7. 4.0 Coinfection with HIV and hepatitis B virus
  8. 5.0 Coinfection with HIV and hepatitis C virus
  9. Conflicts of interest
  10. Appendices

The Writing Group used an evidence-based medicine approach to produce these guidelines. Many important aspects of clinical practice remain to be formally evaluated and many trials have been performed in order to obtain licensing approval for a drug. However, the design of such trials is not ideally suited to addressing questions concerning clinical use. In most cases, the only available data on long-term outcomes are from routine clinical cohorts. While such cohorts are representative of routine clinical populations, the lack of randomization to different regimens means that comparisons between the outcomes of different treatments are susceptible to bias. Expert opinion forms an important part of all consensus guidelines; however, this is the least valuable and robust form of evidence.

3.0 General section: Prevention of viral hepatitis and management principles for patients with viral hepatitis

  1. Top of page
  2. Level of evidence
  3. Audit standards
  4. 1.0 Introduction
  5. 2.0 Methodology
  6. 3.0 General section: Prevention of viral hepatitis and management principles for patients with viral hepatitis
  7. 4.0 Coinfection with HIV and hepatitis B virus
  8. 5.0 Coinfection with HIV and hepatitis C virus
  9. Conflicts of interest
  10. Appendices

There are many prevention and management principles that are common to both hepatitis B and C. We will therefore discuss these before concentrating on issues specific to each type of hepatitis.

3.1 Screening of HIV-positive patients for hepatitis B and hepatitis C

In the disease-specific section of these guidelines we have demonstrated that there is an ongoing epidemic of acute HCV infection amongst HIV-infected men who have sex with men (MSM) in the UK and Western Europe [1,2] linked with mucosal traumatic sexual practices and co-transmitted with other sexually transmitted infections [3]. Early recognition of acute HCV infection is therefore important, as early treatment offers the best chance of viral clearance [4]. Acute HBV infection continues to be a problem for HIV-positive patients. We also know that 5–10% of new HIV-positive patients have chronic hepatitis B or C. There is therefore a need to screen newly diagnosed HIV-positive patients on an ongoing basis.

3.1.1 Recommendations

3.1.1.1 Screening for hepatitis in new HIV-positive patients

  • All newly diagnosed HIV-positive patients should be screened for coinfection with HBV and HCV as part of their initial work-up (III). This screening would normally be with the HBsAg, anti-HBV core antigen (anti-HBc) and anti-HCV antibody tests with appropriate further tests if positive. See also sections 4.2 and 5.2.
  • Initial screening should also include tests for evidence of protective immunity against hepatitis A (HAV) and HBV if not already infected (III).

3.1.1.2 Ongoing hepatitis testing in known HIV-positive patients

  • All HCV-negative patients should have an annual anti-HCV antibody screen, and more frequent tests if at higher risk [e.g. if injecting drug user (IDU) or MSM at sexual risk] (III).
  • All patients with no natural or vaccine-induced protection against HBV should have an annual anti-HBc or HBsAg test and more frequent tests if at higher risk (e.g. if IDU or MSM at sexual risk) (III).
  • Any patient with risk factors for acute HBV or HCV infection [e.g. a history of contact with HBV/HCV, current or recent IDU, recent sexually transmitted infection (STI) or MSM with high-risk sexual practices] and with an unexplained rise in serum aminotransferases should be offered an appropriate screening test for acute viral hepatitis [HAV immunoglobulin M (IgM), HBsAg and HCV antibody] (III). If the hepatitis serology is negative, they should be offered testing for HCV RNA and HBV DNA (III).
  • Any HCV antibody-positive/HCV RNA-negative patient (whether previously treated for HCV or not) with an unexplained rise in serum aminotransferases should be offered testing for HCV RNA and annual HCV RNA screening (III).

3.2 Prevention and immunization

Prevention strategies that work for viral hepatitis include immunization against HAV and HBV, and education on safer sex for everyone and on harm reduction for IDUs. Safer blood and blood products, and medical practices are also important.

3.2.1 Condoms and safer sex

Condoms are an effective means of preventing sexually transmitted hepatitis B [5–7]. A 40% lower prevalence and 66% reduction in incidence of serological evidence of hepatitis B is observed in women reporting consistent condom use for vaginal sex [5]. It seems likely, given the evidence for condom use and the prevention of many other STIs, that they will be effective for preventing hepatitis C and preventing transmission of hepatitis B and C during other forms of penetrative sex such as penile/anal and penile/oral intercourse. Although hepatitis A is thought to be sexually transmitted in MSM, it is linked to fisting and oro-anal contact [8–10], in which case condoms are unlikely to offer protection. There is an epidemic of acute HCV infection amongst HIV-infected MSM in the UK and Western Europe [1,2] linked with mucosal traumatic sexual practices and co-transmitted with other sexually transmitted infections, particularly syphilis and lymphogranuloma venereum (LGV) [3]. In many cases this seems to be related to unprotected sex between men who are both HIV-positive. Safer sex education is therefore also important, with emphasis on the risks of catching HCV and STIs through unprotected anal sex, even if partners are HIV sero-concordant (see also section 5.1.1).

3.2.2 Harm reduction in IDUs

Although needle exchange schemes have been introduced in many parts of the world, the benefit seems to be greater for reducing HIV rather than HBV or HCV infection [11,12]. One study showed an incidence of new HIV, HBV and HCV infection of 0, 11 and 26 cases/100 years at risk, respectively, in IDUs involved in a needle exchange scheme [11]. This reflects the greater infectivity and prevalence of HBV and HCV, but also the fact that sharing of ‘works’ other than the needle or syringe can still lead to transmission. Counselling of IDUs on reducing risk seems to have some effect, but a greater impact on HIV than the hepatitis viruses [12]. However, the challenge in preventative work in IDUs is engaging them in such schemes. Linking vaccination to either monetary inducements or doses of methadone has been successful [13,14].

3.2.3 Recommendations for prevention
  • All patients should be counselled about safer sex and the use of condoms for penetrative sex (II).
  • In the case of IDUs, potentially effective strategies include counselling on harm reduction to include advice to stop injecting, or to use safer injecting practices if stopping is not possible (II).
  • Access to needle/syringe exchange schemes may also be of value, as will incentives to complete vaccination schedules, such as linkage to methadone replacement (II).
3.2.4 Immunization

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 greatest response (c. 80%) at >500 cells/μL and least response (c. 25%) at counts <200 cells/μL [15]. Protective antibodies may be lost more quickly. Anti-HBs levels of >10 IU/L generally confer some protection, but levels of >100 IU/L are ideal [16,17].

The 0, 1 and 6 months and the 0, 1 and 2 months, with an additional dose at 12 months schedules have both been shown to be efficacious in HIV-infected patients [18,19]. There are very few data on the 0, 7–10 and 21 days, with an additional dose at 12 months schedule in HIV-positive patients, although one small study showed a 51% response after the first three doses and an 88% response after six doses [20]. Given the need to immunize patients at higher risk rapidly, this is a strategy that might be considered. Higher dose vaccination may enhance the anti-HBs response [21].

Patients who are anti-HBc positive, but negative for anti-HBs, anti-HBV envelope (anti-HBe) and HBsAg, may either have had previous exposure to HBV and be protected, or have had a false-positive anti-HBc test result and be vulnerable [22]. These patients will need HBV vaccination [23].

Patients coinfected with HBV and/or HCV are also vulnerable to acute HAV infection, which may lead to decompensation of underlying liver disease [24,25]. For a fuller discourse and further details on viral hepatitis vaccination and post-exposure prophylaxis in HIV-positive patients, please refer to the BHIVA immunization guidelines 2008 [23].

3.2.5 Recommendations for immunization
  • All newly diagnosed HIV-infected patients should have an anti-HBc test and additionally an anti-HBs test if they have previously been immunized. If negative for both they should receive a course of vaccination (I).
  • The 0, 1 and 6 months schedule and the 0, 1 and 2 months with a subsequent dose at 12 months schedule are acceptable vaccination schedules (II). The 0, 1 and 3 weeks schedule can be tried for patients who require rapid immunity (II).
  • Anti-HBs levels should be checked at 6–8 weeks post vaccination and up to three further boosters may be given until anti-HBs levels are ideally >100 IU/L (II).
  • Subsequently, anti-HBs levels should be checked yearly and booster doses given if the anti-HBs level falls below 100 IU/L (II).
  • Higher dose vaccine may improve response rates (II).
  • Persons who fail to seroconvert to HBV vaccine [23] should have a repeat vaccination course (which may be at double dose) once the CD4 count rises to >500 cells/μL or after significant immune recovery. While nonimmune they should have HBV marker tests performed (anti-HBc/HBsAg) annually or more frequently if at higher risk (II).
  • Anti-HBc-positive patients should be tested for anti-HBs, anti-HBe and HBsAg. If negative for all, then consider a single dose of HBV vaccine and measure anti-HBs levels 4–6 weeks later. If anti-HBs undetectable consider a full course of vaccination as above (III).
  • All HIV and HBV and/or HCV coinfected patients should be tested for immunity against HAV (HAV IgG or total antibody) and nonimmune patients should be vaccinated using standard recommended vaccination schedules (II).

3.3 General management/care pathways

3.3.1 Assessment of liver disease

The initial evaluation of all patients with chronic viral hepatitis should include a history and clinical examination [26]. The history should include questions about IDU (current and remote), past immunization for hepatitis A/B, episodes of jaundice, travel abroad and potential risk activity there (blood transfusion, IDU and sexual), alcohol use (current and past), family history of HBV infection, liver disease or HCC, and previous investigation for hepatitis [26,27]. A clinical examination for evidence of chronic liver disease (peripheral stigmata, splenomegaly and ascites) should be performed.

3.3.2 Investigations for liver disease

Blood tests should include a full biochemical profile including bilirubin, albumin, aminotransferases, prothrombin time, alpha fetoprotein and full blood count. A baseline battery of tests to look for alternative causes of chronic liver disease should also be performed. This should include serum ferritin, autoantibodies, serum ceruloplasmin, serum angiotensin converting enzyme (ACE), and alpha 1 anti-trypsin levels. A scan of the liver should be performed using imaging with ultrasound, computed tomography (CT) or magnetic resonance imaging (MRI).

3.3.3 Role of liver biopsy, hepatic elastography and other noninvasive markers of liver fibrosis

Liver biopsy remains the silver standard for the staging of liver disease [28]. However, because of sampling error, liver biopsy can overestimate or underestimate the degree of liver fibrosis. Increasingly, some physicians are commencing therapy in individuals without performing liver biopsy [29]. Liver biopsy is an important diagnostic tool in the work-up of patients with liver disease. In those individuals with HIV, who may have other co-factors contributing to liver damage and fibrosis, it remains a useful tool and should always be considered and discussed. Liver biopsy provides utility in the correct staging of liver disease in those considering therapy, in those where disease other than coinfection is being considered and serially for individuals not commencing antihepatitis therapy [30,31]. Unfortunately, hepatitis C has been shown to progress rapidly in some individuals, and, if serial measurement utilizes liver biopsy, rapid changes in liver histology may occur between biopsies [31].

Situations where liver biopsy may not be performed (see also hepatitis B and C sections)

  • 1
    Individuals who decline this test after appropriate discussion and information.
  • 2
    Individuals who will commence therapy for hepatitis C no matter what the liver biopsy shows.
  • 3
    Individuals with genotypes 2 and 3 requesting antihepatitis C therapy.
  • 4
    Individuals with acute hepatitis C.
  • 5
    Individuals who meet criteria for the treatment of hepatitis B and are agreeable to therapy.
  • 6
    Some physicians prefer not to perform a liver biopsy on men with haemophilia.

When a liver biopsy is not performed, liver fibrosis should still be assessed in all patients to exclude early cirrhosis. Therefore, increasingly, noninvasive methods of staging liver disease have been developed.

The most widely used method is hepatic elastography (FibroScan) [32]. The results of FibroScan give a good correlation with a fibrosis score of less than F2 disease (METAVIR) or with F4 disease (cirrhosis) [33,34] and a recent meta-analysis suggested cut-off points of <7.65 kPa for the former and >13 kPa for the latter [34]. In such cases liver biopsy may be avoided. For F2 and F3 disease the correlation is less clear and individuals with readings between 7.65 and 13 kPa should be considered for biopsy when this will alter the treatment of their disease [33,34]. Alternatively, a myriad of noninvasive tests based on biochemical markers are available [33–36]. In individuals with F2/F3 disease on FibroScan, one of these serum biochemical marker tests may be utilized. If the test correlates with the degree of fibrosis suggested by FibroScan then liver biopsy may be avoided [33]. Biochemical markers should not be used as the sole test for fibrosis [33–36].

Individuals requiring a measurement of fibrosis who decline liver biopsy should be referred to a centre offering FibroScan. This test is not National Institute for Health and Clinical Excellence (NICE) approved and there may be a charge for performing such a test. Transient elastography should be repeated every 6–12 months because of the rapid progression of fibrosis in some patients [31], although its utility in this context has not been validated.

3.3.4 Recommendations
  • All patients with chronic hepatitis B or C should be offered a liver biopsy for diagnosis and disease staging (I).
  • A biopsy is not always necessary for a decision regarding therapy if a patient is willing to start treatment for HCV regardless of histological changes (II).
  • It can be appropriate to omit a liver biopsy in certain circumstances, such as in patients who will commence treatment for chronic hepatitis B or C irrespective of the histology (II).
  • If a biopsy is not performed, a noninvasive technique for liver fibrosis assessment, such as hepatic elastography, should be used instead (II).

3.4 Antiretroviral therapy and hepatotoxicity

The use of specific antiretrovirals will be discussed in the HBV and HCV sections. However, when choosing an antiretroviral regimen, the following should also be considered.

All antiretrovirals have the potential to cause acute and long-term hepatotoxicity and this risk is increased two- to threefold in the presence of chronic liver disease such as that caused by hepatitis B or C [37]. This increased risk of hepatotoxicity largely disappears if the hepatitis is successfully treated [37]. Patients should therefore be carefully monitored for hepatotoxicity when highly active antiretroviral therapy (HAART) is commenced or changed. There is some evidence that the risk of early hepatotoxicity with nevirapine and high-dose ritonavir (RTV) (1000 mg/day) is higher than with other ARTs [38,39] and nevirapine may also be linked to increased liver fibrosis [40], although not all studies show this [41]. High-dose RTV is no longer recommended in ART and low-dose RTV [in doses used to boost other protease inhibitors (PIs)] is not associated with significant liver problems.

Didanosine and stavudine have been associated with an increased risk of hepatic steatosis and may potentiate HCV-related liver damage [42,43]. There have been recent reports of portal hypertension and idiopathic liver fibrosis associated with didanosine treatment [44]. The potential for recently developed agents to cause liver damage may only emerge in the post-marketing surveillance phase. For instance, although significant hepatotoxicity was not reported in the clinical trials, there is some evidence from subsequent case reports that tipranavir and darunavir may cause hepatotoxicity [45,46] and should be used with caution in patients with HIV/hepatitis coinfection.

3.4.1 Recommendations
  • Nevirapine, tipranavir, stavudine and didanosine should be used with caution in HIV/hepatitis virus coinfected individuals (II).
  • The possible risks of hepatotoxicity when darunavir is used in coinfected patients should be considered on a case-by-case basis (III).
  • RTV-boosted atazanavir, fosamprenavir and lopinavir should be used with caution in patients with Child–Pugh B/C grade liver disease (III).
  • In patients on didanosine with abnormal liver function tests (LFTs) or evidence of portal hypertension, idiopathic portal hypertension/liver fibrosis should be excluded and didanosine stopped if these conditions are found (II).

3.5 End-stage liver disease and its complications

Combination ART has vastly improved the prognosis of HIV-positive patients. As mortality from AIDS has fallen, there is increasing recognition of the importance of end-stage liver disease (ESLD) as a cause of significant morbidity and mortality in patients coinfected with HCV and HBV [47]. As outlined in the following sections, there is now unequivocal evidence that in the context of HIV infection there is an increased likelihood of and a faster progression to ESLD.

Moreover, recent evidence suggests that, once cirrhosis is established, the median survival in HIV/HCV coinfected patients after first decompensation is a mere 13 months [48]. Episodes of decompensation per se are associated with a high morbidity and mortality in HIV-infected patients [49]. Many cirrhosis-related complications and episodes of decompensation are avoidable and these patients need to be managed in conjunction with hepatologists or gastroenterologists experienced in the care of patients with ESLD. It is therefore prudent to accurately stage disease and monitor for complications (see section 3.3.3).

Cirrhosis associated with hepatitis viral coinfection, particularly HCV coinfection, is a well-recognized risk factor for the development of HCC. Recent studies from Europe and North America suggest a shorter time to HCC development in the context of HIV/HCV coinfection [50,51] and variable survival when compared with an HIV-negative population [52].

