Drugs (2014) 74:2079–2095 DOI 10.1007/s40265-014-0318-1

ADIS DRUG EVALUATION

Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate Single-Tablet Regimen: A Review of Its Use in HIV Infection Emma D. Deeks

Published online: 29 October 2014 Ó Springer International Publishing Switzerland 2014

Abstract The nucleos(t)ide reverse transcriptase inhibitors, emtricitabine and tenofovir disoproxil fumarate (tenofovir DF), and the non-nucleoside reverse transcriptase inhibitor, rilpivirine, are now available as a fixed-dose single-tablet regimen (emtricitabine/rilpivirine/tenofovir DF; CompleraÒ, EvipleraÒ) for the treatment of adults infected with HIV-1. In treatment-naı¨ve adults, once-daily emtricitabine/rilpivirine/tenofovir DF was noninferior to once-daily emtricitabine/efavirenz/tenofovir DF with regard to establishing virological suppression over 96 weeks of therapy in a randomized, open-label, phase IIIb study (STaR). These data confirmed the findings of a pooled subset analysis of two earlier 96-week, doubleblind, phase III trials (ECHO and THRIVE) in which treatment-naı¨ve adults received either rilpivirine or efavirenz in combination with emtricitabine/tenofovir DF. However, the virological benefit of emtricitabine/rilpivirine/tenofovir DF in this setting appeared limited in patients with low CD4? cell counts or high viral loads at baseline. In 48-week phase IIIb (SPIRIT) and IIb (Study 111) trials in treatment-experienced patients already virologically suppressed with a single- or multiple-tablet antiretroviral regimen and without prior virological failure, switching to once-daily emtricitabine/rilpivirine/tenofovir DF maintained virological suppression and was noninferior to

The manuscript was reviewed by: C. Bernardini, Infection Disease Division, Universita¨tsspital Basel, Basel, Switzerland; D.M. Burger, Radboud University Medical Centre, Nijmegen, The Netherlands; R.L. Murphy, Center for Global Health, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. E. D. Deeks (&) Springer, Private Bag 65901, Mairangi Bay 0754, Auckland, New Zealand e-mail: [email protected]

remaining on a more complex multiple-tablet regimen in this regard. Emtricitabine/rilpivirine/tenofovir DF is generally well tolerated and appears to have a more favourable tolerability profile than emtricitabine/efavirenz/tenofovir DF. Thus, emtricitabine/rilpivirine/tenofovir DF is a welcome addition to the other single-tablet regimens currently available for the treatment of HIV-1 infection, providing a convenient and effective option for some adults who are treatment-naı¨ve, as well as those who are already virologically suppressed on their current treatment regimen and wish to switch because of intolerance or to simplify their regimen.

Emtricitabine/rilpivirine/tenofovir disoproxil fumarate fixed-dose single-tablet regimen in HIV-1 infection: a summary Fixed-dose tablet comprising the nucleos(t)ide reverse transcriptase inhibitors (NRTIs) emtricitabine and tenofovir disoproxil fumarate and the non-NRTI rilpivirine Single-tablet regimen with convenient once-daily administration Provides virological suppression noninferior to that seen with emtricitabine/efavirenz/tenofovir disoproxil fumarate in treatment-naı¨ve adults Maintains virological suppression in treatmentexperienced patients without prior virological failure who switch from their current antiretroviral therapy Generally well tolerated, with a tolerability profile consistent with those of the individual agents

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1 Introduction Antiretroviral therapy (ART) prolongs the lives of patients infected with HIV by suppressing replication of the virus and allowing recovery of immunological function [1, 2]. Standard ART regimens combine use of three antiretrovirals from at least two different drug classes, usually two nucleos(t)ide reverse transcriptase inhibitors (NRTIs) plus either a nonnucleoside reverse transcriptase inhibitor (NNRTI), a ritonavir-boosted protease inhibitor (PI) or an integrase strand transfer inhibitor [3–6]. As regimen complexity is known to impact adherence to ART [7], considerable advances have been made to reduce the complexity of these regimens, particularly in terms of administration frequency and pill burden. One such advance has been the introduction of fixed-dose combinations that allow up to four drugs to be coadministered in a single tablet [8, 9], a recent example of which is a tablet comprising the NNRTI rilpivirine and the NRTIs emtricitabine and tenofovir disoproxil fumarate (tenofovir DF) [CompleraÒ; EvipleraÒ]. The emtricitabine/rilpivirine/tenofovir DF single-tablet regimen is indicated in the EU for the treatment of HIV-1 in adults with a HIV-1 RNA level (viral load) of B100,000 copies/mL and no mutations associated with resistance to emtricitabine, tenofovir DF or NNRTIs [10]. The tablet is also indicated in the USA as a complete regimen for the treatment of HIV-1 in ART-naı¨ve adults with a viral load of B100,000 copies/mL and in ART-experienced adults with virological suppression on their current ART regimen without resistance to any of the three components of the fixed-dose tablet [11]. This article reviews pharmacological, therapeutic efficacy and tolerability data relevant to the use of emtricitabine/rilpivirine/ tenofovir DF in these indications. Acronyms of the clinical trials discussed in this review are defined in Table 1.

2 Pharmacodynamic Properties 2.1 Mechanism of Action Emtricitabine (a nucleoside analogue of cytidine) and tenofovir DF (a nucleotide analogue of adenosine Table 1 Clinical trial acronyms and definitions Acronym

Definition

ECHO

Efficacy Comparison in treatment-naı¨ve HIV-infected subjects Of TMC278 and efavirenz

SPIRIT

Switching boosted PI to Rilpivirine In combination with Truvada

STaR

Single Tablet Regimen

THRIVE

TMC278 against HIV in a once-daily Regimen Versus Efavirenz

monophosphate) are NRTIs that require intracellular conversion to their respective active metabolites for antiviral activity [10, 11]. Conversion of emtricitabine to its active form, emtricitabine 50 -triphosphate, occurs via phosphorylation, whereas conversion of tenofovir DF first requires hydrolysis to tenofovir, which is then phosphorylated to active tenofovir diphosphate. Both emtricitabine 50 -triphosphate and tenofovir diphosphate inhibit the activity of HIV-1 through competitive inhibition of its reverse transcriptase, resulting in termination of viral DNA formation, whereas the NNRTI rilpivirine inhibits the reverse transcriptase of HIV-1 non-competitively [10, 11]. Rilpivirine does not inhibit human mitochondrial DNA polymerase c or cellular DNA polymerases a or b [10, 11]. Emtricitabine 50 -triphosphate and tenofovir diphosphate display only weak inhibition of mammalian mitochondrial DNA polymerase c and cellular DNA polymerases a or b, with emtricitabine 50 -triphosphate also inhibiting cellular DNA polymerase e weakly [10, 11]; no mitochondrial toxicity is evident with either compound in vitro or in vivo [10]. 2.2 Antiretroviral Activity Each component of the emtricitabine/rilpivirine/tenofovir DF single-tablet regimen has well established antiretroviral activity. In vitro, the concentration of emtricitabine at which 50 % of viral replication was inhibited (i.e. the effective concentration; EC50) was 0.0013–0.64 lmol/L against laboratory and clinical isolates of HIV-1, with activity displayed against a range of HIV-1 subtypes, including A, B, C, D, E, F and G (EC50 0.007–0.075 lmol/ L) [10, 11]. Tenofovir had EC50 values of 0.04–8.5 lmol/L against laboratory and clinical isolates of HIV-1 in vitro and was active against the HIV-1 subtypes A, B, C, D, E, F and O (EC50 0.5–2.2 lmol/L) [10, 11]. Rilpivirine demonstrated antiviral activity against wildtype HIV-1 in vitro (median EC50 0.73 nmol/L against HIV1IIIB) and was 10- to 15-fold more potent against HIV-1 isolates from group M (A, B, C, D, E, F and G; EC50 0.07–1.01 nmol/L) than group O (EC50 2.88–8.45 nmol/L) [12]. The drug was also active in vitro against a large proportion of clinical isolates of HIV-1 with resistance to at least one first-generation NNRTI (62 % of 4,786 isolates) [12]. Emtricitabine and tenofovir displayed strain-specific activity against HIV-2 (EC50 values of 0.007–1.5 and 1.6–5.5 lmol/L) [10, 11], whereas the activity of rilpivirine against HIV-2 was more limited (EC50 2.51–10.83 lmol/L) [10–12]. Moderate to strong synergistic activity against HIV-1 was seen with emtricitabine, rilpivirine and tenofovir in cell culture when two or all three of the drugs were studied in combination [13]. This phenomenon may be explained,

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at least in part, by enhanced formation of dead-end or deadend-like complexes (structures that stabilize DNA chain termination) and elevated levels of the active metabolites of emtricitabine and tenofovir [13]. The antiretroviral activity of emtricitabine/rilpivirine/ tenofovir DF may be affected by the baseline presence of certain reverse transcriptase resistance-associated mutations (RAMs), including K65R, K70E, K101E/P, E138A/ G/K/Q/R, V179L, Y181C/I/V, M184I/V, Y188L, H221Y, F227C, M230I/L and the combination of L100I and K103N, according to data from in vitro studies and ARTnaı¨ve patients [10].

