Clinical pharmacokinetics and pharmacodynamics of dolutegravir used as a single tablet regimen for the treatment of HIV-1 infection.

This article was downloaded by: [UQ Library] On: 16 August 2015, At: 03:35 Publisher: Taylor & Francis Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: 5 Howick Place, London, SW1P 1WG

Expert Opinion on Drug Safety Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/ieds20

Clinical pharmacokinetics and pharmacodynamics of dolutegravir used as a single tablet regimen for the treatment of HIV-1 infection Pauline Bollen

abc

d

e

, Peter Reiss , Jonathan Schapiro & David Burger

ab

a 1

Radboud University Medical Center, Department of Pharmacy, Geert Grooteplein-Zuid 10 6525 GA Nijmegen, The Netherlands b 2

Radboud Institute for Health Sciences (RIHS), Nijmegen, The Netherlands

c 3

Elisabeth TweeSteden Hospital, Hospital Pharmacy Midden-Brabant, Tilburg, The Netherlands d 4

Click for updates

University of Amsterdam, Academic Medical Center, Division of Infectious Diseases and Department of Global Health, Amsterdam, The Netherlands e 5

National Hemophilia Center, Sheba Medical Center, Ramat Gan, Israel Published online: 03 Jul 2015.

To cite this article: Pauline Bollen, Peter Reiss, Jonathan Schapiro & David Burger (2015): Clinical pharmacokinetics and pharmacodynamics of dolutegravir used as a single tablet regimen for the treatment of HIV-1 infection, Expert Opinion on Drug Safety To link to this article: http://dx.doi.org/10.1517/14740338.2015.1059818

PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions

Downloaded by [UQ Library] at 03:35 16 August 2015

Drug Safety Evaluation

1.

Introduction

2.

Search strategy and methodology

3.

Pharmacology

4.

Pharmacokinetics

5.

Pharmacodynamics

6.

Special populations

7.

Conclusion

8.

Expert opinion

Clinical pharmacokinetics and pharmacodynamics of dolutegravir used as a single tablet regimen for the treatment of HIV-1 infection Pauline Bollen†, Peter Reiss, Jonathan Schapiro & David Burger †

Radboud University Medical Center, Department of Pharmacy, Nijmegen, The Netherlands

Introduction: With the introduction of the coformulated dolutegravir, abacavir and lamivudine, a new single tablet regimen (STR) is made available for the use in treatment-naive and treatment-experienced HIV-infected patients. This drug combination is the fourth STR that will be positioned next to the STRs with efavirenz, rilpivirine or elvitegravir as third agents, respectively. Areas covered: The objective of this review is to provide an overview of the efficacy and safety of the combined dolutegravir/abacavir/lamivudine coformulation. The review will focus on dolutegravir and includes both published data as well as data presented at recent major international HIV/AIDS conferences. Expert opinion: The dolutegravir/abacavir/lamivudine regimen is highly effective in achieving sustained suppression of HIV-1 RNA plasma concentrations. The STR has a favorable safety profile and a low potential for drug interactions, which will contribute to a prominent role in therapy. As this STR contains abacavir as backbone component, the use requires patients to be HLA-B*5701 negative, with good hepatic function. Other first-line treatment combinations are preferred for patients with hepatitis B co-infection or with a high cardiovascular risk. Keywords: abacavir, dolutegravir, fixed-dose combination, HIV, integrase inhibitor, lamivudine, nucleoside reverse transcriptase inhibitor Expert Opin. Drug Saf. [Early Online]

1.

Introduction

Since the introduction of zidovudine in 1987, more than 25 antiretroviral drugs, from six different classes, have become available for the treatment of HIV-infected patients. The use of combination antiretroviral therapy (cART) has significantly reduced morbidity and mortality and prevented the progression to AIDS in the vast majority of HIV-positive patients [1]. HIV can be considered a chronic condition requiring lifelong daily medication. Treatment challenges such as problems with tolerability, high pill burden and medication adherence have become important issues to overcome to guarantee long-term success of therapy [2]. STRs can be useful in these situations and may improve patient satisfaction and long-term adherence. Currently available single tablet formulations are Atripla, Eviplera (named Complera in the USA) and Stribild. Atripla and Eviplera consist of tenofovir and emtricitabine with either one of two non-nucleoside reverse transcriptase inhibitors (NNRTIs), efavirenz or rilpivirine, respectively. Stribild is the first STR combining 10.1517/14740338.2015.1059818 © 2015 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted

1

P. Bollen et al.

Box 1. Drug summary. Drug name Phase Indication Pharmacology description Route of administration Chemical structure

Dolutegravir, abacavir, lamivudine (Triumeq) Phase IV Adults and adolescents from 12 years of age with human immunodeficiency virus (HIV) weighing at least 40 kg Dolutegravir is an integrase inhibitor. Abacavir and lamivudine are nucleoside reverse transcriptase inhibitors Oral Dolutegravir


Abacavir

Lamivudine

Pivotal trial(s)

SINGLE, SPRING-2, FLAMINGO, SAILING

Pharmaprojects -- copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Pipeline (http://informa-pipeline.citeline.com) and Citeline (http://informa.citeline.com).

a backbone of tenofovir and emtricitabine with an integrase strand transfer inhibitor (INSTI), elvitegravir. It also contains cobicistat, for pharmacokinetic enhancement of elvitegravir. In 2014, dolutegravir (Tivicay), a novel second-generation INSTI, became available. According to current guidelines, regimens consisting of dolutegravir combined with abacavir/ lamivudine or tenofovir/emtricitabine are among the recommended regimens for initial therapy [3-5]. Dolutegravir 50 mg combined with 600 mg abacavir and 300 mg lamivudine is now also available in a co-formulated tablet, named Triumeq [6]. The US FDA approval of the fixed-dose combination tablet was based primarily on the 48- and 96-week results of the SINGLE study and a bioequivalence study [7,8]. This review gives an outline of key efficacy and safety data for the fixed-dose combination of dolutegravir, abacavir and 2

lamivudine. The focus will be on dolutegravir. We will briefly discuss the utility of this regimen in particular patient groups, such as patients with hepatitis co-infection, renal or hepatic insufficiency, (pregnant) women and in the elderly and discuss relevant drug--drug interactions. In addition, an overall expert opinion commentary regarding the use of this regimen is provided. 2.

Search strategy and methodology

For this review, we searched the databases PubMed and Embase from inception to January 2015. Also abstracts and posters of previous major HIV/AIDS conferences in 2013 and 2014 were searched for literature. Search terms used: dolutegravir, S/GSK1349572, abacavir, lamivudine,

Expert Opin. Drug Saf. (2015) 14(9)

Dolutegravir, abacavir, lamivudine

summarizes the main pharmacokinetic properties of dolutegravir, abacavir and lamivudine.

Article highlights. .

.

.

.


.

The combined dolutegravir/abacavir/lamivudine is a convenient once-daily highly effective single-tablet regimen (STR) for use in treatment-naive and treatmentexperienced HIV infected patients. Dolutegravir has a favourable safety profile, a relatively high barrier to resistance and a low potency for causing drug-drug interactions. Most reported adverse effects for dolutegravir are nausea, diarrhoea, headache and nasopharyngitis. Dolutegravir causes increases in serum creatinine, but does not affect actual glomerular filtration rate. HLA-B*5701 testing is required prior to use of the STR and avoids most hypersensitivity reactions due to abacavir. Use of the STR in patients with renal or hepatic insufficiency may be restricted due to recommended dose adjustments for lamivudine or abacavir. Individual patient characteristics should be taken into account when choosing an effective and safe HIV-treatment regimen. Dolutegravir as STR would be an attractive treatment option for use in patients with gastrointestinal disturbances, lipid toxicities, kidney abnormalities or HCV-coinfection. In patients with HBV co-infection or high cardiovascular risk, other treatment options may be more effective or safe.

This box summarizes key points contained in the article.

safety, efficacy, toxicity, adverse events and tolerability. Additional articles were found by tracing citations to locate original sources. For efficacy data on dolutegravir only, head-to-head comparison studies are included for this review. 3.

Pharmacology

Mechanism of action The INSTI dolutegravir acts by inhibiting the HIV-encoded integrase enzyme and prevents the integration of the retroviral DNA into the host cell DNA [9-11]. The nucleoside reverse transcriptase inhibitors (NRTIs), abacavir and lamivudine, are substrates of the HIV-1 reverse transcriptase enzyme. After entering the cell, they are converted to their active 5¢-triphosphate (TP) anabolite, which competes with endogenous nucleosides, cytidine (in case of lamivudine) and guanosine (abacavir), to become incorporated into the newly synthesized nucleic acid chain of HIV viral DNA. This incorporation of abacavir or lamivudine TPs, blocks further elongation of the viral DNA and terminates the replication of the HIV virus [12,13]. 3.1

4.

