New Dual Combination of Dolutegravir-Rilpivirine For

Ribera: Switching to dolutegravir-rilpivirine dual therapy

Contents available at PubMed www.aidsreviews.com PERMANYER AIDS Rev. 2018;20:179-186 www.permanyer.com

New Dual Combination of Dolutegravir-Rilpivirine for Switching to Maintenance Antiretroviral Therapy Esteban Ribera © Permanyer 2018 Department of Infectious Diseases, Hospital Universitari Vall d’Hebron and Universitat Autònoma de Barcelona, Barcelona, Spain

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Abstract

Advances in antiretroviral therapy have led to dramatic improvements in survival of HIV-infected persons.  However, HIV cure remains elusive and lifelong treatment is needed. Attempts for reducing long-termof the publisher drug exposure, toxicities, and cost, while maintaining viral suppression, have led to explore whether maintenance strategies with less than triple therapy could be feasible using the newest more potent antiretrovirals. While monotherapies have failed to do so with selection of drug resistance, some dual combinations have proven its efficacy when used sequentially in patients with viral suppression under standard triple regimens. Furthermore, the advent of coformulations makes easier long-term drug adherence. Herein, we review the current experience with the new single tablet regimen of dolutegravir (DTG) and rilpivirine (RPV) (Juluca®). It is the first approved two-drug single-tablet regimen and the first dual nuc-sparing coformulation. Two randomized, non-inferiority clinical trials (SWORD-1 and -2) and five observational studies have evaluated DTG-RPV in treatment-experienced patients. Despite distinct inclusion criteria, more than 95% of patients kept plasma HIV-RNA undetectable for at least 48 weeks. Along with virological efficacy being non-inferior to triple regimens, the tolerance of DTG-RPV was good, being discontinuations due to adverse events only 0.8-7.9%. Moreover, improvements were seen in lipid profiles in patients switched from protease in- hibitors, and in renal and bone biomarkers in those switched from tenofovir disoproxil fumarate. Finally, resistance is rare failing on DTG-RPV. In summary, DTG-RPV is a novel two-drug coformulation that can be effectively and safely used in treatment-experienced patients with viral suppression if the virus is fully susceptible to both drugs. Its unique features make this drug one of the best options as long-term regimen or lifelong maintenance HIV therapy. (AIDS Rev. 2018;20:179-186) Corresponding author: Esteban Ribera, [email protected]

Key words

Dolutegravir. Rilpivirine. Two-drug regimens. Switch. Maintenance. Drug resistance. Toxicity. Adverse events. Long-term regimens.

Correspondence to: Esteban Ribera Department of Infectious Diseases Hospital Universitari Vall d’Hebron No part of this publication may be reproduced or photocopying without the prior written permission Passeig Vall d’Hebron, 119-129 Received in original form: 10/10/2018 08035 Barcelona, Spain Accepted in final form: 23/11/2018 E-mail: [email protected] DOI: 10.24875/AIDSRev.M18000026

179 AIDS Reviews. 2018;20

Introduction The SWORD trials The SWORD-1 and SWORD-2 studies are two Advances in antiretroviral therapy (ART) during the Phase III, randomized, open-label, multicenter, interna- past 30 years have transformed HIV infection in a chron- tional, and well-powered trials, identically designed to ic disease, given that viral replication is suppressed and assess the safety, tolerability, and efficacy of DTG-RPV CD4 counts preserved in most treated patients. Accord- versus current antiretroviral regimens15. Participants ingly, the life expectancy of HIV-positive persons is cur- were enrolled if they were on their first or second anti- 1 rently approaching that of HIV-negative counterparts . retroviral regimen, with stably suppressed viremia© Permanyer 2018 for However, HIV eradication is still far on the horizon and

