www.thelancet.com Vol 382 November 2, 2013 1515
Antiretroviral treatment of HIV-1 prevents transmission of
HIV-1: where do we go from here?
Myron S Cohen, M Kumi Smith, Kathryn E Muessig, Timothy B Hallett, Kimberly A Powers, Angela D Kashuba
Antiretroviral drugs that inhibit viral replication were expected to reduce transmission of HIV by lowering the
concentration of HIV in the genital tract. In 11 of 13 observational studies, antiretroviral therapy (ART) provided to an
HIV-infected index case led to greatly reduced transmission of HIV to a sexual partner. In the HPTN 052 randomised
controlled trial, ART used in combination with condoms and counselling reduced HIV transmission by 96·4%.
Evidence is growing that wider, earlier initiation of ART could reduce population-level incidence of HIV. However, the
full benefi ts of this strategy will probably need universal access to very early ART and excellent adherence to treatment.
Challenges to this approach are substantial. First, not all HIV-infected individuals can be located, especially people
with acute and early infection who are most contagious. Second, the ability of ART to prevent HIV transmission in
men who have sex with men (MSM) and people who use intravenous drugs has not been shown. Indeed, the stable
or increased incidence of HIV in MSM in some communities where widespread use of ART has been established
emphasises the concern that not enough is known about treatment as prevention for this crucial population. Third,
although US guidelines call for immediate use of ART, such guidelines have not been embraced worldwide. Some
experts do not believe that immediate or early ART is justifi ed by present evidence, or that health-care infrastructure
for this approach is suffi cient. These concerns are very diffi cult to resolve. Ongoing community-based prospective
trials of early ART are likely to help to establish the population-level benefi t of ART, and—if successful—to galvanise
treatment as prevention.
Development of many antiretroviral drugs has made
HIV infection a treatable chronic disease.1 Initiation of
antiretroviral therapy (ART) soon after infection off ers
near normal quality of life and lifespan.2 Early ART is
also associated with a reduced latent viral reservoir,3
reduced viral DNA,4 and normalisation of some immune
Yet HIV prevention has been a constant struggle.
Although the estimated incidence of HIV decreased by
50% in 25 countries between 2001 and 2011, 2·5 million
people still became newly infected in 2011.6 Furthermore,
encouraging reductions in the global incidence of HIV
cannot be fully explained or ascribed to one intervention.
Figure 1 shows several strategies for HIV prevention.
However, in the absence of a vaccine (which will probably
be the case for the foreseeable future7), combinations of
intervention strategies must be used.8,9 The combination
prevention approach was put forward in the US
Government’s new national HIV/AIDS strategy,10 and in
the global President’s Emergency Plan for AIDS Relief
Perhaps no part of combination HIV prevention has
attracted more attention than the use of antiretroviral
drugs. There are three ways in which these drugs can be
deployed: as postexposure prophylaxis, as pre-exposure
prophylaxis, and to reduce infectiousness of HIV-infected
people to their sexual partners (treatment as prevention).
First, suspected exposure to HIV can be followed by
postexposure prophylaxis with antiretroviral drugs.12–14
This approach has been accepted as standard policy for
both occupational exposure in health-care workers (eg, a
needlestick injury)12,13 and non-occupational exposure (eg,
an unprotected sexual encounter).14 Recommendations
for postexposure prophylaxis are based on fi ndings from
experiments with macaques and an observational study
in people who have been exposed to needlesticks.15,16
Second, gel-formulated and oral-based ART have been
used successfully as pre-exposure prophylaxis for people
Search strategy and selection criteria
We searched PubMed and PsycInfo databases from
Jan 1, 1990, to Aug 31, 2013, with the terms: (“HIV” OR “AIDS”)
AND (“antiretroviral” OR “ART” OR “ARV”) AND (“treatment as
prevention” OR “TasP” OR “prevent transmission”); and (“HIV”
OR “AIDS”) AND (“treatment” OR “antiretroviral” OR “ART” OR
“ARV”) AND (“discordant” OR “serodiscordant”) AND
(“couples” OR “partners” OR “relationships”). We used no other
inclusion or exclusion criteria.
