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Home , Antiviral drug, Cidofovir, Lobucavir, Penciclovir, Telbivudine

EVALUATION fumarate for the treatment of B : and clinical efficacy

David J Quan1† & Tenofovir is an acyclic diester analogue of adenosine Marion G Peters2 monophosphate with antiviral activity against HIV-1 and virus. After two †Author for correspondence phosphorylations, tenofovir inhibits HIV-1 by competing with the 1Department of Clinical Pharmacy, School of natural substrate, deoxyadenosine 5´-triphosphate. Tenofovir disoproxil fumarate has been Pharmacy, University of approved by the US FDA for the treatment of HIV-1 infection in combination with other California, San Francisco, antiretroviral agents. Although not approved by the FDA for the treatment of chronic 521 Parnassus Avenue, Room C-152, Box 0622, hepatitis B virus infection, tenofovir has anti-hepatitis B virus activity in patients San Francisco, co-infected with HIV and hepatitis B. This paper will review the and clinical CA 94143-0622, USA experience with tenofovir, with a focus on hepatitis B infection. Tel.: +1 415 353 1462; Fax: +1 415 353 1240; E-mail: david.quan@ ucsfmedctr.org 2Division of Gastroenterology, University of California, Chronic hepatitis B virus (HBV) infection is antiretrovirals. In this review, we have used TDF San Francisco, 513 Parnassus thought to affect approximately 400 million when referring to the drug tenofovir disoproxil Ave, Room S-357, Box 0538, individuals worldwide, resulting in 1 million fumarate and tenofovir when referring to the San Francisco, CA 94143-0538, USA deaths annually from or hepatocellular active compound. Tel.:+1 415 476 2777; carcinoma [1]. The majority of hepatocellular E-mail: marion.peters@ carcinoma worldwide is associated with chronic Overview of the market ucsf.edu HBV infection. After exposure of neonates at There are currently six licensed in the USA birth (perinatally), chronic infection is the rule. for the treatment of chronic hepatitis B infection. Few patients (<5%) infected as adults develop Of these six drugs, four are oral antiviral agents chronic infection unless the patient is immuno- (three analogues and one nucleotide compromised. Persistent infection occurs in analogue) and two are immunomodulatory 20% of adults with HIV who become infected agents (Table 1). and is an important cause of morbidity and LAM (Epivir®, GlaxoSmithKline) is a syn- mortality in these co-infected patients [2]. The thetic dideoxy analogue of cytidine that was of HBV in HIV-infected individuals approved by the FDA in 1995 for the treat- varies from 5–10% in the USA and Europe [3] ment of HIV infection at a dosage of to up to 20–30% in Asia and parts of sub-Saha- 300 mg/day in one or two divided doses. In ran Africa [4]. for HBV has expanded 1998, LAM was approved at a dosage of considerably over the last decade. Initially, only 100 mg/day for the treatment of chronic (LAM) monotherapy or inter- hepatitis B under a different trade name, Epi- feron-α were available. Many patients were not vir-HBV®. dipivoxil (ADV; Hep- candidates for and resistance to lam- sera®, ) was the first acyclic ivudine develops at a rate of approximately nucleotide phosphonate approved for the treat- 20% per year (60% at 4 years) [5]. The majority ment of chronic hepatitis B in 2001. of HIV and HBV co-infected patients (90%) (Baraclude™, Bristol-Myers Squibb, NY, USA) treated with LAM as part of antiretroviral ther- and (Tyzeka™, Idenix Pharmaceu- apy develop resistance to HBV after 4 years of ticals, MA, USA) are nucleoside analogues with therapy [6]. selective activity against HBV that were FDA Tenofovir disoproxil fumarate (TDF) is an approved in 2005 and 2006, respectively. Keywords: hepatitis B virus, oral of tenofovir. Tenofovir is an acyclic Interferon-α2b (Intron® A, Schering Corp., HIV, nucleotide analogue, nucleotide analogue of adenosine monophos- NJ, USA) and pegylated (peg)interferon-α2a pharmacokinetics, PMPA, ® tenofovir disoproxil fumarate phate with activity against HIV-1 and HBV [7,8]. (Pegasys , Roche, Basel, Switzerland) are two TDF (Viread®, Gilead Sciences, Inc., CA, USA) biological response modifiers that are licensed part of is approved by the US FDA for the treatment of for the treatment of chronic hepatitis B infec- HIV-1 infection in combination with other tion. Interferon-α2b must be administered by

