haart in patients with advanced disease (powerpoint ppt presentation
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J Sierra-Madero; A Villasis-Keever; P. Méndez; J.L. Mosqueda; I. Torres-Escobar; F. Gutiérrez, I. Juárez; M.
Magaña; C. Ramos; L. Pérez Saleme; L.E. Soto; V. Lima; F. Belaunzarán; B. Crabtree; J. Montaner
A Prospective, Randomized, Open Label Trial of Efavirenz vs Lopinavir/ritonavir based
HAART, among HIV infected Naïve Individuals presenting for Care with CD4+cell
counts<200 cell/mm3 in Mexico
• Advanced disease is the most common form of
presentation to care of HIV infection in resource
limited countries
• 74% of patients in a cohort from Latin America and
77% from one center in Mexico started HAART with
<200 CD4+
• Very low CD4+ count consistently associated with poor
virological outcome to HAART in different studies
HAART in Patients with Advanced Disease HAART in Patients with Advanced Disease (<200 CD4(<200 CD4++ cell/mm cell/mm33))
Tuboi S, CCASAnetgroup; Abstract MOAB0203. ; IAC 2008, Mexico city
DART Virology Goup and Trail Team; AIDS 2006 Jun 26;20 (10):1391-9
Egger M, et al. Lancet 2002; 360:119–129
Charalambous S, et al, [abstract MoPe11.2C41] IAS 2005.
Tuboi S, CCASAnetgroup; Abstract MOAB0203. ; IAC 2008, Mexico city
DART Virology Goup and Trail Team; AIDS 2006 Jun 26;20 (10):1391-9
Egger M, et al. Lancet 2002; 360:119–129
Charalambous S, et al, [abstract MoPe11.2C41] IAS 2005.
Preferred HAART initial componentsPreferred HAART initial components(DHHS: January 2008)(DHHS: January 2008)
*Avoid in pregnant women and women with significant pregnancy potential.**Emtricitabine can be used in place of lamivudine and vice versa.
• Efavirenz*
or
• Atazanavir + ritonavir
• Fosamprenavir + ritonavir (BID)
• Lopinavir/ritonavir (BID)
NNRTI
PI
ABC/3TCABC/3TC TNF/FTCTNF/FTC+
NRTI**
ACTG 5142: LPV/r vs EFV vs LPV/r + EFV
*Lamivudine + ZDV, d4T XR, o TDF, selected by investigator criteria before randomization.
Naïve Patients with HIV-1 RNA
> 2000 copies/mL, no CD4+ restriction
(N = 753)
LPV/RTV SGC 400/100 mg BIDLPV/RTV SGC 400/100 mg BID+ NRTIs*+ NRTIs*(n = 253)(n = 253)
EFV 600 mg QDEFV 600 mg QD+2 NRTI*+2 NRTI*(n = 250)(n = 250)
LPV/RTV SGC 533/133 mg BIDLPV/RTV SGC 533/133 mg BID + +EFV 600 mg QD EFV 600 mg QD
(n = 250)(n = 250)
Week 96Stratified by HIV-1 RNA ≤ or > 100,000, hepatitis coinfection and NRTI selection
Riddler S, et al. IAC 2006. Abstract THLB0204.
