HIV and Premature Aging: A Field Still in Its Infancy - Editorial:
"Age at Cancer Diagnosis Among Persons With AIDS in the United States"
(pdf of published study attached)
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"Although the hypothesis of premature aging in HIV infection is intriguing, we suggest that it remain a hypothesis-for now-and not become ingrained as a complication of HIV infection before its time. To mature this concept from hypothesis to fact will require considerably more research to develop consensus in definitions, valid epidemiologic studies to demonstrate potential examples of premature aging, and a much better understanding of the normal biological process of aging. The latter requirement is probably the hardest to achieve, but it is essential if we are to confirm or refute that HIV truly accelerates aging."
From Jules: in the early days many and and at times most researchers and doctors in HIV did not believe lipodystrophy existed. although there are many researchers who believe HIV accelerates the aging process and there is a lot of data supporting this, here is a recently published statement suggesting otherwise. dont get me wrong i am all for confirmatory research and research that characterizes this problem and improves our understanding, but sometimes critics get in the way and create a barrier to progress, we don't want disbelief to be a barrier to progress and improved care for patients.
Annals of Internal Medicine
Jeffrey Martin, MD, MPH; and Paul Volberding, MD
From University of California San Francisco, San Francisco, CA 94107; and University of California San Francisco and Veterans Affairs Medical Center, San Francisco, CA 94121.
from jules: I have doubts about the study findings. CD4 and viral load increase cancer risks, has been found in many studies suggesting that for some cancers that are associated with immune deficiency people with HIV are at greater risk.
"We see no reason why true acceleration of aging could not increase cancer risk at all ages-another of our scenarios-especially given a relatively low overall incidence in which the pool of susceptible patients is likely not exhausted at younger ages. Of note, lung and liver cancer occurred at higher rates among HIV-infected persons at all ages, which is consistent with 1 scenario of premature aging."
Potent antiretroviral therapy has changed the world for most patients with HIV infection, their clinicians, and researchers. Where therapy is available, most patients experience a successful virologic and immunologic response and avoid the opportunistic infections that initially defined the epidemic. However, antiretroviral therapy cannot be considered an unqualified success. In particular, data from treated populations show that lifespan remains shorter compared with uninfected persons, and this diminished lifespan cannot be obviously attributed to any single complication (1, 2). Instead, a growing number of comorbid conditions seem to be more common in HIV-infected patients, and they often occur at younger ages than would be expected among HIV-uninfected persons (3-7). Collectively, these observations have led to a new concept in the lexicon of HIV medicine and research, premature or accelerated aging (8-10).
What do clinicians mean when they claim HIV causes premature aging? No consensus definition exists, but we suspect that clinicians implicitly require at least 3 criteria. First, HIV should affect conditions that are already known to be associated with aging in the general population. Second, HIV should increase the incidence of more than 1 age-related condition, as we would expect of aging in the general population. Third, and most critical for prematurity or acceleration, the rate of these conditions should be greater among young HIV-infected patients than among uninfected patients of similar age.
What is less clear in the question of premature aging among HIV-infected patients is what happens to the rate of various conditions as this population gets older. At least 3 scenarios are plausible: HIV-infected persons have a higher risk for various conditions at all ages compared with uninfected persons; the rates of these conditions might only be increased at younger ages and then normalize with older age; or, for any population of HIV-infected persons, only a fraction of patients are destined to develop a certain condition. In the last scenario, an increased incidence of a specific comorbid condition among younger HIV-infected patients might be counterbalanced by relatively decreased rates in older HIV-infected patients. From the perspective of the distribution of age of onset among patients who developed a certain condition, the latter 2 scenarios would result in a shift to younger ages of onset for a specific condition among HIV-infected patients compared with uninfected persons, whereas the first scenario would not shift the age distribution of onset for the condition but would simply lead to a higher rate among HIV-infected patients across all ages. Whether HIV-related premature aging must follow the same scenario for each affected condition is a matter of debate, but we argue that this might vary according to the condition. Therefore, premature aging is defined not by what happens among elderly patients but instead solely by a higher rate of "age-related" conditions among nonelderly patients.
