Efficacy and Safety of Rilpivirine-Based Antiretroviral Therapy in Treatment-Naïve and Treatment-Experienced HIV-1-Positive Patients: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

Abstract

Rilpivirine (RPV) is a second-generation non-nucleoside reverse-transcriptase inhibitor used in combination antiretroviral therapy (cART) in naive and experienced HIV-positive adult subjects. To evaluate its efficacy and safety in these patient settings, we performed a metaanalysis of randomized controlled trials with available data at 48 and 96 weeks of follow-up. We considered 4 studies involving 2336 cART-naïve patients and 8 studies involving 3165 cART-experienced virologically controlled patients. Regarding efficacy, the virological response rate and the mean difference in the change from the baseline CD4 cell count were not significantly different between the RPV and comparator arms in both patient groups at both time points. Regarding safety, the discontinuation rates due to any adverse events (AEs), serious AEs, RPV-related AEs and AEs leading to drug discontinuation did not significantly differ from the rates in the comparator group at both time points. A systematic review of lipid changes was also performed: the safety and advantageous metabolic impact of RPV on lipids, especially among cART-naïve subjects at up to 96 weeks of follow-up, were confirmed. Our meta-analysis indicated that RPV-based regimens were effective and tolerable for both types of patients, which was consistent with published data from real-life settings. MetA-AnAlysis *Corresponding author: Dr. Daniela Mancusi, MSc, Biotechnologist, Medical Affairs Department, Infectious Diseases, Janssen-Cilag SpA, Via Michelangelo Buonarroti, 23, 20093 Cologno Monzese, Milano, Italy, Tel: +39-345-9581-944 Check for updates Introduction Rilpivirine (RPV; TMC278; Edurant®) is a secondgeneration non-nucleoside reverse-transcriptase inhibitor (NNRTI) with activity against many viral strains resistant to previous NNRTIs and a moderatehigh genetic barrier to resistance development [1,2]. RPV efficacy and safety have been assessed in registrative randomized controlled clinical trials (RCTs) in HIV-positive treatment-naïve [3-7] and treatmentexperienced patients [8-14] with documented longterm efficacy and tolerability. Real-life data from observational studies [15-21] eventually confirmed these results. Therefore, current Italian [22], European [23], British [24,25] and DHHS (Department of Health and Human Services) [26] HIV/AIDS guidelines recommend the use of RPV as a first-line third agent coupled with a nucleoside reverse transcriptase inhibitor backbone in people living with HIV (PLWH) with CD4 count > 200 cells/μL and HIV RNA < 100,000 copies/mL starting combination antiretroviral therapy (cART) and in optimization strategies represented by RPV-based single tablet regimens (both standard threeISSN: 2469-5831 DOI: 10.23937/2469-5831/1510040 Lazzarin et al. Int J Clin Biostat Biom 2021, 7:040 • Page 2 of 24 • mediated hepatic oxidation, no inhibition or induction of cytochrome P-450 isoenzymes has been reported, and its spectrum of interaction is favorably narrowed [1,2,27]. To date, one meta-analysis in 2014 has been performed on the efficacy and safety of RPV in treatment-naïve only adult PLWH, with efavirenz (EFV) [30] as the comparator. Considering the changing clinical background, as well as the versatility and various advantages of RPV, we conducted a systematic review and meta-analysis to evaluate the 48-week and longterm (defined as at least 96 weeks) efficacy (as the proportion of plasma HIV RNA < 50 cp/mL and as the change in CD4 cell/count) and safety (as the incidence of adverse events and as the change in lipid levels) of RPVbased cART compared to other current cART regimens in both treatment-naïve and treatment-experienced virologically suppressed PLWH. The data reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [31]. drug-based cART and, with some restrictions, dual regimens combined with dolutegravir). Furthermore, susceptibility to RPV is not affected by the presence of single common NNRTI resistance-associated substitutions, so it retains good antiviral activity against K103N and other codon-mutated strains [1,2,27]. Lastly, long-acting injectable formulations allowing oncemonthly or more distanced dosing with RPV sustainedrelease are under investigation (NCT03299049, NCT02938520, NCT03639311, and NCT02951052) or have already shown promising results, [28,29] being ready to be widely prescribed in clinical practice. RPV is administered orally as a 25-mg tablet once daily with food and is available alone or as a fixed-dose combination with emtricitabine/tenofovir (disoproxil or alafenamide) or with dolutegravir. No dosage adjustment is recommended for patients with renal dysfunction or mild-to-moderate hepatic insufficiency [1,2,27]. Although RPV is metabolized by CYP3A4Figure 1: Flowchart describing the literature search and study selection process. *Including two articles from which we extracted