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February 2022, Volume 4, Issue 1, Page 2015-2075
 
 
HAART and Increasing Prostate Cancer Incidence and Risk in Adult Men – Treatment Disparities and Outcome: A Systematic Review of Literature

Samy Allam M.D., M.H.A., Assistant professor of Medical Education
Department of Medical Education, California University of Science and Medicine School of Medicine- Colton, California

Objective:
Aim1: to explore the contribution of HIV to the incidence rate of prostate cancer.
Aim2: to investigate the influence of HIV status and HAART on the risk for developing prostate cancer.

Methods:
In the current study, a meta-analysis is proposed to explore the relationship between prostate cancer incidence, HIV positive status, and the use of HAART therapy. Specifically, the literature is reviewed with respect to the incidence of prostate cancer among patients with HIV and those utilizing HAART therapy. A systematic review and meta-analysis of the literature is proposed utilizing EBSCOHost and MEDLINE keywords “HIV," “prostate cancer," “AIDS," and “HAART." Manual bibliography review of cross-referenced items was performed to identify unique abstracts and full-text articles for inclusion in the research.

Results:
Twenty studies between the year 2000 and the present time and a total 880316 participants were included. Effect sizes, relative hazard, 95% confidence intervals (CIs) and standardized incidence ratio were applied to assess the incidence and association of prostate cancer, HIV and HAART. We found that the incidence rate of prostate cancer is increased in men with HIV (SIR 1.7, 95% CI 16.9) and that HAART will predict the development of prostate cancer PC in HIV positive men (SIR 1.22, 95% CI 0.14-3.6).

Conclusion:
HIV and HAART contribute to the escalating Incidence and risk of Prostate Cancer PC.

INTRODUCTION

Prostate cancer is the most diagnosed non-skin cancer and the second leading cause of cancer death in the United States. In 2008, prostate cancer accounted for 14% of the total new cancers diagnosed worldwide, and 6% of total cancer deaths in men (1,2). Incidence rates of prostate cancer vary by more than 25-fold worldwide, with highest rates found in North America, Europe and Australia (2). The Age –standardized rate of prostate cancer incidence is higher in developed countries than it is in lower-developed countries (56.2 per 100,000 versus 9.4 per 100,000) (3). A similar trend is apparent with prostate cancer-specific mortality between developed and lower developed countries, with an age-standardized mortality rate of 13.5 per 100,000 and 5.2 per 100,000 respectively (3). It was estimated that 240,890 men were diagnosed with the disease and 33,730 died of it in 2011 (9). Also, in 2011, there were approximately 2.4 million prostate cancer survivors in the United States. Given current screening habits, it is estimated that 16.2% (1 in 6) of American men alive today will be diagnosed with the disease and approximately 3% (1 in 33) will die of the disease. While the death rate has been decreasing somewhat over the last decade, the absolute number of men with prostate cancer is projected to increase substantially as a result of the aging baby boomer population. Thus, there is a critical need for a better understanding of the etiological factors that drive prostate cancer development; knowledge that may be utilized for cancer prevention and treatment strategies. Novel insights into the increase of prostate cancer rate have recently underlined the involvement of the chronic inflammatory process in Prostate Cancer (PC) development. Plethora of causes including infections (STIs), hormonal factors and environmental changes stimulates this inflammatory process. Moreover, STIs like HIV are associated with reduced cell-mediated immunity and humoral responses, which are thought to be pro-angiogenic. The chronic immune activation associated with a high viral load has been shown to lead to the release of factors, which inhibit apoptosis, and these factors provide an environment in which cancer cells may flourish (101). The aim of this study is to investigate that HIV positive patient is a high-risk group for developing Prostate Cancer (PC) and that the auscultating risk of PC in that population may be an adverse effect of Highly Active Antiretroviral Therapy HAART.

PROSTATE CANCER INCIDENCE AND MORTALITY

Many studies tracked U.S. Prostate Cancer (PC) incidence and mortality rate over the years to analyze trends and emphasize contributing risks. According to the National Cancer Institute surveillance performed in 2010 (10), the incidence and mortality rates among African Americans follow closely white Americans’ rates. However, African Americans have higher incidence and mortality rates compared to Americans of White race. The overall rise in the incidence rate from 1975 to the late 1980s was estimated as 2% annually. This rise was induced by incidentally detected disease associated with the increased use of transurethral resection of prostate (TURP) for benign prostatic hyperplasia (11). TURP-detected cancers were half of all detected cancers in the mid-1980s. The proportion of TURP-detected tumors fell off as the use of the procedure declined (12). As a result of publishing studies that ascertained the role of screening in cancer diagnosis in the early 1990s, a histrionic rise in incidence occurred (13, 14). Then, the clearing out of prevalent cases caused a significant decline in the late 1990s. As for mortality rates, a drop by 39% from 1991 to 2007 followed the rise from 1975 until 1991. By 2007, the mortality rate was similar to the 1975 rate for unknown reasons. Boyl P et al. (15) suggested that the drop in mortality since 1991 may be due to: screening and treatment, changes in attribution of cause of death by the World Health Organization WHO, or perhaps increased risk of death from other contributing chronic health conditions. Jemal et al (2) in a Global Cancer Stastistics study stated that in 2008, prostate cancer accounted for 14% of the total new cancers diagnosed worldwide, and 6% of total cancer deaths in men.

