Spotlight Center on HIV Prevention Today


The Evidence for U=U: Why Negligible Risk Is Zero Risk

August 10, 2017

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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.14

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 undetectable.

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 criminalisation.

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 cohorts.

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.

Table 1: Key Selected Evidence Supporting U=U
StudyStudy DetailsResultsDateReference
San Francisco cohort Clinical results from small cohort of HIV positive women using triple ART during pregnancy. Transmission from mother to baby was reduced to approaching zero. 1998 Beckerman K et al. [3]
DHHS guidelines Expert opinion included in evidence-based guidelines. Theoretical plausibility of reducing transmission risk was used as a factor for early ART. 1998 DHHS guidelines. [4]
Ugandan cohort (Rakai) Prospective observational cohort in ~ 400 serodifferent couples. Zero transmissions when viral load was less than 1500 copies/mL. 2000 Quinn TC et al. [5]
Spanish cohort Prospective observational study in 393 heterosexual discordant couples enrolled from 1991 to 2003 where the negative partner became HIV positive. Zero transmissions in couples where the HIV positive partner was on ART with undetectable viral load. Cautions emphasised good adherence and no STIs. 2005 Castella A et al. [6]
Swiss Statement Expert opinion and evidence review of >25 smaller studies looking at impact of ART on risk factors for HIV transmission. Concluded that transmission would not occur undetectable with viral load. 2008 Vernazza P et al. [7]
HPTN 052 1763 serodifferent heterosexual couples randomised to immediate or deferred ART.Although condom use was high the impact of ART was highly significant. All 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. 2011 Cohen M et al. [8, 9]
PARTNER Prospective observational European study in ~900 serodifferent couples who were not using condoms. Final results reported zero transmissions after more than 58,000 times couples had sex without condoms when viral load was undetectable <200 copies/mL. 2014 (interim presented).
2016 (final, presented and published)
Rodgers A et al. [10, 11]
Opposite's Attract Prospective observational study in 358 serodifferent gay male couples in Australia, Thailand and Brazil. Zero transmissions when viral load was undetectable <200 copies/mL. 2017 Grulich A et al. [12]
PARTNER2 Extension of PARTNER study to collect additional follow-up in gay male couples. Study is fully recruited and still ongoing (2014-2017). Expected 2018. [13]

This article is based on a talk given to the Positive People's Forum held in Glasgow on 1 July 2017. [15]

[Note from This article was originally published by HIV i-Base on Aug. 9, 2017. We have cross-posted it with their permission.]

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This article was provided by HIV i-Base. It is a part of the publication HIV Treatment Bulletin. Visit HIV i-Base's website to find out more about their activities, publications and services.

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