HBV Treatment in HIV-infected Patients

Candidates for HBV therapy (Dr Geoffrey Dusheiko, UK)

The main goal of therapy for HBV infection is to prevent progression of the disease. If HIV replication can be suppressed, the accompanying reduction in histological activity lessens the risk of progression of liver disease. In addition, patients may require treatment to reduce infectivity.

HIV and its treatment have an effect on the natural history of HBV infection. Conversely, HBV treatment may have an impact on HIV. Therefore, these complex interactions need to be addressed in the treatment of HIV/HBV-coinfected patients.

Current treatments of chronic hepatitis B have limited long-term efficacy [10,11]. Responses may also increase with higher CD4 counts. Eradication of the HBV infection is possible in only a minority of patients, and this should be taken into account before initiating therapy.

There are a number of challenges to treating patients with co-infection, including an impaired immune response, higher levels of HBV replication, the increased likelihood of lamivudine resistance, and drug interactions.

The presence or absence of HBe antigen marks the difference in the end-points of HBV treatment (figure 2). According to a French study, the majority of HBV/HIV-coinfected patients in their cohort were HBeAg positive (78.8% vs. 49.9% in non-HIV subjects) [12]. However, this may vary from country to country.

Figure 2. End-points of antiviral response to anti-HBV treatment.

There is not an established consensus as to which patients should be treated. In general, treatment of chronic hepatitis should be targeted at patients with active disease and viral replication. Alanine amino transferase (ALT) and HBV DNA levels are important pieces of information. Responses to currently licensed anti-HBV drugs are higher when ALT levels are elevated. The decision to treat is usually based on detectable HBV RNA in plasma and ALT > 1.5 times the upper limit of normal.

Dr. Dusheiko made clear that due to their fluctuations, it is necessary to perform several determinations of ALT and HBV DNA levels before deciding that a patient does not need treatment. Regarding biopsy, there is not an agreement on the need to perform it [10,11,13], although there are certain situations where it may be of great help to decide management.

According to Dr. Dusheiko’s algorithm, a liver biopsy should be considered only in patients with HBV DNA levels > 10⁵ log₁₀ (with any ALT level in HBeAg-positive patients and with elevated ALT levels in HBeAg-negative patients). And treatment for HBV (along with anti-HIV treatment) should be given only in those cases in which significant hepatitis was shown in the histology, This is based on the poor response to interferon and nucleos(t)ide analogues (NRTI) when there is mild liver disease.

However, a number of issues were not addressed in his algorithm: 1) What to do in patients with elevated ALT but HBV DNA < 10⁵ copies/mL, especially in those with negative HBeAg?; 2) What to do in HBeAg-negative patients with ALT within normal limits but HBV DNA > 10⁵ copies/mL?; 3) Why not consider a lower threshold of HBV DNA levels (i.e., 10⁴ copies/mL) in HBeAg-negative patients as clinically relevant, as has been proposed by other authors? [10]; 4) Given the availability of antiretrovirals with dual anti-HBV and anti-HIV activity, is it necessary to perform a liver biopsy in those patients with a clear indication to receive anti-HIV therapy and with HBV DNA levels > 10⁵ copies/mL?

In his conclusions, Dr. Dusheiko stated that although it is possible to achieve anti-HBe seroconversion in HBeAg-positive patients, long term suppressive therapy of (HIV) and HBV will be required for HBeAg positive patients who fail to seroconvert, as well as for anti-HBe antibody positive patients, and this should be taken into account before starting therapy.

Algorithm for the treatment of HBV

Dr Yves Benhamou (Pitié-Salpêtrière Hospital, Paris, France), one of the chairs of the conference, was in charge of proposing an algorithm for the treatment of HBV. He emphasized the risk of ALT flares due to HAART-related immune reconstitution, which may occur despite 3TC treatment [14].

This may occur in particular in patients with high serum HBV DNA and low nadir CD4 counts. In cirrhotic patients, ALT flares may be associated with liver decompensation. Therefore, this phenomenon should be taken into account before initiating HAART in order to prevent it.

Regarding available therapies, [standard] interferon (IFN) has been shown to have a lower response in HIV/HBV-coinfected compared to HBV-monoinfected subjects. Pegylated IFN may be more effective than standard IFN, but has never been studied in HIV/HBV-coinfected patients. Both 3TC and emtricitabine (FTC), despite being effective at suppressing HBV replication, in prolonged monotherapy have the ability to very often select resistance mutations, and this is more common in HIV/HBV-coinfected subjects (90% after 4 years of 3TC monotherapy).

Adefovir dipivoxil (ADV) and tenofovir dixoprosil fumarate (TDF) in nearly all cases are effective against wild type and 3TC-resistant HBV after adding to 3TC, and resistance mutations have not been documented so far (48 weeks TDF, 144 weeks ADV) [15,16]. In a very comprehensive table, Dr. Benhamou summarized the results of anti-HBV treatment in HIV-coinfected patients with marketed or very close to approval anti-HBV drugs (table 2).

