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Different Baseline Characteristics and Different Outcomes of HIV-Infected Patients Receiving HAART Through Clinical Trials Compared With Routine Care in Mexico

López-Martínez, Alondra MD*; O` Brien, Nathan M.; Caro-Vega, Yanink MSc*; Crabtree-Ramírez, Brenda MD*; Sierra-Madero, Juan MD*

JAIDS Journal of Acquired Immune Deficiency Syndromes: 1 February 2012 - Volume 59 - Issue 2 - p 155–160
doi: 10.1097/QAI.0b013e31823ff035
Clinical Science

Background: The efficacy of antiretroviral therapy (ART) has been established through clinical trials (CTs). However, selection bias and differences can limit their applicability to the general population.

Methods: All treatment-naive HIV-infected patients who began ART in routine care (RC) between 2000 and 2008 were compared with all patients who initiated ART through a CT in terms of incidence of virological failure (VF), increase in CD4+ count, mortality rate, and loss to follow-up (LTFU).

Results: At baseline, the RC group had less years of education, higher unemployment rate, higher proportion of females (14.2 vs. 5.7%; P < 0.01), lower median CD4+ (97 vs. 158 cells/μL; P < 0.01), and lower proportion of patients with hemoglobin >12 g/dL (74 vs. 83%, P = 0.04). VF at week 48 was less frequent in the CT compared with the RC group (1.8% vs. 6.21%, P = 0.02). In multivariate analysis, participation in CT [odds ratio (OR): 0.20, 95% confidence interval (CI): 0.04 to 0.91, P = 0.03], hemoglobin >12 g/dL (OR: 0.29, 95% CI 0.09-0.89, P = 0.03), and receiving an optimal highly active antiretroviral therapy regimen (OR: 0.09, 95% CI: 0.01 to 0.52, P < 0.01) remained associated with lower risk of VF. All cause mortality was 0.017 (95% CI: 0.002 to 0.122) versus 0.094 (95% CI: 0.053 to 0.17) deaths per 1000 person-days in the CT group and in the RC group, respectively (P = 0.05). No differences were found in the proportion of patients LTFU.

Conclusions: Receiving ART through CT was associated with lower probability of VF, lower mortality (probably related to less severe clinical characteristics at baseline), and similar rates of LTFU than RC.

*Department of Infectious Diseases, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico

Vanderbilt University School of Medicine, Nashville, TN.

Correspondence to: Juan Sierra-Madero, MD, Department of Infectious Diseases, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga 15, Col. Sección XVI, Tlalpan 14000, México, DF, Mexico (e-mail:

Presented at XVIII International AIDS Conference, July 18–23, 2009. Vienna, Austria.

Dr Crabtree-Ramírez has received grants from BMS and is speaker for Merck; Dr Sierra-Madero has received grants from Pfizer, is speaker for ViiV Healthcare, was consultant for ViiV Healthcare, and is currently consultant for MSD.

All others have no funding or other conflicts of interest to disclose.

Received July 14, 2011

Accepted November 1, 2011

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Highly active antiretroviral therapy (HAART) has dramatically increased the life expectancy of individuals infected with HIV.1 The efficacy of this treatment to improve survival and control viral replication has been proven in multiple clinical trials (CTs), which has allowed HAART to become the current gold standard in the treatment of HIV infection.2–5 Additionally multiple cohort studies have corroborated the effectiveness of antiretroviral (ARV) treatment.6

However, because of potential selection biases that exist in CTs, there is concern whether the results of these trials can be paralleled in the general nontrial population. Some examples of these biases are the low participation of groups considered minorities such as Latinos in studies performed in the United States7,8 and female gender in the studies conducted in Latin America.9–12 Additionally, most trials evaluating the efficacy of different regimens in ARV-naive patients have excluded patients with advanced disease (CD4+ T-cell count <50 cells/μL or an active opportunistic infection).13,14 This issue becomes even more important in the context of low-income and middle-income countries, where a greater proportion of patients initiating HAART do so in more advanced stages of HIV infection.15,16 The purpose of this study was to determine if there are differences in the proportion of patients experiencing virological failure (VF) in the first year after initiating HAART between those participating in CTs and those receiving routine care (RC). Additionally, the changes in CD4+ cell count, mortality rate, and loss to follow-up (LTFU) were evaluated in the 2 groups.

