The evidence for U=U: why negligible risk is zero risk
Simon Collins, HIV i-Base:
the last year, hundreds of HIV organisations have joined a new campaign to
endorse the statement that HIV transmission does not occur when viral load is
undetectable on ART.
And while the dramatic impact of ART on
reducing HIV transmission has been known for a long time, saying ART stops this
completely is new.
This change is especially important given
that prejudice and discrimination against HIV positive people is still
widespread. So while it is easy to simply
answer “no” to the question of whether someone with an undetectable viral load is
still infectious, it is more complicated to explain why.
This article summarises selected key
studies from 20 years of accumulating evidence that should directly challenge
the prejudice and fear of HIV that is still widespread.
U=U: Undetectable = Untransmittible
Launched in 2016, the Undetectable = Untransmittable
(U=U) campaign is based on the following statement: “A person living with HIV
who has undetectable viral load does not transmit HIV to their partners”. [1, 2]
The statement has been endorsed by more
than 350 HIV organisations from 34 countries, including by leading scientific
and medical organisations such as the International AIDS Society (IAS), UNAIDS,
and the British HIV Association (BHIVA). 
The support for the statement is also
remarkable given that science is not able to prove a negative - ie that
something will not happen.
Instead, people who claim that HIV
is transmittable when viral load is undetectable, should be challenged to prove
years of accumulating evidence
The scientific approach to understanding
the world usually involves three stages.
on one or more hypotheses that might explain it.
any theory in a suitable experiment.
The strength of this approach is that a
good study, by definition, should be repeatable. If the results are true and
not by accident, other researchers should be able to repeat the study and get similar
and consistent results each time.
The evidence supporting U=U includes
different types of research spanning observational studies, randomised trials,
systematic reviews and expert opinion. See Table 1.
Key stages in this timeline include:
observations that triple therapy ART reduced transmission.
expert opinion that risk would be reduced (including based on reviewing
evidence related to the details of this protection).
– 2005: prospective observational studies and related research (Rakai cohort
further expert opinion and evidence review (Swiss Statement).
first evidence from a randomised clinical trial (HPTN 052).
– 2017: further prospective observational studies (PARTNER and Opposites
Attract) - the first studies to provide data about risks for gay men.
– 2017: further expert opinion (U=U campaign).
Each of these studies is now explained
in more detail.
mother-to-child and Ugandan heterosexual couples
A remarkable report in July 1998 provided
some of the first clinical evidence for the impact of viral load on HIV transmission.
At the IAS conference held in Geneva, Dr
Karen Beckerman reported on a small cohort of HIV positive women in San
Francisco who had used triple therapy during pregnancy. Instead of the 30%
mother-to-infant transmissions reported before ART, or the 10% seen with AZT
monotherapy, triple therapy reduced transmissions to approaching zero. 
Although this study reported on vertical
rather than sexual transmission it provided clinical results showing that an undetectable
viral load stopped a much higher risk of transmission.
Then later that year, the December 1998
update to the US DHHS guidelines, included “possibly decreasing the risk of
viral transmission” as an additional reason for starting early ART. 
These expert guidelines noted the lack of
direct evidence supporting this statement and emphasised that condoms should
still be used even with undetectable viral load – but this inclusion in the
100-page document from leading US doctors this was important.
One of the next key studies provided direct
evidence linking viral load with risk of HIV sexual transmission. This was a
prospective observational cohort study in 415 serodifferent heterosexual couples
in Rakai, Uganda, where one partner was HIV positive and the other was HIV
negative. The study, by Thomas Quinn and colleagues was published in the New
England Journal of Medicine in 2000. 
After median follow-up of 22 months, the
risk of HIV transmission was not only clearly linked to higher viral load. No
transmissions were reported among the 51 couples where the HIV positive partner
had viral load below 1500 copies/mL.
Several details of the Rakai study are
important. It was before ART was available and condom use was low. It found
that transmissions rates were similar for men and women and that other STIs
didn't affect HIV risk. It also reported highly significant impact from
circumcision – all the men who became positive during the study were
These results were 17 years ago.
