Sage Journals: Discover world-class research

Abstract

Treatment for hepatitis B (HBV), a global disease affecting over 400 million persons, has changed over the past 15 years. Many of the current treatments are oral therapies which suppress HBV viral load and improve liver-related outcomes. However, differences exist in the currently available therapies both in terms of potency and resistance. The newest HBV nucleotide to be approved for the treatment of hepatitis B is tenofovir disoproxil fumarate that when phosphorylated to its active form leads to DNA chain termination. Tenofovir is active against human immunodeficiency virus (HIV) and was approved for its treatment in 2001. It is also active against HBV and was approved for its treatment in 2008. Tenofovir has emerged as an effective and potent therapy against lamivudine resistant strains as well as wild type HBV. Tenofovir resistance to HBV is rare. Long-term use of tenofovir has been associated with renal and bone marrow toxicity in some HIV-infected patients. To date, this is the only oral therapy which is both potent and does not lead to viral resistance in both treatment naïve and experienced patients. Further studies in HBV mono-infected persons are needed to evaluate long-term impact of tenofovir use.

Keywords

chronic hepatitis B tenofovir toxicity efficacy resistance pharmacology

Introduction

Hepatitis B (HBV) is the leading cause of liver disease world-wide, with 400 million people infected.¹ Transmission of HBV has decreased substantially in the US due to vaccination efforts, especially in children. However, approximately 51,000 new HBV infections occurred in 1995, mostly in adults.² HBV occurs at the highest frequency in unvaccinated adults who have multiple sexual partners, use injection drugs, or are men who have sex with men.² Although HBV infection when acquired in adulthood may be self-limited, 15%-20% of acutely infected adults will develop chronic liver disease. The complications of HBV infection include cirrhosis of the liver, hepatocellular cancer, and portal hypertension, which can present as variceal bleeding, encephalopathy, and ascites.

In order to reduce the burden of disease and its related complications, many therapeutic options have become available. In the last 15 years, treatment for HBV has changed significantly. Initially, treatment for HBV was limited to interferon therapy. Interferon, given daily or three times weekly for 4-6 months did lead to hepatitis B e antigen (HBeAg) seroconversion and in some cases, hepatitis B surface antigen (HBsAg) loss,^3–6 especially after years of follow-up. HBeAg seroconversion or loss were both endpoints that were considered desirable as the virus was no longer actively replicating.

Although interferon-based therapies can be given for a finite period of time and lead to viral clearance in some patients, there are significant adverse side effects including: flu-like symptoms, depression, myalgias, fatigue, and cytopenias. Furthermore, fear of injections may make some patients reluctant to be treated. Because of these issues, other oral treatments were developed. The first oral nucleoside therapy to be used for the treatment of HBV was lamivudine (Epivir®; GlaxoSmithKline). Lamivudine was initially approved by the Food and Drug Administration (FDA) for the treatment of human immunodeficiency virus (HIV) at the dose of 300 mg per day. Studies in patients with HBV found that 100 mg was effective and led to viral suppression of HBV DNA.⁷ Initial studies examined histological endpoints to see if treatment would improve hepatic fibrosis and delay the emergence of complications. Lamivudine showed both histological improvement and decrease in viral load.^8,9 However, once the drug was stopped, most patients’ HBV viral load would resurge. Thus, one year of treatment was insufficient and longer duration of therapy was needed, which led to the emergence of lamivudine resistant virus. Long-term monotherapy, especially in the setting of incomplete viral suppression, can lead to the emergence of resistance variants which have mutations that allow the virus to replicate leading to increase in HBV viral load despite being on therapy. Subsequently, other nucleosides/nucleotides (nucleos(t)ides) such as adefovir (Hepsera^®; Gilead Sciences) became available for the treatment of lamivudine resistant strains. Adefovir at the dose of 10 mg was well tolerated and was effective against lamivudine resistant virus. Subsequently, other potent nucleos(t)ide inhibitors have been developed for the treatment of HBV such as entecavir (Baraclude®; Bristol-Myers Squibb Co.) and telbivudine (Tyzeka®; Idenix Pharmaceuticals Inc. and Novartis Pharmaceuticals Corp.).

Tenofovir disoproxil fumarate (Viread^®; Gilead Sciences), a second generation nucleotide, was developed for the treatment of HIV and its chemical structure was modified in order to reduce renal side effects. It was then co-formulated with emtricitabine (Emtriva®; Gilead Sciences) and marketed as Truvada® (Gilead Sciences). In this review, we will discuss the pharmacology and safety of tenofovir for the treatment of HBV and how it compares to other nucleos(t)ides in terms of efficacy.

Review of Pharmacology, Mode of Action and Pharmacokinetics

Mechanism of Action

Tenofovir is an analog of adenosine monophosphate, an endogenous purine that plays a vital role in many physiological processes including DNA replication. All purines, pyrimidines, and nucleos(t)ide analogs must undergo a series of phosphorylations by intracellular kinases to become physiologically active. Tenofovir is classified as an acyclic nucleoside phosphonate, or nucleotide analog, because it has the first of three needed phosphonate groups bonded to its alkyl side chain. The monophosphate group bonded at the 5’ position to tenofovir provides a potential advantage over other nucleoside analogs, such as lamivudine, since tenofovir contains the first of three required phosphonate groups making it a potentially more active compound. Once phosphorylated to the active triphosphate form, tenofovir competes with endogenous deoxyadenosine 5‘-triphosphate at HIV-1 reverse transcriptase and HBV polymerase to be incorporated into the growing strand of DNA. Since tenofovir lacks the hydroxyl group in the 3’ position found on deoxyadenosine 5‘-triphosphate another DNA base pair cannot be linked to tenofovir which results in DNA chain termination. All nucleos(t)ide analogs, including tenofovir, are weak inhibitors of human DNA polymerases alpha, beta, and mitochondrial DNA polymerase gamma. Therefore all nucleos(t)ide analogs carry the potential risk for lactic acidosis and severe hepatomegaly with steatosis resulting in an FDA mandate that a black box warning be included in their respective package inserts. Tenofovir is weaker than other nucleoside analogs at inhibiting mitochondrial DNA and therefore has less mitochondrial toxicities compared with other nucleos(t)ide analogs.^10,11

Pharmacokinetics

Tenofovir was FDA approved in 2001 in adults for the treatment of HIV and in 2008 for the treatment of HBV. Most of the pharmacokinetic data available for tenofovir was gathered during clinical trials in HIV infected patients. Emtricitabine is structurally similar to lamivudine, and while not FDA approved for the treatment of HBV, does possess activity against HBV. Patients using co-formulations of emtricitabine and tenofovir (Truvada®) are receiving dual nucleos(t)ide therapy for HBV, which may decrease the emergence of resistance.

Tenofovir has poor oral bioavailability and is commercially available as a diester prodrug, tenofovir disoproxil fumarate, which is hydrolyzed in vivo to tenofovir and subsequently phosphorylated to its active triphosphate form. In addition to improving bioavailability, the diester prodrug also improves potency.¹² Neither tenofovir nor tenofovir disoproxil fumarate are substrates for cytochrome P450 (CYP450) enzymes and no dose adjustments are needed for patients with hepatic impairment. Each commercially available form of tenofovir contains 300 mg of tenofovir disoproxil fumarate, which is equivalent to 245 mg of tenofovir, and is administered once daily for patients without renal impairment for both HIV and HBV indications. The dose of tenofovir used for HIV and HBV treatment is the same, unlike lamivudine and adefovir where lower treatment doses for HBV are used, possibly contributing to the lower potency and differences in response rates. The oral bioavailability of tenofovir in the fasted state is 25% versus 40% when taken with a high fat meal (~700 to 1000 kcal containing 40 to 50% fat). Approximately 7% of tenofovir is bound to serum proteins with a serum half life of 17 hours after a single dose which extends to beyond 24 hours with continued dosing. This allows for convenient once daily dosing without regard to food.¹⁰

Seventy to 80% of tenofovir is recovered as unchanged drug in the urine representing both passive filtration at the glomerulus and active secretion by renal tubular cells. Renal impairment reduces tenofovir clearance and extends its duration of activity. Dose adjustments for tenofovir are recommended based on calculated creatinine clearance (CrCL). The dose of tenofovir remains fixed at 300 mg and the interval is extended for varying degrees of renal insufficiency (see Table 1).

Table 1

Tenofovir dosage adjustments in renal insufficiency. 10

Calculated CrCL^*	Recommended dose	Patient adherence considerations
CrCL ≥ 50 mL/min	300 mg daily	Take same time each day
CrCL 30-49 mL/min	300 mg every 48 hours	Monday, Wednesday, and Friday dosing
CrCL 10-29 mL/min	300 mg every 72-96 hours	Monday and Thursday dosing
Conventional Hemodialysis^** (3 four hour sessions weekly)	300 mg once weekly	Sunday dosing

Cockcroft and Gault equation used for calculated creatinine clearance (CrCL).