Pharmacokinetics

Pharmacokinetic properties of dolutegravir alone as well as combined in the fixed-dose combination tablet are summarized below. Pharmacokinetic data on abacavir and lamivudine have been extensively reviewed elsewhere [12-14]. Table 1

Absorption and distribution The pharmacokinetics of dolutegravir as individual component were evaluated in healthy volunteers and in HIV-1infected patients, as monotherapy and as part of cART [15-18]. After oral administration, dolutegravir is rapidly absorbed and the maximal plasma concentration (Cmax) is reached within ~ 1.5 -- 2.5 h [16]. When doses ranging from 2 to 50 mg were administered orally as monotherapy in HIV-infected patients, a slightly less than dose proportional increase in dolutegravir exposure (in the area under the plasmaconcentration time curve [AUC0-¥] and Cmax) was noticed [16]. The average trough plasma concentration (Ctrough) of dolutegravir as part of cART (n = 399) determined at weeks 4, 24 and 48 (coefficient of variation [%]) was 1.18 µg/ml (60%) [18]. Dolutegravir is highly plasma protein bound (> 99%) and permeates into the cerebrospinal fluid (CSF), despite the fact that it is a substrate for the efflux-pumps P-glycoprotein and breast cancer resistance protein [19,20]. After 16 weeks of treatment, the mean concentration in the CSF obtained 2 -- 6 h post-dose (standard deviation [SD]) was 12.6 (3.64) ng/ml (n = 12) [19]. This is higher than the IC50 of 0.2 ng/ ml [19]. The co-formulated dolutegravir/abacavir/lamivudine tablet is relatively large (22 11 mm, weight ~ 1.7 g) [21]. Dolutegravir in this STR is bioequivalent to the co-administered separate tablets of dolutegravir 50 mg and abacavir 600 mg/ lamivudine 300 mg (Kivexa or Epzicom). In a randomized, open-label, single-dose study in 62 healthy subjects, the 90% confidence intervals for the geometric least squares (GLS) mean ratios for the AUC0-¥ and Cmax were within the accepted range (0.8 -- 1.25) for bioequivalence [21]. The dolutegravir STR can be taken with or without food. A high-fat meal (~ 869 calories, 53% fat) increased the dolutegravir AUC0-¥ and Cmax with 48% (GLS mean ratio [90% CI] = 1.48 [1.36 -- 1.62]) and 37% (GLS mean ratio [90% CI] = 1.37 [1.26 -- 1.48]), respectively, compared with the fasted state. This was in line with the increase in AUC0-¥ (66%) seen for dolutegravir administered with food (870 calories, 53% fat) as single tablet [22]. Contrary to dolutegravir, administration of abacavir with a high fat meal resulted in a 23% lower Cmax compared with the fasted state. The AUC0-¥ of abacavir was not affected (ratio of GLS [90% CI] = 0.926 [0.899 -- 0.953]). A lower Cmax is not likely to affect the efficacy of abacavir, since the total amount of abacavir in plasma available for intracellular uptake is not changed. The observed decrease in Cmax of abacavir was consistent with results seen in earlier studies with the separate tablet [23-25]. Other pharmacokinetic parameters for abacavir and lamivudine in the coformulated tablet did not differ between the fasted and the fed state [21]. 4.1


3

P. Bollen et al.

Table 1. Overview of pharmacokinetic properties for dolutegravir, abacavir and lamivudine [16,18,21,85,86].

Bioavailability Metabolism Excretion Tmax (h) Cmax* AUC0-t (µg·h/ml)* Ctrough (µg/ml) T1/2 (h) T1/2 intracellular (h)

Dolutegravir 50 mg

Abacavir 600 mg

n.d. Glucuronidation, UGT1A1 (major), CYP3A4 (minor) Faeces and urine 1.5 -- 2.5 2.44 44.73 1.18 11 -- 12 -

~ 83% Glucuronidation, alcohol dehydrogenase Urine (major) and faeces (minor) 1 4.03 13.92 2.6 20.6

Lamivudine 300 mg 80 -- 85% Urine 0.5 -- 1.5 2.11 12.75 5 -- 7 10.5 -- 15.5

*As determined for the fixed-dose combination tablet. AUC0-t: Area under the plasma concentration time curve; Ctrough: Trough plasma concentration (measured concentration at the end of a dosing interval at steady state); n.d.: Not determined; T1/2: Elimination half-life; UGT: Uridine diphosphate glucuronosyltransferase.

Metabolism and elimination Dolutegravir is mainly metabolized by glucuronidation by uridine diphosphate glucuronosyltransferase (UGT) 1A1. Approximately 10% of the dose administered is metabolized by cytochrome P450 (CYP) 3A4 [20,26]. In patients carrying UGT1A1 polymorphisms (poor metabolizer status), dolutegravir AUC was 46% higher than observed in patients with normal metabolizing capacities. Based on accumulated safety data, this increase is considered not clinically relevant and no dose adjustments are required [27]. A large proportion (~ 50%) of the total oral dolutegravir dose is excreted in the faeces. Excretion by the kidneys of the unchanged dolutegravir is low (< 1%) [26]. Table 1 shows the metabolism and elimination routes of abacavir and lamivudine. Intracellular elimination half-lives of abacavir and lamivudine correspond to the terminal half-life of dolutegravir. This supports co-formulation of these agents in a once-daily STR.


4.2

Patients with hepatic impairment The use of the STR dolutegravir/abacavir/lamivudine is not recommended in patients with mild-to-severe hepatic impairment (Child--Pugh class A--C). In case of mild hepatic impairment, the use of separate tablets is necessary to allow for a dose adjustment of abacavir to 200 mg twice daily (b.i.d.). In patients with moderate or severe hepatic impairment, the use of abacavir is not recommended. In a single-dose study in eight subjects with mild-to-moderate hepatic impairment (Child--Pugh class B), no dose adjustment was required for dolutegravir 50 mg once daily (QD) [28]. Dolutegravir pharmacokinetics were not evaluated in patients with severe hepatic impairment. Lamivudine is not dependent on hepatic metabolism and a dose adjustment is not required. 4.2.1

Patients with renal insufficiency The dolutegravir/abacavir/lamivudine STR is not recommended for use in patients with an estimated glomerular filtration rate (eGFR) < 50 ml/min. Below this value, a 4.2.2

4

dose adjustment for lamivudine to 150 mg QD is recommended [6,29]. Abacavir requires no dose adjustment in renal insufficiency [30]. Dolutegravir AUC0-¥ was surprisingly ~ 40% lower in subjects with severe renal insufficiency (eGFR < 30 ml/min) [31]. The mechanism behind this reduction in exposure is yet unknown. Careful treatment optimization is advised in situations requiring high dolutegravir exposure, such as in subjects with resistance to INSTIs or drug--drug interactions [31]. Drug--drug interactions A summary of drug--drug interactions with the dolutegravir/ abacavir/lamivudine STR requiring a dose adjustment or treatment alteration is given in Table 2. Co-administration of drugs that inhibit or induce UGT1A1 or CYP3A may cause pharmacokinetic drug--drug interactions with dolutegravir. Dolutegravir itself has no clinically relevant inhibitory or inducing effects on main CYP enzymes. However, dolutegravir inhibits the renal organic cation transporter 2 (OCT2). This inhibition causes an increase in exposure to drugs, such as metformin, which depend on OCT2 transport along the basolateral membrane for subsequent elimination [20,32]. The NRTIs, abacavir and lamivudine have less potential for pharmacokinetic drug--drug interactions, since they do not have inducing or inhibiting effects and are less dependent on metabolism. Several important interactions for clinical practice arise if dolutegravir is co-administered with antacids, metal cationcontaining products or multivitamins (see the recommendations in Table 2) [33,34]. Especially co-administration with metal cations, such as aluminum or magnesium, should be avoided. Co-administration can highly impair dolutegravir absorption (74% decrease in both AUC and minimal plasma concentration 24 h post-dose [Cmin] [34]) and is due to chelation of cations at the active site of dolutegravir [33]. The lowering effect of rifampicin on dolutegravir plasma concentration can be circumvented by the use of rifabutin as an alternative [35]. Since co-administration with efavirenz, 4.3



Table 2. Drug interactions for the fixed-dose combination of dolutegravir, abacavir and lamivudine requiring dose adjustments or treatment alterations.


Interacting drug

Effect

Mechanism

Recommendation for co-administration with DTG/ABC/3TC

Efavirenz

Dolutegravir #

UGT1A1 and CYP3A induction

Nevirapine*

Dolutegravir #


Etravirine

Dolutegravir #


Tipranavir/ritonavir Emtricitabine* Didanosine* Stavudine* Zidovudine* Rifampin Trimethoprim/ sulfamethoxazole Phenobarbital* Oxcarbazepine* Phenytoin* Carbamazepine Cladribine

Dolutegravir # Lamivudine intracellular #

UGT1A1 and CYP3A induction Potential risk for intracellular interaction

Dolutegravir # Lamivudine "

UGT1A1 and CYP3A induction OCT inhibition

Dolutegravir #


Cladribine intracellular # / lamivudine intracellular # Dofetilide "

Inhibition of intracellular phosphorylation of cladribine by lamivudine or vice versa OCT2 transporter inhibition by dolutegravir OCT2 transporter inhibition by dolutegravir Complexation of dolutegravir to polyvalent cations

Dofetilide* Metformin

Metformin " dolutegravir $ Dolutegravir #

Magnesium or aluminum containing antacids Calcium Dolutegravir # supplements/ iron supplements/ multivitamins (cation containing) St. John’s wort* Dolutegravir # Methadone Abacavir $ methadone (CL/F) "

Ref.

DTG 50 mg b.i.d. required. Do not combine in patients with INSTI resistance DTG 50 mg b.i.d. required. Do not combine in patients with INSTI resistance Only combine if co-administered with ATV/r, DRV/r, LPV/r DTG 50 mg b.i.d. required Do not combine

[36]

DTG 50 mg b.i.d. required Do not combine in patients with renal impairment Avoid combination. For combination with carbamazepine, dolutegravir 50 mg b.i.d. required

[35] [88]

Avoid combination

[90]

[87] [36]

[89]

Do not combine. Dofetilide is contraindicated in combination with dolutegravir Monitor safety and efficacy of metformin and [32] adjust dose if necessary Antacid administration: 2 h after or 6 h [34] before DTG/ABC/3TC

Complexation of dolutegravir to polyvalent cations

Supplement administration: 2 h after or 6 h before DTG/ABC/3TC. Calcium or iron supplements can be co-administered if taken with food

UGT1A1 and CYP3A induction Unknown

Do not combine [92,93] Usually no dose adjustment needed, but re-titration of methadone is required in some cases

[33,34,91]

*Not studied interaction. The interaction is derived from another interaction study with a drug from the same class or a known inducing or inhibiting effect or elimination route of this drug. 3TC: Lamivudine; ABC: Abacavir; ATV/r: Atazanavir/ritonavir; CL/F: Total body clearance from plasma after oral administration; DRV/r: Darunavir/ritonavir; DTG: Dolutegravir; INSTI: Integrase strand transfer inhibitor; LPV/r: Lopinavir/ritonavir.

nevirapine, etravirine or tipranavir/ritonavir lowers dolutegravir concentration, an increase to dolutegravir 50 mg b.i.d. is required [36]. In such case, an additional dolutegravir 50 mg tablet can be added to the STR. Ritonavir-boosted fosamprenavir lowered dolutegravir AUC, Cmax and Cmin by 35, 24 and 49%, respectively [37]. No dose adjustment is required according to the European summary of product characteristics (SPC) [6]. Nevertheless, this may need further attention if high dolutegravir levels are required. Other drug--drug interactions for dolutegravir, for example, the combination with rilpivirine, atazanavir/ritonavir, lopinavir/ritonavir, boceprevir, telaprevir and prednisone [38-42], were investigated and require no dose adjustment of the

STR or co-administered drug. For a complete list of the influence and recommendations on known and derived drug--drug interactions, refer to the website http://www.hiv-druginteractions.org/. 5.

