Why do I treat HBeAg-negative chronic hepatitis B patients with nucleos(t)ide analogues?


  • George V. Papatheodoridis

    Corresponding author
    • 2nd Department of Internal Medicine, Athens University Medical School Hippokration General Hospital of Athens, Athens, Greece
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George V. Papatheodoridis, MD, 2nd Department of Internal Medicine, Athens University Medical School, Hippokration General Hospital of Athens, 114 Vas. Sophias ave., 115 27 Athens, Greece

Tel: +30 210 7774742

Fax: +30 210 7706871

e-mail: gepapath@med.uoa.gr


Products that are currently used in the treatment of chronic hepatitis B include interferon-alpha (IFNa: standard or pegylated) (PEG-IFNa) and nucleos(t)ide analogues (NAs). NAs are used in most HBeAg-negative chronic hepatitis B patients for several reasons. They can be prescribed to all chronic HBV patients, even those with contraindications to IFNa; and even IFNa candidates are usually treated with NAs because of their advantages. Administration of NAs is easier (one oral tablet per day compared with subcutaneous IFNa injections), tolerance is excellent and the safety profile is good, whereas IFNa may have adverse events and often worsens the patients’ quality of life. The current first-line NA options, entecavir (ETV) and tenofovir (TDV), have minimal or no risk of long-term resistance and a virological response is achieved in almost 100% of adherent HBeAg-negative patients, thus modifying the long-term outcome. The need for long-term, perhaps indefinite, treatment is the main limitation of NAs and the finite duration (48 weeks), the main advantage of IFNa, especially in young patients of reproductive age. However, at most 25% of IFNa-treated HBeAg-negative patients achieve a sustained off-treatment response and therefore >75% of them will eventually receive NAs, even if they start with IFNa. As there will always be concerns about safety and family planning issues with long-term NA therapy, NAs should be used carefully, particularly in young chronic hepatitis B patients with mild liver disease. Novel therapeutic options are needed to increase the rates of HBsAg loss and sustained off-treatment responses.


adefovir dipivoxil


chronic hepatitis B




hepatitis B virus






nucleos(t)ide analogues


pegylated interferon-alpha




tenofovir disoproxil fumarate


upper limit of normal

The treatment of chronic hepatitis B (CHB) has markedly improved in the last 15 years and virological remission can now be achieved in almost all patients, thus improving their prognosis and long-term outcome [1-3]. However, as hepatitis B virus (HBV) eradication is still an ideal therapeutic target that can only occasionally be attained, only patients who are at risk of progression to advanced liver disease are usually considered for treatment [1, 2, 4]. HBeAg-negative CHB, which is currently the predominant type of CHB worldwide, represents a late phase in the natural history of chronic HBV infection [5]. It may develop immediately after HBeAg seroclearance and anti-HBe seroconversion or more frequently after a long inactive chronic HBV carrier phase [5, 6]. Because of the identical serological profile, it is not always easy to differentiate HBeAg-negative CHB patients from inactive chronic HBV carriers [5]. To avoid treating inactive carriers, but not to delay treatment for patients with active disease, current guidelines recommend that HBeAg-negative patients begin therapy if they have elevated ALT [higher than upper limit of normal (ULN)], HBV DNA >2000 IU/ml and at least moderate necroinflammation and/or fibrosis [2, 3]. However, liver biopsy may not be absolutely necessary before beginning treatment in HBeAg-negative patients with clearly active liver disease (ALT >2xULN and HBV DNA >20 000 IU/ml), whereas no liver biopsy and no therapy are necessary in HBeAg-negative patients with persistently normal ALT and HBV DNA >2000 IU/ml, but <20 000 IU/ml, who should be only followed closely [3, 7, 8].

