Showing papers by "Joseph J. Eron published in 2002"

The safety, plasma pharmacokinetics, and antiviral activity of subcutaneous enfuvirtide (T-20), a peptide inhibitor of gp41-mediated virus fusion, in HIV-infected adults.

Abstract: Enfuvirtide (T-20) is a novel antiretroviral agent that blocks HIV-1 cell fusion. A 28-day randomized dose-comparison study was conducted to determine the safety, pharmacokinetics, and antiviral activity of enfuvirtide in 78 HIV-infected adults, most with extensive treatment experience. Patients received enfuvirtide, added to a failing regimen, either by continuous subcutaneous infusion (CSI: 12.5, 25, 50 or 100 mg/day) or by subcutaneous (SC) injection (50 or 100 mg twice daily). Dose-related decreases in viral load were observed, with a maximum mean reduction from baseline of 1.6 log10 copies/ml (p< 0.001) seen in the 100 mg bid SC group. Most responses diminished by 28 days. Plasma pharmacokinetics and antiviral responses were more consistent for SC injection than for CSI because of technical difficulties experienced with CSI. Injection site reactions were common but generally mild. These results indicate that enfuvirtide is a promising new therapeutic agent for HIV-infected patients, including those w...

Dual vs Single Protease Inhibitor Therapy Following Antiretroviral Treatment Failure: A Randomized Trial

Abstract: ContextManagement of antiretroviral treatment failure in patients receiving protease inhibitor (PI)–containing regimens is a therapeutic challenge.ObjectiveTo assess whether adding a second PI improves antiviral efficacy of a 4-drug combination in patients with virologic failure while taking a PI-containing regimen.DesignMulticenter, randomized, 4-arm trial, double-blind and placebo-controlled for second PI, conducted between October 1998 and April 2000, for which there was a 24-week primary analysis with extension to 48 weeks.SettingThirty-one participating AIDS (acquired immunodeficiency syndrome) Clinical Trials Units in the United States.ParticipantsA total of 481 human immunodeficiency virus (HIV)–infected persons with prior exposure to a maximum of 3 PIs and viral load above 1000 copies/mL.InterventionSelectively randomized assignment (per prior PI exposure) to saquinavir (n = 116); indinavir (n = 69); nelfinavir (n = 139); or placebo twice per day (n = 157); in combination with amprenavir, abacavir, efavirenz, and adefovir dipivoxil.Main Outcome MeasuresPrimary efficacy analysis involved the proportion with viral load below 200 copies/mL at 24 weeks. Other measures were changes in viral load and CD4 cell count from baseline, adverse events, and HIV drug susceptibility.ResultsOf 481 patients, 148 (31%) had a viral load below 200 copies/mL at week 24. The proportions of patients with a viral load below 200 copies/mL in the saquinavir, indinavir, nelfinavir, and placebo arms were 34% (40/116), 36% (25/69), 34% (47/139), and 23% (36/157), respectively. The proportion in the combined dual-PI arms was higher than in the amprenavir-plus-placebo arm (35% [112/324] vs 23% [36/157], respectively; P = .002). Overall, a higher proportion of nonnucleoside reverse transcriptase inhibitor (NNRTI)–naive patients had a viral load below 200 copies/mL compared with NNRTI-experienced patients (43% [115/270] vs 16% [33/211], respectively; P<.001). Baseline HIV-1 hypersusceptibility to efavirenz (≤0.4-fold difference in susceptibility compared with reference virus) was associated with suppression of viral load at 24 weeks to below 200 copies/mL (odds ratio [OR], 3.49; 95% confidence interval [CI], 1.62-7.33; P = .001), and more than 10-fold reduction in efavirenz susceptibility, with less likelihood of suppression at 24 weeks (OR, 0.28; 95% CI, 0.09-0.87; P = .03).ConclusionsIn this study of antiretroviral-experienced patients with advanced immunodeficiency, viral load suppression to below 200 copies/mL was achieved in 31% of patients with regimens containing 4 or 5 new drugs. Use of 2 PIs, being naive to NNRTIs, and baseline hypersusceptibility to efavirenz were associated with a favorable outcome.

Real-time, universal screening for acute HIV infection in a routine HIV counseling and testing population.

