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Background: Antiretroviral therapy in HIV-positive patients leads to insulin resistance which is central to the pathogenesis of various metabolic abnormalities and cardiovascular disease seen in this patient group. We have investigated the dose-response relationship of telmisartan, an antihypertensive, on adipocytes in vitro in order to determine whether it may have metabolic beneficial effects., Methods: Using in vitro chronic toxicity models (3T3-F442A murine and primary human adipocytes), we evaluated the effects of different concentrations of telmisartan on adipocyte differentiation and adipogenic gene expression using lipid accumulation assays and real-time polymerase chain reaction, respectively. Adipokine secretion and expression of insulin signalling mediators were evaluated using enzyme-linked immunosorbent assays., Results: Telmisartan partially reversed the deleterious effects of antiretrovirals on adipocyte lipid accumulation, expression of adipogenic regulators (peroxisome proliferator receptor-gamma and lipin 1), adipokine secretion and expression of the insulin signalling mediator pAkt Ser473 . The metabolic effects of telmisartan followed a non-monotonic response with the maximal effect observed at 5 µM in the primary human adipocyte model., Conclusion: Telmisartan has beneficial metabolic effects in adipocytes in vitro, but its potential to reduce antiretroviral-induced cardiometabolic disease in HIV-infected individuals needs to be evaluated in a well-designed adequately powered clinical trial.

Background: CYP3A4 induction by efavirenz (EFV) persists after drug cessation; we assessed the pharmacokinetics (PK), efficacy and safety of maraviroc (MVC) administered to HIV-infected individuals switching from EFV-containing therapy., Methods: Patients with R5-tropic virus and suppressed viral load on two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) plus EFV switched EFV to MVC 600 mg twice daily for 14 days, and then to MVC 300 mg twice daily. Following screening, three intensive PK visits were performed (sampling was pre-dose and 1, 2, 4, 6, 8 and 12 h post-dose): day 1 (VISIT 1, MVC 600 mg twice daily), day 14 (VISIT 2, steady-state MVC 600 mg twice daily) and day 28 post regimen switch (VISIT 3, steady-state MVC 300 mg twice daily); MVC trough concentration (Ctrough) was determined 3, 6 and 10 days following regimen switch and viral loads up to week 24. MVC PK parameters on visits 1 and 2 and MVC Ctrough on day 6 were compared to visit 3 (reference) via geometric mean ratios (GMR) and 95% CIs., Results: Twelve males completed the study. MVC PK parameters at visit 1 versus visit 3 were: GMR and 95% CI 12-h area under the curve (AUC0-12) 1.25 (1.00, 1.58); Cmax 1.64 (1.16, 2.31); Ctrough 0.61 (0.46, 0.80). Visit 2 MVC PK parameters were significantly higher than visit 3: GMR and 95% CI AUC0-12 2.31 (1.84, 2.90); Cmax 2.42 (1.87, 3.12); Ctrough 2.25 (1.74, 2.91). MVC was well tolerated with no grade 3/4 adverse events; all subjects maintained viral suppression to the end of the study., Conclusions: The EFV induction effect necessitated increased MVC dose to 600 mg twice daily following switch and persisted for approximately one week after EFV cessation. This is less than the 2-week induction observed when switching EFV to etravirine and highlights the importance of studying different tail interactions. Higher dose MVC was well tolerated. All measured MVC Ctrough concentrations exceeded wild-type 90% inhibitory concentration.

Background: Here, we aimed to investigate the pharmacokinetics of abacavir and carbovir triphosphate (CBV-TP) with darunavir/ritonavir 900/100 mg once daily or raltegravir 400 mg twice daily., Methods: HIV-infected subjects on abacavir (600 mg once daily) underwent steady-state pharmacokinetic assessments without and with darunavir/ritonavir or raltegravir. Within-subject changes in plasma and intracellular pharmacokinetic parameters were evaluated by geometric mean ratios (GMRs) and 90% CIs., Results: A total of 19 patients completed the study. With darunavir/ritonavir (versus abacavir alone), abacavir GMRs (90% CI) were 0.73 (0.66, 0.80), 0.62 (0.50, 0.77) and 0.78 (0.69, 0.87) for area under the curve (AUC), trough concentration (C(trough)) and maximum concentration (C(max)), respectively. With raltegravir, they were 1.03 (0.97, 1.10), 0.83 (0.62, 1.11) and 1.06 (0.95, 1.18), respectively. Intracellular CBV-TP GMRs (90% CI) were 0.88 (0.72, 1.07), 0.68 (0.48, 0.95) and 0.98 (0.79, 1.23) for AUC, C(trough) and C(max), respectively, with darunavir/ritonavir, and 0.96 (0.76, 1.20), 0.57 (0.33, 1.00) and 1.07 (0.85, 1.35), respectively, with raltegravir., Conclusions: There was a 27% decrease in abacavir plasma exposure with darunavir/ritonavir and no changes with raltegravir. CBV-TP C(trough) was significantly decreased with darunavir/ritonavir (32%) and showed a high inter-individual variability with raltegravir.

