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
by
, ,
Carmen Hidalgo-Tenorio
1,*,
David Vinuesa
2,
Coral García-Vallecillos
1,
Leopoldo Muñoz-Medina
2,
Sergio Sequera
1,
Rosario Javier
1,
Miguel Ángel López-Ruz
1,
Svetlana Sadyrbaeva-Dolgova
1 and
Juan Pasquau
1 1
Unit of Infectious Diseases, Virgen de las Nieves University Hospital, Biohealth Research Institute, IBS-Granada, 18014 Granada, Spain
2
Unit of Infectious Diseases, San Cecilio University Hospital, Biohealth Research Institute, IBS-Granada, 18012 Granada, Spain
*
Author to whom correspondence should be addressed.
Viruses 2022, 14(12), 2626; https://doi.org/10.3390/v14122626
Submission received: 14 October 2022
/
Revised: 19 November 2022
/
Accepted: 24 November 2022
/
Published: 25 November 2022
(This article belongs to the Special Issue Efficacy and Safety of Antiviral Therapy)
Abstract
:Two-drug regimens (2DRs) are emerging in clinical practice guidelines as treatment option for both naive and treatment-experienced people living with HIV (PLHIV). Objectives: To determine the real-life effectiveness of 2DR with 25 mg RPV plus 50 mg DTG in a single-tablet regimen (RPV/DTGSTR) and its impact on viral and immune status, lipid profile, and inflammatory markers. Methods: This observational study included 291 treatment-experienced PLHIV, starting 2DR with RPV/DTGSTR between 29 January 2019 and 2 February 2022, who were followed up for at least six months. Participants gave verbal informed consent for the switch in antiretroviral therapy (ART) to RPV/DTGSTR. Results: The mean age of the 291 participants was 51.3 years; 77.7% were male; and 42.9% were in the AIDS stage with a CD4 nadir of 283.5 ± 204.6 cells/uL. The median time since HIV diagnosis was 19.7 years (IQR: 10.6–27). Before 2DR, patients received a median of five ART lines (IQR: 3–7) for 22.2 years (IQR: 14–26), with 34.4% (n = 100) receiving a three-drug regimen (3DR), 31.3% (n = 91) receiving monotherapy, and 34.4% (n = 100) receiving 2DR. The median time on RPV/DTGSTR was 14 months (IQR: 9.5–21); 1.4% were lost to the follow-up. Effectiveness was 96.2% by intention-to-treat (ITT) analysis, 97.5% by modified ITT, and 99.3% by per-protocol analysis. Virological failure was observed in 0.69%, blips in 3.5%, and switch to another ART in 1.4%. The mean lipid profile improved, with reductions in TC/HDLc ratio (3.9 ± 0.9 vs. 3.6 ± 0.9; p = 0.0001), LDLc (118.3 ± 32.2 mg/dL vs. 106.2 ± 29.8 mg/dL, p = 0.0001), TG (130.9 ± 73.9 mg/dL vs. 115.9 ± 68.5 mg/dL, p = 0.0001), and CD4/CD8 ratio increase (0.99 ± 0.58 vs. 1.01 ± 0.54; p = 0.0001). The cost-effectiveness of 2DR with RPV/DTGSTR was similar to that of DTG/3TC and superior to those of BIC/TAF/FTC and DRV/c/TAF/FTC, with higher virological suppression and lower annual costs. Conclusions: The switch to RPV plus DTG in STR is a cost-effective, long-lasting, and robust strategy for PLHIV, with a very long experience of treatment, which improves the lipid profile without affecting inflammatory markers.
1. Background
Since the introduction of high-effectiveness antiretroviral therapy (ART) in the mid-1990s, the life expectancy of people living with HIV (PLHIV) has progressively increased, approaching that of the general population [1]. For decades, clinical practice guidelines for the standard treatment of naive and treatment-experienced PLHIV has considered only three drug regimens (3DR) as preferential: ART, comprising two nucleoside analogues combined with one integrase inhibitor, a protease inhibitor, and a non-nucleoside analogue [2]. Two-drug regimens (2DRs) have been studied as a means of minimizing short- and long-term antiretroviral (ARV) toxicity in naive or ARV-experienced patients [3]. They include the combination of lamivudine and dolutegravir (DTG), which achieved excellent outcomes in clinical trials in naive [4,5,6] and treatment-experienced patients [7,8,9]. A 2DR with rilpivirine (RPV) plus DTG demonstrated the same effectiveness in treatment-experienced patients as that obtained with three-drug regimens (3DRs) in two clinical trials, SWORD 1 and 2, which found no risk of increased resistance and improvements in renal function and bone metabolism [10]. Although randomized clinical trials are the gold standard for evaluating drug effectiveness, multiple factors can limit the extrapolation of outcomes to the whole population, including the type of patient, diversity of therapeutic response, and adherence to treatment. Accordingly, real-world evidence studies are performed after drug approval in non-selected patients recruited in a routine clinical setting without the restrictions of trials. The aim is to provide in-depth analysis of the “real-life” safety and effectiveness of the drug, based on all available data from a wider group of patients than those enrolled in clinical trials [11].
