Daniel Bettendorf

Prognostic Value of Baseline Human Immunodeficiency Virus Type 1 DNA Measurement for Disease Progression in Patients Receiving Nucleoside Therapy

Human immunodeficiency virus (HIV) type 1 DNA assay data were obtained at baseline from 111 HIV-1-positive subjects who were treated with nucleosides. Higher baseline DNA level, HIV-1 RNA level, and infectious titer were comparably associated with an increased hazard of disease progression (each P<.03). Only DNA level was significantly associated with survival (adjusted hazard ratio for 1 log(10) higher level, 3.99; 95% confidence interval, 1.44-11.09; P=.008).

Evidence of immune reconstitution in antiretroviral drug-experienced patients with advanced HIV disease

Highly active antiretroviral therapy (HAART) of HIV disease is associated with effective virologic control, immune reconstitution, and clinical improvements. This study addresses the potential for improvements in lymphocyte phenotype and virologic responses of HIV-infected persons with extensive experience with dual nucleoside reverse transcriptase (NRTI) treatment and advanced HIV disease after a change to a potent antiretroviral therapy (NRTI + protease inhibitor). The majority of participants achieved virologic success. There was a median rise in CD4+ lymphocytes of 99 cells/mm(3) by 48 weeks, because of an increase in memory CD4+ cells at 4 and 16 weeks, followed by a later increase in naive CD4+ cells between weeks 16 and 48. The proportion of activated, DR+ CD38+ CD8+ lymphocytes decreased during the 48 weeks of follow-up. The immunologic findings (increased memory and naive T cells and reduced activation levels) were significantly improved in participants with persistent suppression of viral replication over the 48 weeks of the study. Baseline HIV RNA copy number was lower (median, 14,784 copies/ml) in persons who responded virologically than in those not suppressing viral replication (median, 49,454 copies/ml). CD4+ cell counts above the median (125/mm(3)) at time 0 for the participants, was the only baseline immunologic marker significantly associated with viral suppression at week 48. Participants older than 40 years of age demonstrated less immunologic recovery. The results of the study show that patients with extensive experience with NRTIs respond both virologically and immunologically during the first 48 weeks of therapy with a potent antiretroviral regimen.

Performance characteristics of the Cavidi ExaVir viral load assay and the ultra-sensitive P24 assay relative to the Roche Monitor HIV-1 RNA assay.

BACKGROUND The Cavidi viral load assay and the ultra-sensitive p24 antigen assay (Up24 Ag) have been suggested as more feasible alternatives to PCR-based HIV viral load assays for use in monitoring patients infected with HIV-1 in resource-limited settings. OBJECTIVES To describe the performance of the Cavidi ExaVir Load™ assay (version 2.0) and two versions of the Up24 antigen assay and to characterize their agreement with the Roche Monitor HIV-1 RNA assay (version 1.5). STUDY DESIGN Observational study using a convenience sample of 342 plasma specimens from 108 patients enrolled in two ACTG clinical trials to evaluate the performance characteristics of the Up24 Ag assay using two different lysis buffers and the Cavidi ExaVir Load™ assay. RESULTS In analysis of agreement with the Roche assay, the Cavidi assay demonstrated superiority to the Up24 Ag assays in accuracy and precision, as well as sensitivity, specificity, and positive and negative predictive values for HIV-1 RNA ≥ 400, ≥ 1000 and ≥ 5000 copies/mL. Logistic performance curves indicated that the Cavidi assay was superior to the Up24 assays for viral loads greater than 650 copies/mL. CONCLUSIONS The results suggest that the Cavidi ExaVir Load assay could be used for monitoring HIV-1 viral load in resource-limited settings.

Association of Efavirenz Hypersusceptibility with Virologic Response in ACTG 368, a Randomized Trial of Abacavir (ABC) in Combination with Efavirenz (EFV) and Indinavir (IDV) in HIV-Infected Subjects with Prior Nucleoside Analog Experience

Abstract Purpose: To evaluate the association of efavirenz hypersusceptibility (EFV-HS) with clinical outcome in a double-blind, placebo-controlled, randomized trial of EFV plus indinavir (EFV+IDV) vs. EFV+IDV plus abacavir (ABC) in 283 nucleoside-experienced HIV-infected patients. Method and Results: Rates of virologic failure were similar in the 2 arms at week 16 (p = .509). Treatment discontinuations were more common in the ABC arm (p = .001). Using logistic regression, there was no association between virologic failure and either baseline ABC resistance or regimen sensitivity score. Using 3 different genotypic scoring systems, EFV-HS was significantly associated with reduced virologic failure at week 16, independent of treatment assignment. In some patients on the nucleoside-sparing arm, the nucleoside-resistance mutation L74V was selected for in combination with the uncommonly occurring EFV-resistance mutations K103N+L100I; L74V was not detected as a minority variant, using clonal sequence analysis, when the nucleoside-sparing regimen was initiated. Conclusion: Premature treatment discontinuations in the ABC arm and the presence of EFV-HS HIV variants in this patient population likely made it difficult to detect a benefit of adding ABC to EFV+IDV. In addition, L74V, when combined with K103N+L100I, may confer a selective advantage to the virus that is independent of its effects on nucleoside resistance.

