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HIV & Aging Clinical Recommendations
Several lines of evidence indicate that cancer, especially non-AIDS-defining cancers (NADCs), has become an increasing cause of morbidity and mortality in the ART era.
The HIV Outpatient Study, a prospective, multicenter, observational cohort study of subjects treated from 1996 through 2004, showed all-cause mortality among HIV-infected persons in the United States decreasing by almost 80%. Deaths due exclusively to non-AIDS-defining illnesses (NADIs) rose from13.1% to 42.5% in 2004. In the study, the most common causes of NADIs were cardiovascular disease (CVD), hepatic disease, pulmonary disease, and NADC at 23.5% each (Palella 2006).
A retrospective review of 13 European and North American cohorts in the Antiretroviral Therapy Cohort Collaboration (ART-CC) between 1996-2006 found that of 1,597 deaths among 39,272 patients studied and 154,667 person-years (PY) of follow-up, 49.5% were due to AIDS and 50.5% were due to NADI. The most frequent NADI were non-AIDS malignancy (11.8%), followed by non-AIDS infection (8.2%), cardiovascular disease (7.9%), violence (7.8%), and liver disease (7.1%). The proportion of deaths due to AIDS-defining cancers (ADCs) decreased from 20.5% to 12.5%, while that due to NADCs increased from 7.3% to 15.4% over the study periods (ATCC 2010).
Similarly, the Data Collection on Adverse Events of Anti-HIV drugs (D:A:D) Study Group observed 2,482 deaths in 180,176 PY on 33,308 individuals and found that, among primary causes of death, NADIs were more common than AIDS-related causes (n=916 vs. 743) (Smith 2010). The main non-AIDS-related causes of death were liver-related (n=341), CVD-related (n=289), and NADC (n=286).
Data on increased incidence of NADCs in HIV-positive individuals in the ART era compared with HIV-negative persons has been mixed, but increasingly supportive that this number is going up.
A review of the literature shows a statistically significant increase in the age standardized incidence ratio (SIR) of several NADCs for HIV-infected persons compared with HIV-uninfected cohorts (Chiao 2003). Hodgkin’s lymphoma, anal cancer, soft tissue cancer, and multiple myeloma were found to have statistically significant increased SIRs in five large published studies that were reviewed (Frisch 2001; Frisch 2000; Gallagher 2001; Serraino 2000); Grulich 1999). A 2015 study in US Veterans showed increased risk of NADCs but similar age of onset between HIV+ and HIV- veterans (Althoff 2015).
No studies found significant increases in breast cancer, colon cancer, or prostate cancer. In addition, some studies have suggested a higher incidence of invasive cervical cancer in HIV-positive women compared with HIV-negative women (Frisch 2000; Serraino 1999), although this may have diminished in the HAART era and with aggressive cancer screening.
More recently, a meta-analysis of the incidence of NADCs in HIV-infected individuals, in which 4797 non-AIDS cancers occurred among 625,716 HIV-positive individuals, demonstrated that PLWH were twice as likely to develop a NADC as the general population (Shiels 2009).
The HIV/AIDS Cancer Match study, showed that anal, liver, and prostate cancers rates increased between 1996 and 2010, while rates of Kaposi’s sarcoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, and cervical and lung cancer decreased in HIV-positive adults. This study examined the contribution of changing demographics (including aging) over time, trends in rates of cancer in the general population, and HIV-associated relative risks for cancers. Changing demographics, including aging, helped explain changing rates for Kaposi’s sarcoma and breast, colorectal, liver, lung, and prostate cancers (Robbins 2014).
In the meta-analysis by Shiels (Shiels 2009), HIV-positive individuals were found to be particularly at risk for cancers associated with infections (including anal, vaginal, penile, nasopharyngeal, laryngeal, and oral cancers related to human papilloma virus; liver cancer from the hepatitis B and C viruses; and nasopharyngeal cancer and Hodgkin’s lymphoma associated with Epstein-Barr virus) and those associated with smoking (including lung, kidney, stomach, laryngeal, and oral cancers). Prostate and breast cancer were less common in HIV-infected persons (Shiels 2009). A listing of the relative SIRs for HIV-infected persons compared with the general population is shown in Table 1.
