Lipid changes and tolerability in a cohort of adult HIV-infected patients who switched to rilpivirine/emtricitabine/tenofovir due to intolerance to previous combination ART: the PRO-STR study

Lipid changes and tolerability in a cohort of adult HIV-infected patients who switched to... Abstract Objectives To analyse lipid changes and tolerability in a cohort of HIV-infected patients who switched their antiretroviral regimens to rilpivirine/emtricitabine/tenofovir (RPV/FTC/TDF) in a real-world setting. Methods PRO-STR is a 48 week prospective observational post-authorization study in 25 hospitals. Patients with a viral load <1000 copies/mL, receiving at least 12 months of combination ART (cART), with constant posology for at least the prior 3 months, were categorized according to previous treatment [NNRTI or ritonavir-boosted PI (PI/r)]. Analytical tests were performed at the baseline visit, between week 16 and week 32, and at week 48. Results A total of 303 patients were included (mean age 46.6 years; male 74.0%; previous treatment 74.7% NNRTI and 25.3% PI/r). Both groups exhibited significantly reduced lipid profiles, except for HDL cholesterol, for which a non-significant increase was observed. [NNRTI patients: total cholesterol (baseline: 195.5 ± 38.4 mg/dL; week 48: 171.0 ± 35.5 mg/dL), total cholesterol/HDL ratio (baseline: 4.2 ± 1.2; week 48: 4.0 ± 1.2), HDL (baseline: 49.1 ± 12.0 mg/dL; week 48: 49.2 ± 45.8 mg/dL), LDL (baseline: 119.2 ± 30.2 mg/dL; week 48: 114.2 ± 110.7 mg/dL), and triglycerides (baseline: 136.6 ± 86.8 mg/dL; week 48: 113.4 ± 67.8 mg/dL); PI/r patients: total cholesterol (baseline: 203.2 ± 48.8 mg/dL; week 48: 173.4 ± 36.9 mg/dL), total cholesterol/HDL ratio (baseline: 4.7 ± 1.6; week 48: 4.0 ± 1.2), HDL (baseline: 46.4 ± 12.5 mg/dL; week 48: 52.1 ± 54.4 mg/dL), LDL (baseline: 127.0 ± 36.3 mg/dL; week 48: 111.4 ± 35.8 mg/dL), and triglycerides (baseline: 167.6 ± 107.7 mg/dL; week 48: 122.7 ± 72.1 mg/dL)]. The most common intolerances were neuropsychiatric in the NNRTI patients and gastrointestinal and metabolic in the PI/r patients, and these intolerances were significantly reduced in both groups at week 48 [NNRTI: neuropsychiatric (baseline: 81.3%; week 48: 0.0%); PI/r: gastrointestinal (baseline: 48.7%; week 48: 0.0%) and metabolic (baseline: 42.1%; week 48: 0.0%)]. Conclusions RPV/FTC/TDF improved the lipid profiles and reduced the intolerances after switching from NNRTI or PI-based regimens, in a cohort of HIV-infected patients. Introduction The development of HAART has rendered HIV a chronic illness in treated patients, yet the landscape of HIV-associated medical conditions continues to evolve.1 The introduction of combination antiretroviral therapy (cART) has improved morbidity and mortality associated with HIV infection. Additionally, cART has achieved significant benefits in recovering and preserving immune function, in reducing the harmful effects of HIV replication on possible existing comorbidities and in preventing HIV-1 transmission. However, proper management of cART is complex due to the different drug families and multiple aspects related to their efficacy, toxicity, resistance, tropism, interactions and use in special clinical situations.2 For example, a number of cART drugs present interactions among them, resulting in adverse effects and the necessity for dose adjustment in people with kidney or liver failure.3 Therefore, controlling the symptoms associated with adverse effects has been identified as an essential element for improving adherence and therapeutic efficacy.4,5 Advances in cART include the single-tablet regimen (STR), which involves a single tablet that incorporates three antiretrovirals administered once daily. This regimen simplifies the dosing frequency and reduces the number of tablets. The STR approach is associated with improved treatment adherence, a reduction in the rate of hospitalization, a higher therapeutic success rate and decreased mortality, with a potential impact on quality of life of the patients.6–8 Newer STRs are also associated with excellent tolerability and lipid profiles within normal ranges.9,10 Specifically, in addition to being associated with better tolerability, a change to rilpivirine/emtricitabine/tenofovir (RPV/FTC/TDF) maintains virological suppression.11 Nevertheless, studies with highly pragmatic approaches are needed to demonstrate the management of patients and collect data in a real-world setting (RWS) to improve efficiency, reduce treatment side effects and help prevent HIV infection.12–15 To improve decision-making in healthcare, it is essential to obtain information reported directly by patients about their health conditions and the treatment received, including symptoms and their functional status.12,16 The PRO-STR study17 aimed to investigate the impact of switching from an NNRTI- or PI-based cART regimen to the STR regimen (RPV/FTC/TDF), because of therapy intolerance, on patient-reported outcomes in routine clinical practice. In the present analysis in a RWS, the relationship between STR administration and lipid profile and tolerability was explored by categorizing patients according to their previous treatment; NNRTI or ritonavir-boosted PI (PI/r). Patients and methods PRO-STR is a prospective observational multicentre follow-up post-authorization study in a RWS, which was evaluated and approved by the Research Ethics Committees of the participating centres. The study consists of five visits as follows: the baseline visit (change of cART to STR) and visits at weeks 4, 16, 32 and 48. Of those patients who completed the baseline visit and the week 4 visit, some were excluded from the week 16 visit due to missing data among the main variables or due to treatment discontinuation. The HIV-infected adult patients included had viral loads below 1000 copies/mL, were treated for at least 12 months with cART (combination of at least three drugs that included two NNRTIs and one PI/r or a non-nucleoside analogue or an integrase inhibitor), remained unchanged in their cART regimen and posology for at least the prior 3 months and signed the informed consent form. Inclusion in the study resulted from the occurrence of any intolerance to the previous cART treatment (NNRTI or PI/r) that required a switch to an STR (RPV/FTC/TDF). Intolerance was defined as any adverse event or laboratory abnormality of grades 2 to 4 (according to the WHO reference scale) that caused the change to STR, independent of the cardiovascular risk of the patient. The intolerances were classified into the following groups based on symptoms reported by the patients and the results of laboratory tests: neuropsychiatric (sleep disorders and mood disturbances); gastrointestinal (nausea, vomiting or diarrhoea); and metabolic (hypercholesterolaemia, hypertriglyceridaemia, anaemia and abnormal glucose metabolism). For analysis purposes, patients were classified according to the previous treatment received (NNRTI or PI/r). The collected variables included patient sociodemographic data (age, gender, education level and employment status), clinical data (co-infections, viral load and CD4+ count) and intolerances. In this subanalysis of the PRO-STR study,17 the evolution of the clinical profile of the patients is described to assess the lipid profile at the baseline visit, between week 16 and week 32, and at week 48. Within these tests, the following parameters were recorded: total cholesterol, HDL, LDL, total cholesterol:HDL ratio and triglycerides. The statistical analysis was performed using R version 2.13.0. An alpha (α) risk value equal to 0.05 was assumed for all analyses. A P value ≤0.05 was considered significant. Means and standard deviations were used for continuous variables, and frequencies and percentages were used for categorical variables. For quantitative variables that met normality, statistical contrasts were performed for intrapatient comparisons (Student’s t-test for related and independent samples). However, non-parametric equivalent tests were employed in cases where the assumptions for parametric tests were not met (Mann–Whitney and Wilcoxon). Results A total of 303 patients from 25 centres who changed their previous treatment to RPV/FTC/TDF were included in the lipid profile data analysis. All 303 patients completed the baseline and week 16–32 visit, and 240 patients completed the week 48 visit. A total of 300 patients were included in the analyses of sociodemographic and clinical data. All 300 patients completed the baseline visit and the week 4 visit; 275 completed the week 16 visit; 260 the week 32 visit; and 235 the week 48 visit. The mean age was 46.6 years and 74.0% were male; 4.0% were co-infected with HBV and 13.7% with HCV. The previous cART components are shown in Table 1. NNRTI was the previous cART in 74.7% of the patients (89.7% efavirenz); PI/r was the previous cART in the remaining 25.3% (42.1% emtricitabine/tenofovir/darunavir boosted with ritonavir, 31.6% emtricitabine/tenofovir/atazanavir boosted with ritonavir, and 22.4% emtricitabine/tenofovir/lopinavir boosted with ritonavir). Table 1. Baseline characteristics of the treatments Characteristic Value Time since HIV diagnosis, years (mean; median; IQR) 12.72; 11.00; 11.00 Time on ART, years (mean; median; IQR) 8.28; 6.77; 8.77 Time on last ART, years (mean; median; IQR) 4.06; 4.05; 3.42 Number of previous ART regimens (mean; median; IQR) 2.55; 2.00; 2.00 Previous cART components, n (%)  tenofovir/emtricitabine (or lamivudine) 278 (92.6)  abacavir/lamivudine 18 (6.0)  didanosine/lamivudine 2 (0.7)  zidovudine/lamivudine 2 (0.7)  efavirenz 201 (67.0)  nevirapine 13 (4.3)  etravirine 10 (3.3)  lopinavir/ritonavir 16 (5.3)  darunavir/ritonavir 32 (10.7)  atazanavir/ritonavir 24 (8.0)  