RISK FACTORS

Assessing PC risk factors’ formula has always been a thought-provoking topic. Consequently, identifying treatment strategies dictated a better understanding of PC attributing factors. The most documented causes for the development of prostate cancer are: advanced age, family history, and African American ancestry. However, less examined risk factors such as obesity, smoking, and infections/inflammations have not been well clarified.

Age
Older men are known to harbor higher prostate cancer risk with more aggressive features than their younger counterparts. In the setting of demographic change, the percentage of the population aged = 65 years will increase to an estimated 32 – 34% in 2060. Additionally, there has been a marked increase in life expectancy in recent years. Researchers revealed that a 70-years old man today still has an average life expectancy of 13 years and even an 80-year-old can expect to live another 8 years (16). Therefore, there was a great assumption that prostate cancer is confined to older patients prior to the PSA screening era. However, the National Cancer Institute Surveillance Epidemiology and End Results Program NCI SEER data provided some interesting results (10). The trend toward younger men being diagnosed was demonstrated in the change in age-specific incidence since 1985. In 2005, the prostate cancer incidence rate among men aged 80 years and older was 0.56 of the rate in 1986. For men aged 70–79, the 2005 rate was 1.09 times the 1986 rate. Similarly, men aged 60–69 years had a rate 1.91 times greater in 2005 compared to 1986. The corresponding ratio for men aged 50–59 was 3.64 in 2005 compared to 1986, and for men younger than fifty, the 2005 incidence rate was 7.23 times the 1986 incidence rate (10).

Race
There were an estimated 235,590 new cases of prostate cancer diagnosed in the United States in 2013 with 29,720 deaths. From these, African Americans (AA) was found to have both a higher incidence and mortality from prostate cancer PC compared with White Americans (17). Multifactorial explanations were given for this finding including—but not limited to: socioeconomic status, lack of access to care, and a biologic tendency for inheritance is more aggressive disease in AA men (17). As for the socioeconomic status, Zeliadt et al (18) emphasized the fact that African American men are usually supplied with fewer treatment options by physicians, are more concerned about the spread of the tumor and less likely to read all the additional information provided about the cancer diagnosis and treatment options. These trends may possibly lead to higher levels of treatment regret. In addition, African American men may be more concerned about the side effects of invasive treatments – incontinence, bowel dysfunctions, and permanent sexual impairment, therefore, more prone to favor “watchful waiting" – an option to delay aggressive treatments until there are clinical signs of the disease progression (19). Also, Richert-Boe et al. (20) demonstrated the notion of “lack of access to care “ to AA Prostate Cancer PC patients. The authors reviewed medical records of 79 African- American and 158 Caucasian men (matched for age, stage, grade, and year of diagnosis) from the Kaiser Permanente Northwest Tumor Registry to identify all men diagnosed with local- or regional-stage PC between 1980 and 2000. Not only was it found that treatment with curative intent was administered less often to African Americans than to Caucasians, but African American men were less likely to be offered treatment with curative intent by urologists (85% versus 91%, respectively). Caucasian men were 71% less likely to receive androgen deprivation therapy than radical prostatectomy, compared with African Americans, for a low-risk disease (odds ratio 0.29). Caucasians also were less likely to receive radiation treatment than radical prostatectomy for a low-risk disease compared with African Americans. Age may also affect patient-physician communication and quality of treatment available to African Americans. Mullins et al (21) have examined the SEER database of Medicare patients with PC and reported that older, African American men with PC are at increased risk of not being staged by the physician. The previously mentioned studies awaken the calls for examining racial and ethnic disparities in health care, to assure better use of services and hence better prognosis and eliminate loss in productivity.

