Biomedical subjects

J M Raboud

Publications and source records attributed to J M Raboud.

28 records · Page 2Linked to original sources

PubMed1997

Issues in the design of trials of therapies for subjects with human immunodeficiency virus infection that use plasma RNA level as an outcome.

Longitudinal plasma RNA levels were examined in 326 persons infected with human immunodeficiency virus (HIV), who were participating in 4 clinical trials and 1 observational study. Variations in plasma RNA levels among individuals were analyzed, and correlations were made of replicate and longitudinal measurements, plasma RNA levels, CD4 cell counts, and plasma RNA levels at enrollment. Sample sizes were calculated for detection of differences between treatment groups in mean plasma RNA level at one time point, the average change over time, and the area under the curve. On the basis of study findings, study eligibility criteria should specify a minimum plasma RNA level at least as high as the expected size of the treatment effect, and all longitudinal data should be used when determining the effect of treatment on plasma RNA level. Duplicating plasma RNA levels resulted in a decrease in the required sample size of 14%-41%.

Anti-HIV Agents↗

PubMed1997

Meta-analysis of five randomized controlled trials comparing continuation of zidovudine versus switching to didanosine in HIV-infected individuals.

A meta-analysis of the original data from 2411 patients in the ACTG 116A, ACTG116B/117, ACTG175, BMS010 and CTN002 trials was conducted to improve the estimate of the effect of switching from zidovudine to didanosine on rates of clinical progression, to better quantify the rates of neurological events (including AIDS dementia and peripheral neuropathy) and to examine the effects of switching from zidovudine to didanosine among women and racial subgroups. In total, 1012 patients received zidovudine therapy, 557 received high-dose didanosine and 842 received didanosine. The median duration of follow-up was 15 months. Ninety-one percent of patients were male, 78% were white, mean age was 36.5 years. The median CD4 count was 195 cells/mm3 (range: 0-762) and the median duration of prior zidovudine therapy was 14 months (range: 0.1-94). There were 336 deaths and 686 new AIDS-defining illnesses (ADIs) or deaths. After stratification by study and adjusting for baseline CD4 count and presence of an AIDS diagnosis prior to baseline, the relative risks of death associated with switching from zidovudine to high-dose didanosine or to didanosine were 0.94 (P = 0.64) and 0.77 (P = 0.07), respectively. The relative risks of a new ADI or death associated with switching from zidovudine to high-dose didanosine and didanosine were 0.78 (P = 0.01) and 0.66 (P = 0.0001), respectively. There were 21 documented cases of AIDS dementia complex (ADC) during the entire follow-up period. The rates per 100 person years of follow-up were 0.70, 0.65 and 0.41 for the zidovudine, high-dose didanosine and didanosine arms, respectively. There were no significant differences in risks of ADC between treatment arms (zidovudine versus high-dose didanosine: P = 0.30, zidovudine versus didanosine: P = 0.97, didanosine versus high-dose didanosine: P = 0.41). Our data confirm a clinical benefit and CD4 increase associated with a switch from zidovudine to didanosine therapy. No statistical differences were detected between doses of didanosine with respect to survival or progression to a new ADI or death. Furthermore, there was no statistical difference in the frequency of ADC between treatment arms.

AIDS Dementia Complex↗

PubMed1996

Impact of missing data due to dropouts on estimates of the treatment effect in a randomized trial of antiretroviral therapy for HIV-infected individuals. Canadian HIV Trials Network A002 Study Group.

PURPOSE: To evaluate the impact of missing data due to nonrandom dropout on estimates of the effect of treatment on the CD4 count in a clinical trial of antiretroviral therapy for HIV infected individuals. METHODS: The effect of treatment on CD4 counts in a recent study of continued ZDV versus ddI in HIV-infected individuals was estimated from the observed data and after imputing missing CD4 counts for patients who dropped out of the study. Imputation methods studied were (a) carrying forward the last observed CD4 count, (b) predicting missing CD4 counts from regression models, and (c) assuming that CD4 counts of patients who dropped out declined at a rate of 100 cells per year. RESULTS: Of the 245 patients enrolled in the study, 52% completed the planned 48 weeks of follow-up. Patients with lower CD4 counts were more likely to drop out of the study (RR = 1.77; p = 0.0001). Patients receiving ZDV had a greater tendency to drop out than patients receiving ddI (p = 0.07). Mean CD4 counts calculated after imputing missing data were lower than those obtained from the observed data at all follow-up times for both treatment groups. Imputing CD4 counts with regression models yielded higher estimates of the effect of treatment than were obtained using the observed data. CONCLUSION: Missing outcome data due to dropouts can result in an underestimation of the treatment effect and overly optimistic statements about the outcome of participants on both treatment arms due to the selective dropout of participants with lower or decreasing CD4 counts. When there are significant dropout rates in randomized trials, imputation is a useful technique to assess the range of plausible values of the treatment effect.

