Highly active antiretroviral therapy (HAART) regimens are defined as those containing at least 3 antiretroviral agents and combine a nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) backbone with a protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor (NNRTI).1,2 Results from studies in treatment-naive patients have confirmed that NNRTI- and PI-based regimens can provide sustained virologic response;1-3 however, in drug-experienced patients, regimens that include PIs are necessary for complete viral suppression because of their high genetic barrier to resistance and the diversity of available agents within the class.4,5
In PI-based regimens, lopinavir/ritonavir (LPV/r) is a preferred agent because of demonstrated durable treatment responses among those who can tolerate adverse events related to ritonavir (RTV); virologic failure associated with the emergence of resistance is rare.2,6-9 In this combined-dose form, LPV is coformulated with a low dose of RTV, wherein the latter acts as a pharmacokinetic booster of LPV, increasing its bioavailability and increasing drug exposure. This and other RTV-boosted PI regimens generally allow for simpler dosing schedules with lower pill burden and less frequent administration, factors that are known to improve adherence, and thus outcomes of anti-HIV therapy.10,11 Moreover, boosting with RTV allows for high LPV trough concentrations, which have been shown to result in better treatment responses, even in patients whose HIV strains exhibit some degree of reduced susceptibility.
Several options for NRTIs are available, including a fixed-dose combination of tenofovir disoproxil fumarate (TDF) and emtricitabine, which is a recommended preferred backbone in treatment-naive and treatment-experienced patients.1,2 This NRTI combination offers the potential for the highest level of regimen simplicity-once-daily dosing-because of long plasma and intracellular half-lives for tenofovir diphosphate and emtricitabine triphosphate.12-14
Given the demonstrated tolerability, efficacy, and resistance profile of TDF, it is frequently included in LPV/r PI-based regimens.15,16 This necessitates attention to potential pharmacokinetic drug interactions on the coadministration of these drugs. Therefore, we conducted a drug-drug interaction pharmacokinetic study in healthy volunteers to assess the potential for interaction and provide, if necessary, a dosing recommendation for concomitant administration of these compounds. We examined the steady-state pharmacokinetics of LPV/r and tenofovir during multiple-dose administration of these agents relative to administration of LPV/r and TDF alone. As a secondary objective, we evaluated the safety of concomitant administration of these 2 agents.
Male or female subjects in good general health, weighing >60 kg, and between 19 and 59 years of age were eligible for this study. Subjects with a history of or current manifestations of clinically significant diseases or disorders or those who were receiving any prescription medication (30 days before study) or over-the-counter medication and herbal products (1 week before commencement of study), with the exception of vitamins, acetaminophen, and/or oral contraceptives, were excluded. Female subjects were required to use effective methods of contraception, including a barrier method. Moreover, subjects with a history of active alcohol or chemical dependency were excluded. The principal investigator reviewed medical histories and clinical laboratory evaluations and performed physical examinations before subjects were enrolled in the study. During the study period, medications such as chemotherapeutic agents, immunomodulatory agents, nephrotoxic drugs (eg, cidofovir, cyclosporine, tacrolimus), competitors of renal excretion (eg, probenecid, high-dose nonsteroidal anti-inflammatory drugs), investigational agents, or medications highly dependent on CYP3A or CYP2D6 for clearance (eg, midazolam, lovastatin, dihydroergotamine, ergotamine) were not allowed.
Written informed consent was obtained from each study participant. The protocol was approved by the MDS Pharma Services Institutional Review Board (Lincoln, NE) before study initiation. The study was carried out in accordance with the clinical research guidelines established by the basic principles defined in Volume 21 of the US Code of Federal Regulations (CFR), Part 312.20 and the principles enunciated in the latest version of the Declaration of Helsinki.
