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Curr HIV/AIDS Rep. Author manuscript; available in PMC 2015 December 01.

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Published in final edited form as:

Curr HIV/AIDS Rep. 2014 December ; 11(4): 496504. doi:10.1007/s11904-014-0237-5.

Treatment as PreventionWhere Next?

Mark Hull1,2, Joep Lange3,*, and Julio S.G. Montaner1,2
1BC

Centre for Excellence in HIV/AIDS, Vancouver, Canada 2University of British Columbia,

Vancouver, Canada 3University of Amsterdam, the Netherlands

Abstract
Purpose of ReviewUptake of antiretroviral regimens with durable virologic suppression has
been shown to reduce the risk of HIV transmission. Expanding ART programs at a populationlevel may serve as a vital strategy in the elimination of the AIDS epidemic.

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Recent findingsThe global expansion of ART programs has greatly improved access to lifesaving therapies, and is likely to achieve the target of 15 million individuals on therapy set by
UNAIDS. In addition to the incontrovertible gains in terms of life expectancy, growing evidence
demonstrates that durable virologic suppression is associated with significant reductions in HIV
transmission amongst heterosexual couples and men who have sex with men. Expansion in
successful ART programs, best monitored by a program-level continuum of care cascade to
monitor progress in diagnosis, retention in care and virologic suppression, is associated with
reductions in HIV incidence at a population level.

Corresponding Author: Julio S.G. Montaner, MD, BC Centre for Excellence in HIV/AIDS, Room 667, 1081 Burrard Street,
Vancouver, BC, V6Z 1Y6, Canada, jmontaner@cfenet.ubc.ca.
*Dr Joep Lange was murdered in the tragic MH17 bombing, while this manuscript was being developed.
Compliance with Ethics Guidelines
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.

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This article is dedicated to the memory of our colleague, friend and collaborator, Professor Joep Lange, who was a globally
inspirational leader in the field of HIV/AIDS. The photo reproduced above was taken during the opening day of the 2014 International
AIDS Conference in Melbourne, Australia. The slide was shown by the UN Undersecretary General and Executive Director of
UNAIDS, Dr. Michel Sidib, in homage of Professor Lange, as he unveiled the proposed UNAIDS post 2015 Millennium
Development Goals Antiretroviral Therapy Targets. In the slide, he used a famous quote from Professor Lange urging us to learn from
the success of other industries as we attempt to make antiretroviral therapy available to every person in need in any corner of the
world. Dr. Sidibs presentation was interrupted at this point by a community manifestation, asking for virological suppression to
become the new global goal standard for Antiretroviral Therapy monitoring. Indeed, this is what the proposed UNAIDS post 2015
MDG 90-90-90 Antiretroviral Therapy Target calls for. Professor Lange would have been proud to see the consensus emerging on this
issue as he was a champion major contributor to the development of the proposed 90-90-90 target, which specifically proposes that by
2020, 90% of all people living with HIV will know their HIV status, 90% of all people with diagnosed HIV infection will receive
sustained antiretroviral therapy, and 90% of all people receiving antiretroviral therapy will have durable viral suppression. Achieving
this target will lead to 73% of all people living with HIV to be virologically suppressed, globally. This would be expected to meet the
goal of ending the epidemic by 2030, defined as the rapid reduction of AIDS-related deaths as well as new HIV infections, stigma
and discrimination experienced by people living with HIV and vulnerable and key populations, by 90 percent of 2010 levels.
Conflict of Interest
Mark Hull receives support from the U.S. National Institute on Drug Abuse (grant number R01DA031043-01). He has served on
speakers bureau or advisory boards of Merck, Janssen, Vertex, Bristol-Myers-Squibb, ViiV Healthcare, Pfizer.
Julio S. G. Montaner is supported, with grants paid to his institution, by the British Columbia Ministry of Health. He has also received
financial support from the US National Institutes of Health, International AIDS Society, United Nations AIDS Program, World Health
Organization, France Recherche Nord & Sud SIDA HIV Hpatites (ANRS), International Association of Providers of AIDS Care
(IAPAC), UNICEF, MAC AIDS Fund and Open Society Foundation. He has received grants from Abbvie, Boehringer Ingelheim,
Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck and ViiV Healthcare.