10.2217/14750708.4.2.141 © 2007 Future Medicine Ltd ISSN 1475-0708 Therapy (2007) 4(2), 141–151 141 DRUG EVALUATION – Quan & Peters

Table 1. Indications of various antiviral drugs. Drug Indication Adefovir dipivoxil (Hepsera®) Chronic hepatitis B infection Entecavir (Baraclude™) Chronic hepatitis B infection Interferon-α2b (Intron® A) AIDS-related Kaposi’s sarcoma Chronic hepatitis B infection Chronic infection Condylomata acuminata Follicular lymphoma Hairy cell leukemia Malignant melanoma Lamivudine (Epivir®) HIV infection Lamivudine (Epivir-HBV®) Chronic hepatitis infection Peginterferon-α2a (Pegasys®) Chronic hepatitis B infection Chronic hepatitis C infection Telbivudine (Tyzeka™) Chronic hepatitis B infection TDF (Viread®) HIV infection TDF + (Truvada®) HIV infection TDF + emtricitabine + (Atripla™) HIV infection TDF: Tenofovir disoproxil fumarate.

daily injection, while peginterferon-α2a is improve oral , a prodrug was administered weekly. The interferon prepara- developed to mask the negative charges of the tions are associated with significant adverse phosphonate group with lipophilic promoie- effects such as marrow suppression, neu- ties. The addition of these two promoieties not ropsychiatric and autoimmune disorders during only increases absorption from the gastro- therapy [9]. intestinal tract, but also increases the potency by 50-fold [7]. Tenofovir disoproxil, corre- Introduction to TDF sponding to the bis(isopropyloxycarbony- TDF (formerly GS-4331-05) is a prodrug of loxymethyl) ester of PMPA, or bis(POC)PMPA tenofovir. Tenofovir is a nucleotide analogue of is formulated as the salt, TDF or 9-[(R)-2- adenosine monophosphate that inhibits HIV [[bis[[isopropoxycarbonyl)oxy]methoxy]phos- reverse transcriptase (HIV DNA polymerase) phinyl]methoxy]propyl] fumarate as well as HBV reverse transcriptase (HBV (bis[POC]PMPA). Following oral administra- DNA polymerase). Tenofovir belongs to the tion, TDF undergoes esterase hydrolysis, which group of acyclic nucleoside , removes the two ester groups to yield tenofovir which includes ADV and (Vistide®, [10,11]. The molecular formula is Gilead Sciences). TDF is used for the treat- C19H30N5O10P • C4H4O4 and the molecular ment of HIV infection in combination with weight is 635.52. other antiretroviral agents, while adefovir dipivoxil (ADV) is used for the treatment of Pharmacodynamics chronic hepatitis B infection. Cidofovir is The phosphorylation of nucleoside analogues administered intravenously for the treatment can be a rate-limiting step. Tenofovir, and of (CMV) retinitis infection other nucleotide analogues such as adefovir in AIDS patients. Table 2 lists the spectrum of and cidofovir, do not require this initial phos- activity for various antiviral drugs. phorylation. Tenofovir is rapidly taken up by cells and phosphorylated in two steps by ade- Chemistry nylate kinase or in one step by 5-phosphoribo- Tenofovir (9-[-(R)-2-phosphonomethoxy pro- syl 1-pyrophosphate (PRPP) synthetase to pyl]adenine [PMPA]) is an acyclic nucleotide form the active diphosphate form [12–14]. Fol- analogue of adenosine monophosphate. Teno- lowing phosphorylation, tenofovir diphos- fovir has a low oral bioavailability owing to the phate is incorporated by reverse transcriptase ionic nature of the phosphonate group. To into the nascent chain of viral DNA [7,8]. Since

