|Year : 2008 | Volume
| Issue : 1 | Page : 66-80
|Management of lamivudine resistance: An overview
Pietro Lampertico, Mauro Vigano, Massimo Colombo
1st Division of Gastroenterology, Fondazione IRCCS Maggiore Hospital Policlinico, Mangiagalli e Regina Elena, University of Milan, Via Francesco Sforza 35, 20122 Milano, Italy
Click here for correspondence address and email
|Date of Web Publication||9-Jan-2010|
| Abstract|| |
In the nineties, lamivudine (LMV) was the first nucleoside analog to be marketed for the treatment of patients with chronic hepatitis B virus (HBV). Following the advent of LMV, the management of patients with chronic hepatitis B, particularly those with advanced liver disease was markedly improved, with a substantial reduction in the rates of liver-related complications and mortality. In the face of excellent safety profile records of the drug, hepatologists had to face for the first time the issue of high rates of HBV resistance to therapy as the result of years of treatment of large cohorts of patients in the West and East. Initially considered no more than a virological problem, LMV resistance was later recognized to be a relevant clinical issue whose management requires specific therapeutic strategies. New, more active oral analogs have been marketed since, and new agents are to appear in the market scenario in the near future; however, LMV is still the number one prescribed anti-HBV agent worldwide for the treatment of chronic HBV patients, due to its limited cost, excellent safety and well predicted resistance profile.
Keywords: Adefovir, chronic hepatitis B, entecavir, hepatitis B virus (HBV), lamivudine, lamivudine-resistant HBV strains, resistance, tenofovir, YMDD
|How to cite this article:|
Lampertico P, Vigano M, Colombo M. Management of lamivudine resistance: An overview. Hep B Annual 2008;5:66-80
| Incidence of Resistance|| |
Long-term LMV monotherapy selects for resistant strains harboring specific mutations in the HBV Pol gene, i.e. M204I/V as a primary mutation and L80, L180M, V173L as the most relevant secondary mutations. ,, Altogether, the rates of mutations increase over time from 20% after 1 year to 70% after 5 years of administration. ,,, Specific molecular assays are available to identify LMV mutations including direct sequencing and INNOLiPA assay.  Direct sequencing of HBV DNA is a more time consuming, elaborate and less sensitive assay however, identifying not only the already known viral mutations but also new, potentially relevant mutations of HBV. Conversely, INNOLiPA is user-friendly but more sensitive than the direct sequencing assay, which allows the detection of mutated strains weeks or months before direct sequencing. The major constraint of this assay is that only probes for pre-defined, well-known mutations of HBV can be fixed on the strip, thus allowing for the identification of clinically relevant HBV strains only.
Non-Asian ethnicity, high pre-treatment serum HBV DNA level, male sex, and high body mass index emerged as predictors of LMV resistance (LMV-R) in HBeAg positive patients.  Conversely, factors associated with the onset of LMV resistance in HBeAg-negative patients are poorly known. , Since the risk of developing LMV-R directly correlates to the levels of HBV DNA at month 6, incomplete suppression of HBV replication seems to play a key role in the generation of mutated strains, as already suggested with other antiviral regimens. ,,
| Kinetics of Resistance|| |
There is enough evidence to suggest that LMV resistant strains of HBV emerge as a consequence of the survival escape strategy of the virus to overcome treatment pressure. , Indeed, mutated HBV strains are prone to replicate more efficiently in the presence of the antiviral drugs, having a specific selective advantage at hepatocyte level, subsequently diffusing and expanding throughout the liver cell parenchyma and ultimately invading peripheral blood. 
Genotypic resistance to LMV is defined as the presence of circulating mutated HBV strains identified through molecular means, occurring without any virological or clinical breakthrough, or being associated with >1 log increase in HBV DNA with normal ALT levels (virological breakthrough) or being associated with a >1 log HBV DNA increase and ALT elevation (clinical breakthrough). These patterns of lamivudine resistance are stepwise evolutionary phases of the infection generated by compensatory mutations leading to replacement of wild type HBV by LMV-R strains. 
| Clinical Consequences|| |
The initially marginal liver damage associated with low levels of serum HBV DNA characteristic of the onset of genotypic resistance inexorably inflates as mutated HBV strains accumulate to elicit substantial liver injury accompanied by high serum ALT values (clinical resistance). , The clinical implications of clinical resistance to LMV are manifold, since it heralds progression to cirrhosis, and clinical decompensation, hepatocellular carcinoma (HCC) and delisting from liver transplantation, in both HBeAg-positive and HBeAg-negative patients. ,,, A greater proportion of HBeAg-negative patients developing LMV-R had a ≥2 point histological deterioration compared to YMDD negative (64 vs. 15%, P = 0.001).  The emergence of LMV-R is not only a virus reaction to therapy, but also a relevant clinical issue which requires a rescue therapy within a matter of weeks.
