Treatment and Viral Load: What Do We Know About Their Effect on HIV Transmission?
Antiretroviral treatment can reduce the viral load in the blood and other bodily fluids to undetectable levels and research shows this can decrease the risk of HIV transmission. This knowledge has generated interest among people living with HIV and their partners in the use of treatment as an HIV prevention strategy. But how much can treatment reduce the risk of HIV transmission and what is the transmission risk when the viral load is undetectable?
This article explores what we know and don't know about these questions and provides key messages for both people living with HIV, and their partners.
Viral Load, Treatment and HIV Transmission
Viral load refers to the amount of HIV in a bodily fluid. Blood viral load is monitored as part of routine clinical care for a person living with HIV to track HIV disease progression, inform decisions on treatment initiation, and determine whether antiretroviral treatment is working once started. Treatment is generally considered successful when the viral load is reduced and, ideally, lowered to undetectable levels.
While we have known for years that a lower blood viral load can significantly improve the health of people living with HIV, it is only more recently that we have learned about its importance for HIV transmission and prevention. As it turns out, the amount of HIV in a fluid is an important predictor of whether infection occurs after an exposure. Research shows that a lower blood viral load is generally associated with a reduced risk of sexual HIV transmission. For each 10-fold decrease in viral load (for example, from 100,000 to 10,000 copies/ml), the risk of sexual HIV transmission generally reduces by 2-3 fold.1 This is because when the viral load in the blood decreases, it generally also decreases in the sexual fluids (semen, vaginal fluid and rectal fluid),2 which are those commonly involved in the sexual transmission of HIV.
In 2011, a landmark study known as HPTN 052 demonstrated -- among heterosexual serodiscordant couples -- that early treatment can significantly reduce the risk of sexual HIV transmission under certain conditions.3 While uncertainties and information gaps remain, interest in the use of treatment as an HIV prevention strategy is growing, and research shows that some people living with HIV consider their viral load when making decisions around safer sex and condom use.4,5 As a result, frontline service providers need to be prepared to answer potentially difficult questions to help empower clients to make informed decisions.
No Simple Answers
Clients may have many questions when it comes to viral load, treatment and HIV transmission. Two commonly asked questions are: 1) how much can treatment reduce the risk of HIV transmission and 2) what is the risk of HIV transmission when the viral load is undetectable and no condom is used?
While these questions may seem similar and straightforward, they are actually two very different questions and, unfortunately, there are no simple or conclusive answers to either of them. While this uncertainty can be frustrating and makes it difficult to provide meaningful answers, it is important for frontline service providers to communicate to clients what the research does and does not tell us. Below we explore what we know and don't know for each question.
The HPTN 052 study helps answer this question. In this randomized controlled trial, treatment reduced the risk of HIV transmission by 96% (equivalent to a 25-fold decrease) among heterosexual serodiscordant couples who had mostly vaginal sex and received ongoing services and supports including adherence and prevention counselling, free condoms, viral load tests, and testing and treatment of sexually transmitted infections (STIs).3 Although this study improved our understanding, knowledge gaps remain that require further investigation and need to be explored with clients when answering this question.
How does this transfer to the "real world?"
The HPTN 052 study took place in a very controlled setting where a motivated group of participants were provided with ongoing supports and services to help them reduce their risk of HIV transmission and maximize the prevention benefits of treatment. As a result, it is unclear if the significant reduction in risk observed in this study will also apply to heterosexual couples in the "real world" -- outside of a clinical trial setting -- who may not receive, or have access to, the same supports and services as in HPTN 052.
We know that adherence counselling is important to support daily pill-taking in order to reduce the viral load to undetectable levels; regular viral load testing is important to make sure that treatment is working (viral load is undetectable) and HIV has not developed resistance to treatment medications (if the viral load is no longer undetectable, this may indicate that resistance has developed); and STI testing and treatment are important because untreated STIs (in either the HIV-positive or HIV-negative partner) may increase the risk of HIV transmission even when on treatment.6
If medications are missed, drug resistance develops, or untreated STIs are present, treatment may be much less effective than 96% at reducing the risk of HIV transmission. For example, in a "real world" study of heterosexual serodiscordant couples who were not part of a tightly controlled randomized trial like HPTN 052, antiretroviral treatment only reduced the risk of HIV transmission by 26% (equivalent to a 1.35-fold decrease).7
What about anal sex?
Since 97% of the couples in the HPTN 052 study were heterosexual and reported mostly having vaginal sex, we don't know how much these results apply to couples who mostly have anal sex, such as some gay men and other men who have sex with men (MSM). However, the World Health Organization (WHO) recently held a meeting on the subject and concluded that there is no reason to think that treatment won't also reduce the risk of HIV transmission through anal sex, although the reduction in risk may or may not be as high as for vaginal sex.8 There are ongoing studies, such as the Opposites Attract study in Australia, which aim to determine the extent of risk-reduction among gay men and other MSM.
