Implications of transmission with undetectable HIV viral load: lower limit for HIV transmission excluded from model
Simon Collins, HIV i-Base
An Australian research group, led by David Wilson from the University of New South Wales, Sydney, published a study in the Lancet modelling the potential impact of a low-level residual transmission risk.  This was in response to the Swiss Statement relating to low-to-zero risk of HIV transmission when an HIV-positive person had shown a durable response to treatment (> 6 months with viraemia suppressed to <50 copies/mL) and other conditions are met (good adherence, no other STIs etc). 
The model looked at the risk of unprotected sexual transmission per act and cumulatively over many exposures, within couples where one partner is HIV-positive and the other is HIV-negative.
They assumed that each couple had 100 sexual encounters per year, and calculated a cumulative probability of transmission to the HIV-negative partner each year. Transmission risk assumptions were based on the Rakai data (a heterosexual Ugandan study from 1991 looking at transmission risks in 415 sero-defferent couples). The Rakai group reported that each ten-fold increment in viral load is associated with a 2.45-fold (95% CI 1.85-3.26) increase in the risk of HIV transmission per sexual contact. 
The model used per-transmission rates (from studies that hadn’t factored the impact of viral load) from 0.001 to 0.0005 per exposure and an assumption that on-treatment viral load was 10 copies/mL (see Table 1). Current transmission rates were estimated assuming 80% condom use, and 95% effect protection from condom use.
This modelling suggested per exposure risk rates from an HIV-positive partner on ARV treatment, fulfilling the above criteria,from 1 in 43,000 for anal sex to less than 1 in 220,000 for vaginal sex.
This modelling suggested an approximate four-fold increase in risk across all three groups if sero-different stopped using condoms.
While this is interesting, it didn’t closely relate to the motivation behind the Swiss Statement, nor the clinical situations in which they suggested it be applied. These were i) ability to safely conceive a baby without dependence on sperm-washing (a procedure that is
difficult to access or afford and which carries a reduced conception rate) and ii) to allay anxiety and worry over perceived risk of infection during regular sex (using condoms) and in the event of a condom break.
For many HIV-negative partners, single exposure risks of between 1 in 43,000 for anal sex to less than 1 in 220,000 for vaginal sex may often be acceptable in the context of general quality of life for family planning or a less anxious, healthy, sex life.
Importantly, a weakness in the model, from assuming a linear relationship between viral load and transmission was raised both in the original article and in an accompanying comment by Geoffrey Garnet from UCL and Brian Gazzard from the Chelsea and Westminster Hospital, published in the same issue of the Lancet. 
Assuming a log-linear relationship that supposes a risk at every level of viral load they argued “extrapolates the model beyond the available data, assuming that there is a continuous reduction in risk rather than a threshold below which no transmission is possible”.
The model doesn’t address the likelihood that most sero-different couples are likely to continue to use both ARVs and condoms, or the additional reduction in transmission risk from ARVs in this setting.
The comment concludes “In many ways, the Swiss statement provides the opportunity for positive public-health messages, by promoting adherence to treatment and concern over other sexually transmitted infections. The use of condoms, in addition to antiretrovirals, to further reduce risk and prevent other sexually transmitted infections can then also be promoted.”
More than ten years after HAART has been able to reduce viral load to very low levels, it is notable that we have no prospective trial results looking at its impact on transmission, on either a population or individual level. Lack of data on whether treatment brings most people below a minimum threshold for transmission is clearly key in any further discussion.
The lack of data on transmission risk for anal sex (heterosexual and MSM) is also worryingly sparse although some research groups are looking to address this, hopefully with funding for sufficiently powered conclusions, and with some urgency.
The focus on ARVs as a prevention strategy, also a key topic at the Mexico conference, is long overdue. Many research groups have highlighted that 25-50% of new diagnoses are likely to be driven by people who are undiagnosed, especially those recently infected when vireamia is highest by a magnitude of several logs. [5-9]
Many groups have also reported that risk behaviour generally falls after diagnosis, especially once patients are within care. 
Increased testing, reducing late diagnosis and seeing treatment as protective of both health and transmission risk – rather than as something to delay until as late as possible – are likely to develop as increasingly important themes for managing the HIV epidemic in the 21st century.
1. Wilson DP, Law MG, Cooper D et al. Relation between HIV viral load and infectiousness: a model-based analysis.The Lancet: 372, p314-320. ( 26 July 2008).
2. Vernazza P, Hirschel B, Bernasconi E, Flepp M. HIV seropositive persons without sexually transmitted diseases under fully suppressive
antiretroviral treatment do not sexually transmit HIV. Bulletin des médecins Suisses 2008; 89:165-169.
3. Quinn TC, Wawer MJ, Sewankambo N, et al. Viral load and heterosexual transmission of HIV type 1. Rakai Project Study Group. N Engl J Med 2000; 342: 921-929.
4. Garnett GP, Gazzard B. Comment: Risk of HIV transmission in discordant couples. The Lancet 2008; 372:270-271. (26 July 2008).
5. Brenner BG et al. High rates of forward transmission events after acute/early HIV-1 infection. J Infect Dis 195: 951-59, 2007.
6. Hughes G et al. Recent phylodynamics of the HIV epidemic among MSM in the UK 15th Conference on Retroviruses and Opportunistic Infections, Boston. Abstract 13, 2008.
7. Yerly S et al. The contribution of individuals with recent infection to the spread of HIV-1 in Switzerland: a 10-year survey. 15th Conference on Retroviruses and Opportunistic Infections, Boston. Abstract 512, 2008.
8. Pao D et al. Transmission of HIV-1 during primary infection: relationship to sexual risk and sexually transmitted infections. AIDS. 2005 Jan 3;19(1):85-90.
9. Pilcher CD et al. Amplified transmission of HIV-1: comparison of HIV-1 concentrations in semen and blood during acute and chronic infection. AIDS 2007 Aug 20;21(13):1723-30.
10 Metsch LR et al. HIV transmission risk behaviors among HIV-infected persons who are successfully linked to care. Clinical Infectious Diseases 15 August 2008, Vol. 47, No. 4: 577-584.