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Commentary

The Meandrous Route of Rilpivirine in the Search for the Miraculous Drug to Treat HIV Infections

by
Erik De Clercq
Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, B-3000 Leuven, Belgium
Viruses 2025, 17(7), 959; https://doi.org/10.3390/v17070959
Submission received: 5 June 2025 / Revised: 2 July 2025 / Accepted: 4 July 2025 / Published: 8 July 2025
(This article belongs to the Section Viral Immunology, Vaccines, and Antivirals)
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Abstract

Rilpivirine (RPV, R278474) was highlighted in 2005, two years after the death of Dr. Paul Janssen, as the ideal non-nucleoside reverse transcriptase inhibitor (NNRTI) to treat HIV infections. For this purpose, it was subsequently combined with tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), darunavir (boosted with ritonavir or cobicistat) or dolutegravir. Its wide-spread use is thanks to its combination with cabotegravir (CAB) in the form of a long-acting intramuscular injection once per month (QM), later twice per month (Q2M), for the treatment of adults, later extended to adolescents and pregnant women, with HIV infections. The long-acting CAB plus RPV should not be administered in patients treated with rifampicin or rifabutin, patients with virological failure or patients with resistance to CAB or RPV, or patients with hepatitis B virus (HBV) infection. Long-acting CAB+RPV may lead to pain at the site of injection which would diminish over time.

1. Introduction

To commemorate the untimely death of Dr. Paul A.J. Janssen on 11 November 2003, his colleagues postulated that an ideal anti-HIV drug should (i) be highly active against wild-type and mutant HIV without allowing breakthrough; (ii) have high oral bioavailability and long elimination half-life, allowing once-daily oral treatment at low doses; (iii) have minimal adverse effects; and (iv) be easy to synthesize and formulate [1]. The new diarylpyrimidine (DAPY) non-nucleoside reverse transcriptase inhibitor (NNRTI) R278474 (rilpivirine) was thought to fulfill these criteria. The search for this ideal anti-HIV drug started in 1987, yielding first in 1990 TIBO (tivirapine) [2] and, following a meandrous route, successively α-APA, ITU, DATA, and eventually the DAPYs R147681, R165335 (TMC125), and R278474 (RPV, rilpivirine) [1]. As a closely related analog of rilpivirine, TMC125 was found to be highly effective against wild-type and drug-resistant HIV-1 variants [3,4]. TMC25 displays a high genetic barrier to the development of resistance [5].

2. Chemical Structure

The chemical structure of rilpivirine (R278474) is depicted in Figure 1. How it fits within the NNRTI-binding pocket can be seen in Figure 2. How the DAPYs, i.e., TMC125, should be viewed in the scope of other NNRTIs has been further documented by Pauwels [6]. The synthesis of novel DAPY analogs has been optimized by Guillemont et al. [7], and through a series of process optimizations, a practical synthesis method of rilpivirine has been developed, which would be easy to scale up with higher yield and shorter reaction time [8]. The active rilpivirine should be its E-isomer, whereas the Z-isomer should be considered as an impurity [9].

3. Clinical Use of Rilpivirine

In resource-limited settings (RLS) where integrase inhibitors are not affordable, rilpivirine-based regimens are a good alternative option for HIV-infected individuals who cannot tolerate first-line NNRTI or PI (protease inhibitor) regimens [10].
Rilpivirine is active against wild-type and NNRTI-resistant HIV-1 [11]. Long-acting (LA) injectable RPV has been recommended for pre-exposure prophylaxis (PrEP) against HIV [12,13,14]. As to its metabolism, both the 2-hydroxymethyl derivative and the N-glucuronide of RPV have been identified [15]. Although RPV has been claimed as leading to a low risk of resistance mutations [16], more recent data revealed both E138A and E138G mutations over a longer period and a larger patient population [17]. RPV would not have any adverse effects on pregnancy outcomes [18].
RPV has been postulated to possess activity against acute myeloid leukemia (AML), due to an inhibition of Aurora A kinase [19]. According to Pereira and Vale [20], RPV should have potential for cancer treatment. RPV has also been reported to attenuate liver fibrosis through a selective STAT1-mediated apoptosis in hepatic stellate cells (HSC) [21].
RPV might also offer a possible repurposing in the prevention and/or treatment of Zika virus (ZIKV) replication [22]. It would not interfere with the pharmacokinetics of methadone [23]. However, it may interact with the metabolism of rifapentine [24]; thus, co-administration of rilpivirine and rifapentine should be avoided.

4. Combination of Rilpivirine (RPV) with Tenofovir Disoproxil Fumarate (TDF) or Tenofovir Alafenamide (TAF)

Switching to TDF/FTC (emtricitabine)/RPV from TDF/FTC/EFV (efavirenz) was non-inferior in terms of maintaining complete viral suppression at 24 weeks [25,26] (Figure 3). The use of TDF/FTC/RPV for HIV post-exposure prophylaxis has also been recommended by Chauveau et al. [27]. The switch from TDF to TAF further generated weight gain [28]. TAF/FTC/RPV is non-inferior in efficacy but shows less of a decline in bone mineral density and renal function, as compared to TDF/FTC/RPV [29]. A gradually higher prevalence of metabolic syndrome among people living with HIV (PLWH) were noted with changes from RPV/TDF/FTC to RPV/TAF/FTC but plateaued beyond 2 years. However, fewer drugs for dyslipidemia, diabetes, and hypertension were prescribed within the first year after switching to RPV/TAF/FTC [30].
In macaques infected with SHIV (simian/human immunodeficiency virus), oral FTC/TAF and long-acting cabotegravir/rilpivirine achieved an ultra-long-acting antiviral activity that persisted after treatment cessation [31].

5. Combinations of Rilpivirine (RPV) with Darunavir (Boosted with Either Ritonavir or Cobicistat) or Dolutegravir

Dual therapy of RPV with boosted-darunavir (bDRV) proved to be effective and safe in patients with advanced HIV infection [32] (darunavir was boosted with either ritonavir or cobicistat). The combination of RPV with darunavir boosted with ritonavir has also shown its effectiveness in patients with a long-lasting HIV infection [33]. The finding that darunavir/ritonavir in combination with RPV was successful in suppressing HIV infection was also found from the 96-week results of Di Cristo et al. [34]. The combination of RPV plus cobicistat-boosted darunavir effected a sustained virological suppression, demonstrated by Maggiolo et al. [35]. The combination of abacavir/lamivudine plus RPV for both the first-line and maintenance therapy of HIV-1 infections was advocated by Ho et al. [36] and Lim et al. [37].
The use of dolutegravir (DTG) (Figure 4) plus RPV as a dual regimen in virologically suppressed HIV-1 infected patients was first mentioned by Casado et al. [38]. DTG plus RPV provided maintenance of virological suppression [39]. The combination of DTG+RPV sustained suppression of HIV-1 associated with a low frequency of virological failure and a favorable safety profile [40]. The combination of DTG plus RPV may move to a first-line therapy in some lower- and middle-income countries [41]. Durable suppression and low rate of virological failure for 3 years have been attributed to the combination of DTG+RPV [42]. Mehta et al. [43] concluded that the DTG+RPV switch was a safe and effective treatment of HIV infections. As a single-tablet regimen (STR), the combination of RPV+DTG would be a cost-effective and long-lasting treatment strategy for PLWH [44,45]. The combination of RPV+DTG would offer some benefits beyond viral suppression, as this combination would slightly improve the immune status during the first 48 weeks after switching, in terms of both CD4+ T-cell and CD8+ T-cell counts, with persistently high rates of viral control [46]. No consistent pattern of change in biomarkers post-switch to RPV+DTG was observed through weeks 48 and 148 in SWORD-1/SWORD-2 while maintaining virologic suppression [47]. Both the combinations DTG+RPV and DTG+3TC (lamivudine) would be efficacious and safe in curtailing virus replication in people living with HIV (PLWH) [48,49]. In recent years (2023–2024), several studies have repeatedly highlighted the effectiveness of RPV+DTG in the treatment of HIV infections [50,51,52].

