Treatment and Management of HBV-HIV Coinfection: The Goals of Therapy for HBV

This is the second of two articles drawn from the recommendations of an international panel of experts on hepatitis B and C in individuals coinfected with HIV. The first article, posted here on April 27, 2005, focuses on recommendations for the treatment and management of HCV-HIV coinfection.

Both articles were drawn from the "Short Statement of the First European Consensus Conference on the Treatment of Chronic Hepatitis C and B in HIV Co-infected Patients" (March 1-2, 2005, Paris, France). The complete article on both hepatitis C and B in patients coinfected with HIV appears online (free access) and in the hardbound copy of the current (May 2005) issue of the Journal of Hepatology.

In the following document, the "jury panel" of the Consensus Conference offers recommendations on the treatment and management of HBV-HIV coinfection:


Introduction
Despite recent advances in the management of hepatitis and HIV co-infection, there is no clear consensus among hepatology, infectious diseases and virology experts on treatment of co-infections and patient management. This encouraged the organization of a European Consensus Conference to review current knowledge on the treatment of chronic hepatitis B and C in HIV co-infected patients, with the view to developing this consensus statement.
An organizing committee drafted questions to be addressed at the conference, and following two days of presentations and discussions, an independent Jury Panel assessed the evidence and prepared this statement with the aim of addressing eight questions:

What are the reasons to treat viral hepatitis in HIV co-infected patients in
  the HAART era?
How should viral hepatitis be diagnosed and how should disease severity
  be assessed in HIV-infected patients?
What are the current treatment options?
Which patients should be treated and when?
How should co-infected patients be treated (treatment algorithms)?
How should anti-hepatitis treatment be monitored?
How should end-stage liver disease be managed?
What are the most important areas for future research?

This process essentially follows the consensus process used for preparing NIH Consensus Statements. This short version of the consensus summarizes the main conclusions and recommendations from the conference. We will subsequently publish a more detailed version of these recommendations with additional information on the background and supporting data. And in a supplement to Journal of Hepatology, articles prepared by individual presenters will be published to elaborate on the recommendations made here. Statements and recommendations were graded for their strength and quality using a grading system based on the Infectious Diseases Society of America (IDSA) system.


Table 1. Grading Scheme for Recommendations

Screening for HBV

All HIV-positive patients should be tested for HBsAg and anti-HBc antibodies, and questioned about their HBV vaccination history (AII).

If patients are negative for HBsAg and positive for anti-HBc, they should be tested for anti-HBs (AII). In patients with isolated anti-HBc positivity, a test for serum HBV-DNA might be considered to assess occult HBV infection (see below) (CIII).

All patients who are HBsAg-positive should be tested for anti-HDV (AII). However, none of the currently available nucleotide/nucleoside analogues are effective for the treatment of HDV infection, and the only assessed treatment is high dose interferon-a (IFN) (5MU daily or 10MU three-times weekly for 12 months), which has limited efficacy and often poor tolerability in the long term in HBV/HDV patients without HIV and has not been assessed in HIV co-infected cases.

In people who are HBsAg-positive, further evaluation of the severity of HBV disease and the virological profile is important (AII). Tests and evaluations may include those listed below, but the extent of the examinations may be different in different circumstances.
All patients should have:

Examination for signs and symptoms of advanced liver disease.

Alanine aminotransferase (ALT) determination
       - serial measurements are preferred as ALT may fluctuate significantly,
         Particularly when patients are HBeAg-negative
       - although there is not an absolute correlation between ALT levels and
         Disease activity, the higher the ALT levels, the higher the likelihood of the
         presence of significant disease and the faster the progression of fibrosis.

