Efficacy and safety of combination therapy with delavirdine and zidovudine: a European/Australian phase II trial.

The objective of the study was to investigate the safety and antiviral effect of three delavirdine dose regimens or placebo in combination with zidovudine in patients who were already taking zidovudine. Eighty-nine symptomatic HIV-1 seropositive individuals with CD4 cell counts between 50 and 350 cells/microl were included in this trial The influence of combination therapy on viral susceptibility to both zidovudine and delavirdine was investigated. Death or the occurrence, or re-occurrence of an AIDS-defining illness was considered as a clinical endpoint. The addition of delavirdine to the antiretroviral treatment regimen resulted in a significant, but transient, reduction in virus load, as determined by quantitative RNA measurements. CD4+ cell count did not change significantly. Susceptibility to zidovudine remained unchanged after 12 weeks of combination therapy, while 70% of the patients demonstrated a substantial decrease (> 10-fold) in sensitivity to delavirdine. Two patients suffered from an AIDS-defining disease during the study. No deaths occurred. Generally, the drug appeared to be safe. Skin rash was the most frequently observed adverse event (52%). In most patients the rash either resolved spontaneously or was treated successfully with a short course of antihistamines. The definite place of the compound in the management of HIV disease, in particular when given in combination with other antiretroviral agents, remains to be further explored.

In-vitro selection of HIV-1 variants resistant to non-nucleoside reverse transcriptase inhibitors in monocyte-derived macrophages.

Unlike the selection of HIV-1 variants resistant to anti-retroviral drugs in human peripheral blood mononuclear cells and T cell lines, induction of resistance in monocyte-derived macrophages has not been widely studied. Since macrophages serve as a potential HIV-1 reservoir in humans, knowledge of the effect of anti-retroviral drugs on macrophage-tropic HIV-1 isolates may help in the design of a strategy for prolonged suppression of viral replication. In-vitro selection and drug susceptibility testing of macrophage-tropic HIV-1 variants with reduced sensitivity to two non-nucleoside reverse transcriptase inhibitors, atevirdine and delavirdine (both bis-heteroarylpiperazines), is described here. The atevirdine-resistant isolate was cross-resistant to delavirdine, and the delavirdine-resistant isolate was cross-resistant to atevirdine. Interestingly, the atevirdine-resistant isolate, but not the delavirdine-resistant isolate, was also cross-resistant to nevirapin while the inhibition of viral replication of both isolates in macrophages by zidovudine was the same as that in the parental HIV-1 strain. Nucleotide sequence analysis of the resistant macrophage-tropic HIV-1 isolates showed that the atevirdine-induced resistance was due to a single amino acid change at codon 106 and that the delavirdine-induced resistance could be attributed to an amino acid change at codon 236. This study demonstrates that monocyte-derived macrophages can be used to investigate the phenotypic and genotypic acquisition of anti-retroviral drug resistance of macrophage-tropic HIV-1.

Safety, tolerance, and efficacy of atevirdine in asymptomatic human immunodeficiency virus-infected individuals.

Atevirdine is a nonnucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1 (HIV-1). In this study we investigated the effect of atevirdine in asymptomatic antiretroviral naive HIV-infected patients with CD4+ cell counts of between 200 and 750 cells per mm3. Patients were randomized to receive 600 mg of atevirdine (n = 15) or a placebo (n = 15) three times a day for 12 weeks. There was no statistically significant effect of atevirdine on viral loads (HIV p24 antigen and HIV-1 RNA levels by PCR) or CD4+ cell counts. The data do not support the use of atevirdine as a monotherapy in the treatment of HIV-infected patients.

Safety, tolerance, and pharmacokinetics of atevirdine mesylate (U-87201E) in asymptomatic human immunodeficiency virus-infected patients.

Atevirdine mesylate (U-87201E) is a new nonnucleoside (bisheteroarylpiperazine) inhibitor of human immunodeficiency virus type 1 reverse transcriptase. In a double-blind, escalating single-dose study the safety, tolerance, and pharmacokinetics of atevirdine mesylate were investigated in 24 asymptomatic human immunodeficiency virus-seropositive male patients. Each patient received one single oral dose of atevirdine mesylate and placebo separated by an interval of 1 to 3 weeks. For each dose level (400, 800, 1,200, and 1,600 mg) six patients received drug and placebo on separate occasions. Blood samples were collected before dosing and at intervals afterward for safety evaluation and estimation of atevirdine and metabolite levels. The concentrations of atevirdine and its principal metabolite (U-89255) in serum were determined by high-performance liquid chromatography. The results of the study showed that atevirdine mesylate is well tolerated at all dose levels. No clinically significant effects on vital signs, electrocardiograms, or laboratory tests were observed. Occasional headache and nausea were reported both in the drug group and in the placebo group. The times to peak values were relatively short (0.5 to 1.0 h), suggesting a rapid absorption. The maximum concentrations of drug in serum were 1.4 microM (400 mg), 4.2 microM (800 mg), 7.3 microM (1,200 mg), and 5.8 microM (1,600 mg). The values of the pharmacokinetic parameters for atevirdine were found to have relatively large intersubject variabilities, and consequently, the study had little power to detect dose-dependent changes in the values of the pharmacokinetic parameters. The oral clearance of atevirdine tended to increase by 90% as the atevirdine mesylate doses increased from 400 to 1,600 mg, but this change in oral clearance was not statistically significant. The values of the pharmacokinetic parameters determined in the study were similar to those found in a previous single-dose study in healthy volunteers.