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908/r QD in Treatment-Naïve 96 weeks Followup of SOLO
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Reported by Jules Levin
48 week SOLO Study results comparing 908/r with nelfinavir bid were just published, here is link to read study results:
http://www.natap.org/2004/Bangkok/bangkok_33.htm
At the Intl AIDS Conference in Bangkok Joe Gathe et al (poster B4507) reported on a followup study of SOLO. In SOLO patients were randomized to 908/r 1400/200 mg QD compared to nelfinavir bid, plus abacavir/3TC. The followup study reports 96 weeks data.
908 is a new PI recently approved in the US (Lexiva) and under review in Europe (proposed tradename Telzir). In ART-naïve subjects, 908 has been studied in clinical trials as once daily (QD) dosing with ritonavir (RTV), or twice daily (BID) dosing with or without RTV. 908 now comes in 700 mg tablets so the pill burden is4 tablets a day for these regimens. There are no food or fluid restrictions when taking 908 and it has a distinct resistance profile. Similar to Kaletra PI resistance so far has not been seen.
This interim analysis reports 96-week data for ART-naïve subjects who completed at least 48 weeks on a 908/r 1400 mg/200 mg QD regimen in SOLO (APV30002) and continued this 908/r QD regimen in APV30005. In SOLO,subjects received a background regimen of abacavir (ABC) 300 mg BID and lamivudine (3TC) 150 mg BID. Once subjects enrolled in APV30005, background regimens were at the discretion of the investigator and subject to change or optimization at any time.
RESULTS
322 subjects were randomized to and received 908/r QD in SOLO. Of these, 231 subjects completed SOLO on a 908/r QD regimen and 220 enrolled in APV30005. 10/220 were excluded from the 908/r QD population because of changes to their 908 regimen (discontinuing RTV and/or changing to a BID regimen), thus providing 210 subjects for this analysis. Because the data cut was taken at a specific time point, not all subjects had reached Week 96 as of the cut-off date: 115 subjects reached the Week 96 assessment window.
Baseline demographics of the 210 subjects in the APV30005 interim analysis are those collected at the time of entry into SOLO. For this subset, demographics were similar to those of all subjects initially enrolled in SOLO.
BASELINE DEMOGRAPHICS
908/r, n=210
Females: 28%
Median age: 36 yrs
White, Black, Hispanic: 49%, 39%, 8%
Heterosexual contact, MSM: 49%, 37%
HepatitisB, C: 9%, 12%
CDC Class C: 21%
Median viral load: 4.82 log
HIV RNA >100,000: 45
Median CD4: 168
CD4 <50: 20%
175/210 (83%) subjects in the 908/r QD population entered APV30005 on an ABC/3TC background. Of those, 94% (164/175) remained on ABC/3TC as of data cut-off.
PATIENT DISPOSITION
91% (191/210) contuing 908/r
Discontinued from 908/r QD: 9% n=19
Withdrew from study: 8% n=17
Switched to 908/r bid: 1% n=2
REASONS FOR PREMATURE DOSCONTINUATION:
--consent withdraw: 2% n=5
--AE: 2% n=4
--lost to follow-up: 1% n=3
--non-adherence: <1%, n=1
--insufficient VL response: <1% n=1
--other: 2% n=5
VIRAL RESPONSE <400 & <50 (observed)
Responses seen at week 48 in SOLO were maintained. At Week 96, 96% (109/113) and 86% (97/113) of subjects with data had vRNA <400 copies/mL and <50 copies/mL, respectively. Median CD4+ cell count at Week 96 was 461 cells/mm3 (range 103-1333), with median change from baseline increasing from +205 cells/mm3 at wk 48 to +263 cell/mm3 at Week 96.
RESISTANCE
11 subjects in APV30005 met the criteria for inclusion in the virologic failure (VF)/ongoing replication population (>1000 copies/mL at two consecutive time points) as of the cut-off date. 10/11 remained on ABC+3TC background, while the other subject switched to a zidovudine + 3TC background at Week 2.
