scholarly journals Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (TDF) Versus Efavirenz/Emtricitabine/TDF in Treatment-naive Adults With Human Immunodeficiency Virus Type 1 Infection: Week 96 Results of the Randomized, Double-blind, Phase 3 DRIVE-AHEAD Noninferiority Trial

2020 ◽  
Author(s):  
Chloe Orkin ◽  
Kathleen E Squires ◽  
Jean-Michel Molina ◽  
Paul E Sax ◽  
Otto Sussmann ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Adverse Events ◽  
Density Lipoprotein ◽  
Phase 3 ◽  
Double Blind ◽  
Immunodeficiency Virus ◽  
Treatment Naïve ◽  
The Mean ◽  
Hiv 1

Abstract Background Doravirine (DOR) is a nonnucleoside reverse-transcriptase inhibitor. In the phase 3 DRIVE-AHEAD trial in treatment-naive adults with human immunodeficiency virus type 1 (HIV-1) infection, DOR demonstrated noninferior efficacy compared with efavirenz (EFV) and superior profiles for neuropsychiatric tolerability and lipids at 48 weeks. We present data through week 96. Methods DRIVE-AHEAD is a phase 3, multicenter, double-blind, noninferiority trial in antiretroviral treatment-naive adults with HIV-1 RNA ≥1000 copies/mL. Participants were randomized to a daily fixed-dose tablet of DOR (100 mg), lamivudine (3TC; 300 mg) and tenofovir disoproxil fumarate (TDF; 300 mg) (DOR/3TC/TDF) or EFV (600 mg), emtricitabine (FTC; 200 mg) and TDF (300 mg) (EFV/FTC/TDF). The efficacy end point of interest at week 96 was the proportion of participants with HIV-1 RNA levels <50 copies/mL (Food and Drug Administration Snapshot Approach) with a predefined noninferiority margin of 10% to support week 48 results. Safety end points of interest included prespecified neuropsychiatric adverse events and the mean change in fasting lipids at week 96. Results Of 734 participants randomized, 728 received study drugs and were included in analyses. At week 96, HIV-1 RNA <50 copies/mL was achieved by 77.5% of DOR/3TC/TDF vs 73.6% of EFV/FTC/TDF participants, with a treatment difference of 3.8% (95% confidence interval, –2.4% to 10%). Virologic failure rates were low and similar across treatment arms, with no additional resistance to DOR observed between weeks 48 and 96. Prespecified neuropsychiatric adverse events and rash were less frequent in DOR/3TC/TDF than in EFV/FTC/TDF participants through week 96. At week 96, fasting low-density lipoprotein cholesterol and non–high-density lipoprotein cholesterol (HDL-C) levels increased in the EFV/FTC/TDF group but not in the DOR/3TC/TDF group; the mean changes from baseline in total cholesterol/HDL-C ratio were similar. Clinical Trials Registration NCT02403674.

scholarly journals Steady-State Pharmacokinetics of Amprenavir Coadministered with Ritonavir in Human Immunodeficiency Virus Type 1-Infected Patients

2003 ◽  
Vol 47 (1) ◽  
pp. 118-123 ◽  
Author(s):  
Cecile Goujard ◽  
Isabelle Vincent ◽  
Jean-Luc Meynard ◽  
Nathalie Choudet ◽  
Diane Bollens ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Steady State ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Time Curve ◽  
Concentration Time ◽  
Immunodeficiency Virus ◽  
The Mean ◽  
Hiv 1

