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Review

Tumor Initiation and Progression in People Living on Antiretroviral Therapies

by
Seun E. Olufemi
1,2,*,
Daniel A. Adediran
1,
Temitope Sobodu
3,
Isaac O. Adejumo
4,
Olumide F. Ajani
5 and
Elijah K. Oladipo
1,6
1
Division of Genomic Science, Helix Biogen Institute, Ogbomoso 210101, Nigeria
2
International Research Centre for Excellence, Institute of Human Virology, Abuja 900107, Nigeria
3
Department of Endocrinology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
4
Department of Animal Science, University of Ibadan, Ibadan 200005, Nigeria
5
Global Health and Infectious Disease Control Institute, Nasarawa State University, Keffi 961001, Nigeria
6
Laboratory of Molecular Biology, Immunology and Bioinformatics, Adeleke University, Ede 232104, Nigeria
*
Author to whom correspondence should be addressed.
Biologics 2024, 4(4), 390-406; https://doi.org/10.3390/biologics4040024
Submission received: 3 August 2024 / Revised: 13 September 2024 / Accepted: 9 October 2024 / Published: 25 October 2024
Browse Figures
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Abstract

:
Antiretroviral therapy (ART) has significantly extended the lifespan of people living with Human Immunodeficiency Virus (HIV) or Acquired Immunodeficiency Syndrome (AIDS), thereby transforming the disease into a manageable chronic condition. However, this increased longevity has led to a higher incidence of non-AIDS-defining cancers (NADCs) among this population. In this holistic review, we explore the complex interactions between HIV, ART, and cancer development, focusing on how ART influences tumor initiation and progression in people living with HIV/AIDS (PLWHA). Our findings from this reveal several critical aspects of cancer risk in PLWHA. Firstly, while ART restores immune function, it does not fully normalize it. Chronic immune activation and persistent inflammation continue to be prevalent, creating a conducive environment for oncogenesis. Additionally, PLWHA are more susceptible to persistent infections with oncogenic viruses such as human papillomavirus (HPV) and Epstein–Barr virus (EBV), further increasing cancer risk. Some ART drugs have been implicated in genotoxicity and mitochondrial dysfunction, potentially promoting tumorigenesis. ART-induced metabolic changes, including insulin resistance and dyslipidemia, are also associated with heightened cancer risk. Common NADCs in PLWHA include lung cancer, liver cancer, anal cancer, and Hodgkin lymphoma, each with distinct etiologies linked to both HIV-related and ART-related factors. The interplay between HIV infection, chronic inflammation, immune restoration via ART, and the direct effects of ART drugs creates a unique cancer risk profile in PLWHA. Although ART reduces the incidence of AIDS-defining cancers, it does not confer the same protective effect against NADCs. Persistent HIV-related inflammation and immune activation, despite viral suppression, are key factors in cancer development. Additionally, long-term exposure to ART may introduce new oncogenic risks. These insights highlight the need for integrated cancer screening and prevention strategies tailored to PLWHA. Future research is needed to focus on identifying biomarkers for early cancer detection and developing ART regimens with lower oncogenic potential. Healthcare providers should be vigilant in monitoring PLWHA for cancer and adopt comprehensive screening protocols to mitigate the increased cancer risk associated with ART.

1. Introduction

Human Immunodeficiency Virus (HIV) is a retrovirus that targets and progressively weakens the human immune system by primarily infecting CD4+ T cells, which are crucial for immune system functioning [1]. As HIV begins to replicate, it depletes these immune cells, leading to immunodeficiency. Without treatment, this process can progress to Acquired Immunodeficiency Syndrome (AIDS), where the immune system becomes severely compromised, making individuals highly susceptible to opportunistic infections and certain cancers [2]. HIV is mainly transmitted through unprotected sexual contact, sharing of contaminated needles, and from mother to child during childbirth or breastfeeding [3]. The global impact of HIV has been profound, affecting millions of individuals and posing significant public health challenges.
ART has revolutionized the management of HIV infection since its adoption in the mid-1990s. ART works to suppress HIV replication [4], and this suppression not only helps in restoring and maintaining immune function but also significantly reduces the morbidity and mortality associated with HIV/AIDS [5]. ART has transformed HIV from a fatal disease into a manageable chronic condition. The effectiveness of ART in reducing viral load to undetectable levels means that individuals on consistent ART can have a near-normal life expectancy. Additionally, effective ART reduces the risk of HIV transmission, which has profound implications for public health by helping to control the spread of the virus [6].
PLWHA have a higher risk of developing certain cancers compared to the general population [7]. This increased risk is attributed to several factors, including chronic immunosuppression, prolonged inflammation, and a higher prevalence of oncogenic virus co-infections such as human papillomavirus (HPV), Epstein–Barr virus (EBV), and Kaposi’s sarcoma-associated herpesvirus (KSHV) [8]. The weakened immune surveillance in PLWHA facilitates the persistence and proliferation of these oncogenic viruses, which can lead to malignancies. Traditionally, AIDS-defining cancers (ADCs) like Kaposi’s sarcoma, non-Hodgkin lymphoma, and invasive cervical cancer were the most common. However, with the advent of ART and improved immune function, non-AIDS-defining cancers (NADCs) such as lung, liver, and anal cancers have become more prevalent among PLWHA [9].
ART has significantly altered the landscape of cancer risk among PLWHA. By effectively suppressing HIV replication and restoring immune function, ART reduces the incidence of AIDS-defining cancers (ADCs). The restoration of immune surveillance helps control oncogenic virus infections and reduces chronic inflammation, which are key factors in cancer development [10]. However, ART does not completely eliminate the increased cancer risk. Some studies suggest that the long-term use of ART may have oncogenic potential due to its possible mutagenic effects. Additionally, while ART reduces the risk of some cancers, it may contribute to the development of others through metabolic complications such as insulin resistance and dyslipidemia [11]. Consequently, while ART has markedly improved the overall health and longevity of PLWHA, ongoing vigilance in cancer prevention and management remains crucial in this population.

