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HIV and Aging: The Long-term Consequences
of Successful Antiretroviral Therapy
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The times they are a'changin' - Bob Dylan
HIV medical update Summer 2009 vol 4 issue 3
hivmedicalupdate.ca
By Julian Falutz, MD, FRCPC
Director, HIV Metabolic Clinic
and Senior Physician
Division of Geriatrics
McGill University Health Centre
Montreal General Hospital
Montreal, Quebec
Interactions between aging-related conditions and longterm consequences
of successful HIV control will have an impact
on the outcomes of older HIV patients. A fundamental challenge
relates to who will provide the needed medical expertise and
function as advocates for these patients. Historically, HIV
healthcare providers have enthusiastically donned the required
"new hats" as the needs of their patients evolved. They are now
being asked to take on an evenmore daunting task, one for which
there are few signposts and even fewer role models. There is no
doubt that these emerging challenges will be met with the same
resolve that has characterized the response of both the affected
and caregiving communities for almost 3 decades.
Introduction
Successfully-treated patients infected with the human immunodeficiency virus (HIV) continue to have an overall improved long-termprognosis.However, olderHIV patients will likely experience an array of distinct clinical challenges. This issue of HIVMedical Update highlights some of the developments recognized in aging patients that are
increasingly faced by clinicians.
Changing clinical landscape
The clinical practice of geriatrics usually involves the care of patients generally more than 80 years old with multiple, concurrent, biopsychosocial problems. However, in patients infected with HIV, "older" generally refers to those over the age of 50 years. In the pre-highly active antiretroviral therapy (HAART) era, the biological and clinical
differences between these "older" patients, representing about 10% of infected cohorts, and younger patients were recognized. Due to HAART-associated improvements in HIV morbidity and life expectancy, this group is increasing
and will likely represent about 50% of all North American HIV patients by 2015.1 There is growing awareness of the overlap in biological and clinical issues between older HIV and general geriatric patients; indeed, in some respects, HIV patients may be considered as having many features of accelerated aging (Table 1).1
Generally, 2 groups of older HIV patients are identified; the majority are long-term HAART responders with a (nearly) normal lifespan and significantly fewer HIV-related complications. The second group consists of newly infected persons in whom the mean age at seroconversion is increasing.2 The relative frequency of HIV transmission
modes also differs in older versus younger persons; heterosexual transmission occurs more commonly in older patients compared with HIV exposure via male-to-male sex or injection drug use.3 Healthcare providers and at-risk persons must be appropriately informed about these differences. Older HIV patients frequently present with symptomatic HIV disease or with a greater degree of immunosuppression. They have shorter acquired immune deficiency syndrome (AIDS)-free survival, increased mortality, and a greater burden of HIV and non-HIV comorbidities.
However, HIV is less frequently considered as a cause of disease in older patients.3 Nevertheless, HIV is evolving into a manageable chronic illness and subpopulations may have long-term survival rates that are indistinguishable from control populations.4 Generally, however, overall survival in recently infected 20-year-olds is projected to be less than that of the general population, to about 60-65 years of age.5
Immunosenescence and HIV immunosuppression
One key area of overlap between HIV and aging involves physiological immunosenescence and HIV-associated
immunosuppression. Similarities between these processes include: decreased thymic output, reduced naïve T-cells, changes in cytokine profiles, reduced proliferative capacity to mitogen stimulation, shorter telomere length in the cluster
of differentiation (CD)8+ T-cell population, increased susceptibility to activation-induced cell death, accumulation of differentiated CD4+ and CD8+ T-cells, and increased susceptibility to common infections. There is no increase in opportunistic
infections in normal aging such as occurs in HIV. HIV causes a much greater degree of immunosuppression.6 Untreated older patients with HIV have lower CD4+ T cells at initial diagnosis and are more likely to develop AIDS at a given CD4 count than younger patients.7 The ability to achieve an undetectable viral load is actually improved in older patients, likely because of better treatment adherence.8 The time to reach a plateau CD4 level is prolonged and the peak CD4 count reached is lower in older
patients.9 Whether an initially effective antiviral response will
have a similar durability as found in younger patients is unknown.
