Current HIV Research, 2012, 10, 000-000 1
1570-162X/12 $58.00+.00 © 2012 Bentham Science Publishers
Effectiveness of Antiretroviral Therapy in HIV-1-Infected Active Drug
Users Attended in a Drug Abuse Outpatient Treatment Facility Providing
a Multidisciplinary Care Strategy
Gabriel Vallecillo Sánchez*,1,2, Josep M. Llibre3,4, Marta Torrens2, Arantza Sanvisens4,
Gerard Mateu2, Hernando Knobel1, Klaus Langohr5, Jose R. Santos3,4 and Roberto Muga4
1Departments of Internal Medicine and Drug Addiction Unit of Psychiatry, Hospital del Mar, Universitat Autònoma de
Barcelona, Barcelona, Spain; 2Drug Addiction Unit of Psychiatry, Hospital del Mar, Universitat Autònoma de
Barcelona, Barcelona, Spain; 3Lluita contra la SIDA Foundation, Badalona, Spain; 4Department of Internal Medicine,
Hospital Universitari Germans Trias i Pujol, Badalona; Universitat Autònoma de Barcelona, Spain; 5Department of
Statistics and Operations Research, Universitat Politècnica de Catalunya, Barcelona, Spain, Research programme in
neurosciences, IMIM (Hospital del Mar Research Institute), Barcelona, Spain
Abstract: Objective: HIV-1-infected active drug users (ADU) obtain smaller clinical benefits with antiretroviral therapy
(HAART) compared to non-ADU subjects with sexually-transmitted HIV-1 infection. Therefore treatment strategies are
required to address the specific issues arising in this challenging scenario. We describe the effectiveness of HAART
provided in a drug abuse outpatient treatment facility through a comprehensive integrated care that includes medical, drug
dependence, and psychosocial support.
Methods: We included all consecutive HIV-1-infected ADU admitted for drug dependency treatment and who started their
first HAART. A comparator arm consisted of a control group of sexually transmitted HIV-1-infected subjects attended in
a reference hospital under standard care. The strategy did not include directly observed treatment.
Results: A total of 71 ADU and 48 matched subjects infected through sexual transmission were included. ADU had lower
baseline CD4+ T-cell counts (196 vs 279 cells/?L, P=.001), and more advanced CDC stages (P=.001). The estimated
probabilities of patients with virological response (<50 copies/mL) at weeks 48 and 96 were 92.9% (95%-CI:
87.1%—99.1%) and 87.3%% (95%-CI: 78.7%—95.2% for ADU, and 93.7%(95%-CI: 84.1%—99.8%) and 87.5%
% (95%-CI: 77.5%—97.3%) for sexually-infected subjects (P= .1325 and .241). Kaplan-Meier estimates of time to
loss of virological response did not show differences between groups (log rank test, P=.965).
Conclusions: An integrated multidisciplinary care of HIV-1-infected antiretroviral naïve ADU provided in a drug abuse
treatment center obtains high rates of virological suppression, similar to those observed in a comparison group of
sexually-transmitted HIV-1-infected subjects. This strategy should be further evaluated in public health programs and
assessed in randomized trials.
Keywords: Active drug users, HAART, antiretroviral effectiveness, treatment adherence, multidisciplinary care.
therapy (HAART), data show the persistence of a significant
difference in treatment outcomes between HIV-1 infected
drug users and non-drug user subjects [1-3]. HIV-1-infected
drug users start treatment significantly later, have poorer
long-term adherence to HAART, achieve lower rates of
virological suppression, and experience a more rapid disease
progression with higher mortality rates (both HIV-1 related
or not) than HIV-1-infected non–drug users [1-5].
Furthermore, non-active drug
underrepresented in most antiretroviral treatment trials, while
active drug users (ADU) are routinely excluded [1-3].
