Tenofovir disoproxil fumarate–emtricitabine coformulation for once-daily dual NRTI backboneRosa María Muñoz de Benito† and Jose Ramón Arribas López
†Author for correspondenceHospital La Paz, Unidad de HIV, Paseo de La Castellana, 261, 28046 Madrid, SpainTel.: +34 917 277 099Fax: +34 917 290 [email protected]
Truvada® is the coformulation of tenofovir disoproxil fumarate (TDF; 300 mg) and emtricitabine (FTC; 200 mg) in a single tablet, providing the nucleotide backbone for once-daily dosing, as a component of highly active antiretroviral therapy (HAART). TDF (the bioavailable prodrug of tenofovir) is hydrolyzed to tenofovir intracellularly and phosphorylated to the active metabolite, tenofovir diphosphate. Tenofovir is a nucleotide analog of deoxyadenosine monophosphate, with activity against HIV-1, -2 and hepatitis B virus. FTC, the fluorinated derivative of lamivudine, is an analog of deoxycitidine, active against HIV-1, -2 and hepatitis B virus. Their long half-lives in plasma and in peripheral blood mononuclear cells allow once-daily dosing. Both are eliminated renally. Resistance mutation K65R is selected for by tenofovir and confers a two- to fourfold reduced susceptibility to this drug. The incidence of K65R is low (3%) and has not been observed in clinical trials with the concomitant use of tenofovir and FTC. FTC selects for M184V mutation less frequently than lamivudine. Tenofovir drug interactions include increased exposure to didanosine and inferior immmune recovery that preclude their concomitant use. Boosted protease inhibitors increase exposure to tenofovir without dose adjustment required. FTC has no significant drug interactions. They are not metabolized by cytochrome P450, which confers little potential for interactions with drugs metabolized by these enzymes. As tenofovir and FTC are renally eliminated, drugs eliminated by tubular secretion must be avoided. Both antiretrovirals, as individual agents and in coadministration have evidenced antiviral potency in clinical trials. Pivotal study 934 evidenced superior efficacy of the combination TDF/FTC/efavirenz (EFV) versus zidovudine/FTC/EFV. The toxicity profile of tenofovir and FTC has been extensively studied. Lipid profile is more favorable with tenofovir than thymidine analog. Tenofovir requires surveillance of glomerular filtration rate and dosing interval adjustment when creatinine clearance is less than 50 ml/min and avoidance less than 30 ml/min. Fat loss is less likely with tenofovir than with thymidine analog. Clinical trials have assessed the performance of the coformulation of TDFand FTC.
Expert Rev. Anti Infect. Ther. 4(4), 523–535 (2006)
The purpose of antiretroviral treatment(ART) is the long-term suppression of viralreplication. Virological control preventsdisease progression, prolongs survival andimproves quality of life. Currently, highlyactive antiretroviral therapy (HAART) asrecommended by international guidelines,consists of a regimen including two nucleoside
reverse-transcriptase inhibitors (NRTIs) pluseither a non-nucleoside reverse-transcriptaseinhibitor (NNRTI) or a protease inhibitor (PI).
Selection of the appropriate antiretroviralregimen must be guided not only by theintrinsic potency of its components, but alsoby those properties that render it more suitablefor the individual patient, therefore, favoring
compliance. Recently, the first two dual-NRTIs coformulatedas one pill once daily (Truvada®, manufactured by GileadSciences) and Kivexa™/Epzicom™ (manufactured by Glaxo-SmithKline) have been launched, raising the interest of bothpatients and healthcare providers. This article offers an over-view on Truvada, the fixed-dose combination of tenofovir diso-proxil fumarate (TDF) and emtricitabine (FTC). So far, thebackbone combination of TDF and FTC has been assessed intwo clinical trials (GS 934 and ABT 418), on which theauthors shall focus. Besides, this article will review those studieswhere each individual antiretroviral has been used.
Current statusViral response to ARTs has improved with available combina-tions as demonstrated in a recent analysis where the proportionof naive patients achieving HIV RNA less than 50 copies/ml at48 weeks was 57%, compared with a proportion of 45%observed in 2001 [1]. A diversity of characteristics such as druginteractions, adverse events, pill burden and complexity of theregimen (dosing frequency and food restrictions) may havecritical influence on the outcome of antiretroviral therapy. Theavailability of drugs that involve a low pill burden and once-daily dosing is an important aspect to improve the effectivenessof HAART.
Nucleoside/nucleotide analogs for once-daily dosagepresently available are lamivudine (3TC), FTC, abacavir(ABC), didanosine (ddI) and TDF. Appropriate dual-NRTIcombinations for once-daily dosing are 3TC plus ddI, FTCplus ddI, tenofovir plus 3TC, tenofovir plus FTC, ABC plus3TC or ABC plus FTC. On the other hand, combinations thatare not recommended, after unfavorable outcomes reported innaive patients, are 3TC plus ABC plus tenofovir [2], and 3TCplus tenofovir plus ddI in triple NRTI regimens [3].
ABC/3TC (Kivexa or Epzicom) is currently the only alterna-tive to Truvada as coformulation of two NRTIs for once-dailydosing in single-pill combination.
Introduction to the compoundTDF and FTC have been coformulated to provide a singletablet dual-NRTI backbone for once-daily dosing [4]. Truvadais the oral coformulation of TDF (300 mg) and FTC (200 mg),approved for once-daily administration in association withother antiretroviral agents.
Study FTC-114 was a 21-day, randomized, three-waycross-over study to evaluate the steady-state pharmaco-kinetics of FTC (200 mg capsules administered once daily for7 days) and tenofovir (administered as TDF tablets 300 mgonce daily for 7 days) when administered alone and togetherin healthy volunteers. FTC had no effect on the pharmaco-kinetics of tenofovir. TDF also had no clinically significanteffect on the pharmacokinetics of FTC. Although the mini-mum concentration (Cmin) of FTC increased by approxi-mately 20% with TDF coadministration, area under thecurves (AUCs) and maximum concentration (Cmax) were notaffected [5].
Study GS-US-104-0172 was a Phase I 28-day, randomized,four-way crossover, pharmacokinetic study in healthy volun-teers. The study was designed to evaluate the bioequivalence ofthe TDF/FTC tablet compared with TDF and FTC adminis-tered concurrently, and the effect of food (high-fat meal andlight meal) on pharmacokinetics.
The ratios for both the rate and extent (Cmax and AUC) oftenofovir bioavailability after its administration as TDF or asthe combination tablet demonstrated bioequivalence of teno-fovir between the two treatments. Similarly, bioequivalencewas demonstrated between the FTC capsule and theTDF/FTC tablet. There are no data from clinical trials spe-cific to the administration of coformulated tenofovir/FTC incombination therapy.
Chemical propertiesPharmacodynamic profileTenofovir is an acyclic nucleotide (monophosphate nucleo-side) analog of deoxyadenosine monophosphate with a molec-ular weight of 287.2. Its prodrug, TDF, is orally absorbed andhydrolyzed to tenofovir, which is phosphorylated intra-cellularly to tenofovir diphosphate (PMPApp). The activemetabolite competes with natural nucleoside deoxyadenosine5´-triphosphate for incorporation by HIV reversetranscriptase (RT), and causes viral transcription chain termi-nation. Tenofovir has in vitro activity against HIV-1 and -2retroviruses and hepadnavirus.
FTC is a synthetic analog of the pyrimidine nucleoside2´-deoxycytidine with a molecular weight of 247.25. Thisfluorinated derivative of 3TC is more readily incorporated byHIV RT into viral DNA, which has been postulated to justifyits higher in vitro potency [6]. Once inside the cell it is phos-phorylated to the active metabolite FTC 5´-triphosphate(FTCTP), which inhibits HIV-1 and -2 RT and DNApolymerase of hepatitis B virus (HBV).
FTC and tenofovir undergo phosphorylation to their activemetabolites. FTC and tenofovir have long half-lives in plasma(10 and 17 h, respectively) and in peripheral blood mono-nuclear cells (PBMCs) (39 and 60 h) [7,8]. Their prolongedintracellular life is a relevant issue, as viral activity and toxicityare most accurately predicted by intracellular concentration
Incubation of both drugs results in higher phosphorylationrate and active metabolite concentration for each individualcomponent [9]. Increased phosphorylation of the combinationcorrelates with synergistic activity against HIV in vitro, bothwild-type and K65R mutant, and a higher activity of tenofoviragainst M184 mutant in the presence of FTC [10].