Expert opinion and
evidence review: The Swiss Statement
From 2000 to 2008, many smaller studies
reported reductions in other routes of transmission, or supplemented
observational data with supportive research, such as reporting the impact of
ART in genital fluids.
For example, in 2005, a Spanish cohort
reported on 393 heterosexual serodifferent couples where the negative partner
became HIV positive during the period 1991 to 2003. The results were presented
for three time periods – pre-ART (1991–1993), early-ART (1996–1998) and late-ART
(1999–2003) – and reported no transmissions when the positive partner was
on ART. 
Cautions for these results were that
other risks reduced over time, such as condoms being more widely used and
people having less sex as they grew older, but zero transmissions was still
In 2008, Petro Vernazza and colleagues
published the first high profile evidence review that concluded that ART stopped
This paper, published in French but
quickly translated into English, was a response to the laws in Switzerland that
criminalised an HIV positive person if they had sex with a negative partner,
even if condoms were being or if a couple wanted to conceive with full consent.
This paper reviewed more than 25 studies and concluded that transmission didn't
occur. The estimated risk as a very rare event was less than 1 in 100,000 (0.00001%)
- and therefore effectively zero.
Important considerations for the Swiss Statement
included that the HIV positive person should be adherent on effective ART (not
missing doses), have an undetectable viral load, and not have sexual infections
that might increase viral load.
The Swiss Statement was not only widely
publicised but it was also widely cricitised, generating a very high profile.
As such, it set a challenge to other doctors and researchers to report any
cases that disproved the statement. Given the competitive nature of academic
research, it is notable that after almost ten years no cases have been
published that refute the Swiss Statement.
study: HPTN 052
Scientists grade evidence based on the
design of studies to be able to prove a link between and intervention and
outcome. For many questions, the best quality of evidence comes from a
randomised clinical trial. The process of randomly assigning participants to
two or more groups where only the intervention is different, is the best way to
rule out the results having been due to chance.
Because there is always the potential for
other factors to affect outcomes, randomised studies are usually credited as
the gold standard for evidence.
In 2011, US researchers, led by Myron
Cohen and colleagues at the HIV Prevention Treatment Network (HPTN) reported
early results from the HPTN 052 study. 
HPTN 052 recruited more than 1700
serodifferent couples (mainly in southern Africa, Latin America and South-East
Asia. These were almost entirely heterosexual couples, and the HIV positive
partners were randomised to either start ART immediately or wait until their
CD4 count dropped to 350 cells/mm3 (the then threshold in WHO
guidelines for starting treatment).
All couples were supported with condoms
and information on reducing the risk of HIV transmission, but it soon became
clear that HIV transmissions were almost exclusively occurring in the group
waiting for ART. Of the 39 transmissions, 28 were linked to HIV positive
partner. Of these, 27/28 were in group waiting for ART. The single transmission
in the immediate ART group occurred within weeks of starting treatment, when
viral load would have still been high and certainly detectable.
This provided a very high level of
evidence that ART was directly linked to protection against sexual transmission
and as a result the HPTN 052 study was stopped early so that all HIV positive
participants could receive immediate ART. Longer follow-up of HPTN continued
for at least another four years and confirmed these early results. 
HPTN 052 produced evidence to enable HIV
positive people to access ART earlier in order to protect their partners –
called Treatment as Prevention (TasP). But limitations of the study meant that it
could only report relative differences between the two study groups, rather
than quantify any actual risk (even if the risk was theoretical).
Again, this was a heterosexual study,
anal sex was rarely reported and condom use was relatively high. This meant
that while ART could be proved to reduce infection, the study couldn’t estimate
how low this risk became, or the likely risk for different types of sex.
Large observational cohorts:
PARTNER study and Opposite's Attract
In 1999, several years before the results
from HPTN 052, a group of European researchers led by Jens Lundgren from the Centre
of Excellence for Health, Immunity and Infections (CHIP) launched the
prospective observational PARTNER study. [10, 11]
The PARTNER study was important for
enrolling serodifferent couples where the HIV positive partner was on ART and where
the couples were already not always using condoms (often for many years).