Tenofovir extraction coefficient 54% with conventional hemodialysis of approximately 12 hours weekly.

Pediatric and Pregnancy Considerations

Tenofovir is not FDA approved for children less than 18 years of age. Studies conducted by investigators at the National Institute of Health in HIV infected children showed significant declines in bone marrow density (BMD) in children 11-17.5 years of age treated with tenofovir.^13,14 The FDA has given tenofovir a pregnancy category B rating as animal studies have shown tenofovir to cause hepatic adenomas in mice and decreased fetal growth and reduction in fetal bone porosity in monkeys at exposures that exceed the levels anticipated in humans. The Department of Health and Human Services included cautionary statements in their most recent publication of the perinatal HIV treatment guidelines on the use of tenofovir because of limited data regarding fetal bone effects; therefore, tenofovir should only be used as a component of a maternal combination HIV regimen after careful consideration of other alternatives. Furthermore, maternal function should be carefully monitored.¹⁵ It is currently unknown to what extent a decline in renal function or BMD will occur in HBV mono-infected patients treated with tenofovir for chronic viral suppression but expanding tenofovir's use to this population may provide both investigators and clinicians with the first definitive way to estimate tenofovir nephrotoxicity as HIV and other antiretroviral medications will be eliminated as confounding factors.

Efficacy Studies

Nucleos(t)ide Therapy for the Treatment of HBV

In order to understand the impact of tenofovir on the treatment of HBV, it is useful to review the drugs which are currently available for treatment (see Table 2). Initial studies with lamivudine, adefovir, and emtricitabine^8,9,16–18 compared different doses of drug to placebo because no nucleos(t)ide therapy was considered standard of care. All of these studies which compared active drug to placebo found improvement in histology, decrease in log HBV DNA, and a higher proportion with undetectable HBV DNA in those on active drug. As lamivudine became the standard of care, the comparison group became lamivudine.^19–22 Both entecavir and telbivudine were superior to lamivudine with regards to log HBV DNA decrease and proportion achieving undetectable viral load. Entecavir compared to lamivudine had a higher proportion with histological improvement in both HBeAg-positive and negative groups but for telbivudine the improvement in histology was only seen in HBeAg-positive group. Pegylated interferon in combination with lamivudine did show higher level of undetectable virus; and both groups using peginterferon showed significantly higher levels of HBeAg loss, HBeAg seroconversion, and HBsAg loss compared to lamivudine alone.²² With increasing concern over lamivudine resistance, adefovir had become the first line therapy in naïve patients. The most recent treatment trials have used adefovir as the comparison drug.^23–25 Entecavir, telbivudine, and tenofovir were all superior to adefovir with regards to log HBV DNA decrease and proportion with undetectable viral load at 1 year.

Table 2

Outcomes with HBeAg-positive and HBeAg-negative patients treated for HBV with currently available nucleos(t)ides.

Study	Population	Drugs	Number	Change log HBV DNA	% <400 copies/mL undetectable	% with histological improvement	HBeAg loss	HBeAg seroconversion	HBsAg loss
Lamivudine	HBeAg⁺, naïve⁸	LAM 25 mg	142	–	96%^§^*	49%^*	–	13%	–
		LAM 100 mg	143	–	73%^§^*	56%^*	–	16%
		Placebo	73	–	23%^§	25%	–	4%	–
	HBeAg^–, naïve⁹	LAM 100 mg	60	–	63%^¥^*	60%	–	–	0
		placebo	64	–	6%^¥	29%	–	–	<1%
Adefovir dipivoxil	HBeAg⁺, naïve¹⁸	ADv 10 mg	172	-3.57^*	21%^*	53%^*	24^*	12%^*	–
		ADv 30 mg	173	-4.45^*	39%^*	59%^*	27%^*	14%^*	–
		Placebo	170	-0.55	0%	25^{^}%	11%	6%	–
	HBeAg^–, naïve¹⁶	ADv 10 mg	123	-3.91^*	51%^*	64%^*	–	–	–
		Placebo	61	-1.35	0%	33%	–	–	–
Emtricitabine	HBeAg⁺, naïve¹⁷	FTC 200 mg	104	-4.67^*	39%^*	63%^*	14%	12%	–
		Placebo	51	-0.45	2%	25%	14%	12%	–
	HBeAg^–, naïve¹⁷	FTC 200 mg	63	-4.12^*	79%^*	59%^*	–	–	–
		Placebo	30	-0.38	3%	23%	–	–	–
Peginterferon	HBeAg⁺, naïve²²	Peg-IFN q week	271	-4.5	25%	38%	34%^*	32%^*	3%^*
		Peg-IFN + LAM 100 mg	271	-7.2	69%^*	41%	28%^*	27%^*	3%^*
		LAM 100 mg	272	-5.8	40%	34%	21%	19%	0
Entecavir	HBeAg⁺, naïve¹⁹	ETv 0.5 mg	354	-6.9^*	67%^*^{^}	72%^*	22%	21%	2%
		LAM 100 mg	355	-5.4	37%^{^}	62%	20%	18%	1%
	HBeAg^–, naïve²¹	ETv 0.5 mg	325	-5.0^*	90%^*^{^}	70%^*	–	–	<1%
		LAM 100 mg	313	-4.5	72%^{^}	61%	–	–	<1%
Telbivudine	HBeAg⁺, naïve²⁰	TBv 600 mg	458	-6.45^*	60%^*^{^}	65%^*	26%	23%	<1%
		LAM 100 mg	463	-5.54	40%^{^}	56%	23%	22%	<1%
	HBeAg^–, naïve²⁰	TBV 600 mg	222	-5.23^*	88%^*^{^}	67%	–	–	<1%
		LAM 100 mg	224	-4.40	71%^{^}	66%	–	–	<1%
Entecavir	HBeAg⁺, naïve²⁴	ETv 0.5 mg	33	-7.28^*	58%^*^{^}	–	18%	15%	–
		ADC 10 mg	32	-5.08	19%^{^}	–	22%	22%	–
Telbivudine	HBeAg⁺, naïve²³	TBV 600 mg	45	-6.30^*	39%^*^{^}	–	16%	16%	–
		ADV 10 mg	44	-4.97	12%^{^}	–	11%	10%	–
Tenofovir	HBeAg⁺, naïve²⁵	TDF 300 mg	176	-6.18^*	76%^*	74%	–	21%	3.2%^*
		ADV 10 mg	90	-3.93	13%	68%	–	18%	0
	HBeAg^–, naïve²⁵	TDF 300 mg	250	-4.49^*	93%^*	72%	–	–	–
		ADV 100 mg	125	-4.07	63%	69%	–	–	–

Significant p < 0.05;

<1.6 pg/mL;

<2.5 pg/mL;

<300 copies/ml.

References: 8, 20, 23 treated for 52 weeks and data reported is at the end of treatment. References: 16, 17, 18, 19, 21, 24, 25 treated for 48 weeks and data reported is at the end of treatment. Reference 9 data reported is from 24 weeks. Reference 22 treatment was for 48 weeks and HBV DNA change and suppression is at the end of treatment, HBeAg and seronversion data is at 72 weeks (6 months after end of treatment).

Abbreviations: HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen; LAM, lamivudine; ADV, adefovir dipivoxil; FTC, emtricitabine; peg-IFN, Pegylated interferon alfa 2a; ETV, entecavir; TBV, telbivudine; TDF, tenofovir.

Until the recent study comparing adefovir to tenofovir,²⁵ prior studies with tenofovir have been mostly in those with HIV-infection as the drug has been approved for HIV treatment since 2001. Studies evaluating efficacy of tenofovir in combination with lamivudine were first reported in HIV/HBV co-infected patients.^26,27 Further studies examined the efficacy of tenofovir in lamivudine resistant populations showed effectiveness against lamivudine resistant strains.^28–31 Retrospective studies have examined lamivudine compared to lamivudine and tenofovir finding higher HBV DNA suppression in combination therapy.³² Other studies comparing the combination of lamivudine and tenofovir to tenofovir have found similar levels of HBV DNA suppression with combination compared to tenofovir.³³ Tenofovir was associated with higher rate of achieving undetectable HBV viral loads³⁴ in HIV/HBV co-infected patients on antiretroviral therapy. However, tenofovir viral breakthrough has been reported³⁵ but only one reported case of viral resistance has been associated with tenofovir use.³⁶

There are two prospective studies of interest in HIV/HBV. First, a randomized study in HIV/HBV co-infected patients found tenofovir to be non-inferior to adefovir; however, this study was underpowered³⁷ and is in contradiction to the findings in a larger randomized trial of adefovir to tenofovir in HBV monoinfected patients.²⁵ Second, in a prospective, randomized trial in HIV/HBV naïve patients which compared lamivudine to lamivudine plus tenofovir to tenofovir as part of the HIV antiretroviral therapy, the investigators found a higher proportion of patients achieved HBV DNA viral suppression in the treatment arms containing tenofovir.³⁸ Thus, tenofovir may be very effective either as monotherapy or in combination with lamivudine.

