Risk Of Clinical Progression Research Articles

The Role of Adjuvant Hormonal Treatment after Surgery for Localized High-Risk Prostate Cancer: Results of a Matched Multiinstitutional Analysis

Introduction. To assess the role of adjuvant androgen deprivation therapy (ADT) in high-risk prostate cancer patients (PCa) after surgery. Materials and Methods. The analysis case matched 172 high-risk PCa patients with positive section margins or non-organ confined disease and negative lymph nodes to receive adjuvant ADT (group 1, n = 86) or no adjuvant ADT (group 2, n = 86). Results. Only 11.6% of the patients died, 2.3% PCa related. Estimated 5–10-year clinical progression-free survival was 96.9% (94.3%) for group 1 and 73.7% (67.0%) for group 2, respectively. Subgroup analysis identified men with T2/T3a tumors at low-risk and T3b margins positive disease at higher risk for progression. Conclusion. Patients with T2/T3a tumors are at low-risk for metastatic disease and cancer-related death and do not need adjuvant ADT. We identified men with T3b margin positive disease at highest risk for clinical progression. These patients benefit from immediate adjuvant ADT.

Predictors for response to intermittent androgen deprivation (IAD) in prostate cancer cases with biochemical progression after surgery

ObjectiveTo define characteristics of the first cycle of intermittent androgen deprivation (IAD) that would predict for outcomes in a long term follow-up. Material and methodsIn 1996 we started a prospective study of IAD for the treatment of biochemical progression (BP) after radical prostatectomy (RP) for prostate cancer (PC). The end-points of the trial were time to clinical progression (CP) and time to castration resistance PC (CRPC). Eighty-four cases were included in the study. In all cases, after an initial induction period, an acceptable nadir to switch from on-to-off-phase of IAD was considered to be a serum PSA < 1.0 ng/ml. MeasurementsAs possible predictors for time to CP and CRPC, we analyzed pretreatment parameters such as age, Gleason Score, serum PSA, testosterone, chromogranina A (CgA) levels, and characteristics from the first cycle of IAD. ResultsMean follow-up during IAD was 88.6 ± 16.7 months; 29.7% of patients developed CRPC and 14.2% of cases showed a CP with a mean time of 88.4 ± 14.3 months and 106.5 ± 20.6 months, respectively. At univariate and multivariate analysis, the PSA nadir during the first on-phase period and the first off-phase interval resulted in significant and independent predictors (P < 0.001) of the time to CRPC and CP. In particular for cases with a PSA nadir > 0.4 ng/ml and for those with an off-phase interval ≤ 24 weeks, the risk of CRPC and CP during IAD was 2.7–2.5 and 3.0–3.1 times that for patients with a PSA nadir ≤ 0.1 ng/ml and with an off-phase interval > 48 weeks, respectively. ConclusionsCases with BP after RP selected to IAD that show at the first cycle a PSA nadir ≤ 0.1 ng/ml and a off-phase interval ≥ 48 weeks may identify candidates who will experience better response to IAD treatments and delayed CP or CRPC development.