fosamprenavir/ritonavir 2 (0.7)  ritonavira 74 (24.7)  lopinavir 1 (0.3)  fosamprenavir 1 (0.3) Characteristic Value Time since HIV diagnosis, years (mean; median; IQR) 12.72; 11.00; 11.00 Time on ART, years (mean; median; IQR) 8.28; 6.77; 8.77 Time on last ART, years (mean; median; IQR) 4.06; 4.05; 3.42 Number of previous ART regimens (mean; median; IQR) 2.55; 2.00; 2.00 Previous cART components, n (%)  tenofovir/emtricitabine (or lamivudine) 278 (92.6)  abacavir/lamivudine 18 (6.0)  didanosine/lamivudine 2 (0.7)  zidovudine/lamivudine 2 (0.7)  efavirenz 201 (67.0)  nevirapine 13 (4.3)  etravirine 10 (3.3)  lopinavir/ritonavir 16 (5.3)  darunavir/ritonavir 32 (10.7)  atazanavir/ritonavir 24 (8.0)  fosamprenavir/ritonavir 2 (0.7)  ritonavira 74 (24.7)  lopinavir 1 (0.3)  fosamprenavir 1 (0.3) a Patients with ritonavir as PI booster. Table 1. Baseline characteristics of the treatments Characteristic Value Time since HIV diagnosis, years (mean; median; IQR) 12.72; 11.00; 11.00 Time on ART, years (mean; median; IQR) 8.28; 6.77; 8.77 Time on last ART, years (mean; median; IQR) 4.06; 4.05; 3.42 Number of previous ART regimens (mean; median; IQR) 2.55; 2.00; 2.00 Previous cART components, n (%)  tenofovir/emtricitabine (or lamivudine) 278 (92.6)  abacavir/lamivudine 18 (6.0)  didanosine/lamivudine 2 (0.7)  zidovudine/lamivudine 2 (0.7)  efavirenz 201 (67.0)  nevirapine 13 (4.3)  etravirine 10 (3.3)  lopinavir/ritonavir 16 (5.3)  darunavir/ritonavir 32 (10.7)  atazanavir/ritonavir 24 (8.0)  fosamprenavir/ritonavir 2 (0.7)  ritonavira 74 (24.7)  lopinavir 1 (0.3)  fosamprenavir 1 (0.3) Characteristic Value Time since HIV diagnosis, years (mean; median; IQR) 12.72; 11.00; 11.00 Time on ART, years (mean; median; IQR) 8.28; 6.77; 8.77 Time on last ART, years (mean; median; IQR) 4.06; 4.05; 3.42 Number of previous ART regimens (mean; median; IQR) 2.55; 2.00; 2.00 Previous cART components, n (%)  tenofovir/emtricitabine (or lamivudine) 278 (92.6)  abacavir/lamivudine 18 (6.0)  didanosine/lamivudine 2 (0.7)  zidovudine/lamivudine 2 (0.7)  efavirenz 201 (67.0)  nevirapine 13 (4.3)  etravirine 10 (3.3)  lopinavir/ritonavir 16 (5.3)  darunavir/ritonavir 32 (10.7)  atazanavir/ritonavir 24 (8.0)  fosamprenavir/ritonavir 2 (0.7)  ritonavira 74 (24.7)  lopinavir 1 (0.3)  fosamprenavir 1 (0.3) a Patients with ritonavir as PI booster. The viral load remained undetectable (<50 copies/mL) in most of the patients (baseline visit: 97.18%, week 48, visit 97.18%; P value = 1), and CD4+ counts did not exhibit significant changes across visits (baseline visit: 707.76 cells/mm3; week 48 visit: 683.00 cells/mm3; P value = 0.111). The proportion of patients with CD4+ count >500 cells/mm3 remained similar between baseline visit and at week 48 (71.5% and 75.7%, respectively; P value = 0.85). Table 2 describes intolerances to previous cART. Among patients who previously received treatment with NNRTI family drugs, neuropsychiatric intolerances were the main cause of the change from cART (81.3%). For patients previously treated with PI/r family drugs, the primary intolerances were gastrointestinal (48.7%) and metabolic (42.1%), with both occasionally appearing simultaneously (Table 2). The most frequent neuropsychiatric symptoms were sleep disorders (62.1%) and mood disorders (36.3%). Diarrhoea was the most common gastrointestinal symptom (73.0%). Hypercholesterolaemia (21.9%), dyslipidaemia (21.9%), and hypertriglyceridaemia (18.8%) were the most common metabolic symptoms. Table 2. Description of intolerances to previous cART PI/r NNRTI Intolerancea n % n % Gastrointestinal (n = 58)  diarrhoea 27 73 8 38  constipation 0 0 1 5  nausea 2 5 7 33  abdominal discomfort 3 8 3 14  dyspepsia 1 3 1 5  vomiting 0 0 2 10  gastritis 1 3 0 0  others 5 14 2 10 Total gastrointestinal 37 21 Neuropsychiatric (n = 187)  mood alteration 4 80 66 36  sleep disorder 2 40 113 62 Total neuropsychiatric 5 182 Metabolic (n = 58)  dyslipidaemia 7 22 6 23  hypertriglyceridaemia 6 19 5 19  hyperbilirubinaemia 11 34 0 0  hypercholesterolaemia 7 22 7 27  jaundice 5 16 0 0  others 6 19 7 27 Total metabolic 32 26 PI/r NNRTI Intolerancea n % n % Gastrointestinal (n = 58)  diarrhoea 27 73 8 38  constipation 0 0 1 5  nausea 2 5 7 33  abdominal discomfort 3 8 3 14  dyspepsia 1 3 1 5  vomiting 0 0 2 10  gastritis 1 3 0 0  others 5 14 2 10 Total gastrointestinal 37 21 Neuropsychiatric (n = 187)  mood alteration 4 80 66 36  sleep disorder 2 40 113 62 Total neuropsychiatric 5 182 Metabolic (n = 58)  dyslipidaemia 7 22 6 23  hypertriglyceridaemia 6 19 5 19  hyperbilirubinaemia 11 34 0 0  hypercholesterolaemia 7 22 7 27  jaundice 5 16 0 0  others 6 19 7 27 Total metabolic 32 26 a Patients could exhibit more than one type of intolerance. Table 2. Description of intolerances to previous cART PI/r NNRTI Intolerancea n % n % Gastrointestinal (n = 58)  diarrhoea 27 73 8 38  constipation 0 0 1 5  nausea 2 5 7 33  abdominal discomfort 3 8 3 14  dyspepsia 1 3 1 5  vomiting 0 0 2 10  gastritis 1 3 0 0  others 5 14 2 10 Total gastrointestinal 37 21 Neuropsychiatric (n = 187)  mood alteration 4 80 66 36  sleep disorder 2 40 113 62 Total neuropsychiatric 5 182 Metabolic (n = 58)  dyslipidaemia 7 22 6 23  hypertriglyceridaemia 6 19 5 19  hyperbilirubinaemia 11 34 0 0  hypercholesterolaemia 7 22 7 27  jaundice 5 16 0 0  others 6 19 7 27 Total metabolic 32 26 PI/r NNRTI Intolerancea n % n % Gastrointestinal (n = 58)  diarrhoea 27 73 8 38  constipation 0 0 1 5  nausea 2 5 7 33  abdominal discomfort 3 8 3 14  dyspepsia 1 3 1 5  vomiting 0 0 2 10  gastritis 1 3 0 0  others 5 14 2 10 Total gastrointestinal 37 21 Neuropsychiatric (n = 187)  mood alteration 4 80 66 36  sleep disorder 2 40 113 62 Total neuropsychiatric 5 182 Metabolic (n = 58)  dyslipidaemia 7 22 6 23  hypertriglyceridaemia 6 19 5 19  hyperbilirubinaemia 11 34 0 0  hypercholesterolaemia 7 22 7 27  jaundice 5 16 0 0  others 6 19 7 27 Total metabolic 32 26 a Patients could exhibit more than one type of intolerance. Dyslipidaemia at baseline was reported for seven patients in the PI/r group (22%) and six patients (23%) in the NNRTI group. After the therapeutical switch to RPV/FTC/TDF no patients presented with dyslipidaemia. As shown in Table 3, all intolerances were resolved or improved during the monitoring period in both groups of patients. In the patients whose prior treatment was NNRTI, the majority of their intolerances were resolved by the week 4 visit, with only 6.1% of the symptoms persisting. By week 16, only 1.0% of the symptoms remained, and all of the symptoms were resolved by week 48. The vast majority of the intolerances in the group of patients whose prior treatment was PI/r were also resolved during monitoring, with only 6.5% of the intolerances persisting by week 4. Only 2.8% of the symptoms remained at week 16, and both gastrointestinal and metabolic intolerances were resolved by week 48. Table 3. Evolution of intolerancesa to previous cART Total intolerances, n (%) Baseline Week 4 Week 16 Week 32 Week 48 (n = 300) (n = 300) P value (n = 275) P value (n = 260) P value (n = 235) P value  gastrointestinal 58 (19.3) 5 (1.7) <0.001 1 (0.4) <0.001 1 (0.4) <0.001 0 (0.0) <0.001  CNS–psychiatry 187 (62.3) 6 (2.0) <0.001 1 (0.4) <0.001 0 (0.0) <0.001 1 (0.4) <0.001  metabolic 58 (19.3) 5 (1.7) <0.001 2 (0.7) <0.001 1 (0.4) <0.001 0 (0.0) <0.001  others 29 (9.7) 3 (1.0) <0.001 0 (0.0) <0.001 1 (0.4) <0.001 0 (0.0) <0.001 NNRTI intolerances, n (%) Baseline Week 4 Week 16 Week 32 Week 48 (n = 224) (n = 224) (n = 204) (n = 192) (n = 174)  gastrointestinal 21 (9.4) 3 (1.3) <0.001 1 (0.5) <0.001 1 (0.5) <0.001 0 (0.0) <0.001  CNS–psychiatry 182 (81.3) 5 (2.2) <0.001 1 (0.5) <0.001 0 (0.0) <0.001 0 (0.0) <0.001  metabolic 26 (11.6) 3 (1.3) <0.001 0 (0.0) <0.001 0 (0.0) <0.001 0 (0.0) <0.001  others 20 (8.9) 3 (1.3) <0.001 0 (0.0) <0.001 0 (0.0) <0.001 0 (0.0) <0.001 PI/r intolerances, n (%) Baseline Week 4 Week 16 Week 32 Week 48 (n = 76) (n = 76) (n = 71) (n = 68) (n = 61)  gastrointestinal 37 (48.7) 2 (2.6) <0.001 0 (0.0) <0.001 0 (0.0) <0.001 0 (0.0) <0.001  CNS–psychiatry 5 (6.6) 1 (1.3) 0.211 0 (0.0) 0.219 0 (0.0) 0.453 1 (1.6) 0.325  metabolic 32 (42.1) 2 (2.6) <0.001 2 (2.8) <0.001 1 (1.5) <0.001 0 (0.0) <0.001  others 9 (11.8) 0 (0.0) 0.005 0 (0.0) <0.001 1 (1.5) <0.001 0 (0.0) 0.001 Total intolerances, n (%) Baseline Week 4 Week 16 Week 32 Week 48 (n = 300) (n = 300) P value (n = 275) P value (n = 260) P value (n = 235) P value  gastrointestinal 58 (19.3) 5 (1.7) <0.001 1 (0.4) <0.001 1 (0.4) <0.001 0 (0.0) <0.001  CNS–psychiatry 187 (62.3) 6 (2.0) <0.001 1 (0.4) <0.001 0 (0.0) <0.001 1 (0.4) <0.001  metabolic 58 (19.3) 5 (1.7) <0.001 2 (0.7) <0.001 1 (0.4) <0.001 0 (0.0) <0.001  others 29 (9.7) 3 (1.0) <0.001 0 (0.0) <0.001 1 (0.4) <0.001 0 (0.0) <0.001 NNRTI intolerances, n (%) Baseline Week 4 Week 16 Week 32 Week 48 (n = 224) (n = 224) (n = 204) (n = 192) (n = 174)  gastrointestinal 21 (9.4) 3 (1.3) <0.001 1 (0.5) <0.001 1 (0.5) <0.001 0 (0.0) <0.001  CNS–psychiatry 182 (81.3) 5 (2.2) <0.001 1 (0.5) <0.001 0 (0.0) <0.001 0 (0.0) <0.001  metabolic 26 (11.6) 3 (1.3) <0.001 0 (0.0) <0.001 0 (0.0) <0.001 0 (0.0) <0.001  others 20 (8.9) 3 (1.3) <0.001 0 (0.0) <0.001 0 (0.0) <0.001 0 (0.0) <0.001 PI/r intolerances, n (%) Baseline Week 4 Week 16 Week 32 Week 48 (n = 76) (n = 76) (n = 71) (n = 68) (n = 61)  gastrointestinal 37 (48.7) 2 (2.6) <0.001 0 (0.0) <0.001 0 (0.0) <0.001 0 (0.0) <0.001  CNS–psychiatry 5 (6.6) 1 (1.3) 0.211 0 (0.0) 0.219 0 (0.0) 0.453 1 (1.6) 0.325  metabolic 32 (42.1) 2 (2.6) <0.001 2 (2.8) <0.001 1 (1.5) <0.001 0 (0.0) <0.001  others 9 (11.8) 0 (0.0) 0.005 0 (0.0) <0.001 1 (1.5) <0.001 0 (0.0) 0.001 P values are all against baseline; P values ≤ 0.05 are shown in bold. a Patients could exhibit more than one type of intolerance. Table 