Studies examining tenofovir in HBV mono-infected patients also demonstrated the efficacy of tenofovir in lamivudine resistant strains.^39–42 Others have found tenofovir to be effective in patients with adefovir resistance or those with inadequate response to adefovir.^43,44 Comparison of adefovir to tenofovir for lamivudine resistant variants found higher rates of undetectable HBV viral loads in those on tenofovir.^40,42 Patients who achieved undetectable HBV viral loads on tenofovir than switched to adefovir underwent viral breakthrough in several case reports.^45,46 Thus, several studies suggest that tenofovir is superior to adefovir. Finally, a large randomized trial comparing adefovir to tenofovir demonstrated that tenofovir was significantly superior to adefovir in terms of HBV DNA suppression and histological improvement.²⁵ No significant differences were noted between tenofovir and adefovir with regards to histological improvement, but when the combined endpoint of histological improvement and viral suppression was used, tenofovir was superior.²⁵ Interestingly, tenofovir showed a significantly higher proportion of HBsAg loss compared to adefovir.⁴⁷ The rate was similar to what has been observed with peginterferon at the end of treatment.²² However, lifelong suppressive therapy with oral nucleos(t)ides may be necessary as clinical cure defined by HBeAg seroconversion and HBSAg loss does not always occur with current nucleos(t)ide therapy.

Use of Tenofovir in Cirrhosis and Transplant Patients

Although the studies of tenofovir in cirrhotic patients are limited, there are case reports of improvement of decompensated liver disease in patients with lamivudine resistance treated with tenofovir⁴⁸ and in improvement of liver function tests, and other parameters of end-stage liver disease.⁴⁹ Furthermore cirrhotic patients with adefovir resistance have also had improvements when treated with tenofovir.^50,51

Although the data on safety of tenofovir in transplant patients is limited, there are reports of successful use of tenofovir for lamivudine resistant virus following liver transplantation.⁵² In the post-transplant setting, tenofovir is being examined as a prophylaxis without the use of hepatitis B immune globulin.⁵³ A long-term follow-up study of HBV patients post heart transplant found 5 of the 9 deaths occurred due to lamivudine resistance, but successful rescue occurred in 4 patients who were treated with either adefovir or tenofovir.⁵⁴ However, these reports did not examine the impact of tenofovir on renal function especially in the setting of immunosuppressive medications. Tenofovir may lead to increase in serum creatinine levels which has also raised concerns about changes in Model for EndStage Liver Disease (MELD) score, a scoring system currently used to allocate livers for transplantation.⁵⁵ Further studies are needed in patients who are treated with tenofovir prior to transplantation and post-transplant to evaluate long-term efficacy and safety.

Viral Dynamics of Tenofovir

Studies examining viral dynamics with tenofovir are limited to those in HIV/HBV co-infected patients.^56–58 All studies demonstrated a biphasic response to nucleos(t)ide therapy similar to that seen with HIV and hepatitis C. A faster first phase decline was associated with high HBV viral load and HBeAg-positivity.⁵⁷ The investigators also found time to reaching undetectable HBV viral load was longer in those with higher HBV viral load (150 days if HBV DNA < 10⁸ log versus 316 days when HBV DNA > 10⁸ log) and HBe Ag-positive.⁵⁷ A study comparing wild type and lamivudine resistance actually found a slower first phase decline in those with lamivudine resistance.⁵⁶ A larger study of HIV/HBV patients comparing viral kinetics in those on tenofovir, lamivudine, or both found no differences in kinetic parameters by treatment group. Overall treatment effectiveness was 98%, half-live of infected virions was 1.2 days, and median life of infected cells was 7.9 days. The authors reported longer infected half-life of hepatocytes in HBeAg-positive compared to HBeAg-negative patients.⁵⁸ The viral dynamic studies suggest that tenofovir dynamics are similar to other nucleos(t)ides. Furthermore, no differences in viral dynamics are evident between monotherapy vs. combination therapy. There may be lower antiviral effectiveness of tenofovir in lamivudine resistance, but this seems transient. No data to date shows if HBV genotypes affect viral dynamics.

Resistance

One of the problems with nucelos(t)ide therapy is that long-term use is associated with development of resistance. These nucleos(t)ides have begun to be used for longer periods of time, similar to the HIV model of treatment. Lamivudine resistance for HBV has been reported to occur at a rate of 20% per year⁵⁹ and in one study occurred in over 90% of HIV/HBV co-infected patients treated for 4 years.⁶⁰ Viral resistant populations have a characteristic mutation in the reverse transcriptase (RT) polymerase (see Table 3). For example, lamivudine resistance is associated with genotypic resistance in RT polymerase at L180M or M204V/I.^61,62 Both in vitro and in vivo studies have found adefovir and tenofovir to be active against lamivudine resistant virus.^{39,40,45,63,64} Telbivudine, although highly potent in terms of HBV viral load suppression, resistance does occur at the same site as lamivudine.²⁰ Adefovir resistance is associated with emergence of rtA181V or rtN236T.⁶¹ Tenofovir has also been shown to be effective in those who have suboptimal response to adefovir.⁴⁴ In addition there are case reports of patients with adefovir resistance who were treated successfully with tenofovir.^50,65 Entecavir has been found to have a high genetic barrier leading to a cumulative failure of 0.8% at 4 years in naïve HBV patients.⁶⁶ However, once a person has lamivudine resistance, then developing entecavir resistance is easier. Thus, resistance to entecavir occurs more frequently in patients who are lamivudine experienced with a cumulative failure rate of 40% in lamivudine experienced patients on entecavir for 4 years.⁶⁶ Mutations in the RT polymerase seen with entecavir are at rtM204V + rtL180M plus other variants or rtM204I plus other variants.⁶¹ There are case reports of salvaging entecavir resistant virus with tenofovir.⁶⁷ However, in vitro constructs of entecavir resistant virus suggests that there is a 4 fold decreased susceptibility to tenofovir.⁶² Tenofovir resistance has been reported in one case³⁶ associated with rtA194T mutation. A recent study constructed the rtA194T mutation alone or in addition to lamivudine resistance and demonstrated reduced replication efficiency compared to wild type. Viral fitness was restored in precore and basal core promoter mutations. Furthermore, clones harboring rtA194T had partial resistance to tenofovir in vitro but remained susceptible to telbivudine and entecavir.⁶⁸

Table 3

Nucleos(t)ide therapy and potential mutations in RT polymerase gene.

Drug	RT polymerase mutation
Lamivudine, telbivudine, emtricitabine	rtM204V/I + rtL180M; rtV173L
Adefovir	rtA181V; rtN236T
Entecavir	rtM204V + rt180M plus rt184A/C/F/G/I/L/M/S or rtS202C/G/I or rtM250V/L
	rtM204I plus rt184I/S or rtM250I/L
Tenofovir	rtA194T–-one case report

Combination vs. Monotherapy

Monotherapy with drugs such as lamivudine has lead to the development of resistant HBV. Borrowing from the HIV model where combination therapy has been shown to be effective in reducing the emergence of resistant variants, studies in HBV have focused on using combination therapy to improve both viral dynamics and reduce the emergence of resistant variants. Combination therapy trials have evaluated lamivudine plus adefovir versus adefovir⁶⁹ in lamivudine resistant patients; lamivudine plus adefovir versus lamivudine⁷⁰ in naïve patients, or both⁶⁴ (see Table 4). However, these studies failed to show improved antiviral effect compared to appropriate control populations, except for the study by Peters and colleagues which only showed differences when lamivudine was compared to adefovir or combination of lamivudine and adefovir. However, the patients in this study were lamivudine experienced and had resistant variants that would not respond to lamivudine treatment. Other studies examining emtricitabine vs. emtricitabine plus clevudine;⁷¹ lamivudine plus famciclovir vs. lamivudine⁷² also did not show improved antiviral effects with combination therapy.

Table 4

Outcomes from studies comparing monotherapy to combination therapy for HBV treatment.