Abstract: ContextAcute human immunodeficiency virus (HIV) infection cannot be diagnosed by routine antibody tests and is rarely diagnosed in clinical practice. However, HIV nucleic acid–based testing is widely used to screen for antibody-negative acute infection among low-risk blood donors.ObjectiveTo assess the feasibility of screening in high-volume laboratories for acute and long-term HIV infection in a routine HIV testing population, in which HIV infection prevalence is low, using specimen pooling and HIV RNA reverse transcriptase-polymerase chain reaction (RT-PCR) tests.Design and SettingClinical diagnostic performance evaluation at a state-funded public health virology and serology laboratory.ParticipantsA total of 8505 consecutive individuals presenting for routine HIV counseling and testing during a total of 20 business days to simulate a month of testing in August and December 2001 at 110 publicly funded testing sites in North Carolina.Main Outcome MeasuresPrevalence of acute and long-term HIV infection. Serum specimens negative by HIV enzyme immunoassay (EIA) were screened in pools by an ultrasensitive HIV RNA RT-PCR test. Results for individual HIV RNA–positive specimens were reclassified as true or false according to results of confirmatory testing.ResultsOf the 8505 individuals screened, 8194 had not previously tested HIV positive and had sufficient serum to complete the testing protocol. Of those, 39 had long-term HIV infection (prevalence, 47.6 per 10 000 at-risk persons [95% confidence interval, 33.8-65.0 per 10 000]). Of the 8155 at-risk individuals whose antibody tests were negative, 5 were HIV RNA positive. Four of those had true-positive acute infection (prevalence, 4.9 per 10 000 [95% confidence interval, 1.3-12.5 per 10 000]). All 4 were women; 2 developed symptoms consistent with an acute retroviral syndrome in the week after testing. Screening all specimens required 147 HIV RNA tests. Overall specificity of the strategy was 0.9999.ConclusionsThese findings suggest the widespread diagnosis of acute HIV infections in a routine testing population is not only possible but feasible using specimen pooling and nucleic acid testing. These additional procedures may increase diagnostic yield by approximately 10% compared with conventional HIV antibody testing.

Safety and Antiviral Activity at 48 Weeks of Lopinavir/Ritonavir plus Nevirapine and 2 Nucleoside Reverse-Transcriptase Inhibitors in Human Immunodeficiency Virus Type 1-Infected Protease Inhibitor-Experienced Patients

Abstract: The safety and antiviral activity of lopinavir (Lpv), a protease inhibitor (PI) coformulated with ritonavir (Rtv) to enhance its pharmacokinetic properties, were evaluated in 70 patients with plasma human immunodeficiency virus type 1 (HIV-1) RNA levels of 1000-100,000 copies/mL on a first PI-containing regimen. Patients were randomized to substitute only the PI with Lpv/Rtv, 400/100 mg or 400/200 mg twice daily. On day 15, nevirapine (200 mg 2x/day) was added, and nucleoside reverse-transcriptase inhibitors were changed. Despite a >4-fold reduction in phenotypic susceptibility to the preentry PI in 63% of patients, mean plasma HIV-1 RNA levels declined by 1.14 log(10) copies/mL after 2 weeks of Lpv/Rtv. At week 48, 86% of subjects receiving treatment had plasma HIV-1 RNA levels of <400 copies/mL; 76% had levels <50 HIV-1 RNA copies/mL (intent-to-treat: 70% and 60%, respectively). Mean CD4 cell counts increased by 125 cells/muL. Three patients discontinued therapy for drug-related adverse events.

HIV Antigens Can Induce TGF-β1-Producing Immunoregulatory CD8+ T Cells

Abstract: HIV-infected individuals may progressively lose both HIV-specific and unrelated CTL responses despite the high number of circulating CD8+ T cells. In this study, we report that ∼25% of HIV+ donors produced TGF-β1 in response to stimulation with HIV proteins or peptides. The production of TGF-β1 was sufficient to significantly reduce the IFN-γ response of CD8+ cells to both HIV and vaccinia virus proteins. Ab to TGF-β reversed the suppression. We found the source of the TGF-β1 to be predominantly CD8+ cells. Different peptide pools stimulated TGF-β1 and IFN-γ in the same individual. The TGF-β1 secreting cells have distinct peptide specificity from the IFN-γ producing cells. This represents an important mechanism by which an HIV-specific response can nonspecifically suppress both HIV-specific and unrelated immune responses.