The coformulation of FTC and tenofovir has demonstratedbioequivalence to each drug in individual formulation [4].
Antiviral activityTDF concentration required for 50% inhibition (IC50) of HIVwas 0.005 µmol/l in PBMCs. Intracellular uptake of TDF ismore rapid and reaches a higher intracellular concentrationthan tenofovir [11].
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FTC IC50 for clinical isolates of HIV is0.002–0.008 µmol/l [12]. Its potency is four- to tenfold that of3TC in vitro and in vivo as monotherapy [6]. However, thishigher in vitro potency has not translated into superior efficacy incombination therapy in clinical trials.
Cytotoxic effectsMerely a weak interaction exists between PMPApp and humanDNA polymerase, and in an in vitro model tenofovir does notappear to inhibit mitochondrial synthesis to the same extent asother NRTIs [13]. Mitochondrial DNA is not affected inHepG2 cells after incubation with FTC [14].
Resistance mutations K65R
HIV-1 isolates with reduced susceptibility to tenofovir havebeen selected in vitro. These viruses expressed K65R sub-stitution in RT and demonstrated a two- to fourfold reduc-tion in susceptibility to tenofovir. Cross-resistance exists withABC, zalcitabine and ddI, which also select for K65R. On theother hand, a negative impact on viral replication capacity hasbeen observed after its emergence in vitro and in clinicalisolates [15,16].
The emergence of K65R after tenofovir therapy has beenassessed in several clinical trials. Experienced patients in studies902 and 907 developed K65R in 3% of cases after intensifica-tion with tenofovir [17–20]. There is one study in naive patientswith tenofovir (903) in which, at week 144, K65R was observedin 2.6% of individuals (in 17% of the patients who experiencedvirological failure); of note, it was always associated withefavirenz (EFV) resistance [21]. By contrast, the combination oftenofovir plus FTC has not been followed by the emergence ofthis mutation in any case, as assessed in two studies in naivepatients at week 48 (GS 934) [22] and at week 96 (418) [23].
Available data support the notion of an initial progressiveincrease in prevalence of K65R over time, with a stabilizationin the past 2 years as evidenced in different retrospectivestudies [24–27].
A divergent impact on K65R incidence has been observed intwo particular backgrounds. On the one hand, a highemergence of K65R has been reported (50–92%) amongpatients failing on a triple-nucleoside regimen, including teno-fovir (TDF/3TC/ABC or TDF/3TC/ddI) probably as a resultof concomitant use of two drugs selecting for this mutation[28–30]. Alternatively, antiretroviral regimens, including thymi-dine analogs are associated with reduced emergence of K65R;indeed an inverse correlation has been observed between thenumber of thymidine analog-associated mutations (TAMs) andthe emergence of K65R [24]. Nevertheless, in the presence ofthree or more TAMs, including either M41L or L210W,response to tenofovir is reduced [21].
K65R is frequently associated with M184V. Both mutationsconfer increased susceptibility to zidovudine (AZT). Maximalresponse to tenofovir was observed in patients harboring, atbaseline, M184V mutation in the absence of TAMs.
Furthermore, susceptibility to tenofovir was enhanced in strainswith M184V in addition to K65R, when compared with strainswith K65R isolated [15].
M184V
Resistance to FTC is associated with the development ofM184V mutation in the RT. FTC and 3TC select forM184V/I, which confers cross-resistance between them.M184V emerges more frequently after failure in 3TC-treatedpatients (59%) than it does with FTC (17%) [30]. It can bespeculated that it is related to the higher antiviral in vitropotency and extended half-life of FTC. If this is confirmed infurther studies, it might be viewed as a relevant issue owing tothe growing prevalence of this mutation in recent years,representing 80% of NRTI mutations in 2004 [27].
An overview of genotypic findings after virological failure instudies FTC-301A, FTC-302 and MKC-40 evidenced a lowincidence of M184V mutation (4%) [31]. Resistance analyses inclinical trials where the combination of tenofovir and FTChave been studied also revealed a low incidence of this muta-tion. In study GS 934, 1% of patients treated for 48 weeks withtenofovir/FTC/EFV versus 3% in the AZT/3TC/EFV armdeveloped M184V [22]. In study 418, up to 96 weeks of treat-ment with tenofovir/FTC/lopinavir, four out of 190 patientsdeveloped resistance to FTC [23].
Emergence of this mutation was much higher in regimensconsisting of triple nucleosides among which M184Vdeveloped in 98–100% of virological failures [28–30].
In summary, K65R prevalence is low and has reached aplateau after an initial upward trend. Recent data suggest thatusing tenofovir along with FTC and either EFV or lopina-vir/ritonavir (tenofovir/FTC/EFV or tenofovir/FTC/lopina-vir/ritonavir) decreases the risk of development of K65R. Theemergence of M184V (the most prevalent NRTI mutation)may be less likely with FTC than 3TC.
Pharmacokinetic profileTenofovir
TDF has an oral bioavailability of 25% after an overnight fast,which increases to 39% after a high-fat meal. Cmax is reached2.3 h after its administration with a meal [32]. Administrationwith food (high fat or light meal) increases tenofovir’s AUC (35and 34%) as well as Cmax (16 and 13.5%, respectively).
Tenofovir has a long half-life in plasma (17 h), yet inferior totenofovir diphosphate intracellular half-life in peripheral bloodmononuclear cells (PBMCs) (>60 h) [7]. When the ICARE trialstudied the distribution of PMPApp in patients with HIVRNA less than 20 copies/ml, its presence was demonstrated inPBMC (309/1 × 106 cells), while it was undetectable in lymphnode mononuclear cells (LNMCs), posing the question ofsuboptimal penetration in lymph nodes [33].
Pharmacokinetics of tenofovir are not altered by hepaticimpairment. Tenofovir is not a substrate for cytochrome p450(CYP) 3A4 enzymes nor does it inhibit CYP enzymes, whichconfers this agent to a limited potential to interact with drugs
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metabolized by this pathway. Tenofovir is renally excretedunchanged by a combination of glomerular filtration and activetubular secretion.
Emtricitabine
Oral administration of FTC is followed by rapid absorption,with a mean bioavailability of 93% [8]. Cmax is reached 1–3 hafter oral administration. Cmax and AUC are unrelated tofood intake.
FTC does not undergo metabolism by CYP enzymes nordoes it interfere with CYP-mediated metabolism of otherdrugs. Renal elimination (86%) of FTC occurs by glomerularfiltration and active tubular secretion. A small proportion(13%) is eliminated in the feces [8].
FTC’s half-life in plasma is 10 h, while intracellular FTCtriphosphate half-life is 39 h in PBMCs [34], supportingonce-daily dosing.
A pharmacokinetic study has established the formulationbioequivalence of tenofovir/FTC fixed-dose combination tabletrelative to coadministration of tenofovir tablets and FTCcapsules in individual dosage form [4].
Tenofovir and FTC share a symmetric pharmacokineticprofile owing to their extended half-life and similar elimina-tion interval. They have synergistic antiviral activity, and thecoadministration of both drugs in healthy volunteersdemonstrated a lack of pharmacokinetic interactions [5].
Interactions Several unpredicted drug interactions have been observed withtenofovir. Administration of tenofovir with ddI resulted in anincreased plasma concentration of the latter, presumably byinhibition of purine nucleoside phosphorylase (PNP) enzymeinvolved in the catabolism of ddI [35]. ddI’s AUC raised by44–60%, and Cmin increased by 48–64%, making the risk ofadverse events related to ddI exposure (peripheral neuropathyand pancreatitis) more likely [36]. This interaction prompted arecommendation to adjust the dosage of ddI [37] when theircoadministration was not yet precluded.
Interactions also exist with PIs. Such is the case with lopina-vir/ritonavir that increases the AUC of tenofovir by 30% andeventually the risk of kidney toxicity, although this has notbeen proved thus far. Atazanavir’s AUC, Cmax and Cmin arereduced 25, 21 and 40%, respectively in coadministration withtenofovir [7]. The addition of ritonavir reduces the negativeimpact of tenofovir on the Cmin (to 23%), but the AUC isunmodified, yet boosted ATV concentration plus TDF ishigher than unboosted ATV concentration without TDF. Onthe other hand, ATV/ritonavir increases tenofovir AUC 30%.
