The California HIV/AIDS Research Program: History,Impact,and HIV Cure Initiative

More Than 30 Years of State-Funded HIV Research in California

In 1981, physician-scientists in California first reported a devastating undefined syndrome among their young male patients, presenting with wasting syndrome, Kaposi's sarcoma, and/or Pneumocystis carinii pneumonia. ^1,2 Dr. Paul Volberding recalls patients who were not recognizable from one clinic visit to the next due to rapidly progressing illness, commonly compounded by rejection from family ² (Box 1).

As the first AIDS wards were opened in San Francisco, ³ a new community arose in situ: gay men in San Francisco and Los Angeles, their allies, and the clinicians who cared for them, organized. They advocated stridently for research into this new disease. ⁴ A subsequent bill in the California legislature enacted a visionary program with dedicated funding to encourage and support research on this disease of then unknown etiology (Box 1). A line item was created in the State budget, and a task force was convened to manage the funds and solicit research proposals. In 1983, the State legislature began this unique partnership with the University of California, and thus was born the University-wide AIDS Research Program. ⁴ Applicants were limited, then as now, to nonprofit entities such as academic institutions, local governmental agencies, and community-based organizations within California. What now is the California HIV/AIDS Research Program (CHRP) began before we understood the human retrovirus underlying the devastating epidemic.

Originally intended to fund basic biomedical science discovery and clinical research, early initiatives at CHRP pioneered what would become enduring cornerstones of HIV science: the isolation and quantitation of the virus ^5,6 ; the efficacy and toxicities of the first treatments for HIV infection ^{7 –9} ; the emergence of drug resistance ¹⁰ ; the promise of solid organ transplantation for persons living with HIV ¹¹ (Box 2); and best practices for occupational risk among healthcare workers. ¹²

Over time, CHRP's mission evolved with the epidemic to include social–behavioral research, epidemiology, health services research, clinical trials, and policy research. CHRP initiatives led to the first biospecimen banks for HIV-related research, which still house historical specimens and remain essential to current scientific investigations; the first community-based laboratory service to standardize and support HIV diagnostic serology; and the first consortium for rapid evaluation of antiretroviral therapies for HIV. ¹³ The San Francisco General Hospital Cohort, a CHRP-funded longitudinal case-control study, changed the HIV prognosis: “we should regard progression to clinical AIDS after infection with HIV as the norm rather than the exception.” ¹⁴

Recent Targeted Funding Initiatives

CHRP currently funds work in four priority areas: basic biomedical science, policy research, biomedical prevention interventions, and HIV-related health disparities. Our basic biomedical portfolio has recently supported pioneering work establishing zinc-finger nucleases as a method to modify stem-cells, thereby opening a new HIV treatment paradigm ¹⁵ (Box 2); demonstrating cytosine methylation and MBD2 as epigenetic regulators of HIV-1 latency ¹⁶ ; and discovering a new target for novel latency reversal agents. ¹⁷

The CHRP HIV Policy Research Centers recently documented significant disparities in preexposure prophylaxis (PrEP) knowledge and access among young men who have sex with men (MSM) in California, based on a statewide survey, ¹⁸ and worked successfully with the State Office of AIDS to secure funding for a PrEP drug assistance program to help address these disparities. ¹⁹ A policy brief on remote counseling services that are provided as part of over-the-counter, home HIV test kits established critical evidence supporting the need for improved services, and via Food and Drug Administration consultation led the manufacturer to revise their messaging, which now addresses both pre- and postexposure prophylaxis. ²⁰ In a 2015 analysis, the Centers demonstrated that four California laws regarding HIV, which criminalize otherwise legal behavior, had affected 800 persons across the state (1988–2014), the majority being women or people of color, thereby demonstrating the impact of the legal system on HIV-related health disparities. ²¹ Inspired by this work, Senate Bill 239 was proposed in 2017, which would begin to change these laws. ²²

Beginning in 2010, CHRP investigators pioneered the development of the patient-centered medical home (PCMH) model of care for HIV, a new approach that puts primary care physicians at the helm of an integrated care team that includes social workers, psychologists, and medical specialists. These collaborative teams form virtual “patient-centered medical homes” that work together to ensure that patients come to the clinic, take their medications, and get the care they need. CHRP funded five innovative PCMH projects to study the effectiveness of this model for managing HIV/AIDS, and key outcomes included a 44 percent reduction in hospital readmission rates for program patients at one Northern California hospital ²³ and a significant improvement in viral suppression for patients in a medical care coordination PCMH model located at clinical sites in Los Angeles. ²⁴

