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Epidemiological trends of cancers in AIDS patients
HIV & AIDS Review 13 (2014) 6–9
Contents lists available at ScienceDirect
HIV & AIDS Review journal homepage: www.elsevier.com/locate/hivar
Review Article
Epidemiological trends of cancers in AIDS patients Loveleena Agarwal ∗ , Amitabh Agarwal SSR Medical College, Mauritius
a r t i c l e
i n f o
Article history: Received 5 August 2013 Received in revised form 26 November 2013 Accepted 26 November 2013 Keywords: AIDS Malignancy HAART Non-AIDS-defining cancer
a b s t r a c t Since the advent of highly active antiretroviral therapy (HAART), patients with human immunodeficiency virus (HIV) infection have seen a significant improvement in their morbidity, mortality and life expectancy. The incidence of AIDS-defining illnesses, including AIDS-defining 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, anus, and Hodgkin’s lymphoma. The development of NADCs appears to be multifactorial. Risk factors include immunosuppressive effects of the HIV, higher rates of oncogenic viral coinfections and traditional cancer risk factors. New strategies for screening, prevention and treatment of NADCs need to be developed to reverse these epidemiologic trends and improve the survival of HIV-infected patients. © 2013 Polish AIDS Research Society. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.
1. Introduction Since the beginning of the HIV epidemic, cancer has figured prominently in the spectrum of immunodeficiency-related manifestations. Kaposi sarcoma (KS) and aggressive non-Hodgkin lymphoma (NHL), because of their dramatically elevated risk (100,000 and 282, respectively, in the U.S.) with HIV and cervical cancer (CC) with less dramatic increase (10 times), were categorized as AIDS defining cancers (ADCs) to facilitate AIDS surveillance [1]. Only a few other cancers were noted to be modestly elevated with HIV, including Hodgkin lymphoma (10 times), anal cancer (15–30 times) and lung cancer (4 times) and were categorized as non-AIDS-defining cancers (NADCs) [2]. Since 1996 when highly active antiretroviral therapy (HAART), became widely available in the West, dramatic decreases in HIV mortality have been observed and substantial decrease in the incidence of ADCs. Coincidentally, the burden of NADCs has increased as people with HIV age with chronic HIV infection. While ADCs contributed the majority of cancer early in the AIDS epidemic, NADCs have assumed greater importance as survival has lengthened and patients are aging with
Abbreviations: AIDS, acquired immunodeficiency syndrome; HIV, human immunodeficiency virus; HAART, highly active antiretroviral therapy; ADCs, AIDS defining cancers; NADCs, non-AIDS-defining cancers; NADC-IR, non-AIDS-defining cancers-infection related; NADC-IUR, non-AIDS-defining cancers infection unrelated; KS, Kaposi sarcoma; NHL, non-Hodgkin lymphoma; CC, cervical cancer; HPV, human papilloma virus; MSM, men who have sex with men; AIN, anal intraepithelial neoplasia; NADHMs, non-AIDS-defining hematological malignancies; py, personyears; SIR, standardized incidence ratio; HBV, hepatitis B virus; HCV, hepatitis C virus. ∗ Corresponding author. Tel.: +230 7310146. E-mail address: [email protected] (L. Agarwal).
HIV [3]. Apart from a bona fide increased prevalence of NADCs, the spectrum of NADC has expanded as the size of the HIV-positive population has increased [4]. NADCs are responsible for significant morbidity and mortality in the highly active antiretroviral therapy (HAART) era [5]. In general, patients with NADC have been reported to have an overall poor outcome manifesting with advanced cancer at presentation, rapid progression, frequent metastases, a high rate of relapse, and poor therapeutic response. In this paper, we review current literature of NADCs incidence, spectrum, risk factors and outcome.
