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Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG Study A5047

Fichtenbaum, Carl J.a,b; Gerber, John G.c; Rosenkranz, Susan L.d; Segal, Yoninahd; Aberg, Judith A.e; Blaschke, Terrencef; Alston, Beverlyg; Fang, Fangh; Kosel, Bradleye; Aweeka, Francescae; and the NIAID AIDS Clinical Trials Group

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From the aUniversity of Cincinnati College of Medicine, Cincinnati, Ohio, bWashington University, St. Louis, Missouri, the cUniversity of Colorado Health Sciences College, Denver, Colorado, dSDAC/Harvard School of Public Health, Boston, Massachusetts, the eUniversity of California at San Francisco, San Francisco, California, fStanford University, Stanford, California, the gDivision of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, and hPharmacia & Upjohn, Kalamazoo, Michigan, USA.

Requests for reprints to: C. J. Fichtenbaum, University of Cincinnati College of Medicine, Holmes Hospital, Mail Location 0405, Eden Avenue and Albert Sabin Way, Cincinnati, Ohio 45267-0405, USA.

Note: Presented in part at the Seventh Conference on Retroviruses and Opportunistic Infections. San Francisco, January–February 2000 [abstract LB6] and the XIII International Conference on AIDS. Durban, July 2000 [abstract WeOrB544].

Received: 22 June 2001;

revised: 16 October 2001; accepted: 24 October 2001.

Sponsorship: Supported by the National Institute of Allergy and Infectious Diseases, AI-38858 to the AIDS Clinical Trials Group, AI-25897 to the University of Cincinnati, AI-25903 to Washington University, AI-27666 to Stanford University, and AI-38855 to the SDAC/Harvard School of Public Health. Additional support provided by Stanford University GCRC grant 5-M01-RR00070-38, University of California at San Francisco GCRC grant 5-MO1-RR-00083-37 and the University of Colorado Health Sciences College GCRC grant 5-MO1-RR-00051-37. Funded in part by Bristol-Myers Squibb, Inc. and Abbott Laboratories, Inc.

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Objective: Lipid lowering therapy is used increasingly in persons with HIV infection in the absence of safety data or information on drug interactions with antiretroviral agents. The primary objectives of this study were to examine the effects of ritonavir (RTV) plus saquinavir soft-gel (SQVsgc) capsules on the pharmacokinetics of pravastatin, simvastatin, and atorvastatin, and the effect of pravastatin on the pharmacokinetics of nelfinavir (NFV) in order to determine clinically important drug–drug interactions.

Design: Randomized, open-label study in healthy, HIV seronegative adults at AIDS Clinical Trials Units across the USA.

Methods: Three groups of subjects (arms 1, 2, and 3) received pravastatin, simvastatin or atorvastatin (40 mg daily each) from days 1–4 and 15–18. In these groups, RTV 400 mg and SQVsgc 400 mg twice daily were given from days 4–18. A fourth group (arm 4) received NFV 1250 mg twice daily from days 1–14 with pravastatin 40 mg daily added from days 15–18. Statin and NFV levels were measured by liquid chromatography/tandem mass spectrometry.

Results: Fifty-six subjects completed both pharmacokinetic study days. In arms 1–3, the median estimated area under the curves (AUC)0−−24 for the statins were: pravastatin (arm 1, n = 13), 151 and 75 nguu.h/ml on days 4 and 18 (decline of 50% in presence of RTV/SQVsgc), respectively (P = 0.005); simvastatin (arm 2, n = 14), 17 and 548 nguu.h/ml on days 4 and 18 (increase of 3059% in the presence of RTV/SQVsgc), respectively (P < 0.001); and total active atorvastatin (arm 3, n = 14), 167 and 289 nguu.h/ml on days 4 and 18 (increase of 79% in the presence of RTV/SQVsgc), respectively (P < 0.001). In arm 4, the median estimated AUC0−−8 for NFV (24 319 versus 26 760 nguu.h/ml;P = 0.58) and its active M8 metabolite (15 565 versus 14 571 nguu.h/m;P = 0.63) were not statistically different from day 14 to day 18 (without or with pravastatin).

Conclusions: Simvastatin should be avoided and atorvastatin may be used with caution in persons taking RTV and SQVsgc. Dose adjustment of pravastatin may be necessary with concomitant use of RTV and SQVsgc. Pravastatin does not alter the NFV pharmacokinetics, and thus appears to be safe for concomitant use.

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A number of metabolic complications including hyperlipidemia, insulin resistance, and fat redistribution disorders have emerged with the use of potent antiretroviral therapy for HIV infection [1–5]. Individual protease inhibitors may cause metabolic disturbances by different mechanisms. For example, in healthy HIV-seronegative persons, ritonavir (RTV) induces hypertriglyceridemia and hypercholesterolemia [6]. In animal models, RTV increases free fatty acid synthesis [7]. Conversely, indinavir induces insulin resistance in HIV-seronegative persons [8]. Population based studies suggest there is reason to be concerned that these metabolic abnormalities may lead to the development of premature coronary artery disease [1–5,9]. Reports of premature myocardial infarctions and hyperlipidemia have been noted in HIV-infected persons on protease inhibitor-based potent antiretroviral therapy [4–5,9]. Thus, there is a need to provide safe and effective treatment for hyperlipidemia in persons with HIV infection.

Several classes of medications are used to treat hyperlipidemia including the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins). Several statins decrease the risk of myocardial infarction in persons with hyperlipidemia [10–13]. The use of these drugs has increased in persons with HIV infection [14–17]. Cytochrome P4503A4/5 isozymes located within the liver and the gastrointestinal tract are responsible for the metabolism of most statins [10,18, 19]. These isozymes are also responsible for the metabolism of protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors. In addition, all of the clinically available PI are inhibitors of the cytochrome P4503A isozymes. Thus, the possibility exists for significant drug–drug interactions when statins and PI are used concomitantly.

Elevated levels of statins have been reported with the use of other drugs metabolized by the cytochrome P450 3A4 isozyme (CYP3A4) [20–25]. Rhabdomyolysis has been associated with higher levels of statins typically when used in combination with other drugs that inhibit CYP3A4 [26–32]. Therefore, we investigated the pharmacokinetic interactions between three commonly prescribed statins and the PI RTV, saquinavir (SQV) and nelfinavir (NFV) to determine if there are clinically important drug–drug interactions.