Study	HBV population	Type and duration	Treatment	Change log HBV DNA	% undetectable (<1000 c/mL)	HBeAg loss	HBeAg seroconversion
Matthews³⁸	HIV/naïve	R; 48 wks	Lam 300 mg (n = 13)	-4.07	46%	3/9 (33%)	1/9 (11%)
			TDF 300 mg (n = 12)	-4.57	92%^*	1/6 (17%)	1/6 (17%)
			combo (n = 11)	-4.73	91%^*	3/7 (43%)	3/7 (43%)
Schmutz³³	HIV (naïve/exp)	Retro; variable f/u	TDF 300 mg (n = 50)		84%	12/50 (24%)
			Lam 300 mg + TDF (n = 25)		76%	9/25 (36%)
Lau⁷²	HBeAg⁺	R; 12 wks	Lam 150 mg (n = 9)	-1.8
			Lam + famciclovir 500 mg TID (n = 12)	-2.5
Hui⁷³	HBeAg ⁺/naïve	R; 96 wks	ADv 10 mg (n = 16)	-3.98^*	38%^*^{^}		25%
			ADV + FTC 200 mg (n = 14)	-5.3^*	79%^*^{^}		14%
Sung⁷⁰	HBeAg ⁺/naïve	R; 104 wks	Lam 100 mg (n = 57)	-3.41^§	14%^£	24%	20%
			Lam + ADV 10 mg (n = 54)	-5.22^§	26%^£	19%	13%
Lim⁷¹	HBeAg⁺/HBeAg^–/naïve	R; 24 wks	FTC 200 mg (n = 81)		9%^¤	7/44 (16%)	1/44
			FTC + clevudine 10 mg (n = 82)		10%^¤	4/41 (10%)	1/41
Peters⁶⁴	Lam-rest HBeAg⁺	R; 48 wk	Lam 100 mg (n = 19)	0^§	0	0	0
			ADV (n = 19)	-4.04^§^*	26%	16%	11%
			Lam + ADV (n = 20)	-3.59^§^*	35%	17%	6%
Gaia⁶⁹	Lam-rest	C; variable f/u	ADV 10 mg (n = 29)		55%^¥
			Lam + ADV (n = 23)		83%^¥

Abbreviations: HBV, hepatitis B viral load; HBeAg, hepatitis B e Antigen; HIV, human immunodeficiency virus; R, randomized; wks, weeks; Lam, lamivudine; TDF, tenofovir; combo, combination therapy; Retro, retrospective; f/u, follow-up; ADV, adefovir.

p < 0.05;

<300 copies/mL;

DAVG;

<200 copies/mL; FTC, emtricitabine;

<4700 copies/mL; C, cohort study;

<11 lU/mL

A recent study comparing adefovir vs. adefovir plus emtricitabine in HBeAg+ naïve patients⁷³ show improved viral decline in HBV DNA (-5.3 vs. -3.98, p = 0.05) and viral suppression <300 copies/mL (79% vs. 38% p = 0.03) in combination therapy versus monotherapy. Sung et al also showed that in HBeAg⁺ naïve patients on lamivudine had a higher proportion developing viral breakthrough compared to those treated with the combination group of lamivudine and adefovir (45% vs. 19%, p = 0.018).⁷⁰ Both studies^70,73 focused on naïve patients and followed them for an extended period of time to evaluate for efficacy and resistance. Other studies may have been unable to show differences because of short time of follow-up^71,74 or examining a population with lamivudine resistance^64,69 which in effect was equivalent to receiving one active drug. Thus, combination therapy when given over a prolonged period of time in HBV naïve patients appears to be more potent and reduces the emergence of resistant variants.

However, both lamivudine and adefovir are less potent than drugs such as entecavir, tenofovir and telbivudine. Highly potent drugs may not need to be used in combination with other drugs. Most of the studies evaluating combination therapy initially were reported in HIV/HBV co-infected patients. The studies using tenofovir and lamivudine or tenofovir and emtricitabine are limited because of retrospective design, inclusion of both naïve and experienced patients,^32,33 lack of an appropriate control population,^26,30,75 or small number of patients.²⁷ To date, these studies suggest improved efficacy with tenofovir alone or in combination. However, a recent study by Mathews and colleagues³⁸ randomized HIV/HBV treatment naïve patients to receive lamivudine versus tenofovir versus lamivudine and tenofovir as part of the antiretroviral therapy (ART). This study showed a significantly higher proportion of patients achieved <1000 copies/mL in the tenofovir and combination arm compared to the lamivudine alone regimen (92% vs. 91% vs. 46%, respectively, p = 0.013). Thus, nucleos(t)ides with a high genetic barrier to viral resistance and high level antiviral efficacy such as entecavir and tenofovir may be able to be used as monotherapy in treatment naïve patients. However, drugs such as lamivudine, telbivudine, and adefovir are probably best used in combination therapy.

Safety and Tolerability

Nephrotoxicity

Tenofovir is one of three nucleotide analogs which include adefovir, approved for HBV treatment, and cidofovir, approved in 1996 for the treatment of cytomegalovirus (CMV) retinitis. It is interesting to note that, all three nucleotide analogs share nephrotoxicity as an adverse effect. In fact, cidofovir (Vistide^®; Gilead Sciences) carries a black box warning regarding renal impairment with strict criteria for use to reduce the incidence of nephrotoxicity.⁷⁶ Adefovir was initially developed for the treatment of HIV at a dose of 60 mg daily and was halted due the development of nephrotoxicity. A lower 10 mg dose of adefovir was found to be active against HBV with an acceptable balance of efficacy and safety and received FDA approval for HBV treatment in 2002.⁷⁷ The mechanism of nephrotoxicity is mediated by the active uptake of nucleotides from the systemic circulation by human renal organic anion transporter 1 (hOAT1) causing the accumulation of the parent nucleotide or metabolites in the proximal renal tubular cells resulting in mitochondrial DNA depletion and cell toxicity.⁷⁸ Tenofovir, unlike cidofovir and adefovir, is efficiently transported by hOAT1 but has not been shown to produce the degree of nephrotoxicity seen with the other nucleotide compounds.⁷⁸ A recent study found that tenofovir caused ultrastructural abnormalities to mitochondrial DNA in proximal renal tubules⁷⁹ but not to other organs, which suggests that tenofovir toxicity is mostly associated with tubulopathy.

Overall, the degree of nephrotoxicity seen with tenofovir is low and is estimated to range from 0.3 to 2% per year.^80,81 Rather than overt cytotoxicity to the renal proximal tubule epithelial cells, a milder form of nephrotoxicity is associated with tenofovir. Because tenofovir was initially approved for HIV, safety data on long-term tenofovir use is mostly available from use of tenfovir for HIV-infected patients. Tenofovir has been associated with Fanconi's syndrome,⁸² nephrogenic diabetes insipidus,⁸³ renal failure,⁸⁴ and a decrease in glomerular filtration rate.⁸⁵ Fanconi's syndrome, a disorder in which the proximal tubule function is impaired, results in the loss of electrolytes including phosphate, bicarbonate, amino acids, and glucose into the urine. The loss of bicarbonate may result in metabolic acidosis. Winston and colleagues showed a statistically significant increase in anion gap of 0.78 mmol/L and a decline in CrCL of 6.8 mL/min in a retrospective review of 948 HIV patients with no baseline renal impairment. Patients experiencing tenofovir induced nephrotoxicity may have serum creatinine and phosphorus levels within established normal ranges. ⁸⁶ In the registration trial for tenofovir in HIV infected adults, 600 ART naïve HIV patients treated with either tenofovir or stavudine and the same background ART regimen were followed for 144 weeks without developing statistically significant changes in serum creatinine or hypophosphatemia between treatment groups.⁸⁷ However, a recent study of HIV patients treated with tenofovir compared to those on other nucleosides or on no medications found evidence of tubular dysfunction without impairment of glomerular filtration rate (GFR). Furthermore, in a multivariate model tenofovir use and older age was independently associated with increased risk of tubular dysfunction.⁸⁸ Thus, patients on long-term tenofovir should be monitored for serum creatinine and phosphate levels and urinalysis samples to monitor for evidence of glucose and phosphorus.