Pharmacodynamics

Antiviral activity Dolutegravir use results in a rapid decline in HIV-1 RNA, with a clear dose--response relationship [16,17]. After 10 days of monotherapy with dolutegravir 50 mg QD in treatment-naive HIV-infected patients (n = 10), a decline (SD) of 2.46 log10 (0.35) HIV-1 RNA copies/ml was 5.1


5

P. Bollen et al.

observed. This antiviral response was maintained for 4 days after the last 50 mg dose [16]. Dolutegravir dissociates more slowly from wild-type integrase--DNA complexes compared with raltegravir and elvitegravir (dissociation half-life [t1/2, diss] = 71 h vs 8.8 and 2.7 h, respectively) [43]. The in vitro protein adjusted 90% inhibitory concentration (IC90) of dolutegravir against wild-type HIV-1 is 0.064 µg/ml [11,15]. After a single dose of ‡ 5 mg dolutegravir, plasma concentrations remained above the IC90 threshold for more than 30 h in healthy subjects [16]. Trough plasma concentrations of dolutegravir 50 mg (n = 47) were as high as 19 times the IC90 (Ctrough 1.20 µg/ml, coefficient of variation 60%) [17]. Resistance The genetic barrier to resistance relates to the difficulty with which HIV acquires resistance to a drug. It is a function of both virological and pharmacological characteristics. In vitro as well as clinical data show that dolutegravir has a higher barrier to resistance than raltegravir and elvitegravir [11,44]. This is a result of a number of favorable attributes including: i) small reductions in susceptibility from individual integrase mutations [11,45]; ii) slow dissociation rate from the integrase--DNA complex [43]; and iii) trough concentrations substantially above the protein adjusted IC90 for single mutations [16-18]. To date, in drug-naive patients failing a combination of two NRTIs plus dolutegravir drug regimen, there are no key dolutegravir mutations seen [46-48]. Integrase inhibitors have only recently entered the clinical realm and data on the optimal treatment of patients failing this class and selecting for resistance mutations are limited. The drug development program of dolutegravir included considerations of reduced cross-resistance with other integrase inhibitors (elvitegravir and raltegravir) when the initial molecule was chosen. This, together with the, already mentioned, choice of a relatively high exposure was expected to provide at least some activity in the setting of previous failure with raltegravir or elvitegravir. Data from the VIKING studies in which highly treatment-experienced patients who had previously failed on integrase inhibitors were treated with dolutegravir, indeed suggested this was the case. Response to therapy varied, but many of the patients were undetectable with this salvage regimen including dolutegravir 50 mg b.i.d. (see also section 5.3.2) [49-51]. Success was strongly correlated with the degree of integrase resistance that had accumulated with previous integrase inhibitor use (primarily raltegravir). Predictions of response were dependent on both which and how many mutations had accumulated. Selection of mutations at integrase position 148 is known to greatly reduce activity of raltegravir and elvitegravir, precluding their clinical utility. Although dolutegravir retained substantial activity when the 148 mutation alone was present, as additional key mutations such as 140 and 138 accumulated, responses were further reduced. Patients harboring 148 plus two additional key mutations had low response rates to


5.2

6

dolutegravir, and only a small minority achieved viral suppression [49]. More detailed discussions of the resistance characteristics of dolutegravir are beyond the scope this review, but have recently been detailed elsewhere (Llibre et al. [52] or others [53-55]). Efficacy A number of trials have evaluated dolutegravir efficacy in treatment-naive and treatment-experienced patients. Table 3 gives an overview of demographics and key efficacy data for dolutegravir in multicenter, randomized, Phase III, noninferiority clinical trials, conducted mainly in western countries. For these studies, FDA snapshot analysis was used for determination of the primary end point. 5.3

Dolutegravir efficacy in treatment-naive patients In treatment-naive patients, dolutegravir was compared with efavirenz (SPRING-1 and SINGLE), raltegravir (SPRING-2) and ritonavir-boosted darunavir (FLAMINGO). Studies included patients aged ‡ 18 years with an HIV-1 RNA ‡ 1000 copies/ml. In all trials, overall baseline characteristics were similar across different treatment groups. Approximately 30% of patients had baseline HIV-1 RNA levels of > 100,000 copies/ml and in the FLAMINGO trial CD4+ T-cell counts at baseline were slightly higher. Abacavir/lamivudine or tenofovir/emtricitabine was used as NTRI backbone component of the regimens given in these clinical trials. In a previous Phase IIb, multicenter, randomized, partially blinded, dose-ranging study (SPRING-1), which compared dolutegravir 10 mg (n = 53), 25 mg (n = 51) and 50 mg (n = 51) with efavirenz 600 mg (n = 50), a dose of 50 mg was selected for further investigation in Phase III clinical trials [17,56]. The primary analysis at week 16, using the time to loss of virological response (TLOVR) algorithm, showed a high percentage of patients with HIV-1 RNA plasma concentrations < 50 copies/ml in all dolutegravir subgroups: 96, 92 and 90% for 10, 25 and 50 mg dolutegravir, respectively versus 60% of patients in the efavirenz group. Dolutegravir use resulted in sustained high response rates, as was shown by the results of the planned analysis after 48 weeks (91, 88 and 90%) and 96 weeks (79, 78 and 88%) of treatment. Efavirenz response rates were slightly lower: 82% (week 48) and 72% (week 96) [56]. In the SINGLE study, the dolutegravir + abacavir/ lamivudine regimen (n = 414) showed non-inferiority, in a direct comparison, to efavirenz combined with tenofovir and emtricitabine (n = 419). Including matched placebos, a total of three pills QD were taken. Further analysis showed also superiority for the dolutegravir + abacavir/lamivudine regimen (p = 0.003). In Table 3, efficacy results by week 48, 96 and 144 are summarized. Discontinuations due to adverse events (AEs) were the main reason for differences in efficacy. Mean increase in CD4+ T-cell count was higher in the 5.3.1


Week 48 Week 96 Week 144

-339 48 (11%) 29 (7%)

-335 44 (11%) 27 (7%)

267#,†† 325#,†† 379#,††

71**

80

208#,†† 281#,†† 332#,††

81 7 (2 -- 12) 72 8 (2.3 -- 13.8) 63** 8.3 (2.0 -- 14.6)

131 (31%)

134 (32%)

88

EFV/TDF/FTC† (n = 419) 35(18 -- 85) 356 (85%) 4.70

230 276 --

--

81

88

49 (12%)

55 (13%)

359

--

43(11%)

50 (12%)

362

--

116 (28%)

RAL + 2 NRTIs‡ (n = 411) 35(18 -- 75) 355 (86%) 4.58

230 264 --

85 2.5 (-2.2 -- 7.1) 76 4.5 (-1.1 -- 10.0) --

114 (28%)

DTG + 2 NRTIs‡ (n = 411) 37 (16 -- 68) 348 (85%) 4.52

double-blind 10%

double-blind 10% DTG + ABC/ 3TC* (n = 414) 36 (18 -- 68) 347 (84%) 4.67

822

833

SPRING-2

210 ---

--

80

90

26 (11%)

23 (10%)

390

--

61 (25%)

20 (8%)

24 (10%)

400

--

61 (25%)

DRV/r + 2 NRTIs‡ (n = 242) 34 (19 -- 67) 201(83%) 4.48

210 ---

83 7.1 (0.9 -- 13.2) 68 12.4 (4.7 -- 20.2) --

DTG + 2 NRTIs‡ (n = 242) 34 (18 -- 67) 211(87%) 4.49

open-label 12%

484

FLAMINGO

162# ---

--

--

71

49 (14%)

NR

205

65 (18%)

NR

193

107 (30%)

-

RAL + other ARVs (n = 362) 43 (36 -- 49) 238 (66%) 4.21

153# ---

--

64 7.4 (0.7 -- 14.2); --

105 (30%)

-

DTG + other ARVs (n = 357) 42 (35 -- 49) 247 (70%) 4.17

double-blind 12%

715

SAILING

Outcomes are presented as number of patients (%) or median (range) unless otherwise indicated. *Fixed-dose combination abacavir/lamivudine. † Fixed-dose combination efavirenz/tenofovir/emtricitabine. z Investigator selected NRTI backbone, co-formulated tenofovir/emtricitabine or abacavir/lamivudine. § Proportion of participants with HIV-1 RNA level < 50 copies/mL, intention -to-treat analysis. { Primary endpoint analysis for the presented studies. # Mean increase from baseline in CD4+ T-cell count. **Results from open-label extension phase. †† p-value for the difference between groups = < 0.05. 3TC: Lamivudine; ABC: Abacavir; AD: Adjusted difference; ARVs: Anti-retroviral drugs; CI: Confidence interval; DRV/r: Darunavir/ritonavir; DTG: Dolutegravir; EFV: Efavirenz; FTC: Emtricitabine; NR: Not reported; NRTI: Non-nucleoside reverse transcriptase inhibitor; RAL: Raltegravir; TDF: Tenofovir; -: No data.

CD4+ T-cell count increase from baseline (cells/ul)

Week 48{ AD %, (95% CI) Week 96 AD %, (95% CI) Week 144 AD %, (95% CI)

Age Male Baseline plasma HIV-1 RNA (log10 copies/ml) Baseline HIV-1 RNA > 100.000 copies/ml Baseline HIV-1 RNA > 50.000 copies/ml CD4+ T-cell count (cells/ul) CD4+ T-cell count < 200 cells/ul Hepatitis B and/or C virus co-infection

Demographics

Virological succes (%)§

Number of subjects Blinding Non-inferiority margin

Study characteristics

SINGLE

Table 3. Summary of Phase III non-inferiority studies evaluating the efficacy of dolutegravir.



