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The Clinical Edge

Undetectable Equals Untransmittable

Drs. Matthew Spinelli and Monica Gandhi examine the evidence that persons living with HIV who have undetectable viral loads on effective antiretroviral treatment have effectively no risk of passing the virus to an uninfected partner.

In September 2017, the CDC released a "Dear Colleague" letter endorsing the science behind Undetectable=Untransmittable (U=U), stating that people with HIV "... who take ART daily as prescribed and achieve and maintain an undetectable viral load have effectively no risk of sexually transmitting the virus to an HIV-negative partner." The CDC letter follows the U=U consensus statement, backed by over 545 medical and community-based organizations in 70 countries. The U=U consensus statement builds on 20 years of evidence demonstrating that HIV treatment is highly effective in reducing forward HIV transmission, endorsing that "people living with HIV on ART with an undetectable viral load in their blood have a negligible risk of sexual transmission of HIV." Increased awareness of U=U can play an important role in educating people living with HIV, providers, and the public, with the likely benefit of combatting HIV-related stigma.

What Is the Science Supporting U=U?

Early research completed prior to widespread availability of antiretroviral therapy (ART) found that zero HIV transmissions occurred in serodifferent couples (where one person is living with HIV and the other is HIV uninfected) when the partner living with HIV had a low HIV viral load (<1,500 copies/mL).(1) In more recent years, universal ART has been found to provide individual-level health benefits for people living with HIV, as well as to dramatically decrease the risk of HIV transmission. As a result of this evidence, Ward 86 has recommended universal ART, regardless of CD4 count, since 2010 (with United States guidelines and WHO guidelines following suit in 2012 and 2015, respectively). In 2011, interim results from a large, randomized trial in heterosexual serodifferent couples, HPTN 052, demonstrated a 96% reduction in linked (within-partnership) HIV transmissions after the partner living with HIV was treated immediately with ART regardless of CD4 count.(2) Final results published in 2016 found zero linked HIV transmissions when the partner living with HIV was virally suppressed on ART.(3) The same results were found in two observational studies of serodifferent couples (PARTNERS study and Opposites Attract) in which the partner living with HIV had already achieved viral suppression (defined as HIV RNA <200 copies/mL) on ART, the couple did not use condoms, and the HIV-negative partner did not use preexposure prophylaxis (PrEP). After approximately 75,000 combined sex acts, including condomless anal sex among large numbers of men having sex with men (MSM), there were no HIV transmissions within partnerships.(4,5) The release of results from the above studies led Dr. Anthony S. Fauci, director of the NIH National Institute of Allergy and Infectious Diseases, to state, "The science really does verify and validate U=U."

How Should We Use U=U in Clinical Practice?

Multiple partners and STIs: In HPTN 052, approximately one third of new HIV infections were unlinked, ie, the acquisition of HIV was a result of sex with a partner other than the primary partner (who was on ART). ART will not protect HIV-negative persons from HIV acquisition unless all their partners who are living with HIV are consistently virally suppressed on ART. We recommend that HIV-negative persons who have multiple sex partners consider complementary prevention strategies such as condoms and/or PrEP.(3,4) Moreover, other sexually transmitted infections (STIs) were common in the above studies.(3,4) When used correctly, condoms also prevent gonorrhea, chlamydia, and syphilis infection, as well as pregnancy. We recommend offering condoms and quarterly STI screening to all HIV-negative persons at risk of STIs.

People who inject drugs: We do not yet have enough data to know whether ART resulting in a suppressed HIV viral load prevents HIV transmission with the sharing of injection drug equipment; in the trials mentioned above, only 2% or fewer of participants reported injection drug use.(3,4) We recommend consistent use of clean injection equipment for people who inject drugs (PWID), and PrEP for HIV-negative PWID for whom this is not possible, as well as for those who remain at risk of HIV through sexual transmission.

Duration of ART prior to achieving protective efficacy: How long must people with HIV be on ART and maintain virologic suppression before the risk of HIV transmission is essentially zero? Studies have not definitively answered this question. In HPTN 052, no linked transmissions occurred after the positive person had been on effective ART for 90 days, while in another trial, the risk of HIV transmission did not decrease to zero until after 6 months of ART.(3,6) It is important to note that durable HIV suppression is not a given in patients on ART. In a study of almost 15,000 patients followed in 6 U.S. HIV clinics, patients in aggregate had a viral load above 1,500 copies/mL for approximately a quarter of the time; suggesting risk of HIV transmission during a substantial portion of the study follow-up time.(7)

Individualization of care: The decision of whether and when to discontinue use of condoms and/or PrEP and to rely on a seropositive person's ART to protect against forward HIV transmission should follow a discussion among the clinician(s), patient, and her/his partner(s). We suggest that clinicians individualize their HIV prevention recommendations for each person living with HIV or at risk of HIV, after consideration of factors such as duration of viral suppression, ART adherence, presence or absence of outside partners for the HIV-negative partner, desire to discontinue condoms, desire for pregnancy in women, and/or concurrent use of PrEP. Discussing U=U in the clinic is an opportunity to talk with patients about the importance of ART adherence, retention in care, and overall sexual health.

Conclusion

U=U is supported by strong scientific evidence. Recognition of the validity of this simple statement can combat HIV-related stigma, and should motivate providers and patients to redouble efforts to achieve and maintain HIV viral suppression and engagement in care. Zuckerberg San Francisco General Hospital's Ward 86 endorses that people with HIV who take antiretroviral medication daily as prescribed and achieve and persistently maintain an undetectable viral load have effectively no risk of sexually transmitting HIV to an HIV-uninfected partner.

References

  1. Quinn TC, Wawer MJ, Sewankambo N, et al. Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group. N Engl J Med. 2000 Mar 30;342(13):921-9. PMID: 10738050.
  2. Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011 Aug 11;365(6):493-505. PMID: 21767103.
  3. Cohen MS, Chen YQ, McCauley M, et al. Antiretroviral therapy for the prevention of HIV-1 transmission. N Engl J Med. 2016 Sep 1;375(9):830-9. PMID: 27424812.
  4. Rodger AJ, Cambiano V, Bruun T, et al. Sexual activity without condoms and risk of HIV transmission in serodifferent couples when the HIV-positive partner is using suppressive antiretroviral therapy. JAMA. 2016 Jul 12;316(2):171-81. PMID: 27404185.
  5. Bavinton B, Grinsztejn B, Phanuphak N, et al. HIV treatment prevents HIV transmission in male serodiscordant couples in Australia, Thailand, and Brazil. In: Program and abstracts of the 9th IAS Conference on HIV Science; July 23-26, 2017; Paris. Abstract TUAC0506LB.
  6. Mujugira A, Celum C, Coombs RW, et al. HIV transmission risk persists during the first 6 months of antiretroviral therapy. J Acquir Immune Defic Syndr. 2016 Aug 15;72(5):579-84. PMID: 27070123.
  7. Marks G, Gardner LI, Rose CE, et al. Time above 1500 copies: a viral load measure for assessing transmission risk of HIV-positive patients in care. AIDS. 2015 May 15;29(8):947-54. PMID: 25768835.