Nevirapine to Rilpivirine Switch in Suppressed HIV
Of 456 screened HIV-1 patients at the Erasmus University Medical Center between November 12, 2012, and September 4, 2013, 267 were ineligible for participation in the study. Of 189 eligible patients, 139 did not want to switch and remained on nevirapine in routine care as controls. Fifty switchers consented to study participation. Switchers and controls were not significantly different (Table 1) and were predominantly Caucasian males (73.0%) and 45 (IQR: 38–52) years of age with HIV-1 transmission through sexual contact with men (57.7%). Patients were HIV-1 suppressed for 31 (IQR: 25–51) months, on nevirapine for 57 (IQR: 35–120) months, and had 580 (IQR: 480–730) CD4 cells per cubic millimeter.
Week 12 HIV-1 RNA was <50 copies per milliliter in 46/50 switchers (92.0%), comparable with the hypothesized 90% with HIV-1 suppression (P = 0.431). At week 12, 1 switcher discontinued rilpivirine for related AE and 1 had HIV-1 RNA of 51 copies per milliliter with week 24 HIV-1 RNA <50 copies per milliliter. Another switcher had week 12 HIV-1 RNA of 4820 copies per milliliter without acquired resistance, 100% pill count, and week 12 rilpivirine Ctrough of 0.2552 mg/L. This patient's week 4, 16, 18, and 24 HIV-1 RNAs were <50, 1650, <50, and <50 copies per milliliter, respectively. The fourth switcher had HIV-1 RNA of 32,500 copies per milliliter without acquired resistance, 22% pill count, and undetectable week 12 rilpivirine Ctrough. This patient's participation was terminated and switched to darunavir/ritonavir emtricitabine/tenofovir DF after adherence counseling.
Week 24 virological suppression rates in switchers (88.0%, 95% CI: 79.0 to 97.0) and controls (90.6%, 95% CI: 85.8 to 95.5) were not different (difference: 2.6%, 95% CI: −7.6 to 12.8; P = 0.593). One additional switcher had discontinued rilpivirine for related AE, and 3 switchers had viral blips of HIV-1 RNA of 58, 80, and 228 copies per milliliter, respectively. Week 24 medication adherence was >95% in 47/50 switchers. Thirteen controls did not have week 24 HIV-1 RNA <50 copies per milliliter, 6 were lost to follow-up, 5 had HIV-1 RNA 50–100 copies per milliliter, and 2 had HIV-1 RNA of 2540 and 844 copies per milliliter because of poor therapy adherence without acquired resistance and nevirapine concentrations of 0.47 and 0.20 mg/L, respectively.
The baseline GM (95% CI) nevirapine concentration was 5.04 mg/L (3.76–6.33, Fig. 1). Nevirapine was undetectable in 8/20 switchers at week 1, in 19/20 at week 2, and 20/20 at week 3. The week 1 lower 95% CI border of GM rilpivirine Ctrough was >0.05 mg/L. Week 1 rilpivirine GM Ctrough (0.083 mg/L) was comparable with mean rilpivirine Ctrough (0.08 mg/L) of phase 3 trial data (P = 0.747). Rilpivirine Ctrough was >0.05 mg/L in 17/20 at week 1 and in 18/20 at week 2. Rilpivirine Ctrough in 2 switchers remained <0.05 mg/L until week 12 with 100% adherence. The baseline nevirapine concentrations in these 2 were 4.50 and 3.26 mg/L and undetectable by week 1. One had HIV-1 RNA <50 copies per milliliter at all time points, and the other had week 4 HIV-1 RNA of 589 copies per milliliter and HIV-1 RNA <50 copies per milliliter at weeks 6, 12, and 24.
(Enlarge Image)
Figure 1.
Rilpivirine, nevirapine and pharmacokinetics (GM, 95%CI) after a switch from NVP to RPV. CI, confidence interval; GM, geometric mean; NVP, nevirapine; RPV, rilpivirine.
The GFR declined 6.7 mL/min in switchers and 2.6 mL/min in controls over 24 weeks (95% CI of difference: −6.5 to −1.8, P < 0.001). Nine switchers with median baseline GFR between 60 and 71 mL/min had grade 2 GFR decline (49–60 mL/min) without urine abnormalities at week 24. No grade 2 or higher alanine transaminase increases were observed in switchers. Switchers had significant changes (all P < 0.001) in phosphate (+0.14 mmol/L, 95% CI: 0.09 to 0.19), total bilirubin (+2.3 μmol/L, 95% CI: 1.4 to 3.3), and gamma-GT (-54 U/L, 95% CI: −69 to −39). Thirty-six switchers experienced at least one rilpivirine-related AE, including one serious AE for hospitalization; 82% were grade 1 AE. Three grade 3 AE occurred; 1 switcher with insomnia discontinued rilpivirine, and 2 patients on phenprocoumon had International Normalized Ratio increases without hemorrhages. Ten switchers had related grade 2 sleep disturbances, abdominal complaints, or skin rashes. Apart from one discontinuation for sleep disturbance, all grade 2 AE resolved spontaneously. Baseline and week 24 overall treatment satisfaction was comparable (56/60 vs. 55/60, P = 0.925) without differences in clinical (28/30 vs. 29/30, P = 0.687) or convenience satisfaction (26/30 vs. 27/30, P = 0.530).
