Favorable interaction of β- l(−) nucleoside analogues with clinically approved anti-HIV nucleoside analogues for the treatment of human immunodeficiency virus

The combination of l(−)-2-′,3′-dideoxy-3′-thiacytidine ( l(−)SddC, 3TC), l(−)-2′,3′-dideoxy-5-fluorocytidine ( l(−)FddC), or l(−)-2′,3′-dideoxy-5-fluoro-3′-thiacytidine ( l(−)FTC) with 3′-azido-3′-deoxythymidine (AZT) synergistically inhibited replication of human immunodeficiency virus (HIV) in vitro. Similar synergistic activity was also obtained when these compounds were used in combination with 2′,3′-didehydro-2′,3′-dideoxythymidine (D4T). In terms of 2′,3′-dideoxyinosine (ddI) and 2′,3′-dideoxycytidine (ddC), only additive anti-HIV activity was observed. None of the β- l(−) nucleoside analogues had additive toxicity in cell culture, and they could protect against the delayed mitochondrial toxicity associated with AZT, D4T, ddC, and ddI in drug-treated cells. Thus, combinations of β- l(−) nucleoside analogues with any of the approved anti-HIV drugs could have a potentially beneficial outcome.