Furthermore, it is well recognized that HBV is directly carcinogenic and may promote the development of HCC in the absence of cirrhosis, especially in populations where HBV may have been acquired at birth and in early childhood [53]. It has also become evident that high HBV viral loads may be linked to the development of HCC [54]. It is probable that a lower CD4 cell count, particularly in the context of HBV coinfection, is associated with a higher risk of HCC [55]. Over recent years there has been an increasing number of treatment options available for patients with HCC that prolong life, including liver transplantation as a curative option in selected patients [56]. Screening programmes utilizing serum alpha-feto protein (AFP) measurements together with 6-monthly ultrasound scans (USSs) have been demonstrated to improve survival in non-HIV-infected patients [57]. Although AFP may not add to the value of USSs if done twice or more a year, this screening frequency is often impractical within resources and therefore AFP still has a place. Surveillance for HCC needs to be tailored to specific risk. Some patients may warrant more intensive surveillance with shorter frequency or different modality (such as CT or MRI).

Since the advent of HAART, a number of transplant programmes have evaluated liver transplantation in HIV-infected patients. HIV infection is no longer considered a contraindication to liver transplantation and a number of guidelines, including BHIVA guidelines, are now in existence [58,59]. The overall success of liver transplantation in this setting has been adequately demonstrated in a number of recent reports [60–65] showing comparable short- and medium-term graft and patient survival to that for non-HIV recipients. There are, however, reports of aggressive HCV recurrence and shorter post-transplant survival in HIV/HCV coinfected patients [62,65–67]. The use and success of post-transplant anti-HCV therapy in this context are currently under evaluation. What is also not clear is the optimal timing of transplantation in this group of patients. Recent data from a multicentre study suggest increased mortality on transplant waiting lists of HIV-positive patients compared with HIV-negative patients [68]. An important factor in this regard may be late referral for transplantation, as evidenced by higher Model for End-Stage Liver Disease (MELD) scores at referral, in addition to a faster kinetic of decline. It is therefore imperative that HIV-positive patients with a diagnosis of ESLD are co-managed by hepatologists who have links with transplant units, and are referred early for consideration and assessment for liver transplantation. This should occur no later than after their first decompensation.

3.5.1 Recommendations
  • Accurate disease staging is crucial for all patients with HBV and HCV coinfections for the early identification of cirrhosis (II).
  • All cirrhotic patients should be managed jointly with hepatologists or gastroenterologists with a special interest in liver disease, such as in specialist coinfection clinics (II).
  • Screening for, and prophylaxis and management of complications of cirrhosis and portal hypertension should be carried out in accordance with local and national guidelines on the management of liver disease (I).
  • HCC screening with 6-monthly AFP and liver USS should be offered to all cirrhotic patients with HBV and HCV coinfections (II).
  • Noncirrhotic HBV coinfected patients with high HBV viral loads (>2000 IU/mL), low CD4 counts (<100 cells/μL), a family history of HCC and acquisition of HBV in childhood should be considered for HCC screening (II).
  • HIV-positive patients with cirrhosis should be referred early, and certainly after first decompensation, for transplant assessment (II).
  • Eligibility for transplantation should be assessed at a transplant centre and in accordance with guidelines for transplantation in HIV-positive patients (II).

3.6 The role of clinical networks

There should be close liaison with the local hepatology team (gastroenterologist specializing in hepatology or hepatologist) and a 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 coinfection will have equality of access to specialist care by a team of doctors and nurse specialists, irrespective of their main site of HIV care.

4.0 Coinfection with HIV and hepatitis B virus

  1. Top of page
  2. Level of evidence
  3. Audit standards
  4. 1.0 Introduction
  5. 2.0 Methodology
  6. 3.0 General section: Prevention of viral hepatitis and management principles for patients with viral hepatitis
  7. 4.0 Coinfection with HIV and hepatitis B virus
  8. 5.0 Coinfection with HIV and hepatitis C virus
  9. Conflicts of interest
  10. Appendices

4.1 Background

4.1.1 Prevalence

There are approximately 350 million hepatitis B carriers and about 33 million HIV-infected people world-wide [69,70]. 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 [71]. There are no comprehensive data from the UK defining HIV/HBV coinfection rates. However, data from the EuroSIDA study [72] showed a 9.1% prevalence of HBsAg coinfection in participating northern European centres. In a survey of 100 UK clinics in 2004, the dual HIV/HBV infection rate was estimated to be 3–10% of patients in 93% of clinics [73].

In many parts of Africa, HIV/HBV coinfection is common, as seen in South Africa (5%) or Malawi (20%) [74,75]. Recent immigrants from Africa represent the largest group of newly diagnosed HIV-positive people in the UK [76] and therefore high coinfection rates are to be expected. High rates of HBV infection are also seen in IDUs and therefore HIV/HBV is relatively common in this group of patients [77]

4.1.2 Natural history

4.1.2.1 The influence of HBV on HIV infection. The natural history of HIV infection does not seem to be influenced by hepatitis B [71,72,78] although there is an increased rate of antiretroviral-related hepatotoxicity, and immune-reconstitution hepatitis [79–81].

4.1.2.2 The influence of HIV on HBV infection. Although the evidence remains conflicting, acute infection with HBV is more likely to be mild or asymptomatic in HIV-positive patients compared with those who are HIV-negative [82,83]. The rate of hepatitis B clearance is also lower, with up to 20–40% of infected patients progressing to chronic (>6 months) infection [82,83]. Progression to liver cancer is more rapid, with HIV-positive patients with HBV infection developing liver cancer younger than patients with HBV infection alone [52, 82–84].

Once HBV infection is established, liver damage is immunopathic (the immune response to the virus causes most of the liver damage) so liver disease would be expected to be less severe in HIV-related immunosuppression. However, recent evidence suggests that alanine aminotransferase (ALT) and liver inflammatory scores in HIV coinfected patients are no different to those in HBV monoinfected patients [78]. At very high levels of viral replication, HBV may have a direct cytopathic effect. Coinfection with HIV is generally accompanied by an increase in HBV replication [78], which might explain the evidence for an increased rate of progression to cirrhosis and death [72,78,85,86] when compared with HBV monoinfected patients.

There is also a reduction in the rate of natural clearance of HBeAg by about 60% in coinfected patients compared with HIV-negative patients [87]. However, there are reports of patients clearing chronic HBV infection with the recovery of CD4 cell count responses following ART [88,89]. HBV reactivation and re-infection (rare) can also occur and patients who appeared to have cleared HBV infection can present with a further episode of acute hepatitis or chronic hepatitis [88,90]. The risk of reactivation is higher in patients who are positive for anti-HBc antibody but negative for other markers of HBV infection [91]. In one long-term follow-up study of anti-HBc-antibody-positive, HIV-positive patients, transient HBsAg positivity developed in 24% of patients, HBV DNA became positive in 60% of all patients, and about one-third of these had active liver disease [92].

Since the introduction of combination ART and the dramatic improvement in the prognosis of people with HIV, liver disease attributable to chronic viral hepatitis has become an important cause of morbidity and mortality in coinfected patients as a result of cirrhosis and liver cancer [72,75,93].

4.1.2.3 Chronic hepatitis B: classification. Chronic HBV infection should not be regarded as a single entity, as the severity of the liver disease and the prognosis are influenced by the timing of infection (childhood or in later life) and the host immune response. Therefore, in HIV-negative people, four phases of chronic carriage have been described (Table 1).

Table 1.   Classification of chronic hepatitis B
Patient populations in chronic hepatitis B
MarkerImmune tolerant (type 1)Immune active (type 2)Inactive HBsAg carrier (type 3)HBeAg- negative CHB (precore/core promoter mutant) (type 4)
  1. ALT, alanine aminotransferase; CHB, chronic hepatitis B; HBeAg, hepatitis B virus (HBV) envelope antigen; HBsAg, HBV surface antigen.

HBsAg++++
HBeAg++
Anti-HBe++
ALTNormal[UPWARDS ARROW]Normal[UPWARDS ARROW]
HBV DNA (IU/mL)>2 × 104>2 × 104<2 × 102>2 × 103
Inflammation on histologyNormal/mildActiveNormalActive
  • 1
    Immune tolerant phase (HBeAg-positive, normal aminotransferase levels, little or no necro-inflammation on liver biopsy).
  • 2
    Immune active, HBeAg-positive phase (HBeAg-positive, raised aminotransferases, progressive necro-inflammation and fibrosis).
  • 3
    Inactive hepatitis B carrier (HBsAg-positive, HBeAg-negative, low levels of HBV DNA and normal aminotransferases).
  • 4
    HBeAg-negative chronic active hepatitis (pre-core, core-promoter mutations, eAg-negative, detectable HBV DNA, progressive inflammation and fibrosis).

Type 1 is generally seen in people infected in childhood and type 2 in those infected as older children/adults; types 3 and 4 may follow type 1 or 2 after many years of infection. Types 2 and 4 may progress to cirrhosis and liver cancer, with type 4 generally progressing most rapidly [94]. The utility of this classification and the frequency of each type are not yet known for HIV-positive patients.

4.2 Assessment and investigations

4.2.1 Diagnosis of HBV infection in HIV-infected individuals

For the indications of when to test for hepatitis B, see the general section. The number of hepatitis B tests and their interpretation can be quite complex and they are summarized in Table 2.

Table 2.   Interpretation of hepatitis B serology
Stage of infectionSurface antigen (HBsAg)‘e’ antigen (HBeAg)IgM anti-core antibodyIgG anti-core antibodyHepatitis B virus DNAAnti-HBeAnti-HBsALT
  • *

    In very early infection the IgM/IgG anti-core can be negative.

  • In chronic hepatitis B, with raised ALT, anti-core IgM may be weakly reactive.

  • ALT, alanine aminotransferase; CHB, chronic hepatitis B; HBeAg, hepatitis B virus (HBV) envelope antigen; HBsAg, HBV surface antigen; IgG, immunoglobulin G; IgM, immunoglobulin M.

Acute (early)+++*+*+[UPWARDS ARROW][UPWARDS ARROW][UPWARDS ARROW]
Acute (resolving)+++±[UPWARDS ARROW][UPWARDS ARROW]
Chronic (immune tolerant)+++++Normal
Chronic (immune active)++++[UPWARDS ARROW]
Chronic (HBeAg-negative)+++[UPWARDS ARROW]
Chronic (inactive HBsAg carrier)+++Normal
Resolved (immune)+±±Normal
Successful vaccination+Normal
4.2.2 Molecular and serological tests in HBV infection

4.2.2.1 The use of serum HBV DNA. There is controversy over the level below which HBV DNA concentrations are indicative of ‘inactive’ disease, and above which treatment should be initiated. High levels of HBV DNA are associated with more rapid hepatic fibrosis and progression to cirrhosis, decompensation and HCC [93–98]. An arbitrary cut-off value of 2 × 104 IU/mL (105 copies/mL) has been selected as one of the criteria for identifying patients at risk of progressive liver disease [93–98]. However, it must be recognized that some patients with chronic HBV infection, both HBeAg-negative and some HBeAg-positive patients, can have fluctuating levels of HBV DNA which can fall below 2 × 104 IU/mL intermittently, making its use as a predictor of severity of disease unreliable unless repeated [99,100]. Nonetheless, HBV DNA quantification is useful in distinguishing replicative from nonreplicative chronic HBV infection.

HBV DNA levels are also useful in deciding how to treat and for monitoring any response to antiviral therapy. For instance, patients with very high HBV DNA levels (>7 log10 IU/mL) are less likely to respond to treatment with interferon alpha therapy [101]. This has also been observed in patients treated with nucleos(t)ide therapy (lamivudine, adefovir or tenofovir) with reduced rates of eAg seroconversion in patients with a baseline HBV DNA >7 log10 IU/mL [102].

During therapy, HBV DNA testing is used to decide whether to continue or stop interferon treatment (see ‘Therapy’, section 4.3 below) [101]. This also applies to nucleos(t)ide therapy where primary nonresponse is defined as a <1 log10 IU/mL drop in HBV DNA level from baseline at 3 months, and response is defined as an undetectable HBV DNA by real-time polymerase chain reaction (PCR) assay within 48 weeks of therapy. Partial virological response is defined as a >1 log10 IU/mL drop in HBV DNA but detectable HBV DNA by real-time PCR assay [101,102]. In HIV-uninfected patients, a partial virological response should lead to a decision about modifying therapy at 24 weeks of therapy for lamivudine and telbivudine (which have a low barrier to resistance) and at 48 weeks for entecavir, adefovir and tenofovir (which have a high barrier to resistance) [102]. How this should be applied in coinfected patients is uncertain. Virological breakthrough on treatment, defined as a confirmed increase of >1 log10 IU/mL above nadir HBV DNA level on therapy, means either nonadherence or resistance [102]. The lower limit of detection of the assays used to monitor HBV DNA should be 10–15 IU/mL and this level should also be the aim of treatment [103].

Measurement of HBV DNA every 6–12 months is sufficient if the patient is not on HBV therapy [104].

4.2.2.2 Measuring HBV serology during and after therapy. The ideal outcome of treatment is HBe seroconversion in patients who are HBeAg positive and HBs seroconversion (very rare) in all patients [102]. Once HBV DNA is undetectable, HBeAg and eAb in HBeAg-positive patients and HBsAg in all patients should be tested every 12–24 weeks to pick up seroconversion. It should be noted that there is no HBV DNA level at which seroconversion from HBeAg positive to negative is completely predictable [105]. Spontaneous or treatment-induced seroconversion from HBsAg positive to negative is associated with ongoing undetectable HBV DNA but, in patients who convert from HBeAg positive to negative, HBV DNA may still be detectable at low levels [102,106].

4.2.2.3 HBV resistance testing. Resistance testing is becoming more widely available and may be considered as a baseline pretreatment, especially if there is a history of previous exposure to anti-HBV drugs, as a means to inform treatment decisions in those with nonresponse to treatment or with virological breakthrough. A line probe assay for the detection of hepatitis B wild-type virus and a drug-induced mutation using direct sequencing can identify specific resistance mutations [107,108]. Direct sequencing of the HBV polymerase gene can detect variants that are present in 10–20% of the virus population [109]. Restriction fragment length polymorphism and reverse hybridization using strips coated with oligonucleotide probes (line probes) are the most common methods used for detecting antiviral-resistant HBV mutations. They can only detect previously identified mutations, and these methods would need adaptation to detect mutants that confer resistance to a growing list of nucleos(t)ide reverse transcriptase inhibitors [110].

4.2.2.4 HBV genotyping. Currently, there is no indication for performing this as standard of care, except possibly in patients being considered for interferon therapy. It may be more relevant in the future as information on the differences among genotypes emerges.

HBV genotypes have been reported to correlate with spontaneous and interferon-induced HBeAg seroconversion, activity of liver disease, and progression to cirrhosis and HCC [101,111,112]. For example, HBV genotypes C and D are more difficult to treat than genotypes A and B [113,114]. There is also some evidence suggesting an increased pathogenicity of genotype C over B, with a greater likelihood of developing HCC [115,116].

Much of the current data examining the clinical relevance of HBV genotype should be viewed with caution. Many studies were small and cross-sectional in design, comparing two of the major genotypes with each other, and may be affected by referral bias. The predictive values of genotype in prognosis and treatment response have not been evaluated in prospective trials, and, currently, most clinicians do not base their management decisions on the viral genotype. However, this approach is likely to change as more data become available. Further studies are still needed in this area [117].

4.2.3 Screening for hepatocellular carcinoma (see 3.5 General section)

HBV is directly carcinogenic and may promote the development of HCC in the absence of cirrhosis, especially in populations where HBV may have been acquired at birth or in early childhood [53]. High HBV viral loads and low CD4 cell counts may be linked to the development of HCC [54,55]. Screening programmes utilizing serum AFP measurements together with 6-monthly USSs have been demonstrated to improve survival in non-HIV-infected patients [57].

4.3 Therapy

Treatment decisions should be guided by the algorithms in Figures 1 and 2.

image

Figure 1.  Flow chart: hepatitis B virus (HBV) management if CD4 count >500 cells/μL. ALT, alanine aminotransferase; FTC, emtricitabine; HAART, highly active antiretroviral therapy; HBsAg, HBV surface antigen; IFN, interferon; ULN, upper limit of normal.

Download figure to PowerPoint

image

Figure 2.  Flow chart: hepatitis B virus (HBV) management if CD4 count <500 cells/μL. 3TC, lamivudine; FTC, emtricitabine; HAART, highly active antiretroviral therapy; HBsAg, HBV surface antigen; TDF, tenofovir. *Consider close monitoring as an alternative strategy in a patient with a CD4 count of 350–500 cells/μL, HBV DNA of <2000 IU/L and no evidence of liver inflammation or fibrosis.