The main objective of this study was to analyze the effectiveness and safety of changing any ARV regimen (1DR, 2DR, or 3DR) to 2DR with RPV (25 mg/QD) plus DTG (50 mg/QD) in a single-tablet regimen (RPV/DTGSTR) in a cohort of ART-experienced PLHIV. The secondary objectives were to determine the effect of switching on immune and viral status and inflammatory markers and to carry out a pharmacoeconomic study of the change.
2. Patients and Methods
2.1. Study Design and Setting
A multicenter, observational, and retrospective study was undertaken in PLHIV treated with RPV/DTGSTR for at least six months. A 2DR was prescribed by attending physicians after obtaining the informed consent of patients. The study included PLHIV under outpatient treatment at two infectious disease units in the regional health service who had initiated treatment, for any reason, with RPV (25/QD) plus DTG (50 mg/QD) in STR (RPV/DTGSTR). The study was approved by the ethics committee of Virgen de las Nieves University Hospital of Granada, Spain (#1602-N-22), and data were treated in compliance with Spanish legislation on personal data protection.
2.2. Inclusion Criteria
PLHIV treated with any other ART regimen for at least six months who were switched to 2DR with RPV/DTGSTR by the attending physician.
2.3. Variables/Data Sources
At the baseline visit (V0), data were gathered on age, sex, active co-infections, toxic habits (tobacco and alcohol), mode of acquisition of HIV, weight, date of HIV diagnosis, viral load (VL), CD4 and CD8 lymphocyte counts at diagnosis, CD4 nadir, previous ART lines, reasons for change to RPV/DTGSTR (toxicity, intolerance, simplification, optimization, inconvenience, etc.), and analytical data for the month before the change to RPV/DTGSTR. Data were also gathered at V0 and at the end of the follow-up on: VL, CD4, and CD8 lymphocyte counts and percentages, CD4/CD8 ratio, total cholesterol, HDL, LDL, triglycerides, GOT, GPT, GGT, bilirubin, alkaline phosphatase, interleukin-6, D-dimer, and glomerular filtration (CKD-EPI).
Treatment effectiveness was determined by calculating the proportion of participants achieving viral suppression (defined by plasma HIV RNA ≤ 50 cop/mL) at the end of follow-up according to intention-to-treat (ITT) [12], modified ITT (mITT) [13], and per-protocol (PP) [14] analyses.
A blip was defined as VL > 50 copies/mL in one determination and undetectable in the next determination one month later. Virological failure (VF) was defined by VL > 50 HIV-RNA copies/uL at two consecutive determinations in a 6-month period.
The interpretation of the genotypic resistance test was performed following the algorithms of Stanford University and the Spanish AIDS Research Network (RIS) [15].
It was estimated that at least 235 treatment-experienced PLHIV were needed to measure the effectiveness of 2DR with 95% confidence interval (CI) and 3% precision, assuming a loss to follow-up of 15%.
Statistical analysis: In the descriptive analysis, frequencies with 95% CI were calculated for qualitative variables, means with standard deviation for normally distributed quantitative variables, and medians with IQR for non-normally distributed quantitative variables. The Kolmogorov–Smirnov test was applied to check the normality of variable distributions. The paired samples Wilcoxon test was used to compare quantitative variables. p < 0.05 was considered significant in all tests. SPSS 20.0 was used for statistical analyses.
2.4. Pharmacoeconomic Analysis
A pharmacoeconomic analysis was performed, comparing therapy with RPV/DTG vs. BIC/TAF/FTC, DRV/c/TAF/FTC, and DTG/3TC. Data obtained from published research in study populations with similar characteristics [16,17,18] were compared with the effectiveness of RPV/DTGSTR by modified ITT analysis (excluding individuals lost to follow-up). Treatment-cost calculations were based on the laboratory price list for February 2022, without VAT and without considering state discounts. Cost-minimization analysis was performed after one year, to determine the savings generated by switching to RPV/DTG. The cost-effectiveness ratio (CER) was also determined by dividing the cost of each treatment by its effectiveness, and the incremental CER (ICER) of RPV/DTG therapy vs. the others was calculated by dividing the difference in total costs (incremental cost) by the increase in effectiveness.
3. Results
3.1. Study Population
The study included 291 PLHIV with a mean age of 51.3 years; 77.7% (226) were male; and 42.9% had AIDS. The mean CD4 nadir was 283.5 ± 204.6 cells/uL. The median time since HIV diagnosis was 19.7 years (IQR: 10.6–27). Patients had previously received a median of five ART lines (IQR: 3–7) for 15.3 years (IQR: 7.5–2), with 34.4% (n = 100) receiving a three-drug regimen (3DR), 31.3% (n = 91) receiving monotherapy, and 34.4% (n = 100) receiving another 2DR. At baseline (V0), 3.4% (n = 10) had VF and 6.2% (n = 18) had blips. One patient had a chronic VHB infection (HBS antigen positive) and had been under HBV treatment with entecavir for 10 years due to kidney failure after treatment with 600 mg efavirenz, 200 mg emtricitabine, and 245 mg disoproxil tenofovir in STR (Table 1).