Although clinicians and epidemiologists were among the first to hypothesize that premature aging occurs in HIV-infected patients, counting disease occurrences and measuring rates provides only limited information. The numerical appearance of premature aging, by the criteria we have outlined, could be due to HIV acting as an accelerant of true biological aging or, more mundanely, as an independent causal factor for 1 or more comorbid conditions. In the latter case, HIV infection may cause various conditions to occur at higher rates among younger HIV-infected persons by mechanisms that are entirely unrelated to the normal aging process. Although this distinction may not have immediate clinical significance, it may affect primary and secondary prevention strategies for the apparently accelerated condition. This distinction also establishes the crux of the problem in determining whether premature aging is occurring in HIV infection: Until scientists have more meaningful and comprehensive methods for measuring subclinical aging, proving that HIV is a true accelerant of the aging process is impossible.
The article by Shiels and colleagues in this issue (11) is an important stepping stone in our path to clarifying a relationship of HIV with premature aging. The authors focus on cancer, a prototypical age-related condition and one commonly held to demonstrate premature aging in HIV infection (12-15). Of note, the authors illustrate that it is insufficient to observe the distribution of age of onset of cancer in HIV-infected patients compared with HIV-uninfected persons. Such an approach ignores the differences in age distributions between these populations. Because HIV infection affects a younger population, any case series of cancer diagnoses in HIV-infected persons will give the appearance that the typical age at cancer diagnosis is younger than among HIV-uninfected persons. To overcome this common but often ignored pitfall, the authors used data from the U.S. HIV/AIDS Cancer Match Study (16) to compare the age-at-diagnosis distributions of types of cancer among patients diagnosed with AIDS between 1997 and 2006 and the general population in the United States, after adjusting for age differences between the groups. To evaluate for premature cancer occurrence, the authors compared the medians of the age-adjusted age-at-diagnosis distributions. They give several examples in which a naive analytic approach that ignored the differential age structure of the populations would arrive at a very different conclusion (one that supports premature aging) from the more valid age-adjusted analysis. Overall, the authors conclude that their findings do not support premature aging as a cause of cancer among HIV-infected persons.
Although Shiels and colleagues illustrate the importance of heeding age structure, their metric for determining the presence or absence of premature aging is only a first step and cannot account for all elements of the premature aging debate. In particular, the authors assumed that for premature aging to be present, the age-at-cancer-diagnosis curve for the AIDS population must be shifted to the left (indicating a lower median age than in the general population). They further assumed that if HIV was merely an independent risk factor for a particular type of cancer, then the age-at-diagnosis curve for the AIDS population would have the same shape and location as the curve for the general population but would encompass a larger area (signifying an increased overall risk). These assumptions reflect only 1 of the scenarios we have raised, in which premature aging would increase cancer risk preferentially in those at a younger age, with a corresponding decrease in older members. We see no reason why true acceleration of aging could not increase cancer risk at all ages-another of our scenarios-especially given a relatively low overall incidence in which the pool of susceptible patients is likely not exhausted at younger ages. Of note, lung and liver cancer occurred at higher rates among HIV-infected persons at all ages, which is consistent with 1 scenario of premature aging.
It is also important to recall a limitation of most available data when exploring the question of premature aging. Shiels and colleagues appropriately caution that differential exposure to cancer risk factors between the HIV-infected and uninfected populations could result in an apparent increased cancer risk. For example, HIV-infected persons have higher prevalences of smoking and hepatitis B virus co-infection, which are risk factors for lung and liver cancer. To account for such confounding factors in epidemiologic analyses requires very well-characterized patients; unfortunately, because of the relative rarity of cancer and the need for large sample sizes, it is very uncommon to have study populations that are both sufficiently large and well characterized. The large U.S. HIV/AIDS Cancer Match Study, for example, could not provide this level of confounder characterization. It is hoped that recently established cohort consortia, such as the National Institutes of Health-sponsored IeDEA (International Epidemiologic Databases to Evaluate AIDS) program (www.iedea-hiv.org), might provide requisite data.