Despite the availability of highly active antiretroviral
users are routinely
comorbidities (nutritional deficiencies, soft-tissue infections,
HIV-1-infected drug users commonly exhibit several
*Address correspondence to this author at the Department of Internal
Medicine, Hospital del Mar, Passeig Marítim 25-29, 08003 Barcelona,
Spain; Tel: +0034932483251; E-mail: email@example.com
hepatitis C co-infection, tuberculosis) and specific social
issues (poverty, marginalization, homelessness, legal
problems) that may jeopardize their compliance with
HAART. The optimal management of these issues is crucial
to enhance HAART outcomes in HIV-1-infected ADU and
indicates the need for specially designed ancillary services
[1-3]. Nevertheless, services for multiple medical and
psychosocial problems faced by HIV-1-infected ADU are
often provided by a range of health care professionals, who
are often located in different settings, not necessarily
interconnected. This fragmentation of care can lead to poorer
treatment adherence, limited follow-up, increased risk for
treatment interruption, and poorer clinical outcomes .
Hence, integrated models of care could facilitate HAART
success in this setting.
interacting chronic diseases, and one of the strategies
developed to improve outcomes in these subjects is
combining antiretroviral therapy with substance abuse
treatment. Methadone maintenance treatment has been
associated with improved uptake of treatments, adherence,
An active substance use disorder and HIV-1 infection are
2 Current HIV Research, 2012, Vol. 10, No. 4 Sánchez et al.
and HIV-1 outcomes [7-10]. In addition, directly
administered therapy programs which provide daily
supervision of antiretroviral therapy in conjunction with
methadone, have been associated with improved adherence
to HAART and virological response [11-15]. Other opioid
substitution drugs like buprenorphine have a similar
potential [16-17]. Strategies for providing HIV-1 therapy
directly in drug abuse treatment centers have not evaluated
their impact on HAART outcomes over time .
effectiveness of HAART provided to HIV-1-infected active
or recent drug users seeking treatment in a drug abuse
outpatient treatment facility that includes medical care, drug
dependence treatment, and psychosocial support.
The objective of the present study is to evaluate the
SUBJECTS AND METHODS
ADU starting drug dependence treatment in a drug abuse
outpatient center located in the old part of the city of
Barcelona (Spain), and that initiated their first HAART
between January 2005 and December 2009. Its catchment
area has mainly old buildings, has a high unemployment
rate, and there is an overrepresentation of immigrants
coming mainly from Pakistan, South America, and East
Europe, as well as people with legal problems, drug
trafficking, and commercial sex. The access is free and most
subjects arrive self-referred or referred from the primary care
physician, seeking for drug abuse treatment. The centre is
open from Monday to Sunday from 8.00 a.m. to 8.00 p.m.
The staff practice schedule is flexible in accommodating
subjects, and consists of a multidisciplinary health team
including two psychiatrists,
consultant, one social worker, one psychologist, and four
trained nurses. This team designs, according to all individual
characteristics, the drug abuse treatment modality most
suitable for each case (i.e. detoxification, methadone
detoxification referral, or residential treatment). Subjects are
monitored on a regular basis in a multidisciplinary session to
discuss the relevant issues for every subject. The
communication between subjects and the staff takes place
within a framework of confidence, in an empathetic, non-
judgmental, and non-punitive style, and with the regular use
of motivational interviewing.
treatments (antidepressants, antipsychotics, anxiolytics,
mood stabilizers) are prescribed as required according to the
American Pshychiatric Association guidelines .
We included in the study all consecutive HIV-1-infected
subjects’ health problems, in particular the HIV-1 infection,
tuberculosis prophylaxis or treatment, and hepatitis C co-
infection. He assesses when to initiate, the type, and the
monitoring of HAART. Antiretroviral therapy is free of cost,
is provided monthly, and is not directly observed at the
The infectious-disease consultant takes care of the
and supervise urine tests. They review the side effects of
medication including methadone
interactions, identify adherence problems, provide education
on adherence, and when an individual patient does not attend
the scheduled visits, they are responsible for locating the
The nurses dispense the methadone, carry out blood tests,
subjects and ensuring that they come to a return visit to
secure patient retention. It is possible to perform directly
administered treatment (i.e. antipsychotic, antiretroviral
therapy, tuberculosis therapy) for homeless subjects or
patients with extremely difficult adherence challenges. More
details about the CAS-Barceloneta functioning are published
brief questionnaire to collect information on socio-
demographic variables, risk categories, and ongoing risk
behaviors. The subjects also undergo a comprehensive
medical examination and routine laboratory testing including
biochemistry, hematology, and HIV, hepatitis A, B and C,
and syphilis screening.