P. Bollen et al.

dolutegravir treatment group (p < 0.001). In subgroups with baseline HIV-1 RNA > 100,000 copies/ml, CD4+ T-cell counts < 200 cells/µl, in women or subjects aged ‡ 50 years, there seemed no difference in virological success rates between both treatment groups (‘zero’ was included in the 95% CI of the unadjusted difference). However, in the high viral load stratum a slight trend towards favoring the dolutegravir + abacavir/lamivudine regimen was seen, with success rates of 83% (111/134) of patients versus 76% (100/131) of patients in the efavirenz group [7,57]. At 96 weeks, protocol defined virological failure (PDVF) was increased from 4% (week 48) to 6% of patients in each group, which was in 80% (dolutegravir) and 68% (efavirenz) of cases due to low-level viremia (i.e., HIV RNA < 200 copies/ml) [8]. After the following open-label extension phase up to week 144, results for virological success rates, CD4+ T-cell counts, treatment-emergent major resistance-associated mutations and PDVF were consistent with earlier results [46]. In the active controlled, double placebo SPRING-2 trial, dolutegravir 50 mg QD showed non-inferiority to raltegravir 400 mg b.i.d., both combined with an investigator selected NRTI backbone, after 48 weeks (primary analysis) and 96 weeks of treatment (see results in Table 3). The difference in response between week 48 and 96 was mainly explained by discontinuations for reasons other than AEs. Efficacy seemed also comparable in patients with high baseline plasma HIV-1 RNA levels (> 100,000 copies/ml) receiving dolutegravir combined with tenofovir/emtricitabine (83% [64/77]) versus abacavir/lamivudine (81% [30/37]) [57]. In subgroups with baseline CD4+ T-cell counts < 200 cells/µl, there was no difference seen in efficacy between raltegravir and dolutegravir [18]. After 96 weeks, PDVF was seen in 22/411 (5%) patients on dolutegravir and in 29/411 (7%) on raltegravir [47]. In the open-label FLAMINGO study, a higher percentage of patients achieved undetectable plasma HIV-1 RNA at 48 weeks on dolutegravir 50 mg QD compared with ritonavir-boosted darunavir 800/100 mg QD (both combined with investigator-selected NRTI backbone). This difference in efficacy was mainly driven by a lower rate of discontinuations due to AEs in the dolutegravir group. Non-inferiority was shown for dolutegravir over boosted darunavir (Table 3) and in a pre-specified secondary analysis also superiority for dolutegravir was shown (p = 0.025) [58]. After 96 weeks, dolutegravir showed higher sustained virological response rates compared with darunavir/ritonavir (p = 0.002). Virological non-response (8 vs 12%) and non-response due to other reasons (12 vs 21%) was lower in the dolutegravir group. As for the results at 48 weeks, in the stratum with baseline HIV-1 RNA > 100,000 copies/ml virological response rates seemed higher in the dolutegravir group (82 vs 52%, no p-value reported), irrespective of NRTI backbone regimen [48]. In the above-mentioned trials, dolutegravir showed a rapid virological response in the first weeks of treatment, which was 8

sustained throughout the rest of the trial. Difference in mean time to virological suppression was more pronounced for the comparison with efavirenz (SINGLE: 28 vs 84 days) and darunavir/ritonavir [7,58]. Compared with raltegravir there was no difference [18]. In a retrospective pooled data analysis, which included data of the SPRING-2, SINGLE and FLAMINGO studies (n = 2139), the primary efficacy end point was affected by the baseline HIV-1 RNA plasma concentration and CD4+ T-cell count, third agent, age (< 36 or ‡ 36 years), hepatitis co-infection and risk factors (i.e., homosexual sex or intravenous drug use). Overall, there was no difference in response by NRTI backbone used (abacavir/lamivudine; 86% vs tenofovir/emtricitabine; 85%), adjusted difference (AD) = 1.1%; 95% CI: --1.8 to 4.0, or in subgroups with HIV-1 RNA > 100,000 copies/ml, AD = --2.5%; 95% CI: --8.9 to 3.8 [59,60]. Dolutegravir efficacy in treatment-experienced patients

5.3.2

The SAILING study, a Phase III, double-blind non-inferiority trial, was conducted in cART-experienced, but INSTI-naive patients, with resistance in ‡ 2 drug classes [44]. Dolutegravir 50 mg QD was compared with raltegravir 400 mg b.i.d., both combined with an optimized background regimen (OBR) (most commonly darunavir/ritonavir + tenofovir [19%]). Overall baseline characteristics were comparable in both treatment groups. Primary analysis (week 48) not only showed non-inferiority (see results in Table 3), but even superiority for dolutegravir 50 mg (p = 0.03). Virological non-response (mainly due to discontinuation for lack of efficacy) was the main reason for the difference in response rates. In both groups, CD4+ T-cell count increased similarly after 48 weeks (see also Table 3). Dolutegravir showed higher response rates in patients with HIV-1 RNA > 50,000 copies/ml at baseline (62 vs 47%; difference = 15.2%; 95% CI: 1.9 -- 28.4) and in patients who did not use darunavir/ritonavir as backbone or who had primary protease inhibitor mutations (71 vs 62%, difference = 9.3%; 95% CI: 1.6 -- 17.0). A key secondary end point of the SAILING study was the proportion of patients with treatment-emergent integrase-inhibitor resistance, which was found in 4 patients (1%) in the dolutegravir group versus 17 patients (5%) in the raltegravir group (p = 0.003) [44]. The efficacy of dolutegravir in highly treatmentexperienced HIV-1-infected patients was studied in the VIKING Phase II and III trials [49-51]. Here patients who had failed multiple regimens, including INSTIs were enrolled. The VIKING studies had an unique design in which an initial short monotherapy phase with dolutegravir was followed by longer treatment with dolutegravir combined with an OBR. In the Phase IIb open-label, single-arm VIKING study, 78% reached a plasma HIV-RNA < 400 copies/ml or a decrease by ‡ 0.7 log10 at day 11 in cohort I (dolutegravir 50 mg QD, n = 27) compared with 96% in cohort II (dolutegravir 50 mg b.i.d., n = 24). As mentioned in section 5.2, the



Table 4. Summary of adverse events reported in $ 5% of patients receiving dolutegravir in Phase III clinical trials compared with the percentage (or percentage range) of patients experiencing these adverse events in comparator arms.


Adverse event

Diarrhea Nausea Headache Nasopharyngitis Insomnia Fatigue Upper respiratory tract infection Dizziness Cough Abnormal dreams Vomiting Depression Pyrexia Back pain Oropharyngeal pain Bronchitis Influenza Rash Upper abdominal pain Anxiety Urinary tract infection Pharyngitis Somnolence

SINGLE (48 week)

SPRING-2, FLAMINGO, SAILING (48 week)

DTG+ABC/3TC (n = 414)

EFV/TDF/FTC (n = 419)

DTG + backbone regimen (n = 411, 242, 357)

DRV/r or RAL + backbone regimen* (n = 411, 242, 362)

17% 14% 13% 15% 15% 13% 9%

18% 14% 13% 14% 10% 12% 10%

11 -- 20% 8 -- 16% 9 -- 15% 6 -- 11% < 5 -- 7% 4 -- 6% 5 -- 11%

11 -- 29% 8 -- 18% 9 -- 12% 6 -- 12% 4 -- 6% 4 -- 7% 6 -- 10%

9% 6% 7% 5% 6% 6% 6% 5% 5% 3% 3% 3% 3% 1% 2% 2%

35% 7% 17% 5% 6% 5% 4% 3% 4% 1% 14% 3% 6% 3% 2% 5%

< 5 -- 6% < 5 -- 9% < 5% < 5 -- 6% £ 5% £ 5% < 5% < 5% < 5% 3 -- 7% £ 5% £ 5% < 5% < 5 -- 7% £ 5% < 5%

< 5 -- 6% < 5 -- 7% < 5% < 5 -- 6% < 5% < 5 -- 6% £ 5% < 5% £ 5% < 5 -- 7% £ 6% < 5% £ 5% £ 5% 3 -- 5% < 5%

*Backbone regimen used here consisted of two NRTIs (abacavir/lamivudine or tenofovir/emtricitabine) in studies evaluating efficacy and safety in treatment-naive patients (SPRING-II and FLAMINGO), but could also include other anti-retroviral agents (other than NRTIs) as backbone regimen when used in treatmentexperienced patients (in the SAILING study). 3TC: Lamivudine; ABC: Abacavir; DRV/r: Darunavir/ritonavir; DTG: Dolutegravir; EFV: Efavirenz; FTC: Emtricitabine; RAL: Raltegravir; TDF: Tenofovir.

subsequent single-arm VIKING-3 study (n = 183) showed a varied efficacy of dolutegravir 50 mg b.i.d. in this heavily pre-treated population with INSTI resistance during 24 weeks of treatment. At this point, 69% of subjects had a plasma HIV-RNA level < 50 copies/ml [49,50].

Safety Abacavir and lamivudine have already been used in clinical practice for more than 10 years and the safety profiles of these agents are well known. Therefore, the following section will primarily focus on dolutegravir safety aspects. Drugs from the family of integrase inhibitors are known for their good tolerability and favorable safety profile. The most common AEs seen with the use of INSTIs are gastrointestinal disturbances, such as diarrhea and nausea, but headache is also a common AE [61]. In addition, INSTIs have shown infrequent lipid elevations and low rates of metabolic abnormalities [61,62]. Nevertheless, raltegravir has been associated with creatinine phosphokinase (CPK) elevations and cobicistat, in 5.4

the elvitegravir single-tablet formulation, is associated with benign increases in serum creatinine [61]. For dolutegravir, most reported AE experienced by patients in Phase III clinical trials were nausea, diarrhea, headache, insomnia and nasopharyngitis. In general, dolutegravir was well tolerated and so, the dolutegravir safety profile seems in line with the overall safety profile of other INSTIs. Table 4 gives an overview of AEs reported with an incidence of ‡ 5% after 48 weeks of treatment with dolutegravir compared with the percentage (or percentage range) of patients experiencing these AEs in comparator arms in dolutegravir Phase III clinical trials. What is surprising is that in the SINGLE study insomnia was reported in 15% of subjects on treatment with dolutegravir, compared with 10% of subjects receiving the efavirenz-based regimen [7]. Something to note here is that the SINGLE study used a questionnaire for the evaluation of AEs, which included specific questions on insomnia. As expected, neuropsychiatric symptoms such as dizziness and abnormal dreams, but also rash occurred more frequently in the efavirenz group (Table 4). Also, diarrhea


