HBeAg-positive chronic hepatitis B: Why do I treat my patients with Nucleos(t)ide Analogs?


  • Maria Buti

    Corresponding author
    1. Liver Unit, Hospital Universitario Valle Hebron and Ciberehd del Instituto Carlos III, Barcelona, Spain
    • Correspondence:

      Maria Buti, Liver Unit, Hospital Universitario Valle Hebron, Paseo Valle Hebrón 119 Barcelona 08035, Spain

      Tel: +34932704000

      Fax: +34934274495

      e-mail: mbuti@vhebron.net

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The ultimate goal of therapy for hepatitis B virus (HBV) infection is to obtain a clinical benefit for the patient by reducing infection-related complications, including hepatocellular carcinoma (HCC). Two main types of antiviral agents have been approved to treat patients in the immune clearance phase: interferon (IFN) and nucleos(t)ide analogues (NAs). NAs are used in most HBeAg-positive chronic hepatitis B patients for several reasons. They are oral drugs that are taken once a day and can be prescribed to all chronic hepatitis B patients, even those with contraindications for IFN. The current first-line NA options, entecavir (ETV) and tenofovir (TDF), have minimal or no risk of long-term resistance, and the sustained virological response is achieved in almost 100% of adherent HBeAg-positive patients. Tolerance is excellent and the safety profile is good, whereas IFN can be associated with adverse events that affect the patients’ quality of life. There is considerable evidence to show that NAs modify the natural history of chronic hepatitis B, and increasing evidence that they reduce the risk of developing HCC. The need for long-term, perhaps indefinite treatment in patients who do not achieve anti-HBe seroconversion is the main limitation of NAs, but this is offset by their excellent tolerance and safety profile.


adefovir dipivoxil




hepatitis B virus


hepatocellular carcinoma








nucleos(t)ide analogues


nucleos(t)ide analogues


sustained virological response


tenofovir disoproxil fumarate

Hepatitis B is an important disease worldwide and over one-third [ask author to provide a reference. According to WHO, 350 million people are chronically infected with HBV, i.e. about 6% (not 30%) of the world population] of the world population is infected with the hepatitis B virus (HBV). Distribution of the disease is not homogenous; it is more prevalent in certain parts of South East Asia and Africa [1]. HBV infection is a heterogeneous disease. HBeAg-positive patients account for 10% to 35% of chronic hepatitis B cases in Europe [2]. In general, HBeAg-positive patients are in the earlier phases of the disease, the immune-tolerant or immune-clearance phases, which are characterized by high levels of HBV DNA. Chronic HBV infection (CHB) is a cause of considerable morbidity and mortality, both of which are linked to ongoing HBV replication. There is convincing evidence that persistent active viral replication is an independent predictor of disease progression. Indeed, a large prospective cohort study has demonstrated that elevated HBV DNA levels (>104 copies/ml) significantly increase the risk of cirrhosis, hepatocellular carcinoma (HCC) and death over a 10-year period [3, 4]. Therefore, sustained suppression of HBV replication is the cornerstone for preventing disease progression and prolonging survival in CHB patients. In addition, treatment of existing carrier forms is important for controlling the disease by reducing HBV infectivity.

In HBeAg-positive patients, international guidelines on the management of CHB suggest that either pegylated interferon (PEG-IFN) or nucleos(t)ide analogues (NAs) such as entecavir (ETV) or tenofovir disoproxil fumarate (TDF) can be used as first-line therapy, although there are no specific recommendations on how to choose between these two treatments [1, 5, 6]. Therefore, the choice of PEG-IFN or a NA is the personal decision of the treating physician. In this review, the arguments supporting the use of NAs as first-line therapy in HBeAg-positive patients are addressed.

Nucleos(t)ide analogues are currently the most potent drugs for suppressing hepatitis B virus replication, and this action is associated with better disease outcome.

The ultimate aim of CHB treatment is to prevent or decrease the development of HCC and cirrhosis, and these endpoints are reached by the suppression of viral replication. Registration studies in HBeAg-positive patients have shown that ETV and TDF are the most potent drugs for suppressing viral replication and are better than PEG-IFN. Serum HBV DNA levels were reduced to <60–80 IU/ml 48 or 52 weeks after the end of treatment in 67% of patients who received ETV, 76% with (TDF), and only 14% and 7% of patients with PEG-IFN α 2a and 2b respectively [7-10]. After this period, suppression of viral replication increases to almost 100% and persists over time. Serum HBV DNA levels <60–80 IU/ml are achieved in 94% of patients treated with ETV and in 98% to 99% of patients treated with TDF for more than 5 years [11, 12]. In contrast, only a minority of patients treated with PEG-IFN maintain these levels off therapy and approximately 13% have HBV DNA levels below 2000 IU/ml, suggesting some degree of immune control [13].