| Selection of a Rescue Drug|| |
The drug for rescuing a response to therapy should be selected on the basis of its in vitro cross-resistance profile. Nucleoside analogs such as Telbivudine (LdT) and Entecavir (ETV) are not fit for treating LMV-resistance since they share a similar resistance profile characterized by the mutation in position 204 plus several compensatory mutations.  Conversely, the resistance pattern of the nucleotide analog Adefovir dipivoxil (ADV) is based upon changes at position 236 and 181, i.e. N23T and A181V, thereby offering a chance for suppressing LMV-resistant strains. ,, Recently, another nucleotide analog, Tenofovir dipivoxil, entered the market for the treatment of LMV naοve and LMV resistant patients, with a predicted resistant pattern, not yet identified, similar to ADV. ,, As a general rule, a nucleotide analog is recommended to rescue for HBV resistance in patients treated with nucleoside analogues, whereas a nucleoside analog is recommended for a nucleotide-related resistance.
| Selection of Rescue Strategy|| |
Following selection of a rescue drug, the next step is to define whether to treat the patients with monotherapy by switching from LMV to ADV or TDF or other drugs or with a combination therapy ("add-on" strategy). Both approaches have pros and cons: the former strategy is cheaper but less efficacious, the latter is more expensive and with unproven safety, but more effective in the long-term. ,,,
| Adefovir Dipivoxil (ADV)|| |
In a randomized controlled study in HBeAg positive LMV-R patients, 20 patients treated with "add-on" strategy with LMV+ADV were compared to 19 patients treated with ADV monotherapy ("switch" strategy).  Serum HBV DNA declined by approximately 4 log cp/ml in both groups at week 48 of treatment, suggesting that combo therapy was as effective anti-HBV regimen as monotherapy with ADV. However, the limited sample size of the study, the short duration of follow-up, and the endpoint of HBV DNA decline rather than the emergence of ADV-resistance (ADV-R), call for cautious interpretations of the results of this study.
Subsequently, four studies published in 2006 and performed in different geographical areas evaluated the long-term risk of genotypic resistance to ADV in LMV-R patients receiving ADV monotherapy. ,,, More than one quarter of patients developed ADV-resistance within 1-2 years of monotherapy compared to the lower rate (3%) of LMV-naοve patients receiving ADV monotherapy. These and other subsequent studies indicate that the "switch" strategy from LMV to ADV is not the ideal regimen for LMV-resistant patients. ,,,,,,,,
"Add-on" strategy - Cohort studies
A two-year treatment of 74 LMV-R HBeAg-negative patients with "add-on" LMV+ADV resulted in no patient developing either virological breakthrough or genotypic resistance to ADV. This study suggested that the co-administration of LMV with ADV might have been useful in the treatment of LMV-resistant patients. 
The ability of "add-on" therapy with ADV of lowering the risk of ADV-resistance was subsequently confirmed in a French study of 35 HBeAg-positive, HIV-co-infected patients with LMV-R, treated for 3 years. This study showed 50% of patients achieved a virological response, without any patient developing ADV-R. 
The original observation with "add-on" therapy of LMV-R patients was extended to 3 years in 145 LMV-R monoinfected patients mostly with genotype D, and HBeAg-negative cirrhosis. High rates of primary virological response to combo therapy with 80% of the patients achieving HBV DNA levels below 35 copies/ml were reported with no patient developing the rtA181V or the rtN236T mutation of HBV. Three patients showed emergence of rtA181T during therapy however, in the context of a progressively declining HBV DNA. The study also reported low rates of virological breakthrough, as none of the patients who achieved a virological response nor any of those who had an incomplete suppression of HBV replication, showed a HBV DNA rebound. 
These favorable results of "add-on" therapy were confirmed by a cohort study in Japan  in which 132 genotype C infected, HBeAg positive, LMV-R patients were treated with ADV+LMV for 28 months. The cumulative probability of viral response was 69% at year 1 and 81% at year 2, whereas ADV-resistant mutations developed were detected in 2 (1.6%) patients only, with only one patient developing a virological and clinical breakthrough. Interestingly, the 3-year cumulative rate of ADV-R was 1% only.