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Study Design and Population

Retrospective study in the cohort of patients with HIV infection receiving medical care at the HIV/AIDS Clinic of the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ) in Mexico City, Mexico. The study population consists of all patients older than 18 years with HIV infection and no previous antiretroviral therapy who initiated treatment in the HIV/AIDS Clinic of INCMNSZ between 2000 and 2008. The population was divided into 2 groups: those who initiated HAART through CTs conducted at the HIV/AIDS Clinic and those patients who initiated HAART through RC in the same center.

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The database of the HIV/AIDS Clinic records prospective data obtained through clinical questionnaires (including sociodemographic data) performed at each medical visit. Laboratory information obtained includes CD4+ cell count, HIV RNA viral load (VL), and hematology. Hospitalization, mortality, and lost to follow-up are actively collected in the database. Regular internal and external audits are performed to ensure the quality of the data.

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Definition of Variables and Outcomes

The baseline levels of CD4+ cell count and VL were defined as the values determined closest to the date of HAART initiation but no more than 180 days before or 7 days after this date. The baseline weight, hemoglobin (Hb), and clinical stage were defined as the values determined closest to the date of HAART initiation but no more than 30 days after this date. HAART treatment was defined as optimal if it included 2 nucleoside reverse transcriptase inhibitors and a protease inhibitor (PI) boosted with ritonavir, a nonnucleoside reverse transcriptase inhibitor, an integrase inhibitor, or a CCR5 inhibitor. Suboptimal treatment was defined as one that contained 3 or 4 nucleoside reverse transcriptase inhibitor or regimens based on a nonboosted PI. Finally, the number of visits was determined for each patient in each group. The definition of AIDS was made based on the classification of the Centers for Disease Control and Prevention.17 The main outcome of interest was VF, which was defined as the measurement of plasma HIV-1 RNA greater than 400 copies/mL at week 48 after the initiation of HAART (confirmed with a second HIV-VL determination or a single HIV-VL > 400 copies/mL plus an entry in the patient's chart of change in ARV therapy secondary to VF). Other outcomes measured were mortality and LTFU. The change in CD4+ cell count between baseline and week 48 was calculated in both groups. For the RC group, VL and CD4+ cell count measurements made between weeks 40 and 60 were used to represent week 48 values. A patient was considered lost to follow-up if no clinic visits occurred for more than 1 year after initiating HAART. Patients who discontinued follow-up during the first year of treatment were retrospectively assigned as lost to follow-up if the last visit occurred during the first year of HAART initiation and the period between that visit and the next one was more than 365 days or did never return to the clinic. Deaths from any cause occurring during the first year after HAART initiation were recorded.

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Statistical Analysis

The χ2 test or Fisher exact test was used to compare categorical variables, and the student t test or the median was used to compare continuous variables. Kaplan–Meier survival analysis was used to estimate the time between HAART initiation and VF during the first year of treatment. Mortality rates between groups were compared using Cox proportional hazards model. Univariate and multivariate logistic regression models were used to determine risk factors associated with VF and death due to any cause. The statistical analysis was conducted in Stata v10 using a 0.05 level of significance.

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General Characteristics

A total of 513 naive patients were admitted to the HIV/AIDS Clinic of INCMNSZ between 2000 and 2008 of which 159 were in the CT group and 354 in the RC group. During the period of study, the following CTs for ARV-naive subjects were conducted: Alternative Antiretroviral Strategies: a Comparison of Three Initial Regimens (ALTAIR, n = 14), D4T ER versus D4T IR (n = 26); Atazanavir/ritonavir vs Lopinavir/ritonavir, 48 and 96 weeks analysis (n = 9); the Atazanavir/ritonavir vs Nevirapine and Tenofovir/Emtricitabine study (ARTEN, n = 2); DMP 450 in combination with d4t and 3TC (DMP-102 study, n = 9); Emtricitabine vs Stavudine in combination therapy (FTC-301, n = 18); Efavirenz versus Lopinavir/ritonavir in naive subjects (n = 61); Raltegravir vs Efavirenz (n = 8); Maraviroc vs Efavirenz for initial treatment HIV-naive subjects (MERIT, n = 8); Darunavir/ritonavir vs lopinavir/ritonavir (n = 4). Only 1 of these studies had as inclusion criteria the presence of advanced disease (with CD4+ count <200 cells/μL at baseline).18–28