2. Mechanisms of Tumor Initiation in PLWHA

The mechanisms of tumor initiation in PLWHA are multifaceted, involving a combination of HIV-related factors, the effects of antiretroviral therapy (ART), and co-infections with oncogenic viruses. Understanding these mechanisms is critical for developing effective prevention and treatment strategies.

2.1. HIV-Related Factors

2.1.1. Immunosuppression and Chronic Inflammation

One of the primary mechanisms by which HIV contributes to tumor initiation is through immunosuppression. HIV targets CD4+ T cells, leading to their progressive depletion and resulting in a weakened immune system. This immunodeficiency reduces the body’s ability to detect and destroy malignant cells, thereby increasing the risk of cancer development [12].
In addition to immunosuppression, chronic inflammation plays a crucial role in cancer initiation among PLWHA. HIV infection causes persistent immune activation and inflammation, even in individuals receiving ART [13]. This chronic inflammatory state promotes a tumor-friendly environment through various pathways. Inflammatory cytokines such as TNF-α, IL-6, and IL-1β can induce cellular proliferation, inhibit apoptosis, and enhance angiogenesis, all of which contribute to tumorigenesis, as shown in Figure 1 below [14]. Moreover, chronic inflammation can cause DNA damage and mutations, further increasing the risk of cancer.

2.1.2. Direct Oncogenic Effects of HIV Proteins

HIV proteins have been established to have direct oncogenic effects, contributing to the development of malignancies. For example, the HIV transactivator of transcription (Tat) protein is known to promote cellular proliferation and survival [15]. Tat can activate various cellular signaling pathways, including those involving NF-κB and MAPK, which are associated with cancer development. Additionally, Tat can induce angiogenesis by upregulating vascular endothelial growth factor (VEGF), thereby promoting the growth of tumors [15]. The precise mechanisms of Tat’s action, whether direct or mediated through secondary signaling cascades, underscore its complex role in HIV-associated malignancies and necessitate further investigation to differentiate between direct effects and those involving intermediary pathways [16].
Another HIV protein, Nef, has been implicated in oncogenesis. Nef can interfere with apoptosis by modulating the activity of cellular proteins such as p53 and Bcl-2 [17]. By inhibiting apoptosis, Nef allows for the survival of cells that have undergone malignant transformation, as shown in Figure 2 below. Furthermore, Nef can induce cellular proliferation through the activation of Src family kinases, which are involved in signal transduction pathways linked to cancer [18]. Additionally, Nef is known to stimulate the production of exosomes, which can carry viral and host molecules that contribute to immune evasion and inflammation. This exosome-mediated modulation of the immune response may further promote viral persistence and influence oncogenic processes in HIV-infected individuals [17].

2.2. ART-Related Factors

2.2.1. Impact of ART on Immune Restoration

While ART has been transformative in managing HIV infection and restoring immune function, its impact on tumor initiation is complex. ART effectively suppresses HIV replication and helps reconstitute the immune system, which should theoretically reduce the risk of cancer by enhancing immune surveillance and reducing chronic inflammation [19]. Indeed, ART has been shown to decrease the incidence of ADCs such as Kaposi’s sarcoma and non-Hodgkin lymphoma [20]. However, immune reconstitution (recovery and restoration of immune system function following its depletion or suppression, such as after chemotherapy or bone marrow transplantation) under ART is often incomplete, especially in individuals who start treatment at advanced stages of HIV infection. Residual immune dysfunction and chronic immune activation persist in many PLWHA despite effective viral suppression. This incomplete immune restoration can still allow for the development and progression of cancers, particularly NADCs, which are becoming increasingly prevalent among PLWHA [21].

2.2.2. Potential Mutagenic Effects of ART Drugs

Another consideration is the potential mutagenic effects of ART drugs themselves. Some studies suggest that long-term exposure to certain antiretroviral drugs may increase the risk of cancer through mechanisms such as oxidative stress and direct DNA damage. For instance, nucleoside reverse transcriptase inhibitors (NRTIs) can be incorporated into the DNA of host cells, potentially leading to mutations [22]. Additionally, the mitochondrial toxicity associated with some NRTIs can result in the increased production of reactive oxygen species (ROS), which can damage DNA and contribute to carcinogenesis [23]. Protease inhibitors (PIs), another class of ART drugs, have been associated with metabolic complications such as insulin resistance and dyslipidemia, which are risk factors for cancer. The chronic use of ART can also lead to cumulative toxicities, potentially increasing the risk of malignancies over time [24].

2.2.3. Customizing ART Regimens to Mitigate Cancer Risk

When selecting an ART regimen for PLWHA, physicians should carefully weigh the potential oncogenic risks of specific drugs against their efficacy in suppressing HIV replication and restoring immune function. Factors such as the patient’s age, smoking status, and pre-existing conditions should be considered when choosing the most appropriate ART regimen [25]. Regular monitoring for long-term toxicities associated with ART, including potential oncogenic effects, is crucial. Physicians should closely follow up with PLWHA on ART and be vigilant for any signs of malignancy or metabolic complications that may increase cancer risk [26].