Family history and genetics
The hypothesis that strong familial components are involved in the etiology of prostate cancer is supported by many studies Narod SA et al. (22) and Monroe KR et al. (23) have suggested that elevated risk may be associated with affected brothers but not with affected fathers, suggesting a possible X chromosome or shared childhood environment risk. Generally, men with two or more first-degree-affected relatives have a fivefold to 11-fold increase in risk compared with men without a family history of prostate cancer. These studies also provide evidence that the risk of prostate cancer in first-degree relatives of probands is higher among patients with early, compared with late, ages at diagnosis (24, 25, 26).
A genetic contribution to prostate cancer risk is also supported by twin studies. In one such analysis, Gronberg et al. (27) analyzed the incidence of disease among 3840 male twin pairs identified from the Swedish Twin Registry linked to the Swedish Cancer Registry. The study population contained 458 cases of prostate cancer. Results suggest a significant influence of genetics on prostate cancer with proband concordance rates of 0.19 for monozygotic twins and 0.043 for dizygotic twins. Subsequent studies (28, 29) in these and additional cohorts confirmed these initial observations.

Diet
An increased intake of animal fat and possibly red meat has been associated with an increased risk of PC. In contrast, vegetables may protect against PC. High intake of a cruciferous vegetable containing the chemoprotective isothiocyanate sulforaphane was correlated with a diminished risk of PC (30). But the relationship is complex and ill-defined, perhaps due in part to the influence of diet on the production of sex hormones, including increased androgen levels with high fat diets as well as the weak estrogen activity of soy compounds in Asian diets (31). Obesity and alcohol abuse may also be risk factors (32).

Sexually Transmitted Diseases STDs
Numerous infections by different pathogenic organisms were known for inducing an inflammatory response in the prostate (33). These include sexually transmitted organisms (34), such as Neisseria gonorrhoeae, Chlamydia trachomatis (35), and non-sexually transmitted bacteria such as Propionibacterium acnes and those known to cause acute and chronic bacterial prostatitis, primarily Gram-negative organisms such as Escherichia coli. Although each of these pathogens has been identified in the prostate, the extent to which they typically infect this organ varies (33). Many studies like Krieger et al. (36) and Hochreiter et al. (37) uncovered strong association between bacterial components and Prostate Cancer PC/ Prostatitis. Additional remarkable example is the study conducted by Alkahwaji et al. (36) on a mouse model with chronic bacterial prostatitis induced by E. coli. This study proved that a chronic bacterial prostatic infection and inflammation could lead to neoplastic tissue alterations in the prostate (38).

PATHOGENESIS AND PREDICTORS OF PROSTATE CANCER PC

Various factors involve in Prostate cancer PC pathogenesis including molecular, genetic and oncologic. The molecular factor refers to the accumulation of preneoplastic lesions within glandular epithelium leading evolving invasive carcinoma (41). Genetic factors were explained in many cytogenic studies like Lijovic et al (42), Karan et al. (43) and De Marzo et al. (44). They revealed consistent chromosomal abnormalities in particular stages of PC. Most of these abnormal chromosomal regions entail several important genes involved in tumor development and progression. In PC, chromosomal losses are more common than gains: losses of chromosomes 6q, 7q, 8p, 10q, 13q, 16q, 17, and 18q are particularly common events. Knowledge about the role of oncogene amplification process is still inaccurate. The most important oncogenes known for their participation in prostate cancer pathogenesis are: C-myc--which possess a suggested correlation to Gleason grade (45), Ras--frequency of Ras mutations reported in PC is variable, also, mutations in K-, H-, and N-ras were found in less than 5% of tumors in Western populations but were detected in 26% of prostate cancers in Japanese men (46, 47), C-erb (HER-2/neu)-- some studies reported c-erbB2 over-expression in PC and suggested that expression increases as PC progresses to androgen independence (48) and Bcl-2 which encodes an anti-apoptotic protein, is overexpressed in approximately half of prostate cancers, particularly in androgen-independent tumors (49).

Diagnosis of Prostate cancer comprises many tools including direct rectal examination, biopsies, and imaging. Size and shape of prostate cancer can be detected with direct rectal examination in correlation with imaging by ultrasound. Other useful diagnostic tools like Prostate-Specific Antigen (PSA) blood level and ultrasound directed biopsy might ascertain PC diagnosis in patients presented with urinary obstruction or hematuria and bone pain (50). Prostate-specific antigen (PSA) was approved by the U.S. Food and Drug Administration in 1986 for monitoring progression in patients with prostate cancer, and later approved for the detection of the disease in symptomatic men (76). The most widely accepted indication for prostate biopsy is a PSA value in serum greater than 4.0 ng/ml (54). Ten to Twelve cores of tissue from the gland under ultrasound guidance can be obtained from a single transrectal prostate biopsy. The biopsies are examined by a pathologist and routinely graded to the Gleason system. Recently introduced and acknowledged in many studies (51-53), a Gallium-labeled ligand of prostate-specific membrane antigen (Ga-PSMA) has been integrated in PET-imaging of prostate cancer with first promising results (51). Multiparametric studies using Ga-PMSA PET/MRI in correlation with results from cross-section histopathology provides information on the specificity of combined factors and potentially allowing more reliable discrimination between benign and malignant lesion (51).