These potential age-related differences in response are clinically
relevant, since the risk and spectrum of both HIV and non-HIV
complications are related to pre-HAART nadir CD4 counts,HIV
viral loads, and plateau CD4 counts.10 It is unknown whether
functional, not merely numerical, immune restoration is agedependent;
furthermore, there are no data on whether current
treatment recommendations should be age-specific.
Non-HIV complications
Mortality due to a limited spectrum of non-HIV-associated
sequelae has increased in frequency as HIV-associated complications
have diminished. This has been well described in the overall
HIV population, but it is unknown whether age is a cofactor.
Hepatic, renal,malignant, and cardiovascular-metabolic complications
occur more frequently now than were previously observed.
Hepatic disorders
Hepatic function decreases with age. The key role of the liver
in antiretroviral drug metabolism is important given the polypharmacy
existing in HIV patients. This phenomenon increases
as patients age and use more non-HIV drugs. Hepatic disease is
common in HIV infection, due to coinfection with Hepatitis B
virus (HBV) and HCV, or to the hepatotoxic effects of antiretroviral
drugs or anti-infective agents. Immune responses to antiretrovirals
are decreased in patients coinfected with viral hepatitis.
Cirrhosis is more common in coinfected HIV patients and
deaths due to hepatic failure are more common in coinfected
than in HIV monoinfected patients.11 As well, the risk of hepatocellular
carcinoma is greater than in age-matched controls.12
Malignancies
Most common adult malignancies occur more frequently in
the elderly. In HIV infection, immunosuppression and certain
infections are risk factors for AIDS-related cancers, including
Kaposi sarcoma (Human herpesvirus type 8 [HHV-8]), non-
Hodgkin lymphoma (Epstein-Barr virus [EBV]), and cervical
cancer (Human papillomavirus [HPV]). Although the incidence
of Kaposi sarcoma and non-Hodgkin lymphoma was decreasing
prior to the general introduction of HAART, it continued
to decline after HAART became available.13 The incidence of
non-AIDS-related cancers in which immunosuppression, immune
activation, or a possible infectious agent play an etiologic role
may be increasing. These include Hodgkin lymphoma (EBV),
anal cancer (HPV), lung cancer (possible weak link with HPV),
and hepatocellular carcinoma (both HBV and HCV); however,
epithelial cancers (eg, colon, breast, ovary, and prostate) are not
increased in HIV.12
The prevalence of cigarette smoking among HIV patients is
about twice that in seronegative subjects. This contributes to the
higher incidence of lung cancer, but HIV infection itself is a risk
factor.14 Certain malignancies occur more frequently in other
chronically immunosuppressed states, for example, in solid organ
transplant recipients in whom Kaposi sarcoma is also increased.15
Kidney disease
Renal dysfunction is an age-dependent disorder with amultivariate
etiology, some causes of which are more common in HIV
disease (eg, hypertension, and HCV coinfection). HIV infection
is associated with certain types of renal disease; this is attributed
partly to the presence of CD4 receptors on the nephron.16
Microalbuminuria may be more common in HIV disease,
suggesting premature endothelial dysfunction,17 which has
implications for accelerated cardiovascular disease (CVD). Endstage
renal disease occurs and is more common among patients
of African descent. In addition, antiretroviral drug-related
nephropathy may occur. This was formerly a problem with indinavir,
which is now infrequently used, but concerns persist over
the possible long-term, low-grade nephrotoxicity associated
with tenofovir.16
Cardiovascular and metabolic disorders
Cardiovascular and metabolic complications are interrelated
disorders with a known impact on HIV patients. Age is one of
the major CVD risk factors, but several other traditional risk
factors are also more common in HIV patients, whether due to
lifestyle, HIV, or treatment-related causes.18 An inflammatory
component may contribute to this increased risk;19 this occurs
even in successfully treated patients.20 This is relevant for an
aging population in whom abnormal inflammatory markers are
more prevalent.21
In untreated patients, a distinct lipid profile consisting of
elevated triglycerides (TGs), low high-density lipoprotein (HDL),
low low-density lipoprotein (LDL), and an increase in small, dense
LDL is observed. This atherogenic lipid profile is due to defects
in key regulatory processes affecting lipid metabolism.22 This
type of dyslipidemia is not unique to HIV infection, and also
occurs in other chronic infectious and inflammatory states.23
HIV infection may also contribute to the increased CVD risk,
possibly by initiating tissue factor production,24 or by interfering
with normal reverse cholesterol transport, thereby contributing
to the low HDL levels.25
Lipids may be altered by several drugs within the original anti-
HIV drug classes (nucleoside reverse transcriptase inhibitors
[NRTIs], non-nucleoside RTIs [NNRTIs], and protease inhibitors
[PIs]). These are not drug-class specific effects and the extent of
dyslipidemia differs between individual drugs. For newer antiretroviral
agents, the risk of associated dyslipidemia is still under
investigation. Overall, in conjunction with other CVD risks,
dyslipidemiamay be significant enough that some patients require
lipid-lowering therapy. Abnormalities of glucose homeostasis also
occur in some patients due to drug-specific effects on intermediary
metabolism, leading to an increase in insulin resistance and
Type 2 diabetes (T2DM) in a significant minority of patients.