Download figure to PowerPoint

4.3.1 Who to treat?

Central to optimal management is the need for adequate initial assessment of both HBV and HIV status to inform the decision as to whether neither, HBV alone or both viruses require treatment [118]. This includes consideration of the severity of liver disease [119].

In HBV monoinfection, the decision on who to treat is based primarily on the ALT level, liver histology, HBeAg status and HBV DNA level [118–123]. ALT normality should not be used to assume that treatment is not necessary, although raised ALT often reflects HBV-induced inflammation and the need for treatment.

As significant liver damage may be present without raised liver enzymes, assessment of liver fibrosis by transient elastometry (e.g. FibroScan), serum fibrosis marker tests, or ideally liver biopsy should be performed in all patients [120,122]. This informs decisions regarding the need for therapy in patients with high CD4 cell counts and no indication for HAART, as well as the choice of drug treatment and the need for HCC screening if cirrhosis is present. Liver biopsy may provide additional information on the degree of inflammation and fibrosis and the presence of other pathology (e.g. steatosis) [121]. Assessment of fibrosis is essential before a decision is made to defer HBV and/or HIV treatment. Given the accelerated progression of fibrosis in coinfection, any patient with significant necroinflammation or fibrosis should be treated [120].

The key determinants of who needs treatment for HBV are the HBV DNA level and the CD4 cell count. In HBV monoinfected patients, there is a good correlation between high HBV DNA levels, long-term histological progression to cirrhosis and the rate of HCC. It is presumed that this correlation also exists for coinfected persons but whether liver disease progresses at a lower HBV DNA level is unknown [123]. The accepted HBV DNA threshold for consideration for treatment is now >2000 IU/mL. In patients who have significant liver damage but low or undetectable HBV DNA levels, the possibility of HDV coinfection should be considered. The presence of HBV DNA without HBsAg, with or without HBcAb (occult HBV), is very rare and does not account for significant liver damage [119].

The CD4 cell count is integral to deciding when to initiate HIV therapy. A threshold of 350 cells/μL is recommended by BHIVA and other international guidelines as a level below which antiretrovirals are indicated in HIV-monoinfected persons [124]. Because of the negative effect of immune depletion on HBV progression, the availability of single drugs with high level dual activity, and the increased risk of liver-related deaths in patients with CD4 counts below 500 cells/μL, coinfected patients with CD4 counts between 350 and 500 cells/μL should also be treated with drugs active at suppressing both viruses [119].

4.3.1.1 Recommendations

  • ALT elevation is less sensitive as an indicator of disease severity in coinfection and a level below the upper limit of normal should not be used as a reason to defer treatment if otherwise indicated. Normal levels should be considered as 30 IU/L for men and 19 IU/L for women (II).
  • HBV DNA measurement is essential in the decision to treat and subsequent monitoring of disease (I).
  • Assessment for liver fibrosis, using either liver biopsy or a noninvasive technique, should be performed on all patients to define treatment strategy (I).
  • In patients with a CD4 count of >500 cells/μL, HBV treatment should be commenced using the same criteria (HBeAg, HBV DNA, fibrosis assessment, and ALT) as in an HIV-negative person (III).
  • All patients with significant fibrosis (Metavir ≥F3 or Ishak ≥S3 or FibroScan ≥9 kPa) should be treated if HBV DNA is detectable, at any level (IV). It should be noted that cut-offs for FibroScan are not as clearly defined for HBV as they are for HCV coinfection.
  • All patients with an HBV DNA >2000 IU/mL should be considered for treatment (III). The only exception may be young adults with a CD4 count of >500 cells/mL, persistently normal liver enzymes, and no evidence of fibrosis who probably have immunotolerant HBV and where careful monitoring may be an alternative (III).
  • The presence of significant liver damage but a low or undetectable viral load for HBV should prompt exclusion of hepatitis delta (I).
4.3.2 What to treat with?

There are currently seven drugs that have been, or are soon to be, approved for use against HBV: four have additional HIV activity [lamivudine (3TC), emtricitabine (FTC), tenofovir and entecavir] and three are only active against HBV at licensed doses (interferon, adefovir and telbivudine). The data excluding anti-HIV activity for telbivudine are limited and monitoring of HIV viral load and repeat HIV genotyping pre-HAART initiation are advised. The efficacy of these drugs has been assessed in randomized trials extending out to 5 years in monoinfected patients [118].

The strategy used to treat HIV/HBV coinfection depends upon the need for ART determined by the CD4 cell count. Where ART is recommended (all patients with a CD4 count <350 cells/μL), agents with HBV activity should be incorporated into the ART regimen. In patients with CD4 cell counts of 350–500 cells/μL, in whom ART is not otherwise recommended, treatment for HBV infection may best be achieved by using a combined ART/HBV regimen. If ART is not required, that is in patients with CD4 counts of >500 cells/μL, the optimum strategy may be to use agents with exclusive HBV and no HIV activity so that HIV resistance is not induced; however, earlier initiation of ART should still be considered [118–123]. Awareness of the additive hepatotoxic risks of certain antiretroviral drugs should be considered (e.g. nevirapine).

4.3.2.1 HIV therapy not indicated. If the CD4 count is above 500 cells/μL, the HBV DNA is below 2000 IU/L, the ALT is normal, and there is no fibrosis, treatment is not indicated and patients should be monitored on a 3–6-monthly basis.

If the CD4 count is above 500 cells/μL and HBV therapy is indicated, the options are to use drugs only active against HBV, alone or in combination, or early introduction of antiretroviral drugs including tenofovir with FTC.

Limited evidence exists on the use of pegylated interferon in coinfected persons [125] but it appears to be less effective and is associated with greater toxicity. However, resistance does not occur and a 12-month course of pegylated interferon is an option in a patient with elevated ALT, low serum HBV DNA (<2 × 106 IU/L), and minimal liver fibrosis, especially if genotype A [119]. Lack of response, as judged by failure to reduce HBV DNA by 1 log10 by week 12 and to <2000 IU/L by week 24, should prompt discontinuation and consideration for antivirals [119,120]. Pegylated interferon should not be used in patients with decompensated cirrhosis [126].

Adefovir has been evaluated in coinfected persons and is active for both wild-type and 3TC-resistant virus but is less potent than tenofovir [127]. Nevertheless, at the dose used in HBV treatment, it does not affect HIV replication or select resistance mutations that may limit future tenofovir use. It is therefore an option in this situation, unlike tenofovir which must be used only with other ART agents [128,129].

Telbivudine has greater intrinsic activity than adefovir or 3TC but has also not been studied sufficiently in coinfection. Its efficacy is limited by the development of resistance (25% at 24 months in monoinfected persons), with cross-resistance to 3TC/FTC but not adefovir [118]. Adefovir and telbivudine select for nonoverlapping HBV resistance mutations.

Entecavir, although previously thought to be devoid of antiretroviral effect, has been found to possess modest anti-HIV activity and can select for HIV rt M184 V [130]. This drug should not be used in the absence of fully suppressive antiretroviral therapy (ART).

4.3.2.2 HIV therapy indicated. A preferred antiretroviral drug regimen should be used, with a two-nucleoside reverse transcriptase inhibitor (NRTI) backbone that has additional activity against HBV. The two recommended NRTI options for treatment of naïve patients with wild-type HIV alone are abacavir/3TC and tenofovir/FTC [124].

Although 3TC is a potent anti-HBV agent [131], monotherapy is associated with a high likelihood of HBV resistance in coinfected persons (M204 V develops at a rate of 25%/year) and hence therapy with this drug, or FTC, without a second anti-HBV active drug is not recommended [132,133]. 3TC/FTC-resistant strains will normally respond to tenofovir [118–123,134–137]

Tenofovir is effective at suppressing HBV DNA and may induce HBeAg seroconversion although, as for other antivirals in coinfection, this may be less likely than in an HIV-negative person [127,134–136]. Resistance is rare and combination with 3TC or FTC has been demonstrated to be effective at suppressing HBV DNA and may induce HBeAg seroconversion. Combining 3TC/FTC with tenofovir may reduce the risk of breakthrough [137].

If renal toxicity precludes the use of tenofovir, entecavir is an option that can be used along with a fully active antiretroviral regimen [137].

If genotypic HIV resistance to tenofovir and/or 3TC/FTC is present or develops, but HBV DNA suppression is maintained, tenofovir and 3TC/FTC should be continued in addition to an effective new antiretroviral regimen. The presence of mutations conferring 3TC resistance affects the fitness of both viruses which potentially slows down HBV progression and therefore continuing this drug should be considered [131].

ART may lead to an immune reconstitution flare when commenced, and a viral escape inflammatory flare if drugs with anti-HBV activity are stopped, both of which may be severe, particularly in persons with cirrhosis [138,139].

4.3.2.3 Recommendations for patients with a CD4≥500 cells/μL

  • No HBV therapy is recommended for patients who are HBsAg and HBV DNA negative but HBcAb positive (I).
  • HBsAg-positive patients with an HBV DNA<2000 IU/L and no significant degree of fibrosis (Metavir≤F1 or Ishak≤S1 or FibroScan≤8 kPa) or inflammation on biopsy should not be treated and should commence 3–6-monthly sequential monitoring with HBV DNA and ALT (III).
  • Early introduction of antiretrovirals, inclusive of tenofovir and FTC, should be considered as an option for naïve patients with wild-type HIV (III).
  • 12 months of treatment with pegylated interferon is an option in a patient who is HBeAg positive and has a raised ALT, low HBV DNA (<2 × 106 IU/L), minimal fibrosis and (if tested) genotype A (I). Lack of HBV DNA response (<1 log10 reduction at 12 weeks and >2000 IU/L at 24 weeks) should prompt discontinuation (I).
  • After stopping pegylated interferon for HBeAg-positive disease, repeat testing should be performed 3-monthly if seroconversion has occurred (III).
  • Adefovir is an option in all patients and does not generate future resistance to tenofovir and is the drug of choice in patients with evidence of significant fibrosis (II).
  • Telbivudine should not be used alone because of the high rate of HBV resistance (I).
  • Tenofovir, entecavir, 3TC and FTC should not be used without suppressive ART in order to avoid HIV resistance induced by suboptimal anti-HIV treatment (I).
  • Adefovir and telbivudine given together is an option and is likely to reduce risk of HBV resistance to telbivudine (III). The potential for anti-HIV activity in telbivudine is currently unknown and therefore this should be used only if other options are not suitable.
  • Patients started on adefovir, with or without telbivudine, who have suppressed HBV DNA should remain on these drugs until HAART is started (III).

4.3.2.4 Recommendations for patients with a CD4<500 cells/μL

  • Patients with HBV coinfection who have a CD4 count of <500 cells/μL should commence HAART (II). The only exception to this may be the patient with a CD4 count of 350–500 cells/μL, an HBV DNA level of <2000 IU/mL, a normal ALT and no evidence of fibrosis or hepatic inflammation: in this situation, close monitoring is essential.
  • Tenofovir and 3TC/FTC should form the backbone of an antiretroviral regimen in naïve patients with wild-type virus and no contraindications to either drug (II).
  • 3TC/FTC may be omitted from the antiretroviral regimen and tenofovir given as the sole anti-HBV agent if there is clinical or genotypic evidence of 3TC/FTC-resistant HBV (II).
  • If tenofovir is not currently being given as part of HAART it should be added. If tenofovir is contraindicated, an alternative active anti-HBV agent should be used instead (II).
  • 3TC or FTC should not be used as the only active drug against HBV in HAART because of the likelihood of emergent HBV resistance to these agents (I).
  • Tenofovir is active against 3TC/FTC-resistant virus (I).
  • Entecavir is an option when tenofovir has to be discontinued, because of toxicity, if given with a fully active antiretroviral regimen. Where 3TC resistance is also possible, entecavir 1.0 mg dosage combined with adefovir (unless the severity of renal disease precludes) should be used and the patient monitored carefully for HBV breakthrough and probable entecavir resistance. HBV resistance testing should be undertaken where available (II).
  • If patients on suppressive anti-HBV therapy require a switch of their antiretrovirals because of HIV resistance to tenofovir and/or 3TC/FTC, their active HBV therapy (tenofovir with or without 3TC/FTC) should be continued (III) and suitable anti-HIV agents added.

4.3.2.5 Goals of therapy. As in HBV monoinfection, the long-term goal is to prevent cirrhosis and primary hepatoma by sustained suppression of viral replication to the lowest possible level [140].

Seroconversion from HBeAg positive to HBeAg negative and normalization of ALT are endpoints that indicate success of therapy in monoinfected patients and allow consideration for discontinuation of treatment. However, these indicators cannot be expected in most of those who are coinfected and a more realistic goal is long-term suppression of HBV replication to undetectable levels, to reduce liver inflammation and to stop or delay progression of hepatic fibrosis [121,122,124,133–135].

If seroconversion does occur, antiviral treatment should be maintained, as relapse is more likely with discontinuation of therapy than in monoinfection. The ultimate serological endpoint of HBsAg seroconversion is rarely achieved in coinfected patients, and even if it is achieved reactivation on withdrawal of therapy remains a concern [121,122,124,133–135].

4.3.2.6 Clevudine 2′-fluoro-5-methylarabinosyluracil (L-FMAU). Clevudine is a thymidine analogue with anti-HBV activity [141]. On 20 April 2009 the manufacturers Pharmasset announced that all Phase III trials of clevudine for hepatitis B would stop because of reports of treatment-related myopathy [142].

4.4 Acute hepatitis B

In monoinfected persons, >90% of adults with acute HBV will recover spontaneously and seroconvert to HBsAb without antiviral therapy. However, severe or fulminant liver disease occurs rarely (<0.1%) and is life-threatening. Treatment with antivirals is usually recommended in fulminant disease. Small randomized controlled trials with 3TC have demonstrated a more rapid fall in HBV DNA but no difference in outcome in acute infection [143]. In coinfection, fewer (60–80%) patients with acute HBV clear their infection [82,83]. Data suggest that 3TC as part of HAART does not completely protect against the development of acute HBV infection [144], although it is unknown whether this is also the case with tenofovir with or without 3TC/FTC. Because patients with HIV are more likely to develop chronic HBV infection and the consequences thereof, there is a theoretical argument to consider HBV treatment after acute infection to promote clearance. For patients with acute but nonfulminant disease, the options include not giving antivirals, using drugs only active against HBV, or early introduction of antiretrovirals including tenofovir with FTC. There are no data to support any of these approaches but for the majority of patients no antiviral treatment is indicated. For patients with fulminant disease, where a rapid fall in HBV DNA is desirable, a balance has to be found between the need for antivirals, the potential for drug toxicity, and the risk of selecting HBV and HIV drug resistance. Telbivudine in the short term is thought to be safe [145] and, although HBV resistance is likely, probably will not interfere with future ART. The addition of adefovir may theoretically improve efficacy and reduce the risk of telbivudine resistance, although there is no research evidence for this.

4.4.1 Recommendations
  • Most patients with HIV who acquire acute HBV do not require treatment (III).
  • Coinfected patients with fulminant HBV may benefit from telbivudine and/or adefovir although their efficacy remains unknown in this situation (IV).

4.5 Hepatitis delta virus (HDV)

HDV is found as coinfection or superinfection with hepatitis B. It was previously thought to be rare in the UK and seen mostly in IDUs and their sexual partners. Recent evidence suggests a rising incidence in some areas of the UK, and in one study in South London 8.5% of all HBsAg-positive patients were HDV positive, of whom only 27% had evidence of parenteral exposure [146]. Patients with delta virus superinfection are more likely to have severe hepatitis [147]. In HIV-coinfected patients delta virus may further accelerate the progression of liver disease [148]. For these reasons, patients with delta virus are candidates for treatment. However, evidence of treatment activity has been mostly obtained in HIV-negative patients. Interferon has been shown to be active [149,150]. In one study, 72 weeks of treatment with pegylated interferon alpha-2b was associated with sustained virological response (SVR) in about 20% of cases, and ribavirin did not add to this benefit [150]. There is a successful case report of the use of pegylated interferon alpha-2b for 72 weeks in a patient with HIV coinfection on HAART with undetectable HIV RNA [151]. In an earlier study, where standard interferon was used in 16 HIV-infected patients with HDV, the results were poor [152]. There are early efficacy data on tenofovir use [153].

4.5.1 Recommendations
  • Test for delta virus in all patients with hepatitis B (III).
  • Repeat the test for delta virus in all patients with hepatitis B yearly and if they develop an unexpected rise in ALT (II).
  • All delta virus-infected patients should be considered for early treatment by a physician with experience in this problem (II).