Gleason score
The Gleason system was based on histopathological data from over 4000 PC biopsies and resections between 1960 and 1975 (55-57). Architectural patterns seen at low magnification were recorded without preconception and independently correlated with mortality data. Patterns that occurred frequently together and were associated with the same outcomes were grouped together, resulting in five grades:

Gleason grade of prostate cancer
1. Grade 1 (well differentiated), circumscribed mass of evenly spaced, closely packed, uniform shaped glands, with no evidence of infiltration of the stroma.

2. Grade 2 (well differentiated), some infiltration into the surrounding stroma and more variation in gland size and spacing, although this was limited.

3. Grade 3 (moderately differentiated), most common grade with more variation in size, shape, and separation of the glands, less defined boundaries, and less intervening stroma.

4. Grade 4 (poorly differentiated), fusion of the glands forming a solid anastamosing network with a ragged invasive edge.

5. Grade 5 (undifferentiated).

Because of the histological variation within each tumor two grades, the predominant, or primary grade and the less extensive or secondary grade, were recorded as the Gleason sum score in each case. For consistency, if only one grade was present, this was doubled. The primary and secondary grades showed similar correlations with mortality but the sum of these two grades showed the strongest correlation with cancer-specific mortality, hence, a low Gleason score (< or = 6) is indicative of a more indolent malignancy with a good prognosis whereas a high Gleason score (> 8) is associated with aggressive biological behavior and an increased risk of occult systemic disease. Over many years the Gleason system has been shown to be a powerful predictor of prostate cancer behavior and outcome after either prostatectomy (58, 59) radiotherapy, or in patients managed with surveillance (60).

Biomarkers
There are several groups of established biomarkers, but many of them are still under investigation, and a number of new promising markers are being identified by gene expression analysis, e.g. hepsin, AMACR, EZH2, cell cycle proteins, autoantibody signature (61, 62). Among them, PSA, AMACR, and established tissue markers HMW (34betaE12) and p63, which are both basal cell markers, are routinely used in clinical laboratories. A triple antibody cocktail staining, AMACR in combination with p63 and 34betaE12, is currently widely used in diagnosis of PC.

HMW 34betaE12
With the advent of immunohistochemistry, 34betaE12 has become an often useful adjunct in the diagnosis of prostatic adenocarcinoma (63). Specifically, 34betaE12 has been shown to highlight the sometimes-inconspicuous basal cell layer in benign glands and has conventionally been considered negative in carcinomatous glands. 34betaE12 can occasionally be essential in differentiating carcinoma from its many benign mimickers, including adenosis, basal cell hyperplasia, and atrophy (64).

Alpha-methylacyl-CoA-racemase (AMACR)
AMACR is a recently discovered tumor marker whose expression is significantly unregulated in PC. It has been shown to be a highly sensitive marker for the diagnosis of PC. The majority of prostatic ductal and cribriform acinar carcinomas strongly expressed AMACR (65). Two antibodies, P504S and AMACR-p, were usually used for immunohistochemistry (65).

P63
Basal cell marker. P63 is used as a tool to determine the state of the basal cell layer and to distinguish the regions of PIA from those of PIN and PC (66).

PROSTATE CANCER TRIGGER IN HIV-INFECTED INDIVIDUALS

It is known that decreased immune surveillance and increased immune activation play a major role in cancer development. There is also a growing body of data, to suggest that HIV may have a direct role in perhaps activating cellular oncogenes or proto-oncogenes and inhibiting tumor suppressor genes (67). Further, HIV has been found to induce genetic instability as manifested, for example, by a 6-fold higher number of microsatellite alterations in HIV-associated than in non–HIV-associated lung cancer (68). Susceptibility to the effects of certain carcinogens may be greater in HIV-infected than in HIV-uninfected individuals, possibly due to the endothelial abnormalities associated with HIV infection, which may be permissive for tumor growth. HIV-associated immunosenescence may also be associated with increased cancer risk. A number of reports indicate that the aging phenotype of immune markers first defined in Scandinavians aged 80 years to 90 years is also common in younger HIV-infected individuals. Thus, increased CD8+CD28- and CD4+CD28- cells, shortened telomeres, increased CD31-cells (especially in the CD45RA+ naive T cell population), and increased CD56+CD57+ cells are seen in HIV-infected patients compared with age-matched, HIV-uninfected patients. Such findings support the notion that HIV-infected persons experience more rapid immunologic aging, putting them at an increased risk for cancer (69-73). Association between HIV and Non-AIDS Defining Cancers NADC has been determined in many studies. Hessol et al. (81) identified more than 14000 adults diagnosed with AIDS in San Francisco between 1990 and 2001 and identified 482 Non-AIDS defining cancers in the 60 months before or after the diagnosis of AIDS was made. They reported 32 cases of PC and found significantly increased standardized incidence ratios of PC when compared to the general population (SIR.1.7). Biggar et al. (82) linked more than 8000 patients who were over the age of 60 and carried a diagnosis of AIDS to cancer registries and found 1142 cases of malignancy from 60 months before the diagnosis of HIV to 27 months after AIDS onset. Non-AIDS-defining malignancies were identified in 548 patients. Although PC was the most common (118 cases), the risk of PC was lower than expected in both overall (relative risk (RR) 0.8; 95% CI 0.6–0.9) and post-AIDS onset periods (RR 0.5; 95% CI 0.3–0.8) (82). A similar linkage-based population study examining more than 300 000 people throughout the United States aged 15–69 years demonstrated a lower than expected incidence of PC both in the overall (RR 0.7; 95% CI 0.6–0.9) and post-AIDS onset period (RR 0.5; 95% CI 0.4–0.7) (83).