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SummaryExpanding and sustaining successful ART delivery at a global level is a key

component in a comprehensive approach to combating the HIV epidemic over the next two
decades.

Keywords

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Antiretroviral therapy; Treatment as Prevention; Care Cascade; Millennium Development Goals

Introduction

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The last decade has witnessed significant shifts in the approach to the management of HIV.
Clinical trials have demonstrated the efficacy and tolerability of a substantial number of
antiretroviral combinations, with once daily fixed-dose combinations being the norm.
Concomitantly, global efforts have reduced the costs of these medications, allowing for
unprecedented scale up of therapeutic programs in resource-limited settings. While initial
antiretroviral therapy (ART) guidelines focused predominantly on CD4-cell count strata
dependent initiation of treatment as a means to maximize the therapeutic index of therapy
whereby both AIDS-related illness and potential drug toxicity were avoided(1), current
guidelines are more nuanced, taking into account multiple other factors which might now
influence ART initiation(2). One potential consideration for treatment initiation now well
established in current international guidelines(2, 3) is a recognition of the secondary benefit
of successful ART-related virologic suppression; namely decreased onward transmission.
Treatment-related decreases in virologic transmission at a population level was first
observed a decade ago (4, 5), and shortly thereafter formal mathematical models of
expanded Treatment as Prevention (6, 7) paved the way for widespread consideration of
the secondary population-level benefits derived from expanding treatment for individuals
accessing therapy for the ever improving outcomes seen in HIV-related morbidity and
mortality (8, 9).
The last year has seen continued progress in terms of improved access to ART at a global
level. In 2013 approximately two million individuals started ART, the largest ever annual
increase in initiations (10). An estimated 12.9 million individuals were receiving ART by
the end of 2013, the majority (11.7 million individuals) in resource-limited settings.

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These individuals represent 36% of the estimated 32.6 million HIV-infected individuals in
these regions (10). UNAIDS estimates that the world is on track to meet the Millennium
Development Goal-ART target of 15 million people on therapy by 2015(11). The expansion
of ART programs in conjunction with additional ART prevention strategies in the form of
prevention of mother to child transmission (PMTCT) has resulted in overwhelming
individual level benefit. A systematic analysis of the UNAIDS Global Burden of Disease
Study 2013 estimated the impact of these ART-based interventions on mortality, finding that
overall 19.1 million life-years (confidence interval [CI] 16.6 21.5 million life-years) have
been saved over this time period (12). Furthermore, further expansion of global treatment
programs in order to implement current expanded WHO treatment guidelines (with at least
80% global coverage) would prevent an additional three million deaths and avert 3.5 million
infections over the following decade in comparison to prior more conservative treatment
recommendations (11). A cost-effectiveness analysis modelled on the epidemics in South
Africa and India clearly supports the overwhelming benefits of early ART, with early ART
found to be very cost-effective over a lifetime ($590 in South Africa and $1,800 per lifeyear saved) (13). Early ART was found also to prevent a greater number of cumulative
transmissions compared to delayed ART. These data reflect the inextricable dual nature of
successful ART expansion where treatment benefits the individual and secondarily limits
transmission within the community. There is growing consensus that Treatment as
Prevention has definitively moved from a topic of scientific enquiry to the domain of
program design and implementation.

Antiretroviral therapy for the prevention of onward transmission

Recent evaluations of population-level mother to child transmission events in the United
Kingdom and Ireland have demonstrated further decreases in the numbers of HIV-infected
infants over the last decade, with rates dropping from 2.1% in 2000/1 to 0.7% in 2006 (for
vaginal births) and 0.46% in 2010/11(14). Transmission remains clearly associated with the
degree of maternal viremia, and the decrease in transmission events is associated with higher
proportions of women accessing ART at conception as well as enhanced antenatal ART
(14).

