Immunodeficiency Virus Type 1-infected Subjects Research Articles

Pharmacokinetics of Fosamprenavir plus Ritonavir in Human Immunodeficiency Virus Type 1-Infected Adult Subjects with Hepatic Impairment

The effect of hepatic impairment on fosamprenavir/ritonavir pharmacokinetics was investigated. Sixty human immunodeficiency virus type 1-infected subjects, including 13, 20, and 10 subjects with mild, moderate, and severe hepatic impairment, respectively, and a comparator group of 17 subjects with normal hepatic function, were enrolled. Subjects with normal hepatic function received fosamprenavir at 700 mg plus ritonavir at 100 mg twice daily, whereas subjects with hepatic impairment received adjusted doses in anticipation of increased exposures. For subjects with mild hepatic impairment, the studied regimen of fosamprenavir 700 mg twice daily plus ritonavir 100 mg once daily delivered 17% higher values for the maximum plasma amprenavir concentration at the steady state (C(max)), 22% higher values for the area under the plasma concentration versus time curve over the dosing interval at the steady state [AUC(0-tau)], similar values for the concentration at the end of the dosing interval (C(tau)), and 114% higher unbound C(tau) values. For subjects with moderate hepatic impairment, the studied dosage regimen of fosamprenavir at 300 mg twice daily plus ritonavir at 100 mg once daily delivered 27% lower plasma amprenavir C(max) values, 27% lower AUC(0-24) values, 57% lower C(tau) values, and 21% higher unbound amprenavir C(tau) values. For subjects with severe hepatic impairment, the studied dosage regimen of fosamprenavir at 300 mg twice daily plus ritonavir at 100 mg once daily delivered 19% lower plasma amprenavir C(max) values, 23% lower AUC(0-24) values, 38% lower C(tau) values, and similar unbound amprenavir C(tau) values. With a reduced ritonavir dosing frequency of 100 mg once daily, the plasma ritonavir AUC(0-24) values were 39% lower, similar, and 40% higher for subjects with mild, moderate, and severe hepatic impairment, respectively. The results of the study support the use of reduced fosamprenavir/ritonavir doses or dosing frequencies in the treatment of patients with hepatic impairment. No significant safety issues were identified; however, plasma amprenavir and ritonavir exposures were more variable in subjects with hepatic impairment, and those patients should be closely monitored for safety and virologic response.

Virologic Failure in Therapy-Naïve Subjects on Aplaviroc plus Lopinavir-Ritonavir: Detection of Aplaviroc Resistance Requires Clonal Analysis of Envelope

The CCR100136 (EPIC) study evaluated the antiviral activity of the novel CCR5 entry inhibitor aplaviroc in combination with lopinavir-ritonavir in drug-naïve human immunodeficiency virus type 1-infected subjects. Although the trial was stopped prematurely due to idiosyncratic hepatotoxicity, 11 subjects met the protocol-defined virologic failure criteria. Clonal analyses of the viral envelope tropism, aplaviroc susceptibility, and env sequencing were performed on plasma at day 1 and at the time of virologic failure. Molecular evolutionary analyses were also performed. Treatment-emergent resistance to aplaviroc or lopinavir-ritonavir was not observed at the population level. However, aplaviroc resistance was detected prior to therapy at both the clonal and population levels in one subject with virologic failure and in six subjects in a minority (<50%) of clones at day 1 or at the time of virologic failure. Reduced aplaviroc susceptibility manifested as a 50% inhibitory concentration curve shift and/or a plateau. Sequence changes in the clones with aplaviroc resistance were unique to each subject and scattered across the envelope coding region. Clones at day 1 and at the time of virologic failure were not phylogenetically distinct. Two subjects with virologic failure had a population tropism change from CCR5- to dual/mixed-tropic during treatment. Virologic failure during a regimen of aplaviroc and lopinavir-ritonavir may be associated with aplaviroc resistance, only at the clonal level, and/or, infrequently, tropism changes.

