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Resistance to adefovir: A new challenge in the treatment of chronic hepatitis B
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Journal of Hepatology
published online 6 October 2005.
Article in Press, Uncorrected Proof
Patrick Marcellin, Tarik Asselah
Service d'Hˇpatologie and Centre de Recherche INSERM CRB3, H™pital Beaujon, 100 Bd du Gˇnˇral Leclerc, 92 110 Clichy, France
".....that the best way to reduce the number of patients with resistance is to select the right patients for treatment: those with active liver disease who usually have relatively moderate levels of viral replication and who have a good chance of responding well to therapy and a low risk of developing resistance.......Pegylated interferon monotherapy should be considered in patients without contraindications since this treatment is not associated with resistance and gives the best sustained response rate (about one third) with a definite duration (48 weeks) of therapy......During treatment with an analogue, the importance of good compliance and careful monitoring (measurement of HBV DNA levels at least every 3 months) should be emphasized, especially after one year of therapy........patients with HBV DNA levels higher than 1000copies/ml after one year of therapy are at high risk of development of resistance. Early diagnosis of resistance allows to adjust therapy by introducing drug to prevent a flare of hepatitis....."
As expected, the long-term administration of adefovir dipivoxil (adefovir) in large numbers of patients results in the emergence of resistance with viral rebound and potential flares of hepatitis and possible hepatic decompensation. The study reported by Fung et al. [1] in this issue of the Journal describes the clinical course of eight patients who developed adefovir-resistant mutations thus confirming that the use of any analogue for long-term mono-therapy is ineluctably associated with the emergence of resistance even if the resistance threshold is high. This study also emphasizes the importance of a careful and appropriate management of patients with chronic hepatitis B treated with a nucleoside or a nucleotide analogue.
Adefovir was registered for the treatment of chronic hepatitis B in the US in September 2002 and in Europe in March 2003. Two, large randomized controlled trials have shown that adefovir is effective in patients with HBeAg-positive and HBeAg-negative chronic hepatitis B [2,3]. Adefovir administration for 48 weeks induced a mean reduction of HBV DNA of 3.5 and 3.9 log10 copies/mL with normalisation of ALT in 48 and 72% of patients and improvement of liver histology in 53 and 64%, in the two studies respectively. Recently, the results of long-term administration for up to 3 years showed that the benefits of treatment were maintained and virological, biochemical and histological response rates were stable [4]. Also, adefovir effectively suppressed lamivudine-resistant HBV in chronic hepatitis B patients post-liver transplantation, patients with decompensated liver disease and patients co-infected with HIV [5Š7].
Adefovir has been shown to have a safety profile similar to that of placebo [2,3]. The main concern is nephrotoxicity, which appears to be rare with the 10 mg recommended dose. The good safety profile of the drug has been confirmed after up to 3 years of administration with no new adverse events. However, 3 patients had moderate increases in creatinine levels, which resolved with continued treatment (one patient) or after cessation of treatment (2 patients) [4].
Resistance to adefovir occurs relatively late. There was no case of resistance described during 48 weeks of adefovir administration in the 2 pivotal studies performed in HBeAg-positive and HBeAg-negative chronic hepatitis B [2,3,8]. It is interesting to note in the case series of Fung et al., that adefovir-resistant mutations were identified after a mean duration of treatment of 20 months; there were no cases identified in the first year of treatment [1].
To determine the incidence of resistance to adefovir more precisely, an extensive genotyping study was performed in patients who received adefovir for up to 192 weeks in several clinical studies including 293 patients with HBeAg-negative compensated chronic hepatitis B, pre and post-transplantation patients and HIV-HBV co-infected patients [9]. Serum samples with detectable HBV DNA (by PCR assay) were further analysed in all patients in these studies with systematic sequencing of the entire HBV reverse transcriptase (rt) domain (amino acids rt 1 to rt 344). Two adefovir resistance mutations (N236T and A181V) were identified in 22 patients (Fig. 1).
