Biomedical subjects

R A Rode

Publications and source records attributed to R A Rode.

8 recordsLinked to original sources

PubMed2005

Adherence to antiretroviral therapy and its impact on clinical outcome in HIV-infected patients.

We analyse data on patient adherence to prescribed regimens and surrogate markers of clinical outcome for 168 human immunodeficiency virus infected patients treated with antiretroviral therapy. Data on patient adherence consisted of dose-timing measurements collected for an average of 12 months per patient via electronic monitoring of bottle opening events. We first discuss how such data can be presented to highlight suboptimal adherence patterns and between-patient differences, before introducing two novel methods by which such data can be statistically modelled. Correlations between adherence and subsequent measures of viral load and CD4+T-cell counts are then evaluated. We show that summary measures of short-term adherence, which incorporate pharmacokinetic and pharmacodynamic data on the monitored regimen, predict suboptimal trends in viral load and CD4+T-cell counts better than measures based on adherence data alone.

Antiretroviral Therapy, Highly Active↗

PubMed2005

Gender difference in HIV-1 RNA viral loads.

OBJECTIVES: To test and characterize the dependence of viral load on gender in different countries and racial groups as a function of CD4 T-cell count. METHODS: Plasma viral load data were analysed for > 30,000 HIV-infected patients attending clinics in the USA [HIV Insight (Cerner Corporation, Vienna, VA, USA) and Plum Data Mining LLC (East Meadow, NY, USA) databases] and the Netherlands (Athena database; HIV Monitoring Foundation, Amsterdam, Netherlands). Log-normal regression models were used to test for an effect of gender on viral load while adjusting for covariates and allowing the effect to depend on CD4 T-cell count. Sensitivity analyses were performed to test the robustness of conclusions to assumptions regarding viral loads below the lower limit of quantification (LLOQ). RESULTS: After adjusting for covariates, women had (nonsignificantly) lower viral loads than men (HIV Insight: -0.053 log(10) HIV-1 RNA copies/mL, P = 0.202; Athena: -0.005 log(10) copies/mL, P = 0.667; Plum: -0.072 log(10) copies/mL, P = 0.273). However, further investigation revealed that the gender effect depended on CD4 T-cell count. Women had consistently higher viral loads than men when CD4 T-cell counts were at most 50 cells/microL, and consistently lower viral loads than men when CD4 T-cell counts were greater than 350 cells/microL. These effects were remarkably consistent when estimated independently for the racial groups with sufficient data available in the HIV Insight and Plum databases. CONCLUSIONS: The consistent relationship between gender-related differences in viral load and CD4 T-cell count demonstrated here explains the diverse findings previously published.

Adult↗

PubMed2001

Identification of genotypic changes in human immunodeficiency virus protease that correlate with reduced susceptibility to the protease inhibitor lopinavir among viral isolates from protease inhibitor-experienced patients.

The association of genotypic changes in human immunodeficiency virus (HIV) protease with reduced in vitro susceptibility to the new protease inhibitor lopinavir (previously ABT-378) was explored using a panel of viral isolates from subjects failing therapy with other protease inhibitors. Two statistical tests showed that specific mutations at 11 amino acid positions in protease (L10F/I/R/V, K20M/R, L24I, M46I/L, F53L, I54L/T/V, L63P, A71I/L/T/V, V82A/F/T, I84V, and L90M) were associated with reduced susceptibility. Mutations at positions 82, 54, 10, 63, 71, and 84 were most closely associated with relatively modest (4- and 10-fold) changes in phenotype, while the K20M/R and F53L mutations, in conjunction with multiple other mutations, were associated with >20- and >40-fold-reduced susceptibility, respectively. The median 50% inhibitory concentrations (IC(50)) of lopinavir against isolates with 0 to 3, 4 or 5, 6 or 7, and 8 to 10 of the above 11 mutations were 0.8-, 2.7-, 13.5-, and 44.0-fold higher, respectively, than the IC(50) against wild-type HIV. On average, the IC(50) of lopinavir increased by 1.74-fold per mutation in isolates containing three or more mutations. Each of the 16 viruses that displayed a >20-fold change in susceptibility contained mutations at residues 10, 54, 63, and 82 and/or 84, along with a median of three mutations at residues 20, 24, 46, 53, 71, and 90. The number of protease mutations from the 11 identified in these analyses (the lopinavir mutation score) may be useful for the interpretation of HIV genotypic resistance testing with respect to lopinavir-ritonavir (Kaletra) regimens and may provide insight into the genetic barrier to resistance to lopinavir-ritonavir in both antiretroviral therapy-naive and protease inhibitor-experienced patients.