887 PROGNOSTIC PREDICTORS FOR TIME TO CLINICAL PROGRESSION AND CASTRATION RESISTANCE IN

You have accessJournal of UrologyProstate Cancer: Advanced1 Apr 2011887 PROGNOSTIC PREDICTORS FOR TIME TO CLINICAL PROGRESSION AND CASTRATION RESISTANCE IN Alessandro Sciarra, Stefano Salciccia, Andrea Alfarone, Susanna Cattarino, Alessandro Gentilucci, Ulderico Parente, and Vincenzo Gentile Alessandro SciarraAlessandro Sciarra Rome, Italy More articles by this author , Stefano SalcicciaStefano Salciccia Rome, Italy More articles by this author , Andrea AlfaroneAndrea Alfarone Rome, Italy More articles by this author , Susanna CattarinoSusanna Cattarino Rome, Italy More articles by this author , Alessandro GentilucciAlessandro Gentilucci Rome, Italy More articles by this author , Ulderico ParenteUlderico Parente Rome, Italy More articles by this author , and Vincenzo GentileVincenzo Gentile Rome, Italy More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.753AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The purpose of this analysis was to define characteristics of the first cycle of intermittent androgen deprivation (IAD) that would predict for outcomes in a long term follow-up. METHODS In 1996 we started a prospective study of IAD for the treatment of biochemical progression (BP) (PSA increase > 0.2 ng/ml) after radical prostatectomy (RP) for prostate adenocarcinoma (PC). The primary end-point of the trial was time to clinical progression (CP) but also time to castration resistance PC (CRPC). Eighty-four cases fulfilled the inclusion criteria and were included in the study. In all cases, after an initial induction period, an acceptable nadir to switch from on-to-off-phase of IAD was considered to be a serum PSA of less than 1.0 ng/ml. As possible predictors for time to CP and CRPC we analyzed pretreatment parameters such as age, Gleason Score, serum PSA, testosterone and Chromogranina A (CgA) levels and also characteristics from the first cycle of IAD. RESULTS Mean follow-up during IAD was 88.69 À 16.74 months; 29.77% of patients developed CRPC and 14.28% of cases showed a CP with a mean time of 88.40 À 14.34 months and 106.50 À 20.65 months respectively. At the univariate and multivariate analysis the PSA nadir during the first on-phase period and the first off-phase interval resulted significant and independent predictors (p<0.001) of the time to CRPC and CP. In particular for cases with a PSA nadir > 0.4 ng/ml and for those with an off-phase interval Ù 24 weeks, the risk of CRPC and CP during IAD was 2.7–2.5 and 3.0–3.1 times that for patients with a PSA nadir Ù 0.1 ng/ml and with an off-phase interval > 48 weeks respectively. The predictive value of these two parameters resulted significant also after adjusting for age, stage, Gleason score and PSA at diagnosis or at BP. CONCLUSIONS Cases with BP after RP selected to IAD that show at the first cycle a PSA nadir Ù 0.1 ng/ml and a off-phase interval ¡Ý 48 weeks, are the best candidate for long IAD treatments without the development of CRPC or CP. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e355 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Alessandro Sciarra Rome, Italy More articles by this author Stefano Salciccia Rome, Italy More articles by this author Andrea Alfarone Rome, Italy More articles by this author Susanna Cattarino Rome, Italy More articles by this author Alessandro Gentilucci Rome, Italy More articles by this author Ulderico Parente Rome, Italy More articles by this author Vincenzo Gentile Rome, Italy More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

IL-2 therapy: potential impact of the CD4 cell count at initiation on clinical efficacy--results from the ANRS CO4 cohort

We investigated why, despite its beneficial effect on the CD4 cell count, IL-2 therapy had no clinical benefit as shown in the ESPRIT and SILCAAT trials. We focused on subgroups of patients defined according to CD4 cell counts at baseline and over time to assess the threshold above which IL-2 therapy was no longer beneficial in a large cohort of HIV-1 infected patients. Within the French Hospital Database on HIV, a total of 953 IL-2-treated patients were compared with 27 750 IL-2-untreated patients, matched for the date of enrolment, sex, age, and the baseline CD4 cell count and plasma HIV-1 RNA level. The risk of clinical progression, defined as the occurrence of a new AIDS-defining event or death, was studied with multivariable Cox proportional hazards models and Poisson regression models. We found no clinical benefit in patients starting IL-2 with CD4 count ≥200 cells/mm(3) [hazard ratio (HR) =1.13; 95% confidence interval (CI), 0.81-1.57], while a benefit was observed in patients with CD4 count <200 cells/mm(3) (HR=0.64; 95% CI, 0.48-0.86). The observed benefit was due to the risk reduction in the 100-350/mm(3) stratum of updated CD4 cell counts (relative rate=0.30; 95% CI, 0.09-1.03). Higher CD4 cell counts at enrolment and shorter follow-up with low to intermediate CD4 cell counts may explain why IL-2 therapy had no observed clinical benefit in the SILCAAT study. Our findings suggest that the benefit of IL-2 is restricted to a narrow range of CD4 cell counts, arguing against the use of IL-2 in HIV infection to reduce the risk of clinical events.

Combination therapy—a strategy for BPH-related progression

A randomized controlled trial published in European Urology concludes that combination therapy with tamsulosin and dutasteride is superior to monotherapy with either of these therapies in reducing the risk of clinical progression of benign prostatic hyperplasia. This approach might prove an attractive option for men who have troublesome symptoms and wish to avoid surgery.