5.0 Coinfection with HIV and hepatitis C virus

  1. Top of page
  2. Level of evidence
  3. Audit standards
  4. 1.0 Introduction
  5. 2.0 Methodology
  6. 3.0 General section: Prevention of viral hepatitis and management principles for patients with viral hepatitis
  7. 4.0 Coinfection with HIV and hepatitis B virus
  8. 5.0 Coinfection with HIV and hepatitis C virus
  9. Conflicts of interest
  10. Appendices

5.1 Background

5.1.1 Prevalence

There is now widespread recognition of the potential morbidity and mortality associated with HIV and HCV coinfection. Overall, the prevalence of HCV in the general UK population is estimated to be approximately 0.44% [154] but the rate varies by area and population and should be considered as a minimum. The highest risk groups for HCV infection are IDUs and people with bleeding disorders such as haemophilia [154]. Other risk groups include sexual partners of injectors, prisoners, sex workers and children of HCV-infected mothers. There may also be an increased rate in people who have had treatment or were born abroad and healthcare workers subject to sharps injury [154].

Although heterosexual transmission of HCV is uncommon, the higher levels of HCV RNA seen in the setting of HIV infection may facilitate transmission [154,155], particularly in the presence of other sexually transmitted infections such as infectious syphilis. This is of particular concern in the light of the recent rise of syphilis cases within the HIV community [1,3,156–161]. There have been reports from several European countries, Australia and the USA of hepatitis C transmission within the homosexual HIV community linked to possible sexual transmission and/or use of noninjecting recreational drugs, particularly snorting cocaine.

The prevalence of HCV infection in HIV-positive individuals is higher than in the general population but varies among clinics according to risk factors for HIV acquisition.

5.1.2 Natural history

5.1.2.1 The influence of HCV on HIV infection. HCV may have a deleterious effect on HIV progression. The Swiss HIV Cohort study and others demonstrated that HCV infection was independently associated with an increased risk of progression to AIDS or death, despite a similar use of antiretroviral therapies in the coinfected group compared with the group infected with HIV alone [162–164]. A Swiss study also suggested that those patients with dual infection may be less likely to achieve a CD4 count rise of at least 50 cells/μL within 1 year of starting HAART than those with monoinfection. The HIV viral load response to therapy was similar, however, in patients with and without HCV. This deleterious effect is confirmed in some, but not all other studies [165–167].

5.1.2.2 The influence of HIV on HCV infection. Only 20–30% of immunocompetent individuals with HCV will progress to cirrhosis over an average of 15–30 years. Evidence suggests that in HIV-positive individuals progression is likely to occur more frequently and at a faster rate [31,168–171]. One study estimated the median time to cirrhosis as 32 years and 23 years from time of acquisition in HCV-infected and HCV/HIV-coinfected individuals, respectively [168]. This is now manifest as a proportional increase in deaths from ESLD throughout the HIV-infected population such that HCV infection is one of the major causes of death in people with HIV [31,168–173].

In contrast, studies that have considered absolute numbers of deaths (rather than proportions of deaths from different causes) have often reported no increase in the number of deaths from liver failure [174], although one study in the HAART era which compensated for competing risks still showed a small increase in liver-related mortality [175]. It is therefore uncertain if there has been a true increase in deaths from liver failure, or whether the apparent increase is simply a consequence of the longer survival times of individuals with HIV infection. It should also be noted that men with haemophilia and IDUs, in whom many of these studies have been carried out, have generally been infected with HCV for some time before becoming infected with HIV. The impact of HCV seroconversion after HIV seroconversion is unclear.

Coinfected patients have comparably higher levels of HCV viraemia and HCV in other body fluids [176] and these are inversely correlated with the CD4 cell count and degree of immunosuppression present.

Several studies show that liver-related mortality rates are higher in those with a low CD4 cell count, irrespective of ART use [86,177]. Other variables that negatively influence HCV progression have been shown to be alcohol, increasing age at acquisition and the presence of HBV infection [170–178].

HCC is estimated to occur at a rate of 1–4% per annum in patients with HCV-related cirrhosis; in patients who also have HIV infection it tends to occur at a younger age and within a shorter time period [50].

5.2 Assessment and investigations

5.2.1 Diagnosis of HCV infection in HIV-infected individuals

The majority of individuals (75–85%) who become infected with HCV become chronic carriers with detectable HCV RNA in the blood indicating viraemia. The remainder (15–25%) clear virus spontaneously, usually within 6 months of becoming infected [179–182]. Diagnosis of chronic infection is usually made on the basis of a positive anti-HCV antibody test [enzyme-linked immunosorbent assay (ELISA) ± recombinant immunoblot assay (RIBA)], confirmed by a positive HCV RNA [reverse transcriptase–polymerase chain reaction (RT-PCR)] test. However, a proportion of patients will have normal liver enzymes or a negative antibody test in the presence of chronic HCV viraemia [183–187].

Individuals with past resolved infection have positive anti-HCV antibody tests (usually by two different assays) with repeatedly negative HCV RNA tests and would be expected to have normal liver enzymes, in the absence of other causes of liver disease. Over time, anti-HCV antibody levels decline such that it can be difficult to differentiate infection in the distant past from nonspecific false positivity [183–187].

RNA levels may be transiently undetectable during acute infection so it is particularly important to repeat HCV RNA tests in patients if the time at which they were initially infected is unknown [183–187].

With current assays, false negative antibody tests are rare in chronic infection but may be a problem in early acute infection [183–187]. Consideration should be given to HCV RNA testing of HCV antibody-negative HIV-positive individuals where:

  • acute infection is suspected;
  • there are unexplained abnormal liver function tests (rare).

(For the general principles of management, liver assessment and networks see the General section.)

5.3 Therapy

5.3.1 The coadministration of anti-HCV and anti-HIV treatment agents

Patients should ideally be started on anti-HIV therapy when their CD4 count falls to 350 cells/μL or less (see General section). Prior to initiation of anti-HCV therapy, potential interactions and/or overlapping toxicities with anti-HIV therapies need to be considered. Where possible, anti-HIV therapies should be adjusted to enable optimal administration of anti-HCV therapy, although this should never compromise anti-HIV drug efficacy. Consideration needs to be given to which antiretroviral agents should be coadministered with interferon and ribavirin therapy due to:

  • drug interactions which may lower antiretroviral drug levels, thereby raising concerns of reduced efficacy;
  • drug interactions which may increase antiretroviral drug levels, with a risk of increased toxicity;
  • overlapping toxicity profiles which may cause increased morbidity/mortality and reduced completion of treatment.

The increasing availability of newer antiretroviral agents with improved safety profiles usually enables us to avoid such difficulties, but this may be less possible in heavily antiretroviral-pretreated patients. The key potential coadministration issues are summarized in Table 3. While there currently appear to be no theoretical problems with coadministration of interferon or ribavirin with the newer classes of antiretroviral drugs [integrase inhibitors, CCR5 blockers, and second-generation nonnucleoside reverse transcriptase inhibitors (NNRTIs)], clinical data to confirm this are awaited.

Table 3.   Interactions between antiretroviral agents and anti-hepatitis C virus (HCV) therapy [186–192, 239]
Anti-HIV agentAnti-HCV agentReason for concernData suggesting problemRecommendation
  1. CNS, central nervous system; RCT, randomized controlled trial.

AbacavirRibavirin (at 800 mg/day)Reduced intracellular ribavirin levels leading to possible impaired anti-HCV therapy if low-dose ribavirin usedPharmacokinetics; cohort studies suggesting impaired anti-HCV therapy response although some other cohort studies suggest no impact on responsePossibly avoid concomitant use if ribavirin cannot be given at daily dose of≥1000 mg or≥13.2 mg/kg
AtazanavirInterferon/ribavirinIncreased hyperbilirubinaemiaCase reportsObserve
DidanosineRibavirinSignificant toxicity; fatal lactic acidosisCase reports; data from RCTsAbsolute contraindication
EfavirenzInterferonIncreased CNS disturbanceCase reports; data from RCTsClose observation and individualized case management
StavudineRibavirinSignificant mitochondrial toxicityCase reports; data from RCTsAvoid if at all possible
ZidovudineInterferon/ribavirinIncreased myelosuppressionCase reports; data from RCTsAvoid if at all possible
5.3.2 Recommendations
  • When deciding to treat HCV, the choice of anti-HIV therapy should be agreed in association with an experienced HIV physician (IV).
  • The coadministration of didanosine with ribavirin is contraindicated (II).
  • The coadministration of zidovudine and stavudine with pegylated interferon and ribavirin should be avoided (II).
  • Abacavir should only be used as backbone therapy in accordance with the BHIVA HIV treatment guidelines and concomitant use with ribavirin should be avoided if possible (II).
  • When abacavir cannot be avoided, maximum weight-based (1000/1200 mg, >13.2 mg/kg/day) ribavirin should be used and ribavirin dose reductions avoided (II).
  • The coadministration of efavirenz with interferon should be accompanied by careful observation for increased central nervous system (CNS) toxicity with consideration of a switch to an alternative antiretroviral agent temporarily if severe (II).
  • The coadministration of atazanavir and interferon/ribavirin may be associated with increased hyperbilirubinaemia, but this is unlikely to be of clinical importance (II).
5.3.3 General principles of anti-HCV therapy

The main aims of therapy are to clear HCV and thereby limit liver disease progression and viral transmission. Antiviral therapy may also be helpful for those with extrahepatic manifestations of HCV such as cryoglobulinaemia [193]. An SVR is defined as a negative HCV RNA PCR test 6 months following cessation of therapy. Relapse thereafter is very unusual but the patient may be at risk of re-infection, so annual testing is recommended following SVR and in any patient with raised liver function tests that had previously normalized.

A negative HCV RNA test 4 weeks into therapy is defined as a rapid virological response (RVR) and is associated with an increased likelihood of SVR [194,195]. The early virological response (EVR) is defined as a negative HCV RNA or reduction of >2 log10 in HCV viraemia after 12 weeks of therapy [195]. Therapy should be stopped in patients who do not achieve an EVR or where there is detectable viraemia at 24 weeks [194,195].

In the AIDS Pegasys Ribavirin International Co-infection Trial (APRICOT) study, patients treated with peginterferon and ribavirin had a mean CD4 count decrease of 140 cells/μL [196] and there have been previous case reports of interferon-treated patients developing opportunistic infections following an interferon-associated CD4 count decline. Ideally, therefore, patients should have a CD4 count of at least 200 cells/μL and undetectable HIV RNA. CD4 percentage should also be taken into account when making the treatment decision. Patients with low CD4 count (<300 cells/μL at baseline) will require more detailed monitoring.

In patients being evaluated for both antiretroviral and HCV treatment it is advisable to stabilize the patient on ART in the first instance (see above). It has been shown that the immune restoration associated with ART can limit the progression of HCV-associated disease so that even if they do not respond to HCV therapy there may be some long-term indirect benefit from ART [172,197–199].

The liver disease should also be staged both clinically and with either noninvasive tests/biomarkers such as hepatic elastography (see General section) or liver biopsy. Consider liver biopsy particularly for those with genotype 1 or 4 infection where the results of HCV therapy remain disappointing [198,200,201]. The risk–benefit of liver biopsy should be considered in the individual patient. The patient's age should also be taken into account as there is some evidence that response diminishes with increasing age [202].

It is particularly important to establish whether the patient has cirrhosis as:

  • (a)
    HCV therapy can be potentially dangerous in those with severe liver disease, particularly cirrhosis Child–Pugh stage B/C, as deaths have occurred [201,203,204].
  • (b)
    There is less chance of an SVR [196,201,202,205].
  • (c)
    The patient is at risk of varices and HCC, and should be screened for both.
  • (d)
    The complications of cirrhosis can be life-threatening and transplantation may need to be considered. The median survival of patients with decompensated cirrhosis in this setting is reported to be 13 months [48] but the long-term survival of transplant patients in the setting of HIV/HCV coinfection is currently poor [64].

Overall, the SVR rates in coinfected patients are approximately 60% of those seen in HCV-monoinfected patients [194–196,200–202,205]. It is reasonable, therefore, to treat patients with genotype 2 or 3 infection without performing a baseline liver biopsy if there is no evidence of advanced liver disease clinically, or by using noninvasive tests/biomarkers.

In those with genotype 1 or 4 infection, or where there is clinical concern regarding co-existent liver disease such as haemochromatosis, or alcohol-related or other liver disease, a biopsy can be helpful in staging the liver disease(s) and determining the need for HCV therapy [194–196,200–202,205,206]. In those individuals refusing liver biopsy, noninvasive tests/biomarkers such as hepatic elastography can be useful alternate techniques to identify those with earlier stages of fibrosis not requiring therapy (see General section).

Patients should abstain from or minimize alcohol intake, as more rapid progression of liver disease is seen with higher levels of alcohol consumption [85,203]. Patients who are nonimmune for HAV and HBV should be vaccinated, as superinfection of HCV-infected patients with HAV or HBV can be life-threatening (see General section).

There is a high prevalence of psychiatric comorbidity in patients with HIV/HCV infection. Interferon-based regimens have risks of psychiatric complications, so it is recommended that patients with a background of psychiatric disorder are assessed by a psychiatrist or psychiatric nurse prior to commencement of HCV therapy [204,207].

A fundoscopic examination of the eye is also recommended prior to commencement of therapy, and during therapy if eye symptoms occur. A variety of pre-existing eye conditions, such as hypertensive retinopathy, can deteriorate and new conditions, such as central retinal vein occlusion, can occur de novo during anti-HCV therapy [208,209].

5.3.4 Treatment options

The risk versus benefit of HCV therapy must be carefully evaluated for the individual patient. A team approach is vital to manage HIV/HCV-coinfected patients with access to experienced physicians and trained specialist nurses with knowledge of coinfection to support and monitor the patients while on therapy [194–196,200–202,205,206].

5.3.4.1 Peginterferon. Three large controlled studies [APRICOT, AIDS Clinical Trials Group (ACTG) and RIBAVIC] all showed that peginterferons were more efficacious than standard thrice-weekly interferon [196,200,201]. Both peginterferon alpha-2a and peginterferon alpha-2b are licensed for treatment of patients with HIV/HCV coinfection. Peginterferon is given by weekly subcutaneous injection: peginterferon alpha-2a, 180 μg/week, and peginterferon alpha-2b, 1.5 μg/kg/week – i.e. weight-based [196,200,201].

5.3.4.2 Ribavirin. The initial trials of therapy for coinfected patients used relatively low-dose ribavirin. For example, 800 mg/day was prescribed for patients in the APRICOT study (SVR genotype 1, 29%; SVR genotype 3, 62%) [196]. This was mainly because there were concerns regarding risks of anaemia – particularly for patients on zidovudine-containing regimens. However, it was subsequently recognized that higher doses of ribavirin (1000–1200 mg/day) are associated with improved SVR in HCV-monoinfected patients and the Peginterferon Ribavirina España Coinfección (PRESCO) trial confirmed this finding in coinfected patients with an overall SVR of 50% (SVR genotype 1, 35%; SVR genotype 3, 72%) [210].

Since the APRICOT trial there have been many advances in ART, with many more alternatives to zidovudine. Access to erythropoietin and other growth factors to support the patient with ribavirin-induced marrow suppression has also improved [210,211].

5.3.4.3 Monitoring. Monitor the patient weekly for the first 2–4 weeks, with review every 2–4 weeks thereafter if stable [194–196,200–202,205,206,210,212]. If the CD4 count falls below 200 cells/μL, Pneumocystis carinii pneumonia (PCP) prophylaxis should be considered. Cotrimoxazole may have haematological side effects and should be used at the lowest appropriate dosage.

5.3.4.4 Treatment duration. Early trials such as the APRICOT study recognized that this is a ‘hard-to-treat’ group and opted for longer duration of therapy (48 weeks) for all patients whatever the genotype [194–196,200–202,205]. Detailed analysis of the RVR and EVR from various studies has helped predict the SVR for the individual patient and there is increasing use of ‘tailoring the regimen’ for the individual according to the genotype, baseline viral load and initial virological response [194–196].

5.3.4.5 ‘Easier-to-treat’ genotypes. In patients with genotype 2 and 3 infection who have an RVR, a treatment duration of 24 weeks should be strongly considered [194–196]. In patients who do not have an RVR but reach an undetectable HCV viral load by 24 weeks, a 48-week course is recommended [194–196].

Treatment courses longer than 48 weeks are associated with poor compliance but may be considered in an individual patient with a slow but steady decline in the viral load who is tolerating therapy well [210,211,213].

5.3.4.6 ‘Harder-to-treat’ genotypes. In patients with genotypes 1 and 4, a 48-week course of treatment is recommended [194–196,200–202,205,206,210,211]. An extension to 72 weeks of therapy should be utilized in patients not achieving an RVR but who have a 2 log10 drop at 12 weeks and become PCR negative at 24 weeks [210,211,213]. The Sustained Long-term Antiviral Maintenance with Pegylated Interferon in HCV/HIV-co-infected Patients (SLAM-C) study showed 65% completion and 51% SVR after 72 weeks of treatment.

