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Reyataz/r Compared to Kaletra (study 045): 48 week data
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Reported by Jules Levin
Summary of 48 week study results: baseline viral load was 27,000 copies/ml, CD4 count was 290. This patient group was highly experienced with resistance to all classes of HIV drugs. HIV viral load reduction was –1.93 log for ATV/r and –1.87 log for LPV/r; percent of patients <400 copies/ml: 53% ATV/r, 54% LPV/r, 37% ATV/sqv (ITT); percent below 50 copies/ml: 42% LPV/r, 36% ATV/r, 24% ATV/sqv (ITT). CD4 cell counts increased 110 for ATV/r, 121 for LPV/r, 72 for ATV/sqv. ATV/r had favorable lipid profile: total cholesterol decreased 8% on ATV/r vs increase of 6% on LPV/r (p-value: <0.005); fasting triglycerides decreased 4% on ATV/r vs 30% increase on LPV/r (p-value: <0.005). Use of lipid lowering agents: on study 8% of patients receiving ATV/r used lipid lowering agents vs 19% on LPV/r (p<0.05). Adverse events: grade 2-4 diarrhea was the main AE for patients on LPV/r (11%) compared to ATV/r (3%); jaundice was the main AE associated ATV/r (6%) vs 0% for LPV/r (study authors reported there were no patient withdrawals due to jaundice); 3% of patients on ATV/r experienced sceral icterus (yellowing of eyes). 39% of patients receiving ATV/r experienced grade 3 bilirubin elevations and 9% experienced grade 4 elevations vs 0 for LPV/r; grade 3-4 ALT elevations were the same for both ATV/r and LPV/r (3-4%). Useof anti-diarrheal agents on study: 24% for LPV/r vs 6% for ATV/r (p=0.001).
The study authors summarized: ATV/r demonstrated similar efficacy with LPV/r (non-inferior). ATV/r was safe and well tolerated. Total bilitrubin elevations and jaundice/scleral icterus were observed for patients on ATV/r without hepatotoxicity, and neither resulted in discontinuation for any patient. Diarrhea was more common on LPV/r as well as use of diarrheal agents. Lipid profile was more favorable for ATV/r.
Edwin DeJesus and colleagues and BMS reported these study results.
ATV (atazanavir, a/k/a Reytataz) is an azapeptide protease inhibitor (PI) with a pharmacokinetic profile that allows for once-daily dosing. ATV trough levels are boosted 5–8 fold by RTV co-administration. The objectives of this study conducted by Bristol Myers Squibb are to compare the efficacy and safety of ATV/RTV and ATV/SQV to LPV/RTV in 358 highly treatment-experienced HIV-infected patients, each co-administered with tenofovir (TDF) and 1 NRTI in highly treatment-experienced patients. Upon enrollment patients were failing therapy virologically on a PI or NNRTI regimen. Week 48 results are presented here. This study is a registrational study for the FDA, and BMS is submitting it to the agency by this June to gain approval for Reyataz to be officially approved for use of the regimen—Reyataz 300mg/RTV 100mg. Although not officially approved at this moment, BMS presented 24 weeks results from this study at the FDA hearing for approval in the Spring of 2003; Physicians have been using this regimen since Reyataz was approved by the FDA in Spring 2003.
Multinational, multicenter, randomized, open-label study in treatment-experienced patients with virologic failure on >=2 HAART regimens that included, in total, >=1 PI, NRTI, and NNRTI.
Pharmacokinetic enhancement ("boosting") of PI drug levels through co-administration of low-dose RTV has become an important tool in the treatment of HIV-infected patients who have experienced virologic failure. LPV/RTV was the first RTV-boosted PI regimen to receive approval by the US Food and Drug Administration and is currently an accepted standard of care.
ATV treatment has not been associated with clinically relevant elevations in TC, fasting LDL-C, or fasting TG. The primary objective of this study is to compare the magnitude and durability of plasma HIV RNA reductions from baseline through week 48. The secondary study objectives are to:
--evaluate the change from baseline in plasma HIV RNA at week 2
--assess the proportion of patients with plasma HIV RNA <400 and <50 copies/mL through week 48
--assess the change from baseline in CD4 cell count through week 48
--general safety and tolerability
--metabolic parameters: total cholesterol (TC), fasting LDL-C (bad cholesterol), HDL-C (good cholesterol), fasting triglycerides (TG)
Inclusion criteria in this study
--Currently failing HAART regimen with 2 qualifying viral load measurements >=1000 copies/mL
--CD4 cell count >=50 cells/mm3
--Patients received ATV/RTV 300/100 mg QD, ATV/SQV 400/1200 mg QD, or LPV/RTV 400/100 mg BID, each combined with TDF 300 mg QD and 1 NRTI
--In the primary analysis, similarity (noninferiority) of efficacy between either of the ATV regimens and the LPV regimen was based on an upper 97.5 confidence interval (CI) for the time-averaged-difference estimate of <0.5 log10 copies/mL.
