Compared to HIV-unspecified NSCLC patients, HIV-infected NSCLC patients displayed grim postoperative survival. Overall and progression-free survival is equally dismal among HIV-infected patients. Even after adjustment for important clinical prognostic indicators, HIV-infected patients exhibited greater mortality. Furthermore, immunosuppression at surgery correlates with rapid decline in survival. This finding runs contrary to prior recommendations advocating surgery for HIV-infected patients regardless of immune status [16
Given the strong relationship between stage and survival, it was expected that stage would account for the majority of variance in the model and attenuate the effect of HIV-infected status [7
]. Instead, after matching and conditioning on stage, the effect of HIV infection increased, indicating that even with similar NSCLC stage, HIV-infected individuals have significantly poorer survival postoperatively. To account for stage migration over the study's 20 years, the surgical year was included in our regression models and matched study design. Nonetheless, the impact of HIV on survival in either the entire analytic cohort or in the matched sub-cohort estimates remained elevated. Compared to HIV-unspecified patients, HIV-infected individuals underwent surgery a month later after diagnosis. We speculate that this difference is indicative of potential barriers to medical care access commonly associated with HIV-infected populations, including low income, lack of medical insurance, HIV-related co-morbidities, drug abuse, and even transient residence [23
]. Nevertheless, any delay in surgery had no detrimental effect on survival in HIV patients on multivariable analysis.
We show differences in survival between HIV patients by CD4 cell count, corroborating Thurer et al. who found in 4 HIV-positive NSCLC surgical patients, long-term survival in the sole patient with CD4 lymphocytes >200 cells/mm3
]. This value is not completely arbitrary since constitutional symptoms begin in HIV patients with CD4 counts <300 cells/mm3
, serious opportunistic infections occur at CD4 counts <100 cells/mm3
] and from 1992 to 2006, the Center for Disease Control defined AIDS as CD4 cell counts < 200 cells/mm3
]. In this study, the CD4 cell count was measured as a fixed variable at the closest time prior to surgery. CD4 count can vary markedly within an individual, especially when patients are non-compliant with antiretroviral regimens [25
]. Multiple measures of CD4 cell counts or of the nadir CD4 cell counts could reveal persistently low values that may better characterize immunosuppression.
In our study, HIV-infected patients were significantly more likely to develop ≥2 postoperative complications than HIV-unspecified patients. Increased postoperative complications, in general, and postoperative pulmonary complications, in particular, were associated with decreased pulmonary functional status [26
]. Although DLCO might be a relevant factor, we hesitate to make definitive conclusions due to few study patients with DLCO data. HIV-infected patients also showed increased progression to recurrence. This maybe important since it suggests a potential biologic mechanism of NSCLC progression involving immunosuppression [28
The obvious limitation of this study is the lack of precision inherent in a small sample size precluding strong recommendations. The observed estimates of effect could simply be due to random variability. Second, it was uncommon to test for HIV antibodies during the initial work-up of the general NSCLC patient at our institution. It is plausible, albeit unlikely, that at NSCLC diagnosis, some individuals with sub-clinical HIV-infection could have been misclassified. Lastly, the treatment assignment of HIV infection status is a complex construct of many factors related to health and survival. The mechanism through which decreased survival is associated with HIV infection is not fully understood within the context of this study. Notwithstanding, this study utilized a powerful design and analytic methods to improve statistical efficiency and balance on HIV infection status. Unmeasured covariates that could account for the observed effect would have to be strongly associated with HIV infection and survival.
Despite HIV-infected patients having comparable 30-day mortality rates to HIV-unspecified patients, surgery is associated with more postoperative complications, rapid progression to recurrence and poorer survival rates. Shortened progression-free and overall survival seem particularly evident in patients with chronically suppressed immune status, i.e. patients with CD4 counts <200 cells/mm3. Careful HIV-infected patient selection based on DLCO may improve postoperative complication rates, and optimizing immune status preoperatively may ameliorate cancer survival rates, but the lack of statistical power precludes definitive recommendations. Future investigations should consider pooled analytic designs as well as prospective measures of HIV immunosuppression and DLCO.