HBeAg and anti-HBe
       - HBeAg-positive patients almost invariably have high HBV-DNA levels,
         independently of ALT levels
       - anti-HBe-positive cases may or may not have virus replication, as defined
         by HBV-DNA testing

HBV-DNA measurements

       - results should be expressed in International Units (IU) per millilitre, the
         universal, standardized HBV DNA quantification unit and in decimal
         logarithm (log) IU/ml (1IU=5.4-5.8 copies/ml, depending on assay,
         please refer to manufacturers conversion chart)

       - the results should be expressed in decimal logarithm (log) IU/ml, for
         precise assessment of baseline and significant HBV DNA changes upon
         therapy

       - serial measurements should be done if HBV-DNA is initially found at low levels
         (=2000IU/ml in anti-HBe-positive patients with elevated ALT or other signs of
         liver disease), as HBV-DNA may show wide fluctuations in such cases

       - only one type of assay should be used for monitoring in the same individual,
         and if a change of assay is planned, both tests should be used in parallel for
         at least two subsequent samples

       - tests should preferably be quantitative, have a high sensitivity and cover
         a wide range of detection (80-1010IU/ml). Optimum tests are real-time nucleic
         acid amplification tests

       - tests should either be approved according to European regulations or validated
         in a similar way using internationally recognised standards, and should be able
         to detect isolates of different HBV genotypes

       - HBV-DNA assays should be performed in a laboratory that participates in
         external quality control

       - different tests produce different absolute results and this is why the thresholds
         given in these recommendations are only indicative. The reason is that there
         is no standardization of quantification units and the dynamic ranges of
         quantification of the different assays are only partially overlapping (theses
         issues should be resolved with international units and real-time PCR assays).

Liver Biopsy and Other Evaluations
In specific circumstances, additional evaluation is needed:

       - Measurement of the stage of liver fibrosis and of necroinflammatory activity
         is essential to define the stage of disease and the risk of progression to
         clinically significant liver complications and is most useful when a decision to
         treat or not to treat has to be taken. The current gold standard for assessment
         is liver biopsy (BII).

                - liver stiffness measurements (e.g. FibroScan™) or measurement of
                  non-invasive markers of fibrosis (e.g. FibroTest™) can be considered
                  alone or in combination to avoid performing a liver biopsy (CIII). These
                  alternatives remain to be fully validated in the setting of HBV/HIV co-infection.

       - Ultrasound examination of the liver that can reveal cirrhosis, steatosis and
         possibly early HCC.

Occult HBV Infection

If only anti-HBc is present at the initial assessment, this may be indicative of 'occult' HBV infection. Occult HBV is usually assumed when HBV-DNA is detected at low levels by highly sensitive techniques and in the absence of HBsAg.

Occult HBV is found more frequently in HIV-positive patients than in HIV-negative people, but its clinical relevance is uncertain. Currently, there is no evidence for the need to routinely detect or treat occult HBV (CIII). However, occult HBV may become relevant in specific clinical settings. For example, if chemotherapy for cancer is initiated and there is a risk of reactivation, pre-emptive anti-HBV therapy may be considered (BIII). More research is needed before the clinical relevance of occult HBV can be fully established.

The Goals of Therapy

The most ambitious goal of treatment for HBV is to achieve HBsAg clearance with anti-HBs seroconversion, but this endpoint can be reached only in a minority of patients (less than 10% of HBV mono-infected patients having received interferon treatment and is likely to be even less among HIV/HBV co-infected patients). A more realistic goal therefore is to efficiently and persistently suppress HBV replication to reduce liver inflammation and to stop or delay progression of fibrosis, thereby preventing the development of end-stage complications such as cirrhosis, decompensation, HCC and liver-related death (AII).

Drugs that are currently licensed in Europe for the treatment of HBV include standard IFN-alfa 2a [Roferon A] and 2b [Intron A] and pegylated-IFN-alfa (PEG-IFN) 2a [Pegasys], lamivudine [Epivir-HBV], and adefovir [Hepsera].

All these drugs have antiviral activity, and IFN has additional immune modulatory effects. Tenofovir [Viread] and emtricitabine [Emtriva] are approved for HIV and are also active against HBV.

Drugs under development with anti-HBV but not anti-HIV activity include entecavir [Baraclude], clevudine, telbivudine and a number of other compounds.

Data on the efficacy of some of these drugs in HIV/HBV co-infected individuals are still very limited and no large-scale randomized controlled trials have been conducted to define their efficacy and safety when used alone or in combination. Therefore, recommendations for the treatment of HBV in HIV co-infected patients need to be derived from what is known about the treatment of HBV mono-infected patients, and from the limited data available in HBV/HIV co-infected patients.

When Should Treatment for HBV Start?

