Long-term outcome of renal cell carcinoma in patients with HIV who undergo surgery

At the end of 2017, there were 758,610 people living with HIV/AIDS in China, of whom 134,512 had been newly diagnosed that same year [1]. The advent of antiretroviral therapy (ART) has led to decreased mortality from opportunistic infectious diseases. This has improved survival and reduced the frequency of HIV-associated illnesses and complications of AIDS in people living with HIV (PLWH) [2, 3], who are at elevated risk for developing several types of cancer. Since the 1990s, the U.S. Centers for Disease Control and Prevention has defined Kaposi sarcoma, non-Hodgkin’s lymphoma, and cervical cancer as AIDS-defining cancers [4]. In an age without widespread use of ART, active management of other non-AIDS-defining cancers (NADCs) was less common, for the life expectancy of PLWH was relatively short [5]. As survival has improved [6‐8], NADCs have consistently been reported, as reflected in the higher risk for cancer in PLWH compared to the general population [9].

In a large meta-analysis of seven population-based HIV cancer studies that involved more than 400,000 HIV-positive patients, the standardized incidence ratio for renal cell carcinoma (RCC) was 1.50 (95% confidence interval [CI] = 1.23 to 1.83) in PLWH [10]. However, most data on risk for NADCs derive from Western countries; relatively few studies have addressed this risk in Asian people. Surgery is the preferred option for treating RCC, and the prevalence of laparoscopic surgery and nephron-sparing surgery is gradually increasing [11]. Yet it remains unknown whether PLWH who undergo surgery for RCC exhibit a different clinical outcome compared to HIV-negative individuals with RCC. Clinical features such as level of serum albumin and tumor size have been reported as risk factors affect renal cell carcinoma outcomes in general population[12‐16]. Moreover, the ratio of CD4⁺ T cells to CD8⁺ T cells (CD4⁺/CD8⁺ ratio) was also recently reported to be a prognostic marker for other NADCs [17]. We wondered whether PLWH with NADCs have worse outcomes than HIV-negative population and whether the factors above influence their prognosis. Thus, we studied RCC patients referred to our hospital to compare long-term overall survival and progression-free survival between PLWH and patients without HIV and explore potential factors influencing outcomes.

Of the 3259 patients who were managed by the Department of Urology in Beijing Youan Hospital between January 2012 and December 2014, 261 received a diagnosis of RCC. As expected, RCC patients with metastasis had a worse survival time compared to patients without metastasis (Additional file 2: Fig. S2). Patients with early-stage cancer (I–III) underwent surgery. Ultimately, 67 patients met the study criteria: 33 PLWH and 34 HIV-negative patients (Fig. 1). Demographic data and clinical characteristics are presented in Table 1. Most RCC was clear cell carcinoma. Creatinine (77.1 ± 18.8 vs. 85.7 ± 12.9, p = 0.032), hemoglobin (113.6 ± 12.6 vs. 139.3 ± 20.8, p = 0.001), and the CD4⁺/CD8⁺ ratio (0.68 ± 0.40 vs. 0.86 ± 0.33 p = 0.041) were lower among PLWH. No other significant differences in clinical features were found between the groups at baseline.

Kaplan–Meier curves of overall survival and progression-free survival are shown in Fig. 2. During a median follow-up of 73.5 months, the median overall survival time was 74.9 months (95% CI = 64.6 to 85.2) in the PLWH group and 96.4 months (95% CI = 90.0 to 102.9) in the HIV-negative group. Progression-free survival was 66.4 months (95% CI = 53.5 to 79.3) and 90.6 months (95% CI = 81.1 to 100.1), respectively. RCC patients with HIV who underwent surgery had a shorter survival time (HR = 2.8, 95% CI = 1.1 to 7.0, p = 0.016) and a higher incidence of tumor progression (HR = 2.7, 95% CI = 1.1 to 6.8, p = 0.028).

Hemoglobin, serum albumin and creatinine, the CD4⁺/CD8⁺ ratio, and tumor size were entered into Cox regression analyses (Table 2). Univariate and multivariate Cox logistic regression analyses showed that the lower CD4⁺/CD8⁺ ratio (adjusted odds ratio = 0.092, 95% CI = 0.01 to 0.70, p = 0.022) was associated with worse survival among PLWH. The results of a bivariate analysis with scatter plot between the CD4⁺/CD8⁺ ratio and overall survival in PLWH are shown in Additional file 3: Fig. S3.