information on changes in lipid levels separately from the ECHO and THRIVE trials at 48 weeks of follow-up and 2 articles from the TMC278-C204 and SWORD 1&2 trials reporting results at 192 and 148 weeks of follow-up, respectively, that were not used in the meta-analyses. Abbreviations: RCT: Randomized clinical trial; RPV: Rilpivirine. ISSN: 2469-5831 DOI: 10.23937/2469-5831/1510040 Lazzarin et al. Int J Clin Biostat Biom 2021, 7:040 • Page 3 of 24 • were used when reporting results for lipid values, as the publication of the pooled analysis did not detail such quantitative information [36]) and the publications at 148 weeks of follow-up of the SWORD 1-2 trials [35] and at 192 weeks of the TMC278-C204 trial [6] (which were not used in the meta-analyses, as no other study had data for a comparable follow-up period). Thus, a total of 14 publications [5,7-14,28,32-34,36], which provided results on 12 distinct RCTs at 48 and/or 96 (± 8) weeks of follow-up, were included in the metaanalyses. The data were extracted from the selected articles in a standardized format by 2 independent reviewers. The data collected from each study included trial name, enrollment period, geographic area, number of patients included and treatment regimens, patient characteristics at baseline (e.g., cART-naïve or experienced patients, cut-off for plasma viral load and CD4 cell count for inclusion, age, and treatment duration before study inclusion for cART-experienced patients), duration of follow-up, and results for the efficacy and safety endpoints according to the ITT analysis. Data on viral suppression according to plasma viral load and CD4 cell count at baseline were also extracted from trials on cART-naïve patients. When available, the results of the US Food and Drug Administration (FDA) Snapshot algorithm were extracted. Our primary efficacy endpoint was the proportion of participants with viral suppression (defined as HIV RNA levels < 50 copies/mL) at 48 and 96 (± 8) weeks of follow-up. One study that defined viral suppression as HIV RNA levels < 40 copies/mL was also considered [14]. The secondary efficacy endpoint was the change in CD4 cell counts from baseline at 48 and 96 (± 8) weeks of follow-up. Safety endpoints include the number of any AEs, serious AEs, drug-related AEs and AEs leading to study discontinuation. Information on the change in lipids and glucose levels at 48 and 96 weeks of follow-up was also extracted. The TMC278-C204 study was a dose-ranging trial with three once-daily RPV doses (i.e., 25, 75 or 150 mg) [33]. In the meta-analyses, we included the results for the 25 mg dose only. The LATTE trial design included a 24-week induction phase assessing the antiviral activity and safety of 3 different cabotegravir doses over efavirenz in cART-naïve adult PLWH, followed by a 72-week maintenance phase assessing cabotegravir plus RPV (over EFV) for the maintenance of viral suppression [28]. Only results based on the maintenance-exposed population were included in the meta-analyses. That patient population was considered ART-experienced. The individual study quality assessment was performed with Version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB 2) [37] in relation to the specific outcome plasma HIV RNA. Statistical analysis The meta-analyses of the efficacy outcomes (i.e., HIV RNA levels < 50 copies/mL and change in CD4 cell counts from baseline) were conducted separately for the 48week and 96-week time points and for the treatmentMethods Search strategy Relevant studies were identified by systematic electronic literature searches in the Medline/PubMed, EMBASE and Cochrane Library databases from inception to June 2019. No language restriction was applied. The detailed search strategy is described in the Supplementary Methods. In addition, we manually reviewed the references of recent reviews and metaanalyses and of all the papers selected for inclusion to identify additional studies that met the inclusion criteria. The flowchart with detailed information on the search and selection process is presented in Figure 1. Inclusion and exclusion criteria RCTs with at least 48 weeks of follow-up and comparing the efficacy (viral suppression) and safety of RPV use (dose: 25 mg/day) with other cART in adult PLWH were included. Observational studies, reviews, meta-analyses, commentaries without original data, phase 1 studies, pharmacokinetic or bioequivalence studies on healthy subjects, pre-exposure prophylaxis studies, cost-effectiveness analyses, and non-Englishlanguage articles were excluded. The conference abstracts of relevant RCTs were considered only if a fulllength publication was not available. Single-arm studies, studies based on special populations (i.e., pregnant women), studies investigating long-acting RPV, studies in which RPV was used in both arms and for the same time period, and studies with a follow-up shorter than 48 weeks were also excluded. Studies comparing immediate to delayed switch to RPV-based regimens were considered eligible, and the delayed switch a