Antiviral Agents↗

PubMed1996

Variation in plasma RNA levels, CD4 cell counts, and p24 antigen levels in clinically stable men with human immunodeficiency virus infection.

Short-term variability in CD4 cell counts, plasma RNA levels, and p24 antigenemia was measured in clinically stable men with human immunodeficiency virus infection. Blood samples were obtained three times in each of 2 weeks 4 weeks apart. Differences between duplicate assays were considered to be due to technical factors; variation among visits was attributed to physiologic factors. Median enrollment values of CD4 cell counts, plasma RNA levels, and immune complex-dissociated (ICD) p24 antigenemia were 400 cells/mm3, 3.4 log10 copies/mL, and 38 pg/mL, respectively. Median absolute differences between duplicate CD4 cell counts, plasma RNA levels, and ICD p24 antigen were 16 cells/mm3, 0.21 log10 copies/mL, and 9.3 pg/mL. Median intraindividual ranges were 119 cells/mm3, 0.83 log10 copies/mL, and 18 pg/mL. Above 500 copies/mL, plasma RNA levels have a variability of 0.5 log10; the test is unreliable below this level.

CD4 Lymphocyte Count↗

PubMed1995

Effect of thromboplastin and coagulometer interaction on the precision of the International Normalised Ratio.

AIMS: To examine the magnitude of thromboplastin and coagulometer interactions on the precision of International Normalised Ratio (INR) values when the manufacturers' recommended instrument specific International Sensitivity Index (ISI) values are adopted for the INR calculation. METHODS: The variability of INR values obtained from four automated phototopical coagulometers frequently used in North American laboratories was studied. When used with five commercial thromboplastins of moderate to high sensitivity (ISI values 0.92-1.97), 20 prothrombin time results were generated for each of a population of 98 patients on established warfarin treatment. RESULTS: The mean INR values of the patients ranged from 2.05 to 2.81, depending on which reagent/coagulometer combination was used. Within patient variation increased as the median INR value increased. The mean coefficient of variation of within patient INR values was 10%; the mean coefficient of variation of the prothrombin time results in seconds and prothrombin time ratio were 21 and 18%, respectively. CONCLUSIONS: There was considerable bias in the estimated ISI values of the thromboplastins compared with the manufacturers' instrument specific ISI value. Despite this apparent imperfection, our study clearly showed that the INR is preferable to other prothrombin time reporting formats for assessing the degree of anticoagulation for patients on warfarin treatment.

Adult↗

PubMed1995

Quantification of the variation due to laboratory and physiologic sources in CD4 lymphocyte counts of clinically stable HIV-infected individuals.

We have conducted a study to quantify the amount of variation in the CD4 lymphocyte counts of HIV-infected individuals due to laboratory and physiological factors. Thirty HIV-infected male volunteers had blood drawn on six occasions: three times in each of 2 weeks, 4 weeks apart. Two tubes of blood were drawn at each visit, and duplicate measurements were obtained from one of the tubes of blood. Differences between duplicate measurements from a single tube of blood and between CD4 counts obtained from two tubes of blood drawn on the same day were attributed to laboratory factors. Differences between CD4 counts obtained on different days were attributed to a combination of laboratory factors and physiologic factors, which included the effects of exercise, tobacco, and the consumption of alcohol and caffeine. The mean absolute CD4 count at the first visit was 450 (range 86-1,081). The short-term coefficient of variation of CD4 count was 13.7 (95% CI: 12.9, 14.6). Physiologic and laboratory factors accounted for 85% and 15% of the variation in CD4 counts, respectively. Variation in the absolute white blood cell count, lymphocyte percentage, and CD4 percentage accounted fo 52%, 29%, and 19% of the physiologic variation in CD4 counts, respectively. Our results confirm a high degree of short-term variability of CD4 counts among HIV-infected individuals, which can be largely attributed to physiological factors. This variability can be minimized more effectively by repeating CD4 counts over time than by repeating measurements at a single visit.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1995

Variability in leukocyte subset measurements among five laboratories in Vancouver.

Cell counts and percentages of CD4 are widely used in the prognostic and clinical management of HIV-infected patients, and as surrogate outcomes in clinical trials involving HIV-infected individuals. Considerable variability in CD4 counts has been documented due to physiologic and methodologic factors. While studies of variability of CD4 counts among American and French laboratories have been reported in the literature, no published data are available for Canadian laboratories. This paper describes the results of a study to determine the variability of leukocyte subsets among 5 laboratories in Vancouver, British Columbia. Samples were collected in a prospective fashion from 52 HIV-negative patients from July 1991 to November 1993. Coefficients of variation (CV) were calculated for leukocyte subset percentages and absolute cell counts among laboratories. Our results demonstrate that the variability in leukocyte subsets among 5 Vancouver laboratories was lower than or comparable with published findings. The variability remained stable over the time period of the study, although 4 of the 5 laboratories participated in quality assurance programs. This suggests a plateau in the impact of this program. Since the variability among laboratories is less than the variability attributable to physiologic factors, further research efforts to reduce this variability should focus on physiologic sources.