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The prevention of onward transmission associated with ART has also been scrutinized with
the application of the classic Bradford Hill criteria for causality (15). In addition to biologic
plausibility considerations, the accumulated evidence to date for the effect of ART on
transmission satisfies all other epidemiologic criteria, including consistency of association,
with the results of the HPTN 052 randomized clinical trial evaluating the effect of early vs.
deferred ART on transmission risk amongst serodiscordant couples demonstrating very
similar results to those of prior cohort studies and meta-analyses of the effects of ART in
similar populations (1618). In the serodiscordant cohort nested within the Partners in
Prevention study, use of ART was associated with a 92% reduction in transmission, from
2.24 (95% confidence interval [CI] 1.84 2.72)/100 person-years to 0.37 (95%CI 0.09
2.04)/100 person-years (17). Similarly a meta-analysis evaluated 5021 heterosexual couples
and found an overall reduction in the rate of transmission for those receiving ART from 5.64
to 0.46 (95% CI 0.19 1.09)/100 person-years (again a 92% reduction in risk of
transmission) (16). In the HPTN 052 trial involving 1763 couples (54% from Africa, 50%

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male HIV-infected partners), 28 linked transmission events were noted, only one occurring
in the early ART group (hazard ratio 0.04; 95% CI 0.01 0.27), a 96% reduction in
transmission risk (18). Satisfaction of the Bradford Hill criteria for causality help in the
interpretation of other population-level ecologic data highlighting a consistent association
between expansion of ART and decreased community HIV incidence (19, 20).

Evaluation of Treatment as Prevention in resource rich settings recent

findings

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The Province of British Columbia, Canada, offers an ongoing opportunity to assess the
population-level effects of sustained ART expansion, coupled with universal access to
laboratory monitoring (19, 21). Antiretroviral therapy is provided free of charge to HIVinfected individuals within the province via a central Drug Treatment Program which
maintains and monitors a population-based registry of individuals receiving ART, including
monitoring of treatment adherence levels (determined through pharmacy refill data) and
virologic resistance history. Evaluation of the British Columbia Treatment Program has
provided early evidence of the population-level association between expanded access to
ART therapy and concomitant reduction in new diagnoses (Table 1) (21). Ongoing
evaluation of the Program has demonstrated continued expansion in ART uptake - between
1996 and 2012 the number of individuals receiving therapy increased substantially from 837
to approximately 6,672 individuals; a change in ART coverage from 1157% of the
estimated prevalent cases (19). During the time period 1999 2012 (the period for which the
ultrasensitive HIV RNA assay was available) the proportion of individuals with HIV viral
load <50 copies/mL increased from below 10% to 59% (p <0.0001). This dramatic
expansion of successful ART uptake has been associated with matching decreases in the
provincial HIV-related mortality rate (from 6.5/100,000 1.3/100,000 population) (an 80%
decline, p< 0.0115). Significantly, overall new diagnoses of HIV and estimated incident
cases of HIV have also undergone a corresponding decrease; dropping from 702 to 238
cases per year between 1996 and 2012 (a 66% reduction, p <0.0004, Figure 1), and from 632
368 cases per year (a 42% reduction, p<0.0003), respectively. The numbers of HIV
diagnostic tests increased over this time period, and rates of syphilis, Neisseria gonorrhea
and Chlamydia infection increased during this time period suggesting no change in ongoing
sexual risk behaviours. In statistical analysis with HIV incidence as the outcome, and the
explanatory variable being the percentage of individuals suppressed on ART (<500 copies/
mL), for every 1% increase in the numbers of individuals with successful virologic
suppression, the incident rate decreased by a corresponding 1% (estimated rate ratio, 0.9900;
95% CI 0.9887 0.9912).
The Continuum of Care Cascade
The British Columbia experience also highlights the application of a seminal, indeed crucial
framework of evaluation for all HIV care programs the HIV cascade of care. Initially
formulated by Gardner et al. and applied to the United States as a whole, based on estimates
of reported values for each step of the cascade for initial estimates of the entire HIV-infected
population to those achieving virologic suppression on ART (22). Of the 1.2 million HIVinfected individuals in the U.S., approximately 20% were unaware of their diagnosis, and

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ultimately only 19% of individuals were successfully retained and suppressed on ART.
These estimates are remarkably similar to those of the United States CDC using U.S.
national surveillance instruments, where 28% of all HIV-infected individuals were found to
be fully suppressed on ART (23). Each stage of the care cascade is amenable to scrutiny and
this forms the basis of re-inforcing feedback loops for Treatment as Prevention Programs to
assess deficiencies in areas such as diagnosis, linkage to care and adherence and target
interventions accordingly for the population as a whole, or sub-populations of vulnerable
individuals within the care cascade (such as people who inject drugs [PWID] or men who
have sex with men [MSM]. The BC program has been subject to detailed application of the
care cascade (Figure 2), and on a practical basis this is updated on a regular basis for
specific regions within the Province and for specific populations (24).
MSM populations