Although the hypothesis of premature aging in HIV infection is intriguing, we suggest that it remain a hypothesis-for now-and not become ingrained as a complication of HIV infection before its time. To mature this concept from hypothesis to fact will require considerably more research to develop consensus in definitions, valid epidemiologic studies to demonstrate potential examples of premature aging, and a much better understanding of the normal biological process of aging. The latter requirement is probably the hardest to achieve, but it is essential if we are to confirm or refute that HIV truly accelerates aging.
Age at Cancer Diagnosis Among Persons With AIDS in the United States
Meredith S. Shiels, PhD, MHS; Ruth M. Pfeiffer, PhD; and Eric A. Engels, MD, MPH
From the National Cancer Institute, National Institutes of Health, Rockville, Maryland.
Background: Studies have reported young ages at cancer diagnosis in HIV-infected persons and have suggested that HIV accelerates carcinogenesis. However, these comparisons did not account for differences in population age structures.
Objective: To compare ages at diagnosis for non-AIDS-defining types of cancer that occur in both the AIDS and general populations, after adjustment for differences in age and other demographic characteristics between these populations.
Design: Registry linkage study.
Setting: 15 HIV/AIDS and cancer registry databases in the United States.
Participants: 212 055 persons with AIDS enrolled in the U.S. HIV/AIDS Cancer Match Study from 1996 to 2007.
Measurements: Comparison of age-at-diagnosis distributions for various types of cancer in both the AIDS and general populations, after adjustment for age and other demographic characteristics.
Results: The proportion of person-time contributed by older persons (age ≥65 years) was far smaller in the AIDS population (1.5%) than in the general population (12.5%). Reflecting this difference, the ages at diagnosis for most types of cancer were approximately 20 years younger among persons with AIDS. However, after adjustment for differences in the populations at risk, the median ages at diagnosis in the AIDS and general populations did not differ for most types of cancer (for example, colon, prostate, or breast cancer; all P > 0.100). In contrast, ages at diagnosis of lung (median, 50 vs. 54 years) and anal cancer (median, 42 vs. 45 years) were significantly younger in persons with AIDS than expected in the general population (P < 0.001), and the age at diagnosis of Hodgkin lymphoma was significantly older (median, 42 vs. 40 years; P < 0.001).
Limitations: Information on other cancer risk factors, including cigarette smoking, was not available. Analysis was restricted to non-Hispanic white and black persons who had AIDS, which could limit the generalizability of the findings to other racial and ethnic groups or to persons with HIV but not AIDS.
Conclusion: For most types of cancer, the age at diagnosis is similar in the AIDS and general populations, after adjustment for the ages of the populations at risk. Modest age differences remained for a few types of cancer, which may indicate either acceleration of carcinogenesis by HIV or earlier exposure to cancer risk factors.
Primary Funding Source: National Cancer Institute.
Infection with HIV increases the risk for certain types of cancer. The risk for Kaposi sarcoma, non-Hodgkin lymphoma, and cervical cancer is so high among HIV-infected persons that these types of cancer are included in the Centers for Disease Control and Prevention's definition of AIDS (advanced HIV infection) (1). In addition, HIV-infected persons have an elevated risk for certain non-AIDS-defining types of cancer (2-6), which is largely attributable to loss of control of oncogenic infections due to HIV-related immune suppression (7, 8) and a high prevalence of exposure to other carcinogens (such as tobacco or alcohol) (2, 9). Use of highly active antiretroviral therapy (HAART) has dramatically improved survival among HIV-infected persons and decreased the incidence of AIDS (10-12). However, the burden of cancer, particularly non-AIDS-defining cancers, is likely to increase as HIV-infected persons live longer.
This elevated cancer incidence and the increased risk for other conditions that typically occur at older ages (such as cardiovascular and bone disease, cognitive impairment, or general frailty) suggest that HIV-infected persons are vulnerable to a syndrome of premature aging (13, 14). For cancer, premature aging would manifest not only as an overall elevated cancer risk but also as a downward shift in the distribution of ages at cancer diagnosis. In support of this possibility, studies of lung (15-17), liver (18, 19), anal (20), and colorectal cancer (21) have noted ages at diagnosis that are 10 to 20 years younger among persons with HIV compared with the general population.
