Through this Funding Opportunity Announcement (FOA), the National Cancer Institute (NCI) solicits applications from institutions/organizations to participate as the Coordinating Center for the HIV/Cervical Cancer Prevention ‘CASCADE’ Clinical Trials Network. The ‘CASCADE’ Network will conduct pragmatic clinical trials evaluating the effectiveness of clinically proven interventions to overcome barriers and reduce failures in the cervical cancer screening, management, and precancer treatment cascade for women living with HIV. ‘CASCADE’ clinical trials will be conducted in intended-use environments in resource-constrained settings in low- and middle-income countries and in regions with health disparities in the United States, and will have four major scientific focus areas: increasing screening uptake, improving management of screen positives, facilitating precancer treatment access, and optimizing precancer treatments for cervical cancer prevention in women living with HIV. Evidence from these trials is expected to inform clinical practice guidelines and improve the implementation of cervical cancer prevention and control programs globally.
‘CASCADE’ will consist of three organizational components each with its own FOA: U24 Coordinating Center (this FOA), UG1 Research Bases (RFA-CA-21-046), and UG1 Clinical Sites (RFA-CA-21-047).
As an integral part of this Cooperative Agreement-funded network, the U24 Coordinating Center (this FOA) will (i) provide overall network coordination and facilitate scientific review of network clinical trial concepts and protocols, (ii) provide centralized support for data management for network clinical trials, and (iii) conduct independent risk-appropriate auditing of network clinical trials.
Cervical cancer is a highly preventable malignancy, yet it is not fully prevented. Globally, there are estimated to be over 604,000 new diagnoses and over 340,000 deaths due to cervical cancer every year. Despite significant advances in the understanding of human papillomavirus (HPV)-associated etiology and pathogenesis of cervical cancer, as well as the availability of the means of both primary prevention (HPV vaccines) and secondary prevention (screening and treatment of precancerous lesions), millions of women still lack access to such lifesaving healthcare. Resource-constrained settings in low- and middle-income countries (LMICs) shoulder the vast majority of cervical cancer cases and cancer deaths globally. Following substantial reductions in cervical cancer incidence rates in the last half of the twentieth century, rates in the United States (US) have now plateaued for the past two decades, with over 13,000 women continuing to be newly diagnosed with, and over 5,700 women dying annually of this eminently preventable malignancy. Over half of the new cervical cancer cases in the US are among women who have never been screened or who are infrequently screened, reflecting barriers presented by healthcare, socioeconomic, racial/ethnic disparities, and geographic inaccessibility among other factors.
People living with HIV (PLWH) are at high risk for several malignancies, especially HPV-mediated cancers that are refractory to the immune restorative effects of combination antiretroviral therapy. HPV-associated cancers, especially cervical cancer, are significantly more common among women living with HIV (WLWH) than in the general population. WLWH have a higher risk for acquisition, persistence, and progression of cervical HPV to precancerous lesions, which in the absence of effective screening and treatment, can progress to invasive cancer at 5-6 times higher rates than women without HIV.
The massive global mobilization of humanitarian resources spanning over the past couple of decades, especially through initiatives such as the US President’s Emergency Plan for AIDS Relief (PEPFAR), has resulted in millions of PLWH in LMICs now accessing affordable combination antiretroviral therapy (ART), and consequently living longer lives. Yet, their risk for cervical cancer continues unabated in the absence of effective screening and treatment services. The lack of such services has prompted several efforts funded by PEPFAR and several public, private, and philanthropic sector agencies to increase access to cervical cancer prevention services, especially within/linked to the clinics and facilities where WLWH routinely access HIV/AIDS care and treatment services. In addition, the World Health Organization (WHO), with endorsement of 194 countries including the United States, has launched a global initiative to accelerate progress towards the elimination of cervical cancer as a public health problem.
Several approaches to improve efficiency, reduce costs, and facilitate the scale-up of innovations for cervical cancer preventive services have been explored. The focus on evaluating improvements in the implementation of HPV vaccination via a single dose schedule will likely have a significant impact over the next few decades . Yet, prophylactic HPV vaccination will have limited or no impact in women already infected with HPV; therefore, it is still important to focus on improving screening and treatment in the near and intermediate-term future in order to prevent disease and save lives.
In most implementation programs in low-and middle-income country settings, cervical cancer screening methods use low-cost but poorly sensitive approaches such as naked-eye visual inspection with acetic acid (VIA), a point of care clinical test that despite having limited accuracy continues to be used since it can facilitate linkages to same-visit precancer treatment or referral decisions. Treatment of precancerous lesions, wherever possible in a single visit, is conducted by ablative approaches such as cryotherapy or thermal ablation, and women with ablation-ineligible lesions are referred to tertiary facilities for excisional treatment of lesions. Management of screen-detected cancers and late-stage cancers (usual presentation in the absence of cervical cancer prevention programs) is still a major challenge, although efforts are underway to expand access to radiation therapy and build and sustain capacity for cancer surgery, chemotherapy, and palliative care services.
In the US, healthcare, socioeconomic, and racial/ethnic disparities are prominent features influencing the burden patterns of both HIV/AIDS and cervical cancer. Among WLWH, who represent a quarter of all persons living with HIV in the US, women of color, particularly Black women, represent the majority of new infections among women. And despite the widespread availability of combination antiretroviral therapy covered by both private insurance and Medicaid, a large fraction (up to 40%) of persons with HIV in the US is not virally suppressed (far short of the 95% target envisioned by the ‘Ending the HIV Epidemic’ plan targets), and therefore remain at much higher risk of HIV-associated co-infections and co-morbidities. Also, approximately one in five WLWH do not receive recommended cervical cancer screening, especially older women, women from racial/ethnic minorities, those from the low socioeconomic status/educational attainment, and those with low CD4+ counts. Pap smear screening is still a front-line screening approach, although HPV/Pap co-testing, as well as primary screening with HPV, have been recommended for age-appropriate groups to lengthen the intervals of screening. Lack of FDA approval for self-sampling-based HPV testing remains a major barrier to increasing access to HPV-based screening (and is being addressed by the NCI ‘Last Mile’ initiative), but whether and how will self-sampling be effectively implemented as a strategy for HPV-based primary screening for WLWH has not been extensively evaluated.
Regardless of the setting, incidence rates of cervical cancer can be significantly impacted only if the entire cascade of steps/events in the pathway of accessing screening to completing treatment and follow-up are addressed. The mere availability of screening tools is not a guarantee that women will access these services, undergo the recommended screening procedures, return to receive their screening results, receive appropriately recommended precancer treatment, and complete the recommended follow-up visits. These steps in the cascade can be impacted significantly for WLWH. For example, in many settings in LMICs, with the overlaying stigma around HIV/AIDS clinic attendance and care-seeking, WLWH are reluctant to access other ‘wrap around’ services like cervical cancer screening, and are less likely to return for treatment visits, especially if these are not offered as part of a single visit program. Furthermore, both in the US and LMICs, WLWH have a high recurrence rate after cervical precancer treatment, so optimizing the effectiveness of these interventions is critical to reduce the burden and long-term adverse sequelae of repeated cervical treatment procedures. Finally, as the COVID-19 pandemic continues to adversely impact the utilization of cervical cancer prevention interventions both in the US and globally, it remains important to evaluate innovations in overcoming barriers to access and improve on cost-effective clinical care delivery in screening and precancer treatment.
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Filed Under: Funding Opportunities