IDCM CME Issue 1-8: U=U (Undetectable = Untransmittable)

Post Date: 
2019-01-03

By Chris Lippincott, MD, MPH

U=U (Undetectable = Untransmittable)

Every year in December, World AIDS Day offers an opportunity to highlight achievements in HIV care and research. Among the exciting recent discoveries is the concept of U=U (undetectable=untransmittable). For years, experts have hypothesized that HIV cannot be transmitted within serodiscordant couples (where one partner is HIV-infected and the other is not) when the HIV-infected partner is on antiretroviral therapy (ART) with an undetectable viral load. This hypothesis was based on decades of foundational evidence, including basic science research demonstrating the biological plausibility as well as observational reports that ART reduces HIV transmission. Over the last 7 years, four large clinical trials have been conducted of HIV serodiscordant couples that provide the strongest evidence for U=U. Here, we will discuss those clinical trials: HPTN052, PARTNER, Opposites Attract, and PARTNER2.

HPTN052 (HIV Prevention Trials Network study 052)1,2

Overview
This was a randomized, controlled, multi-center international trial to determine whether ART can prevent the sexual transmission of HIV in serodiscordant couples. 

Design and Participants
Participants were enrolled in Malawi, Zimbabwe, South Africa, Botswana, Kenya, Thailand, India, Brazil, and the United States between 2005-2010. HIV-positive participants with CD4 counts between 350-550 cells/mm3 were randomized to receive either immediate ART or delayed ART after their CD4 count declined <250 cells/mm3 or the onset of HIV-1-related symptoms.. The primary transmission endpoint was virologically-linked HIV transmission (meaning they were infected by their partner and not someone else outside of the study). 

Results
In total, 1,763 discordant couples were enrolled — 886 couples in the immediate arm and 877 couples in the delayed arm. 97% of couples were heterosexual. 

On April 28, 2011, the data safety monitoring board for HPTN052 recommended that the results of the study be announced as soon as possible. Based on the preliminary data, all HIV-infected participants were offered ART. The interim analysis of preliminary data demonstrated: 

  • 39 total transmission events
    - 4 in the immediate ART arm; 35 in the delayed ART arm (p<0.0001)
  • 28/39 transmission events were linked 
    - 1 linked transmission in the immediate ART arm; 27 linked transmissions in the delayed ART arm (p<0.0001)
       - The single linked transmission in the immediate ART arm occurred within 90 days of
          the index partner initiating ART and was felt to have occurred prior to viral suppression
          (which occurred on day 28 of therapy)
  • 96% relative reduction of linked HIV transmission in the immediate ART arm compared to the delayed ART arm

The trial continued to follow all participants for 5 more years to determine the durability of the above effect. In 2016, HPTN052 published the final study results:

  • 78 partners were infected during the study and 46 were linked
    - 3 in the immediate ART arm; 43 in the delayed ART arm (p<0.0001)
    - No linked infections were observed after HIV infection was stably suppressed by ART

HPTN052 Bottom Line

In this randomized, controlled, multi-center international trial with 5 years of follow-up, early initiation of ART provided a durable relative reduction (93%) of HIV transmission among predominantly heterosexual serodiscordant couples. Three linked transmissions occurred by HIV-positive individuals who were likely not yet stably suppressed on ART. 

PARTNER (Partners of People on ART—A New Evaluation of the Risks) study3

Overview
This was a European prospective observational study of serodiscordant heterosexual and male homosexual couples (men who have sex with men or MSM) to determine whether ART can prevent HIV transmission. 

Design and Participants
Participants were enrolled from clinics in 75 clinics in 14 European countries between 2010-2014. Serodiscordant couples were enrolled if they reported condomless intercourse and the HIV-positive partner demonstrated virologic suppression (defined as <200 copies/mL). The primary endpoint was phylogenetically linked HIV transmissions and risk of within-couple HIV transmission. 

Results
1,166 couples were enrolled, of which 1,004 couples had follow-up. Of those 1,004 couples : 

  • 116 were excluded for no HIV test in the negative partner, use of PEP (post-exposure prophylaxis) or PrEP, no condomless sex reported, HIV VL >200 copies/mL, or no VL test
  • 888 contributed to 1,238 couple-years of follow-up
    - 548 heterosexual
    - 340 MSM
    - ~58,000 condomless sex acts (MSM 22,000; heterosexual 36,000)

Among couples who had HIV-positive partners who were virally suppressed and reported condomless anal intercourse, 11 new HIV infections occurred (1 heterosexual, 10 MSM). Of these, none were phylogenetically linked transmission events.  

PARTNER Bottom Line

In this European observational study of both heterosexual and MSM serodiscordant couples, virologic suppression of the HIV-positive partner prevented HIV transmission to the HIV-negative partner (0 linked transmissions) without condom or PEP/PrEP use.     

Opposites Attract study4

Overview
This was an international observational cohort study of serodiscordant MSM couples to determine whether ART can prevent HIV transmission. 

Design and Participants
Participants were enrolled from clinics in Australia, Brazil, and Thailand between 2012-2016. Serodiscordant couples were enrolled if they reported anal intercourse at least monthly, expected to continue to have anal intercourse until next viral load visit, and agreed to clinic visits at least twice a year. Couples were eligible regardless of ART status in HIV-positive partners and PrEP use by HIV-negative partners. The primary endpoint was phylogenetically linked HIV transmissions. 

