Are Non-HIV Malignancies Increased in the HIV-Infected Population?

Abstract

Purpose of review

The introduction of antiretroviral therapy (ART) has revolutionized HIV infection management, resulting in improved outcomes and survival for people living with HIV (PLWH). However, as PLWH are living longer and aging, non-AIDS-defining cancers (NADCs) represent a significant source of morbidity and mortality in the HIV-infected population. Here, we review the epidemiology of NADCs in PLWH.

Recent findings

Cancer mortality among PLWH is much higher than that among the general population. Up to 10% of deaths among PLWH have been attributed to NADCs. Furthermore, PLWH have an increased risk for specific NADCs, including lung cancer, hepatocellular carcinoma, head and neck cancers, anal cancer, and Hodgkin lymphoma. In the past decade, the incidence rates of AIDS-defining cancers (ADCs) have been decreasing while the incidence rates of NADCs have been increasing. In particular, the incidence of specific NADCs are changing at different rates. For example through 2010, the incidence rates for anal, liver, and prostate cancers among PLWH had increased, while incidence rates for lung cancer had decreased and incidence rates for colorectal cancer remained relatively stable over time. However, as early ART becomes more prevalent and the percentage of PLWH over 50 increases, these trends may evolve further.

Summary

Incidence of NADCs should be expected to increase further as the PLWH population continues to age. Screening and prevention for these cancers among the HIV-infected population should be emphasized.

Introduction

With the advent and subsequent introduction of effective combination antiretroviral therapy (ART) in 1996, the mortality rate for individuals infected with HIV has decreased by 70% [1]. Nonetheless, there were an estimated 37,600 new HIV infections in the USA in 2014 and the number of individuals living with HIV in the USA is in excess of 1.1 million as of 2015 [2]. With improved outcomes and survival for infected individuals, HIV is now considered a chronic condition and there is considerable public health and clinical interest in the downstream causes of long-term morbidity in these individuals. In particular, there is increasing evidence that non-AIDS-defining cancers (NADCs) may be a future source of considerable morbidity and mortality in the growing and aging HIV-infected population.

In particular, the rates of NADCs have dramatically increased in the past decade among the HIV-infected population in the USA [3, 4]. Indeed, cancers were the leading cause of death among people living with HIV (PLWH) in 2010 [5]. The proportion of all deaths attributable to NADCs has increased, with as many as 20% of deaths among PLWH/AIDS due to invasive NADCs in certain cohorts [6-8]. The likely reasons for why PLWH develop NADCs at a higher rate than the general population [9] are multifactorial, including increased life expectancy, premature aging, loss of control of oncogenic infections due to HIV-related immune suppression, and higher prevalence of known cancer risk factors such as tobacco, alcohol, obesity, viral hepatitis, and human papillomavirus (HPV) infection [10-16]. In this review, we summarize the available literature on trends in incidence of NADCs, with a focus on colorectal cancer, lung cancer, prostate cancer, hepatocellular carcinoma, head and neck cancers, squamous cell cancer of the anus, and Hodgkin lymphoma which contribute > 80% of the NADC burden in terms of total numbers of cases among the HIV-infected population [3], among PLWH.