ABSTRACT The protease inhibitor (PI) ritonavir is used as a strong inhibitor of cytochrome P450 3A4, which boosts the activities of coadministered PIs, resulting in augmented plasma PI levels, simplification of the dosage regimen, and better efficacy against resistant viruses. The objectives of the present open-label, multiple-dose study were to determine the steady-state pharmacokinetics of amprenavir administered at 600 mg twice daily (BID) and ritonavir administered at 100 mg BID in human immunodeficiency virus type 1 (HIV-1)-infected adults treated with different antiretroviral combinations including or not including a nonnucleoside reverse transcriptase inhibitor (NNRTI). Nineteen patients completed the study. The steady-state mean minimum plasma amprenavir concentration (C min,ss) was 1.92 μg/ml for patients who received amprenavir and ritonavir without an NNRTI and 1.36 μg/ml for patients who received amprenavir and ritonavir plus efavirenz. For patients who received amprenavir-ritonavir without an NNRTI, the steady-state mean peak plasma amprenavir concentration (C max,ss) was 7.12 μg/ml, the area under the concentration-time curve from 0 to 10 h (AUC0-10) was 32.06 μg · h/ml, and the area under the concentration-time curve over a dosing interval (12 h) at steady-state (AUCss) was 35.74 μg · h/ml. Decreases in the mean values of C min,ss (29%), C max,ss (42%), AUC0-10 (42%), and AUCss (40%) for amprenavir occurred when efavirenz was coadministered with amprenavir-ritonavir. No unexpected side effects were observed. As expected, coadministration of amprenavir with ritonavir resulted in an amprenavir C min,ss markedly higher than those previously reported for the marketed dose of amprenavir. When amprenavir-ritonavir was coadministered with efavirenz, amprenavir-ritonavir maintained a mean amprenavir C min,ss above the mean 50% inhibitory concentration of amprenavir previously determined for both wild-type HIV-1 isolates and HIV-1 strains isolated from PI-experienced patients. These data support the use of low-dose ritonavir to enhance the level of exposure to amprenavir and increase the efficacy of amprenavir.

scholarly journals Single-Dose Pharmacokinetics and Safety of Abacavir (1592U89), Zidovudine, and Lamivudine Administered Alone and in Combination in Adults with Human Immunodeficiency Virus Infection

1999 ◽  
Vol 43 (7) ◽  
pp. 1708-1715 ◽  
Author(s):  
Laurene H. Wang ◽  
Gregory E. Chittick ◽  
James A. McDowell
Keyword(s):  
Human Immunodeficiency Virus ◽  
Adverse Events ◽  
Nucleoside Analogs ◽  
Neck Stiffness ◽  
Time Curve ◽  
Pharmacokinetic Interactions ◽  
Immunodeficiency Virus ◽  
The Mean ◽  
Clinically Significant ◽  
Hiv 1

ABSTRACT Abacavir (1592U89), a nucleoside reverse transcriptase inhibitor with in vitro activity against human immunodeficiency virus type-1 (HIV-1), has been evaluated for efficacy and safety in combination regimens with other nucleoside analogs, including zidovudine (ZDV) and lamivudine (3TC). To evaluate the potential pharmacokinetic interactions between these agents, 15 HIV-1-infected adults with a median CD4+ cell count of 347 cells/mm3 (range, 238 to 570 cells/mm3) were enrolled in a randomized, seven-period crossover study. The pharmacokinetics and safety of single doses of abacavir (600 mg), ZDV (300 mg), and 3TC (150 mg) were evaluated when each drug was given alone or when any two or three drugs were given concurrently. The concentrations of all drugs in plasma and the concentrations of ZDV and its 5′-glucuronide metabolite, GZDV, in urine were measured for up to 24 h postdosing, and pharmacokinetic parameter values were calculated by noncompartmental methods. The maximum drug concentration (C max), the area under the concentration-time curve from time zero to infinity (AUC0–∞), time to C max(T max), and apparent elimination half-life (t 1/2) of abacavir in plasma were unaffected by coadministration with ZDV and/or 3TC. Coadministration of abacavir with ZDV (with or without 3TC) decreased the meanC max of ZDV by approximately 20% (from 1.5 to 1.2 μg/ml), delayed the median T max for ZDV by 0.5 h, increased the mean AUC0–∞ for GZDV by up to 40% (from 11.8 to 16.5 μg · h/ml), and delayed the medianT max for GZDV by approximately 0.5 h. Coadministration of abacavir with 3TC (with or without ZDV) decreased the mean AUC0–∞ for 3TC by approximately 15% (from 5.1 to 4.3 μg · h/ml), decreased the meanC max by approximately 35% (from 1.4 to 0.9 μg/ml), and delayed the median T max by approximately 1 h. While these changes were statistically significant, they are similar to the effect of food intake (for ZDV) or affect an inactive metabolite (for GZDV) or are relatively minor (for 3TC) and are therefore not considered to be clinically significant. No significant differences were found in the urinary recoveries of ZDV or GZDV when ZDV was coadministered with abacavir. There was no pharmacokinetic interaction between ZDV and 3TC. Mild to moderate headache, nausea, lymphadenopathy, hematuria, musculoskeletal chest pain, neck stiffness, and fever were the most common adverse events reported by those who received abacavir. Coadministration of ZDV or 3TC with abacavir did not alter this adverse event profile. The three-drug regimen was primarily associated with gastrointestinal events. In conclusion, no clinically significant pharmacokinetic interactions occurred between abacavir, ZDV, and 3TC in HIV-1-infected adults. Coadministration of abacavir with ZDV or 3TC produced mild changes in the absorption and possibly the urinary excretion characteristics of ZDV-GZDV and 3TC that were not considered to be clinically significant. Coadministration of abacavir with ZDV and/or 3TC was generally well tolerated and did not produce unexpected adverse events.