The baseline characteristics of the patients are described in Table 1. The CT group had a smaller proportion of women (5.7 vs. 14.2%, P < 0.01) and a trend toward a younger population (32 vs. 35 years, P = 0.06) than the RC group. The proportion of employed patients at entrance was higher in the CT group (74.3 vs. 58.7, P < 0.01). With respect to clinical and laboratory data, the CT patients had a higher proportion of patients with Hb concentration >12 g/dL (83.2 vs. 74.3, P = 0.04) than the RC patients. The overall proportion of patients with AIDS (AIDS-defining events and/or CD4+ < 200 cells/μL) was high (72%). Although not statistically significant, the CT group had a smaller proportion of patients with AIDS at baseline than the RC group (68% vs. 74%, P = 0.14). The CT group also had a lower proportion of patients with baseline VL >75,000 copies/mL (59% vs. 81%, P < 0.01) and a higher median baseline CD4+ cell count (158 vs. 97 cells/μL, P < 0.01) compared with the RC group. On average, the patients of the CT group had a higher mean number of clinic visits 5.56 (SD ± 2.38) versus 4.51 (SD ± 2.24) during the first year of treatment.

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Main Outcome

The number of patients with VF at week 48 was 3 (1.8%) in the CT group and 21 (5.9%) in the RC group, P = 0.04 (Table 2), with a slight difference in the average time to VF [CT 360 days (±30) vs. RC 351 days (±50), P = 0.05; Fig. 1]. In the univariate analysis, baseline Hb concentration >12 g/dL (OR: 0.58, 95% CI: 0.35 to 0.97, P = 0.04) and receiving optimal HAART (OR: 0.23, 95% CI: 0.08 to 0.68, P < 0.01) were associated with lower risk of VF. CT participation was marginally associated with lower risk of VF (OR: 0.30, 95% CI: 0.09 to 1.03, P = 0.06). However, by multivariate analysis (controlling for gender, age, route of transmission, AIDS-defining events on admission, participation in a CT, optimal HAART, year of HAART initiation, baseline Hb, baseline CD4+ count, baseline VL greater 75,000 copies/mL, employment, and years of education at entrance to care), only participation in CT (OR: 0.20, 95% CI: 0.04 to 0.91, P = 0.04), baseline Hb >12 g/dL (OR: 0.29, 95% CI: 0.09 to 0.89, P = 0.03), and receiving optimal HAART (OR: 0.09, 95% CI: 0.01 to 0.52, P < 0.01) remained associated with lower risk for VF (Table 3).

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Other Outcomes

CD4+ Changes From Baseline

The increase in CD4+ count at week 48 for the CT group was 186 cells per microliter [interquartile range (IQR): 119–279] versus 163 cells per microliter (IQR: 90–246) for the RC group, which was statistically significant (P = 0.04).

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Loss to Follow-Up

In the first year after treatment initiation, there were 20 (12%) patients lost to follow-up in the CT group and 61 (17%) patients in RC group, with no statistical difference (P = 0.18).

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During the first year after HAART initiation, all cause mortality was the following: 1 death in the CT group and 13 deaths in the RC group (Table 2) with a rate of 0.017 (95% CI: 0.002 to 0.122) versus 0.094 (95% CI: 0.053 to 0.17) deaths per 1000 person-days, respectively (P = 0.05). In a Cox model, the hazard ratio for mortality comparing CT versus RC was of 0.169 (95% CI: 0.02 to 1.293, P = 0.08). In the multivariate analysis (Table 4), including age at HAART initiation, gender, years of education, employment at entrance to care, men who have sex with men, presence of AIDS-defining event, participation in a CT, year of HAART initiation, change of antiretroviral therapy treatment, and VF, only Hb >12 g/dL (OR: 0.16, 95% CI: 0.03 to 0.84, P = 0.03) was significantly associated with a lower death rate during the first year of treatment.

