We observed a substantial decline in NHL throughout the study period from 2000 to 2011. This demonstrates a continued decline from prior studies that showed decreasing NHL incidence up until 2006 [7, 8, 14]. Declines in prior studies were attributed to the introduction and dissemination of ART; while the continued decline in NHL we observe may be due to earlier initiation of effective ART as evidenced by the higher CD4 counts observed over time. Interestingly, a decreasing trend over calendar time was not evident for KS. Additionally, no clear trends over calendar time were identified for NADCs.
In our study, less than 20% of KS cases were the presenting diagnosis for HIV, while close to 30% of KS cases developed in patients with CD4 counts greater than 200 cells/mm3, and more than 20% developed in patients with undetectable HIV RNA. An interesting development in recent years has been the emergence of KS in subjects on successful long-term ART . These subjects may be the reason why KS incidence in recent years remains significant and unlike NHL did not decline further. Our observation suggests that the damage done by initial HIV infection, ongoing immune activation , sub-optimal immune reconstitution  and perhaps long-term antiretroviral exposure continues to place HIV-infected individuals at increased risk for KS. Longer survival for HIV-infected patients may also allow more time for the emergence of KS. Viral cancers have a long lag time between primary infection and clinical disease. KS in HIV + patients manifests itself approximately seven years after seroconversion for KS-associated herpesvirus [18, 19]. As such, the initiating event for cancer that manifests itself clinically in the early periods of widely available ART could have taken place when patients were exposed to less than optimal antiretroviral therapy or no therapy at all.
While a number of NADCs were observed in our cohort, incidence trends were not apparent for anal cancer or lung cancer, the most frequent types. A recent North American multi-site study of anal cancer including the UCHCC population also found no change in incidence between 2000–2003 and 2004–2007 . Shiels et al. suggest that the clinical impression of more and more NADCs in recent years is largely due to the aging effect of the HIV + population . The HIV population may face larger increases in cancer risk than the general population with advancing age due to more cumulative exposure to environmental carcinogens such as tobacco and alcohol. We urgently need to understand how anti-cancer regimens and ART drugs interact, in order to develop optimal treatment approaches. While the AIDS Malignancy Consortium is beginning to identify such approaches for NHL and KS, further studies will be needed to address similar concerns in treating NADCs in HIV-infected patients [21, 22]. In contrast to the high incidence of anal cancer, few cases of cervical cancer were observed. This is in part because our patient population was disproportionately male, but also likely serves as an indicator of the success of efforts to screen and treat premalignant cervical lesions.
Our study is noteworthy because we included over 10 years of data spanning the most recent calendar years (2000–2011). During these years new antiretroviral agents and their combination were introduced with better tolerability and greater efficacy in controlling HIV replication [23, 24]. The improved effectiveness of these agents is demonstrated in part by the higher CD4 cell counts and greater proportion of our study population with suppressed HIV RNA levels in more recent calendar years. Most prior studies assessing cancer incidence trends did not cover the most recent years [5, 7] . Although our study focuses on a study population receiving care at one academic center, it represents an area of the US with an increasingly large burden of HIV, including a large proportion of women (almost one-third), and large percentage of African American patients. Also close to a third of this cohort resides in rural areas . Our observations reflect these aspects of the changing HIV population [26, 27].
These data do not take into account recent evidence supporting the benefits of earlier ART initiation and the subsequent changes in HIV treatment recommendations in the U.S [23, 28, 29]. It is likely that as these new recommendations are phased in, the spectrum of malignancies affecting HIV-infected individuals will change. Data on intensity or duration of tobacco use were not available, but this was likely a major contributor to the high incidence of lung cancer.
In the calendar years of our study, no decreases in incidence were apparent for KS or NADCs. Given this consistent cancer burden, the lack of validation of most cancer treatment regimens in the HIV population, and the high cancer risk compared to the general population, a focus on increased screening and prevention efforts is warranted.