This study was a 36-day, open-label, multidose, crossover, 3-period, randomized drug-drug interaction study of TDF and LPV/r in healthy volunteers. Subjects enrolled received TDF (300 mg once daily) alone, followed by combination therapy with TDF (300 mg once daily) and LPV/r (400/100 mg [as 3 × 133.3 mg/33.3 mg] twice daily) or LPV/r (400/100 mg twice daily) alone when the sequence of LPV/r administration alone or with TDF was randomized (Fig. 1). All subjects received treatment with TDF alone on days 1 through 7 (period 1); this fixed portion of the study allowed for the study of 2 14-day back-to-back treatments with LPV/r (periods 2 and 3). This hybrid design was used to preclude starting, stopping, and reinitiating LPV/r treatments for some subjects in a fully randomized design that would require longer study duration, result in a higher number of dropouts, and necessitate additional washout periods for potential drug effects, including adverse events, and alterations in drug-metabolizing enzymes.
Subjects were randomized to sequence I or II and were given study drug(s) within 5 minutes of consuming a standard meal (approximately 400 kcal; 20% fat, 68% carbohydrate, and 12% protein). Subjects randomized to sequence I were administered LPV/r and TDF on days 8 through 21 (period 2), with the 2 agents simultaneously coadministered each morning and the second daily LPV/r dose administered each evening. On day 22, subjects discontinued TDF and continued LPV/r alone on days 22 through 35 (period 3).
Subjects randomized to sequence II were administered LPV/r alone from days 8 through 21 (period 2). On days 22 through 35 (period 3), subjects continued receiving LPV/r twice daily with concomitant TDF with the morning dose. Subjects documented timing and administration of study drugs with food with dosing diaries.
Pharmacokinetic assessments were performed over 24 hours on days 7, 21, and 35 after administration of the study drug(s). Subjects reported to the clinic on the evening before each assessment period. Subjects fasted overnight (approximately 12 hours) until a standard meal was served in the morning (30 minutes before dosing), and they received study drugs within 5 minutes of completion of their meal. Blood samples were collected at time 0, or before a dose (after consumption of the meal), and at 0.5, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 8.0, 10.0, 12.0, 16.0 and 24.0 hours after a dose before discharge from the clinic with the next study treatment, if applicable. Blood samples were centrifuged; plasma/serum was collected and frozen at −20°C until analysis.
Clinical laboratory tests, physical examinations, and vital signs were evaluated at screening, before administration of first dose of study drug, and then at each subsequent pharmacokinetic visit. Finally, subjects were contacted by telephone 7 days after the last pharmacokinetic visit to assess adverse events. Adverse events and abnormal laboratory values were graded according to the Gilead Sciences Modified National Institute of Allergy and Infectious Diseases (NIAID) Common Toxicity Grading Scale (mild = 1, moderate = 2, severe = 3, and possibly life-threatening = 4). Assessment of changes from baseline in creatinine clearance was calculated using the Cockcroft-Gault and abbreviated modification of diet in renal disease (MDRD) equations.17-19
Tenofovir, LPV, and RTV concentration assays were conducted at MDS Pharma Services (Montreal, Quebec, Canada). The methodology used to quantify tenofovir in human serum has been described previously.20 The analytic method for the determination of LPV and RTV in human plasma was as follows. LPV and RTV were extracted from human plasma samples by a liquid-liquid extraction method and subjected to high-performance liquid chromatographic separation and quantitation on a Sciex API 3000 system (Applied Biosystems, Foster City, CA). LPV, RTV, and efavirenz (internal standard) were detected and quantified by mass spectrometry (MS) using selected reaction monitoring (SRM) MS/MS conditions with m/z transitions of 629 → 447, 722 → 296, and 316 → 244, for LPV, RTV, and efavirenz, respectively. The lower limit of quantitation (LLOQ) was 20 ng/mL for LPV and 5 ng/mL for RTV. Quality control samples (6 each at the LLOQ and at low, medium, and high concentrations) for LPV and RTV demonstrated an interbatch arithmetic mean (%CV) and bias percentage (%bias) from nominal values of <12% and <10%, respectively.
The serum/plasma concentration-time data after oral administration of multiple doses of TDF and/or LPV/r were analyzed using the noncompartmental approach (WinNonlin, version 3.0; Pharsight, Mountain View, CA) to estimate the area under the concentration-time curve over the dosing interval (AUC(0-τ)), maximum concentration (Cmax), time to reach maximum concentration (Tmax), the concentration at the end of the dosing interval (Cτ), and plasma elimination half-life (T½).