6. Combination of Rilpivirine (RPV) with Cabotegravir (CAB): 2019–2021

Long-acting rilpivirine (RPV) injected intramuscularly once 4- or 8-weekly together with cabotegravir (CAB) (Figure 5) in the treatment of HIV infection was first launched in 2019 [53]. Co-administration of rifampicin (for treatment of tuberculosis) was predicted (based on pharmacokinetic modeling) to result in subtherapeutic concentrations of both RPV and CAB [54]. That notion that monthly injections of long-acting RPV+CAB were non-inferior to standard oral therapy (i.e., dolutegravir-abacavir-lamivudine) was subsequently shown in the ATLAS and FLAIR studies [55,56]. The plasma concentrations of RPV and CAB in the FLAIR study are depicted in Figure 6. The ATLAS and FLAIR trials were hailed as important milestones in the development of HIV therapeutics [57]. The potential of a monthly injectable option for people living with HIV was again emphasized by Murray et al. [58] and Rizzardini et al. [59]. The combination of RPV plus CAB has been approved as Cabenuva™ [60]; it is available at two dosages: CAB (400 mg)+CPV (600 mg) or CAB (600 mg)+RPV (900 mg) [61]. The dual regimen of long-acting RPV and CAB achieved therapeutic concentrations in the cerebrospinal fluid of HIV-infected subjects [62]. Long-acting RPV+CAB has been recommended for use in routine clinical practice; its rate of confirmed virological failure (CVF) has been estimated at about 1% [63]. RPV+CAB is the first complete long-acting injectable regimen for the treatment of HIV-1 infection [64]; it is widely preferred over oral therapy with RPV+CAB [65].

7. Combination of Rilpivirine (RPV) with Cabotegravir (CAB): 2021–2023

The 96-week results reaffirm the 48-week results showing long-acting rilpivirine (RPV) and cabotegravir (CAB) to be non-inferior compared with continuing a standard care regimen in adults with HIV-1 for the maintenance of viral suppression (phase 3 FLAIR study) [66]. This was further confirmed with long-acting RPV and CAB dosed every 2 months (ATLAS–2M study) [67]. CAB is mainly metabolized by uridine diphosphate-glucuronosyl transferase (UGT1A1), and RPV is mainly metabolized by cytochrome P450 CYP3A4; therefore, these agents are susceptible to drug–drug interactions (DDIs) [68]. From the FLAIR, ATLAS and subsequent studies, CAB and RPV have emerged as the first long-acting injectable agents for the treatment of HIV infection [69]. Implementation of these data should be further extended to adolescents, pregnant women, and those with barriers to medication adherence [70].
Few confirmed virological failures (CVF) have been observed [71]: the combination of at least two of the following factors, HIV-1 subtype A6/A1, a body mass index (BMI) of ≥30 kg/m2, and RPV resistance-associated mutations, was associated with an increased risk of CVF at week 48. The RPV resistance mutations are depicted in Figure 7 [72]. Reduced RPV susceptibility was observed across HIV-1 subtypes B and A1 with resistance-associated mutations K101E or E138K [73]. In another study (in Botswana), the pre-existing RPV-associated mutation E138A was observed [74].
The most common adverse effect in several studies with long-acting RPV+CAB was injection site reactions (ISR, i.e., pain) [75], which improved/resolved with subsequent administrations. How the ISRs evolved over time are depicted in Figure 8 [76]. ISRs should not be ignored as they may limit utility for many patients [77].
The acceptability of different long-acting CAB-RPV dosing schedules should be evaluated in adolescents and perinatally infected patients living with HIV [78]. This evaluation should also be extended to pregnant women [79]. Long-acting RPV and CAB nanosuspensions could be considered for pediatric HIV antiretroviral therapy [80]. Dosages of RPV and CAB should be adjusted (i.e., increased) if combined with rifampicin or rifabutin [81].
Long-acting CAB+RPV has been touted as an amazing treatment strategy for HIV [82]. Its cost-effectiveness has been repeatedly discussed [83,84,85]. Adherence to scheduled dosing visits is strongly recommended to maintain virological suppression with CAB+RPV long-acting injectable therapy and to prevent loss of virological control and possible resistance development [86].

8. Combination of Rilpivirine (RPV) with Cabotegravir (CAB): 2024–2025

Those that chose community delivery of the long-acting combination of rilpivirine (RPV) plus cabotegravir (CAB) found it highly acceptable and feasible [87]. In people with HIV (PWH) initiating long-acting injectable CAB+RPV with initial viremia, 48-week viral suppression (<50 copies/mL) was seen in 92% [88]. Real-world data revealed a few virological failures, which were not associated with the acquisition of resistance mutations [89].
Long-acting CAB+RPV was recommended for use in PWH with viremia who were unable to achieve suppression with oral antiretroviral therapy due to suboptimal medication adherence [90]. Long-acting therapy may enhance immune recovery, as attested by an increased CD4+/CD8+ ratio [91]. At-home administration of long-acting CAB+RPV may be comparably safe, effective, and satisfactory, relative to in-clinic administration [92]. For adult participants it would not matter whether the intramuscular injections are administered in the vastus lateralis (lateral thigh) muscles [93] or deltoid muscles [94].
Real-world data would not demonstrate differences in virological outcomes for individuals with body mass index (BMI) ≥ 30 kg/m2 as compared to those with BMI < 30 kg/m2 [95]. Long-acting CAB+RPV was efficacious and well tolerated regardless of the baseline BMI category [96].
Long-acting CAB+RPV given every 4 weeks or 8 weeks could also be recommended in virologically suppressed adolescents aged 12 years and older and weighing at least 35 kg [97].
In the US south among reproductive-aged women, nearly two-thirds reported willingness to try long-acting CAB+RPV antiretroviral therapy [98] (Figure 9).
Long-acting CAB plus RPV dosed once every 2 months (Q2M) was successfully implemented across a range of European locations [99]. This regimen may be beneficial for people with HIV (PWH) who are unable to attain viral suppression on oral therapy [100]. Some cases who were eligible for long-acting CAB/RPV experienced virological failure (VF) in this real-world setting [101]. Across 12 UK clinics, VF occurred in 0.7%, and 6% discontinued CAB+RPV [102]. Long-acting CAB/RPV should also be considered in African treatment programs [103], although individuals with hepatitis B virus (HBV) infection will have to be excluded from this wide-spread implementation [104].
The CAB/RPV implementation study in European locations (five European countries), called the CARISEL study, is illustrated in Figure 10 [105]. The long-acting CAB plus RPV yielded high treatment satisfaction, although participants reported moderate injections site pain, which improved with time [106]. CAB+RPV is the first injectable long-acting combination therapy to be licensed for the treatment of HIV-1 infection. Its suitability has been amply demonstrated [107,108]. Its durability is strongly anticipated.

9. Conclusions

When rilpivirine (RPV) was initially identified as an ideal anti-HIV compound to be used for the treatment of HIV-1 infections in people living with HIV, it could hardly be predicted that it would find its major indication for the long-acting combination with the integrase inhibitor cabotegravir (CAB). The first question raised is why RPV was almost routinely combined with CAB and not other HIV integrase inhibitors such as dolutegravir (with which it was combined in some trials) or bictegravir (which had never been selected for such combinations). The use of long-acting CAB+RPV has been limited to HIV-1 infections with virally suppressed HIV RNA (<50 copies/mL), patients without the history of virological failure (subsequently to the use of other anti-HIV drugs) or resistance to either CAB or RPV, and, obviously, patients not co-infected with hepatitis B virus (HBV).

Funding

This research received no external funding.

Acknowledgments

Dedicated to the memory of Paul A.J. Janssen, discoverer of rilpivirine, who passed away on 11 November 2003. I thank Myriam Cornelis for her proficient editorial assistance.

Conflicts of Interest

The author declares no conflict of interest.

