Dolutegravir: an exciting new kid on the block

Jose Luis Blanco Are´valo† & Gary George Whitlock
†University of Barcelona, IDIBAPS, Hospital Clinic, Barcelona, Spain

10.1517/14656566.2014.868883 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 573
All rights reserved: reproduction in whole or in part not permitted
Box 1. Drug summary.
Drug name Dolutegravir
Phase FDA approved
Indication Treatment-naı¨ve, treatment-naı¨ve
integrase strand transfer inhibitor (INSTI)-naı¨ve, INSTI-experienced with certain INSTI-associated
resistance, adults and children aged or older 12 years and weighing at least 40 kg
Pharmacology INSTI description
Route of Oral administration
Chemical Sodium (4R,12aS)-
formula 9-{[(2,4-difluorophenyl) methyl]carbamoyl}-4-methyl-6,8-dioxo- 3,4,6,8,12,12a-hexahydro-2H-pyrido [1’,2’:4,5]pyrazino[2,1-b][1,3]
oxazin-olate. Formula C20H18F2N3NaO5 Pivotal trial(s) Adults: SPRING-2 (ING113086),
SINGLE (ING114467), SAILING (ING111762), VIKING-3(ING112574).
Pediatric IMPAACT (P1093)
Pharmaprojects — copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Pipeline (http://informa-pipeline. and Citeline (


Introduction: Dolutegravir is the first second-generation integrase inhibitor approved for the treatment of na¨ıve as well as experienced HIV-infected individuals.
Areas covered: Data from pharmacokinetics, efficacy, safety, tolerability and resistance are reviewed from in vitro studies, Phase II and III clinical trials pub- lished in PubMed (Dolutegravir; S/GSK1349572) or presented in international meetings.
Expert opinion: Data from studies and clinical trials indicate that dolutegravir is safe, well tolerated and highly efficacious in the treatment of both antiretroviral-na¨ıve and treatment-experienced patients and appears to have a higher genetic barrier to resistance than first-generation integrase inhibitors.

Keywords: antirtroviral therapy, dolutegravir, HIV, integrase-inhibitors

1. Introduction

Since the approval of raltegravir (RAL) in 2007 and that of elvitegravir (EVG) in a new once-a-day fixed-dose combination pill Stribild® (EVG, cobicistat, emtricita- bine, tenofovir disoproxil fumarate), the challenges for the new drug class of inte- grase inhibitors (INIs) were addressed by improving the weakest points of the first-generation drugs in this class: dose administration and genetic barrier. Dolute- gravir (DTG) (Box 1) (Trivicay®) is the first second-generation INI recently approved by the US FDA. The aim of this review is to assess the clinical efficacy, safety, pharmacokinectic profile, drug interactions and resistance profile of this new antiretroviral (ART) agent.

2. HIV-1 integrase: structure and function

Following reverse transcription, integrase (IN) cleaves the conserved dinucleotide’s GT from the 3¢-ends of double-stranded HIV-1 DNA leaving two CA overhangs (the 3¢-processing reaction). IN remains bound to each of the 3¢-ends, circularizing the HIV-1 pre-integration complex (PIC). IN then binds the host protein, lens- epithelial derived growth factor (LEDGF), which translocates the PIC to the nucleus where IN catalyzes a nucleophilic attack of the viral 3¢-hydroxy ends on the phosphodiester bonds of host genomic DNA (the strand-transfer reaction). Although IN catalyzes both the 3¢-processing and strand-transfer reactions, only those compounds that specifically inhibit strand transfer have been effective INIs. Indeed, the development of a high-throughput screening assay for the identification of strand-transfer inhibitors that bind IN in complex with viral DNA heralded the modern era of INIs development [1].
HIV-1 IN contains 288 amino acids encoded by the 3¢ end of the HIV-1 pol gene. It is composed of three functional domains. The catalytic core domain (CCD), which encompasses amino acids 51 — 212, contains the catalytic triad D64, D116 and E152 and the viral DNA-binding site. D64 and D116 coordinate the positioning of a metallic cationic cofac- tor (Mg2+ or Mn2+), which is essential for IN function. The N-terminal domain (NTD), which encompasses amino acids 1 — 50, is characterized by an HHCC zinc-binding motif. Its primary role appears to be to facilitate IN multimerization through its extensive contacts with adjacent CCD monomers. The C-terminal domain (CTD), which encompasses amino acids 213 — 288, binds host DNA nonspecifically.
There are published crystal structures of the HIV-1 IN
CCD plus CTD domains, the CCD plus NTD domains, the CCD bound to LEDGF and the CCD bound to an active- site inhibitor, the prototype diketo acid inhibitor 5CITEP (reviewed in 2 — 4). But the relative conformation of the CCD, NTD and CTD domains and the tetrameric state of functional HIV-1 IN has been inferred primarily from crystal- lographic studies of the homologous IN of the prototype foamy virus (PFV) [2]. The applicability of the PFV IN struc- ture to HIV-1 IN is validated by the consistency of the PFV IN structure with HIV-1 IN biochemical data and by the ability of PFV IN to co-crystallize with RAL and EVG [2,3].
HIV-1 INIs are structurally diverse molecules that contain a motif for binding the essential divalent metal cations Mg2+ or Mn2+ and a hydrophobic region for binding within the cavity formed by IN and the 3¢ HIV-1 DNA ends containing the terminal CA dinucleotide. RAL, EVG and DTG displace viral DNA in the active site and contact several active-site amino acids — including those in a mobile loop extending between positions 140 — 149 [4-6].