On the day of outpatient admission, subjects answer a
standard whole-blood flow-cytometry. Plasma HIV-1 RNA
was quantified using RT-PCR (Roche Molecular Systems,
Branchburg, NJ), with a minimal detectable level of 50
copies/mL. Urinalyses were carried out weekly to detect the
presence of metabolites of major drugs of abuse (i.e. heroin,
cocaine, benzodiazepines). Subjects were assessed as current
users if urine tests were positive, and former users if all tests
were negative during the follow up.
T cell lymphocyte subpopulations were measured using
drug users HIV-1+ treatment-naive subjects infected through
sexual transmission (STG), that were receiving standard
medical care  at the Infectious Diseases Unit of the
reference hospital. We included in the study only subjects
who received care through the same physician also working
in the CAS-Barceloneta center in the same period of time, to
avoid physician-related biases in the care provided.
The comparison group was selected from a cohort of non
guidelines, and was recommended in all subjects with CD4
cell counts <350 cells/mm3 . HAART was composed of
one of the following combinations: (1) a boosted protease
inhibitor (PI) plus 2 nucleoside reverse-transcriptase
inhibitors (NRTIs), (2) a non-NRTI (NNRTI) plus 2 NRTIs,
or (3) abacavir in combination with lamivudine and
zidovudine or stavudine (3 NRTIs) .
HAART was initiated according to national antiretroviral
virological response (TLOVR), a composite endpoint that
included virological failure (defined as a confirmed plasma
HIV-1 RNA >500 copies/mL after getting HIV-1 RNA <50
copies/ml, or not getting an HIV-1 RNA <50 copies/ml after
week 24), permanent treatment discontinuation (stopping
treatment >15 days by subjects´s choice), death, or loss to
follow-up. Changes in the antiretroviral regimen due to side
effects were not considered as treatment failure as long as
the subject maintained a suppressed plasma viral load. A
secondary endpoint was the CD4+ T-cell count change.
The primary efficacy end-point was the time to loss of
deviation, median and range for the quantitative variables
and absolute frequencies and percentages for the qualitative
variables. Chi-square and/or non parametric tests were
applied to assess whether HIV-1-ADU differed from the
comparison STG with regard to socio-demographic and
clinical characteristics. To analyze the time to loss of
virologic response between groups, Kaplan-Meier curves
were plotted and were compared using the log-rank test. The
Kaplan-Meier estimator was further used to estimate
Descriptive statistics were expressed as mean, standard
ARV Effectiveness in Drug Users Current HIV Research, 2012, Vol. 10, No. 4 3
probabilities of virological response after 48 and 96 weeks.
The Wilcoxon test was applied to compare both populations
of interest with respect to the median increase of CD4+ T-
lymphocytes after 48 and 96 weeks, respectively. Statistical
analysis was performed using SPSS version 15.0 (SPSS,
Chicago, IL, USA), and R, version 2.13.1 (The R Foundation
for Statistical Computing).
Fig. (1). During the period of the study, 84 HIV-1-infected
antiretroviral-naïve ADU were attended (Fig. 1.1). Of them,
76 subjects had an indication for antiretroviral therapy
initiation and were started on it. Five of them were not
included in the analysis because they were placed on directly
observed treatment. A comparison cohort of 123 treatment-
naive subjects with sexually-transmitted HIV-1 infection
(STG) were selected as controls (Fig. 1.2), and 51 of them
had an indication for HIV-1 treatment initiation. Three of
them refused to start treatment, and 48 eventually started
The selection process of the study subjects is depicted in
had significantly higher rates of Spanish origin, older age,
females, lower education
incarceration, unemployment, psychiatric disease, and
chronic hepatitis C compared to the comparison STG. The
main drug dependency was heroin in 87.3%, and cocaine in
12.7%, most of them (94.3%) intravenously. Furthermore,
80.2% of the subjects were also dependent on other drugs
(cocaine 50.7%, hypnosedatives 14.1%, heroin 8.5%, and
alcohol 7.0%). Additionally, 90.1% (64/71) started on
maintenance treatment with methadone, 88.7% with
benzodiazepines, 46.5% with antipsychotics, 31% with
antidepressants, and 29.5% with mood stabilizers.