In vitro susceptibility testing showed that adefovir resistant strains were less susceptible than the wild-type virus by 3.9 to 13.8 times for the N236T mutation and 2.5 to 3 times for the A181V mutation [4]. In vitro and in vivo data suggest that A181V adefovir resistant HBV is less susceptible to lamivudine than N236T adefovir resistant HBV. The overall rate of resistance was 0% at 48 weeks, 2% at 96 weeks and 7% at 144 weeks. In one study with a homogenous population of patients (HBeAg-negative, mostly treatment-naive), the resistance rate was 5, 11 and 18% at 2, 3 and 4 years of therapy, respectively [4,9,17,18] (Fig. 2). Even if more precise rates of resistance need to be determined in larger cohorts with long-term follow up, available data show that emergence of resistance to adefovir is delayed and is much more uncommon than with lamivudine. The high resistance threshold of adefovir may be due to the structural features of adefovir that distinguish it from nucleoside analogues: in particular the minimally flexible acyclic linker that closely resembles the natural substrate and the fact that it is a nucleotide with a phosphorus atom, not a nucleoside.
Interestingly, all 22 patients who developed adefovir-resistant mutations were receiving adefovir monotherapy. No adefovir resistance has been observed to date in patients receiving adefovir combined with lamivudine. In the study by Fung et al., all 8 patients who developed adefovir resistance were receiving adefovir alone [1]. These observations suggest that the combination of adefovir with lamivudine prevents (or delays) adefovir resistance. This hypothesis is consistent with in vitro data, which shows that lamivudine is effective in adefovir-resistant strains. Recently, in a limited number of cases as well as in 2 patients in the series of Fung et al. and in 2 patients in the cohort of Hadziyannis et al., lamivudine has been shown to be effective in patients with adefovir resistance [4] (Fig. 3).
These data support the hypothesis that adefovir should be used in combination with lamivudine instead of alone. However, the safety and efficacy of this combination compared to adefovir monotherapy, have not been assessed. Indeed, except for the increased safety, the combination of adefovir with lamivudine has not been shown to have an increased antiviral effect compared to adefovir alone in either patients with lamivudine resistance [10] or in treatment-naive patients [11]. In addition, the potential development of multiple resistance to adefovir with lamivudine is of concern. Indeed the simultaneous presence of lamivudine-resistant and adefovir-resistant mutations has been described in one case [12] and another case is reported by Fung et al. [1]. This may increase the risk of cross-resistance towards other nucleotide (tenofovir) or nucleoside (entecavir) analogues. A recent study has shown that only patients with previous lamivudine resistance developed resistance to entecavir within the first 48 weeks of treatment [13].
In vitro studies suggest that there is no cross-resistance between nucleotide analogues (adefovir and tenofovir) and nucleoside analogues (lamivudine, entecavir, telbivudine, clevudine). Clinical observations seem to confirm this, although except for the large studies on the efficacy of adefovir in patients with lamivudine resistance, there is little data about the efficacy of lamivudine in patients with adefovir-resistance and no data on the efficacy of adefovir in patients with resistance to the new nucleoside analogues. This must be evaluated in clinical trials. The best combination of analogues might be a nucleotide analogue with a nucleoside analogue. Indeed, one small study suggested that the combination of emtricitabine (FTC) (which is a nucleoside analogue very close to lamivudine (LTC)) with adefovir was more effective than adefovir alone and showed a low rate of resistance to emtricitabine [14]. The best combination may be one of the most potent nucleotide analogues (tenofovir) with one of the most potent nucleotides (entecavir or telbivudine).
Another potential strategy to increase efficacy and reduce the risk of resistance is combining an analogue with pegylated interferon. Indeed, this strategy is supported by results of large clinical trials of pegylated interferon alpha-2a [15,16] which showed that there is an additive antiviral effect of the combination of pegylated interferon alpha-2a with lamivudine compared to pegylated interferon alpha-2a alone and a markedly decreased rate of resistance to lamivudine in the combination arm compared to the lamivudine monotherapy arm (1Š4 versus 18Š27%) [15,16]. However, safety and tolerance to the prolonged administration of pegylated interferon must be determined for long-term combination therapy and the use of a relatively low dose of pegylated interferon for sufficient efficacy and good tolerance must be evaluated.