There are two classes of agents licensed for the treatment of CHB: interferon-alpha (IFNa, standard or pegylated) with both antiviral and immunomodulatory activities; and nucleos(t)ide analogues (NAs) with only antiviral activity [1, 3]. The antiviral agents belong to the same class (HBV polymerase inhibitors) and can be subdivided into nucleoside analogues, which include lamivudine (LAM), entecavir (ETV), telbivudine (TBV) and nucleotide analogues, which include adefovir dipivoxil (ADV) and tenofovir disoproxil fumarate (TDF) [1, 3]. In the last 15 years, NAs have been used in the treatment of most chronic HBV patients for two main reasons [9]. Firstly, NAs can be given to practically all patients, while IFNa has several absolute or relative contraindications. Secondly, NAs are used in most patients even without contraindications to IFNa, because of their many advantages and few limitations, so they are usually chosen by patients. This review summarises the main characteristics, advantages and limitations of NAs for the treatment of HBeAg-negative CHB (Table 1).

Table 1. Pros and cons of (standard or pegylated) interferon-alpha or nucleos(t)ide analogue therapy for HBeAg-negative chronic hepatitis B
Interferon-alphaNucleos(t)ide analogues
  1. Chance of sustained off-treatment responses with treatment of finite duration (usually 48 weeks)
  2. Higher sustained off-treatment response rates after 1-year courses
  3. Durable sustained off-treatment responses associated with improved long-term outcomes including survival and often HBsAg loss
  1. No contraindication for treatment
  2. Oral administration (once daily)
  3. Excellent tolerance, good safety
  4. Long-term on-therapy virological responses practically in all patients under entecavir or tenofovir monotherapy
  5. Improvement of the overall long-term outcome and survival even in patients with cirrhosis
  1. Parenteral administration
  2. Contraindications in specific patient subgroups (e.g. decompensated cirrhosis)
  3. Frequent and potentially severe side effects
  4. Sustained off-therapy responses in a minority of patients (22–25%)
  1. Unknown (perhaps indefinite) duration of treatment
  2. Rare HBsAg loss
  3. Progressively increasing risk of viral resistance (not with entecavir or tenofovir)
  4. Safety concerns with long-term duration of treatment
  5. Concerns in patients of reproductive age – Unclear safety in pregnancy

Excellent tolerance, good safety

Patients usually prefer oral treatment to injections. Patients prefer NAs, which are taken as one tablet per day to subcutaneous IFNa injections [9]. Administration of current pegylated IFNa (PEG-IFNa) is now easier (one instead of three to seven subcutaneous injections per week), which has limited somewhat the disadvantage of the parenteral administration of IFNa.

Clinical trials and cohorts from clinical practice have shown that NAs are generally well tolerated and safe [9]. The better tolerance and safety profile of NAs are a strong advantage over PEG-IFNa, which can negatively affect the patients’ quality of life and daily activities as well as be associated with a wide range of adverse events [10, 11].

Although NAs have a good safety profile, no product can be considered to be absolutely safe. As NAs are often given for years, or even for life, particularly to HBeAg-negative CHB patients, it is reasonable to evaluate safety issues. The most extensive results in this area are with LAM, the first licensed and most widely used oral anti-HBV treatment [12]. However, LAM is not currently considered to be a first-line option for CHB because of its poor resistance profile [3]. Adefovir dipivoxil seems to have a slight risk of nephrotoxicity: 3% of CHB patients have serum creatinine increases of ≥0.5 mg/dl above baseline after 5 years of ADV monotherapy [13]. The risk of ADV-induced nephrotoxicity varies widely among studies, but it appears to be higher in older patients with relatively mild renal impairment at baseline and comorbidities, such as diabetes and hypertension [14, 15]. TBV has been associated with increased creatinine phosphokinase in up to 12% of patients [16, 17], but symptomatic myopathy is extremely rare and no specific monitoring is recommended during TBV therapy [12]. ETV seems to be a safe agent with no specific safety issues so far. Potential nephrotoxicity has been discussed during the long-term therapy with TDF, but 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 TBV, which may even improve creatinine clearance [19]. Potential nephrotoxicity may be greater with nucleotide analogues, particularly ADV [14], while both nucleotide analogues may increase renal phosphorus excretion.

