The rising challenge of Non-AIDS Defining Cancers in HIV-infected patients
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Clinical Infectious Diseases Advance Access published July 9, 2012
"the aging HIV population is now known to be at an increased risk for a multitude of non-
AIDS-defining malignancies.....routine screening is performed less frequently in HIV-infected subjects......patients with NADCs often have more aggressive cancers"
"the general trend of an increased cancer risk - above and beyond that seen in
the general population - presents a challenge to all who care for patients infected with HIV......"
"Clinicians and researchers, policy makers and officials, as well as patients and their advocates
must now strive to confront this challenge, as they did with access to antiretroviral treatment in
the earliest stage of the HIV epidemic, and then with the AIDS defining cancer challenge that
surfaced soon thereafter. With the rising case load of non-AIDS defining cancers, we must do a
better job of detecting cancer as early as possible, ensuring that effective treatments are
available and used in the oncology community, all while continuing to work towards the goal of
preventing these cancers -- and reversing this trend -- in the years ahead."
John F. Deekena, Angelique Tjen-A-Looia, Michelle A. Rudekb, Catherine Okuliara, Mary Younga, Richard F. Littlec, and Bruce J. Dezubed
aGeorgetown University Medical Center, Divisions of Hematology/Oncology (J.F.D.),
Infectious Disease (A.T, M.Y.), and Internal Medicine (C.O.), Washington, D.C. USA; b
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD,
USA; cClinical Investigations Branch/CTEP, National Cancer Institute, Bethesda, MD,
USA; dDepartment of Medicine [Hematology/Oncology], Beth Israel Deaconess Medical
Center, Harvard Medical School, Boston, Massachusetts, USA.
Since the advent of HAART, patients with HIV infection have seen a significant improvement in their morbidity, mortality, and life expectancy. The incidence of AIDSdefining illnesses, including AIDSdefining malignancies, has been on the decline. However, deaths due to non-AIDS defining illnesses have been on the rise. These so-called non-AIDS defining cancers (NADCs) include cancers of the lung, liver, kidney, anal, head and neck, and skin, as well as Hodgkin's Lymphoma. It is poorly understood why this higher rate of NADCs is occurring. The key challenge facing oncologists is how to administer chemotherapy effectively and safely to patients on antiretroviral therapy. The challenge to clinicians caring for HIV-infected patients is to develop and implement effective means to screen, treat, and prevent NADCs in the future. This review presents data on the epidemiology and etiology of NADCs, as well as ongoing research into this evolving aspect of the HIV epidemic.
FIGURES AND TABLES
Table 1. Standard Incidence Ratios of selected Non-AIDS Defining Cancers [refs: 2-8]
Even more than screening, cancer prevention should be a key goal for practitioners caring for HIV-infected patients. This includes smoking cessation
Prevention and/or treatment for viral coinfections of Hepatitis B and C should be routine if patients are eligible for treatment
The strongest epidemiological risk factor for developing a NADC is age
duration of HIV infection is also significantly associated with the risk of developing a NADC, with an increased odds ratio of 1.20 for every year of HIV-infection.
While the duration of HIV-infection increases risk, the severity of HIV infection may not
Research into possible etiologies of NADCs have begun to elucidate potential causes. Explanations include the HIV virus itself, co-infection with oncogenic viruses, cART agents, and tobacco exposure in the setting of HIV.
The HIV virus may have direct tissue, cellular, and/or genetic effects that contribute to the development of cancer, including NADCs. HIV may activate proto-oncogenes [35,36], cause alterations in cell cycle regulation , inhibit tumor suppressor genes including p53 [38,39], or cause microsatellite gene instability and genetic alterations leading to oncogenesis.[40,41] Infected tissues may be more sensitive to the effects of carcinogens from the environment.[42,43,44] Finally, HIV infection can cause endothelial abnormalities including pro-angiogenesis signaling which may enhance the development of tumor growth and metastasis.[45,46,47]
HIV-infected patients have an increased risk of exposure and subsequent infection with cancer causing viruses, including hepatitis B and C (HBV and HCV), Human Papillomavirus (HPV), and the Epstein-Barr virus.[48,49,50,51] Co-infection with HIV and these viruses continues even in the post-HAART era.[52,53,54] HIV infected patients have an accelerated progression of disease from viruses such as HBV and HCV disease.[55,56] This in turn may explain higher rates of liver [13,30,51,54], anal [2,15,57], and head and neck cancers [57,58,59], as well as Hodgkin's Lymphoma.[5,6,60,61,62] For example, while between 20 to 50 percent of
Hodgkin's Disease may be caused by EBV in the general population, between 75 to 100 percent of patients with HIV have EBV-associated Hodgkin's Disease.[5,6,61,62] Local as well as systemic impairment of EBV-specific T cells responses, especially CD4+ T cells, may predispose HIV-patients to development of this disease.