Risk of Non-AIDS-Defining Cancers

Among PLWH, a larger proportion of deaths are due to non-AIDS-defining cancers (NADCs) than AIDS-defining cancers (ADCs). In their analysis of data from almost 47,000 PLWH receiving ART in North American HIV cohorts, estimated 9.8% of deaths were due to cancer [17••]. The fraction of deaths due to NADCs was 7.1%, while only 2.6% of cancer deaths were attributable to AIDS-defining cancers [17••]. Furthermore, the burden of NADCs is likely to increase as PLWH live longer. In fact, Engels et al. [17••] showed that the proportion of all deaths attributed to NADCs has increased over time from 4.2% prior to 2001 to 10.1% between 2006 and 2009. In the US HIV/AIDS Cancer Match Study, PLWH had 21% higher risk of all NADCs combined compared with the general population (standardized incidence ratio [SIR], 1.21; 95% CI, 1.19–1.23) [18••], and the estimated number of NADCs increased by approximately threefold between 1991 and 2005 [3]. However, risk of NADCs among PLWH does vary by site (described in detail below) and has been shown to differ by era and CD4 cell recovery. Nonetheless, the excess risk of NADCs among PLWH highlights the need for aggressive cancer screening and prevention efforts throughout the course of HIV care. In addition, although the epidemiology of NADCs among PLWH in low/middle-income countries may differ from that in high-income countries, and it is reasonable to expect a surge in cases of NADCs among the large and growing HIV-infected population residing in less-developed regions of the world [19, 20], this review will focus on data from high-income countries, particularly data from the USA.

Colorectal Cancer

In the USA, of cancers that affect both males and females, colorectal cancer is the third most common cancer and the second leading cause of cancer-related deaths [21]. Despite growing numbers of PLWH diagnosed annually with colorectal cancer, there is strong evidence that PLWH are not at increased risk for colorectal cancer compared with the general population [3, 4]. Among a 5% sample of US Medicare patients aged ≥ 65 years, the 5-year cumulative incidence of colorectal cancer among PLWH was 0.9% [22]. However, incidence rates for colorectal cancer were no different between individuals with and without HIV infection (adjusted HR, 1.15; 95% CI, 0.86–1.55) [22]. Likewise, a meta-analysis of 4 studies found no association between HIV infection and the risk of colorectal cancer (SIR, 1.1; 95% CI, 0.69–1.7) [9]. In the HIV/AIDS Cancer Match Study, HIV infection was associated with decreased risk for colorectal cancer (colon cancer, SIR, 0.61; 95% CI 0.56–0.67; rectal cancer, SIR, 0.69; 95% CI 0.61–0.77) [18••]. Furthermore, there is no evidence that colorectal cancers are diagnosed at a younger age in PLWH relative to HIV-uninfected individuals [23••]. Because colorectal cancer is increasingly common in older adults (including the older HIV population), and risk is no different between HIV-infected and HIV-uninfected individuals, adherence to the standard screening guidelines for colorectal cancer in the general population is still recommended for PLWH.

Lung Cancer

In the USA, lung cancer is the leading cause of cancer-related deaths and the second most common cancer [21]. There is increasing evidence that HIV infection is independently associated with increased risk for lung cancer (above and beyond higher tobacco usage among PLWH), with lung cancer diagnosed at a younger age in PLWH. Compared with the general population, PLWH infection has an age at diagnosis of lung cancer that is on average 3 to 4 years younger [23••, 24]. The high prevalence of smoking in PLWH (more than 40% of PLWH in the USA smoke, double the smoking rate among the general adult population [16, 25]) is thought to be the primary contributor to the increased risk of lung cancer compared with that in the general population. Using data from the US HIV/AIDS Cancer Match Study, lung cancer rates among PLWH were twofold higher than those among the general population (SIR, 1.97; 95% CI, 1.89–2.05) [18••]. However, the magnitude of the association between HIV infection and lung cancer risk is modest, and heterogeneity in the effect between studies is likely due to the varying ability of studies to control for tobacco smoking. In their study among 37,294 HIV-infected and 75,750 uninfected veterans in the Veterans Aging Cohort Study Virtual Cohort, Sigel et al. [26] found that the incidence rate for lung cancer was 1.7-fold higher (95% CI, 1.5–1.9) among HIV-infected veterans (204 per 100,000 person-years) compared with uninfected veterans (119 per 100,000 person-years) after controlling for potential confounders including tobacco smoking. A retrospective cohort study involving 5238 HIV-infected patients attending a HIV specialty clinic also found increased risk of lung cancer associated with HIV infection after adjustment for tobacco smoking (SIR, 2.5; 95% CI, 1.6 to 3.5) [27]. Among a sample of HIV-infected persons in the US Medicare population, 10.1% developed cancer, of which lung cancer was the most common cancer (5-year cumulative incidence, 2.2%) [22]. Compared with the general population, the incidence of lung cancer was 1.6-fold higher (adjusted HR, 1.61; 95% CI, 1.31–1.98) among PLWH [22]. However, they were unable to control for confounding by tobacco smoking. In a meta-analysis of 18 studies, HIV infection was associated with 3-fold higher risk of lung cancer [9]. Results from analyses of data from the Women’s Interagency HIV Study suggest that increased prevalence of tobacco smoking among HIV-infected individuals explains most, if not all, of the excess risk of lung cancer in women [28, 29]. Sigel et al. [30] found that cumulative bacterial pneumonia episodes were independently associated with risk of lung cancer among participants with HIV from the Veterans Aging Cohort Study; furthermore, Marcus et al. [31] found that the higher risk of lung cancer among PLWH was due to higher prevalence of tobacco smoking and history of pneumonia in HIV-infected vs. HIV-uninfected individuals.