Results
Baseline Characteristics
Of 456 screened HIV-1 patients at the Erasmus University Medical Center between November 12, 2012, and September 4, 2013, 267 were ineligible for participation in the study. Of 189 eligible patients, 139 did not want to switch and remained on nevirapine in routine care as controls. Fifty switchers consented to study participation. Switchers and controls were not significantly different (Table 1) and were predominantly Caucasian males (73.0%) and 45 (IQR: 38–52) years of age with HIV-1 transmission through sexual contact with men (57.7%). Patients were HIV-1 suppressed for 31 (IQR: 25–51) months, on nevirapine for 57 (IQR: 35–120) months, and had 580 (IQR: 480–730) CD4 cells per cubic millimeter.
Efficacy
Week 12 HIV-1 RNA was <50 copies per milliliter in 46/50 switchers (92.0%), comparable with the hypothesized 90% with HIV-1 suppression (P = 0.431). At week 12, 1 switcher discontinued rilpivirine for related AE and 1 had HIV-1 RNA of 51 copies per milliliter with week 24 HIV-1 RNA <50 copies per milliliter. Another switcher had week 12 HIV-1 RNA of 4820 copies per milliliter without acquired resistance, 100% pill count, and week 12 rilpivirine Ctrough of 0.2552 mg/L. This patient's week 4, 16, 18, and 24 HIV-1 RNAs were <50, 1650, <50, and <50 copies per milliliter, respectively. The fourth switcher had HIV-1 RNA of 32,500 copies per milliliter without acquired resistance, 22% pill count, and undetectable week 12 rilpivirine Ctrough. This patient's participation was terminated and switched to darunavir/ritonavir emtricitabine/tenofovir DF after adherence counseling.
Week 24 virological suppression rates in switchers (88.0%, 95% CI: 79.0 to 97.0) and controls (90.6%, 95% CI: 85.8 to 95.5) were not different (difference: 2.6%, 95% CI: −7.6 to 12.8; P = 0.593). One additional switcher had discontinued rilpivirine for related AE, and 3 switchers had viral blips of HIV-1 RNA of 58, 80, and 228 copies per milliliter, respectively. Week 24 medication adherence was >95% in 47/50 switchers. Thirteen controls did not have week 24 HIV-1 RNA <50 copies per milliliter, 6 were lost to follow-up, 5 had HIV-1 RNA 50–100 copies per milliliter, and 2 had HIV-1 RNA of 2540 and 844 copies per milliliter because of poor therapy adherence without acquired resistance and nevirapine concentrations of 0.47 and 0.20 mg/L, respectively.
Pharmacokinetics
The baseline GM (95% CI) nevirapine concentration was 5.04 mg/L (3.76–6.33, Fig. 1). Nevirapine was undetectable in 8/20 switchers at week 1, in 19/20 at week 2, and 20/20 at week 3. The week 1 lower 95% CI border of GM rilpivirine Ctrough was >0.05 mg/L. Week 1 rilpivirine GM Ctrough (0.083 mg/L) was comparable with mean rilpivirine Ctrough (0.08 mg/L) of phase 3 trial data (P = 0.747). Rilpivirine Ctrough was >0.05 mg/L in 17/20 at week 1 and in 18/20 at week 2. Rilpivirine Ctrough in 2 switchers remained <0.05 mg/L until week 12 with 100% adherence. The baseline nevirapine concentrations in these 2 were 4.50 and 3.26 mg/L and undetectable by week 1. One had HIV-1 RNA <50 copies per milliliter at all time points, and the other had week 4 HIV-1 RNA of 589 copies per milliliter and HIV-1 RNA <50 copies per milliliter at weeks 6, 12, and 24.
(Enlarge Image)
Figure 1.
Rilpivirine, nevirapine and pharmacokinetics (GM, 95%CI) after a switch from NVP to RPV. CI, confidence interval; GM, geometric mean; NVP, nevirapine; RPV, rilpivirine.
Safety and Treatment Satisfaction
The GFR declined 6.7 mL/min in switchers and 2.6 mL/min in controls over 24 weeks (95% CI of difference: −6.5 to −1.8, P < 0.001). Nine switchers with median baseline GFR between 60 and 71 mL/min had grade 2 GFR decline (49–60 mL/min) without urine abnormalities at week 24. No grade 2 or higher alanine transaminase increases were observed in switchers. Switchers had significant changes (all P < 0.001) in phosphate (+0.14 mmol/L, 95% CI: 0.09 to 0.19), total bilirubin (+2.3 μmol/L, 95% CI: 1.4 to 3.3), and gamma-GT (-54 U/L, 95% CI: −69 to −39). Thirty-six switchers experienced at least one rilpivirine-related AE, including one serious AE for hospitalization; 82% were grade 1 AE. Three grade 3 AE occurred; 1 switcher with insomnia discontinued rilpivirine, and 2 patients on phenprocoumon had International Normalized Ratio increases without hemorrhages. Ten switchers had related grade 2 sleep disturbances, abdominal complaints, or skin rashes. Apart from one discontinuation for sleep disturbance, all grade 2 AE resolved spontaneously. Baseline and week 24 overall treatment satisfaction was comparable (56/60 vs. 55/60, P = 0.925) without differences in clinical (28/30 vs. 29/30, P = 0.687) or convenience satisfaction (26/30 vs. 27/30, P = 0.530).
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