Lancet 2013; 382: 1515–24
October 21, 2013
Department of Medicine
(Prof M S Cohen MD),
Department of Microbiology
(Prof M S Cohen), Department
(Prof M S Cohen,
M K Smith MPH,
K A Powers PhD), Department
of Health Behavior
(K E Muessig PhD), and
(Prof A D Kashuba PharmD),
University of North Carolina,
Chapel Hill, NC, USA; and
Department of Infectious
Disease Epidemiology, Imperial
College London, London, UK
(Prof T B Hallett PhD)
Prof Myron S Cohen, University
of North Carolina,
130 Mason Farm Road, Suite
2115, CB 7030, Chapel Hill,
NC 27599-7030, USA
• Treatment of an HIV-infected person will greatly reduce
the probability of an HIV transmission event
• Treatment as prevention requires careful attention to the
best drug combinations for clinical and public health
• For treatment to aff ect the epidemic, improved detection
of infection at all stages, universal access to antiretroviral
therapy (ART), and excellent adherence are essential
• Treatment as prevention demands a robust health-care
• Ongoing community-based randomised controlled trials
of early ART are measuring population-level benefi t of
treatment as prevention
www.thelancet.com Vol 382 November 2, 2013
at high risk for HIV infection. The combination of
emtricitabine and tenofovir disoproxil fumarate (Truvada;
Gilead Sciences, Foster City, CA, USA) has been approved
by the US Food and Drug Administration as pre-exposure
prophylaxis for particular high-risk groups. However,
pre-exposure prophylaxis did not provide protection in all
clinical trials, most likely because of poor adherence to
study drugs.17–19 In this Review, we provide a compre-
hensive, timely, and critical assessment of the third use
of ART, as treatment as prevention.
The HIV transmission event
The biology of HIV transmission has been best
characterised in the rhesus macaque. Shortly after
mucosal exposure, several foci of nascent HIV replication
can be seen.20–22 Yet both in macaques exposed to a
physiological dose of simian HIV23–25 and in people with
acute infection25,26 a very small number of HIV variants
(founder viruses) cause infection. These viruses use both
CD4 and CCR5 receptors,25,27 and diff er from other
variants in envelope properties such as glycosylation and
susceptibility to interferon α, suggesting a selective
advantage of founder viruses for conditions at the
HIV transmission effi ciency depends on the inoculum
from the infected person, and the susceptibility of the
exposed person.29 In 2000, Quinn and colleagues30
reported no heterosexual HIV transmission when the
blood plasma viral load was less than 1500 copies per mL,
and the greatest number of transmission events when
viral load was greater than 37 500 copies per mL. The
highest viral loads are noted immediately after infection
(referred to as acute and early infection),4,31 and people
with acute infection are probably the most contagious.31
However, mathematical modelling suggests that infec-
tivity plateaus above a viral load of 80–100 000 copies of
HIV RNA per mL blood plasma.32 Accordingly, the
phenotype of the founder virus might also help to
establish the probability of the HIV transmission event
in addition to inoculum eff ects.27,28,33
The average risk for sexual HIV transmission in a
serodiscordant heterosexual couple is approximately
0·0010–0·0019.34 However, this is probably an under-
estimate because discordant couples enrolled in
longitudinal observational cohort studies inevitably
receive more medical care and counselling than does a
typical patient, and might generally be at lower risk for a
transmission event (ie, due to selection bias since they
have remained discordant despite past exposure).29
Additionally, infl ammation in the genital tract can be
expected to increase the probability of HIV transmission
greatly by increasing the inoculum size in the HIV-
infected individual and the number of receptive cells and
state of cellular activation in the HIV-negative partner.35
Circumcision reduces acquisition
removing access to receptive cells in the foreskin.37 Anal
intercourse with an HIV-infected insertive partner
increases transmission probability,38 presumably because
rectal mucosa is far more friable than vaginal or cervical
mucosa, and is rich in cells that are susceptible to HIV.
effi ciency36 by
Antiretroviral drugs and the genital tract
ART can be expected to reduce HIV transmission by
reducing the concentration of virus in the blood and
genital secretions of the person with HIV infection.
