tenofovir disoproxil fumarate single-tablet regimen (Stribild®): a review of its use in the management of HIV-1 infection in adults.

Drugs (2014) 74:75–97 DOI 10.1007/s40265-013-0158-4

ADIS DRUG EVALUATION

Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate Single-Tablet Regimen (StribildÒ): A Review of Its Use in the Management of HIV-1 Infection in Adults Caroline M. Perry

Published online: 14 December 2013 Ó Springer International Publishing Switzerland 2013

Abstract A new single-tablet, fixed-dose formulation consisting of elvitegravir, an HIV-1 integrase strand transfer inhibitor (INSTI); cobicistat, a pharmacokinetic enhancer; emtricitabine, a nucleoside reverse transcriptase inhibitor; and tenofovir disoproxil fumarate (tenofovir DF), a nucleotide reverse transcriptase inhibitor (elvitegravir/cobicistat/emtricitabine/tenofovir DF 150 mg/150 mg/200 mg/ 300 mg; StribildÒ) is available in some countries for the once-daily treatment of HIV-1 infection in antiretroviral therapy-naı¨ve adults. Elvitegravir/cobicistat/emtricitabine/ tenofovir DF is the first INSTI-based single-tablet regimen available for the complete initial treatment of adults with HIV-1 infection. In two large, randomized, double-blind, phase III trials, once-daily treatment with elvitegravir/cobicistat/emtricitabine/tenofovir DF was effective in reducing plasma HIV-1 RNA levels to\50 copies/mL at the week 48 assessment and showed virological efficacy noninferior to that of the efavirenz/emtricitabine/tenofovir DF single-tablet regimen or a once-daily regimen of atazanavir plus ritonavir (ritonavir-boosted atazanavir) plus the fixed-dose combination of emtricitabine/tenofovir DF. Elvitegravir/cobicistat/ emtricitabine/tenofovir DF also showed durable efficacy in terms of achieving sustained suppression of HIV-1 RNA levels to\50 copies/mL for up to 144 weeks in both of the phase III trials. Elvitegravir/cobicistat/emtricitabine/ The manuscript was reviewed by: T. Klimkait, Department of Biomedicine, Institute for Medical Microbiology, University of Basel, Basel, Switzerland; M. Nelson, Department of HIV Medicine, Chelsea and Westminster Hospital, London, England; C. Torti, University Unit of Infectious Diseases, Mater DominiTeaching Hospital, Magna Graecia University, Catanzaro, Italy. C. M. Perry (&) Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore 0754, Auckland, New Zealand e-mail: [email protected]

tenofovir DF is an important addition to the group of simplified once-daily single-tablet regimens currently available for the effective treatment of HIV-1 infection in antiretroviral therapy-naı¨ve patients and is among the preferred regimens recommended for use as initial treatment. It offers advantages over more complex multiple-tablet regimens that may impair treatment adherence, which is fundamental to the successful management of HIV-1 infection. Elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate fixed-dose single-tablet regimen in HIV-1 infection: a summary Fixed-dose single-tablet regimen of: an HIV-1 integrase strand transfer inhibitor, elvitegravir; a pharmacokinetic enhancer cobicistat; and two nucleos(t)ide reverse transcriptase inhibitors, emtricitabine and tenofovir disoproxil fumarate (tenofovir DF) Individual antiretroviral drug components show good activity against clinical isolates of HIV-1 and have well-characterized resistance profiles Convenient single-tablet once-daily administration schedule with the potential for enhancing adherence to treatment Effective in the treatment of HIV-1 infection in antiretroviral therapy-naı¨ve adults; produces marked and durable suppression of plasma HIV-1 RNA levels to \50 copies/mL Virological efficacy noninferior to that of the once daily, fixed-dose, single-tablet regimen of efavirenz/emtricitabine/ tenofovir DF or ritonavir-boosted atazanavir plus the fixeddose combination of emtricitabine/tenofovir DF

Generally well tolerated; the most common adverse events are nausea and diarrhoea. US prescribing information carries a boxed warning concerning lactic acidosis/severe hepatomegaly with steatosis and posttreatment acute exacerbation of hepatitis B

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1 Introduction According to the WHO, 35.3 million people are living with HIV/AIDS worldwide and the number of people infected with HIV-1 continues to rise [1]. In Europe, the estimated number of children and adults with HIV infection increased to 2.3 million in 2011 [2]. Nevertheless, despite these statistics, it has been said that we may be at the ‘beginning of the end of AIDS’ as a result of developments and improvements in treatments for HIV infection [3]. Highly active antiretroviral therapy (HAART) regimens consisting of two nucleoside/nucleotide reverse transcriptase inhibitors (NRTI), in combination with a non-nucleoside reverse transcriptase inhibitor (NNRTI) [usually efavirenz], a ritonavir-boosted protease inhibitor (PI) or an integrase strand transfer inhibitor (INSTI) are the standard recommended treatments in international guidelines for the treatment of antiretroviral therapy-naı¨ve patients with HIV-1 infection [3–8]. The combination of emtricitabine with tenofovir DF is among the preferred/recommended dual NRTI backbone options in combination antiretroviral therapy regimens in most current treatment guidelines for adults with HIV-1 infection [3–6, 8, 9]. Over recent years, significant advances have been made in terms of simplifying treatment for HIV infection, particularly with the introduction of fixed-dose drug combinations that allow the administration of up to three antiretroviral drugs in one tablet, providing more convenient once-daily administration [3–6, 8, 10]. Evidence from clinical studies has shown that treatment with simple oncedaily HAART regimens results in better treatment adherence and patient satisfaction, together with more persistent viral suppression, than the more complex regimens involving the administration of multiple daily doses of different HAART drugs [11, 12]. Until recently, only two single-tablet formulations containing three antiretroviral drugs (and both including an NNRTI and emtricitabine/ tenofovir DF) have been available in the USA for use as a complete once-daily HAART regimen for the treatment of patients with HIV-1 infection. Both of these single-tablet regimens show good virological efficacy and are generally well tolerated [4] and have an important niche in the treatment of patients with HIV-1 infection. However, the NNRTI component may not be appropriate for all patients; for example, efavirenz is associated with neuropsychiatric effects and may not be suitable for patients with a history of psychiatric disorders [3–6]. Hence, there has been an unmet need for single-tablet, once-daily formulations containing drugs from a new class/different mechanism of action, with good efficacy and tolerability to complement two NRTIs in a triple combination tablet. This has led to the development of a new tablet formulation combining fixed doses of elvitegravir (an INSTI)

C.M. Perry

150 mg, cobicistat (a pharmacokinetic enhancer used to boost plasma concentrations of elvitegravir and improve its effects [13]) 150 mg, emtricitabine 200 mg and tenofovir disoproxil fumarate (DF) 300 mg, equivalent to 245 mg of tenofovir disoproxil or 136 mg tenofovir, (StribildÒ) [hereafter referred to as elvitegravir/cobicistat/emtricitabine/tenofovir DF]. This co-formulated product is the first and only boosted INSTI-based combination of drugs available as a complete once-daily single-tablet regimen for the treatment of HIV-1 infection. Elvitegravir/cobicistat/emtricitabine/tenofovir DF has been evaluated in randomized clinical trials [11, 12, 14, 15] and is approved for use as a once-daily complete regimen for the treatment of HIV-1 infection in antiretroviral therapy-naı¨ve adults in the USA [16, 17]. It has also been granted marketing authorization by the European Commission for use (in all 27 EU countries) as a complete regimen for the treatment of HIV1 infection in adults who are antiretroviral treatment-naı¨ve or are infected with HIV-1 without known mutations associated with resistance to any of the three antiretroviral agents (elvitegravir, emtricitabine or tenofovir DF) in the combination formulation [18, 19]. Elvitegravir/cobicistat/ emtricitabine/tenofovir DF also has market approval in Australia, Turkey and South Korea, and has been accepted by the Scottish Medicines Consortium for use within the National Health System in Scotland [20]. This article provides an overview of the pharmacology of elvitegravir/cobicistat/emtricitabine/tenofovir DF (as the fixed-dose combination or as individual agents) and focuses on its clinical efficacy and tolerability profile in antiretroviral therapy-naive adults with HIV-1 infection.

2 Pharmacodynamic Properties The pharmacodynamic properties of emtricitabine [21, 22], tenofovir [23, 24] and elvitegravir [25–27], the antiretroviral drug components of the fixed-dose elvitegravir/cobicistat/emtricitabine/tenofovir DF combination tablet, have been reviewed previously. This section includes a brief summary of these data together with recent information from the US prescribing information (PI) [16], the European Summary of Product Characteristics (EU SPC) [19] and the phase III clinical trials reviewed in Sect. 4 [11, 12]. Key data on elvitegravir/cobicistat/emtricitabine/tenofovir DF reported in recent abstracts are also reviewed. Tenofovir DF is an ester prodrug of tenofovir (see Sect. 3) that is metabolically converted to tenofovir diphosphate, the active metabolite (Table 1) [10, 23]. The fourth drug included in the formulation is cobicistat; this agent is an inhibitor of human cytochrome P450 3A (CYP3A) isoforms and is used to increase systemic exposure to drugs such as elvitegravir that are metabolized by

Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate: A Review

CYP3A enzymes [13, 16, 19, 25, 28, 29] (see Sect. 3). Cobicistat does not show activity against HIV-1 and in this regard differs from ritonavir, which is also used to boost plasma concentrations of other antiretroviral drugs [28]. The mechanisms of action of each of these drugs are briefly summarized in Table 1. 2.1 Antiretroviral Activity The antiretroviral activities of elvitegravir, emtricitabine and tenofovir are well established. Elvitegravir, emtricitabine and tenofovir, as individual agents and in combination, show good activity against clinical isolates of HIV-1 and laboratory strains of the virus [10, 21, 23, 25, 30]. In cell culture combination antiviral activity assays, elvitegravir, emtricitabine and tenofovir were synergistic and did not display antagonistic antiviral activity. Furthermore, cobicistat did not exhibit detectable antiviral activity against HIV-1, hepatitis B virus (HBV) or hepatitis C virus (HCV) in cell culture investigations and neither enhanced nor antagonized the antiviral activity of elvitegravir, emtricitabine or tenofovir [16, 19]. Investigations of the antiviral activity of elvitegravir, the newest of the three antiretroviral agents in elvitegravir/ cobicistat/emtricitabine/tenofovir DF, have been conducted using laboratory strains and clinical isolates of HIV-1 in peripheral blood lymphocytes, monocyte/macrophage cells and T lymphoblastoid cell lines [19]. The 50 % effective concentration (EC50) values for elvitegravir against HIV-1 ranged from 0.02 to 1.7 nmol/L [19]. Elvitegravir exhibited excellent activity against clinical isolates of HIV-1 subtypes (clades) A, B, C, D, E, F, G and O (mean EC50 values ranged from 0.04 to 0.55 ng/mL [25] and 0.1 to 1.3 nmol/L [19]), including isolates resistant to NRTIs, NNRTIs and

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PIs. Additive/synergistic activity against HIV-1 was observed with elvitegravir in combination with the NRTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, or zidovudine, the NNRTIs efavirenz, etravirine, or nevirapine, the PIs amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, or tipranavir, as well as enfuvirtide (a fusion inhibitor), maraviroc (a CCR5 co-receptor antagonist entry inhibitor) and raltegravir (an INSTI) [16, 25]. Elvitegravir was also active against HIV-2 (EC50 value 0.53 nmol/L) [16, 19]. Marked and rapid suppression of HIV-1 RNA levels were observed in patients with HIV-1 infection during treatment with elvitegravir [31]. In an initial 10-day randomized, double-blind, placebo-controlled monotherapy study, elvitegravir showed good antiretroviral activity (significant vs. placebo; p \ 0.01) over the short term in 40 integrase-naı¨ve patients with HIV-1 infection and a baseline HIV-1 RNA level of 4.75 log10 copies/mL. Mean reductions of up to 2 log10 copies/mL occurred in all patients treated with elvitegravir and there was no emergence of mutations conferring integrase resistance [31]. 2.2 Resistance The resistance profiles of elvitegravir, emtricitabine and tenofovir have been assessed in clinical isolates of HIV-1 from patients receiving treatment with these drugs. This section provides a brief summary of mutations selected in HIV-1 after treatment with these individual agents, together with data on the emergence of resistance mutations in clinical isolates from antiretroviral therapy-naı¨ve patients with HIV-1 infection receiving treatment with elvitegravir/ cobicistat/emtricitabine/tenofovir DF in two major phase III clinical trials (Study 102 [11] and Study 103 [12]; see

