Since the early 1980s, major advances have been made with treatment for persons living in HIV. During the subsequent years since the recognition of this new and devastating disease, numerous landmark studies have resulted in availability of >30 US Food and Drug Administration–approved antiretroviral drugs for the treatment of HIV infection, along with an extensive group of strategies for the prevention and treatment of HIV-associated co-infections and comorbidities.

Over the past 4 decades, implementation of treatment modalities has faced several challenges. The challenges have been associated with drug toxicities, inconsistent adherence to complex treatment regimens, drug resistance, decisions when to initiate treatment, pill fatigue, and limited access to treatment by special populations (6,7). For persons living with HIV who have access to these drugs, these regimens extended their life expectancy. In 1981 and 1982, when the first AIDS patients were seen in the United States, the median survival time for a person with AIDS was 1–2 years (8,9). In contrast, for a person of 20-some years of age with HIV infection being treated with combination antiretroviral therapy (ART) today, the projected life expectancy is ≈53 years (10). This major accomplishment resulted from public–private partnerships among academia, industry, the US government, international collaborators, and the affected community. According to recent reports from the Joint United Nations Programme on HIV/AIDS (UNAIDS) and largely as a result of the efforts of the US President’s Emergency Plan for AIDS Relief and the Global Fund to Fight AIDS, Tuberculosis and Malaria, 19.5 million persons are now receiving lifesaving ART (representing 53% of all persons living with HIV globally), and AIDS-related deaths have been halved since 2005 (11). Increasing the number of persons living with HIV who receive ART will require continued optimization of treatment regimens and implementation of strategies to ensure prompt diagnosis, access to ART, adherence to drug regimens, and retention in care.

Substantial progress has also been made in the development of strategies to prevent HIV transmission/acquisition, beyond the interventions that were available early in the AIDS epidemic (e.g., use of condoms, clean syringes, behavioral interventions, and blood supply screening). The HIV Prevention Trials Network 052 clinical trial, which involved 1,763 HIV-serodiscordant couples in 9 countries, clearly validated the concept of treatment as prevention as an effective HIV prevention strategy. The initial findings from this landmark clinical study showed a 96% reduction in HIV transmission (from 350–550 to <250 CD4+ T cells/μL) when the HIV-infected partner began ART early (12). These results were sustained in a follow-up study 4 years later (13). The results from the recent PARTNER study further demonstrated the benefits of suppressive ART in preventing HIV transmission during sexual activity (14). From this study, Rodger et al. reported that, after ≈58,000 condomless sex acts among HIV-serodiscordant couples, no linked HIV transmissions occurred while the HIV-infected partner was receiving suppressive ART. In addition, the findings from the Opposites Attract study (358 HIV-serodiscordant couples in Australia, Thailand, and Brazil) recently indicated no HIV transmissions among 591 couple-years of follow-up when the HIV-infected partner had an undetectable viral load (results based on 16,889 acts of condomless anal intercourse) (15). Together, these studies demonstrate that when ART effectively suppresses a person’s viral load to undetectable levels, the risk for sexual transmission of HIV to an uninfected sexual partner is essentially zero. These clinical trials provided the crucial scientific evidence for the recent consensus statement that undetectable = untransmittable is achievable if the viral load of a person living with HIV and receiving ART is undetectable (16). The US Centers for Disease Control and Prevention recently stated, “When ART results in viral suppression, defined as less than 200 copies/mL or undetectable levels, it prevents sexual HIV transmission” (17). Accomplishing the undetectable = untransmittable strategy worldwide will require that everyone who is HIV-infected is receiving ART and that their viral load is suppressed to an undetectable level.

Another valuable HIV-prevention strategy is preexposure prophylaxis (PrEP). Results from several key clinical trials, including iPrEX (18), TDF2 (19), Partners PrEP (20), and the Bangkok Tenofovir Study (21), have demonstrated that emtricitabine and tenofovir disoproxil fumarate (Truvada; Gilead Sciences, Inc., Foster City, CA, USA) taken as a single pill daily is ≈95% effective for preventing HIV acquisition. Marcus et al. recently reported that no HIV infections were acquired during 5,104 person-years of PrEP use (22). Although PrEP is highly effective as a prevention intervention, it is currently underutilized in the United States and worldwide; thus, public health officials worldwide need to continue to develop, optimize, and implement HIV prevention strategies for persons at risk for HIV. Clinical trials in several countries are evaluating alternative approaches for mitigating the adherence challenges of daily oral dosing prevention regimens; these approaches include long-acting, injectable antiretroviral drugs such as cabotegravir and other long-acting agents as well as passive transfer of antibodies (23).

The comprehensive portfolio of interventions in our HIV prevention toolbox served as the basis for a recent commentary in the lay press stating that there are “No more excuses. We have the tools to end the HIV/AIDS pandemic” (24). Despite these valuable advances in prevention of HIV infection, several challenges have been encountered in the optimal implementation of these modalities. These challenges include structural, legal, and social barriers resulting in inequalities of access to and uptake of HIV testing and treatment; lack of retention in care; social networks; stigma and discrimination; poor adherence to PrEP; limited access to special populations; and difficulty meeting the UNAIDS targets for enrolling persons living with HIV into treatment programs (25,26).