> 6 months, with no major resistance-associated muta - . antiretroviral treatment needs to be lifelong. In this re- tions (RAMs) at the reverse transcriptase, protease, or gard, concerns on drug-related toxicities, cost, and integrase viral genes. Furthermore, patients should have 2 medication adherence have become major issues . not experienced virological failure. Randomization was In the quest to minimize drug exposure, potentially stratified by age and baseline third-agent class. Results reducing toxicities and cost, and facilitate drug adher- were pooled for both trials, including 1024 patients who  of the publisher ence, several coformulations to be taken once daily as received treatment: 513 randomly assigned to DTG-RPV single-tablet regimens (STR) have been developed as and 511 to maintain their prior antiretroviral regimen HIV therapy3. Moreover, attempts to challenge the clas- consisting of two nucleos(t)ide reverse transcriptase in- sical three-drug combination paradigm have been hibitors (NRTI) plus a third drug: a non-NRTI (NNRTI), made testing monotherapies and dual therapies with an integrase inhibitor (INI), or a PI. In the pooled analy- the newest better antiretroviral agents4,5. Acknowledg- sis at week 48, 95% had plasma HIV-RNA < 50 ing their potential lower antiviral activity, selective drug copies/mL in each group (DTG-RPV, 486/513 and con- removal has been tried in patients with the most favor- trols, 485/511), demonstrating non-inferiority (Fig. 1). able profiles such as those with viral suppression, fol- Efficacy of therapy was concordant in the pooled and lowing the principle of induction-maintenance therapy, separated studies, and by different subgroups. DTG- already well validated for other medical conditions in- RPV was also non-inferior to continue ART in the propor- cluding cancer5. At the moment, long-term regimens tion of patients with virological failure (difference −0.5%, are the most realistic successful HIV therapy. The cur- 95% confidence interval −1.4 to 0.5). Of the three par- rent most common reasons that may prone to switch ticipants with virological failures on DTG-RPV, only one ART in patients with viral suppression under standard that did not take the medication and harbored 1059771 HIV-RNA copies/mL gave resistance results while the triple regimens are regimen simplification (dosing, pill resistance profiles of the other two patients could not be burden, and dietary requirements), improve tolerability, obtained due to low viral load15. The only participant with avoid toxicities, new comorbidities, prevent or improve resistance testing data showed the K101K/E as a mix- drug interactions, and reduce costs and pregnancy. ture, with no decreased susceptibility to RPV, and with The global take-home message from switch studies no integrase resistance substitutions. Following resump- conducted so far is that monotherapies with either tion of DTG-RPV, plasma viremia became undetectable. boosted protease inhibitors (PI) or dolutegravir (DTG) Overall, DTG-RPV was well tolerated, although neu- do not provide enough antiviral coverage, being more ropsychiatric adverse events were more frequent in frequent HIV escape from anatomical or cellular com- patients randomized to receive DTG-RPV (61/513, 12%) partments, often with selection of drug resistance to than in controls (32/511, 6%). The most common were 6,7 DTG . In contrast, a few dual therapies may be con- insomnia (3% vs. 2%), depression (3% vs. 1%), anxiety 4,5,8,9 fidently used . The properties of DTG and rilpivirine (2% vs. 2%), and abnormal dreams (1% vs. 0%)15. (RPV) made it suitable candidates for a two-drug reg- These results are in agreement with the well-known imen10. The rationale was based on the long half-life safety profile of both drugs and confirm that RPV does that supports once-daily dosing without pharmacoki- not potentiate the CNS effects of DTG. Few of these netic boosters, the favorable drug-drug interaction pro- events resulted in withdrawal from either group, how-

file, the tolerability, and the resistance profile of both ever. Adverse events, leading to stopping the No part of this publication may be reproduced or photocopying without the prior written permission study drugs. At this time, the combination of DTG and RPV drugs, occurred in 17 (3%) patients in DTG-RPV group is the most promising11-14. and in 3 (1%) controls. The most common adverse