Gender difference in HIV RNA levels: a meta-analysis of published studies.

Abstract: Summary: Plasma HIV RNA copy number is a strong prognostic marker of progression to AIDS in antiretroviral-naive persons. Recent research suggests women have lower HIV RNA levels than comparable men. Because clinical care recommendations currently include HIV RNA thresholds as a guide to initiating antiretroviral therapy (ART), the authors undertook the present quantitative meta-analysis to explore the relation between gender and plasma HIV RNA levels. A gender difference in HIV RNA levels was observed in the CD4-unadjusted and -adjusted analyses. The summary estimate including only CD4-adjusted results with the lowest heterogeneity indicated that on average, women have 41% lower plasma HIV RNA levels than men (-.23 log10; 95% confidence interval [CI], -.16 to -.31 log10). Because numerous studies have found similar HIV disease progression rates in men and women, adjusted for CD4 but not HIV RNA, the present meta-analysis supports the use of lower HIV RNA thresholds in women than in men to guide initiation of ART. Given the patient characteristics in the original studies used in this meta-analysis, the results are most likely to apply to therapy-naive persons with CD4 lymphocyte counts >200 cells/mm3, a subgroup for whom HIV RNA levels may strongly influence the decision to initiate therapy.

Pharmacokinetic and Pharmacodynamic Investigation of Efavirenz in the Semen and Blood of Human Immunodeficiency Virus Type 1–Infected Men

Abstract: Therapeutic concentrations of antiretroviral agents in seminal plasma (SP) may reduce virus burden and influence sexual transmission of human immunodeficiency virus (HIV) type 1. This study compared the pharmacokinetic, pharmacodynamic, and dose responses of efavirenz (EFV) in SP versus those in blood plasma (BP). A total of 431 BP samples and 157 SP samples were obtained over a period of 40 days, from 9 EFV-naive men (i.e., men about to receive EFV for the first time) and from 12 EFV-experienced men (i.e., men already receiving EFV as part of an antiretroviral regimen). Overall, median EFV exposure in SP was 3.4% (range, 2.0%-5.0%) of that in BP. However, all EFV concentrations in SP were >/=40-fold higher than the wild-type IC(90) (IC(90)(WT)) for HIV-1. During the dosing interval, no single SPrcolon;BP EFV-concentration ratio was significantly predictive of the absolute measure of exposure in SP. By day 40, HIV-1 RNA in SP was undetectable in 8 (89%) of 9 EFV-naive men and remained undetectable in 10 (83%) of 12 EFV-experienced men. In SP, EFV reaches concentrations above the HIV-1 IC(90)(WT) throughout the dosing interval. EFV-containing regimens effectively suppress HIV-1 RNA in SP.

The Pharmacokinetics of Amprenavir, Zidovudine, and Lamivudine in the Genital Tracts of Men Infected with Human Immunodeficiency Virus Type 1 (AIDS Clinical Trials Group Study 850)

Abstract: The AIDS Clinical Trials Group Study 850 (ACTG 850) evaluated the penetration of zidovudine (ZDV), lamivudine (3TC), and amprenavir (APV), given alone and in combination with the 2 nucleoside analogues, into the male genital tract, because these factors may affect human immunodeficiency virus (HIV) type 1 suppression and transmission. Nineteen men receiving APV monotherapy and 12 men receiving triple therapy donated blood plasma (BP) and seminal plasma (SP) during therapy. Paired SP and BP were used to calculate compartmental concentration ratios. APV SP concentrations were consistently lower than BP concentrations, ZDV SP concentrations approximated BP concentrations early but became greater later in the dosing interval, and 3TC SP concentrations were substantially greater than BP concentrations throughout. Observed SP concentrations plotted with population BP concentration-time curves confirmed these findings, suggesting that passive diffusion (APV), slowed elimination (ZDV), and either active accumulation and/or inhibition of elimination (3TC) are responsible for SP concentrations of these agents. The antiretroviral effect of APV monotherapy was related to APV concentrations. The level of human immunodeficiency virus (HIV) type 1 shed from the male genital tract is likely to correlate with the risk of transmission associated with sexual contact with an infected man [1‐4]. The male genital tract is a separate compartment, isolated from the systemic circulation by anatomic and physiologic barriers (reviewed in [5]). Some antiretroviral agents that effectively suppress HIV-1 replication systemically

Analysis of virological efficacy in trials of antiretroviral regimens: drawbacks of not including viral load measurements after premature discontinuation of therapy.

