Bictegravir/emtricitabine/tenofovir alafenamide in older individuals with HIV: Results of a 96-week, phase 3b, open-label, switch trial in virologically suppressed people ≥65 years of age.

OBJECTIVES: Bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) is an effective treatment for HIV-1 infection; however, clinical trial data in older people living with HIV (PLWH) are lacking. The primary 24-week and secondary 48-week analyses of study GS-US-380-4449 (NCT03405935), which assessed the efficacy and safety of switching to B/F/TAF in older PLWH, have been published. Here we report the results of the final 96-week analyses from the study. METHODS: In this 96-week, phase 3b, open-label, single-arm trial, virologically suppressed PLWH aged ≥65 years switched from elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide or a tenofovir disoproxil fumarate-based regimen to B/F/TAF. Viral suppression, resistance, immune response, safety, tolerability and adherence were evaluated through week 96. RESULTS: Of 90 participants screened, 86 were enrolled and switched to B/F/TAF. No participants had HIV-1 RNA ≥50 copies/ml (by FDA Snapshot algorithm) at weeks 72 or 96; virologic suppression rates were 94.2% (81/86; 95% CI 87.0-98.1) and 74.4% (64/86; 95% CI 63.9-83.2), respectively. No treatment-emergent resistance was observed, and CD4 counts remained stable. There were no study drug-related serious adverse events. Three participants experienced drug-related treatment-emergent adverse events that led to premature drug discontinuation. There were no clinically relevant changes from baseline to week 96 in fasting lipid parameters, and the median change in body weight at week 96 was 0.0 kg (IQR -2.3, 2.0). Median self-reported adherence was 100% (IQR 100-100%). CONCLUSIONS: Switching to B/F/TAF is an effective long-term option for virologically suppressed adults ≥65 years of age, with favourable safety and tolerability profiles in this population.

Brief Report: Efficacy and Safety of Bictegravir/Emtricitabine/Tenofovir Alafenamide in Females Living With HIV: An Integrated Analysis of 5 Trials.

BACKGROUND: We characterized the efficacy and safety of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in a broad population of pediatric/adolescent/adult/elderly females living with HIV (FWH). SETTING: Integrated analysis. METHODS: Available data from 5 trials were integrated. Week 48 virologic suppression (HIV-1 RNA <50 copies/mL), resistance, adverse events (AEs), and laboratory parameters were assessed. RESULTS: Three hundred and seventy-three FWH [304 virologically suppressed; 69 antiretroviral therapy (ART)-naive] received B/F/TAF [data from comparator regimens available for 306 individuals (236 virologically suppressed and 70 ART-naive participants)]. Virologic suppression rates with B/F/TAF at week 48 were high regardless of age in participants virologically suppressed at baseline (≥95%) and in ART-naive participants (≥87%). Virologic suppression rates were similar in B/F/TAF and comparator regimens (both virologically suppressed and ART-naive groups). Treatment-emergent resistance was not detected in the B/F/TAF group. AEs considered related to study drugs were experienced by 9.2% (B/F/TAF) and 5.5% (comparator regimen) of virologically suppressed participants and 15.9% (B/F/TAF) and 31.4% (comparator regimen) of ART-naive participants. For virologically suppressed and ART-naive FWH combined, only 1 of the 373 B/F/TAF-treated and 2 of the 306 comparator-regimen participants discontinued because of AEs (none were bone/renal/hepatic AEs); grade 3/4 AEs were experienced by 5.1% (B/F/TAF) and 7.8% (comparator regimen); and grade 3/4 elevation of low-density lipoprotein/total cholesterol occurred in 2.7%/0.3% (B/F/TAF) and 5.9%/2.0% (comparator regimen). At week 48, median changes from baseline estimated glomerular filtration rate in adults were <5 mL/min; results were similar in B/F/TAF and comparator-regimen groups. CONCLUSION: B/F/TAF treatment was effective and well tolerated over 48 weeks, confirming B/F/TAF as an option for a broad population of FWH.

Bictegravir/Emtricitabine/Tenofovir Alafenamide in Virologically Suppressed People with HIV Aged ≥ 65 Years: Week 48 Results of a Phase 3b, Open-Label Trial.