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One of the most challenging aspects of evaluating the transmission benefits of ART
expansion has been amongst MSM populations (25). Unprotected receptive anal intercourse
is associated with high per-act probability transmission risk when compared to vaginal
intercourse (26, 27). Although the HPTN 052 study clearly demonstrated the effectiveness
of ART at decreasing transmission amongst heterosexual couples, few MSM couples were
included, limiting interpretation amongst this population (18). A recent observational study
has provided reassurance that the effects of ART amongst MSM serodiscordant couples is
likely similar to that observed in the HPTN 052 clinical trial. In the PARTNER study 767
serodiscordant couples (445 heterosexual and 282 MSM couples) where the HIV-infected
partner had been stable on ART with HIV viral load of < 200 copies/mL, were followed to
evaluate linked transmission events during periods of condomless sexual activity (28).
Overall, 894 couple-years of followup (CYFU) were eligible for evaluation, with
approximately 44,400 condomless sex acts included. No linked transmission events were
observed amongst either the heterosexual or MSM participants during this period. While the
observed transmission rate was zero, the estimated ten year within-couple transmission risk,
derived from the upper boundary of the 95% confidence interval was 4% overall, and 10%
for any anal sex (translating into a 1% risk per year) (28). Sub-analysis of the risks
specifically amongst MSM were limited by the relatively short periods of observation for
risk-type, however unprotected receptive anal sex with ejaculation was associated with a
potential 10 year transmission risk of 32%, an estimate which may diminish with further
observation and more data. Although these results confirm an individual-level benefit, recent
evaluations of differing populations highlight the importance of establishing and
implementing an HIV care cascade feedback loop if a population-level benefit amongst
MSM is to be seen(19, 2931). HIV incidence rates amongst MSM in England and Wales
between 2001 and 2010 was estimated incorporating data from national surveillance
sources, as well as CD4 cell count at diagnosis (29). Using a CD4-staged back calculation
model, HIV incidence was estimated annually. In addition, engagement in care was assessed
by reported ART uptake at last visit (however, virologic suppression amongst those
accessing ART was not specifically recorded as an endpoint). Overall over the study period,
testing rates increased over three-fold, with 65% of those diagnosed identified with a CD4
cell count > 350 cells/mm3 in late 2010 compared to only 48% of those diagnosed in 2001.
In addition, the proportion of individuals accessing ART after diagnosis increased from 69%

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in 2001 to 80% in 2010. Despite these advances, the estimated overall HIV incidence rate
was static across the time period at approximately 23002500 annual infections. In addition,
the proportion of individuals estimated to be infected but undiagnosed declined slightly over
time, with an estimated 22% of all HIV-infected MSM individuals in 2010 undiagnosed, and
potentially responsible for the majority of forward transmissions in conjunction with overall
increases in condomless sexual encounters (29).

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Similar results were obtained from an analysis of HIV infectivity using the same national
surveillance dataset of MSM in the United Kingdom over the period 20062010 (30). In this
analysis, the proportion of MSM individuals deemed to be infectious, with a viral load >
1,500 copies/mL was evaluated, and infectivity of those undiagnosed was estimated by
applying the viral load distribution amongst those diagnosed but untreated to the
undiagnosed population estimates. The relative importance of undiagnosed individuals in
potential forward transmission was again highlighted. In 2010 the proportion of undiagnosed
individuals was estimated to be 26% (compared to 31% in 2006), however 85% were
deemed to be infectious, compared to 79% of those diagnosed but not on ART, while only
3% of those on ART had a viral load over 1500 copies/mL and therefore would have been
considered to be infectious (30). The overall proportion of infectious individuals (35% of all
HIV-infected MSM) could be reduced to 29% by the expansion of ART initiation criteria to
all individuals with a CD4 cell count < 500 cells/mm3 and to 21% by decreasing the
proportion of those undiagnosed by half. The effects of ART on HIV incidence amongst
MSM in the United Kingdom was more clearly delineated in an individual-based stochastic
model developed to fit parameters for sexual risk behaviour, HIV transmission and
progression, and the effects of ART in this population (31). Overall model outputs were
consistent with observed surveillance data. HIV incidence was found to increase from
0.3/100 person-years in 19901997 to 0.45/100 person-years in 19982010, associated with
increasing rates of condomless sex. The uptake of ART attenuated this risk; HIV incidence
would have been 68% higher over the period 200610 if ART had not been introduced.
Similarly, expansion of testing programs and immediate ART following diagnosis was
modelled to be associated with a 62% lower incidence of HIV (31). In 2010, the majority of
transmission events were associated with the undiagnosed proportion of the population with
an association with acute HIV infection (31).