Importantly, approximately one-third of
the almost 900 couples were gay men and the study included detailed questionnaires
on sexual activity to estimate risk based on actual exposure. As with all
studies, information about reducing HIV transmission, including free condoms,
were included for all participants. All couples were then followed over time,
trying to see whether transmissions occurred.
In a planned early analysis, presented at
a conference in February 2014, PARTNER reported zero linked (within-partner)
transmissions after more than 44,000 times when condoms hadn’t been used and
viral load was undetectable (defined as less than 200 copies/mL). 
PARTNER also provided reassurance for
previous theoretical concerns from viral load blips or other STIs. No transmissions
were seen in the 91 couples where the positive partner reported an STI (approximately
one-third of gay couples had open relationships). The final results, presented
and published in July 2016, reported zero transmissions after 58,000 times
without condoms. 
The PARTNER results made headlines
globally, but a less well-known aspect of this study was that the
ground-breaking results took nearly two years to be published. This is likely
linked to the implications the results would have on HIV prevention campaigns
that were based on always using a condom, even when the limitation of
condom-only prevention were clear from continued high rates of HIV transmission.
Because an important outcome of the
PARTNER study is to quantify the theoretical range of risk (the upper limit of
the 95% confidence interval), the PARTNER 2 study continued to collect results
in gay couples to provide an equal balance of evidence compared to heterosexual
Finally, at the IAS conference held in
Paris in 2017, results from the Opposite's Attract study in 358 gay male
couples from Australia, Thailand and Brazil, also reported zero linked
transmissions after almost 17,000 when condoms were not used. 
Again, STIs were not uncommon (present in
around 1,000 of these occasions) and didn't result in HIV transmission.
Zero to negligible: what
is in a word
HIV transmission, even without a condom
and without ART, is generally an uncommon event.
For example, the average upper range of
estimated per-exposure risk ranges from 0.014 for receptive anal sex (14 in
1000) to from 0.001 for receptive or insertive vaginal sex (1 in 1000) and the
lower ranges are many fold lower. 
However, during the first 2 to 4 weeks
after infection, when viral load can be millions of copies/mL and people still believe
they are HIV negative, risk will be higher. This led to many health campaigns
pointing out that a someone who believes they are HIV negative based on their
last HIV test is associated with a much higher relative risk than any HIV
positive person with undetectable viral load on ART.
Nevertheless, the semantic difference
between zero risk and negligible risk, even when this theoretical risk is increasingly
tiny (as with the Swiss Statement), prevented some people saying that the risk
was effectively zero.
The most significant change over the last
year, driven by the U=U campaign, has been for leading HIV scientists to now assert
that a negligible theoretical risk is effectively zero.
Reversing the challenge
to prove if transmission is possible
Under ideal circumstances, large
prospective studies that were designed to find cases of transmission when viral
load was undetectable have not been able to do so.
So the evidence gap in 2017 is now the
lack of any proof showing that HIV transmission is possible when viral load is
This reverses the scientific challenge from
proving safety to proving risk. Purely theoretical risks are no longer a good
enough level of evidence to sustain stigma and discrimination and certainly not
Instead, there is no evidence to show
that HIV transmission occurs when viral load is undetectable. People who want
to assert the theory that HIV transmission might be possible, now have to provide
some level of proof.
A comprehensive body of evidence now
supports the U=U statement. This ranges from early clinical and theoretical studies,
though small observational studies, randomised trials and the large prospective
In addition, no cases of HIV transmission
have been reported, over nine years since the Swiss Statement set this
challenge. This includes data for gay men, for couples that have anal sex, over
periods when low-level viral blips are likely and even when STIs are present.
In reality, even if the actual risk is
zero, it is not healthy to think about anything in life as being
risk-free. Even if at some point in the future an unlucky and rare case of
transmission is reported with undetectable viral load, the U=U campaign is
still right for closing the gap between zero and the real-life meaning of
negligible in real terms.
1: Key selected evidence supporting U=U
results from small cohort of HIV positive women using triple ART during
from mother to baby was reduced to approaching zero.
K et al. 
opinion included in evidence-based guidelines.
plausibility of reducing transmission risk was used as a factor for early
observational cohort in ~ 400 serodifferent couples.
transmissions when viral load was less than 1500 copies/mL.