2.3. Co-Infections and Oncogenic Viruses

2.3.1. Human Papillomavirus

Co-infection with oncogenic viruses is a significant factor in tumor initiation among PLWHA. HPV is a well-known oncogenic virus that is highly prevalent in PLWHA. HPV infection is strongly associated with cancers of the cervix, anus, penis, and oropharynx [27]. The immunosuppression caused by HIV allows for persistent HPV infection and progression to malignancy. HPV produces proteins such as E6 and E7, which can inactivate the tumor suppressor proteins p53 and Rb, respectively, leading to uncontrolled cellular proliferation and cancer [28]. With the introduction of ART, there has been a reduction in the incidence of HPV-related malignancies among PLWHA due to improved immune function and reduced HIV-related immunosuppression. However, persistent HPV infections still pose a risk, as ART does not completely eliminate the virus or the risk of HPV-related cancers.

2.3.2. Epstein–Barr Virus

EBV is another oncogenic virus commonly found in PLWHA. EBV is associated with several malignancies, including non-Hodgkin lymphoma, Hodgkin lymphoma, and nasopharyngeal carcinoma. HIV-related immunosuppression facilitates EBV reactivation and persistent infection [29]. EBV encodes several oncogenic proteins, such as LMP1 and EBNA2, which can activate signaling pathways that promote cell growth and survival. Chronic EBV infection in the context of HIV can thus significantly increase the risk of developing EBV-associated cancers [30]. ART has led to a decreased incidence of some EBV-associated cancers among PLWHA by restoring immune surveillance and reducing EBV reactivation rates. Nevertheless, the risk of EBV-related malignancies remains elevated in PLWHA compared to the general population, as ART does not fully restore immune function to pre-HIV levels.

2.3.3. Kaposi’s Sarcoma-Associated Herpesvirus

KSHV is the causative agent of Kaposi’s sarcoma (KS), a cancer that is highly prevalent among PLWHA. KSHV infection is often asymptomatic in immunocompetent individuals, but in the context of HIV-induced immunosuppression, it can lead to KS. KSHV encodes several oncogenic proteins, including vGPCR, vIL-6, and LANA, which promote angiogenesis, immune evasion, and cellular transformation [31]. ART has reduced the incidence of KS, but it remains a significant cancer risk for PLWHA, particularly in resource-limited settings where access to ART may be inconsistent [32].

2.3.4. Hepatitis B and C Viruses

HBV and HCV are also important oncogenic viruses in PLWHA, contributing to the high incidence of liver cancer in this population. HIV co-infection with HBV or HCV accelerates the progression of liver disease, leading to higher rates of cirrhosis and hepatocellular carcinoma (HCC) [33]. Chronic inflammation and liver damage caused by these viral infections, combined with HIV-related immunosuppression, create a permissive environment for liver cancer development. Additionally, antiretroviral drugs metabolized by the liver can exacerbate liver toxicity and inflammation, further increasing cancer risk [34].

3. Types of Cancers in People Living with HIV and AIDS on Antiretroviral Therapy

The types of cancers observed in PLWHA on ART can be broadly categorized into ADCs and NADCs [35]. While ART has significantly reduced the incidence of some AIDS-defining cancers, the prevalence of non-AIDS-defining cancers has risen, likely due to improved longevity and persistent risk factors.

3.1. AIDS-Defining Cancers

3.1.1. Kaposi’s Sarcoma

KS is one of the most common AIDS-defining cancers. It is caused by infection with Kaposi’s sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8) [36]. KS is characterized by the growth of abnormal blood vessels that form lesions on the skin, mucous membranes, and internal organs. In PLWHA, KS often presents aggressively, with lesions that can appear purple, red, or brown [37]. ART has dramatically reduced the incidence of KS by improving immune function and reducing HIV viral load. However, KS remains prevalent, particularly in regions where ART access is limited. Treatment for KS in PLWHA includes initiating or optimizing ART, chemotherapy, and local therapies such as radiation [38].

3.1.2. Non-Hodgkin Lymphoma

Non-Hodgkin lymphoma (NHL) encompasses a diverse group of blood cancers that originate in the lymphatic system. In PLWHA, the most common subtypes are diffuse large B-cell lymphoma and primary central nervous system lymphoma [39]. HIV-associated immunosuppression facilitates the reactivation of oncogenic viruses like Epstein–Barr virus (EBV), which plays a significant role in the pathogenesis of NHL [40]. ART has reduced the incidence of NHL by restoring immune function, though it remains a significant cause of morbidity and mortality. Treatment typically involves combination chemotherapy, often accompanied by ART to maintain immune reconstitution [41].

3.1.3. Cervical Cancer

Cervical cancer is closely associated with persistent infection with oncogenic strains of human papillomavirus (HPV). In PLWHA, the immunosuppression caused by HIV infection leads to a higher prevalence and persistence of high-risk HPV types, increasing the risk of cervical dysplasia and progression to invasive cervical cancer [42]. While ART improves immune function, it does not fully eliminate the risk of cervical cancer. Regular cervical cancer screening and HPV vaccination are critical preventive measures for PLWHA. Treatment for cervical cancer may involve surgery, radiation, and chemotherapy, depending on the stage of the disease [43].