Table 1 Summary of the mechanisms of action of elvitegravir, emtricitabine, tenofovir disoproxil fumarate and cobicistat [16, 19, 21, 24–26] Drug

Mechanism of action

Elvitegravir

HIV-1 integrase strand transfer inhibitor that blocks the formation of the HIV-1 provirus and the spread of HIV-1 infection by prevention the integration of HIV-1 DNA into genomic DNA in the host cella

Emtricitabine

Synthetic nucleoside analogue of cytidine that is phosphorylated by cellular enzymes to form emtricitabine 50 -triphosphateb. Emtricitabine 50 -triphosphate inhibits the activity of the HIV-1 RT by competing with the natural substrate deoxycytidine 50 -triphosphate and by being incorporated into nascent viral DNA which results in chain termination

Tenofovir

Acyclic nucleoside phosphonate diester analogue of adenosine monophosphate. Tenofovir disoproxil fumarate is an ester prodrug that requires initial diester hydrolysis for conversion to tenofovir and then phosphorylation by cellular enzymes to produce tenofovir diphosphate. Tenofovir diphosphatec inhibits the activity of HIV-1 RT by competing with the natural substrate deoxyadenosine 50 -triphosphate and, after incorporation into DNA, by DNA chain termination

Cobicistat

Selective, mechanism-based inhibitor of cytochromes P450 of the CYP3A subfamily. By inhibiting CYP3A-mediated metabolism, cobicistat increases systemic exposure to CYP3A substrates (including elvitegravir) that have limited bioavailability and short half-lives due to CYP3A-dependent metabolism

NA not applicable, RT reverse transcriptase a

Does not produce inhibition of human topoisomerases I or II

b

Emtricitabine 50 -triphosphate is a weak inhibitor of mammalian DNA polymerases a, b, e, and mitochondrial DNA polymerase c

c

Weak inhibitor of mammalian DNA polymerases a, b, and mitochondrial DNA polymerase c

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Sect. 4). Resistance data are derived from various sources, including the US PI [16], the EU SPC [19], the clinical trial reports [11, 12] and reviews [32, 33]. Of note, the development of viral resistance to elvitegravir/cobicistat/emtricitabine/tenofovir DF may occur when it is coadministered with drugs that interact with elvitegravir and cobicistat via induction of CYP3A activity (see Sect. 3.6) resulting in decreased plasma concentrations of both drugs [16]. Clinical isolates of HIV-1 with resistance mutations, resulting in decreases in viral susceptibility to elvitegravir, emtricitabine or tenofovir, have been identified in cell culture investigations [16, 19]. A reduction in the susceptibility of HIV-1 isolates to elvitegravir occurred in the presence of the following primary integrase substitutions: T66A/I, E92G/Q, S147G or Q148R. Additional integrase substitutions selected in cell culture included D10E, S17N, H51Y, F121Y, S153F/Y, E157Q, D232N, R263K or V281M [16, 19]. A reduction in the susceptibility of HIV-1 isolates to emtricitabine was associated with the presence of M184V/I substitutions in HIV-1 reverse transcriptase, whereas the K65R mutation in HIV-1 reverse transcriptase was associated with resistance to tenofovir, manifest as a 2–4 fold decrease in the susceptibility to tenofovir [16, 19]. Isolates of HIV-1 expressing C3 thymidine analogue-associated mutations including either L210W or M41L reverse transcriptase mutations had decreased susceptibility to tenofovir [19]. The development of resistance to one or more components of elvitegravir/cobicistat/emtricitabine/tenofovir DF was studied in antiretroviral therapy-naı¨ve adults with HIV-1 infection in two randomized, phase III trials (Studies 102 and 103; see Sect. 4). Data on resistance in participants of Study 102 and 103 are reported in the individual study reports; a pooled analysis of resistance data for elvitegravir, emtricitabine and tenofovir DF is documented in the US PI and EU SPC and is the main focus of this section [16, 19]. In both studies, resistance analyses were performed on HIV-1 samples from patients who were viraemic with plasma HIV-1 RNA levels of [400 copies/mL at virological failure, at week 48 or at the time of early drug treatment discontinuation in the study. Virological failure was defined as a suboptimal virological response (HIV-1 RNA level C50 copies/mL and \1 log10 reduction from baseline at or after the week 8 visit); virological rebound (HIV-1 RNA levels of C400 copies/ mL after achieving an HIV-1 RNA level of\50 copies/mL, or having a [1 log10 increase in HIV-1 RNA levels from their nadir at 2 subsequent visits). In addition, patients who were on study drugs, had not been analyzed previously and who had an HIV-1 RNA level of C400 copies/mL at week 48 or their last visit (at or after week 8) were also analyzed for resistance at their last visit [12].

C.M. Perry

The development of resistance to at least one of the antiretroviral components of elvitegravir/cobicistat/emtricitabine/tenofovir DF was rare in both of the phase III studies [11, 12]. In the pooled analysis, more than half of the viraemic patients with genotypic results (53 % [16 of 30]) had viral samples with C1 primary resistance mutations to elvitegravir, emtricitabine and/or tenofovir. In HIV-1 reverse transcriptase, the most frequent substitutions seen after drug treatment were M184V/I (n = 15); a K65R mutation in HIV-reverse transcriptase was also identified in five patients [16]. Primary substitutions in HIV-1 integrase associated with elvitegravir resistance were T66I (n = 2), E92Q (n = 9), Q148R (n = 3), and N155H (n = 5); additional mutations conferring resistance to elvitegravir were H51Y, L68I/V, G70R, G140C, S153A, E157Q and I73V. The majority of HIV-1 isolates harbouring integrase substitutions exhibited reductions in the susceptibility of elvitegravir of 6 to [198-fold compared with wild-type HIV-1. Most of the patients with viral isolates harbouring integrase substitutions associated with resistance to elvitegravir also had M184I/V reverse transcriptase substitutions associated with emtricitabine resistance. For further details, see the US prescribing information [16]. In Study 102, 8 of 14 patients (2 % of those enrolled in the study) treated with elvitegravir/cobicistat/emtricitabine/ tenofovir DF who were assessed for drug resistance had viral isolates with resistance mutations. The NRTI-associated mutations detected were M184V/I (n = 5) and K65R (n = 3). Integrase mutations (E92Q) were also detected in isolates from seven of the eight patients [11]. In Study 103, 20 (3 %) of patients were assessed for resistance mutations. Five patients treated with elvitegravir/cobicistat/emtricitabine/tenofovir DF and none of the recipients of atazanavir plus ritonavir (ritonavir-boosted atazanavir) plus emtricitabine/tenofovir DF developed resistance mutations in HIV-1 isolates. Four of the five patients had primary integrase mutations: Q148R (n = 2), N155H (n = 1) or a complex mixture of T66I, E92Q, and N155H (n = 1); phenotypic resistance to elvitegravir was also evident [12]. Four patients developed a reverse transcriptase mutation (M184V) and phenotypic resistance to emtricitabine, and one patient developed a K65R mutation. The M184V mutation was also observed in HIV-1 from a patient with no evidence of viral resistance to an INSTI [12]. Several reports of 96-week results from Studies 102 [34, 35] and 103 [36, 37] indicate that resistance to the antiretroviral components of elvitegravir/cobicistat/emtricitabine/tenofovir DF was infrequent. In Study 102, two patients in each treatment group developed resistance mutations after the initial 48 weeks’ treatment and no unique mutations nor new resistance patterns were observed between weeks 48 and 96 [35]. In a report of 96-week data from Study 103, 6 (1.7 %) of the patients


treated with elvitegravir/cobicistat/emtricitabine/tenofovir DF had HIV-1 isolates with resistance mutations and experienced treatment failure. Resistance developed during the first 48 weeks of treatment in five of the six patients; in the sixth patient, resistance developed during weeks 48 to 96 and was attributed to the M184V mutation without evidence of integrase resistance. By comparison, none of the patients treated with ritonavir-boosted atazanavir plus emtricitabine/tenofovir DF developed resistance during the 96-week treatment period [37]. Development of resistance to the antiretroviral components of elvitegravir/cobicistat/ emtricitabine/tenofovir DF was rare (2.3 % of recipients of the drug in the two phase III studies) over a treatment period of up to 96 weeks in another analysis; most of the resistance mutations had occurred by week 48 and the mutations detected during the first 48 weeks of treatment were similar to those seen during the subsequent 48-week treatment period (data reported in an abstract) [38]. The most common resistance mutation patterns were E92Q, Q148R or N155H (in integrase) and M184V/I (in reverse transcriptase). Low rates of viral resistance were also reported at week 144 during long-term follow-up of patients in Studies 102 [39] and 103 [40]. Through week 144, emergent resistance was infrequent with both elvitegravir/cobicistat/emtricitabine/tenofovir DF and efavirenz/emtricitabine/tenofovir DF (3 vs. 4 %) and there was no evidence of the development of resistance to any of the antiretroviral components of elvitegravir/cobicistat/emtricitabine/tenofovir DF after week 96 in Study 102 [39]. In Study 103, emergent drug resistance was reported in 2 % of patients treated with elvitegravir/cobicistat/emtricitabine/tenofovir DF and 1 % of patients in the ritonavir-boosted atazanavir plus emtricitabine/tenofovir DF treatment group [40].

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elvitegravir ([2.5-fold reduction in HIV-1 susceptibility) [16]. In vitro cross-resistance among emtricitabine, tenofovir, lamivudine and other NRTIs is well established [10, 16, 19]. HIV-1 isolates resistant to emtricitabine harbouring an M184V/I substitution in reverse transcriptase showed cross-resistance to lamivudine; nevertheless, sensitivity to didanosine, stavudine, tenofovir and zidovudine was retained [16, 19]. Isolates with the K65R reverse transcriptase substitution showed a decrease in susceptibility to emtricitabine, tenofovir, lamivudine didanosine, abacavir and stavudine [16, 19]. Zidovudine-associated reverse transcriptase mutations (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) in HIV-1 isolates from 20 patients resulted in a 3.1-fold reduction in tenofovir susceptibility. Moreover, eight patients with HIV-1 infection with isolates with an L74V reverse transcriptase substitution (but not zidovudine-associated substitutions) had a reduced response to tenofovir DF. Data are limited regarding cross-resistance to different antiretroviral drugs in patients with a reduced response to therapy in whom HIV-1 isolates were identified with a Y115F (n = 3) or Q151M (n = 2) substitution, or a T69 insertion (n = 4) in HIV-1 reverse transcriptase [16]. Isolates of HIV-1 from patients with plasma HIV-1 RNA levels [400 copies/mL at virological failure, at week 48, or at the time of early study drug discontinuation who had failed treatment with elvitegravir/cobicistat/emtricitabine/tenofovir DF demonstrated variable cross-resistance within the INSTI and NRTI drug classes. As expected, the degree of crossresistance observed depended on the specific substitution. However, all of the isolates retained susceptible to NNRTIs and PIs [11, 12, 16, 19]. 2.4 Metabolic Effects

2.3 Cross-Resistance Cross-resistance has been reported among the INSTIs, including elvitegravir and raltegravir [12, 16, 19]. In clinical studies, viral isolates with mutations conferring resistance to elvitegravir showed cross-resistance to raltegravir in patients receiving treatment with elvitegravir/cobicistat/ emtricitabine/tenofovir DF [12]; cross-resistance between emtricitabine-resistant HIV-1 isolates and lamivudine has also been reported [19]. In cell culture studies, strains of HIV-1 resistant to elvitegravir showed variable cross resistance to raltegravir, with the extent of cross-resistance dependent on the number and type of substitutions in HIV1 integrase. Isolates of HIV-1 with T66A/K, Q148H/K and N155H mutations selected by raltegravir had cross-resistance to elvitegravir [19]. Two primary raltegravir resistance-associated substitutions (Q148H/K/R, and N155H) conferred resistance to

Treatment with certain antiretroviral drugs can lead to metabolic abnormalities, including insulin resistance, hyperglycaemia, hyperlactataemia, lipodystrophy, hypercholesterolaemia and hypertriglyceridaemia [3–5, 10, 41]. Changes in lipid profiles were assessed in the two major phase III studies (Studies 102 and 103; see Sect. 4) and pooled data regarding changes in key lipid parameters at weeks 48 and 96 are reported in the US PI [16]. Compared with the efavirenz/emtricitabine/tenofovir DF group in Study 102, patients treated with elvitegravir/ cobicistat/emtricitabine/tenofovir DF had significantly lower increases from baseline in median fasting total cholesterol (0.25 mmol/L vs. 0.49 mmol/L; p \ 0.001), high-density lipoprotein cholesterol (HDL-C) [0.13 mmol/ L vs. 0.20 mmol/L; p = 0.001] and low-density lipoprotein cholesterol (LDL-C) [0.26 vs. 0.44 mmol/L; p = 0.001] levels [11] at week 48; in Study 103, patients in the