Most cases of acute hepatitis B resolve spontaneously and do not need antiviral therapy (AII). In cases of acute fulminant hepatitis B, lamivudine-therapy should be considered despite the risk of selecting for lamivudine-resistant HIV (AIII). As other drugs with sole anti-HBV activity become available, these are likely to become the preferred approach rather than using lamivudine.

Therapy with tenofovir or adefovir should be avoided because in most such cases, liver failure is often accompanied with renal failure (CIII).

In patients with HIV and chronic hepatitis B, the decision to treat or not to treat should be based as much as possible on an integrated evaluation of the diagnostic parameters described in "Liver Biopsy and Other Evaluations." (AIII).

Candidates for Treatment

The criteria to decide whether to treat include:

       - HBV-DNA level.
       - Liver disease activity and stage (derived from ALT profile, liver necroinflammatory
         activity and fibrosis assessment, when indicated).
       - Careful evaluation of the presence of cirrhosis.

In HBV-HIV co-infected patients, the HBV-DNA threshold for starting therapy has not been defined. In HBeAg-positive HBV mono-infected patients, HBV DNA >approximately 20,000IU/ml is the cut off to indicate antiviral therapy, while a cut-off >approximately 2000IU/ml is more often used for HBeAg-negative (anti-HBe-positive) patients. These thresholds can also be applied to co-infected patients (BIII).


Management and Therapeutic Options

The diagnostic algorithm and the treatment options vary depending on different clinical scenarios that should take into consideration: HBV-DNA levels, severity of liver disease, CD4 count and indication for HAART, contraindications and previous treatments for HBV.

The decision to start anti-HBV therapy should be taken after obtaining evidence that liver disease is active and progressive (AIII).

When initiation of HAART is not indicated and HBV disease is mild and not (or slowly) progressing, the best current strategy may be to monitor the patients without treatment intervention (BIII). More data and the approval of new anti-HBV drugs without anti-HIV activity may, in the near future, allow more informed treatment decisions in these patients.

In patients with high HBV-DNA levels (>20,000IU/ml for HBeAg-positive patients and >2,000IU/ml for HBeAg-negative patients), the presence of liver inflammation and stage of liver fibrosis should be assessed by liver biopsy or validated non-invasive markers, unless hepatic ultrasound is clearly indicative of cirrhosis (BIII).

In the presence of histological evidence of active and/or advanced disease (by liver biopsy this means moderate to severe inflammation and/or fibrous septa-Metavir =A2 and/or =F2) therapy is indicated (AII).

In HBV mono-infected patients, HBeAg positivity, elevated ALT, and/or infection with genotype A or B virus predict a better response to treatment with IFN (AI).

IFN-based therapy may be an option for HBV/HIV co-infected patients who do not need to start HAART (CD4 count >500cells/mm3) (BII). As in the treatment of HBV mono-infected patients, the recommended dose and duration depend on HBeAg/anti-HBe status.

Most recently Peg IFN has been licensed for hepatitis B and is becoming the standard therapy. PEG-IFN 2a [Pegasys] (180µg once weekly) should be given for 48 weeks independently of HBeAg/anti-HBe status (BIII).

When using standard (not pegylated) IFN, HBeAg-positive patients should be treated with 5-6MU/day or 10MU three times weekly for 4-6 months (BIII). HBeAg-negative patients should receive 3-6MU three times weekly for at least 12 months (BIII).

Although the benefit of IFN therapy is expected to be higher in HBeAg-positive patients, anti-HBe-positive patients can also be treated with IFN, particularly when ALT levels are persistently elevated, but the likelihood of sustained response is lower (BIII).

IFN-based therapy should be used as a finite course of therapy and a favourable response defined by sustained (off therapy) anti-HBe seroconversion in initially HBeAg-positive patients, and by sustained (off therapy) ALT normalisation and HBV-DNA suppression (<2000IU/ml) in initially HBeAg-negative patients (AII).

These recommendations are largely derived from data obtained in HBV mono-infected patients due to the very limited and incomplete information on the effect of IFN therapy in HBV/HIV co-infected patients.

