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Preventing Cancer in HIV+: keep CD4 >700 & viral load undetectable,
start HAART Early, control inflammation
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The best way to prevent cancers are keeping CD4 high, viral load undetectable, and healthy lifestyle (diet/exercise). Starting HAART earlier, at CD4 counts above 700 is associated with reduced risk for developing cancer (see link to study below). Jules Levin
"Ongoing inflammation and immunodeficiency in patients who initiate cART at lower CD4 cell counts increases the risk of developing co-morbid conditions as demonstrated by the prognostic value of CD4 cell count and other immunologic markers in patients treated with cART [35,38]. Our results emphasize the importance of prompt and effective treatment of HIV with cART to reduce mortality from AIDS and non-AIDS defining co-morbid conditions, such as cancer......More than 50% of HIV-infected patients diagnosed with cancer in our cohort had advanced (stage IV) disease at the time of diagnosis. Additionally, at least 25% of patients received no cancer treatment. This is surprising, as individuals in this study were receiving cART in specialized HIV clinics and routinely engaged in care with quarterly monitoring on average.....We observed several important findings with regard to mortality rates for individual cancers. Consistent with reports from other HIV-infected populations, the highest.....mortality rates for non-AIDS defining cancers were among patients with liver and lung cancer [20,22], accounting for nearly 50% of deaths after non-AIDS defining cancer. Two-year survival for patients with liver cancer in this study was only 12%"
"investigators proposed that a weakened immune system spurred development of these cancers."
"Regarding the question of 'when to begin HAART', risk for non-AIDS cancers are 2-fold higher (100% higher) when CD4s are below 700 and 3.7 fold higher when CD4 is 200-349 in the pre-HAART era in this study and also 2-fold higher for AIDS-defining risk when CD4s are <500 in the pre-HAART era (see tables 5a and 5d)."
More Time With Low CD4 Count Boosts Non-AIDS Cancer Risk:
"Every year spent with a CD4 count under 200 independently raised the risk of a non-AIDS cancer diagnosis in the Dutch ATHENA cohort"
5th IAS Conference on HIV Pathogenesis, Treatment and Prevention,
July 19-22, 2009, Cape Town ..
www.natap.org/2009/IAS/IAS_64.htm
"This analysis determined that every year with a CD4 count under 200 independently raised the non-AIDS cancer risk about 10% (P = 0.03). There was also a strong trend toward non-AIDS cancer diagnosis for every additional year with a CD4 count between 200 and 350 (P = 0.09). Every year with a CD4 count under 200 independently raised the risk of non-AIDS infection-related cancers about 20% (P = 0.01) but had no significant impact on other non-AIDS cancers. The trend linking time spent with 200 to 350 CD4s and infection-related cancers fell short of statistical significance (P = 0.13).
Every additional 10 years of age (P < 0.0001) and HBV coinfection (P = 0.02) nearly doubled the risk of non-AIDS cancer, and a previous AIDS diagnosis upped the risk about 40% (P = 0.03). Time spent with a viral load above 400 copies did not independently predict cancer."
What CD4 Cell Count Levels are Associated With a Reduced Risk of ...700 CD4 Count & Cancer Risk in HIV
"While the risk of ADCs was highest at CD4 counts < 200 cells/mm3, increased risk was also present at counts <500".....Maintaining robust CD4 counts is useful in reducing AIDS-defining cancers among HIV patients, but did not have a significant impact on NADCs in the HAART ...