Before concluding that HIV-infected persons generally develop cancer at younger ages, it is important to consider the differences in age distribution between the underlying HIV and general populations. Of note, because of the young age at HIV acquisition in the United States and other western countries and the shorter life expectancy of persons with HIV, the proportion of persons with HIV who are older is far smaller than in the general population. For example, in the United States in 2007, only 3% of HIV-infected persons were aged 65 years or older, compared with 13% of the general population (22, 23). Because overall cancer incidence is 10 times higher in persons aged 65 years or older than in persons younger than 65 years (24), the truncated age distribution among persons with HIV precludes observation of most instances of cancer that would occur at older ages, which could explain the dramatic age differences reported in previous studies.
Using data from the U.S. HIV/AIDS Cancer Match Study, we evaluated the ages at diagnosis of 26 non-AIDS-defining types of cancer in both the AIDS and general populations, after adjustment for differences in population age structure. These analyses help clarify the potential effects of HIV infection on cancer development.
Our analysis included 212 055 persons with AIDS who were followed for cancer during the HAART era in the United States. The study sample was predominately male (76.1%) and included a larger proportion of black (57.7%) than white persons (42.3%). The median age at AIDS diagnosis was 38 years. From 1996 to 2007, 2540 cases of non-AIDS-defining cancer occurred during 591 378 person-years of follow-up after the onset of AIDS. The most common types of cancer were lung cancer (605 cases [24%]), anal cancer (282 cases [11%]), and Hodgkin lymphoma (226 cases [9%]).
Figure 2 presents the age distributions in the AIDS and general populations of the included registry areas. Although the median age of persons at risk for cancer was slightly higher in the AIDS population (40 years vs. 35 years in the general population), the age distribution was much wider in the general population. In particular, the proportion of total person-years contributed by persons aged 65 or older, who are at the greatest risk for cancer, was much smaller among persons with AIDS than in the general population (1.5% vs. 12.5%).
Age at Cancer Diagnosis
For most types of cancer, the median observed ages at diagnosis were approximately 20 years younger among persons with AIDS than in the general population (Table 1), which reflects the difference in age structure between the AIDS and general populations. However, after we adjusted for the underlying population structures, we found either no difference or very small differences between the observed ages at cancer diagnosis in the AIDS population and the expected ages at diagnosis in the general population. For example, the median observed age at diagnosis of colon cancer in persons with AIDS was 52 years, compared with 72 years in the general population. However, the median observed age in the AIDS population and the median expected age in the general population were identical (52 years; P = 0.53).
Ages at diagnosis among persons with AIDS were younger than expected in the general population for anal cancer (median, 42 vs. 45 years; P < 0.001) and lung cancer (median, 50 vs. 54 years; P < 0.001) (Table 1). In contrast, the ages at diagnosis of observed Hodgkin lymphoma cases were significantly higher in persons with AIDS than expected cases in the general population (median, 42 vs. 40 years; P < 0.001).
Figure 3 illustrates age-at-diagnosis distributions for anal cancer, lung cancer, Hodgkin lymphoma, and liver cancer, which are common among persons with AIDS, and prostate, breast, and colon cancer, which are common in the general population. For prostate, colon, and breast cancer, the age-at-diagnosis curves for observed cases in the general population are shifted toward much older ages than for the AIDS population, which indicates greater frequency at older ages; however, after adjustment, the age-at-diagnosis distributions for expected cases in the general population are similar to those for observed cases in the AIDS population. Of note, the areas under the curve for these types of cancer are smaller for persons with AIDS than for expected cases in the general population, which reflects a reduced risk for prostate, breast, and colon cancer in the AIDS population. Although the reason for this reduced risk is unclear, it has been seen previously and may reflect a protective effect of HIV infection or differences in cancer screening (5, 6, 28). For liver cancer, the age-at-diagnosis curve is similar for observed cases in persons with AIDS and expected cases in the general population, but the larger area under the curve for persons with AIDS reflects their elevated overall risk for liver cancer.