Predictors of the risk of developing resistant HBV must be well identified. The probability of developing mutations with adefovir, like lamivudine, depends on the ability of the drug to suppress viral replication. An analysis of predictors of resistance was performed in 124 HBeAg-negative patients who received 144 weeks of adefovir [9]. HBV DNA levels at 48 weeks of treatment were associated with the risk of resistance: the risk of resistance was more than 25% in patients with HBV DNA levels above 3 log10 copies/mL, while it was 4% in those with HBV DNA levels below 3 log10 copies/mL. Interestingly, in the study by Fung et al., 6 of the 8 patients with adefovir-resistant mutations had HBV DNA levels above 4 log10 copies/mL after 1 year of treatment [1].
These results show that patients with HBV DNA levels above 1000copies/mL after 1 year of treatment with adefovir should be closely monitored and initiation of lamivudine therapy should be considered. The development of resistance should be diagnosed early. Although reliable assays are available for the detection of specific mutations associated with resistance, they are not always available to clinicians and therefore regular measurements of HBV DNA levels are useful for diagnosing resistance: an increase of one log or more (if compliance is good) is an early indication of resistance before ALT increases. Therapy can be adjusted and another antiviral drug initiated based on the results of monitoring. Lamivudine is currently the best option since its efficacy has been reported; however other drugs (entecavir, telbivudine or pegylated interferon) could be more effective and must be evaluated and the best therapeutic strategy in patients developing resistance to adefovir needs to be determined. Fung et al. report a good antiviral response to entecavir in 2 patients [1].
After the emergence of resistant-mutations and after the increase in HBV DNA, an increase in ALT may be observed. The ALT increase is mild to moderate and is rarely associated with hepatic decompensation: none of the 22 patients who developed adefovir resistance showed a severe flare or decompensation [4,8]. However, like lamivudine, the risk of decompensation exists in the case of resistance to adefovir, in particular in patients with bridging fibrosis or cirrhosis and in transplanted patients. The study by Fung et al. reports a virological breakthrough in 7 and an increase in ALT levels in 4 of their 8 patients with adefovir resistance; 2 patients developed hepatic decompensation, one of whom died; these 2 patients had cirrhosis [1].
In conclusion, it should be remembered that the best way to reduce the number of patients with resistance is to select the right patients for treatment: those with active liver disease who usually have relatively moderate levels of viral replication and who have a good chance of responding well to therapy and a low risk of developing resistance [17,18]. For patients with mild disease, the treatment can be delayed with a regular follow-up. Pegylated interferon monotherapy should be considered in patients without contraindications since this treatment is not associated with resistance and gives the best sustained response rate (about one third) with a definite duration (48 weeks) of therapy [14,15,19]. However, most (about two thirds) patients with chronic hepatitis B do not develop a sustained response and therefore need prolonged therapy with an analogue. During treatment with an analogue, the importance of good compliance and careful monitoring (measurement of HBV DNA levels at least every 3 months) should be emphasized, especially after one year of therapy. Indeed, patients with HBV DNA levels higher than 1000copies/ml after one year of therapy are at high risk of development of resistance. Early diagnosis of resistance allows to adjust therapy by introducing drug to prevent a flare of hepatitis. At present no combination has been shown to have a better antiviral effect or a reduced risk of resistance, compared to monotherapy. However, experimental studies and preliminary clinical data suggest that combinations may decrease the incidence of resistance. Therefore this strategy should probably be considered in patients with cirrhosis to minimise the risk of liver failure, which may be associated with resistance.
Obviously, predictors of the risk of resistance need to be clearly identified and new therapeutic strategies including combinations need to be evaluated. Because the virus can escape new antivirals by developing resistant mutants, new drugs must be developed and therapeutic management of chronic hepatitis B must be improved to meet this new challenge.
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