Virologic Failure in First-Line Human Immunodeficiency Virus Therapy with a CCR5 Entry Inhibitor, Aplaviroc, plus a Fixed-Dose Combination of Lamivudine-Zidovudine: Nucleoside Reverse Transcriptase Inhibitor Resistance Regardless of Envelope Tropism

The CCR102881 (ASCENT) study evaluated the antiviral activity of the novel CCR5 entry inhibitor aplaviroc plus a fixed-dose combination of lamivudine-zidovudine (Combivir) in drug-naïve human immunodeficiency virus type 1-infected subjects with only CCR5-tropic virus detected in plasma. Although the trial was stopped prematurely due to idiosyncratic hepatotoxicity, eight subjects met protocol-defined virologic failure criteria. Clonal analyses of the viral envelope tropism, aplaviroc susceptibility, and env sequencing were performed on plasma at baseline and at the time of virologic failure. Molecular evolutionary analyses were also performed. The majority of the subjects with virologic failure (six of eight) acquired the lamivudine resistance-associated mutation M184V, and none had evidence of reduced susceptibility to aplaviroc at the time of virologic failure, even at the clonal level. Six subjects with virologic failure maintained CCR5 tropism, while two exhibited a change in population tropism readout to dual/mixed-tropic with R5X4-tropic clones detected prior to therapy. Two evolutionary patterns were observed: five subjects had no evidence of population turnover, while three subjects had multiple lines of evidence for env population turnover. The acquisition of the M184V mutation is the primary characteristic of virologic failure in first-line therapy with aplaviroc plus lamivudine-zidovudine, regardless of the envelope tropism.

Clinical Phase 1 Testing of the Safety and Immunogenicity of an Epitope-Based DNA Vaccine in Human Immunodeficiency Virus Type 1-Infected Subjects Receiving Highly Active Antiretroviral Therapy

A DNA vaccine encoding sequence-conserved human immunodeficiency virus type 1 (HIV-1)-derived cytotoxic T-lymphocyte (CTL) epitopes from multiple HIV-1 gene products (designated EP HIV-1090) was evaluated in a placebo-controlled, dose escalation phase 1 clinical trial of HIV-1-infected subjects receiving potent combination antiretroviral therapy. Patients received four intramuscular immunizations with EP HIV-1090 over a 4-month period at one of four doses (0.5, 1.0, 2.0, or 4.0 mg) or received a placebo. The vaccine was determined to be safe and well tolerated at all doses tested. CTL responses were measured from cryopreserved peripheral blood mononuclear cells using gamma interferon enzyme-linked immunospot assays, with and without in vitro peptide stimulation (IVS). Responses to one or more vaccine epitopes were detected throughout the course of vaccination in 37.5% (12/32) and 47% (15/32) of vaccine recipients measured without and with IVS, respectively, indicating possible vaccine-induced priming of epitope-specific T cells. However, differences in rates of response to HIV-1 epitopes between vaccine and placebo recipients did not achieve statistical significance. The HIV-1 epitope-specific CTL responses measured in the peripheral blood after vaccination were often low level and short-lived, and therefore, alternative immunization schedules, routes of delivery, or vaccine formulations may be required to increase vaccine potency.

The Safety, Efficacy, and Pharmacokinetic Profile of a Switch in Antiretroviral Therapy to Saquinavir, Ritonavir, and Atazanavir Alone for 48 Weeks and a Switch in the Saquinavir Formulation

Toxicities observed with current combination antiretroviral therapy (CART) warrant a search for novel options, such as class-sparing regimens. Ritonavir-boosted double-protease inhibitor (PI)-only regimens are such an option but are prone to pharmacokinetic interactions. This 48-week randomized study examined the safety and efficacy of a switch in CART to a once-daily regimen of saquinavir (SQV), ritonavir (RTV), and atazanavir (ATV) that did not include nucleoside reverse-transcriptase inhibitors (NRTIs). The study also assessed the pharmacokinetic profile of a change in the SQV formulation, from 200 mg to 500 mg, in 2 regimens (SQV-RTV twice per day plus NRTIs [arm 1] and SQV-RTV-ATV once per day without NRTIs [arm 2]) in human immunodeficiency virus type 1-infected subjects (plasma human immunodeficiency virus RNA level, <50 copies/mL). Patients underwent an initial SQV formulation change or a CART change to SQV-RTV-ATV with intense pharmacokinetic sampling. All patients were subsequently assigned to receive SQV-RTV-ATV (1500, 100, and 300 mg once per day, respectively) without NRTIs for 48 weeks. The primary end point was the percentage of patients who experienced virologic failure. Of 25 subjects enrolled, scleral icterus was the most common adverse event (3 patients [12.5%]). Three subjects (12.5%) experienced virologic failure; and mean (+/- standard error of the mean) increase in the CD4(+) lymphocyte count was 63 +/- 36 cells/ mu L over 48 weeks (P=.012). The SQV geometric mean area under the time curve parameters were not significantly altered for the 2 SQV formulations (arm 1, 23.32 vs. 18.76 ngxh/mL [geometric mean ratio, 0.80] for the 200-mg vs. 500-mg formulations, respectively; arm 2, 50.31 vs. 44.79 ngxh/mL [geometric mean ratio, 0.88], for the 200-mg vs. 500-mg formulations, respectively). A CART regimen of SQV-RTV-ATV alone demonstrated sustained virologic efficacy and was associated with significant increases in the CD4(+) lymphocyte count.