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Table 2. Antiviral spectrum of activity. Virus Adefovir Tenofovir Lamivudine Entecavir Telbivudine Herpesvirus HSV Active Inactive Inactive Inactive Inactive CMV Active Inactive Inactive Inactive Inactive VZV Active Inactive Inactive Inactive Inactive HIV-1 Active Active Active Inactive Inactive Hepadnavirus HBV Active Active Active Active Active HBV-YMDD Active Active Inactive Less active Inactive mutant CMV: Cytomegalovirus; HBV: Hepatitis B virus; HSV: virus; VZV: Varicella-zoster virus; YMDD: Tyrosine––aspartate–aspartate.

tenofovir diphosphate lacks the 3´ hydroxyl The susceptibility of HBV strains resistant to group, additional cannot be LAM (rtL180M and M204V) and adefovir attached, resulting in chain termination and (rtN236T) to tenofovir was evaluated in Huh7 inhibition of . and HepG2 cells. There was a 3.4-fold resist- The pharmacodynamics and viral dynamics of ance (mutant IC50/wild type IC50) in HBV TDF in HIV-infected patients has been exten- strains with the rtL180M and M204V muta- sively studied and are reviewed elsewhere [12,15,16]. tions, and a 4.5-fold resistance with the N236T For a more thorough discussion on the use of mutation. In a constructed strain with the triple TDF for the treatment of HIV-1 infection, mutation (L180M, M204V and N236T), there see [17–20]. was a 4.4-fold resistance to tenofovir compared There are limited pharmacodynamic and with the wild-type virus. While these mutations hepatitis B viral kinetic data in patients with HBV confer resistance to LAM and adefovir, tenofo- infection. Table 3 summarizes some of the key vir still exhibits antiviral activity in vitro [5]. publications evaluating TDF in the setting of TDF inhibits viral replication in patients with hepatitis B infection. Tenofovir has antiviral activ- LAM-resistant HBV mutants. There was a ity against duck hepatitis B (DHV) in vitro and mean decline of 1.37 ± 0.51 log copies/ml after woodchuck hepatitis B (WHV) in vivo [21,22]. In 4 weeks and 4.95 ± 0.9 log copies/ml after addition, tenofovir has potent antiviral activity 24 weeks when tenofovir 300 mg once daily both in vitro and in vivo against wild-type HBV, was added to existing therapy. The median as well as LAM-resistant mutants [23–27]. Tenofovir effectiveness of blocking viral replication was was found to exhibit long-lasting anti-HBV activ- 93%. The half-life of free virus and infected ity in cell culture, with a 50% effective concentra- hepatocytes was found to be approximately tion (EC50) of 0.03 ± 0.02 µg/ml with continuous 21 h and 5.7 days, respectively [29]. exposure, increasing to 6.5 ± 1.0 and The suppressive activity of TDF was com- 0.8 ± 0.1 µg/ml after just 24 and 48 h of exposure, pared with ADV in 109 patients with LAM respectively [23]. resistance. TDF alone or combined with LAM HBV dynamics were evaluated in 28 resulted in a 3.65 ± 1.75 log10 reduction in HIV–HBV-co-infected patients treated with HBV DNA at 6 months compared with a TDF. The HBV DNA declined by a 1.94 ± 1.98 log10 reduction with ADV. A total mean of 4.6 log copies/ml during a mean of of 63% of patients administered TDF had a 71 weeks of therapy. HBV DNA levels fell below greater than 3-log reduction in HBV DNA lev- the detection limit (200 copies/ml) in 21 out of els compared with 28% of ADV-treated 28 patients after a median of 272 days. Concom- patients [30]. The antiviral effects of TDF were itant LAM therapy did not effect the time taken compared with ADV in patients with high for the HBV DNA levels to become undetecta- HBV DNA levels (>6 log10 copies/ml) and gen- ble. Inhibition of viral replication was associated otypic resistance to LAM. TDF resulted in a with a decrease in alanine aminotransferase more rapid and greater decline in HBV DNA (ALT) levels [28]. levels compared with ADV (-5.5 vs

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Table 3. Summary of tenofovir studies in hepatitis B virus infection. Effect Studied Study design Key findings Ref.

