Abacavir/Tenofovir- and Didanosine/Tenofovir- Containing Antiretroviral Regimens
Abstracts and Commentary
By Dean L. Winslow, MD, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center, Clinical Professor, Stanford University School of Medicine, Section Editor, HIV, is Associate Editor for Infectious Disease Alert.
Synopsis: The ESS30009 study included antiretroviral-naïve patients randomized to either tenofovir (TDF)/abacavir (ABC)/lamivudine (3TC) or efavirenz (EFV)/abacavir/lamivudine. Patients in the TDF/ABC/3TC arm had a significantly higher risk of nonresponse or virologic failure as well as development of K65R and M184V substitutions in RT. The TEDDI trial consisted treatment-naïve patients given TDF/didanosine (ddI)/EFV. A high rate of virologic failure/nonresponse was seen along with the frequent development of K65R, L74V, and typical nnRTI substitutions.
Sources: Gallant JE, et al. Early Virologic Nonresponse to Tenofovir, Abacavir, and Lamivudine in HIV-Infected Antiretroviral-Naïve Subjects. J Infect Dis. 2005;192:1921-1930; Van Lunzen J, et al. High Rate of Virologic Failure During Once Daily Therapy with Tenofovir + Didanosine 250 mg + Efavirenz in Antiretroviral Naïve Patients: Results of the TEDDI Trial. Program and Abstracts of the 3rd IAS Conference on HIV Pathogenesis and Treatment; 2005; Abstract # TuP p0306.
The first article reports the results of an industry-sponsored clinical trial comparing TDF/ABC/3TC vs EFV/ABC/3TC in treatment-naïve patients. Three hundred forty patients were randomized. Baseline characteristics, including CD4 count and HIV RNA level were similar between the arms. In an unplanned interim analysis performed in patients who had received at least 8 weeks of therapy, only 5 patients (5.4%) in the EFV experienced virologic nonresponse, whereas 50 patients (49%) in the TDF group failed to respond. In patients on the TDF/ABC/3TC arm failing therapy, K65R with or without M184V was commonly seen.
The second paper (presented at last summer’s IAS Conference in Brazil) reported the results of European pilot study of TDF/ddI/EFV in 39 treatment-naïve patients. Virologic failure (or initial nonresponse) occurred in 11 (28%) of patients. NRTI substitutions observed in failing patients included K65R and L74V. nnRTI substitutions included 101E, 103N, 188C, and 190S/E. This study was terminated early by European regulatory authorities.
Commentary
The cornerstone of antiretroviral (ARV) therapy, since 1996, has consisted of regimens containing 2 nucleoside analog reverse transcriptase inhibitors (NRTIs) plus either a protease inhibitor (PI) or an non-nucleoside RT inhibitor (nnRTI). However, due to the increased potency of newer NRTIs and toxicities associated with nnRTIs and PIs (especially metabolic side effects with the latter), there has been interest in triple-nucleoside combination therapy. Unfortunately, despite the intrinsic potency of ABC, 3TC, and TDF individually (and in the double combinations of ABC/3TC and TDF/3TC or TDF/FTC), the rate of virologic failure and development of resistance-associated substitutions was surprisingly high with the triple nucleoside combination. Similarly, the double combination of ABC/TDF appears to be much less potent in vivo than either ABC/3TC or TDF/3TC or TDF/FTC, but does select for resistant variants.
The explanation for the poor performance of these regimens is unclear, and may be multifactorial. In vitro studies do not show antagonism between these agents in cell culture. Pharmacokinetic studies do not show any interaction of these drugs, which is reflected in plasma levels. Even in vitro studies of PBMCs to date have not shown conclusively any significant reductions of intracellular levels of nucleoside triphosphates when various combinations of these nucleosides are incubated with PBMCs in vitro. PMPA (the active moiety of TDF) inhibits purine nucleoside phosphorylase (PNP) and may cause accumulation of naturally-occurring dNTP’s, favoring incorporation of the natural dNTPs over the other purine analog NRTIs,1 but data suggesting alteration of nucleotide pools in vivo to the magnitude necessary to produce virologic nonresponse are equivocal. However, this inhibition of PNP by TDF is a likely explanation for the enhanced toxicity and CD4 cell decline seen with TDF combined with ddI in vivo. Another explanation of the high failure rate seen with these regimens includes the possibility that nucleosides and nucleoside analogues are not uniformly distributed or phosphorylated in different CD4+ cell populations.2 Similarly, recent data suggest that distribution and metabolism of nucleoside analogue agents may vary considerably between PBMCs and lymph node mononuclear cells, due to differential expression of multidrug resistance (MDR) proteins in various compartments which affect efflux of nucleoside analogs.3 Lastly, a low genetic barrier to resistance to TDF/ABC/3TC has been postulated since K65R alone may be sufficient to confer resistance to all 3 drugs in this regimen. However, only about half of patients genotyped at the time of virologic failure in the ESS30009 trial had K65R at the time of virologic failure.
While TDF plus either 3TC or FTC clearly provides a potent NRTI backbone for either a PI or nRTI-containing regimen, it is clear that TDF cannot be blindly combined with other agents, despite evidence of genotypic or phenotypic susceptibility test results. In any case, it is my personal opinion that regimens combining either TDF with either ddI or ABC should generally be avoided. The California Collaborative Treatment Group (CCTG) 584 study, which is performing detailed studies of intracellular pharmacokinetics of TDF and ABC (including assessment of PNP and MDR proteins), is currently enrolling patients and may shed light on what are complex drug interaction issues.
References
- Kakuda TN, et al. CD4 Cell Decline with Didanosine and Tenofovir and Failure of Triple Nucleoside/Nucleotide Regimens May Be Related. AIDS. 2004;18:2442-2444.
- Gao WY, et al. Differential Phosphorylation of Azidothymidine, Dideoxycytidine, and Dideoxyinosine in Resting and Activated Peripheral Blood Mononuclear Cells. J Clin Invest. 1993;91:2326-2333.
- Lafuillade A, et al. Investigating Cellular Antiretroviral Resistance: Preliminary Results of the "ICARE" Study. Program and Abstracts of the 3rd IAS Conference on HIV Pathogenesis and Treatment; 2005; Abstract #WeOa0201.
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