Tenofovir disoproxil fumarate: Role in hepatitis B treatment†‡
See Article on Page 318.
Potential conflict of interest: Dr. Lok receives research support and serves on the advisory board of Roche, GlaxoSmithKline, Bristol Myers Squibb, Idenix and Gilead.
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The introduction of lamivudine ushered in a new era in the treatment of chronic hepatitis B when safe, effective, and well-tolerated oral medications were made available. Since then, two new nucleosid(t)e analogs (NAs), adefovir and entecavir, have been approved for the treatment of hepatitis B. In addition, two NAs approved for the treatment of human immunodeficiency virus (HIV) infection, emtricitabine and tenofovir disoproxil fumarate, also have activity against hepatitis B virus (HBV). However, only a small percentage of patients with chronic hepatitis B have sustained viral suppression after a defined course of NA therapy. Thus, long-term treatment is required in most patients to maintain viral suppression.
Problems associated with long-term NA therapy include drug resistance, side effects, cost, and compliance. Emergence of antiviral-resistant HBV mutants can have major consequences including negation of initial response, hepatitis flares and occasionally hepatic decompensation and death, and potential cross-resistance with other NA.1, 2 Several recent studies showed that rapid viral suppression decreases the risk of antiviral resistance.3–5 Therefore, the ideal NA for hepatitis B should have potent antiviral activity against wild-type HBV and HBV mutants resistant to currently approved therapies, high genetic barrier to resistance, and excellent safety profile.
The availability of adefovir brought a lot of excitement because initial studies showed that it was effective in suppressing wild-type and lamivudine-resistant HBV and extensive sequence analysis did not reveal any resistant mutations after 1 year of therapy.6 However, it was quickly evident that response to adefovir was inconsistent, with as many as 50% of patients failing to achieve adequate viral suppression, defined as <3.5 log10 copies/mL decrease in serum HBV DNA compared to baseline after 1 year of treatment7 or serum HBV DNA >4 log10 copies/mL after 6 months of treatment,8 despite the absence of adefovir-resistant mutations. The high proportion of patients with poor initial response may be due to an inadequate dose of adefovir, as the phase III clinical trial in HBeAg-positive patients clearly demonstrated that the approved dose of 10 mg was less potent than the 30 mg dose.9 Furthermore, resistant mutations to adefovir were identified10 and the rate of genotypic resistance was found to increase with the duration of treatment.11 In one study of 125 NA-naïve patients with HBeAg-negative chronic hepatitis B, the rate of genotypic resistance to adefovir increased from none after year 1 to 29% after year 5.12 Several recent studies reported rates of adefovir resistance of 18% to 25% after 1-2 years of treatment.8, 13, 14 The higher rates of adefovir resistance in these latter studies may be related to the inclusion of patients with prior lamivudine resistance switched to adefovir monotherapy and the use of more sensitive techniques to detect resistant mutations.
Entecavir is more potent than lamivudine in suppressing wild-type HBV. Resistant mutants have not been detected after 2 years of treatment in NA-naïve patients.15–17 Although entecavir was approved for the treatment of lamivudine-resistant HBV, in vitro studies showed that its activity against lamivudine-resistant HBV is 6- to 10-fold lower compared to wild-type HBV.1, 18 Thus, despite the use of a higher dose (1 mg vs. 0.5 mg) of entecavir in the phase III trial on lamivudine-refractory patients, 60% of patients still had HBV DNA detectable by PCR after 96 weeks of treatment.19 Entecavir-resistant mutations were detected in 4.4% patients at the start of entecavir, increasing to 12% at the end of year 2.17 Furthermore, while entecavir-resistant mutations alone decrease susceptibility to entecavir by only 6- to 9-fold, the combined presence of lamivudine- and entecavir-resistant mutations decrease susceptibility to entecavir by more than 1,000-fold.18 In addition, we recently demonstrated that lamivudine-resistant HBV mutations were detected in all 20 clones from a patient who developed entecavir resistance, up to 45 months after lamivudine was stopped and treatment switched to entecavir monotherapy.20 Thus, while entecavir is a potent treatment for NA-naïve patients, it is not an optimal treatment for patients with lamivudine resistance.