3.2. Non-AIDS-Defining Cancers

3.2.1. Lung Cancer

Lung cancer has emerged as a leading non-AIDS-defining cancer in PLWHA. Risk factors include smoking, which is highly prevalent in the HIV-positive population, chronic inflammation, and immunosuppression. HIV-associated immune activation and inflammation may contribute to lung carcinogenesis [44]. ART has improved the overall survival of PLWHA, but the risk of lung cancer remains elevated. Screening for lung cancer in high-risk individuals, smoking cessation programs, and early intervention are crucial [45]. Treatment modalities include surgery, radiation, chemotherapy, and targeted therapies, depending on the cancer’s stage and molecular characteristics.

3.2.2. Liver Cancer

Liver cancer, particularly hepatocellular carcinoma (HCC), is more common in PLWHA due to higher rates of co-infection with HBV and HCV. Chronic liver inflammation and cirrhosis from these viral infections are significant risk factors for HCC [46]. ART can reduce liver inflammation and slow the progression of liver disease, but the risk of HCC remains elevated. Management includes regular surveillance with imaging and alpha-fetoprotein (AFP) testing, antiviral treatment for HBV and HCV, and liver transplantation for eligible patients [47]. Other treatments include surgical resection, ablation, and systemic therapies.

3.2.3. Anal Cancer

Anal cancer is strongly associated with persistent infection with high-risk HPV types, similar to cervical cancer. PLWHA are at increased risk due to immunosuppression, which leads to a higher prevalence of HPV infection and progression to malignancy [48]. Screening for anal dysplasia and high-resolution anoscopies are important preventive measures. Treatment for anal cancer typically involves a combination of chemotherapy and radiation therapy [49]. ART helps maintain immune function, which can improve treatment outcomes.

3.2.4. Hodgkin Lymphoma

Hodgkin lymphoma (HL) is more prevalent in PLWHA compared to the general population, with a particularly high incidence of the EBV-associated subtype. Immunosuppression and chronic immune activation contribute to the increased risk [50]. ART has improved the prognosis for PLWHA with HL, but the disease remains aggressive. Treatment usually involves chemotherapy, and sometimes radiation therapy, tailored to the individual’s immune status and overall health [51]. Continuous ART is essential to support immune function and enhance the efficacy of lymphoma treatment.

3.2.5. Others (e.g., Colorectal Cancer, Breast Cancer)

Several other cancers have been observed with increased frequency in PLWHA, including colorectal and breast cancer. The reasons for the increased risk are multifactorial and include prolonged life expectancy due to ART, chronic inflammation, and lifestyle factors such as smoking and alcohol use. Chronic inflammation and immune suppression can contribute to an increased risk of colorectal cancer in PLWHA. Regular screening through colonoscopy is recommended for early detection. Treatment includes surgery, chemotherapy, and sometimes radiation therapy [52]. While the mechanisms linking HIV to an increased risk of breast cancer are not entirely clear, it is thought that chronic immune activation and potential direct effects of HIV or ART on breast tissue might play a role. Routine mammography screening and prompt treatment (surgery, chemotherapy, radiation, and hormone therapy) are critical for managing breast cancer in PLWHA [53]. The Table 1 below highlights AIDS-defining cancers (ADCs) and non-AIDS-defining cancers (NADCs) in respect to Etiology, Impact of ART, Screening and Prevention Treatment, Prognosis, Geographic Variations and Demographic Factors.

4. Tumor Progression and Antiretroviral Therapy

The influence of ART on tumor progression in PLWHA is a complex interplay of immune restoration, ART adherence, drug toxicities, and interactions with cancer treatments [51]. Understanding these factors is essential for optimizing cancer management in this population.

4.1. Antiretroviral Therapy’s Influence on Cancer Progression

4.1.1. Immune Reconstitution Inflammatory Syndrome (IRIS) and Cancer Progression

Immune reconstitution inflammatory syndrome (IRIS) is a phenomenon observed in some PLWHA after initiating ART. It occurs when the recovering immune system mounts an exaggerated inflammatory response to existing infections or malignancies, which were previously asymptomatic due to immunosuppression [54]. IRIS can unmask or exacerbate underlying cancers, leading to accelerated tumor progression. For example, IRIS-associated Kaposi’s sarcoma can present with rapid tumor growth and widespread dissemination shortly after starting ART. The management of IRIS involves balancing the need for continued ART to control HIV with interventions to manage the inflammatory response and underlying malignancy [55]. Corticosteroids are sometimes used to mitigate severe inflammatory responses, but careful monitoring is essential to avoid compromising immune restoration [56].

4.1.2. Antiretroviral Therapy Adherence and Viral Suppression

Adherence to ART is crucial for maintaining viral suppression, which in turn impacts cancer progression. Consistent adherence to ART leads to sustained suppression of HIV replication, preservation of immune function, and reduced chronic inflammation, all of which contribute to better control of malignancies [57]. Conversely, poor adherence can lead to virologic failure, immune system deterioration, and an increased risk of cancer progression. Studies have shown that PLWHA with unsuppressed viral loads are more likely to experience aggressive cancer growth and poorer outcomes. Ensuring high levels of ART adherence through patient education, support programs, and simplified ART regimens is vital for minimizing cancer progression [5].