scholarly journals Potent Anti-R5 Human Immunodeficiency Virus Type 1 Effects of a CCR5 Antagonist, AK602/ONO4128/GW873140, in a Novel Human Peripheral Blood Mononuclear Cell Nonobese Diabetic-SCID, Interleukin-2 Receptor γ-Chain-Knocked-Out AIDS Mouse Model

2005 ◽  
Vol 79 (4) ◽  
pp. 2087-2096 ◽  
Author(s):  
Hirotomo Nakata ◽  
Kenji Maeda ◽  
Toshikazu Miyakawa ◽  
Shiro Shibayama ◽  
Masayoshi Matsuo ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Peripheral Blood ◽  
Interleukin 2 ◽  
Peripheral Blood Mononuclear ◽  
Nonobese Diabetic ◽  
Immunodeficiency Virus ◽  
The Mean ◽  
Nog Mice ◽  
Hiv 1

ABSTRACT We established human peripheral blood mononuclear cell (PBMC)-transplanted R5 human immunodeficiency virus type 1 isolate JR-FL (HIV-1JR-FL)-infected, nonobese diabetic-SCID, interleukin 2 receptor γ-chain-knocked-out (NOG) mice, in which massive and systemic HIV-1 infection occurred. The susceptibility of the implanted PBMC to the infectivity and cytopathic effect of R5 HIV-1 appeared to stem from hyperactivation of the PBMC, which rapidly proliferated and expressed high levels of CCR5. When a novel spirodiketopiperazine-containing CCR5 inhibitor, AK602/ONO4128/GW873140 (molecular weight, 614), was administered to the NOG mice 1 day after R5 HIV-1 inoculation, the replication and cytopathic effects of R5 HIV-1 were significantly suppressed. In saline-treated mice (n = 7), the mean human CD4+/CD8+ cell ratio was 0.1 on day 16 after inoculation, while levels in mice (n = 8) administered AK602 had a mean value of 0.92, comparable to levels in uninfected mice (n = 7). The mean number of HIV-RNA copies in plasma in saline-treated mice were ∼106/ml on day 16, while levels in AK602-treated mice were 1.27 × 103/ml (P = 0.001). AK602 also significantly suppressed the number of proviral DNA copies and serum p24 levels (P = 0.001). These data suggest that the present NOG mouse system should serve as a small-animal AIDS model and warrant that AK602 be further developed as a potential therapeutic for HIV-1 infection.

scholarly journals Phenotypic Susceptibilities to Tenofovir in a Large Panel of Clinically Derived Human Immunodeficiency Virus Type 1 Isolates

2002 ◽  
Vol 46 (4) ◽  
pp. 1067-1072 ◽  
Author(s):  
P. R. Harrigan ◽  
M. D. Miller ◽  
P. McKenna ◽  
Z. L. Brumme ◽  
B. A. Larder
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Tenofovir Disoproxil Fumarate ◽  
Antiretroviral Drug ◽  
Immunodeficiency Virus ◽  
Large Panel ◽  
Treatment Naïve ◽  
Rt Inhibitors ◽  
Hiv 1

