Dyslipidemia and lipodystrophy represent significant healthcare concerns in HIV-infected patients due to their association with diabetes mellitus and increased cardiovascular disease risk. Since the lipid effects of the nonnucleoside reverse transcriptase inhibitors are not well characterized, we systematically summarized the effects of nonnucleoside reverse transcriptase inhibitor treatment on dyslipidemia and lipodystrophy in HIV-1 infection. As with other classes of antiretroviral agents, the nonnucleoside reverse transcriptase inhibitors are associated with lipid changes, although individual agents exhibit differing effects on lipid profiles. Comparative trials have shown that the risk for hypertriglyceridemia is lower with efavirenz than with the use of ritonavir-boosted lopinavir, but there is a greater likelihood of hypercholesterolemia compared to ritonavir-boosted atazanavir. Data also suggest that efavirenz results in greater increases in plasma lipid levels than integrase inhibitors and CC-chemokine-receptor-5 antagonists. Lipid disturbances are less frequent with the newer nonnucleoside reverse transcriptase inhibitors than with efavirenz. However, in most cases, no change in the total:high-density lipoprotein-cholesterol ratio was seen between the efavirenz and comparator groups. Switching from efavirenz to etravirine or rilpivirine, or the integrase inhibitors raltegravir or elvitegravir, resulted in significant reductions in lipid levels. There appears to be minimal potential for efavirenz or rilpivirine to result in development of lipodystrophy. Overall, nonnucleoside reverse transcriptase inhibitors have a smaller impact on plasma lipids than ritonavir-boosted protease inhibitors, with the newer agents exhibiting more favorable lipid profiles than efavirenz. When considering antiretroviral regimens, awareness of the different lipid effect profiles of the third agent is important, without forgetting the critical contribution of the background antiretrovirals.

BACKGROUND:Pooled ECHO/THRIVE lipid and body fat data are presented from the ECHO (Efficacy Comparison in Treatment-Naïve, HIV-Infected Subjects of TMC278 and Efavirenz) and THRIVE (TMC278 Against HIV, in a Once-Daily Regimen Versus Efavirenz) trials. METHODS:We assessed the 96-week effects on lipids, adverse events (AEs), and body fat distribution (dual-energy x-ray absorptiometry) of rilpivirine (RPV) and EFV plus 2 nucleoside/nucleotide reverse transcriptase inhibitors (N[t]RTIs) in treatment-naive adults infected with human immunodeficiency virus type 1 (HIV-1). RESULTS:Rilpivirine produced minimal changes in total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. Compared with RPV, EFV significantly (P < .001) increased lipid levels. Decreases in the TC/HDL-C ratio were similar with RPV and EFV. Background N[t]RTI affected RPV-induced lipid changes; all levels increased with zidovudine/lamivudine (3TC) and abacavir/3TC (except triglycerides, which were unchanged). With emtricitabine/tenofovir, levels of HDL-C were increased, TC and LDL-C were unchanged, and triglycerides were decreased. With EFV, lipid levels increased in each N[t]RTI subgroup (except triglycerides were unchanged with abacavir/3TC). Fewer (P < .001) RPV-treated patients than EFV-treated patients had TC, LDL-C, and triglyceride levels above National Cholesterol Education Program cutoffs. More RPV- than EFV-treated patients had HDL-C values below these cutoffs (P = .02). Dyslipidemia AEs were less common with RPV than with EFV. Similar proportions of patients had a ≥10% decrease in limb fat (16% with RPV and 17% with EFV). Limb fat was significantly (P < .001) increased to a similar extent (by 12% with RPV and 11% with EFV). At week 96, patients receiving zidovudine/3TC had lost limb fat, and those receiving emtricitabine/tenofovir had gained it. CONCLUSIONS:Over the course of 96 weeks, RPV-based therapy was associated with lower increases in lipid parameters and fewer dyslipidemia AEs than EFV-based treatment. Body fat distribution changes were similar between treatments. The N[t]RTI regimen affected lipid and body fat distribution changes.

Background This analysis assessed changes in serum 25-hydroxyvitamin D (25[OH]D; the precursor form of active vitamin D) in antiretroviral-naive adults receiving rilpivirine or efavirenz over 48 weeks in a randomized, double-blind, Phase III trial (ECHO). Methods ECHO included 690 patients randomized 1:1 to receive rilpivirine 25 mg once daily ( n=346) or efavirenz 600 mg once daily ( n=344), plus tenofovir disoproxil fumarate/emtricitabine. 25(OH)D was measured in stored serum samples collected at baseline, and weeks 24 and 48. Proportions of patients with optimal/sufficient (≥30 ng/ml), insufficient (21–29 ng/ml), deficient (10–20 ng/ml) and severely deficient (<10 ng/ml) 25(OH) D levels were determined. Data are presented for patients with paired baseline and week 48 25(OH)D data (rilpivirine, n=292; efavirenz, n=290). Results After 48 weeks, mean 25(OH)D levels remained largely unchanged from baseline with rilpivirine (-0.2 ng/ml; P=0.57 versus no change), but were significantly reduced with efavirenz (-2.5 ng/ml; P<0.0001 versus no change). When adjusting for season of randomization and the combined variable of race (Black/African American, White/Caucasian, Asian, other race) and ethnicity (Hispanic or Latino and not Hispanic or not Latino), the conclusion about the treatment difference between the rilpivirine and efavirenz treatment groups remained valid. At baseline the proportion of patients with severe 25(OH)D deficiency was similar in both groups (5%) but was significantly lower with rilpivirine than efavirenz at week 48 (5% versus 9%, respectively; P=0.032). Furthermore, of the patients with 25(OH)D insufficiency/deficiency at baseline, the proportion who developed severe 25(OH)D deficiency at week 48 was significantly lower with rilpivirine than efavirenz (2% versus 8%, respectively; P=0.0079). Conclusions Rilpivirine had little effect on 25(OH)D, whereas efavirenz resulted in a significant reduction in 25(OH)D levels and an increase in the risk of severe 25(OH)D deficiency.

