Ending the HIV Epidemic: What Is Past Is Not Prologue

PART I. ENDING THE HIV EPIDEMIC

The Centers for Disease Control and Prevention’s (CDC) initiative of Ending the HIV Epidemic (EHE) in the United States is an audacious action plan with a goal of reducing 75% and 90% of new HIV infections by 2025 and 2030, respectively. Targeting focused efforts on HIV prevention, treatment, and comprehensive care is a formidable—but not insurmountable—task, even for the lionhearted.¹

CURRENT STATUS

Globally, at the end of 2021, the number of people with HIV (PWH) was over 38 million.² In the United States (and 6 dependent areas), approximately 1.2 million individuals were estimated to be living with HIV by the end of 2019.³ Approximately 13% of these individuals were unaware of their HIV diagnosis, which highlights the importance of HIV testing.³ The CDC recommends that all individuals aged 13 to 64 years receive HIV testing at least once in their lifetime, and at least annually for those with certain risk factors.⁴ Overall, in the United States, the incidence of new HIV infections has decreased from 37,800 to 34,800 from 2015 to 2019.³ In 2019, less than 1% of these infections were attributed to perinatal transmission.⁵ In 2020, 71% of new HIV infections were among men who have sex with men, per the CDC.⁵ In addition, 2% of new HIV diagnoses were among transgender people.⁵ In 2020, the CDC noted 12,827 and 7999 new HIV diagnoses in Black/African American and Hispanic/Latino adolescents or adults, respectively, in the United States⁶; people who inject drugs (PWID) accounted for 1 in 15 HIV diagnoses.⁵

TARGETS TO END THE HIV EPIDEMIC

Regarding the EHE initiative, the 4 HIV National Strategic Plan (2021-2025) goals are as follows: (1) preventing new HIV infections; (2) improving HIV-related health outcomes of PWH; (3) reducing HIV-related disparities and health inequities; and (4) achieving integrated, coordinated efforts addressing the HIV epidemic among all partners and stakeholders.¹

From a global vantage point, the Joint United Nations Programme on HIV/AIDS (UNAIDS) had set HIV treatment goals in 2013. By 2020, the goal was to reach the HIV treatment targets, titled “90-90-90,” to help end the HIV epidemic: 90% of PWH would know their HIV status, 90% would be receiving treatment, and 90% would be virally suppressed. Although these targets were not universally met, considerable strides toward achieving progress in the field of HIV were made. What is also encouraging is that certain high–HIV burden countries were able to achieve some of these goals.

Although HIV remains a pervasive epidemic, there have been tremendous advancements in HIV prevention, diagnosis, antiretroviral therapy (ART), and continuity of care over the decades. These have ranged from the advent of Rapid Start ART to the Undetectable = Untransmittable (U = U) public health messaging campaign, supported by clinical trial data.⁷ Remarkably, by the end of 2021, roughly 75% of PWH globally were accessing ART.² In 2020, the UNAIDS HIV treatment targets were updated with a new goal, titled “95-95-95,” whereby 95% of PWH would be aware of their HIV status, 95% would be on treatment, and 95% would be virally suppressed by 2025.⁸ To reach such targets, a pragmatic approach is to expand access to HIV care (including both HIV preexposure prophylaxis [PrEP] and treatment) in high-prevalence areas (eg, hot spots), particularly focusing in on where PWH may have limited care, including in rural settings.⁷ Additionally, through task shifting, health care workers including community workers and nurses have helped physicians to amplify the role of providing effective, integrated HIV care. Expanding access includes strengthening the workforce of HIV providers and ensuring there is investment in infectious diseases education and training⁹; especially as, alarmingly, there was a decrease in the percentage of infectious diseases fellowship training programs filling their trainee spots in 2022.¹⁰ That notwithstanding, training other noninfectious diseases providers in comprehensive HIV care can be another pathway to increase the workforce.¹¹

REDUCING HIV-RELATED INEQUITIES AND ACHIEVING INTEGRATED COORDINATED EFFORTS

Notably, in the past decade alone, there has been improved population-wide viral suppression, a decline in HIV diagnoses (especially in key populations), reduced outcome disparities (noted within the Ryan White HIV/AIDS Program), and enhanced health insurance for PWH.¹ In addition, the development of HIV PrEP; enactment of policies to ensure federal funding supports HIV care; and advancements directed by the National Institutes of Health toward novel prevention agents, therapies, vaccine, and cure¹ hold promise for physicians and patients alike that an end to the HIV epidemic is not implausible, though more time and investment are needed. The implementation of community-based outreach has been effective in ensuring linkage to care for PWH. Additionally, medication-assisted treatment for substance use with behavioral therapy and syringe service programs has helped to reduce transmission of HIV in PWID.⁶