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AIDS Clinical Trials Group (ACTG) study A5047 was a randomized, phase I, open-label, multiple dose, pharmacokinetics drug interaction study. The primary objectives were to examine the effects of RTV plus SQV soft-gel capsules (sgc) on the pharmacokinetics of pravastatin, simvastatin, and atorvastatin, and to investigate the effect of pravastatin on the pharmacokinetics of NFV. At the time this study was designed there was no published information about whether statins would alter PI concentrations, an important clinical question. NFV was the most commonly prescribed PI in the USA. Based upon the known metabolism of pravastatin, we hypothesized that pravastatin would not alter the pharmacokinetics of NFV. A secondary objective of the study was to examine the effects of lipid-lowering agents on the pharmacokinetics of RTV and SQVsgc as compared to historic controls. This study was designed and conducted prior to the widespread use of low dose RTV to pharmacologically enhance antiretroviral treatment regimens.

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Study subjects were HIV-seronegative adult volunteers. HIV-seronegative volunteers were selected to avoid unnecessary exposure to PI in suboptimal regimens and to avoid the use of concomitant drugs known to affect CYP3A4. The planned sample size was 56 subjects, 14 per treatment arm. Subjects who did not complete both pharmacokinetic evaluations were replaced. Accrual began in July 1999 and ended in October 1999.

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Study design

The study consisted of four treatment arms. Subjects in arm 1 began taking pravastatin 40 mg every morning on study day 1. These subjects underwent intensive pharmacokinetic sampling on day 4 (after steady-state was achieved) with blood samples taken just prior to the statin dose and 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 h. At the end of the 24 h sampling, subjects discontinued pravastatin and began taking RTV 300 mg twice daily and SQVsgc 400 mg twice daily. The RTV dose was increased to 400 mg on day 8. Pravastatin was added back to the RTV/SQVsgc regimen on day 15. Subjects again underwent intensive pharmacokinetic sampling on day 18 (after steady-state was achieved) using the same schedule as was used on day 4. Subjects took RTV and SQVsgc 30 min after taking the pravastatin. Arms 2 and 3 were identical to arm 1 except that simvastatin 40 mg/day and atorvastatin 40 mg/day, respectively, were the lipid-lowering agents.

Subjects in arm 4 began taking NFV 1250 mg every 12 h on day 1 and underwent intensive pharmacokinetic sampling on day 14 (steady-state for NFV). Blood samples were collected prior to the NFV dose and 0.5, 1, 2, 3, 4, 6 and 8 h. On day 15, pravastatin 40 mg/day was added to the NFV regimen. Subjects underwent intensive pharmacokinetic sampling on day 18 using the same schedule as was used on day 14. The NFV was dosed 30 min after dosing of the pravastatin.

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Drug assays

Statin assays were performed at Advanced Bioanalytical Services, Inc. (Ithaca, New York, USA). Arm 1 samples were assayed to quantify concentrations of pravastatin and a minor active metabolite SQ-31906. In the assay procedure, pravastatin, d5-pravastatin, SQ-31906, d5-SQ-31906, and pravastatin lactone along with their respective internal standards, d3-pravastatin and d3-pravastatin lactone, were extracted from human serum samples using a solid-phase extraction procedure. The solid-phase extraction eluent was evaporated to dryness and reconstituted. Aliquots were analyzed by turbo ion spray liquid chromatography/tandem mass spectrometry (LC/MS/MS) in the positive ion mode. The limit of quantification (LOQ) in serum was 0.5 ng/ml for all analytes. Inter- and intra-assay precision for all analytes were ≤ 8% (coefficient of variation) and accuracy was ≤ 8% (deviation from nominal) [33].

Arm 2 samples were assayed for simvastatin and simvastatin acid using an internally validated LC/MS/MS technique. Lovastatin was used as the internal standard for simvastatin and lovastatin acid was used as the internal standard for simvastatin acid. Serum samples were acidified and extracted by a solid-phase extraction procedure to isolate simvastatin, simvastatin acid and their respective internal standards. Sample extracts were reconstituted and separated by reversed-phase chromatography on a 2 × 50 mm BDS Hypersil C18 column (Keystone Scientific, Inc., Bellefonte, Pennsylvania, USA) with an initial mobile phase of 40% Eluent A (acetonitrile) and 60% Eluent B (4 mM ammonium acetate, pH 4.5). Aliquots were analyzed by turbo ion spray LC/MS/MS in the positive ion mode. The LOQ for this assay was 0.5 ng/ml of simvastatin and simvastatin acid with a coefficient of variation of 5% for simvastatin and simvastatin acid. The inter- and intra-assay precision was 8% for both analytes and the accuracy was within 8% (deviation from nominal).

Arm 3 samples were assayed for atorvastatin and the following metabolites: atorvastatin lactone, 2-hydroxy atorvastatin, 2-hydroxy atorvastatin lactone, 4-hydroxy atorvastatin and 4-hydroxy atorvastatin lactone. These compounds and their respective internal standards (d5-atorvastatin, d5-atorvastatin lactone, d5-2-hydroxy atorvastatin, d5-2-hydroxy atorvastatin lactone, d5-4-hydroxy atorvastatin, and d5-4-hydroxy atorvastatin lactone) were extracted from serum samples using a liquid–liquid extraction procedure. The supernatant was evaporated to dryness and reconstituted. Aliquots were analyzed by turbo ion spray LC/MS/MS in the positive ion mode. The LOQ for this assay was 0.5 ng/ml with a coefficient of variation of 10% for all analytes. The inter- and intra-assay precision and accuracy was ≤ 10% for all analytes [34].

NFV assays were performed at the ACTG Pharmacology Unit at San Francisco General Hospital. NFV and M8 metabolite isolated from plasma were measured by a new validated LC/MS/MS method. A simple acetonitrile precipitation of plasma proteins and centrifugation of samples after addition of internal standard (methyl-indinavir) was performed. Aliquots of the supernatant were analyzed by the LC/MS/MS. The standard curve of the assay is from 5 ng/ml to 4000 ng/ml for both NFV and M8 metabolite with an LOQ of 5 ng/ml for both analytes. The precision of the inter- and intra-assay was < 9% for both analytes. The ACTG Pharmacology Quality Control Program approved the use of these assays for NFV and M8 metabolite after demonstration of appropriate validation.