INTRODUCTION: We report the 48-week results of an ongoing study to assess the efficacy and safety of switching older people with HIV to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF). METHODS: This was a 96-week, phase 3b, open-label, single-arm study (GS-US-380-4449; NCT03405935). Virologically suppressed individuals aged ≥ 65 years receiving elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide or a tenofovir disoproxil fumarate-based regimen were switched to B/F/TAF. Primary endpoint was the percentage of participants with HIV-1 RNA < 50 copies/ml at week 24. RESULTS: Eighty-six participants (median age 69 [range 65-80] years; 87% male; 95% white) were enrolled and treated in five European countries. Rates of virologic suppression were 97.7% at week 24 and 90.7% at week 48; none had HIV-1 RNA ≥ 50 copies/ml, and 100% had virologic suppression by missing = excluded analysis at both time points. No treatment-emergent resistance was observed. There were no grade 3-4 study drug-related adverse events (AEs) or study drug-related serious AEs or deaths. Three AEs led to premature discontinuation; one (moderate abdominal discomfort) was attributed to the study drug by the investigator. At week 48, median changes from baseline in weight and estimated glomerular filtration rate were + 0.1 kg (interquartile range [IQR] - 1.0, 2.3) and - 6.0 ml/min (IQR - 10.2, 0.0), respectively. There were no clinically relevant changes from baseline to week 48 in fasting lipid parameters. Treatment satisfaction improved, and health-related quality of life was maintained from baseline through week 48. Median adherence to the study drug was 98.6% (IQR 96.0, 100). CONCLUSIONS: Switching to B/F/TAF was effective and well tolerated through 48 weeks in virologically suppressed adults aged ≥ 65 years. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03405935.

Randomized study evaluating the efficacy and safety of switching from an an abacavir/lamivudine-based regimen to an elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide single-tablet regimen.

OBJECTIVE: To evaluate the efficacy and safety of switching from an abacavir/lamivudine (ABC/3TC)-based regimen to an elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) single-tablet regimen in virologically suppressed, HIV-1-infected adults. DESIGN: Randomized, open-label, noninferiority study. METHODS: Participants with HIV-1 RNA levels less than 50 copies/ml receiving ABC/3TC plus a third agent for at least 6 months were randomized 2 : 1 to switch immediately to E/C/F/TAF (immediate-switch group) for 48 weeks or to continue receiving ABC/3TC plus a third agent for 24 weeks followed by E/C/F/TAF for 24 weeks (delayed-switch group). The primary endpoint was HIV-1 RNA less than 50 copies/ml at Week 24 by Food and Drug Administration Snapshot algorithm (-12% noninferiority margin). RESULTS: Baseline characteristics of 274 participants (183 in immediate-switch group and 91 in delayed-switch group) were similar. Virologic response was maintained at Week 24 by 93.4 and 97.8% of participants in the immediate-switch and delayed-switch groups, respectively, with a treatment difference of -4.4% (95% confidence interval: -9.4 to 1.9%), confirming noninferiority. Adverse events of any grade were similar between groups through Week 24 (66% E/C/F/TAF, 64% ABC/3TC); adverse event-related drug discontinuations occurred in 4% of participants switching to E/C/F/TAF (no discontinuations because of renal events) and no participants continuing ABC/3TC. Renal biomarkers of urine albumin:creatinine and beta-2-microglobulin:creatinine ratios significantly improved on E/C/F/TAF. Self-reported treatment satisfaction was significantly higher with E/C/F/TAF. CONCLUSION: Switching to E/C/F/TAF was noninferior to continuing ABC/3TC plus a third agent for maintenance of HIV RNA suppression at Week 24. This study supports E/C/F/TAF as an efficacious and well tolerated option for participants switching from ABC/3TC-based regimens.

Lack of clinically important PK interaction between coformulated ledipasvir/sofosbuvir and rilpivirine/emtricitabine/tenofovir alafenamide.