3. Evolution of intolerancesa to previous cART Total intolerances, n (%) Baseline Week 4 Week 16 Week 32 Week 48 (n = 300) (n = 300) P value (n = 275) P value (n = 260) P value (n = 235) P value  gastrointestinal 58 (19.3) 5 (1.7) <0.001 1 (0.4) <0.001 1 (0.4) <0.001 0 (0.0) <0.001  CNS–psychiatry 187 (62.3) 6 (2.0) <0.001 1 (0.4) <0.001 0 (0.0) <0.001 1 (0.4) <0.001  metabolic 58 (19.3) 5 (1.7) <0.001 2 (0.7) <0.001 1 (0.4) <0.001 0 (0.0) <0.001  others 29 (9.7) 3 (1.0) <0.001 0 (0.0) <0.001 1 (0.4) <0.001 0 (0.0) <0.001 NNRTI intolerances, n (%) Baseline Week 4 Week 16 Week 32 Week 48 (n = 224) (n = 224) (n = 204) (n = 192) (n = 174)  gastrointestinal 21 (9.4) 3 (1.3) <0.001 1 (0.5) <0.001 1 (0.5) <0.001 0 (0.0) <0.001  CNS–psychiatry 182 (81.3) 5 (2.2) <0.001 1 (0.5) <0.001 0 (0.0) <0.001 0 (0.0) <0.001  metabolic 26 (11.6) 3 (1.3) <0.001 0 (0.0) <0.001 0 (0.0) <0.001 0 (0.0) <0.001  others 20 (8.9) 3 (1.3) <0.001 0 (0.0) <0.001 0 (0.0) <0.001 0 (0.0) <0.001 PI/r intolerances, n (%) Baseline Week 4 Week 16 Week 32 Week 48 (n = 76) (n = 76) (n = 71) (n = 68) (n = 61)  gastrointestinal 37 (48.7) 2 (2.6) <0.001 0 (0.0) <0.001 0 (0.0) <0.001 0 (0.0) <0.001  CNS–psychiatry 5 (6.6) 1 (1.3) 0.211 0 (0.0) 0.219 0 (0.0) 0.453 1 (1.6) 0.325  metabolic 32 (42.1) 2 (2.6) <0.001 2 (2.8) <0.001 1 (1.5) <0.001 0 (0.0) <0.001  others 9 (11.8) 0 (0.0) 0.005 0 (0.0) <0.001 1 (1.5) <0.001 0 (0.0) 0.001 Total intolerances, n (%) Baseline Week 4 Week 16 Week 32 Week 48 (n = 300) (n = 300) P value (n = 275) P value (n = 260) P value (n = 235) P value  gastrointestinal 58 (19.3) 5 (1.7) <0.001 1 (0.4) <0.001 1 (0.4) <0.001 0 (0.0) <0.001  CNS–psychiatry 187 (62.3) 6 (2.0) <0.001 1 (0.4) <0.001 0 (0.0) <0.001 1 (0.4) <0.001  metabolic 58 (19.3) 5 (1.7) <0.001 2 (0.7) <0.001 1 (0.4) <0.001 0 (0.0) <0.001  others 29 (9.7) 3 (1.0) <0.001 0 (0.0) <0.001 1 (0.4) <0.001 0 (0.0) <0.001 NNRTI intolerances, n (%) Baseline Week 4 Week 16 Week 32 Week 48 (n = 224) (n = 224) (n = 204) (n = 192) (n = 174)  gastrointestinal 21 (9.4) 3 (1.3) <0.001 1 (0.5) <0.001 1 (0.5) <0.001 0 (0.0) <0.001  CNS–psychiatry 182 (81.3) 5 (2.2) <0.001 1 (0.5) <0.001 0 (0.0) <0.001 0 (0.0) <0.001  metabolic 26 (11.6) 3 (1.3) <0.001 0 (0.0) <0.001 0 (0.0) <0.001 0 (0.0) <0.001  others 20 (8.9) 3 (1.3) <0.001 0 (0.0) <0.001 0 (0.0) <0.001 0 (0.0) <0.001 PI/r intolerances, n (%) Baseline Week 4 Week 16 Week 32 Week 48 (n = 76) (n = 76) (n = 71) (n = 68) (n = 61)  gastrointestinal 37 (48.7) 2 (2.6) <0.001 0 (0.0) <0.001 0 (0.0) <0.001 0 (0.0) <0.001  CNS–psychiatry 5 (6.6) 1 (1.3) 0.211 0 (0.0) 0.219 0 (0.0) 0.453 1 (1.6) 0.325  metabolic 32 (42.1) 2 (2.6) <0.001 2 (2.8) <0.001 1 (1.5) <0.001 0 (0.0) <0.001  others 9 (11.8) 0 (0.0) 0.005 0 (0.0) <0.001 1 (1.5) <0.001 0 (0.0) 0.001 P values are all against baseline; P values ≤ 0.05 are shown in bold. a Patients could exhibit more than one type of intolerance. The changes in lipid profile during treatment are detailed in Table 4. A significant decrease (P value ≤0.05) in all analytical values (except for HDL cholesterol, for which an increase was observed) was observed after the change to RPV/FTC/TDF in the two groups of patients. Table 4. Lipid changes Baseline (n = 303) Week 16–32 (n = 303) Change ± SD P value between groups P value between visits Week 48 (n = 240) Change ± SD P value between groups P value between visits Total cholesterol  NNRTI 195.53 ± 38.40 169.96 ± 36.14 25.33 ± 27.97 0.366c <0.001a 170.97 ± 35.48 25.63 ± 30.16 0.550c <0.001b  PI/r 203.16 ± 48.76 178.61 ± 43.14 24.53 ± 32.72 <0.001b 173.44 ± 36.81 28.03 ± 31.93 <0.001b HDL cholesterol  NNRTI 49.07 ± 11.96 43.92 ± 10.10 5.20  ± 8.78 0.012c <0.001b 49.16 ± 45.80 −0.53 ± 47.71 0.024d <0.001a  PI/r 46.40±12.50 44.80 ± 13.02 2.17 ± 11.48 0.345b 52.11 ± 54.44 −5.91 ± 55.07 0.523a LDL cholesterol  NNRTI 119.21 ± 30.23 105.67 ± 31.22 14.42 ± 23.46 0.751c <0.001b 114.20 ± 110.67 5.41 ± 112.21 0.837d <0.001a  PI/r 126.96 ± 36.34 111.05 ± 32.39 14.04 ± 29.04 <0.001b 111.38 ± 35.71 17.38 ± 32.08 <0.001b Total cholesterol:HDL ratio  NNRTI 4.20 ± 1.21 4.01 ± 1.01 0.18 ± 0.81 0.020d 0.004a 3.96 ± 1.16 0.25 ± 1.10 0.018d 0.002a  PI/r 4.68 ± 1.58 4.26 ± 1.72 0.26 ± 1.55 0.067b 4.00 ± 1.16 0.72 ± 1.44 <0.001b Triglycerides  NNRTI 136.55 ± 86.78 105.72 ± 50.56 29.76 ± 68.55 0.016d <0.001a 113.37 ± 67.77 24.60 ± 67.29 0.003d <0.001a  PI/r 167.55 ± 107.71 119.00 ± 63.03 49.73 ± 83.92 <0.001a 122.68 ± 72.13 43.25 ± 92.31 <0.001a Baseline (n = 303) Week 16–32 (n = 303) Change ± SD P value between groups P value between visits Week 48 (n = 240) Change ± SD P value between groups P value between visits Total cholesterol  NNRTI 195.53 ± 38.40 169.96 ± 36.14 25.33 ± 27.97 0.366c <0.001a 170.97 ± 35.48 25.63 ± 30.16 0.550c <0.001b  PI/r 203.16 ± 48.76 178.61 ± 43.14 24.53 ± 32.72 <0.001b 173.44 ± 36.81 28.03 ± 31.93 <0.001b HDL cholesterol  NNRTI 49.07 ± 11.96 43.92 ± 10.10 5.20  ± 8.78 0.012c <0.001b 49.16 ± 45.80 −0.53 ± 47.71 0.024d <0.001a  PI/r 46.40±12.50 44.80 ± 13.02 2.17 ± 11.48 0.345b 52.11 ± 54.44 −5.91 ± 55.07 0.523a LDL cholesterol  NNRTI 119.21 ± 30.23 105.67 ± 31.22 14.42 ± 23.46 0.751c <0.001b 114.20 ± 110.67 5.41 ± 112.21 0.837d <0.001a  PI/r 126.96 ± 36.34 111.05 ± 32.39 14.04 ± 29.04 <0.001b 111.38 ± 35.71 17.38 ± 32.08 <0.001b Total cholesterol:HDL ratio  NNRTI 4.20 ± 1.21 4.01 ± 1.01 0.18 ± 0.81 0.020d 0.004a 3.96 ± 1.16 0.25 ± 1.10 0.018d 0.002a  PI/r 4.68 ± 1.58 4.26 ± 1.72 0.26 ± 1.55 0.067b 4.00 ± 1.16 0.72 ± 1.44 <0.001b Triglycerides  NNRTI 136.55 ± 86.78 105.72 ± 50.56 29.76 ± 68.55 0.016d <0.001a 113.37 ± 67.77 24.60 ± 67.29 0.003d <0.001a  PI/r 167.55 ± 107.71 119.00 ± 63.03 49.73 ± 83.92 <0.001a 122.68 ± 72.13 43.25 ± 92.31 <0.001a All lipid values (mg/dL) shown are mean ± SD. P values ≤0.05 are shown in bold. a The Wilcoxon test was used. b Student’s t-test for related samples was used. c Student’s t-test for independent samples was used. d The Mann–Whitney test was used. Table 4. Lipid changes Baseline (n = 303) Week 16–32 (n = 303) Change ± SD P value between groups P value between visits Week 48 (n = 240) Change ± SD P value between groups P value between visits Total cholesterol  NNRTI 195.53 ± 38.40 169.96 ± 36.14 25.33 ± 27.97 0.366c <0.001a 170.97 ± 35.48 25.63 ± 30.16 0.550c <0.001b  PI/r 203.16 ± 48.76 178.61 ± 43.14 24.53 ± 32.72 <0.001b 173.44 ± 36.81 28.03 ± 31.93 <0.001b HDL cholesterol  NNRTI 49.07 ± 11.96 43.92 ± 10.10 5.20  ± 8.78 0.012c <0.001b 49.16 ± 45.80 −0.53 ± 47.71 0.024d <0.001a  PI/r 46.40±12.50 44.80 ± 13.02 2.17 ± 11.48 0.345b 52.11 ± 54.44 −5.91 ± 55.07 0.523a LDL cholesterol  NNRTI 119.21 ± 30.23 105.67 ± 31.22 14.42 ± 23.46 0.751c <0.001b 114.20 ± 110.67 5.41 ± 112.21 0.837d <0.001a  PI/r 126.96 ± 36.34 111.05 ± 32.39 14.04 ± 29.04 <0.001b 111.38 ± 35.71 17.38 ± 32.08 <0.001b Total cholesterol:HDL ratio  NNRTI 4.20 ± 1.21 4.01 ± 1.01 0.18 ± 0.81 0.020d 0.004a 3.96 ± 1.16 0.25 ± 1.10 0.018d 0.002a  PI/r 4.68 ± 1.58 4.26 ± 1.72 0.26 ± 1.55 0.067b 4.00 ± 1.16 0.72 ± 1.44 <0.001b Triglycerides  NNRTI 136.55 ± 86.78 105.72 ± 50.56 29.76 ± 68.55 0.016d <0.001a 113.37 ± 67.77 24.60 ± 67.29 0.003d <0.001a  PI/r 167.55 ± 107.71 119.00 ± 63.03 49.73 ± 83.92 <0.001a 122.68 ± 72.13 43.25 ± 92.31 <0.001a Baseline (n = 303) Week 16–32 (n = 303) Change ± SD P value between groups P value between visits Week 48 (n = 240) Change ± SD P value between groups P value between visits Total cholesterol  NNRTI 195.53 ± 38.40 169.96 ± 36.14 25.33 ± 27.97 0.366c <0.001a 170.97 ± 35.48 25.63 ± 30.16 0.550c <0.001b  PI/r 203.16 ± 48.76 178.61 ± 43.14 24.53 ± 32.72 <0.001b 173.44 ± 36.81 28.03 ± 31.93 <0.001b HDL cholesterol  NNRTI 49.07 ± 11.96 43.92 ± 10.10 5.20  ± 8.78 0.012c <0.001b 49.16 ± 45.80 −0.53 ± 47.71 0.024d <0.001a  PI/r 46.40±12.50 44.80 ± 13.02 2.17 ± 11.48 0.345b 52.11 ± 54.44 −5.91 ± 55.07 0.523a LDL cholesterol  NNRTI 119.21 ± 30.23 105.67 ± 31.22 14.42 ± 23.46 0.751c <0.001b 114.20 ± 110.67 5.41 ± 112.21 0.837d <0.001a  PI/r 126.96 ± 36.34 111.05 ± 32.39 14.04 ± 29.04 <0.001b 111.38 ± 35.71 17.38 ± 32.08 <0.001b Total cholesterol:HDL ratio  NNRTI 4.20 ± 1.21 4.01 ± 1.01 0.18 ± 0.81 0.020d 0.004a 3.96 ± 1.16 0.25 ± 1.10 0.018d 0.002a  PI/r 4.68 ± 1.58 4.26 ± 1.72 0.26 ± 1.55 0.067b 4.00 ± 1.16 0.72 ± 1.44 <0.001b Triglycerides  NNRTI 136.55 ± 86.78 105.72 ± 50.56 29.76 ± 68.55 0.016d <0.001a 113.37 ± 67.77 24.60 ± 67.29 0.003d <0.001a  PI/r 167.55 ± 107.71 119.00 ± 63.03 49.73 ± 83.92 <0.001a 122.68 ± 72.13 43.25 ± 92.31 <0.001a All lipid values (mg/dL) shown are mean ± SD. P values ≤0.05 are shown in bold. a The Wilcoxon test was used. b Student’s t-test for related samples was used. c Student’s t-test for independent samples was used. d The Mann–Whitney test was used. A multivariate analysis was performed considering the following demographic variables: gender, weight, age and race. This analysis did not show any statistically significant differences for either of the two patient groups (PI/r and NNRTI; data not shown). Significant differences in the various lipid values were found between the two groups of patients at baseline. The patients with prior PI/r treatment had significantly higher (P value ≤0.05) total cholesterol:HDL ratios and triglyceride values than the patients treated with NNRTI. At week 48, those who switched from PI/r treatment had significantly lower (P value ≤0.05) total cholesterol, LDL cholesterol levels, total cholesterol:HDL ratios and triglyceride values. To explore the impact of viral load on the lipid profile, a subanalysis was carried out for patients with undetectable viral load (<50 copies/mL). Contrary to the observation in the primary analysis, a statistically difference (P < 0.001) in the total cholesterol:HDL ratio between week 32 and baseline values was detected for the group of patients previously