Engaging Resource-Constrained Countries in Research Trials of HIV and Cancer: Lessons from Sub-Saharan Africa and the AIDS Malignancy Consortium

Kaposi Sarcoma (KS) was initially described by Moritz Kaposi in 1872¹ as a rare and slowly progressing cancer, often localized to the lower extremities of elderly men of Mediterranean descent. However, as early as 1981,² it became evident that men who have sex with men, particularly those living in urban areas, were being diagnosed with this previously uncommon skin tumor. This diagnosis was frequently accompanied by lethal opportunistic infections and aggressive B-cell non-Hodgkin's lymphoma (NHL). After the discovery of human immunodeficiency virus (HIV) as the causative virus that led to a decline in CD4+ T-helper lymphocyte counts, the United States (US) Centers for Disease Control and Prevention (CDC) recognized the elevated prevalence of certain diseases within this demographic. In response, the CDC compiled a list of AIDS-defining clinical conditions³ that were frequently observed in individuals with severely compromised immune systems due to HIV. This list initially included two malignancies, KS and aggressive B-cell NHL, and was later expanded to include primary central nervous system lymphoma and invasive cervical cancer. The high prevalence of AIDS-defining cancers in countries with inconsistent access to antiretroviral therapy (ART) contributes significantly to the global cancer burden. Worldwide, cervical cancer is the most frequently diagnosed cancer in women living with HIV⁴ and is a leading cause of cancer-related mortality even though it is one of the most preventable and treatable malignancies. There is great geographic disparity in cervical cancer disease burden, and it is worth noting that Sub-Saharan Africa currently bears half of the global HIV burden and accounts for 70% of the worldwide cases of cervical cancer attributed to HIV.⁵ The primary reasons for this include limited access to ART and other healthcare services, low rates of cervical cancer screening and human papillomavirus (HPV) vaccination, and other cultural barriers. The benefits of comprehensive medical care and the widespread availability of effective ART are most evident in the most economically developed countries, where PLWH have experienced a dramatic increase in their quality and duration of life. This has resulted in a profound decline in the incidence of AIDS-defining cancers. However, as PLWH continue to age and the number of HIV-positive adults increases, the prevalence of non-AIDS-defining cancers (NADCs) has also increased.⁶ The chronic immune activation and inflammation related to chronic HIV infection may increase the baseline risk of cancer for PLWH.

The most prominent NADCs are associated with the combined effect of immune dysfunction and viral co-infections, such as HPV in the case of anal cancer and hepatitis B and C viruses in the case of liver cancer. Other cancers are associated with common lifestyle factors in PLWH, such as smoking, alcohol consumption, and recreational substance use. Not only do PLWH have higher incidence of cancer, but they also encounter higher overall cancer-specific mortality compared to HIV-negative individuals.⁵ This disparity is further exacerbated by barriers to equitable access to cancer treatment and the persistent stigma within the medical community toward PLWH.⁷

Prior studies have shown that physicians, including radiation oncologists, are less likely to offer standard curative treatments to PLWH with cancer.⁷ Additionally, medical oncologists may also be reluctant to incorporate newer and more effective treatments to treat cancer in those with HIV infection due to insufficient data on the effects of these therapeutics on immune status and in inducing autoimmune side effects. This gap in data is heightened by the widespread practice of excluding PLWH from cancer clinical trials, which is often rationalized by concerns about potential interactions between ART, cytotoxic chemotherapy, and novel immune-based therapies, as well as the perception that PLWH represent a higher-risk population that may compromise the success of a clinical trial. However, there is growing recognition in the oncology community⁸ that it is imperative to include PLWH with cancer in well-structured clinical trials.

To address this disparity, the US National Cancer Institute (NCI) established the AIDS Malignancy Consortium (AMC) in 1995. The AMC's mission is to evaluate novel treatments, preventive strategies, and standards of care for malignancies and premalignancies in PLWH. The consortium aims to expand scientific knowledge of the pathobiology of cancers and premalignancies in this population, conduct research both domestically and internationally (including regions such as Sub-Saharan Africa, Mexico, and Latin America), and contribute to the worldwide effort to combat HIV-associated malignancies in countries with limited resources.

One of the fundamental challenges in conducting cancer clinical trials in resource-limited countries is the absence of a robust infrastructure to facilitate research. In response, the AMC has dedicated substantial resources towards developing standard protocols for various components of the clinical trial process, including site selection, drug logistics, and chemotherapy administration. It has also been instrumental in training international researchers and support staff on aspects of clinical trials including cancer response assessment, adverse event reporting, data management, and community engagement.

To promote ongoing growth through international collaborations, the AMC is committed to partnering with local international investigators and mentoring new investigators who will help define and contribute to the AMC scientific agenda and emerge as leaders in HIV-related cancer research. The AMC Career Enhancement Program⁹ plays a vital role in this process, awarding formal fellowships and providing mentorship opportunities to early-stage investigators. Additionally, to ensure equitable management of clinical trial specimens, the AMC has established a biorepository in Cape Town, South Africa, at Stellenbosch University to store specimens related to trials conducted in sub-Saharan Africa.

Despite facing numerous obstacles, the AMC has contributed significantly to international cancer trials among PLWH through the publication of four pivotal clinical studies on KS,^10,11 aggressive B-cell NHL,¹² and the management of locally advanced cervical cancer.¹³ While not all trials reached their scientific and clinical endpoints,¹¹ they have consistently provided valuable insights into the strategies needed to navigate the distinct challenges encountered in resource-limited settings such as those in Sub-Saharan Africa.

These research efforts have provided an impetus for transforming clinical practice in low-resource areas. For example, the AMC-066 trial¹⁰ was a three-arm, open-label, randomized, non-inferiority trial on the treatment of advanced AIDS-associated KS in resource-limited settings. It demonstrated that paclitaxel, when combined with ART, outperformed the lower cost regimen of bleomycin, vincristine, and oral etoposide. This superiority was demonstrated in terms of progression-free survival, overall response rate, response duration, and a composite of time to progression or death. This study underscored the need for substantial investment in infrastructure and personnel to make paclitaxel widely available in resource-limited settings. The significance of these findings has been recognized by the US National Comprehensive Cancer Network (NCCN) and incorporated into their regional Harmonized Guidelines,¹⁴ a comprehensive set of best practice recommendations for treating various types of cancer, widely used across the globe.

In conclusion, the high burden of HIV-related cancer worldwide highlights the need for comprehensive research, improved access to high-quality care, and greater inclusion of this population in clinical trials. By addressing these challenges and promoting collaboration among researchers, healthcare providers, and communities, we can work towards reducing the burden of HIV-associated malignancies worldwide.

None

This overview was not funded by a specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Both Dr. Phipps and Dr. Aboulafia are principal investigators of the AMC. Dr. Phipps is the Associate Chair for Sub-Saharan Africa for the AMC.

N/A

The authors wish to thank Virginia M. Green, PhD, for her expert editorial review of the manuscript.

Bowen He, David Aboulafia, Warren Phipps: conception and design

Bowen He, David Aboulafia, Warren Phipps: data collection and assembly

Bowen He, David Aboulafia, Warren Phipps: data analysis, manuscript writing

Bowen He, David Aboulafia, Warren Phipps: other type of contribution: Summarization of a talk by Dr Warren Phipps at 2023 Cancer Care Disparities Conference

All authors approve this manuscript

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