In this retrospective study, we enrolled a cohort of PLWH diagnosed with RCC who were treated in our hospital, a specialized hospital for infectious diseases. After patients underwent surgery, we performed long-term follow-up by telephone until 2021. We investigated numerous clinical features, including tumor status, demographic information, and laboratory tests (e.g., creatinine, estimated glomerular filtration rate, albumin, hemoglobin, and C-reactive protein). PLWH with NADCs may be at greater risk for postoperative complications and infection than the general population and may have tumors that are larger or more advanced at diagnosis [4, 23]. Tumor size was previously shown to be closely related to outcomes in patients with RCC in the general population. Serum albumin has been used in a number of RCC studies in the general population to predict prognosis [15, 22]. However, there was no difference in tumor size or albumin at baseline or surgical complications between the two groups in this study, although there was slightly lower serum creatinine and relatively lower hemoglobin in the PLWH group. Neither creatinine nor hemoglobin has been shown to be clearly associated with RCC prognosis in studies of the general (HIV-negative) population [14, 24, 25], and are probably coincidental factors here. Compared to HIV-negative patients, PLWH had a significantly worse prognosis in terms of both overall survival and progression-free survival.

Previous studies of the relationship between HIV and tumors have mainly focused on the disparity in the incidence of cancer among people living with and without HIV. Data on the prognosis following surgery in PLWH with malignancy are limited. In a national cohort, short-term outcomes after surgical lung resection did not differ significantly between lung cancer patients with and without HIV well managed with ART medication [26]. Another study reported that HIV status did not adversely affect outcomes in African patients with head and neck cancer [27], but this conclusion was limited by the suboptimal medical treatment received by all participants in local areas. Wang et al. [23] suggested that HIV viral load and CD4⁺ T cell counts may affect postoperative outcomes or complications. In our study, even with ART treatment, the CD4⁺/CD8⁺ ratio varied in the PLWH group. Moreover, our study demonstrates an association between a lower CD4⁺/CD8⁺ ratio and worse overall survival.

The main factor affecting the prognosis of PLWH may be the onset of HIV. PLWH who receive ART have a similar, but not equal, prognosis to that of uninfected individuals. In our study, the CD4⁺ T cell count in PLWH was similar to that in the HIV-negative group. Previous studies using the CD4⁺/CD8⁺ ratio as a surrogate marker of immune status have shown that it is independently associated with NADCs and mortality in PLWH, whereas CD4⁺ T cell counts alone do not predict the risk of survival in PLWH with NADCs [17, 28, 29]. Mussini et al. conducted a cohort study to investigate the association between the CD4⁺/CD8⁺ ratio and morbidity in PLWH on ART and found that a CD4⁺/CD8⁺ ratio < 0.5 can identify patients who require more intensive cancer prevention or screening [28]. These findings further validate prior recommendations advocating surgery for PLWH regardless of the CD4⁺ T cell count. The CD4⁺/CD8⁺ ratio seems to be an important prognostic marker in PLWH, and in our study a lower CD4⁺/CD8⁺ ratio in PLWH may have predicted worse survival.

We have not found any study that has directly compared the prognosis of PLWH and HIV-negative patients with RCC. Whether the HIV itself or the tumor itself affects the prognosis is unclear. Although in our study the two groups have a similar pathological stage, general status, KPS, GPS, and CCI, PLWH were still prone to worse overall survival and progression-free survival. These findings further validate prior recommendations advocating surgery for PLWH upon an earlier pathological stage [4, 11].

In the past decade, understanding of the determinants of the ontology of RCC has come a long way. The loss of chromosome 3p is a common genetic abnormality confirmed in both hereditary and sporadic RCC. Tumor genomic features can affect distinct immune phenotypes. For example, PBRM1 mutations are associated with reduced infiltration of T cells; however, whether they are associated with RCC in PLWH remains unclear [30]. The mechanisms behind HIV with RCC may be more complex, and future research is needed on their interactive effects.

Several limitations of our study should be acknowledged. First, it was a single-center retrospective research study with a limited sample size; therefore, the generalizability of the findings to patients in other places may be limited. Second, insufficient information was available in the telephone follow-up. For example, whether socioeconomic status or HIV-related health problems was mostly responsible for the poor prognosis of PLWH is not known.

In our retrospective analysis, RCC patients with HIV had both shorter overall survival and worse progression-free survival than patients without HIV. The lower CD4⁺/CD8⁺ ratio indicated a worse outcome.