Several groups have shown the ability of ART to penetrate
the male and female genital tract39,40 and the ability of
these drugs to suppress viral replication in the genital
tract. Most (but not all) antiretroviral drugs can be
expected to achieve similar or higher concentrations in
the genital tract as in blood (fi gure 2). An important
exception is among some of the protease inhibitors and
non-nucleoside reverse transcriptase inhibitors. When
protease inhibitors were fi rst introduced, several
investigators reported resistant variants in semen,41,42
most probably because the drugs did not reach suffi cient
concentration in this compartment and selected for viral
resistance. A similar potential limitation for the non-
nucleoside reverse transcriptase inhibitors in the female
genital tract has been suggested.43
Patterson and colleagues44 have raised a diff erent
concern. In a study of the female genital tract and
colorectum, the investigators noted that the con-
centrations of tenofovir and emtricitabine and their
respective active metabolites (tenofovir diphosphate and
emtricitabine triphosphate) varied according to mucosal
tissue type. Tenofovir and its metabolite concentrations
were 100-times greater in rectal tissue than in vaginal or
cervical tissue, whereas emtricitabine and its metabolite
concentrations were 10–15-times greater in vaginal or
cervical tissue than in rectal tissue. Diff erential pene-
tration or metabolism of antiretroviral drugs off ers
insight into the greatly variable level of protection
conferred by antiretroviral drugs in some clinical trials
of pre-exposure prophylaxis.39 These results suggest
that selection of antiretrovirals for HIV prevention can
be optimised by choosing drugs that preferentially
Figure 1: Four opportunities for HIV prevention
The four stages of infection risk are listed at the top of the fi gure. Potential interventions during each stage are
listed within each box. The timeline for the intervention is listed in the arrows below the intervention boxes.
STD=sexually transmitted diseases. ART=antiretroviral therapy. PrEP=pre-exposure prophylaxis.
TDF/FTC=tenofovir disoproxil fumarate co-formulated with emtricitabine (Truvada; Gilead Sciences, Foster City,
CA, USA). PEP=post-exposure prophylaxis. *TDF/FTC (Truvada) is the only ART intervention currently approved by
the US Food and Drug Administration for PrEP.
• STD treatment
• Oral (TDF/FTC*)
Treatment of HIV to
www.thelancet.com Vol 382 November 2, 2013 1517
penetrate sites of HIV acquisition or transmission, or
by choosing those with long tissue half-life that might
provide a so-called pharmacological buff er for imperfect
For unknown reasons, combination ART does not
eliminate recovery of HIV from the male or female
genital tract. Even when HIV replication is suppressed in
the blood by ART, copies of HIV RNA can still routinely
be recovered from the male45 and female46 genital tract,
and the rectal mucosa.47 Whether copies of HIV recovered
during treatment are replication competent and capable
of causing infection, or are in fact defective and
innocuous, is unclear.
Preventive use of ART
Findings from ecological studies, observational cohort
studies, and one randomised control trial have shown the
ability of ART to prevent sexual HIV transmission.
Investigators of ecological studies have analysed changes
in regional spread of HIV relative to use of ART to assess
whether a policy of treatment as prevention (eg, frequent
widespread testing coupled with ART initiation at
diagnosis48,49) has slowed population-level HIV trans-
mission. These studies take advantage of natural experi-
ments in settings such as San Francisco (CA, USA)50 or
British Columbia (Canada),51 where existing HIV control
strategies have already achieved high testing and
treatment coverage. The most encouraging results are
from KwaZulu-Natal, South Africa, where investigators
used geospatial techniques to assess the relation between
ART use and HIV incidence. HIV seroconversion was
monitored over several years in an observational cohort of
more than 16 000 participants living in diff erent com-
munities.52 After adjustment for sexual behaviour and
prevalent HIV cases, the investigators reported that each
percentage point increase in ART coverage of HIV-
infected people lowered the HIV-infection risk in a
community by 1·7%. However, not all studies have
reported a fall in HIV with increased availability of ART.53
Additionally, recent studies focused on MSM have not
shown a population prevention benefi t from more
widespread use of ART. Importantly, ecological studies
have methodological limitations,49,53 including insuffi cient
person-level details that are needed to establish the causal
eff ects,54 and inability to exclude all the potential
confounding factors from biological mechanisms and
behavioural risk.49,53,55 Associations inferred from ecological
observations can almost never draw defi nitive conclusions
of causality, and this limitation must be recognised by
researchers and policy makers.
