Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection.
BACKGROUND
We evaluated the efficacy of raltegravir and the development of viral resistance in two identical trials involving patients who were infected with human immunodeficiency virus type 1 (HIV-1) with triple-class drug resistance and in whom antiretroviral therapy had failed.


METHODS
We conducted subgroup analyses of the data from week 48 in both studies according to baseline prognostic factors. Genotyping of the integrase gene was performed in raltegravir recipients who had virologic failure.


RESULTS
Virologic responses to raltegravir were consistently superior to responses to placebo, regardless of the baseline values of HIV-1 RNA level; CD4 cell count; genotypic or phenotypic sensitivity score; use or nonuse of darunavir, enfuvirtide, or both in optimized background therapy; or demographic characteristics. Among patients in the two studies combined who were using both enfuvirtide and darunavir for the first time, HIV-1 RNA levels of less than 50 copies per milliliter were achieved in 89% of raltegravir recipients and 68% of placebo recipients. HIV-1 RNA levels of less than 50 copies per milliliter were achieved in 69% and 80% of the raltegravir recipients and in 47% and 57% of the placebo recipients using either darunavir or enfuvirtide for the first time, respectively. At 48 weeks, 105 of the 462 raltegravir recipients (23%) had virologic failure. Genotyping was performed in 94 raltegravir recipients with virologic failure. Integrase mutations known to be associated with phenotypic resistance to raltegravir arose during treatment in 64 patients (68%). Forty-eight of these 64 patients (75%) had two or more resistance-associated mutations.


CONCLUSIONS
When combined with an optimized background regimen in both studies, a consistently favorable treatment effect of raltegravir over placebo was shown in clinically relevant subgroups of patients, including those with baseline characteristics that typically predict a poor response to antiretroviral therapy: a high HIV-1 RNA level, low CD4 cell count, and low genotypic or phenotypic sensitivity score. (ClinicalTrials.gov numbers, NCT00293267 and NCT00293254.)
Cooper
David A
DA
National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney.
Steigbigel
Roy T
RT
Gatell
Jose M
JM
Rockstroh
Jurgen K
JK
Katlama
Christine
C
Yeni
Patrick
P
Lazzarin
Adriano
A
Clotet
Bonaventura
B
Kumar
Princy N
PN
Eron
Joseph E
JE
Schechter
Mauro
M
Markowitz
Martin
M
Loutfy
Mona R
MR
Lennox
Jeffrey L
JL
Zhao
Jing
J
Chen
Joshua
J
Ryan
Desmond M
DM
Rhodes
Rand R
RR
Killar
John A
JA
Gilde
Lucinda R
LR
Strohmaier
Kim M
KM
Meibohm
Anne R
AR
Miller
Michael D
MD
Hazuda
Daria J
DJ
Nessly
Michael L
ML
DiNubile
Mark J
MJ
Isaacs
Robin D
RD
Teppler
Hedy
H
Nguyen
Bach-Yen
BY
D000293:Adolescent; D000328:Adult; D000368:Aged; D018791:CD4 Lymphocyte Count; D004311:Double-Blind Method; D024882:Drug Resistance, Viral / Q000235:genetics*; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy*; D019427:HIV Integrase / Q000235:genetics*; D019428:HIV Integrase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D015497:HIV-1; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009930:Organic Chemicals / Q000009:adverse effects / Q000627:therapeutic use*; D010641:Phenotype; D011760:Pyrrolidinones; D012367:RNA, Viral / Q000097:blood; D000068898:Raltegravir Potassium; D016896:Treatment Outcome; D019562:Viral Load
D019428:HIV Integrase Inhibitors; D009930:Organic Chemicals; D011760:Pyrrolidinones; D012367:RNA, Viral; D000068898:Raltegravir Potassium; D019427:HIV Integrase