Dolutegravir/Rilpivirine: A Review in HIV‑1 Infection

Hannah A. Blair1

Abstract
Dolutegravir/rilpivirine (Juluca®) is the first two-drug single-tablet regimen (STR) to be approved for the treatment of HIV-1 infection in adults. The fixed-dose STR combines the integrase strand transfer inhibitor dolutegravir with the non-nucleoside reverse transcriptase inhibitor rilpivirine. In two phase III non-inferiority trials (SWORD-1 and SWORD-2) in treatment- experienced patients already virologically suppressed on their current antiretroviral (ART) regimen, switching to once-daily dolutegravir plus rilpivirine maintained virological suppression over 48 weeks. Switching to a two-drug regimen of dolute- gravir plus rilpivirine was also associated with high rates of virological suppression in real-world observational studies. Switching to once-daily dolutegravir plus rilpivirine was generally well tolerated and associated with more favourable renal and bone parameters than remaining on the current ART regimen. Longer-term, dolutegravir plus rilpivirine demonstrated durable maintenance of virological suppression and remained generally well tolerated for up to 100 weeks. Thus, dolute- gravir/rilpivirine provides a convenient alternative treatment option for some adults with HIV-1 infection and no history of virological failure who are already virologically suppressed on (and wish to switch from) their current ART regimen.

Dolutegravir/rilpivirine: clinical considerations in HIV‑1 infection

Two-drug single-tablet regimen with convenient once- daily administration
Maintains virological suppression in treatment-experienced patients without virological failure who switch from their current ART regimen
Generally well tolerated, with more favourable renal and bone parameters vs. the current ART regimen
1 Introduction

Over the years, advances in antiretroviral therapy (ART) have drastically changed the nature and progression of HIV infection, with HIV now considered a chronic yet manage- able disease [1]. Standard ART regimens generally comprise two nucleoside reverse transcriptase inhibitors (NRTIs) plus a third drug from the non-nucleoside reverse transcriptase inhibitor (NNRTI), boosted protease inhibitor (PI) or inte- grase strand transfer inhibitor (INSTI) classes [2, 3]. Chal- lenges associated with lifelong ART include high costs, long-term toxicity, potential drug interactions, increased pill burden and suboptimal adherence [4–6].
Simplification strategies have been adopted to reduce ART regimen complexity, including the use of fixed-dose combinations that allow up to four antiretroviral drugs to be co-administered in a single tablet as a complete regimen

The manuscript was reviewed by: D. M. Burger, Radboud University Medical Centre Nijmegen, Nijmegen, Netherlands; J. M. Llibre, HIV Unit, Lluita Contra La SIDA Foundation,
Barcelona, Spain; M. Nelson, Chelsea and Westminster Hospital, London, United Kingdom.
[7]. Moreover, the development of more effective and bet- ter tolerated antiretrovirals has fuelled renewed interest in simplified, two-drug regimens [6]. Indeed, evidence suggests that once virological suppression has been achieved with at least three antiretroviral agents during the initial treatment

*

[email protected]
phase, switching to a two-drug regimen may be possible [4].
Recently, maintenance therapy options have been further

1 Springer, Private Bag 65901, Mairangi Bay, Auckland 0754, New Zealand
simplified with the approval of the first two-drug single-tablet regimen (STR). This STR (Juluca®) combines the INSTI

dolutegravir with the NNRTI rilpivirine (both of which are already available as single products) and is administered once daily as a complete regimen. The fixed-dose dolutegravir/rilpi- virine STR is indicated in the EU and USA for the treatment of HIV-1-infected adults with virological suppression and no his- tory of virological failure [8, 9]. This article reviews the clinical efficacy and tolerability of the combination of dolutegravir plus rilpivirine in this population and briefly summarizes relevant pharmacology.

2Pharmacodynamic Properties of Dolutegravir/Rilpivirine

The INSTI dolutegravir binds to the active site of HIV inte- grase, thereby blocking the strand transfer step of retroviral DNA integration (an essential part of the HIV replication cycle) [8, 9]. Rilpivirine, a diarylpyrimidine NNRTI, inhib- its HIV-1 replication by non-competitively inhibiting the reverse transcriptase of HIV-1. The human cellular DNA polymerases α, β and γ are not inhibited by rilpivirine [8, 9].

2.1Antiviral Activity

The antiviral activity of dolutegravir and rilpivirine against HIV-1 is well established in vitro [8, 9]. The concentration of dolutegravir at which 50% of viral replication was inhib- ited (i.e. EC50) was 0.5–2 nmol/L against laboratory strains of HIV-1, with activity displayed against HIV-1 groups M (subtypes A–G) and O (EC50 0.02–2.14 nmol/L). Rilpiv- irine demonstrated antiviral activity against wild-type HIV-1 in vitro (median EC50 0.73 nmol/L against HIV-1 IIIB) and was more potent against HIV-1 isolates from group M (sub- types A–H; EC50 0.07–1.01 nmol/L) than group O (EC50 2.88–8.45 nmol/L) [8, 9]. Dolutegravir also demonstrated activity against HIV-2 (EC50 0.09–0.61 nmol/L), whereas the activity of rilpivirine against HIV-2 was limited (EC50 2,510–10,830 nmol/L) [8].
In vitro, dolutegravir was active against HIV strains resistant to NRTIs, NNRTIs or PIs (EC50 0.36–2.1 nmol/L), with activity equivalent to that against wild-type strains [10]. Dolutegravir was also highly active against most HIV-1 strains with resistance to raltegravir and/or elvitegravir (Sect. 2.3) [10].
When tested in combination with other antiretrovirals, there were no antagonistic effects between either dolutegra- vir or rilpivirine and any of the agents tested [9]. Dolutegra- vir had synergistic activity with most tested agents, includ- ing stavudine, abacavir, efavirenz, nevirapine, lopinavir, amprenavir and enfuvirtide [10]. The antiretroviral activity of dolutegravir was unaffected by the presence of the hepa- titis B drug adefovir or the hepatitis C drug ribavirin [10].