References

  1. Janssen, P.A.; Lewi, P.J.; Arnold, E.; Daeyaert, F.; de Jonge, M.; Heeres, J.; Koymans, L.; Vinkers, M.; Guillemont, J.; Pasquier, E.; et al. In search of a novel anti-HIV drug: Multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile (R278474, rilpivirine). J. Med. Chem. 2005, 48, 1901–1909. [Google Scholar] [CrossRef]
  2. Pauwels, R.; Andries, K.; Desmyter, J.; Schols, D.; Kukla, M.J.; Breslin, H.J.; Raeymaeckers, A.; Van Gelder, J.; Woestenborghs, R.; Heykants, J.; et al. Potent and selective inhibition of HIV-1 replication in vitro by a novel series of TIBO derivatives. Nature 1990, 343, 470–474. [Google Scholar] [CrossRef] [PubMed]
  3. Das, K.; Clark, A.D., Jr.; Lewi, P.J.; Heeres, J.; De Jonge, M.R.; Koymans, L.M.; Vinkers, H.M.; Daeyaert, F.; Ludovici, D.W.; Kukla, M.J.; et al. Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants. J. Med. Chem. 2004, 47, 2550–2560. [Google Scholar] [CrossRef]
  4. Andries, K.; Azijn, H.; Thielemans, T.; Ludovici, D.; Kukla, M.; Heeres, J.; Janssen, P.; De Corte, B.; Vingerhoets, J.; Pauwels, R.; et al. TMC125, a novel next-generation nonnucleoside reverse transcriptase inhibitor active against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus type 1. Antimicrob. Agents Chemother. 2004, 48, 4680–4686. [Google Scholar] [CrossRef]
  5. Vingerhoets, J.; Azijn, H.; Fransen, E.; De Baere, I.; Smeulders, L.; Jochmans, D.; Andries, K.; Pauwels, R.; de Béthune, M.P. TMC125 displays a high genetic barrier to the development of resistance: Evidence from in vitro selection experiments. J. Virol. 2005, 79, 12773–12782. [Google Scholar] [CrossRef] [PubMed]
  6. Pauwels, R. New non-nucleoside reverse transcriptase inhibitors (NNRTIs) in development for the treatment of HIV infections. Curr. Opin. Pharmacol. 2004, 4, 437–446. [Google Scholar] [CrossRef] [PubMed]
  7. Guillemont, J.; Pasquier, E.; Palandjian, P.; Vernier, D.; Gaurrand, S.; Lewi, P.J.; Heeres, J.; de Jonge, M.R.; Koymans, L.M.; Daeyaert, F.F.; et al. Synthesis of novel diarylpyrimidine analogues and their antiviral activity against human immunodeficiency virus type 1. J. Med. Chem. 2005, 48, 2072–2079. [Google Scholar] [CrossRef]
  8. Zhang, T.; Yang, J.; Zhou, Z.; Fu, Z.; Cherukupalli, S.; Kang, D.; Zhan, P.; Liu, X. The development of an effective synthetic route of rilpivirine. BMC Chem. 2021, 15, 22. [Google Scholar] [CrossRef]
  9. Mhaske, D.K.; Kumbhar, A.S. Simultaneous quantification of (E) and (Z) isomers of rilpivirine and four degradation products in bulk and tablets by reversed-phase ultra-high-performance liquid chromatography and confirmation of all by molecular weight. J. Sep. Sci. 2023, 46, e2201067. [Google Scholar] [CrossRef]
  10. Gatechompol, S.; Avihingsanon, A.; Apornpong, T.; Han, W.M.; Kerr, S.J.; Ruxrungtham, K. Efficacy and improvement of lipid profile after switching to rilpivirine in resource limited setting: Real life clinical practice. AIDS Res. Ther. 2019, 16, 7. [Google Scholar] [CrossRef]
  11. Azijn, H.; Tirry, I.; Vingerhoets, J.; de Béthune, M.P.; Kraus, G.; Boven, K.; Jochmans, D.; Van Craenenbroeck, E.; Picchio, G.; Rimsky, L.T. TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1. Antimicrob. Agents Chemother. 2010, 54, 718–727. [Google Scholar] [CrossRef] [PubMed]
  12. Jackson, A.G.; Else, L.J.; Mesquita, P.M.; Egan, D.; Back, D.J.; Karolia, Z.; Ringner-Nackter, L.; Higgs, C.J.; Herold, B.C.; Gazzard, B.G.; et al. A compartmental pharmacokinetic evaluation of long-acting rilpivirine in HIV-negative volunteers for pre-exposure prophylaxis. Clin. Pharmacol. Ther. 2014, 96, 314–323. [Google Scholar] [CrossRef] [PubMed]
  13. McGowan, I.; Dezzutti, C.S.; Siegel, A.; Engstrom, J.; Nikiforov, A.; Duffill, K.; Shetler, C.; Richardson-Harman, N.; Abebe, K.; Back, D.; et al. Long-acting rilpivirine as potential pre-exposure prophylaxis for HIV-1 prevention (the MWRI-01 study): An open-label, phase 1, compartmental, pharmacokinetic and pharmacodynamic assessment. Lancet HIV 2016, 3, e569–e578. [Google Scholar] [CrossRef]
  14. Cranston, R.D.; Dezzutti, C.S.; Siegel, A.; Engstrom, J.; Shetler, C.; Richardson-Harman, N.; Abebe, K.Z.; Back, D.; Else, L.; Egan, D.; et al. A multiple dose phase 1 assessment of rilpivirine long acting in a model of preexposure prophylaxis against HIV. AIDS Res. Hum. Retroviruses 2019, 35, 794–804. [Google Scholar] [CrossRef] [PubMed]
  15. Seneviratne, H.K.; Tillotson, J.; Lade, J.M.; Bekker, L.G.; Li, S.; Pathak, S.; Justman, J.; Mgodi, N.; Swaminathan, S.; Sista, N.; et al. Metabolism of long-acting rilpivirine after intramuscular injection: HIV prevention trials network study 076 (HPTN 076). AIDS Res. Hum. Retroviruses 2021, 37, 173–183. [Google Scholar] [CrossRef]
  16. Vannappagari, V.; Ragone, L.; Henegar, C.; van Wyk, J.; Brown, D.; Demarest, J.; Quercia, R.; St Clair, M.; Underwood, M.; Gatell, J.M.; et al. Prevalence of pretreatment and acquired HIV-1 mutations associated with resistance to lamivudine or rilpivirine: A systematic review. Antivir. Ther. 2019, 24, 393–404. [Google Scholar] [CrossRef]
  17. Sayan, M.; Sultanoglu, N.; Sanlidag, T. Dynamics of rilpivirine resistance-associated mutation: E138 in reverse transcriptase among antiretroviral-naive HIV-1-infected individuals in Turkey. AIDS Res. Hum. Retroviruses 2023, 39, 84–90. [Google Scholar] [CrossRef]
  18. Frange, P.; Tubiana, R.; Sibiude, J.; Canestri, A.; Arvieux, C.; Brunet-Cartier, C.; Cotte, L.; Reynes, J.; Mandelbrot, L.; Warszawski, J.; et al. Rilpivirine in HIV-1-positive women initiating pregnancy: To switch or not to switch? J. Antimicrob. Chemother. 2020, 75, 1324–1331. [Google Scholar] [CrossRef]
  19. Islam, S.; Rahaman, M.H.; Yu, M.; Noll, B.; Martin, J.H.; Wang, S.; Head, R. Anti-leukaemic activity of rilpivirine Is mediated by Aurora A kinase inhibition. Cancers 2023, 15, 1044. [Google Scholar] [CrossRef]
  20. Pereira, M.; Vale, N. Evolution of antiretroviral drug rilpivirine and approach to oncology. Int. J. Mol. Sci. 2023, 24, 2890. [Google Scholar] [CrossRef]
  21. Martí-Rodrigo, A.; Alegre, F.; Moragrega, Á.B.; García-García, F.; Martí-Rodrigo, P.; Fernández-Iglesias, A.; Gracia-Sancho, J.; Apostolova, N.; Esplugues, J.V.; Blas-García, A. Rilpivirine attenuates liver fibrosis through selective STAT1-mediated apoptosis in hepatic stellate cells. Gut 2020, 69, 920–932. [Google Scholar]