Their baseline characteristics are shown in Table 1. ADU
level, criminal records,
clinical condition, including a CDC stage C in 54,9% vs
18.9% (P=.001) in the comparison STG, and a lower CD4+
T-cell lymphocyte count, 199 vs 279 cells/?L (P=.001),
HIV-1-infected ADU started HAART with a worse
composition of the HAART started. Boosted PIs were used
in 76.1% (54/71) of HIV-1-infected ADU but in 45.8%
(22/48) of the STG (P=.01).
There were also significant differences in the
(HIV-1-RNA <50 copies/ml) during a median follow-up of
118 weeks (range 24-252) were 87.3% (62/71) in the ADU
group versus 87.5% (42/48) in the STG (P=.1779). The
Kaplan-Meier estimates of time to loss of virological
response did not show significant differences between
groups (log rank test, P=.965) (Fig. 2). The estimated
probabilities of patients with virological response (<50
copies/mL) at weeks 48 and 96 were 92.9% (95%-CI:
87.1%—99.1%) and 87.3%% (95%-CI: 78.7%—95.2% for
ADU, and 93.7%(95%-CI: 84.1%—99.8%) and 87.5% %
(95%-CI: 77.5%—97.3%) for sexually-infected subjects (P=
.1325 and .241) (Fig. 3).
The percentages of subjects with virological response
(12.7%) ADU and in 4/48 (8.3%) subjects in the STG
(P=.177). Eight of the 9 ADU restarted the same therapeutic
Permanent treatment discontinuation occurred in 9/71
regimen prescribed prior to the discontinuation, achieving
again a complete virological suppression, and one control
patient was lost to follow-up. True virological failure
occurred in 0/71, and 2/48 (4.2%) subjects, respectively.
HIV-1-infected ADU maintained a continued use of abuse
drugs. The virological response in the continued drug use
was 81.8% (36/44) and 96.3% (26/27) in former drug users
(P=.1578). The Kaplan-Meier estimates of time to loss of
virological response did not show significant differences
between groups (log rank test, P=.185). There were no
deaths during follow-up.
During the follow-up of the study, 62% (44/71) of all
shown in Fig. (4). At weeks 48 and 96, the median increase
was 83 (95%-CI: 66—112) and 116.5 (95%-CI: 87—144)
cells/mm3 (P=.111), and 167.5 (95%-CI: 133—221) and
254 (95%-CI: 188—286) cells/mm3 (P=.016) in the ADU
and the STG respectively.
The median changes in CD4+ T-lymphocyte counts are
attended in an outpatient drug dependency centre using an
integrated and multidisciplinary care can achieve high rates
of virological and inmunological efficacy with HAART,
similar to those of a comparison STG of HIV-1-infected
subjects. Of interest, the high efficacy results seen were
achieved without providing directly observed treatment,
which is far more labor and cost intensive.
The present study shows that HIV-1-infected ADU
cohort of ADU are unanticipated, considering the frequency
of some strong baseline surrogates of poorer antiretroviral
response, significantly higher than in the comparison STG
cohort. These conditions included psychiatric disorders,
incarceration, unemployment, hepatitis C coinfection, and a
lower level of education. Furthermore, late presenters were
overrepresented among ADU, who started HAART with
significantly lower CD4+ T-cell counts and a more advanced
HIV-1 CDC stage [1-3].
The high rates of virological suppression seen in this
ADU in the present study using a multidisciplinary care
focused in a drug abuse outpatient center are higher and
more sustained compared to other interventions. Mobile
methadone units providing
antiretroviral therapy have reported rates of virological
success of 70-79 % at 6 months and 56 % at 12 months [13-
15]. Actually, in a previous multicenter hospital-based
cohort of HIV-infected patients attending 10 hospitals in
Spain, ADU had a 33% lower risk of initiating HAART
compared to men who have sex with men, and had poorer
viral load suppression after adjusting by baseline VL, AIDS
diagnosis, and prior ART . The continued use of drugs is
one of the most important factors associated with lower
therapeutic adherence and poorer virological response [23,
24]. Even though this study showed a trend to lower
virological response among patients who remained active
drug users during follow-up, their virological response rates
were higher than those obtained in other health strategies in
this subset of highly challenging subjects [13-15, 23, 24],
and unanticipatedly, very similar to those seen in the
matched control STG.
The antiretroviral treatment efficacy rates observed in
4 Current HIV Research, 2012, Vol. 10, No. 4 Sánchez et al.
Fig. (1.1). Selection of the HIV-1-infected active drug users attended in a drug abuse outpatient treatment center.