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elvitegravir/cobicistat/emtricitabine/tenofovir DF treatment group had significantly lower increases in triglycerides compared with ritonavir-boosted atazanavir plus emtricitabine/tenofovir DF [12, 36, 37] (median increase of 0.09 vs. 0.26 mg/dL; p = 0.006) at week 48 [12]. This lipid profile differentiated elvitegravir/cobicistat/emtricitabine/tenofovir DF from an efavirenz-based regimen and a ritonavir-boosted protease inhibitor regimen. Differences between treatment groups in fasting metabolic assessments were also observed at 96 [34–37] and 144 [39] weeks. Lipid levels were significantly lower with elvitegravir/cobicistat/emtricitabine/tenofovir DF than with efavirenz/emtricitabine/tenofovir DF at 96 weeks in study 102: total cholesterol (p \ 0.001), LDL-C (p = 0.011) and HDL-C (p = 0.008) levels [34]. At week 144, compared with recipients of efavirenz/emtricitabine/tenofovir DF, patients treated with elvitegravir/cobicistat/emtricitabine/ tenofovir DF had significantly smaller median increases in total cholesterol (16 vs. 20 mg/dL, p = 0.007) and LDL cholesterol (12 vs. 18 mg/dL, p = 0.007), whereas the two treatment groups had similar increases in triglycerides (2 vs. 2 mg/dL) and similar changes in the total cholesterol : HDL ratio (-0.3 vs. -0.3) [39]. In Study 103, the median increase from baseline in fasting triglyceride levels in the recipients of elvitegravir/ cobicistat/emtricitabine/tenofovir DF at week 96 was significantly (p = 0.012) less than in the ritonavir-boosted atazanavir plus emtricitabine/tenofovir DF treatment group (5 vs. 16 mg/dL), whereas the median increase in total cholesterol was significantly (p = 0.046) greater in the elvitegravir/cobicistat/emtricitabine/tenofovir DF than in the comparator group (14 vs. 8 mg/dL). No significant changes from baseline to week 96 in fasting median levels of LDL-C, HDL-C or fasting TC:HDL-C ratio were observed in either treatment group [36, 37]. No significant between-group differences were reported in the pooled analysis, but it is noteworthy that these analyses were posthoc and not prespecified [16]. In Studies 102 and 103, similar proportions of patients in the different treatment groups (&11 %) were receiving lipidlowering medications at baseline. During the 96-week treatment period, lipid-lowering therapy was initiated in 8 % of patients receiving elvitegravir/cobicistat/emtricitabine/tenofovir DF and in 9 and 8 % of patients receiving efavirenz/emtricitabine/tenofovir DF or ritonavirboosted atazanavir plus emtricitabine/tenofovir DF, respectively [16]. 2.5 Other Effects Data are available on the effects of elvitegravir and cobicistat on the electrocardiogram [16]. In a randomized, placebo- and active-controlled (moxofloxacin 400 mg)

C.M. Perry

parallel-group study, multiple 125 and 250 mg doses of elvitegravir (administered with ritonavir 100 mg) [n = 126 healthy individuals] had a small effect on the corrected QT (QTc) interval; the upper bound of the one-sided 95 % confidence interval (CI) for the largest placebo-adjusted, baseline-corrected QTc based on Fridericia’s correction method (QTcF) was \10 ms, the threshold for regulatory concern [16]. Similarly, in a trial of similar design, with four-period crossover (n = 48 healthy individuals), cobicistat 250 and 400 mg had a small effect on the QTc interval: consistent with the result for elvitegravir, the upper bound of the one-sided 95 % CI for the largest placebo adjusted, baseline-corrected QTc based on individual correction method (QTc) was \10 ms. However, a prolongation of the PR interval was detected in recipients of cobicistat in the same study: the maximum mean (upper bound of the one-sided 95 % CI) difference for cobicistat compared with placebo was 9.5 (12.1) ms and 20.2 (22.8) ms for cobicistat 250 and 400 mg doses, respectively. Nevertheless, given that the dose of cobicistat in the fixeddose combination tablet (150 mg) is less than the lowest dose used in this study, a clinically relevant prolongation of the PR interval in patients receiving treatment with elvitegravir/cobicistat/emtricitabine/tenofovir DF is deemed unlikely. The effects, if any, of emtricitabine, tenofovir DF or elvitegravir/cobicistat/emtricitabine/tenofovir DF on the QT interval are not yet understood [16]. Minor and similar changes in bone mineral density (BMD) were reported in relatively small proportions of patients treated with elvitegravir/cobicistat/emtricitabine/ tenofovir DF or ritonavir-boosted atazanavir plus emtricitabine/tenofovir DF for 48 weeks in Study 103 [12], suggesting that these effects may be related to a component common to both treatment arms. At week 48, mean percentage changes from baseline in BMD in the lumbar spine of -2.6 % for elvitegravir/cobicistat/emtricitabine/tenofovir DF and -3.3 % for ritonavir-boosted atazanavir plus emtricitabine/tenofovir DF were reported; corresponding changes in the hip were -3.1 and -3.9 % [12, 16]. Across Studies 102 and 103, traumatic bone fractures occurred in 14 (2 %), 8 (2.3 %) and 14 (3.9 %) of patients in the elvitegravir/cobicistat/emtricitabine/tenofovir DF, efavirenz/emtricitabine/tenofovir DF and ritonavir-boosted atazanavir plus emtricitabine/tenofovir DF groups, respectively, over 96 weeks [16, 19]. In clinical trials of adults with HIV-1 infection, tenofovir DF, as a component of elvitegravir/cobicistat/ emtricitabine/tenofovir DF, was associated with slightly greater decreases in BMD and increases in biochemical markers of bone metabolism, suggesting an increase in turnover of bone relative to comparator regimens. Levels of serum parathyroid hormone and 1.25 vitamin D were also higher in patients treated with tenofovir DF [16].


Cobicistat affected the estimated glomerular filtration rate (eGFR) but not the actual GFR in an active-comparator and placebo-controlled study in adults with normal renal function [29]. Decreases from baseline in the eGFR of &10 mL/min were seen on day 7 of treatment with cobicistat 150 mg once daily and were reversible after the discontinuation of cobicistat. The changes in eGFR are consistent with the change in proximal tubular secretion of creatinine achieved with the inhibition of drug transporters [29]. The mechanism for the effect of cobicistat, as well as ritonavir, on the eGFR appears to be inhibition of multidrug and toxin extrusion protein-1 (MATE-1)-mediated creatinine efflux [42, 43].

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Table 2 Pharmacokinetic parameters (mean values at steady state) of elvitegravir, emtricitabine, tenofovir and cobicistat after oral administration of the elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate once-daily single-tablet regimen to adults with HIV-1 infection [16, 19] Cmax (lg/mL)

AUC lg h/mL

Elvitegravira

1.7

23.0

0.45

Cobicistatb

1.1

8.3

0.05

Emtricitabineb

1.9

12.7

0.14

Tenofovirb,c

0.45

4.4

0.10

Ctrough (lg/mL)

AUC area under the plasma concentration-time curve, Cmax maximum plasma concentration, Ctrough trough plasma concentration a b

Results are from a population pharmacokinetic analysis (n = 419)

Results are (n = 61–62)

from

an

intensive

pharmacokinetic

analysis

3 Pharmacokinetic Properties

c

The pharmacokinetic properties of elvitegravir/cobicistat/ emtricitabine/tenofovir DF are reviewed briefly in this section. Data are from investigations of the fixed-dose single-tablet formulation and are supplemented with information from studies of the individual components, which have been reported in more detail elsewhere [21, 23, 25, 26, 28]. Data reported in this section are largely derived from studies in healthy adult volunteers or in adults with HIV-1 infection. The US PI [16] and the EU SPC [19] are key sources of data on the pharmacokinetic profile of elvitegravir/cobicistat/emtricitabine/tenofovir DF. As noted in Sect. 2, cobicistat is a selective, mechanism-based inhibitor of CYP3A isoenzymes, and increases the systemic exposure of elvitegravir when the two drugs are administered in combination, as in the co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir DF tablet [19]. As tenofovir is poorly absorbed from the intestine, it is formulated as tenofovir DF, a prodrug of tenofovir, that enhances its oral bioavailability [23].

fat); corresponding mean changes in systemic exposure after single-dose administration of the fixed-dose combination with a high-fat (&800 kcal; 50 % fat) meal were 87 and 23 %, respectively [16]. It is recommended that elvitegravir/cobicistat/emtricitabine/tenofovir DF is taken with food [16, 19]. Changes in mean systemic exposures to emtricitabine and cobicistat were not considered clinically significant after administration of single doses of elvitegravir/cobicistat/emtricitabine/tenofovir DF with a light or high-fat meal [16, 19]. Pharmacokinetic data were also reported in the phase II randomized clinical trial of elvitegravir/cobicistat/emtricitabine/tenofovir DF (see Sect. 4.1.1) [14]. For patients in the elvitegravir/cobicistat/emtricitabine/tenofovir DF group, [90 % of the elvitegravir trough plasma concentrations (Cmin) measured at study visits were higher than the protein binding-adjusted 95 % inhibitory concentration (IC95), with a 10-fold mean Cmin to protein-binding adjusted IC95 ratio (IQ95). Similar results were reported in a pharmacokinetic substudy conducted at week 2 and for all of the assessed patients (n = 38–44 patients) at weeks 8, 24 and 48: mean IQ95 values of 7.3, 9.3 and 8.8 were reported. Of the samples tested, 20 (10 %) had elvitegravir concentrations lower than the IC95; however, elvitegravir concentrations were either [3-fold above the proteinbinding-adjusted IC50 (n = 4) or below the limit of quantification (n = 6) [14]. The pharmacokinetics of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate were studied in a subset of patients (n = 27) enrolled in Study 103, between visits at week 2 and 8 (see Sect. 4) [12]. The pharmacokinetic results for cobicistat, emtricitabine and tenofovir DF were consistent with previously published data. Elvitegravir was found to have low inter- and intra-patient variability, based on the testing of 350 samples. All patients had high plasma elvitegravir concentrations, with

3.1 Absorption After administration of a single dose of elvitegravir/cobicistat/emtricitabine/tenofovir DF with food, the time to achieve a maximum plasma elvitegravir concentration (tmax) was 4 h; for cobicistat and emtricitabine, the tmax was 3 h and the tmax for tenofovir (after rapid conversion from the prodrug tenofovir DF) was 2 h. Other absorption parameters are summarized in Table 2 [16, 19]. When administered with a meal, changes in elvitegravir and tenofovir systemic exposures have been reported. Specifically, relative to fasting conditions, increases in mean systemic exposure to elvitegravir and tenofovir of 34 and 24 %, respectively, were reported after the administration of a single dose of elvitegravir/cobicistat/emtricitabine/tenofovir DF with a light meal (&373 kcal; 20 %

After administration of tenofovir disoproxil fumarate

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Cmin values that were higher than the protein-binding adjusted IC95; the mean Cmin to protein-binding adjusted IC95 ratio was 10:1 over the 48-week duration of the study. 3.2 Distribution Both elvitegravir and cobicistat are extensively bound to human plasma proteins, with preferential binding of elvitegravir to albumin rather than a-acid glycoprotein [25], whereas both emtricitabine and tenofovir show fairly minimal protein binding [16, 19]. For the three antiretroviral drugs, the extent of plasma protein binding was shown to be independent of the drug concentrations tested: i.e. 1 ng/mL–1,600 ng/mL for elvitegravir; 0.02–200 lg/mL for emtricitabine; 0.01–25 lg/mL for tenofovir. For elvitegravir, the extent of plasma protein binding was 98–99 % and for cobicistat it was 97–98 %. This means that it is unlikely that these two agents would be removed to a significant extent by haemodialysis or peritoneal dialysis [19]. The mean blood-to-plasma ratios for elvitegravir and cobicistat were 0.73 and &0.5, respectively [16]. By comparison, \4 % of emtricitabine and \0.7 % of tenofovir were bound to plasma proteins in vitro [16, 19]. At the maximum plasma emtricitabine concentration, the mean plasma-to-blood drug concentration ratio was &1.0 and the mean semen to plasma drug concentration ratio was &4.0 [19]. Hemodialysis removes &30 % of the dose of emtricitabine over a dialysis period of 3 h, starting within 1.5 h of administration of the emtricitabine dose (blood flow rate of 400 mL/min and a dialysate flow rate of 600 mL/min). It is not known whether emtricitabine can be removed by peritoneal dialysis [16]. Tenofovir is removed by hemodialysis with an extraction coefficient of approximately 54 %. After a single 300 mg dose of tenofovir DF, a 4-h hemodialysis session removed &10 % of the administered tenofovir dose [16]. The volumes of distribution of emtricitabine and tenofovir after intravenous administration are &1,400 mL/kg and 800 mL/kg, respectively. Both drugs are also widely distributed throughout the body after oral administration [19]. Studies in a small number of women with HIV-1 infection have shown that both emtricitabine and tenofovir are secreted in human milk. As a result, there is a risk of the development of HIV-1 resistance to emtricitabine and tenofovir in infants being fed breast milk from mothers receiving treatment with these drugs [16]. 3.3 Metabolism The metabolism of elvitegravir is predominantly oxidative and is mediated by CYP3A enzymes (the major route), and to a lesser extent by glucuronidation via UGT1A1/3