Systemic tenofovir exposure increased by 22% aftercoadministration with TMC-114/ritonavir [38], and 32% withthe IP in development brecanavir/ritonavir [39], with no doseadjustment required in any of them. The higher exposure totenofovir in concurrence with boosted PIs, might eventuallyincrease the risk of adverse events, but this is yet to be assessedand no specific recommendation has been made.
Tenofovir is transported by human organic anion transporter(OAT)-1 and then exported from the renal tubule cell by amultidrug resistance-associated protein (MRP)2 efflux pump.
Concurrent administration of drugs that compete for activetubular uptake or secretion and nephrotoxic agents, such asamphotericin B, aminoglycosides, vancomycin, foscarnet andpentamidine should be avoided [7]. FTC is free of interactionwith other drugs. It is not metabolized by CYP enzymes and iscleared renally mostly unchanged.
As tenofovir and FTC do not undergo metabolism by CYPenzymes, there is little potential to interfere with coadministereddrugs metabolized by this pathway. Their renal eliminationmakes it advisable to avoid coadministration with drugs elimi-nated by active tubular secretion (e.g., cidofovir and ganciclovir)for the risk of increased concentrations of them.
Therapeutic efficacyBoth tenofovir and FTC in individual formulation havedemonstrated antiviral efficacy in multiple-drug regimens.
Tenofovir
Three clinical trials have established tenofovir efficacy in acombination antiretroviral regimen, both in experienced (studies902 [17] and 907 [18]) and naive patients (study 903 [40]).
The data from study 903 after 144 weeks (HIV RNA< 50 copies/ml in 68% patients), support the efficacy and dura-bility of tenofovir in association with 3TC and EFV in naivepatients. The combination of tenofovir with PIs lopina-vir/ritonavir and atazanavir/ritonavir in experienced patientshas shown efficacy and tolerability in a clinical trial, BMS-045,after 48 weeks of follow-up [41].
Several studies have raised concerns about the efficacy ofcombination tenofovir/ddI. Early virological failure has beenobserved after initial treatment with TDF plus ddI plus EFV inpatients with viral load greater than 100,000 copies and CD4cell count less than 250 cell/mm3 [42–44].
Of note, a recent study pointed to a different virologicaloutcome when the third component is a PI instead of aNNRTI [45]. A negative impact on immunological recovery hasbeen observed in patients suppressed on a stable antiretroviralregimen who switched to tenofovir, ddI and EFV with a signif-icant median decline in CD4 cell count (-25 cells/µl) after48 weeks [46], a finding consistent with another study thatreported a mean decrease in CD4 count (95 cells/µl) followingcoadministration of tenofovir and ddI [47]. This decline in CD4count was confirmed in suppressed patients, irrespective of aPI- or NNRTI-containing regimen [48]. The rationale for this isthat potent inhibitors of PNP can inhibit T-cell divisioncausing a decline in CD4 count [49]. Recently, a ddI dose-related lymphocyte toxicity has been proposed, after theobservation of unaffected immune recovery following adjustingddI to less than 4.1 mg/kg [50].
Unexpected virological outcome and detrimental immuno-logical effects make it advisable to avoid concurrent use of teno-fovir and ddI, while awaiting guidelines to address this issue.
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The European Agency for the Evaluation of MedicinalProducts (EMEA) issued a recommendation in March 2005 [51]
against coadministration of tenofovir and ddI, especially innaive patients with high viral loads an low CD4 counts. Therecently issued (October, 6th 2005) Department of Health andHuman Services (DHHS) guidelines recommend that NNRTIplus tenofovir and ddI should not be used as an initial regimenin antiretroviral-naive patients owing to reports of early viro-logical failure and rapid emergence of resistance mutations toNNRTI, tenofovir and ddI [101].
A high rate of virological failure (33–95%) has also beenfound with triple nucleoside combinations that includedtenofovir (TDF plus 3TC plus ABC, or TDF plus 3TC plusddI) [28–30].
Emtricitabine
The efficacy of FTC has been assessed in naive and experiencedpatients [52,101]. Studies FTC-301, FTC-302 and FTC-303demonstrated long-term viral efficacy of FTC in combinationtherapy [52,101]. A large trial comparing FTC with stavudine(d4T) in combination with ddI and EFV, evidenced superiorityof FTC-based therapy in terms of virological suppression (HIVRNA < 50 copies/ml at 60 weeks 76 vs 54%), durability andimmunological response (CD4 cell count change from baseline156 vs 119 in an intention-to-treat [ITT] analysis) [52].
FTC is equally effective as 3TC as evidenced in studiesFTC-302 and -303 [53]. The FTC-302 trial compared FTCwith 3TC in combination with d4T and a NNRTI evidencingHIV RNA less than 50 after 48 weeks in 60% of patients withFTC and 64% of those with 3TC, while confirmed virologicalfailures with genotypic modification was 9.6% in botharms [53]. In study 303, FTC was confirmed to be comparablewith 3TC in terms of efficacy, safety and resistance pattern.
Tenofovir plus emtricitabine
It has been shown that the combination ofTDF plus FTC has synergistic activityin vitro against wild-type HIV and K65R,and M184V mutants [10].
The therapeutic efficacy of the combina-tion tenofovir and FTC has been studiedas part of a regimen with either an NNRTIor a PI showing high rates of virologicalcontrol. The only clinical trials that haveassessed the coadministration of tenofovirand FTC in an individual formulation aspart of a combination regimen are studies934 and 418.
Study 418 was designed to assess thesafety and efficacy of a once-daily regimenwith lopinavir/ritonavir 800/200 mg,tenofovir 300 mg and FTC 200 mg in 190antiretroviral-naive patients randomized 3:2to lopinavir/ritonavir 800/200 mg oncedaily or 400/100 mg twice daily [23].
Results after 96 weeks of follow-up evidenced HIV RNA lessthan 50 copies in 53% of patients in the lopinavir/ritonavir oncedaily arm and 57% in the lopinavir/ritonavir twice daily arm.
A pivotal study for the combination of TDF plus FTC isstudy GS01-934, a noninferiority trial where 509 naivepatients were randomized 1:1 to receive a combination regi-men with TDF plus FTC plus EFV versus AZT plus 3TC plusEFV. The primary end point was the percentage of patientswith serum HIV RNA less than less than 400 copies/ml atweek 48. After 48 weeks of treatment, in an ITT analysis,responders (HIV RNA < 400 copies) were 84% in theTDF/FTC group versus 73% in the AZT/3TC group(FIGURE 1), and the proportion of patients with HIV RNA lessthan 50 copies was 80% in the TDF plus FTC versus 70% inthe control group (FIGURE 2). The difference in efficacy in ITTanalysis was due to withdrawal of study medications in ahigher proportion of patients on AZT/3TC/EFV, after adverseevents (mainly anemia) occurred. An increase in CD4 count of190 cells was observed in TDF/FTC group versus 158 cells inthe control arm (FIGURE 3) [54].
Hepatitis B virus
There is a growing interest in therapies for HBV in coinfectedpatients. The prevalence of chronic hepatitis B in HIV patientsis 5–15%, and its natural history is negatively influenced byHIV itself. Tenofovir has demonstrated efficacy to attain HBVDNA undetectability and hepatitis B e antigen seroconversionboth against wild-type and 3TC-resistant HBV with mutationtyrosine–methionine–aspartate–aspartate (YMDD) [55]. In aclinical trial comparing tenofovir and adefovir in coinfectedpatients, tenofovir was found to decrease HBV DNA moreefficiently than adefovir [56].
FTC selectively inhibits HBV DNA polymerase. FTC hasmore potent activity against HBV than 3TC, elicits resistanceless frequently [57] and improves liver histology.
The dual antiviral activity of tenofovir and FTC for HIV andHBV opens new perspectives in the treatment of coinfectedpatients. The combination of tenofovir with FTC may increasevirological outcome and decreases the emergence resistance [58].
Safety & tolerabilityTenofovir
Gastrointestinal disorders (diarrhea, nausea, vomiting and flatu-lence) were most commonly reported as adverse events in clinicaltrials with tenofovir-containing therapy [9,18,40]. Grade 3–4 eventsoccurred in 13% patients versus 14% in the placebo group [17,18],and discontinuation owing to adverse events after 113 monthsfollow-up was 13% [9]. Laboratory abnormalities Grade 3–4 morefrequently reported were elevated creatinine kinase, amilase andhypertriglyceridemia, nevertheless, their occurrence did not differsignificantly from placebo group [18].
