EditorialHIV

A FRESH approach: Combining basic science and social good

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Science Immunology  14 Sep 2018:
Vol. 3, Issue 27, eaau2798
DOI: 10.1126/sciimmunol.aau2798

Abstract

A program to study HIV infection is empowering African women.

Senior classroom facilitator, Casper Mbatha, leading a workshop on communication with FRESH participants.CREDIT: RACHEL REGINA

INTRODUCTION

Over the past decade, there has been considerable progress in the development of new strategies to prevent and treat HIV-1 infection, yet in many areas of the world, new infections continue to occur at an alarming rate. In the hardest hit regions, such as KwaZulu-Natal (KZN), South Africa, incidence rates among young women—a particularly vulnerable population—still approach 10% per year despite rollout of treatment and prevention strategies. Contributing to this high incidence rate is economic dependency on male partners, which limits women’s ability to negotiate safer sex; gender inequality, including home responsibilities that force early school dropout and block future employment options; and low self-esteem resulting from ongoing female disempowerment. The need for an HIV vaccine to prevent infection and a cure for persons already infected remains paramount.

HIV vaccine and cure efforts would be facilitated by a better understanding of factors that modulate acquisition risk and the early immunologic events after exposure that determine long-term outcome. Given the high rates of transmission among young women in KZN, we asked whether one could implement a research project to detect acute HIV infection very early in order to fill important gaps in biomedical knowledge and, at the same time, address the most pressing challenges faced by young women, an understudied group. Here, we describe the establishment and evolution of a longitudinal cohort study termed FRESH (Females Rising through Education, Support and Health) that was created to achieve these aims by combining basic science research with a poverty alleviation program targeting young African women at high risk of HIV infection.

Design of the FRESH program

The extremely high incidence of HIV infection among young women in KZN suggested an opportunity to detect infection at the onset of plasma viremia through very frequent testing of uninfected women at high risk of infection. With incidence rates approaching 10% per year, new infections would likely occur even with implementation of aggressive behavioral interventions.

Given that HIV risk for women in this setting is inseparable from poverty and disempowerment, we designed a study that included an intensive life-skills and job readiness program to address the constraints posed by poverty. On the one hand, FRESH was created as a research study of HIV transmission and the immunology of acute HIV infection in order to identify biological risk factors that affect HIV transmission and to address gaps in vaccine and cure research. At the same time, the study was designed to provide a pathway toward economic independence, delivered in a safe environment where emotional and physical issues could be discussed—including abuse and violence. The curriculum included HIV prevention education but was primarily designed as a poverty alleviation program. By creating an intervention that coincided with the study’s twice-per-week HIV testing, we predicted that the two distinct aims of detecting acute HIV infection and poverty alleviation could be achieved.

To reduce stigma associated with visits to a clinic or hospital, FRESH was set up at a shopping mall in Umlazi, an economically disadvantaged former township in KZN, where unoccupied retail space was converted into classrooms and exam rooms. The site was designed to be welcoming and comfortable, with a reception area in which the women could socialize before class while awaiting blood sampling. Snacks were provided to participants before class, prepared by participant volunteers in the on-site kitchen. A microwave was centrally placed where participants could heat bean bags to warm their hands to facilitate finger prick blood sampling, allowing rapid throughput of up to 80 participants each morning and again in the afternoon.

We recruited uninfected women 18 to 23 years old who were unemployed and not attending school, targeting the highest risk age group and those most vulnerable. We enrolled women in groups of 30 to 40 each month, which created peer support groups. Criteria for enrollment included being sexually active and able to give informed consent, nonpregnant, nonanemic, and without other barriers to participation, such as serious chronic illness, enrollment in other studies, or conflicting family responsibilities.