A genotyping resistance test had been performed in 152 (52.2%) of the participants a median of 13.5 years earlier (IQR: 8.3–17.3); among these, 14 (9.25%) had primary and secondary non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistance mutations conferring either resistance (35.7%) or decreased susceptibility to RPV (42.9%) (Table 1).
Reasons for the 2DR switch were simplification in 69.8% (n = 203), avoidance of potential long-term toxicity in 26.8% (n = 78), and VF in 3.4% (n = 10) due to poor ART adherence in a multi-tablet regimen (MTR). The results for the remaining study variables are reported in Table 1.
3.2. DR Effectiveness and Safety
The median time on RPV/DTGSTR was 14 months (IQR: 9.5–21); five (1.7%) patients were lost to the follow-up. Effectiveness was recorded in 96.2% (280/291) by ITT, 97.5% (280/287) by modified ITT, and 99.3% (281/283) by PP analyses (Figure 1).
During the follow-up period, 0.69% of patients (n = 2) had VF, 3.5% (n = 10) had blips, and 1.4% (n = 4) switched from RPV/DTGSTR due to drug interactions (n = 1), adverse events (diarrhea and depression, n = 2), or by decision of the physician (n = 1) (Table 2). One of the two patients who failed due to suspension of the treatment did not take even one tablet, and the treatment adherence of the other was inadequate (Table 3).
3.3. Analytical Parameters
During the follow-up, the following were observed: an increase in the CD4/CD8 ratio (0.99 ± 0.58 vs. 1.01 ± 0.54; p = 0.0001) and a reduction in the TC/HDLc ratio (3.9 ± 0.9 vs. 3.6 ± 0.9; p = 0.0001), LDLc level (118.3 ± 32.2 mg/dL vs. 106.2 ± 29.8 mg/dL, p = 0.0001), and TG level (130.9 ± 73.9 mg/dL vs. 115.9 ± 68.5 mg/dL, p = 0.0001). No statistically significant changes were found in the IL-6, C-reactive protein, fibrinogen, or D-dimer levels. Table 4 lists the results for the remaining variables.
3.4. Pharmacoeconomic Analysis
The annual cost per patient was EUR 5538.96 for RPV/DTGSTR, EUR 6012.36 for BIC/TAF/FTC, EUR 6094.56 for DRV/c/FTC/TAF, and EUR 4851.24 for DTG/3TC. Switching to 2DR with RPV/DTGSTR would, therefore, yield a potential annual saving per patient of EUR 473.40 vs. BIC/FTC/TAF and EUR 555.60 vs. DRV/c/FTC/TAF. The annual cost per patient would increase by EUR 687.72 in comparison to DTG/3TC (Table 5a).
The virological effectiveness ratio was 97.5% for RPV/DTGSTR, 94.8% for BIC/FTC/TAF, 90.7% for DRV/c/FTC/TAF, and 87.9% for DTG/3TC, and the CER values were around 57, 63, 67, and 55, respectively. The cost-effectiveness of RPV/DTGSTR to treat HIV is, therefore, comparable to that of the other ARTs. The ICER of RPV/DTGSTR was −175 vs. BIC/FTC/TAF, −82 vs. DRV/c/FTC/TAF, and 87 vs. DTG/3TC (Table 5b). These findings place RPV/DTGSTR as a cost-effective option with respect to the other therapies, with improved virological suppression and a slightly lower annual cost (except for the other 2DR with DTG/3TC).
4. Discussion
Most patients in this real-world study on the use of 2DR with RPV/DTGSTR in ART-experienced PLHIV were aged over 50 years, and around half of them were in the AIDS stage. They had a very long history of ART (median of 22.1 years), with a median of five previous lines. They were switched from different ARV regimens and even included a small percentage of non-suppressed patients. Mutations conferring NNRTI resistance had been detected in 5% over 13 years earlier, and previous exposure to integrase standard transfer inhibitors (INSTIs) was recorded in 30%, but none had resistance mutations to DTG. The majority of participants in SWORD 1 and 2 clinical trials were aged <50 years, while around 11% were in the AIDS stage, and the median time with ART was four years, with a maximum of two previous lines; in addition, they were all suppressed before starting the 2DR, <10% had been exposed to DTG, and none had resistance mutations to NNRTI [19].
In the present study, the reason for switching was simplifying the regimen in more than two-thirds of cases, avoiding long-term toxicity in more than one-quarter, and failing to adequately adhere to their MTR in one-tenth; finally, clinicians even trusted in this regimen in one out of ten patients in failure due to poor adherence to treatments in MTR. Owing to the increased survival and life expectancy of PLHIV achieved by ART, it has been estimated that patients will consume ARVs for a mean of 39.1 years, receiving 57,086 ARVs for 3DR with a booster, 42,815 for 3DR without a booster, and 28,543 for 2DR [20]. The potential benefits of a paradigm change from 3DR to 2 DR regimens include a decrease in long-term adverse effects and toxicities, a reduced possibility of interactions, the preservation of ARVs not included in the regimens, improvements in quality of life, and a reduction in treatment costs [21].
