Expansion of HAART Coverage Is Associated with Sustained Decreases in HIV/AIDS Morbidity, Mortality and HIV Transmission: The ‘‘HIV Treatment as Prevention’’ Experience in a Canadian Setting Julio S.G. Montaner1,2*, Viviane D. Lima1,2, P. Richard Harrigan1,2, Lillian Lourenço1, Benita Yip1,
Bohdan Nosyk1,3, Evan Wood1,2, Thomas Kerr1,2, Kate Shannon1,2, David Moore1,2, Robert S. Hogg1,3,
Rolando Barrios1,5, Mark Gilbert4, Mel Krajden4, Reka Gustafson5, Patricia Daly5, Perry Kendall6
1 BC Centre for Excellence in HIV/AIDS, Providence Health Care, Vancouver, British Columbia, Canada, 2 Division of AIDS, Department of Medicine, University of British
Columbia, Vancouver, British Columbia, Canada, 3 Faculty of Health Sciences, Simon Fraser University, Vancouver, British Columbia, Canada, 4 BC Centre for Disease
Control, Vancouver, British Columbia, Canada, 5 Vancouver Coastal Health Authority, Vancouver, British Columbia, Canada, 6 Ministry of Health, Province of British
Columbia, Victoria, British Columbia, Canada
Background: There has been renewed call for the global expansion of highly active antiretroviral therapy (HAART) under the framework of HIV treatment as prevention (TasP). However, population-level sustainability of this strategy has not been characterized.
Methods: We used population-level longitudinal data from province-wide registries including plasma viral load, CD4 count, drug resistance, HAART use, HIV diagnoses, AIDS incidence, and HIV-related mortality. We fitted two Poisson regression models over the study period, to relate estimated HIV incidence and the number of individuals on HAART and the percentage of virologically suppressed individuals.
Results: HAART coverage, median pre-HAART CD4 count, and HAART adherence increased over time and were associated with increasing virological suppression and decreasing drug resistance. AIDS incidence decreased from 6.9 to 1.4 per 100,000 population (80% decrease, p = 0.0330) and HIV-related mortality decreased from 6.5 to 1.3 per 100,000 population (80% decrease, p = 0.0115). New HIV diagnoses declined from 702 to 238 cases (66% decrease; p = 0.0004) with a consequent estimated decline in HIV incident cases from 632 to 368 cases per year (42% decrease; p = 0.0003). Finally, our models suggested that for each increase of 100 individuals on HAART, the estimated HIV incidence decreased 1.2% and for every 1% increase in the number of individuals suppressed on HAART, the estimated HIV incidence also decreased by 1%.
Conclusions: Our results show that HAART expansion between 1996 and 2012 in BC was associated with a sustained and profound population-level decrease in morbidity, mortality and HIV transmission. Our findings support the long-term effectiveness and sustainability of HIV treatment as prevention within an adequately resourced environment with no financial barriers to diagnosis, medical care or antiretroviral drugs. The 2013 Consolidated World Health Organization Antiretroviral Therapy Guidelines offer a unique opportunity to further evaluate TasP in other settings, particularly within generalized epidemics, and resource-limited setting, as advocated by UNAIDS.
Citation: Montaner JSG, Lima VD, Harrigan PR, Lourenço L, Yip B, et al. (2014) Expansion of HAART Coverage Is Associated with Sustained Decreases in HIV/AIDS Morbidity, Mortality and HIV Transmission: The ‘‘HIV Treatment as Prevention’’ Experience in a Canadian Setting. PLoS ONE 9(2): e87872. doi:10.1371/ journal.pone.0087872
Editor: Nicolas Sluis-Cremer, University of Pittsburgh, United States of America
Received November 5, 2013; Accepted December 30, 2013; Published February 12, 2014
Copyright: � 2014 Montaner et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The work here described [Treatment as Prevention in BC initiative (PI: JM)] has been financially supported by the British Columbia Ministry of Health, as well as an Avant-Garde Award (No. 1DP1DA026182) and grant 1R01DA036307-01 from the National Institute of Drug Abuse (NIDA), at the US National Institutes of Health (NIH). In addition, JM was funded through a Knowledge Translation Award from the Canadian Institutes of Health Research (CIHR). VDL is supported by a Scholar Award from the Michael Smith Foundation for Health Research and a New Investigator Award from CIHR, and by a NIDA award (R03DA033851) and CIHR award (MOP-125948). TK was supported in part by a NIDA award (R01DA028532) and a CIHR award (MOP–102742). EW is supported by a Tier 1 Canada Research Chair in Inner City Medicine. Additional limited unrestricted funding was provided by Abbvie, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck and ViiV Healthcare. None of the funders played any role in study design, data collection and analysis, decision to publish, preparation or review of the manuscript.
