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Kaletra: 6 year followup, study 720
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BRIEF SUMMARY
--Through 6 years (312 weeks) of follow-up, antiretroviral-naive patients receiving LPV/r-based therapy exhibited sustained virologic responses, with 63% of patients demonstrating HIV RNA <400 copies/mL and 62% demonstrating HIV RNA <50 copies/mL by intent-to-treat (NC=F) analysis.
--on-treatment response rates were 100% and 98%, respectively.
--Mean CD4 cell count increased 529 cells/mm3 over 312 weeks of follow-up with consistent CD4 cell count increases regardless of baseline CD4 cell count.
--Through 312 weeks of follow-up, no primary protease inhibitor resistance mutations have been observed in subjects with HIV RNA >500 copies/mL any time at or after Week 24.
--rate of study discontinuations due to LPV/r-related adverse events (13/100, 13%).
RESULTS
6 years Followup: efficacy, resistance, CD4 response
--Efficacy
Viral Load Suppression Below the LOQ
Based on the ITT NC=F analysis through Week 312, 63% of patients had HIV RNA <400 copies/mL (on-treatment analysis:100%) and 62% of patients had HIV RNA <50 copies/mL (on-treatment analysis:98%). One patient had HIV RNA between 50 and 400 copies/mL, but demonstrated resuppression to <50 copies/mL at subsequent visits.
--Analysis of Genotypic and Phenotypic Resistance
A total of 33 samples from 28 patients were submitted for resistance testing.
17 patients met criteria for loss of virologic response, and 11 patients had at least 1 "blip"(single HIV RNA value >500 copies/mL bracketed by HIV RNA values <400 copies/mL) after Week 24.
In 18 patients with available results, no lopinavir or stavudine resistance was observed, and 3 patients demonstrated lamivudine resistance. Correspondingly, no evidence of phenotypic resistance to any PI was observed.
6 patients demonstrated a substitution at a new position in protease during viral rebound (1 each at amino acids 15, 36, 43, 57, 63, 70). However, as demonstrated previously, 2 none of these substitutions are primary protease inhibitor mutations, no impact on PI phenotypic resistance was observed, and all 3 patients who remain on study demonstrated HIV RNA <50 copies/mL at the most recent visit.
--CD4 Cell Count Response
Among subjects with values at both baseline and Week 312 (N=63), the mean CD4 cell count increased from 280 cells/mm 3 at baseline to 808 cells/mm3 at Week 312, an increase of 529 cells/mm 3.
CD4 cell count response appeared to be consistent regardless of baseline CD4 cell count. Among patients with baseline CD4 cell count <50 cells/mm 3, mean CD4 cell count increased from 23 cells/mm3at baseline to 576 cells/mm3at Week 312, an increase of 553 cells/mm3. There was a mean increase of 500 cells regardless of baseline CD4 count.
SAFETY
Patients enrolled 100
Discontinuations prior to Week 312- 37
Discontinuations probably or possibly related to study drugs
--AST/ALT increases 2
--Diarrhea 1
--Liver pain, enlargement, fatty deposits 1
--Arthralgia 1
--Elevated lipids 2
--Fat distribution abnormalities 5
--Death 1
Other reasons for discontinuation
--Adverse Event unrelated to study drugs (lymphoma, hyperglycemia in diabetic patient, alcohol detoxification- 3
--Lost to follow-up 9
--Noncompliance 4
--Personal/other reasons (moved (3), drug addiction, "virologic success"- 8
--Patients on study at Week 312- 63
MOST COMMON ADVERSE EVENTS THROUGH WEEK 312
| Incidence through wk 312 | | Diarrhea | 28% | | Nausea | 16% | | Lipodystrophy | 13% | | Abdominal pain | 10% |
MOST COMMON GRADE 3-4 LAB ABNORMALITIES THROUGH WEEK 312
| Incidence Through Week 312 | | Cholesterol (.300 mg/dL) non-fasting: | 23% | | Triglycerides (>750 mg/dL) non-fasting: | 26% | | AST/ALT (>5xULN): | 11% |
DISTRIBUTION OF LIPID VALUES AT WEEK 312 (non-fasting)
| Prevalence at week 312 | | Total cholesterol | | | <240 | 47 (75%) | | >240-300 | 13 (21%) | | 300-400 | 3 (5%) | | >400 | 0 | | Triglycerides | | | <400 | 49 (78%) | | 400-750 | 10 (16%) | | >750-1200 | 3 (5%) | | >1200 | 1 (2%) |
--23 patients with grade 2 or higher lipid values initiated lipid-lowering agents, and all but 2 subsequently demonstrated grade 0-1 lipid values.