Table 1. From Shiels MS. A Meta-Analysis of the Incidence of Non-AIDS Cancers in HIV-Infected Individuals. JAIDS. 52(5);611-622 by Lippincott Williams & Wilkins. Reproduced with permission of Lippincott Williams & Wilkins in the format Journal via Copyright Clearance Center.
|Lung||13||847||2.6||2.1 to 3.1|
|Hodgkin Lymphoma||13||643||11||8.8 to 15|
|Anus||8||253||28||21 to 35|
|Colorectal||4||174||1.1||0.69 to 1.7|
|Liver||11||171||5.6||4.0 to 7.7|
|Melanoma||10||161||1.2||0.88 to 1.6|
|Skin Cancer||7||160||3.5||1.8 to 6.8|
|Prostate||9||159||0.69||0.55 to 0.86|
|Female Breast||11||142||0.74||0.56 to 0.97|
|Kidney||9||109||1.7||1.3 to 2.2|
|Oropharynx||3||108||1.9||1.4 to 2.6|
|Leukemia||10||102||2.6||1.9 to 3.5|
|Stomach||11||96||1.7||1.2 to 2.5|
|Testis||8||96||1.4||1.1 to 1.9|
|Lip, Oral, and Pharynx||2||84||2.2||1.0 to 4.7|
|Brain||9||75||1.8||1.2 to 2.7|
|Multiple Myeloma||9||72||2.6||1.5 to 4.5|
|Larynx||5||62||1.5||1.1 to 2.0|
|Esophagus||8||51||1.5||0.99 to 2.3|
|Bladder||9||48||1.1||0.72 to 1.7|
|Head and Neck||4||42||2.0||1.1 to 3.6|
|Pancreas||9||39||1.0||0.74 to 1.4|
|Colon||4||26||0.81||0.48 to 1.4|
|Vagina||4||25||9.4||4.9 to 18|
|Thyroid||6||24||1.1||0.56 to 2.3|
|Penis||4||16||6.8||4.2 to 11|
|Rectum||2||16||1.5||0.54 to 4.2|
|Ovary||6||14||1.4||0.78 to 2.4|
|Uterus||4||14||1.5||0.68 to 3.4|
|Small Intestine||3||10||2.2||1.4 to 3.3|
|Bone||5||7||2.6||1.3 to 5.0|
|Eye||2||7||3.1||1.6 to 5.9|
|Nasopharynx||2||7||4.1||2.1 to 7.9|
|Gall Bladder||2||3||2.6||1.1 to 6.4|
|All Non-AIDS Cancers||9||3513||2.0||1.8 to 2.2|
Findings were similar in a retrospective cohort study of HIV-positive and matched HIV-negative members of Kaiser Permanente followed between 1996 and 2007 for the incidence of ADCs and NADCs. This study found that rates for most individual infection-related NADCs were significantly higher in the HIV-positive group, including anal squamous cell, vagina/vulva, Hodgkin’s lymphoma, penis, liver, and HPV-related oral squamous cell cancers (Silverberg 2009).
Infection-unrelated NADCs with increased rates among PLWH were other anal, non-melanoma skin, other head and neck, lung cancers and melanoma. Infection-related cancers (ADC and infection-related NADC combined) made up almost 70% of all cancers in PLWH. HIV-positive persons had more than a nine-fold increased risk of infection-related NADC compared with HIV-negative persons, mainly in the risk of anal squamous cell cancer and Hodgkin’s lymphoma. PLWH also had a modest 30% increased risk of infection-unrelated NADC, including a higher risk of other anal, skin, other head and neck, and lung cancers, but lower risk of prostate cancer.