Anti-HBV activity in cell culture In vitro study of lamivudine, adefovir, Adefovir and tenofovir retained significant antiviral [23] tenofovir, and activity when the cells were exposed for only a short sensitivity in HepG2 2.2.15 cells time In vitro susceptibility of In vitro study of drug sensitivity of Lamivudine-resistant HBV with rtL180M and [59] lamivudine-resistant HBV to lamivudine-resistant HBV in HepG2 rtM204V mutations had 2.85- and 3.3-fold increase

adefovir and tenofovir cells in IC50 with adefovir and tenofovir, respectively. Adefovir and tenofovir have activity against lamivudine-resistant strains of HBV

Intracellular and In vitro study in HepG2 cells Tenofovir EC50 was 1 µM, TDF EC50 was 0.02 µM [7] activity against HBV and intracellular half-life was 95 h Susceptibility of antivirals to HBV In vitro study of susceptibility of Triple mutant showed a sixfold decreased [5] strains resistant to lamivudine tenofovir to HBV with rtL180M, susceptibility to adefovir and fourfold decrease to and adefovir M204V and/or N236T mutations tenofovir Pharmacokinetics of tenofovir in Single-dose pharmacokinetic study in Tenofovir pharmacokinetics are not altered in [33] patients with hepatic patients with hepatic insufficiency due patients with mild or moderate hepatic insufficiency impairment to non-HBV/HCV etiologies

Efficacy of tenofovir in HIV–HBV- A 24-week pilot study of six patients HBV DNA load decreased by 3.1 and 4.3 log10 [60] co-infected patients failing who failed lamivudine and copies/ml by 12 and 24 weeks, respectively interferon-α and lamivudine interferon-α Comparison of adefovir and Lamivudine-resistant patients (n = 53) HBV DNA levels declined more rapidly and ALT levels [31] tenofovir in lamivudine-resistant with HBV DNA > 106 copies/ml treated normalized more rapidly in tenofovir-treated patients HBV infection with adefovir or tenofovir

Efficacy of tenofovir in HBV–HIV- Retrospective, multicenter cohort study Median reduction of serum HBV DNA was 4.56 log10 [35]

co-infected patients of HBsAg-positive/HIV-coinfected copies/ml in HBeAg-positive patients and 2.53 log10 patients who received tenofovir as part copies/ml in HBeAg-negative patients of an antiretroviral regimen HBV dynamics in patients with Chronic hepatitis B patients (n = 11) TDF treatment resulted in a HBV DNA decrease of [29] lamivudine-resistant HBV with breakthrough HBV DNA on 2.54-log after 4 weeks and 4.95-log after 24 weeks. mutants lamivudine received TDF 300 mg/day TDF blocked HBV replication in patients with while maintaining existing therapy lamivudine-resistant mutants HBV dynamics in HIV–HBV-co- Prospective, open-label study in HBV DNA load declined by mean of 4.6 log [28] infected patients HIV–HBV-co-infected patients (n = 28) copies/ml during a mean of 71 weeks. Baseline starting TDF-containing regimen to factors associated with rapid initial decline of HBV assess long-term HBV dynamics DNA include high HBV load, positive HBeAg and YMDD mutations. Factors associated with increasing time to reach HBV–DNA levels <200 copies/ml include high HBV load and positive HBeAg Comparison of tenofovir and Case series of patients with chronic Mean reduction of HBV viral load greater with TDF [30] adefovir in patients with hepatitis B (n = 109) with viral than ADV at 6 and 12 months lamivudine-resistant HBV breakthrough on lamivudine given TDF or ADV for 6 months or longer

Comparison of noninferiority of Randomized controlled trial of 52 The mean time-weighted average change in DAVG48 [27]

TDF compared with ADV in HBV–HIV-co-infected individuals, 94% was -4.44 log10 copies/ml for TDF and -3.21 log10 lamivudine-resistant HBV and lamivudine resistant given TDF or ADV copies/ml for ADV HIV patients for 96 weeks Outcome of HIV–HBV-co- Retrospective analysis of 79 HIV–HBV Undetectable plasma HIV-RNA levels (OR: 4.58; [61] infected patients treated with co-infected patients treated with 95%CI:1.25–16.78) and greater CD4 gains while on HAART including anti-HBV lamivudine (37%) or lamivudine and HAART (OR: 1.003; 95% CI: 1.000–1.006) were active drugs tenofovir (58%) associated with undetectable serum HBV DNA at end of follow-up

