Simple adjustments for randomized trials with nonrandomly missing or censored outcomes arising from informative covariates.
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In randomized trials with missing or censored outcomes, standard maximum likelihood estimates of the effect of intervention on outcome are based on the assumption that the missing-data mechanism is ignorable. This assumption is violated if there is an unobserved baseline covariate that is informative, namely a baseline covariate associated with both outcome and the probability that the outcome is missing or censored. Incorporating informative covariates in the analysis has the desirable result of ameliorating the violation of this assumption. Although this idea of including informative covariates is recognized in the statistics literature, it is not appreciated in the literature on randomized trials. Moreover, to our knowledge, there has been no discussion on how to incorporate informative covariates into a general likelihood-based analysis with partially missing outcomes to estimate the quantities of interest. Our contribution is a simple likelihood-based approach for using informative covariates to estimate the effect of intervention on a partially missing outcome in a randomized trial. The first step is to create a propensity-to-be-missing score for each randomization group and divide the scores into a small number of strata based on quantiles. The second step is to compute stratum-specific estimates of outcome derived from a likelihood-analysis conditional on the informative covariates, so that the missing-data mechanism is ignorable. The third step is to average the stratum-specific estimates and compute the estimated effect of intervention on outcome. We discuss the computations for univariate, survival, and longitudinal outcomes, and present an application involving a randomized study of dual versus triple combinations of HIV-1 reverse transcriptase inhibitors. (+info)
Safety, pharmacokinetics, and efficacy of (+/-)-beta-2',3'-dideoxy-5-fluoro-3'-thiacytidine with efavirenz and stavudine in antiretroviral-naive human immunodeficiency virus-infected patients.
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Racivir [RCV; (+/-)-beta-2',3'-dideoxy-5-fluoro-3'-thiacytidine], a 50:50 racemic mixture of the two beta nucleoside enantiomers, is currently in development for the treatment of human immunodeficiency virus type 1 (HIV-1) infections. RCV was administered once a day orally for 14 days at doses of 200, 400, or 600 mg in combination with stavudine and efavirenz to HIV-1-infected treatment-naive male volunteers in a phase Ib/IIa study. Six volunteers at each dose were monitored for a total of 35 days for tolerance, pharmacokinetics, and plasma HIV RNA levels. RCV in combination with stavudine and efavirenz was well tolerated at all doses tested. Pharmacokinetic parameters were dose proportional, and the maximum concentration of drug in serum at all doses exceeded the 90% effective concentration for wild-type HIV-1. Viral loads dropped as expected in all dosage groups, with mean reductions from 1.13 to 1.42 log10 by day 4 and 2.02 to 2.43 log10 by day 14. HIV RNA levels remained suppressed for more than 2 weeks in the absence of any additional therapy, with mean viral loads ranging from 2.1 to 2.6 log10 below baseline through day 28. By day 35, HIV RNA levels began to increase but still remained >1 log10 below baseline levels. (+info)
In vitro selection and analysis of human immunodeficiency virus type 1 resistant to derivatives of beta-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine.
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Serial passage of human immunodeficiency virus type 1 in MT-2 cells in increasing concentrations of the d- and l-enantiomers of beta-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine (d4FC) resulted in the selection of viral variants with reverse transcriptase substitutions M184I or M184V for l-d4FC and I63L, K65R, K70N, K70E, or R172K for d-d4FC. Phenotypic analysis of site-directed mutants defined the role of these mutations in reducing susceptibility to l- or d-d4FC. (+info)
Altered pharmacokinetics of zalcitabine by concurrent use of NSAIDs in rats.
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AIM: To investigate the pharmacokinetic interactions between zalcitabine and nonsteroidal anti-inflammatory drugs (NSAIDs) in rats. METHODS: Zalcitabine was administered to rats via an iv injection (20 mg/kg) in the presence or absence of ketoprofen or naproxen (20 mg/kg), and the pharmacokinetic parameters were determined by using non-compartmental analysis. RESULTS: Compared with the control (zalcitabine alone), pretreatment with ketoprofen or naproxen 30 min prior to intravenous administration of zalcitabine significantly altered the pharmacokinetic profiles of zalcitabine in rats. Renal clearance of zalcitabine was reduced by approximately 3-4-fold in the presence of ketoprofen or naproxen. Consequently, systemic exposure (AUC) to zalcitabine in the rats pretreated with ketoprofen or naproxen was significantly greater than that for the control group given zalcitabine alone. The terminal plasma half-life of zalcitabine was also prolonged by 4-5-fold in the presence of ketoprofen or naproxen. CONCLUSION: The NSAIDs ketoprofen and naproxen effectively altered the pharmacokinetics of zalcitabine. Therefore, concomitant use of ketoprofen or naproxen in patients being treated with zalcitabine may necessitate close monitoring for potential drug interactions. (+info)
Biological comparison of wild-type and zidovudine-resistant isolates of human immunodeficiency virus type 1 from the same subjects: susceptibility and resistance to other drugs.