NON-AIDS DEFINING CANCERS NADC INCIDENCE AMONG HIV-INFECTED INDIVIDUALS

Record linkage studies of population-based registries of people with acquired immunodeficiency syndrome (AIDS) and cancer (83 – 88) have estimated excess cancer risk for people with AIDS compared with that for the general population. HIV-infected individuals are living longer as a result of more effective and better-tolerated antiretroviral treatment and fewer risks of opportunistic diseases. The overall incidence of AIDS-defining cancers (ADCs) among HIV-infected individuals has decreased, reflecting lower rates of such cancers as Kaposi sarcoma and non-Hodgkin lymphoma (NHL) in patients aged 40 years or younger. Concurrently, the number of Non–AIDS-defining cancers (NADCs) such as PC among HIV-infected individuals has increased owing in large part to diagnoses in patients older than 40 years of age. Thus, the number of NADCs diagnosed each year in the HIV-infected population has now surpassed the number of ADCs (39). Data from studies that matched HIV and cancer registries in the United States have shown that among the HIV-infected population, NADCs accounted for 31.4% of all cancers reported from 1991 to 1995 and that this proportion increased to 58% from 1996 to 2002. Standardized incidence ratios were used to compare NADC incidence in the HIV-infected population with that in the general population, with data indicating an increase in the standardized incidence ratio for some NADCs and stable values for others from the earlier to the later period (40).

PREDICTORS OF NADC IN HIV-INFECTED PATIENTS

Predictors for NADCs in HIV-infected patientsentails: white versus black race, lower most-recent CD4+ cell count, lifestyle behaviors, HIV/HBV co-infection, socio-economic disadvantage, treatment disparities, androgen supplements and advancing age with effects of Highly Active Anti-retroviral Therapy HAART (73-75). HIV and PC among Black versus white patients Human Immunodeficiency Virus HIV/Acquired Immunodeficiency Syndrome AIDS exist massively among ethnic minorities in the United States (US) (77). African American descents are the most aggressively impacted community among USA racial and ethnic minority population. Data from CDC revealed that rates of Sexually Transmitted diseases like HIV, chlamydia, and gonorrhea in AAs are the highest in the nation (77).

Consequently, disparities in STDs diagnosis among AAs made them a high-risk group for HIV acquisition and transmission. The available literature suggests that co-transmission of HIV and other STDs may be a common occurrence (Cohen, 2004) and that biological mechanisms, (e.g., impaired integrity of the genital mucosa creating an environment more conducive to transmission) (Cohen, 2004; Gavin, Cohen 2004) and immunologic mechanisms, (e.g., immune activation) (Reynolds, Risbue, Shepherd, Zenilman, Brookmeyer, Paranjape, et al, 2003) are possible explanations for the increased risk for HIV transmission in persons infected with STDs (78, 79). Surveillance and epidemiology data provided by CDC during 2002–2006 shown that black men in the 33 states accounted for nearly one-third (31.4%) of all HIV/AIDS diagnoses and 43.4% of cases of HIV/AIDS diagnosed among men – with 63.1% (54,701) of that group consisting of black men. Among black men diagnosed with HIV/AIDS during 2002–2006, more than half of those HIV infections (29,685, or 54.3%) were attributed to male-to-male sexual contact, 16.1% to inject drug IDU, and 24.7% to high-risk heterosexual contact. Of the HIV/AIDS cases attributed to male-to-male sexual contact, 29.4% of men were aged 35–44 years, 27.6% were aged 25–34 years, and 22.6% were among youth aged 13–24 years (80). HIV/AIDS diagnosis rates were consistently higher for black men than for men of other racial and ethnic groups in the 33 states with name-based HIV reporting in each year of this study. In 2006, the rate of HIV/AIDS diagnosis among black men was 119.1 per 100,000. This rate was seven times as high as the rate among white men (16.7 per 100,000) and more than twice as high as the rate among Hispanic/ Latino men (50.9 per 100,000) and black women (56.2 per 100,000) (80).