3. Pharmacokinetics

DTG is readily absorbed with a median time to peak fasting plasma concentration between 0.5 and 1.25 h, after which its plasma concentration declines biexponentially [7]. In repeat-dose studies in healthy subjects, both the area under the curve (AUC) and the plasma concentration of DTG at the end of the dosing interval were proportional to the dose administered over the range 10 — 50 mg [7,8]. There is little inter-subject variability (coefficient of variation, range 25 — 50%) observed in single- and repeat-dose pharmacoki- netics (PK) studies [7-9]. After multiple doses, steady-state DTG concentrations are reached by day 5 in once-daily dosing studies [7]. The trough concentration for the DTG 50 mg suspension dose was approximately 25-fold above the protein-adjusted 90% inhibitory concentration (IC90) for HIV-1 [9]. The terminal elimination half-life (t1/2) is 13 — 15 h which allows once-daily dosing [7].
In 18 healthy volunteers given DTG 50 mg in the fasting state or with meals of varying fat content, the mean AUC for DTG concentration increased modestly by 66% for subjects given high-fat-content meals compared with those fasted [10]. This increase in plasma concentration is not expected to impact clinical safety, allowing DTG to be administered with or without food.
DTG has a modest drug interaction profile. Its major and minor metabolic pathways are uridine diphosphate glucuro- nosyl transferase (UGT)-1A1 and cytochrome P450 (CYP)- 3A4, respectively [8]. No significant CYP3A induction or inhibition effects have been noted. It is expected that DTG will be available as a fixed-dose coformulation with abacavir and lamivudine. As a class, NRTIs do not undergo hepatic metabolism by the CYP pathway and, therefore, there is a low potential for drug interactions between this class and DTG. An open-label repeat-dose study in 15 healthy volun- teers demonstrated no clinically significant drug interaction between DTG 50 mg and tenofovir disoproxil fumarate 300 mg concomitantly given daily [11]. In fact, no dose adjust- ments are suggested with most ARTs [8]. However, DTG coadministration with etravirine (ETV) led to significant reductions in AUC, Cmax and Ctrough to such an extent that the study authors suggested that DTG and ETV should not be coadministered [12]. Although, they suggest that the addi- tion of ritonavir-boosted PI to the regimen would allow their coadministration with no dose adjustments.
In healthy volunteers there are some data on medications commonly co-prescribed for people living with HIV [8]. For example, there is low potential for DTG to interact with oral contraceptive pills. A study of 16 healthy females receiv- ing twice-daily DTG 50 mg and once-daily Ortho-Cyclen, a combined oral contraceptive containing norgestimate and ethinyl estradiol, demonstrated no change in the pharmacoki- netic profile of DTG, norgestimate or ethinyl estradiol [13]. DTG chelates with products containing metal cations such as antacids, thus preventing DTG binding to magnesium ions located at the catalytic site of the IN enzyme itself. Therefore, although DTG can be taken with antacids with no dose adjust- ment, PK studies suggest that DTG should be administered 2 h before or 6 h after antacids [14]. However, the simultaneous administration of DTG with omeprazole demonstrated a non- significant decrease in DTG exposure and, therefore, may be coadministered at the same time [14].