www.natap.org/2009/IAS/IAS_73.htm
From Jules: Regarding the question of 'when to begin HAART', risk for non-AIDS cancers are 2-fold higher (100% higher) when CD4s are below 700 and 3.7 fold higher when CD4 is 200-349 in the pre-HAART era in this study and also 2-fold higher for AIDS-defining risk when CD4s are <500 in the pre-HAART era (see tables 5a and 5d). This suggests that in the HAART era currently starting HAART at 700 CD4s reduces non-AIDS cancer risk and starting at 500 CD4 count reduces AIDS cancer risk. In other words, these data suggest to start HAART at 700 CD4 to optimally reduce cancer risk. This is something I said 10 years ago and I'm sure others raised this concern also when discussing this in the context of when to begin HAART: that risk for cancers are reduced if you keep the CD4 count higher and start HAART before the CD4 declines below the normal level which is I think generally considered to be 500-700 at the low end of the spectrum. When taking a treatment interruption and thereby allowing CD4 to decline and viral load to increase for a period of time it appears you can increase risk for cancers. A study at IAS I emailed yesterday found cumulative exposure to detectable viral load and independently cumulative exposure to CD4 <350 increased NHL risk, and there have been similar studies reported recently, at CROI 2008 & 2009. Another question is if cd4 is 1000 does that reduce cancer risk further and perhaps that depends on the quality of the cd4s.
NEW STUDY in AIDS Jnl Dec 2010: (published pdf attached)
Mortality after cancer diagnosis in HIV-infected individuals treated with antiretroviral therapy (published pdf attached): "hazard of death was lower among those with higher CD4 cell counts at cancer diagnosis, who achieved HIV RNA suppression (<400 copies/mL) on HAART"
Download the PDF here
"Increased mortality observed among those with lower CD4 cell counts highlights the importance of timely HIV treatment. The majority of patients in this study had very low nadir CD4 cell counts prior to initiation of cARTand were unable to adequately rebuild their immune system
with treatment.
"This finding is consistent with several studies showing that severity of immune suppression at time of cART initiation is predictive of the ability of antiretroviral treatment to significantly increase CD4 cell count [34 - 37]. Ongoing inflammation and immunodeficiency in patients who initiate cART at lower CD4 cell counts increases the risk of developing co-morbid conditions as demonstrated by the prognostic value of CD4 cell count and other immunologic markers in patients treated with cART [35,38]. Our results emphasize the importance of prompt and effective treatment of HIV with cART to reduce mortality from AIDS and non-AIDS defining co-morbid conditions, such as cancer."
"a large proportion of patients engaged in routine HIV care were diagnosed late with stage IV cancer. Our results support earlier initiation of cART and aggressive cancer screening and treatment practices to maintain immunologic function, obtain optimal virologic suppression, control viral co-infections, detect cancers at an early stage, and provide appropriate cancer therapies"
"More than 50% of HIV-infected patients diagnosed with cancer in our cohort had advanced (stage IV) disease at the time of diagnosis. Additionally, at least 25% of patients received no cancer treatment. This is surprising, as individuals in this study were receiving cART in specialized HIV clinics and routinely engaged in care with quarterly monitoring on average. Although it is possible that HIV infection and associated immune system dysfunction accelerate the rate of cancer progression to advanced and untreatable states, our findings could be explained by poor cancer awareness, inadequate screening practices, or lack of prompt therapy. HIV-infected individuals may require novel cancer prevention and treatment strategies"
Chad J. Achenbacha, Stephen R. Coleb, Mari M. Kitahatac,d, Corey Casperc,d,e,f, James H. Willigg, Michael J. Mugaverog and Michael S. Saag
gaFeinberg School of Medicine, Division of Infectious Diseases, and Center for Global Health, Northwestern University, Chicago, IL USA, bGillings School of Global Public Health, Department of Epidemiology, and Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, cUniversity of Washington Department of Medicine, dCenter for AIDS Research, and the, eDepartment of Epidemiology, University of Washington, Seattle, WA, USA, fVaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA, and gDepartment of Medicine and Center for AIDS Research, University of Alabama at Birmingham, Birmingham, AL, USA.
Abstract
Objective(s): To evaluate survival and predictors of mortality after cancer diagnosis among HIV-infected persons receiving combination antiretroviral therapy (cART).
Design: Multi-site cohort study
Methods: We examined all-cause mortality among HIV-infected patients treated with cART in routine care at eight US sites and diagnosed with cancer between 1996 and 2009, and predictors of mortality using Cox proportional hazards regression models. Non-AIDS defining cancers (NADCs) were classified as related and unrelated to viral co-infections.