Others have also found that lung cancer was a major NADC early in the ART era. It was the most common non-AIDS cancer and the third most common cancer among PLWH in the U.S.A., behind Kaposi’s sarcoma and non-Hodgkin’s lymphoma (Engels 2006). In the ART-CC study cohort, the most frequent sites for non-AIDS malignancies were respiratory tract or intrathoracic organs (36.7%); digestive organs and peritoneum (28.7%); lip, oral cavity, and pharynx (6.0%); and skin (4.7%) (ATCC 2010). A recent study of skin cancer, however, suggested that the higher rate of melanoma for HIV-positive persons was more likely due to confounding by sun exposure or perhaps increased medical surveillance than as a result of immunosuppression (Lanoy 2009), and other recent studies found no increased risk (Lanoy 2010).
A 2003 study (Chiao 2003) noted that some malignancies tend to be of higher grade and present with a more aggressive clinical course in HIV-positive persons compared with HIV-negative persons. Some studies have shown that HIV-positive women with invasive cervical cancer are more likely to present with advanced clinical disease and to have persistent or recurrent disease at follow-up, a shorter time to recurrence, and a shorter survival time after diagnosis, and are more likely to die of cervical cancer (Frisch 2000; Holmes 2009; Logan 2010) than HIV-negative women.
A study in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) demonstrated that HIV-positive women were more likely to have invasive cervical cancer than HIV-negative women, although a response to this article points out that some of the results may have been influenced by screening and monitoring, and that in HIV-positive women who were appropriately monitored, increased invasive disease was not seen (Abraham 2013; Nazac 2013).
Other studies have shown that HIV-positive individuals with hepatocellular carcinoma are younger and more frequently symptomatic and infected with HCV or HBV than HIV-negative persons, although tumor staging and survival were similar (Brau 2007).
As discussed by Shiels (Shiels 2011) HIV-positive individuals may have more virulent cancers because: 1) their depressed immune system is less able to fight oncogenic insults, and/or 2) behaviors of HIV-infected individuals expose them to higher levels of carcinogens, e.g., higher levels of exposure to tobacco smoke, HPV, and others.
Finally, a recent report from Italy showed that from 1999 through 2006 the risk of death from NADCs was 6.6-fold higher among Italian people with AIDS than in the general population, particularly elevated were for virus-related cancers (Zucchetto 2010).
As with the general population, older age has been associated with increased risks of NADCs in HIV-positive individuals. In the ART-CC study, older age was strongly associated with increased rates of non-AIDS malignancy (HR per 10 years, 2.32) (ATCC 2010).
Similarly, in the D:A:D: study, older age was associated with an increased risk of death from all causes considered, with the strongest associations for deaths due to non-AIDS malignancies and CVD-related causes (Smith 2010).
In an analysis of the SMART study, cancer rates were compared between the subjects continuously taking ART and those that intermittently took ART. ADC rates were higher in the latter group, while NADCs were similar between groups. In this study, age was also a predictor of NADCs, with an HR of 2.2 per 10 years older (Silverberg 2007a).
The NA-ACCORD study utilized cumulative incidence of cancer by age 75 and found similarly that increased incidence of colorectal, anal and liver cancer were a result HIV positive persons now living long enough to develop these cancers (Silverberg 2015).
A possible explanation for increased rates of cancer related mortality among HIV-positive adults compared with HIV-negative adults may also be explained by differing treatments; a study that looked at cancer registries in three US states showed that higher proportions of PLWH did not receive treatment for cancers that included lung, prostate, and colorectal cancers, as well as diffuse B cell and Hodgkin’s lymphomas. Higher degree of immunosuppression, age, race, male sex, and use of injection drugs were some of the factors associated with lack of treatment (Silverberg 2015). A survey of US oncologists revealed provider-level factors such as concern about toxicities and efficacy may also influence treatment rates (Suneja 2015). Given potential for drug-drug interactions and cancer treatments, HIV providers have a role in working with oncologists to discuss treatment plans (Flepisi 2014). Other studies have shown that, despite increased risk, screening rates are lower in HIV-positive adults for particular cancers (Logan 2010; Reinhold 2005).
Given the higher risk and virulence of some cancers among HIV-positive individuals, consideration must be given to distinct cancer screening guidelines. These guidelines should also be individualized for patients, since life expectancy rather than strict age cutoffs are better determinants of the utility of cancer screenings (Braithwaite 2009).