emtricitabine/tenofovir DF plus either rilpivirine or efavirenz for up to 96 weeks (see Sect. 4) [10]. Up to fivefold more rilpivirine plus emtricitabine/tenofovir DF than efavirenz plus emtricitabine/tenofovir DF recipients developed NNRTI RAMs (7.1 vs. 2.7 %) or NRTI RAMs (7.5 vs. 1.5 %) through 96 weeks of therapy in the overall patient population (n = 550 and 546) [15]. However, during this period, few patients (\4 %) whose viral load was B100,000 copies/mL at baseline developed phenotypic resistance to study drug [16] or genotypic resistance to NRTIs or NNRTIs [17] in either regimen group. Of note, resistance to rilpivirine was fivefold more common in patients whose viral load was high ([100,000 copies/mL) rather than low (B100,000 copies/mL) at baseline (11.5 vs. 2.4 %) [10]. Of the NNRTI RAMs that occurred most frequently in the rilpivirine plus emtricitabine/tenofovir DF group (V90I, K101E, E138K/Q, V179I, Y181C, V189I, H221Y and F227C), E138K was the most common and was often observed in combination with the NRTI RAM M184I. M184I was one of the most frequently occurring NRTI RAMs in this analysis, with others including K65R, K70E, M184V and K219E. Among virologically-suppressed ART-experienced adults switched from a ritonavir-boosted PI plus dual NRTI regimen to the emtricitabine/rilpivirine/tenofovir DF single-tablet regimen for the duration of a 48-week phase IIIb study known as SPIRIT (see Sect. 4), resistance analysis of seven patients through week 48 indicated that four (0.9 % of overall patient population) had developed NRTI and/or NNRTI resistance [18]. Consistent with other trials, the NRTI mutation M184V/I developed in all four of these patients, three of whom also developed NNRTI resistance mutations, including E138K, L100I plus K103N, or V108V/I plus E138K (either alone, in the case of E138K, or in combination with other preexisting NNRTI mutations) [18]. Patients who continued to receive their ritonavir-boosted PI plus NNRTI regimen initially and then switched after 24 weeks to emtricitabine/rilpivirine/tenofovir DF did not meet the criteria for resistance analysis through week 48. Notably, all patients remained susceptible to tenofovir [10]. In a noncomparative phase IIb study (known as study 111; see Sect. 4) in which 49 virologically-suppressed adults were switched from the emtricitabine/efavirenz/ tenofovir DF to the emtricitabine/rilpivirine/tenofovir DF single-tablet regimen [19], the two patients who developed virological failure after switching did not have emergent resistance [10].

2.3 Resistance The pathways of resistance development are well established for emtricitabine and tenofovir DF, with reverse transcriptase amino acid substitutions at position 184 conferring resistance to emtricitabine (M184I/V) and substitutions at positions 65 (K65R) and 70 (K70E) conferring resistance to tenofovir [10, 11]. For rilpivirine, in vitro selection experiments with HIV-1 indicate that resistance to the drug may be conferred by certain reverse transcriptase amino acid substitutions, including the NNRTI RAMs V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C and M230I/L and the novel NNRTI RAM E138R [11, 12]. The NNRTI RAMs were present alone or in combination, with the degree of resistance increasing with the number of RAMs [12]. When development of resistance was evaluated in the clinical setting among ART-naı¨ve adults in the phase IIIb STaR trial (see Sect. 4), up to 10-fold more emtricitabine/ rilpivirine/tenofovir DF (n = 394) than emtricitabine/efavirenz/tenofovir DF (n = 392) single-tablet regimen recipients had developed primary NNRTI RAMs (5.1 vs. 1.0 %) or primary NRTI RAMs (5.1 vs. 0.5 %) over 96 weeks of therapy [14]. Among patients whose baseline viral load was B100,000 copies/mL, approximately threefold more developed resistance with emtricitabine/rilpivirine/tenofovir DF than with emtricitabine/efavirenz/ tenofovir DF [9 of 260 (3.5 %) vs. 3 of 250 (1.2 %)]. Moreover, almost 13-fold more patients with a baseline viral load of [100,000 copies/mL developed resistance with emtricitabine/rilpivirine/tenofovir DF than with emtricitabine/efavirenz/tenofovir DF [12 of 134 (9.0 %) vs. 1 of 142 (0.7 %)]. Among emtricitabine/rilpivirine/tenofovir DF recipients, the most common NNRTI RAMs detected were E138K/Q, Y181C/I and V90I and the most common NRTI RAMs were M184V/I [14]. These findings are generally supported by a pooled subset analysis of two other phase III trials, known as ECHO and THRIVE, in which ART-naı¨ve adults received

2.4 Cross Resistance In cell culture, HIV-1 variants resistant to rilpivirine were not significantly resistant to emtricitabine or tenofovir, and

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no significant resistance to rilpivirine was displayed by emtricitabine- or tenofovir-resistant variants [11]. Indeed, HIV-1 strains harbouring amino acid substitutions associated with emtricitabine and tenofovir resistance, namely K65R, M184V or K65R/M184V, retain full susceptibility to rilpivirine [10]. Similarly, HIV-1 variants with certain NNRTI resistance-associated substitutions remain susceptible to emtricitabine (K103N) and tenofovir (K103N, Y181C), and susceptibility to both these NRTIs is retained by HIV-1 variants with substitutions that confer rilpivirine resistance [11]. It is well established that cross-resistance can develop between certain NRTIs. In cell culture, emtricitabineresistant HIV isolates harbouring the M184V/I substitution displayed resistance to lamivudine but remained susceptible to tenofovir, didanosine, stavudine and zidovudine [10, 11]. Likewise, sensitivity to emtricitabine, lamivudine, didanosine and abacavir can be reduced by the presence of K65R or K70E, substitutions that confer resistance to tenofovir DF [10]. Susceptibility to tenofovir was reduced 3.1-fold among HIV-1 isolates with a mean of three zidovudine-associated reverse transcriptase amino acid substitutions (M41L, D67N, K70R, L210W, T215Y/F or K219Q/ E/N), with most of these mutations also reducing susceptibility to stavudine and zidovudine, but not emtricitabine [11]. Susceptibility to tenofovir is also reduced by the L74V substitution, which confers resistance to didanosine. Cross-resistance can also occur between NNRTIs. Although susceptibility to rilpivirine in vitro was not affected by most (28 of 31 evaluated) single NNRTI RAMs, some did reduce rilpivirine susceptibility considerably, including K101P, Y181I and Y181V (52-, 15- and 12-fold respectively) [12]. Likewise, Y188L reduced susceptibility of clinical isolates to rilpivirine ninefold (sixfold for site-directed mutants) [11]. Some NNRTI RAMs have a greater impact on rilpivirine susceptibility when in combination with other such mutations. For instance, K103N had no impact on rilpivirine susceptibility when present alone, but reduced susceptibility to the drug sevenfold when in combination with L100I; similarly, susceptibility to rilpivirine was reduced 6.7-fold by E138K plus M184I and 2.8-fold by E138K alone [11]. Indeed, among HIV strains with two or three NNRTI RAMs, 38 and 66 % displayed reduced susceptibility to rilpivirine (FC 3.7–554) [11]. ART-naı¨ve patients who develop resistance to rilpivirine may be resistant to the NNRTIs efavirenz, etravirine and/or nevirapine [11, 20, 21]. For instance, among 16 HIV-1 strains with emergent rilpivirine resistance isolated from ART-naı¨ve adults who received the emtricitabine/rilpivirine/tenofovir DF single-tablet regimen for 48 weeks in STaR, reduced susceptibility to efavirenz, etravirine or nevirapine was evident in 7, 15 and 12 of the isolates [20].

E. D. Deeks

Similarly, in a pooled subset analysis of ART-naı¨ve adults with a viral load of B100,000 copies/mL at baseline who received rilpivirine plus emtricitabine/tenofovir DF in ECHO and THRIVE, 4 of 22 patients who developed phenotypic resistance to rilpivirine over 96 weeks were also resistant to efavirenz, etravirine and/or nevirapine (three, three and one patient, respectively) [10]. Moreover, among the 27 recipients of this regimen who had a baseline viral load of [100,000 copies/mL and developed phenotypic resistance to rilpivirine, 24, 25, and 12 were also resistant to efavirenz, etravirine and nevirapine, respectively [10]. In the SPIRIT trial, two virologically-suppressed patients who developed resistance to rilpivirine 48 weeks after switching from a ritonavir-boosted PI-based regimen to emtricitabine/rilpivirine/tenofovir DF displayed crossresistance to efavirenz (both patients), etravirine (one patient) and nevirapine (both patients) [10]. 2.5 Effects on Lipids The emtricitabine/rilpivirine/tenofovir DF single-tablet regimen had minimal impact on fasting lipid levels over 96 weeks of treatment in ART-naı¨ve adults in the STaR trial [22, 23]. Relative to emtricitabine/efavirenz/tenofovir DF, this regimen was associated with significantly (p \ 0.001) smaller mean increases from baseline in levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) and a reduction in triglycerides after 48 weeks of therapy [23]. Moreover, these between-group differences remained significant (p \ 0.001) through 96 weeks, with the exception being differences in triglyceride levels [22]. Notably, the change in the TC: HDL-C ratio at these timepoints was the same in each group (-0.2) [22, 23]. These findings are generally supported by pooled 96-week data from the ECHO and THRIVE trials in ART-naı¨ve patients who received either rilpivirine or efavirenz in combination with emtricitabine/tenofovir DF; lipid-lowering therapies were used by significantly (p = 0.025) fewer patients in the rilpivirine than in the efavirenz group (3 vs. 6 %) [15]. Similar lipid benefits were reported in virologicallysuppressed ART-experienced adults switched from a ritonavir-boosted PI plus NRTI regimen to emtricitabine/ rilpivirine/tenofovir DF in the 48-week SPIRIT trial [18]. At 24 weeks, levels of most serum fasting lipids (TC, LDLC, triglycerides) and the TC : HDL-C ratio had improved significantly (p \ 0.001) in patients switched to emtricitabine/rilpivirine/tenofovir DF relative to patients who continued to receive their original PI-based regimen, although HDL-C levels declined significantly (p \ 0.001) less with the PI-based regimen.

Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate: A Review

Fasting TC, LDL-C and triglyceride levels also declined significantly (p value not reported) in ART-experienced patients 12 weeks after being switched from emtricitabine/ efavirenz/tenofovir DF to emtricitabine/rilpivirine/tenofovir DF in study 111 [19]. The benefits in these lipid parameters remained significant (p B 0.016) after 48 weeks of therapy, although changes from baseline in HDL-C and the TC: HDL-C ratio were not significant at this timepoint [19]. 2.6 Other Effects The recommended dosage of rilpivirine (25 mg once daily) was not associated with clinically relevant QT interval prolongation in a thorough QT study in 60 healthy adults [10, 11], with the maximum mean Fridericia-corrected QT (QTcF) interval differing from placebo by 2.0 ms after baseline correction, which is below the threshold of clinical concern [11]. However, supratherapeutic dosages of rilpivirine (75 and 300 mg once daily) prolonged the QT interval in healthy adults (maximum mean differences in QTcF vs. placebo of 10.7 and 23.3 ms, after baseline correction); thus, caution is necessary when coadministering emtricitabine/rilpivirine/tenofovir DF with drugs with a known risk of Torsade de Pointes [10, 11]. Rilpivirine appears to inhibit the tubular secretion of creatinine [24]. Consistent with this effect, emtricitabine/ rilpivirine/tenofovir DF was associated with small to modest reductions from baseline in estimated glomerular filtration rate (eGFR) over up to 96 weeks of treatment in ART-naı¨ve and—experienced adults in some clinical trials discussed in Sect. 4 [18, 22, 23]. For instance, emtricitabine/ rilpivirine/tenofovir DF significantly reduced eGFR compared with emtricitabine/efavirenz/tenofovir DF after 96 weeks of therapy in ART-naı¨ve adults in the STaR trial, with mean changes from baseline of -5.6 versus ?6.0 mL/ min (absolute values were 103 vs. 120 mL/min; p \ 0.001) [22]. However, most of the reduction in eGFR in emtricitabine/rilpivirine/tenofovir DF recipients occurred within the first 4 weeks of therapy and stabilized thereafter [22, 23]. Likewise, among adults virologically suppressed with a ritonavir-boosted PI-based regimen who participated in the SPIRIT trial [18], a small but significant reduction in eGFR was evident at 24 weeks in patients who had immediately switched to the emtricitabine/rilpivirine/tenofovir DF single-tablet regimen at baseline relative to those who remained on ritonavir-boosted PI-based therapy for the first 24 weeks of the study (-4.4 vs. ?0.1 mL/min; p B 0.001). At 24 weeks, the latter group also switched to the singletablet regimen (i.e. a delayed switch), and at week 48, the mean change in eGFR in the immediate- and delayedswitch groups was -4.0 and -3.0 mL/min [18].

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3 Pharmacokinetic Properties 3.1 Absorption and Distribution Bioequivalence, based on absorption and bioavailability, with respect to emtricitabine, rilpivirine and tenofovir DF, was established for the emtricitabine/rilpivirine/tenofovir DF 200/25/300 mg single-tablet regimen and the corresponding dosages of the individual agents administered concurrently in healthy adults (Table 2) [25]. All drugs in the fixed-dose tablet were readily absorbed, reaching maximum plasma concentrations (Cmax) within 2–4.5 h (Table 2). Systemic exposure to rilpivirine and tenofovir DF was higher when the emtricitabine/rilpivirine/tenofovir DF single-tablet regimen was administered to healthy volunteers (n = 24) in the fed versus the fasted state, whereas emtricitabine exposure was unaffected by food [26]. To ensure optimal absorption, the single-tablet regimen should be administered with food [10, 11]. Rilpivirine displays high plasma protein binding in vitro (99.7 %), with albumin contributing the most to binding, whereas the absolute bioavailability of the drug has not yet been established [10, 11]. Emtricitabine has an estimated absolute bioavailability of 93 % (from 200 mg hard capsules), and the oral bioavailability of tenofovir (from tablets of tenofovir DF) is &25 % in the fasted state [10, 11]. Only a small proportion of emtricitabine (\4 %, regardless of concentration between 0.02–200 lg/mL) and tenofovir (\0.7 % across concentrations of 0.01–25 lg/mL) binds to plasma proteins in vitro [10, 11]. Emtricitabine and tenofovir DF are distributed widely throughout the body after oral administration and have a volume of distribution after intravenous administration of &1,400 and 800 mL/kg [10]. 3.2 Metabolism and Elimination Rilpivirine is metabolized predominantly via oxidation by cytochrome P450 (CYP) 3A enzymes, according to in vitro data [10, 11]. Following a single radiolabelled oral dose of rilpivirine, 85 % of the dose was eliminated via the faeces and 6 % via the urine, with &25 and \1 % of the dose being eliminated via these routes as unchanged parent drug. Metabolism of emtricitabine is limited and involves both oxidation and glucuronidation, producing 30 -sulfoxide diastereomers and 20 -D-glucuronide, which account for &9 and &4 % of an administered dose [10, 11]. Emtricitabine elimination occurs primarily via the kidneys (glomerular filtration and active tubular secretion), with most of a dose being recovered in the urine (&86 %; 13 % as three metabolites) and only &14 % being recovered in the faeces. The drug has a renal clearance of 213 mL/min [11] and an average systemic clearance of 307 mL/min [10].

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Table 2 Pharmacokinetic parameters of the emtricitabine/rilpivirine/tenofovir disoproxil fumarate single-tablet regimen versus those of the individual agents administered concurrently in 34 healthy adults in a single-dose, open-label, crossover, bioequivalence study [25] Parameter

Single-tablet regimen administration

Single-agent concurrent administration

Emtricitabine

Rilpivirine

Tenofovir DF

Emtricitabine

Rilpivirine

Tenofovir DF

1,750a

116a

325

1,650

99.8

291

AUClast (ngh/mL)

a

9,420

3,010a

3,110

9,420

2,600

3,040

AUC? (ngh/mL) tmax (h)

9,640a 2.5

3,390a 4.5

3,310 2.0

9,640 2.0

2,920 4.5

3,250 1.5

t1/2 (h)

18.3

54.2

18.1

19.0

53.1

18.1

Cmax (ng/mL)

Individuals received a single dose of emtricitabine 200 mg, rilpivirine 25 mg and tenofovir DF 300 mg, as the single-tablet regimen or as separate agents administered concurrently under fed conditions. Values are means, with the exception of tmax and t1/2 which are medians AUC area under the plasma concentration-time curve, AUClast AUC from time 0 to last quantifiable concentration, AUC? from time 0 to infinity, Cmax maximum plasma concentration, tmax time to Cmax, t1/2 terminal elimination half-life, DF disoproxil fumarate a

Bioequivalence, with respect to emtricitabine, rilpivirine and tenofovir DF, was established between the single-tablet regimen and concurrent administration of the individual agents, as the 90 % confidence intervals for the geometric least-squares mean ratios for Cmax, AUClast and AUC? were within the bioequivalence range (80–125 %)

