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KALETRA MONOTHERAPY
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"PILOT STUDY of the SAFETY & EFFICACY of LOPINAVIr/ritonavir (KALETRA) as SINGLE AGENT THERAPY in HIV-1 ARV NAÏVE PATIENTS"
Jules Levin
Joe Gathe presented an update, final 48-week analysis, in the first HIV oral session yesterday with a report on data at 48 weeks in his PILOT study of Kaletra as monotherapy. He emphasized this is a pilot study and not ready to be used in patients except in clinical studies.
Gathe provided background. LPV/r has ideal characteristics for single agent therapy: short-term activity comparable to triple HAART; 24 hour pharmacokinetics significantly above IC50 of WT virus; lack of genotypic/phenotypic resistance at time of failure in naïve patients. Gathe said what motivated this study was restricted access to HIV therapy for economic factors. In the USA ADAP funding has been inadequate. Numerous States have pu into place access restrictions to HAART through ADAP due to funding restrictions. Texas, where Gathe is located, is one of those States.
STUDY METHODS
--48 week open label pilot study
--subjects accrued from March 2002 to March 2003 from a single inner city clinic
INCLUSION CRITERIA
Age>18
VL >2000
ARV naïve
No CD4 criteria
EXCLUSION CRITERIA
Life threatening active AIDS defining illness
Viral load by Roche Amplicor 1.5 assay
Resistance testing: genotype by Truegene, phenotype by Phenosense
KALETRA DOSING
<70 kg weight of patient—received 400/100mg bid (3 caps)
>70 kg weight—533/133mg bid (caps)
Intensifcation was allowed at any point with either TDF/SQV or SQV.
PRIMARY ENDPOINTS
--delta VL at 12, 24, and 48 weeks
--% subjects <400 copies at week 48
--incidence of adverse events
SECONDARY ENDPOINTS
--% of subjects <50 copies at 48 weeks
--CD4 count changes
BASELINE CHARACTERISTICS
N=30
93% men
60% white, 20% Black, 20% Hispanic
mean age: 35 years (range 20-58)
mean plasma HIV RNA: 262,000 copies (range 4000 to >750,000 copies)
Mean CD4 count: 169 cells (range 7-425)
CD4 count <400: 70%
Cd4 count <50: 43%
% VL >100,000: 57%
RESULTS
SUBJECT DISPOSITION at WEEK 48
Lost to followup: 2
Adverse events: 2
Virologic failure: 2
Deported: 1
Hepatitis B: 1
--Subject 023 was deported at week 16 and had a VL drop of 2.2 log (259,000 to 621).
--subjects 025 & 026 discontinued therapy due to GI intolerance at W1 & W12
--subject 017 was found to have active hepatitis B and had to add TDF/3TC at week 12.
VIRAL RESPONSES (As-Treated)
Mean baseline VL= 5.41 log, n=30. At week 12, viral load reduction was 2.09 log (n=28); at week 24 (n=21) viral load reduction was 2.57 log; at week 48 (n=20), VL reduction was 3.71 log.
% OF PATIENTS <400 COPIES AT WEEK 48
As-Treated n=20 of 30: 100%
ITT, n=20 of 30: 67%
% OF PATIENTS <50 COPIES AT WEEK 48
AT, n=18 of 20: 90%
ITT, n=18 of 30: 60%
MEAN CD4 COUNT INCREASE (AT)
317 cells, Range (121-514) at week 48. 220 at week 24.
Gathe said he reviewed in detail the 4 patients who did not reach viral loads less than 50.
Subject 010. VL was >500,000 at baseline. And 1500 at week 24. CD4 count increased from 47 at baseline to 250 at week 24. VL was 4200 at week 32 (L63P), cd4 317. LPV trough 6.95 (expected trough 5.50 mg/ml). Intensified with SQV at week 32. At week 40 VL had increased to 12,100 and CD4 was 372. Added 3TC/TDF & stopped SQV at week 40. At week 48, VL was <50 & CD4 was 352.
Subject 016. Baseline VL was 220,000 copies & Cd4 of 22 He had CMV & I think he said atypical mycobacterial… & was given steroids.. Gathe said that despite this, at week 24, VL was down to 170 & cd4 was 31. He lost insurance & went without meds for a period. VL increased to 22,000 copies at week 36 (GT/PT wildtype) & CD4 was 107. At week 36, he restarted Kaletra & intensified with TDF/3TC. At week 44 VL was 695 copies & cd4 was 219. At week 48, VL was <50 copies & CD4 was 221.
Subject 018. Baseline VL 114,000 copies & CD4 count 211. At week 24, VL <400 copies, cd4 count of 570. He lost insurance, unable to receive therapy. At week 32, VL was 1,818 copies, cd4 378 & received donated Kaletra. At week 48, VL was 347, cd4 was 488.
Subject 014. Baseline VL 524,000 copies, cd4 15. At week 24, VL <400 copies & cd4 was 201. He lost job, lost insurance. Took 1/3 pills per day. VL was 5000 copies & cd4 116 at week 36 when he received donated Kaletra. At week 44, VL was 2400 copies, cd4 182. At week 48, cd4 was 268 & VL was 395.
Gathe said: why was intensification necessary in the absence of resistance? 3 thoughts: adherence; potency-no single agent will be able to control virus <50 in all patients particularly with VL >100,000 copies; bioavailability- p-glycoprotein issues, viral sanctuaries/reservoirs; resistance—developing outside of the areas analyzed by standard genotypic/phenotypic assays (ie, substrate resistance, gag cleavage sites); analysis has been hampered by inability to amplify the virus and lack of baseline samples.
GATHE CONCLUSIONS
Kaletra as single agent therapy in naïve subjects, the majority with advanced disease
--achieve viral suppression at 48 weeks
| <400 | <50 | | AT | 100% | 90% | | ITT | 67% | 60% |
Mean CD4 increase of 317 cells at 48 weeks.
--low discontinuation rate
--no definable genotype/phenotype resistance in viremic subjects
--success with intensification with nukes
STUDY IMPLICATIONS BY GATHE—
--studies of important treatment strategies can be successfully accomplished in the USA by African-American investigators with disadvantaged subjects despite zero resource allocation from anyone.
--should single agent therapy be part of routine clinical practice??
Does this concept merit detailed scientific study??
Abbott is proceeding with following up this studies with 2 additional larger studies in the US & in UK.
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