5.3.4.7 Recommendations

  • Anti-HCV treatment should be started before the CD4 count falls below 350 cells/μL and before ART is started, if possible (I).
  • The aim of treatment is an SVR (undetectable viral load 24 weeks post treatment) (I).
  • An RVR (viral load undetectable) at 4 weeks of treatment predicts response. Lack of EVR (nondetectable viral load or >2 log10 fall at 12 weeks) or detectable viral load at 24 weeks of treatment predicts nonresponse and therapy should be stopped (I).
  • Any ART should be stabilized before anti-HCV therapy is commenced (I).
  • Careful assessment of liver fibrosis is recommended, especially for patients with HCV genotypes 1 and 4 or those with suspected cirrhosis (I).
  • In patients with genotype 2 or 3 infection, liver biopsy is not necessary if there is no clinical evidence of advanced liver disease. For genotypes 1 and 4, a pretreatment liver biopsy is recommended, or a hepatic elastography if the biopsy is refused (I).
  • Consider treatment for all patients with genotypes 2/3. Consider treatment for all patients with genotypes 1/4, especially if there is significant liver fibrosis (Ishak grade F3 or more) (I).
  • Treatment in all genotypes should be with pegylated interferon weekly plus ribavirin at 1000–1200 mg daily, supported by erythropoietin/growth factors if necessary (I).
  • Treat patients with genotype 2 or 3 infection for 24 weeks if there is an RVR (II), otherwise for 48 weeks (I).
  • Treat patients with genotypes 1 and 4 for 48 weeks if there is an RVR, or 72 weeks if there was a 2 log10 drop but detectable HCV RNA at week 12 and they become PCR negative at 24 weeks (I).
5.3.5 Nonresponders and relapsers

There are limited data to guide re-treatment of nonresponders and relapsers in the setting of HIV [214]. In the HIV-negative population, re-treatment may be considered in individuals who have failed to respond with an SVR to non-gold standard therapy, i.e. nonpegylated interferon with or without ribavirin, or in individuals with progression of fibrosis [215,216].

Responses in all groups are less than in individuals receiving pegylated interferon and ribavirin de novo [214–216]. When re-treatment is considered, all modifiable factors known to affect response should be changed to meet optimal conditions, where possible.

The factors optimized should include the following.

  • weight-based ribavirin;
  • optimization of HAART with undetectable HIV viral load and substitution of zidovudine, stavudine, didanosine and abacavir with alternative active agents;
  • measurement and control of insulin resistance through weight loss and therapeutic agents such as metformin [212,217];
  • referral to an adherence specialist to ensure maintenance of full adherence to both HIV and hepatitis therapy;
  • use of growth factors where necessary to maintain full dose of pegylated interferon and ribavirin [210,211].

The REtreatment with PEgasys in pATients Not Responding to Peg-Intron Therapy (REPEAT) study in HIV-negative individuals suggested that a prolongation of therapy to 72 weeks led to a significantly higher SVR than 48 weeks of treatment, and prolongation to 72 weeks should be considered in all HIV-positive patients being retreated who are able to tolerate this length of treatment [218]. Although the REPEAT study showed no effect of double-dose peginterferon alpha-2a for the first 12 weeks on the subsequent ability to achieve SVR, a small study in HIV-coinfected patients suggested an improvement in EVR in HIV-positive patients undergoing re-treatment with double-dose pegylated interferon for the first 4 weeks of therapy [219]. Currently, therefore, there is no firm evidence to support the use of induction/double-dose pegylated interferon.

The National Institutes of Health (NIH)-sponsored Hepatitis C Antiviral Long-Term Treatment aganist Cirrhosis (HALT-C) clinical trial failed to show a benefit of maintenance interferon on differences in the rates of mortality, decompensation, HCC, or fibrosis progression between the peginterferon alpha-2a maintenance group and the control group [220]. A similar study in HIV-positive individuals – the SLAM-C study – was also unable to show any beneficial effect on fibrosis progression rates [221]. Pegylated interferon is thus not recommended as maintenance therapy in HIV-positive individuals who have failed previous anti-hepatitis C therapy.

5.3.6 New therapies for hepatitis C

Several new therapeutic avenues are being explored for the treatment of hepatitis C. These include new forms of interferon, ribavirin analogues, and direct antiviral agents including protease inhibitors and polymerase inhibitors [222–227]. None of these new agents has been subject to clinical trial yet in HIV-positive patients. When these agents become available for the treatment of HIV-negative patients, those caring for the coinfected population should balance the possible positive effects of greater SVR with the unknown efficacy in an HIV-positive population, drug interactions with HAART and other drugs widely used in HIV practice and possible toxicities (IV).

Coinfected individuals should be encouraged to enter clinical studies of these new agents. Similarly, pharmaceutical companies should be encouraged to remove the barriers for HIV-positive individuals to enter studies and to study possible drug interactions early in the development of such agents and initiate studies of coinfected populations early in the course of therapy (IV).

5.4 Acute hepatitis C

5.4.1 Epidemiology

Over the past few years there have been increasingly recognized outbreaks of acute hepatitis C amongst MSM; while initially localized in cities with high MSM populations, cases are now being reported more widely and incidence rates appear to be still increasing [2,3,155,158–161,228]. While the exact mode of transmission remains unclear, associations have been seen with HIV-positive status, recent sexually transmitted infections (syphilis, lymphogranuloma venereum and gonorrhoea), multiple sexual partners, unprotected anal intercourse and recreational drug use [2,3,155,158–161,228].

5.4.2 Clinical picture and natural history

The majority of diagnoses of acute hepatitis C have been made in asymptomatic patients with unexplained transaminase levels or on repeat routine HCV antibody testing. Some patients may exhibit a nonspecific illness with jaundice and nausea. The rate of spontaneous clearance of HCV after acute infection in individuals with acute hepatitis is approximately 15–25%. Spontaneous clearance appears to be more commonly seen in those with symptomatic infection, greater transaminase elevations and higher CD4 cell counts, and in those taking ART [180–182,229].

Three different patterns of HCV RNA evolution have been described following acute infection: persistent high levels of viraemia, rapid RNA reduction with subsequent clearance, and fluctuating high and low levels of HCV-RNA. Close monitoring of RNA levels may therefore help to identify those individuals who are or are not likely to clear HCV without intervention [230]. After acute infection, it has been suggested that progressive liver damage may occur more rapidly than has been historically reported in coinfected individuals [231].

5.4.3 Diagnosis of acute HCV infection

For appropriate tests see section 5.2.1.

The timing of acute infection may be more clearly delineated by retrospective testing of stored specimens (e.g. those previously obtained for HIV viral load or syphilis monitoring) using HCV antibody and/or RNA testing. Determination of the timing of infection is likely to assist surveillance, contact tracing and treatment decisions.

5.4.4 Management

There are no randomized controlled trials to guide decisions on whether to treat, with what, and for what duration in this setting. Initial observational data from HIV-uninfected patients with acute HCV infection showed a remarkably high rate (98%) of sustained virological response in 44 individuals [232].

Several case series report experiences of treatment of acute HCV in HIV-infected individuals [180,181,233–238]. Overall, these suggest that, while response rates in those with HIV coinfection appear to be lower than the rates seen in those with HCV monoinfection, clearance is higher than in those with established HCV coinfection, particularly for genotype 1. While there is a suggestion in some cohorts that response rates may be greater with longer duration of therapy and with lower initial HCV viral load, there are no clear data to support the routine addition of ribavirin to pegylated interferon or prolonged duration of therapy.

Given that spontaneous clearance occurs in a minority of individuals, a period of observation may be warranted. Most cohort data suggest that, if a policy of treatment deferral until 24 weeks is used to determine whether spontaneous clearance is achieved, subsequent treatment response is not diminished [235]. However, in some studies, deferred therapy for HCV beyond 12 weeks was associated with impaired response, especially to genotype 1 [237,238]. Individualization in discussion with clinicians experienced in management of HIV/HCV coinfection is recommended to optimize the management and potential of this ‘window of opportunity’ of intervention. It is important to consider entering all patients with acute HCV infection into clinical trials.

5.4.5 Recommendations
  • All HIV-positive patients with unexplained transaminitis should be evaluated for acute HCV infection (with HCV antibody and RNA testing) (II).
  • HIV-infected MSM should be tested for HCV antibody on an annual basis (II).
  • HIV-infected MSM should be informed about current understanding of acute HCV infection and possible transmission risks (IV).
  • Individuals identified as having acute HCV infection should have quantitative RNA measurements performed on a regular (usually 4-weekly) basis for the first 12–24 weeks to inform treatment decisions (III).
  • Those individuals who show no trend towards reduction in HCV RNA or have failed to clear HCV by 3–6 months after initial RNA positivity should be offered treatment (III).
  • The optimal duration and mode of treatment have yet to be determined. At present, a 6–12-month course of pegylated interferon with weight-adjusted ribavirin is recommended (II).
  • Future clinical trials should be established to determine the benefit, optimal regimen and optimal duration of therapy for acute HCV infection in HIV-infected patients (IV).

Conflicts of interest

  1. Top of page
  2. Level of evidence
  3. Audit standards
  4. 1.0 Introduction
  5. 2.0 Methodology
  6. 3.0 General section: Prevention of viral hepatitis and management principles for patients with viral hepatitis
  7. 4.0 Coinfection with HIV and hepatitis B virus
  8. 5.0 Coinfection with HIV and hepatitis C virus
  9. Conflicts of interest
  10. Appendices

Dr Gary Brook has received lecture fees from Bristol-Myers Squibb, Gilead and Jansen-Cilag and participated in clinical trials funded by Gilead.

Dr Janice Main participated in clinical trials, invited talks and advisory committee work for various companies (Roche, Schering-Plough, BMS, GlaxoSmithKline, BI).

Dr Mark Nelson received research grants from Gilead, Schering-Plough, Roche and BMS. He was on the advisory board for Gilead, BMS, Schering-Plough, Roche and Idenix and received speaker fees from Gilead, BMS, Schering-Plough and Roche.

Dr Sanjay Bhagani received speaking honoraria, travel grants and consultation fees from BMS, Gilead Sciences, Roche and Schering Plough. He also received research funding from Gilead Sciences.

Dr Ed Wilkins received educational and personal grants from MSD, Abbott, BMS, GSK, Pfizer, Gilead, and Tibotec for speaking at company-sponsored events, attending conferences and supporting research.

Dr Clifford Leen has received travel grants from, has been on the speakers' bureau of, has received an honorarium for speaking from, has sat on the medical advisory boards of, and/or has acted as an advisor for, the following pharmaceutical companies: Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Gilead, Johnson and Johnson, Roche and Pfizer. He has received research grants from the following companies: ARK, Abbott, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Roche, Pfizer and Tibotec.

Dr Martin Fisher has received honoraria, travelling scholarships and/or research funding from, and/or has acted as an advisor to, the following companies: Abbott, Boehringer Ingelhiem, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck Sharp and Dohme, Pfizer and Roche.

Dr Yvonne Gilleece received sponsorship from Gilead, Tibotec, BMS, Abbott and GSK (conferences, etc).

Dr Richard Gilson has received support from Gilead Sciences, Roche and Schering-Plough to attend conferences, and has received departmental support for research from Gilead Sciences and Roche.

Dr. Andrew Freedman received financial support for attending conferences as well as honoraria for advisory boards and lectures from Tibotec, BMS, Gilead & Abbott.

Dr. Ranjababu Kulasegaram received travel grants and honoraria from Abbott, Bristol-Myers Squibb, GlaxoSmithKline, MSD, Pfizer, Roche and Tibotec.

Dr Kosh Agarwal – None stated.

Professor Caroline Sabin received funding for training, consultancy, advisory board membership etc. from several pharmaceutical companies, including Gilead Sciences, Bristol-Myers Squibb and Jansen-Cilag.

Craig Deacon-Adams received funding from Gilead Sciences and Boehringer for magazine production and attendance at conferences. BMS also supplied travel and accommodation at the IAS Meeting in Cape Town.

Appendices

  1. Top of page
  2. Level of evidence
  3. Audit standards
  4. 1.0 Introduction
  5. 2.0 Methodology
  6. 3.0 General section: Prevention of viral hepatitis and management principles for patients with viral hepatitis
  7. 4.0 Coinfection with HIV and hepatitis B virus
  8. 5.0 Coinfection with HIV and hepatitis C virus
  9. Conflicts of interest
  10. Appendices

Appendix

BHIVA Guidelines Writing Committee acting on behalf of the BHIVA Viral Hepatitis Writing Group:

Writing group chair and hepatitis B co-lead: Dr Gary Brook, North West London Hospitals NHS Trust.

Writing group deputy chair and hepatitis B co-lead: Dr Janice Main, St Mary's Hospital, London.

Hepatitis C lead: Dr Mark Nelson, Chelsea and Westminster NHS Foundation Trust.

General section lead: Dr Sanjay Bhagani, Royal Free Hampstead NHS Trust, London.

Members: Dr Ed Wilkins, North Manchester General Hospital; Dr Clifford Leen, Western General Infirmary, Edinburgh; Dr Martin Fisher, Brighton and Sussex University Hospitals NHS Trust; Dr Yvonne Gilleece, Brighton and Sussex University Hospitals NHS Trust; Dr Richard Gilson, Mortimer Market Centre, London; Dr Andrew Freedman, Cardiff University School of Medicine; Dr Ranjababu Kulasegaram, Guy's & St Thomas' Hospital NHS Foundation Trust, London; Dr Kosh Agarwal, King's College Hospital, London; Prof. Caroline Sabin, Royal Free and University College Medical School, London; Mr Craig Deacon-Adams, community representative.