CYP enzymes do not metabolize tenofovir DF or its nucleoside monophosphate analogue tenofovir in vitro [10]. Elimination of tenofovir occurs mainly via the kidneys (filtration and active tubular transport via human organic anion transporter-1), with most (&70–80 %) of an intravenous dose being excreted via the urine unchanged within 72 h [10, 11]. The drug has an estimated renal clearance of &210 mL/min and an apparent clearance of &307 mL/min [10]. 3.3 Special Patient Populations Exposure to emtricitabine and tenofovir DF is increased by renal impairment [10]. The emtricitabine/rilpivirine/tenofovir DF single-tablet regimen is not recommended for use in patients with moderate or severe renal impairment (CLCR \50 mL/min) [10, 11], including those with endstage disease or requiring dialysis [11], as the necessary adjustment in emtricitabine and tenofovir DF dosage is not achievable with the fixed-dose combination tablet. Use of the single-tablet regimen in patients with mild renal impairment is supported by limited data from clinical studies, and is only recommended in the EU if the potential benefits outweigh the risks [10]. Hepatic impairment does not substantially alter the pharmacokinetics of tenofovir DF [10, 11] and is expected to have limited impact on those of emtricitabine, given that liver enzymes do not play a significant role in its metabolism [11]. However, metabolism and elimination of rilpivirine occurs predominantly via the liver, and exposure to the drug was 47 and 5 % higher in patients with mild or moderate hepatic impairment (Child Pugh score B or C) versus controls [10, 11]. The single-tablet regimen can be used without dosage adjustment in patients with mild or moderate hepatic impairment [10, 11], although caution is

advised in those with moderate hepatic impairment in the EU [10]. The single-tablet regimen has not been studied in patients with severe hepatic impairment [10, 11], and in the EU it is not recommended in these patients [10]. The pharmacokinetics of rilpivirine did not appear to differ with age (range studied 18–78 years) in a population pharmacokinetic analysis, although data for those aged C65 years were limited [10]. As combination therapy with emtricitabine, rilpivirine and tenofovir DF has not been fully evaluated in elderly individuals (aged C65 years), the regimen should be used with caution in these patients [10, 11]. Gender does not appear to have any clinically relevant effect on the pharmacokinetics of emtricitabine, rilpivirine or tenofovir DF [11]. Moreover, race does not seem to alter the pharmacokinetics of emtricitabine or exposure to rilpivirine, whereas data for tenofovir DF are currently insufficient to determine whether the pharmacokinetics of the drug differ according to race or ethnicity [11]. Coninfection with hepatitis B and/or C virus (HBV and/ or HCV) does not affect rilpivirine exposure to any clinically relevant extent. The pharmacokinetics of emtricitabine and tenofovir DF in patients coninfected with HBV/ HCV have not been fully assessed, although current data suggest that emtricitabine displays a similar pharmacokinetic profile in HBV-infected patients as in patients infected with HIV [10]. 3.4 Drug Interactions Pharmacokinetic drug interactions of potential clinical relevance demonstrated or predicted to occur between components of the emtricitabine/rilpivirine/tenofovir DF single-tablet regimen and other drugs are summarized in Table 3. Drug interaction studies were not performed with

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the single-tablet regimen [10]. In the USA, emtricitabine/ rilpivirine/tenofovir DF should not be coadministered with any other antiretrovirals, as the tablet represents a complete regimen [11]. In the EU, concomitant use of emtricitabine/ rilpivirine/tenofovir DF with other NNRTIs is not recommended; ritonavir-boosted PIs, maraviroc or raltegravir require no dosage adjustment [10]. Emtricitabine did not inhibit key CYP isoenzymes in vitro (CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6 or 3A4) or the enzyme responsible for glucuronidation [10]. Additional in vitro data suggest that rilpivirine is a weak substrate of organic cation transporter 1 (OCT1) [but is not a substrate of organic anion-transporting polypeptide (OATP) 1A2 or 1B1, organic anion transporter 1 or 3, or p-glycoprotein] and inhibits OCT1 and OATP1B1 only weakly, with these interactions unlikely to be of any clinical relevance [27]. The multidrug and toxic compound extrusion-2K transporter is also inhibited by rilpivirine in vitro; whether this has any relevance in the clinical setting is not yet known [10].

the treatment of ART-naı¨ve (Sect. 4.1) and ART-experienced (Sect. 4.2) adults with HIV-1 infection, as evaluated in several multicentre trials, with the focus being the fixeddose emtricitabine/rilpivirine/tenofovir DF single-tablet regimen. Efficacy was assessed using surrogate endpoints of virological and immunological response; virological failure was also evaluated and included patients who did not achieve virological suppression [15, 18, 19, 23], experienced virological rebound [15] or discontinued treatment for reasons such as lack of efficacy [18] (criteria varied between studies). Some data were sourced from abstracts/posters/oral presentations [22, 28–41], a conference report [42] or the EU manufacturer’s prescribing information [10].

4 Therapeutic Efficacy This section reviews the efficacy of triple combination therapy with emtricitabine, rilpivirine and tenofovir DF in

4.1 Treatment-Naı¨ve Patients Discussion in this section focuses on the 96-week, randomized, open-label, phase IIIb, STaR study, designed to compare the efficacy of the once-daily emtricitabine/rilpivirine/tenofovir DF single-tablet regimen with that of the once-daily efavirenz/emtricitabine/tenofovir DF singletablet regimen in ART-naı¨ve adults [22, 23]. In two earlier 96-week, randomized, double-blind, phase III trials, known as ECHO [43] and THRIVE [44] (which have been reviewed in detail previously [45]), the efficacy of

Table 3 Pharmacokinetic interactions of potential clinical relevance associated with components of the emtricitabine/rilpivirine/tenofovir disoproxil fumarate single-tablet regimen. Recommendations apply to both the EU [10] and USA [11], unless otherwise specified Anticonvulsants (carbamazepine, oxcarbazepine, phenytoin, phenobarbital), St John’s wort, systemic dexamethasone ([1 dose) and antimycobacterials (rifampin [rifampicin], rifapentine) are contraindicated, as they may ; RPV plasma conc via CYP3A induction Proton pump inhibitors (e.g. dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole) are contraindicated, as they may ; RPV plasma conc by increasing gastric pH Products containing TDF or cytidine analogues (such as FTC or lamivudine) are not recommended The antimycobacterial rifabutin may ; RPV plasma conc via CYP3A induction; an additional RPV 25 mg tablet is recommended RPV coadministration is permitted for RPV dosage adjustment [11] (e.g. during rifabutin coadministration [10, 11]; see above) Adefovir dipivoxil is not recommended Didanosine is not recommended, as didanosine exposure may : Nephrotoxic drugs should be avoided; if unavoidable, renal function monitoring is advised in EU. In patients at risk of renal dysfunction, alternatives to high-dose or multiple NSAIDs should be considered in USA Renally eliminated drugs (e.g. cidofovir) are not recommended, as serum conc of FTC, TDF and/or the coadministered drug may : P-gp substrates (e.g. dabigatran etexilate) should be used with caution, as RPV may : exposure to some p-gp substrates CYP inhibitors should be used with caution, as RPV conc may : H2-receptor antagonists or antacids should be used with caution and administration staggered, as they may ; RPV plasma conc by increasing gastric pH. Once-daily H2-receptor antagonists recommended in EU Alternatives to macrolide/ketolide antibiotics (clarithromycin, erythromycin, telithromycin) should be considered, as RPV plasma conc may : via CYP3A inhibition Azole antifungal drugs (fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole) may : RPV plasma conc via CYP3A inhibition; however, no dosage adjustment required. Clinical monitoring for fungal infections advised If coadministering methadone, no dosage adjustment is required initially; however, clinical monitoring is advised, as adjustment of methadone maintenance dosage may be needed Conc concentration, CYP cytochrome P450, FTC emtricitabine, p-gp permeability glycoprotein, RPV rilpivirine, TDF tenofovir disoproxil fumarate, ; indicates reduce, : indicates increase

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rilpivirine was compared with that of efavirenz, when each was used in combination with a background NRTI regimen comprising either fixed-dose emtricitabine/tenofovir DF [43] or one of three investigator-selected regimens (emtricitabine plus tenofovir DF, zidovudine plus lamivudine, or abacavir plus lamivudine) [44]. Data from a pooled analysis of ECHO and THRIVE in the subset of patients who received rilpivirine plus emtricitabine/tenofovir DF or efavirenz plus emtricitabine/tenofovir DF [10, 15] are discussed further here. 4.1.1 STaR Patients in STaR were treatment-naı¨ve adults (aged C18 years) with a HIV-1 viral load of [2,500 copies/mL and sensitivity to efavirenz, emtricitabine and tenofovir DF; patients with known rilpivirine-associated mutations were among those excluded [23]. Patients were randomized to receive either the emtricitabine/rilpivirine/ tenofovir DF or emtricitabine/efavirenz/tenofovir DF single-tablet regimen, with the randomization process stratifying patients by viral load (B or [100,000 copies/mL). Overall, patients had a median age of &36 years, a mean viral load of 4.8 log10 copies/mL and a mean CD4? cell count of 391 cells/lL; 93 % were male, 67 % were Latino and &65 % had a viral load of B100,000 copies/mL [23]. In treatment-naı¨ve adults, the emtricitabine/rilpivirine/ tenofovir DF single-tablet regimen was noninferior to the emtricitabine/efavirenz/tenofovir DF single-tablet regimen in establishing virological suppression, as measured by the proportion of patients who achieved a viral load of \50 copies/mL after 48 (primary endpoint) [23] or 96 [22] weeks of treatment (Table 4). Improvements from baseline in CD4? cell count did not significantly differ between the two treatment groups at either timepoint [22, 23], and although the rate of virological failure was 1.4and 1.6-fold higher with the rilpivirine- than with the efavirenz-based regimen at 48 [23] and 96 weeks [22], the between-group difference was not significant where specified [23] (Table 4). The virological findings of STaR were generally similar regardless of race (White, Black) and ethnicity (Hispanic/ Latino) [33] and in patients who were female [32, 46], aged [50 years [31] or coninfected with HBV/HCV [30]. By contrast, baseline CD4? cell count and viral load appeared to impact virological response [29]. In particular, significantly more patients with a CD4? cell count of [350 cells/lL or a viral load of \100,000 copies/mL at baseline achieved a response with emtricitabine/rilpivirine/ tenofovir DF than with emtricitabine/efavirenz/tenofovir DF after 48 and/or 96 weeks of therapy (Table 5) [22, 23, 29]. However, in some instances, virological outcomes were slightly more favourable with emtricitabine/