Because of the better safety profile of NAs, on-treatment monitoring is less common and less frequent than with PEG-IFNa [9]. All CHB patients treated with NA(s) need to be tested for serum creatinine levels and estimated creatinine clearance before treatment as NAs are excreted through the kidneys and dosing adjustments are necessary in patients with creatinine clearance <50 ml/min [3]. On-therapy renal monitoring may also be required depending upon the type of NA and the patient's baseline renal risk. Although sufficient data are lacking and clear recommendations cannot be made, recent guidelines suggest that the baseline renal risk should be assessed in all CHB patients before beginning treatment with NAs [3]. Patients with decompensated cirrhosis, creatinine clearance <60 ml/min, poorly controlled hypertension, proteinuria, uncontrolled diabetes, active glomerulonephritis, concomitant nephrotoxic drugs or solid organ transplantation should be considered to have a high renal risk. Serum creatinine (estimated creatinine clearance) and serum phosphate levels should be monitored in all CHB patients treated with ADV or TDF, while serum creatinine levels should only be monitored in CHB patients treated with LAM, TBV or ETV if they have high renal risk. Patients with a low renal risk can be monitored every 3 months for the first year and every 6 months thereafter if there is no worsening, whereas patients with a high renal risk should be monitored every month for the first 3 months, every 3 months until the end of the first year and every 6 months thereafter if there is no worsening. More frequent renal monitoring is required in patients who develop creatinine clearance <60 ml/min or serum phosphate levels <2 mg/dl) [3]. As long as patients and physicians adhere to the few existing follow-up recommendations, the long-term use of NAs appears to be safe with no significant adverse events in most treated patients [9].

Excellent on-therapy virological remission rates

All NAs, except ADV, are more potent than PEG-IFNa. In NAs naïve CHB patients, undetectable HBV DNA can be achieved at year 1 in 60–75% of cases treated with LAM [16, 20-22], 70–75% with ADV [23, 24] and 88–93% with ETV, TBV or TDF [16, 22, 24]. Of course, a 1-year course of NA does not induce a sustained off-therapy response in most HBeAg-negative CHB patients, so NAs are usually given for several years or even indefinitely [1-3]. Thus, the long-term on-therapy virological remission rates, which are linked to the risk of viral resistance, are the key factor for the use and selection of NA therapy.

Prolonged antiviral therapy with any product will logically be associated with a progressive increase in the risk of viral resistance as a result of the emergence and selection of treatment-resistant mutant viral strains [25]. However, the probability of viral resistance is not the same for all anti-HBV agents. LAM has the worst resistance profile with a 5-year cumulative resistance risk of >65%, and <35% of HBeAg-negative CHB patients remain in virological remission after 5 years of LAM monotherapy [26, 27]. Besides the risk of breakthroughs and worsening liver disease, LAM resistance may also negatively affect the efficacy of other nucleoside analogues (TBV, ETV) [28]. Thus, LAM monotherapy is not currently considered to be an optimal first-line long-term therapy for either HBeAg-positive or HBeAg-negative CHB [2, 3]. However, the product is still used in several developing countries mainly because it is inexpensive.

Adefovir dipivoxil has a better resistance profile than LAM with better long-term sustained virological response rates. In patients with HBeAg-negative CHB, ADV monotherapy resulted in a sustained virological response and biochemical remission in 67–69% of cases treated for 5 years [13], whereas ADV resistance first emerged during the second year and cumulative resistance rates reached 3 and 29% at the end of the 2nd and 5th year respectively [13]. Adefovir dipivoxil is no longer used extensively since TDF became available. Tenofovir disoproxil fumarate is a more potent agent with a better resistance profile and is less expensive in most countries.

