Optimal management of chronic hepatitis B patients with treatment failure and antiviral drug resistance

Abstract

The management of treatment failure in patients with chronic hepatitis B, remains a clinical concern. Incomplete viral suppression and the emergence of drug resistance are key determinants of treatment failure. The correct choice of a potent first-line therapy to achieve sustained long-term suppression of viral replication provides the best chance of preventing treatment failure and drug resistance. Clinical studies have demonstrated that drugs with a high barrier to resistance have significantly lower rates of resistance compared with those with a low barrier to resistance. Management of treatment failure requires precise clinical and virological monitoring as well as early treatment intervention with appropriate noncross-resistant antivirals. Long-term surveillance of treatment efficacy and possible emergence of drug resistance is necessary in patients who have been sequentially treated with multiple antivirals. The identification of novel treatment targets remains a major research goal to improve the efficacy of current antiviral therapy through combination therapy regimens.

Abbreviations

ADV

adefovir dipivoxil

ALT

aminotransferase

CHB

chronic hepatitis B

L-FMAU

clevudine

FTC

Emtricitabine

ETV

entecavir

HBIG

Hepatitis B Immune Globulins

LdT

Telbivudine

LMV

lamivudine

MDR

multi-drug resistant

NA

nucleos(t)ide analogues

TFV

tenofovir

Antivirals and treatment failure – main concepts

Effective treatments have been developed for chronic hepatitis B (CHB). Therapeutic efficacy can be affected by factors such as the development of adverse effects, poor patient compliance, previous treatment with suboptimal regimens, infection with drug-resistant viral strains, inadequate drug exposure because of the pharmacological properties of particular drug(s) and individual genetic variation. Interferon alpha and its pegylated form, and five other drugs that belong to the class of nucleos(t)ide analogues (NA) have been approved for treatment of CHB in most parts of the world [1]. NA directly inhibit the reverse transcriptase activity of the HBV polymerase. Approved NAs include lamivudine (LMV), a deoxy cytidine analogue with an unnatural L-conformation, and the related L-nucleoside, telbivudine (LdT; β-L-thymidine). A second group, the acyclic phosphonates, which include adefovir dipivoxil (ADV), a prodrug for the acyclic 2′-deoxy adenosine monophosphate analogue adefovir and the structurally similar tenofovir (TFV). A third group contains a D-cyclopentane sugar moiety and has the most potent anti-HBV drug discovered to date, the deoxy guanosine analogue entecavir (ETV) [2]. This structural classification of NA is useful clinically because it helps predict pathways of NA drug resistance (Table 1).

Table 1. Patterns and pathways of antiviral drug resistance in chronic hepatitis B in the context of cross-resistance [adapted from Zoulim & Locarnini [71]]

Pathway	Amino acid substitutions in the rt domain	LMV	LdT	ETV	ADV	TFV
I, intermediate sensitivity; R, resistant; S, sensitive based on cell culture and clinical data.
	Wild-type	S	S	S	S	S
L-Nucleoside (LMV/LdT)	M204I/V	R	R	I	S	S
Acyclic phosphonate (ADV)	N236T	S	S	S	R	I
Shared (LMV, LdT, ADV)	A181T/V	R	R	S	R	I
Double (ADV, TFV)	A181T/V + N236T	R	R	S	R	R
D-Cyclopentane (ETV)	L180M+M204V/I ± I169 ± T184 ± S202 ± M250	R	R	R	S	S
Multi-Drug Resistance	A181T+N236T+ M250V	R	R	R	R	R

Reduced susceptibility of a virus to the inhibitory effect of a drug, as a consequence of adaptive mutations under the selection pressure of antiviral therapy defines resistance. Two types of mutations have been identified: primary, which are directly responsible for associated drug resistance, and secondary or compensatory mutations, which occur for the virus to facilitate replication competence because primary resistance mutations may be associated with a reduction in replication fitness. Compensatory mutations are important because they reduce the deleterious effects to the virus associated with acquisition of primary drug-resistant mutations [3].