180 Ribera: Switching to dolutegravir-rilpivirine dual therapy © Permanyer 2018

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Figure 1. Efficacy of therapy in the pooled and separated SWORD 1 and SWORD 2 studies and by subgroups. Percentage indicated shows subjects with HIV-1 RNA < 50 copies/mL at week 48 by ITT FDA snapshot. ART: antiretroviral therapy, bPI: boosted protease inhibitor, DTG: dolutegravir, INI: integrase inhibitor, ITT: intent to treat, NN or NNRTI: non-nucleoside reverse transcriptase inhibitor, PI: protease inhibitor, RPV: rilpivirine. Switch Continue previous triple ART events, leading to withdrawal in the DTG-RPV group, decreased, while the total-to-HDL cholesterol ratio de- were psychiatric abnormalities in 7 (1%) and gastroin- creased minimally and equally in both arms. However, testinal disorders in 7 (1%)15. As with most switch stud- we must keep in mind that 54% of patients came from ies, the higher overall rate of withdrawal from the new or remained on NNRTIs, only 26 and 27% were on PIs regimen with respect to controls was attributed to the and 73 and 70% were on TDF. Thus, switching to DTG- fact that controls had stayed on their current regimen RPV had the same beneficial effect on lipids as main- for at least 6 months and were less likely to report new taining TDF. Data on variations in the use of lipid-low- adverse events than switched patients. ering agents in the SWORD study population were not As for the changes in lipids, cardiovascular parame- disclosed. ters, kidney function, and bone biomarkers after switch- Results up to 100 weeks have recently been reported ing to DTG-RPV, the antiretroviral treatment modality for the SWORD trials19. Briefly, DTG-RPV dual therapy taken before randomization played an important role. provided durable virologic efficacy through 2 years in Tenofovir disoproxil fumarate (TDF) was taken by 73% 89% of patients switched from baseline (early switch) of patients. Thus, not surprisingly, tubular renal function, and in 93% of patients who switched at week 52 (de- bone mineral density, and bone turnover markers were layed switch), confirming findings of the primary SWORD all significantly improved after switching to DTG-RPV16. analysis. Virological failure with emergent resistance mu- For renal function, decreases in the estimated glo- tations was low. Only 3 of 990 patients (0.3%) treated merular filtration rates were common after switching to with DTG-RPV selected NNRTI resistance mutations, DTG-RPV. This was most likely caused by the fact that whereas none developed integrase RAMs. The improve- both DTG and RPV increase serum creatinine by inhibi- ment in the renal tubular function and bone turnover tion of the transporter responsible for its tubular secre- biomarkers continued over week 100. The switch to tion17,18, without affecting the renal function. In the DTG-RPV showed no statistically significant difference in SWORD studies, cystatin C was used to calculate the surrogate biomarkers of atherogenesis and inflammation estimated glomerular filtration, and no differences were between baseline and weeks 48 and 100 compared with observed between DTG-RPV and controls15. the three- or four-drug antiretroviral therapies.

The improvement in the lipid profile in the dual ther- A patient-reported outcome study that includedNo part of this publication may be reproduced or photocopying without the prior written permission sev- apy arm compared to controls was non-statistically eral scales, such as the HIV Treatment Satisfaction significant. Total cholesterol did not vary, HDL and LDL Questionnaire, the Symptom Distress Module, and the cholesterol slightly increased, triglycerides slightly European Quality of life, were used to measure the extent 181 AIDS Reviews. 2018;20

of satisfaction of the patients switched in the SWORD 95 patients (91.3%) remained on the same regimen, 92 trials. The results were recently reported20. Overall, of them with HIV RNA < 50 copies/mL, giving an efficacy patients treated with DTG+RPV reached high levels of of 88.4% by ITT and 96.8% per protocol. Three patients treatment satisfaction and health status, supporting the had detectable viral load (532, 316, and 75 copies/mL, long-term expectations for this medication from the pa- respectively), two of them unsuppressed at baseline. The tient’s perspective. Altogether, results at 2 years highlight other two Spanish observational studies were single cen- the advantages of DTG-RPV over any other antiretroviral ter, including 38 and 35 patients, respectively25,26. Both regimen as maintenance therapy in terms of both effi- studies included patients with previous multiple virological

cacy and safety19,20. failures, but without resistance mutations to INI or© Permanyer 2018 RPV. Treatment was safe and highly efficacious. > 90% were

