A Pooled Analysis of Eight Clinical Studies Suggests a Link Between Influenza-Like Symptoms and Pharmacodynamics of the Toll-Like Receptor-7 Agonist Vesatolimod.

Introduction: Vesatolimod is a Toll-like receptor-7 (TLR7) agonist in clinical development as part of a combination regimen for human immunodeficiency virus (HIV) cure. Influenza-like symptoms associated with TLR7-mediated immune activation have been reported in clinical trials of vesatolimod. Therefore, a broader understanding of the safety profile of vesatolimod and association with dose and mechanism of action will help inform future clinical studies.

A Phase 1/2 Randomized, Placebo-Controlled Trial of Romidespin in Persons With HIV-1 on Suppressive Antiretroviral Therapy.

Background: Romidepsin (RMD) is a histone deacetylase inhibitor reported to reverse HIV-1 latency. We sought to identify doses of RMD that were safe and induced HIV-1 expression.

Methods: Enrollees had HIV-1 RNA <40 copies/mL on antiretroviral therapy.

Vesatolimod, a Toll-like Receptor 7 Agonist, Induces Immune Activation in Virally Suppressed Adults Living With Human Immunodeficiency Virus-1.

Background: Treatment with vesatolimod, an investigational, oral, toll-like receptor 7 (TLR7) agonist, leads to sustained viral remission in some non-human primates when combined with anti-envelope antibodies or therapeutic vaccines. We report results of a Phase Ib study evaluating safety, pharmacokinetics, and pharmacodynamics of vesatolimod in adults living with human immunodeficiency virus (HIV)-1.

Methods: In this double-blind, multicenter, placebo-controlled trial, participants on antiretroviral therapy with screening plasma HIV-1 RNA levels <50 copies/mL were randomized (6:2) to receive 6-10 doses of vesatolimod (1-12 mg) or matching placebo orally every other week in sequential dose-escalation cohorts.

Impact of HLA Class I Alleles on Timing of HIV Rebound After Antiretroviral Treatment Interruption.

Background: Identifying host determinants associated with HIV reservoir size and timing of viral rebound after an analytic treatment interruption (ATI) is an important step in the search for an HIV functional cure. We performed a pooled analysis of 103 participants from 4 AIDS Clinical Trials Group ATI studies to identify the association between HLA class I alleles with HIV reservoir size and viral rebound timing.

Methods: Total HIV DNA and cell-associated HIV RNA (CA-RNA) were quantified in pre-ATI peripheral blood mononuclear cell samples, and residual plasma viremia was measured using the single-copy assay.

Taking Control: The Efficacy and Durability of a Peer-Led Uncertainty Management Intervention for People Recently Diagnosed With HIV.

HIV creates substantial uncertainty for people infected with the virus, which subsequently affects a host of psychosocial outcomes critical to successful management of the disease. This study assessed the efficacy and durability of a theoretically driven, one-on-one peer support intervention designed to facilitate uncertainty management and enhance psychosocial functioning for patients newly diagnosed with HIV. Using a pretest-posttest control group design, 98 participants received information and training in specific communication strategies (e.

StudySearch: a web-based application for posting and searching clinical research studies.

Participant accrual into research studies is critical to advancing clinical and translational research to clinical care. Without sufficient recruitment, the purpose of any research study cannot be realized; yet, low recruitment and enrollment of participants persist. StudySearch is a web-based application designed to provide an easily readable, publicly accessible, and searchable listing of IRB-approved protocols that are accruing study participants.

Brief Report: Relationship Among Viral Load Outcomes in HIV Treatment Interruption Trials.

Viral load (VL) rebound timing and set point were analyzed in 235 participants undergoing analytic treatment interruption (ATI) in 6 AIDS Clinical Trials Group studies. There was no significant association between rebound timing and ATI VL set point for those who rebounded ≤12 weeks. VL set points were lower in participants with rebound >12 weeks (P < 0.

The size of the expressed HIV reservoir predicts timing of viral rebound after treatment interruption.

Objectives: Therapies to achieve sustained antiretroviral therapy-free HIV remission will require validation in analytic treatment interruption (ATI) trials. Identifying biomarkers that predict time to viral rebound could accelerate the development of such therapeutics.

Design: A pooled analysis of participants from six AIDS Clinical Trials Group ATI studies to identify predictors of viral rebound.

Comparison of the metabolic effects of ritonavir-boosted darunavir or atazanavir versus raltegravir, and the impact of ritonavir plasma exposure: ACTG 5257.

Background: Metabolic effects following combination antiretroviral therapy (cART) vary by regimen type. Changes in metabolic effects were assessed following cART in the AIDS Clinical Trials Group (ACTG) A5257 study, and correlated with plasma ritonavir trough concentrations (C24).