Findings from observational studies of serodiscordant,
sexually engaged couples have informed individual-
level investigations into the protective eff ects of ART. By
comparing the experiences of serodiscordant couples in
which infected partners were either receiving or not
receiving ART, results of these studies strengthened the
Figure 2: Comparison of antiretroviral exposure at mucosal surfaces
Seminal plasma, cervicovaginal fl uid, and colorectal tissue exposure is plotted as a ratio relative to matched blood plasma exposure. The Y axis is on a log scale.
Y=1 is the line of unity, at which mucosal surface exposure is similar to blood plasma. Total (protein free plus protein bound) drug concentrations were used to
calculate these ratios. Ratios above the line of unity signify that drugs are concentrating at mucosal surfaces, whereas ratios below the line of unity suggest that drug
concentrations are lower than blood plasma at mucosal surfaces. Semen concentration ratios are shown in white, cervicovaginal fl uid in grey, and rectal tissue in blue.
MRV=maraviroc. RAL=raltegravir. DTG=dolutegravir. ETR=etravirine. EFV=efavirenz. NVP=nevirapine. DLV=delavirdine. TFV=tenofovir. FTC=emtricitabine.
3TC=lamivudine. ZDV=zidovudine. ABC=abacavir. DDI=didanosine. D4T=stavudine. RTV=ritonavir. DRV=darunavir. IDV=indinavir. APV=amprenavir. ATV=atazanavir.
LPV=lopinavir. NFV=nelfi navir. SQV=saquinavir. ND=not detected. Figure adapted from reference 40.
Matrix: blood plasma ratio
CCR5 receptor antagonistsIntegrase inhibitorsNon-nucleoside RT inhibitorsNucleoside (tide) RT inhibitors Protease inhibitors
FTC & 3TC (4)
LPV & NFV (0·05)
SQV & RTV (0·03)
www.thelancet.com Vol 382 November 2, 2013
hypothesis that ART could reduce the risk of HIV
transmission.56 On the basis of these results, in 2008,
Swiss experts recommended that suppressive ART,
when properly used, could provide suffi cient protection
to allow unprotected sexual intercourse.57 However, not
every observational study has shown transmission
prevention in couples by ART.58,59
Accordingly, to better defi ne the role of ART for
prevention, the US National Institutes for Health (NIH)
supported a randomised clinical trial, HPTN 052, that
was designed to quantify the magnitude and durability
of benefi t of early ART initiation for prevention of
transmission in serodiscordant couples.60 The study
included measurement of individual-level clinical
consequences of earlier ART.61 1763 HIV discordant
couples (97% heterosexual) were enrolled at 13 sites in
nine countries. Enrolment required having a stable
sexual partnership (>3 months) that led to three or more
episodes of vaginal or anal intercourse during this time,
no previous exposure to ART, and a CD4 count at
enrolment between 350 and 550 cells per μL.
Participants in the HPTN 052 study were fully enrolled
by April, 2009, and the trial will continue until mid-2015.
However, in April, 2011, the trial’s independent data safety
and monitoring board asked that interim results be made
public, and at that time all HIV-infected participants were
off ered ART irrespective of CD4 cell count. The interim
results showed that counselling and earlier initiation of
ART reduced linked HIV transmissions by 96·4%. Linked
transmissions are designated as those in which the viral
sequence in the HIV-infected index case and newly
infected partner are nearly identical, and diff erent from
other unrelated viral strains in the community.62 The
results of the HPTN 052 trial also showed individual-level
clinical benefi ts; earlier treatment signifi cantly reduced
tuberculosis and other less serious infections including
candida and recurrent herpes zoster (shingles).61
In view of these fi ndings, PEPFAR,11 the US
Department of Health and Human Services,63 and
WHO64,65 responded by amending their respective
treatment guidelines to recommend immediate ART for
people in HIV discordant relationships, irrespective of
CD4 cell count. Three systematic reviews of sexual HIV
transmission in heterosexual serodiscordant couples
have shown signifi cant reductions in transmission for
people receiving ART versus those not.66–68
Moving from evidence to application
Translation of research fi ndings into public health
practice represents an exciting prospect but with many
challenges. Effi cacy shown in a randomised controlled
trial might not lead to an eff ective intervention in the
general population. Accordingly, the population-level
benefi ts of treatment as prevention remain unproven.
