Impact of immune reconstitution on outcomes to chemoradiation in cervical cancer

宫颈癌是发展中国家妇女癌症的主要原因，在艾滋病毒（人类免疫缺陷病毒）的情况下，它是艾滋病的决定性疾病。在博茨瓦纳，约17%的人口为艾滋病毒阳性，约60%-80%的宫颈癌患者伴有艾滋病毒感染。在南部非洲，在资源贫乏的环境中，浸润性宫颈癌发病后妇女的生存受到不理想的诊断、治疗反应和随访以及艾滋病毒状况的不利影响。该项目的长期目标是通过确定与浸润性宫颈癌治疗反应相关的临床（耐受性和毒性）和免疫学参数，提高接受化疗放疗的HIV阳性妇女的生存率。这些研究的结果将用于制定未来的多学科战略，以最大限度地治疗博茨瓦纳患有人类乳头瘤病毒（HPV）相关宫颈癌的艾滋病毒阳性妇女。与HIV感染相关的免疫抑制已被确定为多种恶性肿瘤的危险因素，包括非霍奇金淋巴瘤、卡波西肉瘤、默克尔细胞癌、宫颈癌和肺癌。比较研究表明，HIV患者癌症增加的模式与免疫抑制移植患者相似，并且HIV患者的风险与CD4+ t淋巴细胞计数相关，提示免疫缺陷可能是HIV患者恶性肿瘤增加的根本原因。在艾滋病毒阳性的宫颈癌妇女中，前瞻性临床结果研究有限，回顾性研究表明生存率较低，对化疗放疗的耐受性降低，原因不明。因此，我们对艾滋病毒感染和抗逆转录病毒治疗（ART）对耐受性的影响以及免疫重建对宫颈癌治疗反应的贡献的理解存在空白，因为这些研究尚未检查ART对放化疗的影响或免疫状态如何影响结果。我们的提案将解决抗逆转录病毒治疗后免疫重建与接受hpv相关侵袭性宫颈癌化疗的HIV阳性妇女癌症治疗结果之间的关系。这一信息将影响临床实践或治疗剂量，因为抗逆转录病毒治疗或免疫重建的存在目前不被认为是hpv相关宫颈癌治疗反应的决定因素。

Cervical cancer is the leading cause of cancer in women living in the developing world, and in the setting of HIV (human immunodeficiency virus), it is an AIDS defining illness. In Botswana, approximately 17% of the population is HIV positive and approximately 60%-80% of cervical cancer patients have concomitant HIV infection. In Southern Africa as in resource-poor settings, women's survival after the onset of invasive cervical cancer is adversely affected by suboptimal diagnosis, treatment response, and follow-up in addition to HIV status. The long-range goals of this project are to improve survival in HIV+ women undergoing chemo-radiotherapy by defining the clinical (tolerability and toxicity) and immunological parameters associated with invasive cervical cancer therapy response. The results of these studies will be used to shape future multi-disciplinary strategies to maximize treatment of HIV positive women with human papillomavirus (HPV) -associated cervical cancer in Botswana. Immunosuppression associated with HIV infection has been established as a risk factor for a variety of malignancies, including non-Hodgkin lymphoma, Kaposi Sarcoma, Merkel cell carcinoma, cervical cancer, and lung cancer. Comparative studies have shown that the pattern of increased cancers in HIV patients was similar to that observed in immunosuppresed transplant patients and that the risk in HIV patients correlates with CD4+ T-lymphocyte count, suggesting that immunodeficiency is likely the underlying cause of increased malignancy observed in HIV patients. Amongst women who are HIV positive with cervical cancer, prospective clinical outcome studies are limited and retrospective studies have demonstrated inferior survival and decreased tolerability to chemo-radiotherapy for unclear reasons. Therefore,' a gap exists in our understanding of the impact of HIV infection and anti-retroviral therapy (ART) on tolerability and the contribution of immune reconstitution on cervical cancer treatment response as none of these studies have yet examined the impact of ART on chemoradiotherapy or how immunologic status affects outcomes. Our proposal will address the relationship between immune reconstitution following ART and cancer therapy outcomes in HIV+ women receiving chemoradiotherapy for HPV-associated invasive cervical carcinoma. This information will impact clinical practice or therapy dosing as the presence of ART or immune reconstitution is not currently considered as a determinant to HPV-associated cervical cancer treatment response.