References

  1. Top of page
  2. Level of evidence
  3. Audit standards
  4. 1.0 Introduction
  5. 2.0 Methodology
  6. 3.0 General section: Prevention of viral hepatitis and management principles for patients with viral hepatitis
  7. 4.0 Coinfection with HIV and hepatitis B virus
  8. 5.0 Coinfection with HIV and hepatitis C virus
  9. Conflicts of interest
  10. Appendices
  • 1
    Giraudon I, Ruf M, Maguire H et al. Increase in diagnosed newly acquired hepatitis C in HIV positive men who have sex with men across London and Brighton, 2001–2006: is this an outbreak? Sex Transm Infect 2008; 84: 111115.
  • 2
    Van De Laar T, Pybus O, Bruisten S et al. Evidence of a large, international network of HCV transmission in HIV-positive men who have sex with men. Gastroenterology 2009; 136: 16091617.
  • 3
    Danta M, Brown D, Bhagani S et al. Recent epidemic of acute hepatitis C Virus in HIV-positive men who have sex with men linked to high-risk sexual behaviours. AIDS 2007; 21: 983991.
  • 4
    Danta M, Dusheiko G. Acute HCV in HIV-positive individuals – a review. Curr Pharmaceut Design 2008; 14: 16901697.
  • 5
    Sanchez J, Gotuzzo E, Escamilla J et al. Sexually transmitted infections in female sex workers: reduced by condom use but not by a limited periodic examination programme. Sex Trans Dis 1998; 25: 8289.
  • 6
    Bhave G, Lindan CP, Hudes ES et al. Impact of an intervention on HIV, sexually transmitted diseases and condom use among sex workers in Bombay. AIDS 1995; 9 (Suppl 1): S21S30.
  • 7
    Tanaka M, Nakayama H, Sakumoto M et al. Trends in sexually transmitted diseases and condom use patterns among commercial sex workers in Fukuoka City, Japan 1990–93. Genitourin Med 1996; 72: 358361.
  • 8
    Stewart T, Crofts N. An outbreak of hepatitis A among homosexual men in Melbourne. Med J Aust 1993; 158: 519521.
  • 9
    Reintjes R, Bosman A, De Zwart O et al. Outbreak of hepatitis A in Rotterdam associated with visits to ‘darkrooms’ in gay bars. Comm Dis Pub Health 1999; 2: 4346.
  • 10
    Bell A, Ncube F, Hansell A et al. An outbreak of hepatitis A among young men associated with having sex in public venues. Comm Dis Pub Health 2001; 4: 163170.
  • 11
    Mansson AS, Moestrup T, Nordenfelt E et al. Continued transmission of hepatitis B and C viruses, but no transmission of human immunodeficiency virus amongst inatravenous drug users participating in a syringe/needle exchange program. Scand J Infect Dis 2000; 32: 253258.
  • 12
    Amundsen EJ, Eskild E, Stigum H et al. Legal access to needles and syringes/needle exchange programmes versus HIV counselling and testing to prevent transmission of HIV among intravenous drug users. Eur J Pub Health 2003; 13: 252258.
  • 13
    Seal KH, Kral AH, Lorvick J et al. A randomized controlled trail of monetary incentives vs outreach to enhance the adherence to the hepatitis B vaccine series among injection drug users. Drug Alcohol Depend 2003; 71: 127131.
  • 14
    Borg L, Khuri E, Melia D et al. Methadone-maintained former heroin addicts, including those who are anti-HIV-1 seropositive, comply with and respond to hepatitis B vaccination. Addiction 1999; 94: 489493.
  • 15
    Veiga AP, Casseb J, Duarte AJ. Humoral response to hepatitis B vaccination and its relationship with T CD45RA+ (naive) and CD45RO+ (memory) subsets in HIV-1-infected subjects. Vaccine 2006; 24: 71247128.
  • 16
    Francis DP, Hadler SC, Thompson SE et al. The prevention of hepatitis B with vaccine. Report of the Centers for Disease Control multi-center efficacy trial among homosexual men. Ann Int Med 1982; 97: 362366.
  • 17
    Jack AD, Hall AJ, Maine N, Mendy M, Whittle HC. What level of hepatitis B antibody is protective? J Infect Dis 1999; 179: 489492.
  • 18
    Wong EK, Bodsworth NJ, Slade MA, Mulhall BP, Donovan B. Response to hepatitis B vaccination in a primary care setting: influence of HIV infection, CD4+ lymphocyte count and vaccination schedule. Int J STD AIDS 1996; 7: 490494.
  • 19
    Rey D, Krantz V, Partisani M et al. Increasing the number of hepatitis B vaccine injections augments anti-HBs response rate in HIV-infected patients. Effects on HIV-1 viral load. Vaccine 2000; 18: 11611165.
  • 20
    Brook MG, Rubinstein L, King G. Hepatitis B testing and vaccination in patients recently diagnosed with HIV infection. Int J STD AIDS 2008; 19: 8384.
  • 21
    Fonseca MO, Pang LW, De Paula Cavalheiro N et al. Randomized trial of recombinant hepatitis B vaccine in HIV-infected adult patients comparing a standard dose to a double dose. Vaccine 2005; 23: 29022908.
  • 22
    Gandhi RT, Wurcel A, Lee H et al. Response to hepatitis B vaccine in HIV-1-positive subjects who test positive for isolated antibody to hepatitis B core antigen: implications for hepatitis B vaccine strategies. J Infect Dis 2005; 191: 14351441.
  • 23
    Geretti AM, Brook G, Cameron C et al. British HIV Association guidelines for immunization of HIV-infected adults 2008. HIV Med 2008; 9: 795848.
  • 24
    Bianco E, Stroffolini T, Spada E et al. Case fatality rate of acute viral hepatitis in Italy: 1995–2000. An update. Dig Liver Dis 2003; 35: 404408.
  • 25
    Willner IR, Uhl MD, Howard SC, Williams EQ, Riely CA, Waters B. Serious hepatitis A: an analysis of patients hospitalized during an urban epidemic in the United States. Ann Int Med 1998; 128: 111114.
  • 26
    Lok A, McMahon BJ. Practice Guidelines Committee, American Association for the Study of Liver Diseases. Chronic hepatitis B. Hepatology 2001; 34: 12251239.
  • 27
    Chevillotte G, Durbec JP, Gerolami A et al. Interaction between hepatitis B virus and alcoholic consumption in liver cirrhosis: an epidemiological study. Gastroenterology 1983; 85: 141145.
  • 28
    Mehta SH, Lau B, Afdhal NH, Thomas DL. Exceeding the limits of liver histology markers. J Hepatol 2009; 50: 3641.
  • 29
    Vergniol J, Foucher J, Castera L et al. Changes of non-invasive markers and FibroScan values during HCV treatment. J Viral Hepat 2009; 16: 132140.
  • 30
    Cappell MS, Schwartz MS, Biempica L et al. Clinical utility of liver biopsy in patients with serum antibodies to the human immunodeficiency virus. Am J Med 1990; 88: 123130.
  • 31
    Sulkowski MS, Mehta SH, Torbenson MS et al. Rapid fibrosis progression among HIV/hepatitis C virus-co-infected adults. AIDS 2007; 21: 22092216.
  • 32
    Nguyen-Khac E, Capron D. Noninvasive diagnosis of liver fibrosis by ultrasonic transient elastography (Fibroscan). Eur J Gastroenterol Hepatol 2006; 18: 13211325.
  • 33
    Shaheen AA, Wan AF, Myers RP. FibroTest and FibroScan for the prediction of hepatitis C-related fibrosis: a systematic review of diagnostic test accuracy. Am J Gastroenterol 2007; 102: 25892600.
  • 34
    Friedrich–Rust M, Ong M. Performance of transient elastography for the staging of liver fibrosis: a meta-analysis. Gastroenterology 2008; 134: 960974.
  • 35
    Paggi S, Colli A, Fraquelli M et al. A non-invasive algorithm accurately predicts advanced fibrosis in hepatitis C: a comparison using histology with internal-external validation. J Hepatol 2008; 49: 564571.
  • 36
    Gressner OA, Weiskirchen R, Gressner AM. Biomarkers of hepatic fibrosis, fibrogenesis and genetic pre-disposition pending between fiction and reality. J Cell Mol Med 2007; 11: 10311051.
  • 37
    Labarga P, Soriano V, Vispo ME et al. Hepatotoxicity of antiretroviral drugs is reduced after successful treatment of chronic hepatitis C in HIV-infected patients. J Infect Dis 2007; 196: 670676.
  • 38
    Phillips E, Gutiérrez S, Jahnke N et al. Determinants of nevirapine hypersensitivity and its effect on the association between hepatitis C status and mortality in antiretroviral drug-naive HIV-positive patients. AIDS 2007; 21: 15611568.
  • 39
    Gonzalez de Requena D, Nunez M, Jimenez-Nacher I, Soriano V. Liver toxicity caused by nevirapine. AIDS 2002; 25: 290291.
  • 40
    Macǐas J, Castellano V, Merchante N et al. Effect of antiretroviral drugs on liver fibrosis in HIV-infected patients with chronic hepatitis C: harmful impact of nevirapine. AIDS 2004; 18: 767774.
  • 41
    Mocroft A, Rockstroh J, Soriano V et al. Are specific antiretrovirals associated with an increased risk of discontinuation due to toxicities or patient/physician choice in patients with hepatitis C virus coinfection? Antivir Ther Lond 2005; 10: 779790.
  • 42
    Sulkowski MS, Mehta SH, Torbenson M et al. Hepatic steatosis and antiretroviral drug use among adults coinfected with HIV and hepatitis C virus. AIDS 2005; 19: 585592.
  • 43
    McGovern BH, Ditelberg JS, Taylor LE et al. Hepatic steatosis is associated with fibrosis, nucleoside analogue use, and hepatitis C virus genotype 3 infection in HIV-seropositive patients. Clin Infect Dis 2006; 43: 365372.
  • 44
    Maida I, Garcia-Gasco P, Sotgiu G et al. Antiretroviral-associated portal hypertension: a new clinical condition? Prevalence, predictors and outcome. Antivir Ther 2008; 13: 103107.
  • 45
    Chan-Tack KM, Struble KA, Birnkrant DB. Intracranial hemorrhage and liver-associated deaths associated with tipranavir/ritonavir: review of cases from the FDA's Adverse Event Reporting System. AIDS Patient Care Stds 2008; 22: 843850.
  • 46
    Vispo E. Warning on hepatotoxicity of darunavir. AIDS Rev 2008; 10: 63.
  • 47
    Rosenthal E, Poiree M, Pradier C et al. Mortality due to hepatitis-C related liver disease in HIV-infected patients in France (Mortavic 2001 study). AIDS 2003; 17: 18031809.
  • 48
    Merchante N, Giron-Gonzalez J, Gonzalez-Serrano M et al. Survival and prognostic factors of HIV-infected patients with HCV-related end stage liver disease. AIDS 2006; 20: 4957.
  • 49
    Merchante N, Jimenez-Saenz M, Pineda J. Management of HCV-related end-stage liver disease in HIV-coinfected patients. AIDS Rev 2007; 9: 131139.
  • 50
    Garcia-Samaniego J, Rodriguez M, Berenguer J et al. Hepatocellular carcinoma in HIV-infected patients with chronic hepatitis C. Am J Gastroenterol 2001; 96: 179183.
  • 51
    Puoti M, Bruno R, Soriano V et al. Hepatocellular carcinoma in HIV-infected patients: epidemiological features, clinical presentation, and outcomes. AIDS 2004; 18: 22852293.
  • 52
    Brau N, Fox R, Xiao P et al. Presentation and outcome of hepatocellular carcinoma in HIV-infected patients: a U.S.-Canadian multicentre study. J Hepatol 2007; 47: 527537.
  • 53
    Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005; 42: 12081236.
  • 54
    Chen J, Yang HI, Su J et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA levels. JAMA 2006; 295: 6573.
  • 55
    Clifford G, Rickenbach M, Polesel J et al. Influence of HIV-related immunodef iciency on the risk of hepatocellular carcinoma. AIDS 2008; 22: 21352141.
  • 56
    El-Sarag H, Marremo J, Lenhard R, Reddy R. Diagnosis and treatment of hepatocellular carcinoma. Gastroenterology 2008; 135: 17521763.
  • 57
    Zhang BH, Yang BH, Tang JY et al. Randomised controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol 2004; 130: 417422.
  • 58
    Soriano V, Miro J, Garcia-Smaniego J et al. Consensus conference on chronic viral hepatitis and HIV infection: updated Spanish recommendations. J Viral Hepat 2004; 11: 217.
  • 59
    O'Grady J, Taylor C, Brook G. Guidelines for liver transplantation in patients with HIV infection (2005). HIV Med 2005; 6 (Suppl 2): 149153.
  • 60
    Roland M, Stock P. Liver transplantation in HIV-infected recipients. Semin Liver Dis 2006; 26: 273284.
  • 61
    Terrault N, Carter J, Carlson L et al. Outcome of patients with HBV and HIV infections referred for liver transplantation. Liver Transpl 2006; 12: 801807.
  • 62
    Joshi D, Aluvihare V, Belgaumkar A et al. Liver transplantation for HIV: analysis of outcomes suggest HIV/HCV co-infected patients have prohibitively poor survival at 5 years. 59th Annual Meeting of the American Association for the Study of Liver Diseases, San Francisco, October 2008 [Abstract 6].
  • 63
    Miro JM, Aguero F, Laguno M et al. Liver transplantation in HIV/hepatitis co-infection. J HIV Ther 2007; 12: 2435.
  • 64
    Mindikoglu AL, Reger A, Magder LS. Impact of human immunodeficiency virus on survival after transplantation; analysis of United Network for Organ Sharing database. Transplantation 2008; 85: 359368.
  • 65
    Duclos-Vallee JC, Feray C, Sebhag M et al. Survival and recurrence of hepatitis C after liver transplantation in patients co-infected with human immunodeficiency virus and hepatitis C. Hepatology 2008; 47: 407417.
  • 66
    Miro J, Montejo M, Castells L et al. 5-year survival of HCV/HIV co-infected liver transplant recipients: a case-control study. In: Programme and abstracts, 16th Conference on Retroviruses and Opportunistic Infections. Montreal, Canada, February 2009 [Abstract P833].
  • 67
    Suddle A, Aluvihare V, Muiesan P et al. Long Term Outcomes in Non-Heart Beating Donor Grafts in Liver Transplantation for Chronic Hepatitis C: no increase in HCV recurrence or graft loss. 59th Annual Meeting of the American Association for the Study of Liver Diseases. San Francisco, October 2008 [Abstract 596].
  • 68
    Moreno A, Barcena R, Del Campo S et al. Effect of HIV co-infection on the outcome of viral cirrhosis liver transplant candidates on the waiting list at a reference centre 2001–2008. In: Programme and abstracts, 16th Conference on Retroviruses and Opportunistic Infections. Montreal, Canada, February 2009 [Abstract P835].
  • 69
    WHO. Hepatitis B. Fact sheet No. 204 Aug 2008. Available at http://www.who.int/mediacentre/factsheets/fs204/en/ (accessed 22 October 2008).
  • 70
    UNAIDS. 2008 Report on the global AIDS epidemic: HIV and AIDS estimates and data 2001 and 2007. Available at http://data.unaids.org/pub/GlobalReport/2008/jc1510_2008_global_report_pp211_234_en.pdf (accessed 22 October 2008).
  • 71
    Benhamou Y. Hepatitis B in the HIV-coinfected patient. JAIDS 2007; 45 (Suppl 2): S57S65 and S66–S67.
  • 72
    Konopnicki D, Mocroft A, De Wit S et al. Hepatitis B and HIV: prevalence, AIDS progression, response to highly active antiretroviral therapy and increased mortality in the EuroSIDA cohort. AIDS 2005; 19: 593601.
  • 73
    De Silva S, Brook MG, Curtis H, Johnson M, on behalf of the British HIV Association Audit Committee. Survey of HIV and hepatitis B or C co-infection management in the UK 2004. Int J STD AIDS 2006; 17: 799801.
  • 74
    Firnhaber C, Reyneke A, Schulze D et al. The prevalence of hepatitis B co-infection in a South African urban government HIV clinic. South African Med J 2008; 98: 541544.
  • 75
    Nyirenda M, Beadsworth MB, Stephany P et al. Prevalence of infection with hepatitis B and C virus and coinfection with HIV in medical inpatients in Malawi. J Infection 2008; 57: 7277.
  • 76
    Health Protection Agency. HIV data: Black Africans and Black Caribbeans: 2007 Black African and black Caribbean Summary Statistics. Available at http://www.hpa.org.uk/web/HPAweb&HPAwebStandard/HPAweb_C/1203084368853 (accessed 23 September 2009).
  • 77
    Opravil M, Hunziker R, Luthy R et al. Chronic hepatitis B and C in HIV infected patients. Deutsche Med Wochensch 1998; 123: 753760.
  • 78
    Piroth L, Sene D, Pol S et al. Epidemiology, diagnosis and treatment of chronic hepatitis B in HIV-infected patients (EPIB 2005 STUDY). AIDS 2007; 21: 13231331.
  • 79
    Jain MK, Parekh NK, Hester J, Lee WM. Aminotransferase elevation in HIV/hepatitis B virus co-infected patients treated with two active hepatitis B virus drugs. AIDS Patient Care STDS 2006; 20: 817822.
  • 80
    Hoffmann CJ, Charalambous S, Thio CL et al. Hepatotoxicity in an African antiretroviral therapy cohort: the effect of tuberculosis and hepatitis B. AIDS 2007; 21: 13011308.
  • 81
    Omland LH, Weis N, Skinhøj P et al. Impact of hepatitis B virus co-infection on response to highly active antiretroviral treatment and outcome in HIV-infected individuals: a nationwide cohort study. HIV Med 2008; 9: 300306.
  • 82
    Bodsworth NJ, Cooper DA, Donovan B. The influence of human immunodeficiency virus type 1 infection on the development of the hepatitis B virus carrier state. J Infect Dis 1991; 163: 11381140.