The concentrations of RTV and SQV were determined by high-pressure liquid chromatography (HPLC) with ultraviolet (UV) detection at the Stanford ACTG Pharmacology Unit. After solid-phase extraction, a SUPERCOSIL LC-DP column with a phosphate mobile phase was used to chromatograph the samples. RTV, SQV and internal standards were detected by UV absorbance at 205 and 240 nm. The linear dynamic range of the assays was 200 to 24 000 ng for RTV, and 84 to 12 000 ng for SQV. The LOQ was 200 ng/ml and 8 ng/ml for RTV and SQV respectively. The inter- and intra-assay variation was within 15% for both analytes. The ACTG Pharmacology Quality Control Program approved the use of these HPLC assays for RTV and SQV after demonstration of appropriate validation.

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Calculation of area under the curve (AUC)

Systemic exposure to the statins was quantified by calculating the AUC of the drugs from pre-dose to the end of the dosing interval. Concentrations below the LOQ were assigned a value of zero. Steady-state AUC over a dosing interval were estimated according to the linear trapezoidal rule using the non-compartmental analysis component of WinNonlin (version 3.1, Pharsight Corporation, Cary, North Carolina, USA). Actual, rather than scheduled, sample times were used. Extrapolation beyond the dosing interval was not carried out because data was analyzed at steady state. For subjects in arm 2, AUC were calculated for simvastatin acid (the main active metabolite of simvastatin). For subjects in arm 3, AUC were calculated for atorvastatin and also for the ‘total active atorvastatin’ activity. The latter was calculated using the sum of the time-specific concentrations of atorvastatin, 2- and 4-hydroxy atorvastatin at each time point, and calculating an AUC based on the summed concentrations.

Systemic exposure to NFV was quantified by calculating the AUC from time 0 to 8 h. AUC calculations for NFV and its M8 metabolite proceeded as described for the statins. Twelve-hour AUC for RTV and SQV were calculated using the same method described for the statins. Nominal 12 h samples actually occurred between 10.8 and 12.0 h post-dose. No adjustment was made to normalize AUC to 12 h. Subjects with fewer than seven quantifiable concentrations or those with missing nominal 12 h samples were omitted from analysis.

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Historic controls

The analysis of RTV and SQV levels was based upon data from historic controls kindly provided to us by K. Jorga (Roche Pharmaceuticals, Inc., Branchberg, New Jersey, USA). In this project, HIV-seronegative subjects were enrolled in a multiple-dose study of the tolerability and pharmacokinetics of SQVsgc and RTV when dosed separately and in combination. The LOQ were 0.5 ng/ml for SQV and 10 ng/ml for RTV. Blood samples were collected immediately prior to the RTV/SQVsgc dose, and 1, 2, 3, 4, 5, 6, 8, 10, 12, 13, 14, 15, 16, 17, 18, 20, 22, 24, 26, 30 and 34 h. SQV levels were measured by a sensitive radioimmunoassay. RTV levels were analyzed by an HPLC–UV method. The 0 to 12 h AUC were recalculated by the same method as used for calculating AUC for RTV and SQV from our data.

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Statistical analyses

The primary pharmacokinetic statin endpoints were: pravastatin AUC (arm 1), simvastatin acid AUC (arm 2), and atorvastatin and total active atorvastatin AUC (arm 3). The maximum concentration (Cmax) for statins is reported. For each endpoint, day-specific medians and ranges are reported. Within-subject differences are calculated and expressed as both raw differences and as a percent of the first pharmacokinetic day value. Medians of these within-subject comparative measures are reported. The Wilcoxon signed rank test was used to test the hypothesis of no difference in the statin AUC before the initiation of the RTV/SQVsgc versus after dosing to steady state [35]. The primary pharmacokinetic endpoints for NFV are the AUC of NFV and of its active M8 metabolite. The minimum concentration (Cmin) parameter was also analyzed statistically. Within-subject comparisons are based on differences between day 18 and day 14 AUC, and statistical inference based on the Wilcoxon signed rank test. RTV/SQV AUC in subjects from arms 1, 2, and 3 are compared to historical controls not receiving statins. For each agent (RTV and SQV), the Wilcoxon rank sum test was used to compare the AUC between treatments. Median values for Cmin in arms 1, 2, and 3 are reported. All reported Wilcoxon P values are two-sided and were not adjusted for multiple comparisons.

The human studies committees of each participating institution and the regulatory branch of the Division of AIDS, National Institute of Allergy and Infectious Diseases approved this study and informed consent was obtained from the participants.

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Sixty-seven HIV-seronegative subjects were randomized. Eleven subjects failed to complete the second pharmacokinetic analysis because of protocol-defined toxicities. Discontinuations occurred while subjects were taking only the PI during study days 6–11. Diarrhea and gastrointestinal upset were the most common complaints. Subjects were discontinued from the pravastatin (n = 4), atorvastatin (n = 4), simvastatin (n = 2) and NFV (n = 1) arms and were considered ineligible for analysis of pharmacokinetic endpoints. One additional subject was excluded from the pharmacokinetic analysis of pravastatin after there were no measurable levels of this drug on study day 4. This subject was retained in the analysis of RTV and SQV AUC. Thus, a total of 56 subjects were used in one or more of the pharmacokinetic analyses. The median age was 32 years (range, 19–56 years). Women constituted 59% of the study population; 57% were white, 20% were Latino, 13% were African–American and 10% were Asian/Pacific Islanders.

Pharmacokinetic analyses for arms 1–3 are shown in Table 1 and Fig. 1. Pravastatin AUC declined (P = 0.005) while atorvastatin (P < 0.001), total active atorvastatin (P < 0.001) and simvastatin acid AUC (P < 0.001) increased with concomitant use of RTV and SQVsgc. The pharmacokinetic analyses for NFV and its M8 metabolite are shown in Table 2. The changes in NFV and its M8 metabolite AUC with the concomitant use of pravastatin were not significant (P = 0.58 and P = 0.63, respectively). Thirty-three subjects from arms 1, 2 and 3 had pharmacokinetic analyses completed for RTV and SQV (Table 3). There were no statistically significant changes in the levels of RTV and SQV compared to historic controls. There were no significant demographic differences in the subjects analyzed for RTV/SQV levels and the entire cohort (data not shown).

