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

DISCLOSURES Honoraria from Gilead Funding from NIH, NHLBI, NCI

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

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

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 2006. 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

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

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

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

Increasing Calendar Trends In Cancer and Mortality, 1996-2009

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

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

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

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

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

Acknowledgements

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.

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