2. Incidence As shown in Fig. 1 the incidence of NADC has increased in the HAART era. A nationwide epidemiological study was conducted in Japan to evaluate the incidence of non-AIDS-defining hematological malignancies (NADHMs), excluding non-Hodgkin’s lymphomas, in HIV-infected patients. Comparison of patients over the two periods (1991–2000 and 2001–2009) revealed a 4.5-fold increase in the incidence of hematological malignancies [6]. Another recent study retrospectively analyzed all incident NADCs occurring in a cohort of HIV-positive patients in Italy followed up between 1985 and 2011. 5924 patients (4382 males and 1542 females) contributed 50,990 person-years (py) to the follow-up. Among them 144 had new NADC diagnosis. The overall incidence increased from 1.0 case/1000 py in the pre-HAART period (1985–1996) to 4.5 cases/1000 py in the HAART period (1997–2011) (p < 0.01) [7]. Investigators from the National Cancer Institute in the United States linked HIV/AIDS and cancer registries in three states where 57,350 HIV-infected persons were registered during 1991–2002. Risk was shown to be elevated for Hodgkin lymphoma, lung cancer
1730-1270/$ – see front matter © 2013 Polish AIDS Research Society. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved. http://dx.doi.org/10.1016/j.hivar.2013.11.002
L. Agarwal, A. Agarwal / HIV & AIDS Review 13 (2014) 6–9
7
Fig. 1. Increase in incidence of NADC. Adapted and modified from Refs. [6,7].
HAART era
pre HAART
31
NADC
42
ADC
NADC 58
69
ADC
Fig. 2. Increase in prevalence of NADC in HAART era. Adapted and modified from Ref. [8].
and hepatocellular carcinoma. In this study, NADC comprised 31% of cancers in 1991–1995 (pre-HAART) versus 58% in 1996–2002 (HAART era) [8] as is represented in Fig. 2. In another retrospective cohort study for the period from 1999 to 2009 of HIV-infected patients residing in northern Italy a total of 5090 HIV-infected patients were included in the study, with 32,390 person-years of follow-up. 416 tumors were recorded in 390 HIV-infected patients. Two hundred of these (48.1%) were ADCs, 138 (33.2%) were nonvirus-related NADCs and 78 (18.7%) were virus-related NADCs [9]. Similar results 53% ADC and 47% NADCs seen in a sectional study conducted among HIV infected adults attending an AIDS outpatient clinic in Vitória, State of Espírito Santo, Brazil [10]. 3. Spectrum Categorization of cancers in AIDS patient is done in Table 1. In HIV-infected patients cancers are grouped as AIDS-defining canTable 1 Categorization of cancers in HIV infection.
AIDS defining cancers
Kaposi sarcoma Non Hodgkin lymphoma Invasive cervical cancer
Non-AIDS defining cancer-infection related
Anal cancer Hodgkin lymphoma Hepatocellular cancer
Non-AIDS defining cancer-infection unrelated
Lung cancer Cancer of the vulva Tonsil cancer
Adapted and modified from Ref. [7].
cers (ADCs), and non-ADCs. Non-ADCs are further categorized as being infection related (NADC-IR) and unrelated (NADC-IUR). The incidence and spectrum of NADC has increased in different regions of the world. TREAT Asia HIV Observational Database (TAHOD) sites retrospectively reviewed clinic medical records to determine cancer diagnoses since 2000. A total of 617 patients were included in this study. The most common NADCs were lung (6%), breast (5%) and hepatocellular carcinoma and Hodgkin’s lymphoma (2% each). There were also three (1.4%) cases of leiomyosarcoma, a smooth-muscle tumor, usually seen in children and young adults with AIDS, yet overall quite rare, reported in this study [11]. In a study exploring the spectrum of HIV related cancers at the largest tertiary referral cancer center in India amongst the non-AIDS defining cancers anal cancer, testicular cancer, Hodgkin’s disease, colon cancer and certain head and neck cancer sites in men and vaginal cancers among women were found to occur more frequently [12]. A retrospective cohort study using the Taiwan Longitudinal Health Insurance Database between January 1, 2002, and December 31, 2007 found the risk of overall malignancies in the HIV-infected cohort was 1.88 times higher than the risk of a first malignancy in the age-matched non-HIV infected cohort. However, the difference in the risk of developing nasopharyngeal carcinoma (NPC), a highly prevalent malignancy in Taiwan, between the two cohorts was not significant [13]. Similarly, the few studies conducted in sub-Saharan Africa, where two thirds of the HIV epidemic is concentrated, the risks for many cancers with established viral associations, including liver and nasopharynx, which are found in Africa; do not appear to be increased [14]. However, a recent case-referent study conducted in referral hospitals among patients hospitalized for diagnosis or treatment of cancer in West Africa
8
L. Agarwal, A. Agarwal / HIV & AIDS Review 13 (2014) 6–9
Table 2 Risk factors for non-AIDS-defining cancers. S. no.
Risk factor
1. 2. 3. 4. 5. 6.
