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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.6
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 significant.
In 2008, Petro Vernazza and colleagues published the first high profile evidence review that concluded that ART stopped transmission.7
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.
Randomised 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.8
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.9
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).10
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.11
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 data.12
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.13
Again, STIs were not uncommon (present in around 1,000 of these occasions) and didn't result in HIV transmission.
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