Results: Out of 20,677 persons in the CNICS cohort, 650 cART treated individuals developed invasive cancer. Of these, 305 died during 1,480 person-years of follow-up; crude mortality rate was 20.6 per 100 person-years (95%CI: 18.4, 23.1) and overall 2-year survival was 58% (95%CI: 54, 62%). Highest mortality was seen in primary central nervous system non-Hodgkins lymphoma, liver, and lung cancer with rates of 90.6, 84.3, and 68.1 per 100 person-years, respectively. Adjusted hazard of death was higher among those who were older and had stage IV cancer. Adjusted hazard of death was lower among those with higher CD4 cell counts at cancer diagnosis, who achieved HIV RNA suppression (<=400 copies/mL) on cART, received any cancer treatment, and had AIDS-defining cancer or infection-related NADCs compared to infection-unrelated NADCs.
Conclusions: Independent predictors of mortality after cancer diagnosis among HIV-infected persons include poor immune status, failure to suppress HIV RNA on cART, cancer stage, and lack of cancer treatment. Modification of these factors with improved strategies for the prevention and treatment of HIV and HIV-associated malignancies are needed.
Discussion
Cancer has been an important cause of morbidity and mortality for individuals with HIV-infection since the beginning of the epidemic. Indeed, we found that in a large cohort of over 20000 HIV-infected persons receiving care at eight major metropolitan areas across the United States, more than 3% of patients receiving antiretroviral therapy developed cancer. We identified known risk factors for mortality including older age, stage IV cancer at time of diagnosis, and lack of cancer treatment. We also found key factors associated with mortality that are specific to HIV-infected patients and have not been previously reported, including failure to suppress HIV RNA, low CD4 cell count at cancer diagnosis, and cancers unrelated to a viral co-infection. A possible explanation for these findings would be that HIV RNA reduction and immunologic recovery from cART led to suppression of viral co-infection replication and its effects on tumor pathogenesis or growth of these cancers. Alternatively, among HIV-infected patients, these cancers may be less aggressive or more responsive to cancer treatment compared with non-AIDS-defining cancers unrelated to viral co-infection. However, classifying cancers as related to viral co-infection may not be of central clinical importance when studying outcomes such as mortality. For example, in Figure 1 panel C, we observed a notable difference within infection-related NADCs in which mortality was considerably higher for those with liver cancer compared to anal cancer or Hodgkin lymphoma. These findings point to the need for further study of the epidemiology and pathophysiology of cancer progression and viral co-infections in HIV disease. In particular, more information is needed regarding outcomes of individual types of cancer among HIV- infected individuals.
We observed several important findings with regard to mortality rates for individual cancers. Consistent with reports from other HIV-infected populations, the highest mortality rates for non-AIDS defining cancers were among patients with liver and lung cancer [20,22], accounting for nearly 50% of deaths after non-AIDS defining cancer. Two-year survival for patients with liver cancer in this study was only 12%. Previous studies of mortality after liver cancer comparing those with and without HIV-infection have been mixed [30,31]. Mortality after NHL is known to be worse for patients with HIV, although a recent study from Europe suggested improved survival with cART [32]. Our results were consistent with another recent study of survival after NHL that directly compared those with and without HIV-infection in the cART era [33] and found 40% 2- year survival for patients with HIV and 70% for those without HIV. Our findings also suggest that HIV- infection may increase mortality for patients with kidney cancer since 2-year survival was only 58%. Considering immune-modulating therapies are often used for treat- ment of renal cell carcinoma, immune-deficiency or dysregulation due to HIV-infection could unfavorably alter the pathogenesis of this cancer. This finding has not been previously reported and requires further investigation.
