Erle Robertson

Cervical and Tumor-Associated Microbiomes in Botswana Women With and Without HIV With Carcinoma of the Cervix Before and After Definitive Chemoradiation

PURPOSE Cervical cancer remains a significant public health concern globally and particularly in sub-Saharan Africa, where high rates of HIV infection exacerbate cervical cancer incidence. Understanding the cervical microbiome and its role in cancer progression is essential, especially in regions where both cervical cancer incidence and HIV prevalence are high. This study aimed to characterize the cervical microbiome in women living with HIV (WLWH) and HIV-negative women with squamous cell carcinoma of the cervix in Botswana, compare the microbiome between before and after chemoradiation therapy (CRT) in WLWH, and assess the prognostic value of specific microbial taxa for overall survival (OS) in WLWH. PATIENTS AND METHODS Cervical samples were collected from women with cervical cancer presenting to one hospital in 2018-2019. Patients' clinical data, including HIV status, were recorded. Microbial composition was analyzed using 16S rRNA gene sequencing. Microbiome diversity and composition were evaluated using alpha and beta diversity metrics. Differential microbial abundance was analyzed using linear discriminant analysis effect size. The association between microbial taxa and OS was explored using Cox proportional hazards regression. RESULTS WLWH (n = 42) had a significantly lower Pielou evenness index than HIV-negative women (n = 11; 0.6 v 0.7, P = .02), suggesting a more imbalanced microbiome in WLWH. WLWH had higher levels of Parvimonas and members of the Corynebacteriaceae and Micrococcaceae families, suggesting a shift toward a more pathogenic microbiome. In WLWH, CRT did not significantly alter overall microbial diversity. However, Lactobacillus and Sutterella were enriched before treatment, reflecting a less pathogenic microbiome, whereas Ruminococcus and Phascolarctobacterium and the families Caulobacterales and Flavobacteriia were enriched after treatment, reflecting microbial adaptations to the altered immune and treatment environment. Notably, higher levels of Flavobacteriia after CRT were independently associated with worse OS in WLWH. CONCLUSION Microbiome profiles differ between WLWH and HIV-negative women with cervical cancer in Botswana. The microbiome might have prognostic significance. Future research is needed to better understand the significance of the microbiota in cervical cancer progression and treatment outcomes and the potential role of microbiome-targeted interventions.

Overcoming Logistical Barriers to Conducting Collaborative Clinical Research Between a High-Income Country and a Low- and Middle-Income Country

PURPOSE Building equitable research collaborations between high-income countries (HICs) and low- and middle-income countries (LMICs) requires effective coordination among international ethical review committees, which is often logistically challenging. This case report presents the insights gained when acquiring ethical approval for a cervical cancer research program conducted jointly by the University of Pennsylvania and the University of Botswana. METHODS We conducted a descriptive case study of the Ipabalele project, a 6-year HIC-LMIC partnership involving three complex research protocols that required approvals by multiple distinct ethical bodies. We analyzed various challenges affecting review procedures, timelines, and staffing. We then documented strategies employed in Ipabalele and other global initiatives to strengthen ethical review processes and build research capacity in LMICs. RESULTS In Ipabalele, ethical approvals were initially delayed by 2 years because of fragmented review processes with variable timelines and conflicting recommendations. Innovations to the process included centralizing institutional review board oversight within Botswana, implementing joint virtual meetings among review bodies, enhancing digital infrastructure, and streamlining research staffing and communication. CONCLUSION By providing practical strategies, this study highlights how empowered local leadership, centralized review processes, joint review mechanisms, and intentional capacity building can overcome logistical barriers in multinational ethical review.

Cervical cancer treatment outcomes and survival in Botswana by human immunodeficiency virus status: Ipabalele study results

Abstract Background Cervical cancer is a leading morbidity/mortality cause, frequently co-occurring with human immunodeficiency virus (HIV) positivity, in Botswana. We examined long-term outcomes for Ipabalele study participants receiving curative chemoradiation for locally advanced cervical cancer (2015-2019) by HIV status. Methods Clinical and outcome data were collected at baseline, treatment completion, and 3 months thereafter. Patients were followed for up to 5 years. Overall survival (OS) was evaluated using Kaplan-Meier curves and Cox regression. Results The cohort comprised 295 patients (73.8% with HIV, younger at diagnosis [P < .001]) followed for a median of 44.2 months. Complete response was seen in 217/278 (76.1%) patients. Two- and 5-year OS rates were 73.4% and 59.9%, respectively, with no difference by HIV status. OS was associated negatively with advanced disease stage (III: hazard ratio [HR] 13.23, P < .001; IV: HR 7.8, P = .008) and positively with increased radiation (HR 0.977, P = .0005) and chemotherapy (HR 0.85, P = .005). Clinical response was associated negatively with advanced disease (IV: HR 0.113, P = .002) and positively with increased radiation (P = .009). Toxicity did not differ by HIV status. The most common grade-≥-2 non-hematological and hematological toxicities were radiation dermatitis (39.8%) and reduced white blood cell count (66.05%), respectively. Conclusions In this cervical cancer cohort with good HIV status control, treatment outcomes and OS were associated with disease and treatment factors, not the HIV status. Early screening and education regarding treatment protocols are crucial to improve cervical cancer outcomes in Botswana.

Patients with Cervical Cancer with and without HIV Infection Have Unique T-cell Activation Profiles despite Similar Survival Outcomes after Chemoradiation

Abstract The global burden of cervical cancer is highest in low- and middle-income countries. Women living with human immunodeficiency virus (HIV) infection are particularly affected by cervical cancer despite availability and adherence to antiretroviral therapy. Immune profile correlates of survival and treatment response have not been widely explored in patients with and without HIV infection. This study recruited women with cervical cancer undergoing definitive chemoradiation (CRT) in Botswana. Clinical characteristics and blood samples were collected. Flow cytometry was performed on samples prior to initiation, at completion, and 3 months after CRT. Logistic regression analysis identified immune markers that differed by HIV status and correlated with overall survival (OS). The study enrolled 131 consecutive women (HIV+ N = 89 and HIV− N = 42). From initiation to 3 months after CRT, a significant decrease in CD4 frequency (72%–60.55%, P < 0.001) and an increase in CD8 frequency (20.9%–31.5%, P < 0.001) were seen in women without HIV, whereas no significant changes in CD4 frequency (52.5%–50.9%) or CD8 frequency (39.9%–41.4%) were observed in those with HIV. Peripheral T cells underwent similar activation across the cohort regardless of HIV status. Improved OS was associated with reduced frequency of IL-2–expressing CD4 T-cell subsets. In women living with HIV, enhanced OS was associated with the presence of proinflammatory CD8 T cells. CRT induces peripheral T-cell activation and distinct cytokine profiles that differ by HIV status. Despite similar OS, HIV infection may differentially affect immune response to CRT in women with well-managed HIV. Significance: Chemoradiation affects the immune system of patients with cervical cancer with well-controlled HIV infection differently than those without HIV, yet their survival does not differ. This finding is an important step in understanding how management of HIV infection can modify cancer outcomes, particularly in settings with a high burden of HIV.