Evolution of Prevention of HIV: A Personal Journey

When HIV surfaced (1980), I was working on Neisseria gonorrhoeae transmission. As for so many ID specialists, my clinical career was quickly consumed by management of HIV and opportunistic infections. This was particularly urgent in Chapel Hill because more than 5000 patients with hemophilia were under our care, most of whom tragically acquired HIV. By 1985, 10% to 15% of all hospital admissions were for HIV infection. I decided to try to marry my sexually transmitted infection (STI) and HIV interests by studying ways in which gonococcal infection affected transmission of HIV. Working in Malawi, we were able to show that treatment of gonococcal urethritis significantly reduced the concentration of HIV in semen.1 This observation supported the hypothesis that the mass treatment of STIs with antibacterial agents might reduce the incidence of HIV at a population level. However, in the early 1990s, a series of community-based randomized controlled trials in Africa failed to show benefit through treatment of STIs. In 1989, Burroughs Welcome demonstrated that azidothymidine could reduce replication of HIV, ushering in the golden age of development of antiviral drugs (ARVs) directed at HIV. Our University of North Carolina research team (Angela Kashuba, Ron Swanstrom, Joe Eron, Susan Fiscus, and many more faculty, students, and postdoctoral fellows) confirmed the hypothesis that ARVs that concentrated in the genital tract would reduce viral replication of HIV in semen and vaginal secretions. In 2000, Quinn et al.2 reported that the concentration of HIV in blood could be correlated with the probability of sexual transmission. Importantly, in their study, HIV transmission was not observed at below 1500 copies HIV/mL blood plasma. The sum of these observations galvanized our plans to conduct a definitive “treatment as prevention” study. It seemed likely that treatment of HIV reduced sexual transmission of the virus. But the magnitude and duration of such benefit were unknown. It was also not clear how such a study could be conducted. It was widely believed that transmission of HIV within a couple was rapid and inevitable; that is, when one person was infected, the sexual partner took for granted that they had been infected as well. But we and others were able to show that, at the time of detection of HIV in one person (the index case), about half the sexual partners (at risk) were still HIV negative, creating a large number of “discordant couples.” With support from the National Institutes of Health (through the HIV Prevention Trials Network, HPTN) and using highly valued ARVs donated by 6 pharmaceutical companies, we (a clinical research team led by Irving Hoffman, Marybeth McCauley, Theresa Gamble, and investigators at 13 sites in 9 countries) developed the HPTN 052 “treatment as prevention study.” HPTN 052 was very complicated. We needed to recruit a large number (>1300) discordant couples. We developed and deployed a robust “safer sex” strategy because we needed to try to reduce HIV transmission regardless of the potential of ARVs. We needed to start ARVs earlier in the course of infection (randomizing participants to an early vs. delayed treatment arm) than was the standard of care in any country, to attempt to prevent HIV transmission. We needed to develop phylogenetic tools to allow us to determine if a transmission event resulted from virus-acquired from the index case, or through an unrelated exposure. We needed to manage the clinical status of the index case whether in the “early” or “delayed” arms of the study so as to initiate treatment in the delayed arm if CD4 count fell to the level of the standard of care. The HPTN 052 study idea was piloted in 2005, launched in 2007, and completed enrollment in 2010. On April 11, 2011, the NIAID Data Safety Monitoring Board stopped HPTN 052 because early ART had reduced HIV transmission by at least 93%.3 Index participants in the early ART arm of the study had significantly fewer infections.4 In December 2011, Science Magazine identified the findings in HPTN 052 as the “scientific breakthrough of the year.” This “treatment as prevention” journey took more than 30 years. Based on the HPTN 052 results and other studies that confirmed the benefits of early ART (START, TEMPRANO), HIV “test and treat” became a universal standard of care. UNAIDS developed strategies to ensure viral suppression in the largest number of people possible (find 95% of infected people, link 95% to care, and ensure viral suppression in 95% of HIV-infected patients, the 95–95–95 Program). Recognizing the importance of stigma for HIV-infected people, Bruce Richman launched the U=U (Undetectable is Untransmittable) Program. Worldwide, HIV incidence has fallen. And some countries that have achieved 95–95–95 (e.g., Botswana, Eswatini) are reporting near zero HIV incidence of HIV, clearly ascribed to treatment as prevention at a population level. Along this journey, we learned that the penile foreskin is an important site of HIV acquisition, and that circumcision prevents HIV acquisition. And the utility of ARVs for prevention has evolved beyond treatment as prevention. The combination of tenofovir and emtricitabine can prevent HIV acquisition when used as preexposure prophylaxis (PrEP). In HPTN 0835 and 0846 (led by Raphael Landovitz and Sinead Delaney-Moreltwe, respectively), we were able to work with ViiV and BMGF to develop long-acting injectable Cabotegravir (an integrase inhibitor) as PrEP, and we are now working with Gilead to help develop ultralong-acting lenacapavir (a capsid inhibitor) as PrEP. In reality, the prevention of HIV includes many different complimentary approaches. From the beginning of the epidemic, the critical role of “safer sex behavior” and use of condoms was recognized. The past 40 years has included unremitting efforts at HIV vaccine development. Although no credible HIV vaccine has been developed, the methods and results from the effort have revolutionized science. Indeed, it can be strongly argued that COVID-19 vaccines, monoclonal antibodies, and antiviral agents were built on the HIV infrastructure. HIV has gone from a universally fatal disease to a chronic infection treated with a pill once a day. HIV infection can be prevented (even without the benefit of a vaccine) through coordinated behavioral and biological strategies. Over the course of these years, I was recruited by Dr. Julius Schachter to serve on the Editorial Board of STD and starting in 2004 and the next 15 years or so as one of the Associate Editors of the Journal. This was a compelling labor of love. Dr. Schachter and his team were remarkable in their management of the Journal and their commitment to excellence. Not surprisingly, I was particularly focused on the interaction of classical STDs and their interaction with HIV, and serving as an Associate Editor gave me greater insight and breadth as an investigator and teacher. In truth, the pleasure was all mine. Congratulations to STD on its 50th Anniversary.