2. What Is the Risk of HIV Transmission When the Viral Load Is Undetectable and No Condom Is Used?
Unfortunately the HPTN 052 study did not help answer this question. While HPTN 052 showed that being on treatment and having a lower viral load can dramatically reduce the risk of HIV transmission under certain conditions (see Question 1), it remains unclear what the actual risk is reduced to when the viral load is undetectable.
A major reason for this uncertainty is the lack of research among couples who mostly have sex without a condom.9 A review of studies in the literature, performed in November 2012, did not find any reported HIV transmissions between heterosexual serodiscordant couples where the HIV-positive partner had an undetectable viral load (no studies of same sex serodiscordant couples were identified by the review).10 However, the lack of HIV transmissions does not mean the risk is zero, as most of the couples in these studies reported using condoms often. For example, 96% of couples in the HPTN 052 study reported using condoms every time they had sex. While participants of studies often say they are using condoms more regularly than they actually are, condom use may partly explain the lack of HIV transmissions in the HPTN 052 study (when the HIV-positive partner had an undetectable viral load) and other studies included in the literature review.
Also, the risk of HIV transmission when undetectable may not be the same for all types of sex. For example, the risk may be higher for anal sex than for vaginal sex, particularly if the HIV-negative partner is the receptive partner (bottom) during anal sex (also known as receptive anal sex). This is because receptive anal sex has a higher baseline risk than other types of sex. Research shows that, on average, the risk of HIV transmission to an HIV-negative partner can be 10-20-fold higher through receptive anal sex than it is through vaginal sex.11,12 However, this research did not measure the viral load of the HIV-positive partner. Therefore, we don't know if the risk is higher through anal sex when the viral load is known to be undetectable, as this has yet to be studied.
Fortunately, there are ongoing studies, such as the Partner study in Europe, which will provide a better understanding of the risk of HIV transmission when the viral load is undetectable and no condom is used, for both vaginal and anal sex. These studies are enrolling serodiscordant heterosexual and same-sex couples who are taking HIV treatment, have an undetectable viral load, and do not always use condoms.
Coming to a consensus
While we wait for research gaps to be filled, experts and community organizations are using the information currently available to develop an answer to this question.
For example, experts at the British HIV Association (BHIVA) recently released a position statement concluding the risk of HIV transmission through vaginal sex when no condom is used is "extremely low" when the blood viral load is undetectable and the following conditions are met: 1) There are no sexually transmitted infections (STIs) in either partner; 2) the HIV-positive partner has maintained an undetectable viral load for at least 6 months; and 3) the blood viral load is monitored on a regular basis. The statement went on to say that -- despite the lack of research -- they anticipate a similarly "extremely low" risk for anal sex. However, other experts think the risk may be higher for receptive anal sex than for vaginal sex.13
Some community organizations have developed tools to try to translate the research and expert statements into messages for community members. One example is ACON (the AIDS Council of New South Wales), the largest community-based gay, lesbian, bisexual and transgender HIV/AIDS organization in Australia, which recently developed their "Know the risk" website. This site states there is a "medium risk" through anal sex when the viral load is undetectable and it is known (or there is uncertainty) that an STI is present. However, the risk can become "low" when it is confirmed there is no STI and the viral load has been undetectable for six months.
It is important to keep in mind that while expressions such as "extremely low" and "medium" risk are relatively easy to communicate to clients and may reflect risk in a more meaningful way than the use of numbers, they are also open to interpretation. For example, "extremely low" risk may mean different things to different people.
Not "no risk"
There is a general consensus that the risk is not completely eliminated when the viral load is undetectable and no condom is used. In fact, there has been one published case report of HIV transmission between a same sex male serodiscordant couple where the HIV-positive partner was believed to have an undetectable viral load.14
How is HIV transmission still possible when the viral load is undetectable?
Many people who have an undetectable viral load in the blood also have an undetectable viral load in other bodily fluids. However, undetectable does not mean that there is no virus, only that the amount of virus is below the limits that tests can detect (viral load tests used in Canada cannot detect HIV in the blood if there are less than 40-50 copies/ml). Therefore, HIV transmission may still be possible because virus is present.
Also, it is possible for people who have an undetectable viral load in the blood to sometimes have detectable (although lowered) levels of virus in their other bodily fluids.16-19 A higher level of HIV in semen, vaginal fluid and rectal fluid may increase the risk of transmission when the blood viral load is undetectable. However, it is unclear how often this happens and how significant it is in terms of HIV transmission.