Competing Interests: This study received limited unrestricted funding from Abbvie, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck and ViiV Healthcare. The funding provided by the commercial sources has been directed to the institution and not to the investigators. There are no patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials.
* E-mail: email@example.com
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After 30 years, controlling the HIV epidemic remains an
extraordinary challenge. This is despite the availability of a
number of proven prevention tools, including harm-reduction
strategies and emerging biomedical interventions. [1–7] Recently,
increasing attention has been focused on the potential role that the
expansion of HIV treatment may offer to curb progression to
AIDS and premature death among HIV infected individuals and
secondarily reduce HIV transmission, commonly referred to as
HIV treatment as prevention or TasP. [8–11] In brief, HIV-1
RNA concentration (hereafter referred to as viral load) is a key
determinant of the level of risk associated with sexual, vertical and
needle sharing-related HIV transmission. [12–21] Appropriate use
of HAART suppresses HIV replication on a sustained basis,
leading typically to undetectable, viral load in plasma and halting
disease progression to AIDS and premature death.11 In addition,
as viral load rapidly declines in plasma and subsequently in other
biological fluids (including semen, vaginal fluids and rectal
mucosa), the likelihood of HIV transmission per exposure event
is markedly reduced. [12–21] The concept of scaling up highly
active antiretroviral therapy (HAART), commonly referred to as
TasP, has gained substantial momentum, as its efficacy and
effectiveness have become increasingly apparent. [8,9,22–24]
However, the real-world population-level effectiveness and
sustainability of this strategy remains to be adequately character-
British Columbia (BC), Canada, provides a unique environment
to address this issue within a concentrated HIV epidemic.
HAART eligibility in BC has remained consistent with the IAS-
USA guidelines since 1996 to the present. [11,25] BC is an
adequately resourced environment with a publically funded health
care system, that fully subsidizes access to medical services,
centralized laboratory monitoring and access to HAART with no
co-payments or deductibles. In addition, a single agency, the BC
Centre for Excellence in HIV/AIDS (BC-CfE), is responsible for
the centralized distribution of all antiretrovirals and monitoring of
key HIV-related outcomes in BC. Additionally, the availability of
unique personal health numbers for all BC-residents provide
unique opportunities to evaluate the impact of this strategy
throughout the province using anonymized data linkages between
We therefore conducted a longitudinal ecological study to
evaluate the population-level effectiveness and sustainability of
HAART expansion in BC. Specifically, we sought to characterize
the association between HAART coverage, and the proportion of
individuals virologically suppressed with the number of new AIDS
diagnoses, and all-cause mortality among HIV-infected BC
residents, as well as the number of new HIV diagnoses and
estimated HIV incident cases between 1996 and 2012.
Aggregate- and individual-level data on the key study variables
were collected from a number of sources, including the BC-CfE
Laboratory and Drug Treatment Registries, the BC Centre for
Disease Control (BCCDC), the BC Ministry of Health (BC MoH)
population-level health resource utilization files, and the Public
Health Agency of Canada (PHAC).
HIV Incidence and Prevalence We also obtained HIV prevalence estimates for BC from 1996
to 2011, independently generated by the Public Health Agency of
Canada (PHAC)  using previously published methods. 