The development of drug resistance begins with mutations in the polymerase gene, followed by an increase in viral load, an increase in serum alanine aminotransferase (ALT) levels several weeks to months later, and progression of liver disease [4-6]. In patients with LMV resistance, the risk of increased serum ALT is usually correlated with the duration of detectability of the resistant strain [7]. These patients are also at significant risk of ALT flare, which may be accompanied by hepatic decompensation [7]. The detrimental effect of HBV drug resistance on liver histology [8] and then on clinical outcome was shown by a placebo-controlled trial of LMV in patients with advanced fibrosis [9]. In contrast with LMV, the kinetics of emergence of resistance to ADV are typically slower, but follow the same sequence of events [10]. In some cases, the emergence of ADV resistance is also associated with acute exacerbation of disease and liver failure [11].

Only limited data are available on the clinical outcome of patients who are infected with LdT-, ETV-, or TFV-resistant HBV, mainly because treatment adaptation, usually based on in vitro cross-resistance data, has been initiated much earlier.

The availability of antiviral drugs with complementary cross-resistance profiles (Table 1) allows physicians to prevent the worsening of the clinical outcome owing to the emergence of resistance. There are several clinical risk factors associated with the development of NA resistance, including high levels of serum HBV DNA, high serum ALT levels and high body mass index [4, 6, 12]. Prior therapy with NAs and inadequate viral suppression during therapy also predict drug resistance [4, 5, 10, 13]. Typically, the development of NA resistance depends on six factors [14, 15]: (i) magnitude and rate of virus replication; (ii) fidelity of the viral polymerase; (iii) selective pressure exerted by the NA (potency); (iv) amount of available replication space in the liver; (v) replication fitness of the emerging NA resistant HBV; and (vi) genetic barrier to resistance of the NA.

Patterns of resistance of NA resistance in CHB

L-nucleosides

Lamivudine resistance substitutions

Antiviral resistance to LMV has been mapped to the tyrosine-methionine-aspartate-aspartate (YMDD) locus in the catalytic or C domain of HBV P ORF [15, 16]. Primary resistance mutations result in the replacement of the methionine by valine, leucine, or occasionally serine and are designated rtM204I/V/S. Although isolated rtM204I can be found, M204V/S are only found with other changes, in particular rtL180M (in domain B) [17, 18]. Other primary substitutions that also confer LMV resistance include the substitution rtA181T/V [19]. Compensatory changes have been found in other domains of the HBV P ORF, such as rtL80V/I, [20] rtV173L, [21] and rtT184S [22].

LMV resistance increases progressively during treatment at rates of 14–32% annually, exceeding 70% after 48 months of treatment [6]. Both LMV resistance mutations (rtM204V/I and rtA181T) confer cross-resistance to LdT and other members that belong to the L-nucleoside structural group such as Emtricitabine (FTC) and Clevudine (L-FMAU) (see Table 1). The rtM204V/I substitution does not confer cross-resistance to ADV or TFV (see Table 1), but the rtA181T/V is associated with resistance to ADV [11, 22]. The rtM204V/I and the rtL180M reduce susceptibility to ETV (see Table 1) [23].

Telbivudine resistance substitutions

The main resistance substitution in the HBV P ORF found with LdT therapy is rtM204I, and this confers antiviral cross-resistance to LMV (see Table 1). Additional specific resistance mutations described include rtA181T/V by the shared pathway (Table 1, Shared Pathway) and rtL229W/V. During the registration studies of Telbivudine, resistance to LdT steadily increased from 4% of prevalent cases at 12 months rising to over 30% after 24 months of monotherapy.

Acyclic phosphonates

Adefovir resistance substitutions

Resistance to ADV was initially associated with substitutions in the B (rtA181T/V) and D (N236T) domains of HBV P ORF [11, 24, 25]. HBV resistance to ADV occurs less frequently than resistance to LMV, with a prevalence of around 2% after 2 years, reaching progressively 29% after 5 years [26]. These ADV-associated mutations in HBV P ORF result in only a slightly decreased susceptibility to ADV in vitro, and confer partial cross-resistance to TFV (see Table 1). The rtN236T does not significantly affect sensitivity to LMV [24] but the rtA181T mutation confers cross-resistance to LMV (see Table 1).