Fig. 1
Fig. 1
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Table 1
Table 1
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Table 2
Table 2
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Table 3
Table 3
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Adverse events ≥ grade 2 were reported in 25% of the subjects (n = 56). Clinical events were noted in 14% of the subjects and laboratory events were noted in 11% (Table 4). There were no cases of rhabdomyolysis or clinically significant hepatitis. One subject had shoulder and back pain not associated with elevation in creatine phosphokinase (CPK) levels. The relationship to statin use was unclear. One subject with an elevated CPK level was asymptomatic. Arm-specific sample sizes were too small and adverse events too infrequent to evaluate statistical differences between the groups.

Table 4
Table 4
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Elevated lipid levels occur in a significant percentage of patients taking potent antiretroviral therapy. Recent data suggests that specific PI may induce hyperlipidemia directly (increased free fatty acid synthesis) or indirectly (insulin resistance) [6–8]. Clinicians are increasingly prescribing statins to persons with hyperlipidemia and HIV infection. It is important to understand whether significant drug–drug interactions occur and might result in adverse reactions in persons taking statins and PI. Our study was designed to establish whether several statins in clinical use could be safely prescribed with RTV/SQVsgc without concern for major drug–drug interactions. The choice of RTV/SQVsgc was based on the following: the drug combination was commonly used in clinical practice; many statins utilize CYP3A4 for oxidative metabolism; and RTV is the most potent inhibitor of CYP3A4 of all the HIV PI [36]. HIV-seronegative subjects were chosen to avoid suboptimal exposure to PI in HIV-infected persons and to minimize the presence of other concomitant medications that might complicate the interpretation of drug–drug interactions. Although there may be differences in the absolute concentrations of some drugs (e.g., PI) between the HIV-infected and seronegative adults, there are no data to suggest that the nature of drug–drug interactions would be different.

This study demonstrated significant drug–drug interactions between some of the statins and RTV/SQVsgc. Simvastatin acid concentrations increased 30-fold in persons taking RTV/SQVsgc. Atorvastatin and its active metabolite concentrations were also increased though to a lesser degree than simvastatin acid. Conversely, pravastatin levels declined in subjects taking RTV/SQVsgc. Pravastatin had no significant effect on the concentration of NFV or its M8 metabolite. Atorvastatin, pravastatin, and simvastatin did not significantly reduce the concentrations of RTV and SQV compared to historic controls in subjects who were not taking statins. Finally, there were few clinical adverse events associated with the short-term use of statins and NFV or RTV and SQVsgc in this healthy HIV-seronegative population.

The differences in the known metabolism of the drugs investigated may explain the results of this study. The primary route of metabolism for most statins is via the CYP3A4 isozymes. Some statins are administered as inactive lactone pro-drugs and require hydrolysis by non-CYP esterases to the active hydroxy-acid (e.g., simvastatin ← simvastatin acid) while others are administered directly as the active hydroxy-acid (e.g., atorvastatin, cervistatin, and pravastatin) [20]. Lactone pro-drugs are metabolized by intestinal and liver CYP3A4 to active and inactive metabolites. When CYP3A4 is inhibited, more of the lactone pro-drug is available for non-CYP hydrolysis to the active hydroxy-acid. In addition, the role of gastrointestinal metabolism of the statins via CYP3A4 has been investigated and confirms that pravastatin clearance as compared to lovastatin (similar to simvastatin) is minimally affected by intestinal CYP3A4 [37]. Thus, the generation of simvastatin acid would always appear to be greater when CYP3A4 is inhibited than for drugs that are already in the hydroxy-acid form because of this shunting towards hydrolysis.

The more lipophilic lactone pro-drugs probably have a higher affinity for CYP3A4 than the hydroxy-acid forms. Known inhibitors of CYP3A4 have been shown to increase the concentration of selected statins [21–25]. One example is the pharmacokinetic interaction of itraconazole, an inhibitor of CYP3A4 that affects drug metabolism in both the gastrointestinal tract and the liver, with several statins [21–22]. Simvastatin acid and lovastatin acid concentrations are increased 20–30 fold with the addition of itraconazole, while itraconazole has only a relatively small effect on the pharmacokinetics of pravastatin [22]. For the former two statins, itraconazole seems to reduce the formation of active and inactive metabolites during first pass metabolism (requiring CYP3A4 activity in the gastrointestinal tract) resulting in increased bioavailability of the drugs. A similar mechanism probably occurs in the context of RTV coadministration that explains our present findings. Within the active acid group of statins, atorvastatin is more lipophilic than pravastatin, and pravastatin is not a substrate for CYP3A4 [20]. Multiple enzymes are involved in the metabolism of pravastatin but glucuronidation appears to be the predominant pathway [38]. As the primary pathway of elimination of pravastatin is by conjugation and RTV is a known inducer of glucuronidation, this may explain the decrease in pravastatin exposure [38].

This difference in metabolism explains, in part, the differences observed between atorvastatin and pravastatin concentrations when used concomitantly with RTV/SQVsgc. Finally, although most statins are metabolized by CYP3A4, they are not themselves significant inhibitors of CYP3A4 [20]. This could explain why RTV, SQV, and NFV concentrations were not altered significantly by the use of statins despite being substrates for CYP3A4.

There are several important clinical implications of our study. Simvastatin should not be used as a hypolipidemic agent in patients taking RTV/SQVsgc. Lovastatin, which is metabolized similarly to simvastatin, should also be avoided. These statins should probably also be avoided in patients using other PI that inhibit CYP3A4 activity. This recommendation is similar to what is suggested for azole antifungal drugs. Atorvastatin can probably be used with caution in patients taking RTV/SQVsgc. Although we have no clinical data, we suggest that atorvastatin should be initiated at doses of 10 mg/day and probably should not exceed 40 mg/day. Dose escalation should be based on clinical indication with careful monitoring for the development of toxicity. Pravastatin appears to be safe for use with RTV/SQVsgc. It is not clear whether the efficacy of pravastatin will be diminished when used concomitantly with RTV/SQVsgc. Higher doses of pravastatin may be necessary in the presence of certain PI. It would be inappropriate to conclude that the relatively mild drug–drug interaction between RTV/SQVsgc and pravastatin or atorvastatin implies they are safe for use in persons with HIV infection. Moyle recently demonstrated moderate hypolipidemic effects of pravastatin 40 mg daily along with dietary restriction in persons with HIV infection [18]. There were few adverse events attributed to pravastatin in that trial. Overall, there were few adverse events attributed to any of the statins used in our study. The safety and efficacy of statins remains to be established in HIV-infected persons taking PI.