Tenofovir Disoproxil Fumarate
Tenofovir disoproxil fumarate, an acyclic nucleotide analog closely related to adefovir has been approved for the treatment of HIV infection. In vitro studies showed that it has activity against HBV with equimolar potency as adefovir.1
Antiviral Activity Against HBV.
Clinical studies confirmed the efficacy of tenofovir in suppressing HBV replication. Most of the studies were based on retrospective analysis of small subsets of patients with HIV-HBV coinfection who received tenofovir primarily for HIV infection.21–25 Activity of tenofovir was also observed in small case series of patients with HBV monoinfection.26–28 The vast majority of patients in these reports had lamivudine-resistant HBV. Tenofovir resulted in a 4-6 log reduction in serum HBV DNA level, and 30% to 100% of patients had HBV DNA undetectable by PCR assay after more than 24 weeks treatment. (Table 1) The in vivo antiviral activity of tenofovir appears to be similar among patients with and without HIV coinfection.
Table 1. Summary of Studies With HBV DNA > 5 log10 Copies/mL at Start of Tenofovir and With > 24 Weeks of Therapy
|van Bömmel26||20||0||19 (95)||–||20 (100)||48 (16-96)||6.5 (4-9.3)||3.8 (1.4-6.7)||19 (95)||0/19|
|Schildgen27||3||0||2 (67)||–||3 (100)||75 (75-125)||7.7 (7.7-8.7)||6.2 (5.7-6.7)||3 (100)||0/2|
|Kuo28||9||0||9 (100)|| ||9 (100)||48 (24-64)||8 (6.4-9)||4.5 (3.2-6.3)||7 (77.8)||2/9 (22.2)|
|van Bömmel29||35||21 (60)||31 (88.6)||35 (100)||–||(72-130)||9.4||5.5||35 (100)||11/31 (35)|
|Benhamou25||65||65 (100)||54 (83.1)||42 (64.6)||–||48 (32-68)b 40 (28-68)c||8.2 (7.3-8.3)b 4.8 (2.7-6.4)c||4.6 (3.3-5.6)b 2.5 (0.4-4.1)c||16 (29.6)b 6 (55.5)c||2/54 (3.7)|
|Lacombe21||28||28 (100)||24 (85.7)||18 (64.3)||–||74 (21-115)||7.5||4.6||21 (75)||4/24 (16.7)|
|Nunez22||12||12 (100)||9 (75)||7 (58.3)||–||34 (24-48)||6.6 (4.7-8.2)||3.8(0.7-5.7)||7 (58.3)||1/9 (11.1)|
|Dore23||15||15 (100)||14 (93.3)||6 (40)||–||48||8.6||4.5||NA||2/14 (14.3)|
|Stephan24||31||31 (100)||19 (61.3)||15 (48.4)||–||48||NA||5.4 (3.6-7)||22 (71)||1/19 (5.3)|
Several clinical studies suggest that tenofovir results in more marked suppression of HBV replication than does adefovir, possibly related to the use of a higher dose: 300 mg vs. 10 mg. In a non-randomized study of 53 patients with lamivudine-resistant HBV, serum HBV DNA decreased by 5.5 vs. 2.8 log10 copies/mL after 48 weeks of tenofovir and adefovir treatment, respectively.29 In another study, 52 patients with HIV-HBV coinfection—most of whom had prior lamivudine treatment—were randomized to receive tenofovir vs. adefovir; the mean time-weighted average change in serum HBV DNA from baseline to week 48 (DAVG48) for the two groups were −4.44 vs. −3.21 log10 copies/mL, respectively.30
The higher potency of tenofovir 300 mg is highlighted by two reports where viral rebound was documented when 4 patients who had suppression of serum HBV DNA while receiving tenofovir for lamivudine-resistant HBV were switched to adefovir 10 mg.31, 32
In this issue of HEPATOLOGY, van Bommel et al.26 report on their experience in 20 patients with chronic HBV infection who were switched to tenofovir monotherapy after a poor virological response (serum HBV DNA <4 log10 copies/mL) to 4-28 months of adefovir monotherapy. All patients had virologic breakthrough to lamivudine prior to switching to adefovir monotherapy. No adefovir-resistant mutations were identified at the start of tenofovir therapy. Serum HBV DNA decreased by a median of 3.8 log10 copies/ml after 3-24 months (median 12) of tenofovir treatment, and 19 (95%) patients had serum HBV DNA levels undetectable by PCR assay. The only patient with persistently detectable HBV DNA had dose reduction due to renal insufficiency.