4. Clinical trials

4.1 Treatment-naı¨ve patients
SPRING-1 is a 96-week, Phase IIb, randomized, partially blinded, dose-ranging study in treatment-na¨ıve subjects [15]. Two hundred and eight participants were randomized to receive DTG once daily at one of the three doses, 10, 25 or 50 mg, or efavirenz (EFV) 600 mg once daily plus a co-formulated back- bone: either abacavir/lamivudine or tenofovir/emtricitabine. Of the 205 participants who received the study drug, the propor- tion achieving plasma HIV-1 RNA < 50 copies/ml at week 96 was 79, 78 and 88% for DTG 10, 25 and 50 mg, respec- tively, compared with 72% for EFV. DTG at all doses led to rapid viral load reduction, with 82% of all participants receiving the study drug achieving viral load < 50 copies/ml. The median CD4 increase from baseline was 338 cells/µl with DTG (all treatment groups combined) compared with 301 cells/µl with EFV.
DTG has been compared against existing ARTs in two multinational 96-week, Phase III, randomized, double-blind, non-inferiority studies in treatment-na¨ıve subjects: EFV (SINGLE) and RAL (SPRING-2 study).
SINGLE enrolled 833 participants to be randomly allo- cated either once-daily tenofovir/emtricitabine/EFV coformu- lated in single tablet regimen (EFV/tenofovir/emtricitabine) or once-daily DTG 50 mg plus coformulated abacavir/ lamivudine [16]. Apart from being treatment na¨ıve for entry into the study, subjects were required to have a viral load of at least 1000 copies/ml, no primary HIV viral resistance and a negative HLAB*5701. Most participants were men (84%) and two-thirds were white. Median baseline HIV viral load was approximately 50,000 copies/ml in each group and 32% with at least greater than 100,000 copies/ml. The median CD4 count was comparable in both arms (337 cells/µl). The 48-week data were presented at the 52nd Annual ICAAC meeting in San Francisco in September 2012. The results showed that 364 participants (88%) in the DTG plus abacavir/lamivudine arm achieved the primary endpoint of viral load < 50 copies/ml at 48 weeks versus 338 participants (81%) in the EFV arm (adjusted difference 7.4%; 95% confidence interval [CI]: 2.5 -- 12.3). Although designed to test non-inferiority, the SINGLE data established that DTG plus abacavir/lamivudine achieved superiority to EFV/tenofovir/emtricitabine. The response was similar for patients with baseline viral loads above and below 100,000 copies/ml in both arms. Additionally, significantly greater CD4 cell-count increases were seen in the DTG arm (267 vs 208 cells/µl, respectively). In each arm there were 4% protocol-defined virological failures. Of note, fewer partici- pants stopped treatment due to side effects in the DTG versus EFV/tenofovir/emtricitabine arm (2 vs 10%). The authors suggest that the better tolerability of DTG likely explains its better performance against EFV/tenofovir/emtricitabine in the SINGLE trial.
SPRING-2 enrolled 822 participants to be randomly allocated an INI, either RAL given 400 mg twice daily (BID) or DTG 50 mg once daily plus one of two co-formulated back- bones chosen at the investigators’ discretion: abacavir/ lamivudine or tenofovir/emtricitabine [17]. Entry criteria were similar to those of the SINGLE trial including a viral load of at least 1000 copies/ml. Baseline characteristics were similar to those of the SINGLE trial: most participants were men (86%) and white (85%). Median baseline HIV viral load was approximately 33,000 copies/ml in each group with 28% at least greater than 100,000 copies/ml. The median CD4 count was comparable in both arms (360 cells/µl). The 48-week data were published in The Lancet in January 2013 [17]. This showed that the DTG arm was non-inferior to the RAL arm for the primary endpoint of viral load < 50 copies/ml at 48 weeks (361; 88% vs 351; 85%.
Adjusted difference 2.5%; 95% CI: -2.2 to 7.1). The primary endpoint was similar for patients with baseline viral loads above and below 100,000 copies/ml as well as for choice of backbone in both arms. Of note, the choice of backbone was similar in both arms, with 60% receiving tenofovir/ emtricitabine and 40% abacavir/lamivudine. CD4 cell counts increased in both groups by a median 230 cells/µl.
FLAMINGO, a multinational open-label trial, randomized 484 ART-na¨ıve patients to receive either DTG 50 mg once daily or ritonavir-boosted darunavir (DRV/r) 800/100 mg once daily plus one of the two investigator-selected backbones: abacavir/lamivudine or tenofovir/emtricitabine. The 48-week data were presented at the 52nd Annual ICAAC meeting in Denver in September 2013 [18], and more recently at the 14th European AIDS Conference in Brussels, Belgium [19]. Although set up as a non-inferiority trial, the data showed that DTG was superior to DRV/r for the primary endpoint of viral load < 50 copies/ml at 48 weeks by snapshot analysis: 90 versus 83% (adjusted difference 7.1%; 95% CI: 0.9 -- 13.2%; p = 0.025). These results were confirmed in per- protocol analysis: 91 versus 84%, respectively (difference: 7.4%; 95% CI: 1.4 -- 13.3%), and particularly favored individ- uals with baseline HIV-RNA greater than 100,000 copies/ml (90 vs 70%). However, it is important to highlight that there were an equal number of virologic failures in both arms. CD4 cell counts increased in both groups to week 48 by a median 210 cells/µl. Two individuals in each arm (< 1% in each arm) had protocol-defined virologic failure. The investi- gators suggested that DTG’s superiority reflected both its bet- ter tolerability and also a better response rate for participants with baseline viral load greater than 100,000 copies/ml in the DTG arm (proportion with viral load < 50 copies/ml at 48 weeks: 93 vs 70%) [18,19].