The drug-drug interaction (DDI) potential between the fixed-dose combinations of ledipasvir/sofosbuvir 90/400 mg for hepatitis C virus and emtricitabine/rilpivirine/tenofovir alafenamide (TAF) 200/25/25 mg for HIV was evaluated in a randomized, open-label, single-center, multiple-dose, 3-way, 6-sequence, crossover Phase 1 study in 42 healthy subjects. Emtricitabine/rilpivirine/TAF had no relevant effect on the pharmacokinetic parameters of maximum concentration [Cmax ] and area under the concentration versus time curve over the dosing interval [AUCtau ] for ledipasvir, sofosbuvir, and the metabolites GS-566500 and GS-331007. Ledipasvir/sofosbuvir had no effect on the Cmax and AUCtau for rilpivirine and emtricitabine. The Cmax and AUCtau of tenofovir, the major metabolite of TAF, were increased by 62% and 75%, respectively. However, the resulting absolute tenofovir exposures were markedly lower than the historical tenofovir exposures following tenofovir disoproxil fumarate (TDF) and, as such, were not considered to be clinically relevant. In contrast, additional adverse effect monitoring is recommended upon coadministration of ledipasvir and TDF due to elevated tenofovir exposures resulting from the DDI. This difference is explained by the fact that TAF 25 mg results in markedly lower (~90%) plasma tenofovir exposure compared to TDF 300 mg. Ledipasvir/sofosbuvir and emtricitabine/rilpivirine/TAF were generally well tolerated when administered alone or in combination. HIV/hepatitis C virus-coinfected patients can coadminister ledipasvir/sofosbuvir and emtricitabine/rilpivirine/TAF without dosage adjustments.

Clinical Outcomes of Virologically-Suppressed Patients with Pre-existing HIV-1 Drug Resistance Mutations Switching to Rilpivirine/Emtricitabine/Tenofovir Disoproxil Fumarate in the SPIRIT Study.

OBJECTIVES: Antiretroviral regimen switching may be considered for HIV-1-infected, virologically-suppressed patients to enable treatment simplification or improve tolerability, but should be guided by knowledge of pre-existing drug resistance. The current study examined the impact of pre-existing drug resistance mutations on virologic outcomes among virologically-suppressed patients switching to Rilpivirine (RPV)/emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF). METHODS: SPIRIT was a phase 3b study evaluating the safety and efficacy of switching to RPV/FTC/TDF in virologically-suppressed HIV-1-infected patients. Pre-existing drug resistance at baseline was determined by proviral DNA genotyping for 51 RPV/FTC/TDF-treated patients with known mutations by historical RNA genotype and matched controls and compared with clinical outcome at Week 48. RESULTS: Drug resistance mutations in protease or reverse transcriptase were detected in 62.7% of patients by historical RNA genotype and in 68.6% by proviral DNA genotyping at baseline. Proviral DNA sequencing detected 89% of occurrences of NRTI and NNRTI resistance-associated mutations reported by historical genotype. Mutations potentially affecting RPV activity, including E138A/G/K/Q, Y181C, and H221Y, were detected in isolates from 11 patients by one or both assays. None of the patients with single mutants had virologic failure through Week 48. One patient with pre-existing Y181Y/C and M184I by proviral DNA genotyping experienced virologic failure. Nineteen patients with K103N present by historical genotype were confirmed by proviral DNA sequencing and 18/19 remained virologically-suppressed. DISCUSSION: Virologic success rates were high among virologically-suppressed patients with pre-existing NRTI and NNRTI resistance-associated mutations who switched to RPV/FTC/TDF in the SPIRIT study. While plasma RNA genotyping remains preferred, proviral DNA genotyping may provide additional value in virologically-suppressed patients for whom historical resistance data are unavailable.

Rilpivirine vs. efavirenz-based single-tablet regimens in treatment-naive adults: week 96 efficacy and safety from a randomized phase 3b study.