C.M. Perry

enzymes [16, 19, 25]. By contrast, neither emtricitabine nor tenofovir undergo significant metabolism. Although cobicistat does not undergo glucuronidation, it is metabolized by CYP3A and, to a minor extent, by CYP2D6 enzymes (oxidation) [16, 19], and inhibits its own clearance pathway as a result of its inhibitory effects on CYP3A [28]. 3.4 Elimination After administration of elvitegravir/cobicistat/emtricitabine/tenofovir DF, median terminal plasma half-life values are &12.9 h for elvitegravir and &3.5 h for cobicistat [16, 19]. After multiple doses of cobicistat over 6 days followed by a single dose of [14C] cobicistat, 86.2 and 8.2 % of the dose was excreted in the feces and urine, respectively. Both emtricitabine and tenofovir DF are excreted in the urine by a combination of active tubular secretion and glomerular filtration. Approximately 86 and &14 % of the emtricitabine dose were excreted in the urine and feces, respectively; &70–80 % of the tenofovir dose was excreted unchanged in the urine after intravenous administration [19]; the elimination half-lives of emtricitabine and tenofovir are &10 and &12–18 h, respectively [16, 19]. 3.5 Special Populations No clinically relevant differences in the pharmacokinetics of elvitegravir or cobicistat have been observed between individuals with severe renal impairment (creatinine clearance [CLCR] \30 mL/min) and healthy adult volunteers. However the pharmacokinetics of emtricitabine and tenofovir are altered in individuals with an estimated CLCR \50 mL/min or end-stage renal dialysis requiring dialysis (see Sect. 6) [16, 19]. No clinically relevant differences in the pharmacokinetics of elvitegravir or cobicistat have been observed between individuals with moderate hepatic impairment (Child–Pugh Class B) and healthy adult volunteers; the effect of severe hepatic impairment (Child– Pugh Class C) on the pharmacokinetics of elvitegravir or cobicistat has not yet been evaluated [16]. The effect of hepatic impairment on the pharmacokinetics of emtricitabine is anticipated to be limited as emtricitabine is not appreciably metabolized. The pharmacokinetics of tenofovir were not altered to a clinically relevant extent in individuals, compared with healthy volunteers, with moderate to severe hepatic impairment [16]. Although both emtricitabine and tenofovir have been studied in paediatric patients, the pharmacokinetic profiles of elvitegravir and cobicistat have not been established in this population [16]. The pharmacokinetics of emtricitabine and tenofovir DF have not been fully investigated in HIV-1-infected patients with HBV or HCV co-infection. There is no evidence to indicate that HBV or HCV infection have a clinically


relevant effect on systemic exposure to boosted elvitegravir, based on a population analysis (n = 24) [16, 19]. 3.6 Drug Interactions Elvitegravir/cobicistat/emtricitabine/tenofovir DF has a complex pharmacokinetic drug interaction profile, with multiple ([100) known and predicted interactions between its components and other drugs reported. The pharmacokinetic profiles of emtricitabine and tenofovir have been well characterized, whereas fewer data are available regarding drug interactions involving elvitegravir. Of note, the increased elvitegravir systemic exposure occurring as a result of its co-administration with cobicistat has implications for the drug interaction profile of the combination tablet. Plasma/ serum concentrations of drugs metabolized by CYP3A or CYP2D6 may be altered by concomitant administration of elvitegravir/cobicistat/emtricitabine/tenofovir DF. In addition, drugs that are inducers of CYP3A can alter plasma/ serum concentrations of at least one of the components of elvitegravir/cobicistat/emtricitabine/tenofovir DF [16, 19].

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Because of the large number of potential interactions, a discussion of detailed quantitative results of drug interaction studies is beyond the scope of this review; instead, this section provides a brief overview of key drug interactions involving elvitegravir/cobicistat/emtricitabine/tenofovir DF. Summaries of clinically relevant drug interactions, based largely on qualitative data presented in the EU SPC [19], are presented in Table 3 and Table 4. Interactions between elvitegravir/cobicistat/emtricitabine/tenofovir DF and other antiretroviral drugs are not reviewed as this tablet is a complete formulation of antiretroviral drugs and must not be administered with other antiretroviral agents [16, 19]. All reported data are from studies conducted in adults. No clinically significant drug interactions were observed in drug interactions studies conducted with elvitegravir/cobicistat/emtricitabine/tenofovir DF and entecavir, famciclovir, H2 receptor antagonists, methadone, proton pump inhibitors or ribavirin [16]. A lack of an interaction between elvitegravir/cobicistat/emtricitabine/tenofovir DF and telaprevir was reported in a recent study in healthy adults [44].

Table 3 Summary of potentially serious and/or life-threatening clinically relevant interactions between the components of elvitegravir/cobicistat/emtricitabine/tenofovir DF single-tablet regimen and other drugs [16, 19] Druga

Potential reaction/or comment

Drugs that are contra-indicated Dihydroergotamine, ergotamine, ergometrine

Peripheral vasospasm or ischaemia

Simvastatin, lovastatin

Myopathy, including rhabdomyolysis

Orally administered midazolam or triazolam

Prolonged or increased sedation or respiratory depression

Cisapride, pimozide, alfuzosin and sildenafil

Interaction with sildenafil when administered as RevatioÒ for the treatment of pulmonary arterial hypertension; elvitegravir/cobicistat/ emtricitabine/tenofovir DF is not contraindicated with sildenafil when used intermittently for erectile dysfunction

St. John’s wort (Hypericum perforatum), rifampinb

May result in loss of therapeutic effect and development of resistance to elvitegravir

Drugs that are not recommended Drugs that compete for active tubular secretion (e.g. cidofovir)

Increased serum concentration of emtricitabine/tenofovir and/or the co-administered drug

Drugs with the potential for nephrotoxicity (e.g. aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2 (aldesleukin)

Nephrotoxicity

Rifabutin

May decrease plasma concentrations of cobicistat and elvitegravir; if co-administration is required, rifabutin dosage modification is advised

Oral contraceptives containing progestagens other than norgestimate

Not studied, so should be avoided

Boceprevir

Not studied, so should be avoided

Salmeterol

Increased plasma concentrations of salmeterol associated with the potential for serious and/or life-threatening reactions

Atorvastatin

Potential for increased plasma concentrations of atorvastatin

a

Primarily metabolized by cytochrome P450 (CYP) 3A enzymes. Rifabutin was studied in drug interaction investigations with elvitegravir/ cobicistat/emtricitabine/tenofovir DF; all other interaction data shown are based on an understanding of metabolic pathways for the different drugs

b

Inducers of CYP3A that may lead to significant reductions in plasma concentrations of cobicistat and elvitegravir

84

C.M. Perry

Table 4 Summary of potentially clinically relevant interactions between the components of the elvitegravir/cobicistat/emtricitabine/tenofovir DF single-tablet regimen and other drugs: drugs that should be administered with caution and/or clinical monitoring [16, 19] Druga

Comments

Ketoconazole

Potential for increased concentrations of ketoconazole, elvitegravir and cobicistat. Use with caution: clinical monitoring recommended

Itraconazole, voriconazole, posaconazole, fluconazole

Potential for increased concentrations of itraconazole, fluconazole and posaconazole: clinical monitoring recommended. Potential for increased or decreased concentrations with voriconazole: benefit/risk ratio assessment recommended to justify voriconazole use

Clarithromycin

Potential for increased concentrations of clarithromycin and/or cobicistat. Clinical monitoring recommended (see prescribing information for specific recommendations)

Telithromycin

Potential for altered concentrations of telithromycin and/or cobicistat

Carbamazepine, oxcarbazepine, phenobarbital, phenytoinb

Potential for decreased plasma concentrations of cobicistat and elvitegravir, which may result in a loss of therapeutic effect and the development of resistance: consider alternative anticonvulsants

Fluticasone

Potential for increased concentrations of fluticasone, leading to a reduction in serum cortisol levels; clinical monitoring is recommended

Magnesium/aluminium-containing antacid suspension

Reduced plasma concentrations of elvitegravir: separate times of administration by C4 h

Metformin

Potential for increased concentrations of metformin due to interaction with cobicistat: careful monitoring and metformin dose adjustment recommended

Digoxin

Potential for increased concentrations of digoxin: monitoring of digoxin concentrations recommended

Amiodarone, quinidineb

Potential for increased concentrations and serious events; therapeutic concentration monitoring is recommended

Disopyramide, flecainide, systemic lidocaine, mexiletine, propafenone

Potential for increased concentrations of each of these agents due to interaction with cobicistat: caution and clinical monitoring recommended

Metoprolol, timolol

Dose reduction of these agents may be needed; clinical monitoring is recommended

Amlodipine, diltiazem, felodipine, nicardipine, nifedipine, verapamil

Clinical monitoring is recommended

Bosentan

Alternative endothelin receptor antagonists may be considered

Warfarin, dabigatran Tadalafil, vardenafil

Clinical monitoring is recommended Clinical monitoring/dose modification of these agents may be required

Escitalopram, trazodone

Clinical monitoring/dose titration of these agents required

Cyclosporin, sirolimus, tacrolimus

Therapeutic monitoring of these drugs recommended

Buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem

Therapeutic monitoring recommended; dose reduction of these agents may be necessary

Norgestimate/ethinylestradiol

Administer with caution; an alternative method of contraception may be required

Buprenorphine/naloxone

Concentrations of buprenorphine and norbuprenorphine are increased; although no dosage adjustment of buprenorphine/naloxone is required when co-administered with elvitegravir/ cobicistat/emtricitabine/tenofovir DF, patients should be monitored closely for sedation and cognitive effects

Colchicine

Dose reduction of colchicine may be required: should not be administered to patients with renal or hepatic impairment

a

Primarily metabolized by cytochrome P450 (CYP) 3A enzymes. Digoxin, norgestimate/ethinylestradiol, buprenorphine/naloxone and ketoconazole were studied in drug interaction investigations with elvitegravir/cobicistat/emtricitabine/tenofovir DF; all other interaction data shown are based on an understanding of metabolic pathways for the different drugs

b

Contraindicated in the EU, but not the USA

Local prescribing information [16, 19], guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents published by the US Department of Health and Human Services [4], and the University of Liverpool HIV drug interactions website [45] should be referred to for up-to-

date, comprehensive and clinically relevant information, including quantitative results, pertaining to drug interactions with elvitegravir/cobicistat/emtricitabine/tenofovir DF. Local hospital drug information centres are an additional resource for current information on drug interactions.