4.2 Treatment-experienced patients

4.2.1 Antiretroviral-experienced integrase-inhibitor
-na¨ıve SAILING is a 48-week, Phase III, randomized, double-blind, active-controlled, non-inferiority study that evaluated safety, efficacy and emergent resistance in ART-experienced, INI- naive adults with HIV-1 with at least two-class drug resis- tance [20]. From Oct 2010 to Jan 2012, 1441 patients were screened in 156 centers in 5 continents, of whom 724 were randomly assigned (1:1) to DTG (50 mg once a day) or RAL (400 mg BID) plus up to two additional ARTs, with at least one of them fully active. Seven hundred and nineteen par- ticipants were included in the intention-to-treat analysis (DTG, 357; RAL, 362). Sixty-eight percent of the study pop- ulations were male with a median age of 43 years and broad diversity in ethnicity as well as HIV-1 subtypes due to the broad geographical participation. Median (interquartile range) baseline plasma viral load and CD4+ cell counts were 4.18 (3.45 -- 4.84) log10 copies/ml and 200 (95 -- 366) cells/µl, respectively, and around half had HIV advanced disease or a history of AIDS and resistance to at least one drug in each of three or more ART drug classes. The primary endpoint was the proportion of patients with plasma HIV-1 RNA < 50 copies/ml at week 48 assessed with the US-FDA-defined snap- shot analysis, and the statistical analysis tested the superiority of DTG if non-inferiority was established in both primary (all subjects who received at least one drug of study drug) and per-protocol analyses (excluding subjects with prespecified protocol deviations).
At week 48, 251 (71%) of 354 patients receiving DTG had plasma HIV-1 RNA < 50 copies/ml versus 230 (64%) of 361 patients receiving RAL, showing DTG non-inferiority (difference in proportions 7.4%, 95% CI: 0.7 -- 14.2). Statis- tical superiority (p = 0.03) was subsequently shown as part of the prespecified testing procedure. The increase of CD4+ T-cell count was 162 cells/µl in the DTG arm versus 153 cells/µl through week 48. Virological failure was more frequent in the RAL group 45 (12%) versus 21 (6%) in the DTG group by week 48 and earlier, and 19 of 45 virological failures were nonresponders (plasma HIV-1 RNA decrease < 1 log10 copies per ml unless < 400 copies/ml by week 16 or HIV-1 RNA ‡ 400 copies/ml on or after week 24) in the RAL versus only 2 of 21 in the DTG group. For the sec- ondary endpoint, the proportion of patients harboring virus with evidence of treatment-emergent genotypic resistance was significantly lower in the DTG group (see Resistance issues), 1% (4 of 354) compared with 5% (17/361) in the RAL group (adjusted difference -3.7%, 95% CI: -6.1 to -1.2, p = 0.003). The proportion of patients with resistance to the background regimen was also greater in the RAL group (27 vs 19%, of the virological failures).

4.2.2 Antiretroviral-experienced RAL resistance
On the basis of data of limited cross-resistance between DTG and first-generation INIs (RAL and EGV) shown from in vitro studies [21,22], a Phase IIb study (VIKING study) was conducted to assess the activity of DTG in HIV-1-infected individuals with RAL-resistant viral isolates [23]. Fifty-three and 54 subjects were screened, of whom 27 and 24 subjects were enrolled to compose the intention-to-treat of two cohorts: the 50-mg once-daily dose of DTG was first evaluated in a first cohort (cohort I) of 27 participants who replaced RAL with DTG for 10 days in addition to their background therapy, none of which contained active drugs. However, following the assessment of the virological response of cohort I, a proto- col amendment was prompted and a second cohort of 24 participants was evaluated, who received DTG 50 mg BID. Most participants were men with a median age of 48 years. According to the in vitro data of previous cross-resistance between DTG and RAL, subjects were allocated to two groups in order to ensure a broad range of DTG sensitivity (unfortu- nately no analysis was done by these two groups): group 1 included subjects with the worse DTG resistance profile (Q148H/K/R + ‡ 1 secondary RAL resistance mutations); and group 2 included subjects with a better DTG resistance profile (all other mutations, including codon 148 single mutation).
Eighty-six percent of subjects (44 of 51) achieved the pri- mary efficacy endpoint (plasma HIV-1 RNA load of < 400 copies/ml or of ‡ 0.7 log10 copies/ml below the baseline value on day 11): 78% of subjects (21 of 27) in cohort I and 96% of subjects (23 of 24) in cohort II. Subjects from cohort II had a significantly larger reduction in HIV-1 RNA level from baseline on day 11, compared with cohort I (mean adjusted treatment difference, -0.32 log10 copies/ml; -1.76 vs -1.45 log10 copies/ml; p = 0.017). At day 11, the start of the second phase of the study, background therapy could be optimized according to genotypic and phenotypic tests. That was encouraged in cohort I but mandated for cohort II, such that only one subject (4%) from cohort I, compared with 12 (44%), had an optimized background regimen phenotypic susceptibility score of 0. At week 24, the response (viral load £ 400 copies/ml) rate was greater in cohort II, 20 subjects (83%) in contrast to 14 subjects (52%) in cohort I. The increase of CD4+ T-cell count was similar in both cohorts through week 24 (54 and 60 cells/µl for cohorts I and II, respectively).
Based on these findings, DTG 50 mg twice-daily dosing was chosen for VIKING-3, a Phase III, single-arm open-label study, which assessed efficacy and safety of DTG through 24 weeks in treatment-experienced patients with ‡ 3 class resis- tance including INI resistance. One hundred and eighty-three adults with screening HIV-1 RNA ‡ 500 copies/ml started DTG 50 mg BID and continued their failing regimen (with- out RAL/EVG). After 7 days of open-label DTG, background drugs were optimized and DTG continued. There was a drop in mean HIV-1 RNA of an average 1.4 log after 7 days. At week 24, 126 of 183 people (69%) had a viral load < 50 copies/ml, and after 48 weeks of treatment, 64 of 114 (56%) had viral load < 50 copies/ml. There were 50 virologic nonresponders (27%) at week 24 and 44 (39%) at week 48. DTG 50 mg BID was well tolerated despite advanced dis- ease. In multivariate analyses of baseline factors on week 24 response rates, the presence of Q148 + ‡ 2 secondary IN mutations and increasing DTG fold change (FC) were highly correlated with fewer subjects achieving < 50 copies/ml (p £ 0.001) but the optimized background regimen activity score did not impact response [24].