Tenofovir resistance substitutions

Tenofovir (9-[2-phosphonomethoxypropyl] adenine) is closely related to ADV and is also a nucleotide acyclic phosphonate, and like ADV, TFV requires a diphosphorylation process to convert it to the active form. TFV is effective against both HIV and HBV and has been used successfully to treat coinfected patients. TFV, like ADV, is also effective against LMV-resistant virus with rtM204V/I changes. The primary mutations associated with ADV resistance (rtA181T/V and/or rtN236T) can decrease the efficacy of TFV both in vitro [27] and in vivo [28, 29] (Table 1). In two recent clinical trials of TFV in patients failing ADV, the pattern of evolution of viremia was sometimes different, with either slow or rapid kinetics of decline, despite the presence of the same ADV resistance mutations at baseline [28, 30]. This may indicate that viral genome variability outside these positions may impact the fitness of these mutants in the presence of TFV and the viral clearance kinetics. In the study by Patterson and colleagues [31], HBV with the double mutation rtA181T/V+rtN236T was refractory to TFV-rescue treatment, which was consistent with in vitro cross-resistance studies[32] (Table 1). Further studies of the effects of these ADV-associated substitutions on the efficacy of TFV following switching are clearly needed.

D-cyclopentane group

Entecavir resistance substitutions

Resistance to ETV was initially described in patients who were previously LMV resistant [23]. ETV resistance requires rtM204V/I (±L180M) plus the addition of other ETV ‘signature’ substitutions in the B domain (rtI169T or rtS184G), C domain (rtS202G/I), or E domain (rtM250V) (see Table 1). In the absence of rtL180M+rtM204V/I, the rtM250V causes a 10-fold decreased drug susceptibility, whereas the single rtT184G and rtS202G/I changes have little effect [23, 33]. In contrast, when the substitutions rtL180M+rtM204V are also present, a greater than 100-fold decreased drug susceptibility has been observed. The occurrence of resistance to ETV in drug-naive patients is negligible during the first year [34] and remains low (approximately 1%) even after more than 6 years of treatment [35]. In LMV-refractory patients who were subsequently switched to ETV, however, the frequency of virological breakthrough was around 50% [35], limiting the role of ETV salvage therapy in this patient population.

Multi-drug resistance

Monotherapy can promote selection for multi-drug resistant (MDR) strains of HBV, especially when patients are treated sequentially with drugs with overlapping resistance profiles, such as with LMV followed by ETV [36, 37] or LMV followed by ADV [38-41] or ADV followed by TFV[31, 32] (see Table 1). Clonal analyses have shown that MDR usually occurs by the sequential acquisition of resistance mutations on the same viral genome; mutants that arise from this selection process may be fully resistant to multiple drugs. Studies have shown that MDR strains can arise if an ‘add-on’ therapeutic strategy does not result in rapid viral suppression, particularly if there is sufficient replication space available for the mutants to spread (i.e. necroinflammatory activity resulting in hepatocyte proliferation, or liver graft not protected by HBIG because of the pre-existence of escape mutants). These findings emphasize the need to achieve complete viral suppression during antiviral therapy.

A specific single amino acid substitution may confer MDR (see Table 1). This was shown with the rtA181V/T substitutions, which are responsible not only for decreased susceptibility to the L-nucleosides LMV and LdT but also to the acyclic phosphonates ADV and TFV [32, 42]. This highlights the clinical usefulness of genotypic testing (drug resistance testing) in patients with treatment failure, as has been done for HIV therapy management [43], to determine the viral resistance mutation profile and thereby tailor therapy against the major viral circulating strain.

The primary resistance substitutions associated with drug failure for CHB are shown in Table 1. To date, changes to eight codons in the HBV P ORF account for primary treatment failure with the currently approved NAs for CHB. These substitutions commit subsequent viral evolution to six different pathways that are presented in Table 1.

Clinical aspects of resistance and treatment failure

All patients receiving NA therapy for CHB should be closely monitored for virological response and breakthrough during treatment and for durability of response and viral relapse after treatment has stopped [27]. Serum HBV DNA should be tested every 3 months during treatment [44], however, if the patient is compliant and a high genetic barrier, high potency drug (ETV and TFV) is used, then this frequency can be reduced. The reasons for failure of antiviral therapy are based on specific mechanisms; therefore, the clinical implications and response in terms of treatment adaptation will be different. Thus, in a compliant patient, it is important to distinguish between primary nonresponse, partial virological response and virological breakthrough (viral rebound) owing to underlying antiviral drug resistance.