OBJECTIVES: To compare efficacy, safety, tolerability, and patient-reported outcomes between two single-tablet regimens, rilpivirine/emtricitabine/tenofovir disoproxil fumarate (RPV/FTC/TDF) and efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF), in HIV-1-infected, treatment-naive adults. DESIGN: This was a phase 3b, 96-week, randomized, open-label, international, noninferiority trial. METHODS: A total of 799 participants were randomized (1 : 1) to receive RPV/FTC/TDF or EFV/FTC/TDF. The primary efficacy endpoint evaluated proportions of participants with HIV-1 RNA less than 50 copies/ml using the Snapshot algorithm. Additional assessments included CD4 cell counts, genotypic/phenotypic resistance, adverse events, patient-reported outcomes, and quality of life questionnaires. RESULTS: At week 96, trial completion rates were 80.2% (316/394; RPV/FTC/TDF) and 74.0% (290/392; EFV/FTC/TDF). Overall, RPV/FTC/TDF was noninferior to EFV/FTC/TDF [HIV-1 RNA <50 copies/ml: 77.9 vs. 72.4%, respectively; difference -5.5; 95%CI (-0.6, 11.5); P = 0.076]. RPV/FTC/TDF was significantly more efficacious compared with EFV/FTC/TDF in participants with baseline HIV-1 RNA equal to or less than 100 000 copies/ml (78.8 vs. 71.2%; P = 0.046) and in those with CD4 cell count greater than 200 cells/µl (80.6 vs. 73.0%; P = 0.018). There was no significant between-group difference in the CD4 cell count increase (278 ±â€Š189 vs. 259 ±â€Š191 cells/µl; P = 0.17). Few participants developed resistance after week 48 (1.0% RPV/FTC/TDF; 0.3% EFV/FTC/TDF). Compared with EFV/FTC/TDF, RPV/FTC/TDF was associated with fewer adverse event-related discontinuations (3.0 vs. 11.0%; P<0.001), significantly fewer adverse events due to central nervous system issues and rash, greater improvements in patient-reported symptoms, and significant improvements in the SF-12v2 quality of life questionnaire mental health composite score (P = 0.014). CONCLUSION: In treatment-naive, HIV-1-infected participants, 96-week RPV/FTC/TDF treatment demonstrated noninferior efficacy and better tolerability than EFV/FTC/TDF.

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.

The once daily, single-tablet regimen (STR) combining rilpivirine (RPV), emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF) provides a simplified treatment option for antiretroviral therapy (ART)-naïve patients with baseline HIV-1 RNA (BLVL) of ≤100,000 copies/mL. The aim of this analysis is to compare long-term efficacy, safety, and tolerability of RPV+FTC/TDF vs. efavirenz (EFV)+FTC/TDF as individual components in subjects with BLVL ≤100,000 copies/mL. Week 96 efficacy and safety data from subjects with BLVL ≤100,000 copies/mL, who received daily RPV 25 mg or EFV 600 mg with FTC/TDF in the phase 3, randomized, double-blind, double-dummy, active-controlled, registrational trials ECHO and THRIVE, were analyzed. Virologic response was evaluated by intent-to-treat, time to loss of virological response (ITT-TLOVR), and Snapshot algorithms. Through Week 96, RPV+FTC/TDF demonstrated non-inferior efficacy to EFV+FTC/TDF (84% vs. 81%, respectively; ITT-TLOVR) in 543 subjects with BLVL ≤100,000 copies/mL, and overall rates of virologic failure (VF) were 5.9% vs. 2.4%, respectively. Resistance development was lower in Year 2 than Year 1. Subjects in both arms with suboptimal adherence (≤95%) had lower virologic responses (63% vs. 62%, respectively). Treatment with RPV+FTC/TDF was associated with significantly fewer treatment-related adverse events (AEs), grade 2-4 AEs, neurological and psychiatric AEs (including dizziness and abnormal dreams/nightmares), and rash. Additionally, grade 2-4 treatment-emergent laboratory abnormalities and grade 1-3 lipid abnormalities were significantly less common with RPV+FTC/TDF than EFV+FTC/TDF. RPV+FTC/TDF demonstrated non-inferior efficacy to EFV+FTC/TDF in ART-naïve subjects with BLVL ≤100,000 copies/mL and was associated with a higher rate of VF but a more favorable safety and tolerability profile through Week 96.

Efficacy and safety 48 weeks after switching from efavirenz to rilpivirine using emtricitabine/tenofovir disoproxil fumarate-based single-tablet regimens.