For anal cancer, lung cancer, and Hodgkin lymphoma (Figure 3), persons with AIDS have a higher risk than the general population, which corresponds to the greater areas under the age-at-diagnosis curves for the AIDS population than for expected cases in the general population. After adjustment, the expected age-at-diagnosis curves for anal and lung cancer in the general population are shifted downward from the observed curves in the general population but remain shifted toward slightly older ages than those for the AIDS population. In contrast, for Hodgkin lymphoma, the age-at-diagnosis curves show that observed cases in the AIDS population occur at older ages than expected in the general population. Of note, Hodgkin lymphoma has a bimodal age-at-diagnosis distribution in the general population; however, the age-at-diagnosis distributions for observed cases in the AIDS population and expected cases in the general population are unimodal.
SIRs for Cancer
Table 2 shows the SIRs for the same types of cancer shown in Figure 3. The overall SIRs for anal cancer, lung cancer, Hodgkin lymphoma, and liver cancer were elevated. The SIRs for anal and lung cancer were highest in the youngest ages and declined significantly across age groups (P < 0.001 for all trends). In contrast, the SIRs for Hodgkin lymphoma increased significantly across age groups (P < 0.001 for trend), with the highest SIRs at the oldest ages. No significant SIR trends were observed across age groups for liver, prostate, breast, or colon cancer.
The Appendix Table presents SIRs by stage of anal or lung cancer (for which the observed age in persons with AIDS was younger than expected in the general population). The SIR for local-stage anal cancer was higher than that for distant-stage cancer, whereas the SIRs for local- and distant-stage lung cancer were similar.
When we did not account for the underlying population age structures, we found that many types of cancer occurred at much younger ages in persons with AIDS than in the general population, as suggested in previous studies (15-21). However, these differences were almost completely driven by differences in the underlying age structures of the populations at risk for cancer. The previous studies that reported younger ages at cancer diagnosis in persons with HIV/AIDS did not take into account that very few HIV-infected persons who are at risk for cancer have attained older age, when most cases of cancer develop. For example, only 1.5% of person-time among the persons with AIDS in our study was contributed by persons aged 65 years or older. This underlying age difference creates a bias when the ages at cancer diagnosis are compared between these populations.
Cancer has recently been considered as a component of a potential syndrome of premature aging caused by HIV infection, motivated by clinical observations that average age of onset of age-related cancer is younger in HIV-infected persons than in the general population (15-21). However, as we show, these dramatic age differences are influenced by age differences in the populations at risk. Although we are not aware of previous mention of this type of confounding in the literature on HIV/AIDS and cancer, a similar mechanism has been discussed in studies of inherited diseases, such as Crohn disease. Studies of parent-child pairs of patients with Crohn disease have observed that children are diagnosed at younger ages than their parents were (29, 30). However, these generational age differences occurred because the children were younger than their parents when they were assessed for disease status and were thus not followed across the same age range as their parents (31, 32). After the differences in the periods at risk for Crohn disease were properly accounted for, these age differences were eliminated (32). This analysis highlights how statistical adjustment for differences in time at risk is essential when comparing ages at diagnosis (32). In our study, indirect standardization allowed us to compare the ages at cancer diagnosis in the AIDS and general populations after controlling for differences in the distributions of age and other demographic characteristics.
We observed small but statistically significant differences in the ages at diagnosis for anal cancer, lung cancer, and Hodgkin lymphoma after adjusting for differences in population structure. These types of cancer are among the selected group for which cancer risk is elevated among HIV-infected persons (2-5, 8). We propose 2 potential explanations for the younger age at diagnosis of anal and lung cancer among persons with AIDS. First, it may represent an effect of HIV on the development of these types of cancer. For example, HIV increases risk for cancer by inducing loss of immune control of oncogenic infections (such as human papillomavirus for anal cancer) (7, 8). By increasing the transition rate through the intermediate stages of infection on the pathway to cancer, this biological mechanism dramatically increases the number of persons with cancer and may also lead to slightly earlier ages at cancer diagnosis. Second, an early onset of cancer in persons with AIDS could reflect differences in the timing or intensity of exposure to other key risk factors for these types of cancer, such as earlier age at initiation of tobacco smoking or sexual debut (leading to human papillomavirus infection) or a greater number of cigarettes smoked per day. These explanations are not mutually exclusive, and both could explain the younger age at diagnosis for types of cancer known to be linked to HIV infection. Regardless, if AIDS directly accelerates the development of anal and lung cancer, we would expect to observe more cases of rapidly growing, distant-stage cancer. However, we did not observe higher SIRs for distant-stage anal or lung cancer compared with local- or regional-stage cancer.