Moreover, it is important to focus on globally equitable HIV care, including in low-resource settings, so that countries with the highest burdens are achieving HIV treatment and prevention targets. Particular attention is needed in low-resource settings, as a lack of control of HIV in these regions can pose a threat of resurgence in areas that have already achieved control, as we have learned with the COVID-19 pandemic.

Above all, the future of HIV care holds significant potential. Particularly, cutting-edge scientific research developments and clinical trials of HIV prevention and treatment drugs, therapeutics, vaccines, and transplantation have led to tremendous progress—and, rarely, even cure of HIV in the latter case—in this field.

PREVENTING NEW HIV INFECTIONS

HIV Preexposure Prophylaxis

In the United States, daily oral pills of tenofovir disoproxil fumarate/emtricitabine and tenofovir alafenamide/emtricitabine for HIV PrEP were US Food and Drug Administration (FDA) approved in 2012 and 2019, respectively. These milestones heralded a paradigm shift, focusing on HIV preventive therapeutics as a key strategy in reducing HIV transmission. Then, in December 2021, the first long-acting, injectable agent, cabotegravir, was approved by the FDA for HIV PrEP,¹² holding promise for those individuals who are less adherent to daily oral pill regimens. In the pipeline, the long-acting capsid inhibitor lenacapavir—which has an oral lead-in and a long-acting subcutaneous injectable formulation—is being studied as an agent for HIV PrEP in the PURPOSE 1 and 2 clinical trials (NCT04994509 and NCT04925752)^13,14; this potential game changer would allow biannual injections for HIV PrEP. Outside of the United States, the dapivirine vaginal ring has been offered as PrEP for adult women, based on clinical trial data (eg, RING [NCT01539226], ASPIRE [NCT01617096]) from Africa demonstrating HIV-1 risk reduction in women engaging in vaginal sex.^15-17 In recent years, Zimbabwe and South Africa were the first African countries to approve this vaginal ring as PrEP.¹⁷

HIV Vaccines

HIV vaccines^18-20 have been in development for decades, including in clinical trials, unfortunately with unsatisfying results. Promising approaches including messenger RNA (mRNA) vaccine platforms—utilized in arenas such as cancer and in particular for COVID-19 amidst an unprecedented pandemic—employ host machinery to produce immunogens to elicit immune responses. mRNA vaccines for HIV have been developed, and notably, the first randomized control clinical trial for HIV mRNA vaccines in humans began in 2022, with results anticipated in 2023.^18,21

IMPROVING HIV-RELATED HEALTH OUTCOMES

HIV Treatment as Prevention

Bending the arc takes time, and scientific research has played a tremendous role in the process. The randomized controlled trial HPTN 052 (NCT00074581) was a landmark study which examined whether ART could prevent sexual transmission in serodiscordant couples.²² The findings demonstrated that early ART initiation led to a sustained decrease in HIV-1 infection in HIV-negative sexual partners.²² This study was proof of concept for the HIV Treatment as Prevention strategy,²² so much so that in 2013, the World Health Organization recommended that ART be administered to all PWH with uninfected partners to reduce HIV transmission, based on the study’s interim results.²³

Undetectable = Untransmittable (U = U)

The public health messaging of U = U initiated in 2016 by Prevention Access Campaign has helped to educate the public and reduce the stigma of HIV. The concept of U = U with regard to HIV has been supported by evidence from various studies (eg, Rakai Project Study, PARTNER, HPTN 052, Opposites Attract), which helped increase awareness about the lack of risk of HIV transmission in the setting of undetectable viremia.^22-27