treated with a PI/r regimen, whilst no statistically difference (P = 0.051) was found for the NNRTI patient group. Additional differences for the other parameters were not found (data not shown). Discussion The PRO-STR study evaluated the impact of the change from cART to STR in HIV-infected patients. Previous studies in Spain18 have suggested that treatment switch could be associated with improvements in lipid profile of the patients. The present analysis assessed lipid profiles and tolerability in patients who began RPV/FTC/TDF in a RWS. Additionally, to our knowledge, this study is the first to evaluate the impact of the RPV/FTC/TDF regimen on tolerability progression as a function of the previous treatment (NNRTI or PI/r). The results demonstrate significant improvement in lipid profiles in both groups of patients after changing to RPV/FTC/TDF after 48 weeks of follow-up. For example, a significant decrease in total cholesterol, LDL cholesterol, total cholesterol:HDL ratio and triglyceride values was observed at the week 48 visit. Similarly, a study in which 298 patients changed their previous cART to RPV/FTC/TDF reported decreased total, LDL, HDL cholesterol and triglyceride levels at 24 weeks.19 In another study, 51 virologically suppressed HIV-infected patients switched to RPV/FTC/TDF from an unboosted PI. The results showed that this switch was safe and associated with a reduction in triglycerides and cholesterol at week 12.20 In another study with 146 virologically suppressed patients, the switch to an RPV/FTC/TDF regimen was associated with a mild but sustained improvement in lipid parameters at 96 weeks.21 Other studies have also demonstrated significant improvement in the lipid profiles of patients who changed from efavirenz/emtricitabine/tenofovir (EFV/FTC/TDF) to RPV/FTC/TDF.22–25 We also observed improvement in clinical data (viral load and CD4+ counts) during the follow-up visits of our study. The viral load remained undetectable in the majority of patients and the proportion of patients with a CD4+ count >500 cells/mm3 increased significantly at the week 48 visit. Likewise, in the study conducted by Pérez-Hernández et al.,25 good control of viral load was maintained at 24 weeks after a change from EFV/FTC/TDF to RPV/FTC/TDF and 98.9% of the patients in the study by Palacios et al.19 maintained an undetectable viral load and a similar CD4+ level. In 2014, Pinnetti et al.23 suggested that a change to RPV/FTC/TDF was a good strategy for patients with virological suppression because it presented a low risk of virological failure and treatment discontinuation. In the study performed by Behrens et al.,24 patients with suboptimal RPV/FTC/TDF adherence (≤95%) had lower virological responses compared with previous treatments.24 In another study performed by Nelson et al.,26 lasting 96 weeks, non-inferiority of RPV/FTC/TDF versus EFV/FTC/TDF was demonstrated with regard to achieving a virological response, with advantages in both safety and tolerability. The PRO-STR study also confirmed that the majority of intolerances were resolved or improved during monitoring with a change to RPV/FTC/TDF. These results were consistent with those reported for a study lasting 96 weeks in which rilpivirine-based therapy, compared with efavirenz-based treatment, was associated with a lower number of adverse events.27 According to Nelson et al.,26 RPV/FTC/TDF treatment was associated with significantly fewer adverse events related to treatment (adverse event grades 2–4), demonstrating a pattern of safety and more favourable tolerability up to week 96. Improvement in symptoms reported by patients after 48 weeks of monitoring was also observed in another study in which 786 patients changed their previous cART to STR (RPV/FTC/TDF or EFV/FTC/TDF).28 However, none of these studies evaluated symptoms based on previous intolerances. The present study shows the benefits of switching from first-generation NNRTI- or PI-containing regimens to TDF/FTC/RPV. Although current guidelines recommend the use of integrase inhibitor-containing regimens as preferred options to initiate a first ART, these regimens also have limitations such as possible neuropsychiatric events with dolutegravir, drug–drug interactions with cobicistat or the need to be given twice daily in the case of raltegravir. Thus, a switch to TDF/FTC/RPV may be useful in a proportion of these patients. Moreover, with the availability of tenofovir alafenamide/emtricitabine/rilpivirine in many countries currently the tolerability of the fixed-dose rilpivirine regimen will be further improved in terms of renal and bone events. The PRO-STR study analysis has two limitations that should be taken into account when interpreting the results. First, no control group was available with which to compare RPV/FTC/TDF; thus, only intra-subject comparisons were performed for the visits. Second, no comparisons between different groups of patients were performed because some of the patients could belong to more than one group if they had more than one type of intolerance. Despite these limitations, analysis of the PRO-STR study conducted in a RWS showed that HIV-infected patients who changed their NNRTI or PI/r regimen to an STR (RPV/FTC/TDF) due to an intolerance maintained their virological response and CD4+ count. We also demonstrated resolution of intolerances and significant improvements in lipid profiles with RPV/FTC/TDF after 48 weeks of follow-up. Funding This study was supported by a grant from Gilead Sciences. This supported development of the study, performance of the cost analysis and writing and editorial support for this manuscript. Transparency declarations Á. M. and A. C. are employees of Pharmacoeconomics & Outcomes Research Iberia (PORIB), a consulting company specialized in the economic evaluation of health technologies, which received an unrestricted grant from Gilead Sciences to perform the cost analysis and provide writing and editorial support for this manuscript. C. T. is a former employee of PORIB. D. P. has received research grants and/or honoraria for advisory boards and/or conferences from Viiv, BMS, Abbott, Gilead, Janssen and Merck. The remaining authors have none to declare. References 1 George MP , Singh V , Gladwin MT. Non infectious and non neoplastic conditions associated with human immunodeficiency virus infection . Semin Respir Crit Care Med 2016 ; 37 : 289 – 302 . Google Scholar CrossRef Search ADS PubMed 2 GeSIDA . 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Lipid changes in virologically suppressed HIV-infected patients switching from any antiretroviral therapy to the emtricitabine/rilpivirine/tenofovir single tablet: GeSida Study 8114 . J Int Assoc Provid AIDS Care 2016 ; 15 : 189 – 93 . Google Scholar CrossRef Search ADS PubMed 20 Di Biagio A , Riccardi N , Taramasso L et al. Switch from unboosted protease inhibitor to a single-tablet regimen containing rilpivirine improves cholesterol and triglycerides . Int J Antimicrob Agents 2016 ; 48 : 551 – 4 . Google Scholar CrossRef Search ADS PubMed 21 Arrabal-Durán P , Rodríguez-González CG , Chamorro-de-Vega E et al. Switching to a rilpivirine/emtricitabine/tenofovir single-tablet regimen in RNA-suppressed patients infected with human immunodeficiency virus 1: effectiveness, safety and costs at 96 weeks . Int J Clin Pract 2017 ; 71 : doi:10.1111/ijcp.12968. 22 Thamrongwonglert P , Chetchotisakd P , Anunnatsiri S et al. Improvement of lipid profiles when switching from efavirenz to rilpivirine in HIV-infected patients with dyslipidemia . HIV Clin Trials 2016 ; 17 : 12 – 6 . Google Scholar CrossRef Search ADS PubMed 23 Pinnetti C , Di Giambenedetto S , Maggiolo F et al. Simplification to co-formulated rilpivirine/emtricitabine/tenofovir in virologically suppressed patients: data from a multicenter cohort . J Int AIDS Soc 2014 ; 17 : 19812. Google Scholar CrossRef Search ADS PubMed 24 Behrens G , Rijnders B , Nelson M et al. Rilpivirine versus efavirenz with emtricitabine/tenofovir disoproxil fumarate in treatment-naïve HIV-1-infected patients with HIV-1 RNA ≤100,000 copies/mL: week 96 pooled ECHO/THRIVE subanalysis . AIDS Patient Care STDS 2014 ; 28 : 168 – 75 . Google Scholar CrossRef Search ADS PubMed 25 Pérez-Hernández IA , Palacios R , Mayorga M et al. Lipid changes in HIV-patients switching to the coformulated single tablet FTC/RPV/TDF (Eviplera®). Efficacy and safety analysis. GeSida Study 8114 . J Int AIDS Soc 2014 ; 17 : 19795. Google Scholar CrossRef Search ADS PubMed 26 Nelson MR , Elion RA , Cohen CJ et al. Rilpivirine versus efavirenz in HIV-1-infected subjects receiving emtricitabine/tenofovir DF: pooled 96-week data from ECHO and THRIVE Studies . HIV Clin Trials 2013 ; 14 : 81 – 91 . Google Scholar CrossRef Search ADS PubMed 27 Tebas P , Sension M , Arribas J et al. ; ECHO and THRIVE Study Groups . Lipid levels and changes in body fat distribution in treatment-naive, HIV-1-infected adults treated with rilpivirine or efavirenz for 96 weeks in the ECHO and THRIVE trials . Clin Infect Dis 2014 ; 59 : 425 – 34 . Google Scholar CrossRef Search ADS PubMed 28 Wilkins EL , Cohen CJ , Trottier B et al. Patient-reported outcomes in the single-tablet regimen (STaR) trial of rilpivirine/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate in antiretroviral treatment-naive adults infected with HIV-1 through 48 weeks of treatment . AIDS Care 2015 ; 21 : 1 – 8 . © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Antimicrobial Chemotherapy Oxford University Press

Lipid changes and tolerability in a cohort of adult HIV-infected patients who switched to rilpivirine/emtricitabine/tenofovir due to intolerance to previous combination ART: the PRO-STR study

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.