Results
358 couples were enrolled, of which 343 couples had at least one follow-up visit and were followed for 588.4 couple-years. Of those 343 couples: 

  • 258 HIV-positive partners were consistently virally suppressed (HIV viral load <200)
  • 115 HIV-negative partners used daily PrEP
  • 253 couples reported condomless anal intercourse, with a total of 16,800 acts

Among this group, there were 232.2 couple-years of follow-up among couples who had HIV-positive partners who were virally suppressed, had HIV-negative partners who did not use PrEP and reported condomless anal intercourse. There were 3 new HIV infections in the study, all phylogenetically unlinked transmissions. 

Opposites Attract Bottom Line

In this international observational cohort study of MSM serodiscordant couples, virologic suppression of the HIV-positive partner prevented HIV transmission to the HIV-negative partner (0 linked transmissions) without the use other prevention measures such as PrEP and condoms. 

PARTNER25

Overview
This was a European prospective observational study of serodiscordant MSM couples to determine whether ART can prevent HIV transmission. This study is an extension of PARTNER and includes updated data from PARTNER (2010-2014) as well as newly collected data (2014-2018) in order to provide more specific estimates for the risk of HIV transmission in serodiscordant MSM couples. Preliminary data through 2017 were presented at the International AIDS Conference in 2018. 

Design and Participants
Participants were enrolled from 75 European clinics in between 2010-2017. MSM couples were enrolled if they reported condomless anal intercourse, the HIV-positive partner demonstrated virologic suppression (defined as <200 copies/mL), and no reported PEP or PrEP use by the negative partner. The primary endpoint was phylogenetically linked HIV transmissions and risk of within-couple HIV transmission. 

Results
972 MSM couples were enrolled, of which 783 couples were eligible for follow-up with 1,596 couple-years and ~75,000 condomless sex acts. As with PARTNER, there were no linked transmission events in the study. Although 15 new HIV infections did occur, none were phylogenetically linked. 

PARTNER2 Bottom Line

In this European observational study of MSM serodiscordant couples, virologic suppression of the HIV-positive partner prevented HIV transmission to the MSM HIV-negative partner (0 linked transmissions) without condom or PEP/PrEP use. 

Bottom Line: In the last decade, four large studies across six continents have consistently demonstrated that HIV is untransmittable in serodiscordant heterosexual and MSM couples when the HIV-positive partner is receiving ART and has a stably suppressed HIV viral load (<200 copies/mL). These findings highlight the importance of linking HIV-positive individuals to care, early initiation of ART, and stably maintaining a suppressed viral load while receiving ART. 

 

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References

  1. Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, Kumarasamy N, Hakim JG, Kumwenda J, Grinsztejn B, Pilotto JH, Godbole SV, Mehendale S, Chariyalertsak S, Santos BR, Mayer KH, Hoffman IF, Eshleman SH, Piwowar-Manning E, Wang L, Makhema J, Mills LA, de Bruyn G, Sanne I, Eron J, Gallant J, Havlir D, Swindells S, Ribaudo H, Elharrar V, Burns D, Taha TE, Nielsen-Saines K, Celentano D, Essex M, Fleming TR; HPTN 052 Study Team. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011;365:493-505. PMCID: PMC3200068.
  2. Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, Kumarasamy N, Hakim JG, Kumwenda J, Grinsztejn B, Pilotto JH, Godbole SV, Chariyalertsak S, Santos BR, Mayer KH, Hoffman IF, Eshleman SH, Piwowar-Manning E, Cottle L, Zhang XC, Makhema J, Mills LA, Panchia R, Faesen S, Eron J, Gallant J, Havlir D, Swindells S, Elharrar V, Burns D, Taha TE, Nielsen-Saines K, Celentano DD, Essex M, Hudelson SE, Redd AD, Fleming TR; HPTN 052 Study Team. Antiretroviral Therapy for the Prevention of HIV-1 Transmission. N Engl J Med. 2016 Sep 1;375(9):830-9. PMCID: PMC5049503
  3. Rodger AJ, Cambiano V, Bruun T, Vernazza P, Collins S, van Lunzen J, Corbelli GM, Estrada V, Geretti AM, Beloukas A, Asboe D, Viciana P, Gutiérrez F, Clotet B, Pradier C, Gerstoft J, Weber R, Westling K, Wandeler G, Prins JM, Rieger A, Stoeckle M, Kümmerle T, Bini T, Ammassari A, Gilson R, Krznaric I, Ristola M, Zangerle R, Handberg P, Antela A, Allan S, Phillips AN, Lundgren J; PARTNER Study Group. 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.
  4. Bavinton BR, Pinto AN, Phanuphak N, Grinsztejn B, Prestage GP, Zablotska-Manos IB, Jin F, Fairley CK, Moore R, Roth N, Bloch M, Pell C, McNulty AM, Baker D, Hoy J, Tee BK, Templeton DJ, Cooper DA, Emery S, Kelleher A, Grulich AE; Opposites Attract Study Group.Viral suppression and HIV transmission in serodiscordant male couples: an international, prospective, observational, cohort study. Lancet HIV. 2018 Aug;5(8):e438-e447.
  5. 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. 22nd International AIDS Conference, Amsterdam, the Netherlands, July 2018.