2.2Resistance

Dolutegravir has a high genetic barrier to resistance development in vitro [11]. In serial passage experiments with wild-type HIV-1 IIIB, the presence of dolutegra- vir resulted in the following amino acid substitutions at the integrase active site: T124A, T124A/S153F, T124A/
S153Y, L101I/T124A/S153F and S153Y [10]. The highest fold change in EC50 of dolutegravir for these mutations was 4.1-fold (compared with the wild-type integrase geno- type), in contrast to the highly resistant mutants that were isolated in the presence of raltegravir (> 100-fold change) [10]. Amino acid substitutions E92Q, G118R, G193E, S153F/Y and R263K also emerged in different passages [8, 9], conferring a ≤ 4-fold reduction in susceptibility to dolutegravir [9].
Cell culture resistance selection experiments with wild- type HIV-1 and clinical data indicate that resistance to rilpivirine may be conferred by a number of amino acid substitutions, most commonly L100I, K101E, V106I/A, V108I, E138K/G/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C and M230I/L [8, 9]. Rilpivirine resistance was considered to be present when the fold change in EC50 value exceeded the assay’s biological cut-off [8].
Among treatment-experienced adults with HIV-1 infec- tion who switched from their current ART regimen to once- daily dolutegravir plus rilpivirine in the phase III SWORD trials (Sect. 4.1), four patients met the criteria for viro- logical failure (confirmed HIV-1 RNA level of ≥ 400 cop- ies/mL after initial suppression to < 50 copies/mL) [12]. Results of genotypic and phenotypic resistance testing were only possible for one patient, who was identified as being non-adherent to dolutegravir plus rilpivirine. In this patient, the NNRTI mutation K101K/E was observed, with no loss of susceptibility to rilpivirine (1.2-fold change). There were no INSTI resistance-associated mutations (RAMs) or decreases in dolutegravir susceptibility [12].

2.3Cross‑Resistance

Single primary mutations that confer resistance to ralte- gravir or elvitegravir did not reduce the susceptibility of HIV-1 strains to dolutegravir in vitro, including Q148H/
R/K, N155H, Y143R/H/C, E92Q and T66I [8]. In site- directed mutagenesis analyses, susceptibility to dolute- gravir in vitro remained at or near wild-type level when secondary INSTI mutations (for raltegravir or elvitegravir) were added to primary mutations. However, site-directed mutants with Q148-based mutations had decreased dolute- gravir susceptibility. The degree by which dolutegravir susceptibility was reduced by mutations at position Q148

was dependent on the number of secondary mutations pre- sent (i.e. increasing fold change with increasing number of secondary mutations) [8].
Reductions in dolutegravir susceptibility have been observed in site-directed HIV-1 strains with the single INSTI RAMs T66K, I151L and S153Y (2.3- to 3.6-fold change) [8, 9]. Combinations of RAMs, including T66K/L74M, E92Q/
N155H, G140C/Q148H/R/K, Q148R/N155H, T97A/G140S/
Q148, and substitutions at E138/G140/Q148 conferred even greater (2.5- to 21-fold) reductions in dolutegravir suscep- tibility [8, 9].
Cross-resistance is known to develop between certain NNRTIs. Susceptibility to rilpivirine in vitro was reduced by some single NNRTI RAMs, including K101P, Y181I and Y181V [8, 9] (52-, 15- and 12-fold changes, respectively [9]). Some NNRTI RAMs had a greater impact on rilpiv- irine susceptibility when combined with other mutations. For instance, K103N did not reduce rilpivirine susceptibility, while K103N/L100I reduced susceptibility to the drug 7-fold [8, 9]. Similarly, susceptibility to rilpivirine was reduced 2.8-fold by E138K alone and 6.7-fold by E138K/M184I [9]. Among HIV-1 strains with two or three NNRTI RAMs, 38 and 66% displayed reduced susceptibility to rilpivirine (3.7- to 554-fold change) [9].

2.4Other Effects

A single supratherapeutic dose of dolutegravir (250 mg) in healthy adults (n = 42) did not prolong the Fridericia-corrected QT (QTcF) interval [9]. The recommended dosage of rilpiv- irine (25 mg once daily) was not associated with a clinically relevant effect on the QTcF interval in healthy adults (n = 60) [8, 9]. However, supratherapeutic dosages of rilpivirine (75 and 300 mg once daily) prolonged the QTcF interval (dif- ferences vs. placebo of 10.7 and 23.3 ms, after baseline cor- rection) [8, 9]. The effect of dolutegravir/rilpivirine on the QT interval has not been studied [9].