"Add-on" strategy - Randomized controlled studies
A small randomized controlled study comparing "add-on" vs. "switch" strategy was performed in HBeAg negative patients in Greece.  ADV resistance emerged in none of the 28 patients treated for 3 years with ADV+LMV compared to 3/14 (21%) of those receiving ADV monotherapy (P = 0.0174).
"Add-on" strategy - Controlled cohort studies
A large Italian multicenter study compared the long-term efficacy of LMV+ADV vs. ADV monotherapy in more than 600 HBeAg-negative patients with LMV-R. After 3 years of therapy, 30% of the ADV group developed a virology breakthrough compared to 6% of ADV+LMV group (P < 0.001), with 16 and 0% rates of genotypically confirmed virological breakthrough rates respectively.  Three short-term, small sized studies in Europe and Asia confirmed these findings. ,,
Selection of timing for a rescue
Timing of rescue is of strategic importance in the management of LMV-R, i.e. starting treatment during virological or clinical breakthrough.  The virological breakthrough is defined by a >1 log U/ml increase of serum HBV DNA compared to the on-treatment nadir in a compliant patient. HBV DNA levels between 1 and 4 log U/ml and ALT levels are still within the normal range with compensatory mutations being detected in a few patients only. This phase may proceed within weeks or months in the clinical breakthrough phase, featuring >4 log U/ml HBV DNA higher than normal ALT levels. Characteristically, these patients show progression of liver disease and development of such liver related complications as clinical decompensation, HCC and end-stage liver disease. ,,,,,
Most studies on LMV-R therapy focused on rescue therapy starting at the time of clinical resistance, i.e. in patients with > 5 or 6 log cp/ml and high ALT levels. These studies showed partial virological responses in many patients occurring after 2 or 3 years of therapy. This phase therefore is not the best timing for rescue of LMV-R. Being the clinical resistance phase preceded by several weeks by a virologic breakthrough, the latter phase is the ideal timing for starting rescue therapy being featured by HBV strains with primary, but generally not, compensatory mutations. Compensatory mutations are important as they 'fix' the discriminatory primary drug-resistant mutations as a genetic archive with quasispecies memory.  A therapeutic intervention at the time of virologic breakthrough phase would add the potential advantages of lower serum HBV DNA levels and low rates of compensatory mutations. The virological response to "add-on" ADV at the time of virological breakthrough was complete in all patients with baseline HBV DNA below 6 log cp/ml within the first year, compared to only 75% of those with baseline viremia between 6 and 8 log cp and 50% of those with higher than 8 log cp viral load.  Early rescue prevented ALT reactivation too, compared to patients starting on therapy at higher levels of viremia who required more than 18 months of therapy to achieve disease remission. Since hepatitis flares boost clinical decompensation in patients with cirrhosis, early add-on is a safe approach in critically ill patients with chronic hepatitis B and LMV-R.
Effective, early "add on" strategy is made possible by regular monitoring of serum HBV DNA every three months by a sensitive PCR-based assay.
The increased efficacy of early with respect to late add-on treatment with ADV has been subsequently confirmed by others and is now a recommended guideline for rescue of LMV-resistant patients to minimize the risk of partial virological response. ,
Partial response to ADV mono or ADV+LMV in LMV-R patients
Twenty to 50% of patients treated with ADV mono or ADV+LMV still have detectable HBV DNA levels after 48 weeks of treatment, as a consequence of high baseline viral load, not of specific HBV mutations. ,, To overcome partial response to ADV rescue therapy, it has been proposed to either increase ADV dosing to 20 mg or to switch from ADV to TDF.
Two studies have evaluated the anti-HBV efficacy and safety of the approach with conflicting results. In a small uncontrolled study in France, 5 HBeAg-positive, LMV-R patients with > 5 log cp/ml after 30 months of ADV monotherapy showed progressive improvement of HBV DNA upon treatment with 20 mg ADV with a median log decline of 1.78 log U/ml.  Four patients normalized ALT levels and none showed renal toxicity. In a controlled study in Italy,  9 LMV-R partial responders to add-on therapy received ADV 20 mg showing a similar decline of serum HBV DNA as 15 matched controls who continued ADV 10mg+LMV. However, one patient treated with high ADV had increased serum creatinine values. Possible explanations for the contradictory results of these two studies are differences in the targeted populations of ADV partial responders as well as in the definition of partial virological response.