  22. Sariyer, I.K.; Gordon, J.; Burdo, T.H.; Wollebo, H.S.; Gianti, E.; Donadoni, M.; Bellizzi, A.; Cicalese, S.; Loomis, R.; Robinson, J.A.; et al. Suppression of Zika virus infection in the brain by the antiretroviral drug rilpivirine. Mol. Ther. 2019, 27, 2067–2079. [Google Scholar] [CrossRef] [PubMed]
  23. Lei, S.; Hong, L.; Yang, C.; Zhang, S.; Zhang, Y.; Huang, S.; Xie, R.; Li, X.; Ma, Q.; Li, H. Effect of rilpivirine on the pharmacokinetics of methadone in HIV-Infected Chinese patients. Expert. Rev. Clin. Pharmacol. 2019, 12, 565–571. [Google Scholar] [CrossRef] [PubMed]
  24. Grañana-Castillo, S.; Montanha, M.C.; Bearon, R.; Khoo, S.; Siccardi, M. Evaluation of drug-drug interaction between rilpivirine and rifapentine using PBPK modelling. Front. Pharmacol. 2022, 13, 1076266. [Google Scholar] [CrossRef]
  25. Wiriyatanakorn, S.; Sungkanuparph, S. Switching tenofovir/emtricitabine/efavirenz (TDF/FTC/EFV) to TDF/FTC/rilpivirine vs continuing TDF/FTC/EFV in HIV-infected patients with virological suppression: A randomized controlled trial. Open Forum Infect. Dis. 2019, 6, ofz297. [Google Scholar] [CrossRef]
  26. Munderi, P.; Were, E.; Avihingsanon, A.; Mbida, P.A.M.; Mohapi, L.; Moussa, S.B.; Jansen, M.; Bicer, C.; Mohammed, P.; van Delft, Y. Switching at low HIV-1 RNA into fixed dose combinations: TDF/FTC/RPV is non-inferior to TDF/FTC/EFV in first-line suppressed patients living with HIV. S. Afr. J. HIV Med. 2019, 20, 949. [Google Scholar] [CrossRef]
  27. Chauveau, M.; Billaud, E.; Bonnet, B.; Merrien, D.; Hitoto, H.; Bouchez, S.; Michau, C.; Hall, N.; Perez, L.; Sécher, S.; et al. Tenofovir DF/emtricitabine/rilpivirine as HIV post-exposure prophylaxis: Results from a multicentre prospective study. J. Antimicrob. Chemother. 2019, 74, 1021–1027. [Google Scholar] [CrossRef]
  28. Taramasso, L.; Berruti, M.; Briano, F.; Di Biagio, A. The switch from tenofovir disoproxil fumarate to tenofovir alafenamide determines weight gain in patients on rilpivirine-based regimen. AIDS 2020, 34, 877–881. [Google Scholar]
  29. Mu, Y.; Pham, M.; Podany, A.T.; Cory, T.J. Evaluating emtricitabine + rilpivirine + tenofovir alafenamide in combination for the treatment of HIV-infection. Expert. Opin. Pharmacother. 2020, 21, 389–397. [Google Scholar] [CrossRef]
  30. Wu, P.F.; Lin, H.H.; Chen, H.P.; Huang, P.C.; Ke, M.Y. Metabolic outcomes of changing from rilpivirine/tenofovir disoproxil fumarate/emtricitabine to rilpivirine/tenofovir alafenamide/emtricitabine: A longitudinal study. Health Sci. Rep. 2024, 7, e70275. [Google Scholar] [CrossRef] [PubMed]
  31. Daly, M.B.; Dinh, C.; Holder, A.; Rudolph, D.; Ruone, S.; Swaims-Kohlmeier, A.; Khalil, G.; Sharma, S.; Mitchell, J.; Condrey, J.; et al. SHIV remission in macaques with early treatment initiation and ultra long-lasting antiviral activity. Nat. Commun. 2024, 15, 10550. [Google Scholar] [CrossRef] [PubMed]
  32. Pasquau, J.; de Jesus, S.E.; Arazo, P.; Crusells, M.J.; Ríos, M.J.; Lozano, F.; de la Torre, J.; Galindo, M.J.; Carmena, J.; Santos, J.; et al. Effectiveness and safety of dual therapy with rilpivirine and boosted darunavir in treatment-experienced patients with advanced HIV infection: A preliminary 24 week analysis (RIDAR study). BMC Infect. Dis. 2019, 19, 207. [Google Scholar] [CrossRef]
  33. Navarro, J.; González-Cordón, A.; Casado, J.L.; Bernardino, J.I.; Domingo, P.; Portilla, J.; Llibre, J.M.; Colomer, J.; Rial-Crestelo, D.; Vizcarra, P.; et al. Effectiveness of boosted darunavir plus rilpivirine in patients with long-lasting HIV-1 infection: DARIL study. J. Antimicrob. Chemother. 2020, 75, 1955–1960. [Google Scholar] [CrossRef]
  34. Di Cristo, V.; Adorni, F.; Maserati, R.; Annovazzi Lodi, M.; Bruno, G.; Maggi, P.; Volpe, A.; Vitiello, P.; Abeli, C.; Bonora, S.; et al. 96-week results of a dual therapy with darunavir/ritonavir plus rilpivirine once a day vs triple therapy in patients with suppressed viraemia: Virological success and non-HIV related morbidity evaluation. HIV Res. Clin. Pract. 2020, 21, 34–43. [Google Scholar] [CrossRef]
  35. Maggiolo, F.; Gianotti, N.; Comi, L.; Di Filippo, E.; Fumagalli, L.; Nozza, S.; Galli, L.; Valenti, D.; Rizzi, M.; Castagna, A. Rilpivirine plus cobicistat-boosted darunavir as a two-drug switch regimen in HIV-infected, virologically suppressed subjects on steady standard three-drug therapy: A randomized, controlled, non-inferiority trial (PROBE 2). J. Antimicrob. Chemother. 2020, 75, 1332–1337. [Google Scholar] [CrossRef]
  36. Ho, S.; Wong, J.G.; Ng, O.T.; Lee, C.C.; Leo, Y.S.; Lye, D.C.B.; Wong, C.S. Efficacy and safety of abacavir/lamivudine plus rilpivirine as a first-line regimen in treatment-naïve HIV-1 infected adults. AIDS Res. Ther. 2020, 17, 23. [Google Scholar] [CrossRef]
  37. Lim, Z.C.; Hoo, G.S.; Ang, J.H.; Teng, C.B.; Ang, L.W.; Lee, C.C.; Leo, Y.S.; Law, H.L.; Ng, O.T.; Wong, C.S. Safety and effectiveness of switching to Abacavir/Lamivudine plus rilpivirine for maintenance therapy in virologically suppressed HIV-1 individuals in Singapore (SEALS). AIDS Res. Ther. 2021, 18, 80. [Google Scholar] [CrossRef]
  38. Casado, J.L.; Monsalvo, M.; Fontecha, M.; Vizcarra, P.; Rodriguez, M.A.; Vivancos, M.J.; Moreno, S. Dolutegravir plus rilpivirine as dual regimen in virologically suppressed HIV-1 infected patients in a clinical setting. HIV Res. Clin. Pract. 2019, 20, 64–72. [Google Scholar] [CrossRef]
  39. Hester, E.K.; Astle, K. Dolutegravir-rilpivirine, dual antiretroviral therapy for the treatment of HIV-1 infection. Ann. Pharmacother. 2019, 53, 860–866. [Google Scholar] [CrossRef] [PubMed]
  40. Aboud, M.; Orkin, C.; Podzamczer, D.; Bogner, J.R.; Baker, D.; Khuong-Josses, M.A.; Parks, D.; Angelis, K.; Kahl, L.P.; Blair, E.A.; et al. Efficacy and safety of dolutegravir-rilpivirine for maintenance of virological suppression in adults with HIV-1: 100-week data from the randomised, open-label, phase 3 SWORD-1 and SWORD-2 studies. Lancet HIV 2019, 6, e576–e587. [Google Scholar] [CrossRef] [PubMed]
  41. Moorhouse, M.A.; Cohen, K. The role of rilpivirine in Southern Africa. S. Afr. J. HIV Med. 2019, 20, 825. [Google Scholar] [CrossRef]
  42. van Wyk, J.; Orkin, C.; Rubio, R.; Bogner, J.; Baker, D.; Khuong-Josses, M.A.; Parks, D.; Angelis, K.; Kahl, L.P.; Matthews, J.; et al. Brief report: Durable suppression and low rate of virologic failure 3 years after switch to dolutegravir +rilpivirine 2-drug regimen: 148-week results from the SWORD-1 and SWORD-2 randomized clinical trials. J. Acquir. Immune Defic. Syndr. 2020, 85, 325–330. [Google Scholar] [CrossRef]