Primary nonresponse

The failure to achieve a 1.0 log₁₀ IU/ml decline in viral load after 12 weeks of therapy is considered to be a primary nonresponse [27, 44, 45]. It may be because of lack of compliance or the medication may not exhibit its antiviral activity in a particular individual. A suboptimal response has been shown to be owing to host pharmacological effects and/or to patient compliance but not to a reduced susceptibility of the drug to viral strains as measured in vitro by phenotypic assay [46]. With the availability of more potent antiviral drugs such as TFV and ETV, this phenomenon often seen with ADV, is now less frequent. When a primary nonresponse is identified, antiviral treatment should be modified to prevent disease progression and subsequent risk of emergence of populations of drug-resistant mutants. The week 12 time point in therapy is therefore important to determine the antiviral activity of the treatment regimen and assess treatment adherence.

Partial response

A partial response corresponds to the failure to achieve a viral load decline to a threshold that translates to an improvement in liver histology and to a minimum risk of resistance [47]. One of the recommendations of the European Association for the Study of the Liver clinical practice guidelines is to achieve undetectable HBV DNA during therapy; therefore, a partial response is defined by detectable HBV DNA using real-time PCR assay during continuous therapy [1].

With antiviral drugs that have a low genetic barrier to resistance (LMV, LdT), antiviral response at week 24 of therapy was shown to predict the subsequent resistance rate [13, 48]. ADV suppresses viremia levels slower than the other NAs such as LMV, ETV, LdT, or TFV. Therefore, the 48-week time point was proposed to predict resistance to ADV therapy, as assessment of viral load at this point could predict the risk of the development of resistance over time [10]. With the more potent and high genetic barrier drugs such as ETV and TFV, the rate of undetectable HBV DNA after 1 year of therapy is significantly improved, reaching 67 and 74% in HBeAg-positive patients and 90 and 91% in HBeAg-negative patients [27, 49, 50]. Because the rate of viral suppression continues to increase over time with ETV and TFV, the timing of treatment adaptation will mainly depend on the kinetics of viral load decay, especially in patients who start from a very high viral load who may need additional weeks of therapy to reach undetectable HBV DNA by PCR testing [51, 52]. Therefore, the pattern of viral load decline is more useful than a single assessment at a given time point, as the latter may result in a misleading interpretation of treatment response. Although data from long-term clinical studies are lacking, treatment should be adapted in cases of persistent low viremia or when there is a plateau in HBV DNA levels, to maximize viral suppression and minimize the subsequent risk of emergence of resistance [53].

Virological breakthrough and rebound

Virological breakthrough is typically a result of the emergence of drug-resistant viral strains. It is defined by an increase of at least 1.0-log₁₀ IU/ml compared with the lowest value achieved during treatment, confirmed by a second test, in a treatment compliant patient [27, 44, 45]. Depending on the mutation profile selected by the drug, viral load increase may be slow, making the diagnosis of rebound difficult. It usually follows the detection of resistance mutations [5, 27, 44]. In the absence of treatment adaptation, the rise in viremia may be followed in subsequent weeks or months by an increase in ALT levels (biochemical breakthrough) and subsequent progression of liver disease (clinical breakthrough). The increase in viral load associated with the emergence of resistance mutations depends on the fitness of the mutants. It is interesting to note that resistance mutations in the polymerase gene affecting the overlapping surface gene (e.g. rtA181T/sW172*) have been shown to affect both their capacity to be secreted from infected hepatocytes or their infectivity. This may result in a progressive and slow increase in viral load making the rule of a 1-log₁₀ IU/ml increase difficult to apply [42]

Management of treatment failure

The management of treatment failure has changed significantly in recent years. With the availability of potent antivirals and virological monitoring tools, treatment failure can be broadened to include a partial virological response as well as the classic virologic breakthrough. In all cases, treatment adherence should be carefully checked and reinforced when necessary and antiviral drug resistance should be managed according to the resistance profile of the patient's particular HBV Pol DNA sequence, in relation to available cross-resistance data (Table 1).