Telbivudine monotherapy for 2 years resulted in a virological response in most HBeAg-negative CHB patients, but the response rate decreased by almost 10% from the first to the second year (88 and 79%) [16, 17]. Cumulative TBV resistance also increased over time (year-1: 2.7%, year-2: 8.6%) [16, 17]. The absence of residual viraemia (HBV DNA <400 copies/ml) at 6 months of TBV monotherapy was associated with a low probability of resistance at 2 years, particularly in patients with baseline HBV DNA levels <2 000 000 IU/ml [17].

The risk of HBV resistance has decreased with the use of ETV and TDF, which are currently the recommended first-line NA options for the treatment of CHB [3]. In NA naïve patients with CHB, the cumulative rate of resistance has been reported to be only 1.2% at ≥6 years for ETV and 0% at 5 years for TDF [29, 30]. Given the high potency and the minimal or inexistent risk of resistance, extending ETV or TDF monotherapy increases the high virological remission rates. Thus, virological remission rates of 99–100% can be achieved in adherent HBeAg-negative CHB patients and sustained after the 2nd year of ETV or TDF monotherapy [30, 31]. Recently, recommendations on the optimal management of patients with a partial virological response and on optimal virological monitoring during therapy have been modified because of the high long-term efficacy of these two products [3]. In particular, HBV DNA levels at week 48 and viral kinetics should be taken into account in patients with a partial virological response (detectable serum HBV DNA) after 48 weeks of ETV or TDF therapy. Treatment should be continued with the same product in patients receiving ETV or TDF with declining serum HBV DNA levels while another drug is only considered in those few compliant patients without a decrease in HBV DNA [3]. In the same way, although HBV DNA monitoring is generally recommended every 3–6 months for long-term NA therapy in CHB, this can be reduced to every 6 months in patients treated with ETV or TDF once compliance and treatment efficacy are confirmed [3].

With ETV and TDF, the management of viral resistance, if it develops, is also no longer a major concern. In the era of ADV, the early add-on approach was the optimal strategy for LAM resistance [1, 2], while switching to TDF monotherapy has now become the best choice in these patients [3, 32]. ETV has also been licensed for the treatment of LAM resistance, but it is not usually recommended in this setting [1-3], because the cumulative long-term resistance rate is more than 50% at 5 years. This is owing to pre-existing LAM- resistant strains that dramatically increase the probability of ETV resistance [29]. ADV resistant mutants are usually susceptible to nucleoside analogues (LAM, ETV, TBV), but they are also sensitive to TDF, particularly in patients without high virological breakthroughs [32-34]. It is better to treat patients with TBV or the rare patients with ETV resistance strains with switch to or add-on TDF [3, 35]. Finally, genotyping and phenotyping at an expert laboratory should be performed when TDF resistance is suspected, which has not been described so far, and, if confirmed, a nucleoside analogue add-on combination should be begun [3].

Need for long-term, perhaps indefinite, duration of treatment

As HBV cannot be eradicated and HBsAg clearance is very rare in the first 5 years of NA therapy in patients with HBeAg-negative CHB, most of these patients are expected to relapse if treatment is discontinued [1, 9]. Preliminary data on the discontinuation of effective ADV monotherapy after 4–5 years have been promising and show a high proportion of HBeAg-negative patients with an inactive carrier state and often HBsAg loss and the development of anti-HBs [36]. In addition, there are ongoing studies evaluating the safe discontinuation of NA therapy in HBeAg-negative CHB patients who have also received PEG-IFNa at some point during treatment or in patients who develop positive predictive factors (e.g. low serum HBsAg levels) of a sustained off-treatment viral response [37, 38]. However, all these preliminary findings should be confirmed in larger studies before they can be generally accepted and applied to clinical practice. For now, there is a need for long-term, perhaps indefinite, duration of treatment in most HBeAg-negative CHB patients.