Patient Demographics
20% female; 60% White, 22% Hispanic; 17% African-America. 29% had AIDS. Median baseline HIV viral load was 27,000 copies/ml, and 290 CD4s. Prior ART use (median, yr): 2.5 PI, 5 NRTI, 1.4, NNRTI. 16-19% of patients had hepatitis B or C; 28% had AIDS
--Baseline phenotypic sensitivity (<=2.5 x IC50 of a control strain) to the PI to which patients were randomized (ATV or LPV) was present in 73% of the ATV 300/RTV patients, 72% of the LPV/RTV patients, and 73% of the ATV 400/SQV patients
--The mean time on study therapy was approximately 47 weeks for the ATV 300/RTV group, 48 weeks for the LPV/RTV group, and 44 weeks for the ATV 400/SQV group
--Total discontinuations: adverse events- 4 (ATV/RTV), 2 LPV/ RTV, 6 ATV/SQV; treatment faulre/lack of efficacy- 14 (ATV/RTV), 5 LPV/RTV, 10 ATV/SQV; other- 3 ATV/RTV, 3 LPV/RTV, 10 ATV/SQV.
TREATMENT HISTORY OF PATIENTS
You can see from the table immediately below that prior ART use was extensive but comparable between the 3 study arms: 4.5 years prior PI use, almost 2.5 yrs prior NRTI use, 1.5 yrs prior NNRTI use. Regimen patients were taking just prior to randomization to study drugs: ATV/r 36% PI, 61% NNRTI; LPV/r 37% PI, 59%NNRTI; ATV/sqv 31% PI, 66% NNRTI.
| Prior ART Use Weeks (range) |
ATV/r |
LPV/r |
ATV/sqv |
| N |
120 |
123 |
115 |
| Prior PI use |
269 (48-782) |
265 (.1-679) |
255 (25-762) |
| Prior NRTI Use |
133 (.1-321) |
136 (.1-346) |
127 (.1-470) |
| Prior NNRTI Use |
78 (.1-227) |
69 (.1-304) |
86 (7-192) |
RESULTS
MEAN CHANGE in HIV RNA THROUGH WEEK 48
At week 48 viral load reduction was: -1.87 log10 copies/ml for LPV/RTV, -1.93 log10 copies/ml for ATV/RTV, and –1.55 log10 copies/ml for ATV/SQV.
VIROLOGIC RESPONSE <400 copies/ml through 48 weeks (ITT)
ATV/r: 53% (71% as treated)
LPV/r: 54% (66% as treated)
ATV/r: 37% (38% as treated)
VIROLOGIC RESPONSE <50 copies/ml through 48 weeks (ITT)
LPV/r: 42% (54% AT)
ATV/r: 36% (52% AT)
ATV/sqv: 24% (38% AT)
CD4 cell count increased after 48 weeks 121 for LPV/r, 110 for ATV/r, and 72 for ATV/sqv.
LIPID EVALUATION THROUGH 48 WEEKS (patients on lipid lowering therapy excluded)
Total Cholesterol
ATV/r: -8%
LPV/r: +6%*
ATV/sqv: -4%
Fasting LDL-C
ATV/r: -10%
LPV/r: +1%
ATV/sqv: -3%
HDL-C
ATV/r: –7%
LPV/r: +2%
ATV/sqv: +4%
Fasting Triglycerides
ATV/r: -4%
LPV/r: +30%*
ATV/sqv: -14%
*both ATV regimens vs LPV/r: p-value <0.005
REDUCED USE OF LIPID LOWERING AGENTS WITH ATV/r
Serum lipid reducing agents: atorvastatin, bezafibrate, fenofibrate, gemfibtozil, lovastatin, pravastatin)
Prior Use
6% ATV/r
5% LPV/r
7% ATV/sqv
On Study
8% ATV/r (p-value <0.05 for ATV/r vs LPV/r)
19% LPV/r
12% ATV/sqv
ADVERSE EVENTS*
Grade 2-4 related adverse events
| ATV/r | LPV/r | ATV/sqv |
| N | 119 | 118 | 110 |
| Total | 29 | 25 | 26 |
| Diarrhea | 3 | 11 | 6 |
| Jaundice | 6 | 0 | 2 |
| Nausea | 3 | 2 | 8 |
| Vomiting | 0 | <1 | 4 |
| Scleral icterus | 3 | 0 | 0 |
| Withdrawal due to AE** | 5 | 4 | 7 |
*>=5% of patients, **no patients withdrew treatment due to jaundice
LABORATORY CHANGES
Grade 3-4 lab parameter in %
| ATV/r | LPV/r | ATV/sqv |
| N | 119 | 118 | 110 |
| Bilirubin grade 3* | 39 | <1 | 19 |
| Bilirubin grade 4* | 9 | 0 | 2 |
| SGPT | 4 | 3 | 4 |
| SGOT | 3 | 3 | 2 |
*no patient withdrew due to bilirubin elevation
USE OF ANTIDIARREAL AGENTS
6% ATV/r
24% LPV/r (p=0.001 ATV/r vs LPV/r)
13% ATV/sqv (p=0.04 LPV/r vs ATV/sqv)
EFFICACY SUMMARY
The study authors concluded that ATV 300 mg boosted with RTV mg once daily demonstrated efficacy similar (non-inferior) to a standard of care (LPV/r) in highly treatment experienced patients through 48 weeks.
ATV/r was safe & well tolerated
ATV/r (300/100) had a more favorable lipid profile than LPV/r
--lipid levels generally decreased on both ATV-containing regimens and generally increased on LPV/r
--LPV/r produced statistically significant increases in total cholesterol and fasting triglycerides (p<=0.005) compared with ATV 300/rtv (TG: 30% increase in LPV/r vs 4% decrease in ATV/r arm; Total cholesterol: decreased 8% in ATV/r arm vs 6% increase in LPV/r arm)—excluding patients on lipid lowering agents
--fewer patients were administered lipid-lowering therapy while on either ATV-containing regimen than on LPV/r (8% inn ATV/r arm vs 19% in LPV/r arm)
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