4 Therapeutic Efficacy The therapeutic efficacy of elvitegravir/cobicistat/emtricitabine/tenofovir DF in antiretroviral therapy-naı¨ve adults with HIV-1 infection has been evaluated in three randomized, double-blind, double-dummy, active-controlled, multicentre studies [11, 12, 14] . The first of these was a phase II study (NCT00869557; Study 104) and the other two were larger phase III noninferiority studies, referred to as Study 102 (GS-US-236-0102; NCT01095796) [11] and Study 103 (GS-236-0103; NCT01106586) [12]. The efficacy of once-daily fixed-dose elvitegravir/cobicistat/ emtricitabine/tenofovir DF, administered with food, was compared with that of the fixed-dose co-formulated combination of efavirenz 600 mg/emtricitabine 200 mg/tenofovir DF 300 mg (efavirenz/emtricitabine/tenofovir DF; AtriplaÒ) once daily in two of the studies [11, 14] and ritonavir-boosted atazanavir (i.e. atazanavir 300 mg plus ritonavir 100 mg) plus the fixed-dose combination of emtricitabine/tenofovir DF 200 mg/300 mg (TruvadaÒ) once daily in the third study [12]. Virological efficacy results for elvitegravir/cobicistat/emtricitabine/tenofovir DF in the two phase III trials are also reported in the US PI and EU SPC [16, 19]. Tolerability data from these trials are discussed in Sect. 5. The phase III studies (total n = 1,408 randomized and dosed [16, 19]) were conducted in North America [11, 12], Europe, Australia and Thailand [12], and the phase II study took place in the USA [14]. A summary of the key trial design details is presented in Table 5. The majority of patients (C88 %) enrolled in the three studies were male. Although co-infection with HBV and/or HCV was among the exclusion criteria in the phase II study [14], patients with HBV or HCV co-infection [12] or positive HBsAg or hepatitis C serology [11] were eligible for enrolment in the phase III trials. Across the two phase III trials, 1–3 % of patients were HBsAg positive and 3–5 % were HCV positive [11, 12]. The primary endpoint was the proportion of patients with a plasma HIV-1 RNA level of\50 copies/mL at week 24 [14] or 48 [11, 12] after the start of treatment (Table 5). Other endpoints for each of the studies are summarized in Table 5. In all three studies, enrolled patients were stratified by baseline HIV-1 RNA level (B100,000 or [100,000 copies/mL). Analysis of the primary endpoint in the phase III studies was by treatment noninferiority of elvitegravir/ cobicistat/emtricitabine/tenofovir DF compared with efavirenz/emtricitabine/tenofovir DF [11] or ritonavir-boosted atazanavir plus emtricitabine/tenofovir DF [12], based on 95 % CIs and a prespecified noninferiority margin of 12 % in the intention-to-treat population. The same analysis was also conducted for the per-protocol population [11, 12].

85

Review of preliminary results was conducted by an independent data monitoring committee after completion of treatment at week 12 by half of the patients, and after the completion of 24 and 48 weeks of follow-up by all of the patients in the two phase III trials [11, 12]. Patients who had HIV-1 RNA levels of \50 copies/mL in the week 48 window (between days 309 and 378) in these trials were classed as virological success and the other two categories were virological failure or no virological data at week 48, comprising the FDA-defined snapshot analysis algorithm. Differences in treatment efficacy, based on ethnic origin, age, sex, baseline HIV-1 RNA level, baseline CD4? cell count and adherence to study drug treatment were also assessed in subgroup analyses in both phase III trials [11, 12]. 4.1 Comparisons with Fixed-Dose Single-Tablet Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate Regimens 4.1.1 Phase II Trial (Study 104) The phase II trial of elvitegravir/cobicistat/emtricitabine/ tenofovir DF is the first randomized, double-blind study to evaluate the efficacy and tolerability of an INSTI-based single-tablet regimen, compared with the efavirenz/emtricitabine/tenofovir DF once-daily single-tablet regimen in treatment-naı¨ve patients with HIV-1 infection [14]. At baseline, patients had plasma HIV-1 RNA levels of C5,000 copies/mL. After randomization to treatment with either elvitegravir/cobicistat/emtricitabine/tenofovir DF or efavirenz/emtricitabine/tenofovir DF, patients were assessed at weeks 2, 4, 8, 12, 16 and thereafter every 8 weeks until week 48. Resistance testing (see Sect. 2.3) was also conducted in patients with HIV-1 RNA levels of [400 copies/mL on study drug after achieving an undetectable viral load i.e. HIV-1 RNA \50 copies/mL. A pharmacokinetic analysis was also performed (see Sect. 3). The primary and secondary objectives of the study are summarized in Table 5. Intent-to-treat (missing = failure) analysis was used for the analysis of the primary endpoint. Although the study was not powered to detect differences between the two treatment regimens, an a priori planned analysis included the point estimate of treatment difference and the two-sided 95 % CI in response rates that was associated with this, stratified by the HIV-1 RNA level at baseline. The study population included 71 patients randomized to receive treatment with elvitegravir/cobicistat/emtricitabine/tenofovir DF or efavirenz/emtricitabine/tenofovir DF. Disease characteristics were similar in the two treatment groups. Elvitegravir/cobicistat/emtricitabine/tenofovir DF was an effective treatment in antiretroviral-naı¨ve patients with HIV-1 infection, with 90 % of patients achieving a

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C.M. Perry

Table 5 Key trial design details in the phase II and III randomized, double-blind, double-dummy trials of the elvitegravir/cobicistat/emtricitabine/tenofovir DF fixed-dose single-tablet regimen in antiretroviral therapy-naive adults aged C18 years with HIV-1 infection Cohen et al. [14] (phase II)

DeJesus et al. [12] (phase III: Study 103)

Sax et al. [11] (phase III: Study 102)

Inclusion criteria

Screening plasma HIV-1 RNA level C5,000 copies/mL; CD4? count [50 cells/mL; no NRTI, NNRTI or primary PI genotypic resistance mutations; normal ECG, estimated CLCR (eGFR; Cockcroft–Gault) C80 mL/min; AST/ALT levels 2.5 9 or \ULN and total bilirubin B1.5 mg/dL

Screening plasma HIV-1 RNA level C5,000 copies/mL; eGFR of C70 mL/min; virus susceptible to emtricitabine, tenofovir and atazanavir; AST/ALT levels B5 9 ULN, total bilirubin B25.65 lmol/L; adequate haematological function

Plasma HIV-1 RNA level of C5,000 copies/mL; eGFR C70 mL/min; virus susceptible to efavirenz, emtricitabine, and tenofovir; AST/ALT B5 9 ULN; total bilirubin B25.65 lmol/L or a normal direct bilirubin; adequate haematological function

Exclusion criteria

HBV or HCV coinfection; new AIDSdefining condition B30 days of screening or vaccination B90 days of administration of the study drug

New AIDS-defining disorder or other serious infection within 30 days before screening

New AIDS-defining disorders or serious infections within 30 days of screening

Primary endpoints

Proportion of pts with a plasma HIV-1 RNA level of \50 copies/mL at week 24

Proportion of pts in the ITT population with a plasma HIV RNA-1 level of \50 copies/mL at week 48a

Proportion of pts in the ITT population with HIV-1 RNA levels of\50 copies/ mL at week 48a

Secondary/ tertiary endpoints

Proportion of pts with a plasma HIV-1 RNA level of \50 copies/mL at week 48; safety and tolerability findings

Achievement/maintenance of viral suppressionb; pure virological failure; proportion of patients with viral suppressionc; viral suppression (HIV-1 RNA \50 copies/mL) at week 96 according to snapshot analysis; change from baseline in CD4? cell count

Treatment differences by subgroup, achievement/maintenance of HIV-1 RNA level to \50 copies/mLb; proportion of pts with HIV-1 RNA levels \50 copies/mLd; change in HIV-1 RNA level from BL, and change in CD4 cell count

AST/ALT aspartate aminotransferase/alanine aminotransferase, ART antiretroviral treatment, BL baseline, CLCR creatinine clearance, ECG electrocardiogram, eGFR estimated glomerular filtration rate, HBV hepatitis B virus, HCV hepatitis C virus, NR not reported, NRTI nucleoside reverse transcriptase inhibitor, NNRTI non-nucleoside reverse transcriptase inhibitor, PI protease inhibitor, pts patients, ULN the upper limit of normal a

According to the US FDA snapshot algorithm, with a 12 % non-inferiority margin

b

Based on the US FDA time to loss of virological response algorithm

c

When missing data were classed as failure and missing data were classed as excluded

d

When classing missing as failure and missing as excluded

plasma HIV-1 RNA level of \50 copies/mL at weeks 24 (the primary endpoint) and 48 (Table 6). The corresponding response rate in the comparator group at weeks 24 and 48 was 83 %. In addition, compared with efavirenz/emtricitabine/tenofovir DF, recipients of elvitegravir/cobicistat/emtricitabine/tenofovir DF had a more rapid reduction in HIV-1 RNA levels; at weeks 2, 4 and 8, significantly (p \ 0.05) more patients in the elvitegravir/cobicistat/emtricitabine/tenofovir DF group had HIV-1 RNA levels of \50 copies/mL (ITT missing = failure analysis). Comparisons of response rates for the elvitegravir/cobicistat/emtricitabine/tenofovir DF and efavirenz/emtricitabine/tenofovir DF treatment groups showed stratum-weighted differences (95 % CI) of ?5.0 % (-11 to 21.1) at week 24 and ?8.4 % (-8.8 to 25.6) at week 48. HIV-1 RNA levels of \50 copies/mL were achieved in 95 % of patients in both treatment groups at week 48 (ITT missing = excluded analysis) [14]. Both treatment regimens produced beneficial effects on the immune status of study participants. Comparable increases

from baseline in CD4? cell counts occurred in both treatment groups [14]. After completion of the randomized phase of this study, 14 patients with virological suppression switched from treatment with efavirenz/emtricitabine/tenofovir DF to elvitegravir/cobicistat/emtricitabine/tenofovir DF treatment. High rates of virological suppression were maintained in these patients following the switch, with virological suppression maintained in 12 of 14 patients after 24 weeks of treatment, suggesting that elvitegravir/ cobicistat/emtricitabine/tenofovir DF may be a treatment option for patients not able to tolerate efavirenz/emtricitabine/tenofovir DF [46]. 4.1.2 Phase III Study (Study 102) Patients enrolled in Study 102 were randomized to receive either elvitegravir/cobicistat/emtricitabine/tenofovir DF or efavirenz/emtricitabine/tenofovir DF, in a 1:1 ratio (Table 5) plus placebo tablets that matched the alternative

4.59

4.58

EVG 150 mg/COBI 150 mg/FTC 200 mg/TDF 300 mg (48) [week 24]

EFV 600 mg/FTC 200 mg/TDF 300 mg (23) [week 24]

4.78

436 med

354 med

382

391

366 med

351 med

Mean CD4? count (cells/ lL) at BL

206

124; 139e med

96.0

84.1c

239*

83d; 83d,e

94.9

87.6c

211

123; 205e med

97.7

86.8b

207

CD4? count (mean increase from baseline at week 48)

90d; 90d,e

97.5

Proportion of pts (%) with HIV-1 RNA \50 copies/mL at week 48 (per-protocol)

89.5b

Proportion of pts (%) with HIV-1 RNA \50 copies/mL at week 48 (ITT)a

e

d

c

b

a

Results at week 48

Stratum-weighted differences (95 % CI) of ?5.0 % (-11 to 21.1) at week 24 and ?8.4 % (-8.8 to 25.6) at week 48

Adjusted between-group difference 3.6 % (95 % CI -1.6 to 8.8)

Adjusted between-group difference 3.0 % (95 % CI -1.9 to 7.8)

Primary endpoint, assessed at week 24 in the phase II trial and week 48 in the phase III trials

* p = 0.009 vs. EFV/FTC/TDF

ATV atazanavir, BL baseline, EFV/FTC/TDF efavirenz/emtricitabine/tenofovir DF single tablet, EVG/COBI/FTC/TDF elvitegravir/cobicistat/emtricitabine/tenofovir DF single tablet, FTC/TDF emtricitabine/tenofovir single tablet, ITT intention-to-treat, med median, pt(s) patient(s), RTV ritonavir

Cohen et al. [14] (104; NCT00869557)

Phase II trial

Sax et al. [11] (102; NCT01095796)

EFV 600 mg/FTC 200 mg/TDF 300 mg (352) [week 48]

4.8

ATV 300 mg ? RTV 100 mg ? FTC 200 mg/TDF 300 mg (355) [week 48] EVG 150 mg/COBI 150 mg/FTC 200 mg/TDF 300 mg (348) [week 48] 4.73

4.8

Mean plasma HIV-1 RNA level (log10 copies/mL) at BL

EVG 150 mg/COBI 150 mg/FTC 200 mg/TDF 300 mg (353) [week 48]

Treatment regimen, administered once daily (no. of pts) [time of primary assessment]

DeJesus et al. [12] (103; NCT01106586)

Phase III trials

Study (identifier)

Table 6 Efficacy of the elvitegravir/cobicistat/emtricitabine/tenofovir DF fixed-dose single-tablet regimen in antiretroviral therapy-naı¨ve adults with HIV-1 infection in randomized, doubleblind, double-dummy, multicentre clinical trials

Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate: A Review 87

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drug treatment [11]. At enrolment, study participants were aged 18–67 years; 63 % were White, 28 % were Black and 2 % were Asian [16]. Plasma HIV-1 RNA levels ranged from 2.6 to 6.5 log10 copies/mL; baseline CD4? count ranged from 3 to 1348 cells/lL; 13 % of the study population had CD4? cell counts of \200 cells/lL and 33–34 % of patients had a plasma HIV-1 RNA level of [100,000 copies/mL [11, 16, 19]. Further information on other endpoints in this study is summarized in Table 5. The data monitoring committee conducted interim review of the study and at week 48 endorsed an extension of the blinded, comparative phase of the study to week 192 [11]. Longer-term efficacy data from this study are presented later in this section [35]. Elvitegravir/cobicistat/emtricitabine/tenofovir DF was an effective treatment for antiretroviral therapy-naı¨ve patients with HIV infection, with noninferior efficacy, in terms of the primary endpoint, to that of the comparator treatment [11]. At week 48, an HIV-1 RNA level of \50 copies/mL was achieved in 305 (87.6 %) of 348 patients treated with elvitegravir/cobicistat/emtricitabine/tenofovir DF compared with 296 (84.1 %) of 352 patients in the efavirenz/emtricitabine/tenofovir DF treatment group. The criterion for noninferiority was met as the treatment difference was 3.6 % (95 % CI -1.6 to 8.8) (Table 6). Assessments of other virological endpoints showed nonsignificant differences in virological responses between the two treatment groups. Of note, at all evaluations up to week 16, a greater proportion (statistics not reported) of patients in the elvitegravir/cobicistat/emtricitabine/tenofovir DF treatment group had plasma HIV-1 RNA levels of \50 copies/mL (intention-to-treat population: missing data classed as failures); thereafter, there were no marked between-group differences in HIV-1 RNA levels. In the subgroup analyses at week 48, including assessments in patients with high baseline HIV-1 RNA levels, there were no marked between-group differences in treatment efficacy. The CD4? cell count at week 48 was significantly higher in the elvitegravir/cobicistat/emtricitabine/tenofovir DF group than in the patients who received efavirenz/ emtricitabine/tenofovir DF [11]. Elvitegravir/cobicistat/emtricitabine/tenofovir DF showed durable efficacy at 96 weeks, with 84 and 82 % (difference 2.7 %: 95 % CI -2.9 to 8.3) of patients in the elvitegravir/cobicistat/emtricitabine/tenofovir DF and efavirenz/emtricitabine/tenofovir DF treatment groups, respectively, having plasma HIV-1 RNA levels of \50 copies/mL (based on the FDA snapshot analysis) [16, 35]. Longer-term 144-week data for Study 102 study also showed the durable efficacy of elvitegravir/cobicistat/ emtricitabine/tenofovir DF. At week 144, patients treated with either elvitegravir/cobicistat/emtricitabine/tenofovir DF or efavirenz/emtricitabine/tenofovir DF had high

C.M. Perry

virological response rates (80 vs. 75 %) regardless of the baseline viral load and CD4? cell count [39]. 4.2 Comparison with Ritonavir-Boosted Atazanavir Plus Fixed-Dose Single-Tablet Emtricitabine/ Tenofovir DF Regimen 4.2.1 Phase III Study (Study 103) Patients enrolled in Study 103 were randomized in a 1:1 ratio to receive once-daily treatment with either elvitegravir/cobicistat/emtricitabine/tenofovir DF or ritonavirboosted atazanavir 300 mg/100 mg in combination with emtricitabine/tenofovir DF 200 mg/300 mg [12]. To conceal the specific assigned treatment, each study participant received four tablets (active drug or placebos) each day that resembled the single elvitegravir/cobicistat/emtricitabine/ tenofovir DF tablet and the three components of the comparator treatment i.e. atazanavir, ritonavir and fixed-dose emtricitabine/tenofovir. Analysis of the primary endpoint was performed after all enrolled patients had completed their study visit at week 48 or had prematurely stopped taking study medication. The two treatment groups had similar baseline characteristics [12]. As in Study 102, elvitegravir/cobicistat/emtricitabine/ tenofovir DF was an effective initial treatment for adults with HIV-1 infection and was noninferior to the comparator regimen in terms of the primary endpoint assessment (Table 6). At week 48, plasma HIV-1 RNA levels of \50 copies/mL were achieved in 316 (89.5 %) of 353 patients treated with elvitegravir/cobicistat/emtricitabine/tenofovir DF and in 308 (86.8 %) of 355 recipients of the comparator regimen: the criterion for noninferiority was met in that the adjusted difference between treatments was 3.0 % (95 % CI -1.9 to 7.8). Consistent with the findings of Study 102, viral suppression was achieved more rapidly with elvitegravir/cobicistat/emtricitabine/tenofovir DF than with ritonavir-boosted atazanavir plus emtricitabine/tenofovir DF [12]. Marked between-group differences (in favour of the elvitegravir/cobicistat/emtricitabine/tenofovir DF group) in response rates (percentages of patients with plasma HIV-1 RNA levels \50 copies/mL) were evident during the initial 12–16 weeks, but were not seen during weeks 24–48. No notable differences between the two treatments in other virological assessments were observed; these included assessments of efficacy in patients with high HIV-1 RNA levels at baseline ([100,000 copies/mL). Percentages of patients with viral suppression (secondary endpoint data) were also high in both treatment groups, and for the different subgroups, including patients with viral loads ([100,000 copies/mL) at baseline. Improvements in the immunological status of patients in both groups was also


reported: at week 48, mean increases from baseline in CD4? cell counts of 207 and 211 cells/lL were reported for the elvitegravir/cobicistat/emtricitabine/tenofovir DF and comparator groups, respectively [12]. Consistent with the results of Study 102, virological success (based on the FDA snapshot analysis) with elvitegravir/cobicistat/emtricitabine/tenofovir DF treatment was sustained at week 96 [36, 37, 47]. Of 708 patients, HIV-1 RNA levels of \50 copies/mL were achieved in 83 and 82 % of elvitegravir/cobicistat/emtricitabine/tenofovir DF and ritonavir-boosted atazanavir plus emtricitabine/ tenofovir DF recipients, respectively [37]. Elvitegravir/ cobicistat/emtricitabine/tenofovir DF showed durable virological efficacy, with a high rate of virological suppression (78 %) achieved at week 144, regardless of viral load and CD4? cell count at baseline [reported in an abstract] [16, 40]. 4.3 Pooled Efficacy Data Results of pooled analyses of data from at least two randomized clinical trials support the good virological efficacy of elvitegravir/cobicistat/emtricitabine/tenofovir DF in adults with HIV-1 infection (reported as abstracts) [48–50]. In a pre-specified pooled analysis of 48-week data from the phase II study and the two phase III studies (Studies 102 and 103) [using FDA snapshot analysis and ITT results], virological suppression (success) rates (HIV-1 RNA levels \50 copies/mL) at week 48 were 88.8 % for patients treated with elvitegravir/cobicistat/emtricitabine/tenofovir DF (n = 749) and 84.0 and 86. 8 % for the recipients of the comparator regimens in the phase II and Study 102 (n = 375) and 103 (n = 355), respectively [48]. The treatment differences between recipients of elvitegravir/ cobicistat/emtricitabine/tenofovir DF and efavirenz/emtricitabine/tenofovir DF were 5.1 % (95 % CI 0.7–9.4) and 1.9 % (95 % CI -2.3 to 6.1) between elvitegravir/cobicistat/emtricitabine/tenofovir DF and ritonavir-boosted atazanavir plus emtricitabine/tenofovir DF. The efficacy of elvitegravir/cobicistat/emtricitabine/tenofovir DF was consistent across subgroups, based on baseline HIV-1 RNA and CD4? cell counts, and demographics. Integrated analysis of long-term data from Studies 102 and 103 showed that patients treated with elvitegravir/ cobicistat/emtricitabine/tenofovir DF had high rates of virological success (i.e. suppression of HIV-1 RNA levels to \50 copies/mL) [49, 50]. Virological success rates at 96 weeks were 84 % for elvitegravir/cobicistat/emtricitabine/tenofovir DF (n = 701) and 82 % for the comparator groups (n = 352 for the efavirenz/emtricitabine/tenofovir DF group and n = 355 for the ritonavir-boosted atazanavir group); high rates of virological success were evident

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across demographic subgroups (sex, age, race) and for other patient subgroups i.e. baseline plasma HIV-1 RNA levels of B100,000 or [100,000 copies/mL and baseline CD4? cell counts of B350 or [350 cells/lL [49]. At week 96, high rates of virological suppression were achieved with elvitegravir/cobicistat/emtricitabine/tenofovir DF, efavirenz/emtricitabine/tenofovir DF or ritonavirboosted atazanavir plus emtricitabine/tenofovir DF, regardless of age of \50 or C50 years, in another (FDA snapshot) efficacy analysis of data from Studies 102 and 103 [51].

5 Tolerability Elvitegravir/cobicistat/emtricitabine/tenofovir DF was generally well tolerated in the phase II and the two phase III clinical trials in antiretroviral therapy-naı¨ve adults with HIV-1 infection (Studies 102 and 103; see Sect. 4) over the initial 48 week treatment period [11, 12, 48] and for up to 96 [35, 37, 49–51] and 144 weeks [39, 40, 52]. Information on the tolerability profile of elvitegravir/ cobicistat/emtricitabine/tenofovir DF reported in the US PI and EU SPC is based largely on pooled data from Studies 102 [11] and 103 [12]. Of the patients initially enrolled, 701 received treatment with elvitegravir/cobicistat/emtricitabine/tenofovir DF [16]. The rate of treatment discontinuation due to adverse events, regardless of severity, was 4.6 % for elvitegravir/cobicistat/emtricitabine/tenofovir DF compared with 6.8 % of patients treated with efavirenz/ emtricitabine/tenofovir DF (Study 102) and 5.9 % of patients treated with ritonavir-boosted atazanavir plus emtricitabine/tenofovir DF (Study 103) [11, 12, 16]. Treatment-emergent adverse drug reactions (based on all treatment-emergent adverse events and attributed to study drugs) occurring in C5 % of patients in any treatment arm in Studies 102 and 103 [16] are shown in Fig. 1. Nausea and diarrhoea were the most common (incidence C10 %) adverse events recorded for patients treated with elvitegravir/cobicistat/emtricitabine/tenofovir DF for 48 weeks [11, 12, 16, 19]. Abnormal liver function tests were reported for fewer patients treated with elvitegravir/ cobicistat/emtricitabine/tenofovir DF than for the recipients of ritonavir-boosted atazanavir plus emtricitabine/ tenofovir DF in Study 103 [12]. In this study, small median increases in serum creatinine concentrations, accompanied by decreases in eGFR, were reported in both study groups by the second week of treatment; however, these changes had stabilized by week 8 and did not change thereafter [12]. Integrated analyses of safety data (reported in an abstract) for patients included in Studies 102 and 103