3Pharmacokinetic Properties of Dolutegravir/Rilpivirine

Bioequivalence was established for the single-tablet, fixed- dose combination of dolutegravir/rilpivirine and correspond- ing strength tablets of dolutegravir and rilpivirine admin- istered concurrently in healthy adults under fed conditions [13].
Oral dolutegravir and rilpivirine are rapidly absorbed, reaching maximum plasma concentrations (Cmax) within 2–3 h and 4–5 h, respectively (median values) [8, 9]. The absolute bioavailabilities of dolutegravir and rilpivirine have not been determined [8]. Absorption of both dolutegravir and rilpivirine was increased when dolutegravir/rilpivirine

was administered in the fed versus the fasted state [8, 9]. To ensure optimal absorption, dolutegravir/rilpivirine should be administered with a meal (Sect. 6). Both dolutegravir and rilpivirine display high (≈ 99%) plasma protein bind- ing in vitro [8, 9]. The apparent volume of distribution of dolutegravir is 17–20 L [8]. Dolutegravir has minimal asso- ciation with blood cellular components, but is present in cerebrospinal fluid and in the male and female genital tract. The distribution of rilpivirine into compartments other than plasma has not been evaluated in humans [8].
Dolutegravir is metabolized predominantly via glucu- ronidation by UGT1A1, with oxidation by CYP3A being a minor biotransformation pathway [8, 9]. After a single radiolabelled oral dose of dolutegravir, 64% of the dose is excreted in the faeces and 31% in the urine [9]. Fifty-three percent of the dose was recovered as unchanged drug in the faeces and < 1% was recovered unchanged in the urine [8, 9]. Dolutegravir has a terminal elimination half-life (t½) of ≈ 14 h [8, 9] and an apparent oral clearance of ≈ 1 L/h [8]. According to in vitro data, rilpivirine is primarily metabo- lized via oxidation by CYP3A4 [8, 9]. After administration of radioactive rilpivirine, 85% of the dose is eliminated via the faeces and ≈ 6% via the urine, with 25 and < 1% of the dose being eliminated via these routes as unchanged drug. The t½ of rilpivirine is ≈ 45–50 h [8, 9].

3.1Special Patient Populations

Pharmacokinetic data on the use of dolutegravir/rilpiv- irine in patients aged ≥ 65 years are limited [8, 9]. A 25% increase in dolutegravir Cmax was observed in patients aged ≥ 60 years compared with younger subjects, indicating increased dolutegravir absorption [14]. There were no differ- ences between the two age groups in dolutegravir area under the plasma concentration-time curve from 0–24 h (AUC0–24), plasma concentration 24 h post-dose (C24) or t½, suggest- ing a lack of age-associated effect on the main dolutegravir metabolic pathway (UGT1A1) [14]. In population pharma- cokinetic analyses, age, gender and race had no clinically relevant effect on the pharmacokinetics of dolutegravir or rilpivirine [8, 9]. The US prescribing information states that dolutegravir/rilpivirine should be used with caution in elderly patients due to the increased likelihood of decreased renal, hepatic or cardiac function, concomitant disease or treatment with other therapies [9].
In subjects with severe renal impairment (creatinine clearance < 30 mL/min), dolutegravir exposure was reduced modestly (40, 23 and 43% reductions in AUC, Cmax and C24, respectively) compared with healthy controls [9]. Dolutegra- vir/rilpivirine should be used with caution [8] or monitored for adverse effects [9] in patients with severe renal impair- ment or end-stage renal disease. No dosage adjustment is

necessary in patients with mild or moderate renal impair- ment [8, 9].
Dolutegravir exposures in subjects with moderate hepatic impairment (Child-Pugh score B) were similar to those in healthy controls [8, 9]. Exposure to rilpivirine was 47 and 5% higher in patients with mild and moderate hepatic impairment (Child-Pugh score A and B) versus controls. Dolutegravir/rilpivirine can be used without dosage adjust- ment in patients with mild or moderate hepatic impairment [8, 9], although in the EU caution is advised in those with moderate hepatic impairment [8]. Dolutegravir/rilpivirine has not been studied in patients with severe hepatic impair- ment (Child-Pugh score C) [8, 9], and in the EU it is not recommended in these patients [8].
Co-infection with hepatitis B or C virus had no clini- cally relevant effect on dolutegravir or rilpivirine exposure in population pharmacokinetic analyses [8, 9].

3.2Drug Interactions

Dolutegravir is a substrate of UGT1A1, UGT1A3, UGT1A9, CYP3A4, P-gp and BCRP [8, 9]. Therefore, co-administration of drugs that induce or inhibit these enzymes and transport- ers may result in altered dolutegravir plasma concentrations. Similarly, as rilpivirine is metabolized by CYP3A, its plasma concentrations may be altered by co-administration of CYP3A inducers or inhibitors. Concomitant use of dolutegravir/rilpi- virine with drugs that reduce the plasma concentrations of dolutegravir or rilpivirine may require caution, monitoring or dosage adjustment, with some being contraindicated (Table 1) [8, 9].
Dolutegravir has an indirect/weak inhibitory effect on CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, UGT1A1, UGT2B7, P-gp, BCRP, OAT1B1, OATP1B3, OCT1, MATE2K, MRP2, MRP4 and the bile salt export pump [8, 9]. In vitro, dolute- gravir did not induce CYP1A2, CYP2B6 or CYP3A4. Therefore, the pharmacokinetics of drugs that are sub- strates of these enzymes or transporters are not expected to be impacted by dolutegravir. Dolutegravir strongly inhibits