Invasive cervical cancer is considered an AIDS defining cancer and HIV specific guidelines exist for cervical cancer screening. The Infectious Disease Society of America (IDSA) Primary Care Guidelines and the VA Cancer screening in HIV guidelines both recommend that HIV-positive women should receive Pap smears upon starting care and again in six months; if both tests are normal, then the woman needs to be screened only annually thereafter with the VA guidelines recommending q6 month screening until CD4 T-cell count is >200 cells/µL (Aberg 2014a; Justice 2009). The American Congress of Obstetricians and Gynecologists (ACOG) specify that after 3 consecutive normal cytology based screenings, screening could space to every 3 years but screening should continue beyond age 65 in HIV+ women (ACOG 2016). Women with atypical squamous cells; atypical glandular cells; low-grade or high-grade squamous intraepithelial lesion; or squamous carcinoma noted by Pap testing should undergo colposcopy and directed biopsy, with further treatment as indicated by the results of the evaluation (Justice 2009). The ACOG guidelines further delineate the role of HPV co-testing with PAP smear and how to triage results of co-testing (ACOG 2016). In parts of Sub-Saharan Africa, research is ongoing into the role of HPV and even direct exam with acetic acid as screening tools (Firnhaber 2016; Lince-Deroche 2015).
Despite these recommendations and the increased risk of cervical cancer, about 20% of HIV-positive women don’t receive Pap smears within the first year of diagnosis (Logan 2010), and up to 25% do not receive annual screening (Oster 2009; Kaplan 1999). Higher age was a risk factor for not getting a Pap smear. The importance of following screening guidelines is demonstrated in several studies trying to determine if HIV+ women are at increased risk of invasive cervical cancer. In women who followed routine screening protocols and algorithms for abnormal results, the incidence of invasive cervical cancer was like HIV-negative women (Oster 2009; Massad 2009). Increasing immunosuppression is associated with a higher risk of invasive cervical cancer (Abraham 2013).
Screening for colorectal cancer in HIV+ persons should follow the guidelines for the general population as outlined in the IDSA and VA primary care guidelines (Justice 2009; Thorsteinsson 2016). While there is no clear evidence that the incidence of colorectal cancer is higher in HIV-positive persons compared with the HIV-negative population, it is the second leading cause of cancer-related death in the U.S.A. As people with HIV live longer, the incidence of colon cancer has been rising (Keller 2013). Despite this, HIV-positive individuals are less likely to have ever had one or more colorectal cancer screening tests for that testing to be up to date (Braithwaite 2009); Keller 2013).
Current guidelines from multiple sources recommend colorectal cancer screening starting at 50 years of age for all persons at average risk for the disease (Keller 2013; USPSTF 2016). In the 2016 update, the USPSTF recommended that adults aged 50 to 75 years (older on case-by-case basis up to age 86 where risks may outweigh mortality benefit) be screened in one of the following ways: every year with either guaiac based fecal occult blood testing (got) or fecal immunochemical test (FIT); every ten years with colonoscopy; every five years with either CT colonography or flexible sigmoidoscopy alone or a combination of annual FIT testing and sigmoidoscopy every 10 years (Bedimo 2009).
The risk of anal cancer is higher in HIV-positive than in HIV–negative individuals, with the relative risk for developing anal cancer among HIV-positive men 37 times higher than in the general population; and 60 times higher in HIV-positive men who had sex with men (MSM) (Frisch 2000).
Despite this significantly higher risk, currently no national recommendations on screening for anal cancer exist although the New York State Department of Health does recommend screening of HIV-infected individuals. But anal cancer screening has been shown to be cost effective in certain models (USPSTF 2016; Rex 2009; Ong 2016). Some specialists advocate screening similar to that for cervical cancer, with annual screening using the Thin-prep solution, especially for patients with long-term sexual partners.