BACKGROUND: Due to ongoing neuropsychiatric adverse events in some efavirenz (EFV)-treated patients, a switch to an alternative non-nucleoside reverse transcriptase inhibitor may be considered. Rilpivirine (RPV) has been coformulated as a single-tablet regimen (STR) with emtricitabine/tenofovir disoproxil fumarate (FTC/TDF), and the components have demonstrated noninferior efficacy to EFV+FTC/TDF, good tolerability profile, and high adherence. After discontinuation, EFV has an extended inductive effect on cytochrome P450 (CYP) 3A4 that, after switching, may reduce RPV exposures and adversely impact clinical outcomes. OBJECTIVE: This study examines the clinical implications of reduced RPV exposures with concomitant FTC/TDF and declining EFV exposures when patients, intolerant to EFV, switch from EFV/FTC/TDF to RPV/FTC/TDF. METHODS: This 48-week, phase 2b, open-label, multicenter study evaluated the efficacy and safety of switching from EFV/FTC/TDF (≥3 months duration) to RPV/FTC/TDF. Virologic suppression (HIV-1 RNA <50 copies/mL), safety, and EFV and RPV pharmacokinetics were assessed. RESULTS: At weeks 12 and 24, all 49 dosed subjects remained suppressed on RPV/FTC/TDF. At week 48, 46 (93.9%) subjects remained suppressed and virologic failure occurred in 2/49 (4.1%) subjects with no emergence of resistance. EFV concentrations were above the 90th percentile for inhibitory concentration (IC90) for several weeks after EFV discontinuation, and RPV exposures were in the range observed in phase 3 studies by approximately 2 weeks post switch. No subjects discontinued the study due to an adverse event. CONCLUSIONS: Switching from EFV/FTC/TDF to RPV/FTC/ TDF was a safe, efficacious option for virologically suppressed HIV-infected patients with EFV intolerance wishing to remain on an STR.

Formulation preference, tolerability and quality of life assessment following a switch from lopinavir/ritonavir soft gel capsule to tablet in human immunodeficiency virus-infected patients.

BACKGROUND: Lopinavir/ritonavir (LPV/r) tablet compared to the soft gel capsule (SGC) formulation has no oleic acid or sorbitol, has no refrigeration or food-restriction requirements, and has less pharmacokinetic variability. We compared the tolerability, quality of life (QoL), and formulation preference after switching from LPV/r SGC to the tablet formulation. METHODS: In a prospective, single-arm, cohort study-design, 74 human immunodeficiency virus (HIV) infected subjects stable on LPV/r-based therapy were enrolled prior to (n = 25) or 8 weeks (n = 49) after switching from SGC to tablet. Baseline data included clinical laboratory tests, bowel habit survey (BHS) and QoL questionnaire (recalled if enrolled post-switch). Global Condition Improvement (GCI)-score, BHS-score, QoL-score, and formulation preference data were captured at weeks 4 and 12. RESULTS: At week 12 post-enrollment; the tablet was preferred to the SGC (74% vs. 10%, p < 0.0001). GCI-overall-tolerability score was 2.46 +/- 3.30 on a scale of -7 to +7, with 90% admitting to feeling better or about the same. Stool frequency, consistency, volume, and +/- blood improved, however the improvement was significant in "consistency" only (p = 0.03). Aggregate Bowel Habit-Profile improved (BHS-score change = -0.227, p = 0.01). Inverse relationship existed between GCI and BHS (slope = -1.2, p = 0.02) at week-4, suggesting that improved overall-tolerability was related to better gastrointestinal (GI)-tolerance. QoL-scores were stable. Mean reductions in total cholesterol of 9.20 mg/dL (p = 0.02), in triglycerides of 33 mg/dL (p = 0.04), and in HDL of 4.50 mg/dL (p = 0.01) unrelated to lipid-lowering therapy, were observed at week 12. CONCLUSIONS: LPV/r-tablet was well tolerated and preferred to the SGC in HIV infected subjects, with stable QoL and appreciable improvement in GI-tolerability. The unexpected changes in lipid profile deserve further evaluation.

Significant improvements in self-reported gastrointestinal tolerability, quality of life, patient satisfaction, and adherence with lopinavir/ritonavir tablet formulation compared with soft gel capsules.

BACKGROUND: The tablet formulation of ritonavir-boosted lopinavir (LPV/r; Kaletra) has many advantages over the soft gel capsule (SGC) formulation, including lower pill count, no refrigeration requirement, and no dietary restrictions. These advantages may help improve patient compliance and therefore increase adherence to treatment. However, there are limited data regarding patient preferences and only recently was the comparative efficacy and tolerability data of LPV/r SGC versus tablet formulation presented at an international conference. To address this deficit, we conducted a market research survey to assess potential tolerability benefits, patient satisfaction, changes in adherence, and formulation preference in patients switching from SGCs to the tablet formulation. Data from 332 patients who switched from LPV/r SGCs twice-daily (BID) to tablets BID and 41 patients who switched from LPV/r SGCs BID or once daily (QD) to tablets QD were analyzed. RESULTS: Switching from SGCs to a tablet formulation of LPV/r was associated with increased patient satisfaction, tolerability and self-reported adherence to treatment; gastrointestinal side effects were reduced. In addition, respondents indicated that they preferred the tablet formulation to the SGC. CONCLUSION: The LPV/r tablet formulation provides HIV-infected patients with multiple benefits over the SGC in terms of tolerability and convenience. Additional assessments to further define the tolerability profile of the LPV/r tablet, including studies using once-daily dosing, are warranted.