. Observational switch studies virologically suppressed by ITT at week 48. None of the with DTG-RPV virologically suppressed patients at baseline experienced viral rebound at week 48. Only one patient in each study In the SWORD studies and in almost all switch discontinued the medication due to adverse events. Over- clinical trials in virological suppressed patients, the all, improvements in lipid profiles were observed in more  inclusion/exclusion criteria have been very restrictive, than half of patients who switched from boosted PI-conof the publisher - generally only for patients without previous virological taining regimens in most of these observational studies. failures and without RAMs. In real life, the characteris- The good results from the studies discussed above tics of patients who need to switch ART are quite dif- using DTG-RPV in treatment-experienced patients with ferent than in clinical trials. previous virological failures attracted much attention in Several cohorts studied this combination in the clinical the real clinical setting. However, they were limited by setting (Table 1). Italian researchers were the first to small size populations, lack of controls, short observa- assess in a planned manner and testing a larger popu- tional periods, and retrospective design. lation the efficacy and safety of the dual DTG-RPV com- bination through 96 weeks21. In the TivEdo study, 145 Major switch studies with the newest HIV-infected patients were switched to DTG-RPV and antiretroviral combinations in virologically followed for a median of 101 weeks. 81% of patients suppressed patients have had one or more virological failures, with multiple resistance mutations, and 15% were viremic at the time Two strategies have been explored for making eas- of switching (Table 1). In spite of that, 97.2% had unde- ier lifelong HIV therapy using long-term regimens. The tectable viremia at week 48 and 95.2% at week 96. Only first evaluated the benefit of switching to drug cofor- one poorly adherent patient failed virologically with se- mulations (STR), whereas the second evaluated wheth- lection of E138Q and Y181C, without RAMs at the inte- er one drug could be taken off from standard triple grase region. The regimen was very well tolerated and combinations. mean metabolic parameters improved over time. Subsequently, in the Dat’AIDS study22, French authors Switch to the newest STR examined 152 treatment-experienced patients followed for a median of 36 weeks, all with viral suppression, Besides DTG/RPV, newest complete STR available and switched to DTG-RPV. At week 24, 90.5% (105/116) endorsed by well-powered randomized clinical trials are remained free of therapeutic failure and 99.1% (115/116) RPV/FTC/TAF (Odefsey), DRV/c/FTC/TAF (Symtuza), free of virological failure. At the end of the study, three DTG/3TC/ABC (Triumeq), EVG/c/FTC/TAF (Genvoya), patients (2%) experienced virological failure and 7.9% and BIC/FTC/TAF (Biktarvy). Figure 2 summarizes the (12/152) stopped the medication due to side effects. main features of studies that have assessed the efficacy In Spain, the relatively large HIV population along with and safety at 48 weeks of switching to those contemporary economic restrains has pushed clinicians to explore in- STR in treatment-experienced patients stable sup- novative and cheaper antiretroviral regimens23. In this pressed27-32. Rates of viral suppression > 90% were scenario, three smaller Spanish studies tested DTG-RPV achieved with all these regimens, being always non-inferi-

as maintenance in treatment-experienced patients or to controls that kept on their prior regimens dosedNo part of this publication may be reproduced or photocopying without the prior written permission with (Table 1). The DORIVIR study had multicenter contribution24 more than one pill daily or with older STR. < 2% of patients and included 104 patients switched to DTG-RPV, 82 (78%) had virological failure and the selection of emergent RAMs with virologic suppression at baseline. At 24 weeks, was very rare (< 0.3%). 182 Ribera: Switching to dolutegravir-rilpivirine dual therapy

In the STRIVING study33, after 24 weeks, both treat- ment arms (early switch to DTG/3TC/ABC and continue the previous ART) were treated with DTG/3TC/ABC. In the early switch arm, 83% of subjects maintained viral 0 (2.6) (7.9) suppression at week 48 and 4% discontinued treat- 1 (2.9) 1 2 (1.4) 12 ment due to adverse events. As originally shown in studies that assessed switch- adverse events (n,adverse %) Discontinuation due to to due Discontinuation ing from PIs to more convenient antiretrovirals, prior

episodes of treatment failure and/or selection of© Permanyer 2018 drug

RAMs could impair the success of the simplest regi -

. mens with low genetic barrier34-36.