Low CD 4 count Increasing age Smoking Co infection oncogenic virus Male gender HAARTa
a
The impact of HAART is still not well defined.
is the first study reporting a significant association between HIV infection and liver cancer in sub-Saharan Africa [15]. 4. Risk factors The various risk factors associated with development of NADCs in AIDS patients are enlisted in Table 2. The hall mark of HIV infection immunodeficiency (i.e. low CD4 count) is perhaps responsible for the increased risk for the development of NADC as has been shown by several investigators [9,10]. Cumulative exposure to CD4+ cell counts < 200 cells/mm3 is associated with an increased risk of infection-related NADC [16]. In a retrospective observational study conducted in HIV positive patients who developed a malignancy between 1993 and 2010 in a referral hospital, Spain, NADC patients had a longer history of HIV infection and longer exposure to HAART, better level of immunodeficiency and better virological control than ADC patients [17]. Higher prevalence of NADC in the HAART era suggests that factors other than severe immunosuppression may be involved in the pathogenesis of NADC. The impact of HAART is still not well defined. ADC rates decrease with increased duration of anti-retroviral therapy (ART) use. The effect was similar by therapy class. ART, protease inhibitor, or non-nucleotide reverse transcriptase inhibitor (NNRTI) therapy duration was not associated with infection-related or infectionunrelated NADC except a higher anal cancer risk with longer protease inhibitor therapy [18]. Some studies indicate the use of HAART appear to be beneficial in protecting against the development NADC [19]. In a large prospective cohort study of HIV-infected women (N = 1123) from Soweto, South Africa serial cervical smears were analyzed and reported. It was found women using HAART with a normal baseline smear were 38% less likely to have an incident smear abnormality during follow-up than nonusers and there is a significantly increased likelihood of regression of cervical lesions among women on HAART [20]. Similarly the positive impact of HAART on the natural history of human papillomavirusrelated anal intraepithelial neoplasia (AIN) in HIV-positive men who have sex with men (MSM) is seen in a cross-sectional study in 250 HIV-positive MSM. The use of HAART was associated with lower prevalence of AIN and a significantly lower prevalence of HPV [21]. Several other risk factors have been studied that might play a role in NADC tumor genesis. Most of the studies analyzed in their data the HIV positive cohort studied had more male patients [6,11,17,22,23]. Researchers in Italy found stratifying for gender; only HIV-infected males had an increased risk of nonvirus-related NADCs. Assessing further HIV-infected men showed a 2-fold increased risk of NADC-IUR compared to the general population. The only predictors of NADC-IUR included older age [19]. Other studies found increasing age independently associated with all cancers [9,11,22]. Traditional cancer risk factors also contribute to the increased NADC. Smoking plays a significant role in the development of HIVassociated lung cancer, but the cancer risk is two to four times greater in HIV-infected persons than in the general population, even after adjusting for smoking intensity and duration [24]. After
adjusting for age, race and sex: smoking [relative risk = 2.12] is a risk factor for all NADCs [10,22]. Coinfections with oncogenic viruses as human papilloma virus (HPV), hepatitis B virus (HBV) and hepatitis C virus (HCV) among HIV-infected people, familial cancer history and sun exposure are some of the other key factors in NADC tumor genesis. Relationship between cancer risk and two other immune system hall marks of HIV infection, chronic inflammation and immune dysfunction/senescence, remain poorly understood. 5. Clinical outcomes HIV-infected patients often present with NADC at younger ages with more aggressive or advanced stage disease. In a recent study from Canada the average age of onset of lung cancer in the HIVinfected population is 25–30 years earlier than that in the general population [25]. Databases from main institutions in New Orleans 2001–2011 showed malignancies were diagnosed at late stages in the majority of the cases, 81% of the lung cancer patients and 64% Hodgkin Lymphoma patients, presented with worse outcomes and had higher recurrence rates [26]. In HIV infected patients with a lung cancer diagnosis followed in the Clinic of Tropical and Infectious Diseases of Brescia during the period of 1999–2009 91.3% cancer was detected at stage IV with metastases. The median survival was 5.95 months [27]. 