Assessment of treatment adherence

Good adherence to anti-HBV therapies is important to maintain maximum suppression of HBV replication. Poor adherence can result in substantially reduced plasma drug levels, depending on the number of doses missed and the half-life of the drug, and can result in increased viral replication [54]. Investigation of adherence to NA therapy in patients with CHB has shown that nearly 40% may not be fully adherent; this significantly influences the rates of viral suppression [55]. Partial response to ADV has also been linked to poor adherence and also other pharmacological parameters, such as increased body mass index. Low-level viral replication associated with nonadherence increases the pressure on NA potency, thus increasing the risk of selecting for resistance. Specific treatment adherence questionnaires and drug concentration monitoring can be useful for patient management. A study in HIV-infected patients receiving antiviral therapy showed that a bell-shaped curve relationship exists between adherence and resistance, similar to that observed for potency and resistance. In that study, lower rates of detectable HIV RNA and drug resistance were observed in patients receiving the more potent regimen, even at low adherence levels [56].

Assessment of treatment adherence is not easy in clinical practice. Studies have shown that adherence based on self-reporting may be exaggerated compared with pill count or electronically monitored (MEMS) drug adherence [56, 57]. The level of education, type of health insurance, cultural factors as well as low copayment for medications can significantly influence medication adherence. All these data suggest that patient education and providing support on adherence from the clinic play an important role in improving the effectiveness of antiviral therapy in clinical practice.

Adapting treatment according to cross-resistance

Cross-resistance is defined as resistance to drugs which a virus has never been exposed to because of changes that have been selected for by the use of another drug (see Table 1) [43]. The resistance-associated mutations selected by a particular NA confer at least some degree of cross-resistance to other members of its structural group but may also diminish the sensitivity to NAs from a different chemical group [18]. The initial drug choice and subsequent rescue therapies should be based on a knowledge of cross-resistance [1], so that the second agent has a different resistance profile to the initial failing agent [27, 45]. This is particularly important as drug-resistant mutants that have been selected by previous treatments are thought to be archived in viral cccDNA reservoirs in the liver [58]. The advantage of using the add-on combination approach of NAs with complementary cross-resistance profiles has recently been highlighted [1, 27, 45] and a summary of cross-resistance profiles based on the viral resistance ‘pathways’ approach is shown in Table 1. The advantage of an add-on strategy is also to raise the barrier of resistance and increase drug potency thereby making the subsequent development of drug resistance less likely to occur.

Management of antiviral drug resistance

Virological breakthrough in compliant patients is related to viral resistance. Resistance is associated with prior treatment with NA, or in treatment-naïve patients with high baseline levels of HBV DNA, a slow decline in HBV DNA levels and partial virological response to treatment. Resistance should be identified as early as possible, before ALT levels increase, by monitoring HBV DNA levels and if possible identifying the NA resistance profile; the best therapeutic strategy can then be determined based on this information. Clinical and virological studies have demonstrated the benefit of early (as soon as viral load increases) adaptation of treatment [1, 47, 59]. In case of resistance, appropriate rescue therapy should be initiated and should have the most effective antiviral effect and minimal risk of selection of MDR strains. Therefore, adding a second drug that is not in the same cross-resistance group as the first (i.e. L-Nucleoside vs Acyclic Phosphonate vs D-Cyclopentane) is the recommended therapeutic approach.

However, although there is a strong virological rationale for an add-on strategy with a complementary drug to prevent the emergence of MDR strains and raise the barrier to resistance, the current trend is to switch to a complementary drug with a high barrier to resistance based on a relatively short-term clinical observation – these options are being discussed in different national and international guidelines. This critical point must be evaluated in long-term clinical and molecular virology studies. Furthermore, the switch strategy does not apply to patients who have been exposed to multiple monotherapies. These patients should be enrolled in add-on strategies to minimize the risk of subsequent treatment failure.

Table 1 summarizes the cross-resistance data for the most frequent resistant HBV variants [1, 60]. Treatment should be adapted accordingly as summarized in Table 2.