Only four patients were lost to the follow-up of more than 12 months, 2DR with RPV/DTGSTR achieved an effectiveness of 95% by ITT analysis and close to 100% by PP analysis in this cohort of ART-experienced PLHIV, and there was no failure in patients with RPV resistance mutations. These effectiveness data are highly similar to those obtained in registered clinical trials [19]. Despite the likelihood of VF due to archived RPV resistance mutations, a high rate of exposure to INSTIs, and a number of previous ARV lines, the effectiveness of treatment was comparable to that reported by the SWORD trials [18], indicating the robustness and effectiveness of this 2DR in the real world. The maintenance of untransmittable status is of major importance not only for the “treatment as prevention” strategy but also to improve the quality of life of PLHIV, reducing self-stigma.
Only two patients had adverse effects attributable to 2DR with RPV/DTGSTR (diarrhea and depression, respectively). In addition, the treatment was only suspended in two patients, to avoid drug interactions and for the convenience of the patient as decided by the physician. Finally, VF was observed in two patients, which was attributed to poor treatment adherence, with neither having mutations in the historical genotype, demonstrating the robustness of the treatment and/or that strains with mutations were a very small minority and were completely suppressed after a long time with a previous effective ART. These findings are in agreement with a trial of this 2DR that showed the sustained virological suppression of around 90% after a three-year follow-up, with low VF rates and a well-tolerated safety profile [22].
The treatment improved cholesterol and triglyceride levels and the CT/HDL ratio, as also found in clinical trials [19] and previous real-life studies [23,24]. Hence, this 2DR is of interest as an option for older PLHIV with risk factors and/or cardiovascular disease. In comparison to the present investigation, the aforementioned studies [23,24] had a smaller sample size, a shorter follow-up of 24 weeks [23], and a different multi-tablet 2DR regimen; furthermore, all PLHIVs were virologically suppressed for at least six months before the switch to 2DR, which was a second-line treatment in the majority of cases.
An improvement in immunological recovery, with an increased CD4/CD8 ratio, was recorded at one year of treatment with RPV/DTGSTR. A recent retrospective, multicenter Spanish study of the switch from 3DR to 2DR with RPV/DTG in virologically suppressed PLHIV also found an increase in CD4 and a decrease in CD8 at 48 weeks [25]. Bone metabolism was not analyzed in the present study, but an increase in bone density and decrease in turnover markers was reported in patients changing from a 3DR ART with tenofovir disoproxil fumarate (TDF) to 2DR with RPV/DTGSTR [26]. No changes in inflammatory markers (PCR, IL-6, fibrinogen, and D-dimer) were observed during the present follow-up period, and the SWORD trials also found no differences in inflammatory and atherogenic markers at 48 or 148 weeks of treatment with RPV/DTGSTR [27].
The switch to RPV/DTGSTR in stable and mostly virologically suppressed ART-experienced PLHIV proved to be a cost-effective alternative to 3DR ART, offering higher effectiveness at a lower cost in comparison to BIC/FTC/TAF and DRVc/FTC/TAF. These results are in line with previous findings of cost saving with DTG/RPV vs. RPV/FTC/TDF, DTG/ABC/3TC, and EVG/c/FTC/TAF and the delivery of comparable efficacy with reduced cumulative drug exposure [28]. Finally, the cost-effectiveness was highly similar to that of 2DR with DTG/3TC, indicating that 2DR ART with RPV/DTG in STR can stand alongside DTG/3TC as a preferential strategy in treatment-experienced PLHIV. However, these findings do not rule out the other therapies as efficient options.
The main study limitation is its retrospective design. Strengths include the large sample size of this multicenter study. In addition, it is the first to study the switch to this 2DR in PLHIV with long ART experience and no need for treatment suppression for >6 months, including individuals with archived RPV resistance mutations (none failed) and a high rate of exposure to integrase inhibitors. All these characteristics make this a unique study of major interest.
In conclusion, 2DR with RPV plus DTG in STR is an effective, safe, long-lasting, robust strategy for patients with prolonged ART experience, improving their lipid profile without affecting inflammatory markers; it is cost-effective compared to the other treatments.
Author Contributions
Conceptualization, C.H.-T.; Methodology, C.H.-T.; Software, C.G.-V., S.S. and S.S.-D.; Validation, D.V., C.G.-V., S.S. and J.P.; Formal analysis, C.H.-T.; Investigation, C.H.-T., S.S. and S.S.-D.; Resources, D.V., L.M.-M., R.J. and M.Á.L.-R.; Data curation, D.V., C.G.-V., S.S. and S.S.-D; Writing—original draft, C.H.-T.; Writing—review & editing, C.G.-V. and J.P.; Visualization, D.V., C.G.-V., L.M.-M. and R.J.; Supervision, C.G.-V. and J.P. All authors have read and agreed to the published version of the manuscript.