The FRESH curriculum was created to provide a sense of community, allowing time during each class for sharing and discussing personal experiences. This was a valued outlet for participants and gave curriculum facilitators a first-hand glimpse into their challenges and unmet needs. Curriculum content, drawing from best-practice poverty alleviation programs, included interactive sessions on self-esteem, relationship- and gender-based violence, stress management, communication, women’s health, and HIV prevention and treatment. This was followed by career exploration, including field trips to observe job opportunities at local businesses, workshops on starting a small business, workplace etiquette, computer training sessions, preparation of a resume and cover letter, and mock job interviews. Initially, computer training was delivered as a single block toward the end of the program, however—due to its popularity—computer sessions were redistributed throughout the 9- to 12-month program in order to maintain excitement and serve as a tool to reinforce all curriculum topics. Participants interested in returning to school, either to complete high school or to enroll at a tertiary institution, were assisted accordingly. Impact of the social intervention was measured by successful placement in work, starting a business, or enrollment in school during the 12 months after completion of the curriculum. Weekly meetings between the research and curriculum teams fostered a holistic approach to care and support and rapid identification of barriers that affected study participation.

At each twice-weekly visit, participants underwent finger-prick HIV RNA testing before attending class, with results available in less than 24 hours. Peripheral blood and cervical vaginal samples were obtained and cryopreserved every 3 months during preinfection surveillance, accompanied by behavioral risk assessment. During the first 18 months of the program, combination antiretroviral treatment (cART) was not initiated during acute HIV infection; rather, it was started when the CD4+ T cell count dropped to below 350 cells/μl, as per the South African guidelines at that time. Institutional Review Board (IRB) approval was eventually obtained to initiate cART immediately after detection of viremia through use of a boosted regiment that included raltegravir until 2 months after viral suppression. IRB approval to provide preexposure prophylaxis (PrEP) was recently obtained and is now available to all FRESH study participants. This intervention is currently recommended but not yet available through the South African public health care system.

FRESH and socioeconomic empowerment

The FRESH program has been operational for more than 5 years, during which time HIV incidence in the cohort has remained more than 8% per 100 person-years (1), which is consistent with reported incidence rate in South Africa among women in the target age group. Adherence to the FRESH study visits and blood and vaginal mucosal sampling has been outstanding and likely heightened by integration with the socioeconomic empowerment curriculum and the continual iterative development of the curriculum so as to ensure a high level of relevance and perceived benefit by participants. Of those completing the program, a greater than 85% rate of placement in jobs or internships, starting a small business, or returning to school has been sustained (1).

Biologic factors that affect HIV acquisition risk in FRESH

The FRESH study design has provided key mechanistic insights into the biological factors that predispose women to HIV infection. Consistent with data from other South African studies, we found a high prevalence of asymptomatic sexually transmitted infections (2), which calls for a reevaluation of the current syndromic approach to the diagnosis and treatment of sexually transmitted infections in South Africa. The availability of longitudinal follow-up data and pre- and postinfection biological samples enabled key insights regarding biological determinants of HIV acquisition. For example, we identified the vaginal microbiome as having a substantial impact on HIV risk. Healthy HIV-uninfected women in this cohort have a predominance of highly diverse anaerobic bacterial communities that are strongly correlated with elevated levels of proinflammatory genital cytokines and increased rates of HIV acquisition (2, 3). This is in contrast to the prevalence of Lactobacillus-dominant bacterial communities in the female genital tract of women in the United States and Europe. Also crucial to understanding HIV acquisition risk in young women is the demonstration in FRESH that the use of injectable progestin contraception and high endogenous progesterone was associated with increased frequency of activated CCR5-enriched CD4+ HIV target cells in the cervix, providing a biological mechanism for increased HIV acquisition in women with high progestin exposure (4). Taken together, these findings point to new areas for potential intervention through which to reduce the extraordinarily high rates of HIV infection among women in sub-Saharan Africa.

FRESH and the immunology of “hyperacute” infection

The FRESH study design has successfully identified acute HIV infection at the onset of plasma viremia, with the majority of 72 incident infections detected thus far (August 2018) in Fiebig stage I, some with initial viral loads of less than 100 RNA copies/ml of plasma (1, 5). The availability of pre- and postinfection samples revealed the induction of profound CD8+ T cell activation and proliferation in untreated acute infection, involving more than 70% of CD8+ T cells in some individuals, with tetramer staining consistent with the majority of these being HIV-specific. These cells became rapidly proapoptotic and were defective for the production of key antiviral cytokines such as interferon-γ, which may partially explain why the CD8+ T cell response is incompletely effective during the acute phase. Importantly, the rapidity of induction of CD8+ T cell activation and the magnitude of peak activation were associated with a lower viral set point, indicating a key role for these cells in viral control (5). Other findings included very early loss of resting memory B cells after acute HIV-1 infection, which may explain some of the defects seen in response to vaccination in HIV-infected persons, and an irreversible loss of innate lymphoid cells in hyperacute HIV infection, which may partially explain the lymphoid tissue breakdown and persistent immune dysfunction associated with HIV infection.