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In the United States overall rates of new HIV diagnoses have decreased by 33% over the
period 2002 2011, dropping from 24.1/100,000 to 16.1/100,000, however increased in the
sub-group of MSM, particularly those aged 1324 years where testing rates and uptake of
ART were low (32). In contrast, in the British Columbia analysis, HIV diagnosis rates
declined amongst MSM, dropping by 22% from 1.92 1.49 cases/100,000 (p. 0.0046) (19).
These data clearly highlight the need to develop population-specific HIV cascade of care
metrics in order to maximize potential benefit of ART expansion. Increased testing
frequency with associated early diagnosis and immediate linkage to ART is required as a
key component of a Treatment as Prevention strategy, particularly amongst MSM.

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Resource limited settings

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Although ecologic data may not be able to determine causality rather than association,
recent data from an observational cohort in South Africa has shown encouraging results
from an ART expansion program (20). A cohort of 16,667 HIV uninfected individuals was
followed in the Hlabisa sub-district, KwaZulu-Natal. Expansion of ART coverage and HIV
prevalence within the surrounding community was assessed over the time period 2004
2011, and rate of new seroconversions within the cohort was evaluated. As ART coverage
within the community expanded, risk of an individuals acquisition of HIV decreased: for
communities with 3040% ART penetration, risk of new infection dropped 38% compared
to communities with <10% ART uptake, a benefit ratio of almost a 1% drop for every 1% of
ART uptake in a community, a finding very similar to predicted in the British Columbia
model(19).

Moving forward

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Currently a number of clinical trials seek to clarify the benefits of early initiation of ART at
an individual level (the START trial Strategic Timing of Antiretroviral Treatment
comparing outcomes for ART initiation at >500 cells/mm3 compared to < 350 cells/mm3) as
well as that of community level benefit in terms of transmission effect of early ART (33,
34). While the results of these trials will be important, current guidelines have already
incorporated the presently available data to guide clinical decision-making. In this context,
the case for early initiation of ART has been supported by cohort studies (35, 36) and the
recognition that the period of time in which ART may safely be deferred is of relatively
short duration compared to the decades spent on ART regardless of CD4 count threshold
selected (37). Treatment for treatments sake is clearly beneficial and worthy of immediate
implementation, regardless of setting. The challenges remain significant, and serve as the
focus of system-wide operations research and intervention. Prior to the implementation of
the HIV continuum of care cascade as a metric to monitor progress at a regional or countrywide level, purely practical considerations remain. These concern the ongoing need to
monitor and ensure the availability of a wide array of factors such as testing kits, availability
of antiretroviral agents, laboratory supplies, and decisions regarding healthcare staff and
staffing roles for follow-up of patients engaged in ART programs. More distally, global
level financing is crucial for the implementation of treatment programs. Although the costs
associated with ART expansion may seem daunting, cost-effectiveness analyses continue to
confirm the cost-savings associated with this approach. The overall economic benefits of
returning individuals to the workforce must not be overlooked (38). Strategies to minimize
losses along the care cascade continue to be evaluated and recommended using an evidencebased approach where possible (39), and in this context the secondary benefits of successful
ART uptake can be maximized to reduce transmission events. Moving forward beyond
2015, new aggressive targets are required to meet the goal of ending the epidemic by
2030, defined as the rapid reduction of AIDS-related deaths as well as new HIV
infections, stigma and discrimination experienced by people living with HIV and vulnerable
and key populations, by 90 percent of 2010 levels. In this context, there is increasing
momentum behind the the ambitious but achievable UNAIDS proposed post 2015 MDGART target of 90-90-90, which specifically proposes that by 2020, 90% of those infected be

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aware of their infection, 90% of those infected access ART, and 90% of those on ART be
virologically suppressed. All together the strategy would lead to 73% of virological
suppression among people living with HIV globally, and this would dramatically decrease
morbidity, mortality and HIV transmission to levels consistent with ending the epidemic by
2030 as defined above.