The incidence of hypophosphatemia varies among clinical studies and has been reported at 7% in ART naïve HIV patients, 15% in the HIV Outpatient Study (HOPS) cohort by investigators at the Center for Di sease Control (CDC), and up to 31% in a United Kingdom cohort.^87,89,90 Two reports concluded that moderate, asymptomatic hypophosphatemia is frequently seen in HIV infected patients treated with ART but often the cause of renal dysfunction cannot be entirely accounted for by the use of tenofovir^91,92 as all three studies did not show statistical differences in the incidence of hypophosphatemia between treatment groups. Some associations with nephrotoxicity and hypophosphatemia that have been established in tenofovir treated HIV patients include: older age, African-American race, co-morbidities that also lead to renal dysfunction such as diabetes and hypertension, concurrent nephrotoxic medications such as NSAIDs, low body mass index, medications known to increase tenofovir exposure (lopinavir/ritonavir (Kaletra®; Abbott Laboratories), duration of ART use, and potentially genetic haplotype differences.^90,93–95 There does not appear to be a definitive time course relationship to the development of tenofovir induced nephrotoxicity as patients may experience nephrotoxicity at any time point during tenofovir therapy. Fortunately, renal function usually returns to baseline within four to six weeks of discontinuation of tenofovir.

Bone Marrow Toxicity

Phosphorus is a critical electrolyte to the function of the human body and is carefully balanced by an elegant feedback system involving the kidney, parathyroid gland, and skeletal system. Increased urinary excretion of phosphorus is a sensitive marker of proximal renal tubular dysfunction and causes the parathyroid gland to release parathyroid hormone stimulating catabolism of bone by osteoclasts in order to maintain serum phosphorus levels at physiologic levels. This can result in osteopenia or osteomalacia with loss of BMD placing individuals at risk for fracture. In the registration trial for tenofovir in HIV infected adults, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine (-2.2% tenofovir vs. -1.0% stavudine, p = 0.001) but only a trend toward a difference at the hip (-2.8% tenofovir DF vs. -2.4% stavudine, p = 0.06) in tenofovir treated study participants at week 144.⁹⁶ Case reports of bone fracture due to osteomalacia have been reported in HIV patients.^97,98 Unfortunately, HIV infection itself has been associated with a decline in BMD creating treatment challenges for clinicians. Long term safety data with tenofovir in patients with HBV mono-infection is not available. Further studies and monitoring are needed in this population to help determine how much of the renal and bone toxicity associated with tenofovir may be confounded by concomitant medications used to treat HIV or HIV itself.

Non-Renal Adverse Events

Over 12,000 patients have received tenofovir in clinical trials and expanded access studies where the most common adverse reactions of Grade 2-4 severity occurring in ≥10% of study patients included rash, diarrhea, headache, pain, depression, asthenia, and nausea.¹⁰ In addition to these side effects, tenofovir may interact with other medications, most of these are HIV medications, and the dose may require adjustment (see Table 5).

Table 5

Tenofovir associated drug interactions. 10

Antiretroviral medications	Pharmacokinetic effect	Potential adverse reaction	Recommendation
Atazanavir	Tenofovir AUC ↑24% Atazanavir AUC ↓25%	Potential for increased toxicity with tenofovir and loss of HIV virologic control with atazanavir	Use atazanavir 300 mg with ritonavir 100 mg daily
Didanosine	Didanosine AUC ↑44%-60%	Pancreatitis, peripheral neuropathy, suppressed CD4 cell count	Reduce didanosine: 250 mg EC daily ≥ 60 kg 200 mg EC daily < 60 kg
Lopinavir/Ritonavir	Tenofovir AUC ↑32%	Potential for increased toxicity with tenofovir	No dosage adjustment

Patient Focused Perspective

Tenofovir is a nucleotide analogue that is highly potent for the treatment of HBV. There is little evidence for development of tenofovir resistance to date, but this remains a possibility. In addition, tenofovir has been shown to affect HBsAg clearance²⁵ at the end of treatment, which may turn out to be of importance especially if long-term follow-up studies show increasing rates of HBsAg clearance. Unlike interferon-based therapy which requires weekly injections and has many side effects, tenofovir is well tolerated. However, long-term use of tenofovir may lead to kidney and bone toxicity. The use of the drug requires monitoring of serum creatinine and phosphorous levels as well as urinalysis. The drug can be taken once daily making it a simple regimen.

Conclusions and Place in Therapy

Tenofovir is a potent drug for the treatment of HBV and leads to significant viral suppression. Both entecavir and tenofovir in naïve patients rarely lead to viral resistance which makes both these drugs attractive as first line therapies. In the case of entecavir, we know that multiple mutations are needed to lead to entecavir resistance. Telbivudine, another potent drug for HBV treatment, is limited by the emergence of lamivudine resistance making it a less desirable drug for long-term therapy. Tenofovir, has activity against lamivudine resistant strains, and to date only one case report has shown possible tenofovir resistance. Thus, the drug of choice in lamivudine experienced patients would be tenofovir. In HBV treatment naïve patients, entecavir remains a viable alternative. In the HIV-infected patients, Truvada^® has become the drug of choice. Yet, there remain populations in which tenofovir may not be suitable including those with renal insufficiency.

However, if the goal of therapy is HBsAg loss, a clinical cure, and not viral suppression, than peginterferon is more likely to produce these results.⁹⁹ HBeAg seroconversion and HBsAg loss is also more likely with peginterferon²² than nucleos(t)ide.^16–21,25 Recent data suggests that tenofovir may be more likely to lead to HBsAg seronconversion.²⁵ Further studies are needed to evaluate the impact of tenofovir in combination with peginterferon.

Tenofovir is a potent and relatively safe drug that can suppress HBV DNA. Data on long-term therapy is limited but to date viral resistance is uncommon. Safety data are limited to patients with HIV-infection, and it remains unknown if the long-term renal and bone toxicity will be similar to that seen in HIV-infected patients and if it will limit long-term use for HBV treatment. Since the risk of toxicity is low compared to the potential benefit of viral suppression, HBeAg seronconversion, and in some patients HBsAg loss, tenofovir has become a very important drug in the arsenal of therapeutic options available for the treatment of HBV.

Disclosures

The authors report no conflicts of interest.

References

Lai

C.L.

, Ratziu

, Yuen

M.F.

, Poynard

Viral hepatitis B. Lancet. 2003 Dec 20;362(9401): 2089–94.

Mast

E.E.

, Weinbaum

C.M.

, Fiore

A.E.

, Alter

M.J.

, Bell

B.P.

, Finelli

. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) Part II: immunization of adults. MMWR Recomm Rep. 2006 Dec 8; 55(RR-16): 1–33;quiz CE1-4

Lau

D.T.

, Everhart

, Kleiner

D.E.

, Park

, Vergalla

, Schmid

. Longterm follow-up of patients with chronic hepatitis B treated with interferon alfa. Gastroenterology. 1997 Nov; 113(5): 1660–7.

Niederau

, Heintges

, Lange

, Goldmann

, Niederau

C.M.

, Mohr

. Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B. N Engl J Med. 1996 May 30; 334(22): 1422–7.

van Zonneveld

, Honkoop

, Hansen

B.E.

, Niesters

H.G.

, Murad

S.D.

, de Man

R.A.

. Long-term follow-up of alpha-interferon treatment of patients with chronic hepatitis B. Hepatology. 2004 Mar; 39(3): 804–10.

Yuen

M.F.

, Hui

C.K.

, Cheng

C.C.

, Wu

C.H.

, Lai

Y.P.

, Lai

C.L.

Long-term follow-up of interferon alfa treatment in Chinese patients with chronic hepatitis B infection: The effect on hepatitis B e antigen seroconversion and the development of cirrhosis-related complications. Hepatology. 2001 Jul; 34(1): 139–45.

Dienstag

J.L.

, Perrillo

R.P.

, Schiff

E.R.

, Bartholomew

, Vicary

, Rubin

A preliminary trial of lamivudine for chronic hepatitis B infection. N Engl J Med. 1995 Dec 21; 333(25): 1657–61.

Lai

C.L.

, Chien

R.N.

, Leung

N.W.

, Chang

T.T.

, Guan

, Tai

D.I.

. A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. N Engl J Med. 1998 Jul 9; 339(2): 61–8.

Tassopoulos

N.C.

, Volpes

, Pastore

, Heathcote

, Buti

, Goldin

R.D.

. Efficacy of lamivudine in patients with hepatitis B e antigen-negative/hepatitis B virus DNA-positive (precore mutant) chronic hepatitis B. Lamivudine Precore Mutant Study Group. Hepatology. 1999 Mar; 29(3): 889–96.

10.

Tenofovir. Tenofovir disproxil fumarate (Viread) [package insert]. Foster City, CA: Gilead Sciences; 2003.

11.

Fung

H.B.

, Stone

E.A.

, Piacenti

F.J.

Tenofovir disoproxil fumarate: a nucleotide reverse transcriptase inhibitor for the treatment of HIV infection. Clin Ther. 2002 Oct; 24(10): 1515–48.

12.

Delaney

WEt

, Ray

A.S.