Detection of HIV drug resistance during antiretroviral treatment and clinical progression in a large European cohort study

To investigate the relationship between detection of HIV drug resistance by 2 years from starting antiretroviral therapy and the subsequent risk of progression to AIDS and death. Virological failure was defined as experiencing two consecutive viral loads of more than 400 copies/ml in the time window between 0.5 and 2 years from starting antiretroviral therapy (baseline). Patients were grouped according to evidence of virological failure and whether there was detection of the International AIDS Society resistance mutations to one, two or three drug classes in the time window. Standard survival analysis using Kaplan-Meier curves and Cox proportional hazards regression model with time-fixed covariates defined at baseline was employed. We studied 8229 patients in EuroSIDA who started antiretroviral therapy and who had at least 2 years of clinical follow-up. We observed 829 AIDS events and 571 deaths during 38,814 person-years of follow-up resulting in an overall incidence of new AIDS and death of 3.6 per 100 person-years of follow-up [95% confidence interval (CI):3.4-3.8]. By 96 months from baseline, the proportion of patients with a new AIDS diagnosis or death was 20.3% (95% CI:17.7-22.9) in patients with no evidence of virological failure and 53% (39.3-66.7) in those with virological failure and mutations to three drug classes (P = 0.0001). An almost two-fold difference in risk was confirmed in the multivariable analysis (adjusted relative hazard = 1.8, 95% CI:1.2-2.7, P = 0.005). Although this study shows an association between the detection of resistance at failure and risk of clinical progression, further research is needed to clarify whether resistance reflects poor adherence or directly increases the risk of clinical events via exhaustion of drug options.

Has Cytogenetic Evolution Any Prognostic Relevance in Myelodysplastic Syndromes (MDS)? A Study on 153 Patients.

Defining the incidence and the prognostic relevance of cytogenetic evolution (CE) in MDS, excluding any effect of the primary defect and other well-known prognostic variables, are the main goals of the present study which included 153 patients (pts) examined between January 1990 and December 2005. They were 73 females and 80 males with a median age of 60.5 years (inter-quartile, IQ, range:49.8-68.3). FAB, IPSS score, IPSS cytogenetic categories were applied to all pts, WHO to 142. On clinical diagnosis 94 pts presented an abnormal karyotype. Median follow-up was 45.2 months (IQ range:22.8-75.6). At the time of analyses 107pts (69.9%) are alive and 46 (30.0%) have died. A clinical progression (CP) occurred in 65 (42.4%) pts and a CE in 47 (30.7%). Median progression-free survival was 65.2 months (IQ range:16.6-not reached). When a Cox model analysed CE as a time-dependent variable predicting disease outcome, a true CE occurred in a total of 40 pts who presented a survival significantly shorter than that of pts without such an evolution (Hazard ratio, HR=7.1, p<0.000 [95% confid. intervals, CI=3.9-12.8]), death rates 47.5 (95% CI=30.3-74.4) versus 5.4 (95%CI=3.7-7.9). A bivariable analysis was applied in order to test whether the relevance of CE remained significant also when it was adjusted for other variables with a well-known impact on disease outcome. This investigation revealed that CE predicted survival independently of the presence of the primary defect (HR=6.6, p<0.000 [95%CI=3.6-12.0]), IPSS cytogenetic categories (HR=6.6, p<0.000 [95%CI=3.6-12.2]), FAB subtypes (HR=4.2, p<0.000 [95%CI=2.3-7.8]), WHO subtypes (HR=4.4, p<0.000 [95%CI=2.3-8.5]) and IPSS categories (HR=3.8, p<0.000 [95%CI=2.0-7.2]). No single secondary defect had a significant impact on survival. When considering CP, the 40 pts with CE presented a risk of disease progression higher than that of pts without CE (HR=35.8, p<0.000 [95%CI=20.6-62.1]), progression rates: 183.9 (95% CI=129.3-261.5) versus 7.3 (95%CI=5.2-10.3). The relevance of CE remained significant when it was adjusted for the presence of primary cytogenetic aberrations (HR=33.9, p<0.000, [95% CI=19.1-60.0]). CE impact was much more significant in pts without than in those with primary defects: HR=61.8 (p<0.000, [95%CI=18.0-212.5]) versus 21.2 (p<0.000, [95%CI=11.1-40.3]). Bivariable analyses revealed that the impact of CE remained significant in all IPSS cytogenetic categories (HR=32.8, p<0.0000 [95%CI=18.6-57.8]), FAB subtypes (HR=21.6, p<0.000 [95%CI=12.2-38.1]), WHO subtypes (HR=27.7, p<0.0000 [95%CI=14.6-52.8]) and IPSS categories (HR=27.3,p<0.0000 [95%CI=14.6-50.9]). Monosomy 7, del(7q) and del(17p) were the secondary defects significantly effecting the risk of disease progression (p<0.0000). In conclusion, in our series CE presented:i.i) an incidence of 30%;ii.ii) a significant impact on survival independently of the primary defect, FAB/WHO classifications, IPSS score and IPSS cytogenetic categories;iii.iii) a significant impact on the risk of CP independently of the primary defect, FAB/WHO classification, IPSS score and IPSS cytogenetic categories.In addition, monosomy 7, del(7q) and del(17p) were the secondary defects significantly effecting the risk of CP.