In addition, there is a complex interrelationship between CD4 cell count, degree of immunosuppression, and risk of lung cancer [32, 33]. In their analysis of data from a cohort of 20,775 HIV-infected and 215,158 HIV-uninfected individuals, Silverberg et al. [32] found some evidence for an overall increased risk of lung cancer associated with HIV infection (adjusted RR, 1.2; 95% CI, 0.9–1.6). However, recent CD4 cell count modified the association. While HIV infection was associated with twofold higher risk of lung cancer among individuals with CD4 cell count ≤ 200 (adjusted RR, 2.2; 95% CI, 1.3–3.6), there was no association with lung cancer risk for PLWH with CD4 cell counts of 201–499 (adjusted RR, 1.0; 95% CI, 0.6–1.5) or ≥ 500 (adjusted RR, 1.2; 95% CI, 0.7–1.9) [32]. Likewise, in their cohort study involving 84,504 PLWH, Hleyhel et al. [24] found that the risk of lung cancer among PLWH with CD4 cell recovery on ART was not different to that of the general population (SIR, 0.9; 95% CI, 0.6–1.3). Reddy et al. [34•] found that tobacco smoking but not the HIV infection itself impacts risk of lung cancer-related mortality among PLWH that adhere to ART.

Although lung cancer incidence may not be significantly elevated among those who initiate ART early, lung cancer remains one of the highest causes of morbidity and mortality among PLWH. For example, among a cohort of 83,282 people with HIV infection and AIDS, lung cancer was the most common NADC-related cause of death [8]. Among individuals with AIDS onset between 1996 and 2006, 28 of 130 cancer-related deaths (22%) were due to lung cancer [8]. Large excess mortality from lung cancer was observed among males with HIV infection in another study, where they showed 35–54% excess mortality among PLWH with lung cancer than would be expected among PLWH and lung cancer patients separately [35•]. However, as early ART becomes more widespread, lung cancer incidence rates may decrease in the future. Between 1996 and 2010, lung cancer rates among PLWH decreased by 2.8% per year (95% CI, − 4.5 to − 1.1) [4], as did their excess risk for lung cancer relative to the general population [18••]. Nonetheless, if current smoking rates remain unchanged, estimated 9.3% of PLWH in the USA are expected to die from lung cancer [34•]. Thus, given the high rate of morbidity and mortality from lung cancer among PLWH, current lung cancer screening guidelines with low-dose CT scanning for the general population should be followed for PLWH.

