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The safety and antiviral activity of the second-generation nonnucleoside inhibitor HBY 097 was investigated in asymptomatic or mildly symptomatic human immunodeficiency virus (HIV)-1-infected patients in a randomized, double-blinded, dose-escalation study. Mean maximum virus load decreases ranged from -1.31 log10 copies/mL of plasma at week 1 in the group receiving HBY 097 monotherapy (250 mg three times daily) to -2.19 log10 copies/mL at week 4 in the group receiving zidovudine plus HBY 097 (750 mg three times daily). After 12 weeks, these patients had viral RNA copy numbers 1.05 log10 below baseline. Genotypic analysis of resistance development revealed reverse transcriptase K103N variants in most patients, which was associated with less durable efficacy of HBY 097 treatment. Fewer patients receiving combination therapy with high-dose HBY 097 developed the K103N variant (P.01). HBY 097 caused pronounced acute suppression of HIV-1 replication both in combination with zidovudine and alone. Therefore, sustained antiviral activity can be expected from multiple combination therapy regimens including a quinoxaline derivative.

Plasma human immunodeficiency virus (HIV) type 1 RNA levels, CD4 lymphocyte changes, and drug resistance were studied in HIV-infected patients with 200-500 CD4 lymphocytes/microL who received zidovudine and didanosine combination therapy for 2 years. Among 35 patients, 10 had sustained and 16 had transient10-fold reductions in HIV RNA: 9 did not have 10-fold HIV RNA reductions. Only patients with sustained HIV suppression maintained increased CD4 cell counts for 2 years (370 to 501 cells/microL; P = .006). Patients with transient HIV suppression were more likely to develop drug-resistant HIV strains (12/16 vs. 5/19, P = .01) and reverse transcriptase (RT) mutations (4.5 vs. 2.5/strain; P = .02) than were patients with sustained or no HIV suppression. Zidovudine resistance occurred with RT mutations at codons 41, 67, 70, 215, and 219. Multidrug resistance occurred with mutations at codons 62, 75, 77, 116, and 151. Mutations occurred at codons 60, 68, 118, 210, and 228 inor = 4 patients each. Heterogeneity exists among individual virologic responses to zidovudine and didanosine combination therapy. HIV resistance mechanisms during combination therapy appear more complex than reported with monotherapy.

Different tissues or body fluids in which human immunodeficiency virus type 1 (HIV-1) can reside may contain viruses with distinct characteristics. Sixteen HIV-1-infected patients receiving zidovudine or didanosine were studied cross-sectionally and 1 patient who switched from zidovudine to didanosine was followed sequentially to determine if drug resistance mutations within the HIV-1 pol gene at codons 74 and 215 differed depending on the compartment from which the gene was isolated (plasma, seminal fluid, peripheral blood mononuclear cells, or seminal nonspermatozoal mononuclear cells). Cell-free virus in plasma and semen developed detectable mutations first, followed by proviral DNA in seminal nonspermatozoal and peripheral blood mononuclear cells. Study of the appearance of HIV-1 mutations in various compartments may help elucidate how the populations and dynamics of the virus differ throughout the body and determine whether seminal cell-free virus or provirus is the major sexually transmitted form.

Using the murine LP-BM5 retrovirus-induced immunodeficiency model, the therapeutic value of zidovudine (AZT) was analyzed. Continuous low dose (60 mg/kg per day) oral AZT administration for 6 weeks increased survival time by 5-6 weeks. Decreasing the duration of therapy to 3 weeks decreased the mean survival time. Extending the therapy from 6 to 14 weeks increased the median survival time (8 weeks). This dose was nontoxic and reduced virus titers, splenomegaly, and lymphadenopathy. AZT also retarded the immune dysfunction syndrome characteristic of this model. Hypergammaglobulinemia was reduced by AZT and was also a marker for disease progression. AZT reduced hyperproliferation of large blast cells and delayed the loss of splenic B cells.