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