Recent Updates

Myriad landmark developments in HIV prevention, transmission, and novel therapeutics have occurred since then. Currently, per the 2022 International Antiviral Society–USA HIV treatment and prevention guidelines, the standard HIV regimen recommended for the majority of PWH is one of the following: (1) bictegravir/tenofovir alafenamide/emtricitabine, (2) dolutegravir plus tenofovir (alafenamide or disoproxil fumarate) with either emtricitabine or lamivudine, or (3) dolutegravir/lamivudine (if HIV RNA < 500,000 copies/mL and hepatitis B coinfection is not present).⁸ Additionally, an expanding repertoire of agents for heavily treatment-experienced (HTE) people with multidrug-resistant (MDR) HIV-1 include the gp120 attachment inhibitor fostemsavir (excluding HIV subtype CRF01_AE), the capsid inhibitor lenacapavir, the CCR5 antagonist maraviroc (if R5-tropic), the CD4 postattachment inhibitor ibalizumab, and the fusion inhibitor enfuvirtide.¹²

On December 22, 2022, the landmark FDA approval of lenacapavir—a first-in-class, long-acting capsid inhibitor which can be given via biannual injection—for MDR HIV-1 treatment was a breakthrough for HTE PWH with limited treatment options.²⁸ This drug can be used in combination with other antiretroviral agents, based on data from the CAPELLA study (NCT04150068).²⁸ Potential partner agents for lenacapavir are being investigated further for treatment of HIV in up-and-coming clinical trials. Additionally, in January 2021, a milestone for adults with HIV-1 (with virologic suppression on a daily oral ART regimen) was the FDA approval of a combination of the long-acting injectable agents cabotegravir and rilpivirine administered every 4 or 8 weeks.¹² Furthermore, HIV broadly neutralizing antibodies and other novel antiretroviral agents (in combination) are being investigated in innovative research studies, including in clinical trials. In addition, human clinical trials are underway to evaluate the efficacy of gene-editing treatment in HIV, particularly the CRISPR-based HIV intravenous infusion therapy EBT-101, although this underlying technology is still exploratory in nature.²⁹

PART II. AN HIV CLINICIAN’S PERSPECTIVE: FORMATIVE MILESTONES THROUGH MY LENS

Foundation

I was born in the 1980s—a time when HIV was emerging, blatantly stigmatized, and not yet fully described. If the virus is left to its own devices, its natural history permits progression to the syndrome of AIDS—once described as “enigmatic and deadly.”³⁰ For the medical community and PWH during that time, fighting for a treatment option was the only option, when antiretrovirals were still in development. In 1987, zidovudine (AZT) would eventually be the first FDA-approved medication to treat HIV/ AIDS.³¹ Growing up in the United States as a child of indefatigable immigrants, perhaps I was an infracaninophile. I witnessed how the challenges of struggles and inequity could be counterbalanced by resilience and willpower. Those foundational years, paired with my inclination for science and predilection to care for the vulnerable, would be the building blocks for my becoming a physician focused on global health. In 2003, I remember in high school watching the news when the US President’s Emergency Plan for AIDS Relief (PEPFAR) was announced. PEPFAR would initially provide $15 billion in funding over 5 years to combat HIV, and inevitably change the global landscape of HIV, particularly affecting PWH in countries with a high prevalence of HIV.³¹ I recall feeling a pang of justice—followed by a sense of relief—as I understood that political will could coexist with empathy for the well-being of the underserved. In 2007, in college, when my predilection for biomedical engineering grew, it was timely that I learned of the “Berlin patient,” who was the first person living with HIV designated as cured after receiving a bone marrow transplant.³¹

START OF MY JOURNEY IN PROVIDING HIV CARE

Later, in 2012, when I was in medical school, my commitment to global health, understanding health disparities, and the linkage between vulnerable populations and illness grew. These underpinnings led me through the years to live and work in medical settings, including Izcuchaca in Peru and Austria, where I saw more clearly the contrasting health disparities in underdeveloped and developed health care settings in the world. Meanwhile, in 2012, the first oral HIV PrEP agent, tenofovir disoproxil fumarate/emtricitabine, was approved by the FDA.³¹ In 2016, after graduating medical school, I began my residency in internal medicine. At that time, I read Mountains Beyond Mountains, describing the late Dr Paul Farmer’s vision that health care is an intrinsic right regardless of socioeconomic status or regionality, backed by his ideology that glaring global health disparities could be transformed.³² Needless to say, I was inspired. Thus, I was grateful for the opportunity to work on the medicine wards in hospitals in Rwanda during 2017 and 2019, where I saw fascinating pathology in tropical medicine and even tremendous strides in a developing health care system in Africa; however, I also witnessed the tragic reality of many people needlessly dying from HIV, its related opportunistic infections, and other ailments that could have been addressed more readily in more resource-rich, developed health care settings. “Geography is destiny,” a doctor told me on the ward in Rwanda, but I did not want that to be the case when it came to treatable diseases with human lives at stake. It was in that ward that I decided to advocate for those who were affected by HIV and infectious diseases by becoming an infectious diseases physician.