Table 2. Suggested treatment adaptation in patients with treatment failure

Type of failure	Treatment adaptation
Lamivudine resistance	add TFV (add ADV if TFV not available) a switch to TFV is also advised by some guidelines a switch to ADV is not recommended because of a high rate of resistance and its low potency
Adefovir resistance	switch to TFV if available and add a second drug without cross-resistance if no history of LMV, switching to ETV is also effective If rtN236T substitution, consider adding LMV, ETV, or LdT to the TFV or switch to TFV plus FTC; if no history of LMV, consider switching to ETV If rtA181V/T substitution, alone or in combination with rtN236T, switch to TFV plus ETV; as before, if no history LMV, consider switching to ETV
Telbivudine resistance	add TFV a switch to TFV has also been considered in some guidelines a switch to ADV is not recommended
Entecavir resistance	add TFV
Tenofovir resistance	not been confirmed so far genotyping and phenotyping required may add ETV

Management of primary nonresponse and partial responses

(i) Primary nonresponse

A primary nonresponse is observed more frequently in patients treated with ADV (approximately 10–20% of patients) than in those treated with other NA, probably because of the low potency of the former [46]. Patients who do not respond to ADV should be switched as soon as possible to TFV or ETV therapy. A primary nonresponse to LMV, LdT, ETV, or TFV is rarely observed [1] It is important to determine the level of compliance in these patients. If a patient with a primary nonresponse to these drugs is compliant, analysis of the HBV polymerase for NA-resistance mutations can help identify alternate treatment strategies [1](see Table 1).

(ii) Partial virological response

Partial virological responses have been observed with all NA used in the treatment of CHB. Once again, it is important to check for compliance. There are two strategies for treating patients who have a partial virological response to LMV, ADV, or LdT: change to a more potent drug (ETV or TFV) as soon as possible (week 24) or add a more potent drug with no cross-resistance profiles. As already discussed and based on in vitro data, TFV monotherapy should not replace ADV therapy if the patient is infected with an HBV variant that is already resistant to ADV (i.e. rtA181T/V ± rtN236T) because these drugs belong to the same chemical group of NA, the acyclic phosphonates [1, 54, 61, 62]. In case of partial response to TFV or ETV, a switch to the other drug or preferably the addition of the other drug is recommended to achieve HBV DNA undetectability. However, these strategies have not been fully validated by large multicenter clinical studies.

Persistent low level viremia

The persistence of very low level viremia is becoming an issue in patients treated with drugs with a high barrier to resistance (ETV, TFV). Indeed, the sensitivity of HBV DNA detection by real-time PCR assays is now less than 10–15 IU/ml while it was approximately 60–80 IU/ml with older PCR assays when these drugs were originally evaluated in phase III clinical trials. In on-treatment analysis studies, up to 5% of NA naïve patients remain HBV DNA positive in during long-term ETV or TFV therapy [63, 64]. Usually, analysis of the viral genome sequence is not possible with these very low levels of viremia either by population analysis, specific hybridization or clonal analysis. The clinical and biological role of this phenomenon is unknown especially in terms of the emergence of drug resistance. However, in vitro studies performed in primary human hepatocyte cultures as well as in vivo studies in the duck HBV model have generated data suggesting that the persistence of viremia during antiviral therapy can result in the infection of new cells and the formation of new cccDNA molecules in these cells, thus delaying clearance of infected cells from the liver [65, 66].

The case of a patient treated with multiple antiviral regimens

By now many patients have been treated with multiple antivirals, including for example LMV, ADV, sequential therapy with LMV and ADV, and even switches to ETV, raising the question of the choice of drugs for second- or third-line therapy. Also, the antiviral effect achieved with rescue therapy may be compromised by previous treatment history.

In a retrospective European multicenter study, the long-term efficacy of TFV monotherapy was assessed in patients with prior failure or resistance to different NA treatments. Pretreatment consisted of either monotherapy with LMV, ADV and sequential LMV-ADV therapy, or add-on combination therapy with both drugs. The overall cumulative proportion of patients achieving HBV DNA levels <400 copies/ml (<60 IU/ml) was 79% after a mean 23 months of treatment. Although LMV resistance did not influence the antiviral efficacy of TFV, the presence of ADV resistance impaired TFV efficacy. However, virological breakthrough was not observed in any of the patients during the entire observation period [29].