Although treatment of discordant couples is now
standard, the eff ects of this approach on the overall
epidemic are debated for several reasons.69,70
For example, the generalisability of results of treatment
as prevention from studies of heterosexual couples is
unknown. Will treatment reduce transmission by similar
magnitudes in other high-risk heterosexual people (eg,
sex workers and their clients), MSM, and intravenous
drug users? HIV transmission through unsafe injection
of drugs71 or anal sex38,72 has considerable transmission
probability, which could limit the prevention benefi ts of
ART. Similarly, the diff erential concentration and
metabolism of antiviral drugs in the genital tract and
rectum,39,40,44 and specifi c behavioural practices in high-
risk groups,73 might compromise the effi cacy of ART for
prevention. Widespread use of ART in MSM populations
in London (UK),74 Australia,75 and the Netherlands76 has
not led to reductions in HIV incidence. This dis-
appointing fi nding could have several explanations.
First, imperfect use of ART by treated men might limit
the transmission prevention benefi t. Second, untreated
men probably represent the source of continued spread
of HIV in MSM, and men with acute and early HIV
might represent the greatest risk for spread.74,77 Third, an
increased number of HIV-infected cells and varying
pharmacology of some antiretroviral drugs in rectal
tissues (fi gure 2) could reduce the ability of ART to
prevent HIV transmission associated with unprotected
receptive anal intercourse. Similarly, vulnerable rectal
mucosa might remain susceptible to a relatively small
viral inoculum during unprotected insertive anal
Rapid ART rollout for preventive purposes raises the
possibility of other substantial negative consequences.
Increased risk behaviours in MSM associated with
widespread availability of ART in some wealthier
countries74,76,78,79 could presage similar patterns in other
populations. A 2004 meta-analysis (most studies included
MSM) showed no association between being on ART and
increased sexual risk behaviour. Yet, beliefs about the
protective and preventive benefi ts of ART were
signifi cantly associated with increased unprotected sex
irrespective of HIV serostatus.79 An updated systematic
review of studies published from 2009 to 2012 reported
continuity in these fi ndings, with associations noted
between optimistic ART-related beliefs and increased
risk of HIV transmission.80 Additionally, fi ndings from
some mathematical models have suggested that wider
use of ART could lead to greater drug resistance,
compromising both treatment and prevention.81
To address these and other concerns, more than
50 empirical studies of treatment as prevention are
planned or ongoing.82 Several community randomised
trials have already been launched.83 PEPFAR, NIH, the US
Centers for Disease Control and Prevention, and the Bill &
Melinda Gates Foundation are supporting very large-scale
trials. In Zambia and South Africa, communities
participating in the HPTN 071 trial (NCT01900977) have
been randomly assigned to one of three groups so that
HIV-infected people receive: standard of care, enhanced
www.thelancet.com Vol 382 November 2, 2013 1519
standard of care when CD4 count falls to 350 cells per μL,
or immediate ART irrespective of CD4 count, depend-
ing on their community. In Botswana, the Mochudi
Prevention Project (NCT01583439)84 is a targeted strategy
being tested in which earlier treatment of HIV-infected
patients will be directed towards those with the highest
viral loads, who are arguably most contagious. The
SEARCH (Sustainable East Africa Research in Community
Health) study (NCT01864603) is designed to assess the
health, economic, and educational eff ects of early HIV
diagnosis and immediate initiation of ART with a
streamlined care delivery system in rural communities in
east Africa. The Agence Nationale de Recherche sur le
Sida (ANRS) has designed a community randomised trial
of 34 clusters in rural KwaZulu Natal; individuals in the
intervention clusters will be started on ART irrespective of
CD4 cell count when untreated HIV is detected in a
screening campaign.85 All these studies are expected to
use combination prevention with counselling, condoms,
and treatment for sexually transmitted diseases, in
addition to wider and earlier use of ART.