9


P. Bollen et al.

(17 vs 29%) was reported more frequently for ritonavirboosted darunavir than for the dolutegravir treatment regimen [48,58]. And not surprisingly, raltegravir and dolutegravir in the SPRING-2 and SAILING studies showed overall similar safety profiles [18,44,47]. Dolutegravir did not show any signs of dose-related trends in type, frequency or severity of AEs or laboratory abnormalities, as was shown with increasing doses of dolutegravir (10, 25 and 50 mg) in the SPRING-1 study [17,56]. Also patients receiving dolutegravir 50 mg b.i.d. in the VIKING studies showed a similar safety profile to the dolutegravir 50 mg QD regimen [51]. Especially in the SINGLE study, the rate of discontinuations due to AEs was lower with the use of the dolutegravir/ abacavir/lamivudine regimen compared with the efavirenz/ tenofovir/emtricitabine comparator regimen (2 vs 10%) [7,8]. Other studies also showed this low rate of discontinuations due to AEs after 48 weeks of treatment for a dolutegravir treatment regimens (2% for dolutegravir vs 2 and 4% in comparator arms with raltegravir or ritonavir-boosted darunavir, respectively) [18,58]. In the SAILING study, 3 and 4% of patients discontinued treatment with dolutegravir or raltegravir, respectively, due to AE. Serious AE (SAEs) occurred in 7 -- 11% of patients on a dolutegravir treatment regimen in Phase III clinical trials [7,18,44,58]. Similar rates of SAEs were experienced in comparator arms, except in the FLAMINGO trial, where SAEs were frequently more reported in the dolutegravir arm (11%) than in the subjects that were treated with ritonavirboosted darunavir (5%) [58]. In general, there was no pattern or trend seen in the rate of reported SAEs and most SAEs did not seem to be drug-related. However, SAEs in Phase III clinical trials that were attributed to the dolutegravir/abacavir/lamivudine regimen were a suspected hypersensitivity reaction and a case of osteonecrosis [7,46]. Other unique SAEs attributed to dolutegravir were aphasia, hypersensitivity, a case of hepatitis [18] and a suicide attempt in a patient who had a history of suicidal ideation [58]. Drug-induced liver injury, or hepatotoxicity, can be a side effect of many antiretroviral drugs. The hepatic safety profile of dolutegravir was in general similar to the profile of raltegravir and other comparator drugs [63]. The hepatic safety of dolutegravir in HIV and HBV/HCV co-infected patients is discussed in more detail in section 6.1. Notable is a typical increase in serum creatinine which is seen after treatment initiation with a dolutegravir-containing regimen. Dolutegravir decreased the creatinine clearance by 10 -- 14% in an open-label study in 34 healthy subjects. However, actual glomerular filtration rate, as measured by iohexol clearance and effective renal plasma flow, was not affected [64]. The cause of this apparent benign phenomenon is inhibition of the OCT2 transporter by dolutegravir (see also section 4.3) [20,65]. Small non-progressive increases in serum creatinine (mean change from baseline ~ 10 to 16 µmol/l) were seen in patients receiving dolutegravir in Phase II and III 10

clinical trials [7,17,18,47,48,51,58]. These increases appeared within 2 weeks of starting treatment and stabilized to reach a plateau phase. In treatment-naive patients, no grade 3 -- 4 renal toxicities or discontinuations due to renal AEs related to dolutegravir were seen [7,58]. A pooled data analysis of dolutegravir Phase IIb--III clinical trials in treatment-naive patients informs more on the specific lipid profiles of dolutegravir and comparator drugs [66]. Dolutegravir showed a neutral lipid profile (total cholesterol, lowdensity lipoprotein [LDL] and triglycerides) compared with darunavir/ritonavir and efavirenz [7,58,66]. Fasting LDL elevations (grade 2) in the FLAMINGO study (week 96) were significantly more frequent in the darunavir/ritonavir group (22 vs 7%, p < 0.001) [58,66]. Small, non-clinical relevant increases in total cholesterol, LDL and triglycerides were seen in both the dolutegravir and raltegravir groups in the SPRING-2 study [18,66]. An integrated safety analysis by Curtis et al. informed more on clinical and laboratory safety of dolutegravir, including CPK elevations [63]. The incidence of CPK elevations (grade 3 -- 4) during the use of dolutegravir (5%), efavirenz (5%), raltegravir (4%) or darunavir/ritonavir (4%) was similar [63]. In the treatment-experienced patients in the SAILING study, grade 3 -- 4 CPK elevations developed in 2 and 1% with the use of dolutegravir and raltegravir, respectively [63]. Furthermore, dolutegravir does not affect cardiac repolarization, since a single supratherapeutic dose of 250 mg did not show any relevant QT-interval prolongation [67]. 6.

Special populations

HBV/HCV co-infection Dolutegravir Phase III clinical trials included only 7 -- 16% of hepatitis B virus (HBV) or C virus (HCV) co-infected patients (Table 3) [7,18,44,58]. The dolutegravir STR is not preferred as first-line therapy in co-infected patients in need of HBV therapy. Dolutegravir and abacavir itself are not active against HBV and the remaining lamivudine monotherapy has a low barrier for resistance [6,68]. Tenofovir has a higher barrier to resistance against HBV and therefore tenofovircontaining regimen is recommended in HBV co-infection [3,4]. HBV or HCV co-infected patients receiving antiretroviral therapy are at increased risk for developing severe hepatic AEs. This was also shown for dolutegravir, which caused grade 2 -- 3 ALT elevations in 16% of co-infected patients versus 3% in non-coinfected [63]. In treatment-naive co-infected patients, the incidence of grade 2 -- 4 liver enzyme elevations was highest with efavirenz and raltegravir, intermediate with dolutegravir and the lowest with darunavir/ritonavir. In co-infected treatment-experienced patients, grade 2 -- 4 ALT elevations were more frequent with dolutegravir than with raltegravir use (22 vs 8%). This finding was attributed to occurrence of HBV flares or HBV/HCV immune reconstitution inflammatory syndrome (IRIS). It could also be a result 6.1




of differences in efficacy between dolutegravir and raltegravir in these groups, rather than dolutegravir-induced liver toxicity [44,63,69]. Hepatic flares were probably the result of the lack of HBV treatment. This underscores the importance of adequate treatment for HBV in co-infected patients, when starting an HIV treatment regimen containing a highly active drug, such as dolutegravir. In the context of HIV and HCV co-infection, it is important to pay special attention to drug--drug interactions between concurrently used antiretroviral drugs. With the use of the dolutegravir STR, the potential for drug--drug interactions with HCV drugs is low. No dose adjustments are needed for the combination with boceprevir or telaprevir [41]. In addition, no relevant drug--drug interactions are expected with the concomitant use of simeprevir, sofosbuvir, daclatasvir or ledipasvir. Elderly There are very limited data on the use of dolutegravir in the elderly. The mean age of patients included in clinical trials is ~ 35 years and treatment-experienced patients included in the SAILING study were slightly older (median age 43 years) [44]. So far, there is no evidence for altered efficacy and safety in older patients and therefore no dose-adjustments are required. However, monitoring for AEs, renal function and hematological parameters is important in this particular group. 6.2

Women There is only limited experience with the use of dolutegravir in women, but so far there are no data demonstrating a difference in efficacy or safety. The efficacy of HIV therapy and the incidence or severity of AEs may be different between men and women [70]. Like most studies, dolutegravir Phase III clinical trials included only a minority of women (circa 15%), with a somewhat higher proportion (32%) in the SAILING study. No conclusions can be drawn for efficacy of dolutegravir in men versus women from subgroup analyses due to this low number of subjects. Importantly, dolutegravir did not influence pharmacokinetic or pharmacodynamic parameters of ethinylestradiol and norgestimate [71] and contraceptive efficacy is unlikely to be compromised if dolutegravir/abacavir/lamivudine is co-administered with estrogen and progesterone oral contraceptives. 6.3

Children and adolescents There are only limited data available on clinical efficacy and safety of dolutegravir for use in children and adolescents aged 12 -- 18 years. Licensing of dolutegravir by the FDA for use in this group was based on the 24-week results of this age-defined cohort in a trial by the IMPAACT network [73]. This study included treatment-experienced, but INSTI-naive, children (n = 23) whose median age (range) was 14 years (12 -- 17). Dolutegravir dosing was based on weight (~ 1 mg/kg) and consequently 19 children received 50 mg/day and 4 children 35 mg dolutegravir per day. An OBR was added after a short period of dolutegravir monotherapy with the failing backbone regimen. At week 48, 73.9% of children had HIV-1 RNA concentrations < 400 copies/ml and dolutegravir was well tolerated with no discontinuations due to AEs. One patient developed elevated unconjugated bilirubin levels (grade 3) and another patient lipase elevation (grade 3), both considered not related to dolutegravir [73]. The dolutegravir, abacavir and lamivudine regimen is currently under investigation in pediatric patients and a granular formulation of dolutegravir is being developed [74,75]. 6.5

7.

The new once-daily STR consisting of dolutegravir/abacavir/ lamivudine is superior in efficacy to efavirenz/tenofovir/emtricitabine, one of the current most frequently used regimens in treatment-naive patients. In a drug-naive population, dolutegravir combined with a nucleoside backbone is also superior to ritonavir-boosted darunavir and non-inferior to raltegravir. Moreover, in treatment-experienced patients, dolutegravir was non-inferior and seemed even superior to raltegravir in suppressing the HIV-1 RNA viral load. Dolutegravir as part of cART is well tolerated and has a favorable safety profile. Most reported AEs are nausea, diarrhea, headache and nasopharyngitis. Dolutegravir causes a benign increase in serum creatinine resulting from inhibition of tubular creatinine excretion. Compared with other INSTIs, dolutegravir has a higher barrier to resistance. Due to the favorable pharmacokinetic profile of dolutegravir, the STR regimen is less prone to interactions and only causes a few interactions itself. 8.

6.4

Conclusion

Expert opinion

Pregnancy

Use of dolutegravir/abacavir/lamivudine during pregnancy should be considered with caution. Abacavir and lamivudine are among the preferred NRTIs for use in pregnancy [72]. However, so far, there is no documented experience with the use of dolutegravir in pregnant women. Animal studies showed placental passage for dolutegravir, but no evidence for teratogenicity [6]. In addition, excretion in breast milk was shown [6]. Placental transfer to the fetus and teratogenicity in humans is unknown.