The IDSA guidelines suggest consideration of screening for MSM, HIV-positive women with abnormal cervical cytology, and HIV-positive adults with genital warts (Aberg 2014a). A 2014 review summarizes current evidence for screening and notes that additional studies are warranted as anal cancer screening is adopted more widely, even in the absence of official recommendations (Goldie 1999).
Studies have found that HIV-positive individuals develop hepatic cancer at approximately seven times the rate of HIV-negative individuals (Brau 2007; Ong 2016). Screening for hepatic cancer is currently recommended only in patients with cirrhosis, although screening may also be warranted in HBV carriers over 40 years of age with persistent or intermittent ALT elevation and/or HBV DNA level >2000 (Patel 2008; Wells 2014) This screening involves liver ultrasound at six- to twelve-month intervals (Aberg 2004; Ghany 2009). Alpha-fetoprotein (AFP) has poor specificity and sensitivity, and its use is currently optional, with abnormalities confirmed by liver imaging studies (Bruix 2005; Lok 2009).
Screening in persons living with HIV should follow the same guidelines as the general population as risk of breast cancer does not appear to be elevated in HIV. Screening as outlined in the IDSA recommendations and others include annual mammograms in all women over 50 years old (every one to two years if lifetime risk is <20%). For women 40 to 49 years old, providers should periodically perform individualized assessments of risk for breast cancer and discuss pros and cons of earlier screening (Aberg 2004).
Lung cancer is the leading cause of cancer-related death in the U.S.A. and higher in HIV-positive patients, possibly because of the higher rate of smoking in this population. Recent data also supports a possible role of HIV-related inflammation and prior lung damage from HIV (Hessol 2015; Meijide 2015). Updated screening guidelines for the general population were developed after results from the National Lung Screening Trial (NLST), showed 20% fewer lung cancer deaths among heavy smokers screened with low-dose helical CT compared to standard chest X-ray (Aberle 2011) .
The USPSTF recommends annual screening with low dose CT for adults age 55 to 80 with at least a 30 pack/year history and are either current smokers or quit within the preceding 15 years. Although there is concern of possible increased false positive findings on CT in HIV-positive adults, a study in veterans did not find increased risk of abnormal findings on CT or follow-up testing, suggesting a favorable balance of harms and benefits in HIV-infected adults (Sigel 2011). Two studies have provided preliminary evidence that screening with low dose CT is feasible and detected differing incidence of lung cancer, of note older age was an important consideration for detection (Sigel 2011; Bruix 2005; Makinson 2016). More data will be needed to understand the role of these screening guidelines in HIV-infected adults.
Risk does not appear to be elevated in HIV-positive men, with a study in the Kaiser Permanente system even demonstrating a lower incidence rate of prostate cancer in HIV-positive compared to HIV-negative men that did not appear to be explained by risk factors or screening rates (Marcus 2014a). The increased rate of prostate cancer over time seen in the US HIV/AIDS Cancer Match study was influenced primarily by increasing age (Robbins 2014).
Screening recommendations for prostate cancer are controversial (the USPSTF recommends against routine screening) and include annual digital rectal exams and PSA levels in men over 50 years of age, and earlier for certain high-risk groups such as African-Americans. The American Urological Association (AUA) guidelines recommend that screenings begin at age 55 and stop at age 70 or if the patient has less than a 10-year survival (Kaplan 1999; Hessol 2015; Carter 2013).
HIV-positive individuals may be at increased risk of infection-related NADCs, especially anal, cervical, vaginal, penile, nasopharyngeal, laryngeal, and oral cancers related to HPV; liver cancer from HBV and HCV; and nasopharyngeal cancer and Hodgkin’s lymphoma related to EBV. Patients may also be at risk for smoking-related NADCs, especially non-melanoma skin, other head and neck, lung, and less likely melanoma. Screening guidelines should be followed as in the general population for many cancers such as breast, prostate and lung cancer. HIV specific guidelines exist for cervical cancer and although no national guidelines exist some experts recommend screening for anal cancer in PLWH. As PLWH continue to age, incorporating cancer screening, guided by life expectancy needs to become an integral part of HIV primary care.