Undetectable Equals Untransmittable
A breakthrough message for patients that must be delivered correctly by health care providers. The Undetectable Equals Untransmittable, or U=U, move­ment is a global campaign definitively stating that people living with HIV (PLWH) who have undetectable HIV RNA are unable to transmit HIV. By educating people, the hope is that they will get tested and, if necessary, start and stay on treatment. This message has been endorsed by many organizations, including the US Centers for Disease Control and Prevention and the HIV Medicine Association.
Antiretroviral therapy (ART) has advanced consider­ably, from the approval of zidovudine (AZT) in 1987 through the emergence of triple-drug therapy and single-tablet regimens.1,2 Newer agents have fewer adverse effects and provide a life expectancy similar to individuals without HIV infection.3 With clear mortality benefits linked to ART, attention has now turned to the benefits of ART in preventing HIV transmission. HIV treatment as preven­tion (TasP) has now become an important part of the HIV prevention toolbox.4
The Undetectable Equals Untransmittable, or U=U, move­ment is a global campaign definitively stating that people living with HIV (PLWH) who have undetectable HIV RNA are unable to transmit HIV.5 By educating people, the hope is that they will get tested and, if necessary, start and stay on treatment. This message has been endorsed by many organizations, including the US Centers for Disease Control and Prevention6 and the HIV Medicine Association.7
For many PLWH, the message of U=U can be life changing. This message that they are not able to transmit the virus if they have undetectable HIV RNA removes some of the stigma of living with HIV. Some patients may have chosen to completely avoid relationships for fear of trans­mission, but they now can have a feeling of empowerment to make decisions in their own sexual relationships. The U=U message may allow them to feel comfortable pursuing relationships. For health care providers, the U=U move­ment gives them evidence to present to patients in support of starting therapy. In addition to the mortality benefits patients will receive from ART and achieving virologic suppression, there are transmission benefits to their part­ners and the general public. Patients are playing their own part in ending the HIV epidemic.
FOUR STUDIES SUPPORT U=U
There have been 4 main studies providing data behind the U=U movement. Each builds on the next, with U=U becoming more and more definitive. Although they all have slightly different populations and inclusion criteria, in each study, transmissions were essentially zero.
The HIV Prevention Trials Network (HPTN) 052 study reported an interim data analysis and a study including more than 5 years of follow-up data to assess the effect of ART as prevention of HIV transmission.8,9 The study assigned 1763 index participants (serodiscordant couples, 97% hetero­sexual) to either early ART (started at enrollment; n = 886) or delayed ART (started when 2 consecutive CD4 measure­ments fell below 250 cells/mm3 or if the patient had an AIDS-defining illness; n = 877). Couples were required to have had a stable relationship for at least 3 months and reported at least 3 episodes of vaginal or anal intercourse over this time. HIV-negative partners were encouraged to attend study visits to receive counseling on risk reduction and condom use, treatment of sexually transmitted infec­tions, and management of other medical conditions. After 10,031 person-years of follow-up in the index participants and 8509 person-years in the partners, there were 72 HIV infections for which viral-linkage status could be determined, with 46 virologically linked to partners (3 in the early and 43 in the delayed ART groups) and 26 virologically unlinked to partners. There were no linked infections when the index participant had stably suppressed HIV RNA. The authors concluded that early initiation of ART led to a sustained decrease in linked HIV infections in sexual partners.8 HPTN 052 laid the groundwork for U=U; however, the majority of couples were heterosexual and condom use and risk reduc­tion were emphasized. More evidence of men having sex with men (MSM) was needed.
Opposites Attract was an observational cohort study of serodiscordant male homosexual couples recruited from 2012 to 2016.10 To be included, positive partners must have had HIV RNA less than 200 copies/mL. There were 343 couples with at least 1 follow-up visit, for a total of 588.4 couple-years. In this study, HIV-negative partners were permitted to use pre-exposure prophylaxis. Three new HIV infections occurred; however, none were phylogenetically linked. The authors concluded that HIV treatment as prevention in MSM is effective and that increased HIV testing and linkage to treatment is an important strategy for HIV prevention.10 Opposites Attract included MSM couples; however, the numbers were small and more evidence was necessary.
The PARTNER (Partners of People on ART—A New Evaluation of the Risks) study enrolled serodiscordant couples between September 2010 and May 2014 who reported condomless sex.11 PLWH must have had an HIV RNA less than 200 copies/mL. Any transmissions to nega­tive partners were analyzed to determine if the transmis­sion could be linked to the positive partner. Among the 1166 serodiscordant couples enrolled (548 heterosexual and 340 MSM), 888 provided 1238 eligible couple-years of follow-up, with a median of 2 years (interquartile range [IQR], 0.5-6.3) of condomless sex (median 37 condomless sex acts per year).