There is considerable indirect evidence that adequate suppression of viral replication leads to improved outcomes, with a reduction in morbidity and mortality. In small subsets of patients, treatment of CHB with the older polymerase/reverse transcriptase inhibitors, lamivudine (LAM) and adefovir (ADV), has been reported to reverse advanced fibrosis and cirrhosis; however, in long-term use, these agents often lead to incomplete virological suppression, and resistance develops in 20% to 75% of patients, resulting in poor clinical outcomes [14-17]. Studies with ETV have shown low resistance rates in treatment-naive patients. Furthermore, clear reversal of fibrosis was reported in 57 patients who received a median 6 years of therapy, but only four of them had cirrhosis at entry [18, 19]. In a study involving TDF, 96/348 patients had cirrhosis at baseline, and sequential histology data were obtained over 5 years. All patients receiving TDF had undetectable HBV DNA early on, and this was associated with the prevention of the progression of fibrosis in 96% and the regression of cirrhosis in 74% of patients [12]. The histological response and regression of fibrosis seen in this study are probably because of the potent viral suppression achieved with long-term use of the drug and the absence of TDF resistance-associated variants.

In clinical practice maintaining viral suppression is feasible because of an overall favourable safety profile and the absence of treatment-limiting toxicity of NAs. This has also been proven in a single randomized controlled trial using LAM, in which patients with HBV cirrhosis were treated with LAM or placebo for 3 years [15]. A clear reduction in complications (hepatic decompensation and HCC) was observed in the treated group. This relationship was stronger in patients with complete viral suppression than in those who developed virological breakthrough with LAM. Most studies investigating oral antiviral agents (LAM or ADV) have shown a decrease in the incidence of HCC, but these were retrospective studies without adequate controls. Recently, Hosaka et al. presented data in a large cohort matched for the risk of HCC with historical controls. This study showed a reduction in the incidence of HCC with ETV [20]. The cumulative HCC incidence rates at 5 years were 3.7% in the ETV group and 13.7% in controls (< 0.001). Treatment was more effective in patients with a higher risk of HCC; that is, those with low platelet counts, pre-existing cirrhosis, HBeAg-positive status, or HBV DNA levels >5 log10 copies/ml, older patients, males and consumers of alcohol. In addition, ETV was better than LAM without rescue therapy in reducing the risk of developing HCC.

In a long-term study with TDV, 14 patients developed HCC: 8/482 (1.5%) patients without cirrhosis at baseline and 6/152 (4.5%) with cirrhosis. The incidence of HCC in patients without cirrhosis was lower than that predicted by the REACH-B model. The effect of TDF becomes noticeable after 2 to 3 years of therapy, and there is a 55% reduction in the predicted risk of HCC after 6 years of therapy [21]. This is the first evidence in a prospective study that the risk of HCC can be reduced in patients without cirrhosis. These results contrast with those from a meta-analysis of 27 trials including 7034 patients that showed a minor reduction in the incidence of HCC in patients with cirrhosis and no effect in patients without cirrhosis [22]. The problem in patients without cirrhosis is that if treatment is begun early enough to reduce the incidence of HCC, follow-up would have to last more than 10 years to determine whether there is a beneficial effect [23]. Results from IFN studies are inconsistent; hence, it is difficult to prove that IFN therapy reduces the incidence of HCC. Because HBeAg-positive patients have a higher risk of developing HCC, it could be important to use NAs in this population.

Seroconversion to anti-HBe is similar between patients treated with NAs and those receiving interferon

Seroconversion to anti-HBe is a desired, intermediate endpoint for HBeAg-positive patients. Traditionally, patients who reach this endpoint are candidates to stop treatment with NAs or PEG-IFN. Anti-HBe seroconversion is achieved in 29% and 32% of patients treated with PEG-IFNα 2b and PEG-IFNα 2a, respectively, and in 21% of those treated with ETV or TDF at 1 year [7-10]. Prolonging treatment is associated with an increase in anti-HBe seroconversion. In the TDR study, HBeAg loss rates increased to 50% and anti-HBe seroconversion to 37% at year 6 of therapy [11, 12].