6. Mortality Data from a US population-based record linkage study assessed cancer mortality in 372,364 people with AIDS (1980–2006). Among individuals with AIDS and cancer who subsequently die, most deaths are attributable to cancer. The fraction of all deaths in people with AIDS attributable to ADC (i.e. populationattributable risk) decreased significantly from 6.3% (1980–1990) to 3.9% (1996–2006), but NADC population attributable mortality increased significantly over time from 0.5% (1980–1989) to 2.3% (1996–2006). These results highlight the need for improved cancer prevention and treatment [28]. 7. Prevention The rising number of cases of non-AIDS-defining cancers makes prevention and treatment of these malignancies an increasing priority in HIV care. Counseling by clinicians will play a role in prevention programs. Given the role of tobacco in lung cancer and other illnesses, programs to encourage HIV-infected individuals to quit smoking should be a priority. Encouraging HIV-infected people to limit the number of their sexual partners may reduce their risk of acquiring new HBV and HPV infections, but condom use is of unproven benefit (e.g., for anal HPV) [29]. Screening is targeted at identifying early-stage pre-malignant lesions, with the goal of eliminating those lesions to prevent progression to cancer. While reviewing cancer screening strategies for people living with HIV and compare and contrast them with those of the general population scientists found the most noticeable differences occur in anal and cervical cancer screening. Although anal cancer is uncommon in the general population, it is more prevalent in men who have sex with men and people at high risk for human papillomavirus infection, especially those infected with HIV. An anal Pap test is recommended during the anogenital exam after initial HIV diagnosis, with a second Pap six months later, then annually if the results are normal. A colposcopy should follow an abnormal result. In lung cancer screening, preliminary data suggest that lowdose computerized tomography may play an important role, but further research is needed. Screening for breast and colon cancer should follow guidelines for the general population. Early screening
L. Agarwal, A. Agarwal / HIV & AIDS Review 13 (2014) 6–9
for prostate cancer based on a diagnosis of HIV lacks clear benefit [30].
[10]
8. Conclusion [11]
Through direct and indirect benefits of HAART, people with HIV/AIDS are living longer, developing less AIDS-defining cancers and more cancers commonly seen in the seronegative population. Mortality of patients with HIV infection and malignancy is still very high. Strategies for maintaining higher CD4 cell counts and successful smoking cessation may reduce the NADC incidence in and improve the survival of the HIV-infected population. 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.
[12] [13]
[14]
[15]
[16]
Conflict of interest None declared. Financial disclosure statement
[17]
[18]
None declared. [19]
Acknowledgement We are grateful for helpful comments and suggestions from Dr. Namrata Chhabra at SSR Medical College, Mauritius.
[20]
References
[21]
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Contents lists available at ScienceDirect
HIV & AIDS Review journal homepage: www.elsevier.com/locate/hivar
Review Article
Epidemiological trends of cancers in AIDS patients Loveleena Agarwal ∗ , Amitabh Agarwal SSR Medical College, Mauritius
a r t i c l e
i n f o
Article history: Received 5 August 2013 Received in revised form 26 November 2013 Accepted 26 November 2013 Keywords: AIDS Malignancy HAART Non-AIDS-defining cancer
a b s t r a c t Since the advent of highly active antiretroviral therapy (HAART), patients with human immunodeficiency virus (HIV) infection have seen a significant improvement in their morbidity, mortality and life expectancy. The incidence of AIDS-defining illnesses, including AIDS-defining 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, anus, and Hodgkin’s lymphoma. The development of NADCs appears to be multifactorial. Risk factors include immunosuppressive effects of the HIV, higher rates of oncogenic viral coinfections and traditional cancer risk factors. New strategies for screening, prevention and treatment of NADCs need to be developed to reverse these epidemiologic trends and improve the survival of HIV-infected patients. © 2013 Polish AIDS Research Society. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.