Background: Potential drug-drug interactions (PDDIs) might expand with new combination antiretroviral therapies (ART) and polypharmacy related to increasing age and comorbidities. We investigated the prevalence of comedications and PDDIs within a large HIV cohort, and their effect on ART efficacy and tolerability., Methods: All medications were prospectively recorded in 1,497 ART-treated patients and screened for PDDIs using a customized version of the Liverpool drug interactions database., Results: Overall, 68% (1,013/1,497) of patients had a comedication and 40% (599/1,497) had > or = 1 PDDI. Among patients with comedication, 2% (21/1,013) had red-flag interactions (contraindicated) and 59% (597/1,013) had orange-flag interactions (potential dose adjustment and/or close monitoring required). The latter involved mainly central nervous system drugs (49%), cardiovascular drugs (34%) and methadone (19%). In the multivariate analysis, factors associated with having a comedication were advanced age, female gender, obesity and HCV infection. Independent risk factors for PDDIs were regimens combining protease inhibitors and non-nucleoside reverse transcriptase inhibitors (odds ratio [OR] 3.06, 95% confidence interval [CI] 1.44-6.48), > or = 2 comedications (OR 1.89, 95% CI 1.32-2.70), current illicit drug use (OR 2.00, 95% CI 1.29-3.10) and patients with HCV infection (OR 1.74, 95% CI 1.19-2.56). Viral response was similar in patients with and without PDDIs (84.5% versus 86.4%; P=0.386). During follow-up, ART was modified in 134 patients with comedication regardless of the presence of PDDIs (P=0.524)., Conclusions: PDDIs increase with complex ART and comorbidities. No adverse effect was noted on ART efficacy or tolerability; however, most PDDIs affected comedication but were manageable through dose adjustment or monitoring.

Background: Drug efflux (for example, P-glycoprotein [P-gp], multidrug resistance-associated proteins [MRPs] and breast cancer resistance protein [BCRP]) and influx (for example, human organic anion transporting polypeptide [hOCTP] or human organic anion transporting polypeptide [hOATP]) transporters alter the cellular concentrations of some HIV protease inhibitors (HPIs). Here, we studied the lipophilicity and uptake of [(3)H]-atazanavir (ATV) in CEM (parental), CEM(VBL) (P-gp-overexpressing), CEM(E1000) (MRP1-overexpressing) and peripheral blood mononuclear cells (PBMCs), and evaluate the effects of modulators of drug transporters on uptake., Methods: Lipophilicity was measured by octanol/saline partition method. The influence of influx/efflux transporters on uptake was evaluated in the absence and presence of inhibitors of P-gp (GPV031), P-gp/BCRP (tariquidar and GF120918), P-gp/MRP1 (dipyridamole and daidzein), MRP1/2 (frusemide and genistein), hOATP/hOCTP (estrone-3-sulfate [E-3-S]) and hOATP/hOCTP/MRP (probenecid). The effects of a number of HPIs on uptake were also evaluated. Data from digitonin permeabilized cells allowed the evaluation of the contribution of cellular binding to total drug uptake, whereas the inhibitory effect of ATV on P-gp was assessed by daunomycin efflux/uptake assays., Results: [(3)H]-ATV is lipophilic and accumulates in the cultured cells as follows: CEM>CEM(E1000)>CEM(VBL). Tariquidar, GF120918 and daidzein significantly increased the uptake of [(3)H]-ATV in the cultured cells. By contrast, only daidzein and tipranavir significantly increased uptake in PBMCs, with tariquidar and frusemide devoid of effects, whereas dipyridamole, E-3-S, GPV031 and genistein significantly decreased accumulation. ATV inhibits P-gp activity; manipulation of uptake with digitonin suggests binding of [(3)H]-ATV to P-gp., Conclusions: [(3)H]-ATV is lipophilic, a P-gp, MRP and hOATP substrate and an inhibitor of P-gp. Concomitant administration of ATV with drugs and dietary components (for example, daidzein and genistein) that interact with these transporters could alter its pharmacokinetics.