In this review, we outlined the available data on the pharmacokinetics and pharmacodynamics of dolutegravir used as STR, focusing on dolutegravir. Dolutegravir is effective and safe for the treatment of HIV-1 in adults. This was assessed in large well-designed Phase III clinical trials. Dolutegravir has favorable pharmacokinetic and pharmacodynamic characteristics. It is the first INSTI that can be administered once daily, without the need for a pharmacokinetic booster, in contrast to elvitegravir (cobicistat as booster) and raltegravir


11


P. Bollen et al.

(400 mg b.i.d. [76]). Because of the above-mentioned aspects and its convenient use, the dolutegravir STR may gain a prominent place in therapy. The dolutegravir/abacavir/lamivudine regimen can also be used in patients with baseline viral loads > 100,000 copies/ ml. The efficacy of the abacavir/lamivudine backbone regimen combined with a number of different third agents, other than dolutegravir, in patients with initial high baseline viral loads was previously discussed [77,78]. Official indications do not distinguish between patients with high or low baseline HIV-1 RNA levels for the use of abacavir/lamivudine [79,80]. In some dolutegravir Phase III clinical trials (SPRING-2 and FLAMINGO), inclusion bias can be an issue for results in subgroups stratified by baseline HIV-1 RNA level, because the backbone regimen were selected by the investigator. Abacavir/lamivudine and tenofovir/emtricitabine were selected as NRTI-backbone in ~ 35 and 65% of patients, respectively. However, baseline HIV-1 RNA levels did not differ between these groups. In addition, sub-analysis with a limited number of patients revealed no evidence of compromised efficacy in patients with high baseline HIV-1 RNA levels receiving a backbone regimen of abacavir/lamivudine compared with tenofovir/emtricitabine [59]. Dolutegravir used as STR will be a good treatment option for patients with gastrointestinal disturbances and (pre-existing) lipid disturbances. In patients with HCV coinfection, dolutegravir as STR would be an attractive option because of its low potential to induce drug--drug interactions. It can also be an alternative to a tenofovir-containing regimen in patients with renal toxicity. However, the dolutegravir STR is not recommended for use in patients with an eGFR < 50 ml/min, because of lamivudine. In addition, dolutegravir causes small benign increases in serum creatinine. Consequently, this basically results in a new lower ‘eGFR set point’. This should be taken into account when interpreting the eGFR value in patients using dolutegravir. Due to the combination of dolutegravir in this STR with an abacavir/lamivudine nucleoside backbone, there are a couple of aspects to keep in mind. HLA-B*5701 testing is required prior to abacavir use and prevents the occurrence of a vast majority of hypersensitivity reactions to this agent [81]. Since ~ 6% of the population is positive for the HLA-B*5701 allele, there will be patients who are ineligible for treatment with the dolutegravir/abacavir/lamivudine STR [81]. Furthermore, the assumed increased cardiovascular risk associated with the use of abacavir remains a matter of debate [82-84]. Therefore, the combination of dolutegravir/ abacavir/lamivudine might not be the optimal choice for patients with a high cardiovascular risk. Although there are few drug--drug interactions caused by dolutegravir, it is important to take these into account when prescribing the dolutegravir/abacavir/lamivudine combination. Dose adjustments or treatment regimen optimization is needed for some drug--drug interactions or in special patient situations. This is especially important when simultaneous 12

pharmacokinetic interactions occur and/or in case of patients requiring high dolutegravir plasma concentrations. The dolutegravir/abacavir/lamivudine regimen has no interactions with frequently prescribed drugs such as omeprazol, simvastatin or commonly used antidepressants. However, the interactions with metformin, some non-prescription antacids and mineral containing supplements or multivitamins require good patient instruction. Dolutegravir (and other integrase inhibitors) show a more rapid decrease in HIV-1 RNA in the first weeks of treatment compared with efavirenz and darunavir/ritonavir. The (longterm) relevance of this in clinical practice is not clear, but it can possibly be beneficial in specific situations, for example, late presenting pregnant women. Selection of resistance mutations upon loss of viral suppression is a hallmark of antiretroviral therapy and commonly seen with most drugs, albeit with varying rates. The only drug class to show an extremely low rate of mutations are the ritonavir-boosted protease inhibitors, such as lopinavir/ ritonavir and darunavir/ritonavir. This has been attributed to a number of factors including a high genetic barrier to resistance. Although poorly defined, it is characterized by small increments of loss of activity by single mutations together with very high drug levels. Dolutegravir is the only approved integrase inhibitor that shares these characteristics with boosted PIs, thus it also might be expected to rarely select for mutations upon failure. What has been surprising to date is the complete lack of key dolutegravir mutations seen in drug-naive patients failing a combination of two NRTI + dolutegravir drug regimen. This may be a result of the unique virological and pharmacological characteristics of dolutegravir dosed at 50 mg QD, together with the potency and long intracellular half-life of the additional two NRTIs included in the regimen (abacavir/lamivudine or tenofovir/ emtricitabine). However, one must be cautious as many of these patients were treated in the setting of clinical trials, and other have only been on therapy for a limited amount of time. Although it is possible that dolutegravir will continue to display this high barrier to resistance, we may also begin to see some patients failing with mutations with more widespread and long-term use. Time will tell. Unfortunately, in case of baseline resistance to elvitegravir or raltegravir the advantage of a once-daily dosing schedule with the STR is lost, since a dolutegravir dose of 50 mg b.i.d. preferably taken with food is recommended in this situation. In addition, abacavir/lamivudine may not be the optimal partner drugs. This also applies to HBV co-infected patients, since the antiretroviral activity of this STR is not robust enough against HBV (tenofovir required instead of lamivudine). To date, there is no published data on long-term (> 3 years) safety and efficacy with the use of dolutegravir. These data will be of particular interest with regards to resistance profile and side effects. Post-marketing data and ongoing studies will hopefully shed more light on pharmacokinetics and




efficacy in special populations, underrepresented in Phase III clinical trials. A more representative population might contain more women, patients with HCV co-infection, patients with higher baseline viral loads or more severely immunocompromised patients. In addition, there would be more variation in race and ethnicity. The ongoing ARIA study will further investigate the efficacy and safety of dolutegravir/abacavir/ lamivudine compared with ritonavir-boosted atazanavir and tenofovir/emtricitabine in treatment-naive women. However, more data on the use of dolutegravir in children, adolescents and elderly are also desired. Other new antiretroviral agents or regimen for the treatment of HIV are under development and will be available in the future. Regimen containing tenofovir alafenamide fumarate or reduced doses of efavirenz are currently under investigation and aim to reduce side effects. Together with the present efforts to reduce HIV-drug treatment expenses and the introduction of cheaper generic alternatives, it will be interesting to see how the development, the use in clinical practice and the prices of STR will evolve in the upcoming years. Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

2.

3.

4.

5.

Antiretroviral Therapy Cohort Collaboration. Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies. Lancet 2008;372(9635):293-9 Nachega JB, Parienti JJ, Uthman OA, et al. Lower pill burden and once-daily antiretroviral treatment regimens for HIV infection: A meta-analysis of randomized controlled trials. Clin Infect Dis 2014;58(9):1297-307

Gunthard HF, Aberg JA, Eron JJ, et al. Antiretroviral treatment of adult HIV infection: 2014 recommendations of the

P Reiss has received independent scientific grant support from Gilead Sciences, Janssen Pharmaceuticals Inc., Merck & Co, Bristol-Meyers Squibb and ViiV Healthcare. He has also served on scientific advisory boards for Gilead Sciences and ViiV Healthcare and serves on a data safety monitoring committee for Janssen Pharmaceuticals Inc. for which this institution has received remuneration. J Shapiro has received honorarium from or served in the last 12 months as an advisor, consultant or advisory board member of the following companies: AbbVie, Bristol-Meyers Squibb, Gilead, GlaxoSmithKline, ViiV Healthcare, Teva, Virology Education and Janssen-Cilag. D Burger has received honoraria for presenting at symposia and advisory boards and research grants from ViiV Healthcare. P Bollen has no conflicts of interests relevant to the content of this work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. integrase inhibitor. Antimicrob Agents Chemother 2011;55(2):813-21

International Antiviral Society-USA Panel. JAMA 2014;312(4):410-25 6.

EMA. Triumeq; Summary of Product Characteristics. 2014

7.

Walmsley SL, Antela A, Clumeck N, et al. Dolutegravir plus abacavirlamivudine for the treatment of HIV-1 infection. N Engl J Med 2013;369(19):1807-18 This large Phase III clinical trial directly compared the dolutegravir, abacavir and lamivudine regimen with the current first-line regimen of efavirenz, tenofovir and emtricitabine.

..

8.

DHHS. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. 2014.1-282 Available from: http:// aidsinfo.nih.gov/contentfiles/lvguidelines/ adultandadolescentgl.pdf [cited 22 December 2014] EACS. European AIDS Clinical Society. European Guidelines for treatment of HIV infected adults in Europe. 2014. Version 7.1 Available from: http:// www.eacsociety.org/files/guidelines_ english_71_141204.pdf [cited 4 December 2014]

Declaration of interest

9.

Walmsley S, Berenguer J, Khuong-Josses MA, et al. Dolutegravir regimen statistically superior to efavirenz/ tenofovir/emtricitabine: 96-week results from the SINGLE study (ING114467). 21st Conference on Retroviruses and Opportunistic Infections. Boston, MA 2014 Hazuda D, Iwamoto M, Wenning L. Emerging pharmacology: inhibitors of human immunodeficiency virus integration. Annu Rev Pharmacol Toxicol 2009;49:377-94

10.

Pommier Y, Johnson AA, Marchand C. Integrase inhibitors to treat HIV/AIDS. Nat Rev Drug Discov 2005;4(3):236-48

11.

Kobayashi M, Yoshinaga T, Seki T, et al. In Vitro antiretroviral properties of S/ GSK1349572, a next-generation HIV


12.

Yuen GJ, Weller S, Pakes GE. A review of the pharmacokinetics of abacavir. Clin Pharmacokinet 2008;47(6):351-71

13.

Johnson MA, Moore KH, Yuen GJ, et al. Clinical pharmacokinetics of lamivudine. Clin Pharmacokinet 1999;36(1):41-66

14.

Kumar PN, Patel P. Lamivudine for the treatment of HIV. Expert Opin Drug Metab Toxicol 2010;6(1):105-14

15.

Min S, Song I, Borland J, et al. Pharmacokinetics and safety of S/ GSK1349572, a next-generation HIV integrase inhibitor, in healthy volunteers. Antimicrob Agents Chemother 2010;54(1):254-8

16.

