Potent combinations of zidovudine and drugs that select for the K65R mutation in the HIV polymerase

Abstract

Combinations of antiretroviral nucleoside reverse transcriptase inhibitors, and methods for their use in treating retroviral infections, are provided. In one embodiment, the combinations include non-thymidine nucleoside antiretroviral agents, such as tenofovir-DF, abacavir, APD and DAPD, that select for the K65R mutation and relatively low doses of zidovudine (AZT) or other thymidine nucleoside antiretroviral agents. The thymidine nucleoside antiretroviral agents retard development of the K65R mutation, and at the low doses, are less likely to produce side effects. In another embodiment, the combinations include DAPD and AZT. DAPD retards the development of TAMs, and AZT retards the development of the K65R mutation. In a third embodiment, the combinations include adenine, cytosine, thymidine, and guanine nucleoside antiviral agents, in further combination with at least one additional antiviral agent that works via a different mechanism than a nucleoside analog. This combination has the potential to eliminate the presence of HIV in an infected patient.

Description

Background technique [0001] In 1983, the cause of AIDS was identified as human immunodeficiency virus (HIV). In 1985, the synthetic nucleoside 3'-azido-3'-deoxythymidine (AZT) was reported to inhibit the replication of human immunodeficiency virus. Since then, many other synthetic nucleosides have been shown to be effective against HIV, including 2′,3′-dideoxyinosine (DDI), 2′,3′-dideoxycytidine (DDC), 2′ , 3′-Dideoxy-2′, 3′-Didehydrothymidine (D4T), ((1S, 4R)-4-[2-amino-6-(cyclopropylamino)-9H-purine-9 -yl]-2-cyclopentene-1-methanol sulfate (salt) (ABC), cis-2-hydroxymethyl-5-(5-fluorocytosine-1-yl)-1,3-oxo Thiolane (FTC), (-)-cis-2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane (3TC). In the use of cells Following cellular phosphorylation of 5′-triphosphate by kinases, these synthetic nucleosides are incorporated into the growing strand of viral DNA, causing chain termination due to the lack of a 3′-hydroxyl group. They are also capable of inhibiting the viral enzyme reve...

AI Technical Summary

Problems solved by technology

However, these multiagent therapies do not eliminate HIV-1, and long-term treatment often leads to multiagent resistance

Also, many of these agents are highly toxic and / or require complex dosing regimens that can reduce compliance and limit efficacy

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