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Keywords:

  • chronic hepatitis;
  • HBV-DNA;
  • nucleos(t)ide analogue;
  • resistance

Abstract

  1. Top of page
  2. Abstract
  3. Nucleos(t)ide monotherapy
  4. Management of nucleos(t)ide resistance
  5. De novo’ combination
  6. Conclusions
  7. Conflicts of interest
  8. References

Antiviral therapy is aimed to persistently suppress hepatitis B virus (HBV) to prevent liver complications and improve survival and long-term administration of nucleos(t)ide analogues represents an attractive treatment strategy.

Five oral analogues are available, and all inhibit viral replication in most patients during the first year of therapy. By converse, long-term monotherapy is associated to high rates of resistance with lamivudine, and intermediate rates with Adefovir and Telbivudine. Third-generation analogues such as Entecavir and Tenofovir may efficiently inhibits viral replication in most patient for many years as they couple potency and high genetic barrier. In patients developing drug-resistance, specific rescue protocols based upon ‘early add-on’ have been developed to rapidly and efficiently control viral replication. In cirrhotics, long-term effective analog-based therapy prevented clinical decompensation for many years, but not liver cancer development. Long-term administration of NUCs, either as a monotherapy or as a sequential combination, inhibits HBV replication in most HBeAg-negative patients for at least 5 years, preventing clinical decompensation in cirrhotics.

The goal of therapy of HBeAg-negative chronic hepatitis B patients is persistent suppression of hepatitis B virus (HBV) replication aimed at the halting progression of liver damage and preventing the development of liver-related complications, such as liver cancer [hepatocellular carcinoma (HCC)] and clinical decompensation. This can be achieved either by a short-term ‘curative’ treatment with pegylated interferon or a long-term ‘suppressive’ therapy with nucleos(t)ide analogues (NUC).

Both strategies have advantages and disadvantages, but recent data on the long-term efficacy of NUCs have tipped the balance towards long-term suppression therapy as the first-line option for most patients with HBeAg-negative chronic hepatitis B.

Nucleos(t)ide monotherapy

  1. Top of page
  2. Abstract
  3. Nucleos(t)ide monotherapy
  4. Management of nucleos(t)ide resistance
  5. De novo’ combination
  6. Conclusions
  7. Conflicts of interest
  8. References

Lamivudine

The recommended dose of lamivudine (LAM) is 100 mg/day. A virological response is achieved in 70% of patients after a 1-year therapy with this NUC, but LAM-resistant strains emerge at the rate of approximately 20% per year. By year 5, up to 70–80% of patients have become resistant to LAM, many of these patients experiencing clinical and histological progression of the underlying liver disease (1, 2). Despite its high safety record, long-term LAM monotherapy therefore is not the best option for the long-term treatment of HBeAg-negative patients.

Adefovir dipivoxil

The recommended does of adefovir dipivoxil (ADV) is 10 mg a day. In a 5-year cohort study, HBV DNA became undetectable (<1000 copies/ml) and alanine aminotransferase (ALT) levels declined within the normal range in approximately 70% of the patients (3). Six patients (5%) had HBsAg loss and five developed anti-HBs at the last available time point. The 5-year cumulative rates of genotypic, virological, defined as>1 log rebound compared with on-treatment nadir, and clinical resistance, defined as virological and biochemical rebounds, are 29, 20 and 11% respectively. The only adverse effect of ADV monotherapy is renal toxicity, and serum creatinine was reported to be slightly elevated in 3% of the patients. Altogether, these data indicate that ADV 10 mg for 5 years provides long-term suppression of HBV replication in most patients.

Adefovir dipivoxil withdrawal in patients with persistently undetectable HBV DNA by PCR assays during the 5 years of treatment resulted in a virological relapse in all patients, but with approximately 70% of them maintaining HBV DNA below 10 000 copies/ml and ALT levels within the normal range in the following 12–18 months (4). If these results are confirmed by other studies and if on-treatment predictors of a sustained virological response can be defined, ADV treatment could be stopped in some HBeAg-negative patients with long-term maintained viral suppression.

Telbivudine

In a randomized-controlled study comparing 104 weeks of 600 mg/day telbivudine (LDT) and 100 mg/day LAM for the treatment of nucleoside-naïve HBeAg-negative chronic hepatitis B (5), a greater proportion of LDT-treated patients achieved undetectable HBV DNA by a PCR assay compared with those treated with LAM (82 vs 57%, P<0.019). ALT normalized in 78 and 70% of the patients, respectively, but resistance to LDT developed in 9% of the patients after 2 years.

A retrospective, sub-group analysis showed that patients with HBV DNA<7 log copies/ml at baseline and<400 copies/ml at week 24 benefit most from LDT monotherapy, showing high rates of a virological primary response with low rates of resistance (2%) after 104 weeks of LDT monotherapy (6, 7). These data provide the rationale for adapting and tailoring antiviral therapy with LDT in 24-week suboptimal responders.