Some biological factors known to increase viral load in genital and rectal fluids, and potentially the risk of HIV transmission, include inflammation at the penis, vagina or rectum caused by tearing, STIs and some vaginal conditions (such as bacterial vaginosis), and hormonal changes caused by the menstrual cycle, pregnancy or use of injectable hormonal contraceptives.20-24
Key Messages for People Living With HIV and Their Sexual Partners
While the above questions about HIV transmission risk are difficult to answer, there are key messages we can give to both people living with HIV, and their partners, to help maximize the prevention benefit of treatment and lower their risk of HIV transmission.
Key messages for monogamous serodiscordant couples
- Don't assume that the viral load is undetectable once treatment is started. It normally takes a few months after starting treatment for the viral load to reach undetectable levels. Your viral load should be undetectable for at least 6 months to ensure the risk of HIV transmission is reduced as much as it can be.
- Getting regular viral load tests is the only way to make sure the viral load is undetectable and stays that way. If medications are missed or drug resistance develops, the viral load may no longer be undetectable. Wait until your next viral load test to be sure.
- Both partners should get tested regularly for STIs and, if diagnosed, seek treatment as soon as possible. The risk of HIV transmission may be higher when there is an STI in either partner.6
- The risk of HIV transmission when the viral load is undetectable may be higher for receptive anal sex. Generally speaking, insertive anal sex (topping) is lower risk than receptive anal sex (bottoming) for the HIV-negative partner.11,25 Therefore, for same-sex male couples, the risk of HIV transmission may be reduced if the HIV-positive partner is the bottom (takes the receptive role) during anal sex.
- Condoms are highly effective at reducing the risk of HIV transmission when used consistently and correctly. Using condoms (with condom-compatible lube) as often as possible -- particularly when the risk of HIV transmission may be elevated, such as when medications are missed or either partner is diagnosed with an STI -- will help reduce the overall risk of HIV transmission.
Additional considerations for people with casual sexual partners
Although the above key messages apply to people who are not in a monogamous serodiscordant relationship, additional factors need to be considered for those who are having sex with casual partners.
For example, there is generally a higher risk of STI transmission in this context because it is more difficult to know for certain if either partner has an STI. This is because these infections don't always produce symptoms and a person may have become infected with an STI since their last test. Since STIs may increase the risk of HIV transmission when the viral load is undetectable, consistent use of condoms and regular screening for STIs may be important to lower the risk of STI and HIV transmission. In the context of casual sex, it is also important that HIV-negative individuals do not assume a casual partner (of known or potential HIV-positive status) has an undetectable viral load.
Those who have casual partners -- and are also in a stable serodiscordant relationship that is "open" -- may want to discuss and agree upon what is and isn't allowed outside of their relationship. One agreement may be the use of condoms with casual partners to avoid the transmission of STIs and, subsequently, an increased risk of HIV transmission.
Your sexual health from Managing your health, CATIE's guide for people living with HIV
HIV viral load, HIV treatment and sexual HIV transmission -- CATIE Fact sheet
- Quinn TC, Wawer MJ, Sewankambo N, Serwadda D, Li C, Wabwire-Mangen F, et al. Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group. New England Journal of Medicine. 2000 Mar 30;342(13):921-9.
- Baeten JM, Kahle E, Lingappa JR, Coombs RW, Delany-Moretlwe S, Nakku-Joloba E, et al. Genital HIV-1 RNA predicts risk of heterosexual HIV-1 transmission. Science Translational Medicine. 2011 Apr 6;3(77):77ra29.
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- Hasse B, Ledergerber B, Hirschel B, Vernazza P, Glass TR, Jeannin A, et al. Frequency and determinants of unprotected sex among HIV-infected persons: the Swiss HIV cohort study. Clinical Infectious Diseases. 2010 Dec 1;51(11):1314-22.
- Van Den Boom W, Stolte IG, Witlox R, Sandfort T, Prins M, Davidovich U. Undetectable Viral Load and the Decision to Engage in Unprotected Anal Intercourse Among HIV-Positive MSM. AIDS and Behavior. 2013 Jul;17(6):2136-42.
- Ward H, Rönn M. The contribution of STIs to the sexual transmission of HIV. Current Opinion in HIV and AIDS. 2010 Jul;5(4):305-10.
- Jia Z, Ruan Y, Li Q, Xie P, Li P, Wang X, et al. Antiretroviral therapy to prevent HIV transmission in serodiscordant couples in China (2003-11): a national observational cohort study. Lancet. 2012 Nov 30;
- World Health Organization. WHO and U.S. NIH Working Group Meeting on Treatment for HIV Prevention among MSM: What Additional Evidence is Required. Geneva; 2011 Nov.
- Rodger AJ, Bruun T, Vernazza P, Collins S, Estrada V, Van Lunzen J, et al. Further research needed to support a policy of antiretroviral therapy as an HIV prevention initiative. Antiviral Therapy. 2013;18(3):285-7.