TC et al. 
observational study in 393 heterosexual discordant couples enrolled from 1991
to 2003 where the negative partner became HIV positive.
transmissions in couples where the HIV positive partner was on ART with
undetectable viral load. Cautions emphasised good adherence and no STIs.
A et al. 
opinion and evidence review of >25 smaller studies looking at impact of
ART on risk factors for HIV transmission.
that transmission would not occur undetectable with viral load.
P et al. 
serodifferent heterosexual couples randomised to immediate or deferred ART.
condom use was high the impact of ART was highly significant.
infections occurred in people with detectable viral load: n=17 in the
deferred ART group and one early infection in the ART group before VL was
undetectable. Follow-up reported out to four years.
M et al. [8, 9]
observational European study in ~900 serodifferent couples who were not using
results reported zero transmissions after more than 58,000 times couples had
sex without condoms when viral load was undetectable <200 copies/mL.
(final, presented and published)
A et al. [10, 11]
observational study in 358 serodifferent gay male couples in Australia,
Thailand and Brazil.
transmissions when viral load was undetectable <200 copies/mL.
A et al. 
of PARTNER study to collect additional follow-up in gay male couples.
is fully recruited and still ongoing (2014–2017).
article is based on a talk given to the Positive People’s Forum held in Glasgow
on 1 July 2017. 
consensus statement: Risk of sexual transmission of HIV from a person living
with HIV who has an undetectable viral load.
K et al. Control of maternal HIV-1
disease during pregnancy. Int Conf AIDS 1998 Jun 28-Jul 3; 12:41. Poster
Department of Health and Human Services (DHHS). Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults
and Adolescents. December 1998.
5. Quinn TC et al. Viral load and heterosexual
transmission of HIV type 1. Rakai Project Study Group. N Engl J Med 2000; 342:
921-929. Free online access.
6. Castilla J, del
Romero J, Hernando V, Marincovich B, Garcia S, Rodriguez C. Effectiveness of
highly active antiretroviral therapy in reducing heterosexual transmission of
HIV. J Acquir Immune Defic Syndr. 2005;40:96-101. Free full text.
7. Vernazza P et al. HIV-positive individuals not
suffering from any other STD and adhering to an effective antiretroviral
treatment do not transmit HIV sexually. (Les personnes séropositives ne
souffrant d’aucune autre MST et suivant un traitment antirétroviral efficace ne
transmettent pas le VIH par voie sexuelle). Bulletin des médecins suisses
89 (5), 30 January 2008. Included with English translation.
8. Cohen MS et al for the HPTN
052 Study Team. Prevention of HIV-1 infection with early antiretroviral
therapy. Supplementary information. NEJM 2011; 365:493-505.
9. Cohen MS et al. Final results of the HPTN
052 randomized controlled trial: antiretroviral therapy prevents HIV
transmission. IAS 2015, 19 – 22 July 2015, Vancouver. MOAC0101LB.
10. Rodger A et al. HIV transmission risk through
condomless sex if HIV+ partner on suppressive ART: PARTNER Study. 21st CROI,
3-6 March 2014, Boston. Oral late breaker abstract 153LB.
11. Rodger AJ et al for the PARTNER study group.
Sexual activity without condoms and risk of HIV transmission in serodifferent
couples when the HIV-positive partner is using suppressive antiretroviral
therapy. JAMA, 2016;316(2):1-11. DOI: 10.1001/jama.2016.5148. (12 July 2016).
Full free access.
12. PARTNER2 Study (2014–2017).
13. Grulich A et al. HIV treatment prevents HIV
transmission in male serodiscordant couples in Australia, Thailand and Brazil.
IAS 2017, Paris. Oral abstract TUAC0506LB.
14. Fox J et al. Quantifying
sexual exposure to HIV within an HIV-serodiscordant relationship:
development of an algorithm. AIDS 2011, 25:1065–1082.
DOI:10.1097/QAD.0b013e328344fe4a. Free online
15. Collins S. Undetectable = Uninfectious.
Positive Person's Forum, 1 July 2017, Glasgow.