5. Safety and tolerability

In the SINGLE study, insomnia was the only side effect reported more commonly in the DTG arm (15 vs 10%). Oth- erwise the most common side effects seen in the DTG arm were gastrointestinal and were found with comparable fre- quency in both arms (18% diarrhea; 14% nausea) [16]. Ten (2%) participants in the DTG arm stopped treatment before 48 weeks due to side effects. This compares with 42 (10%) in the EFV/tenofovir/emtricitabine arm. As one might expect, nervous system and psychiatric disorders accounted for 15 (4%) and 13 (3%) withdrawals in the EFV/tenofovir/ emtricitabine arm, compared with none and 2 (< 1%), respec- tively, in the DTG arm. Two deaths were seen in the EFV/ tenofovir/emtricitabine arm, both unrelated to the study drugs. No deaths were seen in the DTG arm. In SPRING-2, the rates of side effects were similar in each arm, most com- monly nausea (14%), headache (12%), nasopharyngitis (11%) and diarrhea (11%) [17]. The rates of side effects leading to discontinuation in each arm were also low (2%). The two deaths, one in each arm, were unrelated to the study drugs. In the SAILING 48-week analysis, the most common adverse event was diarrhea, seen in 20% in the DTG group and 18% in the RAL group [20]. Side effects leading to discontinuation were also infrequent (3% DTG, 4% RAL). In FLAMINGO, there were fewer withdrawals due to adverse events with DTG compared with DRV/r (1 vs 4%). There was a lower incidence of diarrhea with DTG (17 vs 29%) but greater inci- dence of headache (15 vs 10%). No serious adverse event was reported in ‡ 1% of patients in any treatment group [19]. The VIKING 24 week data showed that the proportion of partici- pants with serious adverse events was low (15 and 13%, respec- tively), none of which were considered related to DTG [23]. In VIKING-3, 6 of 183 people (3%) discontinued treatment because of adverse events [24]. There were two serious drug- related adverse events -- hyperbilirubinemia, elevated ALT, and drug eruption in a patient taking DTG with ETV, and grade 2 syncope in another patient.
In both SINGLE and SPRING-2, there were similar low rates of renal adverse events (4 -- 5% in each arm) [25]. Increases in serum creatinine were noted with DTG in SPRING-1, SPRING-2, FLAMINGO, VIKING and SINGLE, which occurred early (by week 2) and were stable by week 48 [15-17,23,25,19]. In SPRING-2, the mean change in creatinine clearance from baseline was -16.5 ml/min in the DTG arm compared with -5.4 ml/min in the RAL arm [17]. No change from baseline was seen in the urine albumin-to-creatinine ratio in either arm. There were no discontinuations to week 48 in either group due to renal events. The mechanism is due to DTG-medicated inhibition of the organic cation transporter OCT2 which decreases tubular secretion of creatinine, thus increasing serum creatinine without changing glomerular fil- tration. Hence, the changes in creatinine for DTG are not regarded as clinically significant although its long-term effect is still unknown.
From the week 96 data from SPRING-1, the mean changes in cholesterol were found to be lower in the DTG arm than in the EFV arm [15]. In SPRING-2, there were no clinically sig- nificant changes over time in the fasting lipid profiles in either the DTG or RAL arm [17].
In SPRING-2, hepatic adverse events also occurred at low rates: 11 (1%) participants had increases in alanine amino- transferase greater than five times the upper limit of normal and met criteria to discontinue, 7 on DTG and 4 on RAL [17]. Of these, two patients in each arm had possible drug-induced liver injury due to the INI prescribed. Of note, the entry criteria for the SPRING-2 trial excluded those with moderate or severe hepatic impairment.
DTG is a well-tolerated drug. The most common side effects are nausea, diarrhea and headaches, all seen at low rates (< 20%). In all studies, there is a low rate of discontinuations due to reported side effects. Laboratory-observed adverse events are also infrequent. Although decreases are seen in cre- atinine clearance in all studies, these are not considered to be clinically significant.