Also, variations according to race in prostate cancer diagnosis and treatment was previously explained and examined in many studies (88,89). Denberget al. (90)studied a cohort of nearly 28,000 white, African American, and Hispanic men without comorbidities to identify predictors of curative therapy for prostate cancer. They found that African Americans underwent prostatectomy less often than whites, although they did not receive less curative treatment overall, and that Hispanics underwent prostatectomy more often than whites. Underwood et al. (91) also used SEER data to examine treatment trends by race for localized and regional prostate cancer. They found that, from 1992 to 1999, African American and Hispanic men were more likely to receive only hormonal therapy or expectant therapy and less likely to receive treatment with curative intent TCI than white men. Care cost may have contributed to TCI (treatment with curative intent) racial differences in these studies because men in the samples may have been uninsured or had health insurance with large copayments. Studies have examined the decision-making process for treatment of localized prostate cancer (92, 93) but little research examines the roles of race and ethnicity or socioeconomic status in treatment preferences. Combining previous findings will support the belief that HIV/PC cancer incidence census among AAs is dominant and more progressive.

Lifestyle behaviors
Lifestyle behaviors play a substantial role in HIV/ PC census evolvement, this wide arena of lifestyle behaviors includes: smoking and drug abuse, alcohol and sexual orientation/practices. Hallfors et al. (94) examined HIV association among smokers, drug abusers and risky sexual behaviors in AAs. The authors provided an approximate continuum of risk behaviors ranging from categories such as “few partners, low alcohol and other drug use" to “marijuana and other drug use," together with the prevalence of STD by white and black race. Blacks with few partners and low drug use had a STD prevalence of 20.3% (3.2% for whites with the same behaviors); blacks engaging in marijuana and other drug use had a prevalence of 28.8% (7.5% for whites). The evidently variant prevalence for the same behaviors across race indicates the greater risk blacks encounter, compared to whites, for each level of risk and illustrate the role of context. Furthermore, Prostate Cancer PC prognosis proved to have a significant correlation to sexual orientation. According to Chicago department of public health Men who have Sex with Men MSM are considered a PC high-risk group (95). After MSM/PC patients performed prostatectomies, a large sample in this group reported post-operative erectile dysfunction. Anal insertion during sex requires a higher degree of erectile function than vaginal sex, thus the risk of erectile dysfunction may deter MSM away from radical prostatectomy and open radical prostatectomy in particular (96). With that said, we can conclude that lifestyle associated discrepancies affects directly and indirectly HIV/PC diagnosis and treatment options and hence their incidence rate. Highly Active Antiretroviral Therapy HAART

The potent Highly Active Antiretroviral Therapy HAART has vastly revolutionized the treatment of Human immunodeficiency virus HIV infection. This therapy is a multidrug regimen that caused a substantial regression in AIDS, opportunistic infections, hospitalization, and death (97). The long-term goals of HAART are to: reduce HIV-related morbidity and mortality (from both infectious and non-infectious causes) and prevent the transmission of HIV to others (98-100). To achieve and sustain these goals, HAART should result in maximal suppression of HIV RNA. Suppression of plasma viremia below the level of detection by commercial assays also prevents the selection of drug-resistant mutations and allows for improvements in immunologic function (as measured by the CD4 cell count) (98-100). Large studies have expanded knowledge of HAART anchored by Integrase Strand transfer Inhibitors (INSTIs) (101-103),and several INSTI-based regimens are now recommended. At present, HAART is considered lifelong, and sustained viral suppression is the foundation for immune recovery, optimal health, and prevention of resistance and transmission. Thus, maximizing adherence and minimizing toxicity is paramount; the goal is to treat with an effective therapy that is well tolerated and convenient, and has limited drug interactions and effects on comorbid conditions. In resource-rich regions, individualization of therapy is common (104),whereas in resource-limited settings, a public health approach as described in the World Health Organization WHO guidelineshave been adopted (105). Ideally, definitive studies to determine the optimal regimen for the majority of Antiretroviral Therapy-naive patients would simplify treatment strategies. However, such studies would be costly and are unlikely to be conducted. Wider availability of effective generic drugs (106)and the development of comorbid conditions as patient’s age will have a strong influence on initial HAART choice.