ADV: Adefovir dipivoxil; ALT: Alanine aminotransferase; CI: Confidence interval; DAVG48: Serum HBV DNA from baseline to week 48; HAART: Highly active antiretroviral therapy; HBV: Hepatitis B virus; HCV: ; OR: Odds ratio; TDF: Tenofovir disoproxil fumarate; YMDD: Tyrosine–methionine–aspartate–aspartate.

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-2.8 log10 copies/ml at 48 weeks, respectively). 164 ± 51 ml/h/kg, while the calculated creati- No differences in viral response was found nine clearance (CLCR) was 81.2±12.3ml/h/kg. between HBV-infected and HIV–HBV-co- The large CLR relative to glomerular filtration infected patients [31]. In a randomized, control- suggests that PMPA undergoes active tubular led trial of TDF and ADV in patients co- secretion by the kidneys [15]. infected with HIV and HBV, TDF has been Tenofovir is eliminated primarily by the kid- shown to be efficacious after 48 weeks of ther- neys via glomerular filtration and active tubular apy in LAM-resistant and wild-type HBV [27]. secretion. Following multiple oral dosing, The mean time-weighted average change in approximately 32% of the dose is recovered in serum HBV DNA from baseline to week 48 the urine over 24 h [32]. The elimination half- (DAVG48) was -4.44 log10 copies/ml for TDF life is approximately 12–18 h. The elimination and -3.21 log10 copies/ml for ADV. of tenofovir is altered in patients with renal dys- function. The clearance of tenofovir decreased, Pharmacokinetics & metabolism while the Cmax and AUC0-∞ increased in The majority of the available data on the pharma- patients with declining renal function (Table 5). cokinetics of tenofovir are based on clinical trials Thus, the dosage of TDF should be adjusted in in patients infected with HIV-1. The oral bioa- patients with renal dysfunction (Table 6). vailability is approximately 21–25% in the fasted The pharmacokinetics of TDF were evalu- state and 34–39% in the fed state [16]. The phar- ated in healthy subjects with hepatic insuffi- macokinetics are proportional over the dose range ciency due to non-HBV/HCV etiologies. of 75 to 600 mg, and are not affected with multi- Following a single 300-mg dose, the pharma- ple dosing. The apparent volume of distribution cokinetic parameters evaluated were not signif- is approximately 1.3 l/kg and the serum icantly altered in patients with mild or severe binding is approximately 7.2%. Table 4 summa- hepatic impairment (Table 7) [33]. No dosage rizes the key tenofovir pharmacokinetic parame- adjustment is necessary in patients with ters. The pharmacokinetics of an intravenous hepatic impairment. formulation of PMPA was evaluated in 20 HIV- infected adults. Following a single dose, the max- Clinical efficacy imal serum concentration (Cmax) was dose pro- TDF 300 mg, while licensed for the treatment portional at 2.7 ± 0.09 and 9.1 ± 2.1 µg/ml in of HIV-1, has been shown in one randomized, the 1 and 3 mg/kg doses, respectively. The mean controlled trial and a number of case series to AUC was also dose proportional at 4.41 ± 0.93 be active in mono- and co-infected HBV and 16.6 ± 6.05 µg·h/ml in the 1 and 3 mg/kg patients. A prospective, randomized, double- groups, respectively. The renal clearance (CLR) in blind, placebo-controlled trial of daily ADV the 1 and 3 mg/kg groups was 161 ± 60.6 and 10 mg versus TDF 300 mg was performed in

Table 4. Tenofovir pharmacokinetic parameters. Pharmacokinetic parameter Value Bioavailability (%) ~25 (fasted) ~40 (fed) Volume of distribution (l/kg) 1.3 ± 0.6 Protein binding (%) <0.7% (plasma) 7.2 (serum)

Tmax (h) 1.0 ± 0.4 (single dose, fasted)