STUDY BACKGROUND
Lopinavir (LPV) is an HIV protease inhibitor (PI) that is co-formulated with ritonavir, which functions as an inhibitor of cytochrome P450 3A. Even at low ritonavir doses, there is a substantial increase in LPV exposure. At a dosage of 400 mg of LPV/100 mg ritonavir twice daily (3 co-formulated capsules BID), ritonavir concentrations are below those required for antiviral activity. By contrast, the mean LPV C trough/IC50ratio (Inhibitory Quotient or IQ) for wild-type HIV is >=70 when dosed at 400/100 mg twice a day, potentially serving as a barrier to the emergence of drug resistance and providing activity against drug resistant virus. Lopinavir/ritonavir (LPV/r, marketed as KaletraTM) has been studied in both antiretroviral-naïve and experienced HIV-infected patients. However, few long-term data are available on continued safety and efficacy. The M97-720 study is an ongoing phase II trial of LPV/r in combination with d4T and 3TC in antiretroviralnaïve patients. This was the first trial of LPV/r in HIV-infected patients and hence provides the longest duration of follow-up for patients treated with LPV/r.This poster presents data on antiviral activity, immunologic parameters, and safety through 6 years (312 weeks).
METHODS
Entry Criteria
--Antiretroviral-naïve patients with confirmed HIV-1 infection.
--Plasma HIV RNA >=5,000 copies/mL with no CD4 cell count restriction.
--Exclusion criteria included ALT or AST >2.5x Upper Limit Normal (ULN) and creatinine >1.5x ULN.
Study Design and Analysis
--One hundred antiretroviral-naïve patients were randomized to receive one of three dosage levels of LPV/r (200/100 mg BID, 400/100 mg BID or 400/200 mg BID), together with d4T (40 mg BID) and 3TC (150 mg BID) given either after 3 weeks of monotherapy (Group I) or from study entry (Group II) (Figure 1).
--Enrollment into Group II began following an evaluation of preliminary efficacy and safety of LPV/r in Group I.
--After 48 weeks, all patients converted to open-label LPV/r 400/100 mg BID dosing.
--Patients were evaluated every 2-4 weeks for the first 24 weeks and every 12 weeks thereafter.
Efficacy
--Proportion of patients with HIV RNA below the limit of quantitation (LOQ) was measured using an on-treatment method (missing values and values obtained during treatment interruptions excluded) and an intent-to-treat, noncompleter=failure method (ITT NC=F, missing values considered failure unless the immediately preceding and following values were below the LOQ).
--Immunologic response was assessed by the mean change in CD4 count from baseline to each study visit.
Virologic Evaluation
--Samples from any patient with HIV RNA >500 copies/mL any time at or after Week 24 were submitted for genotypic and phenotypic analyses. Genotype (GeneSeq TM) and phenotype (PhenoSenseTM) analyses were performed by ViroLogic, Inc.
--Genotypic resistance to LPV was defined as the development of any primary or active site mutation in protease (amino acids 8, 30, 32, 46, 47, 48, 50, 54, 82, 84, and 90) confirmed by phenotypic analysis (>=2.5 fold increase in IC 50to LPV relative to wild type HIV).Resistance to 3TC was defined as the presence of an M184V and/or M184I mutation in reverse transcriptase.
--Resistance to stavudine (d4T) was defined as any thymidine analog mutation in reverse transcriptase (amino acids 41, 67, 70, 210, 215, 219).
Safety
--Cumulative incidence through Week 312 for adverse events and grade 3/4 laboratory values was summarized, as was the prevalence at Week 312, defined as the presence of an ongoing adverse event or a grade 3/4 lab measurement obtained at the Week 312 visit.
--All laboratory measurements were obtained without regard to fasting.
--Events of fat distribution abnormalities/lipodystrophy were based on patient reports and investigator assessment of symptoms.
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