E. D. Deeks

efavirenz/tenofovir DF than with emtricitabine/rilpivirine/ tenofovir DF among patients with high viral loads ([100,000 copies/mL) or low CD4? cell counts (B200 or B350 cells/lL) [22, 23], although differences between groups were not significant where reported [23] (Table 5). Notably, the [500,000 copies/mL stratum was small (n = 61) and the study was not powered to assess betweenstrata differences. 4.1.1.1 Patient-Reported Outcomes Some differences in health-related quality of life were evident between the two single-agent regimens, as assessed using the 12-item ShortForm Health Survey [28]. After 48 weeks of therapy, emtricitabine/rilpivirine/tenofovir DF recipients had significantly (p = 0.025) greater improvements in mental health composite score than emtricitabine/efavirenz/tenofovir DF recipients, whereas changes in physical health composite score were significantly more favourable with the emtricitabine/efavirenz/tenofovir DF regimen (p = 0.013 vs. emtricitabine/rilpivirine/tenofovir DF). However, neither treatment group displayed changes in the eight subdomains of the questionnaire, including general and mental health, physical, social and role functioning or bodily pain and vitality. When clinical symptoms associated with HIV infection or its treatment were evaluated using the HIV Symptom Index questionnaire, the emtricitabine/rilpivirine/tenofovir DF single-tablet regimen appeared to provide clinical benefit [28]. At week 48, several assessed symptoms were significantly lower than at baseline in emtricitabine/rilpivirine/tenofovir DF recipients, including gastrointestinal symptoms (diarrhoea, appetite loss, bloating), psychiatric symptoms (sad/down/depressed, nervousness/anxiety, difficulty falling/staying asleep), constitutional symptoms (fevers/chills/sweats, fatigue, weight loss/wasting, muscle aches/joint pain), dizziness/lightheadedness, cough/trouble catching breath, headache, skin problems, pain/numbness/ tingling in the hands or feet and problems with sex. The emtricitabine/efavirenz/tenofovir DF group also had significant reductions in many of these symptoms; however, significantly more patients in this group than in the emtricitabine/rilpivirine/tenofovir DF group reported diarrhoea (39 vs. 27 %) or pain/numbness/tingling in the hands or feet (37 vs. 29 %). Neither group had significant changes in how the body looks, nausea/vomiting, hair loss or trouble remembering. Treatment satisfaction did not differ significantly between the two single-tablet regimens after 48 weeks of therapy, as indicated by the mean treatment satisfaction scale total score of the HIV Treatment Satisfaction questionnaire (HIV-TSQ) [28]. Almost all patients (97.3–99.0 of emtricitabine/rilpivirine/tenofovir DF vs. 93.5–99.3 % of emtricitabine/efavirenz/tenofovir DF recipients) were

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Table 4 Efficacy of oral emtricitabine, rilpivirine and tenofovir disoproxil fumarate combination therapy in treatment-naı¨ve adults with HIV-1 infection in phase III trials Study

Regimena (no. of pts)

Week of eval

Ref

Plasma HIV-1 RNA level \50 copies/mLb (% of pts) [95 % CIc]

Virological failure (% of pts)

Mean change from BL [BL] in CD4? cell count (cells/lL)

STaR

FTC/RPV/TDF (394)

48

[23]

85.8 [-1.1, 9.2]d

8.1

200 [396]

81.6

5.6

191 [385]

96

[22]

77.9 [-0.6, 11.5]d

9.4e

278 [396]

72.4

5.9e

259 [385]

9.5e

193e,f [247]

e

182e,f [261]

FTC/EFV/TDF (392) FTC/RPV/TDF (394) FTC/EFV/TDF (392) ECHO & THRIVE (pooled FTC/TDF subset analysis)

RPV ? FTC/TDF (550)

48

[10]

EFV ? FTC/TDF (546) RPV ? FTC/TDF (550)

96

[15]

EFV ? FTC/TDF (546)

d

83.5 [-3, 6] 82.4

4.2

77 [-5.4, 4.6]d

11.5e

226 [247]

77

5.1e

222 [261]

Endpoints were assessed in the intent-to-treat population [10, 15] or the full analysis set [22, 23], using the time-to-loss-of-virological response [10, 15] or snapshot [22, 23] algorithm to evaluate virological outcomes BL baseline, EFV efavirenz, eval evaluation, FTC emtricitabine, pts patients, Ref reference, RPV rilpivirine, TDF tenofovir disoproxil fumarate a

Pts received FTC/RPV/TDF 200/25/300 mg or FTC/EFV/TDF 200/600/300 mg as once-daily single-tablet regimens in STaR, and RPV 25 mg or EFV 600 mg once daily in combination with FTC/TDF in ECHO and THRIVE

b

Primary endpoint at week 48

c

95 % confidence interval for the difference between the RPV group and comparator group

d

The RPV regimen was noninferior to the EFV regimen, based on a noninferiority margin of 12 % for the between-regimen difference

e

Statistical analysis for the between-group difference was not reported

f

Data sourced from a poster [40]

‘satisfied’, ‘moderately satisfied’ or ‘very satisfied’ with their treatment regimen across all ten domains of the questionnaire, including the convenience, flexibility and satisfaction domains. 4.1.2 Pooled Analysis of ECHO and THRIVE Patients included in the pooled emtricitabine/tenofovir DF subset of ECHO and THRIVE had a median age of &36 years and a median viral load of 5 log10 copies/ mL; most were male (78 %) and 50 % had a viral load of B100,000 copies/mL [15]. The findings of this analysis were generally consistent with those of the STaR study, with rilpivirine plus emtricitabine/tenofovir DF demonstrating efficacy noninferior to that of efavirenz plus emtricitabine/tenofovir DF in terms of the proportion of treatment-naı¨ve adults who achieved a plasma viral load of \50 copies/mL after 48 (primary endpoint) and 96 weeks of therapy (Table 4) [10, 15]. At each of these timepoints, CD4? cell counts had improved with both treatment regimens (between-group difference not significant, where specified), although the rate of virological failure was more than twofold higher in the rilpivirine than in the efavirenz group (Table 4) [10, 15]. Notably, when rates of virological response at 96 weeks were assessed by baseline viral load, noninferiority of the rilpivirine versus the efavirenz regimen was established in patients whose viral load at baseline was B100,000 copies/

mL (83 vs. 80 %; 95 % CI -3.9 to 9.1) or 100,001–500,000 copies/mL (74 vs. 73 %; 95 % CI -7.8 to 9.0), but not [500,000 copies/mL (60 vs. 75 %; 95 % CI -31.0 to 1.8) [15]. Rates of virological failure with the rilpivirine and efavirenz regimens were 5.9 and 2.4 % in patients whose baseline viral load was B100,000 copies/ mL and 17.6 and 7.6 % in patients whose baseline viral load was [100,000 copies/mL. 4.2 Treatment-Experienced Patients The efficacy of switching ART-experienced adults (aged C18 years) with virological suppression to the oncedaily emtricitabine/rilpivirine/tenofovir DF single-tablet regimen has been evaluated in a randomized, open-label, phase IIIb study, known as SPIRIT [18], and a noncomparative phase IIb trial, known as study 111 [19], each of 48 weeks’ duration. In SPIRIT [18], patients had to have received C6 months of therapy with their first or second ART regimen, which was a multiple-tablet regimen comprising a ritonavir-boosted PI plus two NRTIs. In Study 111 [19], patients had to have received C3 months of treatment with the emtricitabine/efavirenz/tenofovir DF single-tablet regimen as their first ART regimen and also want to change the regimen because of efavirenz intolerance [20]. Patients in these studies must also have maintained a HIV-1 RNA level of \50 copies/mL for C8 weeks [19] or C6 months [18], have no history of virological

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E. D. Deeks

Table 5 Analyses of virological outcomes by baseline viral load and CD4? cell count in the STaR trial. The 95 % confidence intervals for between-group differences are provided where available Pt subgroupa

Week of eval

Plasma HIV-1 RNA level \50 copies/mL (% of pts)

Virological failure (% of pts)

FTC/RPV/TDF

FTC/RPV/TDF

FTC/EFV/TDF

(95 % CI)

FTC/EFV/TDF

(95 % CI)

Baseline viral load (copies/mL) [22, 23] B100,000

48

89

82

(1.1 to 13.4)*

5

3

96

79

71

(0.2 to 15.1)*

7

4

[100,000

48

80

82

(-11.1 to 7.5)

14

10

96

76

75

(-8.7 to 11.6)

15

9

[100,000 to 500,000

48

83

82

(-9.6 to 10.8)

10

9

96

82

75

NR

8

9

48

72

80

(-29.2 to 13.7)

25

16

96

61

72

NR

33

8 14

[500,000

(-1.6 to 5.2) (-3.4 to 12.0) (-6.2 to 9.5) (-1.7 to 5.2)