  43. Mehta, R.; Lagishetty, C.V.; Angelis, K.; Aylott, A.; Kahl, L.; Blair, L.; Matthews, J.; Wynne, B.; Crauwels, H.; Underwood, M.; et al. Pharmacokinetic and pharmacokinetic/pharmacodynamic characterization of the dolutegravir/rilpivirine two-drug regimen in SWORD-1/-2 phase 3 studies. Br. J. Clin. Pharmacol. 2023, 89, 2190–2200. [Google Scholar] [CrossRef]
  44. Hidalgo-Tenorio, C.; Vinuesa, D.; García-Vallecillos, C.; Muñoz-Medina, L.; Sequera, S.; Javier, R.; López-Ruz, M.; Sadyrbaeva-Dolgova, S.; Pasquau, J. Rildo: Real-world multicenter study on the effectiveness and safety of single-tablet regimen of dolutegravir plus rilpivirine in treatment-experienced people living with HIV. Viruses 2022, 14, 2626. [Google Scholar] [CrossRef]
  45. Palacios, R.; Gómez-Ayerbe, C.; Casado, J.L.; Tejerina, F.; Montes, M.L.; Castaño, M.; Ocampo, A.; Rial, D.; Ribera, E.; Galindo, M.J.; et al. Efficacy and safety of dolutegravir/rilpivirine in real-world clinical practice. GeSIDA study 1119. HIV Med. 2023, 24, 933–937. [Google Scholar] [CrossRef]
  46. Troya, J.; Dueñas, C.; Irazola, I.; de Los Santos, I.; de la Fuente, S.; Gil, D.; Hernández, C.; Galindo, M.J.; Gómez, J.; Delgado, E.; et al. Dolutegravir plus rilpivirine: Benefits beyond viral suppression: DORIPEX retrospective study. Medicine 2022, 101, e29252. [Google Scholar] [CrossRef]
  47. Llibre, J.M.; López Cortés, L.F.; Aylott, A.; Wynne, B.; Matthews, J.; Van Solingen-Ristea, R.; Vandermeulen, K.; van Wyk, J.; Kahl, L.P. Brief report: Evaluation of inflammation and atherogenesis biomarkers through 148 weeks postswitch to dolutegravir and rilpivirine in SWORD-1/SWORD-2. J. Acquir. Immune Defic. Syndr. 2022, 91, 73–78. [Google Scholar] [CrossRef]
  48. Dueñas-Gutiérrez, C.; Buzón, L.; Pedrero-Tomé, R.; Iribarren, J.A.; De Los Santos, I.; De la Fuente, S.; Pousada, G.; Moran, M.A.; Moreno, E.; Ferreira, E.; et al. Efficacy and safety of two-drug regimens with dolutegravir plus rilpivirine or lamivudine in HIV-1 virologically suppressed people living with HIV. Viruses 2023, 15, 936. [Google Scholar] [CrossRef]
  49. Ciccullo, A.; Baldin, G.; Borghi, V.; Cossu, M.V.; Giacomelli, A.; Lagi, F.; Farinacci, D.; Iannone, V.; Passerotto, R.A.; Capetti, A.; et al. Analysing the efficacy and tolerability of dolutegravir plus either rilpivirine or lamivudine in a multicentre cohort of virologically suppressed PLWHIV. J. Antimicrob. Chemother. 2022, 78, 117–121. [Google Scholar] [CrossRef]
  50. Lemaitre, F.; Lagoutte-Renosi, J.; Gagnieu, M.C.; Parant, F.; Venisse, N.; Grégoire, M.; Bouchet, S.; Garraffo, R.; Lê, M.P.; Muret, P.; et al. Therapeutic drug monitoring and virological response at week 48 in a cohort of HIV-1-infected patients switching to dolutegravir/rilpivirine dual maintenance therapy (ANRS-MIE-BIRIDER study). Br. J. Clin. Pharmacol. 2024, 90, 264–273. [Google Scholar] [CrossRef]
  51. Ramos-Ruperto, L.; Arcos-Rueda, M.D.M.; de Miguel-Buckley, R.; Busca-Arenzana, C.; Mican, R.; Montejano, R.; Delgado-Hierro, A.; Montes, M.L.; Valencia, M.E.; Serrano, L.; et al. Sex differences in the effectiveness and tolerability of dolutegravir plus rilpivirine as a switch strategy in people living with HIV. HIV Med. 2024, 25, 684–691. [Google Scholar] [CrossRef]
  52. Schneider, S.; Blick, G.; Burke, C.; Ward, D.; Benson, P.; Felizarta, F.; Green, D.; Donovan, C.; Harper, G.; Merrill, D.; et al. Two-drug regimens dolutegravir/lamivudine and dolutegravir/rilpivirine are effective with few discontinuations in US real-world settings: Results from the TANDEM study. Infect. Dis. Ther. 2024, 13, 891–906. [Google Scholar] [CrossRef]
  53. Fernandez, C.; van Halsema, C.L. Evaluating cabotegravir/rilpivirine long-acting, injectable in the treatment of HIV infection: Emerging data and therapeutic potential. HIV AIDS 2019, 11, 179–192. [Google Scholar] [CrossRef]
  54. Rajoli, R.K.R.; Curley, P.; Chiong, J.; Back, D.; Flexner, C.; Owen, A.; Siccardi, M. Predicting drug-drug interactions between rifampicin and long-acting cabotegravir and rilpivirine using physiologically based pharmacokinetic modeling. J. Infect. Dis. 2019, 219, 1735–1742. [Google Scholar] [CrossRef]
  55. Swindells, S.; Andrade-Villanueva, J.F.; Richmond, G.J.; Rizzardini, G.; Baumgarten, A.; Masiá, M.; Latiff, G.; Pokrovsky, V.; Bredeek, F.; Smith, G.; et al. Long-acting cabotegravir and rilpivirine for maintenance of HIV-1 suppression. N. Engl. J. Med. 2020, 382, 1112–1123. [Google Scholar] [CrossRef]
  56. Orkin, C.; Arasteh, K.; Górgolas Hernández-Mora, M.; Pokrovsky, V.; Overton, E.T.; Girard, P.M.; Oka, S.; Walmsley, S.; Bettacchi, C.; Brinson, C.; et al. Long-acting cabotegravir and rilpivirine after oral induction for HIV-1 infection. N. Engl. J. Med. 2020, 382, 1124–1135. [Google Scholar] [CrossRef]
  57. Currier, J.S. Monthly injectable antiretroviral therapy—Version 1.0 of a new treatment approach. N. Engl. J. Med. 2020, 382, 1164–1165. [Google Scholar] [CrossRef]
  58. Murray, M.; Antela, A.; Mills, A.; Huang, J.; Jäger, H.; Bernal, E.; Lombaard, J.; Katner, H.; Walmsley, S.; Khuong-Josses, M.A.; et al. Patient-reported outcomes in ATLAS and FLAIR participants on long-acting regimens of cabotegravir and rilpivirine over 48 weeks. AIDS Behav. 2020, 24, 3533–3544. [Google Scholar] [CrossRef]
  59. Rizzardini, G.; Overton, E.T.; Orkin, C.; Swindells, S.; Arasteh, K.; Górgolas Hernández-Mora, M.; Pokrovsky, V.; Girard, P.M.; Oka, S.; Andrade-Villanueva, J.F.; et al. Long-acting injectable cabotegravir + rilpivirine for HIV maintenance therapy: Week 48 pooled analysis of phase 3 ATLAS and FLAIR trials. J. Acquir. Immune Defic. Syndr. 2020, 85, 498–506. [Google Scholar] [CrossRef]
  60. Markham, A. Cabotegravir plus rilpivirine: First approval. Drugs 2020, 80, 915–922. [Google Scholar] [CrossRef]
  61. Cabotegravir and Rilpivirine. Am. J. Health Syst. Pharm. 2021, 78, 925–931. [CrossRef] [PubMed]
  62. Letendre, S.L.; Mills, A.; Hagins, D.; Swindells, S.; Felizarta, F.; Devente, J.; Bettacchi, C.; Lou, Y.; Ford, S.; Sutton, K.; et al. Pharmacokinetics and antiviral activity of cabotegravir and rilpivirine in cerebrospinal fluid following long-acting injectable administration in HIV-infected adults. J. Antimicrob. Chemother. 2020, 75, 648–655. [Google Scholar] [CrossRef] [PubMed]
  63. Cutrell, A.G.; Schapiro, J.M.; Perno, C.F.; Kuritzkes, D.R.; Quercia, R.; Patel, P.; Polli, J.W.; Dorey, D.; Wang, Y.; Wu, S.; et al. Exploring predictors of HIV-1 virologic failure to long-acting cabotegravir and rilpivirine: A multivariable analysis. AIDS 2021, 35, 1333–1342. [Google Scholar] [CrossRef]