- Loutfy MR, Wu W, Letchumanan M, Bondy L, Antoniou T, Margolese S, et al. Systematic Review of HIV Transmission between Heterosexual Serodiscordant Couples where the HIV-Positive Partner Is Fully Suppressed on Antiretroviral Therapy. PLoS ONE. 2013 Feb 13;8(2):e55747.
- Baggaley RF, White RG, Boily M-C. HIV transmission risk through anal intercourse: systematic review, meta-analysis and implications for HIV prevention. International Journal of Epidemiology. 2010 Aug;39(4):1048-63.
- Boily M-C, Baggaley RF, Wang L, Masse B, White RG, Hayes RJ, et al. Heterosexual risk of HIV-1 infection per sexual act: systematic review and meta-analysis of observational studies. Lancet Infectious Diseases. 2009 Feb;9(2):118-29.
- Wilson DP, Grulich AE, Boyd M. Overly Optimistic Forecasts for the Impact of Treatment of HIV Prevention for Men Who Have Sex With Men. Clinical Infectious Diseases. 2011 Sep 15;53(6):611-2.
- Stürmer M, Doerr HW, Berger A, Gute P. Is transmission of HIV-1 in non-viraemic serodiscordant couples possible? Antiviral Therapy. 2008;13(5):729-32.
- Cu-Uvin S, DeLong AK, Venkatesh KK, Hogan JW, Ingersoll J, Kurpewski J, et al. Genital tract HIV-1 RNA shedding among women with below detectable plasma viral load. AIDS. 2010 Oct 23;24(16):2489-97.
- Sheth PM, Kovacs C, Kemal KS, Jones RB, Raboud JM, Pilon R, et al. Persistent HIV RNA shedding in semen despite effective antiretroviral therapy. AIDS. 2009 Sep 24;23(15):2050-4.
- Politch JA, Mayer KH, Welles SL, O'Brien WX, Xu C, Bowman FP, et al. Highly active antiretroviral therapy does not completely suppress HIV in semen of sexually active HIV-infected men who have sex with men. AIDS. 2012 Jul 31;26(12):1535-43.
- Marcelin A-G, Tubiana R, Lambert-Niclot S, Lefebvre G, Dominguez S, Bonmarchand M, et al. Detection of HIV-1 RNA in seminal plasma samples from treated patients with undetectable HIV-1 RNA in blood plasma. AIDS. 2008 Aug 20;22(13):1677-9.
- Lampinen TM, Critchlow CW, Kuypers JM, Hurt CS, Nelson PJ, Hawes SE, et al. Association of antiretroviral therapy with detection of HIV-1 RNA and DNA in the anorectal mucosa of homosexual men. AIDS. 2000 Mar 31;14(5):F69-75.
- Kiviat NB, Critchlow CW, Hawes SE, Kuypers J, Surawicz C, Goldbaum G, et al. Determinants of human immunodeficiency virus DNA and RNA shedding in the anal-rectal canal of homosexual men. Journal of Infectious Diseases. 1998 Mar;177(3):571-8.
- Atashili J, Poole C, Ndumbe PM, Adimora AA, Smith JS. Bacterial vaginosis and HIV acquisition: a meta-analysis of published studies. AIDS. 2008 Jul 31;22(12):1493-501.
- Mugo NR, Heffron R, Donnell D, Wald A, Were EO, Rees H, et al. Increased risk of HIV-1 transmission in pregnancy: a prospective study among African HIV-1 serodiscordant couples. AIDS. [Internet]. 2011 Jul 21 [cited 2011 Sep 12]; Available from: http://www.ncbi.nlm.nih.gov.myaccess.library.utoronto.ca/pubmed/21785321
- Curlin ME, Leelawiwat W, Dunne EF, Chonwattana W, Mock PA, Mueanpai F, et al. Cyclic changes in HIV shedding from the female genital tract during the menstrual cycle. Journal of Infectious Diseases. 2013 May 15;207(10):1616-20.
- Polis CB, Phillips SJ, Curtis KM. Hormonal contraceptive use and female-to-male HIV transmission: a systematic review of the epidemiologic evidence. AIDS. 2013 Feb 20;27(4):493-505.
- Vallabhaneni S, Li X, Vittinghoff E, Donnell D, Pilcher CD, Buchbinder SP. Seroadaptive Practices: Association with HIV Acquisition among HIV-Negative Men Who Have Sex with Men. PLoS ONE. 2012;7(10):e45718.
James Wilton is the coordinator of the Biomedical Science of HIV Prevention Project at CATIE. James is currently completing his master's degree of Public Health in Epidemiology at the University of Toronto and has completed an undergraduate degree in microbiology and immunology at the University of British Columbia.