Is Moderate HIV Viremia Associated With a Higher Risk of Clinical Progression in HIV-Infected People Treated With Highly Active Antiretroviral Therapy

To assess the risk of clinical progression (CP) according to the duration of time spent without complete viral load (VL) suppression compared with that associated with periods of stably suppressed viremia in HIV-infected people who started highly active antiretroviral therapy (HAART) when previously naïve to antiretrovirals. A cohort study of patients having started HAART after enrollment in the Italian Cohort of Antiretroviral-Naive Patients (ICoNA) and being followed for at least 6 months. Person-years spent in different categories according to the VL level and the change in VL from the most recent value before the initiation of HAART were calculated. A multivariable Poisson regression model, including potential confounders, was constructed. A total of 3023 patients were studied. The overall rate of CP was 13.4 per 1000 person-years. Evidence for a higher risk of CP was observed for people with a current VL >10,000 copies/mL. For each year longer spent on HAART with a VL >100,000 copies/mL, a 5-fold increased risk was observed (relative risk [RR] = 5.34, 95% confidence interval [CI]: 2.83 to 1.08; P = 0.0001). An increased risk of CP in patients with current suppression <1.5 log10 copies/mL (RR = 2.34, 95% CI: 1.16 to 4.74; P = 0.02) and in those with no suppression or a VL higher than their set point (RR = 2.39, 95% CI: 1.17 to 4.89; P = 0.02) was observed compared with those with suppression of >3 log10 copies/mL, although it was not significant. Longer duration on HAART with a VL suppressed below set point seemed to confer protection against CP. Virologic failure to antiretroviral drugs is common. The risk of CP may remain low despite a low but detectable level of HIV viremia.

The CD4 lymphocyte count and risk of clinical progression

The CD4 lymphocyte count was identified as a key predictor of risk of AIDS defining diseases almost 20 years ago, early in the HIV epidemic. Several issues concerning its use to predict AIDS have arisen since. These include the difference between short and long-term prediction, the use of CD4 percentage compared with absolute counts, the impact of antiretroviral therapy on the predictive value of the CD4 count, the role relative to other markers such as viral load, the derivation of scores to predict AIDS diseases, the use of CD4 count as a surrogate endpoint, the role of the CD4 count nadir compared with the current value and the differential ability to predict different AIDS diseases. All the above issues have been clarified further and this process has continued through 2004 and 2005. These developments are briefly described in this review. The CD4 count remains the strongest short-term predictor of risk of AIDS so far identified in both treated and untreated patients and should continue to be a mainstay of monitoring for both untreated and treated patients.

CD4+Cell Count Increase Predicts Clinical Benefits in Patients with Advanced HIV Disease and Persistent Viremia after 1 Year of Combination Antiretroviral Therapy

The relationship between 12-month CD4(+) cell count response and clinical outcome (AIDS-defining event or death) in a subset of 228 patients with a human immunodeficiency virus load >400 copies/mL despite receiving combination antiretroviral therapy as part of a larger randomized trial was defined by use of Cox models. The 12-month CD4(+) cell count responses were divided into 5 categories, ranging from decrease or no change (29% of patients) to a > or =100-cell/mm(3) increase (27% of patients). There was a lower risk of clinical progression for each incremental increase in CD4(+) cell count response. A 25-cell/mm(3) increase in CD4(+) cell count was associated with a 21% reduction in the risk of an AIDS-defining event or death (P<.0001).