  64. Durham, S.H.; Chahine, E.B. Cabotegravir-rilpivirine: The first complete long-acting injectable regimen for the treatment of HIV-1 infection. Ann. Pharmacother. 2021, 55, 1397–1409. [Google Scholar] [CrossRef] [PubMed]
  65. Mills, A.; Richmond, G.J.; Newman, C.; Osiyemi, O.; Cade, J.; Brinson, C.; De Vente, J.; Margolis, D.A.; Sutton, K.C.; Wilches, V.; et al. Long-acting cabotegravir and rilpivirine for HIV-1 suppression: Switch to 2-monthly dosing after 5 years of daily oral therapy. AIDS 2022, 36, 195–203. [Google Scholar] [CrossRef]
  66. Orkin, C.; Oka, S.; Philibert, P.; Brinson, C.; Bassa, A.; Gusev, D.; Degen, O.; García, J.G.; Morell, E.B.; Tan, D.H.S.; et al. Long-acting cabotegravir plus rilpivirine for treatment in adults with HIV-1 infection: 96-week results of the randomised, open-label, phase 3 FLAIR study. Lancet HIV 2021, 8, e185–e196. [Google Scholar] [CrossRef]
  67. Jaeger, H.; Overton, E.T.; Richmond, G.; Rizzardini, G.; Andrade-Villanueva, J.F.; Mngqibisa, R.; Hermida, A.O.; Thalme, A.; Belonosova, E.; Ajana, F.; et al. Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 96-week results: A randomised, multicentre, open-label, phase 3b, non-inferiority study. Lancet HIV 2021, 8, e679–e689. [Google Scholar] [CrossRef]
  68. Hodge, D.; Back, D.J.; Gibbons, S.; Khoo, S.H.; Marzolini, C. Pharmacokinetics and drug-drug interactions of long-acting intramuscular cabotegravir and rilpivirine. Clin. Pharmacokinet. 2021, 60, 835–853. [Google Scholar] [CrossRef]
  69. Zeuli, J.D.; Rivera, C.G.; Smith, B.L.; Otto, A.; Temesgen, Z. Cabotegravir: A novel HIV integrase inhibitor combined with rilpivirine as the first long-acting injectable program for the treatment of HIV infection. Drugs Today 2022, 58, 555–576. [Google Scholar] [CrossRef]
  70. Bares, S.H.; Scarsi, K.K. A new paradigm for antiretroviral delivery: Long-acting cabotegravir and rilpivirine for the treatment and prevention of HIV. Curr. Opin. HIV AIDS 2022, 17, 22–31. [Google Scholar] [CrossRef]
  71. Rusconi, S.; Santoro, M.M.; Capetti, A.F.; Gianotti, N.; Zazzi, M. The future of long-acting cabotegravir plus rilpivirine therapy: Deeds and misconceptions. Int. J. Antimicrob. Agents 2022, 60, 106627. [Google Scholar] [CrossRef]
  72. Steegen, K.; Chandiwana, N.; Sokhela, S.; Venter, W.D.F.; Hans, L. Impact of rilpivirine cross-resistance on long-acting cabotegravir-rilpivirine in low and middle-income countries. AIDS 2023, 37, 1009–1011. [Google Scholar] [CrossRef]
  73. Jeffrey, J.L.; St Clair, M.; Wang, P.; Wang, C.; Li, Z.; Beloor, J.; Talarico, C.; Fridell, R.; Krystal, M.; White, C.T.; et al. Impact of Integrase Sequences from HIV-1 Subtypes A6/A1 on the In Vitro Potency of Cabotegravir or Rilpivirine. Antimicrob. Agents Chemother. 2022, 66, e0170221. [Google Scholar] [CrossRef] [PubMed]
  74. Maruapula, D.; Moraka, N.O.; Bareng, O.T.; Mokgethi, P.T.; Choga, W.T.; Seatla, K.K.; Kelentse, N.; Koofhethille, C.K.; Zuze, B.J.L.; Gaolathe, T.; et al. Archived rilpivirine-associated resistance mutations among ART-naive and virologically suppressed people living with HIV-1 subtype C in Botswana: Implications for cabotegravir/rilpivirine use. J. Antimicrob. Chemother. 2023, 78, 2489–2495. [Google Scholar] [CrossRef] [PubMed]
  75. Masich, A.M.; Gomes, D.; Higginson, R.T.; Morgan, Z.; Nixon, D.; Tran, M.; Winthrop, E.; Fulco, P.P. HIV virologic response and baseline genotypic resistance in a long-acting cabotegravir/rilpivirine initiation program. AIDS 2023, 37, 1641–1642. [Google Scholar] [CrossRef] [PubMed]
  76. Overton, E.T.; Richmond, G.; Rizzardini, G.; Thalme, A.; Girard, P.M.; Wong, A.; Porteiro, N.; Swindells, S.; Reynes, J.; Noe, S.; et al. Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with human immunodeficiency virus 1 type 1 infection: 152-week results from ATLAS-2M, a randomized, open-label, phase 3b, noninferiority study. Clin. Infect. Dis. 2023, 76, 1646–1654. [Google Scholar] [CrossRef]
  77. Qazzaz, H.; Parganas, C.; Cory, T.J. An evaluation of long-acting cabotegravir + rilpivirine for the treatment of virologically suppressed adults living with HIV. Expert. Opin. Pharmacother. 2022, 23, 1485–1495. [Google Scholar] [CrossRef]
  78. Rakhmanina, N.; Richards, K.; Adeline Koay, W.L. Transient viremia in young adults with HIV after the switch to long-acting cabotegravir and rilpivirine: Considerations for dosing schedule and monitoring. J. Acquir. Immune Defic. Syndr. 2023, 92, e14–e17. [Google Scholar] [CrossRef]
  79. Patel, P.; Ford, S.L.; Baker, M.; Meyer, C.; Garside, L.; D’Amico, R.; Van Solingen-Ristea, R.; Crauwels, H.; Polli, J.W.; Seal, C.; et al. Pregnancy outcomes and pharmacokinetics in pregnant women living with HIV exposed to long-acting cabotegravir and rilpivirine in clinical trials. HIV Med. 2023, 24, 568–579. [Google Scholar] [CrossRef]
  80. Moffatt, K.; Tekko, I.A.; Vora, L.; Volpe-Zanutto, F.; Hutton, A.R.J.; Mistilis, J.; Jarrahian, C.; Akhavein, N.; Weber, A.D.; McCarthy, H.O.; et al. Development and evaluation of dissolving microarray patches for co-administered and repeated intradermal delivery of long-acting rilpivirine and cabotegravir nanosuspensions for paediatric HIV antiretroviral therapy. Pharm. Res. 2023, 40, 1673–1696. [Google Scholar] [CrossRef]
  81. Bettonte, S.; Berton, M.; Stader, F.; Battegay, M.; Marzolini, C. Management of drug-drug interactions between long-acting cabotegravir and rilpivirine and comedications with inducing properties: A modeling study. Clin. Infect. Dis. 2023, 76, 1225–1236. [Google Scholar] [CrossRef]
  82. Llibre, J.M.; Kuritzkes, D.A.R. Long-acting cabotegravir and rilpivirine: Innovation, new challenges, and opportunities. Clin. Infect. Dis. 2023, 76, 1655–1657. [Google Scholar] [CrossRef]
  83. Parker, B.; Ward, T.; Hayward, O.; Jacob, I.; Arthurs, E.; Becker, D.; Anderson, S.J.; Chounta, V.; Van de Velde, N. Cost-effectiveness of the long-acting regimen cabotegravir plus rilpivirine for the treatment of HIV-1 and its potential impact on adherence and viral transmission: A modelling study. PLoS ONE 2021, 16, e0245955. [Google Scholar] [CrossRef]
  84. Moreno, S.; Rivero, A.; Ventayol, P.; Falcó, V.; Torralba, M.; Schroeder, M.; Neches, V.; Vallejo-Aparicio, L.A.; Mackenzie, I.; Turner, M.; et al. Cabotegravir and rilpivirine long-acting antiretroviral therapy administered every 2 months is cost-effective for the treatment of HIV-1 in Spain. Infect. Dis. Ther. 2023, 12, 2039–2055. [Google Scholar] [CrossRef]