1. Introduction Since the beginning of the HIV epidemic, cancer has figured prominently in the spectrum of immunodeficiency-related manifestations. Kaposi sarcoma (KS) and aggressive non-Hodgkin lymphoma (NHL), because of their dramatically elevated risk (100,000 and 282, respectively, in the U.S.) with HIV and cervical cancer (CC) with less dramatic increase (10 times), were categorized as AIDS defining cancers (ADCs) to facilitate AIDS surveillance [1]. Only a few other cancers were noted to be modestly elevated with HIV, including Hodgkin lymphoma (10 times), anal cancer (15–30 times) and lung cancer (4 times) and were categorized as non-AIDS-defining cancers (NADCs) [2]. Since 1996 when highly active antiretroviral therapy (HAART), became widely available in the West, dramatic decreases in HIV mortality have been observed and substantial decrease in the incidence of ADCs. Coincidentally, the burden of NADCs has increased as people with HIV age with chronic HIV infection. While ADCs contributed the majority of cancer early in the AIDS epidemic, NADCs have assumed greater importance as survival has lengthened and patients are aging with
Abbreviations: AIDS, acquired immunodeficiency syndrome; HIV, human immunodeficiency virus; HAART, highly active antiretroviral therapy; ADCs, AIDS defining cancers; NADCs, non-AIDS-defining cancers; NADC-IR, non-AIDS-defining cancers-infection related; NADC-IUR, non-AIDS-defining cancers infection unrelated; KS, Kaposi sarcoma; NHL, non-Hodgkin lymphoma; CC, cervical cancer; HPV, human papilloma virus; MSM, men who have sex with men; AIN, anal intraepithelial neoplasia; NADHMs, non-AIDS-defining hematological malignancies; py, personyears; SIR, standardized incidence ratio; HBV, hepatitis B virus; HCV, hepatitis C virus. ∗ Corresponding author. Tel.: +230 7310146. E-mail address: [email protected] (L. Agarwal).
HIV [3]. Apart from a bona fide increased prevalence of NADCs, the spectrum of NADC has expanded as the size of the HIV-positive population has increased [4]. NADCs are responsible for significant morbidity and mortality in the highly active antiretroviral therapy (HAART) era [5]. In general, patients with NADC have been reported to have an overall poor outcome manifesting with advanced cancer at presentation, rapid progression, frequent metastases, a high rate of relapse, and poor therapeutic response. In this paper, we review current literature of NADCs incidence, spectrum, risk factors and outcome.
2. Incidence As shown in Fig. 1 the incidence of NADC has increased in the HAART era. A nationwide epidemiological study was conducted in Japan to evaluate the incidence of non-AIDS-defining hematological malignancies (NADHMs), excluding non-Hodgkin’s lymphomas, in HIV-infected patients. Comparison of patients over the two periods (1991–2000 and 2001–2009) revealed a 4.5-fold increase in the incidence of hematological malignancies [6]. Another recent study retrospectively analyzed all incident NADCs occurring in a cohort of HIV-positive patients in Italy followed up between 1985 and 2011. 5924 patients (4382 males and 1542 females) contributed 50,990 person-years (py) to the follow-up. Among them 144 had new NADC diagnosis. The overall incidence increased from 1.0 case/1000 py in the pre-HAART period (1985–1996) to 4.5 cases/1000 py in the HAART period (1997–2011) (p < 0.01) [7]. Investigators from the National Cancer Institute in the United States linked HIV/AIDS and cancer registries in three states where 57,350 HIV-infected persons were registered during 1991–2002. Risk was shown to be elevated for Hodgkin lymphoma, lung cancer
1730-1270/$ – see front matter © 2013 Polish AIDS Research Society. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved. http://dx.doi.org/10.1016/j.hivar.2013.11.002
L. Agarwal, A. Agarwal / HIV & AIDS Review 13 (2014) 6–9
7
Fig. 1. Increase in incidence of NADC. Adapted and modified from Refs. [6,7].
HAART era
pre HAART
31
NADC
42
ADC
NADC 58
69
ADC
Fig. 2. Increase in prevalence of NADC in HAART era. Adapted and modified from Ref. [8].
and hepatocellular carcinoma. In this study, NADC comprised 31% of cancers in 1991–1995 (pre-HAART) versus 58% in 1996–2002 (HAART era) [8] as is represented in Fig. 2. In another retrospective cohort study for the period from 1999 to 2009 of HIV-infected patients residing in northern Italy a total of 5090 HIV-infected patients were included in the study, with 32,390 person-years of follow-up. 416 tumors were recorded in 390 HIV-infected patients. Two hundred of these (48.1%) were ADCs, 138 (33.2%) were nonvirus-related NADCs and 78 (18.7%) were virus-related NADCs [9]. Similar results 53% ADC and 47% NADCs seen in a sectional study conducted among HIV infected adults attending an AIDS outpatient clinic in Vitória, State of Espírito Santo, Brazil [10]. 3. Spectrum Categorization of cancers in AIDS patient is done in Table 1. In HIV-infected patients cancers are grouped as AIDS-defining canTable 1 Categorization of cancers in HIV infection.