Cmax (mg/ml) 296 ± 90 (single dose, fasted) 326 ± 119 (multiple dose, fed) Half-life (h) 17

CLrenal (ml/min) 243.5 ± 33.3 CL/F (ml/min) 1043 ± 115.4 AUC (ng • h/ml) 2287 ± 685 (single dose, fasted) 3324 ± 1370 (multiple dose, fed)

CLrenal: Renal clearance; Cmax: Maximum serum concentration; F: Oral bioavailability; Tmax: Time to Cmax.

futurefuture sciencescience groupgroup www.futuremedicine.com 145 DRUG EVALUATION – Quan & Peters

Table 5. Pharmacokinetic parameters in patients with renal dysfunction. Pharmacokinetic Baseline creatinine clearance (ml/min) parameter >80 50–80 30–49 12–29

Cmax (ng/ml) 335.4 ± 31.8 330.4 ± 61.0 372.1 ± 156.1 601.6 ± 185.3

AUC0-∞ (ng • h/ml) 2184.5 ± 257.4 3063.8 ± 927.0 6008.5 ± 2504.7 15984.7 ± 7223.0 CL/F (ml/min) 1043.7 ± 115.4 807.7 ± 279.2 444.4 ± 209.8 177.0 ± 97.1

CLrenal (ml/min) 243.5 ± 33.3 186.6 ± 27.5 100.6 ± 27.5 43.0 ± 31.2

AUC: Area under the curve to infinite time; CL: Clearance; CLrenal: Renal clearance; Cmax: Maximum serum concentration; F: Oral bioavailability.

patients with HBV and HIV co-infection, on to LAM. Undetectable HBV DNA less than stable antiretroviral therapy, with serum HBV 1000 copies/ml was not different between the DNA of at least 100,000 copies/ml and two strategies and was achieved in 19 out of plasma HIV-1 RNA of 10,000 copies/ml or 25 (76%) patients receiving TDF plus LAM less. Of the 52 patients randomized, the and in 42 out of 50 (84%) receiving TDF majority had compensated liver disease and alone (p = 0.53). Similar loss of HBeAg was were hepatitis B e- (HBeAg) positive, observed in nine out of 25 (36%) patients on with LAM resistance. The mean time- TDF plus lamivudine and in 12 out of 50 weighted average change in DAVG48 was (24%) patients on TDF (p = 0.29). HBsAg loss -4.44 log10 copies/ml for TDF and -3.21 log10 was found in one out of 25 (4%) and three out copies/ml for ADV. There was no difference in of 50 (6%) patients, respectively. Thus, full toxicity between the two treatment arms, with HBV DNA suppression was achieved in the 11 subjects (five ADV and six TDF) experi- majority of patients, independent of whether encing ‘flares’ or elevations of serum ALT on they started combination anti-HBV therapy or treatment without adverse events in these well sequential therapy over a median treatment compensated patients. Both drugs were safe period of 116 weeks [36]. No randomized, con- and efficacious for patients co-infected with trolled studies of combination therapy are HBV and HIV. available as yet. TDF has been shown in case studies to have anti-HBV activity in both HBV mono- and Safety & tolerability co-infected subjects [31] and to rescue HBV- Most of the clinical safety and tolerability infected patients who have failed treatment experience with TDF is derived from its use with LAM and ADV [34]. In a recent retrospec- for the treatment of HIV infection in conjunc- tive study of 65 HIV–HBV-co-infected tion with other antiretrovirals. TDF is gener- patients treated with TDF 300 mg/day, 80% ally well tolerated in this patient population. were HBeAg positive at entry and serum HBV Commonly reported adverse events include DNA decreased by 4.56 log10 copies/ml on asthenia, pain, nausea, diarrhea, flatulence and TDF [35]. Another cohort series of HBV–HIV- dizziness. Nephrotoxicity is a dose-limiting co-infected patients starting an antiretroviral toxicity that is associated with the use of cido- regimen compared those starting TDF plus fovir and high-dose ADV [37–39]. Milder forms LAM with those starting TDF as the only of injury without cellular necrosis or apopto- active HBV polymerase inhibitor subsequent sis, such as Fanconi-like syndrome and distal

Table 6. Dosage adjustment for patients with renal dysfunction. Creatinine clearance (ml/min) Hemodialysis ≥50 30–49 10–29 TDF 300 mg Every 24 h Every 48 h Twice weekly Every 7 days or after a total of ~12 h of dialysis TDF 300 mg/ Every 24 h Every 48 h Not recommended Not recommended emtricitabine 200 mg TDF: Tenofovir disoproxil fumarate.