There is a paucity of data on the safety of statins when used concomitantly with PI. Several small series have reported that statins are generally safe for the treatment of hyperlipidemia in persons with HIV infection [15–18]. However, two cases of rhabdomyolysis were recently reported with the use of statins in the setting of PI [39]. One patient was taking simvastatin 40 mg daily and began using indinavir 800 mg and RTV 200 mg twice daily 1 month prior to the onset of rhabdomyolysis. The other patient added atorvastatin 10 mg daily to a regimen that included indinavir 800 mg every 8 h 1 month before developing rhabdomyolysis. These case reports highlight the potential dangers of using statins in patients taking PI.

There are several important limitations to this study. It was not feasible to study all combinations of statins and PI. This study was designed and conducted prior to the approval of lopinavir/RTV or the widespread use of low dose RTV to pharmacologically enhance antiretroviral therapy. Whether the results will be similar for other PI at varying doses is not known. Several recent reports suggest that our results may be generalized to other PI [40,41]. Carr reported a fivefold increase in atorvastatin concentrations and a large decrease in the formation of the active metabolite in combination with lopinavir/RTV [40]. They also noted a non-significant increase in pravastatin concentrations with the addition of lopinavir/RTV (33%; 90% confidence interval, − 9% to 94%). The different doses of RTV used in the study by Carr (100 mg twice daily) and our study (400 mg twice daily) may account for the disparate findings for pravastatin. Similarly, Hsyu reported that NFV increased the AUC of active simvastatin by 506% and the AUC of active atorvastatin by 74% similar to our results [41].

This study was not designed primarily to determine the effect of statins on RTV and SQV concentrations. This was a secondary objective and, as such, the sample size was not sufficient to exclude a clinically important drug interaction. However, our observations on the relative lack of effect of statins on the concentrations of PI are consistent with the findings of Carr and Hsyu for lopinavir and NFV/M8 metabolite concentrations, respectively [40–41].

The relationship between parent and metabolite drug concentrations and the overall effect on HMG-CoA reductase activity is also an important issue. Both atorvastatin and simvastatin have active metabolites that contribute to the drugs’ lipid-lowering activity and probably their toxicity. These active metabolites are generated via CYP3A4. Consequently, inhibition of CYP3A4 would be associated with decreased generation of these active metabolites, combined with greater exposure to the parent compound. For atorvastatin, we clearly demonstrated decreased generation of these active metabolites with the use of RTV/SQVsgc. Thus, the actual increase in total atorvastatin activity, which is the sum of the parent compound and active metabolites, was much less than the increase in exposure to the parent, atorvastatin itself. We did not measure the active metabolites of simvastatin acid. As a result, it is quite likely that we have over-estimated the true effect of RTV/SQVsgc on the increase in total simvastatin activity as an inhibitor of HMG-CoA reductase activity. Nonetheless the effect of RTV/SQVsgc was much greater for simvastatin acid than for atorvastatin, making the former drug–drug interaction likely to be more clinically significant. In future pharmacokinetic studies with simvastatin total HMG-CoA reductase activity should be measured to evaluate the overall pharmacokinetic effects.

In conclusion, this study demonstrates significant drug–drug interactions with RTV/SQVsgc and selected statins. Simvastatin (and lovastatin) should be avoided in persons using PI. Atorvastatin may be used with caution in persons using PI, and dose escalation should be based on clinical indications with careful monitoring for toxicity. Pravastatin appears relatively safe for use in persons taking PI but the clinical effect of a 50% reduction in exposure secondary to RTV/SQVsgc is unknown. Simvastatin, atorvastatin, and pravastatin do not appear to significantly affect the concentrations of RTV or SQV. Pravastatin does not significantly affect the concentrations of NFV or its M8 metabolite. Further research is required to determine the long-term clinical safety and efficacy of statins in persons taking PI.

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The ACTG A5047 team would like to thank the 67 volunteers for graciously donating their time to this study. We would also like to thank all the study coordinators and sites for the hard work. Special thanks to K. Lamb, W. J. Burning, P. Lizak, E. Ferguson, H. Edmondson-Melancon, S. Brobst, N. Pugh, P. Clax, A. Japour, J. Staggers, K. Jorga, J. Wiehe, A. Jayewardene, and M. Royal for their invaluable assistance. Participating ACTG A5047 sites and investigators: LAC/USC Medical Center, F. R. Sattler, D. Johnson, H. Edmondson-Melancon; Tulane University, J. J. L. Lertora, D. M. Mushatt; University of Hawaii/Manoa, Leahi Hospital, L. Oshita, D. Ogata-Arakaki, S. Souza; San Francisco General Hospital, M. Simmons, C. Arri, P. Barnett; University of Colorado HSC, S. Canmann, S. Fiorillo; Indiana University, J. Richardson, D. Heise; Washington University School of Medicine, L. Stiffler, M. Klebert; Johns Hopkins University, D. Jones, D. Wright, V. Williams; Stanford University, S. Valle, D. Slamowitz, S. Stoudt; University of Miami, M. A. Fischl, J. Castro, R. Monroig; University of Washington, T. M. Hooton, L. Houseworth, M. Schwartz.

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Journal of Biological Regulators and Homeostatic Agents, 20(): 1-9.

Drug Safety
Risk management of simvastatin or atorvastatin interactions with CYP3A4 inhibitors
Molden, E; Skovlund, E; Braathen, P
Drug Safety, 31(7): 587-596.