OCT2 and MATE1, and may increase the plasma concen- trations of drugs that require these renal transporters for excretion. Such drugs may require dosage adjustment (e.g. metformin) or are contraindicated (e.g. dofetilide; Table 1) [8, 9]. Rilpivirine is an in vitro inhibitor of P-gp, and may increase the exposure to drugs that are transported by P-gp [8]. The MATE2K transporter is also inhibited by rilpivirine in vitro; whether this has any relevance in the clinical setting is unknown [8].

4Therapeutic Efficacy of Dolutegravir + Rilpivirine

4.1SWORD Trials

The efficacy of switching virologically-suppressed, treatment-experienced adults to once-daily dolutegravir plus rilpivirine was evaluated in two identically designed, randomized, open-label, active comparator-controlled, multicentre, phase III non-inferiority trials (SWORD-1 and SWORD-2) [12]. A pooled analysis of all SWORD-1 and SWORD-2 data was predefined [12]. Some data are available as abstracts [15–18] plus posters [16, 17].
Patients included in these 148-week trials were adults (aged ≥ 18 years) who were on their first or second ART reg- imen (consisting of two NRTIs plus a third agent) and were stably suppressed (HIV-1 RNA level of < 50 copies/mL) for ≥ 6 months before screening, with no history of viro- logical failure and no known resistance to any NNRTI or INSTI [12]. Patients co-infected with hepatitis B were among those excluded. Eligible patients were randomized to switch to dolutegravir 50 mg plus rilpivirine 25 mg once daily or to continue receiving their current ART regimen for 52 weeks. Randomization was stratified by age (< 50 or ≥ 50 years), baseline third-agent class (INSTI, NNRTI or PI) and planned participation in a bone mineral density (BMD) substudy (Sect. 5.2). At baseline, the median age was 43 years; most patients were male (78%) and were receiving

Table 1 Drugs contraindicated for co-administration with dolutegravir/rilpivirine in the EU [8] and USA [9]
Reason Examples

Potential for loss of STR therapeutic effect a
Carbamazepine, dexamethasone (except as a single dose), oxcarbazepine, phenobarbital, phenytoin, PPIs (e.g. esomeprazole, lansoprazole, omeprazole, pantoprazole, rabepra- zole), rifampicin, rifapentine, St. John’s wort (Hypericum perforatum)

Potential for serious/life-threatening toxicityb
PPIs proton pump inhibitors, STR single-tablet regimen
Dofetilide

aDue to reduced rilpivirine and/or dolutegravir plasma concentrations via gastric pH increase (PPIs) or enzyme induction bDue to increased dolutegravir plasma concentrations via inhibition of OCT2 transporter

ART that included tenofovir disoproxil fumarate (tenofovir DF; 72%) or emtricitabine (68%) [12].
Switching to once-daily dolutegravir plus rilpivirine was non-inferior to remaining on the current ART regimen, as assessed by the proportion of patients with an HIV-1 RNA level of < 50 copies/mL at week 48 in the intent-to-treat (ITT) population (primary endpoint; Table 2) [12]. A sen- sitivity analysis in the pooled per-protocol population was consistent with this result (adjusted treatment difference
- 0.7%; 95% CI - 3.3 to 1.8) [12]. Findings for this param- eter were generally consistent across baseline subgroups including patient age (< 50 or ≥ 50 years), sex and race [12, 16], CD4+ cell count (< 200, 200 to < 350, 350 to < 500 or ≥ 500 cells/μL) [12], third-agent class (NNRTI, INSTI or PI) [12, 15] and geographic region [15]. With regard to other outcomes, both regimens were associated with improve- ments in CD4+ cell count and low rates of virological failure (Table 2) [12].
Some differences in treatment satisfaction, as assessed using the HIV Treatment Satisfaction Questionnaire (HIVTSQ), and symptom burden, as assessed using the Symptom Distress Module (SDM), were evident between the two regimens [17]. The HIVTSQ total score (p ≤ 0.002), life- style/ease subscore (p < 0.001) and general satisfaction/clini- cal subscore (p ≤ 0.009) were significantly better in patients who switched to dolutegravir plus rilpivirine than in those who remained on current ART at all timepoints (4, 24 and 48 weeks), except for the general satisfaction/clinical subscore at week 48 (p = 0.107) [17]. At week 48, there was a signifi- cant reduction from baseline in mean SDM symptom bother score in the ‘switch’ group compared with the ‘remain’ group

(- 1.4 vs. - 0.7; p = 0.014) [12]. Patient-reported adherence to treatment (assessed using a visual analogue scale) was 98% in both groups [12]. Health-related quality of life did not dif- fer significantly between the switch and remain groups after 48 weeks of treatment, as indicated by utility scores on the European Quality of Life 5-Dimensional 5-Level Instrument [17].

