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Atazanavir in PI-Experienced Patients
Reported by Jules Levin
  In study 043 patients with PI experience received atazanavir (400 mg) or Kaletra, with NRTIs. Kaletra performed better in terms of antiviral effectiveness. Study 045 compared Atazanavir (ATV) 300 mg boosted by 100 mg of ritonavir (ATV/RTV) to Kaletra (lopinavir/r or LPR/RTV)). In study 045 a different set of PI experienced patients received ATV/r 300mg/100mg, Kaletra, or ATV/SQV 400mg/1200mg. In this study preliminary weeks 16 and 24 data show comparable antiviral activity between ATV/r (300/100) and Kaletra; and the early data suggests better affect on lipids by ATV/r compared to Kaletra. The FDA is currently reviewing this data. The FDA Antiviral Advisory Committee voted unanimously to approve atazanavir and the FDA is expected to issue their decision soon.
Immediately below are excerpts from information submitted by BMS to the FDA for the atazanavir FDA hearing, including a report of the data submitted on antiviral efficacy and lipids at weeks 16 and 24 of this study. Following this is a corresponence letter from German researchers that was published in the May 23 issue of the journal AIDS comparing cross-resistance to atazanavir, amprenavir (APV), and Kaletra in a group of PI-experienced patients. ATV and APV were unboosted in this analysis. There has not yet been a direct study comparison of APV/r to ATV/r. A direct comparison of Kaletra and APV/r suggests similar antiviral activity although Kaletra appeared to perform better. GSK suggested the difference could be due to baseline differences between patients. The lipid profile of ATV should be considered when contemplating a comparison of APV/r and ATV/r.
These are week 16 results and are therefore early/preliminary data. In the highly treatment-experienced population (AI424045), both ATV-containing regimens were associated with superior lipid parameters compared to LPV/RTV, as assessed by the mean percent change from baseline at Week 16 in total cholesterol (ATV/RTV: -7%; ATV/SQV: -10%; LPV/RTV: +5%) and fasting triglycerides (ATV/RTV: 2%; ATV/SQV: -15%; LPV/RTV: +34%). Mean percent changes from baseline in fasting LDL-cholesterol at Week 16 for ATV 400/SQV were superior compared to LPV/RTV (ATV/SQV: -10%; LPV/RTV: +1%). At Week 16, fasting LDL-cholesterol concentrations outside the desirable range (values >130 mg/dL) were comparable across the three treatment regimens. Thirty-eight subjects (11%) took serum lipid reduction therapy while on study, 7% on ATV 300/RTV, 12% on ATV 400/SQV, and 14% on LPV/RTV. More importantly, 3% of subjects each on ATV 300/RTV and ATV 400/SQV and 8% of subjects on LPV/RTV initiated serum lipid reduction therapy while on study. HDL-chol declined 6% in the ATV/r arm vs no change for patients on LPV/r. To my understanding of this data "data from subjects who initiated lipid-lowering therapy were censored from these analyses".
The Phase III study AI424045 is an ongoing multi-national, open-label, randomized, three-arm study designed to determine the antiviral activity and tolerability of ATV (300 mg)/RTV (100 mg), ATV (400 mg)/SQV (1200 mg), and LPV/RTV, each in combination with TFV and an NRTI (after two weeks), through 48 weeks. The study targeted subjects who were highly treatment-experienced, having failed at least two prior HAART regimens that included members of each of the three classes of approved HIV treatments. Analysis suggested the ATV/RTV boostedld regimen was providing efficacy comparable to LPV/RTV, while the combination of ATV 400/SQV appeared to be less effective. Additionally, data on all randomized subjects through Week 24 have recently become available; however, they have not been formally reviewed by the FDA. The majority of randomized subjects had recently taken a NRTI (96%) or NNRTI (60%), whereas only 34% had taken a PI. The most common ARV agents taken within 90 days of study entry were d4T (63%), 3TC (54%), and EFV (38%). For randomized subjects, the mean exposure to any PI, NRTI, or NNRTI therapy was 138, 280, and 85 weeks, respectively.
Sensitivity to a specific PI ( 2.5 x IC50 of control strain) ranged from 56% to 83%, with 23% of the treated subjects highly resistant (> 10 x IC50 of control strain) to NFV and 21% of the subjects highly resistant to RTV. Seventy-four percent (74%) and 75% of subjects were susceptible to ATV and LPV, respectively. Susceptibility to ATV or LPV was comparable across the treatment regimens. An important caveat regarding interruption of baseline PI susceptibility data is that only 34% of randomized subjects were taking a PI at study entry. This would lead to PI susceptibility measurements that are overstated (ie, resistance, therefore, being understated). A total of 347 subjects (97%) started therapy. Of those treated, 20 subjects (6%) discontinued prior to the Week 16 visit. A total of 312 subjects (87%) continued on study therapy, 91% on ATV 300/RTV, 83% on ATV 400/SQV, and 87% on LPV/RTV.