Prostate Cancer

Other than skin cancer, prostate cancer is the most common cancer among males in the USA [21]. It remains unclear however whether or not HIV infection is associated with the risk of prostate cancer. While some studies have reported lower risk of prostate cancer associated with HIV infection [18••, 36-39], others reported no association [40] or higher risk [41]. In a recent analysis of a 5% sample of data from the US Medicare file, HIV infection was associated with over 20% lower risk of prostate cancer (adjusted HR, 0.78; 95% CI, 0.63–0.98) [22]. The inverse association was found for both localized/regional and distant stage cases of prostate cancer [22]. In a recent study using data from the US HIV/AIDS Cancer Match Study and the National Center for Health Statistics, there was no excess mortality for HIV-infected males with prostate cancer [35•]. However, the burden of prostate cancer among HIV-infected males remains substantial. Using data from the US HIV/AIDS Cancer Match Study, Robbins et al. [4] showed that incidence rates for prostate cancer among PLWH increased by 9.8% per year (95% CI, 6.4–13.3) between 1996 and 2010. Incidence of prostate cancer is expected to rise further as the HIV-infected population continues to age.

Hepatocellular Carcinoma

Hepatocellular carcinoma is the most common primary malignancy of the liver, accounting for over 70% of all liver cancer cases. The incidence of and mortality from hepatocellular carcinoma has been increasing in the USA for the past three decades [42], with hepatitis C virus (HCV) and hepatitis B virus (HBV) accounting for most cases of hepatocellular carcinoma in the USA [43]. PLWH are at especially high risk for HBV and HCV infections compared with the general population, and may therefore be at subsequently greater risk for developing hepatocellular carcinoma. In an analysis of PLWH aged ≥ 65 years in 5% samples from the USA Medicare file, the risk of liver cancer was threefold higher than that for the general population (adjusted HR, 3.35; 95% CI, 2.21–5.07) [22]. Similarly, compared with the general population, PLWH infection in the HIV/AIDS Cancer Match Study had incidence rates for liver cancer that were threefold higher (SIR, 3.21; 95% CI, 3.02–3.41) [18••]. Using data from 20,775 HIV-infected and 215,158 HIV-uninfected individuals enrolled in Kaiser Permanente California, Silverberg et al. [32] reported that HIV infection was associated with almost twofold higher risk of liver cancer (adjusted RR, 1.8; 95% CI, 1.1–2.8). A meta-analysis using SIRs from 18 studies of NADCs in PLWH found that PLWH had sixfold increased risk of liver cancer (SIR, 5.6; 95% CI, 4.0–7.7) [9]. Like that seen for lung cancer, recent CD4 cell count modified the association between HIV infection and risk of liver cancer. While HIV infection was associated with two- to threefold higher risk of liver cancer among individuals with lower CD4 cell counts (≤ 200, adjusted RR, 2.9; 95% CI, 1.2–6.6; 201–499, adjusted RR, 2.1; 95% CI, 1.2–3.7), there was no association with liver cancer risk for PLWH with a CD4 cell count ≥ 500 (adjusted RR, 1.0; 95% CI, 0.4–2.4) [32]. Similarly, in their study nested within the Swiss HIV Cohort Study, Clifford et al. [44] found that low CD4 cell count in PLWH infection was associated with increased risk for hepatocellular carcinoma (OR per 100 cells/μl decrease, 1.33; 95% CI, 1.06–1.68). However, most studies assessing the association between HIV infection and risk of liver cancer have been limited in their ability to measure and control for all potential confounders. Because PLWH are at substantially greater risk for HCV and vice versa and have higher prevalence of alcohol abuse, both HCV and alcohol abuse need to be accounted for when evaluating the relationship of HIV with hepatocellular carcinoma.

