This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Primary Objectives 1. To evaluate the relative potencies of two monotherapy regimens (Tenofovir(TDF) alone vs. Abacavir(ABC) alone) compared to a dual NRTI regimen of TDF + ABC as assessed by the short-term virologic response (slope of the phase I viral decay and change in HIV RNA at day 7). 2. To compare the plasma and intracellular PK data of the two monotherapy regimens compared to the dual NRTI regimen. Secondary Objectives 1. To evaluate the change in cellular regulatory enzymes involved with nucleoside analogue transport across cell membranes as assessed by RT-PCR of specific mRNA transcripts after 21 days of TDF+ABC exposure. 2. To determine if NRTI-associated mutations emerge after 7 days of ABC or TDF monotherapy or after 7 days of dual NRTI therapy with ABC + TDF. 3. To compare the relative viral potency of TDF monotherapy versus ABC monotherapy. 4. To evaluate the long-term viral response to Efavirenz (EFV) + ABC + 3TC after two 7-day sequences of mono/dual-therapy. 5. To evaluate the relative toxicities of the two monotherapy treatment regimens. Background and Rationale Dual nucleoside analogues form the backbone of most potent antiretroviral regimens. Although many possible combinations are used there are relatively few clinical trials that have evaluated the relative potency of these dual NRTI regimens. Recently, several studies have suggested increased rates of early virologic failure when the combination of abacavir, tenofovir and lamivudine were used[1-3]. This is in contrast to other settings in which a four NRTI combination was used without evidence of increased rates of early virologic failure (eg. Trizivir + tenofovir)[4]. Therefore, further studies are needed to evaluate potential mechanisms for this clinical observation. Individually the relative potency of tenofovir and abacavir are among the more potent in this class. There are several reasons to evaluate the dual NRTI combination of TDF and ABC alone and in combination: 1. TDF combined with ABC is a potentially potent regimen that has not been fully evaluated. 2. The relative potency of the dual NRTI (TDF + ABC) combination can be evaluated by short term phase I viral decay kinetics relative to the decay rates of each NRTI given alone. 3. Plasma and intracellular concentrations of the dual NRTI combination (TDF + ABC) can be evaluated and compared to pharmacokinetic data when the NRTI is given as monotherapy. 4. Induction or suppression of certain metabolic enzymes that control influx and efflux of nucleoside analogues can be evaluated by measuring baseline and steady state mRNA expression in PBMCs via RT-PCR. Possible explanations for the increased rates of virologic failures when the TDF + ABC + 3TC combination was used include: (1) a pharmacodynamic phenomena in which drug-drug antagonism results; decreasing relative NRTI potency, (2) a pharmacokinetic interaction resulting in reduced intracellular or plasma levels, or finally (3) a low viral genetic barrier to resistance results from the combination of this particular nucleoside combination. First, the evaluation of the relative antiviral potency of individual nucleosides or dual combinations is complicated by the inability to administer these regimens for long durations due to the risk of development of resistance. Antiretroviral potencies of drugs and drug doses has been evaluated in studies of first phase decay rates and magnitude of HIV RNA reductions in studies of 2 weeks or less. One supposition of these studies is that the phase one decay rate is a predictor of antiviral potency of a regimen and that differences between the decay rates of different regimens might translate into differences in longer term virologic suppression. Analysis of phase I HIV RNA decay kinetics in studies of 2 weeks or less has been used as a predictor of antiviral potency of perspective NRTI regimens. It is unclear whether the gain in precision of the measurement (by doing multiple HIV RNA measures over the 1- 2 week interval) of virologic potency truly justifies the cost and inconvenience of calculating the slopes. Thus, if some simpler method could give the same information as the slope, then that measure could be used instead of the slope. Wu et al have shown a high correlation between the change in HIV RNA at week 1 and the slope of the phase I decay. The short duration of NRTI mono or dual therapy also allows for the prompt addition of drugs to comprise a fully acceptable combination regimen before significant risk of drug resistance develops. Brief courses of monotherapy for several antiretroviral drugs, including TDF and ABC, have been given and found to be safe without the emergence of premature resistance: In a viral dynamics study of TDF monotherapy in 10 antiretroviral-nanve patients no evidence of nucleoside mutations were detected after 21 days of treatment.. An escalating-dose study of TDF monotherapy for 28 days in 38 antiretroviral patients also did not show emergence of new nucleoside mutations from baseline. Abacavir monotherapy has been