Entecavir

In a randomized-controlled study comparing 52 weeks of 0.5 mg/day entecavir (ETV) and 100 mg/day LAM for the treatment of nucleoside-naïve HBeAg-negative chronic hepatitis B (8), significantly more patients in the former group than in the latter one achieved undetectable HBV DNA by PCR assay (90 vs 72%), normalized ALT (78 vs 71%) and had improved histology (70 vs 61%). Moreover, virological rebound and genotypically confirmed drug resistance occurred less frequently in the former than in the latter group (2 vs 8%, 0 vs 6%), the safety profile being similar in both groups. However, when at the end of the first year of therapy, virological responders withdrew from ETV, viral replication reoccurred in all. The virological response was maintained in the few who continued treatment for 2 (25 patients) and 3 years (16 patients) (9).

Although long-term resistance data in HBeAg-negative patients are not available, the low resistance rates observed in HBeAg-positive partial responders provide strong evidence that ETV monotherapy can control viral replication in most HBeAg-negative patients for many years (10).

Tenofovir

In a randomized-controlled trial, patients were treated with either 300 mg tenofovir (TDF) or 10 mg ADV. After 72 weeks, 91% of the TDF-treated patients had undetectable HBV DNA (<400 copies/ml) compared with 88% of those treated with ADV for 48 weeks and then switched to TDF for 24 additional weeks (NS) (11). No patient on TDF developed renal failure or drug resistance. The virological response to TDF was similar in cirrhotic and non-cirrhotic patients, in LAM naïve and LAM experienced, as well as in patients infected by different genotypes.

Management of nucleos(t)ide resistance

  1. Top of page
  2. Abstract
  3. Nucleos(t)ide monotherapy
  4. Management of nucleos(t)ide resistance
  5. De novo’ combination
  6. Conclusions
  7. Conflicts of interest
  8. References

Lamivudine resistance

Lamivudine-resistant patients have been treated with ADV, either as monotherapy (‘switch to’ strategy) or in combination with LAM (‘add on’ strategy). Both cohort prospective studies and a randomized-controlled study showed that the combination of LMV+ADV is superior to ADV monotherapy, as it minimizes the emergence of ADV resistance for at least the first 3 years of treatment (12–16). The timing of ADV administration is crucial, because ADV is not a very potent drug requiring to be started as soon as a virological rebound is identified, i.e. when viraemia starts to increase above the nadir and ALT levels are still within the normal range (HBV DNA<5 log copies/ml) (13). The virological breakthrough phase precedes the clinical resistance phase by several weeks or months, characterized by >5 log copies/ml HBV DNA and >ULN ALT. Suppression of hepatitis is more frequently achieved in patients treated with ‘add-on’ ADV during the early genotypic or virological breakthrough phase than in patients with a clinical breakthrough (13).

The ‘add-on’ strategy has also been successfully tested in HBeAg-negative cirrhotics, providing long-term control of viral replication and clinical compensation in most of them. While this strategy could improve the rate of development and progression of oesophageal varices, it could not prevent HCC (16, 17).

Adefovir or telbivudine resistance

There are no large studies specifically assessing the management of ADV or LDT resistance in HBeAg-negative patients. Given the resistance profile of these drugs, the in vitro cross-resistance data and some preliminary clinical data, the use of a nucleoside analogue to rescue for ADV resistance and of a nucleotide analogue for LDT resistance seems the most appropriate approach, ‘add on’ as the suggested strategy.

Entecavir or tenofovir resistance

There are no published cases of HBeAg-negative patients developing resistance to these drugs. This is because of the lower level of viral load at baseline in HBeAg-negative patients compared with the HBeAg-positive ones, and the limited long-term data available with these two drugs. Experts suggest that a non-cross-resistant drug should be used as a rescue, although it is still unknown whether ‘switch’ or ‘add-on’ is the most cost-effective therapeutic strategy.

De novo’ combination

  1. Top of page
  2. Abstract
  3. Nucleos(t)ide monotherapy
  4. Management of nucleos(t)ide resistance
  5. De novo’ combination
  6. Conclusions
  7. Conflicts of interest
  8. References

There are no published studies assessing the long-term efficacy and safety of a ‘de novo’ combination of two anti-HBV analogues in HBeAg-negative patients.

Conclusions

  1. Top of page
  2. Abstract
  3. Nucleos(t)ide monotherapy
  4. Management of nucleos(t)ide resistance
  5. De novo’ combination
  6. Conclusions
  7. Conflicts of interest
  8. References

Long-term administration of NUCs, either as a monotherapy or as a sequential combination, inhibits HBV replication in most HBeAg-negative patients for at least 5 years. In cirrhotic patients, NUC-suppressive therapy prevents clinical decompensation, whereas it is still unclear whether it reduces the risk of HCC, too. NUC resistance can be identified and managed easily according to specific rescue protocols recently agreed upon by international experts. Prevention of NUC resistance requires careful selection of candidates, early adaptation of a therapeutic strategy in case of a primary non-response or a partial response and the use of third-generation NUCs, such as TDF and ETV, as first-line agents. No significant safety issues have arisen following long-term administration of NUCs, although clinical experience with third-generation NUCs is still limited.

A therapeutic challenge for HBeAg-negative patients under long-term suppressive NUC therapy is how to increase the rates of HBsAg seroconversion, the recommended stopping rule for HBeAg-negative CHB.

References

  1. Top of page
  2. Abstract
  3. Nucleos(t)ide monotherapy
  4. Management of nucleos(t)ide resistance
  5. De novo’ combination
  6. Conclusions
  7. Conflicts of interest
  8. References
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