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Fosamprenavir/r QD v Reyataz/r ALERT Study 48 Weeks
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Once-Daily Ritonavir (100mg) Boosting of Fosamprenavir (FPV/r) or Atazanavir (ATZ/r) with Tenofovir(TDF)/Emtricitabine(FTC) in
ART-Naive HIV-Infected Patients: 48-week Safety/Efficacy Results from COL103952 (ALERT)
Reported by Jules Levin
4th IAS Conference, 22-25 July, 2007, Sydney, Australia
Smith K.1, Weinberg W.2, DeJesus E.3, Fischl M.4, Liao Q.5, Ross L.5, Pappa K.5, Lancaster T.5
1Rush University Medical Center, Chicago, United States; 2Kaiser Permanente, Atlanta, United States; 3Orlando Immunology Center, Orlando, United States;
4University of Miami, Miami, United States; 5GlaxoSmithKline, Research Triangle Park, United States
AUTHOR DISCUSSION
Despite being randomized, the baseline characteristics were slightly different with respect to racial composition and CD4 cell count.
Discontinuations unrelated to efficacy contributed to some of the ITT (MD=F) differences at Week 48.
Differences in the use of lipid lowering agents was attributable to higher proportion of FPV/r patients with triglyceride shifts from baseline that met NCEP III guidelines for treatment.
GFR changes were noted on both arms.
AUTHOR CONCLUSION
FPV/r QD and ATV/r QD, both in combination with TDF/FTC FDC, provided similar rates of virologic and immunologic improvements through week 48
Lipid changes were similar for both arms
Overall, fewer grade 2-4 treatment-related adverse effects occurred with FPV/r than with ATV/r and differences were due primarily to bilirubin.
GFR should be monitored closely when TDF/FTC is used with boosted PIs.
Introduction
Prior to COL10053 (Ruane et. al., Table 1 below), the usual once-daily (QD) FPV/r dose was 1400mg FPV + 200mg RTV for ART-naive patients. PK results from COL10053 showed a lower dose of RTV was possible with QD FPV.
This study compared FPV/r 1400mg QD boosted with low-dose RTV (100 mg) (FPV/r) to ATV 300mg QD + RTV 100mg QD (ATV/r).
Both boosted PI regimens were combined with the combination tablet
tenofovir 300mg with emtracitibine 200mg (TDF/FTC).
In 2006, IAS Treatment Guidelines added boosted PIs + 2 NRTIs as
recommended initial therapy.
Figure 1. Median Plasma Amprenavir Concentration-Time Profiles
from COL10053 and Historical Data Lexiva 1400 qd + rtv 100mg qd compared to rtv 200 mg qd)
METHODS
STUDY DESIGN
This is a randomized (1:1), open-label, 48 week study. 106 ART-naive patients received either FPV 1400mg once daily (QD), RTV 100mg qd plus TDF/FTC qd (n=53) or Reyataz (ATV) 300mg qd, RTV 100mg qd plus TDF/FTC qd (n=53).
Entry requirement was HIV RNA >1,000 cp/ml with no CD4 restrictions. Stratification by entry HIV RNA <100k >100k cp/ml. No baseline resistance testing was done.
Study Endpoints (Week 48)
Primary
--Proportion of patients with HIV RNA VL <50 cp/ml
Secondary
--Proportion of patients with HIV RNA VL<400 cp/ml
--Change from baseline in CD4 cell count
--HIV treatment-emergent resistance
--Differences in adverse experiences (incidence, type and severity)
RESULTS
Table 1. Baseline Characteristics
80-90% men age-40. 62% African-Americans taking FAPV/r, 49% taking ATV/r, 23% Hispanic in both groups. Median HIV RNA 4.9 logs, and CD4 176 in FPV/r and 205 in ATV/r arms. % >100,000: 45% in both groups. Median CD4 count <50: 26% in FAPV, 17% in ATV/r. 50-200 cells: 40% FAPV, 36% ATV/r. Mean GFR (GFR by MDRD in mL/min/1.73m2): 87.7 FPV, 90.6 ATV.
Table 2. Completion Status at Week 48
Discontinuation: 15% in FPV/r, 8% ATV/r.
Figure 3. VL <50 c/mL at Week 48 Figure 4. VL <400 c/mL at Week 48
<50 c/ml (MD=F): ATV/r 83%, FPV/r 75% (p=0.338)
<400 c/ml (MD=F): 87% ATV/r, 79% FPC/r (p=0.303)
Table 3. Patients Counted as Failures in the ITT(MD=F) <50 cp/mL
Analysis at Week 48
Rates of viral failure were similar.
Figure 5. Mean (±SD) CD4 Cell Counts
Mean increase in CD4 from baseline to 48 weeks is 355 for FPV/r and 392 for ATV/r.
Figure 6. Median Fasting Cholesterol and Trigs at Baseline and
Week 48
Cholesterol increased from 160 to 171 mg/dl for FPV/r and from 153 to 180 mg/dl for ATV/r from baseline to week 48. Triglycerides increased from 116 to 150 mg/dl for FPV/r and from 124 to 131 for ATV/r from baseline to week 48. Fasting lipids from 5 FPV/r patients were censored after starting lipid lowering agents post-baseline.
Figure 7. Median Fasting HDL and LDL-Cholesterol at Baseline and
Week 48
HDL increased from 38 to 43 mg/dl for FPV/r from baseline to week 48, and for ATV/r from 37 to 48 mg/dl. LDL increased from 95 to 99 for FPV/r, and from 97 to 101 for ATV/r.
Figure 8. Highest Post-Baseline Shift in Triglycerides by Treatment
Arm using NCEP III Categories (not censored, all patients)
Table 4. Grade 2-4 Treatment-Related AEs by Overall Frequency >5%
As expected there were bilirubin increases and hyperbilirubinemia associated
with ATV/r. Diarrhea was 8%, n=4 in FPV and 4% n=2 in ATV.
Figure 9. GFR Declines from Baseline at Week 48 or Last
Observation Carried Forward While on TDF/FTC*
*3 patients switched from TDF/FTC to ABC/3Tc
Mean (SD) change in GFR (mL/min/1.73m2) at Week 48
or LOCF on TDF/FTC
FPV/r + TDF/FTC= +4.0 (19.8)
ATV/r + TDF/FTC = -3.5 (15.3)
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