AIDS defining cancers
Kaposi sarcoma Non Hodgkin lymphoma Invasive cervical cancer
Non-AIDS defining cancer-infection related
Anal cancer Hodgkin lymphoma Hepatocellular cancer
Non-AIDS defining cancer-infection unrelated
Lung cancer Cancer of the vulva Tonsil cancer
Adapted and modified from Ref. [7].
cers (ADCs), and non-ADCs. Non-ADCs are further categorized as being infection related (NADC-IR) and unrelated (NADC-IUR). The incidence and spectrum of NADC has increased in different regions of the world. TREAT Asia HIV Observational Database (TAHOD) sites retrospectively reviewed clinic medical records to determine cancer diagnoses since 2000. A total of 617 patients were included in this study. The most common NADCs were lung (6%), breast (5%) and hepatocellular carcinoma and Hodgkin’s lymphoma (2% each). There were also three (1.4%) cases of leiomyosarcoma, a smooth-muscle tumor, usually seen in children and young adults with AIDS, yet overall quite rare, reported in this study [11]. In a study exploring the spectrum of HIV related cancers at the largest tertiary referral cancer center in India amongst the non-AIDS defining cancers anal cancer, testicular cancer, Hodgkin’s disease, colon cancer and certain head and neck cancer sites in men and vaginal cancers among women were found to occur more frequently [12]. A retrospective cohort study using the Taiwan Longitudinal Health Insurance Database between January 1, 2002, and December 31, 2007 found the risk of overall malignancies in the HIV-infected cohort was 1.88 times higher than the risk of a first malignancy in the age-matched non-HIV infected cohort. However, the difference in the risk of developing nasopharyngeal carcinoma (NPC), a highly prevalent malignancy in Taiwan, between the two cohorts was not significant [13]. Similarly, the few studies conducted in sub-Saharan Africa, where two thirds of the HIV epidemic is concentrated, the risks for many cancers with established viral associations, including liver and nasopharynx, which are found in Africa; do not appear to be increased [14]. However, a recent case-referent study conducted in referral hospitals among patients hospitalized for diagnosis or treatment of cancer in West Africa
8
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Table 2 Risk factors for non-AIDS-defining cancers. S. no.
Risk factor
1. 2. 3. 4. 5. 6.
Low CD 4 count Increasing age Smoking Co infection oncogenic virus Male gender HAARTa
a
The impact of HAART is still not well defined.
is the first study reporting a significant association between HIV infection and liver cancer in sub-Saharan Africa [15]. 4. Risk factors The various risk factors associated with development of NADCs in AIDS patients are enlisted in Table 2. The hall mark of HIV infection immunodeficiency (i.e. low CD4 count) is perhaps responsible for the increased risk for the development of NADC as has been shown by several investigators [9,10]. Cumulative exposure to CD4+ cell counts < 200 cells/mm3 is associated with an increased risk of infection-related NADC [16]. In a retrospective observational study conducted in HIV positive patients who developed a malignancy between 1993 and 2010 in a referral hospital, Spain, NADC patients had a longer history of HIV infection and longer exposure to HAART, better level of immunodeficiency and better virological control than ADC patients [17]. Higher prevalence of NADC in the HAART era suggests that factors other than severe immunosuppression may be involved in the pathogenesis of NADC. The impact of HAART is still not well defined. ADC rates decrease with increased duration of anti-retroviral therapy (ART) use. The effect was similar by therapy class. ART, protease inhibitor, or non-nucleotide reverse transcriptase inhibitor (NNRTI) therapy duration was not associated with infection-related or infectionunrelated NADC except a higher anal cancer risk with longer protease inhibitor therapy [18]. Some studies indicate the use of HAART appear to be beneficial in protecting against the development NADC [19]. In a large prospective cohort study of HIV-infected women (N = 1123) from Soweto, South Africa serial cervical smears were analyzed and reported. It was found women using HAART with a normal baseline smear were 38% less likely to have an incident smear abnormality during follow-up than nonusers and there is a significantly increased likelihood of regression of cervical lesions among women on HAART [20]. Similarly the positive impact of HAART on the natural history of human papillomavirusrelated anal intraepithelial neoplasia (AIN) in HIV-positive men who have sex with men (MSM) is seen in a cross-sectional study in 250 HIV-positive MSM. The use of HAART was associated with lower prevalence of AIN and a significantly lower prevalence of HPV [21]. Several other risk factors have been studied that might play a role in NADC tumor genesis. Most of the studies analyzed in their data the HIV positive cohort studied had more male patients [6,11,17,22,23]. Researchers in Italy found stratifying for gender; only HIV-infected males had an increased risk of nonvirus-related NADCs. Assessing further HIV-infected men showed a 2-fold increased risk of NADC-IUR compared to the general population. The only predictors of NADC-IUR included older age [19]. Other studies found increasing age independently associated with all cancers [9,11,22]. Traditional cancer risk factors also contribute to the increased NADC. Smoking plays a significant role in the development of HIVassociated lung cancer, but the cancer risk is two to four times greater in HIV-infected persons than in the general population, even after adjusting for smoking intensity and duration [24]. After