In addition,well-described changes in body fatmass occur in some
patients. Thymidine NRTI-associated mitochondrial toxicity
causes apoptosis of peripheral adipocytes and presents as peripheral
lipoatrophy (LA), which has a significant impact on quality
of life and drug-treatment adherence. Increased visceral adipose
tissue (VAT) and lipohypertrophy (LH) occur in some treated
HIV patients; this biologically complex phenomenon is associated
with several PIs and possibly NNRTIs. Significantly, it is not
pathophysiologically associated with the development of LA.
Increased VAT is a well-known risk factor for T2DM, CVD, and
overall mortality in the general population.26
In normal aging, changes in fat distribution occur, including
increased VAT and loss of subcutaneous fat, and are similar to
those occurring in some treated HIV patients.27 In addition, ageassociated
changes, eg, hypogonadism, decreased exercise, and
poor diet may also contribute to increased VAT. As well, dyslipidemia
and impaired glucose control are more common in the
elderly. Overall, the lipid, glucose, and body composition changes
that occur in some treated HIV patients are similar to agerelated
changes.
In industrialized countries, the prevalence of the metabolic
syndrome (MS), a risk factor for T2DM and CVD, increases
with age in the general population and, by age 60 years, can
approach 40%-50%.28 The features of the MS - an atherogenic
lipid profile, glucose abnormalities, increased VAT, and hypertension
- are similar to what occurs in treated HIV infection.
Although the functional utility of an MS diagnosis remains controversial
in both the general and the HIV population,29 the
prevalence of the individual components do increase with age.
Studies suggest that the prevalence of theMS in HIV is similar to
that in age-matched controls.
Overall, the risk of myocardial infarctions is increased in
treated HIV patients compared with uninfected populations,
especially in older HIV patients.30While common CVD risk factors
play as important a role in HIV as in uninfected persons, a
residual 10%-15%per year increase in the relative risk compared
with untreated HIV patients may be attributed to some antiretroviral
drugs, particularly several PIs and possibly abacavir.
The variable association of antiretroviral drugs and CVD risks
allows for the individualization of HAART regimens appropriate
to a patient's specific CVD risk profile, and this assessment is
now the standard of care for all HIV patients.
Bone disorders
Bone abnormalities occur more frequently in HIV-infected
patients, including osteonecrosis and reduced bone mineral
density (BMD).31 The use of dual-energy x-ray absorptiometry
(DXA) scans to assess body composition in HIV infection provided
initial data revealing that both HIV males and females have
a several-fold higher prevalence of decreased BMD compared
with controls.32 Prospective studies confirm that duration of
HIV infection, as well as common risk factors contribute to this
bone loss.33 Laboratory studies suggest that several antiretroviral
drugs may affect osteoblast and osteoclast function,34 but most
studies do not implicate antiretroviral drugs in BMD loss.35
Hormonal abnormalities that occur in HIV infection,
including low vitamin D3 levels, decreased 1-alpha hydroxylase
activity, and changes in parathyroid hormone biology may
contribute to bone demineralization.31 Ongoing malnutrition,
hypogonadism, and low weight are also involved. Interestingly,
abnormalities of vitamin D metabolism have recently been associated
with metabolic disorders in the general population.36 The
absolute short-term risk of osteoporotic fractures remains low,
but emerging data suggest that this risk may be greater than in
controls.37 Whether HIV-infected women are at greater risk of
postmenopausal osteoporotic fractures is uncertain. In general,
osteoporosis is underdiagnosed in elderly males.