Antiretroviral pharmacokinetic profile: a review of sex differences.

BACKGROUND: Emerging evidence suggests that female sex may be associated with increased risk of developing antiretroviral toxicities. Although the mechanisms of sex-related antiretroviral pharmacodynamic differences remain poorly understood and may be multifactorial, they appear to be mediated through a common pathway of pharmacokinetic variability between the sexes. OBJECTIVE: This article reviews sex differences in the pharmacokinetics of the major classes of antiretroviral drugs currently approved for HIV treatment by the US Food and Drug Administration, identifies knowledge gaps, and provides recommendations for future research directions. METHODS: To identify pertinent articles for this review, the MEDLINE database was searched from 1990 to June 2006 using the terms sex, gender, antiretroviral therapy, ART, HAART, pharmacokinetics, pharmacodynamics, NRTI, NNRTI, and protease inhibitors. Search results were restricted to English language and human studies. The reference lists of identified articles were also used, as well as abstracts from relevant conferences. In addition, individual antiretroviral drugs were searched by sex/gender or by pharmacokinetics. RESULTS: Current evidence, though limited, does suggest the existence of a sex disparity in antiretroviral pharmacokinetics, and such disparity has been shown to have pharmacodynamic implications for some drugs. Sex-mediated intracellular pharmaco-enhancement was associated with superior antiviral activities for the zidovudine and lamivudine members of the nucleoside reverse transcriptase inhibitor class. There appears to be divergent opinions about whether sex is a significant determinant of either nevirapine or efavirenz plasma concentrations. For certain protease inhibitors (PIs) (eg, saquinavir [SQV] and indinavir [IDV]), clinically significant relationships between sex differences in plasma drug concentrations and clinical outcomes have been observed. There appears to be a trend toward higher drug exposure in women than in men when PIs are boosted with ritonavir (RTV). Nelfinavir, the only PI that is currently administered unboosted with RTV, does not exhibit a sex difference in its plasma concentrations. Unboosted amprenavir exposure was lower in women compared with men. Sex differences in the pharmacokinetics of SQV and IDV were observed only in the setting of RTV boosting. CONCLUSIONS: A common weakness in many studies addressing sex-based differences in the pharmacokinetics of antiretroviral drugs is the relatively small number of women participating. Many of these studies were retrospective in design, and some had limited pharmacokinetic parameters for comparison. Antiretroviral treatment trials should be designed with sufficient power (adequate female participation) to detect sex-based differences both in pharmacokinetics and in clinical response. Future studies should explore the molecular basis for sex-based differences in plasma drug concentrations and antiretroviral drug response. The roles of drug transporter proteins and cellular kinases, and the activities of metabolizing enzymes in mediating differential plasma and intracellular antiretroviral concentrations, should be further assessed.

Lopinavir/Ritonavir pharmacokinetic profile: impact of sex and other covariates following a change from twice-daily to once-daily therapy.

The aim of this study was to determine the impact of sex on the pharmacokinetics of lopinavir/ritonavir. Interaction between lopinavir/ritonavir and tenofovir was also evaluated. Steady-state plasma samples were obtained from virologically suppressed HIV-infected patients on lopinavir/ritonavir 800/200-mg soft gel capsule taken once daily. Drug assays were performed by high-performance liquid chromatography. Pharmacokinetic parameters estimated by noncompartmental method were reported as 90% confidence intervals (CIs) about the geometric mean ratio (GMR). There were 9 males and 11 females. No sex differences were observed in lopinavir/ritonavir pharmacokinetics profile. The GMR(sex) (women compared with men) for lopinavir area under the concentration-time curve (AUC(24)), maximum concentration (C(max)), and minimum concentration (C(min)) was 0.95 (90% CI, 0.70-1.29), 0.88 (90% CI, 0.67-1.15), and 1.27 (90% CI, 0.60-2.66), respectively. Similarly, the GMR(sex) for ritonavir AUC(24), C(max), and C(min) was 0.84 (90% CI, 0.57-1.24), 0.79 (90% CI, 0.50-1.22), and 1.02 (90% CI, 0.58-1.80), respectively. Tenofovir coadministration led to a reduction in lopinavir/ritonavir plasma exposure, giving a lopinavir GMR(tenofovir) for C(max) of 0.72 (90% CI, 0.57-0.93) and AUC(24) of 0.74 (90% CI, 0.56-0.98), respectively. No difference in lopinavir/ritonavir plasma concentrations between sexes was demonstrated in this study. However, tenofovir coadministration lowered lopinavir/ritonavir plasma exposure.