adjusting for age, race and sex: smoking [relative risk = 2.12] is a risk factor for all NADCs [10,22]. Coinfections with oncogenic viruses as human papilloma virus (HPV), hepatitis B virus (HBV) and hepatitis C virus (HCV) among HIV-infected people, familial cancer history and sun exposure are some of the other key factors in NADC tumor genesis. Relationship between cancer risk and two other immune system hall marks of HIV infection, chronic inflammation and immune dysfunction/senescence, remain poorly understood. 5. Clinical outcomes HIV-infected patients often present with NADC at younger ages with more aggressive or advanced stage disease. In a recent study from Canada the average age of onset of lung cancer in the HIVinfected population is 25–30 years earlier than that in the general population [25]. Databases from main institutions in New Orleans 2001–2011 showed malignancies were diagnosed at late stages in the majority of the cases, 81% of the lung cancer patients and 64% Hodgkin Lymphoma patients, presented with worse outcomes and had higher recurrence rates [26]. In HIV infected patients with a lung cancer diagnosis followed in the Clinic of Tropical and Infectious Diseases of Brescia during the period of 1999–2009 91.3% cancer was detected at stage IV with metastases. The median survival was 5.95 months [27]. 6. Mortality Data from a US population-based record linkage study assessed cancer mortality in 372,364 people with AIDS (1980–2006). Among individuals with AIDS and cancer who subsequently die, most deaths are attributable to cancer. The fraction of all deaths in people with AIDS attributable to ADC (i.e. populationattributable risk) decreased significantly from 6.3% (1980–1990) to 3.9% (1996–2006), but NADC population attributable mortality increased significantly over time from 0.5% (1980–1989) to 2.3% (1996–2006). These results highlight the need for improved cancer prevention and treatment [28]. 7. Prevention The rising number of cases of non-AIDS-defining cancers makes prevention and treatment of these malignancies an increasing priority in HIV care. Counseling by clinicians will play a role in prevention programs. Given the role of tobacco in lung cancer and other illnesses, programs to encourage HIV-infected individuals to quit smoking should be a priority. Encouraging HIV-infected people to limit the number of their sexual partners may reduce their risk of acquiring new HBV and HPV infections, but condom use is of unproven benefit (e.g., for anal HPV) [29]. Screening is targeted at identifying early-stage pre-malignant lesions, with the goal of eliminating those lesions to prevent progression to cancer. While reviewing cancer screening strategies for people living with HIV and compare and contrast them with those of the general population scientists found the most noticeable differences occur in anal and cervical cancer screening. Although anal cancer is uncommon in the general population, it is more prevalent in men who have sex with men and people at high risk for human papillomavirus infection, especially those infected with HIV. An anal Pap test is recommended during the anogenital exam after initial HIV diagnosis, with a second Pap six months later, then annually if the results are normal. A colposcopy should follow an abnormal result. In lung cancer screening, preliminary data suggest that lowdose computerized tomography may play an important role, but further research is needed. Screening for breast and colon cancer should follow guidelines for the general population. Early screening
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for prostate cancer based on a diagnosis of HIV lacks clear benefit [30].
[10]
8. Conclusion [11]
Through direct and indirect benefits of HAART, people with HIV/AIDS are living longer, developing less AIDS-defining cancers and more cancers commonly seen in the seronegative population. Mortality of patients with HIV infection and malignancy is still very high. Strategies for maintaining higher CD4 cell counts and successful smoking cessation may reduce the NADC incidence in and improve the survival of the HIV-infected population. 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.
[12] [13]
[14]
[15]
[16]
Conflict of interest None declared. Financial disclosure statement
[17]
[18]
None declared. [19]
Acknowledgement We are grateful for helpful comments and suggestions from Dr. Namrata Chhabra at SSR Medical College, Mauritius.
[20]
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[21]
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