Drug Resistance↗

PubMed1998

The duration of viral suppression during protease inhibitor therapy for HIV-1 infection is predicted by plasma HIV-1 RNA at the nadir.

OBJECTIVE: To determine markers that are associated with the durability of virologic response to therapy with HIV protease inhibitors in HIV-infected individuals. DESIGN: This study encompassed two retrospective analyses of the duration of virologic response to protease inhibitor therapy. The first analysis included 29 patients receiving either monotherapy or combination therapy with the protease inhibitor ritonavir whose plasma HIV RNA levels rebounded from the point of greatest decline with mutations associated with resistance to ritonavir. The second analysis included a cohort of 102 patients who initially responded to randomized treatment with either monotherapy with ritonavir or combination therapy with ritonavir and zidovudine. METHODS: Durability of response was defined as the time from the initiation of therapy to the point at which plasma HIV RNA displayed a sustained increase of at least 0.6 log10 copies/ml from the nadir value. In the first analysis, durability of response was analyzed with respect to baseline HIV RNA, HIV RNA at the nadir, and the drop in HIV RNA from baseline to the nadir. In the second analysis, time to rebound was examined using Kaplan-Meier analysis, stratifying by either baseline HIV RNA or HIV RNA at the nadir. RESULTS: In both analyses, the durability of response was not highly associated with either baseline RNA or the magnitude of RNA decline from baseline. Instead, a strong relationship was observed between the durability of response and the nadir plasma HIV-1 RNA value (P < 0.01). The nadir in viral load was generally reached after 12 weeks of randomized therapy. CONCLUSIONS: Viral RNA determinations at intermediate timepoints may be prognostic of impending virologic failure of protease inhibitor therapy. Therapeutic strategies that allow intensification of initial antiretroviral regimens in the subset of patients with incomplete virological response before the emergence of high level resistance should be investigated.

Anti-HIV Agents↗

PubMed1991

The effect of pituitary suppression and the women's age on embryo viability and uterine receptivity.

OBJECTIVE: To examine the effect of pituitary suppression and the women's age on embryo viability and uterine receptivity. DESIGN: Retrospective analysis of 394 embryo transfers (ET) after in vitro fertilization (IVF). SETTING: Community hospital IVF program from 1986 to 1990. PATIENTS: Three groups were studied: women less than 40 years with pituitary suppression (group 1) and without pituitary suppression (group 2); women 40 years of age and older with pituitary suppression (group 3). INTERVENTIONS: Pituitary suppression was achieved in groups 1 and 3 with daily leuprolide acetate starting in the luteal phase; human menopausal gonadotropin and progesterone were given intramuscularly. MAIN OUTCOME MEASURES: Ongoing and multiple ongoing pregnancy rates (PRs) were compared in the three groups. A mathematical model of implantation was used to estimate embryo viability and uterine receptivity. RESULTS: Ongoing and multiple ongoing PRs per ET in group 1 (28.6% and 12.3%) were significantly higher than the corresponding rates in group 2 (16.9% and 2.4%) and in group 3 (16.9% and 3.4%). Implantation analysis revealed higher embryo viability without change in uterine receptivity with pituitary suppression (group 1 versus 2). Decrease in both embryo viability and uterine receptivity was noted in women greater than 40 (group 1 versus 3). CONCLUSIONS: (1) Pituitary suppression improved implantation outcome by increasing embryo viability with no change in uterine receptivity and was associated with a high multiple PR in women less than 40; (2) in women greater than 40 both embryo viability and, to a lesser extent, uterine receptivity were decreased; (3) transfer of a larger number of embryos in older patients may improve IVF outcome without excessive risk of multiple pregnancy.

