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Changes in Clinical Context for Kaposi's Sarcoma and Non-Hodgkin Lymphoma Among People With HIV Infection in the United States
 
 
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"Across all calendar periods, KS incidence in every ART, CD4 count, and HIV RNA category was higher than general population rates (Table 3). Compared with the general US population, KS incidence in 2007 to 2011 was 710 times higher among those who received ART for > 6 months, 430 times higher among those with CD4 counts > 500 cells/mL, and 430 times higher among those with HIV RNA , <500 copies/mL.
 
NHL incidence was also higher than general population rates in almost every category across all periods. Compared with the general population, NHL incidence in 2007 to 2011 was 3.4 times higher among those who received ART for > 6 months, 3.1 times higher among those with CD4 counts > 500 cells/mL, and 2.9 times higher among those with HIV RNA , < 500 copies/mL.
 
In this study, even patients with HIV who received ART, had high CD4 counts, or had suppressed HIV RNA had higher KS and NHL incidence than the general population. This could be due to lingering weaknesses in the immune system. For instance, although ART initiation corresponds with gradual increases in immune responses to human herpesvirus-8,23-25 these responses might not be as robust as in individuals with no history of immunosuppression. HIV could also have persistent direct effects on KS and NHL risk because the HIV latent reservoir is not eliminated with ART use. HIV viremia after ART initiation predicts NHL risk independently of CD4 count,26 and recent studies provide evidence that HIV proteins may directly encourage B-cell clonogenicity.27
 
Changes in the clinical context of these cancers may have important implications for treatment and prognosis. For KS and NHL cases diagnosed in the setting of uncontrolled HIV, initiation of ART is a major component of cancer treatment.2 For KS, ART alone can lead to significant regression, presumably due to improved immune function and control of human herpesvirus-8.2.....however, as the current study shows, KS and NHL develop in many patients despite ART, and intensification or other ART changes may not be beneficial.28,29
 
For NHL, how the immunologic and virologic context at diagnosis influences tumor biology and disease aggressiveness currently is unclear. A previous CNICS study found that patients with NHL diagnosed while receiving ART had worse survival than those with NHL diagnosed before ART initiation.20 However, for HIV-associated NHL, and specifically DLBCL, patients with higher CD4 counts have been observed to have better responses and improved survival.30,31 Further study could help to determine whether associations reflect differences in patterns of care or whether consistent predictors can be identified that correspond to underlying biologic differences.
 
In conclusion, KS and NHL presented a continued burden in the HIV population in the modern ART era, but presenting characteristics for these malignancies are changing. In the United States, more cases are diagnosed while patients are in routine care, receive ART, have a relatively intact immune system, and have suppressed HIV replication. These changes largely reflect the dramatic changes over time in treatment of the underlying HIV population. In the future, more studies are needed to understand whether KS and NHL cases that arise during ART use differ biologically from cases that arise during severe immunosuppression and uncontrolled HIV replication. If biologic differences are demonstrated, they may suggest different approaches to effectively prevent and treat these cancers in the modern ART era."
 
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Changes in Clinical Context for Kaposi's Sarcoma and Non-Hodgkin Lymphoma Among People With HIV Infection in the United States
 
JOURNAL OF CLINICAL ONCOLOGY Published Ahead of Print on August 9, 2016
Elizabeth L. Yanik, Chad J. Achenbach, Satish Gopal, Anna E. Coghill, Stephen R. Cole, Joseph J. Eron, Richard D. Moore, W. Christopher Mathews, Daniel R. Drozd, Ayad Hamdan, Mary E. Ballestas, and Eric A. Engels
Johns Hopkins University, Baltimore, MD; Chad J. Achenbach, Northwestern
University, Chicago, IL; Satish Gopal, Stephen R. Cole, and Joseph J. Eron, University of North Carolina at Chapel Hill, Chapel Hill, NC; W. Christopher Mathews, University of California, San Diego, San Diego, CA; Daniel R. Drozd, University of Washington, Seattle, WA; Ayad Hamdan, Beth Israel Deaconess Medical Center, Boston, MA; and Mary E. Ballestas, University of Alabama at Birmingham, Birmingham, AL.
 
Purpose
 
The biology of HIV-associated cancers may differ depending on immunologic and virology context during development. Therefore, an understanding of the burden of Kaposi's sarcoma (KS) and non-Hodgkin lymphoma (NHL) relative to antiretroviral therapy (ART), virologic suppression, and CD4 count is important.
 
Patients and Methods
 
KS and NHL diagnoses during 1996 to 2011 were identified among patients with HIV infection in eight clinical cohorts in the United States. Among patients in routine HIV clinical care, the proportion of cases in categories of ART use, HIV RNA, and CD4 count at diagnosis were described across calendar time. Person-time and incidence rates were calculated for each category.
 