Methods: Treatment-naive adult subjects were randomized to ritonavir-boosted atazanavir or darunavir, or raltegravir-based cART.

Impact of chemotherapy for HIV-1 related lymphoma on residual viremia and cellular HIV-1 DNA in patients on suppressive antiretroviral therapy.

The first cure of HIV-1 infection was achieved through complex, multimodal therapy including myeloablative chemotherapy, total body irradiation, anti-thymocyte globulin, and allogeneic stem cell transplantation with a CCR5 delta32 homozygous donor. The contributions of each component of this therapy to HIV-1 eradication are unclear. To assess the impact of cytotoxic chemotherapy alone on HIV-1 persistence, we longitudinally evaluated low-level plasma viremia and HIV-1 DNA in PBMC from patients in the ACTG A5001/ALLRT cohort on suppressive antiretroviral therapy (ART) who underwent chemotherapy for HIV-1 related lymphoma without interrupting ART.

The design of single-arm clinical trials of combination antiretroviral regimens for treatment-naive HIV-infected patients.

Single-arm clinical trials are useful to evaluate antiretroviral regimens in certain populations of HIV-infected treatment-naive patients for whom a randomized controlled trial is not feasible or desirable. They can also be useful to establish initial estimates of efficacy and safety/tolerability of novel regimens to inform the design of large phase III trials. In this article, we discuss key design considerations for such single-arm studies.

Polymorphism in glutamate cysteine ligase catalytic subunit (GCLC) is associated with sulfamethoxazole-induced hypersensitivity in HIV/AIDS patients.

Background: Sulfamethoxazole (SMX) is a commonly used antibiotic for prevention of infectious diseases associated with HIV/AIDS and immune-compromised states. SMX-induced hypersensitivity is an idiosyncratic cutaneous drug reaction with genetic components. Here, we tested association of candidate genes involved in SMX bioactivation and antioxidant defense with SMX-induced hypersensitivity.

HIV and asthma, is there an association?

Objective: To evaluate whether asthma and airway hyper-responsiveness are associated with HIV infection.

Methods: We reviewed the literature on HIV-associated pulmonary diseases, pulmonary symptoms, and immune changes which may play a role in asthma. The information was analyzed comparing the pre-HAART era to the post-HAART era data.

Human N-acetyltransferase 1 *10 and *11 alleles increase protein expression through distinct mechanisms and associate with sulfamethoxazole-induced hypersensitivity.

Objectives: N-acetyltransferase 1 (NAT1) metabolizes drugs and environmental carcinogens. NAT1 alleles *10 and *11 have been proposed to alter protein level or enzyme activity compared with wild-type NAT1 *4 and to confer cancer risk, through uncertain pathways. This study characterizes regulatory polymorphisms and underlying mechanisms of NAT1 expression.

Phase I/II trial of the anti-HIV activity of mifepristone in HIV-infected subjects ACTG 5200.

Background: Mifepristone is a glucocorticoid receptor inhibitor shown in vitro to have anti-HIV activity and anti-simian immunodeficiency virus activity in a macaque model. A phase I/II trial was performed to assess the drug's safety and anti-HIV activity.

Methods: A 28-day double-blind, placebo-controlled trial of mifepristone at doses of 75 mg, 150 mg, and 225 mg given daily was conducted in HIV+ persons with CD4+ lymphocyte counts >or=350 cells per cubic millimeter who had no recent antiretroviral therapy.

No evidence for decay of the latent reservoir in HIV-1-infected patients receiving intensive enfuvirtide-containing antiretroviral therapy.

Human immunodeficiency virus type 1 (HIV-1) persists in a latent reservoir of infected resting memory CD4 cells in patients receiving antiretroviral therapy. We assessed whether multitarget therapy with enfuvirtide, 2 reverse-transcriptase inhibitors, and a ritonavir-boosted protease inhibitor leads to decay of this reservoir. Nineteen treatment-naive patients initiated this regimen; 9 experienced virologic suppression and continued enfuvirtide-containing therapy for at least 48 weeks.

HIV testing outside of the study among men who have sex with men participating in an HIV vaccine efficacy trial.

Objectives: Participants who obtain an HIV test outside of an HIV vaccine efficacy trial could potentially unblind themselves which could result in differential behavior change and loss to follow-up based on assignment status. In a reanalysis of the VaxGen VAX004 data, the objectives were to determine: 1) the proportion of participants who were tested for HIV outside of the study (despite instructions not to do this) and reasons why; 2) demographic and risk factors associated with reported testing outside of the study; and 3) if outside testing was related to participant loss to follow-up.

Methods: Analyses were restricted to men who have sex with men (MSM) who completed a survey at one or more annual visits in a randomized, double-blind, placebo-controlled efficacy trial of a bivalent rgp 120 vaccine conducted from 1998-2002.