181181190190178178515152525151
CD4+ (median)
% HIV-1 RNA > 105
ObjectivesObjectives
Primary Objective
Demonstrate non inferiority of Efavirenz vs LPV/r in ARV naïve
individuals with CD4+ cell counts <200 cell/mm3,
Primary Endpoint
Proportion of subjects with HIV RNA <50 copies at 48 weeks
Secondary Endpoints• Change in CD4• Change in lipids• Safety
Methods
• 11 Clinical Sites
• Registered in www.clintrials.gov
• 11 Clinical Sites
• Registered in www.clintrials.gov
Coordinator Center
INCMNSZ, Mexico City
Coordinator Center
INCMNSZ, Mexico City
Higher Prevalence of HIVHigher Prevalence of HIV
Sites outsite Mexico CitySites outsite Mexico City
Methodological Support provided by the BC Centre for Excellence in HIV/AIDS, Methodological Support provided by the BC Centre for Excellence in HIV/AIDS, Vancouver, CanadaVancouver, CanadaMethodological Support provided by the BC Centre for Excellence in HIV/AIDS, Methodological Support provided by the BC Centre for Excellence in HIV/AIDS, Vancouver, CanadaVancouver, Canada
Study Design
Screened (N= 264)
ZDV/ 3TC 300/150 mg BIDZDV/ 3TC 300/150 mg BIDSubstitution of AZT for ABC allowedSubstitution of AZT for ABC allowed
(N= 14; EFV 6 and LPV/r 8)(N= 14; EFV 6 and LPV/r 8)
(1:1)
National multicenter, open-label, randomized, 48-week study
to compare the virological success of EFV vs LPV/r in treatment-naïve HIV-1 infected subjects
189 ARV naïve; >18 years; HIV RNA 1,000 c/mL, CD4+<200Randomization stratified by CD4+(> and < 100 cells/mL)
EFV 600 mg QD (n = 95) LPV/r 400/100 mg BID (n = 94)
ScreeningFailure N=75
Follow upFollow up
• Virological Failure (VF) definition:– After 6 months: HIV RNA >50 copies/mL (confirmed)
– At 8 weeks: Failure to decline > 1 log HIV RNA
Randomization Baseline
24 48
Weeks
HIV RNA, CD4HIV RNA, CD4++ counts, CBC, LFT and Lipid Profile counts, CBC, LFT and Lipid Profile
Screening
4 8 16 32 40-40 to -30 -7 a -4 1
Days
Follow up
AnalysisAnalysis
• Primary endpoint:
- Proportion of patients with VL (<50 copies/mL) at 48 (TLOVR)
- ITT Missing = Failure
• Non Inferiority was to be concluded if the lower limit of the 95% CI of the difference between groups in virological response was higher than -12%
Results
Baseline Characteristics
Efavirenz
n = 95Lopinavir/r
n = 94P value
Women; n(%) 16 (16.8) 12 (12.8) 0.53
Age; median (IQR) 36.7 (34.8 , 38.6) 36 (33.8 , 38.2) 0.30
CD4+; median (IQR) 64 (49.4 , 78.5) 52 (37.1 , 66.8) 0.18
CD4+< 50 cel/mm3; n(%) 42 (44) 45 (48) 0.55
Viral Load ≥ 75000c/ml; n(%) 83 (87.4) 82 (87.2) 0.72
Patient disposition at week 48Patient disposition at week 48
Efavirenzn = 95
Lopinavir/rn = 94
P value
Completed 48 weeks 68 (71) 55 (58) 0.05
Viral Load <50 copies/mL 67 (70) 50 (53) 0.01
Discontinuation
Virological Failure 7 (7) 17 (18) 0.02
Lost to follow up 15 (16) 11 (12) 0.4
Adverse Events 5 (5) 11 (12) 0.1
Death 2 (2) 5 (5)
Tuberculosis 1 (1) 2 (2)
Proportion of Patients with HIV RNA <50 c/mLProportion of Patients with HIV RNA <50 c/mL
Number Of Patients With Viral Load <50/ml
Efavirenz 29 70 68 67
Lopinavir/r 8 53 56 50
0 8 16 24 32 40 48
0
10
20
30
40
50
60
70
80
90
100
TLOVR (p=0.017)
Efavirenz (n=95)
Lopinavir/r (n=94)
AT (p=0.000)
Efavirenz (n=78)
Lopinavir/r (n=81)
85.9%
70.5%
61.7%
53.2%
% <
50 c
opie
s/ m
L
Week
Δ 17% (CI 95% 3.5 - 31)Δ 17% (CI 95% 3.5 - 31)
Virological Suppression Stratified by Baseline CD4+ Counts (>/< 50 cell/mm3)
79
64
4957
0
20
40
60
80
100
1 2
Serie1
Serie2
% <
50
c/m
L
Baseline CD4+ CountBaseline CD4+ Count <50 cell/mm3<50 cell/mm3 >50 cell/mm3>50 cell/mm3
