By Jared Stern
Recently, there has been a paradigm shift in understanding that having an undetectable viral load means a person living with HIV cannot transmit HIV. This has been strongly promoted as “Undetectable=Untransmittable” or “U=U”, for short1, 2, 3, 4. It is also termed “Treatment as Prevention” (TasP) since it is recognised as a viable method to prevent further transmissions and help in ending the HIV/AIDS epidemic. Since the turn of the century, there has been an association between an HIV-positive person’s viral load and the likelihood of transmission (whether it be vertical5 or sexual6), thus implying the use of antiretroviral therapy (ART) to lower viral loads could lower transmissions7. Conversely, there is little evidence indicating that a reduction in HIV in the blood can reduce transmissions by injecting drug use27, 28, 29.
In the late 1990s, people did not see being on treatment and having an undetectable viral load (UVL) as a means to prevent transmission altogether8. Yet now, with more potent and effective ART, more evidence has arisen to indicate that achieving an UVL means that an individual cannot pass on HIV. The HIV Prevention Trials Network-clinical trial, HPTN 052, followed 1763 serodiscordant couples (one partner is HIV-positive and one is HIV-negative) and either assigned the HIV-positive participants to start early ART or delayed treatment until the prescribed threshold of <250 CD4 T-cells/mL9. In 2011, interim results showed that there was a 93% decrease in transmission starting ART early compared to delaying treatment9. Further analysis showed that there were no linked transmissions (i.e. the virus being genetically similar to that of the HIV-positive partner) when the HIV-positive partner was virally suppressed with a viral load below 400 copies per millilitre10.
Then in 2016, results from the Partners of people on ART – a New Evaluation of Risk (PARTNER) study (an observational study following serodiscordant couples) also showed no linked transmissions of HIV when the HIV-positive partner had suppressed viral loads (this time being less than 200 copies/mL)11. In contrast to the HPTN 052 study which saw just around 5% of sex acts occurring without condoms9, 99.7% of participants in the PARTNER study reported having condomless sex - equating to over 58,000 condomless sex acts during the study period11, 12. Further evidence for U=U arose last year from the Opposites Attract Study. The Opposites Attract Study was also a multinational observational study of 358 serodifferent couples, specifically homosexual male couples12. During the four years of the study, there were over 12,000 condomless anal sex acts between an HIV-negative partner and HIV-positive partner with an UVL. Again, there were no phylogenetically linked transmissions of HIV from HIV-positive partner to HIV-negative partner.
With the combined data from the PARTNER and Opposites Attract Study the estimated transmission risk of U=U has been statistically calculated to be between 0-0.25 transmissions per 100 couple years. This means that although there were no cases of linked transmission when a person living with HIV had a UVL, we can be confident that there will be at most one transmission in a couple over 400 years13. It is important to remember that this is the “upper” risk calculated to provide a 95% confidence interval that the risk could fall in and this number may become smaller as more data is collected, making the statistical analysis more powerful.
There are some important caveats for U=U/TasP to be effective; a person living with HIV needs to have a maintained UVL, been on ART for at least six months, and adherent to their treatment regimen. These are important as they take into account the fact that it may take up to six months for someone’s viral load to drop to being undetectable. Furthermore, not taking one’s medication can result viral rebound within three weeks on average but as quickly as a few days14. Indeed there were eight linked transmissions in the HPTN 052 study when the HIV-positive partner had initiated ART – three in the “early” treated and five in the “delayed” treatment. These were either due to transmission occurring in less than 90 days since ART initiation or due to treatment failure – both contributing to the HIV-positive partner not being virally suppressed10.
Each study had different thresholds of blood viral loads to determine if they are virally suppressed or not. HPTN 052 deemed <400 copies/mL to be the cutoff, whilst PARTNER’s and Opposites Attract’s threshold was <200 copies/mL – although, the viral load in the PARTNER study was self-reported by participants, unless a transmission occurred. What level a viral load is determined to be “undetectable” depends upon the test being used and how sensitive it is. In fact, there are ultrasensitive tests that can detect down to one copy/mL and, when used, majority of people have greater than one copy/mL on average – even after years of being on ART15, 16, 17, 18. Similar to blood plasma viral loads, levels of HIV in the genital tracts of people living with HIV decrease when on ART but they can often still be detected17, 18, 20, 21, 22, 23. Therefore what makes undetectable = untransmittable is not the absence of any virus but the fact that the levels of the virus present are very low - especially in contrast to levels of virus achieved during acute HIV infection which can reach 1 million copies/mL24.
Similarly to the prevention of sexual transmissions achieved by TasP, maintaining a UVL during pregnancy, labour, and breasfeeding has been shown to drastically reduce the transmission risk of vertical transmissions.25, 26 Thus, it is very clear that U=U will play an important role in ending the HIV epidemic. It also highlights the need for improved linkage to care and availability of ART to provide benefits to both people living with HIV and those at risk of acquiring HIV.
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