There is a clear relationship between ALT levels at baseline and the probability of HBeAg seroconversion. In patients with normal ALT levels, the probability of seroconversion was found to be null or minimal (<1%), while in those with ALT levels >5-fold the upper normal limit, HBeAg seroconversion occurred in 30% to 40% of patients treated with PEG-IFN or ETV, LAM or ADV. These rates were much higher than in the placebo group [24]. HBeAg seroconversion is an important outcome because it is associated with a better prognosis. However, HBeAg seroconversion does not always persist. Some patients who seroconvert with PEG-IFN or NAs require long-term follow-up because of potential HBeAg seroreversion or progression to HBeAg-negative CHB [25, 26]. In the REVEAL study, one major reason for disease progression after HBeAg seroconversion was the emergence of precore and core promoter mutations, which occurs even before HBeAg seroconversion. Yuan et al. reported the incidence of core promoter mutations 24 months before HBeAg seroconversion, at seroconversion, and at 12 months later in 76 patients. Overall, 88.1% had core promoter mutations, with or without precore mutations [27]. For the disease not to progress after HBeAg seroconversion (whether spontaneous, IFN-induced or NA-induced), HBV DNA levels must be persistently low (preferably below the detection limit of PCR assays) and this endpoint is more frequently achieved with NAs.

Low rates of HBsAg loss regardless of the type therapy

In HBeAg-positive patients, the ideal endpoint is sustained off-therapy HBsAg loss, with or without seroconversion to anti-HBs. This is associated with complete and definitive remission of CHB activity and a better long-term outcome. HBsAg loss occurs after 1 year of treatment in 3% of patients treated with PEG-IFNα 2a, in 7% treated with PEG-IFNα 2b, in 2% treated with ETV and in 3% treated with TDF [7-10]. In HBeAg-positive CHB, pretreatment factors predictive of anti-HBe seroconversion are low viral load (HBV DNA <108 IU/mL), high serum ALT levels and high activity scores on liver biopsy [8, 28, 29]. In the long-term study with TDF, 11% of patients lost HBsAg. The most important characteristics associated with HBsAg loss were loss of HBeAg in the first 24 weeks of TDF treatment, high baseline levels of HBsAg, an HBsAg slope from baseline to week 12 and an ALT flare in the first 12 weeks of therapy [30] A decline in HBsAg during NA treatment in HBeAg-positive patients may identify cases with subsequent HBeAg or HBsAg loss [30-32].

NAs have an excellent tolerance and safety profile

Patients usually prefer oral treatment to injections. Thus, patients prefer NAs, which are taken as one tablet per day, to weekly subcutaneous PEG-IFN injections [9]. Clinical trials and cohorts from clinical practice have shown that NAs are generally well-tolerated and safe [33], which gives them an important advantage compared with PEG-IFN, which is associated with several contraindications and a wide range of adverse events that can negatively affect the patients’ quality of life [10, 11]. ETV seems to be safe, with no specific safety issues so far. Potential nephrotoxicity has been discussed during long-term therapy with TDF, because abnormal kidney function has been described in the HIV population. Nevertheless nephrotoxicity rarely occurs in monoinfected patients. No significant changes in serum creatinine or creatinine clearance and very low (<1%) rates of hypophosphataemia have been reported after 5 years of TDF therapy in CHB patients [18]. It should be noted that minimal declines in creatinine clearance have been reported with all NAs, except for telbivudine, a drug that may even improve creatinine clearance [19]. Although NAs have a good safety profile, no agent can be considered absolutely safe, as these drugs are often given for years or even life, particularly to HBeAg-positive patients who do not achieve anti-HBe seroconversion and HBsAg loss. Because of the better safety profile of NAs, on-treatment monitoring is less common and less frequent than with PEG-IFN [9]. All CHB patients treated with NAs should be tested for serum creatinine levels and estimated creatinine clearance before treatment. These drugs are cleared through the kidneys and dosing adjustments are needed in patients with creatinine clearance <50 ml, regardless of the type of NAs.

All patients can be treated with NAs

NA therapy is widely applicable. All patients in different stages of HBV infection can be treated with these agents (chronic hepatitis B, patients with cirrhosis, decompensated patients and in the liver transplant setting) with excellent results and easy follow-up and monitoring. This makes NA therapy a simple option that physicians and patients can appropriately manage.

The only drawback of NAs is that they must be given for a long time, probably for life in many patients, but this is also the case of other diseases, such as diabetes or hypertension, in which therapy is needed indefinitely. As a result to obtain persistent suppression of viral replication and favourable disease control it is important to educate patients regarding adherence to therapy [34, 35].

In conclusion, therapy with NAs in HBeAg-positive CHB patients modifies disease outcome, and increasing evidence indicates that it reduces the risk of HCC. NAs can be used in all patients, even those with contraindications for PEG-IFN. NA treatment is preferred by physicians because it is easy to managed, and by patients because of better tolerance and safety, as well as on-treatment efficacy. Patients must be made aware of the importance of drug compliance and the possible prospect of lifelong therapy.