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We used a viral endpoint dilution assay to show changes in the proportion of zidovudine (azidothymidine; AZT)-resistant viruses within a heterogeneous mixture of human immunodeficiency virus type 1 (HIV-1) quasispecies isolated from patients on long-term AZT therapy. Several HIV-1 isolates, which could replicate in 10 microM AZT, were susceptible to both 2',3'-dideoxycytidine and a novel cytosine analog BCH-189, in which a sulfur atom replaces the 3' carbon of the pentose ring. In certain instances, cross-resistance was seen with 3'-didehydro-2',3'-dideoxythymidine. Although most strains of AZT-resistant HIV-1 displayed reduced susceptibility to 3'-azido-2',3'-dideoxyuridine, two strains were identified for which this was not the case. (+info)
Inhibition of the replication of hepatitis B virus in vitro by 2',3'-dideoxy-3'-thiacytidine and related analogues.
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Several 2',3'-dideoxy-3'-thiapyrimidine nucleosides were studied for their ability to inhibit hepatitis B virus (HBV) DNA replication in a HBV-transfected cell line (2.2.15). 2',3'-Dideoxy-3'-thiacytidine (SddC) and 5-fluoro-2',3'-dideoxy-3'-thiacytidine(5-FSddC) were found to be the most potent anti-HBV compounds of those examined. Both compounds resulted in nearly complete cessation of viral DNA replication at 0.5 microM, as monitored by the absence of both intracellular episomal and secreted viral DNAs. The HBV-specific RNAs were not reduced at concentrations that completely blocked HBV DNA replication, suggesting that the inhibitory target is HBV DNA synthesis. The antiviral action of SddC and 5-FSddC was reversible. The concentration of SddC and 5-FSddC required to inhibit 50% of 4-day cell growth in culture was 37 microM and more than 200 microM, respectively. Unlike 2',3'-dideoxycytidine, these two compounds do not affect mitochondrial DNA synthesis in cells at concentrations lower than that required to inhibit cell growth. In view of the potent and selective antiviral activity, both SddC and 5-FSddC should be further evaluated for the treatment of human HBV infection. (+info)
Differential inhibition of 2'-deoxycytidine salvage as a possible mechanism for potentiation of the anti-human immunodeficiency virus activity of 2',3'-dideoxycytidine by dipyridamole.
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Dipyridamole, a commonly used coronary vasodilator and antithrombotic drug, was recently shown to potentiate the activity of 3'-azido-3'-deoxythymidine and 2',3'-dideoxycytidine against the human immunodeficiency virus type 1 (HIV-1) in human monocyte-macrophages in vitro. We report in the present paper that in uninfected monocyte-macrophages dipyridamole significantly inhibits cellular salvage of [3H]deoxycytidine, whereas it does not affect the salvage of [3H]dideoxycytidine. Similar differential inhibition by dipyridamole of the salvage of thymidine, as opposed to 3'-azido-3'-deoxythymidine, was reported previously (G. V. Betageri, J. Szebeni, K. Hung, S. S. Patel, L. M. Wahl, M. Corcoran, and J. N. Weinstein, Biochem. Pharmacol. 40:867-870, 1990). Taken together, these observations suggest that inhibition of the salvage of competing physiological nucleosides may explain or contribute to the potentiating effect of dipyridamole on these antiviral dideoxynucleoside drugs. (+info)
Real-time nucleic acid sequence-based amplification assay to quantify changes in mitochondrial DNA concentrations in cell cultures and blood cells from HIV-infected patients receiving antiviral therapy.
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BACKGROUND: To study the clinical relevance of changes in mitochondrial DNA (mtDNA) in peripheral blood mononuclear cells (PBMCs) attributable to HIV infection and/or combination antiretroviral therapy (cART), a high-throughput molecular assay to quantify mtDNA is required. METHODS: We developed a quantitative real-time duplex nucleic acid sequence-based amplification assay in which both mtDNA and nuclear DNA are simultaneously amplified in 1 tube. The assay could accurately quantify mtDNA in a range of 15-1500 copies of mtDNA per 2 genomic copies with an intrarun variation of 11% and an interrun variation of 16%. We compared this real-time assay with the lactate/pyruvate ratios in fibroblasts incubated with glucose and exposed to zalcitabine. Additionally, we studied the effects of platelet contamination and the in vivo effects of cART on mtDNA in PBMCs from a small group of patients. RESULTS: Decreases in mtDNA preceded the increase in lactate/pyruvate ratios and vice versa when zalcitabine was eliminated from the culture. Platelets affected the mtDNA in PBMCs if >5 platelets per PBMC were present. Within 12 weeks, mtDNA increased and remained increased in PBMCs from patients on continuous treatment with zidovudine/lamivudine/indinavir therapy (P = 0.03), but increased if patients were switched to stavudine/didanosine therapy (P = 0.008). CONCLUSION: After drug exposure, the mtDNA assay can detect changes in mtDNA concentrations in cell lines and PBMCs, when properly controlled for platelet effects, earlier than traditional assays. (+info)