Recently, CHRP-funded community-based clinical studies demonstrated PrEP utilization and adherence among women and MSM at risk for HIV. ^25,26 In 2016, CHRP launched the first multisite research initiative in the United States to evaluate the efficacy and pharmacokinetics of PrEP when offered to transgender persons, dedicating $9.4 million to this important effort. ²⁷ For this initiative and the previous PrEP studies involving MSM and women, CHRP established a public–private partnership to secure drug product donations from Gilead Sciences, Inc. ²⁸ Through the HIV Disparities Initiative, also launched in 2016, CHRP provided support to three academic centers and six community-based organizations, all of whom are investigating innovative methods to address health disparities in HIV care and treatment. ²⁹ These projects focus on African American gay, bisexual, and transgender youth; homeless youth; and women of color in multiple geographic regions of California.

External Oversight and Scientific Best Practices

These recent initiatives and all of CHRP's funding priorities are developed in concert with a statewide Advisory Council, which draws members from the community of HIV scientists and advocates in California, and are approved by University of California leadership. CHRP surveys key thought leaders to identify vital or emerging areas for research and creates a model, which maps these to the niche which CHRP serves: the ability to address critical, big-picture HIV/AIDS issues in California. The Advisory Council works with this model to nominate research initiatives and Program staff design Calls for Applications, which will stimulate investigator-initiated research protocols. Incorporated into these Calls is funding to foster multisector and multidisciplinary collaborations as well as support for academic training and career development for emerging independent investigators. When possible, CHRP seeks other funding partners to cosupport these initiatives.

Applications are received from nonprofit institutions across California, are reviewed and scored for scientific merit, and the most meritorious of those are approved for funding in rank order. To determine merit scores, all applications receive rigorous assessment by an external peer review panel of senior-level productive investigators who are well-regarded in their fields. Protocols involving human subjects receive an additional and equally weighted merit score from a community-based reviewer. To minimize the potential for conflicts of interest, we require that all scientific and community peer reviewers be based outside California and be recused from all review activities and discussion regarding applications with which they are in conflict. Our scientific merit review mechanisms are similar to those used by the National Institutes of Health (NIH), with chaired study section meetings and open electronic voting, standardized across multiple special research programs housed at the University of California, Office of the President. Scores and detailed critiques (“summary statements”) are provided to applicants at the end of the review process, and Program Officers are available for in-depth consultation.

After peer review, ranked lists of merit scores are used to develop funding models, and recommendations for funding are made by the statewide Advisory Council, based upon relative merit and availability of funds. All funding models, decisions, and expenditures receive direct oversight at multiple levels within the University of California, as well as regular formal auditing by external bodies and semiannual reporting to the Advisory Council.

Impact of CHRP's Research on the HIV Epidemic in California and Beyond

CHRP's current mission is to foster outstanding and innovative research that responds to the needs of all people of California, especially those communities who are underserved, by accelerating progress in prevention, education, care, treatment, and a cure for HIV/AIDS. To measure our progress toward this mission, CHRP program staff conducted an extensive program evaluation in 2016, covering CHRP initiatives funded between 2009 and 2013; data from that evaluation is presented in Table 1. ²³ The total funding for those initiatives was more than $44 million, and this led to more than $77 million in leveraged subsequent funding (based on responses from n = 86 grantees; a 69.4% response rate)—nearly $62 million of which was from NIH. Therefore, for every $1 invested by CHRP, $1.73 in federal and other grant support was newly secured for California. In addition, a total of 148 peer-reviewed publications resulted from these 98 grants, with an average ratio of 1.5 publications per funded grant. Two recent examples of groundbreaking CHRP-funded research, one in basic biomedical discovery and one in clinical care, are highlighted in Box 2.

Initiative to Fund HIV Cure Research

Historically, CHRP's investment in basic biomedical sciences has been via relatively small, investigator-initiated pilot studies, which were open to all ideas rather than targeted. By contrast, in 2013, CHRP sought to fund work directly related to HIV cure science, seeking innovative new ideas to identify ways to eradicate the virus from the body. Through the HIV Cure Initiative, CHRP granted $1,413,013 in research awards to nine investigators, including senior faculty, postdoctoral fellows, and doctoral students for dissertation awards. ³⁰ Taken together, the body of research from these awards comprises the “CHRP HIV Cure Initiative,” and selected results are presented in this special dedicated issue of AIDS Research and Human Retroviruses. CHRP is pleased to share this exciting collection of work and hopes to continue to move science forward by supporting California investigators in basic biomedical science and beyond.