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0305-7453
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1460-2091
D.O.I.
10.1093/jac/dky175
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Abstract

Abstract Objectives To analyse lipid changes and tolerability in a cohort of HIV-infected patients who switched their antiretroviral regimens to rilpivirine/emtricitabine/tenofovir (RPV/FTC/TDF) in a real-world setting. Methods PRO-STR is a 48 week prospective observational post-authorization study in 25 hospitals. Patients with a viral load <1000 copies/mL, receiving at least 12 months of combination ART (cART), with constant posology for at least the prior 3 months, were categorized according to previous treatment [NNRTI or ritonavir-boosted PI (PI/r)]. Analytical tests were performed at the baseline visit, between week 16 and week 32, and at week 48. Results A total of 303 patients were included (mean age 46.6 years; male 74.0%; previous treatment 74.7% NNRTI and 25.3% PI/r). Both groups exhibited significantly reduced lipid profiles, except for HDL cholesterol, for which a non-significant increase was observed. [NNRTI patients: total cholesterol (baseline: 195.5 ± 38.4 mg/dL; week 48: 171.0 ± 35.5 mg/dL), total cholesterol/HDL ratio (baseline: 4.2 ± 1.2; week 48: 4.0 ± 1.2), HDL (baseline: 49.1 ± 12.0 mg/dL; week 48: 49.2 ± 45.8 mg/dL), LDL (baseline: 119.2 ± 30.2 mg/dL; week 48: 114.2 ± 110.7 mg/dL), and triglycerides (baseline: 136.6 ± 86.8 mg/dL; week 48: 113.4 ± 67.8 mg/dL); PI/r patients: total cholesterol (baseline: 203.2 ± 48.8 mg/dL; week 48: 173.4 ± 36.9 mg/dL), total cholesterol/HDL ratio (baseline: 4.7 ± 1.6; week 48: 4.0 ± 1.2), HDL (baseline: 46.4 ± 12.5 mg/dL; week 48: 52.1 ± 54.4 mg/dL), LDL (baseline: 127.0 ± 36.3 mg/dL; week 48: 111.4 ± 35.8 mg/dL), and triglycerides (baseline: 167.6 ± 107.7 mg/dL; week 48: 122.7 ± 72.1 mg/dL)]. The most common intolerances were neuropsychiatric in the NNRTI patients and gastrointestinal and metabolic in the PI/r patients, and these intolerances were significantly reduced in both groups at week 48 [NNRTI: neuropsychiatric (baseline: 81.3%; week 48: 0.0%); PI/r: gastrointestinal (baseline: 48.7%; week 48: 0.0%) and metabolic (baseline: 42.1%; week 48: 0.0%)]. Conclusions RPV/FTC/TDF improved the lipid profiles and reduced the intolerances after switching from NNRTI or PI-based regimens, in a cohort of HIV-infected patients. Introduction The development of HAART has rendered HIV a chronic illness in treated patients, yet the landscape of HIV-associated medical conditions continues to evolve.1 The introduction of combination antiretroviral therapy (cART) has improved morbidity and mortality associated with HIV infection. Additionally, cART has achieved significant benefits in recovering and preserving immune function, in reducing the harmful effects of HIV replication on possible existing comorbidities and in preventing HIV-1 transmission. However, proper management of cART is complex due to the different drug families and multiple aspects related to their efficacy, toxicity, resistance, tropism, interactions and use in special clinical situations.2 For example, a number of cART drugs present interactions among them, resulting in adverse effects and the necessity for dose adjustment in people with kidney or liver failure.3 Therefore, controlling the symptoms associated with adverse effects has been identified as an essential element for improving adherence and therapeutic efficacy.4,5 Advances in cART include the single-tablet regimen (STR), which involves a single tablet that incorporates three antiretrovirals administered once daily. This regimen simplifies the dosing frequency and reduces the number of tablets. The STR approach is associated with improved treatment adherence, a reduction in the rate of hospitalization, a higher therapeutic success rate and decreased mortality, with a potential impact on quality of life of the patients.6–8 Newer STRs are also associated with excellent tolerability and lipid profiles within normal ranges.9,10 Specifically, in addition to being associated with better tolerability, a change to rilpivirine/emtricitabine/tenofovir (RPV/FTC/TDF) maintains virological suppression.11 Nevertheless, studies with highly pragmatic approaches are needed to demonstrate the management of patients and collect data in a real-world setting (RWS) to improve efficiency, reduce treatment side effects and help prevent HIV infection.12–15 To improve decision-making in healthcare, it is essential to obtain information reported directly by patients about their health conditions and the treatment received, including symptoms and their functional status.12,16 The PRO-STR study17 aimed to investigate the impact of switching from an NNRTI- or PI-based cART regimen to the STR regimen (RPV/FTC/TDF), because of therapy intolerance, on patient-reported outcomes in routine clinical practice. In the present analysis in a RWS, the relationship between STR administration and lipid profile and tolerability was explored by categorizing patients according to their previous treatment; NNRTI or ritonavir-boosted PI (PI/r). Patients and methods PRO-STR is a prospective observational multicentre follow-up post-authorization study in a RWS, which was evaluated and approved by the Research Ethics Committees of the participating centres. The study consists of five visits as follows: the baseline visit (change of cART to STR) and visits at weeks 4, 16, 32 and 48. Of those patients who completed the baseline visit and the week 4 visit, some were excluded from the week 16 visit due to missing data among the main variables or due to treatment discontinuation. The HIV-infected adult patients included had viral loads below 1000 copies/mL, were treated for at least 12 months with cART (combination of at least three drugs that included two NNRTIs and one PI/r or a non-nucleoside analogue or an integrase inhibitor), remained unchanged in their cART regimen and posology for at least the prior 3 months and signed the informed consent form. Inclusion in the study resulted from the occurrence of any intolerance to the previous cART treatment (NNRTI or PI/r) that required a switch to an STR (RPV/FTC/TDF). Intolerance was defined as any adverse event or laboratory abnormality of grades 2 to 4 (according to the WHO reference scale) that caused the change to STR, independent of the cardiovascular risk of the patient. The intolerances were classified into the following groups based on symptoms reported by the patients and the results of laboratory tests: neuropsychiatric (sleep disorders and mood disturbances); gastrointestinal (nausea, vomiting or diarrhoea); and metabolic (hypercholesterolaemia, hypertriglyceridaemia, anaemia and abnormal glucose metabolism). For analysis purposes, patients were classified according to the previous treatment received (NNRTI or PI/r). The collected variables included patient sociodemographic data (age, gender, education level and employment status), clinical data (co-infections, viral load and CD4+ count) and intolerances. In this subanalysis of the PRO-STR study,17 the evolution of the clinical profile of the patients is described to assess the lipid profile at the baseline visit, between week 16 and week 32, and at week 48. Within these tests, the following parameters were recorded: total cholesterol, HDL, LDL, total cholesterol:HDL ratio and triglycerides. The statistical analysis was performed using R version 2.13.0. An alpha (α) risk value equal to 0.05 was assumed for all analyses. A P value ≤0.05 was considered significant. Means and standard deviations were used for continuous variables, and frequencies and percentages were used for categorical variables. For quantitative variables that met normality, statistical contrasts were performed for intrapatient comparisons (Student’s t-test for related and independent samples). However, non-parametric equivalent tests were employed in cases where the assumptions for parametric tests were not met (Mann–Whitney and Wilcoxon). Results A total of 303 patients from 25 centres who changed their previous treatment to RPV/FTC/TDF were included in the lipid profile data analysis. All 303 patients completed the baseline and week 16–32 visit, and 240 patients completed the week 48 visit. A total of 300 patients were included in the analyses of sociodemographic and clinical data. All 300 patients completed the baseline visit and the week 4 visit; 275 completed the week 16 visit; 260 the week 32 visit; and 235 the week 48 visit. The mean age was 46.6 years and 74.0% were male; 4.0% were co-infected with HBV and 13.7% with HCV. The previous cART components are shown in Table 1. NNRTI was the previous cART in 74.7% of the patients (89.7% efavirenz); PI/r was the previous cART in the remaining 25.3% (42.1% emtricitabine/tenofovir/darunavir