Response to Highly Active Antiretroviral Therapy at 6 Months and Long-Term Disease Progression in HIV-1 Infection

To compare the long-term prognostic significance of different definitions of immunologic and virologic responses to highly active antiretroviral therapy (HAART) at 6 months. This was a prospective study conducted in 68 French hospitals. HAART was initiated in 2236 protease inhibitor-naive patients included in the French Hospital Database on HIV. Multivariate Cox proportional hazard models measuring time from 6 months after starting HAART were used to compare the strength of the association between different definitions of immunologic and virologic responses at 6 months and subsequent progression to AIDS or death. The Akaike's Information Criteria were used to identify the most appropriate model. During a median follow-up of 58 months, 325 patients experienced an AIDS-defining event or died. The model that fitted best was the model in which the CD4 cell count and plasma HIV-1 RNA values attained at 6 months were considered. The risk of clinical progression at 5 years ranged from 7% (95% confidence interval [CI]: 4-10) in patients whose CD4 cell count at 6 months was >or=350 cells/microL and whose HIV-1 RNA concentration was <3 log10 copies/mL to 63% (95% CI: 52-75) in patients whose CD4 cell count at 6 months was <100 cells/microL and whose HIV-1 RNA concentration was >or=5 log10. Plasma HIV-1 RNA concentration and CD4 cell count should be taken into account independently when evaluating early response to treatment. The persistent impact of early response on clinical progression at 5 years emphasizes the major importance of the success of first-line HAART.

Impact of Newly Available Drugs on Clinical Progression in Patients with Virological Failure after Exposure to Three Classes of Antiretrovirals

To study the prognosis of HIV-infected patients with virological failure after exposure to three classes of antiretroviral drugs (ARVs). Cohort study. French Hospital Database on HIV. Patients previously exposed to at least two nucleoside reverse transcriptase inhibitors (NRTIs), two protease inhibitors and one non-NRTI, with viral load (/L) values of > 5000 copies/ml after the exposure criteria were met and a new treatment initiated between 1998 and 2001 with VL > 5000 copies/ml. Risk of new AIDS-defining-events (ADEs) or death from first introduction of a drug never used before occurring between 1998 and 2001 defined as baseline. The main baseline characteristics of the 1092 patients were: previous ADE in 49% of cases, median CD4 cell count 181 microl, median VL 4.9 log10 copies/ml, median duration of ARV therapy 5.0 years and previous exposure to a median of nine ARVs. The crude progression rates were 20.1/100 patient-years among patients included in 1998, 15.1 in 1999, 11.1 in 2000 and 8.6 in 2001. After adjustment for baseline characteristics, the calendar year of inclusion was associated with the risk of clinical progression (P < 0.001). When the types of newly available drugs used at baseline or during follow-up were introduced into the model, year of inclusion was no longer associated with the risk of clinical progression (P = 0.42), while exposure to amprenavir/r, lopinavir/r, abacavir or tenofovir was associated with a lower risk. The clinical prognosis of heavily pretreated patients experiencing virological failure improved between 1998 and 2001, mainly thanks to the use of newly available drugs with more favourable resistance profiles.

Clinical outcome after 4 years follow‐up of HIV‐seropositive subjects with incomplete virologic or immunologic response to HAART

The duration of the clinical, virologic, and immunologic response to HAART, is not well defined. In this observational multi-center study 2,143 patients were enrolled classified according to virologic suppression (<500 cp/ml) and immune recovery (>100 CD4+ cells/mul from baseline) at month 12 of HAART as complete responders, virologic only responders, immunologic only responders and non-responders. Kaplan Meyer curves, multivariate and politomous regression analysis were used. Complete responders patients were 781 (36.4%), immunologic only responders 441 (20.6%), virologic only responders 336 (15.7%), and non-responders 585 (27.3%). Using multivariate analysis, being antiretroviral-naive increased the probability of having both a virologic only or a complete response and reduced the probability of an immunologic only response (P < 0.001 for all tests). Older age was associated directly with a virologic only response and inversely associated with an immunologic only response (P = 0.027 and P = 0.035, respectively). Using politomous analysis, patients baseline HIV-RNA level more than 5 log cp/ml had a 1.9-fold higher probability of an immunologic response than of a complete response (P = 0.001). After 4 years, the clinical progression rate was six times greater in non-responders, 1.9 times greater in virologic only responders, and 2.3 times greater in immunologic only responders than for responders. However, patients with virologic only response or with immunologic only response had a significantly reduced risk for clinical progression than non-responders (P < 0.001). After 4 years of HAART, the risk of clinical progression in patients with immunologic only or virologic only response is low but still higher than in complete responder patients.

