Browsing by Author "DeJesus, Edwin"

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    Abacavir Once or Twice Daily Combined With Once-Daily Lamivudine and Efavirenz for the Treatment of Antiretroviral-Naive HIV-Infected Adults: Results of the Ziagen Once Daily in Antiretroviral Combination Study
    (2005-04-01) Moyle, Graeme J; DeJesus, Edwin; Cahn, Pedro; Castillo, Steve A; Zhao, Henry; Gordon, David N; Craig, Charles; Scott, Trevor R
    The long intracellular half-life of abacavir (ABC) supports its once-daily use, and this would be expected to simplify treatment if ABC could be given as part of a complete once-daily regimen. A randomized double-blind clinical trial compared the efficacy and safety of 600 mg of ABC administered once daily (n = 384) versus 300 mg of ABC administered twice daily (n = 386) in combination with 300 mg of lamivudine (3TC) and 600 mg of efavirenz (EFV) administered once daily in antiretroviral-naive patients over 48 weeks. The baseline median plasma HIV-1 RNA level was 4.89 log10 copies/mL (44% with viral load >100,000 copies/mL), and the median CD4+ cell count was 262 cells/mm3. ABC administered once daily was non-inferior to the twice-daily regimen, with 66% and 68% of patients in these respective treatment arms achieving a confirmed plasma HIV-1 RNA level <50 copies/mL (95% confidence interval: −8.4%, 4.9%). The ABC once-daily and twice-daily regimens were similar with respect to infrequency of virologic failure (10% vs. 8%), emergence of resistance mutations, CD4+ cell increases from baseline (median, 188 vs. 200 cells/mm3), safety profile, and incidence of ABC-related hypersensitivity reactions (9% vs. 7%). ABC administered once daily in combination with 3TC and EFV administered once daily was non-inferior to the ABC twice-daily dosing schedule when combined with 3TC and EFV over 48 weeks. Current clinical management of HIV-1 disease necessitates use of a multidrug regimen generally including 2 nucleoside reverse transcriptase inhibitors (NRTIs) and a third agent.1 Good adherence to potent antiretroviral therapy is critical in achieving a successful outcome. High pill burdens, dosing frequencies, risk of adverse events (AEs), drug interactions, and inconvenient dietary restrictions all potentially affect adherence and, ultimately, treatment efficacy.2,3 Patient preference surveys suggest that persons with HIV may prefer compact once-daily regimens if the efficacy and tolerability of these regimens are similar to those of the twice-daily standard of care regimens.3 Some antiretroviral drugs that have half-lives suitable for administration once a day (OAD) cannot be used together because of drug interactions and dietary restrictions. An expansion in the number of antiretroviral drugs approved for OAD dosing increases the potential for OAD therapy to become the preferred initial therapy. The NRTI abacavir (ABC) has demonstrated durable efficacy as a component of numerous regimens administered at a dose of 300 mg twice daily.4-6 A multidrug combination of 300 mg of ABC administered twice daily with lamivudine (3TC) and efavirenz (EFV) has been compared with 300 mg of zidovudine (ZDV) administered twice daily with 3TC and EFV and has resulted in similarly potent and durable virologic suppression (<50 copies/mL), superior CD4+ cell recovery, and good tolerability, including an improved hematologic profile over 48 weeks.7 Recent pharmacokinetic studies in HIV-1-infected adults have shown that the active drug moiety of ABC, carbovir triphosphate (CBV-TP), has a long intracellular half-life (>20 hours) that would support OAD dosing of 600 mg of ABC.8-10 A small clinical study in which 600 mg of ABC administered OAD was compared with 300 mg of ABC 300 administered twice daily suggested that ABC could be administered OAD and supported further investigation of this dosing schedule.11 The Ziagen Once Daily in Antiretroviral Combination (ZODIAC) therapy study was a noninferiority clinical trial conducted over 48 weeks that compared the efficacy and safety of triple drug therapy with 600 mg of ABC administered OAD versus 300 mg of ABC administered twice daily, combined with OAD 3TC and EFV, in the treatment of antiretroviral-naive adults.
