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Premature Aging and Age-Related Conditions in People with HIV

Older HIV positive people were more likely to have multiple health problems at an earlier age, matching those of HIV negative individuals 10 years older, according to an Italian study described in the December 2011 issue of Clinical Infectious Diseases. A Swiss study in the same issue found that non-AIDS-related conditions including cardiovascular disease, cancer, bone loss, and diabetes are a growing concern as people with HIV survive to older ages due to effective antiretroviral treatment.

Italian Study

The first study compared the prevalence of and risk factors for non-infectious comorbidities in a cohort of 2854 HIV positive adults receiving antiretroviral therapy (ART) at Modena University during 2002-2009, and 8562 matched control subjects in an Italian general population database (CINECA ARNO). Just under two-thirds were men, the average age was 46 years, and HIV positive patients had been on ART for an average of about 10 years.

This case-control analysis looked at age-related non-infectious conditions including cardiovascular disease, hypertension (high blood pressure), diabetes, bone fractures, and kidney failure; because these conditions are not caused by infectious pathogens, they are not directly linked to immune function (CD4 T-cell count) and are considered non-AIDS related. They also assessed "polypathology," or concurrent presence of 2 or more non-infectious conditions.

Results

• Prevalence of all individual non-infectious comorbidities and polypathology were significantly higher among HIV positive patients compared with HIV negative controls.
• Prevalence of polypathology among HIV positive people age 41-50 years was similar to that of HIV negative control subjects age 51-60 years.
• Differences in the prevalence of cardiovascular disease, bone fractures, diabetes, and kidney failure remained statistically significant after adjusting for sex, age, and hypertension.
• In a multivariate analysis, the following factors were independent predictors of polypathology:
  • Older age: odds ratio (OR) 1.11;
  • Male sex: OR 1.77;
  • Nadir or lowest-ever CD4 count below 200 cells/mm³: OR 4.46, or more than 4-fold higher risk;
  • Longer exposure to ART: OR 1.01, reflecting a small difference in risk.
• Hypertension was strongly and independently associated with increased likelihood of having other non-infectious comorbidities for both HIV positive and negative individuals.

"Specific age-related non-infectious comorbidities and polypathology were more common among HIV-infected patients than in the general population," the study authors concluded.

"The prevalence of polypathology in HIV-infected persons anticipated polypathology prevalence observed in the general population among persons who were 10 years older," they continued. "These data support the need for earlier screening for non-infectious comorbidities in HIV-infected patients."

The simultaneous presence of cardiovascular disease, hypertension, diabetes, kidney failure, and bone fractures "can reasonably be considered to represent a frailty phenotype that has been associated with aging in the general population and is a major determinant of disability associated with geriatric syndromes," they added.

Factors that could account for the occurrence of multiple progressive non-infectious conditions at younger ages "are not immediately apparent," but there are several hypothesized culprits including immune depletion due to late initiation of effective ART, effects of long-term viremia, chronic systemic inflammation, reduced blood vessel elasticity, and increased clotting and fibrosis.

Several other studies have also found that both lower nadir CD4 count and greater cumulative ART exposure are associated with higher prevalence of non-AIDS conditions. The reasons for the association with longer duration of ART are not fully understood, suggesting caution when considering very early treatment that would entail prolonged exposure to therapy.

"[O]ur findings suggest that an aggressive approach to the screening, diagnosis, and treatment of non-infectious comorbiditiesis warranted as part of routine healthcare for HIV-infected patients," the reserachers recommended. "Furthermore, our data suggest that onset of such screening should commence at a substantially earlier age...possibly at least a decade in advance."

Swiss Study

As described in the second report, investigators with the Swiss HIV Cohort Study assessed the influence of aging on the epidemiology of non-AIDS diseases in this large prospective observational cohort, which was established in 1988 with continues to enroll new participants.

The researchers calculated the incidence of clinical events from January 2008 (when a new non-AIDS-related morbidity questionnaire was introduced) through December 2010.

A total of 8444 HIV positive participants contributed data from 40, 720 semiannual visits; within this group 2233 (26.4%) were age 50-64 years and 450 (5.3%) were age 65 or older. The median duration of HIV infection was 15.4 years and nearly one-quarter had prior clinical AIDS.

Results

• Rates of death, AIDS-defining illness, and any clinical endpoint were 7.81, 4.32, and 53.3 cases per 1000 person-years, respectively.
• 994 new non-AIDS events were observed during the study period:
  • 201 cases of bacterial pneumonia;
  • 123 trauma-associated fractures;
  • 115 non-AIDS-defining malignancies (all except Kaposi sarcoma, non-Hodgkin lymphoma, and cervical cancer);
  • 70 cases of diabetes;
  • 55 myocardial infarctions (heart attacks);
  • 39 strokes;
  • 37 fractures with minimal trauma.
• Stroke, myocardial infarction, non-traumatic fractures, osteoporosis, diabetes, and non-AIDS malignancies were more common among people age 50-64 years and 65 or older, compared with participants younger than 50.
• In a multivariate analysis, the risk of stroke (HR 17.7), non-traumatic fractures (HR 10.5), osteoporosis (HR 9.13), non-AIDS-defining malignancies (HR 6.88), myocardial infarction (HR 5.89), and diabetes (HR 3.75) were elevated for people age 65 and over.