Modelling of the eff ect of ART on pandemics
Early modelling work of the eff ects of ART to reduce
transmission led to very conservative estimates of benefi t.86
However, newer model analyses suggest that the costs and
attendant risk of expanding ART programmes will be
justifi ed by their benefi ts, especially in the long term.87
There are three possible ART expansion routes.88 The
fi rst is a low-cost, low-impact strategy of expanding
treatment eligibility for those who are already attending
clinic. A medium-cost, medium-impact strategy would
use resources to reach groups who could benefi t most
from early initiation of ART. These groups vary between
settings, but in generalised epidemics might include
people with long-term uninfected partners, infected
pregnant women, and sex workers. In concentrated
epidemics, target groups might include sex workers,
intravenous drug users, and MSM. A high-cost, high-
impact strategy would launch massive outreach cam-
paigns to connect all HIV-infected people with the clinic
and start treatment. Importantly, cost diff erences
between the scenarios are strongly related to the
resources needed for outreach programmes, testing and
linkage to care, and the cost of ART drugs themselves.
Optimised spending across the HIV continuum of care
thus represents the next frontier to control cost in
response to HIV epidemics worldwide.
Despite the increasing amount of modelling evidence
for a net benefi t for expanded ART, the cost–benefi t
equations are more uncertain than commonly acknow-
ledged. Three main areas of limitations in present model
analyses stem from insuffi cient data and reliance on
credible but unproven assumptions. First, most of the
presumed population-level health benefi ts of expanded
ART come from a reduction in HIV transmission. These
gains are calculated from a complicated set of processes
determined by the network of sexual contacts, and a set
of assumptions about the biology of HIV infection and
the transmission event.87–89 Indeed, the eff ect of ART in
reducing transmission through routes other than
heterosexual contact is not defi nitively known.90
Second, all model analyses must extrapolate from past
performance of ART programmes to make future
projections. This approach often works well, but the use
of treatment to prevent HIV is unprecedented and data
may be too scant for mathematical models to reliably and
accurately refl ect all the relevant contributing factors.
For example, the assumptions for the adherence and
retention of patients initiated on ART while still healthy
are made from cohorts of patients who were started on
ART after having had serious disease. Furthermore, most
models have assumed that risk behaviour patterns would
not change after ART initiation aimed at reduction of
trans mission. If, in fact, people starting ART much
earlier have poorer adherence91 or increased risk
behaviours,73,74,76,78,92 then models will overestimate the
benefi ts of expanded treatment.
A closely related problem is the diffi culty in estimation
of the cost of a new intervention, particularly when the
new intervention diff ers in scale to what has come before.
For example, the costs of treating the most peripherally
located HIV-infected people (both geographically and
socially) are unlikely to equal the costs of treating typical
residents in urban areas near medical facilities.93 Guides
to estimate these cost increases are inadequate. Costing
models also make assumptions about how programmes
adapt to changing circumstances. For example, as
programmes expand, the number of HIV-infected people
not in care will decrease, but how effi ciently programmes
will be able to adapt their approach to fi nd those
remaining cases is unknown. Furthermore, cost-
eff ectiveness research has yet to adequately quantify
estimates for the costs of staff time, new infrastructure
development, and expansion of the drug supply chain.
Model analyses have used all data available to account for
these factors, but the fundamental little experience with
such programmes means that costs are a key source of
uncertainty in discussions about the cost-eff ectiveness of
The fi nal limitation in present model analyses is in the
unknown operationalisation of treatment as prevention.
For example, how will clinics prioritise patients with CD4
counts less than 350 cells per μL, as recommended by the
new WHO guidelines?65 In settings with low coverage of
ART, implementation of new guidelines designed to start
ART sooner for HIV infection could (for many reasons)
actually reduce the opportunities for treatment of HIV-
infected people with very low CD4 cell counts or more
advanced disease, especially in resource-constrained
settings. The extent to which this scenario might happen
is unknown, but such an unintended consequence would
be deleterious from both an equity and epidemio-
logical perspective. Similarly, if a programme prioritised
www.thelancet.com Vol 382 November 2, 2013
treatment for those in stable discordant relationships,
how would such people be identifi ed and how would the
programme defi ne stable? Model projections will not be
useful or relevant for programmes if they have not
correctly anticipated such operational issues.