  • 83
    Puoti M, Torti C, Bruno R, Filice G, Carosi G. Natural history of chronic hepatitis B in co-infected patients. J Hepatol 2006; 44 (Suppl): S65S70.
  • 84
    Thio CL. Hepatitis B and human immunodeficiency virus coinfection. Hepatology 2009; 49 (Suppl): S138S145.
  • 85
    Marcellin P, Pequignot F, Delarocque-Astagneau E et al. Mortality related to chronic hepatitis B and chronic hepatitis C in France: evidence for the role of HIV coinfection and alcohol consumption. J Hepatol 2008; 48: 200207.
  • 86
    Weber R, Sabin CA, Friis-Moller N et al. Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study. Arch Int Med 2006; 166: 16321641.
  • 87
    Mai AL, Yim C, O'Rourke K et al. The interaction of human immunodeficiency virus infection and hepatitis B virus infection in homosexual men. J Clin Gastroenterol 1996; 22: 299304.
  • 88
    Sheng WH, Kao JH, Chen PJ et al. Evolution of hepatitis B serological markers in HIV-infected patients receiving highly active antiretroviral therapy. Clin Infect Dis 2007; 45: 12211229.
  • 89
    Miailhes P, Trabaud MA, Pradat P et al. Impact of highly active antiretroviral therapy (HAART) on the natural history of hepatitis B virus (HBV) and HIV coinfection: relationship between prolonged efficacy of HAART and HBV surface and early antigen seroconversion. Clin Infect Dis 2007; 45: 624632.
  • 90
    Manegold C, Hannoun C, Wywiol A et al. Reactivation of hepatitis B virus replication accompanied by acute hepatitis in patients receiving highly active antiretroviral therapy. Clin Infect Dis 2001; 32: 144148.
  • 91
    Nebbia G, Garcia-Diaz A, Ayliffe U et al. Predictors and kinetics of occult hepatitis B virus infection in HIV-infected persons. J Med Virol 2007; 79: 14641471.
  • 92
    Hofer M, Joller-Jemelka HI, Grob PJ et al. Frequent chronic hepatitis B virus infection in HIV-infected patients positive for antibody to hepatitis B core antigen only. Swiss cohort study. Eur J Clin Microbiol Infect Dis 1998; 17: 613.
  • 93
    Martin-Carbonero L, Soriano V, Valencia E et al. Increased impact of chronic viral hepatitis on hospital admissions and mortality among HIV-infected patients. AIDS Res Hum Retroviruses 2001; 17: 14671471.
  • 94
    Pungpapong S, Kim WR, Poterucha JJ. Natural history of hepatitis B virus infection: an update for clinicians. Mayo Clin Proc 2007; 82: 967975.
  • 95
    IIoeje UH, Yang HI, Su J et al. Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-In HBV (the REVEAL-HBV) Study Group. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology 2006; 130: 678686.
  • 96
    Chen CJ, Yang HI, Yeh SH et al. for the REVEAL-HBV Study Group. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006; 296: 6573.
  • 97
    Yuen MK, Ng IO, Fan ST et al. Significance of HBV DNA levels in liver histology of HBeAg and Anti-HBe positive patients with chronic hepatitis B. Am J Gastroenterol 2004; 99: 20322037.
  • 98
    Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology 2007; 45: 507539.
  • 99
    European Association for the Study of Liver. EASL Clinical Practice Guidelines: management of chronic hepatitis. Br J Hepatol 2009; 50: 227242.
  • 100
    Carreno V, Rico MA, Pardo M, Quiroga JA. Extended follow-up of anti-HBe-positive patients with chronic hepatitis B retreated with ribavirin and interferon-alpha. Antivir Res 2001; 52: 147152.
  • 101
    Bonino E, Marcellin P, Lau GK et al. for the Pegintron Alfa-2a HBeAg-Negative Chronic Hepatitis B Study Group. Predicting response to peginterferon alpha-2a, lamivudine and the two combined for HBeAg-negative chronic hepatitis B. Gut 2007; 56: 699705.
  • 102
    Idilman R, Kaymakoglu S, Oguz Onder F et al. A short course of add-on adefovir dipivoxil treatment in lamivudine-resistant chronic hepatitis B patients. J Viral Hepat 2009; 16: 279285.
  • 103
    Pawlotsky JM. Virologic techniques for the diagnosis and monitoring of hepatitis B. Gastroenterol Clin Biol 2008; 32: S56S63.
  • 104
    Papatheodoridis GV, Manesis EK, Manolakopoulos S et al. Is there a meaningful serum hepatitis B virus DNA cutoff level for therapeutic decisions in hepatitis B e antigen-negative chronic hepatitis B virus infection? Hepatology 2008; 48: 14511459.
  • 105
    Giovanna F, Bortolotti F, Francesco D. Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors. J Hepatol 2008; 48: 335352.
  • 106
    Lai CL, Yuen MF. The natural history of chronic hepatitis B. J Viral Hepat 2007; 14 (Suppl 1): 610.
  • 107
    Stuyver L, Van Geyt C, De Gendt S et al. Line probe assay for monitoring drug resistance in hepatitis B virus-infected patients during antiviral therapy. J Clin Microbiol 2000; 38: 702707.
  • 108
    Lok AS, Zoulim F, Locarnini S et al. Monitoring drug resistance in chronic hepatitis B virus (HBV)-infected patients during lamivudine therapy: evaluation of performance of INNO-LiPA HBV DR assay. J Clin Microbiol 2002; 40: 37293734.
  • 109
    Zoulim F, Buti M, Lok AS. Antiviral-resistant hepatitis B virus: can we prevent this monster from growing? J Viral Hepat 2007; 14 (Suppl 1): 2936.
  • 110
    Zoulim F. New nucleic acid diagnostic tests in viral hepatitis. Semin Liver Dis 2006; 26: 309317.
  • 111
    Flink HJ, Van Zonneveld M, Hansen BE et al. for the 99-01 Study Group. Treatment with Peg-interferon alpha-2b for HBeAg-positive chronic hepatitis B:HBsAg loss is associated with HBV genotype. Am J Gastroenterol 2006; 101: 297303.
  • 112
    Yang HI, Yeh SH, Chen PJ et al. for the REVEAL-HBV Study Group. Associations between hepatitis B virus genotype and mutants and the risk of hepatocellular carcinoma. J Natl Cancer Inst 2008; 100: 11341143.
  • 113
    Wai CT, Chu CJ, Hussain M, Lok AS. HBV genotype B is associated with better response to interferon therapy in HBeAg(+) chronic hepatitis than genotype C. Hepatology 2002; 36: 14251430.
  • 114
    Erhardt A, Reineke U, Blondin D et al. Mutations of the core promoter and response to interferon treatment in chronic replicative hepatitis B. Hepatology 2000; 31: 716725.
  • 115
    Kao JH, Chen PJ, Lai MY et al. Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B. Gastroenterology 2000; 118: 554559.
  • 116
    Tsubota AK, Arase Y, Ren FR et al. Genotype may correlate with liver carcinogenesis and tumor characteristics in cirrhotic patients infected with hepatitis B virus subtype adw. J Med Virol 2001; 65: 257265.
  • 117
    Pawlotsky JM, Dusheiko G, Hatzakis A et al. Virologic monitoring of hepatitis B virus therapy in clinical trials and practice: recommendations for a standardized approach. Gastroenterology 2008; 134: 405415.
  • 118
    EASL Clinical Practice Guidelines: management of hepatitis B. European association for the study of the liver. J Hepatol 2009; 50: 227242.
  • 119
    Soriano V, Puoti M, Peters M et al. Care of HIV patients with chronic hepatitis B: updated recommendations from the HIV-Hepatitis B virus international panel. AIDS 2008; 22: 13991410.
  • 120
    Carosi G, Rizzeto M. Treatment of chronic hepatitis B: recommendations from an Italian workshop. Dig Liver Dis 2008; 40: 603617.
  • 121
    Rockstroh JK, Bhagani S, Benhamou Y et al. European AIDS Clinical Society (EACS) guidelines for the clinical management and treatment of chronic hepatitis B and C coinfection in HIV-infected adults. HIV Med 2008; 9: 8288.
  • 122
    Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. November 3, 2008. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf (accessed 3 August 2009).
  • 123
    Sorrell MF, Belongia EA, Costa J et al. National Institutes of Health Consensus Development Conference Statement: management of Hepatitis B. Ann Int Med 2009; 150: 104110.
  • 124
    Gazzard B, Anderson A, Babiker A et al. British HIV Association guidelines for the treatment of HIV-1-infected adults with antiretroviral therapy 2008. HIV Med 2008; 9: 563608.
  • 125
    Johnson R, Ristig M, Overton E et al. Safety and tolerability of sequential pegylated IFN-alpha2a and tenofovir for hepatitis B infection in HIV+individuals. HIV Clin Trials 2007; 8: 173181.
  • 126
    Chu CM, Liaw YF. Hepatitis B virus-related cirrhosis: natural history and treatment. Semin Liver Dis 2006; 26: 142152.
  • 127
    Peters MG, Andersen J, Lynch P et al. Randomized controlled study of tenofovir and adefovir in chronic hepatitis B virus and HIV infection: ACTG A5127. Hepatology 2006; 44: 11101116.
  • 128
    Sheldon JA, Corral A, Rodes B et al. Risk of selecting K65R in antiretroviral-naive HIV-infected individuals with chronic hepatitis B treated with adefovir. AIDS 2005; 19: 20362038.
  • 129
    Lampertico P, Vigano M, Manenti E et al. Colombo M. Low resistance to adefovir combined with lamivudine: a 3-year study of 145 lamivudine-resistant hepatitis B patients. Gastroenterology 2007; 133: 14451451.
  • 130
    McMahon M, Jilek B, Brennan T et al. The HBV drug entecavir – effects on HIV replication and resistance. N Engl J Med 2007; 356: 26142621.
  • 131
    Dore GJ, Cooper DA, Barrett C et al. Dual efficacy of lamivudine treatment in human immunodeficiency virus/hepatitis B virus–coinfected persons in a randomized, controlled study (CAESAR). CAESAR Coordinating Committee. J Infect Dis 1999; 180: 607613.
  • 132
    Matthews G, Bartholomeusz A, Locarnini S et al. Characteristics of drug resistant HBV in an international collaborative study of HIV-HBV-infected individuals on extended lamivudine therapy. AIDS 2006; 20: 863870.
  • 133
    Benhamou Y, Bochet M, Thibault V et al. Long-term incidence of hepatitis B virus resistance to lamivudine in human immunodeficiency virus-infected patients. Hepatology 1999; 30: 13021306.
  • 134
    Benhamou Y, Fleury H, Trimoulet P et al. Anti-hepatitis B virus efficacy of tenofovir disoproxil fumarate in HIV-infected patients. Hepatology 2006; 43: 548555.
  • 135
    Dore G, Cooper D, Pozniak A et al. Efficacy of tenofovir disoproxil fumarate in antiretroviral therapy-naive and experienced patients coinfected with HIV-1 and hepatitis B virus. J Infect Dis 2004; 189: 11851192.
  • 136
    Matthews GV, Avihingsanon A, Lewin SR et al. A randomized trial of combination hepatitis B therapy in HIV/HBV coinfected antiretroviral naive individuals in Thailand. Hepatology 2008; 48: 10621069.
  • 137
    Jain MK, Comanor L, White C et al. Treatment of hepatitis B with lamivudine and tenofovir in HIV/HBV-coinfected patients: factors associated with response. J Viral Hepat 2007; 14: 176182.
  • 138
    Bartholomeusz A, Locarnini S. Hepatitis B virus mutations associated with antiviral therapy. J Med Virol 2006; 78 (Suppl 1): S52S55.
  • 139
    Kwon SY, Choe WH, Lee CH, Yeon JE, Byun KS. Rapid re-emergence of YMDD mutation of hepatitis B virus with hepatic decompensation after lamivudine retreatment. World J Gastroenterol 2008; 14: 44164419.
  • 140
    Sung JJ, Tsoi KK, Wong VW, Li KC, Chan HL. Meta-analysis: treatment of hepatitis B infection reduces risk of hepatocellular carcinoma. Aliment Pharmacol Ther 2008; 28: 10671077.
  • 141
    Yoo BC, Kim JH, Chung YH et al. Twenty-four-week clevudine therapy showed potent and sustained antiviral activity in HBeAg-positive chronic hepatitis B. Hepatology 2007; 45: 172178.
  • 142
    Pharmasset Inc. Pharmasset voluntarily halts clinical studies with clevudine in hepatitis B infected patients. Available at http://investor.pharmasset.com/releasedetail.cfm?ReleaseID=378789 (accessed 12 May 2009).
  • 143
    Kumar M, Satapathy S, Monga R et al. A randomized controlled trial of lamivudine to treat acute hepatitis B. Hepatology 2007; 45: 97101.
  • 144
    Kellerman SE, Hanson DL, McNaghten AD, Fleming PL. Prevalence of chronic hepatitis B and incidence of acute hepatitis B infection in human immunodeficiency virus-infected subjects. J Infect Dis 2003; 188: 571577.
  • 145
    Hou J, Yin YK, Xu D et al. Telbivudine versus lamivudine in Chinese patients with chronic hepatitis B: results at 1 year of a randomized, double-blind trial. Hepatology 2008; 47: 447454.
  • 146
    Cross TJS, Rizzi P, Horner M et al. The increasing prevalence of hepatitis delta virus (HDV) infection in South London. J Med Virol 2008; 80: 277282.
  • 147
    De Pouplana M, Soriano V, Samaniego JG, Enriquez A, Munoz F, Gonzalez-Lahoz J. More severe course of delta hepatitis in HIV-infected patients. Genitourin Med 1995; 71: 132133.
  • 148
    Sheng W, Hung C, Kao J et al. Impact of hepatitis D virus infection on the long-term outcomes of patients with hepatitis B virus and HIV coinfection in the era of HAART: a matched cohort study. Clin Infect Dis 2007; 44: 988995.
  • 149
    Manesis E, Schina M, Le Gal F et al. Quantitative analysis of hepatitis D virus RNA and hepatitis B surface antigen serum levels in chronic delta hepatitis improves treatment monitoring. Antivir Ther 2007; 12: 381388.
  • 150
    Niro GA, Ciancio A, Gaeta GB et al. Pegylated interferon alpha-2b monotherapy and in combination with ribavirin in chronic hepatitis delta. Hepatology 2006; 44: 713720.
  • 151
    Rosa I, Costes L, Garrait V, Chousterman M. Efficacy of pegylated interferon alpha-2b for the treatment of chronic delta hepatitis in a patient co-infected with HIV. AIDS 2005; 19: 21772178.
  • 152
    Puoti M, Rossi S, Forleo MA et al. Treatment of chronic hepatitis D with interferon alpha-2b in patients with human immunodeficiency virus infection. J Hepatol 1998; 29: 4552.
  • 153
    Sheldon J, Ramos B, Toro C et al. Does treatment of hepatitis B virus (HBV) infection reduce hepatitis delta virus (HDV) replication in HIV/HBV/HDV co-infected patients? Antivir Ther 2008; 13: 97102.
  • 154
    Health Protection Agency. Hepatitis C in the UK. Available at http://www.hpa.org.uk/web/HPAwebFile/HPAweb_C/1228894676145 (accessed 24 December 2008).
  • 155
    Low E, Vogel M, Rockstroh J, Nelson M. Acute hepatitis C in HIV-positive individuals. AIDS Rev 2008; 10: 245253.
  • 156
    Richardson D, Fisher M, Sabin CA. Sexual transmission of hepatitis C in MSM may not be confined to those with HIV infection. J Infect Dis 2008; 197: 12131214.
  • 157
    Turner J, Rider A, Imrie J et al. Behavioural predictors of subsequent hepatitis C diagnosis in a UK clinic sample of HIV positive men who have sex with men. Sex Transm Infect 2006; 82: 298300.
  • 158
    Ghosn J, Deveau C, Goulard C et al. Increase in hepatitis C virus incidence in HIV-1 infected patients followed up since primary infection. Sex Transm Infect 2006; 82: 458460.
  • 159
    Rauch A, Rickenbach M, Weber R et al. Unsafe sex and increased incidence of hepatitis C virus infection among HIV infected men who have sex with men: the Swiss HIV cohort study. Clin Infect Dis 2005; 41: 395402.
  • 160
    Cohen DF, Russell CJ, Golub SA, Mayer KH. Prevalence of hepatitis C infection among men who have sex with men at a Boston Community Health Centre and its association with markers of high-risk behaviour. AIDS Patient Care STDs 2006; 20: 557564.
  • 161
    Browne R, Asboe D, Gilleece Y et al. Increased numbers of acute hepatitis C infections in HIV positive homosexual men; is sexual transmission feeding the increase? Sex Transm Infect 2004; 80: 326327.
  • 162
    Greub G, Ledergerber B, Battegay M et al. Clinical progression, survival, and immune recovery during antiretroviral therapy in patients with HIV-1 and hepatitis C virus coinfection: the Swiss HIV Cohort Study. Lancet 2000; 356: 18001805.
  • 163
    Antonucci G, Girardi E, Cozzi-Lepri A et al. Role of hepatitis C virus (HCV) viremia and HCV genotype in the immune recovery from highly active antiretroviral therapy in a cohort of antiretroviral-naive HIV-infected individuals. Clin Infect Dis 2005; 40: e101e109.
  • 164
    Rockstroh JK, Mocroft A, Soriano V et al. for the EuroSIDA Study Group. Influence of hepatitis C virus infection on HIV-1 disease progression and response to highly active antiretroviral therapy. J Infect Dis 2005; 192: 9921002.
  • 165