4.2. Antiretroviral Therapy-Related Toxicity and Cancer Progression

4.2.1. Long-Term Toxicities of Antiretroviral Therapy Drugs

While ART has transformed HIV into a manageable chronic condition, long-term use of ART drugs can lead to toxicities that may influence cancer progression. Some antiretroviral drugs are associated with mitochondrial toxicity, leading to oxidative stress and potential DNA damage, which can contribute to oncogenesis [58]. Additionally, certain nucleoside reverse transcriptase inhibitors (NRTIs) have been linked to an increased risk of malignancies due to their mutagenic effects. Long-term exposure to these drugs necessitates careful monitoring and, when possible, the use of less toxic alternatives to mitigate the risk of cancer progression [59].

4.2.2. Metabolic Complications

ART, particularly protease inhibitors (PIs) and some NRTIs, is associated with metabolic complications such as insulin resistance, dyslipidemia, and lipodystrophy. These metabolic abnormalities increase the risk of cardiovascular diseases and have been linked to an elevated risk of certain cancers [60]. Insulin resistance and hyperinsulinemia can promote tumor growth through various mechanisms, including the activation of insulin-like growth factor (IGF) pathways that stimulate cellular proliferation and inhibit apoptosis [61]. Dyslipidemia can lead to chronic inflammation, further contributing to a tumor-promoting environment [62]. Managing these metabolic complications through lifestyle interventions, medications, and adjustments in ART regimens is essential for reducing cancer progression risks.

4.3. Drug Interactions and Cancer Treatment

4.3.1. Antiretroviral Therapy and Chemotherapy Interactions

The concurrent use of ART and chemotherapy in PLWHA with cancer presents significant challenges due to potential drug–drug interactions. Many antiretroviral drugs and chemotherapeutic agents are metabolized by the cytochrome P450 (CYP) enzyme system, leading to altered drug levels when used together [60]. For instance, protease inhibitors can inhibit CYP enzymes, potentially increasing the toxicity of certain chemotherapeutic drugs. Conversely, some non-nucleoside reverse transcriptase inhibitors (NNRTIs) can induce CYP enzymes, reducing the efficacy of chemotherapy [63]. These interactions can impact both the efficacy and safety of cancer treatments. Oncologists and HIV specialists must collaborate to carefully select and adjust drug regimens, considering potential interactions and using therapeutic drug monitoring to optimize treatment outcomes [64].

4.3.2. Impact on Efficacy and Toxicity of Cancer Therapies

ART can also impact the efficacy and toxicity of cancer therapies beyond drug–drug interactions. The immunomodulatory effects of ART can influence the tumor microenvironment and the body’s response to cancer treatment. For example, effective ART can enhance immune function, potentially improving the response to immunotherapies [65]. However, ART-related toxicities, such as peripheral neuropathy from certain NRTIs, can exacerbate the side effects of chemotherapeutic agents, leading to dose reductions or the discontinuation of cancer treatment [66]. Managing these complexities requires a personalized approach, considering the individual’s ART regimen, cancer type, and overall health status. Strategies may include dose adjustments, the use of alternative antiretrovirals with fewer interactions, and supportive care measures to mitigate toxicity [67]. Additionally, clinical trials specifically designed for PLWHA with cancer are essential to generate evidence-based guidelines for this unique population. In all, Table 2 provides a summary of key factors involved in tumor initiation and progression in people living with HIV and AIDS who are undergoing antiretroviral therapy.

5. Epidemiological Studies and Data

Epidemiological studies have been shown to provide critical insights into the incidence, prevalence, and distribution of cancers among PLWHA. These studies highlight comparative risks, trends over time, and variations across different geographic and demographic groups.

5.1. Incidence and Prevalence of Cancers in People Living with HIV and AIDS

5.1.1. Comparative Studies Between PLWHA and the General Population

Epidemiological data indicate that PLWHA experience a significantly higher incidence of certain cancers compared to the general population. For example, PLWHA have an incidence rate of Kaposi’s sarcoma (KS) that can be up to 20,000 times greater than that of HIV-negative individuals [68]. Additionally, non-AIDS-defining cancers (NADCs) occur more frequently among PLWHA, with incidence rates that can be two to three times higher than those in the general population. A study found that among 81,865 PLWHA, 814 (0.9%) were diagnosed with cancer, with lung cancer, liver cancer, and anal cancer being notably prevalent among this group [69].

5.1.2. Trends over Time with the Advent of Antiretroviral Therapy

The introduction of antiretroviral therapy (ART) in the mid-1990s has led to a significant decline in the incidence of AIDS-defining cancers (ADCs). For instance, the incidence of KS and non-Hodgkin lymphoma (NHL) has decreased substantially, with a reported reduction in cancer-attributable mortality rates from 484-per-100,000-people-years in 2001–2005 to 313.6-per-100,000-people-years in 2011–2015 [68,69]. However, as PLWHA live longer due to effective ART, there has been an increase in the incidence of NADCs. The incidence of lung cancer among PLWHA, for example, has been reported to be significantly elevated, with a standardized incidence ratio (SIR) of 2.95, indicating a higher risk compared to HIV-negative cohorts [7].

5.2. Geographic and Demographic Variations

5.2.1. Differences by Region and Access to ART

Geographic disparities in cancer incidence and prevalence among PLWHA are influenced by varying access to ART and healthcare infrastructure. In high-income countries, ADCs have significantly declined, while NADCs have become more common [70]. For example, in the United States, 29.2% of cancer cases among PLWHA were ADCs, while 67.0% were NADCs [71]. In contrast, low- and middle-income countries continue to face a significant burden of ADCs, particularly KS and cervical cancer, due to limited ART access [72].