6. Resistance issues

6.1 Resistance in vitro data
With the exception of one report of transmitted INI resis- tance [26], fewer than 0.1% of INI-na¨ıve individuals harbor viruses with primary INI resistance mutations [27,28]. Sixty- five percent of the residues in the In gene, which are involved in protein stability, multimerization, DNA binding and cata- lytic activity and in binding with the human cellular cofactor LEDGF/p75, are fully conserved [29]. From the most variable sites, the most prevalent polymorphic amino acid change at these positions did not affect susceptibility to DTG in vitro or in vivo [30].
To date, few data have been generated with regard to the mutations of resistance selected by DTG. In in vitro serial pas- sage studies, no highly resistance viruses have been selected; however, different INI mutations have been reported. In the first studies reported by Shionog & Co., Ltd, resistance passage assays up to day 112 with DTG showed only four substitutions or combinations of substitutions (T124A, S153Y, T124A/S153Y and L101Y/T124A/S153Y) [21,22]. These changes did not cause an increase of > 4.1 in the DTG FC. These in vitro studies also demonstrated that the selection of resistant mutations from a wild-type population was greatly delayed in a DTG- containing medium in contrast with that of first-generation INIs [30,31]. Another serial passage in vitro study reported R263K as the first mutation most commonly selected, without homogeneity in the secondary mutation co-selected (G118R, S153Y, H51Y, E138K, V151I, M50I) [32].
In vitro data have demonstrated that DTG retains substan- tial activity against Y143 and N155H pathway virus with additional secondary mutations and against virus with Q148 mutations alone [31]. There is a broader range of FC resistance against Q148 pathway virus according to the RAL secondary mutations; resistance generally increases with increasing number of mutations, particularly when these include G140S and/or E138K [31,32]. The main patterns of combined mutations associated with DTG resistance are Q148R or Q148H with additional substitutions including T97A, E138K, G140S and M154I.

6.2 Resistance in ARV-naı¨ve studies
Low rates of resistance were seen in SPRING-1, SPRING-2 and SINGLE. No IN or reverse transcriptase (RT) resistance was seen in the DTG arm of the SINGLE and FLAMINGO trials [16,19]. Of the virological failures in SPRING-1 and SPRING-2, no patients on DTG had the emergence of a virus with IN resistance mutations, and only one patient receiving DTG 10 mg developed virus with the mutation M184M/V in RT (SPRING-1). In the RAL arm of SPRING-2, one patient, whose baseline HIV viral load was greater than 3 million copies per ml, developed both IN and nucleos(t)ide RT inhibitor resistance with a FC at viro- logical failure of 2.02 for DTG and 34 for RAL. Two addi- tional patients, one in each arm, at protocol-defined virological failure but with no emergent genotypic resistance had increased phenotypic resistance to RAL but not to DTG (SPRING-2).

