title: Two-drug combinations of zidovudine, didanosine, and recombinant interferon-alpha A inhibit replication of zidovudine-resistant human immunodeficiency virus type 1 synergistically in vitro.
abstract: Optimal management of human immunodeficiency virus type 1 (HIV-1) infections may require combinations of anti-HIV-1 agents. Zidovudine (AZT, 3'-azido-3'-deoxythymidine), didanosine (ddI, 2',3'-dideoxyinosine), and recombinant interferon-alpha A (rIFN-alpha A) were evaluated in two-drug regimens against replication of AZT-resistant HIV-1 in vitro. AZT-sensitive and AZT-resistant isolate pairs derived from two individuals before and after extended AZT monotherapy were studied. Drug interactions using peripheral blood mononuclear cells infected with HIV-1 were evaluated mathematically. Synergistic interactions were seen among AZT, ddI, and rIFN-alpha A in two-drug regimens against AZT-resistant HIV-1 in vitro, even when AZT was included in the treatment regimen. Mixtures of wild-type and mutant reverse transcriptase genes were found in one of the late-AZT therapy isolates, suggesting that the mechanism of synergy of AZT-containing regimens may involve inhibition of AZT-sensitive viruses in the viral pool. These studies suggest that AZT may be useful in drug combination regimens, even when AZT-resistant viruses are isolated in vitro.
authors.affiliation: Infectious Disease Unit, Massachusetts General Hospital, Boston 02114.
authors.forename: V A
authors.initials: VA
authors.lastname: Johnson
authors.forename: D P
authors.initials: DP
authors.lastname: Merrill
authors.forename: J A
authors.initials: JA
authors.lastname: Videler
authors.forename: T C
authors.initials: TC
authors.lastname: Chou
authors.forename: R E
authors.initials: RE
authors.lastname: Byington
authors.forename: J J
authors.initials: JJ
authors.lastname: Eron
authors.forename: R T
authors.initials: RT
authors.lastname: D'Aquila
authors.forename: M S
authors.initials: MS
authors.lastname: Hirsch
mesh_terms: D001483:Base Sequence; D002478:Cells, Cultured; D003062:Codon / Q000737:chemistry; D004279:DNA, Viral / Q000737:chemistry; D016049:Didanosine / Q000494:pharmacology*; D004352:Drug Resistance, Microbial / Q000235:genetics; D004357:Drug Synergism; D005838:Genotype; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000382:microbiology; D008969:Molecular Sequence Data; D009154:Mutation; D012194:RNA-Directed DNA Polymerase; D011994:Recombinant Proteins; D014779:Virus Replication / Q000187:drug effects; D015215:Zidovudine / Q000494:pharmacology*
chemical_list: D003062:Codon; D004279:DNA, Viral; D007370:Interferon Type I; D011994:Recombinant Proteins; D015215:Zidovudine; D012194:RNA-Directed DNA Polymerase; D016049:Didanosine