5/11 subjects were new failures in APV30005. The other 6 subjects had been previously classified as failures in SOLO and either resuppressed or stayed on a failing regimen in APV30005.
There were no primary PI mutations and only one reverse transcriptase mutation, a M184m/v mixture. 9/11 subjects had susceptibility data, and no phenotypic resistance was observed for any PI or RTI. A small shift was detected for 3TC in the subject with M184m/v, indicating the mixture was predominantly wild-type.
SAFETY
Median duration of exposure to 908/r QD was approximately 92 wks (range 53-121 wks).
Drug-related Grade 2-4 AEs were reported by 41% of subjects on 908/r QD throughout SOLO and APV30005. There were no new cases of drug-related Grade 2-4 drug hypersensitivity or diarrhea and only 1 new case of drug-related Grade 2-4 nausea reported during APV30005.
After Week 48, few subjects experienced new Grade 3/4 laboratory abnormalities in APV30005:
--Grade 3/4 ALT elevations (2%)
--Grade 3/4 AST elevations (<1%)
--Grade 3/4 triglyceride elevations (1%)
DRUG-RELATED ADVERSE EVENTS OF AT LEAST MODERATE SEVERITY
| Number (%) of subjects with adverse events | SOLO + APV30005
908/r QD
n=210 | SOLO
908/r QD
n=322 | | Diarrhea | 19 (9%) | 28 (9%) | | Drug hypersensitivity* | 14 (7%) | 24 (7%) | | Nausea | 15 (7%) | 21 (7%) | | Vomiting | 7 (3%) | 19 (6%) | | Fatigue | 6 (3%) | 11 (2%) | | Headache | 8 (4%) | 8 (2%) | | Abdominal Pain | 3 (1%) | 8 (2%) | | ALT increased | 4 (2%) | 8 (2%) | | AST increased | 3 (1%) | 8 (2%) |
*All 14 cases of drug hypersensitivity occurred while the subjects participated in SOLO and were attributed to ABC, which was defined as a study drug in SOLO. There were no new cases of drug hypersensitivity in APV30005.
MEAN CHANGE FROM SOLO BASELINE IN LIPIDS
Baseline lipids in SOLO were normal.
TG: +77
Total chol: +49
HDL Chol: +12
Fasting HDL cholesterol levels continuously improved to a mean percent increase from baseline of +36% at Week 96.
There was no clinically relevant mean percent change from baseline observed for the TC/HDL-C ratio (+2.5% at Week 96).
At Week 96, small mean changes from baseline were observed in fasting glucose (+10 mg/dL), and mean decreases from baseline were observed for ALT (-7 µ/L) and AST (-14 µ/L).
New use of anti-hyperlipidemics in APV30005 (after Week 48) was reported by only 5 subjects (2%).
AUTHOR'S DISCUSSION
APV30005 included subjects with advanced HIV disease (at SOLO baseline, 45% had vRNA >100,000 copies/mL, median CD4 cell count was 168 cells/mm3, and 21% were CDC Class C). Females (28%) and minorities (39% Black, 8% Hispanic) were well represented.
Long-term treatment with 908/r QD in this study population resulted in sustained virological suppression over the 96-week study period: 96% had vRNA <400 copies/mL and 86% had <50 copies/mL (observed)
Median change from baseline CD4+ cell count increased to +263 cell/mm3 at Week 96 indicating continued immune system reconstitution.
The absence of PRO and few NRTI mutations observed in both SOLO and APV30005 (VF/ongoing replication population) is indicative of the high efficacy and high overall genetic barrier of this triple combination of 908/r QD with ABC+3TC.
The low percentages of new AEs and low number of discontinuations due to AEs (4 subjects) in APV30005 indicates no new safety concerns for the treatment regimen.
There was no additional mean increase in triglycerides or total cholesterol in the second year of this study, although the number of subjects is smaller at the 96-week timepoint. HDL cholesterol continued to increase with a mean change from baseline of +12 mg/dL at Week 96.
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