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From JAIDS: Journal of Acquired Immune DeficiencySyndromes

Authors and Disclosures

Juan Sierra-Madero, MD,* Angelina Villasis-Keever, MD, MSc,* Patricia Mndez, MD, Juan Luis

Mosqueda-Gmez, MD, Indiana Torres-Escobar, MD, MPH, Fernanda Gutirrez-Escolano, MD, Irene

Jurez-Kasusky, MD,|| Martn Magana-Aquino, MD,# Carmen Ramos-Santos, MD,** Leticia Prez-Saleme,

MD, Sigfrido Rangel-Frausto, MD, Barbara Antuna-Puente, MD,* Luis Enrique Soto-Ramrez, MD,*

Vivian Lima, PhD, Franciso Belaunzarn-Zamudio, MD, MPH,* Brenda Crabtree-Ramrez, MD,* and JulioMontaner, MD, FRCPC, FCCP

*Department of Infectious Diseases, Instituto Nacional de Ciencias Mdicas y Nutricin Salvador Zubirn, Mexico

City; Hospital General de Zona (IMSS) # 53, Mexico City; Hospital General Regional de Leon and Facultad de

Medicina de la Universidad de Guanajuato; CAPASITS Puebla; ||Hospital General de Zona (IMSS) # 72, Mexico

City; Hospital General de Zona (IMSS) # 29, Mxico City; #Hospital General de Zona SLP; **Hospital General

de Zona (IMSS) # 25, Mexico City; Hospital de Especialidades Centro Mdico Nacional Siglo XXI (IMSS),

Mexico City; Unidad de Investigacin de Epidemiologa Hospitalaria, IMSS, Mexico City; and Division of

AIDS, Department of Medicine, University of British Columbia and the BC Centre for Excellence in HIV/AIDS, St

Paul's Hospital, Providence Health Care, Vancouver, Canada.

Correspondence to

Juan Sierra-Madero, MD, Department of Infectious Diseases. Instituto Nacional de Ciencias Mdicas y Nutricin

Salvador Zubirn, Mexico City, Vasco de Quiroga 15, Col. Seccin XVI, C.P. 14000 Tlalpan, Mexico City (e-mail:

[email protected]).

Disclosures

Juan G. Sierra Madero; Research grants from Pfizer, Merck, BMS, Abbot, Tibotec, Roche, Boeringher

Ingleheim. Speaker for Merck, Pfizer, BMS, Tibotec Advisory fees for Pfizer, Merck, Stendahl. A. Villasis-

Keever; Speaker for MSD, Pfizer, BMS, Schering-Plough. B. Crabtree-Ramrez; Research grant from Merck,

speaker for BMS. Mosqueda-Gmez; Research grants from Pfizer, Boeringher Ingleheim; speaker for MSD. S.Rangel-Frausto; Speaker for Pfizer, Merk, Bristol Myers Squibb. I. Torres- Escobar; Research Grants from

BMS, MSD, Jansen and Roche. Consultancy fees from MSD, ABBOT, Stendhal. Traveling expenses and

registration fees from GSK, MSD, BMS, Stendhal, ABBOT, Stendhal, Jansen, Roche and Boeringher Ingleheim.

Leticia Prez-Saleme; Research grants from Janssen, Abbott; Speaker for Merck, BMS, Tibotec, Abbott,

Boeringher Ingleheim, GSK. Advisory fees from Merck, Abbott. M. Magaa-Aquino; Research grants from BMS

and Pfizer. F. Gutirrez-Escolano; Advisory fees from Abbott. P. Belaunzarn; No conflict of interest. B.

Antuna; No conflict of interest. Luis Soto-Ramirez; Research grants from Abbot, BMS, GSK, Janssen, Merck,

Roche. Speaker for Abbott, BMS, GSK, Janssen; Merck. Advisory fees for Abbott, GSK, Merck, Roche. P.

Mndez; no conflict of interest. I. Jurez-Kasuski; no conflict of interest. C. Ramos; no conflict of interest. V.

Lima; no conflict of interest. J. Montaner; has received grants from, served as an ad hoc advisor to, or spoke atvarious events sponsored by; Abbott, Argos Therapeutics, Bioject Inc, Boehringer Ingelheim, BMS, Gilead

Sciences, GlaxoSmithKline, Hoffmann-La Roche, Janssen-Ortho, Merck Frosst, Panacos, Pfizer, Schering,

Serono Inc, TheraTechnologies, Tibotec (J&J), Trimeris.

Prospective, Randomized, Open Label Trial ofEfavirenz vs Lopinavir/Ritonavir in HIV+Treatment-naive Subjects With CD4+


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Abstract and Introduction

Abstract

Objective: To compare the efficacy of efavirenz (EFV) vs lopinavir/ritonavir (LPV/r) in combination with

azidothymidine/lamivudine in antiretroviral therapy naive, HIV+ individuals presenting for care with CD4+ counts


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and a neutrophil count higher than 1000/mL. Patients who had an opportunistic infection diagnosed were allowed

to participate after specific treatment for the infection was initiated and clinical symptoms were controlled.