Adult↗

PubMed1990

Enhancement of the in vitro and in vivo activities of clarithromycin against Haemophilus influenzae by 14-hydroxy-clarithromycin, its major metabolite in humans.

MICs of clarithromycin and its major human metabolite, 14-hydroxy-clarithromycin, for Haemophilus influenzae in combination were reduced two- to fourfold compared with the MICs of each compound alone. Serum reduced the MICs of the parent compound and metabolite two- to fourfold compared with the MICs in medium without serum. In serum spiked with clinically relevant concentrations of clarithromycin and 14-hydroxy-clarithromycin at a fixed ratio of 4:1, 15 of 16 strains (94%) were inhibited and killed by combinations containing 1.2 and 0.3 micrograms/ml, respectively. In time kill experiments, the combination of parent compound and metabolite at one-fourth and one-half of their individual MICs, respectively, reduced bacterial counts by greater than 5 log CFU. The postantibiotic effect of clarithromycin combined with 14-hydroxy-clarithromycin was twice that of clarithromycin when tested alone. When orally administered to gerbils with H. influenzae otitis media, the 14-hydroxy metabolite was significantly more active than clarithromycin in reducing bacterial counts from the middle ear. The in vivo activity of the two compounds in combination was synergistic or additive, depending on the level of H. influenzae present at the time treatment was initiated. Significant reductions in bacterial counts and increases in cure rates were observed when clarithromycin at 50 or 100 mg/kg of body weight was combined with 14-hydroxy-clarithromycin at 12 mg/kg or higher. Results from in vitro and in vivo combinations suggest that routine susceptibility tests and animal efficacy studies with clarithromycin alone may underestimate its potential efficacy against H. influenzae.

Animals↗

PubMed1988

Bioassay for A-56268 (TE-031) and identification of its major metabolite, 14-hydroxy-6-O-methyl erythromycin.

A-56268 is a new macrolide which is generally two-fold more potent than erythromycin. A new bioassay is described in which plasma samples are extracted with acetonitrile prior to bioassay. The concentration range for the assay is between 0.05-4.0 micrograms/ml, and the concentrations measured are within 6% of those measured by high-power liquid chromatography. An active metabolite which is as active as erythromycin was identified in the plasma. The plasma half-life and area under the plasma curve values of A-56268, as determined by bioassay, were significantly greater than those of erythromycin.

Biological Assay↗

PubMed1987

Regression analysis, proposed interpretative zone size standards, and quality control guidelines for a new macrolide antimicrobial agent, A-56268 (TE-031).

A-56268 is a 6-O-methyl derivative of erythromycin A which has a spectrum of activity similar to that of erythromycin and is 1 log2 dilution more potent than erythromycin against most organisms that have been tested. The correlation of zone size diameters and MICs of A-56268 for 461 strains of bacteria isolated from clinical specimens was investigated. Based on anticipated levels in human serum of 2 micrograms/ml, 15-microgram disks have been recommended with zone size standards of greater than or equal to 15 mm for susceptibility (MIC correlate, less than or equal to 2.0 micrograms/ml) and less than or equal to 11 mm for resistance (MIC correlate, greater than or equal to 8 micrograms/ml). Selection of these tentative breakpoints resulted in no very major errors (false susceptible), a major error (false resistant) rate of 0.22%, and an acceptable minor error (intermediate) rate of 2.82%. MIC ranges and zone diameter limits for quality control organisms used in the standardized agar dilution and disk diffusion susceptibility tests with A-56268 are given.

Clarithromycin↗