Microvessel density as a prognostic marker in bladder carcinoma: Correlation with tumor grade, stage and prognosis

The aim of our study was to evaluate tumor angiogenesis as a prognostic marker of transitional cell carcinoma of the bladder and to asses its relationship to established variables for survival and response to therapy. Microvessel density (MVD), a measure of tumor angiogenesis, were evaluated in 77 primary bladder cancers. Forty-three superficial carcinomas and 34 invasive carcinomas were analysed. Tumor specimens of all patients were obtained by transurethral resection (TUR) and all the tumors were transitional cell carcinomas. Twenty-two patients with invasive bladder cancer have undergone M-VEC chemotheraphy. The correlation between MVD and histopathological grade, tumor stage and prognosis was evaluated. MVD was identified by immunostaining of endothelial cells using anti-CD34 antibody. For statistical analysis Kruskal-Vallis, Mann-Whitney U and Fisher's exact tests were used. MVD was correlated with tumor grade, stage and prognosis. Significantly higher MVD was determined in invasive tumors than superficial tumors (p < 0.05). MVD increased with tumor grade and stage (p < 0.05). High MVD was correlated with the risk of clinical progression in both superficial and invasive bladder carcinomas (p < 0.05, p < 0.001 respectively). Invasive tumors with remission after M-VEC chemotheraphy had lower MVD than tumors with progression after M-VEC. These data demonstrate that MVD in bladder carcinoma correlates with grade, stage and malignant potential of the tumor. Quantification of tumor angiogenesis may allow selection of the type of treatment for bladder cancer patients.

Clinical, immunological and virological evolution in patients with CD4 T-cell count above 500/mm3: is there a benefit to treat with highly active antiretroviral therapy (HAART)?

To assess the clinical, immunological and virological evolution in HIV-1 infected patients with CD4 T-cell count above 500/mm3, a historical cohort of 202 untreated and 96 patients treated with HAART was longitudinally studied (median follow-up 36 months). Fourteen untreated and 2 treated patients experienced clinical progression (p = 0.09). The difference between baseline CD4 T-cell count and after 3 years, was -240/mm3 in the untreated group +19/mm3 in the HAART group (p < 10(-3)). A better immunological outcome was significantly associated with a HIV sexual contamination (p = 0.01), HAART (p = 0.01), high baseline CD4 T-cell count (p < 10(-3)) and low baseline HIV viral load (p = 0.01). In the HAART group, the incidence rate of antiretroviral modification due to tolerance difficulties was 0.23+/-0.36/patient year. A sustained undetectable HIV viral load was correlated with a low baseline HIV viral load (p = 0.003) and to be antiretroviral naive (p < 10(-3)). Thus, HAART provide a better immunological outcome in patients with high CD4 T-cell count. However, the CD4 decay slope after 3 years, the risk of therapeutic side-effects and the low risk of clinical progression do not support systematic treatment of those patients.

The effect of race/ethnicity on the outcome of highly active antiretroviral therapy for human immunodeficiency virus type 1-infected patients.

We performed a population-based cohort study to assess the impact of nonwhite origin on the outcome of highly active antiretroviral therapy (HAART) for a Danish cohort of human immunodeficiency virus (HIV)-infected patients. A total of 389 whites and 135 nonwhites started receiving HAART before 1 April 2001. After 1 year of treatment, 78% of nonwhites and 76% of whites achieved a virus load of <500 HIV RNA copies/mL. No major differences were found between the 2 groups with respect to achievement of a virus load of <500 copies/mL (relative risk [RR], 0.94; 95% confidence interval [CI], 0.74-1.18), risk of clinical progression (RR, 0.63; 95% CI, 0.32-1.24), or response measured by total CD4+ cell count. One year after fulfilling Danish recommendations for initiation of HAART, 91% of nonwhites and 93% of whites had started receiving HAART. Race and ethnic origin play no major role in the outcome associated with HAART if access to health care is free.