Darunavir (TMC114) is a new HIV protease inhibitor that has demonstrated substantial antiretroviral activity against wild-type HIV-1 virus and multidrug-resistant strains. Darunavir inhibits and is primarily metabolized by cytochrome P450 3A (CYP3A) isoenzymes and is coadministered with low-dose ritonavir (darunavir/r); ritonavir is an inhibitor of CYP3A isoenzymes and pharmacologically enhances darunavir, resulting in increased plasma concentrations and allowing for a lower daily dose. The t1/2 (terminal elimination half-life) of darunavir is 15 h in the presence of ritonavir. An extensive darunavir/r drug-drug interaction programme has been undertaken, covering a wide range of therapeutic areas. Studies conducted in HIV-negative healthy volunteers and in HIV-infected patients show that the potential for interactions is well characterized and the interactions are manageable. For most drugs investigated, no dose adjustments of darunavir/r or the co-administered drug are required. This article reviews all the pharmacokinetic and drug-drug interaction studies conducted to date for darunavir/r, providing guidance on how to co-administer darunavir/r with many other antiretroviral or non-antiretroviral medications commonly used in HIV-infected individuals.

Objective: To evaluate the effects of stopping treatment with protease inhibitors (PIs) on tumour necrosis factor (TNF)-alpha and TNF-receptor levels, and on the metabolic and morphological abnormalities seen in patients with lipodystrophy., Design: Longitudinal study., Methods: Ten HIV-positive patients with lipodystrophy (LD) were studied whilst on PIs (LD1) and 3 months after stopping PIs (LD2) together with 10 HIV-positive subjects on PIs without LD (controls). TNF-alpha and TNF-receptor levels, insulin resistance parameters, lipid and hormonal profiles, body composition and fat distribution were measured in all subjects., Results: TNF-alpha, TNF-receptor I (-RI) and TNF-RII levels were significantly lower in controls (P=0.02) than in subjects with LD, and there was a significant decrease in TNF-RI and TNF-RII levels (P=0.01 and 0.03, respectively) on stopping PIs. Insulin levels and the homeostasis model assessment for insulin resistance (HOMA-IR) index were significantly higher in LD1 subjects (P=0.02) than in controls but did not alter when PIs were stopped. Bioelectrical impedance analysis showed a significant decrease on stopping PIs but CT scans showed no significant difference in fat distribution. Apart from high-density lipoprotein, there was no change in lipid parameters on stopping PIs. There was no difference in the level of testosterone, sex hormone binding globulin and cortisol between the three groups., Conclusion: Our results show that TNF-alpha activity in patients with LD is modulated by PIs. This was not accompanied by significant changes in body habitus or insulin resistance, although this may have been a consequence of the short follow-up in this study.

Objective: To evaluate the steady-state pharmacokinetics and safety of two once-daily saquinavir/ritonavir (SQV/RTV) regimens, 1600/100 and 2000/100 mg, in HIV-positive patients., Methods: Eighteen HIV-infected adults treated with the standard twice-daily SQV/RTV 1000/100 mg regimen were enrolled in this open-label, two-phase, crossover pharmacokinetic study. The steady-state pharmacokinetics of SQV administered with 100 mg RTV were investigated following once-daily doses of 1600 mg or 2000 mg or a twice-daily dose of 1000 mg. Plasma drug concentrations were determined by high performance liquid chromatography-tandem mass spectrometry and pharmacokinetic parameters were calculated using a non-compartmental model., Results: Compared with SQV 1000 mg twice daily, the Cmax of SQV following a 1600 mg and 2000 mg dose increased in a dose-proportional manner [geometric mean (95% CI) 1915 (1656-2850) ng/ml for 1000 mg, 2782 (2249-4330) ng/ml for 1600 mg and 4179 (3429-6105) ng/ml for 2000 mg doses, respectively]. SQV Ctrough values were 539 (453-1011), 106 (76-223) and 231 (75-822) ng/ml, respectively. A SQV Ctrough value greater than 100 ng/ml was achieved in all subjects on the twice-daily regimen, in 9/18 (50%) subjects on the 1600/100 mg once-daily regimen, and in 14/17 (82%) subjects on the 2000/100 mg once-daily regimen. The once-daily regimens were well tolerated, with mild-to-moderate gastrointestinal symptoms being the only events reported by a small number of patients., Conclusion: This is the first study to evaluate the pharmacokinetics of once-daily SQV/RTV 2000/100 mg in HIV-infected subjects. Our findings suggest that this regimen may be an alternative to twice-daily 1000/100 mg doses and should be further evaluated in efficacy studies. The data indicate that most patients (14/17) on once-daily 2000/100 mg achieve trough concentrations above target values (determined for HIV wild-type) for efficacy of SQV with the use of just 100 mg RTV/day and with good tolerability.

