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Objective: To determine the durability of zidovudine-induced delay in clinical progression of asymptomatic human immunodeficiency virus (HIV) disease and to assess the relationship between this effect and the entry CD4+ cell count.Design and Interventions: Extended follow-up data from subjects participating in protocol 019 of the AIDS [acquired immunodeficiency syndrome] Clinical Trials Group were examined. Subjects were offered a total daily dose of 500 mg of open-label zidovudine after the unblinding of the original randomized trial in 1989. Original treatment groups included placebo, 500 mg of zidovudine, or 1500 mg of zidovudine daily in divided doses. Three distinct analyses were conducted to assess the duration of zidovudine's effect on progression to AIDS or death: (1) analysis of all follow-up information from all subjects, (2) analysis of all subjects but with follow-up of original placebo-assigned subjects censored at the time open-label zidovudine was initiated, and (3) analysis of the effect of initiating zidovudine in subjects initially assigned to receive placebo.Setting: University-based and university-affiliated AIDS research clinics participating in AIDS Clinical Trials Group protocol 019.Patients: A total of 1565 asymptomatic HIV-infected subjects with entry CD4+ cell counts less than 0.50 x 10(9)/L (500/microL).Main Outcome Measure: Time to progression to AIDS or death.Results: During follow-up of up to 4.5 years (mean, 2.6 years), 232 subjects progressed to AIDS or died. In each of the three analyses described herein, zidovudine was associated with a significant (P = .008, .004, .007) decrease in the risk of such progression. However, each of these analyses also indicated a decreasing placebo:zidovudine relative risk with duration of use (P = .002, .08, .04), suggesting a nonpermanent effect. The duration of benefit appeared to be related to entry CD4+ cell count, with greater benefit in those with higher counts at entry. No significant differences in survival were found between those originally randomized to zidovudine or placebo.Conclusions: Zidovudine at 500 mg/d caused a significant delay in progression to AIDS or death, but its earlier use in asymptomatic disease was not associated with an additional prolongation of survival compared with delayed initiation. The delay in progression diminished over time especially in subjects with entry CD4+ cell counts less than 0.30 x 10(9)/L (300/microL). Treatment strategies that alter drug regimens before the loss of zidovudine benefit should be explored. [ABSTRACT FROM AUTHOR]

Forty-four men with penile intraepithelial neoplasia (PIN) and a matched control group of 88 men with condyloma acuminatum were evaluated in three centers studying anogenital human papillomavirus (HPV) infections. PIN and condyloma groups could not be distinguished on the basis of historical features or clinical presentation. Although PINs were more likely than condylomata to be pigmented (31/46 [67%] vs. 33/97 [34%], P < .001), 43% of PIN III were not pigmented, suggesting that pigmentation is not a sensitive indicator of high-grade PIN. HPV-16 infection, as determined by in situ hybridization, was closely associated with PIN III (0/24 PIN I contained HPV-16 vs. 12/13 PIN III, P < .001). Southern blot analysis demonstrated only episomal viral genomes, suggesting that integration is not an early event in penile neoplasia. [ABSTRACT FROM AUTHOR]

Objective: To assess the toxicity, efficacy, and pharmacology of combined zidovudine and ganciclovir therapy in patients with the acquired immunodeficiency syndrome (AIDS) and serious cytomegalovirus (CMV) disease.Design: Prospective, phase I multicenter trial (ACTG 004) with patients grouped by previous study drug history.Setting: Three university-based AIDS Clinical Trials Units sponsored by the National Institute of Allergy and Infectious Diseases (NIAID).Patients: Forty-one patients with AIDS-related CMV disease. Previous therapy with either zidovudine or ganciclovir was allowed.Interventions: Patients were treated with zidovudine, 600 to 1200 mg/d; or, if on ganciclovir maintenance, ganciclovir, 5 mg/kg body weight; blood was sampled for pharmacokinetic studies. The other drug was then administered to the patient with blood sampling and, finally, the two drugs in combination were given. Patients were continued on both drug therapies with dose reduction of zidovudine only for grade 3 or 4 toxicity.Measurements and Main Results: Forty patients were eligible. Hematologic toxicity was frequent, with 9 of the 10 patients requiring dose reductions for grade 3 or 4 toxicity at zidovudine doses of 1200 mg/d. With zidovudine doses of 600 mg/d, 82% experienced such hematologic toxicity. Median survival was 6 months; 10 patients developed intercurrent infection and 19, progressive CMV disease. Pharmacokinetic variables (alpha and beta half-lives, volume of distribution, clearance) were not affected in combination therapy.Conclusion: The combination of zidovudine and ganciclovir is poorly tolerated in patients with AIDS and serious-CMV disease, with 82% developing severe to life-threatening hematologic toxicity. Such toxicity is not a result of pharmacologic interactions, drug metabolism, or excretion. [ABSTRACT FROM AUTHOR]

Study Objective: To determine the efficacy and toxicity of intralesionally administered interferons in the treatment of condyloma acuminatum.Design: Randomized, double-blind, and placebo-controlled study.Setting: Outpatient clinics at university medical centers.Patients: Seventy-nine patients with biopsy-proved condyloma acuminatum that was refractory to conventional therapy were enrolled in the study.Interventions: Alpha-2b, alpha-nl-, and beta-interferons were used. One wart on each patients was injected three times per week for 4 weeks with either 1 x 10(6) units of interferon or placebo.Measurements and Main Results: Forty-seven percent of warts injected with interferon resolved completely, compared with 22% of placebo-injected warts (P = 0.009). In addition, more recipients of interferon had a complete resolution of uninjected lesions. No differences in rates of response were noted among the different interferon groups. Approximately one third of interferon-injected warts recurred, compared with none of four placebo-injected warts. Intralesionally administered interferon was nontoxic and well tolerated, although transient pain on injection was observed frequently.Conclusions: Intralesional administration of each of these three interferons appears to be useful in treating condyloma acuminatum. However, the frequent recurrence of disease and the failure of many lesions to resolve indicate that different regimens, such as longer courses of therapy or different routes of administration, should be evaluated to maximize beneficial effects of interferon for treating this common sexually transmitted disease. [ABSTRACT FROM AUTHOR]

Background: The increasing interest in applying therapeutic drug monitoring (TDM) to antiretroviral therapy is related to the inter-individual variation in antiretroviral pharmacokinetics. This variation may be due to certain genetic variations such as the efflux pump P-glycoprotein MDR1 polymorphisms G2677T and C3435T.Method: To facilitate the application of TDM, a real-time PCR based genotyping method for the detection of MDR1 polymorphisms was developed in 62 HIV-positive patients. This method was used to determine the MDR1 genotypes in both substance abuser and non-abuser groups. The contribution of MDR1 polymorphisms to pharmacokinetic variability of antiretroviral therapy was further assessed.Results: Genotype assignments based on PCR growth curve, fluorescence melt-curve analysis, and gel electrophoresis of PCR products were in good agreement. Although no significant difference in MDR1 polymorphism distribution was noted between substance users and non-users (G=4.4, G2677T; G=0.6, C3435T), it appeared to be racially dependent with 75% and 92% African Americans having wild type C3435T and G2677T, versus 22% and 26% in Caucasians, respectively. A clear link between G2677T and C3435T was also noted. No relationship was observed in these initial patients between MDR1 genotypes and pharmacokinetic measures.Conclusion: This method is being incorporated into the TDM program implemented in the pharmacotherapy research center.Clinical Pharmacology & Therapeutics (2005) 79, P67–P67; doi: 10.1016/j.clpt.2005.12.243 [ABSTRACT FROM AUTHOR]