4.2Long‑Term Efficacy (100 Weeks)

Once-daily dolutegravir plus rilpivirine continued to main- tain virological suppression through 100 weeks of treatment, without increased risk of virological failure [18]. Patients who were initially randomized to switch to once-daily dolutegravir plus rilpivirine continued to receive the two- drug regimen for 100 weeks (‘early switch’ group). Virologi- cal suppression was maintained through week 100 in 89% of these patients; 3% of patients had virological non-response. Patients who were initially randomized to remain on their current ART regimen (and who had confirmed virological suppression at week 48) were switched to dolutegravir plus rilpivirine at week 52 (‘late switch’ group). Virological sup- pression was maintained through week 100 in 93% of these patients; 2% of patients had virological non-response [18].

4.3Real‑World Setting

Results from several small (n = 35–152) observational cohort studies (of prospective [19], retrospective-prospective [20] or retrospective [21, 22] design, where specified), one of which is only available as an abstract plus poster

Table 2 Efficacy of switching to once-daily dolutegravir + rilpivirine in virologically-suppressed, treatment-experienced adults with HIV-1 infection in the phase III SWORD trials

Study [12]
Regimen (no. of pts)
Plasma HIV-1 RNA level
< 50 copies/mLa (% of pts)
Virological failure (% of pts)
Median change from BL [BL]
in CD4+ cell count (cells/μL)

SWORD-1 CAR → DOL + RPV (252) 95 < 1
CAR (256) 96 < 1
Adjustedb difference (95% CI) - 0.6 (- 4.3 to 3.0)
SWORD-2 CAR → DOL + RPV (261) 94 < 1
CAR (255) 94 2
Adjustedb difference (95% CI) 0.2 (- 3.9 to 4.2)

SWORD-1 and -2 (pooled analysis)
CAR → DOL + RPV (513) CAR (511)
95c < 1d + 28 [611]
95 1 + 22 [638]

Adjustedb difference (95% CI) - 0.2 (- 3.0 to 2.5) - 0.5 (- 1.4 to 0.5)
Endpoints were assessed at week 48 in the intent-to-treat population; the US FDA snapshot algorithm was used to assess virological response BL baseline, CAR current antiretroviral regimen, DOL dolutegravir, pts patients, RPV rilpivirine, → indicates ‘switched to’
aPrimary endpoint
bAdjusted for age and BL third-agent class
cSwitching from CAR to DOL + RPV was non-inferior to continued CAR, based on a predefined non-inferiority margin of - 8% dSwitching from CAR to DOL + RPV was non-inferior to continued CAR, based on a predefined non-inferiority margin of 4%

[23], confirm the efficacy of dolutegravir plus rilpivirine in treatment-experienced patients with HIV-1 infection. In these studies, patients were switched to dolutegravir plus rilpivirine for reasons such as tolerability/toxicity, treatment simplification, drug interactions, salvage therapy or viro- logical failure [19–23]. Switching to a two-drug regimen of dolutegravir plus rilpivirine was associated with high rates of virological suppression (97–100%) [19–23]. For example, in the Dat’AIDS cohort (n = 152), the cumulative proportions of patients remaining free of confirmed virological failure and therapeutic failure at week 24 were 99 and 91%, respec- tively [22]. At week 96 in the TivEdO cohort (n = 145), the viral load was < 50 copies/mL in 95% of patients and unde- tectable in 85% of patients [20]. It should be noted that, unlike the SWORD trial populations, a large proportion of patients in the Dat’AIDS (52%) and TivEdO (81%) cohorts had a history of virological failure [20, 22].

5Tolerability of Dolutegravir + Rilpivirine

Once-daily dolutegravir plus rilpivirine was generally well tolerated when used for up to 100 weeks in virologically- suppressed, treatment-experienced adults with HIV-1 infec- tion in the phase III SWORD trials discussed in Sect. 4.1 [12, 18]. Through 48 weeks, treatment-related adverse events (AEs) occurred in 19% of patients who switched to dolute- gravir plus rilpivirine and 2% of patients who remained on their current ART regimen [12]. The most common (≥ 2% incidence) treatment-related AEs were headache (2 vs. 0%) and diarrhoea (2 vs. < 1%). Grade 3 or 4 AEs were uncom- mon with dolutegravir plus rilpivirine or current ART (6 vs. 4%), as were serious AEs (5 vs. 4%) and AEs leading to study withdrawal (3 vs. 1%) [12].
Dolutegravir plus rilpivirine had a neutral effect on the lipid profile, which may reflect the absence of a booster drug [12]. Compared with remaining on the current ART regi- men, switching to dolutegravir plus rilpivirine had no effect on serum levels of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein (HDL) cholesterol or triglycerides, and no effect on the total:HDL cholesterol ratio [12]. Switching to dolutegravir plus rilpivirine was not associated with loss of inflammatory control [12]. Changes from baseline to week 48 in inflammatory and cardiovascu- lar biomarkers (i.e. interleukin-6, C-reactive protein, soluble vascular cell adhesion molecule-1, soluble CD14, soluble CD163, fatty acid binding protein-2 and d-dimer) were simi- lar in both treatment groups (abstract plus oral presentation) [24].
Depressive disorders (including suicidal ideation and suicidal behavior) have been reported in patients receiv- ing rilpivirine or dolutegravir [9]. In the SWORD trials, treatment-related neuropsychiatric AEs (most commonly