In patients with CD4 count >500cells/mm3 and with contraindications to the use of IFN (including those with advanced liver disease and cirrhosis, those who do not tolerate IFN and IFN non-responders), adefovir at a dose of 10mg daily (the dose currently used in the treatment of HBV mono-infected patients and thought to have no activity against HIV) may be an option. However, this is controversial due to the theoretical risk of inducing HIV resistance (CIII). In this scenario, the use of drugs with potent antiviral activity solely against HBV and no activity against HIV (such as entecavir, telbivudine) may be the best solution when these agents become available.

In patients with a CD4 count lower than 500cells/mm3 the best option is to consider earlier initiation of HAART including two drugs with dual activity against both HBV and HIV (tenofovir plus either lamivudine or emtricitabine) (BIII).

Monotherapy using drugs with activity against HIV must be avoided (AI).

Current research in HBV suggests that, as in HIV, combination therapy reduces the risk of selecting for resistance. Avoidance of monotherapy for HBV may thus be equally important.

In this scenario, the decision on how to treat should be based mainly on HBV-DNA levels, without a stringent need for measurement of the liver necroinflammatory activity and stage of fibrosis. Liver biopsy may be useful to assess the stage of disease at baseline to allow meaningful follow-up of the disease course (CIII).

If HBV-DNA is high (>20,000IU/ml), HAART including two drugs with dual anti-HBV and anti-HIV activity is recommended (AIII).

In patients with low HBV-DNA levels (<2000IU/ml), the recommendation is to initiate the HAART regimen of choice (it is optional to use a HAART regimen containing two dual-activity drugs) (CIII).

HBV/HIV Co-infected patients with Lamivudine-resistant HBV Requiring HBV Therapy

In the presence of suspected lamivudine-resistance, the first step is to confirm the lamivudine resistance in HBV (BIII).

If confirmed, we recommend a HAART regimen that has maximal activity against both HIV and HBV. If HIV is already controlled substitute one of the nucleoside reverse transcriptase inhibitors (NRTIs) with tenofovir, if feasible and appropriate from the perspective of maintaining HIV suppression (BIII). If HIV is not controlled, tenofovir can be added in the context of currently accepted practices for management of HAART treatment failure (AIII).

HBV/HIV Co-infected Patients with Cirrhosis

In these cases, the HBV-DNA threshold for starting therapy for HBV is lower (>200IU/ml) (BIII). IFN-based therapy is rarely indicated and often contraindicated due to the very poor tolerability profile (DIII).

The risk of severe reactivation of hepatitis B during immune reconstitution after starting HAART, with life-threatening hepatitis flare, should be considered in this setting, particularly when CD4 counts are <200cells/mm3.

In this specific situation, and particularly in the presence of high baseline HBV-DNA levels, reduction of HBV-DNA levels may be preferred before starting HAART to reduce the likelihood of immune reconstitution. However, given the lack of available drugs with sole anti-HBV activity, this cannot currently be done safely. Furthermore, an induction treatment with two drugs with dual activity against HBV and HIV carries the risk of selecting drug-resistance in HIV, particularly in those with high HIV-RNA levels. For these reasons, initiation for full HAART regimens in this setting remains the preferred approach (BIII).

Some experts believe that adefovir (10mg daily) should be considered in these cases but this approach is controversial, as stated above (CIII).

In this scenario, the use of drugs with potent antiviral activity solely against HBV and no activity against HIV may be the best solution in the near future.

In patients with decompensated liver cirrhosis (Child Pugh stage B or C), (EI) liver transplantation, where feasible, should be the primary treatment option for patients (CII).

Monitoring and Assessment of Response

A clinically relevant response to anti-HBV therapy is defined as a durable anti-HBe seroconversion in initially HBeAg-positive patients, and as a durable normalization of ALT and adequate (<2000IU/ml) and durable HBV-DNA suppression in initially HBeAg-negative patients.

When using nucleotide and nucleoside analogues with anti-HBV activity, an initial response is defined as at least 1 log10 drop in HBV-DNA levels within 1-3 months. HBV-DNA should then be measured every 3 months. The extent of treatment efficacy is measured by the Log HBV DNA reduction or by HBV DNA negativation below the lower limit of detection of the assay.
Resistance should be suspected in compliant patients if HBV-DNA levels increase by 1 log10 or more. Where available, resistance testing should be performed.