Common geriatric conditions
Common health concerns in older subjects will also have an
impact on agingHIVpatients.Common geriatric problems involve:
polypharmacy; medical comorbidities; neuropsychiatric disorders;
mobility restriction; incontinence; frailty; loss of independence;
complex family and peer relations; and diminished quality
of life and mortality-related issues.
Cognitive dysfunction
The prevalence of Alzheimer disease, the most common
cause of dementia, is >30% in persons older than 80 years.38
Since the availability of HAART, HIV-associated dementia, a
form of subcortical dementia, has decreased significantly.
However, concern exists that milder degrees of HIV-related
cognitive decline may persist in older subjects responding to
HAART,39 despite penetration into the cerebrospinal fluid (CSF)
by some antiretrovirals.40 Aging HIV patients may be at particular
risk of Alzheimer disease given new data demonstrating
that vascular risk factors may also be involved.41
Frailty
Frailty refers to a geriatric syndrome with clinical features that
include overall poor health, increased risk of falls, poor appetite,
loss of musclemass, and bone demineralization. Frailty arises from
interrelated processes at the molecular, cellular, and organ-system
levels, and increases the risk of disability, dependency, loss of autonomy,
and mortality. Using a modified version of a published
definition of frailty, investigators suggested that HIV infection was
associated with an earlier occurrence of this condition,42 and that
a low CD4 count predicted the development of this phenotype.43
Social support
Older persons often require social, nursing, home-care, and
community services in order tomaintain functional independence.
Furthermore, the elderly frequently live on fixed incomes with
limited flexibility to increase healthcare expenditures and are at
particular risk due to limited social support. Little information
exists on how these realities will interact with a varied yet distinct
HIV population where issues related to alternative lifestyles,
social discrimination, illegal drug use, misinformation, and
social ostracism may also be involved. The emergence of HIV in
aboriginal, immigrant, and minority communities poses multiple
and still inadequately identified problems as these patients
become older.
Summary
Interactions between aging-related conditions and longterm consequences
of successful HIV control will have an impact
on the outcomes of older HIV patients. A fundamental challenge
relates to who will provide the needed medical expertise and
function as advocates for these patients. Historically, HIV
healthcare providers have enthusiastically donned the required
"new hats" as the needs of their patients evolved. They are now
being asked to take on an evenmore daunting task, one for which
there are few signposts and even fewer role models. There is no
doubt that these emerging challenges will be met with the same
resolve that has characterized the response of both the affected
and caregiving communities for almost 3 decades.
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15. Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis.
Lancet. 2007;370(9581):59-67.
16. Fine DM, Perazella MA, Lucas GM, Atta MG. Renal disease in patients with HIV infection: epidemiology, pathogenesis and management. Drugs. 2008;68(7):963-980.
17. Szczech LA, Grunfeld C, Scherzer R, et al.Microalbuminuria in HIV infection. AIDS. 2007; 21(8):1003-1009.
18. Grunfeld C, Kotler DP, Arnett DK, et al. Contribution of metabolic and anthropometric abnormalities to cardiovascular disease risk factors. Circulation. 2008;118(2):e20-28.
19. Kuller LH, Tracy R, Belloso W, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med. 2008;5(10):e203.
20. Hsue PY, Hunt PW, Schnell A, et al. Role of viral replication, antiretroviral therapy, and immunodeficiency in HIV-associated atherosclerosis. AIDS. 2009;23(9):1059-1067.
21. Nicklas BJ, Hsu FC, Brinkley TJ, et al. Exercise training and plasma C-reactive protein and interleukin-6 in elderly people. J Am Geriatr Soc. 2008;56(11):2045-2052.
22. Falutz J. Therapy insight: Body-shape changes and metabolic complications associated with HIV and highly active antiretroviral therapy. Nat Clin Pract Endocrinol Metab. 2007: 3(9):651-661.
23. KhovidhunkitW, KimMS,Memon RA, et al. Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host. J Lipid Res. 2004; 45(7):1169-1196.
24. Schecter AD, Berman AB, Yi L, et al. HIV envelope gp120 activates human arterial smooth muscle cells. Proc Natl Acad Sci U S A. 2001;98(18):10142-10147.
