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Overview of HIV Prevention

Joseph J. Eron, Jr., MD
Program Director
Daniel R. Kuritzkes, MD
Program Director
Sharon L. Hillier, PhD
Released: September 17, 2020

Antiretroviral Therapy for Prevention

The concept of HIV treatment-as-prevention (TasP), in which full suppression of virus in a person with HIV renders their infection unable to be sexually transmitted to others, is now a key tenet of the DHHS recommendation that ART be offered to all persons with HIV, regardless of disease stage or CD4+ cell count and particularly those at risk of transmitting HIV to sexual partners, including heterosexuals and other risk groups.[114] The public health benefits for prevention of transmission add to the substantial and well established health benefits of early treatment for individuals with HIV infection. According to the DHHS guidelines, evidence has definitively demonstrated that ART prevents sexual HIV transmission when plasma HIV-1 RNA levels are consistently < 200 copies/mL, including any measurable HIV-1 RNA level that is below this threshold value. The studies contributing to this body of evidence are described below and have led to an important concept for individuals with HIV and their care providers, that U = U or Undetectable = Untransmittable. In addition to the motivational strength of this message in supporting treatment adherence, U = U also has important implications for addressing and overcoming the stigma that has long been associated with HIV. For many people with HIV, the knowledge that with effective treatment, they will not transmit infection through sex is empowering and liberating. For providers, it is important to share this message with their patients living with HIV. The DHHS guidelines note that providers should make an individualized assessment for each patient regarding their risk tolerance, history of maintaining viral suppression with ART, personal health, healthcare service/ART access, and factors that may have an effect on their ability to maintain a high level of ART adherence when counselling patients who plan to rely on ART as an HIV prevention strategy.

The earliest evidence on the efficacy of ART to prevent HIV transmission come from studies aimed at reducing the risk of vertical HIV transmission. Indeed, the use of ART in pregnancy has dramatically reduced the incidence of perinatally acquired HIV infections, with rates of mother-to-child HIV transmission decreasing from approximately 20% without intervention to < 2% with ART.[115,116] The efficacy of ART in preventing mother-to-child transmission is primarily through lowering plasma HIV-1 RNA, and a higher HIV-1 RNA is strongly associated with vertical HIV transmission.[117]

Early results suggesting that decreases in HIV-1 RNA levels may also be associated with decreased heterosexual HIV transmission began emerging in the 2000s, including several large observational studies.[18,118,119] In a study of 2993 serodiscordant couples in Rwanda and Zambia, the rate of HIV infection was 0.7% if the partner with HIV was receiving ART and 3.4% if the partner with HIV was not receiving ART—a reduction in HIV incidence of 80% (rate ratio: 0.21; 95% CI: 0.08-0.59).[119] In a second study conducted in Tororo, Uganda, evaluating home-based ART in a rural community, 926 adults were followed after starting therapy.[18] Risky sexual practices decreased by 70% (P = .002), and the median HIV-1 RNA decreased from 122,500 copies/mL to an undetectable level (HIV-1 RNA < 50 copies/mL). In this study, the estimated HIV transmission risk was reduced by 98%. Finally, a randomized study of 3381 serodiscordant couples in southern and eastern Africa demonstrated a 92% lower risk of HIV transmission to the uninfected partner when the partner with HIV was receiving ART vs those couples in which the partner with HIV was not receiving therapy (P = .004).[19] These data suggested that broader implementation of treatment could substantially reduce the incidence of HIV infection.

HPTN 052
At that time, concerns had been raised that the observational cohort studies may overestimate the effectiveness of treatment for prevention, suggesting the need for a randomized controlled trial to address this important question. The HPTN 052 study[12] was a phase III randomized trial designed to evaluate the role of ART in the prevention of HIV transmission among serodiscordant couples. Within each couple, the partners with HIV (who had CD4+ cell counts of 350-550 cells/mm3 at baseline) were randomized either to immediate therapy or delayed therapy (when the CD4+ cell count fell to ≤ 250 cells/mm3 or after the development of an AIDS-related illness). This trial, which enrolled 1763 couples, was halted by the data and safety monitoring board in May 2011 based on the very clear benefit demonstrated in the immediate treatment group: Out of the 28 genetically linked transmissions that occurred among study subjects, 27 were in the control arm vs only 1 in the intervention arm (HR: 0.04; 95% CI: 0.01-0.27; P < .001), representing 96% efficacy. In a final study analysis aimed at determining the durability of HIV transmission prevention provided by ART, early ART was associated with a 93% reduction in the risk of linked HIV transmission during a 10-year period from 2005-2015.[13] None of the 8 linked HIV transmission events (from index participant to partner) that were diagnosed after the index participant initiated ART occurred while the index participant was receiving ART and had stable virologic suppression. In addition, immediate therapy was associated with a 41% reduction in the risk of HIV-related clinical events compared with delayed therapy (HR: 0.59; 95% CI: 0.40-0.88; P = .01).[12] The increase in clinical events in the delayed arm vs the early-therapy arm was attributed primarily to an increased incidence of extrapulmonary tuberculosis (17 vs 3 cases; P = .002). 

PARTNER1/2
Following the findings of HPTN 052, several prospective observational studies have added to the body of evidence supporting the efficacy of HIV treatment-as-prevention in more diverse populations of serodiscordant couples, including the PARTNER1 and PARTNER2 trials. The PARTNER trials are prospective, observational, multicenter studies that evaluated HIV transmission rates within serodiscordant couples in which the partner with HIV was receiving virologically suppressive ART. Inclusion criteria included self-report of condomless sex and no pre-exposure/postexposure prophylaxis usage by the HIV-negative partner. PARTNER1 evaluated both heterosexual (n = 548) and MSM (n = 340) couples. Following 1238 eligible couple-years of follow-up (CYFU), there were no linked cases of HIV transmission, yielding a zero rate of within-couple HIV transmission, with upper 95% CI limits of 0.30/100 CYFU overall and 0.71/100 CYFU for condomless anal sex.[120]

PARTNER2 evaluated MSM couples, including some couples who continued from the PARTNER1 study. No within-couple HIV transmissions were observed among 782 serodiscordant MSM couples contributing 1593 CYFU who reported condomless sex while the partner with HIV was receiving suppressive ART. Therefore, the within-couple HIV transmission rate was effectively zero, with an upper 95% CI limit of 0.23/100 CYFU.[121] Although 15 HIV-negative men acquired HIV infection during the course of the study, none of these infections was phylogenetically linked to the partner with HIV.

Effect of ART on Community Viral Load and HIV Incidence
In addition to the benefits of ART for preventing HIV transmission in serodiscordant couples, data have shown that widespread use of ART may also benefit entire communities. Indeed, one study conducted in San Francisco, California, showed a significant association between declining mean community viral load (defined as the mean of patients with HIV’s individual HIV-1 RNA results per year) and rate of newly diagnosed HIV cases between 2004-2008 (P = .003).[122] Furthermore, the declining total community viral load was significantly associated with increasing virologic suppression in the community (P = .011).[122] Similarly, during a period of increased testing and treatment in Vancouver, British Columbia, Canada, investigators found an association between decreased community viral load and decreased number of new HIV diagnoses, even though rates of other sexually transmitted infections were increasing.[123] In addition, data from Washington, DC, have shown that increased HIV testing efforts can improve rates of early diagnosis and treatment, which could have further implications in reducing community viral loads.[124] Therefore, it appears that as the viral load in the community declines, the number of new HIV infections is likely to decline as well, although more research is needed in this area to confirm this association.

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