An additional explanation for these age differences is increased medical surveillance of persons with AIDS, resulting in lead-time bias. This explanation is partly supported by our data for anal cancer. The SIR for anal cancer was highest for local-stage disease, which would be consistent with a stage shift due to screening with anal Papanicolaou tests (targeted toward HIV-infected men who have sex with men). However, because many HIV-infected persons do not receive regular medical care or cancer screening (33, 34), the overall magnitude and direction of this effect on age at cancer diagnosis are uncertain.
Among persons with AIDS, Hodgkin lymphoma was diagnosed at an older age than in the general population; however, the complexities of Hodgkin lymphoma epidemiology hinder the interpretation of this observation. In the general population, Hodgkin lymphoma exhibits a bimodal pattern in its age at onset. Nodular sclerosis often affects teenagers and young adults and is less strongly associated with Epstein-Barr virus (EBV) than other subtypes, whereas mixed cellularity (often EBV-positive) is the most common subtype among older adults (35). Among persons with HIV, Hodgkin lymphoma mainly resembles this second peak, in which the mixed cellularity subtype predominates (36, 37) and EBV is detectable in 80% to 100% of cases (38). Of note, the age distribution of persons with AIDS who have Hodgkin lymphoma did not show the bimodal pattern seen in the general population (Figure 3), which reflects the relative lack of young and old persons with AIDS (Figure 2). Thus, the single peak in persons with AIDS represents a mixture of both EBV-negative and EBV-positive cases of Hodgkin lymphoma. We speculate that the apparent shift to older ages in the observed cases among persons with AIDS represents a strong increase in the risk for the EBV-positive cases that occur at older ages, rather than a shift of EBV-negative cases to older ages. The development of EBV-positive Hodgkin lymphoma could be accelerated by HIV, possibly by a loss of immune control of EBV infection.
Our study has several strengths. Most important, our comparisons of age at cancer diagnosis were corrected for bias due to the differing underlying age structures of the AIDS and general populations. In addition, the HIV/AIDS Cancer Match Study includes data from a large and representative sample of persons with AIDS in the United States (for example, these analyses included approximately 20% of the 1.05 million cumulative AIDS cases in the United States).
The main limitation of our study was the lack of risk factor information, including information on cigarette smoking, which prevented us from directly assessing how exposure to known cancer risk factors influenced the age at cancer diagnosis. In addition, our study was restricted to non-Hispanic white and black persons with AIDS, which may limit the generalizability of our findings. However, any biological effect of HIV that accelerates the development of cancer should be similar across racial and ethnic groups, and the lack of acceleration in cancer development among persons with AIDS, who are most immunocompromised, argues against an important effect in persons with earlier HIV disease. Finally, we assumed that cancer rates were known without error, because the cancer registries included in our study cover a very large population with more than 875 million person-years of follow-up. If this assumption is incorrect, then the variance of our estimates would be underestimated, which would increase the probability of observing a statistically significant age difference when one does not exist. However, we do not believe that making this assumption biased our results because we observed no age differences for most types of cancer.
In conclusion, our results do not support including cancer as part of a general syndrome of premature aging in HIV-infected persons. Ages at cancer diagnosis are observed to be younger in HIV-infected persons largely because very few persons with AIDS have been followed during older age, when most cases of cancer occur. As the AIDS population continues to age, we would expect more cases of non-AIDS-defining cancer to occur at older ages, which would attenuate or eliminate the apparent age differences at cancer diagnosis. Our results do not support an accelerated screening schedule in HIV-infected persons for most types of cancer (such as prostate, colon, or breast cancer). However, HIV-infected persons should still receive regular cancer screening, on the basis of recommendations made for the general population and established guidelines made specifically for HIV-infected persons, for those types of cancer for which the risk is particularly high, such as cervical or anal cancer (39).