Baseline CD4? cell count (cells/lL) [29] B200

48

72

71

(-16.8 to 19.0)

28

[200

48

88

83

(-0.7 to 10.0)

5

4

B350

48

81

83

(-10.6 to 6.1)

14

8

[350

48

89

81

(1.8 to 15.3)

4

4

See Table 4 for regimen details. Some data were sourced from abstracts/posters [22, 29] EFV efavirenz, FTC emtricitabine, eval evaluation, NR not reported, pt(s) patient(s), RPV rilpivirine * p \ 0.05 for between-group difference a

All subgroup analyses were conducted post hoc, except for baseline viral loads B100,000 or [100,000 copies/mL. The number of FTC/RPV/TDF and FTC/EFV/TDF recipients was generally similar in each of the baseline viral load strata (260 vs. 250, 134 vs. 142, 98 vs. 117 and 36 vs. 25 in the B100,000, [100,000, [100,000 to 500,000 and [500,000 copies/mL strata, respectively) and baseline CD4 ? cell count strata (53 vs. 51, 341 vs. 341, 159 vs. 181 and 235 vs. 211 in the B200, [200 to B350 and [350 cells/lL strata, respectively)

failure and no resistance to the study drugs [18, 19]. Across the trials, patients had a median age of 39–43 years, a median time since first ART of 2.5–2.9 years and were predominantly male (86–92 %) [18, 19]. In SPIRIT, patients were randomized to switch immediately to the single-tablet regimen (i.e. immediate-switch arm) or to continue receiving their current multiple-tablet regimen for the first 24 weeks of the study, with a subsequent switch (at week 24) to the single-tablet regimen (i.e. delayed-switch arm) [18]. The most common dual NRTI combination in the baseline ART regimen of this study was fixed-dose emtricitabine/tenofovir DF (&81 % of patients) and the most common ritonavir-boosted PIs were atazanavir and lopinavir (37 and 33 %) [18]. 4.2.1 SPIRIT Trial Switching to the emtricitabine/rilpivirine/tenofovir DF single-tablet regimen was noninferior to remaining on the original multi-tablet ritonavir-boosted PI plus NRTI regimen in terms of the proportion of patients who achieved a viral load of \50 copies/mL after 24 weeks of therapy, as assessed via the snapshot algorithm (primary endpoint) (Table 6) [18]. Findings for this parameter were generally

similar, regardless of baseline characteristics such as viral load (B or [100,000 copies/mL) [39], CD4? cell count (B or [200 cells/lL; B or [350 cells/lL) [39], age (B or [40 years) [38], race (White or Black) [37] or Hispanic/Latino ethnicity [36], as well as in patients coinfected with HBV/HCV [35] or whose HIV strain contained the reverse transcriptase resistance mutation K103N [34]. With regard to other outcomes, changes from baseline in CD4? cell count did not significantly differ between the treatments, although the proportion of patients who experienced virological failure was more than fivefold lower in recipients of the single- than of the multi-tablet regimen (Table 6) [18]. After 48 weeks of therapy, the emtricitabine/rilpivirine/ tenofovir DF single-tablet regimen continued to maintain virological suppression and be associated with a low incidence (\3 %) of virological failure (Table 6) [18]. In patients who switched to the single-tablet regimen at week 24 (i.e the delayed switch group), outcomes at week 48 (i.e. 24 weeks after the switch) were generally consistent with those seen at week 24 in the immediate-switch group (Table 6) [18]. Levels of antiretroviral drug adherence were high ([97 %) in both treatment groups, as evaluated by visual analogue scale.

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Table 6 Efficacy of switching to the oral emtricitabine/rilpivirine/tenofovir disoproxil fumarate single-tablet regimen in virologically-suppressed, treatment-experienced adults with HIV-1 infection in phase IIb [19] or IIIb [18] trials Study

Regimena (no. of pts)

Week of eval

Plasma HIV-1 RNA level \50 copies/mL (% of pts)

VF (% of pts)

Changeb from BL [BL] in CD4? (cells/lL)

SPIRIT [18]

rPI ? 2 NRTIs ? FTC/RPV/TDF od at BL [immediate Sw] (317)

24

93.7c,d

0.9e

20 [576]

89.9c,d

5.0e

32 [600]

89.3e

2.5e

10e

92.1e

1.3e

-7e

12

100d

NR

NR

24

100

NR

NR

48

93.9

4.1

-2 [653]

rPI ? 2 NRTIs (159) rPI ? 2 NRTIs ? FTC/RPV/TDF od at BL [immediate Sw] (317)

48

rPI ? 2 NRTIs ? FTC/RPV/TDF od at week 24 [delayed Sw] (152) Study 111 [19]

EFV/FTC/TDF ? FTC/RPV/TDF od (49)

Efficacy was assessed in pts who received C1 dose of study drug [18, 19] (defined as intent-to-treat population, where specified [18]) BL baseline, EFV efavirenz, eval evaluation, FTC emtricitabine, NR not reported, NRTIs nucleos(t)ide reverse transcriptase inhibitors, od once daily, pts patients, rPI ritonavir-boosted protease inhibitor, RPV rilpivirine, Sw switch, TDF tenofovir disoproxil fumarate, VF virological failure. ? indicates ‘switched to’ a

The dosage of antiretrovirals, where specified, was FTC/RPV/TDF 200/25/300 mg in both SPIRIT [18] and study 111 [51]

b

Changes from BL and BL values are means [18] or medians [19]

c

The between-group difference was 3.8 % (95 % CI -1.6 to 9.1 %) at 24 weeks; noninferiority of switching from rPI ? 2 NRTIs to RPV/FTC/TDF vs. continued rPI ? 2 NRTIs was established at this timepoint (assessment of noninferiority used a normal 95 % confidence interval approach; the noninferiority margin was 12 %) d

Primary endpoint, determined using the US FDA snapshot algorithm

e

Between-group statistical analyses were not reported

4.2.1.1 Patient-Reported Outcomes Several of the symptoms assessed by the HIV Symptom Index questionnaire, including fatigue, memory loss, headache, depression, anxiety/nervousness, problems having sex and muscle aches/joint pain, were reported with a significantly (p B 0.022) lower incidence 24 weeks after switching to the emtricitabine/rilpivirine/tenofovir DF single-tablet regimen than at baseline [41]. The switched group did not have a significant improvement from baseline in difficulty falling/staying asleep, body perception or appetite loss at this timepoint, although did have a significantly (p \ 0.001) lower incidence of some gastrointestinal symptoms (diarrhoea and stomach pain/bloating, but not nausea/vomiting) than patients who remained on a ritonavir-boosted PI plus NRTI regimen. Treatment satisfaction was significantly (p \ 0.001) higher in the switched than in the non-switched group at 24 weeks, as measured by the HIV-TSQ [41]. 4.2.2 Phase IIb Trial (Study 111) All patients who were already virologically suppressed with the emtricitabine/efavirenz/tenofovir DF single-tablet regimen, but wished to change their regimen because of efavirenz intolerance, sustained a viral load of \50 copies/ mL 12 weeks after switching to the emtricitabine/rilpivirine/tenofovir DF single-tablet regimen (primary endpoint),

with most patients continuing to sustain this degree of suppression at 24 and 48 weeks (Table 6) [19]. Moreover, at the 48 week timepoint, no significant change in CD4? cell count was evident and fewer than 5 % of patients experienced virological failure (Table 6). Of the two patients considered to have virological failure, one had low level viraemia (95 copies/mL at week 48) and the other had an undetectable week 48 rilpivirine trough level and poor adherence to study drug. However, most patients (92 %) were C95 % adherent through week 48, as measured by pill count [19].

5 Tolerability 5.1 General Profile Once-daily triple combination therapy with emtricitabine, rilpivirine and tenofovir DF for up to 96 weeks was generally well tolerated in treatment-naı¨ve (Sect. 5.2) and treatment–experienced (Sect. 5.3) adults infected with HIV-1 in pivotal trials discussed in Sect. 4, displaying a tolerability profile generally consistent with those of the individual agents. The adverse reactions most frequently associated with rilpivirine (incidence C2 %, grades 2–4) include depressive disorders, insomnia and headache, and those most commonly associated with emtricitabine and