Performance of Human Immunodeficiency Virus Type 1 gp41 Assays for Detecting Enfuvirtide (T-20) Resistance Mutations

The performance of a gp41 assay, created using reagents designed for use with the OpenGene DNA Sequencing System, was evaluated using a panel of plasma samples obtained from enfuvirtide-naive and -experienced human immunodeficiency virus type 1-infected subjects. Resulting sequence data were highly accurate compared to a "home brew" assay and clonal sequence analysis.

Distinct Mechanisms of T Cell Reconstitution Can Be Identified by Estimating Thymic Volume in Adult HIV‐1 Disease

We have attempted to identify factors associated with T cell reconstitution in response to highly active antiretroviral therapy. In a prospective, multicenter cohort study, we compared clinical, immune, and viral responses to an initial antiretroviral regimen in older (>or=45 years old) versus younger (18-30 years old) human immunodeficiency virus type 1-infected subjects. Multivariable linear-regression models identified independent factors associated with changes in T cell counts. Older subjects had smaller increases in naive T cells but greater T cell receptor-excision circle DNA content after 48 weeks, despite similar virologic responses and comparable reductions in immune activation. Changes in T cell counts were associated with plasma interleukin (IL)-7 levels in subjects with low thymic scores, whereas first-phase T cell increases (perhaps mediated by redistribution to the circulation of tissue-associated lymphocytes) were associated with reductions in immune activation in subjects with high thymic scores. Reductions in immune activation were associated with reductions in spontaneous lymphocyte apoptosis. Distinct processes may underlie T cell restoration, according to estimated thymic volumes. IL-7-mediated peripheral expansion may drive T cell restoration in persons with low thymic volume, whereas therapy-associated reversal of immune reactivation may drive T cell losses and their restoration in persons with larger thymic volume.

CD4+-T-cell counts, spontaneous apoptosis, and Fas expression in peripheral blood mononuclear cells obtained from human immunodeficiency virus type 1-infected subjects.

We examined the relationships among CD4+-T-cell counts, spontaneous apoptosis, and Fas expression among peripheral blood mononuclear cells obtained from human immunodeficiency virus type 1 (HIV-1)-infected patients. After 2 days of incubation, propidium iodide DNA staining and flow cytometry revealed that peripheral blood mononuclear cells from subjects with the lowest CD4+-cell numbers (0 to 99/microl; n = 20) showed the highest frequency of apoptosis: 22.4% +/- 2.7% (mean +/- standard error) versus 13.8% +/- 1.2% and 12.7% +/- 1.4% among peripheral blood mononuclear cells obtained from patients with 100 to 499 CD4+ cells/microl (n = 19) and >500 CD4+ cells/microl (n = 17), respectively. Each of these means differed significantly from the mean frequency of apoptosis (6.3% +/- 0.7%) of peripheral blood mononuclear cells obtained from HIV-1-seronegative controls (P < 0.001, Student's t test). After incubation, the percentage of peripheral blood mononuclear cells expressing Fas antigen was increased for the HIV-1-infected subjects, and this was most evident for patients with more advanced disease. Among patients with fewer than 100 CD4+ cells/microl, 64.4% +/- 5.4% of peripheral blood mononuclear cells were Fas+, as opposed to 25.8% +/- 3.0% and 14.5% +/- 1.7% Fas+ cells among patients with more than 100 CD4+ cells/microl and healthy controls, respectively (P < 0.05 for each group comparison). Interestingly, in all populations, most apoptotic cells did not express Fas. Thus, apoptosis and Fas expression are increased in incubated peripheral blood mononuclear cells obtained from HIV-1-infected patients and these phenomena are enhanced as disease progresses.

Diagnosis of human cytomegalovirus-induced retinitis in human immunodeficiency virus type 1-infected subjects by using the polymerase chain reaction.

In 13 of 16 AIDS patients with retinitis, a herpesviruslike infection was diagnosed by clinical investigation. In 12 of the 13 patients, human cytomegalovirus (HCMV) DNA was detected in 5 microliters of aqueous humor by using the polymerase chain reaction (PCR). In the aqueous humor of 12 control patients HCMV DNA could not be detected by PCR. PCR may be used to monitor specific antiviral long-term therapy in HCMV retinitis.