90

C.M. Perry

Fig. 1 Tolerability profile of the elvitegravir/cobicistat/emtricitabine/tenofovir DF [EVG/COBI/FTC/TDF] once-daily single-tablet regimen (n = 701) compared with that of the efavirenz/emtricitabine/tenofovir DF [EVG/FTC/TDF] single-tablet regimen (n = 352) and ritonavirboosted atazanavir plus the emtricitabine/tenofovir DF single tablet [ATV ? RTV ? FTC/TDF] (n = 355) in the phase III trials in treatmentnaı¨ve adults with HIV-1 infection. Treatment-emergent adverse drug reactions (all grades) reported in C5 % of subjects in any treatment arm in Studies 102 and 103 (week 96 analysis) [16]. Adverse reactions occurring at an incidence of\1 % are not shown. See Tables 5 and 6 for further details of treatment regimens

showed that elvitegravir/cobicistat/emtricitabine/tenofovir DF was well tolerated over a 96-week treatment period [49]. Cumulative neuropsychiatric adverse events and rash were reported in fewer recipients of elvitegravir/cobicistat/ emtricitabine/tenofovir DF (incidence 44 and 21 %, respectively) than in the efavirenz/emtricitabine/tenofovir DF group (incidence 66 and 31 %) [49]. Adverse reactions associated with elvitegravir/cobicistat/emtricitabine/tenofovir DF (data from Studies 102 and 013) and adverse reactions to treatment with tenofovir DF and emtricitabine in combination with other antiretroviral drugs) [data from clinical studies and postmarketing experience] categorized as very common (incidence C10 %) in the EU SPC are: hypophosphataemia, headache, dizziness diarrhoea, vomiting, nausea, rash, elevated creatine kinase and asthenia [19]. Tenofovir DF is associated with rare renal impairment events, renal failure and proximal renal tubulopathy (PRT) [including Fanconi syndrome], sometimes leading to bone abnormalities and occasionally contributing to fractures (see Sect. 2.5) [19]. Monitoring of renal function is recommended. Tenofovir DF and emtricitabine are also associated with lactic acidosis, severe hepatomegaly with steatosis (see Sect. 6) and lipodystrophy (see Sect. 2.5) [19]. During 48 weeks of treatment, 6 (0.9 %) of 701 patients in the elvitegravir/cobicistat/emtricitabine/tenofovir DF

treatment group and 1 (0.3 %) of the recipients of ritonavirboosted atazanavir plus emtricitabine/tenofovir DF discontinued treatment because of a renal adverse reaction [19]. Over 96 weeks, 10 (1.4 %) of 701 patients and 2 (0.3 %) of patients in the combined comparator groups (n = 707) discontinued study drug as a result of a renal adverse reaction; 8 patients in the elvitegravir/cobicistat/ emtricitabine/tenofovir DF group and 1 patient in the comparator groups discontinued treatment during the first 48 weeks [16]. Laboratory findings consistent with PRT, resulting in the discontinuation of treatment, were recorded in 4 (0.6 %) of the elvitegravir/cobicistat/emtricitabine/ tenofovir DF recipients. All four patients [two of whom had renal impairment (eCLCR \ 70 mL/min)] at baseline) had an improvement in laboratory findings, although these did not completely resolve, after discontinuation of elvitegravir/cobicistat/emtricitabine/tenofovir DF treatment [16, 19]. Pooled data from Studies 102 and 103 were also examined for renal outcomes over 96 weeks (data reported in abstract) [53]. The rate of renal event discontinuations for the patients treated with elvitegravir/cobicistat/emtricitabine/tenofovir DF was similar to that for the recipients of ritonavir-boosted atazanavir plus emtricitabine/tenofovir DF (1.6 vs. 2.0 %); none of the patients who received efavirenz/emtricitabine/tenofovir DF discontinued


treatment because of a renal event [53]. Four of the recipients of elvitegravir/cobicistat/emtricitabine/tenofovir DF developed a PRT before week 24 and none of the patients treated with elvitegravir/cobicistat/emtricitabine/ tenofovir DF developed a new-onset PRT after week 24. The renal safety of elvitegravir/cobicistat/emtricitabine/ tenofovir DF was not influenced by baseline or on-treatment eGFR [53]. Relative to week 48, there were no new cases of PRT with elvitegravir/cobicistat/emtricitabine/ tenofovir DF at week 96 and no further reductions in GFR in Study 102 [34, 35]. Two patients discontinued elvitegravir/cobicistat/emtricitabine/tenofovir DF treatment because of a renal event after week 48 [35]. There was no evidence of renal safety signals in patients who received elvitegravir/cobicistat/emtricitabine/tenofovir DF for 144 weeks in Studies 102 [39] and 103 [40]. Decreases in estimated CLCR, as a result of the inhibition of tubular secretion of creatinine, without an effect on renal glomerular function, have been observed in recipients of cobicistat (see Sect. 2.5). In Studies 102 and 103, decreases in CLCR occurred during the initial stages of treatment with elvitegravir/cobicistat/emtricitabine/tenofovir DF and comparator treatments, and then stabilized. The mean change in eGFR by Cockcroft-Gault method after treatment for 48 weeks was -13.9 mL/min for elvitegravir/cobicistat/emtricitabine/tenofovir DF, and -1.6 and -9.3 mL/min for recipients of efavirenz/emtricitabine/ tenofovir DF and ritonavir-boosted atazanavir plus emtricitabine/tenofovir DF, respectively [19]. In vitro studies have shown that cobicistat and ritonavir inhibit the renal creatinine efflux transporter, MATE-1, leading to a rise in serum creatinine without affecting renal glomerular function (Sect 2.5) [42]. Elvitegravir/cobicistat/emtricitabine/tenofovir DF has a long-term tolerability profile that is different from that of ritonavir-boosted atazanavir plus emtricitabine/tenofovir DF or efavirenz/emtricitabine/tenofovir DF, according to preliminary data reported in an abstract [52]. In a 96-week integrated analysis, data were analysed on treatment-emergent adverse events occurring in C10 % of patients and at rates that differed between the different treatment arms. Most of the adverse events were of grade 1 severity and occurred during the first 4 weeks of treatment. The cumulative prevalence of several treatment-emergent adverse events was significantly (p \ 0.05) lower with elvitegravir/cobicistat/emtricitabine/tenofovir DF than with efavirenz/emtricitabine/ tenofovir DF (p-values not reported for continuing prevalence for any adverse event comparisons], including: abnormal dreams (9 vs. 28 % [continuing prevalence 4 vs. 14 %]), dizziness (7 vs. 26 % [1 vs. 4 %]), headache (16 vs. 11 % [5 vs. 2 %]), insomnia (10 vs. 16 % [6 vs. 8 %]) and rash (21 vs. 31 % [6 vs. 6 %]). In addition,

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the cumulative incidence of several adverse events was significantly (p \ 0.05) lower with elvitegravir/cobicistat/ emtricitabine/tenofovir DF than with ritonavir-boosted atazanavir plus emtricitabine/tenofovir DF, including: diarrhoea (25 vs. 31 % [continuing prevalence 4 vs. 9 %]) and ocular icterus (\1 vs. 14 % [0 vs. 7 %]). Compared with the efavirenz/emtricitabine/tenofovir DF group, patients treated with elvitegravir/cobicistat/emtricitabine/tenofovir DF had significantly lower treatment discontinuation rates due to neurological-psychiatric events (\1 vs. 3 %, p = 0.002), rash (\1 vs. 1 %; p = 0.045), and, compared with ritonavir-boosted atazanavir plus emtricitabine/tenofovir DF, a lower treatment discontinuation rate due to rash (\1 vs. 1 %; p = 0.046) [52].

6 Dosage and Administration The recommended dosage of elvitegravir/cobicistat/ emtricitabine/tenofovir DF for the treatment of antiretroviral therapy-naı¨ve adults with HIV-1 infection is one tablet (containing elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg and tenofovir DF 300 mg) taken once daily with food [16, 19]. As elvitegravir/cobicistat/ emtricitabine/tenofovir DF is formulated as a film-coated tablet, it should not be crushed or chewed [19]. Data are not yet available concerning the use of elvitegravir/cobicistat/emtricitabine/tenofovir DF in patients aged [65 years; thus, it should be used with caution in this population [19]. Furthermore, the efficacy and safety of elvitegravir/cobicistat/emtricitabine/tenofovir DF in paediatric patients aged 6–\18 years are not established and dosage recommendations are not available. Elvitegravir/cobicistat/emtricitabine/tenofovir DF should not be used for the treatment of paediatric patients \6 years of age [19]. Initiation of treatment with elvitegravir/cobicistat/ emtricitabine/tenofovir DF is not recommended for patients with an estimated CLCR of \70 mL/min [16, 19]. Furthermore, because elvitegravir/cobicistat/emtricitabine/ tenofovir DF is a fixed-dose combination tablet, treatment with elvitegravir/cobicistat/emtricitabine/tenofovir DF should be discontinued in patients with an estimated CLCR of \50 mL/min, as the dose interval adjustment required for emtricitabine and tenofovir DF cannot be achieved [16, 19]. CLCR, urine glucose and urine protein should be assessed before initiating treatment with elvitegravir/ cobicistat/emtricitabine/tenofovir DF and CLCR, urine glucose, and urine protein should be monitored in all patients. Serum phosphorus should be monitored in patients at risk for renal impairment. Administration of

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elvitegravir/cobicistat/emtricitabine/tenofovir DF with concurrent or recent use of nephrotoxic drugs should be avoided [16]. Before the start of treatment with elvitegravir/cobicistat/emtricitabine/tenofovir DF, patients should be tested for HBV infection. Dose adjustment of elvitegravir/cobicistat/emtricitabine/ tenofovir DF is not required for patients with mild (Child– Pugh Class A) or moderate (Child–Pugh Class B) hepatic impairment [16, 19]. As there are no available pharmacokinetic or safety data relating to the use of elvitegravir/ cobicistat/emtricitabine/tenofovir DF in patients with severe hepatic impairment (Child–Pugh Class C), it is not recommended for use in this patient group [16, 19]. Elvitegravir/cobicistat/emtricitabine/tenofovir DF should be avoided with the recent or concurrent use of a nephrotoxic agent, such as high-dose or multiple non-steroidal anti-inflammatory drugs (NSAIDs). Cases of acute renal failure after initiation of high dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on tenofovir DF. Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered, if required, in patients at risk for renal dysfunction. The effects of tenofovir DF-associated changes in BMD and biochemical markers (see Sect. 2) on long-term bone health and future fracture risk are not yet known. Assessment of BMD should be considered for patients with HIV-1 infection who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D has not been studied, such supplementation may be beneficial for all patients. Appropriate consultation should be obtained if bone abnormalities are suspected [16]. Cases of osteomalacia associated with PRT, manifest as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of tenofovir DF [16]. In addition, arthralgias and muscle pain or weakness have been reported in patients with PRT. Hypophosphatemia and osteomalacia secondary to PRT should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing tenofovir DF. Persistent or worsening bone pain, pain in extremities, fractures and/or muscular pain or weakness may be manifestations of PRT and should prompt an evaluation of renal function in at-risk patients [16]. The US PI for elvitegravir/cobicistat/emtricitabine/ tenofovir DF carries a boxed warning concerning lactic acidosis/severe hepatomegaly with steatosis and posttreatment acute exacerbation of hepatitis B [16]. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of

C.M. Perry

NRTIs, including tenofovir DF, in combination with other antiretroviral drugs [16]. Elvitegravir/cobicistat/ emtricitabine/tenofovir DF is not approved for the treatment of patients with chronic HBV infection and its safety and efficacy have not been established in patients with HIV-1 and HBV co-infection [16]. In the event of elvitegravir/cobicistat/emtricitabine/tenofovir DF being discontinued in HIV-1-infected patients with HBV co-infection, patients should be monitored for evidence of hepatitis exacerbation [19]. In addition, elvitegravir/cobicistat/emtricitabine/tenofovir DF is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which increased plasma concentrations are associated with serious and/or life threatening events [16, 19]. Local prescribing information should be consulted for detailed information regarding other contraindications, use in special patient populations, drug interactions, warnings and precautions.

7 Place of the Elvitegravir/Cobicistat/Emtricitabine/ Tenofovir Disoproxil Fumarate Single-Tablet Regimen in the Management of HIV-1 Infection in Adults Since approval of the first antiretroviral drug more than 25 years ago, treatment regimens have improved dramatically in terms of antiviral potency, tolerability, simplification of administration and availability. As a result, in countries where antiretroviral treatment can be accessed, there has been a substantial reduction in HIV-associated morbidity and mortality [3]. The number of AIDS-related deaths worldwide has decreased from 2.3 million in 2005 to 1.7 million in 2011, and in countries with major improvements in access to treatments for HIV-1 infection, such as Brazil or China, there has been an 80 % decrease in the AIDS-related mortality rate [54]. If the positive trend in access to treatment can be maintained, the United Nations’ global target of providing antiretroviral therapy to 15 million people by the end of 2015 can be reached [54]. The main goals of antiretroviral therapy are the achievement of durable viral suppression, restoration and preservation of good immunological function, delayed disease progression, improved survival, and improved health-related quality-oflife [3–6]. Treatment options for HIV-1 infection continue to increase with the development of new classes of antiretroviral drugs agents and the availability of novel drugs for use in combination with established dual NRTI regimens. The most recent additions to the broad range of drugs currently approved for use (as components of combination therapies) in the USA and Europe are elvitegravir, an