given in several studies for short durations with subsequent good clinical responses upon addition of a fully potent regimen. Miller et al. evaluated antiviral potency and genotypic and phenotypic susceptibility of abacavir monotherapy followed by the addition of zidovudine and lamivudine. Sixty antiretroviral-nanve patients were randomized to receive 100, 300 or 600mg abacavir twice daily. With the exception of one patient at week 8 who developed the K65R mutation, no subjects developed new RT mutations prior to week 12. However at week 12, 26/38 subjects were still on abacavir monotherapy and had genotypic data: 18 out of 26 subjects had new RT mutations. These data indicate that short courses of TDF and/or ABC monotherapy should be safe and unlikely to result in new on-treatment RT mutations. The pharmacokinetic interaction of ABC + TDF will be evaluated by comparing steady-state intracellular and plasma concentrations of each nucleoside alone and then again when dosed in combination. Although preliminary data has not suggested a significant intracellular interaction: The Tonus Study, a pilot study of once daily ABC/TDF/3TC, plasma concentrations were evaluated at month 1: 32/37 patients had adequate Cmin concentrations for all three nucleosides. In a random subset of 14 patients intracellular nucleoside concentrations were also measured and failed to show a major interaction. In a study by Hawkins et al, Carbovir-TP(CBV-TP) and TDF-DP were evaluated in a cohort of 13 subjects with viral suppression and on a stable regimen of ABC/TDF/3TC. After substitution of either TDF or ABC with another nucleoside, intracellular concentrations were measured of the companion nucleoside. No change in either the intracellular interaction was noted for either TDF-DP or CBV-TP. This study is limited, however, because all patients had successfully suppressed their plasma HIV RNA on the triple nucleoside regimen. Thus, if altered pharmacokinetics only occurs in patients with failure on this triple nucleoside regimen, then this study would not be able to detect this difference as no patients were failing at enrollment. CCTG 584 will better evaluate a potential PK interaction by: (1) evaluating monotherapy and combination therapy separately, (2) comparing intracellular triphosphate levels and (3) by evaluating the induction or suppression of certain cellular enzymes critical for cellular nucleoside transportation. Finally, the third possibility of a low genetic barrier to resistance leading to increased rates of virologic resistance will be evaluated by serial genotypic evaluations. Specimens for genotypic analysis will be collected and run in real-time at baseline and after NRTI dual-therapy with ABC + TDF. If significant mutations are detected, then day 7, post-monotherapy, samples will be analyzed and mutations can be discerned as either preexisting or de novo. If more than one patient develops any new NRTI or NNRTI-associated resistance mutations as defined by the updated IAS-USA mutation list, the study will hold enrollment and study progression for those subjects in Sequence I and present the data to an independent review committee for evaluation. Based upon the independent committee's recommendations the study may either continue, continue with study design modification or be discontinued. Multiple specimens for stored plasma will be collected during the mono- and dual-therapy sequences for possible future genotypic analysis of low frequency mutant variants not detected on standard pooled genotypes. References: 1. J G. Early Virologic Failure Rates with combination of Lamivudine, Abacavir and Tenofovir in Therapy Naive Patients: GSK 30009. In: 43rd Annual ICAAC. Chicago, IL, 2003 2. Farthing C KHaYV. Early virologic failure in a pilot study evaluating the efficacy of abacavir, lamivudine and tenofovir in the treatment naive HIV-infected patients. In: The 2nd IAS Conference on HIV Pathogenesis and Treatment. Paris, France, 2003 3. Landman R ea. Low genetic barrier to resistance is a possible cause of early virologic failures in once-daily regimen of abacavir, lamivudine and tenofovir: The Tonus Study. In: 11th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA, 2004 4. Elion R ea. COL40263: Resistance and efficacy of once-daily trzivir and tenofovir DF in antiretroviral naive subjects: Abstract 53. In: 11th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA, 2004 5. Miller MD MN, Schooley R, et al. Baseline and week 48 final phenotypic analysis of HIV-1 from patients adding tenofovir DF therapy to background ART [Abstract 441]. In: 8th Conference on Retroviruses and Opportunistic Infections. Chicago, IL, 2001 6. Squires K, Pozniak AL, Pierone G, Jr., et al. Tenofovir disoproxil fumarate in nucleoside-resistant HIV-1 infection: a randomized trial. Ann Intern Med 2003;139:313-20 7. Staszewski S GJ, Pzniak A, et al. Efficacy and safety of tenofovir DF versus stavudine when used in combination with lamivudine and efavirenz in HIV-1 infected patients naive to antiretroviral therapy; 48 week interim results [Abstract LbOr17]. In: 14th