Conclusion
Ongoing evaluation of ART expansion at a global level confirms an overwhelming
individual-level benefit in terms of morbidity and mortality. There can be no doubt that
continued sustained and successful expansion of ART programs is necessary. The secondary
reduction in transmission events accrued by ART expansion is clear at an individual level,
with compelling evidence of benefit in communities and the general population. Expanded
treatment programs require innovative implementation of the HIV continuum of care with
close monitoring and feedback to maximize ART success and associated prevention
benefits. Full implementation of the UNAIDS proposed post 2015 MDG-ART target of
90-90-90 provides a unique evidence-based opportunity to dramatically decrease morbidity,
mortality and HIV transmission, to levels consistent with ending the epidemic by 2030.

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Papers of particular interest, published recently, have been highlighted as:
** Of major importance
* Of great interest

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Key Points

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Virologic suppression associated with antiretroviral therapy is associated with

decreased risk of transmission amongst individuals, including men who have
sex with men.

Expanded ART programs with associated durable virologic suppression is

associated with decreasing HIV incidence at a population level in studies in
developed world and resource-limited settings.

Given the incontrovertible primary benefits of ART, and compelling evidence of

decreased transmission associated with a robust HIV cascade of care designed to
improve diagnosis and retention in care, efforts must shift to operationalize
program expansion at a global level in order to meet UNAIDS Development
Goal targets for the next decade as the means of combating the HIV epidemic.

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Figure 1. Changes in rates of HIV incidence and individuals accessing ART, British Columbia,
Canada 19962012

Adapted from Montaner et al (19), with permission.

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Figure 2. The HIV cascade of care as a monitoring metric, British Columbia, Canada

The HIV prevalence estimates are based on estimates from the Public Health Agency of
Canada. From Nosyk et al (24) with permission.

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Table 1

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Population-level-and-observational cohorts evaluating expansion of treatment and risk of new HIV infection.
Setting

Time Period

Evaluation

Outcomes

Reference

Taiwan

1984 2002

National HIV surveillance data.

Transmission rate estimated by use
of exponential model.

Transmission rate 0.391 new cases/

prevalent cases pre-ART
Transmission rate 0.184 new cases/
prevalent cases post-HAART.
Overall decrease 53%.

(4)

Prospective cohorts of injection

drug users.
Median CVL*.
Cox regression model to association
with HIV incidence.

CVL associated with time to HIV

seroconversion (Hazard ratio 3.32 per
log10 increase).
After median viral load fell to <20,000
copies/mL, no statistical association with
HIV incidence observed.

(40)

HIV/AIDS public health

surveillance for new diagnoses and
calculated HIV incidence.
Mean Community viral load.
Poisson models for CVL and new
HIV diagnoses.

Significant decline in mean CVL 2004

2008 (p=0.037).
Reduction in CVL associated with
decrease in new HIV diagnoses
(p=0.003).

ART coverage from centralized

registry.
HIV public health surveillance for
new diagnoses with estimated HIV
incidence.
General additive models with
Poisson regression.

709% increase in ART uptake.

42% decrease in HIV incidence.
For every 1% expansion in individuals
suppressed on ART, a corresponding 1%
drop in HIV incidence was predicted.

Cohort of 16,667 HIV uninfected

individuals.
ART coverage and HIV prevalence
within the surrounding community
assessed, and rate of new
seroconversions captured.

As ART coverage within a community

expands, risk of acquisition decreases: for
communities with 3040% ART
penetration, risk of new infection
dropped 38% compared to communities
with <10% ART uptake.

Vancouver, British
Columbia, Canada

1996 2007

San Francisco

20042008

British Columbia, Canada

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Hlabisa sub-district,
KwaZulu-Natal, South
Africa

19962012

20042011

CVL = community viral load

ART = highly active antiretroviral therapy. Adapted from (42) with permission.

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(41)

(19)

(20)