Progression to AIDS or Death as Endpoints in HIV Clinical Trials

Purpose: To assess progression to AIDS or death from month 4 after a protease inhibitor-containing regimen is initiated in a cohort of 1,281 patients. Method: We used Kaplan-Meier estimates of probability of clinical progression. RESULT: At month 4, most patients had an HIV-1 RNA plasma value below 500 copies/mL (78%) and a CD4 cell count above 300 cells/mm3 (62%). Starting from month 4, clinical progression at 1 and 2 years of follow-up was low (<3% at 1 year) in patients with HIV RNA <500 copies/mL or 500-10,000 copies/mL and in patients with CD4 between 50 and 300 cells/mm3 or >300 cells/mm3. A higher risk of clinical progression (10% at 1 year) was evidenced only in patients with poor response to antiretroviral therapy, that is, with CD4 <50 cells/mm3 or CD4 between 50-300 cells/mm3 together with an HIV RNA >10,000 copies/mL. Conclusion: In patients currently on antiretroviral therapy, clinical trials with clinical progression as endpoint are almost not feasible, except in patients with a poor immunovirological response to first- or second-line HAART.

The use of plasma HIV RNA as a study endpoint in efficacy trials of antiretroviral drugs.

To evaluate the utility of HIV RNA as an endpoint in antiretroviral efficacy studies. Data collected from antiretroviral efficacy trials were analyzed to explore relationships between clinical progression and the magnitude, nadir and duration of HIV RNA reductions. The proportion of patients suppressing HIV RNA below assay quantification, time to maximal virologic response, and loss of virologic response in relation to pretreatment characteristics were also analyzed. Analyses were conducted using data from individual antiretoviral efficacy trials or groups of trials that studied similar types of drug regimens and used similar HIV RNA assays. Treatment regimens were pooled for most analyses. Clinical progression was defined as the occurrence of an AIDS-defining event (essentially Centers of Disease Control criteria) or death. Treatment-induced reductions in HIV RNA approximating total assay variability of about 0.5 log10 copies/ml were associated with decreases in the risk of clinical progression. Larger and more sustained reductions in HIV RNA were directly associated with lower risks for disease progression. Lower initial HIV RNA reductions were associated with more durable HIV RNA suppression. For antiretoviral efficacy studies, plasma HIV RNA is a suitable study endpoint that is likely to predict a decreased risk for AIDS progression and death. Because greater and more sustained reductions in HIV RNA appear to confer greater reductions in clinical risk, maintaining maximal suppression of plasma HIV RNA, particularly below the limits of assay quantification, appears to be a rigorous benchmark for assessing the efficacy of antiretroviral regimens.

Effects of vitamin a on survival in patients with chronic myelogenous leukemia: A SWOG randomized trial

A national cooperative group trial was conducted in 153 patients with chronic myelogenous leukemia (CML) in chronic phase treated with oral pulse busulfan to determine if oral vitamin A can increase the time to blast crisis and enhance survival of patients. Patients diagnosed within 1 year and in the chronic phase of CML were randomized to receive oral pulse busulfan or the alkylator plus continuous oral vitamin A. Distributions of clinical progression and overall survival were estimated using the method of Kaplan and Meier. Associations of these endpoints with treatment and other patient characteristics were analyzed using the proportional hazards regression method of Cox. Both regimes were well tolerated. Patients in the busulfan plus vitamin A arm had somewhat longer durations of clinical progression-free survival (median 46 months) and overall survival (51 months) compared to those in the busulfan arm (medians 38 and 44 months). However, the differences were not statistically significant (one-tailed P = 0.11 for clinical progression-free survival, 0.081 for survival). After adjustment for significant factors identified in an additional exploratory multivariate analysis, risk of clinical progression or death was 53% ( P = 0.022) greater and risk of death 60% ( P = 0.014) greater among busulfan patients. Given the relatively large though non-significant difference between treatment arms, the limited statistical power of the study, and the likelihood that oral vitamin A may not be the most effective means of delivering retinoid therapy, we conclude that further investigation of retinoids in chronic phase CML is warranted.