Eight couples reported condomless sex with other part­ners. There were 11 HIV transmissions; however, there were no phylogenetically linked transmissions within couples. The authors concluded that among serodiscordant couples in which the positive partner was virologically suppressed on ART, there were no documented cases of within-couple HIV transmission.11
As the PARTNER study only included 38% of MSM couples, the PARTNER2 study was conducted to expand the evidence in this particular population. Inclusion criteria were the same as for the PARTNER study.12 There were 779 couples providing 1561 couple-years of follow-up between September 2010 and July 2017. A median of 1 year (IQR, 0.4-2.9) of condomless sex (median 42 condomless sex acts per year) was reported. Condomless sex outside of the main partnership was reported by 285 HIV-negative men. There were 17 HIV transmissions; however, none were phylogenetically linked within couples. The authors concluded that the PARTNER2 study provides a similar level of confidence of evidence for MSM couples as for heterosexual couples.12
It is important to note that in all of these studies, to prevent transmissions, the PLWH who were on ART had an HIV RNA at least less than 200 copies/mL. In a clin­ical trial, there are many resources to ensure that patients have access to ART, which may not occur in clinical prac­tice. Patients may not have the resources to achieve an undetectable HIV RNA due to medication access issues. They may choose not to start treatment or they may not be ready to start treatment.
HIV RNA MEASURES 1 TIME POINT
HIV RNA measurement is a snapshot in time. Patients may start taking medication in the weeks leading up to a doctor’s appointment because they know that they will have bloodwork drawn. They want to be “undetectable” to avoid “being in trouble” with their provider. They want that “pat on the back” from their provider for having their HIV RNA under control and may not understand the far-reaching implications of having detectable HIV RNA between appointments. Patients may have up to 1 year between visits. Providers may believe that patients are undetectable for the entire duration between appointments when, in reality, they were undetectable for that snapshot analysis and their appointment. Patients should be coun­seled to remain adherent to ART in order to stay undetect­able. They should also be encouraged to keep all medical appointments so that they and their partners can be aware of their HIV RNA status.
The message of U=U is an important and groundbreaking one. However, we must be careful of the message that is reaching our patients. The patient must be undetectable at the time of possible transmission, not just 6 months earlier at the appointment when bloodwork was drawn. Medication access and adherence continue to be an important underpin­ning issue of U=U. The research and data are there behind the message; the delivery remains an important factor.
Dr. McLaughlin is an associate professor of pharmacy practice at Midwestern University Chicago College of Pharmacy and an HIV/infectious disease clinical pharmacist at Northwestern Memorial Hospital in Chicago, Illinois. She is currently the co-chair of the Great Lakes Chapter of the American Academy of HIV Medicine.
1. A timeline of HIV and AIDS. HIV.gov website. hiv.gov/hiv-basics/overview/history/hiv-and-aids-timeline. Published and updated January 10, 2019. Accessed January 18, 2019.
2. Gulick RM, Mellors JW, Havlir D, et al. 3-year suppression of HIV viremia with indinavir, zidovudine, and lamivudine. Ann Intern Med. 2000;133(1):35-39. doi: 10.7326/0003-4819-133-1-200007040-00007.
3. Antiretroviral Therapy Cohort Collaboration. Survival of HIV-positive patients starting antiretroviral therapy between 1996 and 2013: a collaborative analysis of cohort studies. Lancet HIV. 2017;4(8):e349-e356. doi: 10.1016/S2352-3018(17)30066-8.
4. National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention. New HIV infections drop 18 percent in six years. HIV.gov website. hiv.gov/blog/new-hiv-infections-drop-18-percent-in-six-years. Published February 14, 2017. Updated December 4, 2018. Accessed January 18, 2019.
5. Prevention Access Campaign. Undetectable = Untransmittable. PAC website. preventionaccess.org/undetectable. Published July 2016. Updated August 23, 2018. Accessed January 9, 2019.
6. McCray E, Mermin JH. HIV & AIDS in the United States. Information from CDC's Division of HIV/AIDS prevention. US Centers for Disease Control and Prevention. docs.wixstatic.com/ugd/de0404_1f9f737da1674cdda5a42f7857cd4fa6.pdf. Published September 27, 2017. Updated September 27, 2017. Accessed January 9, 2019.
7. HIV Medicine Association. HIV treatment as prevention and U=U. HIV Medicine Association website. hivma.org/globalassets/hivma/clinical-practice/hivma-uu--resources-postcard-oct-2018.pdf. Published October 2018. Updated October 2018. Accessed January 9, 2019.
8. Cohen MS, Chen YQ, McCauley M, et al; HPTN 052 Study Team. Antiretroviral therapy for the prevention of HIV-1 transmission. N Engl J Med. 2016;375(9):830-839. doi: 10.1056/Nejmoa1600693.
9. Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral Therapy. N Engl J Med. 2011;365(6):493-505. doi: 10.1056/Nejmoa1105243.
10. Bavinton BR, Pinto AN, Phanuphak N, et al; Opposites Attract Study Group. Viral suppression and HIV transmission in serodiscordant male couples: an international, prospective, observational, cohort study. Lancet HIV. 2018;5(8):e438-e447. doi: 10.1016/S2352-3018(18)30132-2.
11. Rodger AJ, Cambiano V, Bruun T. Sexual activity without condoms and risk of HIV transmission in serodifferent couples when the HIV-positive partner is using suppressive antiretroviral therapy. JAMA. 2016;316(2):171-181. doi: 10.1001/jama.2016.5148.
12. Rodger A, Cambiano V, Bruun T, et al. Risk of HIV transmission through condomless sex in MSM couples with suppressive ART: the PARTNER2 study extended results in gay men. Presented at: 22nd International AIDS Conference; July 23-27, 2018; Amsterdam, The Netherlands. Abstract 13470. www.aidsmap.com/Zero-transmissions-mean-zero-risk-PARTNER-2-study-results-announced/page/3311249/.