Based on the known pharmacokinetic profile of tenofovir, LPV, and RTV, the sample size of 27 subjects provided >80% power to discriminate 20% differences in exposures by pharmacokinetic equivalence testing using an analysis of variance (ANOVA) model appropriate for a 2-way crossover. From the ANOVA model, geometric means were estimated for AUC(0-τ), Cmax, and Cτ. Ninety percent confidence intervals (CIs) about the ratio of the geometric means (GMR) for each pharmacokinetic parameter between the test (TDF + LPV/r together) and the reference (TDF or LPV/r administered alone) were constructed and compared with “no-effect” bounds of 80% to 125% of a standard applied criterion for defining bioequivalence.21 Demographic baseline characteristics such as age, weight, height, gender, and race were summarized by descriptive statistics. Pharmacokinetic parameters were summarized by treatment using descriptive statistics. The T½ of tenofovir was assessed ad hoc to explore potential differences in drug elimination using the Wilcoxon signed-rank test (GraphPad Software; San Diego, CA).
Twenty-seven subjects were enrolled in the study; all subjects satisfied all inclusion and exclusion criteria. The mean (standard deviation [SD]) age for the subjects was 34 (12) years, the average weight was 74.6 (7.5) kg, and the average height was 173 (6) cm. Sixteen subjects (59%) were men, and 11 (41%) were women (nonpregnant and nonlactating); 25 (93%) were white, 1 (4%) was African American, and 1 (4%) was European/Middle Eastern. Two subjects were discontinued by the Principal Investigator because of noncompliance with study requirements; 2 additional subjects withdrew consent because of adverse events, including ongoing diarrhea, while receiving LPV/r.
TDF, LPV/r, and the combination were generally well tolerated. Of the 27 subjects dosed with at least 1 study treatment, 23 (85%) experienced at least 1 treatment-emergent adverse event: 12 subjects following TDF monotherapy, 19 subjects following LPV/r alone, and 18 subjects with TDF plus LPV/r combination therapy. Headache was the most common adverse event reported by subjects during TDF administration (22% subjects receiving TDF alone and 26% receiving TDF + LPV/r), and gastrointestinal events, including diarrhea, were the adverse events reported by the greatest number of subjects during administration of LPV/r (48% receiving LPV/r alone and 56% receiving LPV/r + TDF). No serious adverse events or deaths were experienced during this study. There were no changes in serum creatinine concentrations or calculated creatinine clearance by the Cockcroft-Gault or MDRD equations when patients were receiving TDF alone or in combination with LPV/r (Table 1).
The pharmacokinetic analyses data set for tenofovir alone included 27 subjects, whereas the data set for LPV/r alone and their coadministration included 24 subjects. The mean (SD) serum concentration-time profiles for tenofovir after oral administration of TDF alone and in combination with LPV/r are presented in Figure 2. The mean (CV%) pharmacokinetic parameters estimated after the 2 treatments are summarized in Table 1. As seen in Figure 2, the tenofovir concentration-time profile is shifted upward throughout the dosing interval when TDF was coadministered with LPV/r. As a result, the pharmacokinetic parameters, AUC(0-τ), Cmax, and Cτ for TDF coadministered with LPV/r were approximately 32%, 15%, and 51% higher, respectively, as compared with those for TDF administered alone. The 90% CI of the GMR for AUC(0-τ) and Cτ fell outside the a priori range for pharmacokinetic equivalence. The Tmax and T½ for TDF administered alone or in combination with LPV/r were not different (P > 0.05; see Table 1).
The mean (SD) plasma concentration-time profiles for LPV and RTV after oral administration of LPV/r alone and in combination with TDF were superimposable (Fig. 3). Values for AUC(0-τ), Cmax, and Cτ and the 90% CI of their GMR for LPV and RTV were well within the bounds of pharmacokinetic equivalence after dosing alone or with TDF (Table 2). This indicates that the pharmacokinetics of LPV and RTV were unaltered by coadministration of TDF.
This phase 1/2 study adds to the body of data regarding the drug-drug interaction potential between TDF and compounds cleared by metabolic biotransformation via cytochrome P450 isozymes.
