A Nucleoside- and Ritonavir-Sparing Regimen Containing Atazanavir Plus Raltegravir in Antiretroviral Treatment-Naïve HIV-Infected Patients: SPARTAN Study Results

Kozal, Michael J.; Lupo, Sergio; DeJesus, Edwin; Molina, Jean‐Michel; McDonald, Cheryl; Raffi, François; Benetucci, Jorge; Mancini, Marco; Yang, Rong; Wirtz, Victoria; Percival, Lisa; Zhang, Jenny; Zhu, Li; Arikan, Dilek; Farajallah, Awny; Nguyen, Bach‐Yen; Leavitt, Randi Y.; McGrath, Donnie; Lataillade, Max

doi:10.1310/hct1303-119

Cited by 85 publications

(67 citation statements)

References 22 publications

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“…These results coupled with the relatively limited CNS penetration of atazanavir [31] have reduced enthusiasm for MVC/ATV/r. In the SPARTAN study, atazanavir 300 mg twice daily plus raltegravir 400 mg twice-daily was associated with high rates of raltegravir resistance during VF and treatment-limiting hyperbilirubinemia [3]. Similarly, LPV/r 400/100 mg twice-daily plus EFV 600 mg daily was associated with high rates of NNRTI resistance during VF [1].…”

Section: Discussionmentioning

confidence: 99%

Virologic Response, Early HIV-1 Decay, and Maraviroc Pharmacokinetics With the Nucleos(t)ide-Free Regimen of MaravIroc Plus Darunavir/Ritonavir in a Pilot Study

Taiwo

Acosta

Ryscavage

et al. 2013

JAIDS Journal of Acquired Immune Deficiency Syndromes

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Objective To address the need for nucleos(t)ide reverse transcriptase inhibitor (NRTI)-sparing regimens, we explored the virologic and pharmacokinetic characteristics of maraviroc plus ritonavir-boosted darunavir in a single-arm, open-label, 96-week study. Methods 24 antiretroviral-naïve R5 HIV-1-infected participants received maraviroc 150 mg and DRV/r 800/100 mg (MVC/DRV/r) once-daily. The primary outcome was virologic failure (VF) = confirmed viral load (VL) >50 copies/mL at week 24 in the modified intent-to-treat population. To determine viral dynamics, participant-specific first- and second-phase empirical Bayes estimates were compared to decay rates from efavirenz plus lopinavir/ritonavir, lopinavir/ritonavir plus 2NRTIs and efavirenz plus 2NRTIs. Maraviroc plasma concentrations were determined at weeks 2, 4,12, 24 and 48. Results Baseline median (Q1, Q3) CD4 count and VL were 455 (299, 607) cells/mm3 and 4.62 (4.18, 4.80) log10 copies/mL, respectively. VF occurred in 3/24 participants (12.5 % [95% CI 2.7, 32.4]) at week 24. One of these resuppressed, yielding a week 48 VF rate of 2/24 (8.3 % [95% CI 1.0, 27.0]). The week 48 failures were 2 of the 4 (50%) participants with baseline VL >100,000 copies/mL. Week 96 VF rate was 2/20 (10 % [95% CI 1.2, 31.7]). Phase 1 decay was faster with MVC/DRV/r than reported for ritonavir-boosted lopinavir plus 2 NRTIs (p=0.0063) and similar to efavirenz-based regimens. Individual maraviroc trough concentrations collected between 20–28 hours post dose (n=59) was 13.7 to 130 ng/mL (Q1, 23.4 ng/mL; Q3, 46.5 ng/mL), and modeled steady-state concentration was 128 ng/mL. Conclusion MVC/DRV/r 150/800/100 mg once-daily has potential for treatment-naïve patients with R5 HIV-1.

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Section: Discussionmentioning

confidence: 99%

Virologic Response, Early HIV-1 Decay, and Maraviroc Pharmacokinetics With the Nucleos(t)ide-Free Regimen of MaravIroc Plus Darunavir/Ritonavir in a Pilot Study

Taiwo

Acosta

Ryscavage

et al. 2013

JAIDS Journal of Acquired Immune Deficiency Syndromes

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“…This may be due to increased potency of these regimens, although studies of NRTI sparing regimens have not been proven to be better than NRTI containing regimens in naïve patients. [12][13][14] It is possible that the use of additional drugs is beneficial in the setting of NRTI resistance. Alternatively, the additional pill burden may have induced higher rates of adherence, at least upon initiation of the regimen.…”

Section: Discussionmentioning

confidence: 99%

Development of the M184V Mutation in HIV-1 Infection and Subsequent Treatment Outcomes