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Table 7. Pharmacokinetic parameters in patients with hepatic impairment. Pharmacokinetic Control Moderate impairment Severe impairment parameter (Child’s class A) (Child’s class B) (Child’s class C)

Cmax (ng/ml) 223 (120–353) 289 (163–552) 305 (210–440)

Tmax (h) 1.00 (0.5–1.00) 1.00 (0.5–1.00) 0.75 (0.5–2.0) Half-life (h) 17.3 (10.1–23.2) 17.0 (13.1–19.3) 18.0 (9.74–26.5)

AUC 0-∞ (ng • h/ml) 2050 (1090–4060) 2310 (1220–4340) 2740 (1460–5230)

AUC 0-∞: Area under the curve to infinite time; Cmax: Maximum serum concentration; Tmax: Time to Cmax.

tubular acidosis, have been associated with been implicated in the development of dose- acyclic nucleotide phosphonates (e.g., ADV limiting toxicities, such as peripheral neuropa- and cidofovir) and . Increased cellular thy, pancreatitis, myopathy, lactic acidosis and uptake mediated by human renal organic steatosis. Tenofovir is a weak inhibitor of transporter (hOAT)1 is believed to cause prox- human DNA polymerase-γ and is incorpo- imal tubular dysfunction. This has been shown rated into nascent mitochondrial DNA less to occur in vitro with cidofovir and ADV, but efficiently than other nucleoside reverse tran- not tenofovir [40]. Unlike other nucleotide scriptase inhibitors [48]. Tenofovir is less cyto- phosphonates, TDF appears to have a low toxic compared with other nucleoside nephrotoxic potential and rarely causes serious analogues, with weak antiproliferative effects renal impairment [41]. In a 3-year on human liver and cells [40]. comparing TDF with in treatment- The co-administration of TDF and didanos- naive patients, the renal safety profile (serum ine has been associated with the development creatinine and serum phosphorus levels) was of pancreatitis [49,50]. The combination of similar. No patients experienced grade 4 hypo- TDF and may lead to increased phosphatemia (phosphorus <1 mg/dl) or ele- toxicity due to the drug–drug interaction vated serum creatinine levels over 6 mg/dl. between these two agents. There is increased The of glycosuria and proteinuria didanosine exposure when co-administered were also similar [42,43]. A small but statistically with tenofovir [51]. Three subjects in one study significant rise in the mean time-weighted developed pancreatitis, two of whom received change from baseline in anion-gap concomitant didanosine (ddI) [27]. (0.78 mmol/l) and a decrease in the creatinine The use of tenofovir in patients with chronic clearance (-6.8 ml/min) was noted in patients hepatitis B infection with or without HIV-co- receiving TDF-based highly active antiretrovi- infection is generally well tolerated. There were ral therapy (HAART) compared with non- no changes in renal function, levels TDF-based HAART [44]. In the randomized, or serum creatinine reported [29,31]. However, controlled study of ADV and TDF, transient headache and decreased urine volume was mild hypophosphatemia was noted but no ele- reported in one study [33]. The number of vations in serum creatinine of at least patients in these studies were small, making 0.5 mg/dl above baseline were noted, nor interpretation of the actual incidence of changes in serum creatinine in either arm over adverse events difficult. There has been one the course of the study [27]. However, tenofo- report of a Q215S mutation in the DNA vir-induced proximal tubulopathies manifest- polymerase with resistance to TDF [52]. ing as normoglycemic glycosuria, mild Decreased bone density has emerged proteinuria and hypophosphatemia have been as a long-term consequence among HIV- reported [45,46]. Tenofovir-related nephrotoxic- infected patients [53]. Bone loss has been possi- ity typically manifests after approximately bly linked to the use of highly active antiretro- 20 weeks of therapy, but resolves after a viral therapy, particularly those utilizing median of 4.7 weeks following discontinuation inhibitors [53–55]. Metabolic bone dis- of the drug [47]. orders have been observed in animals given Human DNA polymerase-γ is the high-dose tenofovir [56,57] and in humans [42]. that is responsible for replication of mitochon- TDF has been associated with a decrease in drial DNA. Inhibition of DNA polymerase-γ bone mineral density in children, which may sta- by nucleoside and nucleotide analogues has bilize after 24 weeks. Markers of bone turnover,