Conflicting evidence has been presented as to whether -- or which - antiretroviral therapy increases, decreases, or has no effect on the risk of developing a NADC [6,8,10,13], with no clear pattern emerging from these epidemiological reviews. More work needs to be done to further answer this important question.
Tobacco, the causative agent for a number of NADCs including lung and head and neck cancers, is used more commonly in HIV-infected individuals, with smoking rates among HIVinfected patients in the U.S. between 52-60%, and as high as 80% in some urban areas. This mirrors high smoking rates seen in other countries. However, after controlling for smoking status, HIV-infected individuals are still at a 2.5 to 3.6 higher risk of developing lung cancer compared to the overall population. Whether this higher cancer rate is due to an increased tissue sensitivity to tobacco carcinogens in the setting of HIV infection is unknown.
Unfortunately, patients with NADCs often have more aggressive cancers, and present with more advanced stage disease.[15,22], For example, HIV patients with hepatocellular carcinoma show a greater degree of infiltrative disease, with more advanced cirrhosis on presentation, and experience poorer outcomes. Skin squamous cell cancers are more aggressive in HIV-infected patients, with a higher risk of local recurrence and metastasis - leading to a 50% mortality rate. While HIV patients diagnosed with early stage breast
cancer have similar survival rates compared to non-HIV infected patients, breast cancer in HIV-infected patients is more commonly poorly differentiated, bilateral, with early metastases. In Hodgkin's Lymphoma, treatment outcomes may be favorable but disease recurrence remains a problem.
Whatever the etiologies of these higher rates of NADCs, the central clinical questions facing primary care physicians, infectious disease specialists, and medical oncologists is how best to screen, treat, and ideally prevent these cancers in their patients.
Should HIV infected patients be screened differently
than the general population? Should HIV-patients undergo screening at a younger age, at more frequent intervals, or with different tests than the general population? Should we be screening HIV infected patients for cancers for which we do not screen the general population?
The only recommendations that exist for these particular cancers are geared towards the general population. However, the European AIDS Clinical Society has proposed screening recommendations in HIV-positive patients for
anal, breast, cervical, colorectal, liver, and prostate cancers.
Clearly, clinicians caring for HIV-infected patients should be performing age-appropriate screening in their patients, including for colon, breast, and prostate cancers. However, past
research has found that routine screening is performed less frequently in HIV-infected subjects.
However, past research has found that routine screening is performed less frequently in HIV-infected subjects. For example, rates of breast cancer screening using mammography was significantly lower in
HIV-infected women compared to the general population (67% vs 79%). Similarly, age-appropriate screening for colon cancer was done at a lower rate (56 vs. 78%) - a difference that was statistically significant -- in HIV-infected subjects compared to age-and gender-matched controls.
A few caveats deserve mentioning. For colon cancer screening, HIV-positive patients typically present with more advanced stage disease, and more commonly have right sided disease that would be missed by flexible sigmoidoscopy. Thus, full colonoscopies should be performed.
a new avenue recently opened that may aid in the screening for lung cancer in at-risk individuals, including those infected with HIV. Whether the findings of the National Lung Screening Trial (NLST), which showed that screening high-risk smokers reduced lung cancer mortality by 20
percent, are adopted for the general population is not yet known. If they are, then applying this screening technique to HIV-positive patients with a high-risk tobacco use history should be equally warranted.
a vaccine against HPV is safe and highly immunogenic in HIV-infected men.