Lipid profile
Metabolic abnormalities, such as dyslipi-demia, have been described after the use ofHAART, justifying the assessment of itsincidence with different antiretrovirals.
A favorable lipid profile has been observedin patients receiving TDF/FTC in study934. Serum lipid abnormalities were lessfrequently found with this combinationthan in the arm receiving AZT/3TC, withmean change in fasting cholesterol 21 versus35 mg/dl (p < 0.001) and a mean change intriglycerides 3 versus 31 mg/dl (not reachingstatistical significance) [59].
Lipid parameters have been extensivelystudied in patients receiving tenofovir. Acomparison with d4T demonstrated
inferior increase in triglycerides, totalcholesterol and low-density lipoprotein(LDL) cholesterol, along with higherelevation in high-density lipoprotein(HDL) cholesterol in the group withtenofovir [40].
Furthermore, switching from d4T totenofovir modified the lipid profile with anobserved 24-week decrease from baselinetriglycerides level of -62 mg/dl [60]. Follow-up through 48 weeks confirmed a furtherdecrease in serum triglycerides (-72 mg/dl)beyond that observed at week 24; totalcholesterol (-38) and LDL cholesterol (-16)also decreased significantly after this periodof observation [61]. Interestingly, an impacton cardiovascular risk factors has beenobserved after switching d4T to TDFowing to lipoatrophy, with an estimatedcardiovascular risk (Framingham equation)significantly reduced from baseline (7.2) to
week 48 (6.6) [62]. In RAVE study, switching a thymidine analogto tenofovir resulted in a favorable metabolic outcome in totalcholesterol, LDL cholesterol and triglycerides after 48 weeks [63].
Fat distribution
Abnormal fat distribution has been associated with antiretro-virals, especially with thymidine analogs [64]. Trial 934 assessedlipoatrophy after 48 weeks of follow-up in a subgroup ofpatients with an unfavorable result in the arm using a thymi-dine analog. At that time point, total limb fat in the TDF/FTCarm was 8.9 versus 6.8 kg in the in comparator arm withAZT/3TC [59].
Study 903 demonstrated a reduced incidence of lipoatrophyafter 144 weeks of follow-up in patients receiving tenofovircompared with the group receiving d4T (3 vs 19%) [40].
A comparison between tenofovir and d4T has demonstrateda progressive limb fat gain in patients on tenofovir after96 weeks (7.9 kg) and 144 weeks (8.6 kg); whereas patients ond4T experienced a decrease from 5.0 to 4.5 kg in the sameperiod [65]. Further substitution of tenofovir for d4T wasaccompanied by a gain in limb fat from 4.60 to 5.02 kg after48 weeks of follow-up [61]. In thymidine analog recipients withmoderate-to-severe lipoatrophy, switching to tenofovir allowedrestoration of limb fat and subcutaneous adipose tissue after48 weeks [63].
Tenofovir does not interfere with mitochondrial DNAsynthesis, which confers this drug to a low potential to developadverse events related to mitochondrial toxicity, such as myo-pathy, cardiopathy, polyneuropathy, pancreatitis, lipoatrophyand lactic acidosis. In study 903, neuropathy and lactic acidosiswere less frequently observed with tenofovir than with d4T [39].
Bone density
Tenofovir reduces phosphate absorption, posing an eventualrisk to loss of mineral density. Bone effects were observed inanimals receiving high doses of tenofovir and changes inbiomarkers associated with increased bone metabolism havebeen reported. In study 903, a decline in bone mineral densitywas observed in tenofovir- and d4T-treated patients, but themagnitude of decrease in lumbar spine was higher in the groupwith tenofovir. Spine density decrease appeared between weeks24 and 48 [66], with minimal progression in osteopenia after along follow-up (-3.3% at week 48, -1.6% at week 144 and-1.0% at week 192) and no occurrence of spontaneous frac-tures [67]. The clinical significance of these changes isunknown, since a high prevalence of baseline osteopenia hasbeen reported and HIV infection itself [66,68], and antiretro-virals have also been linked to bone demineralization. A longi-tudinal study has demonstrated that HAART independentlypredicts a decrease in bone mineral content (-1.6% per year inextremitiy). PI-based regimens predict bone mineral loss inextremitiy (-1.9%), while AZT predicts a decrease in bonemineral content (-2.6%) [69].
Renal toxicity
Renal dysfunction is the dose-limiting toxicity of acyclic nucleo-tide compounds (cidofovir, adefovir) at high doses [70]. Renaltoxicity of tenofovir has been assessed in clinical trials (902, 903,907, 934 and 418) and in cohort studies with differing results.
Renal safety of a regimen with TDF/FTC/EFV was followedafter 48 weeks in study 934 in which no toxicity Grade (1–4) inserum creatinine level occurred. The median change in glomer-ular filtration rate (GFR) estimated by Cockroft–Gault (CG)equation was -1 ml/min in the TDF/FTC/EFV group and6 ml/min in the AZT/FTC/EFV arm, while by modification ofdiet in renal diseases (MDRD) method it was-1 ml/min/1.73 m2 in both groups [54].
After coadministration of FTC/tenofovir/lopinavir for96 weeks in a study (418) involving 195 naive patients, creati-nine was less than or equal to 1.5 mg/dl in 98% of the patients.
In two subjects, serum creatinine increased by more than3 mg/dl; one of them had baseline creatinine clearance (ClCr)less than 40 ml/h, the other developed tubulointerstitialnephropathy requiring hemodialysis temporarly [23].
The discontinuation of tenofovir owing to renal impairmentwas less than 1% in three large studies (902, 903 and 907).Among naive patients from study 903 [40], renal parameterswere compared in 299 subjects receiving tenofovir and 301 inthe d4T arm for a period of 144 weeks [71]. Creatinine toxicityGrade 1 (≥ 0.5 mg/dl above baseline) occurred in 4% ofpatients with TDF and 2% in the control group with d4T;Grade 2 (2.1–3 mg/dl) in less than 1% with TDF and 0% withd4T, while no Grade 3 (3.1–6mg/dl) was detected in the TDFgroup and less than 1% in the d4T arm as reproducedin TABLE 1.
Abnormal creatinine results were observed before week 48and resolved without discontinuation of the drug. There wasno significant difference between both groups in mean ClCrand serum creatinine values.
The incidence of hypophosphatemia (7%) was equal over144 months of treatment with TDF and d4T (TABLE 2).
Grade 1, 2 and 3 proteinuria, glucosuria and hematuria didnot differ between groups and no case of Fanconi syndromewas observed.
In the Recover study, 0.67 per 100 patient-years discontin-ued tenofovir for renal impairment; risk factors were identifiedin all of them [72]. In cohort studies, renal impairment has beenrarely observed. In tenofovir expanded access progam, 0.3% ofpatients had Grade 3–4 creatinine level and 0.6% Grade 3–4hypophosphatemia [73]. Serum creatinine alteration, in theabsence of risk factors, was observed in 0.01% of subjects in alarge cohort of 1058 patients with normal baseline renal func-tion [74]. The reported median increase of creatinine was0.11 mg/ml after a follow-up of 227 patient-years [75]; similarto the findings of a retrospective study where median increasein creatinine values was 0.1 mg/ml after 3 months, with nofurther modification beyond this time point [76]. An observa-tional cohort found no difference in renal toxicity after48 months between the comparator arm (AZT/3TC/EFV;n = 313) and the arm with TDF/3TC/EFV (n = 163); meanGFR -9.9 versus -9% [77].
A decrease in renal function was disclosed in an observationalcohort comparing TDF with alternative NRTIs for 322 dayswith a relative decline of 4% in ClCr in the TDF group [78].
Table 1. Renal toxicity grades.
Creatinine TDF (%) d4T (%)
Grade 1 (≥ 0.5 mg/dl) 4 2
Grade 2 (2.1–3 mg/dl) < 1 0
Grade 3 (3.1–6 mg/dl) 0 < 1
d4T: Stavudine; TDF: Tenofovir disoproxil fumarate.Adapted from [71].
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Another cohort study reported a mean difference in ClCr of6.8 ml/min comparing 290 patients on TDF-containingHAART with 618 patients on non-TDF HAART [79].
In summary, renal safety was demonstrated in clinical trials, butthere are cases of renal impairment reported when TDF wasimplemented in ‘real life’. Although some cases were unrelated torisk factors, most of the patients had underlying conditions orconcomitant use of nerphrotoxic agents. Furthermore, an associa-tion has been observed with advanced HIV disease [78]. Clinicalsignificance of these data is uncertain. Currently, a safety study(GS-235) is being carried in order to clarify the impact oftenofovir in different grades of renal impairment.