Future Lipidology
Current and future treatments of HIV-associated dyslipidemia
Bennett, MT; Johns, KW; Bondy, GP
Future Lipidology, 3(2): 175-188.
Antimicrobial Agents and Chemotherapy
Pilot Pharmacokinetic Study of Human Immunodeficiency Virus-Infected Patients Receiving Tenofovir Disoproxil Fumarate (TDF): Investigation of Systemic and Intracellular Interactions between TDF and Abacavir, Lamivudine, or Lopinavir-Ritonavir
Pruvost, A; Negredo, E; Theodoro, F; Puig, J; Levi, M; Ayen, R; Grassi, J; Clotet, B
Antimicrobial Agents and Chemotherapy, 53(5): 1937-1943.
Impact of protease inhibitor substitution with efavirenz in HIV-infected children: Results of the first pediatric switch study
McComsey, G; Bhumbra, N; Rathore, M; Alvarez, A
Pediatrics, 111(3): -.
ARTN e275
Nephrology Dialysis Transplantation
Pharmacokineties of atorvastatin and its metabolites after single and multiple dosing in hypercholesterolaemic haemodialysis patients
Lins, RL; Matthys, KE; Verpooten, GA; Peeters, PC; Dratwa, M; Stolear, JC; Lameire, NH
Nephrology Dialysis Transplantation, 18(5): 967-976.
HIV Medicine
Fibrates or statins and lipid plasma levels in 245 patients treated with highly active antiretroviral therapy. Aquitaine Cohort, France, 1999-2001
Bonnet, F; Balestre, E; Thiebaut, R; Mercie, P; Dupon, M; Morlat, P; Dabis, F
HIV Medicine, 5(3): 133-139.

Clinical Infectious Diseases
Niacin in HIV-infected individuals with hyperlipidemia receiving potent antiretroviral therapy
Gerber, MT; Mondy, KE; Yarasheski, KE; Drechsler, H; Claxton, S; Stoneman, J; DeMarco, D; Powderly, WG; Tebas, P
Clinical Infectious Diseases, 39(3): 419-425.

American Journal of Cardiology
Comparative pharmacokinetic interaction profiles of pravastatin, simvastatin, and atorvastatin when coadministered with cytochrome P450 inhibitors
Jacobson, TA
American Journal of Cardiology, 94(9): 1140-1146.
Clinical Infectious Diseases
Randomized study of the safety and efficacy of fish oil (omega-3 fatty acid) supplementation with dietary and exercise counseling for the treatment of antiretroviral therapy-associated hypertriglyceridemia
Wohl, DA; Tien, HC; Busby, M; Cunningham, C; MacIntosh, B; Napravnik, S; Danan, E; Donovan, K; Hossenipour, M; Simpson, RJ
Clinical Infectious Diseases, 41(): 1498-1504.

HIV Clinical Trials
Ecological study of the predictors of successful management of dyslipidemia in HIV-infected patients on ART: the Swiss HIV Cohort Study
Glass, TR; Weber, R; Vernazza, PL; Rickenbach, M; Furrer, H; Bernasconi, E; Cavassini, M; Hirschel, B; Battegay, M; Bucher, HC; Study, SHC
HIV Clinical Trials, 8(2): 77-85.
Scandinavian Journal of Infectious Diseases
Antiretroviral treatment of HIV infection: Swedish recommendations 2007
Josephson, F; Albert, J; Flamholc, L; Gisslen, M; Karlstrom, O; Lindgren, SR; Navter, L; Sandstrom, E; Svedhem-Johansson, V; Svennerholm, B; Sonnerborg, A
Scandinavian Journal of Infectious Diseases, 39(): 486-507.
HIV Medicine
Cardiovascular disease risk factors and antiretroviral therapy in an HIV-positive UK population
Smith, CJ; Levy, I; Sabin, CA; Kaya, E; Johnson, MA; Lipman, MCI
HIV Medicine, 5(2): 88-92.

Pravastatin does not have a consistent antiviral effect in chronically HIV-infected individuals on antiretroviral therapy
Sklar, PA; Masur, H; Grubb, JR; Voell, J; Witek, J; Ono, A; Freed, EO; Maldarelli, F
AIDS, 19(): 1109-1111.

Medical Care
Inappropriate drug combinations among privately insured patients with HIV disease
Hellinger, FJ; Encinosa, WE
Medical Care, 43(9): 53-62.

Antiviral Therapy
Management of dyslipidaemia in HIV-infected patients receiving antiretroviral therapy
Martinez, E; Tuset, M; Milinkovic, A; Miro, JM; Gatell, JM
Antiviral Therapy, 9(5): 649-663.

Clinical Infectious Diseases
Simvastatin-nelfinavir interaction implicated in rhabdomyolysis and death
Hare, CB; Vu, MP; Grunfeld, C; Lampiris, HW
Clinical Infectious Diseases, 35(): E111-E112.

HIV Infection and the Cardiovascular System
HAART and cardiology - Current controversies and consequences
Hoffmann, C; Jaeger, H
HIV Infection and the Cardiovascular System, 40(): 1-14.

Clinical Pharmacokinetics
Pharmacokinetic comparison of the potential over-the-counter statins simvastatin, lovastatin, fluvastatin and pravastatin
Neuvonen, PJ; Backman, JT; Niemi, M
Clinical Pharmacokinetics, 47(7): 463-474.

Cardiovascular Effects of Noncardiovascular Drugs
Raj, SR; Stein, CM; Saavedra, PJ; Roden, DM
Circulation, 120(): 1123-1132.
European Journal of Clinical Pharmacology
Successful strategy to improve the specificity of electronic statin-drug interaction alerts
Seidling, HM; Storch, CH; Bertsche, T; Senger, C; Kaltschmidt, J; Walter-Sack, I; Haefeli, WE
European Journal of Clinical Pharmacology, 65(): 1149-1157.
Clinical Pharmacokinetics
Interactions between antiretroviral drugs and drugs used for the therapy of the metabolic complications encountered during HIV infection
Fichtenbaum, CJ; Gerber, JG
Clinical Pharmacokinetics, 41(): 1195-1211.

Journal of Infection
HIV-associated upodystrophy syndrome: Assessment and management
Bodasing, N; Fox, R
Journal of Infection, 46(2): 87-93.
Clinical Pharmacokinetics
Clinical pharmacokinetics of atorvastatin
Lennernas, H
Clinical Pharmacokinetics, 42(): 1141-1160.

Enfermedades Infecciosas Y Microbiologia Clinica
Spanish GESIDA/Nacional AIDS plan recommendations for antiretroviral therapy in HIV-infected adults (October 2004)
Iribarren, JA; Labarga, P; Rubio, R; Berenguer, J; Miro, JM; Antela, A; Gonzalez, J; Moreno, S; Arrizabalaga, J; Chamorro, L; Clotet, B; Gatell, JM; Lopez-Aldeguer, J; Martinez, E; Polo, R; Tuset, M; Viciana, P; Santamaria, JM; Kindelan, JM; Ribera, E; Segura, F
Enfermedades Infecciosas Y Microbiologia Clinica, 22(): 564-642.