HIV-1 RNA Levels and Antiretroviral Drug Resistance in Blood and Non-Blood Compartments from HIV-1- Infected Men and Women enrolled in AIDS Clinical Trials Group Study A5077

Background Detectable HIV-1 in body compartments can lead to transmission and antiretroviral resistance. Although sex differences in viral shedding have been demonstrated, mechanisms and magnitude are unclear. We compared RNA levels in blood, genital-secretions and saliva; and drug resistance in plasma and genital-secretions of men and women starting/changing antiretroviral therapy (ART) in the AIDS Clinical Trials Group (ACTG) 5077 study. Methods Blood, saliva and genital-secretions (compartment fluids) were collected from HIV-infected adults (≥13 years) at 14 United-States sites, who were initiating or changing ART with plasma viral load (VL) ≥2,000 copies/mL. VL testing was performed on all compartment fluids and HIV resistance genotyping on plasma and genital-secretions. Spearman rank correlations were used to evaluate concordance and Fisher’s and McNemar’s exact tests to compare VL between sexes and among compartments. Results Samples were available for 143 subjects; 36% treated (23 men, 29 women) and 64% ‘untreated’ (40 men, 51 women). RNA detection was significantly more frequent in plasma (100%) than genital-secretions (57%) and saliva (64%) (P<0.001). A higher proportion of men had genital shedding versus women (78% versus 41%), and RNA detection was more frequent in saliva versus genital-secretions in women when adjusted for censoring at the limit of assay detection. Inter-compartment fluid VL concordance was low in both sexes. In 22 (13 men, 9 women) paired plasma-genital-secretion genotypes from treated subjects, most had detectable resistance in both plasma (77%) and genital-secretions (68%). Resistance discordance was observed between compartments in 14% of subjects. Conclusions HIV shedding and drug resistance detection prior to initiation/change of ART in ACTG 5077 subjects differed among tissues and between sexes, making the gold standard blood-plasma compartment assessment not fully representative of HIV at other tissue sites. Mechanisms of potential sex-dependent tissue compartmentalization should be further characterized to aid in optimizing treatment and prevention of HIV transmission. Trial Registration ClinicalTrials.gov NCT00007488

Chronic Periglandular Inflammation on Prostate Needle Biopsy Does Not Increase the Likelihood of Cancer on Subsequent Biopsy

PURPOSE Recent literature suggests a role for chronic inflammation in the development of prostate cancer. We investigated the association of chronic periglandular inflammation on prostate needle biopsy with subsequent prostate cancer development and clinical disease features at presentation. METHODS Six hundred fifty-five patients were abstracted from a prostate/needle biopsy registry from Brigham and Womens Hospital presenting with prostate-specific antigen (PSA) > 4 ng/mL or abnormal digital rectal examination (DRE) between the years 1990 and 2004. DRE, PSA, PSA density, prostate volume, histology, and age were analyzed to identify clinical and pathologic associations with inflammation. Chronic inflammation was defined as an inflammatory cell infiltrate composed predominately of lymphocytes in a periglandular distribution. A subset of patients (n = 308) with follow-up biopsy results were used to identify if prostate inflammation predicted development of prostate cancer. RESULTS Modeling performed based on 4 biopsy samples revealed prostate volume (P < .001) and DRE (P = .02) as significant predictors of inflammation; DRE lost significance in models accounting for volume. Kaplan-Meier analysis demonstrated inflammation does not predict subsequent prostate cancer (P = .2). Cox models with the same endpoint show inflammation at initial biopsy (P = .3), inflammation at last biopsy (P = .4), and inflammation on any previous biopsy (P = .08) are not associated with time-to-positive biopsy. CONCLUSIONS Although inflammation on initial and subsequent biopsy does not predict prostate cancer in this cohort, we cannot dismiss its role in prostate cancer pathogenesis. Additional research is necessary to explore the relationship between prostate inflammation and prostate cancer development.