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    Fostemsavir in Adults with Multidrug Resistant HIV-1 Infection
    (2020-3) Kozal, Michael; Aberg, Judith; Pialoux, Gilles; Cahn, Pedro; Thompson, Melanie; Molina, Jean-Michel; Grinsztejn, Beatriz; Diaz, Ricardo; Castagna, Antonella; Kumar, Princy; Latiff, Gulam; DeJesus, Edwin; Gummel, Mark; Gartland, Margaret; Pierce, Amy; Ackerman, Peter; Llamoso, Cyril; Lataillade, Max
    BACKGROUND Among some patients with human immunodeficiency virus type 1 (HIV-1) infection who have undergone multiple antiretroviral therapies and have limited options for treatment, new classes of antiretroviral drugs with novel mechanisms of action are needed. Fostemsavir is the prodrug of temsavir, a first-in-class investigational HIV-1 attachment inhibitor. METHODS In this ongoing phase 3 trial in 23 countries, we enrolled patients with multidrug-resistant HIV-1 infection in two cohorts, according to their remaining treatment options. In the first cohort, we assigned (in a 3:1 ratio) patients who had the option of using at least one fully active, approved antiretroviral drug in at least one but no more than two antiretroviral classes to add either fostemsavir (at a dose of 600 mg twice daily) or placebo to their failing regimen for 8 days, followed by open-label fostemsavir plus optimized background therapy (randomized cohort). In the second cohort, patients who had no remaining antiretroviral options were started on open-label fostemsavir plus optimized background therapy on day 1 (nonrandomized cohort). The primary end point was the mean change in the HIV-1 RNA level from day 1 through day 8 in the randomized cohort. RESULTS A total of 371 patients were treated, including 272 in the randomized cohort and 99 in the nonrandomized cohort. At day 8, the mean decrease in the HIV-1 RNA level was 0.79 log10 copies per milliliter in the fostemsavir group and 0.17 log10 copies in the placebo group (P<0.001). At week 48, a virologic response (HIV-1 RNA level, <40 copies per milliliter) had occurred in 54% of the patients in the randomized cohort and in 38% of those in the nonrandomized cohort; the mean increase in the CD4+ T-cell count was 139 cells per cubic millimeter and 64 cells per cubic millimeter, respectively. Adverse events led to the discontinuation of fostemsavir in 7% of the patients. In the randomized cohort, glycoprotein 120 (gp120) substitutions were found in 20 of 47 patients (43%) with virologic failure. CONCLUSIONS In patients with multidrug-resistant HIV-1 infection with limited therapy options, those who received fostemsavir had a significantly greater decrease in the HIV-1 RNA level than those who received placebo during the first 8 days. Efficacy was sustained through 48 weeks. (Funded by Bristol-Myers Squibb and GSK/ViiV Healthcare; BRIGHTE ClinicalTrials.gov number, NCT02362503.)
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    Week 96 Genotypic and Phenotypic Results of the Fostemsavir Phase 3 BRIGHTE Study in Heavily Treatment-Experienced Adults Living with Multidrug-Resistant HIV-1
    (ASM Journals, 2022-05) Gartland, Margaret; Cahn, Pedro; DeJesus, Edwin; Diaz, Ricardo Sobhie; Grossberg, Robert; Kozal, Michael; Kumar, Princy; Molina, Jean-Michel; Mendo Urbina, Fernando; Wang, Marcia; Du, Fangfang; Chabria, Shiven; Clark, Andrew; Garside, Louise; Krystal, Mark; Mannino, Frank; Pierce, Amy; Ackerman, Peter; Lataillade, Max
    In the phase 3 BRIGHTE study in heavily treatment-experienced adults with multidrug-resistant HIV-1, fostemsavir plus optimized background therapy (OBT) resulted in sustained rates of virologic suppression through 96 weeks. HIV-1 RNA <40 copies/mL was achieved in 163/272 (60%) Randomized Cohort (RC) participants (with 1 or 2 remaining approved fully active antiretrovirals) and 37/99 (37%) Non-randomized Cohort (NRC) participants (with 0 fully active antiretrovirals). Here we report genotypic and phenotypic analyses of HIV-1 samples from 63/272 (23%) RC participants and 49/99 (49%) NRC participants who met protocol-defined virologic failure (PDVF) criteria through Week 96. The incidence of PDVF was as expected in this difficult-to-treat patient population and, among RC participants, was comparable regardless of the presence of predefined gp120 amino acid substitutions that potentially influence phenotypic susceptibility to temsavir (S375H/I/M/N/T, M426L, M434I, M475I) or baseline temsavir 50% inhibitory concentration fold change (IC50 FC). The incidence of PDVF was lower among participants with higher overall susceptibility score to newly used antiretrovirals (OSS-new), indicating that OSS-new may be a preferred predictor of virologic outcome in heavily treatment-experienced individuals. Predefined gp120 substitutions, most commonly M426L or S375N, were emergent on treatment in 24/50 (48%) RC and 33/44 (75%) NRC participants with PDVF, with related increases in temsavir IC50 FC. In BRIGHTE, PDVF was not consistently associated with treatment-emergent genotypic or phenotypic changes in susceptibility to temsavir or to antiretrovirals in the initial OBT. Further research will be needed to identify which factors are most likely to contribute to virologic failure in this heavily treatment-experienced population (ClinicalTrials.gov, NCT02362503).