Increased mortality observed among those with lower CD4 cell counts highlights the importance of timely HIV treatment. The majority of patients in this study had very low nadir CD4 cell counts prior to initiation of cARTand with treatment. This finding is consistent with several studies showing that severity of immune suppression at time of cART initiation is predictive of the ability of antiretroviral treatment to significantly increase CD4 cell count [34 - 37]. Ongoing inflammation and immunodeficiency in patients who initiate cART at lower CD4 cell counts increases the risk of developing co-morbid conditions as demonstrated by the prognostic value of CD4 cell count and other immunologic markers in patients treated with cART [35,38]. Our results emphasize the importance of prompt and effective treatment of HIV with cART to reduce mortality from AIDS and non-AIDS defining co-morbid conditions, such as cancer.
More than 50% of HIV-infected patients diagnosed with cancer in our cohort had advanced (stage IV) disease at the time of diagnosis. Additionally, at least 25% of patients received no cancer treatment. This is surprising, as individuals in this study were receiving cART in specialized HIV clinics and routinely engaged in care with quarterly monitoring on average. Although it is possible that HIV infection and associated immune system dysfunction accelerate the rate of cancer progression to advanced and untreatable states, our findings could be explained by poor cancer awareness, inadequate screening practices, or lack of prompt therapy. HIV-infected individuals may require novel cancer prevention and treatment strategies that incorporate key prognostic factors such as those found in our study, including suppression of HIV RNA, prevention of CD4 cell count decline, and cancer screening initiated at a younger age than in the general population. Further research is needed to define the optimal timing and modalities for cancer screening and treatment among HIV-infected populations.
This study has several limitations. First, associations presented here reflect observational evidence and there- fore, could have been influenced by unmeasured risk factors for death such as active substance abuse, or other co-morbid disease. Second, while the present work reflects a large study of mortality after cancer diagnosis, information regarding tobacco exposure, alcohol abuse, viral hepatitis co-infection, non-cancer AIDS diagnoses, cancer stage, and cancer treatment were subject to imprecision and potential misclassification. Third, despite extensive medical record review, detailed cancer staging information was not available for 26% of cancer diagnoses, a key predictor of mortality. However, we used multiple imputation to account for missing staging information in the final adjusted model for the full cohort, and our results were consistent with multivariable analyses conducted on two subsets of patients with known cancer stage. Fourth, we did not account for changes over time for certain factors, such as CD4 cell count and cART, which will be the focus of subsequent analyses. Lastly, we did not have information on cause of death and were unable to provide direct comparisons of our findings with a matched population of patients without HIV- infection. In the modern era of cART, patients with cancer and HIV-infection have several competing risks for death that vary depending on individual cancer type. We were limited by a small number of cases of specific cancer types and aggregate findings may not accurately capture outcomes for less common cancers. Future research in this area will require multi-center cohorts with large numbers of individuals with specific cancer types and detailed information about cause of death.
Despite these limitations, this work has several strengths. First, this was a multi-center collaborative effort from a large and diverse population with cancer diagnoses rigorously verified to minimize misclassification. Second, the occurrence and timing of mortality was based on active and passive surveillance also leading to minimal misclassi- fication. Finally, distinct from previous studies, we were able to examine multiple risk factors for mortality among HIV-infected patients with cancer including CD4 cell count, HIV RNA level, cancer stage, viral hepatitis co- infection, smoking, and alcohol exposure.
In conclusion, among individuals with cancer and HIV- infection treated with cART, we observed independent effects on mortality of low CD4 cell count, lack of HIV RNA suppression and cancer treatment, and cancers unrelated to infection. In addition, a large proportion of patients engaged in routine HIV care were diagnosed late with stage IV cancer. Our results support earlier initiation of cART and aggressive cancer screening and treatment practices to maintain immunologic function, obtain optimal virologic suppression, control viral co-infections, detect cancers at an early stage, and provide appropriate cancer therapies. These findings exemplify the dynamic nature of the HIV epidemic in the current era of cART and highlight the need for continued research on prevention, diagnosis, and treatment of non-AIDS- defining conditions, including cancer.
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