British Columbia↗

PubMed1993

Ongoing high-risk sexual behaviors in relation recreational drug use in sexual encounters. Analysis of 5 years of data from the Toronto Sexual Contact Study.

The current study investigated the association between the use of recreational drugs at the time of sexual activity and high-risk sexual behavior in a Toronto cohort of 249 homosexual and bisexual men over a 5-year period commencing in 1984 to 1985 and concluding in 1989 to 1990. The main analysis was based on a total of 2536 visits. Univariate and multivariate Liang-Zeger regression models were used to relate the log of the sexual activity score (SARS) to the independent variables over the 20 follow-up visits while controlling for intercorrelations between variables from the same respondent. We found that there was a significant decline, over time, in the sexual activities that pose a higher risk of infection with human immunodeficiency virus. Recreational drugs still appear to be playing an important role in the continuation of higher-risk sexual activities. The use of poppers in conjunction with sex is a strong predictor of high-risk activity, as is use of alcohol and marijuana in conjunction with sex. Also, simultaneously strongly associated with higher-risk score is the Centers for Disease Control classification II. More emphasis needs to be placed on educating the population about the potential risks of combining reactional drugs with sexual activity.

Acquired Immunodeficiency Syndrome↗

PubMed1993

Clinical correlates of in vitro HIV-1 resistance ot zidovudine. Results of the Multicentre Canadian AZT Trial.

OBJECTIVE: To describe the rate of development of in vitro HIV resistance to zidovudine (ZDV) and its prognostic implications within the Multicentre Canadian AZT Trial (MCAT). METHODS: HIV-infected subjects in Centers for Disease Control (CDC) stages IIB, III and IVC-2 with CD4 cell counts > 270 x 10(6)/l were treated with ZDV as part of a dose-range study. Participating volunteers underwent prospective clinical and laboratory evaluations at regular intervals. Viral cultures and sensitivity testing were performed every 12 weeks in a predefined subset of 50 volunteers. An isolate was designated ZDV-resistant if it had a median inhibitory concentration (IC50) for ZDV at least 50-fold higher than that of virus isolated from the same subject before initiation of antiviral chemotherapy. The relationship between resistance and subsequent disease progression was studied using the Mantel and Byar method, for which, at each instance of disease progression, 2 x 2 tables classifying progression versus resistance status were constructed. The observed number of progressions was compared with that expected under the null hypothesis using Mantel-Haenszel methods adjusted for baseline CD4:CD8 ratio. RESULTS: The Kaplan-Meier estimate for the cumulative development of in vitro resistance was 64% [95% confidence interval (CI), 41-78] at 180 weeks. Baseline CD4:CD8 ratio was negatively associated (P = 0.10) with the subsequent development of resistance (proportional hazard, 0.44; 95% CI, 0.17-1.10). After adjusting for baseline CD4:CD8 ratio, the numbers of observed and expected progressions following the development of resistance were 15 and 7.6, respectively (P = 0.008). A similar relative risk of progression between resistant and non-resistant states was found in the two CD4:CD8 strata; observed and expected progressions were 4 and 2.3 and 11 and 5.2 in the high and low CD4:CD8 strata, respectively. CONCLUSIONS: In vitro resistance to ZDV developed in 64% of subjects after 180 weeks of ZDV therapy. Lower CD4:CD8 ratio at baseline was associated with faster development of resistance. In addition, the development of resistance was found to be a marker of subsequent disease progression. This association persisted after adjustment for baseline CD4:CD8 ratio. Whether in vitro resistance to ZDV is merely a surrogate marker or a determinant of disease progression remains to be established.

Adult↗

PubMed1993

Combining pooling and alternative algorithms in seroprevalence studies.

Data from two seroprevalence studies and one comparative study of confirmatory algorithms were used to compare the costs and sensitivities of six algorithms for determining seropositivity to human immunodeficiency virus (HIV). We evaluated confirmatory strategies by using the CBC Recombigen HIV enzyme immunoassay (EIA; Cambridge BioScience, Worcester, Mass.) and immunoblotting followed by radioimmunoprecipitation assay to confirm indeterminate immunoblotting results with and without pooling of samples during screening. The least expensive algorithm was that in which sera were pooled during screening and EIA was used to confirm positive test results. The cost savings associated with this confirmatory test were greater when the prevalence of HIV infection was higher. Savings from pooling of sera for screen testing diminished as HIV prevalence increased. The sensitivity and specificity of EIA with respect to immunoblotting and radioimmunoprecipitation assay were estimated to be 0.9992 and 0.9977, respectively. We found that the implementation of pooling during screening and the use of EIA as the confirmatory test do not affect the statistical reliability of estimates of seropositivity but do result in considerable cost savings.

Algorithms↗