P = 0.012P = 0.012 P = 0.15P = 0.15
%%
%%
%%%%
nn 45454242 5353 4949
EFV
LPV/r
Proportion of Patients with HIV RNA <400 c/mLProportion of Patients with HIV RNA <400 c/mL
Number Of Patients With Viral Load <400/ml
Efavirenz 69 76 71 69
Lopinavir/r 40 76 68 61
0 8 16 24 32 40 48
0
10
20
30
40
50
60
70
80
90
100
TLOVR (p=0.275)
Efavirenz (n=95)
Lopinavir/r (n=94)
AT (p=0.032)
Efavirenz (n=78)
Lopinavir/r (n=81)
88%
75%73%
65%
% <
400
copi
es/m
L
Week
Change of median CD4Change of median CD4++ cell counts cell counts
Resistance Mutations in Patients with Virological Failure
EFVN= 7
LPV/rN= 17
Genotypes 3 5
Major Mutations PI, n 0 0
NNRTI Mutations, n 3 0
NRTI Mutations, n 2 1
Mutations in 2 classes, n 2 0
Percent Change of Lipids at Week 48
0
20
40
60
80
100
120
1 2 3 4
Lipids
(%)
Po
rcen
t C
han
ge,
Wee
k 48
%
EFV
LPV/r
p = 0.37p = 0.37p = 0.17p = 0.17 p = 0.60p = 0.60 p = 0.01p = 0.01
HDLTC LDL TG
% C
han
ge
Adverse Events in both Groups
EFVn = 95
LPV/rn = 94
Serious Adverse Events (SAEs)(Death, Hospitalization, Surgery) n(%)
17 (17.8) 21 (22.3)
All grade 2-4 treatment-related AEs 62 62
Most commonGrade 2-4 AEs treatment-related
Gastrointestinal 11 15
CNS disorders 24 13
Rash 3 2
Anemia 9 9
Lipids disorders 14 22
LFT disorders 2 1
Summary Summary • In HIV-infected ARV naïve subjects with advanced disease,
Efavirenz achieved a higher proportion of virological suppression than Lopinavir/r at <50 copies/mL in the ITT analysis at 48 weeks
• No difference was observed between arms when the <400 copies/ml threshold was used as the endpoint
• The larger proportion of subjects with <50 copies/mL at week 48 in the Efavirenz arm is accounted for both by higher rate of virologic failure and higher rate of discontinuations because of adverse events in the Lopinavir/r arm
• Efavirenz based HAART was associated with lower triglyceride levels after 48 weeks
CaveatsCaveats
• One country study
• No baseline genotypes
• The Nucleoside backbone was Zidovudine/ Lamivudine, which may be contributing to more discontinuations in both groups, specially in those with more advanced disease
• Use of Lopinavir/r capsules may have contributed to a higher pill burden and probably lower adherence
Conclusions
• Until we improve our capacity to detect HIV infections in earlier stages in those regions of the world in which HIV disease is presenting at such late stages we will continue to face the challenges that involve treating this group of patients
• New studies should focus on this population
AcknowledgmentsAcknowledgmentsHospital General de Zona (IMSS) # 72
Fernanda Gutiérrez
Hospital General de Zona (IMSS) # 53
Patricia Méndez
CMN sXXI
Leticia Pérez Saleme
Sigfrido Rangel-Frausto
Hospital Regional de León, Guanajuato
Luis Mosqueda
Hospital General de Zona (IMSS) # 29
Juárez Kasusky
Hospital General de Zona SLP
Magaña Aquino
Hospital General de Zona (IMSS) #25
Carmen Ramos Santos
Vargas Madrid
SEAVS Puebla
Javier Reyes Mar
Indiana Torres-Escobar
Inst.Nacional de la Nutrición Salvador ZubiránJuan Sierra-MaderoA. Villasis-KeeverF. Belaunzarán-ZamudioLE Soto-Ramírez Fernando SilvaL Naranjo AlbarránAudeliaAlanis
Teresa MuñozElena GarcíaBerenice CruzDenise FrancoBarbaraAntunaAlicia PiñeirúaGabriela MontejanoJezer LezamaLucrecia ArreguínRaúl López SaucedoVenancio RuízBrenda CrabtreeNorma RiveraG Ruíz PalaciosRocío Velazquez
Funded by CONACyT and Infectious Diseases Dept INCMNSZ and IMSS
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