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
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
HAART in Patients with Advanced Disease
(<200 CD4+ cell/mm3)
• 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
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 components
(DHHS: January 2008)
NNRTI
• Efavirenz*
or
NRTI**
+
 ABC/3TC
 TNF/FTC
PI
• Atazanavir + ritonavir
• Fosamprenavir + ritonavir (BID)
• Lopinavir/ritonavir (BID)
*Avoid in pregnant women and women with significant pregnancy potential.
**Emtricitabine can be used in place of lamivudine and vice versa.
ACTG 5142: LPV/r vs EFV vs LPV/r + EFV
Stratified by HIV-1 RNA ≤ or > 100,000,
hepatitis coinfection and NRTI selection
Week 96
LPV/RTV SGC 400/100 mg BID
+ NRTIs*
(n = 253)
Naïve Patients with
HIV-1 RNA
> 2000 copies/mL, no
CD4+ restriction
EFV 600 mg QD
+2 NRTI*
(n = 250)
LPV/RTV SGC 533/133 mg BID +
EFV 600 mg QD
(n = 250)
(N = 753)
*Lamivudine + ZDV, d4T XR, o TDF, selected by investigator criteria before randomization.
% HIV-1 RNA > 105
CD4+ (median)
51
178
Riddler S, et al. IAC 2006. Abstract THLB0204.
52
190
51
181
Objectives
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
Coordinator Center
INCMNSZ, Mexico City
Sites outsite Mexico City
Higher Prevalence of HIV
Methodological Support provided by the BC Centre for Excellence in HIV/AIDS,
Vancouver, Canada
Study Design
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
Screened (N= 264)
Screening
Failure N=75
189 ARV naïve; >18 years; HIV RNA 1,000 c/mL, CD4+<200
Randomization stratified by CD4+(> and < 100 cells/mL)
(1:1)
EFV 600 mg QD (n = 95)
LPV/r 400/100 mg BID (n = 94)
ZDV/ 3TC 300/150 mg BID
Substitution of AZT for ABC allowed
(N= 14; EFV 6 and LPV/r 8)
Follow up
Days
-40 to -30
Screening
-7 a -4
Randomization
Weeks
1
4
8
Baseline
16
24
Follow up
HIV RNA, CD4+ counts, CBC, LFT and Lipid Profile
• Virological Failure (VF) definition:
– After 6 months: HIV RNA >50 copies/mL (confirmed)
– At 8 weeks: Failure to decline > 1 log HIV RNA
32
40
48
Analysis
• 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
Lopinavir/r
n = 95
n = 94
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
42 (44)
45 (48)
0.55
83 (87.4)
82 (87.2)
0.72
Women; n(%)
CD4+< 50 cel/mm3; n(%)
Viral Load ≥ 75000c/ml; n(%)
P value
Patient disposition at week 48
Efavirenz
n = 95
Lopinavir/r
n = 94
P value
Completed 48 weeks
68 (71)
55 (58)
0.05
Viral Load <50 copies/mL
67 (70)
50 (53)
0.01
7 (7)
17 (18)
0.02
15 (16)
11 (12)
0.4
5 (5)
11 (12)
0.1
Death
2 (2)
5 (5)
Tuberculosis
1 (1)
2 (2)
Discontinuation
Virological Failure
Lost to follow up
Adverse Events
Proportion of Patients with HIV RNA <50 c/mL
100
90
85.9%
% <50 copies/ mL
80
70.5%
70
61.7%
60
53.2%
50
40
30
AT (p=0.000)
TLOVR (p=0.017)
20
10
Efavirenz (n=95)
Efavirenz (n=78)
Lopinavir/r (n=94)
Lopinavir/r (n=81)
Δ 17% (CI 95% 3.5 - 31)
0
0
8
16
24
32
40
48
Week
Number Of Patients With Viral Load <50/ml
Efavirenz
29
Lopinavir/r 8
70
68
67
53
56
50
Virological Suppression Stratified by Baseline
CD4+ Counts (>/< 50 cell/mm3)
P = 0.012
100
Serie1
EFV
79 %
80
% < 50 c/mL
P = 0.15
LPV/r
Serie2
64 %
60
57%
49 %
40
20
0
n
Baseline CD4+ Count
1
42
45
<50 cell/mm3
53
2
49
>50 cell/mm3
Proportion of Patients with HIV RNA <400 c/mL
100
88%
90
% <400 copies/mL
80
75%
73%
70
65%
60
50
40
30
TLOVR (p=0.275)
AT (p=0.032)
20
Efavirenz (n=95)
Efavirenz (n=78)
10
Lopinavir/r (n=94)
Lopinavir/r (n=81)
0
0
8
16
24
32
40
48
Week
Number Of Patients With Viral Load <400/ml
Efavirenz
69
76
71
69
Lopinavir/r 40
76
68
61
Change of median CD4+ cell counts
Resistance Mutations in Patients with
Virological Failure
EFV
N= 7
LPV/r
N= 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
p = 0.17
p = 0.37
p = 0.60
p = 0.01
(%) Porcent
ChangeWeek 48%
%Change,
120
100
80
EFV
60
LPV/r
40
20
0
TC
1
HDL
2
LDL
3
Lipids
TG
4
Adverse Events in both Groups
EFV
n = 95
LPV/r
n = 94
17 (17.8)
21 (22.3)
62
62
Gastrointestinal
11
15
CNS disorders
24
13
Rash
3
2
Anemia
9
9
Lipids disorders
14
22
LFT disorders
2
1
Serious Adverse Events (SAEs)
(Death, Hospitalization, Surgery) n(%)
All grade 2-4 treatment-related AEs
Most common
Grade 2-4 AEs
treatment-related
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
Caveats
• 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
Acknowledgments
Inst.Nacional de la Nutrición Salvador Zubirán
Juan Sierra-Madero
A. Villasis-Keever
F. Belaunzarán-Zamudio
LE Soto-Ramírez
Fernando Silva
L Naranjo Albarrán
AudeliaAlanis
Teresa Muñoz
Elena García
Berenice Cruz
Denise Franco
BarbaraAntuna
Alicia Piñeirúa
Gabriela Montejano
Jezer Lezama
Lucrecia Arreguín
Raúl López Saucedo
Venancio Ruíz
Brenda Crabtree
Norma Rivera
G Ruíz Palacios
Rocío Velazquez
Hospital 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
Funded by CONACyT and Infectious Diseases Dept INCMNSZ and IMSS