Treatment of LMV-R patients with a partial virological response can also be achieved by switching from ADV to TDF. In a small study, van Bommel and coworkers  reported 19 (95%) patients becoming PCR negative, three seroconverting to anti-HBe and one to anti-HBs following 48 weeks of therapy with 300 mg TDF. This preliminary study suggests that TDF might be a highly effective rescue therapy for LMV-R patient with partial response to ADV.
| Tenofovir Dipivoxil (TDF)|| |
There are no long-term studies assessing the efficacy and safety of TDF as a rescue therapy for HBV monoinfected, LMV-R patients. However, studies from HIV/HBV co-infected patients and some preliminary clinical data in HBV monoinfected patients suggest the importance of TDF because of its high potency and low risk of resistance profile. TDF is superior anti-HBV agent compared to ADV, ,, but whether TDF should be used as an "add-on" or "switch" therapy in LMV-R patients, is still unknown. Most experts support the combination therapy of TDF+LMV in the treatment of LMV-R patients with chronic hepatitis B.
| Entecavir (ETV)|| |
Monotherapy with ETV has been tested in the rescue of HBeAg-positive, LMV-R patients, however with poor virological responses in the face of high rates of genotypic resistance (51%), virologic breakthrough (43%) and clinical resistance to entecavir (50). While ETV is not a recommended treatment for LMV-R patients as a monotherapy, a combination of ETV and ADV (or TDF) could be a more effective therapy for LMV-R patients, with some concerns for cost and safety.
| Prevention of LMV Resistance|| |
LMV resistance can be delayed or prevented by careful selection of patients to be treated with LMV, early adaptation of antiviral therapy and administration of de-novo combination therapy.
Selection of patients to be treated with nucleoside/nucleotide analogs (NUC) is based upon careful evaluation of individual patient, in terms of age, severity of liver disease, concomitant medications and/or diseases, as well as estimated duration of therapy, baseline viral load and ability of the patient to comply with regular monitoring.  This is particularly true for HBeAg-negative patients who are likely to receive therapy long-term, possibly lifelong.
In the search for predictors of resistance to improve the cost-effectiveness of HBV therapy a relationship between residual viral load at week 24, of developing resistance at week 48 or 96 has been demonstrated.  Patients with undetectable HBV DNA at week 24 of LMV have a negligible (5%) risk of LMV-R in the following 18 months. LMV monotherapy therefore is recommended in these patients provided that a regular HBV DNA monitoring is established to early identify the emergence of resistance and start an appropriate rescue strategy. Patients with a detectable viremia at week 24 have a greater risk of developing LMV-R, requiring early adaptation of antiviral therapy by either switching to a more potent antiviral agent or adding-on with another analog with a different resistance profile. Since these two strategies have not been evaluated either independently or head-to-head in large studies, it is very difficult to provide an evidence based indication on which strategy is better to treat patients with a partial virological response to LMV.
A de-novo combination might represent the best approach for highly viremic patients, to increase the antiviral efficacy while rescuing the risk of resistance, as suggested by studies in HIV patients. Only one study assessed the efficacy of de-novo combo LMV+ADV vs LMV in HBeAg positive, HBV mono-infected patients.  Fifty-four patients were randomized to receive LMV + ADV whereas 57 were given LMV monotherapy. After 104 weeks of treatment, the two groups of patients showed similar rates of virological (26 vs. 16%), serological (13 vs. 20%), and biochemical response (45 vs. 34%). However, the rate of LMV-R resistance was significantly lower in the combo group than in the monotherapy group (15 vs. 43%, P < 0.001).
| Conclusions|| |
In patients with chronic hepatitis B, LMV resistance develops at a pace of 20% per year, and being asymptomatic at onset, it can be early identified by regular monitoring of serum HBV DNA by a sensitive PCR based assay, only. Patients with LMV-R are efficiently rescued by "early add-on" therapy with ADV, a strategy which has been proved to effectively last for years, thereby making LMV monotherapy not a therapeutic option any more. LMV-R in HBV patients can be prevented by careful selection of patients to be treated, as well as by early adaptation of treatment in patients with partial virological response within the first year of therapy. Rescue monotherapies should not be used in principle to avoid the emergence of multiple drug HBV resistance strains. TDF, a recently marketed, potent nucleotide analog, could take over ADV as a rescue therapy of LMV-R patients, studies being necessary to confirm whether a combination therapy is superior to monotherapy.
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1st Division of Gastroenterology, Fondazione, Policlinico, Via Francesco Sforza 35, 20122 Milano
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