It is advisable to determine ClCr, especially in patients withHIV-associated nephropathy, diabetes or hypertension and toadjust the dose of tenofovir appropriately. Clearance should bereassessed if serum creatinine raises (even within normal values)or during intercurrent conditions that might impair renal func-tion. In patients with ClCr of 30–49 ml/min, dosing intervaladjustment every 48 h and close monitoring are advised. Incase clearance is less than 30 ml/min, administration should beavoided [9].
Proximal tubule dysfunction has been described in patientsreceiving TDF [70], mostly in association with nephrotoxicagents or previously impaired renal function. There is noestablished clear indication to monitor phosphorus level.
Tenofovir has been studied in the context of hepatic impair-ment with no alteration in its exposure, proving unnecessaryany dosage adjustment.
Patients with chronic hepatitis B who have been treatedwith tenofovir should be carefully monitored wheneverdiscontinuation of these drugs for a possible ‘flare’ ofacute hepatitis.
Emtricitabine
Most frequently reported adverse events in clinical trials withFTC in combination therapy were headache, diarrhea, nauseaand rash [8]. FTC has been associated with skin discoloration.Skin hyperpigmentation has also been associated with otherantiretrovirals, mainly AZT. Overall incidence of skin discolora-tion reported is less than 1.7% [8]. In Phase III clinical trials, theincidence of hyperpigmentation was significantly higher whencompared with d4T: (3 versus less than 1% [52]) and (3TC 6 ver-sus 1% [53]). The severity is generally Grade 1 (80%) not requir-ing discontinuation in any case, location predominates on palms
and soles, appears in the first weeks to months of treatment andaffects black individuals (8%), less frequently Asians (4%), His-panics (3%) and Caucasians (1%) [80]. Lesions do not progressdespite continuing administration for more than 6 months [81].
Although no results on FTC in liver disease are available, itsrenal elimination and minimal hepatic metabolism (< 13%)raise no restriction issue in that clinical setting. As mentionedabove for tenofovir, FTC discontinuation in patients withchronic hepatitis B can result in liver function alteration.Tenofovir and FTC are classified Pregnancy category B.
Emerging treatment guidelinesRecommendations of recent guidelines include tenofovir andFTC among preferred antiretrovirals in nucleoside backbonefor the initial treatment in naive patients.
Guidelines issued by the DHHS makes a selection of twoNRTIs as part of combination therapy that includes AZT ortenofovir with either 3TC or FTC [101]. These guidelines cate-gorize AZT with either 3TC or FTC as a preferred NRTIbackbone to be administered with EFV or lopinavir/ritonavir.The combination of FTC, TDF and EFV is listed as one of thepreferred NNRTI-based treatments for use in naive treatment,and as alternative when associated with nevirapine orlopinavir/ritonavir.
Expert commentaryConsistent data from clinical trials on FTC and tenofovircoadministered in individual formulation have demonstrated tobe effective and safe when studied in multiple-drug regimens,therefore supporting the potential for this new coformulation.
The accomplishment of transforming HIV infection into achronic illness led patients to demand antiretrovirals that,besides potency, have other characteristics that facilitate theirtreatment. On the other hand, prolonged survival and improve-ment in quality of life raised concern about long-term toxicitiesrelated to HAART.
NRTIs are associated with metabolic alterations. Lipoatrophyhas been related particularly with thymidine analogs, andabnormalities in lipid profile are not infrequent in patientstreated with d4T. This has prompted the search for regimensthat minimize these adverse events.
AdherenceEfficacy of ART correlates to the degree of adherence. Lapses indosing may lead to loss of full viral suppression and eventuallyto resistance. A large pill burden, frequent dosage, dietaryrequirements or poor tolerability may compromise adherence,and therefore, the potency of a regimen. Simplified dosing isdeemed essential among strategies to improve adherence.Patient preferences point to a reduced number of pills, once-daily dosing, lack of food restrictions and forgiveness, support-ing the present trend toward once-daily regimens [82]. An asso-ciation has been evidenced between satisfaction, adherence andeffectiveness of once- versus twice-daily regimens [83]. Further-more, patient satisfaction is enhanced with symmetric dosing
Table 2. Hypophosphatemia toxicity grades.
Phosphorus TDF (%) d4T (%)
Grade 1 (2–2.2 mg/dl) 4 4
Grade 2 (1.5–1.9 mg/dl) 3 2
Grade 3 (1.0–1.4 mg/dl) <1 <1
Adapted from [71].d4T: Stavudine; TDF: Tenofovir disoproxil fumarate.
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www.future-drugs.com 531
such that patients on a pure once-daily schedule demonstratedmore satisfaction than those with both twice- and once-dailycomponents in the same regimen [84].
Tenofovir and FTC have been coadministered in individualformulation as part of once-daily combination therapy (withEFV in study 934 and with lopinavir/ritonavir in study418 [23,54]) demonstrating effective antiviral activity and afavorable safety profile.
Long half-lives extends the exposure to a particular drug.Both TDF and FTC are dosed once daily owing to the longplasma half-life and long intracellular half-life of their activemetabolites [34,36].
Pharmacokinetic properties and interaction with other anti-retrovirals are important considerations to build a combinationART. Symmetryc drugs, that is, those with similar half-life andelimination time can be administered at equivalent intervals [85].Tenofovir and FTC share similar half-life and elimination inter-val, the symmetry of their pharmacokinetic profile is a relevantcharacteristic for the combination of these drugs both in terms ofpatient preference and safety in case of therapeutic interruptions.
Currently, there are two NRTI coformulations available foronce-daily dosing: Truvada and Kivexa/Epzicom. Both sharesimilar antiviral potency, but differ in their safety profile. Theuse of any of them allows to avoid the toxicities associated tothymidine analogs (hyperlipidemia and lipoatrophy), but addsconcerns about ABC hypersensitivity reaction with Kivexa/Epzi-com, and renal function surveillance in the case of Truvada.Patients must receive information about the risk and symptomsof ABC hypersensitivity reaction. In patients with renal dys-function, the election will favor the use of Kivexa/Epzicom,while patients coinfected with HBV would benefit from theadministration of Truvada owing to the antiviral effectiveness ofboth tenofovir and FTC against HBV.
It would be of interest to clarify in clinical trials the renalsafety of tenofovir and related risk factors such as immuno-logical status, concomitant use of PI or NNRTI in the regimenas well as other factors (hypertension, anemia) that mightexplain the conflicting results reported on this issue so far.
Five-year viewIn the foreseeable future, once-daily dosing is bound to become anew paradigm in ART. Simplification of therapeutic schedules isalready in progress and will proceed in the coming years.
Coformulation is expected to be the base for the strategy toreduce the pill burden. The search of new drugs for once dailyor the adaptation of twice-daily drugs for once-daily dosing(lopinavir/ritonavir) and modification in absorption to prolonghalf-life is the present trend in pharmaceutical companies.There are ongoing clinical trials to assess the efficacy and toler-ability of a once-daily schedule with the administration ofTruvada and the PI TMC-114.
The aim to administer all components of HAART with the low-est number of pills and once-daily dosing is intended to minimizelapses in treatment, and therefore, to overcome the emergence ofresistance, hence improving the outcome of a regimen.
Backbone selection will favor pharmacokinatically symmetricdrugs with extended plasma and intracellular half-lives. Alongwith intrinsic potency, a good tolerance profile with minimalpotential for drug interactions or interference by food will,obviously, influence the choice.
A fixed-dose formulation containing tenofovir, FTC andefvirenz is expected to be launched since the formulation of thefixed-dose combination has demonstrated bioequivalence tothe individual products dosed separately. There are clinicaltrials under development to test TMC 114 in once-daily dosagein association with tenofovir/FTC.
The joint venture of the manufactures of Truvada (GileadSciences) and Sustiva® (Bristol-Myers Squibb) has recentlysubmitted a New Drug Application to the US FDA in April2006. This will represent the first coformulation of thecomplete components of HAART in one single pill for once-daily administration, therefore, achieving a long-term expectedscope by both patients and healthcare providers. This will pavethe way to future company agreements.