ABSTRACT Tenofovir is a nucleotide analogue human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) inhibitor, and its oral prodrug, tenofovir disoproxil fumarate, has recently been approved for the treatment of HIV-1 infection in the United States. The objective of this study was to characterize the in vitro susceptibility profiles of a large panel of clinically derived HIV-1 isolates for tenofovir. The distribution of tenofovir susceptibilities in over 1,000 antiretroviral-naive, HIV-1-infected individuals worldwide was determined using the Virco Antivirogram assay. In addition, phenotypic susceptibilities to tenofovir and other RT inhibitors were determined in a panel of nearly 5,000 recombinant HIV-1 clinical isolates from predominantly treatment-experienced patients analyzed as a part of routine drug resistance testing. Greater than 97.5% of isolates from treatment-naive patients had tenofovir susceptibilities <3-fold above those of the wild-type controls by the Antivirogram. The clinically derived panel of 5,000 samples exhibited a broad range of antiretroviral drug susceptibilities, including 69, 43, and 16% having >10-fold-decreased susceptibilities to at least one, two, and three antiretroviral drug classes, respectively. Greater than 88% of these 5,000 clinical isolates were within the threefold susceptibility range for tenofovir, and >99% exhibited <10-fold-reduced susceptibilities to tenofovir. Decreased susceptibility to tenofovir was not directly associated with resistance to other RT inhibitors; r 2 values of log-log linear regression plots of susceptibility to tenofovir versus susceptibility to other RT inhibitors were <0.4. The results suggest that the majority of treatment-naive and treatment-experienced individuals harbor HIV that remains within the normal range of tenofovir susceptibilities and may be susceptible to tenofovir disoproxil fumarate therapy.

scholarly journals PCR-Based Assay To Quantify Human Immunodeficiency Virus Type 1 DNA in Peripheral Blood Mononuclear Cells

2000 ◽  
Vol 38 (2) ◽  
pp. 630-634 ◽  
Author(s):  
Cindy Christopherson ◽  
Yorda Kidane ◽  
Brian Conway ◽  
John Krowka ◽  
Haynes Sheppard ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Immunodeficiency Virus ◽  
Blood Mononuclear Cells ◽  
The Mean ◽  
Long Term Survivors ◽  
Hiv 1

An assay that quantifies the amount of human immunodeficiency virus type 1 (HIV-1) DNA in peripheral blood mononuclear cells has been developed. PCR amplification of the HIV-1 DNA is performed in the presence of an internal quantitation standard, and colorimetric detection of the amplified product is performed with microwell plates. The copies of HIV-1 DNA are normalized to total genomic DNA input. The assay has an analytical sensitivity of 10 input copies per amplification reaction and a three-log detection range. In an analysis of sequential samples from patients on combination therapy, HIV-1 DNA was quantifiable for all individuals tested, including those with undetectable plasma HIV-1 RNA. In a separate study, a comparison of HIV-1 DNA levels was made with a group of long-term survivors and progressors. The mean HIV-1 DNA levels were lower in the long-term survivors than in the progressors (P, 0.04). The mean HIV-1 RNA levels were also lower, but the difference was not statistically significant (P, 0.164). A quantitative DNA assay will provide an additional tool to gain insight into the natural history of infection and the continued efficacy of potent antiretroviral therapies.

scholarly journals ACTG 260: a Randomized, Phase I-II, Dose-Ranging Trial of the Anti-Human Immunodeficiency Virus Activity of Delavirdine Monotherapy

1999 ◽  
Vol 43 (6) ◽  
pp. 1373-1378 ◽  
Author(s):  
Michael F. Para ◽  
Patricia Meehan ◽  
Jeanne Holden-Wiltse ◽  
Margaret Fischl ◽  
Gene Morse ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Open Label ◽  
Immunodeficiency Virus ◽  
Dose Ranging ◽  
The Mean ◽  
Hiv Type 1 ◽  
Anti Hiv ◽  
Hiv 1 ◽  
Rapid Emergence