25. Mujawar Z, Rose H, Morrow MP, et al. Human immunodeficiency virus impairs reverse cholesterol transport from macrophages. PLoS Biol. 2006;4(11):e365.
26. Despres JP, Lemieux I.Abdominal obesity andmetabolic syndrome.Nature. 2006; 444(7121): 881-887.
27. Beaufrere B,Morio B. Fat and protein redistribution with aging: metabolic considerations. Eur J Clin Nutr. 2000;54 Suppl 3:S48-53.
28. Churilla JR, Fitzhugh EC, Thompson DL. The Metabolic Syndrome: How Definition Impacts the Prevalence and Risk in U.S. Adults: 1999-2004 NHANES. Metab Syndr Relat Disord. 2007;5(4):331-342.
29. Worm SW, Sabin CA, Reiss P, et al. Presence of the metabolic syndrome is not a better predictor of cardiovascular disease than the sum of its components in HIV-infected individuals: data collection on adverse events of anti-HIV drugs (D:A:D) study. Diabetes Care. 2009;32(3):474-480.
30. Triant VA, Lee H, Hadigan C, Grinspoon SK. Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease. J Clin Endocrinol Metab. 2007;92(7):2506-2512.
31. Thomas J, Doherty SM. HIV infection - a risk factor for osteoporosis. J Acquir Immune Defic Syndr. 2003;33(3):281-291.
32. Brown TT, Qaqish RB. Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review. AIDS. 2006;20(17):2165-2174.
33. Mondy K, Yarasheski K, Powderly WG, et al. Longitudinal evolution of bone mineral density and bone markers in human immunodeficiency virus-infected individuals. Clin Infect Dis. 2003;36(4):482-490.
34. Jain RG, Lenhard JM. Select HIV protease inhibitors alter bone and fat metabolism ex vivo. J Biol Chem. 2002;277(22):19247-19250.
35. Bruera D, Luna N, David DO, Bergoglio LM, Zamudio J. Decreased bone mineral density in HIV-infected patients is independent of antiretroviral therapy. AIDS. 2003;17(13):1917-1923.
36. Lee JH, O'Keefe JH, Bell D, Hensrud DD, Holick MF. Vitamin D deficiency an important, common, and easily treatable cardiovascular risk factor? J Am Coll Cardiol. 2008;52(24): 1949-1956.
37. Triant VA, Brown TT, Lee H, Grinspoon SK. Fracture prevalence among human immunodeficiency virus (HIV)-infected versus non-HIV-infected patients in a large U.S. healthcare system. J Clin Endocrinol Metab. 2008;93(9):3499-3504.
38. Blennow K, de Leon MJ, Zetterberg H. Alzheimer's disease. Lancet.
2006;368(9533):387-403.
39. Dulioust A LN, Dolphin P, Boufassa F, et al. High frequency (50%) of neurocognitive disorders in older (>60 yrs) HIV-infected patients despite a sustained virological and immunological response on cart: the Sigma Study. Paper presented at CROI 2009; Montreal, Canada.
40. Giancola ML, Lorenzini P, Balestra P, et al. Neuroactive antiretroviral drugs do not influence neurocognitive performance in less advanced HIV-infected patients responding to highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2006;41(3):332-337.
41. Viswanathan A, Rocca WA, Tzourio C. Vascular risk factors and dementia: how to move forward? Neurology. 2009;72(4):368-374.
42. Desquilbet L, Jacobson LP, Fried LP, et al. HIV-1 infection is associated with an earlier occurrence of a phenotype related to frailty. J Gerontol A Biol Sci Med Sci. 2007;62(11):1279-1286.
43. Desquilbet L, Margolick JB, Fried LP, et al. Relationship between a frailty-related phenotype and progressive deterioration of the immune system in HIV-infected men. J Acquir Immune Defic Syndr. 2009;50(3):299-306.
Dr. Falutz has acted as a Consultant for Theratechnologies Canada Inc.,
has participated in Advisory Boards for Abbott Laboratories Canada, Ltd.,
and Tibotec Canada Ltd., and has taken part in Speaker Bureaus for Abbott
Laboratories Canada, Ltd., and GlaxoSmith Kline Canada Inc.
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