1. Cancer Trends in North America Over the Past Decade
Benigno Rodríguez, MD, MSc, FIDSA
Durban, 19 July 2016

2. DISCLOSURES
Honoraria from Gilead
Funding from NIH, NHLBI, NCI

3. OUTLINE Cancer trends among PLWH in North America
Overall frequency
Cancer-specific patterns
Effect of infectious etiologies and immune status
Conclusions: Strategies to bend the trend

4. Background
A greater incidence of malignancy has been observed among HIV-infected persons relative to the general population since the beginning of he epidemic
Even after controlling for conventional risk factors
The introduction of cART has changed the patterns of occurrence of malignancy to various degrees

5. CNICS Cancers Over Time
The most dramatic trends happened with the introduction of cART, which led to a massive reduction in the incidence of ADCs – KS, NHL, and to a lesser extent invasive cervical cancer. Of note, all of these are linked to an infectious etiology. But the trend was opposite for many NADCs.
Number of people living with AIDS, AIDS-defining cancers, non-AIDS-defining cancers, and all cancers in the United States during 1991–2005. A) US AIDS population by calendar year and age group. B) The estimated counts and standardized rates of AIDS-defining cancers among people living with AIDS in the United States by calendar year and age group. C) The estimated counts and standardized rates of non-AIDS-defining cancers among people living with AIDS in the United States by calendar year and age group. Of note, the bars for 0–12 year olds in panels (B) and (C) are difficult to see because of small numbers of cancers in this age group during 1991–2005 (122 AIDS-defining cancers and 25 non-AIDS-defining cancers). D) The estimated counts and standardized incidence rates of total cancers among people living with AIDS in the United States, stratified by AIDS-defining cancers, non-AIDS-defining cancers, and poorly specified cancers. Bars depict the estimated number of cancers, and points connected by lines depict incidence rates standardized to the 2000 US AIDS population by age group, race, and sex.
And this is ilustrated in data from th CNCS consortium, in which we can see clearly NADCs overtaking ADCs around So, for the rest of the presentation, I will focus on the post-cART era
When we look at yearly cancer case counts, 2006 to 2007 is when non-AIDS cancers of aging start to consistently dominate the spectrum of cancer cases in CNICS.
*Excluding non-melanoma skin

6. Examined secular trends in 3 periods: 1996-1999. 2000-2004, 2005-2009
N= 86,620 HIV-infected (475,660 PY of FU); 196,987 HIV-uninfected (1,847,932 PY of FU)
Nine target cancers (centrally adjudicated); KS, NHL, HL, lung, anal, colorectal, liver, OP, melanoma
Key features:
Competing risks analysis, adjusted for sex, race, and cohort
Cumulative cancer risk at age75
Contrast to cancer-specific hazard rate
The comparison of cumulative CA incidence hazard rate to the cancer-specific hazard ratio is useful because if the cumulative incidence HR has actually remained stable for a given cancer, as the cohort aged, more people would have survived to spend more time at risk due to HAART and so, the csHR would be artificially inflated

7. Crude Cancer-specific Incidence Rates, HIV+ and HIV-
Cant see the numbers, but bottom line is, for every single cancer and death, the incidence rate is higher in HIV-infected, sometimes massively so. For example, 650-fold for KS, 12-fold for NHL, over 4-fold for mortality. Keep in mind that this is during the cART era.
Same for crude cumulative incidence at age 65 or 75, except for melanoma and colorectal/OP cancer

8. Decreasing Calendar Trends In Cancer and Mortality, 1996-2009
* Significant trend in cause-specific HR only * * *

9. Increasing Calendar Trends In Cancer and Mortality, 1996-2009

11. Interval Summary
ADC incidence has decreased drastically among HIV- infected persons in North America
But risk remains massively higher than in the general population
Incidence and risk of certain NADCs has increased despite the introduction of cART
Including anal, colorectal, and liver
At least partly d/t improved survival (no change in csHR)
Cumulative incidence trend in HIV+ and HIV- was similar for liver cancer, but opposite for colorectal

12. Delayed vs. Immediate ART Initiation: Effect on Cancer Incidence
INSIGHT Study Group. NEJM 2015; 373: 9

13. HBV Vaccine Response among HIV-infected Patients and Risk of Cancer
N=1,578; 96 (6%) developed incident cancer during follow up
P=0.03*
*Adjusted for age, CD4 (nadir and time-updated), history of OI

14. Effect of Viremia on NHL Incidence
3-month lagged viremia levels shown
Viremia as a continuous value was associated with a HR for NHL of 1.42/log10 copies/mL
Achenbach C, et al. CID 2014; 58:1599

15. Conclusions
Most ADCs have decreased dramatically, but HIV-infected persons remain at considerable risk
The risk of NADCs has surpassed that of ADCs in the cART era and in some cases continues to rise
A strong link to immune competence, persistent viremia, and infectious etiologies suggests possible strategies to modulate these trends:
Early, universal, suppressive ARV therapy
Increased screening and aggressive treatment for many NADCs
Vigorous treatment of coinfecting oncogenic pathogens
Reduction of residual inflammation/immune activation

16. Acknowledgements

17. CNICS Malignancy Data Update
Cancer data collection through 2014
3,897 verified cancer diagnoses
66% non-KS with histopathology
48% KS with histopathology
Details on diagnosis confirmation method, histopathology, stage, grade, family history, exposures to tobacco and alcohol
59% with staging (summary or TNM)
UAB and Fenway have ascertained and submitted cancer diagnoses, but still working on histopathology, staging, etc. The 59% known stage is among cancer diagnoses that utilize summary or TNM staging systems. Excludes KS, NHL CNS, leukemia, multiple myeloma, brain (primary), skin: non-melanoma and other cancer types.

18. CNICS Digital Record Abstraction (DRA)
This slide show the process for Digital Record Abstraction to support centralized event adjudication
We centrally ascertain patients meeting study criteria in the CNIC platform
Sites then generate specified digital EMR abstractions that are transmitted to the DMC
Where we process and upload them to a secure website for review by multiple adjudicators remotely