Funding
This study has not received any funding for its execution.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki and was approved by the ethics committee of Provincial Research of Granada (CEIM/CEI) (protocol code RiLDo study and 10 November 2022); the verbal consent of patients was obtained before their inclusion in the cohort.
Informed Consent Statement
This cohort of patients was established after obtaining approval from the ethical committee of the coordinating center, and the verbal consent of patients was obtained before their inclusion in the cohort.
Data Availability Statement
The authors confirm the accuracy of the data provided for the study as well as its availability.
Conflicts of Interest
The authors declare no conflict of interest.
References
- Palella, F.J., Jr.; Delaney, K.M.; Moorman, A.C.; Loveless, M.O.; Fuhrer, J.; Satten, G.A.; Aschman, D.J.; Holmberg, S.D.; HIV Outpatient Study Investigators. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N. Engl. J. Med. 1998, 338, 853–860. [Google Scholar] [CrossRef]
- European AIDS Clinical Society GUIDELINES Version 10.1 October 2020. Available online: https://www.eacsociety.org/guidelines/guidelines-archive/ (accessed on 17 September 2022).
- Perez-Molina, J.A.; Rubio, R.; Rivero, A.; Pasquau, J.; Suárez-Lozano, I.; Riera, M.; Estébanez, M.; Santos, J.; Sanz-Moreno, J.; Troya, J.; et al. Dual treatment with atazanavir-ritonavir plus lamivudine versus triple treatment with atazanavir-ritonavir plus two nucleos(t)ides in virologically stable patients with HIV-1 (SALT): 48week results from a randomised, open-label, non-inferiority trial. Lancet Infect. Dis. 2015, 15, 775–784. [Google Scholar] [CrossRef] [PubMed]
- Cahn, P.; Madero, J.S.; Arribas, J.R.; Antinori, A.; Ortiz, R.; Clarke, A.E.; Hung, C.-C.; Rockstroh, J.K.; Girard, P.-M.; Sievers, J.; et al. Dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naive adults with HIV-1 infection (GEMINI-1 and GEMINI-2): Week 48 results from two multicentre, double-blind, randomised, non-inferiority, phase 3 trials. Lancet 2019, 393, 143–155. [Google Scholar] [PubMed]
- Rolle, C.P.; Berhe, M.; Singh, T.; Ortiz, R.; Wurapa, A.; Ramgopal, M.; Leone, P.A.; Matthews, J.E.; Dalessandro, M.; Underwood, M.R.; et al. Dolutegravir/lamivudine as a first-line regimen in a test-and-treat setting for newly diagnosed people living with HIV. AIDS 2021, 35, 1957–1965. [Google Scholar] [CrossRef]
- Hidalgo-Tenorio, C.; Pasquau, J.; Vinuesa, D.; Ferra, S.; Terrón, A.; SanJoaquín, I.; Payeras, A.; Martínez, O.J.; López-Ruz, M.Á.; Omar, M.; et al. DOLAVI Real-Life Study of Dolutegravir Plus Lamivudine in Naive HIV-1 Patients (48 Weeks). Viruses 2022, 14, 524. [Google Scholar] [CrossRef] [PubMed]
- van Wyk, J.; Ajana, F.; Bisshop, F.; De Wit, S.; Osiyemi, O.; Portilla Sogorb, J.; Routy, J.-P.; Wyen, C.; Ait-Khaled, M.; Nascimento, M.C.; et al. Efficacy and Safety of Switching to Dolutegravir/Lamivudine Fixed-Dose 2-Drug Regimen vs Continuing a Tenofovir Alafenamide-Based 3- or 4-Drug Regimen for Maintenance of Virologic Suppression in Adults Living With Human Immunodeficiency Virus Type 1: Phase 3, Randomized, Noninferiority TANGO Study. Clin. Infect. Dis. 2020, 71, 1920–1929. [Google Scholar]
- Llibre, J.M.; Brites, C.; Cheng, C.Y.; Osiyemi, O.; Galera, C.; Hocqueloux, L.; Maggiolo, F.; Degen, O.; Taylor, S.; Blair, E.; et al. Efficacy and Safety of Switching to the 2-Drug Regimen Dolutegravir/Lamivudine Versus Continuing a 3- or 4-Drug Regimen for Maintaining Virologic Suppression in Adults Living With HIV-1: Week 48 Results From the Phase 3, Non-inferiority SALSA Randomized Trial. Clin. Infect. Dis. 2022, ciac130. [Google Scholar]
- Hidalgo-Tenorio, C.; Cortés, L.L.; Gutiérrez, A.; Santos, J.; Omar, M.; Gálvez, C.; Sequera, S.; De Jesús, S.E.; Téllez, F.; Fernández, E.; et al. DOLAMA study: Effectiveness, safety and pharmacoeconomic analysis of dual therapy with dolutegravir and lamivudine in virologically suppressed HIV-1 patients. Medicine 2019, 98, e16813. [Google Scholar] [CrossRef]
- 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]
- Maissenhaelter, B.E.; Woolmore, A.L.; Schlag, P.M. Real-world evidence research based on big data: Motivation-challenges-success factors. Onkologe 2018, 24, 91–98. [Google Scholar] [CrossRef] [Green Version]
- Wertz, R.T. Intention to treat: Once randomized, always analyzed. Clin. Aphasiol. 1995, 23, 57–64. [Google Scholar]
- Abraha, I.; Montedori, A. Modified inten- tion to treat reporting in randomised controlled trials: Systematic review. BMJ 2010, 340, c2697. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Day, S. Analysis Issues, ITT, Post-Hoc, and Subgroups. Johns Hopkins University. 2008. Available online: http://ocw.jhsph.edu/courses/Biostat-MedicalProductRegulation/biomed_lec7_day.pdf (accessed on 17 September 2022).