It is important to note that different results have been obtained in a clinical trial comparing different treatments in patients with CHB who had an incomplete response to ADV. A combination of fixed-dose FTC and TFV from the start (early combination) vs TFV as monotherapy was evaluated. Viral decay curves were identical in the groups through week 24 (direct comparison of blinded therapy). At week 48, 81% of patients initially given TFV or TFV+FTC (Truvada) had undetectable HBV DNA levels. The presence of baseline LMV- or ADV-associated mutations did not affect the virological response. Adherence to therapy appeared to be the primary factor associated with achieving undetectable HBV DNA levels at week 48 [30]. In contrast, a recent Australian study analysed the efficacy of TFV in mainly Asian patients with CHB who had previously failed LMV and had significant viral replication despite at least 24 weeks of treatment with ADV. At 48 and 96 weeks, 46 and 64% patients achieved undetectable HBV DNA. The response was independent of baseline LMV therapy or mutations conferring ADV resistance. The presence of ADV resistance substitutions (rtA181T vs rtN236T ± rtA181T/V) at baseline affected the subsequent virologic response to the TFV switch, compared with naïve patients [28], with significant levels of persistent viremia especially if the double mutation rtA181T/V+rtN236T was present at baseline (Table 1).

The antiviral efficacy of the combination of TFV+FTC (Truvada) for treatment intensification in patients who failed different lines of NA therapies as shown by persistently detectable viremia is very good. Kaplan–Meier analysis has shown that after treatment intensification with this combination, the probability achieving undetectable HBV DNA was 76% by week 48, and 94% by week 96. No viral breakthrough occurred [67]. It is important to note that the combination of TFV plus LMV has not shown to be beneficial compared with TFV alone in most studies [28].

European studies of ETV in clinical practice have shown that this drug is as effective in achieving viral suppression in naïve patients as in LMV or ADV exposed patients, as long as LMV resistance (detectable rtM204V/I) does not develop [68]; not surprisingly, the presence of ADV resistance did not adversely influence the effect of ETV in this cohort [68]. A recent European multicentre study showed that rescue therapy with a combination of ETV and TFV in 57 patients with viral resistance patterns or with partial antiviral responses to prior treatment was efficient, safe, and well tolerated in patients with or without advanced liver disease [69].

These results suggest that different antiviral strategies may be applied depending on treatment history, the exposure to several different groups of NAs and the presence of resistance mutations at the time of treatment modification, as the efficacy of a simple switch to one new drug or the addition of two new NAs (TFV or ETV) may be necessary to achieve HBV DNA undetectability.

Conclusions

Clinical studies have shown that drugs with a high barrier to resistance, such as ETV and potentially TFV, have significantly lower rates of resistance compared with those with a low barrier to resistance such as LMV, ADV or LdT. The correct choice of first-line therapy should include a highly potent agent with a high genetic barrier to resistance to achieve sustained long-term suppression of viral replication, thus providing the best chance of achieving the primary goal of therapy: preventing the progression of liver disease [14]. Most patients receiving antiviral treatment require long-term therapy making the development of antiviral resistance a major concern especially if low potency, low genetic barrier drugs are used. Treatment with a potent drug that has a high barrier to resistance such as ETV or TFV, minimizes the chance of developing resistance in the future, preserves future treatment options and maximizes the chances of long-term treatment success [14]. Management of treatment failure requires precise clinical and virological monitoring as well as early treatment intervention with the antivirals in relation to their cross-resistance profile (Table 1). If these recommendations are followed, most patients who need antiviral therapy for CHB can benefit from treatment at least in the short to medium term. Long-term surveillance for treatment efficacy and possible emergence of drug resistance is necessary in patients who have been sequentially treated with multiple antivirals. Finally, the identification of novel treatment targets remains a major research challenge to improve the efficacy of current antiviral therapy and achieve HBsAg loss which is the most desirable therapeutical endpoint [70].

Disclosure

The authors have no disclosure.