Wilson¹,

Cross²,

Nurutdinova³

et al. 2015

HIV/AIDS Res Treat Open J

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CitationThe purpose of this study was to describe the occurrence of the M184V mutation in a single clinic setting over a period of 10 years. We examined the combination Antiretroviral Therapy (cART) being taken at the time of first identification of the M184V mutation as well as Second Line Regimens (SLR) started immediately after the documentation of M184V. SLR were evaluated for frequency and time to Virologic Suppression (VS) as well as frequency and time to subsequent Virologic Failure (VF). Prevalence of the M184V mutation, ART regimen leading to M184V acquisition, and outcomes of SLR in patients with M184V (as measured by time to initial VS and subsequent VF on SLR) were analyzed in a retrospective cohort study of all HIV-infected persons receiving care at a university clinic. Results: Of 2500 screened clinic patients, 220 had an acquired MI184V mutation (8.8%). There were 158(72%) male and 171(78%) African-American patients. The mean time from the start of a regimen to the documented M184V mutation was 575(0-3253) days. Independent of Nucleoside Reverse Transcriptase Inhibitor (NRTI) backbone, the mean time to development of M184V in Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) (n=109) and Protease Inhibitor (PI) based (n=84) regimens was 538(+/-556) and 622 (+/-620) days, respectively (p=0.325) approximately, 78% of patients achieved VS on a SLR in a mean of 179 days. Of the 122(57%) of patients whose SLR retained FTC/3TC, VS was achieved in 80% compared to 74% without FTC/3TC (p=0.285) with no significant difference in time to VS (152(+/-187) and 181(+/-257) days respectively, p=0.406). There were no significant differences in achievement of VS in PI (n=158) and NNRTI (n=27) -based SLRs independent of the NRTI backbone, 76% vs. 78%, respectively (p=0.837) with a similar time to VS (180(+/-228) vs. 128(+/-158) days, p=0.313). All patients on PI+Raltegravir (RAL) (n=10) and PI+NNRTI (n=12) -based regimens achieved VS (vs. 76% in PI+2NRTI (p=0.078 and p=0.054, respectively). Regardless of SLR, about 50% of each group experienced VF after VS with a similar time to failure. Conclusions: M184V mutation developed in 9% of patients in a mean of 575 days with no significant differences between ART regimens. Following initiation of an SLR, the majority of patients achieved VS in approximately 179 days irrespective of the regimen. The addition of 3TC/FTC did not significantly affect VS. Although numbers were small, 100% of patients on two fully active non-NRTI-backbone-based regimens attained VS. Approximately half of all patients subsequently failed on SLR, regardless of regimen used, suggesting that the development of M184V is a marker of noncompliance to therapy.

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“…Several trials addressed efficacy of NRTI-sparing regimens using boosted PIs and the integrase inhibitor raltegravir. In the randomized Spartan trial, which was not powered for statistical comparison of efficacy, twice-daily unboosted atazanavir plus raltegravir was compared to once-daily atazanavir plus two NRTIs in therapy naive patients (Kozal et al 2012). At 24 weeks of treatment, 74.6 % of patients in the dual arm had confirmed virological response, compared with 63.3 % in the standard of care arm.…”

Section: Double Boosting Protease Inhibitor-based Therapymentioning

confidence: 99%

HIV Protease Inhibitor Resistance

Wensing

Fun

Nijhuis

2014

Handbook of Antimicrobial Resistance

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HIV protease is pivotal in the viral replication cycle and directs the formation of mature infectious virus particles. The development of highly specific HIV protease inhibitors (PIs), based on thorough understanding of the structure of HIV protease and its substrate, serves as a prime example of structure-based drug design. The introduction of first-generation PIs marked the start of combination antiretroviral therapy. However, low bioavailability, high pill burden, and toxicity ultimately reduced adherence and limited long-term viral inhibition. Therapy failure was often associated with multiple protease inhibitor resistance mutations, both in the viral protease and its substrate (HIV gag protein), displaying a broad spectrum of resistance mechanisms. Unfortunately, selection of protease inhibitor resistance mutations often resulted in cross-resistance to other PIs.Therefore, second-generation approaches were imperative. Coadministration of a cytochrome P-450 3A4 inhibitor greatly improved the plasma concentration of PIs in the patient. A second advance was the development of PIs that were efficacious against first-generation PI-resistant HIV. Both approaches increased the number of protease mutations required by the virus to develop clinically relevant resistance, thereby raising the genetic barrier towards PI resistance. These improvements greatly contributed to the success of PI-based therapy.

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A Nucleoside- and Ritonavir-Sparing Regimen Containing Atazanavir Plus Raltegravir in Antiretroviral Treatment-Naïve HIV-Infected Patients: SPARTAN Study Results

Cited by 85 publications

References 22 publications

Virologic Response, Early HIV-1 Decay, and Maraviroc Pharmacokinetics With the Nucleos(t)ide-Free Regimen of MaravIroc Plus Darunavir/Ritonavir in a Pilot Study

Virologic Response, Early HIV-1 Decay, and Maraviroc Pharmacokinetics With the Nucleos(t)ide-Free Regimen of MaravIroc Plus Darunavir/Ritonavir in a Pilot Study

Development of the M184V Mutation in HIV-1 Infection and Subsequent Treatment Outcomes

HIV Protease Inhibitor Resistance

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