Vitamin D deficiency in HIV infection has attracted much interest. The best known clinical outcomes of vitamin D deficiency are rickets (children) and osteomalacia (adults). Several non-skeletal disorders have also been linked to suboptimal vitamin D levels in the general population. The prevalence of vitamin D deficiency varies widely (6-100%) across diverse patient populations, with no evidence that it is higher in HIV-positive versus noninfected adults. Vitamin D deficiency may blunt immune restoration and exacerbate HIV complications (e.g. opportunistic infections, poor perinatal outcomes, wasting, HIV disease progression, AIDS events, and death). The nonnucleoside reverse transcriptase inhibitor efavirenz was associated with a relatively high risk of vitamin D deficiency; nevirapine, etravirine, and rilpivirine were noted to have less or no impact on vitamin D versus efavirenz in the limited data available. Protease inhibitors have either no or a low association with vitamin D deficiency. Nucleoside/nucleotide reverse transcriptase inhibitors (with the possible exception of zidovudine) also did not appear to be associated with vitamin D deficiency. Management of vitamin D deficiency in HIV-positive adults has not been rigorously evaluated; some guidelines recommend more vitamin D supplementation for HIV-positive adults on antiretrovirals versus the general population (e.g. 2-3 times higher vitamin D daily intake for the age group; loading dose up to 10,000 IU/day for 8-10 weeks and a maintenance dose of 800-2,000 IU/day). In conclusion, although vitamin D deficiency in HIV-positive adults can be prevalent, current evidence for its causes and impact is relatively weak. More data, particularly from large, controlled, long-term trials, regarding the benefits of correcting vitamin D levels in HIV-positive adults are needed.

Rilpivirine (RPV, TMC278, Edurant®) is a next‐generation non‐nucleoside reverse transcriptase inhibitor (NNRTI), which demonstrated high virologic response rates and non‐inferiority versus efavirenz in two Phase III trials in HIV‐infected patients through 96 weeks [1,2]. RPV has been shown to inhibit P‐glycoprotein (P‐gp) in vitro with an apparent IC50 of 9.2 µM (3.4 µg/mL). This study evaluated the in‐vivo effect of steady‐state RPV 25 mg once daily (qd) on the single‐dose pharmacokinetics of the probe P‐gp substrate digoxin. This was a Phase I, open‐label, randomised, crossover trial in 22 HIV‐negative volunteers. Participants received in one session a single 0.5 mg dose of digoxin, and in another session RPV 25 mg qd for 16 days with a single 0.5 mg dose of digoxin in the morning of Day 11. All study drugs were taken with a breakfast. Pharmacokinetic profiles of digoxin in plasma and urine were determined over 144 hours after dosing in each session. Steady‐state RPV 24‐hour pharmacokinetic profiles in plasma were determined on Day 11. Plasma and urine samples were analysed using validated LC‐MS/MS methods. Pharmacokinetic parameters were calculated with non‐compartmental methods. The least square (LS) means and associated 90% confidence intervals (CI) of treatment ratios were calculated based on log‐transformed pharmacokinetic parameters. Safety and tolerability were assessed throughout the trial. Digoxin pharmacokinetic parameters and statistical results are summarised in Table 1. Single dose pharmacokinetic parameters of digoxin in the absense and presence of steady‐state RPV Parameter digoxin 0.5 mg alone (reference) digoxin 0.5 mg + RPV 25 mg qd (test) N 21 22 AUC4h ng.h/mL 4.44±1.21 4.46±1.31 AUClast ng.h/mL 26.6±7.38 26.0±7.86 Cmax, ng/mL 1.93±0.637 2.05±0.678 tmax, h 1.50 (0.68–3.00) 1.74 (0.65–3.02) t½, h 38.8±6.30 38.3±8.17 Durine total, % 47.7±9.51 55.7±12.2 CLR, L/h 9.46±2.54 11.2±2.66 LS means (90% CI) of digoxin pharmacokinetic parameter ratios* AUClast 0.98 (0.93–1.04)a Cmax 1.06 (0.97–1.17)a CLR 1.16 (1.07–1.25)b Ratios presented as test/reference, calculated based on log‐transformed pharmacokinetic parameters. N=21 for test and N=22 for reference. N=18 for test and N=22 for reference. The plasma and urine digoxin pharmacokinetics were unaffected by co‐administration of steady‐state RPV. The 90% CIs of the LS means ratios of the main pharmacokinetic parameters were contained within the 0.80‐1.25 boundaries of no effect. The terminal elimination half‐life of digoxin was similar in the absence or the presence of steady‐state RPV. RPV pharmacokinetic parameters were comparable to those in previous clinical trials in healthy volunteers. Administration of digoxin and RPV was generally safe and well tolerated. There were no discontinuations due to adverse events. In conclusion, RPV does not affect the pharmacokinetics of the probe P‐gp substrate digoxin. In vivo, at the recommended RPV dose of 25mg qd, the observed in‐vitro inhibition of P‐gp by RPV is not clinically relevant.