Based on these findings, the investigators concluded, "Comorbidity and multimorbidity because of non-AIDS diseases, particularly diabetes mellitus, cardiovascular disease, non-AIDS-defining malignancies, and osteoporosis, become more important in care of HIV-infected persons and increase with older age."

In their discussion they noted that comparison with an age-matched HIV negative group -- as was done in the Italian study -- was difficult because there is no suitable population with similar comorbidities and behavior in Switzerland. However, comparison with the non-age-matched European Cancer Observatory and a large German general population cohort suggest that people in the Swiss HIV Cohort have higher overall incidence of cancer, myocardial infarction, and diabetes.

When attempting to compare populations, they wrote, "[i]t is especially important to consider that HIV-infected persons differ from HIV-uninfected control subjects with respect to metabolic changes because of long-term toxicity of ART, with respect to alcohol consumption, smoking, body mass index, and rates of [hepatitis B or C virus] coinfections...This co-occurrence of multiple diseases or risk factors leads to novel patterns of multimorbidity that substantially differ by HIV status and age."

Like the Italian researchers, the Swiss team also suggested that residual immunodeficiency and chronic inflammation may add to the risk of age-associated non-AIDS conditions among HIV positive people on ART.

"We observed that individuals with higher CD4 cell counts were less likely to develop HIV-associated and non-AIDS events, and they were less likely to die," they wrote. "Patients with lower CD4 cell counts are known to have a higher mortality, but they also seemed to develop age-related events more frequently in our analyses."

"Because age is a non-modifiable factor, it is particularly important to carefully screen for and prevent age-related modifiable risks of non-AIDS comorbidity," they advised.  

Editorial

In an accompanying editorial, Jacqueline Capeau from the University of Paris and Hôpital Tenon reviewed the 2 studies and summarized current knowledge about age-related diseases in people with HIV, posing the philosophical query, "What is aging?"

"Aging is defined by the decreased ability to face stresses, leading to an increased susceptibility to diseases," she wrote. "Normal aging is associated with chronic sterile low-grade inflammation, as shown by the concept of inflammaging...chronic inflammation is probably related to long-term immune activation in response to the antigenic burden that we encounter throughout life...chronic low-grade inflammation constitutes a common soil for age-related comorbidities and could result in the simultaneous occurrence of different comorbidities (i.e., polypathology)."

"[I]f we consider that increased immune activation and long-term chronic inflammation are major players in the aging process in the general population," she continued, "it is obvious that these processes are more prevalent in HIV-infected patients, even when the infection is well controlled, than in the general population; HIV-infected patients will be more prone to develop, in advance, age-related diseases."

Considering whether all HIV positive people are prone to rapid aging, she suggested that the problem may primarily affect individuals with long-term HIV infection who experienced severe immune deficiency before the advent of effective and well-tolerated treatment.

"These long-term infected patients were probably older, with a more severe initial infection, and were exposed long-term to the virus at a time when the quality of the viral control was often poor; they may have also been exposed to toxic ART and remain lipodystrophic," she wrote. "These older patients have accumulated deleterious conditions and are now affected by comorbidities."

While the picture may appear grim for those with long-term HIV, she emphasized that in addition to all the factors related to the virus and its treatment, a number of modifiable environmental factors also contribute to premature aging, such as smoking, sedentary lifestyle, poor diet and resulting fat gain, and drug use.

"Even if difficult to do," she emphasized, "these factors need to be aggressively taken in charge."

Investigator affiliations:

Italian study: Department of Medicine and Medical Specialities, University of Modena and Reggio Emilia, Italy; Health Care Systems Department, CINECA Consortium of Universities, Italy; Department of Statistical Sciences, Alma Mater Studiorum, University of Bologna, Italy; Division of Infectious Diseases, Northwestern University, Feinberg School of Medicine, Chicago, IL.

Swiss study: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich and University of Zurich; Division of Infectious Diseases, Bern University Hospital and University of Bern; Division of Infectious Diseases, University Hospital Basel; Division of Infectious Diseases, University Hospital Geneva; Division of Infectious Diseases, Centre Hospitalier Universitaire Vaudois and University of Lausanne; Division of Infectious Diseases, Cantonal Hospital of St. Gallen; Division of Infectious Diseases, Regional Hospital, Lugano, Switzerland.

12/6/11

References

G Guaraldi, G Orlando, G Zona, F Palella, et al. Premature Age-Related Comorbidities Among HIV-Infected Persons Compared With the General Population. Clinical Infectious Diseases 53(11):1120-1126. December 2011.

B Hasse, B Ledergerber, H Furrer, et al (Swiss HIV Cohort Study). Morbidity and Aging in HIV-Infected Persons: The Swiss HIV Cohort Study. Clinical Infectious Diseases 53(11):1130-1139. December 2011.

J Capeau. Premature Aging and Premature Age-Related Comorbidities in HIV-Infected Patients: Facts and Hypotheses. Clinical Infectious Diseases 53(11):1127-1129. December 2011.