Many theories linked HAART with rapid auscultation of prostate cancer PC incidence rate. Some studies (107-109) demonstrated case reports of rapid prostate cancer progression in AIDS patients. Authors explained that this was likely due to their severely depressed immune systems and poor response to androgen deprivation therapy ADT, as they were often hypogonadal. Proposed mechanisms for the increased rate of PC in AIDs patients include suppressed cell mediated immunity, impaired immune surveillance, increased angiogenesis and reduced apoptosis. After the introduction of HAART in 1995, it delayed the progression of HIV to AIDS as well as AIDS deaths. Also, HAART decreased AIDS defining cancers like Hodgkin’s lymphoma, Kaposi sarcoma and cervical cancer (110) whereas, it increased incidences of non-AIDS defining cancers NADC like Prostate cancer PC, colorectal cancer, and lung cancer (111). Other literature suggested that HAART is protective against NADC; nevertheless, HIV-positive patients are now living longer and not succumbing to deaths secondary to other causes, resulting in greater cumulative opportunity for Non-AIDS Defining Cancers NADC to develop.

HBV/HIV co-infection
Super-infection with bacterial, fungal, or viral pathogens in individuals with chronic viral infections, such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) is common. Patients with HBV/HIV co-infection deteriorate much faster than those with HBV or HIV individual infections. A multi-centric cohort study conducted by Thio et al. 2002 (113) revealed that HIV/HBV co-infected men were almost 19 times more likely to die of liver disease than those infected with HBV alone, and 8 times more likely to die of liver disease than those infected with HIV-1 alone. In the general adult population in western countries such as Australia, US, and Italy, the risk of developing chronic hepatitis after contracting HBV is 5–10%; this number, however, can be doubled or even tripled in HBV/HIV co-infected patients, not to mention in HBV/HIV/HCV-infected individuals (114, 115, 116).

On the other hand, HBV and/or HCV infection can drive HIV infection with more rapid progression to AIDS, perhaps explained by an increased viral load in HIV-infected cells and a faster decline as well as lower nadir of CD4+ cell counts (117, 118). Additionally, activation factors such as Nef, Tat, Rantes, Mip-1 for HIV, and X-protein, nuclear factor (NF)-1, NF-3, AP-1 for HBV, are activated intracellularly as well as extracellularly and lead to enduring activation of cells. Co-infection of HBV in HCV patients leads to more severe liver disease as well, with higher rates and faster progression to liver cirrhosis and liver cancer (114, 116).

Testosterone replacement therapy
It is important for clinicians to consider the side effects of androgen testosterone replacement therapy when treat hypogonadism in HIV+ men. Decreased serum testosterone levels occur in up to 60% of men with HIV infection, depending on stage of disease, weight loss, and receipt of antiretroviral therapy (119, 120,121, 122). Some studies like Klein et al. documented a strong association between low testosterone level and HIV infection only in men who reported having had sex with men. However, among all HIV-seropositive men, very low testosterone level was associated with a high viral load. Also, Testosterone deficiency in HIV patients with history of drug abuse (opiate addicts) has been reported. Opiates cause testosterone deficiency by suppressing the hypothalamo-pituitary-gonadal axis (123).

The theoretical relationship between an increased risk of prostate cancer development and Testosterone Replacement Therapy has been a robust debate for decades. It has been demonstrated in several trials that Testosterone Replacement Therapy increases serum PSA levels in some men, while androgen deprivation therapy can be used in the successful treatment of prostate cancer. The supportive argument posits that by treating men with Testosterone Replacement Therapy, thereby increasing PSA levels and administering Testosterone to a steroid responsive cancer, a man’s risk of development of prostate cancer is significantly increased. However, prior literature has failed to definitively demonstrate an increased risk in a cause-and-effect relationship. A meta-analysis, looking at the adverse events associated with TRT in older men, found that men receiving TRT were 11 times more likely to undergo biopsy than the placebo group; however, there was no difference in the number of men diagnosed with prostate cancer between the two groups (Calof et al. 2005) (124). A retrospective study reviewed Surveillance, Epidemiology, and End Results Medicare data on nearly 150,000 men over a 15-year period and compared prostate cancer outcomes in men who had received TRT prior to prostate cancer diagnosis and those who did not (Kaplan and Hu 2013) (125). The authors found no statistically significant difference in disease-specific survival (p = 0.2586), overall survival (p = 0.2882), or need for salvage androgen deprivation therapy (p = 0.5250). They also found favorable results with regard to prostate cancer specific outcomes, including tumor grade and clinical staging. Compared with men without prior TRT use, men who used TRT prior to diagnosis were more likely to have moderately differentiated cancer (64.6% versus 59.2%, p< 0.001) and less likely to have poorly differentiated cancer (28.3% versus 34.2%, p< 0.001). With regard to clinical staging, men with prior TRT use were more likely to be diagnosed with stage T3 disease (4.0% versus 3.1%, p< 0.001) and less likely to be diagnosed with stage 4 disease (4.3% versus 6.5%, p< 0.001).