5.2.2. Variations by Age, Sex, and Race

Demographic factors such as age, sex, and race also impact cancer epidemiology among PLWHA. Younger individuals are more likely to develop ADCs, while older individuals face a higher risk of NADCs [73]. For instance, cervical cancer remains a significant concern for HIV-positive women, with high rates of persistent HPV infection contributing to this increased risk. Racial disparities are evident as well, with African Americans with HIV experiencing higher cancer incidence rates than their white counterparts, partly due to differences in healthcare access and socioeconomic status [74].

6. Prevention and Management Strategies

Effective prevention and management strategies are essential to address the increased cancer risk among PLWHA. These strategies encompass screening and early detection, modifying ART regimens, integrative cancer care, and vaccination and prophylaxis.

6.1. Screening and Early Detection

6.1.1. Guidelines for Cancer Screening in People Living with HIV and AIDS

Cancer screening is crucial for early detection and improving outcomes in PLWHA. Guidelines for cancer screening in this population should be tailored to their elevated risk and specific cancer types [75]. Key recommendations include:
  • Cervical cancer: regular Pap smears and HPV testing for HIV-positive women are essential for early detection of cervical cancer. Screening should start at the time of HIV diagnosis and be repeated annually [76].
  • Anal cancer: for high-risk groups, such as men who have sex with men (MSM) and individuals with a history of anal HPV infection, anal Pap smears or high-resolution anoscopies are recommended [77].
  • Liver cancer: screening for hepatocellular carcinoma (HCC) with ultrasound and alpha-fetoprotein (AFP) levels is advised for PLWHA co-infected with hepatitis B or C viruses [78].
  • Other cancers: regular screenings for breast, colorectal, and lung cancers should be conducted according to general population guidelines, with adjustments based on individual risk factors and health status.

6.1.2. Role of Regular Monitoring and Check-Ups

Regular monitoring and check-ups play a critical role in the early detection and management of cancers in PLWHA. Continuous health assessments help in identifying new symptoms, tracking disease progression, and ensuring timely interventions [79]. These check-ups should include comprehensive physical examinations, routine laboratory tests to monitor immune function and viral load, and imaging studies and specific cancer markers based on individual risk factors. Early detection through consistent monitoring allows for prompt treatment and better prognosis.

6.2. Modifying ART Regimens

6.2.1. Selection of ART Drugs with Lower Carcinogenic Potential

The choice of ART drugs can influence cancer risk. Selecting antiretroviral medications with lower carcinogenic potential is crucial for long-term health. Clinicians should consider avoiding drugs with known mutagenic effects such as nucleoside reverse transcriptase inhibitors (NRTIs), which have been associated with mutagenesis and an increased risk of malignancies [59]. Alternatives with better safety profiles should be preferred. More also, individualized ART regimens should be tailored based on the patient’s overall health, comorbid conditions, and cancer risk factors, which can help minimize potential adverse effects [80].

6.2.2. Addressing ART-Related Toxicities

Managing ART-related toxicities is vital to prevent long-term complications that may contribute to cancer development. Strategies include monitoring and managing metabolic complications by regularly screening for insulin resistance, dyslipidemia, and other metabolic issues, allowing for early intervention through lifestyle changes, medications, or ART regimen adjustments [81], and minimizing cumulative toxicity by periodically reviewing and adjusting ART regimens to reduce the burden of long-term toxicity, which can help mitigate cancer risks [66].

6.3. Integrative Cancer Care

6.3.1. Multidisciplinary Approach to Cancer Treatment

An integrative, multidisciplinary approach is essential for effective cancer care in PLWHA. This involves collaboration between various healthcare professionals, including oncologists leading cancer treatment and coordinating with other specialists, HIV specialists ensuring optimal HIV management and addressing ART-related issues, primary care physicians overseeing overall health and preventive care, and other specialists, which may include radiologists, surgeons, and palliative care experts as needed [80]. A coordinated approach would ensure comprehensive care, addressing both cancer and HIV-related health needs.

6.3.2. Supportive Care and Quality of Life

Supportive care is crucial for maintaining the quality of life for PLWHA undergoing cancer treatment. This includes:
  • Pain management and symptom control: using medications, physical therapy, and complementary therapies to alleviate symptoms.
  • Nutritional support: ensuring adequate nutrition to support immune function and recovery.
  • Psychosocial support: providing counseling, support groups, and mental health services to address emotional and psychological needs.
  • Palliative care: offering palliative care services to improve comfort and quality of life for patients with advanced cancer [80].

6.4. Vaccination and Prophylaxis

6.4.1. HPV Vaccination

HPV vaccination is a critical preventive measure for reducing the risk of HPV-related cancers, such as cervical and anal cancers [82]. Recommendations include administering the HPV vaccine to all PLWHA, regardless of age, due to their higher risk of persistent HPV infection and related cancers and providing catch-up vaccinations for those who were not vaccinated at the recommended age.

6.4.2. Prophylactic Treatments for Co-Infections

Preventing and managing co-infections is vital for reducing cancer risk in PLWHA. Strategies include screening for and treating hepatitis B and C infections can significantly reduce the risk of liver cancer. Antiviral therapies and regular monitoring are essential [83]. For individuals at high risk of opportunistic infections, prophylactic antibiotics can prevent infections that may contribute to cancer development [84].