Switch to dual therapy regimens Treatment emergent emergent Treatment resistance ‑ Baseline RAMs 1 (138Q, 181C) 2 no RAMs 2 no 1 resupressed genotype) (no ‑ Removing one drug from a successful triple combina-  of the publisher tion might reduce toxicities, costs, potentially harmful drug interactions, and save drugs for the future. Different dual regimen combinations have been evaluated in viro- 0 1 (2.8) 1 (0.7) 3 (2.0) 3 (2.9) logically suppressed patients. In addition to DTG-RPV, only combinations of a PI and lamivudine have demon- > 50 copies/mL (%)> 50

Virological failures VL VL failures Virological strated non-inferiority as compared with the respective PI and two NRTI in sufficiently powered randomized

A < A < clinical trials and in a meta-analysis of aggregated 37-41 RN

‑ data (Fig. 3). In the randomized trials switching to PI + lamivudine rates of viral suppression, > 84% were achieved with all these regimens, being always non-in- 91.4% at w 48 97.2% at w 24 at 97.2% w 48 at 97.2% w 96 at 95.2% 92.1% at w 48 at 92.1% 90.5% at w 24 at 90.5% 88.4% at w 24 at 88.4% 50 copies/mL (ITT)50 Plasma HIV Plasma ferior to continue PI + 2 NRTI. Between 1.5 and 4.2% of those patients had virological failure and only one patient with dual therapy with LPV/r + 3TC (0.19%) and two with triple therapy (0.36%) developed RAMs to NRTI. These studies included only patients without previous virologi- cal failures. In a randomized trial with patients sup- pressed on triple therapy and with previous virological failures and resistance mutations and baseline resis- ilpivirine r

‑ tance to lamivudine, PI plus lamivudine was superior to PI monotherapy42. Furthermore, the dual therapy with : 36 weeks : 101 weeks up ‑ NA < 50 c/mL: 100% < 50 c/mL: NA NA < 50 c/mL: 85% NA < 50 c/mL: NA < 50 c/mL: 100% < 50 c/mL: NA 78% < 50 c/mL: NA DTG and lamivudine has shown promising results in a up R R R R ‑ RNA < 50 c/mL: 91% ‑ ‑ ‑ ‑ ‑ pilot randomized trial43, not sufficiently powered, and in a prospective, non-comparative study44 (Fig. 3). Plasma HIV Plasma VF previous All 4.3 PI 2 NNRTI 3.8 NRTI RAMs Median Median previous ART regimens: 5 regimens: ART Median previous classes RAMs: 37%, with 14% to three Baseline study population study Baseline ≥ 1 Previous VF: 81% VF: ≥ 1 Previous 11% (4% NNRTI 46%, NRTI RAMs: 52% PI RPV), follow Mean Plasma HIV Plasma Plasma HIV Plasma 52% VF: ≥ 1 Previous follow Median VF allowed Previous HIV Plasma Future prospects for DTG-RPV

The advent of the coformulation of DTG and RPV 35 Plasma HIV 38 145 152 104 (Juluca®) should be viewed as a major step in the path

Patients (n) for optimizing ART using long-term regimens. Both mol- associated mutations, NRTI: nucleos(t)ide reverse transcriptase inhibitors, RPV: rilpivirine, ART: antiretroviral therapy antiretroviral ART: rilpivirine, RPV: inhibitors, transcriptase reverse nucleos(t)ide NRTI: mutations, associated ‑

24 ecules are second-generation within their respective 26 22 21

25 drug classes, with potent antiviral inhibitory effect and et al. et al. et al.

retention of activity in the presence of RAMs withinNo part of this publication may be reproduced or photocopying without the prior written permission their et al. drug families9-14,17,45,46. Moreover, their safety profiles iaz Revuelta et al. Capetti Capetti Palacios Gantner Gantner (Ti’vedo) (Dat’AIDS) (DORIVIR) D Cohort study Cohort are good, with a low proportion of patients stopping RAMS: resistance RAMS: Table 1. dolutegravir with studies observation Switching therapy due to adverse events, mostly occasional neu- 183 AIDS Reviews. 2018;20 © Permanyer 2018

