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| |  ROI CONFERENCE: Cellular Concentrations Of Nucleoside Analogues Linked With Viral Load Response CHICAGO, IL -- February 2, 1998 -- For the first time, researchers demonstrated that intracellular concentrations of AIDS drugs known as nucleoside analogues correlate significantly with HIV viral load response (viral load is a measurement of the amount of HIV in the blood). To be effective, these drugs must penetrate and be activated in infected cells. Studies presented today at the Fifth Conference on Retroviruses and Opportunistic Infections show that when the active form of these agents are at decreased levels within a cell, viral load response is diminished. "These findings provide an additional explanation for why some patients with HIV do not do well on combination therapy," explained Jean-Pierre Sommadossi, Ph.D., professor of clinical pharmacology and associate director of the Center for AIDS Research, University of Alabama, Birmingham. "It is well established that the success of drug therapy in HIV can be negatively affected by such factors as drug resistance, the existence of latent viral reservoirs [pools of cells that provide sanctuaries for the HIV virus] and incomplete adherence to the treatment regimen. "We now know that the intracellular metabolism of nucleoside analogues, correlated with its effect on viral load, can also impact treatment failure." In order for nucleoside analogues to be effective, they must be metabolised into an active form of drug, known as a triphosphate -- this process is known as phosphorylation. Dr. Sommadossi and colleagues examined the effects of this process in the ALTIPHAR study, which compared the effects of the combination d4T (Zerit(R), stavudine) and 3TC (Epivir(R), lamivudine) in treatment-experienced and treatment-naive patients. "In this study, we found that patients who had failed long-term AZT-based treatments subsequently appeared to have a decreased phosphorylation of d4T and 3TC," Dr. Sommadossi said. "This result was highly correlated with ALTIPHAR is a pharmacologic follow-up study of patients who were enrolled in the ALTIS 1 and 2 clinical trials. Christine Katlama, M.D., of the Hopital de la Pitie-Salpetriere in Paris, found that in patients who had taken no previous anti-HIV medication, the combination of d4T+3TC produced a 1.66 log reduction in viral load; 21% of these antiretroviral-naive patients had undetectable levels of HIV in the blood. Among patients who had previously been treated with AZT (Retrovir(R), zidovudine) (mean exposure 14 months), but who had not received d4T/3TC prior to the study, the d4T/3TC combination was associated with a 0.66 viral load reduction -- a difference of one log -- and viral load was undetectable in five percent of these patients. "The results of ALTIS 1 and 2 raised questions which the ALTIPHAR study was designed to answer," Dr. Katlama explained. "To achieve this we considered a sub-group of patients -- selected in a blinded fashion -- from ALTIS to explore the pharmacologic means to explain this phenomenon." The ALTIPHAR investigators examined blood samples from 19 patients enrolled in both arms of the ALTIS study and analysed the intracellular levels of active drug based on patients' viral load responses. They found that the intracellular concentrations of d4T and 3TC triphosphates were lower among patients previously treated with AZT, AZT/ddI (Videx(R), didanosine) and AZT/ddC (Hivid(R), zalcitabine). Diminished viral load response correlated directly with reduced intracellular levels of both d4T and 3TC in these patients. "These results demonstrate that intracellular levels of activated nucleoside analogues correlate significantly with HIV viral load response," Dr. Sommadossi said. "Further research should shed light on the underlying molecular basis for these pharmacologic observations."
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