Objective: The pathogenesis of lipodystrophy caused by the HIV protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs) is unclear. We have investigated the disposition of these drugs in adipocytes and the consequent effect on adipocyte metabolism and viability., Design: Laboratory study utilizing two murine cell lines, 3T3-L1 and 3T3-F442A., Methods: Intracellular NRTI phosphate and PI concentrations were determined by HPLC and HPLC-MS/MS, respectively. The cytotoxicity of the drugs was examined on the different adipogenic stages together with their effects on glucose uptake plus or minus insulin, and on glycerol and triglyceride levels., Results: There was rapid intracellular accumulation and phosphorylation of [3H]-zidovudine and -stavudine to their phosphate metabolites in adipocytes. The NRTIs were not cytotoxic, did not affect preadipocyte protein synthesis and did not inhibit adipogenesis or induce lipolysis. PIs accumulated in adipocytes (nelfinavir>saquinavir>ritonavir>indinavir). All PIs, except indinavir, were cytotoxic and inhibited adipogenesis, increased lipolysis and impaired preadipocyte protein synthesis. PIs inhibited glucose uptake in the rank order: indinavir>saquinavir>ritonavir>nelfinavir., Conclusion: These data demonstrate that PIs may play a role in the insulin resistance observed in lipodystrophy by affecting glucose uptake, adipogenesis and lipolysis. NRTIs alone do not seem to have any effect on adipocyte metabolism despite undergoing phosphorylation to their triphosphorylated anabolites, although their effects in combination with PIs in perturbing adipocyte metabolism warrants further investigation.

Objective: To determine intracellular concentrations of indinavir (IDV) and investigate the relationship between plasma and intracellular IDV pharmacokinetics in HIV-infected patients., Methods: A pharmacokinetic study of 10 patients receiving IDV plus dual nucleoside analogue therapy. Peripheral blood mononuclear cells were isolated by density gradient centrifugation and cell counts estimated. IDV was extracted from cells in the presence of 60% methanol and evaporated to dryness. Both plasma and intracellular IDV samples were assayed by high performance liquid chromatography linked to mass spectrometry. Data were subjected to non-compartmental pharmacokinetic analysis., Results: The mean intracellular IDV area under the curve over 8 h (AUC0-8) was lower than the plasma AUC0-8 (7574 +/- 1003 vs 25060 +/- 4171 ng/ml/h; P<0.004). However, both the elimination half-life (t1/2) and the mean residence time (MRT) of IDV intracellularly were prolonged compared with plasma (t1/2: 2.0 +/- 0.3 vs 1.2 +/- 0.09 h; MRT: 3.6 +/- 0.6 vs 2.1 +/- 0.1 h; P<0.05). All patients were responsive to therapy at the time of the study, as assessed by HIV plasma RNA levels. Individual plasma versus intracellular time course results suggest that, due to the prolonged intracellular half-life, some patients may achieve acceptable intracellular IDV concentrations despite sub-therapeutic plasma levels. Similarly, potentially inadequate intracellular concentrations may occur despite therapeutic plasma concentrations., Conclusions: There is no significant intracellular accumulation of IDV within the lymphocytes of HIV-1-infected patients relative to plasma. However, intracellular concentrations are compatible with reported IDV-free drug concentrations in plasma. The intracellular elimination half-life and mean residence time of IDV are significantly prolonged compared with plasma. This may in part explain why certain patients maintain adequate viral suppression despite sub-therapeutic plasma IDV levels.