The method is a modified back-projection method to estimate
HIV incidence and prevalence. Unlike the back-projection
methods used the literature, this new method does not require
linking HIV and AIDS diagnostic registries. It is based on linking
the estimated parametric distribution between the time to HIV
testing and time since HIV infection. These distributions were
adjusted for testing practices over time (e.g. HIV testing trends),
reporting delays, multiple reporting of cases, AIDS cases reporting
(adjusting for the effect of HAART), survival time before and after
HAART was introduced, and birth cohort effects. [28,29] Data for
2012 are not yet available, and therefore, we extrapolated the
available data to obtain preliminary estimates for these two
indicators for the year 2012.
New HIV Diagnoses and AIDS Morbidity and Mortality The BCCDC collates all BC HIV surveillance data and houses
HIV testing data from the provincial public health reference
laboratory, which accounts for approximately 90% of all HIV
screening and all confirmatory testing in BC. Of note, HIV
infection became provincially reportable in 2003.30 Data regard-
ing new HIV diagnoses were extracted from annual and monthly
BCCDC HIV/AIDS Update and Reportable Diseases reports
from 1996 to 2012.  The AIDS case-reports were allocated
according to the year when a client was diagnosed with the first
AIDS defining illness.
HIV Treatment and Monitoring HIV/AIDS care is fully publically funded by the health care
system in BC. This includes publically funded access to medical
services, virological and laboratory monitoring and HAART (with
no co-payments or deductibles). HAART use in BC is driven by
the BC-CfE HIV treatment guidelines,  which have remained
consistent with those of the International AIDS Society-USA (IAS-
USA) since 1996. [11,25].
Clinical, treatment and laboratory data were obtained from the
BC-CfE, which has a centralized system capturing all antiretro-
viral distribution, all plasma viral load testing, and all resistance
testing, as well as baseline CD4 count for 96% of all patients
starting antiretroviral therapy in BC. Specifically, HAART
coverage, CD4 cell counts, viral load, treatment adherence (as
measured by validated prescription refill compliance),  and
genotypic drug resistance were obtained from the BC-CfE
databases. For HAART coverage, we obtained the yearly number
of individuals on HAART in BC. Viral Load data were adjusted
for changes in viral load assay sensitivity over time, as previously
described.  For the purpose of these analyses, we recorded the
highest viral load for every individual per year. To accommodate
irregular frequency of measurements or missing values, the highest
yearly value was carried forward until a new measurement was
available. Individuals were censored if they moved out of the
province or died.
Population-level adherence to antiretroviral therapy was assess-
ed by prescription refill compliance for each year as previously
described.  In brief, this was estimated by dividing the number
of months of medications dispensed by the number of months of
follow-up during each calendar year. Resistance testing was
performed on stored viral load samples collected immediately
before starting HAART and upon virological rebound thereafter.
Samples were assigned to 1 of 4 resistance categories on the basis
of a modified International AIDS Society-USA table, as previously
described.  In brief, samples were considered to be resistant if
they displayed one or more major resistance mutations in any of
the following 4 categories: I) lamivudine, or emtracitabine; II)
other nucleoside reverse transcriptase inhibitors; III) protease
TasP Experience in Canada
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inhibitors; and IV) non-nucleoside reverse-transcriptase inhibitors.
Then, the data were classified into the following categories: I)
individuals with no evidence of HIV resistance or with wild type
HIV only II) those who were never genotyped, and individuals
demonstrating HIV resistance to III) one, IV) two or V) three
antiretroviral drug classes, respectively. Those who were never
genotyped include individuals with viral load samples ,250 copies/mL, which were not tested given that sequence analysis is
not reliable in this setting. Antiretroviral resistance data are
displayed by calendar year, and include all individuals who have
ever enrolled on the BC-CfE program – whether or not they ever
used antiretrovirals, from January 1996 to December 2012.