Abstract: ObjectivesTo compare two analytic approaches to assess the virological effect of HAART according to the intention-to-treat (ITT) principle.MaterialData from 2318 patients enrolled in 10 randomised ...

Effects of formulation and dosing strategy on amprenavir concentrations in the seminal plasma of human immunodeficiency virus type 1-infected men.

Abstract: We compared seminal plasma pharmacokinetic data for the investigational amprenavir prodrug GW433908 with those for amprenavir and an amprenavir-ritonavir combination regimen. All 3 regimens resulted in detectable blood plasma and seminal plasma concentrations of amprenavir. The majority of these concentrations were greater than the plasma protein--corrected 50% inhibitory concentration for wild-type human immunodeficiency virus type 1.

Durability of Response to Treatment among Antiretroviral-Experienced Subjects: 48-Week Results from AIDS Clinical Trials Group Protocol 359

Abstract: The 24-week extension of AIDS Clinical Trials Group Protocol 359, a study of human immunodeficiency virus (HIV)‐infected, indinavir-experienced patients, was designed to study the durability of “salvage” treatment regimens. Patients received saquinavir in combination with either ritonavir or nelfinavir and, in addition, delavirdine, adefovir, or both. Patients who demonstrated a virologic response at weeks 12‐16 were eligible to continue therapy in the extension through week 48. Of the 105 eligible subjects who were enrolled in the extension, 86 (82%) completed 48 weeks, and 49 (57%) of those 86 had HIV RNA levels 500 copies/ mL at week 48. For these 86 subjects who completed 48 weeks, the median change in CD4 cell count from baseline was +72 cells/mm 3 . Greater body weight, higher CD4 cell count, and greater degree of phenotypic susceptibility to indinavir and saquinavir at baseline were significantly associated with durable virologic suppression. These results show that some patients who experience treatment failure can demonstrate durable virologic and immunologic responses with salvage antiretroviral regimens. Current treatment guidelines recommend starting therapy for human immunodeficiency virus (HIV) infection with 2 nucleoside analogue reverse-transcriptase inhibitors in combination with 1 or 2 protease inhibitors or a nonnucleoside analogue reversetranscriptase inhibitor [1, 2]. However, 20%‐63% of patients from clinical cohorts experience virologic treatment failure while receiving combination antiretroviral therapy [3‐7]. Recent prospective studies have attempted to identify strategies for treatment of the treatment-experienced patient [8‐13], but these studies have focused primarily on 8‐24-week virologic responses to treatment. The durability of virologic and immunologic re

Entry and Fusion Inhibitors: an Update

Abstract: radication of hiv has not been possible with currently available reverse transcriptase inhibitors and protease inhibitors; and multiclass drug-resistant mutants of hiv—along with a multitude of disabling and sometimes life-threatening side effects—are a growing threat. Thus, there is a great need for compounds that target non-protease and reverse transcriptase elements of the hiv lifecycle. Not only might such novel therapies increase the potency of initial hiv treatment, but they may also provide hope for patients who have exhausted current treatment options. This article, based on prn lectures delivered by Drs. Joseph Eron and Christine Hogan in January 2002, reviews one of the most promising areas of hiv drug development: inhibitors of hiv fusion and entry. As reviewed by both investigators, two fusion inhibitors targeting hiv’s gp41 envelope protein (T-20 and T-1249) continue to advance through clinical trials and have both received fast-track designations by the U.S. Food and Drug Administration. As for other entry inhibitors targeting cellular proteins in the earlier stages of development (e.g., inhibitors of CD4, CCR5, and CXCR4), Drs. Eron and Hogan noted some of the advances and setbacks that have occurred over the past few years.