    Lichterfeld M, Schmeisser N, Qurishi N et al. Clinical outcomes of HIV-HCV co-infection in a large cohort of hemophiliac patients. J Infect 2005; 50: 221228.
  • 166
    Stebbing J, Waters L, Mandalia S, Bower M, Nelson M, Gazzard B. Hepatitis C virus infection in HIV type 1-infected individuals does not accelerate a decrease in the CD4+ cell count but does increase the likelihood of AIDS-defining events. Clin Infect Dis 2005; 41: 906911.
  • 167
    Sullivan PS, Hanson DL, Teshale EH, Wotring LL, Brooks JT. Effect of hepatitis C infection on progression of HIV disease and early response to initial antiretroviral therapy. AIDS 2006; 20: 11711179.
  • 168
    Mohsen AH, Easterbrook PJ, Taylor C et al. Impact of human immunodeficiency virus (HIV) infection on the progression of liver fibrosis in hepatitis C virus infected patients. Gut 2003; 52: 10351040.
  • 169
    Bonnard P, Lescure FX, Amiel C et al. Documented rapid course of hepatic fibrosis between two biopsies in patients coinfected by HIV and HCV despite high CD4 cell count. J Viral Hepat 2007; 14: 806811.
  • 170
    Darby SC Ewart D, Giangrande PL et al. Mortality from liver cancer and liver disease in haemophiliac men and boys in the UK given blood products contaminated with hepatitis C. UK Haemophilia Centre Directors' Organisation. Lancet 1997; 350: 14251431.
  • 171
    Rodríguez-Torres M, Rodríguez-Orengo JF, Ríos-Bedoya CF et al. Effect of hepatitis C virus treatment in fibrosis progression rate (FPR) and time to cirrhosis (TTC) in patients co-infected with human immunodeficiency virus: a paired liver biopsy study. J Hepatol 2007; 46: 613619.
  • 172
    Girón-González JA, Brun F, Terrón A, Vergara A, Arizcorreta A. Natural history of compensated and decompensated HCV-related cirrhosis in HIV-infected patients: a prospective multicentre study. Antivir Ther 2007; 12: 899907.
  • 173
    Pineda JA, García-García JA, Aguilar-Guisado M et al. Clinical progression of hepatitis C virus-related chronic liver disease in human immunodeficiency virus-infected patients undergoing highly active antiretroviral therapy. Hepatology 2007; 46: 622630.
  • 174
    Cacoub P, Geffray L, Rosenthal E et al. Mortality among HIV-infected patients with cirrhosis or hepatocellular carcinoma due to hepatitis C virus in French Departments of Internal Medicine/Infectious Diseases in 1995 and 1997. Clin Infect Dis 2001; 32: 12071214.
  • 175
    Mocroft A, Brettle R, Kirk O et al. for the EuroSIDA study group. Changes in the cause of death among HIV positive subjects across Europe: results from the EuroSIDA study. AIDS 2002; 16: 16631671.
  • 176
    Smit C, Geskus R, Walker S et al. for the CASCADE Collaboration. Effective therapy has altered the spectrum of cause-specific mortality following HIV seroconversion. AIDS 2006; 20: 741749.
  • 177
    Cribier B, Rey D, Schmitt C et al. High hepatitis C viraemia and impaired antibody response in patients coinfected with HIV. AIDS 1995; 9: 11311136.
  • 178
    Tedaldi E, Peters L, Neuhaus J et al. Opportunistic disease and mortality in patients coinfected with hepatitis B or C virus in the strategic management of antiretroviral therapy (SMART) study. Clin Infect Dis 2008; 47: 14681475.
  • 179
    Shores NJ, Maida I, Soriano V, Núnez M. Sexual transmission is associated with spontaneous HCV clearance in HIV-infected patients. J Hepatol 2008; 49: 323328.
  • 180
    Gilleece Y, Browne R, Asboe D et al. Transmission of hepatitis C virus among HIV positive homosexual men and response to a 24-week course of pegylated interferon and ribavirin. JAIDS 2005; 40: 4146.
  • 181
    Leurkemyer A, Bradley Hare C, Stansell J et al. Clinical presentation and course of acute hepatitis C infection in HIV-infected patients. JAIDS 2006; 41: 3136.
  • 182
    Gerlach JT, Diepolder HM, Zachoval R et al. Acute hepatitis C: high rate of both spontaneous and treatment-induced viral clearance. Gastroenterology 2003; 125: 8088.
  • 183
    Villano SA, Vlahov D, Nelson KE, Cohn S, Thomas DL. Persistence of viremia and the importance of long-term follow-up after acute hepatitis C infection. Hepatology 1999; 29: 908914.
  • 184
    Thomson EC, Nastouli E, Main J et al. Delayed anti-HCV antibody response in HIV-positive men acutely infected with HCV. AIDS 2009; 23: 8993.
  • 185
    Pawlotsky JM. Use and interpretation of virological tests for hepatitis C. Hepatology 2002; 36: S65S73.
  • 186
    Montes RML, Rodriguez ZM. Report of three cases of hyperlactacidemia/lactic acidosis after treatment of hepatitis C with pegylated interferon and ribavirin in HIV coinfected patients. Rev Clin Esp 2002; 202: 543545.
  • 187
    Bani-Sadr F, Denoeud L, Morand P et al. Early virologic failure in HIV-coinfected hepatitis C patients treated with the peginterferon-ribavirin combination: does abacavir play a role? JAIDS 2007; 45: 123125.
  • 188
    Bräu N, Rodriguez-Torres M, Prokupek D et al. Treatment of chronic hepatitis C in HIV/HCV-coinfection with interferon alpha-2b+ full-course vs. 16-week delayed ribavirin. Hepatology 2004; 39: 989998.
  • 189
    Bani-Sadr F, Carrat F, Pol S et al. Risk factors for symptomatic mitochondrial toxicity in HIV/hepatitis C virus-coinfected patients during interferon plus ribavirin-based therapy. JAIDS 2005; 4: 4752.
  • 190
    Mira JA, López-Cortés LF, Barreiro P et al. Efficacy of pegylated interferon plus ribavirin treatment in HIV/hepatitis C virus co-infected patients receiving abacavir plus lamivudine or tenofovir plus either lamivudine or emtricitabine as nucleoside analogue backbone. J Antimicrob Chemother 2008; 62: 13651373.
  • 191
    Amorosa V, Slim J, Mounzer K et al. Abacavir use is not associated with lack of virologic response in ARV-treated HIV/HCV-co-infected patients receiving pegylated interferon and ribavirin. 16th Conference on Retroviruses and Opportunistic Infections. Montreal, Canada, February 2009 [Abstract 850].
  • 192
    Quereda C, Corral I, Moreno A et al. Effect of treatment with efavirenz on neuropsychiatric adverse events of interferon in HIV/HCV-coinfected patients. JAIDS 2008; 49: 6163.
  • 193
    Saadoun D, Resche-Rigon M, Sene D et al. Rituximab combined with Peg-interferon-ribavirin in refractory hepatitis C virus-associated cryoglobulinaemia vasculitis. Ann Rheumat Dis 2008; 67: 14311436.
  • 194
    Shea DO, Tuite H, Farrell G et al. Role of rapid virological response in prediction of sustained virological response to Peg-IFN plus ribavirin in HCV/HIV co-infected individuals. J Viral Hepat 2008; 15: 482489.
  • 195
    Martin-Carbonero L, Nuñez M, Mariño A et al. Undetectable hepatitis C virus RNA at week 4 as predictor of sustained virological response in HIV patients with chronic hepatitis C. AIDS 2008; 22: 1521.
  • 196
    Van den Eynde E, Crespo M, Estaban JI et al. Response-guided therapy for chronic hepatitis C virus infection in patients coinfected with HIV: a pilot trial. Clin Infect Dis 2009; 48: 11521159.
  • 197
    Martin-Carbonero L, Benhamou Y, Puoti M et al. Incidence and predictors of severe liver fibrosis in human immunodeficiency virus-infected patients with chronic hepatitis C: a European Collaborative Study. Clin Infect Dis 2004; 38: 128133.
  • 198
    Verma S, Wang CH, Govindarajan S et al. Do type and duration of antiretroviral therapy attenuate liver fibrosis in HIV-hepatitis C virus-coinfected patients? Clin Infect Dis 2006; 42: 262270.
  • 199
    Qurishi N, Kreuzberg C, Luchters G et al. Effect of antiretroviral therapy on liver-related mortality in patients with HIV and hepatitis C virus coinfection. Lancet 2003; 362: 17081713.
  • 200
    Carrat F, Bani-Sadr F, Pol S et al. Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomized controlled trial. JAMA 2004; 292: 28392848.
  • 201
    Chung R, Anderson J, Volberding P et al. Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med 2004; 351: 451459.
  • 202
    Foster GR, Fried MW, Hadziyannis SJ, Messinger D, Freivogel K, Weiland O. Prediction of sustained virological response in chronic hepatitis C patients treated with peginterferon alfa-2a (40KD) and ribavirin. Scand J Gastroenterol 2007; 42: 247255.
  • 203
    Castellares C, Barreiro P, Martin-Carbonero L et al. Liver cirrhosis in HIV-infected patients: prevalence, aetiology and clinical outcome. J Viral Hepat 2008; 15: 165172.
  • 204
    Evon DM, Verma A, Simpson K et al. Psychiatric symptoms during interferon treatment for hepatitis C: experiences from a tertiary care hepatology centre. Aliment Pharmacol Ther 2008; 27: 10711080.
  • 205
    Heathcote EJ, Shiffman ML, Cooksley GE et al. Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis. N Engl J Med 2000; 343: 16731680.
  • 206
    Mira JA, Lopez-Cortes LF, Merino D et al. Predictors of severe haematological toxicity secondary to pegylated interferon plus ribavirin treatment in HIV-HCV-coinfected patients. Antivir Ther 2007; 12: 12251235.
  • 207
    Ho SB, Groessl E, Dollarhide A et al. Management of chronic hepatitis C in veterans: the potential of integrated care models. Am J Gastroenterol 2008; 103: 18101823.
  • 208
    Sene D, Touitou V, Bodaghi B et al. Intraocular complications of IFN-alpha and ribavirin therapy in patients with chronic viral hepatitis C. World J Gastroenterol 2007; 13: 31373140.
  • 209
    Andrade RJ, Gonzalez FJ, Vazquez L et al. Vascular ophthalmological side effects associated with antiviral therapy for chronic hepatitis C are related to vascular endothelial growth factor levels. Antivir Ther 2006; 11: 491498.
  • 210
    Nunez M, Miralles C, Berdun MA et al. Role of weight-based ribavirin dosing and extended duration of therapy in chronic hepatitis C in HIV-infected patients: the PRESCO trial. AIDS Res Hum Retroviruses 2007; 23: 972982.
  • 211
    Nunez M, Ocampo A, Aguirrebengoa K et al. Incidence of anaemia and impact on sustained virological response in HIV/HCV-coinfected patients treated with pegylated interferon plus ribavirin. J Viral Hepat 2008; 15: 363369.
  • 212
    Squillace N, Lapadula G, Torti C et al. Hepatitis C virus antibody-positive patients with HIV infection have a high risk of insulin resistance: a cross-sectional study. HIV Med 2008; 9: 151159.
  • 213
    Chung R et al. SLAM-C (ACTG A5178): Role of early virologic response in extended therapy with PEG-interferon and weight-based ribavirin in HCV/HIV co-infection. 16th Conference on Retroviruses and Opportunistic Infections. Montreal, February 8–11, 2009 [Abstract 103LB].
  • 214
    Crespo M, Mira JA, Pineda JA et al. Efficacy of pegylated interferon and ribavirin for retreatment of chronic HCV infection in HIV co-infected patients failing a previous standard interferon-based regimen. J Antimicrob Chemother 2008; 62: 793796.
  • 215
    Basso M, Torre F, Grasso A et al. Pegylated interferon and ribavirin in re-treatment of responder-relapser HCV patients. Dig Liver Dis 2007; 39: 4751.
  • 216
    Ciancio A, Picciotto A, Giordanino C et al. A randomized trial of pegylated-interferon-alpha2a plus ribavirin with or without amantadine in the re-treatment of patients with chronic hepatitis C not responding to standard interferon and ribavirin. Aliment Pharmacol Ther 2006; 24: 10791086.
  • 217
    Giordanino C, Bugianesi E, Smedile A et al. Incidence of type 2 diabetes mellitus and glucose abnormalities in patients with chronic hepatitis C infection by response to treatment: results of a cohort study. Am J Gastroenterol 2008; 103: 24812487.
  • 218
    Jensen DM, Freilich B, Andreone P et al. Pegylated interferon alfa-2a (40kd) plus ribavirin (RBV) in prior non-responders to pegylated interferon alfa-2b (12kd)/RBV: final efficacy and safety outcomes of the REPEAT study. Program and abstracts of the 58th Annual Meeting of the American Association for the Study of Liver Diseases. Boston, Massachusetts, November 2–6, 2007 [Abstract LB4].
  • 219
    Murphy AA, Rozenberg I, Polis MA et al. Twice-Weekly Peg IFN-alpha-2a with Ribavirin Improves Early Viral Kinetics over Standard Therapy among HIV/HCV Co-Infected African American Patients. 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2008). Washington, DC, October 25–28, 2008 [Abstract V-4220].
  • 220
    Everson GT, Hoefs JC, Seeff LB et al. Impact of disease severity on outcome of antiviral therapy for chronic hepatitis C: lessons from the HALT-C trial. Hepatology 2006; 44: 16751684.
  • 221
    Sherman K, Andersen J, Butt A et al. Sustained Long-term Antiviral Maintenance with Pegylated Interferon in HCV/HIV-co-infected Patients: Early Viral Response and Effect on Fibrosis in Treated and Control Subjects. 16th Conference on Retroviruses and Opportunistic Infections. Boston, February 3–6, 2008 [Abstract 59].
  • 222
    Zeuzem S, Yoshida EM, Benhamou Y et al. Albinterferon alfa-2b dosed every two or four weeks in interferon-naive patients with genotype 1 chronic hepatitis C. Hepatology 2008; 48: 407417.
  • 223
    Stauber RE, Kessler HH. Drugs in development for hepatitis C. Drugs 2008; 68: 13471359.
  • 224
    Roberts SK, Cooksley G, Dore GJ et al. Robust antiviral activity of R1626, a novel nucleoside analog: a randomized, placebo-controlled study in patients with chronic hepatitis C. Hepatology 2008; 48: 398406.
  • 225
    Gish RG. Treating HCV with ribavirin analogues and ribavirin-like molecules. J Antimicrob Chemother 2006; 57: 813.
  • 226
    Sheldon J, Barreiro P, Vincent V et al. Novel protease and polymerase inhibitors for the treatment of hepatitis C virus infection. Expert Opin Invest Drugs 2007; 16: 11711181.
  • 227
    Liu-Young G, Kozal MJ. Hepatitis C protease and polymerase inhibitors in development. AIDS Patient Care Stds 2008; 22: 449457.
  • 228
    Gotz HM, Van Doornum G, Niesters HG et al. A cluster of acute hepatitis C among men who have sex with men: results from contact tracing and public health implications. AIDS 2005; 19: 969974.
  • 229
    Bhagani S, Dante M, Huj C et al. Acute hepatitis C in a cohort of HIV positive men: outcomes and response to pegylated interferon-alfa 2b and ribavirin. BHIVA Spring Conference. Cardiff, April 15–17, 2004 [Abstract O20].
  • 230
    Danta M, Semmo N, Fabris P et al. Impact of HIV on host-virus interactions during early hepatitis C virus infection. J Infect Dis 2008; 197: 15581566.
  • 231
    Soriano V, Mocroft A, Rockstroh J et al. for the EuroSIDA Study Group. Spontaneous viral clearance, viral load, and genotype distribution of hepatitis C virus (HCV) in HIV-infected patients with anti-HCV antibodies in Europe. J Infect Dis 2008; 198: 13371344.
  • 232
    Fierer DS, Uriel AJ, Carriero DC et al. Liver fibrosis during an outbreak of acute hepatitis C virus infection in HIV-infected men: a prospective cohort study. J Infect Dis 2008; 198: 683686.
  • 233
    Matthews GV, Hellard M, Haber P et al. Characteristics and treatment outcomes among HIV-infected individuals in the Australian Trial in Acute Hepatitis C. Clin Infect Dis 2009; 48: 650658.
  • 234
    Audagnotto S, De Rosa F, Bargiacchi O et al. Treatment of acute hepatitis in HIV infected patients. JAIDS 2005; 40: 110111.
  • 235
    Danta M, Turner J, Johnstone R et al. Use of pegylated interferon-alpha with or without ribavirin in the treatment of acute HCV in HIV-positive individuals. HIV Med 2005; 6 (Suppl 1): 40.
  • 236
    Dominguez S, Ghosn J, Valantin M et al. Efficacy of early treatment of acute hepatitis C infection with pegylated interferon and ribavirin in HIV-infected patients. AIDS 2006; 20: 11571161.
  • 237
    Vogel M, Natterman J, Baumgarten A et al. Pegylated interferon-alpha for the treatment of sexually transmitted acute HCV-infection in HIV-positive individuals. Antivir Ther 2006; 11: 10971101.
  • 238
    Kamal S, Fouly A, Kamel R et al. Peginterferon alfa-2b therapy in acute hepatitis C: impact of onset of therapy on sustained virologic response. Gastroenterology 2006; 130: 632638.
  • 239
    Rodríguez-Nóvoa S, Morello J, González M et al. Increase in serum bilirubin in HIV/hepatitis-C virus-coinfected patients on atazanavir therapy following initiation of pegylated-interferon and ribavirin. AIDS 2008; 22: 25352537.