Systemic exposure of tenofovir, AUC(0-τ), was increased (by 32%) when TDF was dosed with LPV/r. Given the different mechanisms of clearance of these compounds (renal vs. hepatic), an interaction at the biotransformation level is unlikely. Additionally, the elimination of tenofovir T½ was unchanged, suggesting that LPV/r did not alter tenofovir elimination. The human organic anion transporter (hOAT) and human multidrug-resistant protein 4 (MRP4) transporters are responsible for the influx and efflux, respectively, of tenofovir across renal proximal tubule cells.22 PIs have been shown not to alter hOAT- or MRP4-mediated tenofovir transport.23
Although tenofovir is metabolically stable and not a substrate for P-glycoprotein, the prodrug form of tenofovir (disoproxil) has been shown to have greater intestinal stability and cellular permeability in vitro with agents known to inhibit cellular esterase and P-glycoprotein activity.24,25 Recently, Ray et al26 have shown that a potential explanation for the increased tenofovir exposure with LPV/r may be via increased absorption in the gut. LPV/r and atazanavir have been shown to increase circulating tenofovir concentrations and are known to be transported by, and to potentially inhibit, P-glycoprotein.27-35
Of note, although this study was conducted before the availability of the new tablet formulation of LPV/r, the putative biologic mechanism on increasing the absorbed tenofovir dose indicates that the interaction between these 2 agents would likely occur with this new dosage form.
Tenofovir is eliminated as unchanged drug in the urine and is not a substrate, inducer, or inhibitor of CYP3A enzymes when evaluated in vitro and in a number of pharmacokinetic drug interaction studies in human beings.13 Moreover, to date, TDF has not been implicated in any clinically relevant drug-drug interactions with a number of agents that are hepatically metabolized, including efavirenz, indinavir, methadone, and oral contraceptives (ethinyl estradiol/norgestimate).15 On this basis, TDF would not be expected to exhibit a pharmacokinetic interaction with LPV or RTV, which undergo P450 metabolism via CYP3A.36-38 As expected, we observed that TDF did not alter the pharmacokinetics of LPV or RTV, as evidenced by the GMR and 90% CI for the GMR of AUC0-τ and Cmax falling well within the 80% to 125% bounds associated with pharmacokinetic equivalence. The LPV and RTV pharmacokinetics observed in this study were comparable to those observed in historical controls comprising healthy volunteers and HIV patients.38-40 Importantly, while not powered for this comparison a priori due to an expectation of large variability, lopinavir trough concentrations were equivalent when lopinavir/r was dosed with or without tenofovir DF. Considering that Cτ is the parameter responsible for the high barrier to the development of PI resistance, this finding is important to note.41,42 In addition, AUC0-τ, Cmax, and Cτ values for RTV, the pharmacokinetic booster, were demonstrated to be unaffected by TDF.
Higher tenofovir exposures did not result in any evidence of alterations in the safety profile for TDF in this short pharmacokinetic study. Specifically, there were no changes in serum creatinine or calculated creatinine clearance using the Cockcroft-Gault or MDRD equations.
This pharmacokinetic study confirms the lack of a clinically relevant pharmacokinetic drug-drug interaction between TDF and LPV/r that is consistent with the favorable safety and efficacy results from a 2-year study of once- versus twice-daily LPV/r coadministration with TDF plus emtricitabine.38,43,44
1. Yeni PG, Hammer SM, Hirsch MS, et al. Treatment for adult HIV infection: 2004 recommendations of the International AIDS Society-USA Panel. JAMA
2. Department of Health and Human Services (DHHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. AIDSInfo Web site. Available at: http://AIDSinfo.nih.gov
. Accessed July 10, 2006.