7. Future Directions

Addressing the increased cancer risk in PLWHA requires a concerted effort to advance our understanding of the underlying mechanisms, improve existing treatments, and develop novel therapeutic strategies. Future research should focus on several key areas, including understanding molecular mechanisms, developing safer ART drugs, and enhancing immune function.
To better manage and prevent cancers in PLWHA, it is critical to deepen our understanding of how HIV and ART contribute to carcinogenesis. Research should explore HIV-related factors, such as the direct oncogenic effects of HIV proteins like Tat and Nef, which are implicated in promoting cell proliferation and inhibiting apoptosis. Additionally, understanding the role of chronic immunosuppression and inflammation in cancer initiation and progression is essential. Studies are also needed to assess the potential mutagenic effects of long-term ART use. While ART effectively suppresses HIV replication and restores immune function, some ART drugs may have genotoxic properties that contribute to cancer risk. Research should focus on identifying which ART components are most associated with carcinogenesis and elucidating the underlying mechanisms.
Genetic and epigenetic research can provide insights into individual susceptibility to cancer among PLWHA. Identifying genetic variants that increase cancer risk in PLWHA can help tailor prevention and treatment strategies. Genome-wide association studies (GWASs) and other genetic research methods can reveal how inherited genetic factors influence cancer development in the context of HIV and ART. Understanding how HIV infection and ART influence epigenetic changes, such as DNA methylation and histone modification, can shed light on the mechanisms driving carcinogenesis. Epigenetic research may uncover potential biomarkers for early cancer detection and novel therapeutic targets.
The development of ART drugs with improved safety profiles is crucial for reducing long-term cancer risk. Future research should prioritize creating ART drugs that maintain viral suppression while minimizing adverse effects, including designing drugs with lower mutagenic potential and reduced metabolic complications. Advances in drug delivery technologies, such as nanoparticle-based systems, can enhance the specificity and efficacy of ART drugs, reducing off-target effects and overall toxicity.
Comprehensive long-term safety studies are essential to understand the full impact of prolonged ART use on cancer risk. These studies should monitor diverse populations, ensuring that findings are generalizable and relevant to all PLWHA. This includes considering factors such as age, sex, race, and comorbid conditions. Longitudinal studies should track the cumulative impact of ART over decades, providing insights into how long-term use affects cancer risk and other health outcomes. Enhancing immune function in PLWHA is vital for reducing cancer risk and improving overall health. Research should focus on developing therapies that specifically boost immune surveillance and response to help control oncogenic virus infections and reduce cancer risk. This includes exploring cytokine therapies, immune checkpoint inhibitors, and other immunomodulatory approaches. Investigating the use of adjuvant therapies in combination with ART to enhance immune function without increasing toxicity is crucial. These therapies can help maintain robust immune responses in the face of chronic HIV infection.
Chronic inflammation is a significant risk factor for cancer in PLWHA. Research should aim to identify strategies to mitigate this inflammation, including developing and testing drugs that specifically target inflammatory pathways implicated in carcinogenesis. This includes both existing anti-inflammatory medications and novel compounds. Studying the impact of lifestyle changes, such as diet, exercise, and stress reduction, on inflammation and cancer risk in PLWHA can provide practical, non-pharmacological approaches to improving health outcomes.

8. Conclusions

While ART has significantly improved the lifespan and quality of life for PLWHA, it has also introduced new challenges, including an increased risk of NADCs. The interplay between HIV, chronic inflammation, immune restoration, and the direct effects of ART drugs creates a unique cancer risk profile in this population. Comprehensive cancer screening, prevention strategies, and tailored ART regimens are essential to mitigate these risks. Future research should focus on identifying biomarkers for early cancer detection and developing ART regimens with lower oncogenic potential to enhance the long-term health outcomes for PLWHA.

Author Contributions

S.E.O.—Conceptualization, Writing, Editing, and Reviewing; D.A.A.—Writing, Editing, and Reviewing; T.S., I.O.A., O.F.A. and E.K.O.—Editing and Reviewing. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflicts of interest.