- Imaz, A.; Garcia, F.; di Yacovo, S.; Llibre, J.M. Perfil de resistencias a rilpivirina. Enferm. Infecc. Y Microbiol. Clín. 2013, 31, 36–43. [Google Scholar] [CrossRef]
- Mazzitelli, M.; Trunfio, M.; Putaggio, C.; Sasset, L.; Leoni, D.; Lo Menzo, S.; Mengato, D.; Cattelan, A.M. Viro-Immunological, Clinical Outcomes and Costs of Switching to BIC/TAF/FTC in a Cohort of People Living with HIV: A 48-Week Prospective Analysis. Biomedicines 2022, 10, 1823. [Google Scholar] [CrossRef]
- Eron, J.J.; Orkin, C.; Cunningham, D.; Pulido, F.; Post, F.A.; De Wit, S.; Lathouwers, E.; Hufkens, V.; Jezorwski, J.; Petrovic, R.; et al. Week 96 efficacy and safety results of the phase 3, randomized EMERALD trial to evaluate switching from boosted-protease inhibitors plus emtricitabine/tenofovir disoproxil fumarate regimens to the once daily, single- tablet regimen of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) in treatment-experienced, virologically-suppressed adults living with HIV-1. Antivir. Res. 2019, 170, 104543. [Google Scholar]
- Punekar, Y.S.; Parks, D.; Joshi, M.; Kaur, S.; Evitt, L.; Chounta, V.; Radford, M.; Jha, D.; Ferrante, S.; Sharma, S.; et al. Effectiveness and safety of dolutegravir two-drug regimens in virologically suppressed people living with HIV: A systematic literature review and meta-analysis of real-world evidence. HIV Med. 2021, 22, 423–433. [Google Scholar] [CrossRef]
- Llibre, J.M.; Hung, C.C.; Brinson, C.; Castelli, F.; Girard, P.M.; Kahl, L.P.; Blair, E.A.; Angelis, K.; Wynne, B.; Vandermeulen, K.; et al. Efficacy, safety, and tolerability of dolutegravir-rilpivirine for the maintenance of virological suppression in adults with HIV-1: Phase 3, randomised, non-inferiority SWORD-1 and SWORD-2 studies. Lancet 2018, 391, 839–849. [Google Scholar] [CrossRef]
- Nakagawa, F.; Lodwick, R.K.; Smith, C.J.; Smith, R.; Cambiano, V.; Lundgren, J.D.; Valerie, D.; Phillips, A.N. Projected life expectancy of people with HIV according to timing of diagnosis. AIDS 2012, 26, 335–343. [Google Scholar] [CrossRef] [Green Version]
- Back, D. 2-Drug regimens in HIV treatment: Pharmacological considerations. GERMS 2017, 7, 113–114. [Google Scholar] [CrossRef] [Green Version]
- van Wyk, J.; Orkin, C.; Rubio, R.; Bogner, J.; Baker, D.; Khuong-Josses, M.A. 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]
- Palacios, R.; Mayorga, M.; González-Domenech, C.M.; Hidalgo-Tenorio, C.; Gálvez, C.; Muñoz-Medina, L.; de la Torre, J.; Lozano, A.; Castaño, M.; Omar, M.; et al. Safety and Efficacy of Dolutegravir plus Rilpivirine in Treatment-Experienced HIV-Infected Patients: The DORIVIR Study. J. Int. Assoc. Provid. AIDS Care 2018, 17, 2325958218760847. [Google Scholar] [CrossRef] [PubMed]
- Capetti, A.F.; Cossu, M.V.; Sterrantino, G.; Barbarini, G.; Di Giambenedetto, S.; De Socio, G.V.; Orofino, G.; Di Biagio, A.; Celesia, B.M.; Rusconi, S.; et al. Dolutegravir Plus Rilpivirine as a Switch Option in cART-Experienced Patients: 96-Week Data. Ann. Pharmacother. 2018, 52, 740–746. [Google Scholar] [CrossRef]
- 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] [PubMed]
- McComsey, G.A.; Lupo, S.; Parks, D.; Poggio, M.C.; De Wet, J.; Kahl, L.P.; Angelis, K.; Wynne, B.; Vandermeulen, K.; Gartland, M.; et al. Switch from tenofovir disoproxil fumarate combination to dolutegravir with rilpivirine improves parameters of bone health. AIDS 2018, 32, 477–485. [Google Scholar] [CrossRef]
- Llibre, J.M.; Cortés LF, L.; 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]
- Anderson, S.J.; Hsu, C.Y.; Ou, H.T.; Ko, N.Y.; Yang, C.T.; Lopes, S. Cost-Effectiveness of Juluca for Human Immunodeficiency Virus Infection Treatment in Virologically Suppressed Adults in Taiwan. Value Health Reg. Issues 2021, 24, 216–223. [Google Scholar] [CrossRef]
Figure 1.