2090

tenofovir DF (incidence C10 %) include diarrhoea, nausea, fatigue, headache, dizziness, insomnia, abnormal dreams, rash and depression [11]. A boxed warning regarding cases of lactic acidosis and hepatic steatosis with nucleoside analogues, such as tenofovir DF, is included in both the US [11] and EU [10] manufacturer’s prescribing information for the emtricitabine/rilpivirine/tenofovir Df single-tablet regimen. In the USA, emtricitabine/rilpivirine/tenofovir DF treatment should be suspended in patients with clinical or laboratory evidence indicative of lactic acidosis or pronounced hepatotoxicity, and requires particular caution in patients with known hepatic disease risk factors [11]. Similar recommendations apply in the EU [10]. Tenofovir DF may increase bone turnover relative to some other agents, as indicated by greater reductions in bone mineral density and greater elevations in bone metabolism markers; whether these effects have a longterm impact on bone health and fracture risk is not yet known [11]. For patients with prior pathological bone fracture or other osteoporosis/bone loss risk factors, bone mineral density assessment should be considered [11]. Tenofovir DF use has also been associated with renal function impairment that has led to bone abnormalities in some instances but rarely contributed to bone fracture [10, 11]. Creatinine clearance should be assessed prior to starting therapy in all patients [10, 11] and as clinically appropriate thereafter [11]. In patients without renal risk factors, the EU recommends creatinine clearance and serum phosphate monitoring after 2–4 weeks and 3 months of therapy and every 3–6 months subsequently [10]. Periodical renal function monitoring is also recommended (at increased frequency [10]) in patients at risk of renal dysfunction [11]. Some patients receiving rilpivirine-based ART have experienced hepatic adverse events [11]. In patients with hepatic dysfunction (including those coinfected with HBV/ HCV), appropriate laboratory testing should be conducted before emtricitabine/rilpivirine/tenofovir DF therapy is initiated [11] and monitoring performed during treatment [10, 11]. 5.2 Treatment-Naı¨ve Patients In treatment-naı¨ve adults, combination therapy with emtricitabine, rilpivirine and tenofovir DF appeared to have a more favourable overall tolerability profile than combined use of emtricitabine, efavirenz and tenofovir DF, according to data from the STaR trial [22] and a pooled analysis [15] of the ECHO and THRIVE studies (Table 7). For instance, in STaR, although most patients ([90 %) experienced treatment-emergent adverse events over 96 weeks of therapy, the proportion who discontinued

E. D. Deeks

treatment because of adverse events was 3.6-fold higher with the emtricitabine/efavirenz/tenofovir DF than with the emtricitabine/rilpivirine/tenofovir DF single-tablet regimen (Table 7), with psychiatric disorders (6 %) and neurological disorders (0.8 %) being the events most commonly causing discontinuation in the respective groups [22]. Moreover, significantly fewer patients in the emtricitabine/ rilpivirine/tenofovir DF group experienced adverse neurological, psychiatric or rash events (any grade) than in the emtricitabine/efavirenz/tenofovir DF group (Table 7), although these adverse events, as well as gastrointestinal disorders, were generally mild or moderate (i.e. grade 1 or 2) in severity in both groups (Table 7). Generally similar findings were reported in an earlier analysis of STaR at 48 weeks [23] as well as in the pooled analysis of ECHO and THRIVE at 96 weeks (Table 7) [15]. In terms of grade 3–4 laboratory abnormalities, those that occurred most frequently (incidence [3 %) over 48 weeks of therapy with emtricitabine/rilpivirine/tenofovir DF or emtricitabine/efavirenz/tenofovir DF in STaR were increased creatine kinase (5.1 % in both groups), increased ALT (3.3 vs. 3.4 %) and increased AST (3.3 vs. 3.3 %) [23]. These grade 3–4 laboratory abnormalities were also among those most commonly reported with both treatment regimens at 96 weeks, at which time, 22 % of emtricitabine/rilpivirine/tenofovir DF recipients and 20 % of emtricitabine/efavirenz/tenofovir DF recipients had experienced laboratory abnormalities of this severity [22]. These findings were generally consistent with those of the pooled analysis of 96-week data from ECHO and THRIVE [15]. Notably, in the pooled analysis, there was a significantly (p \ 0.001) lower incidence of grade 2–4 laboratory abnormalities with rilpivirine plus emtricitabine/ tenofovir DF than with efavirenz plus emtricitabine/tenofovir DF (37.0 vs. 50.9 %) [15]. These included significantly (p \ 0.02) lower incidences of ALT (6.9 vs. 11.0 %), AST (6.6 vs. 11.0 %), fasting LDL-C (6.4 vs. 17.0 %) and fasting TC (6.2 vs. 20.4 %) abnormalities, although significantly (p \ 0.001) more rilpivirine than efavirenz recipients developed grade 2–4 hyperbilirubinaemia (4.9 vs. 0.9 %). Grade 1 elevations in serum creatinine also occurred in more rilpivirine than efavirenz recipients (35 of 41 vs. 4 of 8 patients; p = 0.04). 5.3 Treatment-Experienced Patients In treatment-experienced adults with virological suppression on their current ART regimen, switching to the oncedaily emtricitabine/rilpivirine/tenofovir DF single-tablet regimen was generally well tolerated in 48-week phase IIIb [18] and IIb [19] trials, with most adverse events being

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Table 7 Tolerability of oral, triple combination therapy with emtricitabine, rilpivirine and tenofovir disoproxil fumarate in treatment-naive adults with HIV-1 infection. Results of a phase IIIb trial and pooled subset analysis of two phase III studies at 96 weeks Adverse events

Causing discontinuation

STaRa [22, 52]

ECHO & THRIVE (pooled) [15]

FTC/RPV/TDF (n = 394)

FTC/EFV/TDF (n = 392)

3

11

RPV ? FTC/TDF (n = 550)

Serious 17

EFV ? FTC/TDF (n = 546)

4**

9

9.5

11.2

[17***]

[33]

Gr3–4 [Gr2–4]

10

All Grs

92

Of particular importance

All Grs

Gr3–4

All Grs

Gr3–4

All Grsb

Gr2–4b

All Grsb

Gr2–4b

Neurological

27**

1.5

47

1.5

17***

3

37

12

Dizziness

7**

23

8***

26

Somnolence

3

8

3*

6

Headache

14

16

94

Attention disturbance Psychiatric

1* 28**

1.8

49

Abnormal dreams

6**

26

Insomnia

11

15

Depression Anxiety

9 7

12 9

Rash events Rash

16**

0.3

8

Gastrointestinal

24

4.3

2 7

27

9**

15

5***

16

11

0.8

13 1.0

16***

1.8

Values are percentages of patients EFV efavirenz, FTC emtricitabine, Gr(s) grade(s), RPV rilpivirine, TDF tenofovir disoproxil fumarate * p \ 0.05, ** p \ 0.005, *** p \ 0.0001 vs. comparator group a

Data available as an abstract/poster

b

Adverse events considered to be treatment related

grade 1 or 2 in severity [19] and no new adverse reactions identified [10, 11]. In the large phase IIIb SPIRIT study, adverse reactions occurred with a 20 % higher frequency after patients switched from their current ritonavir-boosted PI-based ART regimen to emtricitabine/rilpivirine/tenofovir DF [11], with those considered possibly/probably related to the study regimen and occurring most frequently over 48 weeks of treatment being fatigue (3 %), diarrhoea (3 %), nausea (2 %) and insomnia (2 %) [10]. Adverse events were not often grade 3–4 in severity in this trial, regardless of whether patients switched immediately to emtricitabine/rilpivirine/tenofovir DF singletablet regimen (i.e. immediate-switch arm) (5.7 % incidence over 48 weeks of therapy) or continued to receive their original ritonavir-boosted PI-based regimen for the first 24 weeks of the study (6.9 %) and switched to the single-tablet regimen thereafter (i.e. delayed switch arm) (7.9 % incidence between weeks 24 and 48) [18]. The incidence of grade 3–4 laboratory abnormalities was 8.8 % over 48 weeks of treatment in the immediate-switch arm,

11.3 % over 24 weeks of treatment in the delayed-switch arm (i.e. while patients continued to receive their original ritonavir-boosted PI-based regimen) and 15.2 % in the delayed-switch arm through week 48 [18]. Increases in AST, ALT and creatine kinase were among the most common (incidence C1 %) grade 3–4 laboratory abnormalities to occur across these populations. Discontinuation of therapy because of adverse events in this trial occurred in 2.2 % of the patients in the immediate switch arm; none of the patients in the delayed-switch arm discontinued therapy because of adverse events while continuing to receive their ritonavir-boosted PI-based regimen and 3.9 % discontinued treatment for this reason after switching to emtricitabine/rilpivirine/tenofovir DF [18]. In the small phase IIb trial in which patients switched from the emtricitabine/efavirenz/tenofovir DF to the emtricitabine/rilpivirine/tenofovir DF single-tablet regimen for 48 weeks, no adverse event resulted in discontinuation of study drug [19]. Grade 2 adverse events considered to be treatment-related (fatigue, gastritis and increased blood bilirubin) occurred in 3 of 49 (6.1 %) emtricitabine/

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rilpivirine/tenofovir DF recipients, whereas none of the grade 3 or 4 adverse events (reported in three patients) were considered to be related to therapy [19].

6 Dosage and Administration The emtricitabine/rilpivirine/tenofovir DF single-tablet regimen is indicated in the EU for the treatment of HIV-1 in adults with a viral load of B100,000 copies/mL and without any known mutations associated with resistance to the NNRTI class, emtricitabine or tenofovir DF [10]. The regimen is also indicated in the USA for the treatment of HIV-1 infection in adults with no ART history and a viral load of B100,000 copies/mL, and in certain adults who have had virological suppression (i.e. a viral load \50 copies/mL) for C6 months on their current (first or second) ART regimen in order to replace that regimen, provided they do not have resistance to any of the three components of the single-tablet regimen [11]. The recommended dosage of emtricitabine/rilpivirine/tenofovir DF is one tablet (200/25/300 mg) taken orally once daily with food [10, 11]; of note, tenofovir DF 300 mg corresponds to tenofovir disoproxil 245 mg. No adjustments in dosage are necessary when switching from an efavirenz- to a rilpivirine-containing ART regimen [10]. Local prescribing information should be consulted for detailed information regarding other contraindications, use in special patient populations, drug interactions, warnings and precautions.