The movement towards treatment as prevention has
unmasked a massive gap in the strategy—namely, the
diffi culty to fi nd and treat people at greatest risk for
transmission, who may be hardest to reach. This
limitation has both scientifi c and social underpinnings.
Scientifi cally, routine HIV testing will not identify people
with acute infection. In view of the potential importance
of such people to the spread of HIV,31,94,95 we need to set an
even higher scientifi c priority on fi nding means to
identify early infections.96 Socially, those most likely to
transmit HIV are often among the most stigmatised
groups in society. Encouraging those at most risk to seek
testing, and to adhere to ART if infected, will take political
will and new resources to invest in evidence-based
programmes for these marginalised key populations.
Additionally, the challenge of the HIV treatment
cascade remains a major problem.97 Almost everywhere,
large gaps exist between the number of people infected,
those who know that they are infected, and those
receiving reliable treatment. So-called leakage from the
various stages of the cascade leads to programme
ineffi ciencies and missed opportunities for both
treatment and prevention. Furthermore, treatment
providers can face logistical challenges in optimisation of
therapy, and provision of HIV prevention services in
treatment clinics has been diffi cult, whether such
services are directed at infected people or their sexual
partners, or HIV-negative people at risk for infection.
The treatment as prevention strategy also seems to be
compromised by a lack of universal agreement about
when to start ART for HIV infection, whether for
individual health, to prevent HIV transmission, or for
both benefi ts combined. Confusion among patients and
providers about when to start ART must inevitably make
cascade leakage worse, because of the de-facto message
that treatment of HIV infection is not urgent. If early
treatment is not perceived to be crucial, testing and
linkage to care become optional, and retention becomes
more diffi cult. Adakun and colleagues91 reported poor
adherence to ART started at a CD4 count greater than
250 cells per μL, arguing that lack of recognised clinical
benefi t (since many participants were not symptomatic at
baseline) and lack of social support otherwise available for
patients with AIDS contributed to poor adherence among
such individuals. At the same time, several investigators
have reported that patients who seek care and are not
off ered ART have a remarkable rate of loss to follow-up.98,99
The debate about when to start ART has mixed the
results of observational trials, randomised clinical trials,
expert opinion, treatment guidelines, and logistical
challenges, which makes a dispassionate evaluation of
the topic confusing and diffi cult. Clearly, severe and fatal
complications of HIV can be expected when CD4 count
falls to less than 200 cells per μL. Findings from several
observational studies,100–103 two randomised clinical trials
(CIPRA Haiti104 and HPTN 05260), and one post-hoc
analysis (SMART105) suggest a clinical benefi t when ART
is started between a CD4 count of 350 and 550 cells per μL.
Investigators from the COHERE cohort, following more
than 200 000 people for 1 154 803 person-years, reported
measurable clinical benefi t when ART was started at a
CD4 count as high as 750 cells per μL, but not greater.106
On the basis of available evidence, WHO has recom-
mended that all HIV-infected people in a discordant
relationship64,65 and HIV-infected pregnant women107
start ART immediately. WHO now recommends that
ART be started at a CD4 count of 500 cells per μL,65
and the International AIDS Society USA108 and US
Department of Health and Human Services63 recom-
mend immediate treatment for everyone, including
people with acute HIV infection.
These results notwithstanding, some experts argue
that there has not been suffi cient evidence of meaningful
clinical benefi t to justify starting ART in asymptomatic
people at CD4 counts greater than 350 cells per μL.109 And
in fact, expansion of earlier ART in resource-constrained
settings where older, more toxic regimens are still the
standard of care could pose specifi c ethical and clinical
challenges.110,111 Additionally, valid concerns exist about
the degree of benefi t of very early ART, which itself might
be modest. First, although the infl ammation associated
with untreated HIV is assumed to be harmful, the exact
degree to which earlier ART will reduce infl ammation
and the degree of resulting benefi t—if any—are un-
known. Second, early ART could add additional years of
treatment, and the side-eff ects of ART over many years
are unknown. Third, the logistical challenges of early
ART in resource-constrained settings (eg, less toxic drugs
unavailable, second-line drugs unavailable, no viral-load
measurement, no resistance testing, drug stock outs)
could compromise treatment, and lead to earlier treat-
ment failure.111,112 Fourth, ART might lead to sexual
disinhibition that might negate ART prevention benefi ts.