Management of protease inhibitor-associated hyperlipidemia.

Dyslipidemia, characterized by elevated serum levels of triglycerides and reduced levels of total cholesterol, low-density lipoprotein-cholesterol (LDL-C) and high-density lipoprotein-cholesterol, has been recognized in patients with human immunodeficiency virus (HIV) infection. It is thought that elevated levels of circulating cytokines, such as tumor necrosis factor-alpha and interferon-alpha, may alter lipid metabolism in patients with HIV infection. Protease inhibitors, such as saquinavir, indinavir and ritonavir, have been found to decrease mortality and improve quality of life in patients with HIV infection. However, these drugs have been associated with a syndrome of fat redistribution, insulin resistance, and hyperlipidemia. Elevations in serum total cholesterol and triglyceride levels, along with dyslipidemia that typically occurs in patients with HIV infection, may predispose patients to complications such as premature atherosclerosis and pancreatitis. It has been estimated that hypercholesterolemia and hypertriglyceridemia occur in greater than 50% of protease inhibitor recipients after 2 years of therapy, and that the risk of developing hyperlipidemia increases with the duration of treatment with protease inhibitors. In general, treatment of hyperlipidemia should follow National Cholesterol Education Program guidelines; efforts should be made to modify/control coronary heart disease risk factors (i.e. smoking; hypertension; diabetes mellitus) and maximize lifestyle modifications, primarily dietary intervention and exercise, in these patients. Where indicated, treatment usually consists of either pravastatin or atorvastatin for patients with elevated serum levels of LDL-C and/or total cholesterol. Atorvastatin is more potent in lowering serum total cholesterol and triglycerides compared with other hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, but it is also associated with more drug interactions compared with pravastatin. Simvastatin and lovastatin are significantly metabolized by cytochrome P450 enzymes (CYP3A4) and are therefore not recommended for coadministration with protease inhibitors. A fibric acid derivative (gemfibrozil or fenofibrate) should be used in patients with primary hypertriglyceridemia. However, it must be kept in mind that protease inhibitors, such as nelfinavir and ritonavir, induce enzymes involved in the metabolism of the fibric acid derivatives and may, therefore, reduce the lipid-lowering activity of coadministered gemfibrozil or fenofibrate. In certain patients HMG-CoA reductase inhibitors may be used in combination with fibric acid derivatives but patients should be carefully monitored for liver and skeletal muscle toxicity. Select patients may experience improvements in serum lipid levels when their offending protease inhibitor(s) is/are exchanged for efavirenz, nevirapine, or abacavir; however each patient's virologic and immunologic status must be taken closely into consideration.

Risk-benefit of HMG-CoA reductase inhibitors in the treatment of HIV protease inhibitor-related hyperlipidaemia.

HIV protease inhibitors decrease mortality and improve quality of life in patients with HIV infection. However, these drugs have been associated with serum lipid elevations, which may pose an increased risk of cardiovascular disease and pancreatitis. Treatment of protease inhibitor-related hyperlipidaemia (PIH) is complicated by drug interactions, which significantly increase concentrations of most 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins). Although pravastatin and atorvastatin effectively lower cholesterol and triglyceride concentrations in HIV-infected patients, a significant number of patients did not achieve their National Cholesterol Education Program low density lipoprotein concentration goals. Nonetheless, due to the increased risk of rhabdomyolysis with elevated statin concentrations, atorvastatin should be considered a second-line agent. The limited available PIH data supports the fact that pravastatin and atorvastatin are well-tolerated in HIV-infected individuals. More data are needed on the appropriate starting doses, maximum safe doses, role of combination statin-fibrate therapy, documentation of coronary heart disease benefit and incidence of myotoxicity and hepatotoxicity. Pravastatin has an acceptable risk-benefit ratio in PIH, while theoretical toxicity concerns exist with atorvastatin.