Dr. Benhamou divided the patients into those who require anti-HIV treatment and those who do not. For those not meeting criteria for anti-HIV therapy but with need of anti-HBV treatment, he proposed pegylated IFN for 48 weeks in HBeAg-positive subjects, with the objective of achieving anti-HBe seroconversion.

As an alternative in these subjects with positive HBeAg, and as first choice for those with negative HBeAg, ADV was proposed.

The use of 3TC, FTC, or TDF in monotherapy was discouraged due to their anti-HIV activity, since they could select resistance mutations in the HIV genome. However, the jury questioned the safety of ADV regarding the selection of mutations in the HIV genome, despite the low doses used for HBV treatment, apparently inactive against HIV. In addition, new drugs with only-anti-HBV activity are currently under development that also will be indicated in this setting.

For those patients needing anti-HIV therapy, there would be a subset not requiring treatment for the HBV infection. Dr. Benhamou distinguished among them, those with HBV DNA levels > 10⁴ copies/mL, for whom he recommended  including NRTI with dual activity (anti-HIV and anti-HBV) in their HAART regimens in order to avoid hepatic flares associated with immune reconstitution.

If HBV DNA levels are below that figure, NRTI with dual activity might not be needed, but both HBV DNA and ALT levels should then be checked 3 to 4 times a year.

In subjects requiring both treatment for HIV and for HBV infections, the inclusion of NRTI with dual activity is mandatory, preferentially in combination (i.e., TDF plus 3TC or FTC). Alternatively, only a NRTI with dual activity and high genetic barrier would be included (i.e., TDF). As a second alternative, ADV might be added to a HAART regimen with no or only one NRTI with dual activity.

In case of HBV resistant to 3TC and FTC, Dr. Benhamou recommended to continue the prior NRTI (3TC or FTC) and to add TDF, or alternatively ADV. Pegylated interferon might be indicated in those subjects with HBV DNA levels > 10⁴ copies/mL.

However, it was argued from the audience that the distinction of whether treatment for HBV was needed or not might not be as important in those patients meeting criteria for initiating HAART. It would be a more theoretical than practical issue, given that the three currently marketed NRTI with dual activity are widely prescribed for HIV in general, and the favorable resistance profile of TDF.  On the other hand, anti-HBV treatment would be given anyway in order to prevent hepatic flares due to immune reconstitution.

Treatment options for HBV treatment

Dr. Antonio Craxi (University of Palermo, Italy) reviewed the treatment options for HBV treatment. He summarized the treatment options according to the objective of the treatment: curative versus suppressive (table 2).

IFN is approved for the treatment of HBV, and it is the most effective available  therapy to achieve sustained virological response, although the proportion of responders is low. Better results are obtained in HBeAg-positive patients, and also with the pegylated forms of IFN. Dr. Craxi spoke of the results of two large randomized trials performed in HBV-moninfected patients with pegylated IFN [17,18]. Both studies compared monotherapy pegylated IFN with combination 3TC and pegylated IFN, showing no benefit by adding 3TC.

One of the studies was performed in HBeAg negative patients who were treated for 48 weeks with pegylated IFN-a-2a plus placebo (177), pegylated IFN-a-2a plus 3TC (179), or 3TC alone (181) [17]. At 24 weeks after treatment discontinuation (sustained virological response, SVR), 19-20% of subjects in the IFN arms had undetectable HBV DNA (< 400 copies/mL).

HBsAg loss was achieved by 3.4% of patients receiving IFN. In the other trial, HBeAg positive subjects were treated with either pegylated IFN-a-2b plus placebo (136) or with pegylated IFN-a-2b plus 3TC (130) for 52 weeks [18]. HBeAg loss, SVR, and HBsAg loss was achieved by 36%, 7%, and 7% of subjects in the monotherapy arm, respectively. There are no studies with pegylated IFN in HIV/HBV-coinfected patients.

Table 3. HBV treatment options according to the objective.

Less effective at achieving SVR, the nucleos(t)ide analogues 3TC and ADV are anti-HBV drugs currently approved for the treatment of HBV. They are especially indicated when the aim of therapy is suppression. The strengths and weaknesses of both drugs are summarized in table 3.

TDF, a nucleotide analogue very active against HBV, is not approved for treatment of HBV, but is being used in HIV/HBV-coinfected patients as therapy of both infections. In addition, there are anti-HBV drugs under development, some also with anti-HIV activity (such as FTC), which are summarized in table 4.

Table 4. Anti-HBV drugs under development.

Regarding the role of HBV genotypes in the response to treatment, there are studies suggesting better response to interferon in genotype B compared to C (genotypes prevalent in the Far East), and in A compared to D (prevalent in Europe). However, in the questions session it was pointed out that there is not enough data to recommend different therapeutic strategies according to HBV genotypes.

Among the future research needs, the following were mentioned:

• Identify correlates of disease progression and response to therapy;
• Define the role of combination therapy, the role of long term therapy, the role of new drugs and combinations;
• Develop in vitro HBV phenotypic assays for “a la carte” therapy;
• Define thresholds for HBV treatment based on IU/mL of HBV DNA (rather than on copies/mL); and
• Perform trials with pegylated IFN in HIV/HBV-coinfected patients.
  

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