  85. Nachega, J.B.; Scarsi, K.K.; Gandhi, M.; Scott, R.K.; Mofenson, L.M.; Archary, M.; Nachman, S.; Decloedt, E.; Geng, E.H.; Wilson, L.; et al. Long-acting antiretrovirals and HIV treatment adherence. Lancet HIV 2023, 10, e332–e342. [Google Scholar] [CrossRef]
  86. Patel, P.; Teichner, P.; Elliot, E.; Boffito, M.; Murray, M.; Polli, J.W.; Baker, M.; Ford, S.L.; Han, K.; Russu, A.; et al. Practical dosing guidance for the management of clinician-administered injections of long-acting cabotegravir and rilpivirine. Ther. Adv. Infect. Dis. 2023, 10, 20499361231214626. [Google Scholar] [CrossRef]
  87. Orkin, C.; Hayes, R.; Haviland, J.; Wong, Y.L.; Ring, K.; Apea, V.; Kasadha, B.; Clarke, E.; Byrne, R.; Fox, J.; et al. Perspectives of people with HIV on implementing long acting cabotegravir plus rilpivirine in clinics and community settings in the UK: Results from the anti-sexist, anti-racist, anti-ageist ILANA study. Clin. Infect. Dis. 2025, 80, 1103–1113. [Google Scholar] [CrossRef]
  88. Hickey, M.D.; Gistand, N.; Grochowski, J.; Mayorga-Munoz, F.; Imbert, E.; Szumowski, J.D.; Oskarsson, J.; Shiels, M.; Dilworth, S.; Appa, A.; et al. 48-week viral suppression rates in people with HIV starting long-acting CAB/RPV with initial viremia. Clin. Infect. Dis. 2025, 80, 864–870. [Google Scholar] [CrossRef]
  89. Serris, A.; Ferre, V.M.; Le Hingrat, Q.; Bachelard, A.; Charpentier, C.; Exarchopoulos, M.; Damond, F.; Phung, B.C.; Landman, R.; Yazdanpanah, Y.; et al. Real-world data on long-acting intramuscular maintenance therapy with cabotegravir and rilpivirine mirror Phase 3 results. J. Antimicrob. Chemother. 2024, 79, 2932–2938. [Google Scholar] [CrossRef]
  90. Davis, J.M.; Rana, A.; Sax, P.E.; Bares, S.H. Long-acting cabotegravir plus rilpivirine in people with HIV with adherence challenges and viremia: Current data and future directions. Clin. Infect. Dis. 2024; online ahead of print. [Google Scholar] [CrossRef]
  91. Muccini, C.; Gianotti, N.; Lolatto, R.; Nozza, S.; Diotallevi, S.; Castagna, A. CD4+/CD8+ improvement after switch from a second-generation integrase inhibitor regimen to long-acting cabotegravir and rilpivirine. AIDS 2024, 38, 1890–1892. [Google Scholar] [CrossRef]
  92. Kirk, S.E.; Young, C.; Berry, H.; Hanson, R.; Moreland, A.; Fonner, V.; Gebregziabher, M.; Williams, J.; Meissner, E.G. Comparison of at-home versus in-clinic receipt of long-acting injectable cabotegravir/rilpivirine. Clin. Infect. Dis. 2025, 80, 613–617. [Google Scholar] [CrossRef]
  93. Han, K.; Gevorkyan, H.; Sadik Shaik, J.; Crauwels, H.; Leemereise, C.; Bontempo, G.; Win, B.; Chounta, V.; Seal, C.; DeMoor, R.; et al. Pharmacokinetics and tolerability of cabotegravir and rilpivirine long-acting intramuscular injections to the vastus lateralis (lateral thigh) muscles of healthy adult participants. Antimicrob. Agents Chemother. 2024, 68, e0078123. [Google Scholar] [CrossRef] [PubMed]
  94. Cossu, M.V.; D’Avolio, A.; Gervasoni, C.; Giacomelli, A.; Cattaneo, D.; Moschese, D. Switching to deltoid intramuscular injections maintains therapeutic trough concentrations of rilpivirine and cabotegravir in people with HIV. Antimicrob. Agents Chemother. 2024, 68, e0017524. [Google Scholar] [CrossRef] [PubMed]
  95. Maguire, C.; Rueve, K.; Farmer, E.; Huesgen, E.; Karaj, A.; Binkley, A.; Mounzer, K.; Brizzi, M.; Chary, P.; Sung, P.; et al. Real world virologic outcomes in patients with elevated body mass index receiving long acting cabotegravir/rilpivirine. Clin. Infect. Dis. 2024; online ahead of print. [Google Scholar] [CrossRef] [PubMed]
  96. Elliot, E.R.; Polli, J.W.; Patel, P.; Garside, L.; Grove, R.; Barnett, V.; Roberts, J.; Byrapuneni, S.; Crauwels, H.; Ford, S.L.; et al. Efficacy, safety, and pharmacokinetics by body mass index category in phase 3/3b long-acting cabotegravir plus rilpivirine trials. J. Infect. Dis. 2024, 230, e34–e42. [Google Scholar] [CrossRef]
  97. Gaur, A.H.; Capparelli, E.V.; Calabrese, K.; Baltrusaitis, K.; Marzinke, M.A.; McCoig, C.; Van Solingen-Ristea, R.M.; Mathiba, S.R.; Adeyeye, A.; Moye, J.H.; et al. Safety and pharmacokinetics of oral and long-acting injectable cabotegravir or long-acting injectable rilpivirine in virologically suppressed adolescents with HIV (IMPAACT 2017/MOCHA): A phase 1/2, multicentre, open-label, non-comparative, dose-finding study. Lancet HIV 2024, 11, e211–e221. [Google Scholar] [CrossRef]
  98. Collins, L.F.; Sheth, A.N.; Tisdale, T.; Mehta, C.C.; Daniel, G.; Westreich, D.; Kassaye, S.; Topper, E.F.; Konkle-Parker, D.; Rana, A.; et al. Interest in and preference for long-acting injectable antiretroviral therapy in the era of approved cabotegravir/rilpivirine among reproductive-aged women in the U.S. south. Clin. Infect. Dis. 2025, 80, 164–167. [Google Scholar] [CrossRef]
  99. Gutner, C.A.; Hocqueloux, L.; Jonsson-Oldenbüttel, C.; Vandekerckhove, L.; van Welzen, B.J.; Slama, L.; Crusells-Canales, M.; Sierra, J.O.; DeMoor, R.; Scherzer, J.; et al. Implementation of long-acting cabotegravir and rilpivirine: Primary results from the perspective of staff study participants in the Cabotegravir and Rilpivirine Implementation Study in European Locations. J. Int. AIDS Soc. 2024, 27, e26243. [Google Scholar] [CrossRef]
  100. Hickey, M.D.; Grochowski, J.; Mayorga-Munoz, F.; Oskarsson, J.; Imbert, E.; Spinelli, M.; Szumowski, J.D.; Appa, A.; Koester, K.; Dauria, E.F.; et al. Identifying implementation determinants and strategies for long-acting injectable cabotegravir-rilpivirine in people with HIV who are virally unsuppressed. J. Acquir. Immune Defic. Syndr. 2024, 96, 280–289. [Google Scholar] [CrossRef]
  101. van Welzen, B.J.; Van Lelyveld, S.F.L.; Ter Beest, G.; Gisolf, J.H.; Geerlings, S.E.; Prins, J.M.; Van Twillert, G.; Van Nieuwkoop, C.; Van der Valk, M.; Burger, D.; et al. Virological failure after switch to long-acting cabotegravir and rilpivirine injectable therapy: An in-depth analysis. Clin. Infect. Dis. 2024, 79, 189–195. [Google Scholar] [CrossRef] [PubMed]
  102. Ring, K.; Smuk, M.; Shongwe, M.; Okonta, L.; Mackie, N.E.; Ayres, S.; Barber, T.J.; Akodu, J.; Ferro, F.; Chilton, D.; et al. Multicentre service evaluation of injectable cabotegravir and rilpivirine delivery and outcomes across 12 UK clinics (SHARE LAI-net). HIV Med. 2024, 25, 1125–1134. [Google Scholar] [CrossRef]