Patients with active tuberculosis or any neoplasm requiring chemotherapy were excluded. The study was

approved by the institutional ethics review committee at each clinical site. All patients provided written informed

consent. The study was registered with ClinicalTrials.gov (NCT00162643).

Study Design

This was a prospective, open label, multicenter, and randomized trial. Eligible patients were randomized toreceive 1 of 2 regimens: 600 mg of EFV once daily or a fixed-dose LPV/r 400/100 mg [three 133/33.3 mg

capsules (fixed-dose, soft-gel formulation) bid], each given with zidovudine/lamivudine 300/150 mg bid for 48

weeks. Changes to abacavir (300 mg, bid) and lamivudine (150 mg, bid) were allowed in cases of severe anemia

or gastrointestinal intolerance attributed to zidovudine.

Randomization was stratified on the basis of the screening CD4+ cell count (!100 vs >100/mm3), using a central

telephone to ensure balance across treatments groups. After screening, study evaluations were completed at

entry, and at weeks 4, 8, 16, 24, 32, and 48. CD4+ count, plasma HIV-1 RNA (Roche Amplicor HIV-1 Monitor

assay, ultrasensitive version 1.5; Roche Diagnostic Systems, Branchburg, NJ; lower and upper limits of assay

detection 50 and 75,000 copies/mL, respectively), and fasting lipid profile were measured at a central laboratory

(INCMNSZ) at entry, at weeks 8, 24, 32, and 48.

Adverse clinical and laboratory events were assessed by the site investigators and were scored with the use of

the division of AIDS table for grading the severity of adult and pediatric adverse events, version 2004.[18] At the

time of virologic failure, drug-resistance genotyping was performed in the central laboratory (Viroseq Celera

Diagnostics v2.0, Alameda, CA).

The primary endpoint of the study was the proportion of patients with HIV-1 RNA < 50 copies/mL at week 48.

Secondary efficacy endpoints included the proportion of patients with HIV-1 RNA < 400 copies/mL at week 48,

and change in CD4+ cell count from baseline through week 48. Safety endpoints included the incidence of

adverse events, serious adverse events, discontinuations due to adverse events, and the incidence of grade 3 or

4 laboratory abnormalities.

Statistical Analysis

The predefined primary analysis was a noninferiority test of the primary outcome (proportion of patients with HIV-

1 RNA


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characteristics of the 189 patients who received study drugs are provided in Table 1; 28 patients were women; 16

in the LPV/r group and 12 in the EFV group. At baseline, the median CD4+ cell count was 64 (interquartile range

49.4 to 78.5)/mm3 in the EFV group and 52 [interquartile range (37.1, 66.8)/mm3] in the LPV/r group. The

percentage of patients with CD4+ counts !50/mm3 was 44% and 48%, respectively. HIV-1 RNA viral load level

was >75,000 copies/mL in 83 (87.4%) patients in the EFV group and in 82 (87.2%) patients in the LPV/r group.

Table 1. Baseline Characteristics of Randomized Patients

EFV, N = 95 LPV/r, N = 94 Total, N = 189 P

Women; n (%) 16 (16.8) 12 (12.8) 28 0.53

Age; median (IQR) 36.7 (34.8, 38.6) 36 (33.8, 38.2) 35 (29, 42) 0.30

CD4+; median (IQR) 64 (49.4, 78.5) 52 (37.1, 66.8) 56 (25, 117) 0.18

CD4+ ! 50 cell/mm3; n (%) 42 (44) 45 (48) 87 (46) 0.55

CDC-C3; n (%) 36 (37.8) 43 (45.7) 79 (41.7) 0.10

HIV-RNA > 75,000 copies/mL; n (%) 83 (87.4) 82 (87.2) 165 (87.3) 0.72


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Figure 1. General study design.

Patient disposition at 48 weeks is shown in Table 2. Seven patients in the EFV group and 17 in the LPV/r group

had virologic failure during follow-up (P = 0.02). There were 11 subjects who discontinued the study in the LPV/r

group because of adverse events which included the following: death (5), gastrointestinal intolerance (4) and

tuberculosis (2), and 5 in the EFV group: death (2), tuberculosis (1), neurologic toxicity (1), and rash (1). Rates of

loss to follow-up were similar among groups (16% and 12%, respectively, P = 0.40). During the study, 6 subjects

in the EFV group and 8 in the LPV/r group switched from zidovudine/lamivudine to abacavir/lamivudine because

of anemia.

Table 2. Patient Disposition After 48 Weeks


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As shown in Figure 2, 67 of 95 patients (70%) in the EFV group and 50 of 94 (53%) in the LPV/r group reached

HIV-1 RNA levels


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Figure 2. Virologic response (HIV-RNA < 50 copies/mL) from baseline to week 48. A, TLOVR analysis. B,

As treated analysis .

Figure 3 shows the median CD4+ increase from baseline was 234 cells/mm3 in the EFV group vs 239 in the

LPV/r group (P = 0.80).


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Figure 3. CD4+ mean change from baseline.

The virologic response by baseline CD4+ cell count and treatment group at 48 weeks, using the previously

selected stratification CD4+ cell count threshold (100 CD4+ cells) is shown in Table 2. Patients who had a

baseline CD4+ cell count !100/mm3 had a higher rate of HIV-1 RNA levels


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Figure 4. Median change in fasting lipids over 48 weeks.

