Introduction

Switching antiretroviral therapy in stable, virologically suppressed patients with the aim of improving tolerability and convenience is an expanding strategy in clinical practice [1]. Rilpivirine (RPV), a second-generation nonnucleoside reverse-transcriptase inhibitor (NNRTI), is active against wild-type viruses and remains efficient against some NNRTI-resistant HIV strains [2]. RPV and its coformulation with emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) as a single-tablet regimen ([STR] RPV/FTC/TDF) is a good option for simplification strategies [3]. Significant improvements in clinical and analytical adverse events have been observed in virologically suppressed HIV-infected patients switching to RPV/FTC/TDF from a ritonavir-boosted protease inhibitor (PI/r) and NNRTI based regimens [4–6]. However, few data on RPV plus abacavir/lamivudine (ABC/3TC) are available, all of them concerning naïve patients [3].

The objective of this study was to analyse, in a real-world setting, the efficacy and safety of switching from a regimen based on NNRTI or integrase inhibitors (INI) to ABC/3TC plus RPV in virologically suppressed HIV-infected patients.

Methods

A cohort of 7,270 HIV-infected patients was followed prospectively in five hospitals from Andalusia, southern Spain. In this open-label, multicentre, non-controlled study, we retrospectively analysed the asymptomatic patients from this cohort who switched from a regimen based on two nucleoside reverse transcriptase inhibitors (NRTI) plus a NNRTI or INI to ABC/3TC plus RPV from February 2013 to December 2013. All the patients had to have had an undetectable (<50 copies/mL) viral load (VL) for at least the last 3 months prior to switching. Patients with previous failures on ART including ABC and/or 3TC, or with genotype tests showing resistance to ABC, 3TC or RPV were excluded. We assessed the percentage of patients with an undetectable VL and the CD4 responses with the new regimen at 48 weeks, and the percentage of patients who ceased ABC/3TC plus RPV due to adverse events. Changes were analysed in the lipid profile, including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), and the TC to HDL-C ratio, and in the cardiovascular risk (CVR) assessed by the Framingham equation, between baseline and 48 weeks after switching.

Institutional review board/ethics committee approval was obtained for the study protocol for the analysis of anonymous routine clinical data of patients. The study was sponsored by the Sociedad Andaluza de Enfermedades Infecciosas (SAEI) and registered as the SAEI 00/0067 study.

Data for each patient were included in a database for statistical analysis. A descriptive analysis of the variables was done with point estimation and 95 % confidence interval. Continuous variables are shown as the mean and standard deviation or the median, depending on the distribution. Categorical variables are shown as frequencies or percentages. Comparison of continuous data between baseline and 48 weeks was done with the Student t test for paired samples. The statistical program used was SPSS version 17.0 (SPSS, Chicago, IL, USA).

Results

Of the initial 97 patients recruited 12 were excluded as they did not fulfil the inclusion criteria (3 were naïve, 7 had already been treated with IP/r, 1 with three NTRI, and 1 with a regimen that included maraviroc), giving a final study sample of 85 cases. The median age was 47.4 (42.5–53.7) years, and 74.1 % were male. Most of the patients switched from a regimen based on NNRTI (97.6 %), mainly efavirenz (EFV). The main reason for switching was the presence of adverse events. The clinical characteristics of the patients at the time of switching are shown in Table 1.

Table 1 Baseline characteristics of the study patients (n = 85)
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At 48 weeks after switching to ABC/3TC plus RPV, 78 (91.8 %) patients were still taking the same regimen, with an increase in CD4 count (855 vs. 718 cells/μL); efficacy was 88 % by intention to treat (75 out of 85 with <50 copies/ml at 48 weeks), and 96 % by per protocol. Two of the other seven patients were lost to follow-up, and 5 (5.9 %) ceased the new regimen; there were four due to adverse events (2 digestive intolerance, 1 nephrotoxicity and 1 arthralgias) and one due to virologic failure with emergence of the E138K mutation. In addition to this last case, there were two patients with 64 cop/mL and 61 cop/mL at 48 weeks, which were considered blips. The mean levels of fasting TC and LDL-C fell at 24 and 48 weeks, with no changes detected in TG, HDL-C, TC to HDL-C ratio or CVR; lipid profile did not change in patients who switched from TDF (Table 2). The mean level of creatinine increased at 48 weeks (0.93 vs 0.97 mg/dL; p = 0.02), but it did not reach statistical significance when analysed depending on previous TDF or ABC use (0.95 vs 0.99 mg/dL; p = 0.1, and 0.91 vs 0.95 mg/dL; p = 0.08, respectively). All patients who switched from EFV improved CNS adverse events.

Table 2 Comparison of lipid levels at baseline and at 48 weeks
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Discussion

This study shows that stable suppressed patients who switch from a regimen of NRTI plus first-generation NNRTI or INI to ABC/3TC + RPV maintained good immuno-virologic control at 48 weeks and showed an improvement in their lipid profile. RPV has proven to have a better lipid profile compared with EFV in naïve patients [7]. Although more than half of the patients changed from the fixed dose TDF/FTC to ABC/3TC, we observed an improvement in lipid components, with decreases in TC and LDL-C. TDF has a better lipid profile than ABC. Although previous switch studies from ABC/3TC to TDF/FTC also show improvements in the lipid profile, the third antiretroviral is maintained in all these studies [8–10]. Here with the benefit seen in the lipid profile in our study, attributable mainly to RPV. Only five patients discontinued ABC/3TC plus RPV, four due to adverse events and one due to virologic failure. Although after discontinuation, EFV has an extended inductive effect on cytochrome P450 (CYP) 3A4 that, after switching, may reduce RPV exposure, this strategy was safe, as has been previously reported [6]. The main advantage of this scheme is the avoidance of TDF. Large meta-analyses have demonstrated a significantly greater loss of renal function in those on TDF compared to non-TDF-containing regimens [11] and TDF-induced tubular dysfunction in patients randomly assigned to either a TDF- or ABC-containing regimen [12]. Moreover, TDF is associated with increased bone toxicity [13]. In the randomized ASSERT study, patients on TDF experienced a significantly greater decline in hip bone mineral density compared to those in the ABC arm [14]. On the other hand, RPV has an excellent tolerance, without the central nervous system effects of EFV, and with few adverse events leading to suspension.

This study has certain limitations. First, the absence of a control group prevents us determining the evolution of the lipid profile and the effectiveness and safety in patients who would have continued with the prior regimen. The second limitation concerns the retrospective design of the study, and perhaps the small number of patients included.

In summary, at 48 weeks after switching from a regimen based on NRTI plus NNRTI or INI to ABC/3TC plus RPV, good immuno-virologic control was maintained and the lipid profile improved. This strategy therefore seems convenient for many HIV-infected patients.