Fifth, earlier initiation guidelines could make ART
unavailable to people with more advanced disease.110,111
Finally, adherence to ART started early might not be as
reliable as treatment off ered to patients with more
These important concerns lead to a counterpoint
discussion. First, ART has unequivocal public health
benefi t in prevention of HIV transmission at all CD4 cell
counts.60 A substantial proportion of people in Africa
have shown high viral load throughout the course of HIV
infection (irrespective of CD4 cell count),84 so the public
health benefi ts of ART might be greatest in the epicentre
of the pandemic. Second, although the extent to which
people treated for HIV engage in risky behaviour is
www.thelancet.com Vol 382 November 2, 2013 1521
debated, HIV-infected people who are treated are
probably far less contagious than are those who are
untreated.52,60,66–68 Parenthetically, perhaps a greater
concern is the reported increase in risk behaviour of
people who are untested or untreated.74 Third, ongoing
viral replication must be of some consequence.113 With
ongoing replication, CD4 cell count will fall and might
not recover quickly or completely.61,114 Increasing evidence
suggests that ART reverses the T-cell activation that
favours replication and some markers of infl ammation.5,115
Two randomised controlled trials of early initiation of
ART, TEMPERANO (NCT00495651) and START
(NCT00867048), are in progress. However, randomised
controlled trials designed to compare the costs and
benefi ts of ART started at high CD4 cell counts (relative
to a delay in therapy) are unlikely to last long enough to
detect all the clinical events associated with delayed ART
or long-term side-eff ects of earlier ART, either of which
might not arise for decades.116 Finally, WHO guidelines
suggest treatment of so many people irrespective of CD4
cell counts (eg, HIV-infected people in discordant sexual
relationships, HIV-infected pregnant women, and
perhaps people with acute HIV infection) that the
number of people who might logically defer ART will
continue to decrease, making the argument of the best
time to start ART less relevant.
The logistical challenges needed to properly provide
optimised treatment with earlier ART initiation are
important and real.111 If safe, well tolerated antiretroviral
drugs are not available, early treatment is far less likely to
off er health benefi t, and should be deferred. Similarly, if
so little infrastructure is available that therapy cannot be
monitored or sustained, early treatment makes little
sense. But at the same time, logistical challenges must
not prevent development of the best available medical
care, or in this case the best use of medicine for public
health. Logistical challenges will certainly slow ART
rollout, but they should not be used as a reason to
abandon the desire to treat more people, or to treat them
sooner in the course of the disease.
ART, as a key component of combination prevention, has
galvanised the call for an AIDS-free generation.11 In this
Review we have provided the rationale for the develop-
ment of treatment as prevention, described population-
level evidence suggesting a chance for success with this
approach, and outlined four community randomised
trials designed to measure the population-level benefi t
from earlier or immediate ART. We have also stressed
the many limitations and challenges of implementation
of treatment as prevention to emphasise that sustained,
population-level prevention benefi t from earlier and
wider use of ART is not guaranteed. Where do we go
from here? The observational measurements tied to ART
roll-out, and the large community trials in progress will
inform estimates of HIV incidence under various
circumstances for treatment as prevention, as well as
HIV resistance, and population-level behaviour change.
We hope to witness success in these studies, and to gain
critical information to inform improved treatment as
prevention and combination prevention approaches.
MSC conceived of the primary idea and led the development of all parts
of the Review. MKS and KEM completed literature reviews and
syntheses of ecological, observational, and experimental studies. TBH
and KAP reviewed and synthesised relevant modelling and cost-
eff ectiveness studies. ADK served as primary pharmacological expert. All
authors contributed substantively to the subsequent writing and
development of the Review.
Confl icts of interest
We declare that we have no confl icts of interest.
We thank Joseph Eron and Ward Cates for review of this manuscript,
and Christophe Fraser, Andrew Phillips, and Joel Gallant for helpful
comments. This work was supported by University of North Carolina
Center for AIDS Research and National Institute of Diabetes and
Digestive and Kidney Diseases (grant DK R37 49381).
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