guanosine-triphosphate and Acquired-Immunodeficiency-Syndrome

The frequency of human immunodeficiency virus, type 1 (HIV-1) mutations in response to antiviral therapy and resulting drug resistance is of major concern. Amdoxovir ((-)-beta-D-2,6-diaminopurine dioxolane), the prodrug of dioxolane guanosine (DXG), is currently in phase I/II clinical development for the treatment of HIV-1 infection. In vitro, HIV-1 mutants resistant to 3'-azido-3'-deoxythymidine (M41L/D67N/K70R/T215Y/K219Q) and (-)beta-L-2',3'-dideoxy-3'-thiacytidine (3TC) (M184V) remain sensitive to DXG. HIV-1 with the reverse transcriptase mutations K65R, L74V, and/or Q151M were less sensitive to DXG, whereas the mutation K103N re-sensitized the virus to the inhibitory effect of DXG. In order to understand these observations at the enzyme level, we investigated the inhibition of the HIV-1 reverse transcriptase-catalyzed viral DNA synthesis by dioxolane guanosine 5'-triphosphate (DXG-TP), 3'-azido-3'-deoxythymidine-TP, and 3TC-TP by using steady state kinetic analysis and the incorporation of DXG-5'-monophosphate by using pre-steady state kinetic analysis. This mechanistic study provided detailed information on the amdoxovir-related drug resistance at a molecular level. Overall, the enzymatic data correlated well with the antiviral data obtained from cell culture experiments and further supported the use of amdoxovir for the treatment of nucleoside reverse transcriptase inhibitor-experienced patients.

Topics: Acquired Immunodeficiency Syndrome; Cytidine Triphosphate; Deoxycytidine Monophosphate; Deoxyguanine Nucleotides; Dideoxynucleotides; Dioxolanes; DNA, Viral; Drug Resistance, Viral; Guanosine; Guanosine Triphosphate; HIV Reverse Transcriptase; HIV-1; Lamivudine; Mutation; Reverse Transcriptase Inhibitors; Substrate Specificity; Thymidine Monophosphate; Thymine Nucleotides; Zidovudine

Two novel antiviral pharmacologic strategies were used for therapy of life- and sight-threatening cytomegalovirus (CMV) infection; these were continuous drug infusion by portable pump and individualized patient regimen. 9-(1,3-Dihydroxy-2-propoxymethyl)-guanine (DHPG), an active and recently licensed antiviral drug against cytomegalovirus infection, was administered to five immunocompromised patients with chorioretinitis (all patients), colitis (two), and pneumonitis (three). Through dosage escalation, correlations between plasma levels, toxicity (i.e., myelosuppression), and clinical benefit were ascertained for therapy of acute disease (pneumonitis) as well as long-term therapy (chorioretinitis). Resolution of viremia, pneumonitis, colitis, and chorioretinitis was accomplished with steady-state plasma levels of DHPG approximating the mean ID50 of CMV isolates. The most notable clinical benefit was survival from CMV pneumonia and stabilization of vision. Although no adverse toxicity occurred during the DHPG continuous long-term therapy, survival was limited by the underlying disease.

Topics: Acquired Immunodeficiency Syndrome; Antiviral Agents; Cytomegalovirus Infections; Female; Guanosine Triphosphate; Humans; Infusion Pumps; Retinitis

Nine patients with acquired immunodeficiency syndrome (AIDS) and cytomegalovirus (CMV) retinitis on maintenance therapy with ganciclovir: 9(1,3-dihydroxy-2-propoxymethyl) guanine (DHPG) at high dose (30 mg/kg/week) or low dose (20 mg/kg/week) were tested every 1-2 weeks for CMV isolation from blood, saliva, and urine. Duration of therapy ranged from 1.5 to 12 months (average 5.3 months). During pretreatment and low-dose and high-dose maintenance therapy, CMV was isolated from 48/59 (81%), 90/211 (43%), and 40/290 (14%) of specimens, respectively. Three patients with progressive retinitis had viraemia more frequently than did six patients with stable retinitis, CMV being isolated from 29/47 (62%) and 17/121 (14%) of blood samples, respectively.

Topics: Acquired Immunodeficiency Syndrome; Adult; Cytomegalovirus; Cytomegalovirus Infections; Guanosine Triphosphate; Humans; Male; Middle Aged; Prevalence; Retinitis; Viremia