Atazanavir Plus Ritonavir or Efavirenz as Part of a 3-Drug Regimen for Initial Treatment of HIV-1

Daar, Eric S.; Tierney, Camlin; Fischl, Margaret A.; Sax, Paul E.; Mollan, Katie R.; Budhathoki, Chakra; Godfrey, Catherine; Jahed, Nasreen C.; Myers, Laurie; Katzenstein, David; Farajallah, Awny; Rooney, James F.; Pappa, Keith A.; Woodward, William C.; Patterson, Kristine B.; Bolívar, Héctor; Benson, Constance A.; Collier, Ann C.

doi:10.7326/0003-4819-154-7-201104050-00316

Cited by 286 publications

(262 citation statements)

References 24 publications

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“…The combination of two nucleoside reverse transcriptase inhibitors (NRTIs) plus a ritonavir-boosted protease inhibitor (PI) is one of the first-line options, and atazanavir (ATV) is one of the two recommended PIs in such a regimen. Atazanavir with ritonavir boosting is the only PI for which noninferiority to efavirenz-based regimens has been demonstrated in a randomized trial (1,2). The recommended dose of ATV in adults is 300 mg, with 100 mg of ritonavir, once daily.…”

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confidence: 99%

Pharmacokinetic-Pharmacodynamic Modeling of Unboosted Atazanavir in a Cohort of Stable HIV-Infected Patients

Goutelle

Baudry

Gagnieu

et al. 2013

Antimicrob Agents Chemother

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Limited data on the pharmacokinetics and pharmacodynamics (PK/PD) of unboosted atazanavir (uATV) in treatment-experienced patients are available. The aim of this work was to study the PK/PD of unboosted atazanavir in a cohort of HIV-infected patients. Data were available for 58 HIV-infected patients (69 uATV-based regimens). Atazanavir concentrations were analyzed by using a population approach, and the relationship between atazanavir PK and clinical outcome was examined using logistic regression. The final PK model was a linear one-compartment model with a mixture absorption model to account for two subgroups of absorbers. The mean (interindividual variability) of population PK parameters were as follows: clearance, 13. ؊1 ; P ‫؍‬ 0.001) were significantly lower in patients with virological failure than in patients without failure. In the logistic regression analysis, both the absorption rate constant and ATV trough concentration significantly influenced the probability of virological failure. A significant relationship between ATV pharmacokinetics and virological response was observed in a cohort of HIV patients who were administered unboosted atazanavir. This study also suggests that twice-daily administration of uATV may optimize drug therapy.

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confidence: 99%

Pharmacokinetic-Pharmacodynamic Modeling of Unboosted Atazanavir in a Cohort of Stable HIV-Infected Patients

Goutelle

Baudry

Gagnieu

et al. 2013

Antimicrob Agents Chemother

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“…Several PI agents are now available, providing options for individualized therapy, and most regimens are boosted with the pharmacological enhancer, ritonavir. 2 In clinical trials, convenient once-daily ritonavir-boosted atazanavir (ATV/r)-based regimens have proven efficacy and safety in both treatment-naive [3][4][5] and -experienced patients. 6,7 These regimens are recommended as a preferred therapeutic option for initiation of therapy in treatment-naive patients by the current treatment guidelines in both the United States 8,9 and Europe.…”

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confidence: 99%

Long-Term Efficacy and Safety of Atazanavir/Ritonavir Treatment in a Real-Life Cohort of Treatment-Experienced Patients with HIV Type 1 Infection

Jansen

Sönnerborg

Brockmeyer

et al. 2013

AIDS Research and Human Retroviruses

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Atazanavir-based regimens have established efficacy and safety in both antiretroviral (ARV)-naive and -experienced patients. However, data evaluating effectiveness beyond 2 years is sparse. Therefore, we assessed the long-term outcomes of ritonavir-boosted atazanavir (ATV/r)-containing regimens in ARV-experienced patients in a clinical setting in a noncomparative, retrospective, observational study collecting data from three European HIV databases on ARV-experienced adults with HIV-1 infection starting an ATV/r-based regimen. Data were extracted every 6 months (maximum follow-up 5 years). Primary outcome was the proportion of patients remaining on ATV/r by baseline HIV-1 RNA ( < 500 or ‡ 500 copies/ml). Secondary outcomes included time to virologic failure, reasons for discontinuation, and long-term safety profile. The duration of treatment and time to virologic failure were analyzed using the Kaplan-Meier method. Data were analyzed for 1,294 ARV-experienced patients (male 74%; mean ART exposure 5.7 years). After 3 years, 56% (95% CI: 52%, 60%) of patients with baseline HIV-1 RNA < 500 copies/ml and 53% (95% CI: 49%, 58%) of those with HIV-1 RNA ‡ 500 copies/ml remained on ATV/r. After 3 years, 75% (95% CI: 69%, 80%) of patients with baseline HIV-1 RNA < 50 copies/ml remained suppressed and 51% (95% CI: 47%, 55%) of those with baseline HIV-1 RNA ‡ 50 copies/ml achieved and maintained virologic suppression. Although adverse events (AEs) were the main known reason for discontinuation, no unexpected AEs were observed. In a real-life setting ATV/r-based regimens demonstrated sustained virologic suppression in ARV-experienced patients. After long-term therapy the majority of patients remained on treatment and no unexpected AEs were observed.