Min S, Sloan L, DeJesus E, et al. Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-1-infected adults. AIDS 2011;25(14):1737-45

17.

van Lunzen J, Maggiolo F, Arribas JR, et al. Once daily dolutegravir (S/ GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial. Lancet Infect Dis 2012;12(2):111-18

13

P. Bollen et al.

18.

19.


20.

21.

.

22.

23.

Raffi F, Rachlis A, Stellbrink HJ, et al. Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study. Lancet 2013;381(9868):735-43 Letendre SL, Mills AM, Tashima KT, et al. ING116070: a study of the pharmacokinetics and antiviral activity of dolutegravir in cerebrospinal fluid in HIV-1-infected, antiretroviral therapynaive subjects. Clin Infect Dis 2014;59(7):1032-7 Reese MJ, Savina PM, Generaux GT, et al. In vitro investigations into the roles of drug transporters and metabolizing enzymes in the disposition and drug interactions of dolutegravir, a HIV integrase inhibitor. Drug Metab Dispos 2013;41(2):353-61 Weller S, Chen S, Borland J, et al. Bioequivalence of a dolutegravir, abacavir, and lamivudine fixed-dose combination tablet and the effect of food. J Acquir Immune Defic Syndr 2014;66(4):393-8 This is a pharmacokinetic study that demonstrated bioequivalence of the dolutegravir, abacavir and lamivudine fixed-dose co-formulation versus the separate tablets of dolutegravir and abacavir/lamivudine. Song I, Borland J, Chen S, et al. Effect of food on the pharmacokinetics of the integrase inhibitor dolutegravir. Antimicrob Agents Chemother 2012;56(3):1627-9 Yuen GJ, Lou Y, Thompson NF, et al. Abacavir/lamivudine/zidovudine as a combined formulation tablet: bioequivalence compared with each component administered concurrently and the effect of food on absorption. J Clin Pharmacol 2001;41(3):277-88

24.

Chittick GE, Gillotin C, McDowell JA, et al. Abacavir: absolute bioavailability, bioequivalence of three oral formulations, and effect of food. Pharmacotherapy 1999;19(8):932-42

25.

Baker KL, Lou Y, Yuen GJ. The bioequivalence and effect of food of a new once-a day fixed dose combination tablet of abacavir (ABC) and lamivudine (3TC). >44th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC 2004

14

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

subjects. J Acquir Immune Defic Syndr 2013;62(1):21-7

Castellino S, Moss L, Wagner D, et al. Metabolism, excretion, and mass balance of the HIV-1 integrase inhibitor dolutegravir in humans. Antimicrob Agents Chemother 2013;57(8):3536-46

36.

Chen S, St Jean P, Borland J, et al. Evaluation of the effect of UGT1A1 polymorphisms on dolutegravir pharmacokinetics. Pharmacogenomics 2014;15(1):9-16

Song I, Borland J, Chen S, et al. Effects of enzyme inducers efavirenz and tipranavir/ritonavir on the pharmacokinetics of the HIV integrase inhibitor dolutegravir. Eur J Clin Pharmacol 2014;70(10):1173-9

37.

Song I, Borland J, Savina PM, et al. Pharmacokinetics of single-dose dolutegravir in HIV-seronegative subjects with moderate hepatic impairment compared to healthy matched controls. Clin Pharmacology in Drug Development 2013;2(4):342-48

Song I, Borland J, Chen S, et al. Effect of fosamprenavir-ritonavir on the pharmacokinetics of dolutegravir in healthy subjects. Antimicrob Agents Chemother 2014;58(11):6696-700

38.

Heald AE, Hsyu PH, Yuen GJ, et al. Pharmacokinetics of lamivudine in human immunodeficiency virus-infected patients with renal dysfunction. Antimicrob Agents Chemother 1996;40(6):1514-19

Ford SL, Gould E, Chen S, et al. Lack of pharmacokinetic interaction between rilpivirine and integrase inhibitors dolutegravir and GSK1265744. Antimicrob Agents Chemother 2013;57(11):5472-7

39.

Izzedine H, Launay-Vacher V, Aymard G, et al. Pharmacokinetics of abacavir in HIV-1-infected patients with impaired renal function. Nephron 2001;89(1):62-7

Song I, Borland J, Chen S, et al. Effect of atazanavir and atazanavir/ritonavir on the pharmacokinetics of the nextgeneration HIV integrase inhibitor. S/ GSK1349572. Br J Clin Pharmacol 2011;72(1):103-8

40.

Song I, Min SS, Borland J, et al. The effect of lopinavir/ritonavir and darunavir/ritonavir on the HIV integrase inhibitor S/GSK1349572 in healthy participants. J Clin Pharmacol 2011;51(2):237-42

41.

Zong J, Borland J, Jerva F, et al. The effect of dolutegravir on the pharmacokinetics of metformin in healthy subjects. J Int AIDS Soc 2014;17(4 Suppl 3):19584

Johnson M, Borland J, Chen S, et al. Effects of boceprevir and telaprevir on the pharmacokinetics of dolutegravir. Br J Clin Pharmacol 2014;78(5):1043-9

42.

Song I, Borland J, Arya N, et al. Pharmacokinetics of dolutegravir when administered with mineral supplements in healthy adult subjects. J Clin Pharmacol 2014;1-7

Song IH, Borland J, Chen S, et al. Effect of prednisone on the pharmacokinetics of the integrase inhibitor dolutegravir. Antimicrob Agents Chemother 2013;57(9):4394-7

43.

Hightower KE, Wang R, Deanda F, et al. Dolutegravir (S/GSK1349572) exhibits significantly slower dissociation than raltegravir and elvitegravir from wild-type and integrase inhibitor-resistant HIV-1 integrase-DNA complexes. Antimicrob Agents Chemother 2011;55(10):4552-9

44.

Cahn P, Pozniak AL, Mingrone H, et al. Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study. Lancet 2013;382(9893):700-8

Weller S, Borland J, Chen S, et al. Pharmacokinetics of dolutegravir in HIVseronegative subjects with severe renal impairment. Eur J Clin Pharmacol 2014;70(1):29-35

Patel P, Song I, Borland J, et al. Pharmacokinetics of the HIV integrase inhibitor S/GSK1349572 coadministered with acid-reducing agents and multivitamins in healthy volunteers. J Antimicrob Chemother 2011;66(7):1567-72 Dooley KE, Sayre P, Borland J, et al. Safety, tolerability, and pharmacokinetics of the HIV integrase inhibitor dolutegravir given twice daily with rifampin or once daily with rifabutin: results of a phase 1 study among healthy



45.

46.


47.

Canducci F, Ceresola ER, Saita D, et al. In vitro phenotypes to elvitegravir and dolutegravir in primary macrophages and lymphocytes of clonal recombinant viral variants selected in patients failing raltegravir. J Antimicrob Chemother 2013;68(11):2525-32 Pappa K, Baumgarten A, Felizarta F, et al. Dolutegravir (DTG) + Abacavir/ Lamivudine Once Daily Superior to Tenofovir/Emtricitabine/Efavirenz in Treatment Naive HIV Subjects: 144-Week Results from SINGLE (ING114467). 54th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC 2014:Abstract H-647a Raffi F, Jaeger H, Quiros-Roldan E, et al. Once-daily dolutegravir versus twice-daily raltegravir in antiretroviralnaive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, noninferiority trial. Lancet Infect Dis 2013;13(11):927-35

48.

Molina JM, Clotet B, van Lunzen J, et al. Once-daily dolutegravir is superior to once-daily darunavir/ritonavir in treatment-naive HIV-1-positive individuals: 96 week results from FLAMINGO. J Int AIDS Soc 2014;17(4 Suppl 3):19490

49.

Castagna A, Maggiolo F, Penco G, et al. Dolutegravir in antiretroviral-experienced patients with raltegravir- and/or elvitegravir-resistant HIV-1: 24-week results of the phase III VIKING-3 study. J Infect Dis 2014;210(3):354-62

50.

51.

Akil B, Blick G, Hagins DP, et al. Dolutegravir versus placebo in subjects harbouring HIV-1 with integrase inhibitor resistance associated substitutions: 48-week results from VIKING-4, a randomized study. Antivir Ther 2014 Eron JJ, Clotet B, Durant J, et al. Safety and efficacy of dolutegravir in treatmentexperienced subjects with raltegravirresistant HIV type 1 infection: 24-week results of the VIKING Study. J Infect Dis 2013;207(5):740-8

52.

Llibre JM, Pulido F, Garcia F, et al. Genetic barrier to resistance for dolutegravir. AIDS Rev 2015;17(1):56-64

53.

Quashie PK, Mesplede T, Wainberg MA. Evolution of HIV

aminohippurate clearance in healthy subjects. Br J Clin Pharmacol 2013;75(4):990-6

integrase resistance mutations. Curr Opin Infect Dis 2013;26(1):43-9 54.

55.

56.

57.

58.

59.

Grobler JA, Hazuda DJ. Resistance to HIV integrase strand transfer inhibitors: in vitro findings and clinical consequences. Current opinion in virology 2014;8:98-103 White KL, Raffi F, Miller MD. Resistance analyses of integrase strand transfer inhibitors within phase 3 clinical trials of treatment-naive patients. Viruses 2014;6(7):2858-79 Stellbrink HJ, Reynes J, Lazzarin A, et al. Dolutegravir in antiretroviral-naive adults with HIV-1: 96-week results from a randomized dose-ranging study. AIDS 2013;27(11):1771-8 Eron J, Rockstroh J, Pozniak A, et al. Dolutegravir treatment response by baseline viral load and NRTI backbone in treatment-naive HIV-infected individuals. 11th International Congress on Drug Therapy in HIV Infection. Glasgow, UK 2012;Poster Abstract P204 Clotet B, Feinberg J, van Lunzen J, et al. Once-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study. Lancet 2014;383(9936):2222-31 Raffi F, Rachlis A, Brinson C, et al. Dolutegravir efficacy at 48 weeks in key subgroups of treatment-naive HIVinfected individuals in three randomized trials. AIDS 2015;29(2):167-74

60.

Sax PE, Tierney C, Collier AC, et al. Abacavir-lamivudine versus tenofoviremtricitabine for initial HIV-1 therapy. N Engl J Med 2009;361(23):2230-40

61.