Flowchart of patients with rilpivirine plus dolutegravir (STR).
Table 1.
General description of 2DR population.
| Variable | N = 291 |
|---|---|
| Age (years), mean (± SD) | 51.3 (±11.4) |
| Male, n (%) | 226 (77.7) |
| Time from HIV diagnosis (year), median (IQR) | 19.7 (10.6–27) |
| CD4 nadir, mean (± SD) | 283.5 ± 204.6 |
| Baseline VL < 50 copies/mL, n (%), 95% CI | 287 (98.6) (97.1–99.9) |
| Viral load of HIV, log10, median (IQR) | 0 (0–0) |
| Baseline CD4, (cell/uL), mean (± SD) | 785.4 (±355.7) |
| Baseline CD4/CD8 ratio, mean (± SD) | 0.99 (±0.58) |
| History of AIDS (A3, B3, C), n (%), 95% CI | 12 5(42.9) (37.9–49.7) |
| HBs antigen positive, n (%) HB core antibody positive, n (%), 95% CI IgG HCV-positive (cured), n (%), 95% CI History of infectious transmission diseases, n (%) Smoking, n (%), CI 95% | 1 (0.3) 8 (2.7) (1.2–5.4) 67 (23) (18.8–29) 35 (12) 155 (53.3) (44.8–56.7) |
Risk factor for HIV infection, n (%)
| 54 (18.6) 184 (63.2) 48 (16.5) 2 (2.2) |
| Previous ART lines, median (IQR) | 5 (3–7) |
| Time on ART (years), median (IQR) | 15.3 (7.5–22.1) |
| Previous ART regimen, n (%) 3DR INSTI NNRTI PI 2DR INSTI + NNRTI Lamivudine + PI PI + NNRTI 1DR DRV/r or cob LOP/r | 100 (34.4) 53 (53) 20 (20) 27 (27) 91 (31.3) 40 (43.9) 26 (28.6) 25(27.4) 100 (34.4) 98 (98) 2 (2) |
| History of ARV with INSTI, n (%) History of ARV with NNRTI, n (%) | 87 (29.9) 111 (38.1) |
| Time (years) since genotype resistance test, median (IQR) | 13.5 (8.3–17.3) |
| Resistances to a NNRTI by patient | Resistance to RPV Y 181C, V179I Y181C, G190A, M184V M 184v, Y181C, V179I K103N, Y181C, V 106M K103N, V108I, M184I Decreased susceptibility to RPV K103N, G190A, M184V (2 patients) M184V, V106A, V 179D (2 patients) K103N, V108I, Y181C K101/E, G190A Sensible to RPV K103N, E138A K103N, M184V, P225HG106A, M184V |
| Median time (months) of RPV/DTGSTR administration (IQR) | 14 (9.5–21) |
| Reason for change to RPV/DTGSTR, n (%) | |
| Simplification/optimization Avoiding long-term drug toxicity Virological failure due to poor adherence to MTR | 203 (69.8) 78 (26.8) 10 (3.4) |
MSM: men who have sex with men; Ex-IVDU: ex-intravenous drug user; RPV: rilpivirine; DTG: dolutegravir; STR: single-tablet regimen; 3DR: three-drug regimen; 2DR: two-drug regimen; 1DR: monotherapy; NNRTI: non-nucleoside reverse transcriptase inhibitor; INSTI: integrase standard transfer inhibitor; MTR: multi-tablet regimen; PI: protease inhibitor.
Table 2.
Outcomes of RILDO study.
| Effectiveness | N = 291 |
|---|---|
| Intention-to-treat (ITT) analysis, (%) n/N * Modified ITT (mITT) analysis, (%) n/N ** Per-protocol (PP) analysis, (%) n/N *** | 96.2 (280/291) 97.5 (280/287) 99.3 (281/283) |
| n = 287 | |
| Blips, n (%) | 10 (3.5) |
| Virological failure, n (%) | 2 (0.69) |
| Adverse effects, n (%) | 2 (0.69) |
n = number of patients with undetectable viral load at end of follow-up. N * = number of patients in the study. N ** = number of patients in the cohort, excluding losses to follow-up. N *** = number of patients included, excluding those who discontinued treatment due to adverse effects, to avoid drug interactions, or by physician decision.
Table 3.