INSTI, and rilpivirine, an NNRTI [4, 33, 55]. Another INSTI, dolutegravir, is currently being evaluated in phase III trials and has recently been approved for use as a component of combination therapy in the USA [56]. New therapies designed to block the assembly of HIV-1 or the entry of the virus into the host cell, as well as investigations into HIV-1 resistance to NRTIs, NNRTIs and INSTIs, are important areas of current research [33]. In current US, European, British and international guidelines, preferred initial treatment regimens for adults with HIV-1 infection are based on a dual NRTI backbone in combination with a drug from another class e.g. an NNRTI, a PI or an INSTI, with fixed-dose combinations preferred when available (see Sect. 1). Preferred initial regimens in treatment guidelines from the US Department of Health and Human Services (DHHS) include the following drugs: emtricitabine (or lamivudine) and tenofovir DF in combination with efavirenz, or ritonavir-boosted atazanavir, or ritonavir-boosted darunavir or raltegravir or dolutegravir; elvitegravir/cobicistat/emtricitabine/tenofovir DF has recently been added to these guidelines as a preferred initial INSTI-based treatment, based on long-term (including 144-week) follow-up data from randomized, clinical trials indicating that it demonstrates durable efficacy and safety, together with post-marketing clinical experience of its use in patients with HIV-1 infection [4, 8]. BHIVA treatment guidelines also include elvitegravir/cobicistat/emtricitabine/tenofovir DF as a preferred initial treatment option [57]. Currently available once-daily single-tablet regimens (in the USA) also include efavirenz/emtricitabine/tenofovir DF (see Sect. 4) and rilpivirine/emtricitabine/tenofovir DF. Other fixed-dose combinations of three antiretroviral drugs are available in other countries [9]. Like raltegravir, which was the first INSTI to be approved by the US FDA for clinical use in combination therapy regimens, elvitegravir shows good antiretroviral activity in clinical isolates of HIV-1 and has a well-characterized resistance profile. Elvitegravir and raltegravir do however allow for the development of cross-resistance in HIV-1 and this has clinical implications for sequencing with raltegravir-based regimens for treatment-experienced patients with HIV-1 infection [55]. Raltegravir is administered orally twice daily and is approved for use (in combination regimens) both as an initial treatment and for treatment-experienced patients with HIV-1 infection [55, 58]. Elvitegravir is the first integrase inhibitor for oncedaily administration to be approved for clinical use as a component of a once-daily single-tablet regimen: elvitegravir/cobicistat/emtricitabine/tenofovir DF. Data from in vitro studies of antiretroviral activity support the clinical use of elvitegravir in combination with the well-established NRTIs emtricitabine and tenofovir DF as an initial treatment for patients with HIV-1 infection;

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isolates resistant to elvitegravir were seldom detected after treatment with elvitegravir/cobicistat/emtricitabine/tenofovir DF for up to 96 weeks in fully published studies and thereafter for up to 144 weeks (preliminary data) [see Sect. 2]. The addition of cobicistat to the combination tablet boosts systemic exposure to elvitegravir, in common with the use of ritonavir with PIs. In contrast to ritonavir, cobicistat is devoid of anti-HIV activity and these two agents have markedly different tolerability profiles. For example, increased lipid levels, insulin resistance, and gastrointestinal intolerance (that may affect treatment adherence) are well-known adverse effects of ritonavir [28]. In vitro data and clinical findings from Study 103 indicate that both ritonavir and cobicistat inhibit the tubular secretion of creatinine; this is achieved via inhibition of the MATE-1 creatinine efflux transporter on the apical surface of renal tubule cells (see Sect. 2.5) [12, 42]. In study 103, increases in serum creatinine and the reflected declines in creatinine clearance with elvitegravir/cobicistat/emtricitabine/tenofovir DF at weeks 48 and 96 were similar to those reported for ritonavir-boosted atazanavir plus emtricitabine/tenofovir DF [12, 37]. In large randomized clinical trials in adults with HIV-1 infection, elvitegravir/cobicistat/emtricitabine/tenofovir DF, administered as a single tablet once daily showed good virological efficacy (HIV-1 RNA levels \50 copies/mL) at the 48-week primary endpoint assessments and thereafter for up to 144 weeks, and improved patients’ immune status, as evidenced by increases in CD4? cell counts. Elvitegravir/cobicistat/emtricitabine/tenofovir DF showed virological efficacy noninferior to that of standard triple therapy regimens consisting of an NNRTI or a PI in combination with a backbone of emtricitabine/tenofovir DF (see Sect. 4). Elvitegravir/cobicistat/emtricitabine/tenofovir DF was generally well tolerated over periods of up to 144 weeks, with gastrointestinal adverse events occurring most commonly. Its tolerability profile was distinctly different from that of the efavirenz-containing comparator regimen, which was characterized by abnormal dreams, dizziness and rash. In addition, elvitegravir/cobicistat/ emtricitabine/tenofovir DF had a more favourable lipid profile overall than efavirenz/emtricitabine/tenofovir DF, in terms of total cholesterol and LDL-C levels in Study 102, and ritonavir-boosted atazanavir plus emtricitabine/ tenofovir DF, in terms of triglycerides in Study 103 (see Sect. 2.4). However, the use of elvitegravir/cobicistat/emtricitabine/tenofovir DF may be limited by renal adverse effects that occur in a small proportion of patients and it requires judicious prescribing and monitoring for adverse effects, including those caused by interactions with other drugs. Nevertheless, there have been no more cases of

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PRT reported with elvitegravir/cobicistat/emtricitabine/ tenofovir DF than in other studies in which tenofovir DF was a component of treatment. All patients who developed PRT during treatment with elvitegravir/cobicistat/ emtricitabine/tenofovir DF had resolution of tubulopathy and improvement in renal function after the discontinuation of elvitegravir/cobicistat/emtricitabine/tenofovir DF (see Sect. 5), indicating that this is a reversible adverse effect if treatment is discontinued in a timely manner. The availability of the elvitegravir/cobicistat/emtricitabine/tenofovir DF combination tablet is an important advance in the treatment of HIV-1 infection and, as mentioned previously, is a preferred first-line treatment option for adults with HIV-1 infection with a pre-treatment CLCR C70 mL/min in recently updated DHHS treatment guidelines [4, 8]. Further data on its efficacy in HIV-1 infected patients with HBV and/or HCV co-infection will be of interest. In contrast to raltegravir, elvitegravir is not approved for use in the treatment of paediatric patients with HIV-1 infection and it must be taken with food. Of note, an international study of elvitegravir/cobicistat/emtricitabine/ tenofovir DF in treatment-naı¨ve women with HIV-1 infection (WAVES) is ongoing [59]. Although no direct comparisons of elvitegravir/cobicistat/emtricitabine/tenofovir DF with raltegravir-containing regimens have been published, efficacy results achieved in treatment-naı¨ve patients with HIV-1 infection treated with once-daily elvitegravir/cobicistat/emtricitabine/tenofovir DF in Study 102 were similar to results reported for recipients of raltegravir plus emtricitabine/tenofovir DF in the STARTMRK Study in an indirect treatment comparison [60]. At week 48, 89 % of patients in both treatment groups had HIV-1 RNA levels of \50 copies/mL. The two treatment regimens also showed similar resistance and tolerability profiles. Durable efficacy with elvitegravir as a component of antiretroviral therapy (as separate components) was also reported in Study 145 (GS-US-183-0145), a 96-week, double-blind, active-controlled study in which once-daily elvitegravir was compared with twice-daily raltegravir in treatment-experienced patients with HIV-1 infection. The elvitegravir regimen was noninferior to the raltegravir regimen in terms of HIV-1 RNA levels of \50 copies/ mL; both regimens were well tolerated [61, 62]. Clinical evidence from recent studies indicate that elvitegravir/ cobicistat/emtricitabine/tenofovir DF may be an effective and well tolerated switch option for patients unable to tolerate other treatment regimens, including efavirenz/ emtricitabine/tenofovir DF (see Sect. 4.1.1). Patients who switched from a multiple-tablet regimen consisting of twice-daily raltegravir and once-daily emtricitabine/tenofovir DF continued to have virological suppression

C.M. Perry

when switched to once-daily elvitegravir/cobicistat/ emtricitabine/tenofovir DF, suggesting that it may be a useful option for raltegravir-treated patients requiring a simple once-daily regimen [63]. Two phase III elvitegravir/cobicistat/emtricitabine/tenofovir DF 96-week switch studies, (GS-US-236-0115 (NCT01475838) [64] and GS-US-236-0121 NCT01495702 [65] are ongoing in patients who are virologically suppressed on an NNRTI plus emtricitabine/tenofovir DF or a ritonavir-boosted protease inhibitor plus emtricitabine/tenofovir DF and then switch to elvitegravir/cobicistat/emtricitabine/tenofovir DF. The primary endpoint is to demonstrate that switching to elvitegravir/cobicistat/emtricitabine/tenofovir DF is noninferior to remaining on baseline therapy. These are 96 week studies and results for week 48 will be presented in early 2014. In US treatment guidelines, treatment should be initiated for any adult with HIV-1 infection, regardless of the CD4? cell count, to reduce the risk of disease progression [4]. In the WHO guidelines, the recommended immunological threshold for initiating antiretroviral drug therapy is 500 cells/lL, based on evidence of prolongation of life with early treatment, together with a lower risk viral transmission from an infected to an uninfected person [9, 54]. Importantly, treatment selection should be individualized based on various factors, including the results of resistance testing, efficacy, toxicity, frequency of administration, pill burden, the potential for clinically relevant drug interactions, and comorbidities [4]. According to recent guidelines from the International Antiviral Society (USA Panel) [3], complete regimens in fixed-dose combinations are more popular today, being preferred for their convenience of administration and the likelihood of improved adherence to treatment. New consolidated guidelines from the WHO recommend a fixeddose combination of three antiretroviral drugs in a single tablet as a preferred first-line treatment [9]. According to the British HIV Association (BHIVA) guidelines, fixeddose drug combinations can increase adherence to treatment and these treatment options should be considered for patients with low adherence to more complex regimens; however, the benefit of potentially better adherence must be weighed against other treatment characteristics such as effectiveness, tolerability and resistance profile [5]. Finally, the simplicity of treatment achieved by use of the combination of antiretroviral agents in a single tablet has several potential advantages in addition to the possibility of improved treatment adherence; these include less selective noncompliance, the reduced likelihood of a prescription error, and patient preference. Collectively, these factors are likely to reduce the emergence of drug resistance and treatment failure [11]. A possible shortcoming of singletablet regimens in the clinical setting is the difficulty in


adjusting the dosage of an individual antiretroviral drug component or to change one of the drug components. Elvitegravir/cobicistat/emtricitabine/tenofovir DF is the first and only INSTI-based NRTI-containing co-formulation currently available as a single-tablet once-daily regimen for the initial antiretroviral drug treatment of adults with HIV-1 infection. Based on recent evidence from major, randomized, clinical trials, elvitegravir/cobicistat/ emtricitabine/tenofovir DF provides an effective and well tolerated alternative to an efavirenz- or protease inhibitorbased NRTI-containing once-daily regimen in treatmentnaı¨ve adults, and may be particularly useful in patients for whom NNRTI therapy is unsuitable. Elvitegravir/cobicistat/emtricitabine/tenofovir DF is an important addition to the group of simplified once-daily single-tablet regimens currently available for the effective treatment of HIV-1 infection in antiretroviral therapy-naı¨ve patients and is among the preferred regimens recommended for use as initial treatment. It offers advantages over more complex multiple-tablet regimens that may impair treatment adherence, which is fundamental to the successful management of HIV-1 infection.

4.

5.

6.

7. 8.

9.

10. Data selection sources:Relevant medical literature (including published and unpublished data) on elvitegravir/cobicistat/ emtricitabine/tenofovir disoproxil fumarate (DF) combination tablet was identified by searching databases including MEDLINE (from 1946) and EMBASE (from 1996) [searches last updated 19 Nov 2013], bibliographies from published literature, clinical trial registries/databases and websites. Additional information was also requested from the company developing the drug. Search terms: Elvitegravir-cobicistat-emtricitabine-tenofovir, elvitegravir and cobicistat and emtricitabine and tenofovir, cobicistat plus elvitegravir plus emtricitabine plus tenofovir disoproxil, Stribild, HIV-1 infection. Study selection: Studies in patients with HIV-1 infection who received elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (DF). When available, large, well designed, comparative trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

11.

12.

13.

14. 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 an opportunity to comment on this article. Changes resulting from comments received were made by the authors on the basis of scientific and editorial merit.

15.

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tenofovir disoproxil fumarate single-tablet regimen: a review of its use in HIV infection.

tenofovir disoproxil fumarate for the treatment of HIV-1 infection in adults.

tenofovir disoproxil fumarate in treatment-naive HIV-1-infected adults.

Randomized comparison of tenofovir disoproxil fumarate vs emtricitabine and tenofovir disoproxil fumarate in patients with lamivudine-resistant chronic hepatitis B.

tenofovir disoproxil fumarate, an antiretroviral single-tablet regimen for the treatment of HIV infection.

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Topical Tenofovir Disoproxil Fumarate Nanoparticles Prevent HIV-1 Vaginal Transmission in a Humanized Mouse Model.

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Efficacy of tenofovir disoproxil fumarate therapy in Chinese chronic hepatitis B patients after multiple antiviral failures.