All-Cause Mortality among HIV-Positive Individuals HIV-related mortality data were obtained from BC Vital
Statistics for all HIV-positive individuals regardless of whether or
not they had or not ever accessed antiretroviral therapy between
1996 and 2011.  Data for 2012 were not yet available. The
HIV-related diagnoses were based on the 10th revision of the
International Statistical Classification of Diseases and Related
Health Problems (ICD-10) codes B20 to B24. .
Population Data Population estimates were obtained for the years 1996–2011 to
calculate mortality and AIDS rates. These estimates were obtained
through Statistics Canada through BCStats.  Data for 2012
were not yet available.
Statistical Analysis To be consistent throughout the text, we included the year 2012
for all variables. However, since the estimates of the Public Health
Agency of Canada were complete until 2011, we used a
polynomial function of degree three to extrapolate the data. This
polynomial function provided the best fit for the incidence and
prevalence data from 1996 to 2011, and we therefore used
estimated values of these two indicators for 2012.
We modeled trends using generalized additive models, which
accounts for the non-linear temporal trends in these longitudinal
data. [38,39] We fitted different Poisson regressions,  with
correction for over dispersion in the data, for each of the following
outcomes: estimated HIV incidence rate, HIV-related mortality
rate and the rate of AIDS cases. The primary explanatory
variables of interest were the number of individuals actively on
HAART and the percentage of individuals with the highest yearly
viral load lower than 500 copies/mL. Note that for the rates, the
size of the BC population was used as an offset in the models.
These models were performed using the statistical package SAS
(version 9.3). All p values reported were two-sided, and
significance was set at the 5% level.
Ethics Approval The BC-CFE received approval for this study from the
University of British Columbia ethics review committee at the St
Paul’s Hospital, Providence Health Care site (P05–123). The study
complies with the BC’s Freedom of Information and Protection of
Privacy Act. The study was conducted primarily using anon-
ymized laboratory and administrative databases, and therefore
informed consent was not required. Incidence data were
augmented with data collected through prospective research
cohort studies, which include written informed consent by study
participants and separate IRB approval.
Role of the Funding Source The sponsors had no role in the design, data collection, data
analysis, data interpretation, or writing of the report. The
corresponding author had full access to all data in the study and
had final responsibility to submit for publication.
From January 1st 1996 to December 31st 2012, the estimated
HIV prevalence in BC increased from 7,900 to 11,972 cases (52%;
p-value ,0.0001), and the number of individuals actively on HAART increased from 837 to 6772 (709%; p-value ,0.0001). Based on these figures, we estimated that HAART coverage
increased from 11% to 57% (p-value 0.0004) during this period.
HIV Disease Progression As shown in Figure 1, the trend in the number of HIV-related
deaths from 1996 to 2011, with 253 individuals dying in 1996 and
only 59 individuals dying in 2011. Using the overall BC population
as a denominator, the HIV-related mortality rate decreased from
6.5 to 1.3 per 100,000 of the BC population during 1996–2011
(80% decrease, p-value 0.0115). Figure 1 also shows that the AIDS
rates decreased from 6.9 to 1.4 per 100,000 population over the
study period (80% decrease, p-value 0.0330).
As shown in Figure 2, the overall median baseline or pre-
therapy CD4 cell count increased from 270 cells/mL (25–75th
percentile 130–390) in 1996 to 380 cells/mL (25–75th percentile 235–550) in 2012 (41% increase; p-value ,0.0001). The median pre-therapy CD4 cell count among individuals with a history of
injection drug use (IDU) was 350 cells/mL (25–75th percentile 180–500) in 2012.
As shown in Figure 3, HAART adherence levels for individuals
who ever started therapy in BC increased over time. While only
37% of individuals had adherence levels $95% in 1996, this increased to 71% for individuals (p-value 0.0032) by 2012.