ART- Antiretroviral therapy; DOT- Directly observed treatment
Fig. (1.2). Selection of the comparison cohort of HIV-1+ subjects infected through sexual transmission and attended with standard care in a reference hospital.
ART- antiretroviral therapy
Fig. (1). Selection of the study HIV-1-infected subjects.
ARV Effectiveness in Drug Users Current HIV Research, 2012, Vol. 10, No. 4 5
adherence rates seen in ADU can potencially increase the
risk of treatment failure and development of HIV-1 drug
resistance, that jeopardize the success of subsequent
regimens and can be transmitted to the community [1-3]. In
the present study, no HIV-1-infected ADU developed true
virological failure, and those subjects who abandoned the
treatment restarted their previous antiretroviral regimen,
achieving complete virological suppression again. These
results are consistent with findings of some studies in which
antiretroviral therapy in HIV-1-infected drug users did not
This is of particular interest and controversial, as lower
have an impact on rate of antiretroviral resistance .
Moreover, a recent meta-analysis
antiretroviral resistance rates in drug users (current or
previous) with those in HIV-positive patients infected by
other routes failed to identify a higher risk for drug
resistance among drug users .
HAART to drug users. At the contrary, the strategy in these
individuals should focus on treatment adherence and subject
retention to scheduled visits at the center providing a
multidisciplinary treatment strategy.
Therefore, ADU is an insufficient reason to withhold
Characteristics of the Study Population of HIV-1-Infected Subjects at HAART Initiation
Active Drug Users
Age (mean+SD) 41.3+5.9 37.4+8.8 0.005
Male n, (%) 46 (64.8%) 40 (83.3%) 0.045
Ethnicity n, (%)
White 69 (97.2%) 43 (89.6%)
Black 2 (2.8%) 5 (10.4%)
Origin n, (%)
Spanish 64 (90.1%) 30 (62.5%)
European 5 (7.0%) 4 (8.3%)
African 2 (2.8%) 4 (8.3%)
South-American 0 (0%) 10 (20.8%)
Incarceration n,(%) 23 (32.4%) 0 (0%) 0.001
Employed n, (%) 22 (29.7%) 35 (72.9%) 0.001
Level of education n, (%)
No formal education 28 (39.4%) 9 (18.8%)
Primary education 29 (40.8%) 17 (35.4%)
Secondary education 14 (19.7%) 17 (35.4%)
University studies 0 (0%) 5 (10.4%)
Hepatitis coinfection n, (%)
Hepatitis C virus 68 (95.8%) 3 (6.2%) 0.001
Hepatitis B virus 5 (7.0%) 7 (14.6%)
Psychiatric disorders n, (%)
Personality disorder 17 (23.9%) 0 (0%)
Depresssion 14 (19.7%) 4 (8.3%)
Psychotic disorder 6 (8.5%) 0 (0%)
Bipolar disorder 1 (1.4%) 0 (0%)
CDC stage n, (%)
A 14 (19.7%) 26 (54.2%)
B 17 (23.9%) 13 (27.1%)
C 39 (54.9%) 9 (18.9%)
CD4 count (cells/?L) (median, range) 209(3-427) 294(29-465) 0.001
Viral load (median log10) 5.00+4.2 4.96+3.9 0.674
Baseline HAART regimen n,(%)
NNRTI 9 (12.6%) 25 (52.1%)
PI 54 (76.1%) 22 (45.8%)
NRTI 8 (11.3%) 1 (2.1%)
NNRTIS: non-nucleoside reverse-transcriptase inhibitor; PI: protease inhibitor; NRTI: 3 nucleoside reverse-transcriptase inhibitors.
6 Current HIV Research, 2012, Vol. 10, No. 4 Sánchez et al.
- active drug users - subjects infected through sexual transmission.
Median follow-up: 118 weeks (range 24-252). Log-rank test (P=.965).
Fig. (2). Time to loss of virologic response between groups.