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Figure 2. Efficacy and safety of therapy by regimen from pivotal Phase III switching studies with contemporary single-tablet regimens. Percentage indicated shows subjects with HIV-1 RNA < 50 copies/mL at week 48 by ITT FDA snapshot. 3TC: lamivudine, ABC: abacavir, ART: antiretroviral therapy, bATV: boosted atazanavir, BIC: bictegravir, bPI: boosted protease inhibitor, C: cobicistat, DRV/r: darunavir/ritonavir, DTG: dolutegravir, EFV: efavirenz, EVG/c: elvitegravir/cobicistat, FTC: emtricitabine, INI: integrase inhibitors, ITT: intent to treat, NN: non-nucleoside reverse transcriptase inhibitor, NRTI: nucleos(t)ide reverse transcriptase inhibitor, PI: protease inhibitor, RPV: rilpivirine, TAF: tenofovir alafenamide, TDF: tenofovir disoproxil fumarate. Switch Continue previous triple ART

ropsychiatric effects already well described for DTG46. From the Phase III and observational studies report- Furthermore, DTG and RPV as individual drugs and ed so far with DTG-RPV that included a total of 987 Juluca® as complete STR are the smallest tablets avail- subjects, 95% of patients were virologically suppressed able and can be particularly useful for patients who by ITT at 48 weeks of treatment. Only 11 (1.1%) devel- have difficulty swallowing larger pills47. oped virologic failure (HIV RNA > 50 copies/mL) main- Before considering a widely use of DTG-RPV, some ly due to poor drug adherence. Five of them had viral considerations must be kept on mind. First, patients resistance testing with one (TIVEDO) that selected should be on viral suppression under another antiret- E138Q and Y181C RAMs, with extensive NNRTI roviral regimen before starting the medication. Second, cross-resistance (only sparing doravirine) and one that patients should not have suffered prior treatment fail- selected K101K/E (SWORD) with no decreased sus- ures or at least not selected resistance to DTG or RPV. ceptibility to RPV (1.2-fold change), further resup- Furthermore, information confirming the absence of pressed still taking DTG-RPV. Of note, no resistance to these mutants before patients began any ARV would DTG was selected in any of these studies15,20,21,23-25. be worthy, especially for excluding the chances of Dual therapy with DTG and RPV, available as STR, originally transmitted NNRTI-resistant strains. Third, demonstrates a similar high efficacy for maintaining neither RPV nor DTG is likely to have a clinically rele- virological suppression than the newest triple therapy vant effect on the exposure of medicinal products me- STR (Fig. 2). The combination is well tolerated and tabolized by CYP450 enzymes, and therefore, DRT- metabolic friendly, accordingly to the characteristics of RPV would exhibit a low drug-drug interaction profile. the individual drugs. A potential benefit of the dual Fourth, the need of prolonged therapy with proton- therapy with DTG-RPV compared to the triple-drug STR pump inhibitors and the inability to take the treatment is to minimize the long-term exposure to antiretroviral with food limits the use of RPV. Finally, DTG-RPV should drugs. No part of this publication may be reproduced or photocopying without the prior written permission not be used in subjects with chronic hepatitis B and Randomized trials have also shown non-inferiority of there is not experience enough to use it in pregnant switching to PI and lamivudine compared to continue women. with the respective PI and two NRTIs in virologically 184 Ribera: Switching to dolutegravir-rilpivirine dual therapy © Permanyer 2018