Resistance Mutations at Failure

Five of 17 samples from patients who failed virologically in the LPV/r group and 3 of the 7 in the EFV group could

be amplified for genotypic analysis (1 sample was not available and the others had a viral load below 1000

copies/mL). All 3 patients experiencing virologic failure on the EFV group had resistance associated mutations (2

K103N without nucleoside mutations and 1 G190A with K65R), whereas only 1 of 5 genotypes from the LPV/r

group had a single resistance associated mutation (M184V).

Discussion

Our results show that the primary hypothesis of the trial for noninferiority between EFV and LPV/r-based HAARTwas reached using the


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previously suggested that antiretroviral therapy is better tolerated at earlier stages of HIV disease. [20,21] Our

findings suggest that this may affect EFV to a lesser extent than ritonavir-boosted lopinavir-based HAART. Also,

it should be noted that the soft gel formulation of ritonavir-boosted lopinavir was used in this study-the only

formulation available in Mexico at the time of the study. A newer heat stable tablet formulation of ritonavir-

boosted lopinavir is currently available, which may offer the advantage of lower number of pills and potentially

better adherence, although probably not through better tolerability.[2224] The extent to which the formulation of

ritonavir-boosted lopinavir used in our study may have influenced our results remains to be further elucidated.

Nevertheless, the low response rate observed in the lopinavir arm (53% < 50 copies/mL in the intention-to-treat

analysis) is lower than the response rate reported in other studies with lopinavir including subanalysis of patients

with less than 50 CD4 cells at baseline (63% and 67% in Castle and Artemis studies, respectively). [12,13] This

difference is hard to explain, but we can speculate that it may be a consequence of an even more advanced

population included in our study in which more than 40% of the patients had experienced an AIDS-defining illness

before starting ARVs, whereas in the 2 mentioned studies only up to 10% had this characteristic.

Of note, most patients who were not suppressed at 48 weeks showed low levels of viremia (between 50 and 400

copies/mL), especially in the LPV/r group. Also relevant in this context is the very low frequency of resistance

associated mutations seen in the limited number of patients evaluated. The latter finding is also consistent with

the results of ACTG 5142.[14] Taken together these findings suggest that over 48 weeks of treatment in nave

patients, EFV-based HAART is associated with higher rate of overall virologic success, and although virologicfailures are infrequent, these are more often associated with the emergence of resistance-associated mutations

to 1 or 2 classes (ie, nucleoside reverse transcriptase inhibitor and nonnucleoside reverse transcriptase inhibitor).

In contrast, lopinavir-based HAART, is associated with higher rate of virologic failure, more often due to adverse

effects (predominately gastrointestinal intolerance), typically associated with low levels of HIV-1 RNA viral load in

plasma and low rates, if any, of emergent resistance-associated mutations, typically restricted to a single

nucleoside reverse transcriptase inhibitor (ie, lamivudine). Long-term strategy trials will be needed to elucidate the

relative long-term consequences of these findings.

Consistent with previous studies, our results showed a larger increase of triglycerides with LPV/r than with

EFV.[11,14] Also, our results showed a trend toward greater increases in CD4+ cell counts in the LPV/r group,

however, the difference was not significant. Whether a larger sample size may have shown a significant

difference in this metric and whether this would be of clinical significance remains unknown.

Several limitations of our study are noteworthy. We believe that some of the poor performance of LPV/r in this

study may be due to adherence problems (both because of gastrointestinal intolerance and much higher pill

burden). The low frequency of mutations in the lopinavir virologic failures points to this even more strongly.

However, the lack of data on adherence during the trial precludes any confirmation of this hypothesis. Because

our study was conducted in Mexico, the results may be generalized mainly to similar settings such as middle

income countries. However, we feel that this is not likely to be a relevant problem as our results are generally

consistent with those of the recent ACTG 5142.[14] Zidovudine used in the nucleoside backbone, which has now

been shown to produce higher toxicity than other nucleoside backbones, especially in patients with advanceddisease, is not considered a preferred nucleoside reverse transcriptase inhibitor for first-line therapy. [24] However,

the rate of loss to follow-up was comparable between study arms and zidovudine was used in both study arms to

the same extent. Therefore, we believe that these issues are not significant confounders. Also, resistance testing

was not performed at baseline because this is not a standard practice in Mexico considering that the prevalence

of primary resistance in the country has been reported to be less than 5% in recent studies.[25,26] Therefore, even

though inclusion of subjects with undetected primary resistance could have contributed to some of the cases of

virologic failure observed we consider this a potentially small conservative bias, given that EFV resistance is

predominately expected in areas with high prevalence of primary resistance, and this would have

disproportionately adversely affected the virologic efficacy of the EFV arm. [2729]

In summary, our results show that in antiretroviral therapy-naive, HIV-infected subjects presenting to care with a

CD4+ count


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with caution among HIV-infected patients who present to care with very advanced disease.

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Supported by National Council for Science and Technology (Conacyt, Mexico 123-A1).

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