Safety, pharmacokinetics, and antiviral activity of HGS004, a novel fully human IgG4 monoclonal antibody against CCR5, in HIV-1-infected patients.

Background: HGS004 is a fully human immunoglobulin (Ig) G4 monoclonal antibody against CC chemokine receptor 5 (CCR5) with robust in vitro activity against a diverse panel of CCR5-tropic human immunodeficiency virus type 1 (HIV-1) isolates.

Methods: A single-blind, randomized, placebo-controlled study was conducted in patients infected with CCR5-tropic HIV-1 to evaluate the safety, pharmacokinetics, and antiviral activity of HGS004. Sixty-three subjects were randomized into 5 dose cohorts (0.

Pharmacokinetic interaction between efavirenz and dual protease inhibitors in healthy volunteers.

The combination of efavirenz with HIV-1 protease inhibitors (PI) results in complex interactions secondary to mixed induction and inhibition of oxidative metabolism. ACTG A5043 was a prospective, open-label, controlled, two-period, multiple-dose study with 55 healthy volunteers. The objective of the present study was to evaluate the potential pharmacokinetic interaction between efavirenz and dual PIs.

Antiretroviral Drug Levels and Interactions Affect Lipid, Lipoprotein, and Glucose Metabolism in HIV-1 Seronegative Subjects: A Pharmacokinetic-Pharmacodynamic Analysis.

Background: HIV-infected patients treated with antiretroviral medications (ARVs) develop undesirable changes in lipid and glucose metabolism that mimic the metabolic syndrome and may be proatherogenic. Antiretroviral drug levels and their interactions may contribute to these metabolic alterations.

Methods: Fifty six HIV-seronegative adults were enrolled in an open-label, randomized, pharmacokinetic interaction study, and received a nonnucleoside reverse transcriptase inhibitor (efavirenz on days 1-21) plus a protease inhibitor (PI; amprenavir on days 11-21), with a second PI on days 15-21 (saquinavir, nelfinavir, indinavir, or ritonavir).

Compartmental pharmacokinetic analysis of oral amprenavir with secondary peaks.

Amprenavir is a protease inhibitor that has been shown to have secondary peaks postulated to be due to enterohepatic recycling. We propose a model to describe the pharmacokinetics of amprenavir which accommodates the secondary peak(s). A total of 82 healthy human immunodeficiency virus (HIV)-seronegative subjects were administered a single 600-mg dose of amprenavir as part of adult AIDS Clinical Trials Group protocol A5043.

Partner-specific sexual behavioral differences between phase 3 HIV vaccine efficacy trial participants and controls: Project VISION.

Objective: To assess and compare sexual behaviors using partner-specific data between HIV-negative men who have sex with men (MSM) recruited for an HIV vaccine efficacy trial and a control group.

Methods: HIV-negative MSM from an HIV vaccine trial (n = 525) and controls (n = 732) were recruited by similar strategies and interviewed about behaviors with the 3 most recent partners in the past 6 months, obtained by audio computer-assisted self-interview (A-CASI).

Results: Vaccine trial participants were more likely than controls to report an HIV-positive partner (24.

Third-trimester maternal toxicity with nevirapine use in pregnancy.

Objective: Nevirapine-based therapy is associated with increased frequency of adverse events among women with CD4+ cell count of 250 cells/microL or greater. We evaluated the safety of nevirapine-based antiretroviral therapy in human immunodeficiency virus (HIV)-1-infected pregnant women.

Methods: We retrospectively evaluated 23 pregnancies managed with nevirapine-based regimens from July 2001 to April 2005.

Amprenavir and efavirenz pharmacokinetics before and after the addition of nelfinavir, indinavir, ritonavir, or saquinavir in seronegative individuals.

Adult AIDS Clinical Trials Group 5043 examined pharmacokinetic (PK) interactions between amprenavir (APV) and efavirenz (EFV) both by themselves and when nelfinavir (NFV), indinavir (IDV), ritonavir (RTV), or saquinavir (SQV) is added. A PK study was conducted after the administration of single doses of APV (day 0). Subjects (n = 56) received 600 mg of EFV every 24 h (q24h) for 10 days and restarted APV with EFV for days 11 to 13 with a PK study on day 14.

HIV sexual risk behavior over 36 months of follow-up in the world's first HIV vaccine efficacy trial.

Increased risk behavior among participants in HIV vaccine efficacy trials has been a concern. This study evaluated HIV sexual risk behavior among 5095 HIV-negative men who have sex with men (MSM) and 308 women enrolled in a randomized, double-blind, placebo-controlled efficacy trial of a bivalent rgp120 vaccine at 61 sites, primarily in North America. Sexual risk behavior data were collected at baseline and semiannually for 36 months.