insomnia, depression, anxiety and abnormal dreams) were reported in 26 (5%) patients who switched to dolutegravir plus rilpivirine and two (< 1%) patients who remained on their current ART regimen [12]. However, most neuropsy- chiatric AEs were grade 1 or 2 in severity. Grade 3 or 4 treatment-related neuropsychiatric AEs included grade 3 depression (n = 2), grade 3 suicidal ideation (n = 1) and grade 4 anxiety (n = 1) in the dolutegravir plus rilpivirine group and grade 4 suicide attempt (n = 1) in the current ART group. Only 1% of patients treated with dolutegravir plus rilpivirine discontinued treatment due to psychiatric disor- ders [12]. The US prescribing information indicates that the risks and benefits of dolutegravir/rilpivirine therapy should be carefully considered in patients with severe depressive symptoms [9].
Hypersensitivity reactions to dolutegravir have been observed, including rash, constitutional findings, organ dys- function and liver injury [8, 9]. Rilpivirine has been associ- ated with severe skin and hypersensitivity reactions, includ- ing cases of DRESS syndrome [9]. Dolutegravir/rilpivirine should be discontinued immediately if a patient develops signs or symptoms of a hypersensitivity reaction; monitoring of clinical status (including laboratory parameters) in these patients is also recommended [8, 9]. The manufacturer’s pre- scribing information [8, 9] should be consulted for warnings and precautions pertaining to other AEs that may occur/have occurred with components of dolutegravir/rilpivirine (e.g. hepatotoxicity with dolutegravir- or rilpivirine-containing regimens) or ART in general (e.g. immune reactivation syn- drome, osteonecrosis).
Serious cases of fetal neural tube defects involving the brain, spine and spinal cord have been reported in babies born to HIV-infected women treated with dolutegravir [25]. In an ongoing observational study, women who received dolute- gravir-containing regimens at the time of conception or early in the first trimester of pregnancy appeared to be at higher risk for fetal neural tube defects, although no cases were reported in women who started a dolutegravir-containing regimen later in pregnancy [25]. The use of dolutegravir/
rilpivirine during pregnancy is not recommended (Sect. 6) [8, 9].

5.1Renal Profile

Switching to once-daily dolutegravir plus rilpivirine was associated with more favourable changes in renal tubular function than remaining on the current ART regimen [24]. At week 48, the median changes from baseline in urine retinol-binding protein in the switch and remain groups were - 1.87 and - 0.76 nmol/L. Similarly, the median change from baseline in urine β2-microglobulin favoured the switch to dolutegravir plus rilpivirine (- 3.39 vs. 0.00 nmol/L). No change from baseline was observed in

serum cystatin C or estimated glomerular filtration rate in both groups, regardless of baseline tenofovir DF use [24].
Dolutegravir and rilpivirine have been shown to increase serum creatinine via inhibition of creatinine tubu- lar secretion, without affecting renal glomerular function [9]. Serum creatinine elevations occurred during the first 4 weeks of treatment with dolutegravir plus rilpivirine, and remained stable through week 48 [8, 9]. The mean change from baseline in serum creatinine after 48 weeks of treatment was + 0.093 mg/dL (or 8.22 μmol/L); this change was not considered to be clinically relevant [8, 9].

5.2Bone Profile

Switching to once-daily dolutegravir plus rilpivirine was associated with significant improvements in biomarkers of bone health compared with remaining on the current ART regimen [24]. At week 48, mean reductions from baseline in markers of bone resorption (osteocalcin, procollagen type 1 N-propeptide, bone-specific alkaline phosphatase and type 1 collagen C-telopeptide) were significantly (p < 0.001) greater with dolutegravir plus rilpivirine than the current ART regimen [24].
In a substudy of the SWORD trials, switching from tenofovir DF-based therapy to dolutegravir plus rilpiv- irine significantly improved BMD versus remaining on a tenofovir DF-based regimen [26]. Of the 102 patients in SWORD-1 or SWORD-2 who were receiving a stable ART regimen containing tenofovir DF and (therefore) eligible to enter the substudy, 81 had evaluable dual-energy X-ray absorptiometry (DXA) scans. At week 48, the percent- age change from baseline in total hip BMD (primary end- point) was significantly (p = 0.014) greater in patients who switched to dolutegravir plus rilpivirine (+ 1.34%) than in those who continued their current tenofovir DF-con- taining ART regimen (+ 0.05%). Similar results were seen with regard to lumbar spine BMD (+ 1.46 vs. + 0.15%; p = 0.039). These improvements were seen with dolute- gravir plus rilpivirine across all subgroups (age, sex, body mass index and baseline third-agent class) [26].
The change from baseline to week 48 in the 10-year probability of hip fracture and osteoporotic fracture (assessed by FRAX scores) was - 0.08 and - 0.12% in the dolutegravir plus rilpivirine group compared with + 0.03 and - 0.04% in the current tenofovir DF-containing ART group [26]. A ≥ 5% reduction in lumbar spine BMD was observed in 2% of patients who switched to dolutegravir plus rilpivirine and 5% of patients who remained on their current tenofovir DF-containing ART regimen [9]. Cor- responding rates of fracture (excluding fingers and toes) were 0.6 and 1.8%, respectively [9].