At present new classes of antiretrovirals are being assessed inclinical trials. Entry inhibitors, among them CCR5 coreceptorantagonists maraviroc (Pfizer) and vicriviroc (Schering-Plough)are in Phase III studies, and preliminary results are expected inthe following months. Integrase inhibitors, that preventintegration of viral DNA into host genome are about to betested in clinical trials.
New drugs from ‘old’ classes are soon to be available inpractice, these include tipranavir (Aptivus®, Boehringer), thefirst nonpeptidic PI which is already in the clinic, andTMC-114 (Tibotec), another PI under expanded access aftergood results from clinical trials. In the next 5 years, new drugsan new classes of drugs will make a wider scenario possible forthe best choice in the individual patient.
Key issues
• Adherence is a determinant for a regimen success. Implementation of convenient schedules favors adherence to treatment.
• Once-daily dosing, low pill burden, nonstaged schedules and well tolerated drugs, all together enhance adherence.
• The coformulation of tenofovir and emtricitabine joints two nucleoside reverse-transcriptase inhibitors (NRTIs) with a good pharmacological profile: long half-life allowing once-daily dosing, effective antiretroviral activity (plus additional activity against hepatitis B virus), lack of interference with drugs metabolized by cytochrome P450 3A4 pathway, absent interference with mitochondrial DNA, favorable toxicity profile (with two issues that deserve surveillance: mineral bone density and renal function).
• The above considerations make this dual NRTI backbone a good option in terms of both efficacy, convenience and safety.
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532 Expert Rev. Anti Infect. Ther. 4(4), (2006)
ReferencesPapers of special note have been highlighted as:• of interest•• of considerable interest
1 Bartlett J, Fath M, De Masi R. An updated systematic overview of triple combination therapy in anti-retroviral naïve HIV-infected adults. 12th Conference on Retroviruses and Opportunistic Infections. MA, USA, February 22–25, Abstract 586 (2005).
2 Gallant JE, Rodríguez A, Weinberg W et al. Early non-response to tenofovir DF (TDF) + abacavir (ABC) and lamivudine (3TC) in a randomized trial compared to efavirenz (EFV) + ABC + 3TC: ESS30009 unplanned interim analysis. 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy. IL, USA, Abstract H-1722a (2003).
3 Jemsek J, Hutcherson P, Harper E. Poor virologic responses and early emergence of resistance in treatment naïve, HIV-infected patients receiving a once daily triple nucleoside regimen of didanosine, lamivudine and tenofovir DF. 11th Conference on Retroviruses and Opportunistic infections. CA, USA, Abstract 51 (2004).
• Reports on poor outcome after a triple nucleoside combination.
4 Kearney BP, Zong J, Begley J, Shah J. Bioequivalence of combination tenofovir DF/emtricitabine tablets for one-pill once daily administration. 5th International Workshop on Clinical Pharmacology of HIV Therapy. Rome, Italy, Poster 7.3 (2004).
5 Blum MR, Begley J, Zong J et al. Lack of pharmacokinetic interaction between emtricitabine and tenofovir DF when coadministration to steady state in healthy volunteers. 43rd ICAAC. IL, USA, Abstract A-1621 (2003).
6 Schinazi RF. Assessment of the relative potency of emtricitabine and lamivudine. J. Acquir. Immune Defic. Syndr. 34, 243–245 (2003).
7 Viread®, package insert. Gilead Sciences, Inc., CA, USA, October (2003).
8 Emtriva®, package insert. Gilead Sciences, Inc., CA, USA, July (2003).
9 Truvada® (emtricitabine and tenofoivir disoproxil fumarate) tablets package insert. Gilead Sciences, Inc., CA, USA, January (2005).
10 Myrick F, Vela JE, Ray AS, Borroto-Esoda K, Miller MD. In vitro evaluation of the anti-HIV activity and metabolic interactions of emtricitabine and tenofovir. 3rd IAS. Rio de Janeiro, Brazil, 24–27th July, Poster WePe3.3C05 (2005).
11 Robbins BL, Srinivas RV, Kim C et al. Anti-human immunodeficiency virus activity and cellular metabolism of a potential prodrug of the acyclic nucleoside phosphonate 9-R-(2-phosphonomethoxypropyl) adenine(PMPA), Bis (isopropyloxy methylcarbonyl) PMPA. Antimicrob. Agents Chemother. 42, 612–617 (1998).
12 Rousseau FS, Wakeford D, Mommeja-Marin H et al. FTC-102 clinical trial group. Prospective randomized trail of emtricitabine versus lamivudine short-term monotherapy in human immunodeficiency virus infected patients. J. Infect. Dis. 188(11), 1652–1658 (2003).
13 Birkus G, Hitchkock MJM, Cihlar T et al. Assessment of mitochondrial toxicity in human cells treated with tenofovir: comparison with other nucleoside reverse transcriptase inhibitors. Antimicrob. Agents Chemother. 46(3), 716–723 (2002).
14 Cui L, Schinazi RF, Gosselin G et al. Effects of f-enantiomeric and racemic nucleoside analogues on mitochondrial functions in HepG2 cells. Biochem. Pharmacol. 52, 1577–1584 (1996).
15 White KL, Margot NA, Wrin T et al. Molecular mechanisms of resistance to human immunodeficiency virus type 1 with reverse transcriptase mutations K65R and K65R+M184V and their effects on enzyme functions and viral replication capacity. Antimicrob. Agents Chemother. 46, 3437–3446 (2002).
• Analyzes resistance mutations selected by tenofovir and emtricitabine (FTC) and their effect on viral replication.
16 Weber J, Chakraborty B, Weberova J et al. Diminished replicative fitness of primary human immunodeficiency virus type 1 isolates harboring the K65R mutation. J. Clin. Microbiol. 43, 1395–1400 (2005).
• Describes the negative impact of K65R mutation on the replicative capacity of HIV-1.
17 Schooley RT, Ruane P, Myers RA et al. Tenofovir DF in antiretroviral-experienced patients: results from a 48-week, randomized, double-blind study. AIDS 14, 16(9), 1257–1263 (2002).
• Study 902 assessed different doses of tenofovir disoproxil fumarate (TDF) in antiretroviral-experienced patients.
18 Squires K, Pozniak AL, Pierone G Jr et al. Tenofovir disoproxil fumarate in nucleoside-resistant HIV-1 infection: a randomized trial. Ann. Intern. Med. 139, 313–320 (2003).
• Study 907 analyzed intensification with TDF in virological failure.
19 McColl DJ, Margot NA, Wulfsohn M. Patterns of resistance emerging in HIV-1 treatment-experienced patients undergoing intensification therapy with tenofovir disoproxyl fumarate. J. Acquir. Immune Defic. Syndr. 37, 1340–1350 (2004).
20 Mcoll DJ, Margot N, Cheng A et al. Development of K65R versus thymidine analog-associated mutations (TAMs) in antiretroviral-treated patients. 6th International Congress of Drug Therapy in HIV Infection. Glasgow, UK, Abstract P206 (2002).
• Describes two divergent pathways for resistance.
21 Miller MD, Margot N, Mcoll JD et al. Final 144 week resistance analysis for treatment-naïve patients taking tenofovir DF or stavudine in combination with lamivudine and efavirenz. 15th International AIDS Conference. Bangkok, Thailand, WePeB5757 (2004).
• Study 903 is a pivotal clinical study of tenofovir in naive patients.
22 McColl DJ, Margot NA, Lu B et al. Lack of resistance to tenofovir DF at week 48 and impact of baseline resistance mutations on treatment response in study 934. 3rd IAS Conference on HIV Pathogenesis and Treatment. Rio de Janeiro, Brazil, Abstract TuPp0305 (2005).
23 Molina JM, Wilkin A, Domingo P et al. Once-daily vs twice-daily lopinavir/ritonavir in antiretroviral-naïve patients: 96-week results. 3rd IAS. Rio de Janeiro, Brazil, 24–27th July, Abstract WePe 123c12 (2005).
• In study 418, the combination of tenofovir and FTC is association with lopinavir is assessed.
24 Valer L, Martín-Carbonero L, de Mendoza C, Corral A, Soriano V. Predictors of selection of K65R: tenofovir use and lack of thymidine analogue mutations. AIDS 18(15), 2094–2096 (2004).
25 Winston A, Mandalia S, Pillay D et al. The prevalence and determinants of the K65R mutation in HIV-1 reverse transcriptase in tenofovir-naive patients. AIDS 16, 2087–2089 (2002).