Treatment Discontinuation

Discontinuation of anti-HIV drugs with additional activity against HBV has to be approached with caution. Resistance of HIV and HBV are separate and independent. Stopping the anti-HBV treatment can result in potentially fatal hepatitis flares, particularly in patients with more advanced liver disease, and should therefore be avoided whenever possible (EII). Patient counselling is important to avoid discontinuation of effective anti-HBV drugs.

Future Studies and Recommendations

A wide variety of unresolved issues exist in the management of patients co-infected with hepatitis B or C and HIV. During the conference*, a number of potential areas for future research were identified.

* First European Consensus Conference on the Treatment of Chronic Hepatitis C and B in HIV Co-infected Patients. March 1-2, 2005, Paris, France.


Future research

General

As the transmission of HIV, HBV and HCV continues to expand across the European continent, there is a clear and important need to enhance efforts to prevent and control these infections
Studies addressing the optimal time-during the course of chronic HIV infection-to commence antiretroviral therapy in HBV and HCV co-infected patient should be initiated
Studies on the epidemiology and the social impact of HBV and HCV in patients infected with HIV should be actively investigated, with a special emphasis on vulnerable populations
Phases II and III trials of new drugs should be performed in HIV/HBV and HIV/HCV co-infected patients as a priority due to the accelerated course of the hepatitis infections in these populations
As the current therapies are suboptimal-in terms of efficacy, tolerability and quality of life-the development of new drugs to circumvent these issues should be actively pursued
Studies to validate the utility of non invasive methods of liver disease progression should be performed

HBV/HIV Co-infection

Better understanding of the pathogenesis and mechanisms of HBV-related liver damage in HIV co-infected patients is needed.
Prevalence, diagnosis and clinical significance of occult HBV in HIV patients should be investigated.
The significance and threshold (if any) of HBV-DNA serum levels in relation to liver disease activity and progression and indication for anti-HBV therapy should be better defined in HIV co-infected cases.
The efficacy, safety and tolerability of PEG-IFN and the optimal treatment schedule for HBV treatment in HIV co-infected patients need to be investigated in clinical studies of adequate design and size.
Correlates of disease progression and treatment response need to be identified-including the predictive value of viral load, the effect of anti-HBV therapy on liver disease: biopsy or non-invasive markers, the impact of long-term treatment on HBsAg clearance and intrahepatic cccDNA, the impact of HBV drug resistance on liver disease, and the role of cross-resistance testing in patients with HBV treatment failure.
The value of combination versus monotherapy should be evaluated.
The prevalence and natural history of HBeAg-negative chronic hepatitis B in HIV co-infected patients should be better defined.
The impact of HBV treatments on liver-related morbidity and mortality in HIV patients receiving HAART needs to be understood.

Jury Panel
Alfredo Alberti (Italy) (President), Nathan Clumeck (Belgium) (President), Simon Collins (UK), Wolfram Gerlich (Germany), Jens Lundgren (Denmark), Giorgio Palu (Italy), Peter Reiss (Netherlands), Rodolphe Thiebaut (France), Ola Weiland (Sweden), Yazdan Yazdanpanah (France), Stefan Zeuzem (Germany).

Link to full article "Short Statement of the First European Consensus Conference on the Treatment of Chronic Hepatitis C and B in HIV Co-infected Patients" (March 1-2, 2005, Paris, France).

Reference
A Alberti and others (Jury Panel). Short Statement of the First European Consensus Conference on the Treatment of Chronic Hepatitis C and B in HIV Co-infected Patients" (March 1-2, 2005, Paris, France). Journal of Hepatology 42(5): 615 - 624. May 2005.

HIV and Hepatitis.com Articles on HIV-HBV Coinfection
HIV and Hepatitis.com Lamivudine (Epivir-HBV)
HIV and Hepatitis.com Pegylated interferon alfa-2 (Pegasys)
                                          (approved for treatment of HBV infection in Europe)
HIV and Hepatitis.com Intron A (standard interferon alfa-2b)
HIV and Hepatitis.com Adefovir dipivoxil (Hepsera)
HIV and Hepatitis.com Entecavir (Baraclude)
HIV and Hepatitis.com Experimental Treatments for HBV (US)
HIV and Hepatitis.com Most Recent Conference Report

4/27/05