, Yang

, Qi

, Xiong

, Zhu

. Intracellular metabolism and in vitro activity of tenofovir against hepatitis B virus. Antimicrob Agents Chemother. 2006 Jul; 50(7): 2471–7.

13.

Gafni

R.I.

, Hazra

, Reynolds

J.C.

, Maldarelli

, Tullio

A.N.

, DeCarlo

. Tenofovir disoproxil fumarate and an optimized background regimen of antiretroviral agents as salvage therapy: impact on bone mineral density in HIV-infected children. Pediatrics. 2006 Sep; 118(3): e711–8.

14.

Purdy

J.B.

, Gafni

R.I.

, Reynolds

J.C.

, Zeichner

, Hazra

Decreased bone mineral density with off-label use of tenofovir in children and adolescents infected with human immunodeficiency virus. J Pediatr. 2008 Apr; 152(4): 582–4.

15.

Group

PHGW

. Public Health Service Task Force Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. 2009; (May 10): Available from: http://aidsinfo.nih.gov/ContentFiles/PerinatalGL.pdf.

16.

Hadziyannis

S.J.

, Tassopoulos

N.C.

, Heathcote

E.J.

, Chang

T.T.

, Kitis

, Rizzetto

. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med. 2003 Feb 27; 348(9): 800–7.

17.

Lim

S.G.

, Ng

T.M.

, Kung

, Krastev

, Volfova

, Husa

. A doubleblind placebo-controlled study of emtricitabine in chronic hepatitis B. Arch Intern Med. 2006 Jan 9; 166(1): 49–56.

18.

Marcellin

, Chang

T.T.

, Lim

S.G.

, Tong

M.J.

, Sievert

, Shiffman

M.L.

. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med. 2003 Feb 27; 348(9): 808–16.

19.

Chang

T.T.

, Gish

R.G.

, de Man

, Gadano

, Sollano

, Chao

Y.C.

. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med. 2006 Mar 9; 354(10): 1001–10.

20.

Lai

C.L.

, Gane

, Liaw

Y.F.

, Hsu

C.W.

, Thongsawat

, Wang

. Telbivudine versus lamivudine in patients with chronic hepatitis B. N Engl J Med. 2007 Dec 20; 357(25): 2576–88.

21.

Lai

C.L.

, Shouval

, Lok

A.S.

, Chang

T.T.

, Cheinquer

, Goodman

. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2006 Mar 9; 354(10): 1011–20.

22.

Lau

G.K.

, Piratvisuth

, Luo

K.X.

, Marcellin

, Thongsawat

, Cooksley

. Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med. 2005 Jun 30; 352(26): 2682–95.

23.

Chan

H.L.

, Heathcote

E.J.

, Marcellin

, Lai

C.L.

, Cho

, Moon

Y.M.

. Treatment of hepatitis B e antigen positive chronic hepatitis with telbivudine or adefovir: a randomized trial. Ann Intern Med. 2007 Dec 4; 147(11): 745–54.

24.

Leung

, Peng

C.Y.

, Hann

H.W.

, Sollano

, Lao-Tan

, Hsu

C.W.

. Early hepatitis B virus DNA reduction in hepatitis B e antigen-positive patients with chronic hepatitis B: A randomized international study of entecavir versus adefovir. Hepatology. 2009 Jan; 49(1): 72–9.

25.

Marcellin

, Heathcote

E.J.

, Buti

, Gane

, de Man

R.A.

, Krastev

. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. 2008 Dec 4; 359(23): 2442–55.

26.

Bani-Sadr

, Palmer

, Scieux

, Molina

J.M.

Ninety-six-week efficacy of combination therapy with lamivudine and tenofovir in patients coinfected with HIV-1 and wild-type hepatitis B virus. Clin Infect Dis. 2004 Oct 1; 39(7): 1062–4.

27.

Dore

G.J.

, Cooper

D.A.

, Pozniak

A.L.

, DeJesus

, Zhong

, Miller

M.D.

. Efficacy of tenofovir disoproxil fumarate in antiretroviral therapy-naive and -experienced patients coinfected with HIV-1 and hepatitis B virus. J Infect Dis. 2004 Apr 1; 189(7): 1185–92.

28.

Benhamou

, Fleury

, Trimoulet

, Pellegrin

, Urbinelli

, Katlama

. Anti-hepatitis B virus efficacy of tenofovir disoproxil fumarate in HIV-infected patients. Hepatology. 2006 Mar; 43(3): 548–55.

29.

Nelson

, Portsmouth

, Stebbing

, Atkins

, Barr

, Matthews

. An open-label study of tenofovir in HIV-1 and Hepatitis B virus co-infected individuals. Aids. 2003 Jan 3; 17(1): F7–10.

30.

Ristig

M.B.

, Crippin

, Aberg

J.A.

, Powderly

W.G.

, Lisker-Melman

, Kessels

. Tenofovir disoproxil fumarate therapy for chronic hepatitis B in human immunodeficiency virus/hepatitis B virus-coinfected individuals for whom interferon-alpha and lamivudine therapy have failed. J Infect Dis. 2002 Dec 15; 186(12): 1844–7.

31.

Stephan

, Berger

, Carlebach

, Lutz

, Bickel

, Klauke

. Impact of tenofovir-containing antiretroviral therapy on chronic hepatitis B in a cohort co-infected with human immunodeficiency virus. J Antimicrob Chemother. 2005 Dec; 56(6): 1087–93.

32.

Jain

M.K.

, Comanor

, White

, Kipnis

, Elkin

, Leung

. Treatment of hepatitis B with lamivudine and tenofovir in HIV/HBV-coinfected patients: factors associated with response. J Viral Hepat. 2007 Mar; 14(3): 176–82.

33.

Schmutz

, Nelson

, Lutz

, Sheldon

, Bruno

, von Boemmel

. Combination of tenofovir and lamivudine versus tenofovir after lamivudine failure for therapy of hepatitis B in HIV-coinfection. AIDS. 2006 Oct 3; 20(15): 1951–4.

34.

Nunez

, Ramos

, Diaz-Pollan

, Camino

, Martin-Carbonero

, Barreiro

. Virological outcome of chronic hepatitis B virus infection in HIV-coinfected patients receiving anti-HBV active antiretroviral therapy. AIDS Res Hum Retroviruses. 2006 Sep; 22(9): 842–8.

35.

Alvarez-Uria

, Ratcliffe

, Vilar

Long-term outcome of tenofovir disoproxil fumarate use against hepatitis B in an HIV-coinfected cohort. HIV Med. 2009 May; 10(5): 269–73.

36.

Sheldon

, Camino

, Rodes

, Bartholomeusz

, Kuiper

, Tacke

. Selection of hepatitis B virus polymerase mutations in HIV-coinfected patients treated with tenofovir. Antivir Ther. 2005; 10(6): 727–34.

37.

Peters

M.G.

, Andersen

, Lynch

, Liu

, Alston-Smith

, Brosgart

C.L.

. Randomized controlled study of tenofovir and adefovir in chronic hepatitis B virus and HIV infection: ACTG A5127. Hepatology. 2006 Nov; 44(5): 1110–6.

38.

Matthews

G.V.

, Avihingsanon

, Lewin

S.R.

, Amin

, Rerknimitr

, Petcharapirat

. A randomized trial of combination hepatitis B therapy in HIV/HBV coinfected antiretroviral naive individuals in Thailand. Hepatology. 2008 Oct; 48(4): 1062–9.

39.

Kuo

, Dienstag

J.L.

, Chung

R.T.

Tenofovir disoproxil fumarate for the treatment of lamivudine-resistant hepatitis B. Clin Gastroenterol Hepatol. 2004 Mar; 2(3): 266–72.

40.

van Bommel

, Wunsche

, Mauss

, Reinke

, Bergk

, Schurmann

. Comparison of adefovir and tenofovir in the treatment of lamivudine-resistant hepatitis B virus infection. Hepatology. 2004 Dec; 40(6): 1421–5.

41.

van Bommel

, Wunsche

, Schurmann

, Berg

Tenofovir treatment in patients with lamivudine-resistant hepatitis B mutants strongly affects viral replication. Hepatology. 2002 Aug; 36(2): 507–8.

42.

van Bommel

, Zollner

, Sarrazin

, Spengler

, Huppe

, Moller

. Tenofovir for patients with lamivudine-resistant hepatitis B virus (HBV) infection and high HBV DNA level during adefovir therapy. Hepatology. 2006 Aug; 44(2): 318–25.

43.

Santos

S.A.

, Uriel

A.J.

, Park

J.S.

, Lucas

, Carriero

, Jaffe

. Effect of switching to tenofovir with emtricitabine in patients with chronic hepatitis B failing to respond to an adefovir-containing regimen. Eur J Gastroenterol Hepatol. 2006 Dec; 18(12): 1247–53.