Results
 
We identified 466 patients with KS and 258 with NHL. In recent years, KS was more frequently diagnosed after ART initiation (55% in 1996 to 2001 v 76% in 2007 to 2011; P-trend = .02). The proportion of patients with NHL who received ART was higher but stable over time (83% overall; P-trend = .81). An increasing proportion of KS and NHL occurred at higher CD4 counts (P,.05 for KS and NHL) and with undetectable HIV RNA (P , .05 for KS and NHL). In recent years, more person time was contributed by patients who received ART, had high CD4 counts and had undetectable HIV RNA, whereas incidence rates in these same categories remained stable or declined.
 
Conclusion
 
Over time, KS and NHL occurred at higher CD4 counts and lower HIV RNA values, and KS occurred more frequently after ART initiation. These changes were driven by an increasing proportion of patients with HIV who received effective ART, had higher CD4 counts, and had suppressed HIV RNA and not by increases in cancer risk within these subgroups. An improved understanding of HIV-associated cancer pathogenesis and outcomes in the context of successful ART is therefore important.
 
Overall, KS and NHL incidence rates decreased 5% and 8% per year, respectively, during 1996 to 2011 (incidence rate ratios, 0.95 and 0.92 per year, respectively; Table 2). KS incidence decreased across time among patients who had not received ART and increased among those with HIV RNA values between 500 and 50,000 copies/mL. KS incidence did not significantly change for any other ART, CD4 count, or HIV RNA category, although a borderline decrease was observed among patients with HIV RNA , 500 copies/mL (Table 2).
 
NHL incidence decreased among patients who received ART for >6 months, among those with CD4 counts , <200 cells/mL, and among those with HIV RNA values <500 copies/mL (Table 2). No changes in NHL incidence over time were observed for other ART, CD4 count, or HIV RNA categories.
 
Across all calendar periods, KS incidence in every ART, CD4 count, and HIV RNA category was higher than general population rates (Table 3). Compared with the general US population, KS incidence in 2007 to 2011 was 710 times higher among those who received ART for > 6 months, 430 times higher among those with CD4 counts > 500 cells/mL, and 430 times higher among those with HIV RNA , <500 copies/mL.
 
NHL incidence was also higher than general population rates in almost every category across all periods. Compared with the general population, NHL incidence in 2007 to 2011 was 3.4 times higher among those who received ART for > 6 months, 3.1 times higher among those with CD4 counts > 500 cells/mL, and 2.9 times higher among those with HIV RNA , < 500 copies/mL.
 
In this study, even patients with HIV who received ART, had high CD4 counts, or had suppressed HIV RNA had higher KS and NHL incidence than the general population. This could be due to lingering weaknesses in the immune system. For instance, although ART initiation corresponds with gradual increases in immune responses to human herpesvirus-8,23-25 these responses might not be as robust as in individuals with no history of immunosuppression. HIV could also have persistent direct effects on KS and NHL risk because the HIV latent reservoir is not eliminated with ART use. HIV viremia after ART initiation predicts NHL risk independently of CD4 count,26 and recent studies provide evidence that HIV proteins may directly encourage B-cell clonogenicity.27
 
Changes in the clinical context of these cancers may have important implications for treatment and prognosis. For KS and NHL cases diagnosed in the setting of uncontrolled HIV, initiation of ART is a major component of cancer treatment.2 For KS, ART alone can lead to significant regression, presumably due to improved immune function and control of human herpesvirus-8.2.....however, as the current study shows, KS and NHL develop in many patients despite ART, and intensification or other ART changes may not be beneficial.28,29
 
For NHL, how the immunologic and virologic context at diagnosis influences tumor biology and disease aggressiveness currently is unclear. A previous CNICS study found that patients with NHL diagnosed while receiving ART had worse survival than those with NHL diagnosed before ART initiation.20 However, for HIV-associated NHL, and specifically DLBCL, patients with higher CD4 counts have been observed to have better responses and improved survival.30,31 Further study could help to determine whether associations reflect differences in patterns of care or whether consistent predictors can be identified that correspond to underlying biologic differences.
 
In conclusion, KS and NHL presented a continued burden in the HIV population in the modern ART era, but presenting characteristics for these malignancies are changing. In the United States, more cases are diagnosed while patients are in routine care, receive ART, have a relatively intact immune system, and have suppressed HIV replication. These changes largely reflect the dramatic changes over time in treatment of the underlying HIV population. In the future, more studies are needed to understand whether KS and NHL cases that arise during ART use differ biologically from cases that arise during severe immunosuppression and uncontrolled HIV replication. If biologic differences are demonstrated, they may suggest different approaches to effectively prevent and treat these cancers in the modern ART era.
 
 
 
 
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