Africa faces a rapidly growing cancer burden, driven by both population growth and the high prevalence of HIV. By 2030, cancer incidence in Africa is expected to double, and by 2040, low- and middle-income countries are expected to account for 70% of global cancer deaths. The number of people with HIV (PWH) in Africa is rising due to population growth and antiretroviral therapy (ART) availability, diffuse large B-cell lymphoma (DLBCL) a major cause of mortality. HIV and ART alter DLBCL tumor biology, but few studies of DLBCL include PWH or African patients, which limits treatment strategies. As cancer therapies increasingly depend on molecular and genomic characterization, disparities in translational research persist, with significant overrepresentation of patients of European ancestry. These gaps are further exacerbated by the frequent exclusion of people with HIV (PWH) from translational and clinical studies of cancer, despite their growing proportion of cancer patients.
Yuri Fedoriw, MD, director of Global Cancer Pathology at the Institute for Global Health and Infectious Diseases, and co-director of the UNC Project-Malawi Cancer Program, together with Jenifer Vaughan from the University of the Witwatersrand in Johannesburg, South Africa led a study that characterized how HIV and ART shape the mutational profile of DLBCL—an extensively studied malignancy among HIV- individuals in high-income countries.
“In Eastern and Southern Africa, where more than half of the global population of PWH resides, the intersection of HIV and cancer has become a pressing public health issue,” said Fedoriw, the LabCorp Distinguished Professor, and Vice Chair of Clinical Research and Academic Affairs for the Department of Pathology and Laboratory Medicine.
“While antiretroviral therapy has significantly improved life expectancy, cancer, particularly aggressive B-cell lymphomas like diffuse large B-cell lymphoma (DLBCL), remains a leading cause of mortality.”
Even when well-controlled on ART, PWH are over ten times as likely to develop DLBCL compared to people without HIV. Before ART, survival rates for HIV + DLBCL patients were dismal, with overall survival rates below 20%. Current treatments that combine full-dose chemotherapy and ART have significantly improved survival, making outcomes comparable to those in HIV-negative (HIV-) patients.
To understand how HIV, ART exposure, and African ancestry influence the DLBCL mutational profile, the team performed whole exome sequencing on 48 DLBCL tumors and paired germline samples from cohorts in Malawi and South Africa, including 40 from PWH. Specifically, the team compared clinical and histological features between cohorts, assessed ART’s impact on the mutational landscape, and identified recurrent mutations and molecular characteristics in this historically understudied population.
The Findings
Clinical parameters differed significantly between the two cohorts, with South African patients showing poorer HIV control, elevated LDH, higher ECOG scores at diagnosis, and inferior survival. Although the study did not have an epidemiological focus, disparities observed between the cohorts likely stem from variations in access to HIV care, healthcare infrastructure, and time to diagnosis and treatment. The differential mutation patterns between HIV+/ART-exp and HIV+/ART-naïve tumors supported the hypothesis that ART exposure shapes the mutational profile of lymphomas. The findings also support prior evidence that HIV infection promotes lymphomagenesis through increased DNA damage, highlighting a potential mechanistic link between HIV and lymphoma development.
“This study begins to fill the critical gap in our understanding of the molecular mechanisms driving HIV-associated DLBCL,” Fedoriw said. “Our findings highlight the importance of ART exposure in shaping the mutational landscape of PWH and lymphoma, with potential implications for developing tailored therapeutic strategies.”
However, the relatively small number of cases, differences in health systems, and potential selection biases limit the generalizability of our results to all HIV + DLBCL patients across the continent.
Fedoriw says broader studies including additional geographic regions and larger sample sizes will be essential to confirm these observations and assess their relevance to the wider population. As the burden of HIV in Africa remains high, these insights will be crucial for ensuring that emerging therapies are accessible and effective for HIV + DLBCL patients in low-resource settings.