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“…In this trial, both NRTI and NNRTI RAMs were more frequently observed in subjects who received EFV compared with those who received ATV + RTV. 23 In a separate randomised trial (SINGLE), which compared dolutegravir (DTG) + ABC + 3TC and EFV + FTC + TDF, no subjects in the DTG + ABC + 3TC group had detectable antiviral resistance whereas one TDF-associated mutation and four EFV-associated mutations were detected in the EFV-TDF-FTC group. 24 BMS-986001 was generally well tolerated through Week 48.…”

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confidence: 99%

Efficacy, safety, bone and metabolic effects of HIV nucleoside reverse transcriptase inhibitor BMS-986001 (AI467003): a phase 2b randomised, controlled, partly blinded trial

Gupta

McComsey

Lombaard³

et al. 2016

The Lancet HIV

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MethodsAI467003 was a Phase 2b, randomised, active-controlled, blinded-to-BMS-986001 dose trial.HIV-1-infected adults with plasma HIV-1 RNA greater than 5000 copies per mL and CD4+ T-cell counts greater than 200 cells/mm 3 were randomised 2:2:2:3 to three BMS-986001 arms (100, 200 or 400 mg once daily), or reference arm (TDF 300 mg once daily), each with efavirenz (600 mg once daily) and lamivudine (300 mg once daily). Both subjects and investigators remained blinded to BMS-986001 dose, but not allocation, through Week 48. Proportion of subjects with plasma HIV-1 RNA less than 50 copies per mL and safety (serious adverse events [SAEs] and AEs leading to discontinuation) through Week 24 were primary endpoints. Resistance analysis was a secondary endpoint, and additional safety parameters were exploratory endpoints.AI467003 is registered with ClinicalTrials.gov (NCT01489046). FindingsA total of 757 subjects were assessed for eligibility and 301 randomised. Randomised subjects were assigned to receive either BMS-986001 (n=67 for the 100 mg once-daily group, n=67 for the 200 mg once-daily group, n=66 for the 400 mg once-daily group) or TDF (n=101 In a Phase 2a, dose-escalating, monotherapy study conducted for 10 days in treatment-experienced, HIV-1-infected, subjects who were not exposed to any antiretroviral treatment in the previous 3months, BMS-986001 demonstrated a median decrease in HIV-1 RNA from baseline of at least 1 log10 copies per mL for all doses. 19 These findings were used to support the design of this dosefinding Phase 2b study, which assessed the efficacy and safety of three doses of BMS-986001 (100, 200, and 400 mg once daily) versus tenofovir disoproxil fumarate (TDF 300 mg once daily), when coadministered with efavirenz (EFV 600 mg once daily) and lamivudine (3TC 300 mg once daily) in treatment-naïve, HIV-1-infected subjects. A detailed assessment of bone, renal, metabolic and mitochondrial parameters was performed to assess the safety of BMS-986001. 6 METHODS Study designAI467003 was a Phase 2b, randomised, active-controlled, blinded-to-BMS-986001 dose trial carried out at 47 sites across South America, North America, South Africa, Australia, Asia, and Europe.This study was conducted in accordance with Good Clinical Practice (GCP), as defined by the ParticipantsEligible subjects were treatment-naïve (defined as no current or previous exposure to an antiretroviral drug for more than 1 week), HIV-1-infected adults aged at least 18 years with plasma HIV-1 RNA greater than 5,000 copies per mL and CD4+ T-cell counts greater than 200 cells/mm 3 at screening.Exclusion criteria included a history of phenotypic and/or genotypic drug resistance testing showing resistance to EFV, TDF, or 3TC, presence of hepatitis B surface antigen, hepatitis C virus antibody or RNA, history of abnormal liver transaminases (defined as greater than three times the upper limit of normal) at screening, and creatinine clearance less than 60 mL/min at screening. All subjects provided written informed consent in agreement wi...

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Atazanavir Plus Ritonavir or Efavirenz as Part of a 3-Drug Regimen for Initial Treatment of HIV-1

Cited by 286 publications

References 24 publications

Pharmacokinetic-Pharmacodynamic Modeling of Unboosted Atazanavir in a Cohort of Stable HIV-Infected Patients

Pharmacokinetic-Pharmacodynamic Modeling of Unboosted Atazanavir in a Cohort of Stable HIV-Infected Patients

Long-Term Efficacy and Safety of Atazanavir/Ritonavir Treatment in a Real-Life Cohort of Treatment-Experienced Patients with HIV Type 1 Infection

Efficacy, safety, bone and metabolic effects of HIV nucleoside reverse transcriptase inhibitor BMS-986001 (AI467003): a phase 2b randomised, controlled, partly blinded trial

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