Using data from the US Veterans Affairs databases (involving 14,018 with HIV infection), McGinnis et al. [45] found that veterans with HIV infection had 1.7-fold higher risk of hepatocellular carcinoma compared to HIV-negative veterans (IRR, 1.68; 95% CI, 1.02–2.77). However, after adjusting for HCV infection and alcohol use, there was no association between HIV infection and risk of hepatocellular carcinoma (IRR, 0.96; 95% CI, 0.56–1.63) [45]. Historically, HIV/HCV co-infected patients received suboptimal ART, and uncontrolled HIV infection might have contributed to the excess risk of hepatocellular carcinoma compared with HCV monoinfected individuals. In their prospective cohort study involving HCV-infected patients with and without HIV infection during the early ART era, Di Benedetto et al. [46] found that HIV co-infection was not associated with a higher incidence of hepatocellular carcinoma. However, in a French cohort study, HIV infection was associated with increased risk for hepatocellular carcinoma regardless of era and CD4 cell count [24]. In the US HIV/AIDS Cancer Match Study, liver cancer rates among PLWH increased by 8.5% per year (95% CI, 4.6–12.5) between 1996 and 2010 [4], making screening and prevention of hepatocellular carcinoma among PLWH a high priority. In fact, guidelines from various clinical societies recommend liver cancer screening and surveillance for patients with hepatitis and HIV co-infection [47-50].

Head and Neck Cancers

Approximately 63,000 individuals in the USA will be newly diagnosed with head and neck cancers each year [21]. HPV infection, in particular the HPV-16 genotype, is an important cause of head and neck cancers (e.g., HPV-16 accounts for 90–95% of HPV-positive oropharyngeal cancers) [51]. PLWH are at high risk for most HPV-associated cancers and epidemiological studies have consistently reported approximately twofold higher risk of head and neck cancers for PLWH compared with the general population [52, 53]. In their analysis of data from the US HIV/AIDS Cancer Match Study, Hernandez-Ramirez et al. [18••] found that HIV infection was associated with increased risks of cancers of the oral cavity or pharynx (HPV-related, SIR, 1.64; 95% CI, 1.46–1.84; HPV-unrelated, SIR, 2.20; 95% CI, 1.98–2.45), nasal cavity (SIR, 2.66; 95% CI, 1.72–3.93), and larynx (SIR, 2.11; 95% CI, 1.89–2.34). Data from NA-ACCORD shows younger ages at diagnosis of oral cavity/pharynx cancers for PLWH compared with the general population (with an average difference of 2 years) [23••]. Although Silverberg et al. [32] reported only a modest effect of HIV infection on the risk of oral cavity/pharynx cancer after adjusting for potential confounders including tobacco smoking (adjusted RR, 1.4; 95% CI, 0.9–2.1), when they stratified by CD4 cell count, there was a strong and statistically significant association with HIV infection for individuals with low CD4 cell count (≤ 200, adjusted RR, 2.5; 95% CI, 1.2–5.4) and no association for those with a high CD4 cell count (≥ 500, adjusted RR, 0.7; 95% CI, 0.3–1.7). In a study among 40,996 HIV-infected male veterans, although age > 50 and recent CD4 < 200 were associated with increase risk, other factors such as era of HIV diagnosis, utilization of ART, and nadir CD4 cell count were not associated with risk of oropharynx cancer [54].