  103. Kityo, C.; Mambule, I.K.; Musaazi, J.; Sokhela, S.; Mugerwa, H.; Ategeka, G.; Cresswell, F.; Siika, A.; Kosgei, J.; Shah, R.; et al. Switch to long-acting cabotegravir and rilpivirine in virologically suppressed adults with HIV in Africa (CARES): Week 48 results from a randomised, multicentre, open-label, non-inferiority trial. Lancet Infect. Dis. 2024, 24, 1083–1092. [Google Scholar] [CrossRef] [PubMed]
  104. Orkin, C.; Ring, K. Implementing long-acting injectable cabotegravir and rilpivirine in Africa. Lancet Infect. Dis. 2024, 24, 1060–1061. [Google Scholar] [CrossRef]
  105. Jonsson-Oldenbüttel, C.; Ghosn, J.; van der Valk, M.; Florence, E.; Vera, F.; De Wit, S.; Rami, A.; Bonnet, F.; Hocqueloux, L.; Hove, K.; et al. Safety and effectiveness from the cabotegravir and rilpivirine implementation study in European locations study: Phase 3b hybrid type III implementation study integrating cabotegravir + rilpivirine long-acting into European clinical settings. J. Acquir. Immune Defic. Syndr. 2024, 96, 472–480. [Google Scholar] [CrossRef] [PubMed]
  106. Luc, C.M.; Max, B.; Pérez, S.; Herrera, K.; Huhn, G.; Dworkin, M.S. Acceptability of long-acting cabotegravir + rilpivirine in a large, urban, ambulatory HIV clinic. J. Acquir. Immune Defic. Syndr. 2024, 97, 409–415. [Google Scholar] [CrossRef]
  107. Ring, K.; Orkin, C. Long-acting antiretroviral therapy in the context of viral suppression. Curr. Opin. HIV AIDS 2025, 20, 4–10. [Google Scholar] [CrossRef]
  108. Christopoulos, K.A.; Hickey, M.D.; Rana, A. Use of long-acting injectable cabotegravir/rilpivirine in people with HIV and adherence challenges. Curr. Opin. HIV AIDS 2025, 20, 11–18. [Google Scholar] [CrossRef]
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Figure 1. Chemical structure of rilpivirine (R278474).
Figure 1. Chemical structure of rilpivirine (R278474).
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Figure 2. R278474 in the NNRTI-binding pocket (modeled structure) [1].
Figure 2. R278474 in the NNRTI-binding pocket (modeled structure) [1].
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Figure 3. Percentages of patients with HIV RNA <50 copies/mL at week 24 after switching from TDF/FTC/EFV to TDF/FTC/RPV [25].
Figure 3. Percentages of patients with HIV RNA <50 copies/mL at week 24 after switching from TDF/FTC/EFV to TDF/FTC/RPV [25].
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Figure 4. Chemical structure of the HIV integrase inhibitor dolutegravir (DTG).
Figure 4. Chemical structure of the HIV integrase inhibitor dolutegravir (DTG).
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Figure 5. Chemical structures of the HIV integrase inhibitor cabotegravir.
Figure 5. Chemical structures of the HIV integrase inhibitor cabotegravir.
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Figure 6. Plasma concentration-time profiles in the FLAIR study [56].
Figure 6. Plasma concentration-time profiles in the FLAIR study [56].
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Figure 7. Prevalence of rilpivirine drug resistance mutations in 1372 patients failing NNRTI-based treatment [72].
Figure 7. Prevalence of rilpivirine drug resistance mutations in 1372 patients failing NNRTI-based treatment [72].
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Figure 8. ISRs over time. a AE grade is the maximum grade reported by the participant at each visit. b There were no grade 4 or 5 ISRs. Abbreviations: AE, adverse event; CAB, cabotegravir; ISR, injection-site reaction; LA, long-acting; NA, not applicable; Q4W, every 4 weeks; Q8W, every 8 weeks; RPV, rilpivirine [76].
Figure 8. ISRs over time. a AE grade is the maximum grade reported by the participant at each visit. b There were no grade 4 or 5 ISRs. Abbreviations: AE, adverse event; CAB, cabotegravir; ISR, injection-site reaction; LA, long-acting; NA, not applicable; Q4W, every 4 weeks; Q8W, every 8 weeks; RPV, rilpivirine [76].
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Figure 9. Summary of reproductive-aged women with HIV enrolled in STAR surveyed between December 2022 and October 2023 on willingness to try LAI-ART ((A), n = 100 had not yet used LAI-ART); preference for LAI over daily pills for HIV treatment ((B), n = 103); and potential reproductive health concerns related to LAI-ART use ((C), n = 102, except for 1 participant declined to answer the question related to medication abortion). Abbreviations: ART, antiretroviral therapy; HIV, human immunodeficiency virus; LAI, long-acting injectable; STAR, Study of Treatment and Reproductive Outcomes [98].
Figure 9. Summary of reproductive-aged women with HIV enrolled in STAR surveyed between December 2022 and October 2023 on willingness to try LAI-ART ((A), n = 100 had not yet used LAI-ART); preference for LAI over daily pills for HIV treatment ((B), n = 103); and potential reproductive health concerns related to LAI-ART use ((C), n = 102, except for 1 participant declined to answer the question related to medication abortion). Abbreviations: ART, antiretroviral therapy; HIV, human immunodeficiency virus; LAI, long-acting injectable; STAR, Study of Treatment and Reproductive Outcomes [98].
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Figure 10. * Four hundred thirty-seven patient study participants (PSPs), and 430 received CAB+RPV LA (long-acting). Oral lead-in (OLI) on day 1. † Dose 1 was received at month 1, dose 2 at month 2, with the remaining doses Q2M thereafter [105].
Figure 10. * Four hundred thirty-seven patient study participants (PSPs), and 430 received CAB+RPV LA (long-acting). Oral lead-in (OLI) on day 1. † Dose 1 was received at month 1, dose 2 at month 2, with the remaining doses Q2M thereafter [105].
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De Clercq, E. The Meandrous Route of Rilpivirine in the Search for the Miraculous Drug to Treat HIV Infections. Viruses 2025, 17, 959. https://doi.org/10.3390/v17070959

AMA Style

De Clercq E. The Meandrous Route of Rilpivirine in the Search for the Miraculous Drug to Treat HIV Infections. Viruses. 2025; 17(7):959. https://doi.org/10.3390/v17070959

Chicago/Turabian Style

De Clercq, Erik. 2025. "The Meandrous Route of Rilpivirine in the Search for the Miraculous Drug to Treat HIV Infections" Viruses 17, no. 7: 959. https://doi.org/10.3390/v17070959

APA Style

De Clercq, E. (2025). The Meandrous Route of Rilpivirine in the Search for the Miraculous Drug to Treat HIV Infections. Viruses, 17(7), 959. https://doi.org/10.3390/v17070959

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