Antiviral Therapy
Therapeutic drug monitoring and drug-drug interactions involving antiretroviral drugs
Boffito, M; Acosta, E; Burger, D; Fletcher, CV; Flexner, C; Garaffo, R; Gatti, G; Kurowski, M; Perno, CF; Peytavin, G; Regazzi, M; Back, D
Antiviral Therapy, 10(4): 469-477.

Ezetimibe effectively decreases LDL-cholesterol in HIV-infected patients
Coll, B; Aragones, G; Parra, S; Alonso-Villaverde, C; Masana, L
AIDS, 20(): 1675-1677.

Contemporary Clinical Trials
Heart positive: Design of a randomized controlled clinical trial of intensive lifestyle intervention, niacin and fenofibrate for HIV lipodystrophy/dyslipidemia
Samson, SL; Pownall, HJ; Scott, LW; Ballantyne, CM; Smith, EO; Sekhar, RV; Balasubramanyam, A
Contemporary Clinical Trials, 27(6): 518-530.
Current HIV Research
Coronary artery bypass graft in HIV-infected patients: A multicenter case control study
Boccara, F; Cohen, A; Di Angelantonio, E; Meuleman, C; Ederhy, S; Dufaitre, G; Odi, G; Teiger, E; Barbarini, G; Barbaro, G
Current HIV Research, 6(1): 59-64.

Enfermedades Infecciosas Y Microbiologia Clinica
Rosuvastatin for the treatment of dyslipidemia in HIV-infected patients receiving highly active antiretroviral therapy. Preliminary experience
Bottaro, EG; Caravello, O; Scapellato, PG; Stambulian, M; Vidal, GI; Loggia, V; Scapellato, JL; Thompson, F; Cassetti, I
Enfermedades Infecciosas Y Microbiologia Clinica, 26(6): 325-329.

Pre-clinical pharmacokinetics of UK-453,061, a novel non-nucleoside reverse transcriptase inhibitor (NNRTI), and use of in silico physiologically based prediction tools to predict the oral pharmacokinetics of UK-453,061 in man
Allan, G; Davis, J; Dickins, M; Gardner, I; Jenkins, T; Jones, H; Webster, R; Westgate, H
Xenobiotica, 38(6): 620-640.
New England Journal of Medicine
Medical progress - Acquired and inherited lipodystrophies
Garg, A
New England Journal of Medicine, 350(): 1220-1234.

Journal of Pharmacology and Experimental Therapeutics
Mechanism-based inactivation of CYP3A by HIV protease inhibitors
Ernest, CS; Hall, SD; Jones, DR
Journal of Pharmacology and Experimental Therapeutics, 312(2): 583-591.
HIV Medicine
Use of metabolic drugs and fish oil in HIV-positive patients with metabolic complications and associations with dyslipidaemia and treatment targets
Normen, L; Yip, B; Montaner, J; Harris, M; Frohlich, J; Bondy, G; Hogg, RS
HIV Medicine, 8(6): 346-356.

Future Lipidology
Dyslipidemia in HIV infection
Mangili, A; Wanke, CA
Future Lipidology, 1(6): 719-728.
Archives of Internal Medicine
The new national cholesterol education program guidelines
Eidelman, RS; Lamas, GA; Hennekens, CH
Archives of Internal Medicine, 162(): 2033-2036.

Annals of Internal Medicine
Narrative Review: Statin-Related Myopathy
Joy, TR; Hegele, RA
Annals of Internal Medicine, 150(): 858-U63.

Drugs of Today
Drug-drug interactions: An important negative attribute in drugs
Obach, RS
Drugs of Today, 39(5): 301-338.

Journal of Clinical Oncology
Potential antiretroviral drug interactions with cyclophosphamide, doxorubicin, and etoposide
Bower, M; Powles, T; Stebbing, J; Thirlwell, C
Journal of Clinical Oncology, 23(6): 1328-1329.
Cleveland Clinic Journal of Medicine
Dyslipidemia in HIV patients
Tungsiripat, M; Aberg, JA
Cleveland Clinic Journal of Medicine, 72(): 1113-1120.

Effects of statins on endothelial function and lipid profile in HIV infected persons receiving protease inhibitor-containing anti-retroviral combination therapy: a randomised double blind crossover trial
Hurlimann, D; Chenevard, R; Ruschitzka, F; Flepp, M; Enseleit, F; Bechir, M; Kobza, R; Muntwyler, J; Ledergerber, B; Luscher, TF; Noll, G; Weber, R
Heart, 92(1): 110-112.
European Journal of Pharmaceutical Sciences
Transporters as a determinant of drug clearance and tissue distribution
Shitara, Y; Horie, T; Sugiyama, Y
European Journal of Pharmaceutical Sciences, 27(5): 425-446.
Annals of Clinical Biochemistry
The basis and management of metabolic abnormalities associated with cardiovascular risk in human immunodeficiency virus infection and its treatment
Crook, M
Annals of Clinical Biochemistry, 44(): 219-231.

Drug interactions with lipid lowering drugs
Becquemont, L
Therapie, 58(1): 85-90.

HIV Clinical Trials
Coronary heart disease risk, dyslipidemia, and management in HIV-infected persons
Fichtenbaum, CJ
HIV Clinical Trials, 5(6): 416-433.

Substitution of nevirapine or efavirenz for protease inhibitor versus lipid-lowering therapy for the management of dyslipidaemia
Calza, L; Manfredi, R; Colangeli, V; Tampellini, L; Sebastiani, T; Pocaterra, D; Chiodo, F
AIDS, 19(): 1051-1058.

Antiviral Therapy
Safety and efficacy of extended-release niacin for the treatment of dyslipidaemia in patients with HIV infection: AIDS Clinical Trials Group Study A5148
Dube, MP; Wu, JW; Aberg, JA; Deeg, MA; Alston-Smith, BL; McGovern, ME; Lee, D; Shriver, SL; Martinez, AI; Greenwald, M; Stein, JH
Antiviral Therapy, 11(8): 1081-1089.