Virological failure.
| PLHIV | Age Years | S | Years Since HIV Diagnosis Stage | ART (Total Time, Previous ART and Time) Previous Lines | Baseline VL | VL in VF | ** RS | Month VF | Observations |
|---|---|---|---|---|---|---|---|---|---|
| 1 | 59 | M | 28.7 and B3 | 27 years in ART DRV/cob (49 months) 8 lines | <50 cop/mL | 173,000 cop/mL | Not available | 3 months | Abandoned ART and follow-up |
| 2 | 57 | F | 33.3 and B2 | 26 years in ART EVG/c/TAF/FTC (27 months) 14 lines | 25,700 cop/mL | 122,200 cop/mL | Not available | 19 months | Null adherence |
M: male; F: female; ART: antiretroviral therapy; DRV/cob: darunavir/cobicistat; EVG/C/FTC/TAF: elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide; VL: HIV viral load; VF: virological failure; ** RS: genotypic resistance test.
Table 4.
Analytical changes between baseline visit and last visit.
| Baseline | Last Visit | p Value | |
|---|---|---|---|
| CD4 (cells/uL), mean ± SD | 785.4 ± 355.7 | 772.7 ± 342.3 | 0.43 |
| CD4/CD8 ratio, mean ± SD | 0.99 ± 0.58 | 1.01 ± 0.54 | 0.013 |
| Creatinine clearance mL/h, mean ± SD | 117.5 ± 458.3 | 122.8 ± 592.3 | 0.001 |
| Total cholesterol (mg/dL), mean ± SD | 190.6 ± 39.4 | 176.8 ± 35.5 | 0.0001 |
| HDL cholesterol (mg/dL), mean ± SD | 52.1 ± 15.4 | 54.2 ± 15.1 | 0.482 |
| LDL cholesterol (mg/dL), mean ± SD | 118.9 ± 32.2 | 106.2 ± 29.8 | 0.0001 |
| TC/HDL ratio, mean ± SD | 3.9 ± 0.9 | 3.6 ± 0.9 | 0.0001 |
| Triglycerides (mg/dL), mean ± SD | 130.9 ± 73.9 | 115.3 ± 68.5 | 0.0001 |
| Bilirubin (mg/dL), mean ± SD | 0.7 ± 0.4 | 0.7 ± 0.3 | |
| GPT (UI/dL), mean ± SD | 26.8 ± 21.9 | 29.5 ± 25.1 | 0.0001 |
| GGT (UI/dL), mean ± SD | 38.9 ± 63.8 | 34.9 ± 56.2 | 0.794 |
| FA (UI/dL), mean ± SD | 77.8 ± 39.6 | 73.4 ± 32.5 | 0.0001 |
| Interleukin-6 (pg/mL), mean ± SD | 3.9 ± 5.8 | 4.1 ± 0.6 | 0.851 |
| D-dimer (UEF/mL), mean ± SD | 0.4 ± 0.4 | 0.4 ± 0.6 | 0.251 |
| Fibrinogen, mg/dL, mean ± SD | 283.9 ± 92.3 | 273.5 ± 116.8 | 0.054 |
| PCR, mg/dL | 3.3 ± 4.2 | 3.1 ± 4.5 | 0.093 |
Table 5.
(a) Cost minimization among the different ARTs. (b) Cost-effectiveness table.
| (a) Cost Minimization among the Different ARTs | ||||
| ARTs Compared | Differential Cost Per Year | |||
| RPV/DTGSTR vs. BIC/TAF/FTC | EUR −473.40 | |||
| RPV/DTGSTR vs. DRV/c/TAF/FTC | EUR −555.60 | |||
| RPV/DTGSTR vs. DTG/3TC | EUR 687.72 | |||
| (b) Cost-Effectiveness Table | ||||
| ART | Effectiveness | Cost (€/Year) | CER | ICER |
| DTG/3TC | 87.9% | EUR 4851 | 55 | 87 |
| BIC/FTC/TAF | 94.8.0% | EUR 6012 | 63 | −175 |
| DRV/c/FTC/TAF | 90.7% | EUR 6095 | 67 | −82 |
| RPV/DTGSTR | 97.5% | EUR 5539 | 57 | - |
CER cost-effectiveness ratio; ICER: incremental cost-effectiveness ratio. Bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF); darunavir/cobicistat/emtricitabine/tenofovir alafenamide (DRV/c/FTC/TAF).
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
MDPI and ACS Style
Hidalgo-Tenorio, C.; Vinuesa, D.; García-Vallecillos, C.; Muñoz-Medina, L.; Sequera, S.; Javier, R.; López-Ruz, M.Á.; 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. https://doi.org/10.3390/v14122626
AMA Style
Hidalgo-Tenorio C, Vinuesa D, García-Vallecillos C, Muñoz-Medina L, Sequera S, Javier R, López-Ruz MÁ, 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(12):2626. https://doi.org/10.3390/v14122626
Chicago/Turabian StyleHidalgo-Tenorio, Carmen, David Vinuesa, Coral García-Vallecillos, Leopoldo Muñoz-Medina, Sergio Sequera, Rosario Javier, Miguel Ángel López-Ruz, Svetlana Sadyrbaeva-Dolgova, and Juan Pasquau. 2022. "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 14, no. 12: 2626. https://doi.org/10.3390/v14122626
Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.