Treatment disparities
Treatment disparities of HIV+ men with prostate cancer HIV+ patients with cancers experience disparities in cancer treatment and outcome. They are less likely to receive a standard-of-care treatment due to variety of etiology including provider reluctance, ethnic minority status, lack of insurance, poverty, and poor social support (128, 129). At the end of 2005, 40.3 million people were living with HIV infection and in 2005 alone, 3.1 million people died of HIV-related causes (UNAIDS/WHO 2005) (196). HIV/AIDS is now the fourth largest cause of death worldwide (WHO2003) (197). The burden of new infections and of death is highest in developing countries (UNAIDS/WHO 2005; UNAIDS 2004) (198,199).

In the 1990s, highly active antiretroviral therapy (HAART) became widely available in many industrialized countries, which resulted in a sharp and sustained decline in the incidence of AIDS and AIDS-related mortality in those countries (Sepkowitz 2001) (200). The United Nations' 2001 Declaration of Commitment on HIV/AIDS emphasized that all people infected with HIV have the right to treatment (UN2001) (201). Furthermore, the Declaration recognized that treatment, care and support, including antiretroviral therapy, are fundamental components of any effective response (UN2003) (202). However, there are substantial challenges to the provision of care and of antiretroviral medications in both developed and developing country settings. Several of the key issues involved relate to where care should be provided and how it should be organized. For example, there is debate about whether care should be concentrated in regional centers or decentralized to communities, what type of health workers and what kind of health worker teams are needed, which interventions and mix of programs are best and what hours of operation are most appropriate. There is evidence from examining other types of health conditions that disease management models for chronic illnesses can improve a variety of health outcomes (Ofman 2004, Badamgarav 2003) (203,204). Case management approaches have been effective for certain chronic diseases including chronic obstructive pulmonary disease (COPD) (Egan 2002) (205), congestive heart failure (Taylor 2005) (206) and diabetes mellitus (Choe 2005, Howe 2005, Krein 2004, Aubert 1998) (207,208,209,210). Care provided by multidisciplinary teams has been shown to be effective in depression (Katon 2004) (211), diabetes mellitus (Maislos 2004, Majumdar 2003) (212,213) and COPD (Rea 2004) (214). Regionalization of care and high volume care have been associated with improved outcomes of several kinds of specialized care and procedures, most likely as a result of accumulated expertise of the health care team and better adherence to evidence-based care (Glance 2006, Battaglia 2006) (215,216).

METHODS

The 754 articles initially identified for the meta-analysis were located utilizing search terms found in the table below. Limiters for the search including: full-text articles published in peer-reviewed journals in the last 10 years. Once the articles were identified, the abstract for each of the articles was first reviewed to determine the relevance of the article for inclusion into the investigation. If the abstract was deemed relevant, the full-text article was saved to a file for later review utilizing the PRISMA 2009 Checklist (130). After reviewing the literature, it became evident that cohort studies were more abundant when looking at the correlation between HIV and prostate cancer. As a result, cohort studies were sought for the calculation of standardized incident ratios (SIRs) instead of odds ratios.

Table 1

Inclusion criteria for the articles included the following: cohort studies which provided data regarding prostate cancer among individuals with HIV and in the general population. Articles were excluded if they were meta-analyses, systematic reviews of the literature, case control studies or they did not specifically provide data regarding prostate cancer, including the number of individuals in the population that had both HIV and prostate cancer. Most of the studies were national or regional investigations that included data from HIV and cancer registries.

Key words: prostate cancer, STI, HIV, AIDS, HAART, incidence.

RESULTS

20 articles met the inclusion criteria with a total 883016 participant of which 12 studies contain data with HAART.

Table 2: Summary of the 20 articles that met inclusion criteria.




Figure 2: SRI of PC with HIV and HAART, Forest Plot of the results.

DISCUSSION

It was found that HIV+ status is associated with the auscultating risk and increased incidence of Prostate Cancer. Additionally, it was evident that HAART use also impacted outcomes. Arguably, HAART contributed to the increased survival of people living with HIV by providing greater control on viral replication and increased immunity. However, HAART associated hypogonadism and toxicities consequently increased the need for androgen testosterone replacement therapy, and hence, contributed to PC growing incidence. This finding introduced the demand for additional investigation regarding androgen supplementation for HIV positive men receiving HAART.


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