6.3 Resistance in ARV-experienced studies
At week 48, the proportion of patients in the SAILING study harboring virus with evidence of treatment-emergent genotypic or phenotypic INI resistance was 1% (4 of 354) in the DTG group versus 5% (17 of 361) in the RAL group (adjusted differ- ence -3.7%, 95% CI: -6.1 to -1.2, p = 0.003). Of these four patients from the DTG arm, one had a RAL primary resis- tance mutation at baseline (Q148H/G140S). Two patients selected IN substitutions at R263 position (R263R/K and V260I/R263K) and one with a polymorphic change at V151 (V151V/I), all of them with DTG or RAL FC of < two, suggest- ing no high-level resistance to both RAL and DTG. Viruses with R263K and V260I/R263K site-directed mutants retain good activity against DTG -- with lower than twofold change
IC50 for both RAL and DTG -- and a prolonged binding to IN enzyme (with half of the 3H-DTG retained for about 50 h) [33]. The proportion of patients with resistance to the background regimen was also greater for the RAL group (27 vs 19%, of the virological failures). Recently, an interesting potential explanation for the relationship between the R263K mutation and the absence of resistance mutations in ART drug-naive patients treated with DTG has been postulated in another in vitro experiment. In that study, the combination of mutations at positions R263K and H51Y shows a unique resis- tance pathway for DTG, where the secondary mutation H51Y, instead of compensating and restoring both enzymatic function and viral fitness, the effect of the first substitution (R263K), which occurs most commonly [34], increases the level of resis- tance against DTG with a dramatic cost to both enzymatic activity and viral replication that could explain the absence of detection of resistance mutations by the conventional assays used for detecting drug resistance in the DTG clinical studies in INI-na¨ıve patients [35].
In VIKING, the baseline RAL FC was greater than the maximum concentration for all viruses, but, in contrast, DTG FC was higher for virus with mutations Q148 than for Y143 and N155H pathway viruses [22]. Seventy patients had protocol-defined virologic failure through week 24, 12 of 27 (44%) and 5 of 24 (21%) subjects in cohorts I and II, respectively. New INI genotypic resistance mutations emerged after virological failure was observed in 7 subjects, 4 of the 12 cohort I subjects and 3 of the 5 cohort II subjects. At virologic failure, all 7 subjects harbored ‡ 4 RAL resistance-associated mutations, and 5 of the 7 subjects (2 in cohort I; 3 in cohort II) had virus with Q148 + ‡ 1 RAL resistance-associated mutation at screening or baseline. It is important to point out that in the VIKING study, 5 out of 33 subjects (15%) with > 150 copies/ml at day 11 (after the end of the functional monotherapy phase) and with baseline IN mutations (4 of these 5 harbored viruses with Q148H + ‡ 1 secondary RAL resistance mutations) selected additional IN resistance mutations over the 10-day study period. This datum suggests that, as with protease inhibitors, the apparent high genetic barrier of DTG in IN-na¨ıve patients, in which the selection of IN-genotypic resistance mutations after virological failure is very slow and uncom- mon, does not seem to demonstrate the same behavior in patients with previous virological failure and selected muta- tions to INIs, where the selection of new IN mutations could occur at a faster rate.
In the VIKING-3 study, which examined the efficacy and safety of DTG 50 mg BID in patients with resistance to multi- ple ARTs including INI, baseline IN genotypes and phenotypes were assessed to identify correlates to virological response. Esti- mated DTG phenotypic cutoffs showed wide confidence inter- vals; however, for those patients with baseline DTG FC < 9.45, 87% achieved full response (reduction > 1 log10 HIV RNA) at day 8, and 69% viral load < 50 copies/ml at week 24. No patient with DTG FC > 9.45 reached < 50 copies/ml at week 24. Three baseline genotypic resistance groups were identified based on their impact on DTG antiviral response i) No Q148 (N155H, Y 143C/H/R, T66A, E92Q or historical IN resis- tance); ii) Q148 + 1 and iii) Q148 + ‡ 2 (secondary mutations fromG140A/C/S, E138A/K/T, L74I)] and were used to assess response at week 24. Median decline in viral load at day 8 in log10 HIV RNA were -1.65 (no Q148), -1.10 (Q148 + 1)
and -0.74 (Q148 + ‡ 2); at week 24 the percentage of patients with < 50 copies/ml in the three groups were 79% (no Q148), 45% (Q148 + 1), and 11% (Q148 + ‡ 2) [36].

7. Conclusions

DTG has been assessed in various clinical scenarios and com- pared with several ART drugs. In naive subjects, DTG 50 mg once daily has demonstrated a favorable virological outcome compared with EFV, driven by its better tolerability, and with RAL, with lower risk of antiviral resistance to IN or NRTI following virological failure. More recently, DTG has even shown superiority compared with DRV/r in the FLA- MINGO study, mainly driven by its better response in indi- viduals with baseline viral load greater than 100,000 copies/ ml, but with equal number of virological failures in both arms. In treatment-experienced subjects who are INI naive, in combination with up to two other ART drugs, DTG 50 mg once daily has shown higher virological efficacy than RAL 400 mg BID with a lower selection of IN and NRTI mutations. In treatment-experienced subjects with at least triple-class resistance including resistance to INIs, although DTG 50 mg BID with an optimized background therapy is at present being evaluated in an ongoing Phase III trial, exist- ing data show excellent virological response in subjects with a genotypic resistance profile different from Q148 + 2 or more secondary mutations.
DTG has been generally well tolerated when administered at either 50 mg once daily or 50 mg BID. The most common side effects reported include nausea, headache, upper respira- tory tract infections and diarrhea. With regard to resistance, data to date show that DTG possesses a resistance profile dis- tinct from that of the first-generation INIs, retaining substan- tial activity against viruses harboring two of the three main pathways of resistance selected after virological failure to the first-generation INIs, Y143 and N155H, and demonstrates a higher genetic barrier than them, with uncommon and slower selection of IN-genotypic resistance mutations after first INI- containing regimen virological failure, which may be due to its longer half-life and its slower dissociation from HIV-IN complexes [37].