26 Winston A, Pozniac A, Mandalia S et al. Which nucleoside and nucleotide backbone combinations select for the K65R mutation in HIV-1 reverse transcriptase. AIDS 18(6), 949–951 (2004).
27 Fernandes H, Sultana M, Chew D, Reilly E, Fisher A, Burstin S. NRTI resistance in relationship to K65R: a study of inner city HIV patients who present with virological failure. 3rd IAS. Rio de Janeiro, Brazil, 24–27th July, WePe4.4C20 (2005).
Tenofovir disoproxil fumarate–emtricitabine
www.future-drugs.com 533
28 Gallant JE, Rodriguez AE, Weinberg W et al. Early non-response to tenofovir DF (TDF) + abacavir (ABC) and lamivudine (3TC) in a randomized trial compared to efavirenz (EFV) + ABC and 3TC: ESS30009 unplanned interim analysis. 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy. IL, USA, September 14–17, Abstract H-H-1722a (2003).
29 Landman R, Peytabin G, Descamps D et al. Low genetic barrier to resistance is a possible cause of early virologic failures in once-daily regimen of abacavir, lamivudine and tenofovir: the tonus study. 11th Conference on Retroviruses and Opportunistic Infections. Abstract 52 (2004).
30 Harris J, Shaw A, Borroto-Esoda K et al. Genotypic analysis of HIV-1-infected antiretroviral therapy-naïve patients receiving emtricitabine or lamivudine in double-blind equivalence trial. 5th International Workshop on Drug Resistance and Treatment Strategies. Poster 104 (2001).
31 Quinn JB, Borroto-Esoda K, Hinkle J et al. Overview of the genotypic findings from emtricitabine-treated HIV+ patients. 43rd Inter Science Conference on Antimicrobial Agents and Chemotherapy. Poster H-908 (2003).
32 Barditch-Crovo P, Deeks SG, Collier A et al. Phase I/II trials of the pharmacokinetics, safety and antiretroviral activity of tenofovir disoproxil fumarate in human immunodeficiency virus-infected adults. Antimicrob. Agents Chemother. 45, 2733–2739 (2001).
33 Lafeuillade A, Hittinger G, Poggi C et al. Investigating cellular antiretroviral resistance: preliminary results of the ICARE study. 3rd IAS Conference on HIV Pathogenesis and Treatment. Rio de Janeiro, Brazil, Abstract WeOa0201 (2005).
34 Wang LH, Begley J, Feng JY. Pharmacokinetic and pharmacodynamic characteristics of emtricitabine supports its once daily dosing. XIV International AIDS Conference. Barcelona, Spain, Abstract 4546 (2002).
35 Robbins B, Wilcox C, Fridland A, Rodman J. Metabolism of tenofovir and didanosine in quiescent or stimulated human peripheral blood mononuclear cells. Pharmacothetrapy 23, 695–701 (2003).
36 Kearney B, Flaherty J, Shah J. Tenofovir disoproxil fumarate: clinical pharmacology and pharmacokinetics. Clin. Pharmacokinet. 43, 596–612 (2004).
37 Kearney BP, Isaacson E, Sayre J et al. Didanosine and tenofovir DF drug-drug interaction: assessment of didanosine dose reduction. 10th CROI, MA, USA, Abstract 233 (2003).
• Report of important drug interaction of tenofovir with didanosine.
38 Hetelmans R, Marien K, De Paw M et al. Pharmacokinetic interaction between TMC114/ritonavir (RTV) and tenofovir in healthy volunteers. 15th International AIDS Conference. Bangkok, Thailand, TuPeB4634 (2004).
39 Ford SL, Shelton MJ, Murray SC. A study to investigate the interaction between 640385/ritonavir and tenofovir (TDF) in healthy subjects. 45th ICAAC. Washington, DC, USA, A-1198 (2005).
40 Gallant JE, Staszewski S, Pozniak AL et al. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naïve patients. JAMA 292(2), 191–201 (2004).
• Discloses relevant safety issues on the use of tenofovir versus a thymidine analog.
41 Johnson M, Grinsztejn B, Rodríguez C et al. Atazanavir plus ritonavir or saquinavir, and lopinavir/ritonavir in patients experiencing multiple virological failures. AIDS 19, 685–694 (2005).
42 Moyle G, Maitland D, Hand J, Mandalia S, Nelson M, Gazzard B. Early virologic failure in persons with viral loads >100,000 copies and CD4 counts <200 cells/mm3 receiving ddI/tenofovir/efavirenz as initial therapy: results from a randomized comparative trial. 44th ICAAC Meeting. Abstract H-566 (2004).
43 Maitland D, Moyle G, James H et al. Early virologic failure in HIV-1 infected subjects on didanosine/tenofovir/efavirenz: 12-week results from a randomized trial. AIDS 19, 1183–1188 (2005).
• Evidences virological failure with the concurrent use of TDF and didanosine.
44 van Lunzen J, Schewe K, Kuhlman B et al. High rate of virological failure during once a daily therapy with tenofovir + didanosine 250 mg + efavirenz in antiretroviral naïve patients: results of the 12 weeks interim analysis of the TEDDI trial. 3rd IAS. Rio de Janeiro, Brazil, 24–27th July, Abstract TuPp0306 (2005).
45 Leon A, Mallolas J, Martínez E. High rate of virologic failure in maintenance antiretroviral therapy with didanosine and tenofovir. AIDS 19, 1695–1697 (2005).
46 Barrios A, Rendon A, Negredo E et al. Paradoxical CD4 T-cell decline in HIV infected patients with complete virus suppression taking tenofovir and didanosine. AIDS 19(06), 569–575 (2005).
47 Negredo E, Molto J, Burger D et al. Unexpected CD4 cell count decline in patients receiving didanosine and tenofovir-based regimens despite undetectable viral load. AIDS 18(13), 459–463 (2004).
48 Van Leth F, Prins JM, Lange J, Geerlings S. Protease inhibitors and NNRTIs have a comparable effect on the cell change after switching to tenofovir-based regimens. AIDS 19(15), 1722–1723 (2005).
49 Bzowska A, Kulikowska E, Shugar D. Purine nucleoside phosphorylases: properties, functions and clinical aspects. Pharmacol. Ther. 88, 349–425 (2000).
50 Karrer U, Ledergerber B, Furrer H et al. Dose-dependent influence of ddI on immune recovery in HIV treated treated with tenofovir. AIDS 19(17), 1987–1994 (2005).
51 European agency for the evaluation of medicinal products. EMEA/62331/2005.
52 Saag MS, Cahn P, Raffi F et al. Efficacy and safety of emtricitabine vs stavudine in combination therapy in antiretroviral-naïve patients. JAMA 292, 180–190 (2004).
• Demonstrates efficacy of FTC compared with stavudine.
53 Sanne I, Van Der Horst C, Shaw et al. Two randomized, controlled, equivalence trials of emtricitabine to lamivudine. 14th International AIDS Conference. Barcelona, Spain, Poster 4432 (2002).
54 Gallant JE, DeJesus E, Arribas JR et al. Tenofovir DF, emtricitabine and efavirenz vs. zidovudine, lamivudine and efavirenz for HIV. N. Engl. J. Med. 354, 251–260 (2006).
• Evidences efficacy and safety of the combination TDF/FTC/ efavirenz in naive patients compared with zidovudine/3TC/ efavirenz.
55 Bochet M, Tubiana R, Benhamou Y et al. Tenofovir disoproxil fumarate suppresses lamivudine resistant HBV replication in patients coinfected with HIV/HBV. 9th CROI. WA, USA (2002).
56 Peters M, Anderson J, Lynch P et al. Tenofovir disoproxil fumarate is not inferior to adefovir dipivoxil for the treatment of hepatitis B virus in subjects who are co-infected with HIV: results of ACTG A5127. 12th Conference on Retrovirus and Opportunistic Infections. Abstract 124 (2005).
57 Gish R, Leung N, Wang C et al. Antiviral activity, safety, and incidence of resistance in chronically infected hepatitis B patients (CHB) given once daily emtricitabine for 2 years. Presented at the 53rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD). MA, USA, November 1–5, Abstract 838 (2002).
Muñoz de Benito & Arribas López
534 Expert Rev. Anti Infect. Ther. 4(4), (2006)
58 Gish R, Trinh H, Leung N et al. Safety and antiviral activity of emtricitabine for the treatment of chronic hepatitis B infection: a two-year study. J. Hepatol. 43, 60–66 (2005).