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such as calcium , are elevated, indi- not been shown as yet in in vivo or in vitro cating that TDF may increase bone resorption. studies. It is important, when changing antiret- Decreases in viral load and young age are cor- roviral regimens, to continue agents with anti- related with reduced bone mineral density, HBV activity as there is a risk of ‘flares’ or suggesting that younger treatment responders marked elevation in transaminases in an are at greater risk of tenofovir-related bone immunocompetent patient. toxicity [58]. Regulatory affairs Expert commentary TDF was approved by the FDA in October Addition of TDF to the armamentarium for 2001 for the treatment of HIV infection. The the treatment of HBV infection will be of European Commission granted marketing great value. Resistance to LAM leads to cross authorization for TDF in 2002 for all 15 mem- resistance to emtricitabine and telbivudine ber states of the EU. In addition, TDF was and requires an increased dosage of entecavir. granted marketing approval in Australia, Ice- Adefovir resistance begins to emerge after land and Norway in 2002. TDF is currently 2 years of therapy, and while there is only one undergoing Phase III trials for the management reported case of TDF resistance as yet, more of chronic hepatitis B. may emerge with time. TDF has been shown Tr uvad a ® is a fixed-dose combination of to be successful as de novo therapy as well as in TDF and emtricitabine (Emtriva®) that was rescuing nucleoside-resistant and decompen- approved for use in the USA in August 2004 sated HBV disease. We await randomized, and in Europe in 2005 for the treatment of controlled studies in HBV mono-infected HIV-1 infection in adults. Atripla™ (Bristol- patients and expect that approval for HBV will Myers Squibb and Gilead Sciences) is a combi- follow after completion of these studies. nation product of efavirenz, emtricitabine, and When treating HIV–HBV-co-infected TDF that was approved in July 2006. It is the patients, recent Department of Health and first single-tablet, once-daily regimen approved Human Services (DHHS) [101] and other expert for the treatment of HIV infection alone or in panel guidelines recommend treating all such combination with other antiretrovirals. HIV–HBV-co-infected patients with two active Although not approved by the FDA for the HBV drugs when HIV or both require treatment of chronic hepatitis B, TDF or the treatment. In fact, the panel recommended combination product of TDF and emtricitab- TDF and emtricitabine (or LAM) as the pre- ine (Truvada) can be used for the treatment of ferred agents, although TDF does not have chronic HBV infection, and are logical choices FDA approval for HBV management as yet. as part of an antiretroviral regimen in patients Co-infected patients who require therapy for with HIV–HBV co-infection. HBV but not HIV should not receive any HBV with anti-HIV activity; instead, Disclosure they should be treated with agents with HBV Marion G Peters has received honoraria from Gilead Sci- activity alone, such as entecavir, interferon, tel- ences and Roche, research support from Achillion Phar- bivudine or ADV. There is a theoretical risk of maceuticals, and served as an advisor for Novartis, Idenix HIV resistance to ADV 10 mg/day, but this has and Bristol-Myers Squibb.

Executive summary

• Tenofovir disoproxil fumarate (TDF) was the first nucleotide analogue approved by the US FDA for the treatment of HIV-1 infection.

• TDF is active against HIV, hepatitis B virus (HBV) and lamivudine-resistant strains of HBV.

• Tenofovir is eliminated by glomerular filtration and active tubular secretion. The dosage of TDF must be adjusted in the setting of renal dysfunction.

• The pharmacokinetics of TDF are not significantly altered in mild-to-moderate liver disease. No dosage adjustment is necessary in patients with hepatic dysfunction.

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