8. Expert opinion

DTG is the first of the second generation of IN strand- transfer inhibitors developed by Shionogi-ViiV Healthcare and Glaxo-SmithKlein. In similarity with the other drugs belonging to this new class of INIs (RAL and EGV), DTG has demonstrated potent anti-HIV activity with a similar or higher decline in HIV-1 RNA after 10 days of monotherapy compared with other ARTs. Its excellent PK, approximately 15 h plasma half-life with low intersubject variability without pharmacokinetic boosters, and phamacodynamics, a trough concentration for the 50 mg once daily dose around 25-fold above the protein-adjusted IC90 for HIV-1 parameters, make DTG an appealing option in ART-naive patients with several advantages over the other INIs. Much like RAL, DTG has a very good tolerance and the same metabolic path- way through the UGT-1A1, as well as being a minor substrate for CYP. This explains its modest drug interaction profile and its small laboratory abnormality of total bilirubin increase. The advantages over RAL are its better pharmacokinetic pro- file and genetic barrier, and over EGV, its better drug--drug interactions profile because EGV is metabolized primarily by CYP, as well as its genetic barrier.
Because of its favorable PK, pharmacodynamics, safety and tolerability profile, DTG is an extremely good candidate for i) a single-tablet regimen formulation (at present, under evalu- ation combined with abacavir 600 mg and lamivudine 300 mg); ii) treatment in organ transplant recipients infected by HIV-1; iii) post-exposure prophylaxis; iv) the elderly with or without co-morbidities or polypharmacy; and v) acute HIV seroconversion where, due to very high viral loads, it is important that drugs have high ART potency and genetic barrier.
The potential drawbacks of DTG are the changes in creat- inine levels, which, despite being modest and non-progressive and without changing the glomerular filtration rate, may be an inconvenience in some subjects particularly when tenofovir is included in the regimen. DTG has a different resistance profile to other INIs. In data reported to date when DTG is used as the first INI, the selection of genotypic resistance mutations in IN is really uncommon. These data, along with the data in vitro, strongly suggest a high genetic barrier of this compound. However, it is important to highlight that, to date, few patients with a virological failure to DTG as first INIs and only from clinical trials have so far been reported and, on the other hand, genotypic resistance testing in those clinical trials were performed per protocol on the initial viral load that rebounded not on the viral load from the virological failure confirmation 4 weeks later. In ART- experienced patients failing on a first-generation INI, from the three pathways of resistance more commonly selected (involving N155, Y143 and Q148 residues), the activity of DTG is markedly diminished through Q148, especially when is accompanied by two or three mutations (G140A/C/ S, E138A/K/T, L74/I). With regard to the role of the combination of Q148H + G140S substitutions -- the most frequent pathway associated with RAL failure -- in DTG resistance, it is important to highlight that, although this combination is not selected immediately at RAL or EGV virological failure, due to their replicative advantages, variants harboring this combi- nation of mutations have a high selective advantage when there is persistent viral replication under first-generation
INIs-containing regimen. That makes extremely important a prompt monitoring of genotypic resistance after virological failure to avoid the potential evolution to this combination of mutations associated with a greater reduction in DTG sus- ceptibility [38,39]. In our opinion, although the data available to date point out that DTG has a high genetic barrier, perhaps even comparable to PI/r, we are still in the process of evaluation of this area.
DTG has shown to be an excellent option in treatment- naive patients even in individuals with high baseline viral loads (25% of patients in the FLAMINGO study had baseline viral load greater than 100,000 copies/ml). It demonstrates either noninferiority or superiority to its comparators (EFV, RAL, DRV/r). It has over one or more advantages in addition to them in terms of pill burden, the need for boosting, drug-- drug interactions, side effects, cessations and selection of resis- tances. Because of its potential high genetic barrier, it could be considered as the best IN inhibitor for rescue therapy -- unless the combinations of changes at residues Q148 + G140 or E138 are presented -- however, its excellent results in terms of resistance with no cases of emergent resistance in patients who had virologic failure do not limit its use in first-line therapy by not losing other ART options.
DTG is an extremely interesting agent with a wide range of indications as ART therapy, due its high ART potency and favorable tolerability, safety, drug--drug interactions and resistance profile.

Declaration of interest
JL Blanco Arevalo has received research funding, consultancy fees, travel expenses or lecture sponsorships from Abbott, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen-Cilag, Merck Sharp and Dohme, and ViiV Health- care. GG Whitlock has received travel expenses from Janssen- Cilag and ViiV Healthcare.


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