--- active drugs users (n 71) ---sexual contact group (n 48). p= 0.1325 for week
48 and p=0.241 for week 96
Fig. (3). Percentages of patients with virologic response (HIV RNA
antiretroviral therapy with substance abuse treatment has
been short in many previous reports [13-15], usually shorter
than one year. Moreover, it has been well documented that
the effectiveness of these measures disappears once the
therapeutic intervention ends . However, in the present
study, a durable and sustained benefit was observed beyond
two years while the intervention continued. As adherence to
antiretroviral treatment is a dynamic variable that changes
over time , these results reinforce the need to maintain
this therapeutic intervention in the long term.
The duration of the interventions that combine
ADU compared to their comparison STG, starting treatment
with a significantly lower CD4+ T-cell count and a more
advanced CDC stage. These data are consistent with findings
from many other studies which confirm that this subset of
patients present later during the course of HIV-1 disease and
have often developed AIDS-defining events [1-3]. This
increases the risk for spreading their HIV-1 infection to the
community, and compromises
immunological response [1-3, 29, 30]. In the present study
we have observed significant differences in the CD4+ T-cell
recovery between groups, favoring a higher CD4 cell
recovery in the STG. There are several factors that could be
influencing a lower increase of CD4 cell counts in ADUs,
mainly hepatitis C coinfection,
significantly lower CD4 cell counts at HAART initiation
We also observed a delayed initiation of HAART in
of this therapeutic intervention that may have been
associated with higher adherence and virological response to
HAART in ADU. Firstly, the drug abuse treatment center is
situated in the same area where the subjects live. Despite
being a highly troubled and marginalized area, it has been
observed in previous reports that the distance to the medical
center and the lack of willpower of the patient to travel to it
is a predictive factor for abandoning treatment .
Furthermore, all the crew responsible for the health care is
located in the same physical space, avoiding fragmentation
of clinical care and subject losses during referral [34, 36].
Secondly, stigma and discrimination by care providers play a
key role in decreased care quality and subject retention to the
treatment program. Increasing physician education in the
area of evidence-based HIV-1 care and substance abuse
treatment has a significant and powerful potential to improve
comprehensive HIV and drug abuse care in this population
that discourages many physicians without widespread
experience in this particularly challenging scenario [37-39].
Therefore, when designing public health strategies directed
to specially disturbing HIV-1-infected populations, like
ADU, it is crucial that the healthcare personnel, and
particularly the medical specialists, have the appropriate
experience and knowledge in the management of both HIV-1
infection and drug abuse, and are used to work in a
multidisciplinary environment. Furthermore, the physician-
patient relationship must be based on the confidence and
respect of the patient, since the interpersonal relationship
between the patient and health team encourages adherence to
treatment and retention to the program [40, 41]. Finally, the
healthcare personnel must use the motivation interview in all
the visits, as this increases patient awareness of their disease
and their capacity to act on it by improving adherence, even
when drug abuse withdrawal is not achieved by the subject
It is important to highlight the pivotal points in the design
selection bias exists in the inclusion of individuals who
voluntarily came to the drug abuse center and used the
services. Subjects who were most concerned for their own
medical health and more motivated to start a drug abuse or
HIV-1 treatment could be overrepresented among this
cohort. However, the subjects were selected from a
particularly troubled urban catchment area and represent a
group with notably high incidence of poor adherence
The present study has some limitations. An intrinsic
ARV Effectiveness in Drug Users Current HIV Research, 2012, Vol. 10, No. 4 7
unemployment and criminal records, as well as ADU [1-3].
Furthermore, all consecutive subjects attended during a
recruitment period of 5 years have been included. Secondly,
the study did not randomize the studied comprehensive
treatment strategy. However, the comparator arm is a STG
cohort with individuals with similar socio-demographic and
HIV-1 baseline variables and with a specific effort made to
avoid physician-driven biases. Finally, the study sample size
is small which underpowers the statistical results. However,
the high efficacy seen with HAART in active drug users with
the describes strategy in this single-center pilot study gives
support to the performance of a multicenter randomized
markers, including psychiatric illness,
the integrated and multidisciplinary care of HIV-1-infected
ADU in a drug abuse treatment center greatly improves the
efficacy of HAART, achieving efficacy rates similar to those
obtained in a control STG without records of drug addiction.
This strategy should be considered in the management of
these subjects, especially in areas of the world where the
HIV-1 epidemic is driven by injecting drug users. These
results should be confirmed in randomized studies.
In conclusion, the data obtained in this study show that
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Received: November 2, 2011
Revised: January 2, 2012 Accepted: April 14, 2012