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Figure 3. Efficacy and safety of therapy from major switching studies with dual antiretroviral regimens. Percentage indicated shows subjects with HIV-1 RNA < 50 copies/mL at week 48 by ITT. 3TC: lamivudine, ART: antiretroviral therapy, ATV: atazanavir, bPI: boosted protease inhibitor, DRV/r: darunavir/ritonavir, DTG: dolutegravir, FTC: emtricitabine, INI: integrase inhibitors, ITT: intent to treat, LPV: lopinavir, NN: non-nucleoside reverse transcriptase inhibitor, NRTI: nucleos(t)ide reverse transcriptase inhibitor, RPV: rilpivirine, TAF: tenofovir alafenamide, TDF: tenofovir disoproxil fumarate. Switch Continue previous triple ART suppressed patients without RAMs (Fig. 3); however, Accordingly, switch to DTG-RPV coformulation would dual therapy with DTG-RPV has some advantages: has minimize concerns about cardiovascular, kidney, and demonstrated non-inferiority as compared to continue bone toxicities associated with long-term exposure to from a PI-, an NNRTI-, or an INI-based regimens, a ART and/or aging. Altogether, DTG-RPV must be complete STR is available, and can avoid the drug- viewed as one of the currently preferred long-term HIV drug interactions and in even some metabolic side regimens. effects of boosted PIs. In view of the future availability of long-acting anti- References retroviral therapies that would include cabotegravir, 1. Teeraananchai S, Kerr SJ, Amin J, Ruxrungtham K, Law MG. Life expec- which is a DTG analog, and RPV long acting, the cur- tancy of HIV-positive people after starting combination antiretroviral ® therapy: a meta-analysis. HIV Med. 2017;18:256-66. rent advent of Juluca as long-term regimen may be 2. Fernandez-Montero JV, Eugenia E, Barreiro P, Labarga P, Soriano V. viewed in some patients as an intermediate step Antiretroviral drug-related toxicities-clinical spectrum, prevention, and 48 management. Expert Opin Drug Saf. 2013;12:697-707. forward it . In this regard, patients suspected or known 3. Llibre JM, Clotet B. Once-daily single-tablet regimens: a long and winding road to excellence in antiretroviral treatment. AIDS Rev. 2012;14:168-78. to be non-adherent should probably be deferred from 4. Colasanti J, Marconi VC, Taiwo B. Antiretroviral reduction: is it time to starting daily oral DTG-RPV and wait for the long-acting rethink the unthinkable? AIDS. 2014;28:943-7. 5. Soriano V, Fernandez-Montero JV, Benitez-Gutierrez L, et al. Dual anti- medications that would help to solve most adherence retroviral therapy for HIV infection. Expert Opin Drug Saf. 2017;16:923-32. 6. Arribas JR, Girard PM, Paton N, et al. Efficacy of protease inhibitor challenges, provided that patients attend their planned monotherapy vs. Triple therapy: meta-analysis of data from 2303 pa- visits for drug administration. tients in 13 randomized trials. HIV Med. 2016;17:358-67. 7. Blanco JL, Marcelin AG, Katlama C, Martinez E. Dolutegravir resistance muta- tions: lessons from monotherapy studies. Curr Opin Infect Dis. 2018;31:237-45. Conclusion 8. Rossetti B, Montagnani F, De Luca A. Current and emerging two-drug approaches for HIV-1 therapy in ART-naïve and ART-experienced, viro- logically suppressed patients. Expert Opin Pharmacother. 2018;19:713-38. 9. Boswell R, Foisy MM, Hughes CA. Dolutegravir dual therapy as mainte- Randomized clinical trials and observational studies nance treatment in HIV-infected patients: a review. Ann Pharmacother. demonstrate that DTG-RPV is a switch regimen for 2018;52:681-9. 10. Capetti AF, Astuti N, Cattaneo D, Rizzardini G. Pharmacokinetic drug many patients with viral suppression under effective evaluation of dolutegravir plus rilpivirine for the treatment of HIV.No part of this publication may be reproduced or photocopying without the prior written permission Expert Opin Drug Metab Toxicol. 2017;13:1183-92. triple antiretroviral combinations. Benefits are 11. Sun HY, Chang SY, Hung CC. Dolutegravir-rilpivirine coformulation. Curr generally seen in the lipid profile, renal function, bone Opin HIV AIDS. 2018;13:320-5. 12. Capetti AF, Cossu MV, Paladini L, Rizzardini G. Dolutegravir plus rilpivirine dual reabsorption, and fewer drug-drug interactions. therapy in treating HIV-1 infection. Expert Opin Pharmacother. 2018;19:65-77. 185 AIDS Reviews. 2018;20

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