Thus, accumulating evidence indicate that tenofovir 300 mg is more potent than adefovir 10 mg in suppressing HBV replication. Data from the ongoing phase III trials will confirm if this difference applies to nucleoside-naïve HBV monoinfected patients, and whether it persists beyond 1 year.
To date, there has only been one report of tenofovir-resistant mutation, possibly related to the limited clinical experience thus far and to the fact that most patients had concomitant administration of a second antiviral (lamivudine or emtricitabine). It is possible that, as with adefovir,4, 8 switching patients with lamivudine-resistant HBV to tenofovir monotherapy may be associated with a higher likelihood of tenofovir resistance. One study found rtA194T (alanine to threonine substitution at codon 194) in conjunction with lamivudine-resistant mutations in 2 of 43 (5%) HIV-HBV coinfected patients who had persistently detectable HBV DNA levels despite ≥24 weeks of combination therapy of tenofovir and lamivudine.33 The A194T mutation was detected 48-77 weeks after initiation of tenofovir. One patient had a hepatitis flare at the time A194T was first detected. However, the hepatitis flare coincided with an increase in CD4 cell count, and serum HBV DNA level remained suppressed. Serum HBV DNA increased from 2.6 to 4.1 log10 copies/mL over the next 14 months but aminotransferase levels remained normal. The other patient had progressive decrease in serum HBV DNA and normal ALT levels after the detection of A194T mutation. Transfection experiments showed that the rtA194T mutation alone resulted in a 7.6-fold decrease in susceptibility to tenofovir but in association with lamivudine-resistant mutations led to a > 10-fold decrease in susceptibility. The significance of the A194T mutation needs to be confirmed as the 2 cases reported above do not represent the typical clinical pattern seen in patients who develop antiviral-resistant mutations, and surveillance for other tenofovir-resistant mutations should be continued.
Long-term use of tenofovir is clouded by concerns regarding nephrotoxicity. Several case reports have been published on the occurrence of renal insufficiency and tubular dysfunction in patients treated with tenofovir. In most instances, the renal problems resolved after tenofovir was discontinued.34–36 It is important to note that all cases of tenofovir-related nephrotoxicity occurred in patients with HIV infection who were receiving multiple medications, some of which may be nephrotoxic or compete for renal tubular secretion of tenofovir.37, 38 In addition, renal dysfunction and hypophosphatemia are not uncommon in HIV patients.39 One study showed that 31% of HIV patients had hypophosphatemia at baseline, and this proportion did not increase with tenofovir treatment.35 Registration trials of tenofovir for HIV infection and a large retrospective cohort analysis showed that a decrease in creatinine clearance occurred in a small proportion of patients (<1 to 4%) after 12-36 months of tenofovir treatment.40–42 In addition, most of the changes were mild and did not result in the discontinuation of tenofovir.
Early studies on animals given much higher doses of tenofovir showed adverse effects of tenofovir on the skeletal system. To date, the effects appear to be non-progressive in humans and manifested only as a mild decrease in bone mineral density.41
Role in HBV Treatment.
Among the antivirals currently undergoing phase 2 or phase 3 studies, tenofovir appears to be the most promising. Accumulating evidence suggest that tenofovir is more potent in suppressing HBV replication than adefovir. Tenofovir appears to be equally effective against wild-type and lamivudine-resistant HBV. With the widespread use of lamivudine worldwide, and the development of compounds that select for cross-resistant mutants (emtricitabine, telbivudine and clevudine), a safe and effective rescue therapy that has potent and long-lasting antiviral activity against lamivudine-resistant HBV is urgently needed. Whether tenofovir will replace adefovir in the treatment of hepatitis B will depend on the confirmation of superior antiviral activity and comparable safety in the phase 3 trials of tenofovir in hepatitis B patients. The role of tenofovir in the rapidly expanding armamentarium of hepatitis B treatments will depend on the demonstration of long-term safety (renal and skeletal), efficacy against wild-type HBV and HBV mutants that involve substitution of methionine within the tyrosine-methionine-aspartate-aspartate (YMDD) motif (mutants resistant to lamivudine, emtricitabine, telbivudine, or clevudine), and a very low rate of tenofovir resistance in NA-naïve as well as NA-experienced patients.