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Figure 1. HIV particles activate CD4+ T cells, leading to inflammation through the release of cytokines like TNF-α, IL-6, and IL-1β. This inflammation drives increased Cellular proliferation, reduced apoptosis, and enhanced angiogenesis, ultimately contributing to tumorigenesis.
Figure 1. HIV particles activate CD4+ T cells, leading to inflammation through the release of cytokines like TNF-α, IL-6, and IL-1β. This inflammation drives increased Cellular proliferation, reduced apoptosis, and enhanced angiogenesis, ultimately contributing to tumorigenesis.
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Figure 2. HIV proteins Tat and Nef activate NF-κB and MAPK pathways in host cells. NF-κB promotes VEGF production, leading to angiogenesis, while MAPK influences cell survival by regulating p53 and Bcl-2. This manipulation aids HIV replication and contributes to disease progression, including cancer and immune dysregulation.
Figure 2. HIV proteins Tat and Nef activate NF-κB and MAPK pathways in host cells. NF-κB promotes VEGF production, leading to angiogenesis, while MAPK influences cell survival by regulating p53 and Bcl-2. This manipulation aids HIV replication and contributes to disease progression, including cancer and immune dysregulation.
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Table 1. Comparison of AIDS-defining cancers (ADCs) and non-AIDS-defining cancers (NADCs) in PLWHA on antiretroviral therapy.
Table 1. Comparison of AIDS-defining cancers (ADCs) and non-AIDS-defining cancers (NADCs) in PLWHA on antiretroviral therapy.
CategoryAIDS-Defining Cancers (ADCs)Non-AIDS-Defining Cancers (NADCs)
Common TypesKaposi’s sarcoma (KS), non-Hodgkin lymphoma (NHL), cervical cancerLung cancer, liver cancer, anal cancer, Hodgkin lymphoma
EtiologyPrimarily linked to severe immunosuppression and oncogenic virus co-infections (e.g., Kaposi’s Sarcoma-Associated Herpesvirus (KSHV), Epstein-Barr Virus (EBV), Human Papillomavirus (HPV))Linked to chronic inflammation, co-infections (e.g., Human Papillomavirus (HPV), Hepatitis B Virus (HBV), Hepatitis C Virus (HCV)), lifestyle factors (e.g., smoking), and ART-related metabolic changes
Impact of ARTSignificant reduction in incidence due to improved immune function and reduced Human Immunodeficiency Virus (HIV) viral loadIncreased incidence due to longer life expectancy, persistent chronic inflammation, and ART-related factors
Screening and PreventionRegular Pap smears and HPV testing for cervical cancer; monitoring for KS and NHLRegular screenings for lung, liver, and anal cancers; HPV vaccination; liver ultrasound and Alpha-Fetoprotein (AFP) levels for Hepatocellular Carcinoma (HCC)
TreatmentAntiretroviral Therapy (ART) optimization, chemotherapy, radiation, surgery for cervical cancerMultimodal approach including surgery, chemotherapy, radiation, targeted therapies, and continuous ART
PrognosisImproves with ART but varies based on cancer type and stage at diagnosisGenerally poorer prognosis compared to ADCs due to later stage at diagnosis and complex interplay of factors
Geographic VariationsHigher prevalence in regions with limited ART accessMore common in high-income countries with widespread ART access
Demographic FactorsYounger people living with HIV/AIDS (PLWHA) more affected; higher incidence in women for cervical cancerOlder PLWHA more affected; higher incidence in men for lung and anal cancers
Table 2. Summary of key factors in tumor initiation and progression in people living with HIV and AIDS in antiretroviral therapy.
Table 2. Summary of key factors in tumor initiation and progression in people living with HIV and AIDS in antiretroviral therapy.
CategoryFactorsDescription
HIV-Related FactorsImmunosuppressionHuman Immunodeficiency Virus (HIV) depletes CD4+ T cells, weakening immune surveillance.
Chronic inflammationPersistent immune activation promotes a tumor-friendly environment.
Oncogenic HIV proteinsProteins like Tat and Nef promote cell proliferation and inhibit apoptosis.
ART-Related FactorsIncomplete immune restorationART does not fully normalize immune function, allowing cancer risk to persist.
GenotoxicitySome Antiretroviral Therapy (ART) drugs may cause DNA damage, leading to mutations.
Metabolic changesART-induced insulin resistance and dyslipidemia are linked to cancer risk.
Co-InfectionsHuman Papillomavirus (HPV)Increases risk of cervical, anal, and oropharyngeal cancers.
Epstein-Barr Virus (EBV)Associated with non-Hodgkin lymphoma and Hodgkin lymphoma.
Kaposi’s Sarcoma-Associated Herpesvirus (KSHV)Causes Kaposi’s sarcoma, particularly in immunocompromised individuals.
Cancer TypesAIDS-defining cancers (ADCs)Kaposi’s sarcoma, non-Hodgkin lymphoma, cervical cancer.
Non-AIDS-defining cancers (NADCs)Lung cancer, liver cancer, anal cancer, Hodgkin lymphoma.
Prevention and ManagementScreeningRegular Pap smears, HPV testing, liver ultrasound, and AFP levels.
ART regimen modificationSelecting drugs with lower carcinogenic potential and managing toxicities.
Integrative careMultidisciplinary approach involving oncologists, HIV specialists, and primary care physicians.
VaccinationHPV vaccination to reduce the risk of HPV-related cancers.
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MDPI and ACS Style

Olufemi, S.E.; Adediran, D.A.; Sobodu, T.; Adejumo, I.O.; Ajani, O.F.; Oladipo, E.K. Tumor Initiation and Progression in People Living on Antiretroviral Therapies. Biologics 2024, 4, 390-406. https://doi.org/10.3390/biologics4040024

AMA Style

Olufemi SE, Adediran DA, Sobodu T, Adejumo IO, Ajani OF, Oladipo EK. Tumor Initiation and Progression in People Living on Antiretroviral Therapies. Biologics. 2024; 4(4):390-406. https://doi.org/10.3390/biologics4040024

Chicago/Turabian Style

Olufemi, Seun E., Daniel A. Adediran, Temitope Sobodu, Isaac O. Adejumo, Olumide F. Ajani, and Elijah K. Oladipo. 2024. "Tumor Initiation and Progression in People Living on Antiretroviral Therapies" Biologics 4, no. 4: 390-406. https://doi.org/10.3390/biologics4040024

APA Style

Olufemi, S. E., Adediran, D. A., Sobodu, T., Adejumo, I. O., Ajani, O. F., & Oladipo, E. K. (2024). Tumor Initiation and Progression in People Living on Antiretroviral Therapies. Biologics, 4(4), 390-406. https://doi.org/10.3390/biologics4040024

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