boosted with ritonavir, 31.6% emtricitabine/tenofovir/atazanavir boosted with ritonavir, and 22.4% emtricitabine/tenofovir/lopinavir boosted with ritonavir). Table 1. Baseline characteristics of the treatments Characteristic Value Time since HIV diagnosis, years (mean; median; IQR) 12.72; 11.00; 11.00 Time on ART, years (mean; median; IQR) 8.28; 6.77; 8.77 Time on last ART, years (mean; median; IQR) 4.06; 4.05; 3.42 Number of previous ART regimens (mean; median; IQR) 2.55; 2.00; 2.00 Previous cART components, n (%)  tenofovir/emtricitabine (or lamivudine) 278 (92.6)  abacavir/lamivudine 18 (6.0)  didanosine/lamivudine 2 (0.7)  zidovudine/lamivudine 2 (0.7)  efavirenz 201 (67.0)  nevirapine 13 (4.3)  etravirine 10 (3.3)  lopinavir/ritonavir 16 (5.3)  darunavir/ritonavir 32 (10.7)  atazanavir/ritonavir 24 (8.0)  fosamprenavir/ritonavir 2 (0.7)  ritonavira 74 (24.7)  lopinavir 1 (0.3)  fosamprenavir 1 (0.3) Characteristic Value Time since HIV diagnosis, years (mean; median; IQR) 12.72; 11.00; 11.00 Time on ART, years (mean; median; IQR) 8.28; 6.77; 8.77 Time on last ART, years (mean; median; IQR) 4.06; 4.05; 3.42 Number of previous ART regimens (mean; median; IQR) 2.55; 2.00; 2.00 Previous cART components, n (%)  tenofovir/emtricitabine (or lamivudine) 278 (92.6)  abacavir/lamivudine 18 (6.0)  didanosine/lamivudine 2 (0.7)  zidovudine/lamivudine 2 (0.7)  efavirenz 201 (67.0)  nevirapine 13 (4.3)  etravirine 10 (3.3)  lopinavir/ritonavir 16 (5.3)  darunavir/ritonavir 32 (10.7)  atazanavir/ritonavir 24 (8.0)  fosamprenavir/ritonavir 2 (0.7)  ritonavira 74 (24.7)  lopinavir 1 (0.3)  fosamprenavir 1 (0.3) a Patients with ritonavir as PI booster. Table 1. Baseline characteristics of the treatments Characteristic Value Time since HIV diagnosis, years (mean; median; IQR) 12.72; 11.00; 11.00 Time on ART, years (mean; median; IQR) 8.28; 6.77; 8.77 Time on last ART, years (mean; median; IQR) 4.06; 4.05; 3.42 Number of previous ART regimens (mean; median; IQR) 2.55; 2.00; 2.00 Previous cART components, n (%)  tenofovir/emtricitabine (or lamivudine) 278 (92.6)  abacavir/lamivudine 18 (6.0)  didanosine/lamivudine 2 (0.7)  zidovudine/lamivudine 2 (0.7)  efavirenz 201 (67.0)  nevirapine 13 (4.3)  etravirine 10 (3.3)  lopinavir/ritonavir 16 (5.3)  darunavir/ritonavir 32 (10.7)  atazanavir/ritonavir 24 (8.0)  fosamprenavir/ritonavir 2 (0.7)  ritonavira 74 (24.7)  lopinavir 1 (0.3)  fosamprenavir 1 (0.3) Characteristic Value Time since HIV diagnosis, years (mean; median; IQR) 12.72; 11.00; 11.00 Time on ART, years (mean; median; IQR) 8.28; 6.77; 8.77 Time on last ART, years (mean; median; IQR) 4.06; 4.05; 3.42 Number of previous ART regimens (mean; median; IQR) 2.55; 2.00; 2.00 Previous cART components, n (%)  tenofovir/emtricitabine (or lamivudine) 278 (92.6)  abacavir/lamivudine 18 (6.0)  didanosine/lamivudine 2 (0.7)  zidovudine/lamivudine 2 (0.7)  efavirenz 201 (67.0)  nevirapine 13 (4.3)  etravirine 10 (3.3)  lopinavir/ritonavir 16 (5.3)  darunavir/ritonavir 32 (10.7)  atazanavir/ritonavir 24 (8.0)  fosamprenavir/ritonavir 2 (0.7)  ritonavira 74 (24.7)  lopinavir 1 (0.3)  fosamprenavir 1 (0.3) a Patients with ritonavir as PI booster. The viral load remained undetectable (<50 copies/mL) in most of the patients (baseline visit: 97.18%, week 48, visit 97.18%; P value = 1), and CD4+ counts did not exhibit significant changes across visits (baseline visit: 707.76 cells/mm3; week 48 visit: 683.00 cells/mm3; P value = 0.111). The proportion of patients with CD4+ count >500 cells/mm3 remained similar between baseline visit and at week 48 (71.5% and 75.7%, respectively; P value = 0.85). Table 2 describes intolerances to previous cART. Among patients who previously received treatment with NNRTI family drugs, neuropsychiatric intolerances were the main cause of the change from cART (81.3%). For patients previously treated with PI/r family drugs, the primary intolerances were gastrointestinal (48.7%) and metabolic (42.1%), with both occasionally appearing simultaneously (Table 2). The most frequent neuropsychiatric symptoms were sleep disorders (62.1%) and mood disorders (36.3%). Diarrhoea was the most common gastrointestinal symptom (73.0%). Hypercholesterolaemia (21.9%), dyslipidaemia (21.9%), and hypertriglyceridaemia (18.8%) were the most common metabolic symptoms. Table 2. Description of intolerances to previous cART PI/r NNRTI Intolerancea n % n % Gastrointestinal (n = 58)  diarrhoea 27 73 8 38  constipation 0 0 1 5  nausea 2 5 7 33  abdominal discomfort 3 8 3 14  dyspepsia 1 3 1 5  vomiting 0 0 2 10  gastritis 1 3 0 0  others 5 14 2 10 Total gastrointestinal 37 21 Neuropsychiatric (n = 187)  mood alteration 4 80 66 36  sleep disorder 2 40 113 62 Total neuropsychiatric 5 182 Metabolic (n = 58)  dyslipidaemia 7 22 6 23  hypertriglyceridaemia 6 19 5 19  hyperbilirubinaemia 11 34 0 0  hypercholesterolaemia 7 22 7 27  jaundice 5 16 0 0  others 6 19 7 27 Total metabolic 32 26 PI/r NNRTI Intolerancea n % n % Gastrointestinal (n = 58)  diarrhoea 27 73 8 38  constipation 0 0 1 5  nausea 2 5 7 33  abdominal discomfort 3 8 3 14  dyspepsia 1 3 1 5  vomiting 0 0 2 10  gastritis 1 3 0 0  others 5 14 2 10 Total gastrointestinal 37 21 Neuropsychiatric (n = 187)  mood alteration 4 80 66 36  sleep disorder 2 40 113 62 Total neuropsychiatric 5 182 Metabolic (n = 58)  dyslipidaemia 7 22 6 23  hypertriglyceridaemia 6 19 5 19  hyperbilirubinaemia 11 34 0 0  hypercholesterolaemia 7 22 7 27  jaundice 5 16 0 0  others 6 19 7 27 Total metabolic 32 26 a Patients could exhibit more than one type of intolerance. Table 2. Description of intolerances to previous cART PI/r NNRTI Intolerancea n % n % Gastrointestinal (n = 58)  diarrhoea 27 73 8 38  constipation 0 0 1 5  nausea 2 5 7 33  abdominal discomfort 3 8 3 14  dyspepsia 1 3 1 5  vomiting 0 0 2 10  gastritis 1 3 0 0  others 5 14 2 10 Total gastrointestinal 37 21 Neuropsychiatric (n = 187)  mood alteration 4 80 66 36  sleep disorder 2 40 113 62 Total neuropsychiatric 5 182 Metabolic (n = 58)  dyslipidaemia 7 22 6 23  hypertriglyceridaemia 6 19 5 19  hyperbilirubinaemia 11 34 0 0  hypercholesterolaemia 7 22 7 27  jaundice 5 16 0 0  others 6 19 7 27 Total metabolic 32 26 PI/r NNRTI Intolerancea n % n % Gastrointestinal (n = 58)  diarrhoea 27 73 8 38  constipation 0 0 1 5  nausea 2 5 7 33  abdominal discomfort 3 8 3 14  dyspepsia 1 3 1 5  vomiting 0 0 2 10  gastritis 1 3 0 0  others 5 14 2 10 Total gastrointestinal 37 21 Neuropsychiatric (n = 187)  mood alteration 4 80 66 36  sleep disorder 2 40 113 62 Total neuropsychiatric 5 182 Metabolic (n = 58)  dyslipidaemia 7 22 6 23  hypertriglyceridaemia 6 19 5 19  hyperbilirubinaemia 11 34 0 0  hypercholesterolaemia 7 22 7 27  jaundice 5 16 0 0  others 6 19 7 27 Total metabolic 32 26 a Patients could exhibit more than one type of intolerance. Dyslipidaemia at baseline was reported for seven patients in the PI/r group (22%) and six patients (23%) in the NNRTI group. After the therapeutical switch to RPV/FTC/TDF no patients presented with dyslipidaemia. As shown in Table 3, all intolerances were resolved or improved during the monitoring period in both groups of patients. In the patients whose prior treatment was NNRTI, the majority of their intolerances were resolved by the week 4 visit, with only 6.1% of the symptoms persisting. By week 16, only 1.0% of the symptoms remained, and all of the symptoms were resolved by week 48. The vast majority of the intolerances in the group of patients whose prior treatment was PI/r were also resolved during monitoring, with only 6.5% of the intolerances persisting by week 4. Only 2.8% of the symptoms remained at week 16, and both gastrointestinal and metabolic intolerances were resolved by week 48. Table 3. Evolution of intolerancesa to previous cART Total intolerances, n (%) Baseline Week 4 Week 16 Week 32 Week 48 (n = 300) (n = 300) P value (n = 275) P value (n = 260) P value (n = 235) P value  gastrointestinal 58 (19.3) 5 (1.7) <0.001 1 (0.4) <0.001 1 (0.4) <0.001 0 (0.0) <0.001  CNS–psychiatry 187 (62.3) 6 (2.0) <0.001 1 (0.4) <0.001 0 (0.0) <0.001 1 (0.4) <0.001  metabolic 58 (19.3) 5 (1.7) <0.001 2 (0.7) <0.001 1 (0.4) <0.001 0 (0.0) <0.001  others 29 (9.7) 3 (1.0) <0.001 0 (0.0) <0.001 1 (0.4) <0.001 0 (0.0) <0.001 NNRTI intolerances, n (%) Baseline Week 4 Week 16 Week 32 Week 48 (n = 224) (n = 224) (n = 204) (n = 192) (n = 174)  gastrointestinal 21 (9.4) 3 (1.3) <0.001 1 (0.5) <0.001 1 (0.5) <0.001 0 (0.0) <0.001  CNS–psychiatry 182 (81.3) 5 (2.2) <0.001 1 (0.5) <0.001 0 (0.0) <0.001 0 (0.0) <0.001  metabolic 26 (11.6) 3 (1.3) <0.001 0 (0.0) <0.001 0 (0.0) <0.001 0 (0.0) <0.001  others 20 (8.9) 3 (1.3) <0.001 0 (0.0) <0.001 0 (0.0) <0.001 0 (0.0) <0.001 PI/r intolerances, n (%) Baseline Week 4 Week 16 Week 32 Week 48 (n = 76) (n = 76) (n = 71) (n = 68) (n = 61)  gastrointestinal 37 (48.7) 2 (2.6) <0.001 0 (0.0) <0.001 0 (0.0) <0.001 0 (0.0) <0.001  