SPECIALIZATION AND EVOLUTION

In 2019, in the first year of my infectious diseases fellowship, I committed myself to becoming an HIV, infectious diseases, and global health physician. I continued to treat PWH in the HIV clinic and on the HIV/infectious diseases/internal medicine service and teach trainees on the wards. In fellowship, I was inspired by my mentors and senior physicians who had helped blaze the trail in HIV and global health. Concurrently, during that year, the EHE initiative was proposed. In addition, a second person living with HIV was designated as cured after receiving a bone marrow transplant.³¹ As the COVID-19 pandemic emerged in late 2019/early 2020 during my infectious diseases fellowship, the focus shifted—but my passion to treat patients with HIV had not faded. At a time when so much about SARS-CoV-2 was still unknown and enigmatic, I remember hearing senior professors and physicians relate how this hearkened back to and paralleled in many ways the HIV epidemic. During this time, we studied SARS-CoV-2 immunogenicity among PWH receiving COVID-19 vaccines. Also, as a COVID-19 vaccine clinical trials (pediatric, adult, and booster studies) subinvestigator, I learned a great deal about clinical trials, research developments, and supply and demand of highly efficacious mRNA COVID-19 vaccines developed at warp speed and in a condensed time frame. Later, in 2021, as an HIV clinical trials subinvestigator, I helped study the efficacy of a switch from daily oral bictegravir/tenofovir alafenamide/ emtricitabine to the injectable antiretrovirals, cabotegravir and rilpivirine. In January 2021, cabotegravir and rilpivirine would eventually become the first FDA-approved, long-acting, extended-release injectable complete ART regimen for HIV; and in December 2021, cabotegravir (extended release) would become the first FDA-approved long-acting agent for HIV PrEP. These milestones motivated me to study novel HIV therapies further.

In 2021-2022, now as an infectious diseases attending physician, I recall breaking news headlines of another milestone—a woman in the United States had been cured of HIV after a cord blood transplant.³³ “More momentum,” I thought. Around this time, I valued my experiences teaching and working in hospitals in South Africa and Liberia, where I continued to see the impact of a high burden of tropical and infectious diseases, including HIV and tuberculosis, and noncommunicable diseases on patients. Back in the United States, I continued research as a subinvestigator, now for an HIV clinical trial studying HTE people with MDR HIV. In this trial, we studied the efficacy of adding the long-acting capsid inhibitor lenacapavir to a complex antiretroviral regimen with great effect. In December 2022, lenacapavir became the first-in-class FDA-approved long-acting capsid inhibitor for treatment of adults with MDR HIV-1.²⁸ This advent would have a profound impact for HTE PWH with limited treatment options and incited me further to study the efficacy of lenacapavir in HIV PrEP clinical trials. Of course, robust, long-term studies will need to be expanded upon to better understand the safety, efficacy, and resistance profiles of novel ART for the prevention and treatment of HIV.

CONCLUSIONS

As we have seen with the HIV epidemic, a revolution does not typically occur overnight. We should strive to achieve the aspirational goals we set—important benchmarks—such as those of EHE. Yet, we do not need to wait until 2030 to see the manifestation of such a revolution, because this cultivation of novel prophylactics and treatments for HIV has already begun and is happening before our eyes. Thus far, the milestones that have already been reached are a promise and a foreshadowing of an ever-evolving development in the pipeline of prophylactics and therapeutics in the field of HIV. These innovations will unequivocally provide improved health outcomes for community members, including PWH, now and in the future. Moreover, I am inspired by the decades-long commitment of physicians and health care workers to HIV care, whose wisdom and mentorship have ensured a promulgation of the next generation of HIV and infectious diseases doctors.

From treating patients with HIV on the wards, in my community and globally, to giving long-acting antiretrovirals such as cabotegravir and lenacapavir in clinical trials, I bear witness to this field’s staggering progress, which is proof of concept for me that we can use our collective brainpower and willpower to redefine what effective prevention and treatment of HIV/AIDS means for our patients.

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