The necessity of long-term treatment is the main limitation of NA therapy for several reasons [9]. With the availability of ETV and TDF, the initial concerns about increasing viral resistance and a decrease in on-therapy virological remission have disappeared. On the other hand, concerns about the long-term safety of these products still exist, although the safety profile of ETV and TDF as well as of many NA seems to be acceptable even during long-term use [9]. In current clinical practice, however, the most common concern is safety in case of pregnancy and generally in relation to family planning whenever NA(s) are taken by CHB patients of reproductive age. All licensed anti-HBV agents have warnings for potential risks of adverse fetal outcomes when they are used immediately before and during pregnancy [9, 12]. Therefore, both treated men and women of child-bearing age should use contraception. On the other hand, the risk of teratogenicity is not the same for all drugs. LAM, ADV and ETV are listed by the FDA as pregnancy category C drugs, and TBV and TDF as category B drugs, whereas PEG-IFNa is contraindicated during pregnancy [3]. Moreover, safety data from the Antiretroviral Pregnancy Registry in pregnant HIV-positive women who have received TDF and/or LAM are reassuring [39]. Thus, TDF seems to be the best first-line NA option for CHB in young patients of reproductive age whenever pregnancy is still a possibility [3].

While long-term NA therapy is necessary in HBeAg-negative CHB patients, PEG-IFNa therapy offers a chance of sustained virological responses with a finite duration (usually 48 weeks) of therapy [1, 3]. This is the main advantage of PEG-IFNa therapy, particularly in young patients of child-bearing age [3, 9]. However, although sustained viral responses after PEG-IFNa therapy are usually durable and may lead to HBsAg loss and improve long-term outcomes [40, 41], only 22–25% of PEG-IFNa-treated HBeAg-negative CHB patients achieve these responses [40, 41]. Thus, patients may be discouraged by the low rates of PEG-IFNa-induced sustained virological responses and choose NA despite the need for long-term therapy [9]. The recently published strong PEG-IFNa stopping rule for European HBeAg-negative CHB patients infected with genotype D, based on the combination of serum HBsAg and HBV DNA levels at 12 weeks of therapy, could encourage more patients to begin PEG-IFNa [3, 42]. The new PEG-IFNa stopping rule is not yet extensively used and will only lead to early discontinuation of PEG-IFNa in one-third of the eventual HBeAg-negative CHB non-responders [42]. Thus, most candidates for PEG-IFNa may still prefer to start treatment with a NA.


NAs are the therapeutic choice for most HBeAg-negative CHB patients for several reasons [9]. NAs can be used in all patients even those with contraindications to PEG-IFNa. Moreover, PEG-IFNa candidates often prefer to be treated with NAs, because of the better tolerance and safety profiles as well as on-treatment efficacy. In particular, the current first-line NA options, ETV and TDF, have minimal or no risk of long-term resistance and a virological response is achieved in almost 100% of compliant patients with HBeAg-negative CHB modifying the long-term outcome in these patients [18, 26]. Even if a proportion of HBeAg-negative CHB patients begin treatment with PEG-IFNa, >75% of them will eventually receive NAs, because they will not achieve a sustained virological response [1].

Despite the excellent on-treatment efficacy, NAs including ETV and TDF are not an optimal therapeutic approach. NA therapy does not eliminate the risk of hepatocellular carcinoma, particularly in patients with pre-existing cirrhosis who should be monitored [43, 44]. As HBV cannot be eradicated, there is clearly need for long-term, perhaps indefinite, treatment, which is the major limitation of this treatment option in HBeAg-negative CHB patients and raises safety and family planning issues. Therefore, NAs should be used carefully, particularly in young HBeAg-negative CHB patients with mild liver disease.

In the future, novel therapeutic targets or creative combination therapies are needed to increase sustained virological responses after treatment is discontinued. In addition, new research efforts are needed to identify therapeutic approaches to achieve HBV eradication or at least HBsAg loss and seroconversion in a large proportion of patients.


The author has no disclosure.