Anal Cancer

Like head and neck cancers, anal cancer is known to be associated with the HPV virus, and epidemiological studies have consistently reported increased risk of anal cancer among PLWH compared with the general population. Meta-analyses published in 2007 [55] and 2009 [9] found that risk of anal cancer was almost 30-fold higher among PLWH. More recently, in their analysis of data from 13 cohorts from North America, Silverberg et al. [56] found that HIV infection was associated with 80-fold higher risk of anal cancer among HIV-infected men who have sex with men (MSM) compared with HIV-uninfected individuals. Risk of anal cancer was also higher among HIV-infected non-MSM men and women compared with HIV-uninfected individuals [56]. In a study involving 20,775 HIV-infected and 215,158 HIV-uninfected individuals enrolled in Kaiser Permanente California, HIV infection was associated with 56-folder higher risk of anal cancer (adjusted RR, 55.7; 95% CI, 33.2–93.4) [32]. As seen for other NADCs, the magnitude of the association with anal cancer was modified by CD4 cell count. However, while the magnitude of the association was stronger for PLWH with CD4 cell counts ≤ 200 (adjusted RR, 91.5; 95% CI, 48.0–174.5), the risk of anal cancer among PLWH with CD4 cell count ≥ 500 was still 34-fold higher compared with that among the general population (adjusted RR, 33.8; 95% CI, 17.8–64.3) [32]. Furthermore, compared with the general population, PLWH have a diagnosis of anal cancer that is on average 4 years younger [23••]. The decline in standardized incidence ratios for anal cancer among PLWH compared with the general population over time [18••], and the fact that two recent studies showed that decreased HIV viral load is associated with decreased risk of anal cancer [57, 58], suggests the importance of intact immune system in controlling oncogenic HPV infection and a role for ART in suppressing the effect of HIV infection on an individual’s future risk of developing anal cancer.

Hodgkin Lymphoma

PLWH are at increased risk of Hodgkin lymphoma likely associated with underlying Epstein-Barr virus (EBV). In the US HIV/AIDS Cancer Match Study, compared with the general population, PLWH had almost eightfold higher risk of Hodgkin lymphoma (SIR, 7.70; 95% CI, 7.20–8.23) [18••]. Silverberg et al. [32] found that among all PLWH, risk for Hodgkin lymphoma was 19-fold higher than the general population (adjusted RR, 18.7; 95% CI, 11.8–29.5); however, the risk for Hodgkin lymphoma increased with decreasing recent CD4 cell count. Importantly, recent data from the US HIV/AIDS Cancer Match Study show that incidence rates for Hodgkin lymphoma among PLWH have decreased by 4.0% per year between 1996 and 2010 [4]. Furthermore, the SIR for Hodgkin lymphoma has declined at a rate of 3.2% annually since 1996 [4] and a study among HIV-infected veterans found that decreased HIV viral load was associated with lower risk of Hodgkin lymphoma (≥ 80% undetectable HIV vs. < 20% undetectable HIV, adjusted HR, 0.62; 95% CI, 0.37–1.02) [57], demonstrating that like anal cancer, prolonged HIV viral load control also decreases the risk of Hodgkin lymphoma.

Conclusions

With the aging HIV infection population, NADCs are an increasing public health problem. There is strong evidence that compared with the general population, PLWH are at increased risk for lung cancer, head and neck cancers, anal cancer, hepatocellular carcinoma, and Hodgkin lymphoma. Although most NADCs are not diagnosed at younger ages, there is strong evidence that PLWH are diagnosed with lung cancer, head and neck cancers, and anal cancer at younger ages compared with the general population (Table 1). The reasons are unclear; however, this may reflect faster cancer progression, distinct etiologies or etiologic heterogeneity, and/or risk factor profiles that are more prone to developing these cancers. Screening and prevention for NADCs, especially infection-related NADCs, among PLWH should be a priority. However, given that immunodeficiency may modify risks of certain NADCs among PLWH, as early ART treatment initiation recommendations become more widespread, the incidence for certain NADCs may continue to change over the next several decades, with NADCs that have increased incidence among the elderly (lung cancer, prostate cancer, and colorectal cancer) causing an increasing proportion of cancer morbidity and mortality among PLWH.

Table 1.

Association between HIV infection and risk of non-AIDs-defining cancers

Cancer	Magnitude and direction of association	Difference in age at diagnosis
Colorectal cancer	None	N/A
Lung cancer	+	−3 to −4 years
Prostate cancer	−	N/A
Hepatocellular carcinoma	+	0
Head and neck cancers	+	−2 years
Anal cancer	+ + +	−4 years
Hodgkin lymphoma	+ + +	0

+ indicates a standardized incidence ratio (SIR) < 5; + + indicates an SIR of 5–10; and + + + indicates an SIR > 10