CNS–psychiatry 5 (6.6) 1 (1.3) 0.211 0 (0.0) 0.219 0 (0.0) 0.453 1 (1.6) 0.325  metabolic 32 (42.1) 2 (2.6) <0.001 2 (2.8) <0.001 1 (1.5) <0.001 0 (0.0) <0.001  others 9 (11.8) 0 (0.0) 0.005 0 (0.0) <0.001 1 (1.5) <0.001 0 (0.0) 0.001 Total intolerances, n (%) Baseline Week 4 Week 16 Week 32 Week 48 (n = 300) (n = 300) P value (n = 275) P value (n = 260) P value (n = 235) P value  gastrointestinal 58 (19.3) 5 (1.7) <0.001 1 (0.4) <0.001 1 (0.4) <0.001 0 (0.0) <0.001  CNS–psychiatry 187 (62.3) 6 (2.0) <0.001 1 (0.4) <0.001 0 (0.0) <0.001 1 (0.4) <0.001  metabolic 58 (19.3) 5 (1.7) <0.001 2 (0.7) <0.001 1 (0.4) <0.001 0 (0.0) <0.001  others 29 (9.7) 3 (1.0) <0.001 0 (0.0) <0.001 1 (0.4) <0.001 0 (0.0) <0.001 NNRTI intolerances, n (%) Baseline Week 4 Week 16 Week 32 Week 48 (n = 224) (n = 224) (n = 204) (n = 192) (n = 174)  gastrointestinal 21 (9.4) 3 (1.3) <0.001 1 (0.5) <0.001 1 (0.5) <0.001 0 (0.0) <0.001  CNS–psychiatry 182 (81.3) 5 (2.2) <0.001 1 (0.5) <0.001 0 (0.0) <0.001 0 (0.0) <0.001  metabolic 26 (11.6) 3 (1.3) <0.001 0 (0.0) <0.001 0 (0.0) <0.001 0 (0.0) <0.001  others 20 (8.9) 3 (1.3) <0.001 0 (0.0) <0.001 0 (0.0) <0.001 0 (0.0) <0.001 PI/r intolerances, n (%) Baseline Week 4 Week 16 Week 32 Week 48 (n = 76) (n = 76) (n = 71) (n = 68) (n = 61)  gastrointestinal 37 (48.7) 2 (2.6) <0.001 0 (0.0) <0.001 0 (0.0) <0.001 0 (0.0) <0.001  CNS–psychiatry 5 (6.6) 1 (1.3) 0.211 0 (0.0) 0.219 0 (0.0) 0.453 1 (1.6) 0.325  metabolic 32 (42.1) 2 (2.6) <0.001 2 (2.8) <0.001 1 (1.5) <0.001 0 (0.0) <0.001  others 9 (11.8) 0 (0.0) 0.005 0 (0.0) <0.001 1 (1.5) <0.001 0 (0.0) 0.001 P values are all against baseline; P values ≤ 0.05 are shown in bold. a Patients could exhibit more than one type of intolerance. Table 3. Evolution of intolerancesa to previous cART Total intolerances, n (%) Baseline Week 4 Week 16 Week 32 Week 48 (n = 300) (n = 300) P value (n = 275) P value (n = 260) P value (n = 235) P value  gastrointestinal 58 (19.3) 5 (1.7) <0.001 1 (0.4) <0.001 1 (0.4) <0.001 0 (0.0) <0.001  CNS–psychiatry 187 (62.3) 6 (2.0) <0.001 1 (0.4) <0.001 0 (0.0) <0.001 1 (0.4) <0.001  metabolic 58 (19.3) 5 (1.7) <0.001 2 (0.7) <0.001 1 (0.4) <0.001 0 (0.0) <0.001  others 29 (9.7) 3 (1.0) <0.001 0 (0.0) <0.001 1 (0.4) <0.001 0 (0.0) <0.001 NNRTI intolerances, n (%) Baseline Week 4 Week 16 Week 32 Week 48 (n = 224) (n = 224) (n = 204) (n = 192) (n = 174)  gastrointestinal 21 (9.4) 3 (1.3) <0.001 1 (0.5) <0.001 1 (0.5) <0.001 0 (0.0) <0.001  CNS–psychiatry 182 (81.3) 5 (2.2) <0.001 1 (0.5) <0.001 0 (0.0) <0.001 0 (0.0) <0.001  metabolic 26 (11.6) 3 (1.3) <0.001 0 (0.0) <0.001 0 (0.0) <0.001 0 (0.0) <0.001  others 20 (8.9) 3 (1.3) <0.001 0 (0.0) <0.001 0 (0.0) <0.001 0 (0.0) <0.001 PI/r intolerances, n (%) Baseline Week 4 Week 16 Week 32 Week 48 (n = 76) (n = 76) (n = 71) (n = 68) (n = 61)  gastrointestinal 37 (48.7) 2 (2.6) <0.001 0 (0.0) <0.001 0 (0.0) <0.001 0 (0.0) <0.001  CNS–psychiatry 5 (6.6) 1 (1.3) 0.211 0 (0.0) 0.219 0 (0.0) 0.453 1 (1.6) 0.325  metabolic 32 (42.1) 2 (2.6) <0.001 2 (2.8) <0.001 1 (1.5) <0.001 0 (0.0) <0.001  others 9 (11.8) 0 (0.0) 0.005 0 (0.0) <0.001 1 (1.5) <0.001 0 (0.0) 0.001 Total intolerances, n (%) Baseline Week 4 Week 16 Week 32 Week 48 (n = 300) (n = 300) P value (n = 275) P value (n = 260) P value (n = 235) P value  gastrointestinal 58 (19.3) 5 (1.7) <0.001 1 (0.4) <0.001 1 (0.4) <0.001 0 (0.0) <0.001  CNS–psychiatry 187 (62.3) 6 (2.0) <0.001 1 (0.4) <0.001 0 (0.0) <0.001 1 (0.4) <0.001  metabolic 58 (19.3) 5 (1.7) <0.001 2 (0.7) <0.001 1 (0.4) <0.001 0 (0.0) <0.001  others 29 (9.7) 3 (1.0) <0.001 0 (0.0) <0.001 1 (0.4) <0.001 0 (0.0) <0.001 NNRTI intolerances, n (%) Baseline Week 4 Week 16 Week 32 Week 48 (n = 224) (n = 224) (n = 204) (n = 192) (n = 174)  gastrointestinal 21 (9.4) 3 (1.3) <0.001 1 (0.5) <0.001 1 (0.5) <0.001 0 (0.0) <0.001  CNS–psychiatry 182 (81.3) 5 (2.2) <0.001 1 (0.5) <0.001 0 (0.0) <0.001 0 (0.0) <0.001  metabolic 26 (11.6) 3 (1.3) <0.001 0 (0.0) <0.001 0 (0.0) <0.001 0 (0.0) <0.001  others 20 (8.9) 3 (1.3) <0.001 0 (0.0) <0.001 0 (0.0) <0.001 0 (0.0) <0.001 PI/r intolerances, n (%) Baseline Week 4 Week 16 Week 32 Week 48 (n = 76) (n = 76) (n = 71) (n = 68) (n = 61)  gastrointestinal 37 (48.7) 2 (2.6) <0.001 0 (0.0) <0.001 0 (0.0) <0.001 0 (0.0) <0.001  CNS–psychiatry 5 (6.6) 1 (1.3) 0.211 0 (0.0) 0.219 0 (0.0) 0.453 1 (1.6) 0.325  metabolic 32 (42.1) 2 (2.6) <0.001 2 (2.8) <0.001 1 (1.5) <0.001 0 (0.0) <0.001  others 9 (11.8) 0 (0.0) 0.005 0 (0.0) <0.001 1 (1.5) <0.001 0 (0.0) 0.001 P values are all against baseline; P values ≤ 0.05 are shown in bold. a Patients could exhibit more than one type of intolerance. The changes in lipid profile during treatment are detailed in Table 4. A significant decrease (P value ≤0.05) in all analytical values (except for HDL cholesterol, for which an increase was observed) was observed after the change to RPV/FTC/TDF in the two groups of patients. Table 4. Lipid changes Baseline (n = 303) Week 16–32 (n = 303) Change ± SD P value between groups P value between visits Week 48 (n = 240) Change ± SD P value between groups P value between visits Total cholesterol  NNRTI 195.53 ± 38.40 169.96 ± 36.14 25.33 ± 27.97 0.366c <0.001a 170.97 ± 35.48 25.63 ± 30.16 0.550c <0.001b  PI/r 203.16 ± 48.76 178.61 ± 43.14 24.53 ± 32.72 <0.001b 173.44 ± 36.81 28.03 ± 31.93 <0.001b HDL cholesterol  NNRTI 49.07 ± 11.96 43.92 ± 10.10 5.20  ± 8.78 0.012c <0.001b 49.16 ± 45.80 −0.53 ± 47.71 0.024d <0.001a  PI/r 46.40±12.50 44.80 ± 13.02 2.17 ± 11.48 0.345b 52.11 ± 54.44 −5.91 ± 55.07 0.523a LDL cholesterol  NNRTI 119.21 ± 30.23 105.67 ± 31.22 14.42 ± 23.46 0.751c <0.001b 114.20 ± 110.67 5.41 ± 112.21 0.837d <0.001a  PI/r 126.96 ± 36.34 111.05 ± 32.39 14.04 ± 29.04 <0.001b 111.38 ± 35.71 17.38 ± 32.08 <0.001b Total cholesterol:HDL ratio  NNRTI 4.20 ± 1.21 4.01 ± 1.01 0.18 ± 0.81 0.020d 0.004a 3.96 ± 1.16 0.25 ± 1.10 0.018d 0.002a  PI/r 4.68 ± 1.58 4.26 ± 1.72 0.26 ± 1.55 0.067b 4.00 ± 1.16 0.72 ± 1.44 <0.001b Triglycerides  NNRTI 136.55 ± 86.78 105.72 ± 50.56 29.76 ± 68.55 0.016d <0.001a 113.37 ± 67.77 24.60 ± 67.29 0.003d <0.001a  PI/r 167.55 ± 107.71 119.00 ± 63.03 49.73 ± 83.92 <0.001a 122.68 ± 72.13 43.25 ± 92.31 <0.001a Baseline (n = 303) Week 16–32 (n = 303) Change ± SD P value between groups P value between visits Week 48 (n = 240) Change ± SD P value between groups P value between visits Total cholesterol  NNRTI 195.53 ± 38.40 169.96 ± 36.14 25.33 ± 27.97 0.366c <0.001a 170.97 ± 35.48 25.63 ± 30.16 0.550c <0.001b  PI/r 203.16 ± 48.76 178.61 ± 43.14 24.53 ± 32.72 <0.001b 173.44 ± 36.81 28.03 ± 31.93 <0.001b HDL cholesterol  NNRTI 49.07 ± 11.96 43.92 ± 10.10 5.20  ± 8.78 0.012c <0.001b 49.16 ± 45.80 −0.53 ± 47.71 0.024d <0.001a  PI/r 46.40±12.50 44.80 ± 13.02 2.17 ± 11.48 0.345b 52.11 ± 54.44 −5.91 ± 55.07 0.523a LDL cholesterol  NNRTI 119.21 ± 30.23 105.67 ± 31.22 14.42 ± 23.46 0.751c <0.001b 114.20 ± 110.67 5.41 ± 112.21 0.837d <0.001a  PI/r 126.96 ± 36.34 111.05 ± 32.39 14.04 ± 29.04 <0.001b 111.38 ± 35.71 17.38 ± 32.08 <0.001b Total cholesterol:HDL ratio  NNRTI 4.20 ± 1.21 4.01 ± 1.01 0.18 ± 0.81 0.020d 0.004a 3.96 ± 1.16 0.25 ± 1.10 0.018d 0.002a  PI/r 4.68 ± 1.58 4.26 ± 1.72 0.26 ± 1.55 0.067b 4.00 ± 1.16 0.72 ± 1.44 <0.001b Triglycerides  NNRTI 136.55 ± 86.78 105.72 ± 50.56 29.76 ± 68.55 0.016d <0.001a 113.37 ± 67.77 24.60 ± 67.29 0.003d <0.001a  PI/r 167.55 ± 107.71 119.00 ± 63.03 49.73 ± 83.92 <0.001a 122.68 ± 72.13 43.25 ± 92.31 <0.001a All lipid values (mg/dL) shown are mean ± SD. P values ≤0.05 are shown in bold. a The Wilcoxon test was used. b Student’s t-test for related samples was used. c Student’s t-test for independent samples was used. d The Mann–Whitney test was used. Table 4. Lipid changes Baseline (n = 303) Week 16–32 (n = 303) Change ± SD P value between groups P value between visits Week 48 (n = 240) Change ± SD P value between groups P value between visits Total cholesterol  NNRTI 195.53 ± 38.40 169.96 ± 36.14 25.33 ± 27.97 0.366c <0.001a 170.97 ± 35.48 25.63 ± 30.16 0.550c <0.001b  PI/r 203.16 ± 48.76 178.61 ± 43.14 24.53 ± 32.72 <0.001b 173.44 ± 36.81 28.03 ± 31.93 <0.001b HDL cholesterol  NNRTI 49.07 ± 11.96 43.92 ± 10.10 5.20  ± 8.78 0.012c <0.001b 49.16 ± 45.80 −0.53 ± 47.71 0.024d <0.001a  PI/r 46.40±12.50 44.80 ± 13.02 2.17 ± 11.48 0.345b 52.11 ± 54.44 −5.91 ± 55.07 0.523a LDL cholesterol  NNRTI 119.21 ± 30.23 105.67 ± 31.22 14.42 ± 23.46 0.751c <0.001b 114.20 ± 110.67 5.41 ± 112.21 0.837d <0.001a  PI/r 126.96 ± 36.34 111.05 ± 32.39 14.04 ± 29.04 <0.001b 111.38 ± 35.71 17.38 ± 32.08 <0.001b Total cholesterol:HDL ratio  NNRTI 4.20 ± 1.21 4.01 ± 1.01 0.18 ± 0.81 0.020d 0.004a 3.96 ± 1.16 0.25 ± 1.10 0.018d 0.002a  PI/r 4.68 ± 1.58 4.26 ± 1.72 0.26 ± 1.55 0.067b 4.00 ± 1.16 0.72 ± 1.44 <0.001b Triglycerides  NNRTI 136.55 ± 86.78 105.72 ± 50.56 29.76 ± 68.55 0.016d <0.001a 113.37 ± 67.77 24.60 ± 67.29 0.003d <0.001a  PI/r 167.55 ± 107.71 119.00 ± 63.03 49.73 ± 