44.

Tan

, Degertekin

, Wong

S.N.

, Husain

, Oberhelman

, Lok

A.S.

Tenofovir monotherapy is effective in hepatitis B patients with antiviral treatment failure to adefovir in the absence of adefovir-resistant mutations. J Hepatol. 2008 Mar; 48(3): 391–8.

45.

Del Poggio

, Zaccanelli

, Oggionni

, Colombo

, Jamoletti

, Puhalo

Low-dose tenofovir is more potent than adefovir and is effective in controlling HBV viremia in chronic HBeAg-negative hepatitis B. World J Gastroenterol. 2007 Aug 14; 13(30): 4096–9.

46.

Schildgen

, Hartmann

, Gerlich

W.H.

Replacement of tenofovir with adefovir may result in reactivation of hepatitis B virus replication. Scand J Gastroenterol. 2006 Feb; 41(2): 245–6.

47.

Marcellin

, Pequignot

, Delarocque-Astagneau

, Zarski

J.P.

, Ganne

, Hillon

. Mortality related to chronic hepatitis B and chronic hepatitis C in France: evidence for the role of HIV coinfection and alcohol consumption. J Hepatol. 2008 Feb; 48(2): 200–7.

48.

Gutierrez

, Guillemi

, Jahnke

, Montessori

, Harrigan

P.R.

, Montaner

J.S.

Tenofovir-based rescue therapy for advanced liver disease in 6 patients coinfected with HIV and hepatitis B virus and receiving lamivudine. Clin Infect Dis. 2008 Feb 1; 46(3): e28–30.

49.

Matthews

G.V.

, Cooper

D.A.

, Dore

G.J.

Improvements in parameters of end-stage liver disease in patients with HIV/HBV-related cirrhosis treated with tenofovir. Antivir Ther. 2007; 12(1): 119–22.

50.

Choe

W.H.

, Kwon

S.Y.

, Kim

B.K.

, Ko

S.Y.

, Yeon

J.E.

, Byun

K.S.

. Tenofovir plus lamivudine as rescue therapy for adefovir-resistant chronic hepatitis B in hepatitis B e antigen-positive patients with liver cirrhosis. Liver Int. 2008 Jul; 28(6): 814–20.

51.

Ratziu

, Thibault

, Benhamou

, Poynard

Successful rescue therapy with tenofovir in a patient with hepatic decompensation and adefovir resistant HBV mutant. Comp Hepatol. 2006; 5: 1.

52.

Neff

G.W.

, Nery

, Lau

D.T.

, O'Brien

C.B.

, Duncan

, Shire

N.J.

. Tenofovir therapy for lamivudine resistance following liver transplantation. Ann Pharmacother. 2004 Dec;38(12): 1999–2004.

53.

Nath

D.S.

, Kalis

, Nelson

, Payne

W.D.

, Lake

J.R.

, Humar

Hepatitis B prophylaxis post-liver transplant without maintenance hepatitis B immunoglobulin therapy. Clin Transplant. 2006 Mar-Apr; 20(2): 206–10.

54.

Potthoff

, Tillmann

H.L.

, Bara

, Deterding

, Pethig

, Meyer

. Improved outcome of chronic hepatitis B after heart transplantation by long-term antiviral therapy. J Viral Hepat. 2006 Nov; 13(11): 734–41.

55.

Bruno

, Sacchi

, Filice

Could tenofovir modify the model end-stage liver disease (MELD) score in patients with end-stage liver disease eligible for liver transplantation?

J Acquir Immune Defic Syndr. 2007 May 1; 45(1): 123.

56.

de Vries-Sluijs

T.E.

, van der Eijk

A.A.

, Hansen

B.E.

, Osterhaus

A.D.

, de Man

R.A.

, van der Ende

M.E.

Wild type and YMDD variant of hepatitis B virus: no difference in viral kinetics on lamivudine/tenofovir therapy in HIV-HBV co-infected patients. J Clin Virol. 2006 May; 36(1): 60–3.

57.

Lacombe

, Gozlan

, Boelle

P.Y.

, Serfaty

, Zoulim

, Valleron

A.J.

. Long-term hepatitis B virus dynamics in HIV-hepatitis B virus-co-infected patients treated with tenofovir disoproxil fumarate. Aids. 2005 Jun 10; 19(9): 907–15.

58.

Lewin

S.R.

, Ribeiro

R.M.

, Avihingsanon

, Bowden

, Matthews

, Marks

. Viral dynamics of hepatitis B virus DNA in human immunodeficiency virus-1-hepatitis B virus coinfected individuals: similar effectiveness of lamivudine, tenofovir, or combination therapy. Hepatology. 2009 Apr; 49(4): 1113–21.

59.

Benhamou

, Bochet

, Thibault

, Di Martino

, Caumes

, Bricaire

. Long-term incidence of hepatitis B virus resistance to lamivudine in human immunodeficiency virus-infected patients. Hepatology. 1999 Nov; 30(5): 1302–6.

60.

Matthews

G.V.

, Bartholomeusz

, Locarnini

, Ayres

, Sasaduesz

, Seaberg

. Characteristics of drug resistant HBV in an international collaborative study of HIV-HBV-infected individuals on extended lamivudine therapy. Aids. 2006 Apr 4; 20(6): 863–70.

61.

Baldick

C.J.

, Tenney

D.J.

, Mazzucco

C.E.

, Eggers

B.J.

, Rose

R.E.

, Pokornowski

K.A.

. Comprehensive evaluation of hepatitis B virus reverse transcriptase substitutions associated with entecavir resistance. Hepatology. 2008 May; 47(5): 1473–82.

62.

Brunelle

M.N.

, Jacquard

A.C.

, Pichoud

, Durantel

, Carrouee-Durantel

, Villeneuve

J.P.

. Susceptibility to antivirals of a human HBV strain with mutations conferring resistance to both lamivudine and adefovir. Hepatology. 2005 Jun; 41(6): 1391–8.

63.

Lada

, Benhamou

, Cahour

, Katlama

, Poynard

, Thibault

In vitro susceptibility of lamivudine-resistant hepatitis B virus to adefovir and tenofovir. Antivir Ther. 2004 Jun; 9(3): 353–63.

64.

Peters

M.G.

, Hann Hw

, Martin

, Heathcote

E.J.

, Buggisch

, Rubin

. Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology. 2004 Jan; 126(1): 91–101.

65.

Deterding

, Manns

M.P.

, Wedemeyer

Does the presence of adefovir-resistant variants lead to failure of tenofovir monotherapy?

J Hepatol. 2008 Nov; 49(5): 862–3.

66.

Colonno

R.J.

, Rose

R.E.

, Pokornowski

, Baldick

C.J.

, Eggers

B.J.

, Yu

. Four year assessment of ETV resistance in nucleoside-naive and lamivudine refractory patients[abstract]. Journal of Hepatology. 2007; 46(Supplement 1): S294.

67.

Leemans

W.F.

, Niesters

H.G.

, van der Eijk

A.A.

, Janssen

H.L.

, Schalm

S.W.

, de Man

R.A.

Selection of an entecavir-resistant mutant despite prolonged hepatitis B virus DNA suppression, in a chronic hepatitis B patient with preexistent lamivudine resistance: successful rescue therapy with tenofovir. Eur J Gastroenterol Hepatol. 2008 Aug; 20(8): 773–7.

68.

Amini-Bavil-Olyaee

, Herbers

, Sheldon

, Luedde

, Trautwein

, Tacke

The rtA194T polymerase mutation impacts viral replication and susceptibility to tenofovir in hepatitis B e antigen-positive and hepatitis B e antigen-negative hepatitis B virus strains. Hepatology. 2009 Apr; 49(4): 1158–65.

69.

Gaia

, Barbon

, Smedile

, Olivero

, Carenzi

, Lagget

. Lamivudine-resistant chronic hepatitis B: an observational study on adefovir in monotherapy or in combination with lamivudine. J Hepatol. 2008 Apr; 48(4): 540–7.

70.

Sung

J.J.

, Lai

J.Y.

, Zeuzem

, Chow

W.C.

, Heathcote

E.J.

, Perrillo

R.P.

. Lamivudine compared with lamivudine and adefovir dipivoxil for the treatment of HBeAg-positive chronic hepatitis B. J Hepatol. 2008 May; 48(5): 728–35.

71.

Lim

S.G.

, Krastev

, Ng

T.M.

, Mechkov

, Kotzev

I.A.

, Chan

. Randomized, double-blind study of emtricitabine (FTC) plus clevudine versus FTC alone in treatment of chronic hepatitis B. Antimicrob Agents Chemother. 2006 May; 50(5): 1642–8.