ABSTRACT ACTG 260 was an open-label, four-arm trial designed to study the safety and anti-human immunodeficiency virus (anti-HIV) activity of delavirdine monotherapy at three ranges of concentrations in plasma compared to those of control therapy with zidovudine or didanosine. Delavirdine doses were adjusted weekly until subjects were within their target trough concentration range (3 to 10, 11 to 30, or 31 to 50 μM). A total of 113 subjects were analyzed. At week 2, the mean HIV type 1 (HIV-1) RNA level declines among the subjects in the three delavirdine arms were similar (0.87, 1.08, and 1.02 log10 for the low, middle, and high target arms, respectively), but by week 8, the subjects in the pooled delavirdine arms showed only a 0.10 log10 reduction. In the subjects in the nucleoside arm, mean HIV-1 RNA level reductions at weeks 2 and 8 were 0.67 and 0.55 log10, respectively. Because viral suppression by delavirdine was not maintained, the trial was stopped early. Rash, which was usually self-limited, developed in 36% of subjects who received delavirdine. Delavirdine monotherapy has potent anti-HIV activity at 2 weeks, but its activity is time limited due to the rapid emergence of drug resistance.

scholarly journals Single-Dose Escalation and Multiple-Dose Safety, Tolerability, and Pharmacokinetics of IDX899, a Candidate Human Immunodeficiency Virus Type 1 Nonnucleoside Reverse Transcriptase Inhibitor, in Healthy Subjects

2009 ◽  
Vol 53 (5) ◽  
pp. 1739-1746 ◽  
Author(s):  
Xiao-Jian Zhou ◽  
Keith Pietropaolo ◽  
David Damphousse ◽  
Bruce Belanger ◽  
Jie Chen ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Single Dose ◽  
Adverse Events ◽  
Transcriptase Inhibitor ◽  
Nonnucleoside Reverse Transcriptase Inhibitor ◽  
Immunodeficiency Virus ◽  
Reverse Transcriptase Inhibitor ◽  
Hiv 1

ABSTRACT IDX899 is a novel nonnucleoside reverse transcriptase inhibitor (NNRTI) with potent in vitro activity against wild-type and NNRTI-resistant strains of human immunodeficiency virus type 1 (HIV-1) and with a high genetic barrier to resistance. Single rising doses of 50 and 100 (given by use of a 50-mg capsule) and 200, 400, 800, and 1,200 mg (given by use of a 200-mg capsule) of IDX899 or matching placebo were administered sequentially to cohorts of healthy male subjects, followed by the administration of multiple doses of 800 mg once daily (QD) or 400 mg twice daily (BID) for 7 days. A single dose of 400 mg was also administered to a cohort of females. IDX899 was administered orally under fasted (50- to 400-mg doses) and then fed (≥200-mg doses) conditions. Exposure to IDX899 was dose proportional and comparable in males and females. With a different drug-to-excipient ratio, the 50-mg capsule led to a higher exposure but a shorter mean terminal half-life (t 1/2) of 6.2 to 6.8 h. The 200-mg capsule resulted in a more sustained exposure with a longer mean t 1/2 of 7.9 to 14.6 h. Food enhanced absorption by approximately twofold, while it delayed the time to the maximum concentration. The mean concentration at 24 h following the administration of a single 200-mg dose under fed conditions exceeded the in vitro protein binding-adjusted 90% inhibitory concentration by fourfold. The levels of plasma exposure were similar between the single dosing and the repeat dosing with 800 mg QD and was approximately twofold higher with 400 mg BID. Mean steady-state trough levels were 0.9 μg/ml (range, 0.2 to 2.5 μg/ml) and 2.1 μg/ml (range, 0.5 to 4.5 μg/ml) for the 800-mg QD and 400-mg BID regimens, respectively. The level of excretion of unchanged drug in urine was negligible. IDX899 was well tolerated; and no serious adverse events, dose-dependent adverse events, or laboratory abnormalities were detected. These favorable safety and pharmacokinetic results support further clinical studies with patients with HIV-1 infection by the use of a QD regimen.

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