83.92 <0.001a 122.68 ± 72.13 43.25 ± 92.31 <0.001a Baseline (n = 303) Week 16–32 (n = 303) Change ± SD P value between groups P value between visits Week 48 (n = 240) Change ± SD P value between groups P value between visits Total cholesterol  NNRTI 195.53 ± 38.40 169.96 ± 36.14 25.33 ± 27.97 0.366c <0.001a 170.97 ± 35.48 25.63 ± 30.16 0.550c <0.001b  PI/r 203.16 ± 48.76 178.61 ± 43.14 24.53 ± 32.72 <0.001b 173.44 ± 36.81 28.03 ± 31.93 <0.001b HDL cholesterol  NNRTI 49.07 ± 11.96 43.92 ± 10.10 5.20  ± 8.78 0.012c <0.001b 49.16 ± 45.80 −0.53 ± 47.71 0.024d <0.001a  PI/r 46.40±12.50 44.80 ± 13.02 2.17 ± 11.48 0.345b 52.11 ± 54.44 −5.91 ± 55.07 0.523a LDL cholesterol  NNRTI 119.21 ± 30.23 105.67 ± 31.22 14.42 ± 23.46 0.751c <0.001b 114.20 ± 110.67 5.41 ± 112.21 0.837d <0.001a  PI/r 126.96 ± 36.34 111.05 ± 32.39 14.04 ± 29.04 <0.001b 111.38 ± 35.71 17.38 ± 32.08 <0.001b Total cholesterol:HDL ratio  NNRTI 4.20 ± 1.21 4.01 ± 1.01 0.18 ± 0.81 0.020d 0.004a 3.96 ± 1.16 0.25 ± 1.10 0.018d 0.002a  PI/r 4.68 ± 1.58 4.26 ± 1.72 0.26 ± 1.55 0.067b 4.00 ± 1.16 0.72 ± 1.44 <0.001b Triglycerides  NNRTI 136.55 ± 86.78 105.72 ± 50.56 29.76 ± 68.55 0.016d <0.001a 113.37 ± 67.77 24.60 ± 67.29 0.003d <0.001a  PI/r 167.55 ± 107.71 119.00 ± 63.03 49.73 ± 83.92 <0.001a 122.68 ± 72.13 43.25 ± 92.31 <0.001a All lipid values (mg/dL) shown are mean ± SD. P values ≤0.05 are shown in bold. a The Wilcoxon test was used. b Student’s t-test for related samples was used. c Student’s t-test for independent samples was used. d The Mann–Whitney test was used. A multivariate analysis was performed considering the following demographic variables: gender, weight, age and race. This analysis did not show any statistically significant differences for either of the two patient groups (PI/r and NNRTI; data not shown). Significant differences in the various lipid values were found between the two groups of patients at baseline. The patients with prior PI/r treatment had significantly higher (P value ≤0.05) total cholesterol:HDL ratios and triglyceride values than the patients treated with NNRTI. At week 48, those who switched from PI/r treatment had significantly lower (P value ≤0.05) total cholesterol, LDL cholesterol levels, total cholesterol:HDL ratios and triglyceride values. To explore the impact of viral load on the lipid profile, a subanalysis was carried out for patients with undetectable viral load (<50 copies/mL). Contrary to the observation in the primary analysis, a statistically difference (P < 0.001) in the total cholesterol:HDL ratio between week 32 and baseline values was detected for the group of patients previously treated with a PI/r regimen, whilst no statistically difference (P = 0.051) was found for the NNRTI patient group. Additional differences for the other parameters were not found (data not shown). Discussion The PRO-STR study evaluated the impact of the change from cART to STR in HIV-infected patients. Previous studies in Spain18 have suggested that treatment switch could be associated with improvements in lipid profile of the patients. The present analysis assessed lipid profiles and tolerability in patients who began RPV/FTC/TDF in a RWS. Additionally, to our knowledge, this study is the first to evaluate the impact of the RPV/FTC/TDF regimen on tolerability progression as a function of the previous treatment (NNRTI or PI/r). The results demonstrate significant improvement in lipid profiles in both groups of patients after changing to RPV/FTC/TDF after 48 weeks of follow-up. For example, a significant decrease in total cholesterol, LDL cholesterol, total cholesterol:HDL ratio and triglyceride values was observed at the week 48 visit. Similarly, a study in which 298 patients changed their previous cART to RPV/FTC/TDF reported decreased total, LDL, HDL cholesterol and triglyceride levels at 24 weeks.19 In another study, 51 virologically suppressed HIV-infected patients switched to RPV/FTC/TDF from an unboosted PI. The results showed that this switch was safe and associated with a reduction in triglycerides and cholesterol at week 12.20 In another study with 146 virologically suppressed patients, the switch to an RPV/FTC/TDF regimen was associated with a mild but sustained improvement in lipid parameters at 96 weeks.21 Other studies have also demonstrated significant improvement in the lipid profiles of patients who changed from efavirenz/emtricitabine/tenofovir (EFV/FTC/TDF) to RPV/FTC/TDF.22–25 We also observed improvement in clinical data (viral load and CD4+ counts) during the follow-up visits of our study. The viral load remained undetectable in the majority of patients and the proportion of patients with a CD4+ count >500 cells/mm3 increased significantly at the week 48 visit. Likewise, in the study conducted by Pérez-Hernández et al.,25 good control of viral load was maintained at 24 weeks after a change from EFV/FTC/TDF to RPV/FTC/TDF and 98.9% of the patients in the study by Palacios et al.19 maintained an undetectable viral load and a similar CD4+ level. In 2014, Pinnetti et al.23 suggested that a change to RPV/FTC/TDF was a good strategy for patients with virological suppression because it presented a low risk of virological failure and treatment discontinuation. In the study performed by Behrens et al.,24 patients with suboptimal RPV/FTC/TDF adherence (≤95%) had lower virological responses compared with previous treatments.24 In another study performed by Nelson et al.,26 lasting 96 weeks, non-inferiority of RPV/FTC/TDF versus EFV/FTC/TDF was demonstrated with regard to achieving a virological response, with advantages in both safety and tolerability. The PRO-STR study also confirmed that the majority of intolerances were resolved or improved during monitoring with a change to RPV/FTC/TDF. These results were consistent with those reported for a study lasting 96 weeks in which rilpivirine-based therapy, compared with efavirenz-based treatment, was associated with a lower number of adverse events.27 According to Nelson et al.,26 RPV/FTC/TDF treatment was associated with significantly fewer adverse events related to treatment (adverse event grades 2–4), demonstrating a pattern of safety and more favourable tolerability up to week 96. Improvement in symptoms reported by patients after 48 weeks of monitoring was also observed in another study in which 786 patients changed their previous cART to STR (RPV/FTC/TDF or EFV/FTC/TDF).28 However, none of these studies evaluated symptoms based on previous intolerances. The present study shows the benefits of switching from first-generation NNRTI- or PI-containing regimens to TDF/FTC/RPV. Although current guidelines recommend the use of integrase inhibitor-containing regimens as preferred options to initiate a first ART, these regimens also have limitations such as possible neuropsychiatric events with dolutegravir, drug–drug interactions with cobicistat or the need to be given twice daily in the case of raltegravir. Thus, a switch to TDF/FTC/RPV may be useful in a proportion of these patients. Moreover, with the availability of tenofovir alafenamide/emtricitabine/rilpivirine in many countries currently the tolerability of the fixed-dose rilpivirine regimen will be further improved in terms of renal and bone events. The PRO-STR study analysis has two limitations that should be taken into account when interpreting the results. First, no control group was available with which to compare RPV/FTC/TDF; thus, only intra-subject comparisons were performed for the visits. Second, no comparisons between different groups of patients were performed because some of the patients could belong to more than one group if they had more than one type of intolerance. Despite these limitations, analysis of the PRO-STR study conducted in a RWS showed that HIV-infected patients who changed their NNRTI or PI/r regimen to an STR (RPV/FTC/TDF) due to an intolerance maintained their virological response and CD4+ count. We also demonstrated resolution of intolerances and significant improvements in lipid profiles with RPV/FTC/TDF after 48 weeks of follow-up. Funding This study was supported by a grant from Gilead Sciences. This supported development of the study, performance of the cost analysis and writing and editorial support for this manuscript. Transparency declarations Á. M. and A. 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Patient-reported outcomes in the single-tablet regimen (STaR) trial of rilpivirine/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate in antiretroviral treatment-naive adults infected with HIV-1 through 48 weeks of treatment . AIDS Care 2015 ; 21 : 1 – 8 . © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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Journal of Antimicrobial ChemotherapyOxford University Press

Published: May 16, 2018

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