3. van Leeuwen R, Katlama C, Murphy RL, et al. A randomized trial to study first-line combination therapy with or without a protease inhibitor in HIV-1-infected patients. AIDS
4. Barreiro P, de Mendoza C, Gonzalez-Lahoz J, et al. Superiority of protease inhibitors over nonnucleoside reverse-transcriptase inhibitors when highly active antiretroviral therapy is resumed after treatment interruption. Clin Infect Dis
5. Hammer SM, Vaida F, Bennett KK, et al. Dual vs. single protease inhibitor therapy following antiretroviral treatment failure: a randomized trial. JAMA
6. Johnson M, Grinsztejn B, Rodriguez C, et al. 96-Week comparison of once-daily atazanavir/ritonavir and twice-daily lopinavir/ritonavir in patients with multiple virologic failures. AIDS
7. Benson CA, Deeks SG, Brun SC, et al. Safety and antiviral activity at 48 weeks of lopinavir/ritonavir plus nevirapine and 2 nucleoside reverse-transcriptase inhibitors in human immunodeficiency virus type 1-infected protease inhibitor-experienced patients. J Infect Dis
8. Cohen C, Nieto-Cisneros L, Zala C, et al. Comparison of atazanavir with lopinavir/ritonavir in patients with prior protease inhibitor failure: a randomized multinational trial. Curr Med Res Opin
9. Kaplan SS, Hicks CB. Lopinavir/ritonavir in the treatment of human immunodeficiency virus infection. Expert Opin Pharmacother
10. Paterson DL, Swindells S, Mohr J, et al. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med
11. Boyle BA, Elion RA, Moyle GJ, et al. Considerations in selecting protease inhibitor therapy. AIDS Rev
12. Hawkins T, Veikley W, St. Claire RLI, et al. Intracellular pharmacokinetics of tenofovir diphosphate, carbovir triphosphate, and lamivudine triphosphate in patients receiving triple-nucleoside regimens. J Acquir Immune Defic Syndr
13. Kearney BP, Flaherty JF, Shah J. Tenofovir disoproxil fumarate: clinical pharmacology and pharmacokinetics. Clin Pharmacokinet
14. Wang LH, Begley J, St. Claire RL III, et al. Pharmacokinetic and pharmacodynamic characteristics of emtricitabine support its once daily dosing for the treatment of HIV infection. AIDS Res Hum Retroviruses
15. Viread. VIREAD (US prescribing information). Foster City, CA: Gilead Sciences, Inc., 2005.
16. Gallant JE, Deresinski S. Tenofovir disoproxil fumarate. Clin Infect Dis
17. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron
18. Levey AS, Coresh J, Balk E, et al. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med
. 2003;139:137-147. [Erratum in Ann Intern Med
19. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med
20. Kearney BP, Ramanathan S, Cheng AK, et al. Systemic and renal pharmacokinetics of adefovir and tenofovir upon coadministration. J Clin Pharmacol
21. Department of Health and Human Services (DHHS). Guidance for Industry. Bioavailability and Bioequivalence Studies for Orally Administered Drug Products-General Considerations (Revision 1)
. Rockville, MD: DHHS; 2003.
22. Cihlar T, Ho ES, Lin DC, et al. Human renal organic anion transporter 1 (hOAT1) and its role in the nephrotoxicity of antiviral nucleotide analogs. Nucleosides Nucleotides Nucleic Acids
23. Ray AS, Vela JE, Robinson KL, et al. Efflux of tenofovir by the multidrug resistance-associated protein 4 (MRP4) is not affected by HIV protease inhibitors. Presented at: 10th European AIDS Conference (EACS); 2005; Dublin.
24. Ray A, Cihlar T, Robinson KL, et al. Mechanism of active tubular secretion of tenofovir and potential for a renal drug-drug interaction with HIV protease inhibitors. Presented at: Seventh International Workshop on Clinical Pharmacology of HIV Therapy; 2006; Lisbon.
25. van Gelder J, Deferme S, Naesens L, et al. Intestinal absorption enhancement of the ester prodrug tenofovir disoproxil fumarate through modulation of the biochemical barrier by defined ester mixtures. Drug Metab Dispos
26. Ray A, Tong L, Robinson K, et al. Role of intestinal absorption in increased tenofovir exposure when tenofovir disoproxil fumarate is co-administered with atazanavir or lopinavir/ritonavir. Presented at: Seventh International Workshop on Clinical Pharmacology of HIV Therapy; 2006; Lisbon.