Table 1 shows the estimated aggregate viral load levels at the
population-level over time. Using a 500 copies/mL cut-off, we
estimated that the proportion of individuals virologically sup-
pressed increased from 8% in 1996 to 74% in 2012 (p-value , 0.0001). The analysis was repeated using a 50 copies/mL cut-off;
however, this was restricted to the period of 1999–2012, as the
more sensitive test was not available prior to 1999. Using a 50
copies/mL cut-off, the proportion of individuals suppressed
increased from 6% to 59% (p-value ,0.0001). As shown in Figure 4, emergent antiretroviral drug resistance
among individuals with unsuppressed viral load (including
individuals on or off therapy) decreased from 1996 to 2012 in
BC. Since 1996, the number of individuals never genotyped
decreased markedly from 64% in 1996 to 10% in 2012 (p-value , 0.0001). At the same time, the prevalence of individuals with wild
type virus (i.e.: no drug resistance) increased from 15% in 1996 to
69% in 2012 (p-value ,0.0001).
HIV New Diagnoses As shown in Figure 5, there was a steady decline in the number
of HIV new diagnoses from 702 to 238 cases (266%; p-value 0.0004) and for estimated reduction of HIV incident cases from
632 to 368 cases per year (242%; p-value 0.0003) between 1996 and 2012. New HIV diagnoses decreased by 92% (p-value 0.0013)
among individuals with a history of injection drug use, and by 22%
(p-value 0.0046) among MSM. Further, when the size of the MSM
population was factored in, based on US CDC estimates, the rates
of HIV new diagnoses was found to have declined from 4.43 per
1000 in 1996 to 3.21 per 1000 in 2004 to 1.81 per 1000 in 2012.
TasP Experience in Canada
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All confirmed HIV positive tests have been documented since
1989, however HIV became reportable in 2003 in BC with
systematic follow-up of positive test results from that time forward.
Therefore reports prior to 2003 are biased because duplicate
positive tests were not consistently removed. All longer-term trends
in Figure 5 after 2003 are statistically significant. Therefore it is
unlikely that over-counting cases prior to 2003 substantially
impacted the overall conclusions of the paper.
Statistical Models Next, we developed two statistical models with the outcome
being the estimated HIV incidence rate and the explanatory
variables being the number of individuals actively on HAART and
the percentage of individuals suppressed on HAART (using a 500
copies/mL cut-off to allow a consistent definition of suppression
over time). The model showed that for each 100 individuals
actively on HAART the estimated incidence rate decreased by
1.2% (estimated rate ratio 0.9879; 95% CI 0.9868; 0.9891) and for
each 1% increase in the number of individuals suppressed on
HAART, the HIV incidence decreased by 1% (estimated rate
ratio 0.9900; 95% CI 0.9887; 0.9912).
For the model with HIV-related mortality rate as the outcome
and the explanatory variables being the number of individuals
actively on HAART and the percentage of individuals suppressed
on HAART (using a 500 copies/mL cut-off), we observed that for
each 100 individuals actively on HAART the estimated mortality
rate decreased by 2.51% (estimated rate ratio 0.9749; 95% CI
0.9703; 0.9795) and for each 1% increase in the number of
individuals suppressed on HAART, the mortality rate decreased
by 2.06% (estimated rate ratio 0.9794; 95% CI 0.9754; 0.9834).
For the model with the outcome being the AIDS rate and the
explanatory variables being the number of individuals actively on
HAART and the percentage of individuals suppressed on HAART
(using a 500 copies/mL cut-off), we observed that for each 100
individuals actively on HAART the estimated AIDS rate
decreased by 2.48% (estimated rate ratio 0.9752; 95% CI
0.9679; 0.9826) and for each 1% increase in the number of
individuals suppressed on HAART, the AIDS rate decreased by
1.95% (estimated rate ratio 0.9805; 95% CI 0.9737; 0.9874).
Our results demonstrate that between 1996 and 2012, the
expansion of HAART coverage in BC was strongly and
statistically significantly associated with population level decreases
in incident AIDS diagnoses and all cause mortality among HIV
infected individuals. In addition, the expansion of HAART
coverage in BC was strongly and statistically significantly
associated with decreased HIV new diagnoses and estimated