7 Current Status of Emtricitabine/Rilpivirine/ Tenofovir Disoproxil Fumarate in HIV-1 Infection ART regimens currently recommended for first-line use in treatment-naı¨ve adults combine a dual NRTI backbone with either an NNRTI, a ritonavir-boosted PI or an integrase strand transfer inhibitor [3–6], with suitable regimens being selected on a patient-by-patient basis [3, 5]. The NRTI backbone most commonly preferred/recommended across current treatment guidelines is emtricitabine with tenofovir DF [3–6], and for patients for whom an NNRTI is considered a suitable third agent, efavirenz is generally the preferred/recommended option [3–6]; however, the more recently introduced NNRTI rilpivirine is also a recommended option in certain circumstances (see later discussion for further details) in some guidelines [4– 6], with others including rilpivirine as an alternative NNRTI in this setting [3]. ART regimen selection should be done on the basis of factors such as the resistance profile of the infecting HIV strain [5, 6] and the characteristics of the regimen [3, 5, 47] and patient [3, 5, 6, 47] with fixed-dose combinations

E. D. Deeks

generally being preferred so that convenience, and consequently patient adherence, is maximized [47]. Indeed, coformulated antiretrovirals are now standard of care, with some formulations combining three active agents and thus providing a complete ART regimen in a single tablet [48]. Emtricitabine/efavirenz/tenofovir DF was the first singletablet regimen to be approved and is now a frequently prescribed first-line treatment option [48]. However, as the efavirenz component of the regimen is associated with concerns of resistance and toxicity, other single-tablet regimens have been sought [48]. One such single-tablet regimen (and the only other NNRTI-containing singletablet regimen commercially available at present) is emtricitabine/rilpivirine/tenofovir DF (see Sect. 6 for US and EU indication details). According to a large randomized study (STaR), the once-daily emtricitabine/rilpivirine/tenofovir DF singletablet regimen is no less effective than the once-daily emtricitabine/efavirenz/tenofovir DF single-tablet regimen in establishing virological suppression over 96 weeks of therapy in ART-naı¨ve adults (Sect. 4.1.1), confirming the findings of earlier trials of the same duration (ECHO and THRIVE) in which ART-naı¨ve patients received either rilpivirine or efavirenz in combination with emtricitabine/ tenofovir DF (Sect. 4.1.2). However, emtricitabine/rilpivirine/tenofovir DF may provide more effective virological suppression than emtricitabine/efavirenz/tenofovir DF in patients with high baseline CD4? counts ([350 cells/lL) or low baseline viral loads (B100,000 copies/mL), at least according to the STaR trial, whereas pretreatment low CD4? cell counts and high viral loads could potentially limit the virological benefit of emtricitabine/rilpivirine/ tenofovir DF (Sects. 4.1.1 and 4.1.2). Thus, guidelines recommend rilpivirine regimens in the ART-naı¨ve setting only if the viral load is B 100,000 copies/mL [3–6], with one guideline also including the criteria of a CD4? cell count of [200 cells/lL [5]. For treatment-experienced patients who already have virological suppression on their current ART, regimen modification may be necessary for various reasons, including to facilitate adherence, manage toxicity or address drug interactions [4, 5], although virological suppression should be maintained [5]. Regimens may also be simplified for reasons such as to reduce pill burden or the frequency/difficulty of administration [4, 5]. In this regard, data from randomized and noncomparative trials show that most (C89 %) treatment-experienced adults already virologically suppressed with ART and without prior virological failure can be switched to receive the once-daily emtricitabine/rilpivirine/tenofovir DF single-tablet regimen with maintenance of virological suppression (Sect. 4.2). In one of these trials (SPIRIT), patients were successfully switched from a more complex, multi-tablet PI-based

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regimen, supporting the use of emtricitabine/rilpivirine/ tenofovir DF in regimen simplification strategies, whereas in the other study, patients were switched from the emtricitabine/efavirenz/tenofovir DF single-tablet regimen because of efavirenz intolerance, suggesting emtricitabine/ rilpivirine/tenofovir DF may be an option in this setting when single-tablet therapy is preferred. Notably, the emtricitabine/rilpivirine/tenofovir DF fixed-dose tablet is smaller than some other fixed-dose tablets, including emtricitabine/efavirenz/tenofovir DF [5], and as a result some patients may find them easier to swallow. However, as with most other single-tablet regimens, the inability to change or adjust the dosage of the individual components of emtricitabine/rilpivirine/tenofovir DF is a potential limitation. The adverse events associated with ART can impact patient adherence to treatment and thus jeopardize virological suppression [5, 49], making tolerability an important aspect to consider. Once-daily triple combination therapy with emtricitabine, rilpivirine and tenofovir DF is generally well tolerated in ART-naı¨ve and -experienced adults (Sect. 5). The combination appears to have a more favourable tolerability profile than combined use of emtricitabine, efavirenz and tenofovir DF in ART-naı¨ve patients, with the STaR trial demonstrating a lower incidence of adverse neurological, psychiatric and rash events with emtricitabine/rilpivirine/tenofovir DF than with emtricitabine/efavirenz/tenofovir DF (Sect. 5.2). Emtricitabine/rilpivirine/tenofovir DF may therefore be a useful option for individuals at increased risk of CNS events, as certain drugs, including efavirenz, are contraindicated in such patients [47]. How an ART regimen affects modifiable risk factors for comorbidities like cardiovascular disease may also be important to consider when choosing antiretrovirals [18]. Emtricitabine/rilpivirine/tenofovir DF appears to have minimal impact on lipid levels and may be associated with smaller increases in levels of TC, LDL-C and HDL-C than emtricitabine/efavirenz/tenofovir DF, according to 96-week data from STaR (Sect. 2.5). Consistent with these findings, switching to emtricitabine/rilpivirine/tenofovir DF improved the lipid profiles of ART-experienced patients receiving PI-based therapy or the emtricitabine/ efavirenz/tenofovir DF single-tablet regimen in randomized and noncomparative studies (Sect. 2.5). Thus, emtricitabine/rilpivirine/tenofovir DF may be preferred for patients at high cardiovascular risk [47], as hyperlipidaemia/dyslipidaemia can occur with some other antiretrovirals, such as ritonavir-boosted PIs, efavirenz, the NRTIs abacavir, stavudine and zidovudine and cobicistat-boosted regimens (e.g. the elvitegravir/cobicistat/tenofovir DF/ emtricitabine single-tablet regimen) [5]. However, caution is necessary when administering emtricitabine/rilpivirine/

tenofovir DF with drugs that carry a risk of Torsade de Pointes, as QT interval prolongation has been seen with rilpivirine at supratherapeutic doses (Sect. 2.6). In addition to poor tolerability, the development of resistance to drugs within ART regimens can limit the long-term maintenance of virological suppression [49]. ART-naı¨ve and -experienced patients receiving combination therapy with emtricitabine, rilpivirine and tenofovir DF who develop resistance to rilpivirine may consequently be resistant to other NNRTIs, such as efavirenz, etravirine and/or nevirapine (Sect. 2.4). Future NNRTI treatment options may therefore be limited in these patients, perhaps more uniformly than with other NNRTIs [48]. The cost of ART is another factor that may impact regimen selection [5]. Pharmacoeconomic data for the emtricitabine/rilpivirine/tenofovir DF single-tablet regimen are currently limited. However, data from an analysis (available as an abstract) based on the SPIRIT trial suggest that switching virologically-suppressed patients from a ritonavir-boosted PI regimen to emtricitabine/rilpivirine/ tenofovir DF may be cost saving relative to remaining on PI-based therapy, with estimated wholesale acquisition costs of US$10,275 versus US$12,272 per patient over 24 weeks of treatment (2012 costing) [50]. Further pharmacoeconomic data would be of interest. In conclusion, current clinical data indicate that the emtricitabine/rilpivirine/tenofovir DF single-tablet regimen provides a convenient, effective and generally well tolerated treatment option for use in some adults who are ARTnaı¨ve, as well as those who are already virologically suppressed on their current ART regimen and wish to switch for simplification or because of intolerance. Data selection sources: Relevant medical literature (including published and unpublished data) on emtricitabine/rilpivirine/ tenofovir disoproxil fumarate was identified by searching databases including MEDLINE (from 1946) and EMBASE (from 1996) [searches last updated 10 October 2014], bibliographies from published literature, clinical trial registries/databases and websites. Additional information was also requested from the company developing the drug. Search terms: Complera, Eviplera, emtricitabine and rilpivirine and tenofovir, emtricitabine/rilpivirine/tenofovir, rilpivirine/ emtricitabine/tenofovir. Study selection: Studies in patients with HIV-1 infection who received emtricitabine/rilpivirine/tenofovir disoproxil fumarate. When available, large, well designed, comparative trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Disclosure The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered the opportunity to comment on this article. Changes resulting from comments received were made by the author on the basis of scientific and editorial merit. Emma Deeks is a salaried employer of Adis/Springer.

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Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate: A Review

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