59 Pozniak AL, Gallant JE, DeJesus E et al. Superior out-come for tenofovir DF, emtricitabine and efavirenz compared to fixed dose zidovudine/lamivudine and efavirenz in antiretroviral naïve patients. 3rd IAS. Rio, Abstract WeOa0202 (2005).
60 Suleiman JMAH, Lu B, Enejosa J, Cheng A. Improvement in lipid parameters associated with substitution of stavudine to tenofovir DF in HIV-infected patients participating in GS 903. 44th ICAAC. Washington DC, USA. Poster H-158 (2004).
• Assesses the lipidic profile of tenofovir versus stavudine.
61 Madruga JVR, Cassetti I, Suleiman JMAH, Zhong L, Enejosa J, Cheng A. Improvement in lipoatrophy and lipid abnormalities following switch from stavudine (d4T) to tenofovir (TDF) in combination with lamivudine (3TC) and efavirenz (EFV) in HIV-infected patients: a 48-week follow-up from study 903E. 3rd IAS. Poster TuPe2.2B12 (2005).
62 Palacios R, Santos J, Domigo P et al. Impact of switching from stavudine (d4T) to tenofovir DF (TDF) on cardiovascular risk factors in patients with lipoatrophy. 3rd IAS. Rio de Janeiro, Brazil, 24–27th July, Poster TuPe2.3C15 (2005).
63 Moyle G, Sabin C, Cartledge J et al. A randomised. Open-label comparative trial of abacavir or tenofovir DF as replacement for a thymidine analogue in persons with lipoatrophy and suppressed HIV RNA on HAART. The RAVE study. 12th Conference on Retroviruses and Opportunistic Infections. MA, USA, Abstract 44LB (2005).
64 Dube MP, Zackin R, Tebas P. Prospective study of regional body composition in antiretroviral-naïve subjects randomized to receive zidovudine + lamivudine or didanosine + stavudine combined with nelfinavir, efavirenz, or both: A5005s, a substudy of ACTG 384. 4th International Workshop on Adverse Drug Reactions and Lipodistrophy in HIV. CA, USA, Abstract 27 (2002).
65 Gallant JE, Stazewski S, Pozniac AL et al. Long-term efficacy and safety of tenofovir disoproxil fumarate (TDF): a 144-week comparison versus stavudine (d4t) in antiretroviral-naïve patients. XV International AIDS Conference. Bangkok, Thailand, TuPeB 4538 (2004).
66 Powderly W, Cohhen C, Gallant J, Lu B, Enejosa J, Cheng AK. Similar incidence of osteopenia and osteoporosis in antiretroviral-naïve patients treated with tenofovir DF or stavudine in combination with lamivudine and efavirenz over 144 weeks. 12th CROI. MA, USA, Abstract 823 (2005).
67 Cassetti I, Madruga JVR, Suleiman J et al. Tenofovir DF in combination with lamivudine and efavirenz in antiretroviral-naïve patients: a 4 year follow-up. 3rd International AIDS Conference on HIV Pathogenesis and Treatment. Rio de Janeiro, Brazil, WePe6.3C05 (2005).
68 Bongiovanni M, Fausto A, Cicconi P et al. Potential predictors of bone demineralization in HIV-infected patients. 3rd IAS Conference on HIV Pathogenesis and Treatment. Abstract TuPe2.2B08 (2005).
69 McDermott AY, Terrin N, Wanke C et al. CD4 cell-count, viral load and high active antiretroviral therapy use are independent predictors of body composition. Clin. Infect. Dis. 41(11), 1662–1670 (2005).
70 Izzedine H, Isnard-Bagnis C, Hulot JS et al. Renal safety of tenofovir in HIV treatment experienced patients. AIDS 18, 1074–1076 (2004).
71 Izedine H, Hulot JS, Vittecoq D et al. Long term renal safety of tenofovir disoproxil fumarato in antiretroviral-naïve HIV-1 infected patients. Data from a double-blind randomized active-controlled multicentre study. Nephrol. Dial. Trasnplant. 20, 743–746 (2005).
72 Estrada V, Ena J, Domingo P et al. Renal safety of tenofovir DF in HIV treatment-experienced patients with adverse events related to NRTI use (Recover study). 44th ICAAC. Washington DC, USA, Abstract H-169 (2004).
73 Gallais H, Lazzarin A, Adam A et al. The Viread expanded access program (EAP) in Europe/Australia: summary of the safety and efficacy of tenofovir disoproxil fumarate (TDF) in antiretroviral experienced patients. 15th International AIDS Conference. Bangkok, Thailand, Abstract TuPeB4552 (2004).
74 Jones R, Stebling J, Nelson M et al. 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. 37, 1489–1495 (2004).
75 Jaeguel-Guedes E, Wolf E, Ruemalein N et al. Incidence of tenofovir-related nephrotoxicity in a larger out-patient cohort. 15th Iternational AIDS Conference. Bangkok, Thailand, Abstract WePpB5937 (2004).
76 Horberg MA, Klein DB, Yu J et al. Effect of tenofovir on renal function in a “real world” clinic setting. 15th International AIDS Conference. Bangkok, Thailand, Abstract WePpB2066 (2004).
77 Keiser P, Nassar N, Armas L, Sanchez J, Sandoval J, Moreno S. An observational cohort comparison of zidovudine-lamivudine-efavirenz vs tenofovir-lamivudine-efavirenz in antiretroviral naïve patients in a large urban clinic. 3rd IAS. Rio de Janeiro, Brazil, 24–27th July, WePe12.2C20 (2005).
78 Gallant JE, Parish MA, Keruly JC, Moore RD. Changes in renal function associated with tenofovir disoproxil fumarate treatment, compared with nucleoside reverse-transcriptase inhibitor treatment. Clin. Infect. Dis. 40, 1194–1198 (2005).
• Overview of tenofovir renal safety.
79 Winston A, Amin J, Mallol P et al. Minor changes in calculated creatinine clearance and anion-gap are associated with tenofovir disoproxil fumarate-containing highly active antiretroviral therapy. HIV Med. 7(2), 105–111 (2006).
80 Mondou E, Quinn JB, Shaw A, Hinkle J, Adda N, Rousseau F. Incidence of skin discoloration across phase 3 clinical trials with emtricitabine (FTC) in adults. XV AIDS Conference. Bangkok, Thailand (2004).
81 Rashbaum B. Evaluation of hyperpigmentation in HIV-infected patients receiving emtricitabine. 3rd IAS Rio de Janeiro, Brazil, 24–27th July, Poster TuPe2.4C15 (2005).
82 Moyle G. The assessing patient’s preferred treatments (APPT-1) study. Int. J. STD AIDS 14(Suppl. 1), 1–5 (2003).
83 Arribas JR, Iribarren JA, Knobel H et al. Adherence, treatment satisfaction and effectiveness of once-daily (QD) vs twice-daily (BID) antiretroviral therapy (AT), in a large prospective observational cohort (CUVA). XV International AIDS Conference. Bangkok, Thailand, Abstract WePeB5780 (2004).
84 Watson M, Hill-Zabala C, Sosa N et al. Patients satisfaction with abacavir (ABC)-lamivudine (3TC) fixed-dose combination (FDC) tablet once daily (QD) compared with ABC and 3TC twice daily (BID) in HIV-infected patients (ESS30008). 3rd IAS Rio de Janeiro, Brazil, 24–27th July, WePe6.3c08 (2005).
85 Back D, Burguer D, Flexner C, Gerber J. The pharmacology of antiretroviral nucleoside and nucleotide reverse transcriptase inhibitors: implications for once-daily dosing. J. AIDS 39(Suppl. 1), S1–S23 (2005).
Tenofovir disoproxil fumarate–emtricitabine
www.future-drugs.com 535
Website
101 Department of Health and Human Services: guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. October 6, 2005 http://aidsinfo.nih.gov
Affiliations
• Rosa María Muñoz de Benito, MD, PhD
Hospital La Paz, Unidad de HIV, Paseo de La Castellana, 261, 28046 Madrid, SpainTel.: +34 917 277 099Fax: +34 917 290 [email protected]
• Jose Ramón Arribas López, MD, PhD
Associate Professor, Universidad Autónoma de Madrid, Facultad de Medicina, Unidad de HIV, Hospital La Paz, Paseo de La Castellana, 261, 28046 Madrid, SpainTel.: +34 917 277 099Fax: +34 917 290 [email protected]