FRESH and the HIV cure agenda

As data emerged that suggested improved outcomes with earlier cART initiation, we obtained IRB approval to provide immediate treatment during acute infection, before change in the South African government guidelines. With rapid turnaround of HIV RNA results and careful preparation of study participants, we have been able to initiate treatment less than 24 hours after a positive test. This has resulted in preserved CD4+ T cell counts and lack of seroconversion as determined with both HIV rapid antibody and Western blot testing. These very early treated individuals comprise an ideal cohort for cure research in sub-Saharan African women, who have hitherto been underrepresented in cure research despite their disproportionate burden of HIV infection.

Opportunities and challenges

The FRESH study has been successful in achieving the goals of the social intervention and research components: offering a pathway out of poverty for high-risk disempowered women while providing key insights into HIV transmission and pathogenesis. We consider combining frequent HIV testing with the socioeconomic empowerment curriculum to be a key component for the success of this approach. The sample processing and laboratory investigations have all been performed in KZN, contributing to local capacity building. Key adaptations during program implementation—including approval to initiate treatment during acute HIV infection, providing access to PrEP, and iterative development of the socioeconomic educational program—all provide direct benefits while contributing to visit adherence and study retention.

However, challenges remain. Whether addition of PrEP will reduce incidence rates in FRESH remains to be seen. The FRESH curriculum has empowered women to become employed, but whether this will lead to decreased risk of infection after completion of the program will require further follow-up. Replication and scale-up of this program, initially funded by private philanthropy and subsequently expanded with support from the Gates Foundation, are a challenge in terms of cost and time investment. FRESH was designed specifically for young women because of the demonstrated higher rates of infection in this age group compared with men and the relative paucity of data on HIV pathogenesis in women; however, programs that target men are needed in order to gain broader insight into the epidemic.

Despite these challenges, the FRESH approach has been successful in showcasing how basic science research and a program that delivers social good can be combined. The continued high acquisition rates underscore the need for expanded research and new interventions to prevent and cure HIV infection. FRESH represents one innovative strategy to address individual and community needs while advancing scientific knowledge.

REFERENCES AND NOTES

Funding: This work was supported in part by grants from the Bill and Melinda Gates Foundation (OPP1066973 and OPP1146433), Gilead Sciences (grant 00406), the International AIDS Vaccine Initiative (IAVI; UKZNRSA1001), the NIAID (R37AI067073), the Witten Family Foundation, Dan and Marjorie Sullivan Foundation, the Mark and Lisa Schwartz Foundation, Ursula Brunner, the AIDS Healthcare Foundation, and the Harvard University Center for AIDS Research (CFAR; P30 AI060354, which is supported by the following institutes and centers cofunded by and participating with the U.S. NIH: NIAID, NCI, NICHD, NHLBI, NIDA, NIMH, NIA, FIC, and OAR); raltegravir used for immediate treatment was donated by Merck & Co. This work was also partially supported through the Sub-Saharan African Network for TB/HIV Research Excellence (SANTHE), a DELTAS Africa Initiative (grant DEL-15-006). The DELTAS Africa Initiative is an independent funding scheme of the African Academy of Sciences (AAS)’s Alliance for Accelerating Excellence in Science in Africa (AESA) and supported by the New Partnership for Africa’s Development Planning and Coordinating Agency (NEPAD Agency) with funding from the Wellcome Trust (grant 107752/Z/15/Z) and the UK government. The views expressed in this publication are those of the author(s) and not necessarily those of AAS, NEPAD Agency, Wellcome Trust, or the UK government.

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