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Protease Gene Mutations in a Trial Comparing First Line LPV/r Monotherapy to LPV/r + AZT/3TC (MONARK Trial)
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Reported by Jules Levin
16th Intl HIV Drug Resistance Workshop, June 12-16, 2007, Barbados
C Delaugerre1, P Flandre2, ML Chaix1, P Dellamonica3, F Raffi4, H Jaeger5, D Schürmann6, P NgoVan7, M Norton8, I Cohen Codar7, JF Delfraissy 9 , C Rouzioux1
1Virology Necker-APHP, Paris, France; 2Inserm U720 Pierre et Marie Curie University, Paris, France; 3Infectious Diseases, Nice, France; 4Infectious Diseases, Nantes, France; 5HIV Research and Clinical Care Centre, Munich, Germany; 6Infectious Disease, Berlin, Germany; 7Abbott France, Rungis, France; 8Abbott Laboratories, New Jersey USA; 9Internal Medecine, Bicêtre-APHP, France
AUTHOR CONCLUSIONS:
Five out of the 83 (6%) subjects starting LPV/r monotherapy and none of the 53 subjects starting a LPV/r-based 3 drug regimen selected major PI resistance mutation
The genetic barrier for the selection of PI resistance mutation appears to be lower with LPV/r monotherapy than with LPV/r-based 3-drug regimens
The L76V mutation emerged in 3 subjects infected with HIV-1 CRF02_AG
Full viral suppression was achieved in 3 subjects who selected a major PI mutation while on LPV/r monotherapy, after intensification with AZT/3TC
BACKGROUND
In antiretroviral-naïve patients, combination therapy with LPV/r rarely selects for PI resistance
During single-drug maintenance therapy with LPV/r in randomized trials, some cases of PI resistance have been described
Primary Endpoint : HIV-1 RNA <400c/mL at week 24 and <50c/ml at week 48
Sub-optimal response
1. failure to achieve a decline in viral load of at least 1.0 log10 copies/mL by week 4
2. failure to achieve a viral load below 400 copies/mL by week 24
3. any viral rebound > 1 log, after HIV RNA < 400 copies/mL, confirmed by a second measurement at least 14 days later
OBJECTIVES & METHODS
Our objective was to analyze protease resistance outcome in Monark study
Genotypic resistance tests were performed by population based sequencing* in protease gene at :
--screening
--time of sub-optimal response
--study discontinuation
--if requested by investigator or suggested by study team for safety
Phenotypes (Phenosense GT, Monogram Biosciences) were performed in all subjects who selected at least one major PI mutation
* Necker Virology Laboratory (ANRS technique)
RESULTS
Genotypic Resistance Testing
In the monotherapy group there were 83 patients at baseline and 32 patients qualified for genotyping. 17 patients had ANY protease gene changes from screening in the monotherapy arm and 5 patients had major PI mutations. In the triple drug group there 53 patients and 7 patients qualified for genotyping. 4 patients had any protease gene change and no patients had a major PI mutation.
L76V mutation emerged in 3/5 patients
All 3 patients were infected with HIV-1 CRF02_AG
In 2 patients, L76V emerged alone.
This mutation is included in darunavir score (Power studies).
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