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Strict study inclusion criteria used in CTs to evaluate different HAART regimens and less acceptability to participate in trials by more vulnerable groups may influence the applicability of the results to the general population in a given region. We undertook this analysis to compare the characteristics of patients receiving first HAART regimens through CTs with those receiving it through RC.

Our results show important differences at baseline in those participating in trials compared with those not participating. At baseline, patients in trials had higher CD4+ count values, higher proportion of patients with Hb >12 g/dL, lower proportion of employment, and higher proportion of VL >75,000 copies/mL. In addition, a significantly lower proportion of female subjects were included in trials compared with RC. Including less sick patients in trials is most likely a reflection of strict study inclusion and exclusion criteria, which gives preference to patients who the investigator considers less likely to interrupt the study because of complications related to AIDS.29–33 In fact most of the CTs conducted in our center during the study period (except for the efavirenz vs. lopinavir/ritonavir study in advanced patients) excluded those with very low CD4+ counts or AIDS-defining events.18–28 However, it turns out that late presentation to care is highly prevalent in our region as was recently described,15 which is clearly reflected in the characteristics of the RC group. Another significant finding was the extremely low frequency of female subjects inclusion into trials. An explanation for this is strictly speculative and deserves further detailed exploration. A perception of higher vulnerability, less social support, and a lower acceptance rate by females to volunteer due to family commitments may be some explanations for this finding.7–9

Regarding the outcomes measured in this analysis, the proportion of patients developing VF was 3 times higher in the RC group than the CT group. This finding could be explained at least in part, by the larger proportion of patients in the high viral load stratum and more severe markers of advanced clinical stage of HIV infection in the RC group, which have been associated with lower virological responses in different studies34–41 even though this was not supported by our multivariate analysis. Additionally a bias toward enrolling patients who are more reliable and stable psychosocially for consistent follow-up and better adherence to treatment may have also contributed to the better outcomes in the CT group.

Smith et al13 evaluated patients from a cohort in the United Kingdom with findings similar to ours in terms of improved virological outcomes in patients participating in CTs (94 vs. 86%, OR: 2.71, P = 0.007), other studies have also found the same results.42 They also found that the CT group had more follow-up visits during the first year than the RC group [7 vs. 6 (IQR: 5–9), P < 0.0001]. This issue may reflect that patients in CT have better disposition to attend the clinic visits. Moreover, the study staff made efforts to keep an active follow-up of the subjects, rescheduling missed visits, and taking immediate action to identify and resolve unfavorable events which may not always happen in RC. In contrast to our results, in similarly designed studies, other authors have found a higher rate of LTFU in RC43 and no differences in virological outcomes.14

The increased mortality seen in our analysis for the RC group compared with the CT group occurred mostly during the first year. This is similar to the early mortality described in cohort studies of patients starting HAART in limited resource settings.4,44,45

The results of this study clearly point out that patients starting HAART who participate in CTs in Mexico are different in many aspects from those who do not. Extrapolating CT results to general population may thus be appropriate for certain outcomes and populations, but not for others. Underrepresentation of females and late presenters is characteristic of trial population in our country and should be considered when translating results of trials into clinical practice in the region.

Limitations of our study are its retrospective nature and the inclusion of data only from a single center. A possible bias generated by conceivably a better capture of mortality and VF in the CT group would rather underestimate the differences between both groups observed in the study and may account actually for some lessening of the differences. Another factor that may have lessen the differences observed in the outcomes of the study is the fact that subjects in the RC group received more frequently simpler nonnucleoside reverse transcriptase inhibitor–based regimens compared with higher pill burden, more complex boosted-PI–based regimens in the CT group (Table 1). Finally, we recognize that an analysis of the CT group that included patients who were rejected from trial participation because of screening failures and investigator decision may have reflected a more realistic view of this group; however, published results of CTs only analyze the outcomes and baseline characteristics of those randomized subjects.

In our region, patients initiating ARV therapy in CTs have a lower probability of viral failure during the first year and a lower mortality rate than patients in RC, which probably reflects a more advanced clinical stage at baseline, even though this finding was not confirmed in the multivariate model. More studies including other centers in the region may help understand these findings in a wider perspective.

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active antiretroviral therapy; clinical trial; HIV; HAART; standard of care; virological failure

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