72.

Lau

G.K.

, Tsiang

, Hou

, Yuen

, Carman

W.F.

, Zhang

. Combination therapy with lamivudine and famciclovir for chronic hepatitis B-infected Chinese patients: a viral dynamics study. Hepatology. 2000 Aug; 32(2): 394–9.

73.

Hui

C.K.

, Zhang

H.Y.

, Bowden

, Locarnini

, Luk

J.M.

, Leung

K.W.

. 96 weeks combination of adefovir dipivoxil plus emtricitabine vs. adefovir dipivoxil monotherapy in the treatment of chronic hepatitis B. J Hepatol. 2008 May; 48(5): 714–20.

74.

Lau

D.T.

, Khokhar

M.F.

, Doo

, Ghany

M.G.

, Herion

, Park

. Longterm therapy of chronic hepatitis B with lamivudine. Hepatology. 2000 Oct; 32(4 Pt 1): 828–34.

75.

Nelson

, Bhagani

, Fisher

, Leen

, Brook

, Mandalia

. editors. A 48-week study of tenofovir or lamivudine or a combination of tenofovir and lamivudine for the treatment of chronic hepatitis B in HIV/HBV co-infected individuals. Conference on Retroviruses and Opportunisitic Infections; 2006 February 5-8, Denver, Colorado.

76.

Cidofovir. Cidofovir injection (Vistide) [package insert]. Foster City, CA: Gilead Sciences; 2000.

77.

Adefovir. Adefovir dipivoxil (Hepsera) [package insert]. Foster City, CA: Gilead Sciences; 2008.

78.

Cihlar

, Ho

E.S.

, Lin

D.C.

, Mulato

A.S.

Human renal organic anion transporter 1 (hOAT1) and its role in the nephrotoxicity of antiviral nucleotide analogs. Nucleosides Nucleotides Nucleic Acids. 2001 Apr-Jul; 20(4-7): 641–8.

79.

Kohler

J.J.

, Hosseini

S.H.

, Hoying-Brandt

, Green

, Johnson

D.M.

, Russ

. Tenofovir renal toxicity targets mitochondria of renal proximal tubules. Lab Invest. 2009 May; 89(5): 513–9.

80.

Gupta

S.K.

Tenofovir-associated Fanconi syndrome: review of the FDA adverse event reporting system. AIDS Patient Care STDS. 2008 Feb; 22(2): 99–103.

81.

Jones

, Stebbing

, Nelson

, Moyle

, Bower

, Mandalia

. Renal dysfunction with tenofovir disoproxil fumarate-containing highly active antiretroviral therapy regimens is not observed more frequently: a cohort and case-control study. J Acquir Immune Defic Syndr. 2004 Dec 1; 37(4): 1489–95.

82.

Verhelst

, Monge

, Meynard

J.L.

, Fouqueray

, Mougenot

, Girard

P.M.

. Fanconi syndrome and renal failure induced by tenofovir: a first case report. Am J Kidney Dis. 2002 Dec; 40(6): 1331–3.

83.

Karras

, Lafaurie

, Furco

, Bourgarit

, Droz

, Sereni

. Tenofovir-related nephrotoxicity in human immunodeficiency virus-infected patients: three cases of renal failure, Fanconi syndrome, and nephrogenic diabetes insipidus. Clin Infect Dis. 2003 Apr 15; 36(8): 1070–3.

84.

Coca

, Perazella

M.A.

Rapid communication: acute renal failure associated with tenofovir: evidence of drug-induced nephrotoxicity. Am J Med Sci. 2002 Dec; 324(6): 342–4.

85.

Guaraldi

, Roverato

, Giovanardi

, Ravera

, Squillace

, Orlando

. Glomerular filtration rates in HIV-infected patients treated with and without tenofovir: a prospective, observational study. J Antimicrob Chemother. 2009 Feb; 63(2): 374–9.

86.

Winston

, Amin

, Mallon

, Marriott

, Carr

, Cooper

D.A.

. Minor changes in calculated creatinine clearance and anion-gap are associated with tenofovir disoproxil fumarate-containing highly active antiretroviral therapy. HIV Med. 2006 Mar; 7(2): 105–11.

87.

Izzedine

, Hulot

J.S.

, Vittecoq

, Gallant

J.E.

, Staszewski

, Launay-Vacher

. Long-term renal safety of tenofovir disoproxil fumarate in antiretroviral-naive HIV-1-infected patients. Data from a double-blind randomized active-controlled multicentre study. Nephrol Dial Transplant. 2005 Apr; 20(4): 743–6.

88.

Labarga

, Barreiro

, Martin-Carbonero

, Rodriguez-Novoa

, Solera

, Medrano

. Kidney tubular abnormalities in the absence of impaired glomerular function in HIV patients treated with tenofovir. Aids. 2009 Mar 27; 23(6): 689–96.

89.

Buchacz

, Brooks

J.T.

, Tong

, Moorman

A.C.

, Baker

R.K.

, Holmberg

S.D.

. Evaluation of hypophosphataemia in tenofovir disoproxil fumarate (TDF)-exposed and TDF-unexposed HIV-infected out-patients receiving highly active antiretroviral therapy. HIV Med. 2006 Oct; 7(7): 451–6.

90.

Day

S.L.

, Leake Date

H.A.

, Bannister

, Hankins

, Fisher

Serum hypophosphatemia in tenofovir disoproxil fumarate recipients is multifactorial in origin, questioning the utility of its monitoring in clinical practice. J Acquir Immune Defic Syndr. 2005 Mar 1; 38(3): 301–4.

91.

Badiou

, De Boever

C.M.

, Terrier

, Baillat

, Cristol

J.P.

, Reynes

Is tenofovir involved in hypophosphatemia and decrease of tubular phosphate reabsorption in HIV-positive adults?

J Infect. 2006 May; 52(5): 335–8.

92.

James

C.W.

, Steinhaus

M.C.

, Szabo

, Dressier

R.M.

Tenofovir-related nephrotoxicity: case report and review of the literature. Pharmacotherapy. 2004 Mar; 24(3): 415–8.

93.

Izzedine

, Hulot

J.S.

, Villard

, Goyenvalle

, Dominguez

, Ghosn

. Association between ABCC2 gene haplotypes and tenofovir-induced proximal tubulopathy. J Infect Dis. 2006 Dec 1; 194(11): 1481–91.

94.

Marcotte

, Talbot

, Trottier

Acute renal failure in four HIV-infected patients: Potential association with tenofovir and nonsteroidal anti-inflammatory drugs. Can J Infect Dis Med Microbiol. 2008 Jan; 19(1): 75–6.

95.

Moore

, Keruly

, Gallant

J.E.

, editors. Tenofovir and Renal Dysfunction in Clinical Practice [abstract #832]. 14th Conference on Retroviruses and Opportunistic Infections; 2007; Los Angeles: Programs and Abstracts.

96.

Gallant

J.E.

, Staszewski

, Pozniak

A.L.

, DeJesus

, Suleiman

J.M.

, Miller

M.D.

. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. Jama. 2004 Jul 14; 292(2): 191–201.

97.

Parsonage

M.J.

, Wilkins

E.G.

, Snowden

, Issa

B.G.

, Savage

M.W.

The development of hypophosphataemic osteomalacia with myopathy in two patients with HIV infection receiving tenofovir therapy. HIV Med. 2005 Sep; 6(5): 341–6.

98.

Perrot

, Aslangul

, Szwebel

, Caillat-Vigneron

, Le Jeunne

Bone pain due to fractures revealing osteomalacia related to tenofovir-induced proximal renal tubular dysfunction in a human immunodeficiency virus-infected patient. J Clin Rheumatol. 2009 Mar; 15(2): 72–4.

99.

Perrillo

Benefits and risks of interferon therapy for hepatitis B. Hepatology. 2009 May; 49(5 Suppl): S103–11.

Pharmacotherapy of Chronic Hepatitis B in Adults: Focus on Tenofovir Disoproxil Fumarate

Abstract

Keywords

Introduction

Review of Pharmacology, Mode of Action and Pharmacokinetics

Mechanism of Action

Pharmacokinetics

Pediatric and Pregnancy Considerations

Efficacy Studies

Nucleos(t)ide Therapy for the Treatment of HBV

Use of Tenofovir in Cirrhosis and Transplant Patients

Viral Dynamics of Tenofovir

Resistance

Combination vs. Monotherapy

Safety and Tolerability

Nephrotoxicity

Bone Marrow Toxicity

Non-Renal Adverse Events

Patient Focused Perspective

Conclusions and Place in Therapy

Disclosures

References