Comparable antiviral efficacy of the ATV 300/RTV regimen to the LPV/RTV regimen was the primary efficacy endpoint through Week 16 and was apparent. In contrast, the antiviral efficacy of the ATV 400/SQV regimen was less than that of the LPV/RTV regimen. During the first two weeks, HIV RNA levels declined by 1.18 log10 c/mL for ATV 300/RTV, 1.14 log10 c/mL for ATV 400/SQV, and 1.30 log10 c/mL for LPV/RTV and appear comparable across treatment regimens. At Week 16, the virologic failure rate was 32% on ATV 300/RTV, 40% on ATV 400/SQV, and 28% on LPV/RTV. The most common reason for virologic failure was lack of confirmed response. The proportion of subjects in response was comparable between ATV 300/RTV and LPV/RTV (ITT: [LOQ = 400 c/mL]: 63% vs 65%; [ITT: LOQ = 50 c/mL]: 30% vs 33%). Week 16 (ITT) response rates for ATV/SQV were lower than those for the LPV/RTV regimen (46% vs 65% for LOQ = 400 c/mL). ITT week 16 response for ATV/SQV was 23% <50 copies/ml. Week 24 data was presented by BMS at the FDA hearing and showed similar findings. Week 24 data was not reviewed by the FDA because they did not have the time to review it based on when it was submitted and the date of the hearing but presumably they are reviewing it now as they prepare the label for ATV.
AIDS 2003; 17(8):1258-1261
Distinct cross-resistance profiles of the new protease inhibitors amprenavir, lopinavir, and atazanavir in a panel of clinical samples
Tanja Schnell; Barbara Schmidt; Gitta Moschik; Christine Thein; Christiane Paatz; Klaus Korn; Hauke Walter. Institute of Clinical and Molecular Virology, German National Reference Centre for Retroviruses, University of Erlangen-Nurnberg, Erlangen, Germany.
A panel of 245 clinical samples with known treatment histories was retrospectively evaluated for cross-resistance to new protease inhibitors (PI). Samples with resistance to previously approved PI displayed high cross-resistance to atazanavir, whereas cross-resistance to amprenavir was considerably lower. A similar cross-resistance profile was observed for lopinavir, if a higher cut-off for resistance (9.5-fold) was applied. The enhanced efficacy of boosted PI is discussed with respect to clinically relevant cut-offs for drug resistance.
Protease inhibitor (PI)-based regimens play an important role in combination therapy for HIV-infected patients. However, PI use is limited because of severe side-effects, high pill counts and pharmacokinetic constraints, e.g. short plasma elimination half-lives and variable oral bioavailability. Furthermore, broad cross-resistance has been described for the previously approved PI. These limitations may be overcome by new PI with favourable cross-resistance profiles and by exploiting drug interactions through cytochrome P450 3A4 (CYP3A4) isoenzymes. The boosting of PI trough levels by low doses of ritonavir and combinations of PI are becoming increasingly popular, particularly for PI salvage therapy. The effect of this boosting on clinically relevant cut-offs, however, is largely unknown. Recently, the new PI amprenavir and lopinavir have been approved, and atazanavir will follow soon. However, the cross-resistance profiles of these drugs remain to be defined.
To analyse the cross-resistance profiles of the new PI, a panel of 245 clinical samples was retrospectively evaluated. These were derived from 226 HIV-infected patients treated at more than 20 centres in Germany between January 1998 and July 2002. Samples were selected for the availability of treatment histories. Previous PI use included indinavir (n = 108), saquinavir (n = 119), ritonavir (n = 116), nelfinavir (n = 109), amprenavir (n = 35), and lopinavir (n = 18). Nineteen per cent of patients had received no PI, 20% had received one PI, 24% two PI, 16% three PI, 14% four PI, 5% five PI, and 1% had been treated with six PI. All patients were naive for atazanavir.
Resistance testing was performed retrospectively by a recombinant virus assay as described previously. In brief, patient-derived protease and reverse transcriptase genes were cloned into a matched proviral deletion mutant. The drug susceptibility of recombinant viruses was determined on an indicator cell line. The fold reduced susceptibility to the respective PI was determined by dividing the IC50 of the recombinant virus from the patient by the IC50 of the non-resistant reference virus.
A more than 3.5-fold reduced susceptibility was observed in 113 samples for indinavir (46.1%), 106 for saquinavir (43.3%), 107 for ritonavir (43.7%), 125 for nelfinavir (51.0%), 81 for amprenavir (33.1%), 90 for lopinavir (36.7%), and 106 for atazanavir (43.3%). For lopinavir, analysis was also performed for more than 9.5-fold reduced susceptibility, because this clinical cut-off was suggested in the Food and Drug Administration (USA) approval --(http://www.fda.gov/cder/drug/infopage/kaletra/default.htm). The number of lopinavir-resistant samples was reduced to 65 (26.5%).
To compare the cross-resistance profiles of amprenavir, lopinavir, and atazanavir, all samples derived from patients pretreated with amprenavir or lopinavir (n = 43) were excluded. In a first analysis, cross-resistance was evaluated for all samples with more than 3.5-fold reduced susceptibility to indinavir, saquinavir, ritonavir, and nelfinavir, respectively. Samples resistant against at least one of these PI frequently displayed cross-resistance to atazanavir (78.3-85.5%), whereas cross-resistance to lopinavir (62.0-75.0%) and in particular to amprenavir (58.7-67.1%) was considerably lower. If 9.5-fold reduced susceptibility was used as a cut-off for lopinavir, cross-resistance was reduced to 44.6-53.9%.
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