AIDS Reader
Treatment of HIV-associated dyslipidemia: A role for omega-3 fatty acids
Metroka, CE; Truong, P; Gotto, AM
AIDS Reader, 17(7): 362-+.

Expert Opinion on Drug Metabolism & Toxicology
Clinical pharmacokinetics of antiretroviral drugs in older persons
Schoen, JC; Erlandson, KM; Anderson, PL
Expert Opinion on Drug Metabolism & Toxicology, 9(5): 573-588.
Journal of the American College of Cardiology
HIV and Coronary Heart Disease Time for a Better Understanding
Boccara, F; Lang, S; Meuleman, C; Ederhy, S; Mary-Krause, M; Costagliola, D; Capeau, J; Cohen, A
Journal of the American College of Cardiology, 61(5): 511-523.
Assessment of a pharmacokinetic and pharmacodynamic interaction between simvastatin and Ginkgo biloba extracts in healthy subjects
Dai, LL; Fan, L; Wu, HZ; Tan, ZR; Chen, Y; Peng, XD; Shen, MX; Yang, GP; Zhou, HH
Xenobiotica, 43(): 862-867.
Pharmacokinetic interaction between nelfinavir and pravastatin in HIV-seronegative volunteers: ACTG Study A5108
for the ACTG A5108 team, ; Aberg, JA; Rosenkranz, SL; Fichtenbaum, CJ; Alston, BL; Brobst, SW; Segal, Y; Gerber, JG
AIDS, 20(5): 725-729.
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Effect of pravastatin on body composition and markers of cardiovascular disease in HIV-infected men—a randomized, placebo-controlled study
Mallon, PW; Miller, J; Kovacic, JC; Kent-Hughes, J; Norris, R; Samaras, K; Feneley, MP; Cooper, DA; Carr, A
AIDS, 20(7): 1003-1010.
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Cardiovascular disease in HIV-positive patients
Kamin, DS; Grinspoon, SK
AIDS, 19(7): 641-652.
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American Journal of Therapeutics
Antiretroviral Therapy With Heart
Randell, P; Moyle, G
American Journal of Therapeutics, 16(6): 579-584.
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Cardiology in Review
Antiretroviral and Statin Drug-Drug Interactions
Ray, GM
Cardiology in Review, 17(1): 44-47.
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Cardiology in Review
Statin–Drug Interactions: Not a Class Effect
Frishman, WH; Horn, J
Cardiology in Review, 16(4): 205-212.
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Journal of Cardiovascular Pharmacology
Effects of Atazanavir/Ritonavir or Fosamprenavir/Ritonavir on the Pharmacokinetics of Rosuvastatin
Busti, AJ; Bain, AM; Hall, RG; Bedimo, RG; Leff, RD; Meek, C; Mehvar, R
Journal of Cardiovascular Pharmacology, 51(6): 605-610.
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Current Opinion in Infectious Diseases
Lipid profiles associated with antiretroviral drug choices
van der Valk, M; Reiss, P
Current Opinion in Infectious Diseases, 16(1): 19-23.

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Current Opinion in Lipidology
Lipodystrophy: lessons in lipid and energy metabolism
Simha, V; Garg, A
Current Opinion in Lipidology, 17(2): 162-169.
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Current Opinion in Lipidology
Safety considerations for statins
Bolego, C; Baetta, R; Bellosta, S; Corsini, A; Paoletti, R
Current Opinion in Lipidology, 13(6): 637-644.

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JAIDS Journal of Acquired Immune Deficiency Syndromes
Prescribing of Contraindicated Protease Inhibitor and Statin Combinations Among HIV-Infected Persons
Hulgan, T; Sterling, TR; Daugherty, J; Arbogast, PG; Raffanti, S; Ray, W
JAIDS Journal of Acquired Immune Deficiency Syndromes, 38(3): 277-282.

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Drug/Drug Interaction Between Lopinavir/Ritonavir and Rosuvastatin in Healthy Volunteers
Kiser, JJ; Gerber, JG; Predhomme, JA; Wolfe, P; Flynn, DM; Hoody, DW
JAIDS Journal of Acquired Immune Deficiency Syndromes, 47(5): 570-578.
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Association of Hypercholesterolemia Incidence With Antiretroviral Treatment, Including Protease Inhibitors, Among Perinatally HIV-Infected Children
Tassiopoulos, K; Williams, PL; Seage, GR; Crain, M; Oleske, J; Farley, J; for the International Maternal Pediatric Adolescent AIDS Clinical Trials 219C Team,
JAIDS Journal of Acquired Immune Deficiency Syndromes, 47(5): 607-614.
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Effect of Efavirenz on the Pharmacokinetics of Simvastatin, Atorvastatin, and Pravastatin: Results of AIDS Clinical Trials Group 5108 Study
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JAIDS Journal of Acquired Immune Deficiency Syndromes, 39(3): 307-312.

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Changes in Lipids and Lipoprotein Particle Concentrations After Interruption of Antiretroviral Therapy
Lampe, FC; Duprez, DA; Kuller, LH; Tracy, R; Otvos, J; Stroes, E; Cooper, DA; Hoy, J; Paton, NI; Friis-Møller, N; Neuhaus, J; Liappis, AP; Phillips, AN; for the INSIGHT SMART Study Group,
JAIDS Journal of Acquired Immune Deficiency Syndromes, 54(3): 275-284.
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Grade 4 Events Are as Important as AIDS Events in the Era of HAART
Reisler, RB; Han, C; Burman, WJ; Tedaldi, EM; Neaton, JD
JAIDS Journal of Acquired Immune Deficiency Syndromes, 34(4): 379-386.

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Pharmacogenetics and Genomics
HIV protease inhibitors are substrates for OATP1A2, OATP1B1 and OATP1B3 and lopinavir plasma concentrations are influenced by SLCO1B1 polymorphisms
Hartkoorn, RC; Kwan, WS; Shallcross, V; Chaikan, A; Liptrott, N; Egan, D; Sora, ES; James, CE; Gibbons, S; Bray, PG; Back, DJ; Khoo, SH; Owen, A
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Back to Top | Article Outline

HIV infection; HMG-CoA reductase inhibitors; statins; protease inhibitors; drug interactions

© 2002 Lippincott Williams & Wilkins, Inc.


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