5.3Long‑Term Tolerability (100 Weeks)

At week 100, the incidence of grade 2–4 treatment-related AEs was low, regardless of whether patients switched imme- diately to dolutegravir plus rilpivirine (‘early switch’ group) (6% incidence over 100 weeks of therapy) or continued to receive their current ART regimen for the first 52 weeks of the study and switched to dolutegravir plus rilpivirine there- after (‘late switch’ group) (3% incidence between weeks 52 and 100) [18].

6Dosage and Administration of Dolutegravir/Rilpivirine

Oral dolutegravir/rilpivirine is indicated in the EU [8]
and the USA [9] for the treatment of HIV-1 infection in adults who are virologically suppressed (HIV-1 RNA level of < 50 copies/mL) on a stable antiretroviral regimen for ≥ 6 months with no history of virological failure and no known (or suspected [8]) resistance to dolutegravir or rilpi- virine [9] or to any NNRTI or INSTI [8]. The recommended dosage of dolutegravir/rilpivirine is one tablet (50/25 mg) taken once daily with a meal [8, 9]. During co-administration with rifabutin, an additional rilpivirine 25 mg tablet is rec- ommended. Otherwise, dolutegravir/rilpivirine should not be used in combination with other ART agents [8, 9].
The efficacy and tolerability of dolutegravir/rilpivirine in children and adolescents has not been established [8, 9]. Lower rilpivirine exposure during pregnancy has been asso- ciated with an increased risk of virological failure [9]. There are limited data regarding the use of dolutegravir/rilpivirine in pregnant women; thus, its use during pregnancy is not rec- ommended [8, 9]. Women receiving dolutegravir/rilpivirine should not breastfeed their infants [8, 9]. Local prescribing information should be consulted for detailed information regarding contraindications, warnings and precautions, drug interactions and use in special patient populations.

7Place of Dolutegravir/Rilpivirine
in the Management of HIV‑1 Infection

Many effective antiretroviral agents are available for the treatment of HIV-1 infection. Selection of an ART regimen should be individualized based on regimen-specific factors such as tolerability, drug interactions, genetic barrier to resistance, convenience and cost, as well as patient-specific factors such as baseline viral load, CD4+ cell count, HIV genotypic drug resistance and comorbidities (including preg- nancy and co-infections) [3].
For treatment-experienced patients who are already virologically suppressed on their current ART, regimen

switching may be required to avoid drug interactions, enhance tolerability or reduce/prevent toxicity, although virological suppression should be maintained [2, 3]. Regi- mens may also be simplified to improve adherence by reduc- ing pill burden and/or the frequency/difficulty of administra- tion [2, 3]. While triple agent ART regimens are generally recommended when switching virologically suppressed patients to a new regimen, there is growing evidence that two-drug regimens can maintain virological suppression [3]. The potential benefits of two-drug regimens include reduced toxicity, fewer drug interactions, better adherence, improved health-related quality of life, cost efficiency and preservation of antiretroviral agents for future use [5, 6, 27].
In this regard, data from two pivotal phase III trials (SWORD-1 and SWORD-2) demonstrated that most (95%) virologically-suppressed, treatment-experienced adults could be switched from their current ART regimen to once- daily dolutegravir plus rilpivirine, with maintenance of viro- logical suppression over 48 weeks (Sect. 4.1). Switching to a two-drug regimen of dolutegravir plus rilpivirine was also associated with high rates of virological suppression (97–100%) in real-world observational studies (Sect. 4.3). In the SWORD trials, durable virological suppression was maintained through week 100, regardless of when patients switched from their current ART regimen to dolutegravir plus rilpivirine (i.e. at baseline or at week 52) (Sect. 4.2). With the exception of a single patient who experienced virological failure with rilpivirine resistance development, resistance did not emerge, consistent with the high genetic resistance barrier of dolutegravir (Sect 2.2).
The SWORD trials excluded patients with a previous his- tory of virological failure or documented resistance [12]. Although some patients in the real-world observational studies switched to dolutegravir plus rilpivirine as salvage therapy or due to virological failure (Sect. 4.3), these stud- ies are limited by small patient numbers and short follow-up durations. Whether two-drug regimens (dolutegravir plus rilpivirine or other antiretroviral agents) can be used as maintenance therapy in patients with a previous history of virological failure remains to be determined [28].
Switching to once-daily dolutegravir plus rilpivirine was generally well tolerated in the SWORD trials (Sect. 5). Although more patients experienced treatment-emergent AEs after switching to dolutegravir plus rilpivirine than when continuing their current ART regimen (Sect. 5), this finding may have been confounded by the open-label design of the trials [12]. Of note, the more frequent occurrence of treatment-emergent AEs in the ‘switch’ group than in the ‘remain’ group has also been observed in other similarly- designed studies comparing switching with remaining on a stable (well-tolerated) ART regimen [12]. Dolutegravir plus rilpivirine significantly improved biomarkers of bone health (Sect. 5.2). This finding is not unexpected, given that many