Internation Aids Conference. Barcelona, Spain, 2002 8. A. V. Abacavir combivir is comparable to indinavir/combivir in HIV-1 infected ARV naive adults: results of a 48 week open-label study (CNA3014) (poster 063). In: 1st IAS Conference on HIV Pathogenesis and Treatment. Buenos Aires, Argentina, 2001 9. Piliero P S-CA, Para M, et al. A study examining the pharmacokinetics of abacavir and intracellular carbovir triphosphate (GSK Protocol CNA 10905) [Abstract A-1797]. In: 43rd ICAAC. Chicaco, IL, 2003 10. Gazzard BG DJE, Cahn P, et al. Abacavir once daily plus lamivudine in combination with efavirenz is well-tolerated and effective in the treatment of antiretroviral therapy naive adults with HIV-1 infection (Zodiac Study: CNA30021) [Abstract: H-1722b]. In: 43rd ICAAC. Chicaco, IL, 2003 11. Clay PG. The abacavir hypersensitivity reaction: a review. Clin Ther 2002;24:1502-14 12. Loeliger AE, Steel H, McGuirk S, Powell WS and Hetherington SV. The abacavir hypersensitivity reaction and interruptions in therapy. Aids 2001;15:1325-6 13. Frissen PH, de Vries J, Weigel HM and Brinkman K. Severe anaphylactic shock after rechallenge with abacavir without preceding hypersensitivity. Aids 2001;15:289 14. Berenguer J, Padilla B, Estrada V, et al. Safety of abacavir therapy after temporary interruptions in patients without hypersensitivity reactions to the drug. Aids 2002;16:1299-301 15. Thompson M SM, Brown L, et al. Interruptions in abacavir dosing are not associated with increased risk of hypersensitivity in the HEART (NZT 4006) study. (Abstract: L-14). In: 40th ICAAC. Toronto, Canada, 2000 16. Moore KH, Barrett JE, Shaw S, et al. The pharmacokinetics of lamivudine phosphorylation in peripheral blood mononuclear cells from patients infected with HIV-1. Aids 1999;13:2239-50 17. Yuen GJ, Lou Y, Bumgarner NF, et al. Equivalent steady-state pharmacokinetics of lamivudine in plasma and lamivudine triphosphate within cells following administration of lamivudine at 300 milligrams once daily and 150 milligrams twice daily. Antimicrob Agents Chemother 2004;48:176-82 18. Staszewski S HA, Gute P, et al. Nevirapine/didanosine/lamivudine once daily in HIV-1 infected intravenous drug users. Antiviral Therapy 1998;3:55-56 19. Bowonwatanuwong C MK, Supparatpinyo S, et al. In: 1st IAS Conference on HIV Pathogenesis and Treatment. Buenos Aires, Argentina, 2001 20. Sension MG, Bellos NC, Johnson J, et al. Lamivudine 300 mg QD versus continued lamivudine 150 mg BID with stavudine and a protease inhibitor in suppressed patients. HIV Clin Trials 2002;3:361-70 21. Staszewski S, Morales-Ramirez J, Tashima KT, et al. Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 Team. N Engl J Med 1999;341:1865-73 22. Blum M Q, Delehanty J, et al. Very early changes in viral load as a tool for antiviral dose selection (abstract: 12468LB). In: 12th World AIDS Conference. Geneva, Switzerland, 1998 23. Wu H, Ding AA. Population HIV-1 dynamics in vivo: applicable models and inferential tools for virological data from AIDS clinical trials. Biometrics 1999;55:410-8 24. Wu H, Ding AA and De Gruttola V. Estimation of HIV dynamic parameters. Stat Med 1998;17:2463-85 25. Wu H, Lathey J, Ruan P, et al. Relationship of plasma HIV-1 RNA dynamics to baseline factors and virological responses to highly active antiretroviral therapy in adolescents (aged 12-22 years) infected through high-risk behavior. J Infect Dis 2004;189:593-601 26. Louie M, Hogan C, Hurley A, et al. Determining the antiviral activity of tenofovir disoproxil fumarate in treatment-naive chronically HIV-1-infected individuals. Aids 2003;17:1151-6 27. Barditch-Crovo P, Deeks SG, Collier A, et al. Phase i/ii trial of the pharmacokinetics, safety, and antiretroviral activity of tenofovir disoproxil fumarate in human immunodeficiency virus-infected adults. Antimicrob Agents Chemother 2001;45:2733-9 28. Saag MS, Sonnerborg A, Torres RA, et al. Antiretroviral effect and safety of abacavir alone and in combination with zidovudine in HIV-infected adults. Abacavir Phase 2 Clinical Team. Aids 1998;12:F203-9 29. Miller V, Ait-Khaled M, Stone C, et al. HIV-1 reverse transcriptase (RT) genotype and susceptibility to RT inhibitors during abacavir monotherapy and combination therapy. Aids 2000;14:163-71 30. Hawkins T VW, St Claire R, et al. Intracellular pharmacokinetics of tenofovir DF and carbovir TP in patients recieving triple nucleoside regimens (Poster # 2.4). In: 5th International Workshop on Clinical Pharmacology of HIV Therapy. Rome, Italy, 2004 31. Notermans DW, Goudsmit J, Danner SA, de Wolf F, Perelson AS and Mittler J. Rate of HIV-1 decline following antiretroviral therapy is related to viral load at baseline and drug regimen. Aids 1998;12:1483-90 32. Ding AA, Wu H. A comparison study of models and fitting procedures for biphasic viral dynamics in HIV-1 infected patients treated with antiviral therapies. Biometrics 2000;56:293-300 33. Wu H ZC, Liang H. Comparison of linear, nonlinear and semiparametric models for estimating HIV dynamic parameters. Biometrics 2004;46:233-245

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