Gutierrez Mdel M, Mateo MG, Vidal F, Domingo P. Drug safety profile of integrase strand transfer inhibitors. Expert Opin Drug Saf 2014;13(4):431-45

62.

Lee FJ, Carr A. Tolerability of HIV integrase inhibitors. Curr Opin HIV AIDS 2012;7(5):422-8

63.

Curtis L, Nichols G, Stainsby C, et al. Dolutegravir: clinical and laboratory safety in integrase inhibitor-naive patients. HIV Clin Trials 2014;15(5):199-208

64.

Koteff J, Borland J, Chen S, et al. A phase 1 study to evaluate the effect of dolutegravir on renal function via measurement of iohexol and para-


65.

Urakami Y, Kimura N, Okuda M, Inui K. Creatinine transport by basolateral organic cation transporter hOCT2 in the human kidney. Pharm Res 2004;21(6):976-81

66.

Quercia R, Roberts J, Martin-Carpenter L, Zala C. Comparative changes of lipid levels in treatment-Naive, HIV-1-Infected adults treated with dolutegravir vs. efavirenz, raltegravir, and ritonavir-boosted darunavir-based regimens over 48 weeks. Clin drug investig 2015;35(3):211-19

67.

Chen S, Min SS, Peppercorn A, et al. Effect of a single supratherapeutic dose of dolutegravir on cardiac repolarization. Pharmacotherapy 2012;32(4):333-9

68.

Benhamou Y, Bochet M, Thibault V, et al. Long-term incidence of hepatitis B virus resistance to lamivudine in human immunodeficiency virus-infected patients. Hepatology 1999;30(5):1302-6

69.

Min S, Roberts J, Almond S, et al. Efficacy and Safety of Dolutegravir (DTG) in Hepatitis (HBV or HCV) Coinfected Patients: Results From the Phase 3 Program. 20th International AIDS Conference. Melbourne, Australia 2014:WEPE062

70.

Kwakwa H, Spencer D, Evans C, et al. Gender differences in virologic outcomes in a meta-analysis of randomized controlled clinical trials in HIV-1-infected patients on antiretroviral therapy. XIX International AIDS Conference. Washington DC, USA 2012:Poster THPE041

71.

Song I, Mark S, Borland J, et al. Dolutegravir has no effect on the pharmacokinetics of methadone or oral contraceptives with norgestimate and ethinyl estradiol. 20th Conference on Retroviruses and Opportunistic Infections. Atlanta, GA 2013

72.

DHHS. Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States. 2014.p.1--225. Available from: http://aidsinfonihgov/contentfiles/ lvguidelines/perinatalglpdf http://aidsinfo. nih.gov/contentfiles/lvguidelines/ perinatalgl.pdf [Cited 4 December 2014]

15

P. Bollen et al.

73.

74.


75.

76.

77.

Viani RM, Alvero C, Fenton T, et al. Safety and efficacy of dolutegravir in HIV treatment-experienced adolescents: 48-week result. 21st Conference on Retroviruses and Opportunistic Infections. Boston, MA 2014:Abstract 906LB

82.

Viani RM, Alvero C, Fenton T, et al. Safety pharmacokinetics and efficacy of dolutegravir in treatment-experienced HIV+ children [abstract 901]. 21st Conference on Retroviruses and Opportunistic Infections. Boston, MA 2014

83.

Patel P, Song I, Borland J, et al. Relative bioavailability of a paediatric granule formulation of the HIV integrase inhibitor dolutegravir in healthy adult subjects. Antivir Ther 2014;19(3):229-33

Cruciani M, Mengoli C, Malena M, et al. Virological efficacy of abacavir: systematic review and meta-analysis. J Antimicrob Chemother 2014;69(12):3169-80 Sax PE, Tierney C, Collier AC, et al. Abacavir-lamivudine versus tenofoviremtricitabine for initial HIV-1 therapy. N Engl J Med 2009;361(23):2230-40

79.

FDA. Epzicom: Prescribing information. 2012. Available from: http://www. accessdata.fda.gov/scripts/cder/drugsatfda/ index.cfm [cited 21 January 2015]

81.

16

85.

Eron JJ Jr, Rockstroh JK, Reynes J, et al. Raltegravir once daily or twice daily in previously untreated patients with HIV1: a randomised, active-controlled, phase 3 non-inferiority trial. Lancet Infect Dis 2011;11(12):907-15

78.

80.

84.

EMA. Kivexa; Summary of Product Characteristics. 2014. Available from: http://www.ema. europa.eu/docs/en_GB/document_library/ EPAR_-_Product_Information/ human/000581/WC500043730.pdf [Cited 21 January 2015] Mallal S, Phillips E, Carosi G, et al. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med 2008;358(6):568-79

86.

(PK) [abstract H-1013]. Interscience Conference of Antimicrobial Agents and Chemotherapy. Washington DC 2014

Sabin CA, Worm SW, Weber R, et al. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multicohort collaboration. Lancet 2008;371(9622):1417-26

90.

Cruciani M, Zanichelli V, Serpelloni G, et al. Abacavir use and cardiovascular disease events: a meta-analysis of published and unpublished data. AIDS 2011;25(16):1993-2004

Chtioui H, Millius C, Lammle B, Lauterburg BH. Concomitant treatment with lamivudine renders cladribine inactive by inhibition of its phosphorylation. Br J Haematol 2009;144(1):136-7

91.

Ding X, Andraca-Carrera E, Cooper C, et al. No association of abacavir use with myocardial infarction: findings of an FDA meta-analysis. J Acquir Immune Defic Syndr 2012;61(4):441-7

FDA. Triumeq: Prescribing Information. 2014. Available from: http://www. accessdata.fda.gov/drugsatfda_docs/ label/2014/205551s000lbl.pdf [Cited 15 February 2015]

92.

Song I, Mark S, Chen S, et al. Dolutegravir does not affect methadone pharmacokinetics in opioid-dependent, HIV-seronegative subjects. Drug Alcohol Depend 2013;133(2):781-4

93.

Sellers E, Lam R, McDowell J. The pharmacokinetics (PK) of abacavir and methadone (M) following coadministration: CNAA1012 [abstract 663]. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco, CA 1999

Moyle G, Boffito M, Fletcher C, et al. Steady-state pharmacokinetics of abacavir in plasma and intracellular carbovir triphosphate following administration of abacavir at 600 milligrams once daily and 300 milligrams twice daily in human immunodeficiency virus-infected subjects. Antimicrob Agents Chemother 2009;53(4):1532-8 Yuen GJ, Lou Y, Bumgarner NF, et al. Equivalent steady-state pharmacokinetics of lamivudine in plasma and lamivudine triphosphate within cells following administration of lamivudine at 300 milligrams once daily and 150 milligrams twice daily. Antimicrob Agents Chemother 2004;48(1):176-82

87.

Song I, Borland J, Min S, et al. Effects of etravirine alone and with ritonavirboosted protease inhibitors on the pharmacokinetics of dolutegravir. Antimicrob Agents Chemother 2011;55(7):3517-21

88.

Moore KH, Yuen GJ, Raasch RH, et al. Pharmacokinetics of lamivudine administered alone and with trimethoprim-sulfamethoxazole. Clin Pharmacol Ther 1996;59(5):550-8

89.

Weller S, Borand L, Wynne B, et al. Effect of Carbamazepine (CBZ) on Dolutegravir (DTG) Pharmacokinetics


Affiliation

Pauline Bollen†1,2,3, Peter Reiss4, Jonathan Schapiro5 & David Burger1,2 † Author for correspondence 1 Radboud University Medical Center, Department of Pharmacy, Geert GrootepleinZuid 10 6525 GA Nijmegen, The Netherlands E-mail: [email protected] 2 Radboud Institute for Health Sciences (RIHS), Nijmegen, The Netherlands 3 Elisabeth TweeSteden Hospital, Hospital Pharmacy Midden-Brabant, Tilburg, The Netherlands 4 University of Amsterdam, Academic Medical Center, Division of Infectious Diseases and Department of Global Health, Amsterdam, The Netherlands 5 National Hemophilia Center, Sheba Medical Center, Ramat Gan, Israel

lamivudine single-tablet regimen: a review of its use in HIV-1 infection.

lamivudine single-tablet regimen: a review of its use in HIV-1 infection.

Single Tablet Regimen Usage and Efficacy in the Treatment of HIV Infection in Australia.

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

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

Review article: The pharmacokinetics and pharmacodynamics of drugs used in inflammatory bowel disease treatment.

Clinical Pharmacokinetics and Pharmacodynamics of Afatinib.

Clinical Pharmacokinetics and Pharmacodynamics of Lenalidomide.

Clinical Pharmacokinetics and Pharmacodynamics of Dexmedetomidine.

Non-clinical pharmacokinetics and pharmacodynamics of rVIII-SingleChain, a novel recombinant single-chain factor VIII.

Clinical Pharmacokinetics and Pharmacodynamics of Biologic Therapeutics for Treatment of Systemic Lupus Erythematosus.

Ticagrelor: pharmacokinetics, pharmacodynamics, clinical efficacy, and safety.

Clinical pharmacokinetics and pharmacodynamics of the novel SGLT2 inhibitor ipragliflozin.

Clinical pharmacokinetics and pharmacodynamics of the endothelin receptor antagonist macitentan.

Population pharmacokinetics of dolutegravir in HIV-infected treatment-naive patients.

Clinical pharmacokinetics and pharmacodynamics of ganciclovir and valganciclovir in children with cytomegalovirus infection.

Pharmacokinetics and pharmacodynamics of an orally disintegrating tablet formulation of dexlansoprazole.

Once-Daily, Single-Tablet Regimens For the Treatment of HIV-1 Infection.

Efficacy of switching to dolutegravir plus rilpivirine, the small-tablet regimen, in patients with dysphagia: two case reports.

Pharmacokinetics and Pharmacodynamics of the Oral Disintegrating Tablet of Desmopressin in Adults with Nocturnal Polyuria: A Pilot Study.

The pharmacokinetics, pharmacodynamics and clinical efficacy of elvitegravir + cobicistat + emtricitabine + tenofovir combination therapy for the treatment of HIV.

Pharmacokinetics and pharmacodynamics of antifungals in children: clinical implications.

An evaluation of the pharmacokinetics and pharmacodynamics of ivabradine for the treatment of heart failure.

Effects of boceprevir and telaprevir on the pharmacokinetics of dolutegravir.