patients were receiving ART regimens containing tenofovir DF (a drug closely associated with bone demineralization and bone loss) at baseline [12]. Indeed, in a BMD substudy, switching from a tenofovir DF-based regimen to dolutegra- vir plus rilpivirine significantly improved BMD relative to remaining on tenofovir DF-based therapy (Sect. 5.2).
Based on the results of the SWORD trials, the US Depart- ment of Health and Human Services (DHHS) and the European AIDS Clinical Society (EACS) recently updated recommendations for regimen switching in virologically suppressed, treatment-experienced patients to include the option of dual therapy with dolutegravir plus rilpivirine [2, 3]. The updated DHHS guidelines state that dolutegravir plus rilpivirine may be a reasonable option when the use of NRTIs is not desirable, and resistance to agents used in the two-drug regimen is not expected [3]. Similarly, the most recent EACS guidelines recommend a two-drug regimen of dolutegravir plus rilpivirine as a class-sparing strategy for virologically suppressed patients without chronic hepatitis B infection [2].
Fixed-dose combinations and STRs represent an impor- tant advance in ART regimen simplification [7, 29]. STRs allow for once-daily administration, making once-complex ART regimens simpler and easier for patients to take, result- ing in better adherence and improved clinical outcomes [29]. The novel two-drug regimen of dolutegravir plus rilpivirine has been formulated into a fixed-dose STR. Some STRs can result in a larger pill size than the individual components, thereby reducing tolerability for patients who have difficulty swallowing larger tablets [7]. However, dolutegravir/rilpiv- irine has the smallest tablet size among the STRs currently available in major markets, and as a result some patients may find it more convenient and easier to swallow [8].
As ART is a lifelong commitment, cost is another factor that may impact ART regimen selection [3]. Pharmacoeco- nomic data for dolutegravir/rilpivirine are currently limited. In a modelled cost-utility analysis conducted in Canada, the estimated probability of dolutegravir plus rilpivirine being more cost-effective than currently available three- or four- drug regimens was 100% at a willingness-to-pay (WTP) threshold of $85,000 per quality-adjusted life-year (QALY) gained and 92% at a WTP threshold of $200,000 per QALY gained [30]. General cost analyses have suggested that STRs are a cost-effective option in the USA in comparison to generic multiple-tablet regimens [31]. Therefore, addi- tional pharmacoeconomic analyses relating to the use of the fixed-dose dolutegravir/rilpivirine STR would be beneficial.
In conclusion, current clinical data indicate that once- daily dolutegravir plus rilpivirine is effective and well tol- erated in virologically-suppressed, treatment-experienced adults with HIV-1 infection and no history of virological failure. As the first two-drug STR, dolutegravir/rilpiv- irine provides a convenient alternative treatment option

for some adults who are already virologically suppressed on (and wish to switch from) their current ART regimen.

7.Caplan MR, Daar ES, Corado KC. Next generation fixed dose combination pharmacotherapies for treating HIV. Expert Opin Pharmacother. 2018;19(6):589–96.

Data Selection Dolutegravir/Rilpivirine: 335 records identified
8.European Medicines Agency. Juluca 50 mg/25 mg film-coated tablets: EU summary of product characteristics; 2018. http://www. ema.europa.eu. Accessed 29 Oct 2018.
9.ViiV Healthcare. JULUCA (dolutegravir and rilpivirine) tablets, for oral use: US prescribing information; 2017. https://www.fda. gov. Accessed 29 Oct 2018.

Duplicates removed 69
Excluded during initial screening (e.g. press releases; news reports; not relevant drug/indication; preclinical
study; reviews; case reports; not randomized trial) 182
Excluded during writing (e.g. reviews; duplicate data; small patient number; nonrandomized/phase I/II trials) 53
Cited efficacy/tolerability articles 15
Cited articles not efficacy/tolerability 16
Search Strategy: EMBASE, MEDLINE and PubMed from 1946 to present. Clinical trial registries/databases and websites were also searched for relevant data. Key words were dolutegravir, rilpivirine, Juluca, HIV. Records were limited to those in English language. Searches last updated 22 October 2018
10.Kobayashi M, Yoshinaga T, Seki T, et al. In vitro antiretroviral properties of S/GSK1349572, a next-generation HIV integrase inhibitor. Antimicrob Agents Chemother. 2011;55(2):813–21.
11.McCormack PL. Dolutegravir: a review of its use in the man- agement of HIV-1 infection in adolescents and adults. Drugs. 2014;74(11):1241–52.
12.Llibre JM, Hung CC, Brinson C, et al. Efficacy, safety, and tol- erability of dolutegravir-rilpivirine for the maintenance of viro- logical suppression in adults with HIV-1: phase 3, randomised, non-inferiority SWORD-1 and SWORD-2 studies. Lancet. 2018;391(10123):839–49.
13.Mehta R, Wolstenholme A, Di Lullo K, et al. Bioequivalence of a fixed-dose combination tablet of the complete 2-drug regimen dolutegravir and rilpivirine for the treatment of HIV-1 infection. Antimicrob Agents Chemother. 2018;62(9):e00748-18.
14.Elliot ER, Wang X, Singh S, et al. Increased dolutegravir peak

concentrations in people living with HIV aged 60 and over and

Acknowledgements During the peer review process, the manufacturer of dolutegravir/rilpivirine was also offered an opportunity to review this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.

Compliance with Ethical Standards

Funding The preparation of this review was not supported by any external funding.

Conflict of interest Hannah Blair is a salaried employee of Adis/
Springer, is responsible for the article content and declares no relevant conflicts of interest.

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