27. Lee CG, Gottesman MM, Cardarelli CO, et al. HIV-1 protease inhibitors are substrates for the MDR1 multidrug transporter. Biochemistry
28. Srinivas RV, Middlemas D, Flynn P, et al. Human immunodeficiency virus protease inhibitors serve as substrates for multidrug transporter proteins MDR1 and MRP1 but retain antiviral efficacy in cell lines expressing these transporters. Antimicrob Agents Chemother
29. Washington CB, Duran GE, Man MC, et al. Interaction of anti-HIV protease inhibitors with the multidrug transporter P-glycoprotein (P-gp) in human cultured cells. J Acquir Immune Defic Syndr Hum Retrovirol
30. Drewe J, Gutmann H, Fricker G, et al. HIV protease inhibitor ritonavir: a more potent inhibitor of P-glycoprotein than the cyclosporine analog SDZ PSC 833. Biochem Pharmacol
31. Vishnuvardhan D, Moltke LL, Richert C, et al. Lopinavir: acute exposure inhibits P-glycoprotein; extended exposure induces P-glycoprotein. AIDS
32. Taburet AM, Piketty C, Chazallon C, et al. Interactions between atazanavir-ritonavir and tenofovir in heavily pretreated human immunodeficiency virus-infected patients. Antimicrob Agents Chemother
33. Agarwala S, Eley T, Villegas C, et al. Pharmacokinetic interaction between tenofovir and atazanavir coadministered with ritonavir in healthy subjects. Presented at: Sixth International Workshop on Clinical Pharmacology of HIV Therapy; 2005; Quebec City.
34. Perloff ES, Duan SX, Skolnik PR, et al. Atazanavir: effects on P-glycoprotein transport and CYP3A metabolism in vitro. Drug Metab Dispos
35. Kaul S, Bassi K, Damle B, et al. Pharmacokinetic (PK) evaluation of the combination of atazanavir (ATV), enteric coated didanosine (ddI-EC) and tenofovir disoproxil fumarate (TDF) for a once-daily antiretroviral regimen. Presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy, 2003; Chicago.
36. Kumar GN, Dykstra J, Roberts EM, et al. Potent inhibition of the cytochrome P-450 3A-mediated human liver microsomal metabolism of a novel HIV protease inhibitor by ritonavir: a positive drug-drug interaction. Drug Metab Dispos
37. Kumar GN, Rodrigues AD, Buko AM, et al. Cytochrome P450-mediated metabolism of the HIV-1 protease inhibitor ritonavir (ABT-538) in human liver microsomes. J Pharmacol Exp Ther
38. Kaletra. Kaletra (US prescribing information). North Chicago, IL: Abbott Laboratories; 2005.
39. Crommentuyn KM, Mulder JW, Mairuhu AT, et al. The plasma and intracellular steady-state pharmacokinetics of lopinavir/ritonavir in HIV-1-infected patients. Antivir Ther
40. la Porte CJ, Colbers EP, Bertz R, et al. Pharmacokinetics of adjusted-dose lopinavir-ritonavir combined with rifampin in healthy volunteers. Antimicrob Agents Chemother
41. Castagna A, Gianotti N, Galli L, et al. The NIQ of lopinavir is predictive of a 48-week virological response in highly treatment-experienced HIV-1-infected subjects treated with a lopinavir/ritonavir-containing regimen. Antivir Ther
42. Bertz R, Foit C, Ye X, et al. Pharmacokinetics of once-daily vs. twice-daily Kaletra (lopinavir/ritonavir) in HIV+
subjects. Presented at: Ninth Conference on Retroviruses and Opportunistic Infections; 2002; Seattle.
43. Johnson MA, Gathe JC Jr., Podzamczer D, et al. A once-daily lopinavir/ritonavir-based regimen provides noninferior antiviral activity compared with a twice-daily regimen. J Acquir Immune Defic Syndr
. 2006 Aug 31; [Epub ahead of print].
44. Chiu Y-L, Foit C, Gathe J, et al. Multiple-dose pharmacokinetics and initial antiviral effect of once daily lopinavir/ritonavir (LPV/r) in combination with tenofovir (TDF) and emtricitabine (FTC) in HIV-infected antiretroviral-naive subjects (study 418) [poster]. Presented at: Second International AIDS Society Conference on HIV Pathogenesis and Treatment; 2003; Paris.
Keywords:© 2006 Lippincott Williams & Wilkins, Inc.
drug interaction; lopinavir; ritonavir; tenofovir