Important note: Information in this article was accurate in November 2004. The state of the art may have changed since the publication date.
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HIV is primarily thought of as a young person’s disease; however, the prevalence of HIV infection in people over the age of 50 years is growing. The reasons for this change include increased longevity due to HAART as well as a growing number of older patients becoming infected with HIV through high risk exposures. The number of AIDS cases reported in adults 50 years and over quintupled between 1990 and 2001 from 16,288 to 90,513. As a result, the number of HIV-infected persons over 65 years has grown 10-fold in the past 10 years. Occult HIV infection is a problem in older adults, because physicians are less likely to ask older patients about high risk behaviors or to suspect HIV in older patients. In addition, older patients may be less likely to admit to high risk sexual activity or injection drug use because of social norms. It is essential to ask all patients about HIV risk behaviors in a non-judgmental manner, regardless of age.
Consistent with the general trend in the AIDS epidemic, an increasing number of older women and minority adults are being infected by HIV.
This is particularly concerning, given that these groups are more likely to be disadvantaged and more likely to suffer from lower levels of physical functioning and emotional support than their younger counterparts.
In the pre-HAART and early HAART eras, numerous studies demonstrated that older patients had higher mortality and decreased AIDS-free survival compared to younger patients. AIDS-related illnesses have been shown to occur at higher CD4 cell counts in patients over the age of 30 years than in younger patients, and older AIDS patients have worse outcomes with AIDS-related conditions than younger patients. Prior to 2003, the principal clinical AIDS defining conditions were Pneumocystis jiroveci (formerly carinii) pneumonia, Kaposi’s sarcoma, and Mycobacterium avium complex. More recently, multiple groups have reported a lower incidence of these diseases and higher rates of other conditions, including neurologic complications, malignancies, and bacterial pneumonia which are more common in older people.
HAART is effective at reducing HIV viral load and increasing CD4 cell counts. However, data regarding clinical, immunologic, and virologic benefit in older patients treated with HAART have been mixed (Table 1). Some investigators have hypothesized that the degree of immune recovery after treatment with HAART may be dependent on the thymus, which loses function with advancing age [Douek DC, et al. Nature. 1998 Dec 17;396(6712):690-55; Haynes BF, et al. Annu Rev Immunol. 2000;18:529-60; Mackall CL and Gress RE, Immunol Rev. 1997 Dec;160:91-102; Zhang L, et al. J Exp Med. 1999 Sep 6;190(5):725-32; Jamieson BD, et al. Immunity. 1999 May;10(5):569-75]. Data from the early HAART era suggested that the speed of immune recovery after initiation of HAART is inversely proportional to age and that older patients did not respond as well as younger patients [Manfredi R and Chiodo F, AIDS. 2000 Jul 7;14(10):1475-7; Viard JP, et al. J Infect Dis. 2001 Apr 15;183(8):1290-4; Yamashita TE, et al. AIDS. 2001 Apr 13;15(6):735-46]. Some studies have suggested that older patients are less likely to achieve virologic suppression than younger patients [Manfredi R, et al. J Acquir Immune Defic Syndr. 2003 May 1;33(1):112-4; Goodkin K, et al. AIDS. 2004 Jan 1;18 Suppl 1:S87-98; Knobel H, et al. AIDS. 2001 Aug 17;15(12):1591-3], while others have suggested the opposite [Manfredi R and Chiodo F, AIDS. 2000 Jul 7;14(10):1475-7; Yamashita TE, et al. AIDS. 2001 Apr 13;15(6):735-46]. One study demonstrated a decreased 3-month CD4 cell count response to HAART in patients over 45 years, but this effect was not sustained at 6 months [Yamashita TE, et al. AIDS. 2001 Apr 13;15(6):735-46]. A consistent finding across studies, however, has been a smaller CD4 cell count increase in older patients compared to younger patients treated with HAART [Manfredi R and Chiodo F, AIDS. 2000 Jul 7;14(10):1475-7; Viard JP, et al. J Infect Dis. 2001 Apr 15;183(8):1290-4; Knobel H, et al. AIDS. 2000 Jul 7;14(10):1475-7]. All of these trials were relatively small, however, with fewer than 400 patients over the age of 50 years.
Data regarding the impact of age on HIV progression and mortality in the HAART era have also been conflicting. A study of an urban cohort by Perez and Moore demonstrated a benefit to HAART in patients over 50, with no difference in 3-year survival in older and younger patients treated with HAART [Clin Infect Dis. 2003 Jan 15;36(2):212-8]. In contrast, Anastos and colleagues recently found an increased hazard of death and of new OIs in older women followed in the Women’s Interagency Health Study (WIHS) after HAART initiation. [Ann Intern Med. 2004 Feb 17;140(4):256-64]. Age above 50 was also found to be a risk factor for AIDS progression and death in the EuroSIDA Study [Egger M et al., Lancet. 2002 Jul 13;360(9327):119-29].
Conclusions regarding choice of HAART regimen in older patients are limited; most data come from small non-randomized trials. Larger observational studies or controlled trials involving older patients are needed to evaluate the efficacy of various anti-retroviral regimens in this population, as measured by virologic suppression, CD4 cell count response, HIV disease progression, and mortality.
Adults with HIV infection are now surviving long enough to experience HIV as a chronic disease and are suffering from other medical comorbidities that they previously did not live long enough to endure, including liver disease, cancer, and vascular disease. Liver disease from hepatitis B virus (HBV), hepatitis C virus (HCV), and alcohol abuse has become a common cause of hospitalization, morbidity and mortality in HIV-infected individuals. In addition, there is an increased rate of liver toxicity due to use of multidrug HAART and lipid lowering agents in HIV patients coinfected with hepatitis. Older people are more likely to have end-stage liver disease than younger adults, due either to a longer or more rapid course of hepatitis. As a result, end-stage liver disease mortality has increased dramatically in the past 10 years, and hepatitis has become an important predictor of mortality in the HIV-infected population. It is unclear whether HIV/HCV-coinfected older patients will experience more rapid HIV disease progression than HIV mono-infected older patients, or whether HIV/HCV-coinfected older patients will have different rates of HIV disease progression or HCV mortality than HIV/HCV-coinfected younger patients.
HIV infection increases the risk for some tumors, particularly Kaposi’s sarcoma and non-Hodgkin’s lymphoma. HIV infection is also associated with increased risk of certain cancers, such as cervical cancer and hepatocellular carcinoma, due to coinfection with other viruses, including human papilloma virus (HPV), HBV, and HCV. In addition, the risk of certain cancers, particularly lung, breast, colon, and prostate, are known to increase with age. Recent data from the Women's Interagency HIV Study suggested an increased risk of lung cancer in HIV-infected women compared to national controls [Hessol NA, et al. J Acquir Immune Defic Syndr. 2004 Aug 1;36(4):978-85]. Other data have shown decreased rates of prostate cancer in HIV-infected men compared to age matched HIV seronegative male controls [Biggar RJ, et al. J Acquir Immune Defic Syndr. 2004 Jul 1;36(3):861-8]. Data from observational cohorts with more clinical information are needed to assess differences in incidence rates between HIV-infected older and younger patients as well as comparison to age-matched HIV-negative historical controls. Appropriate cancer screening, including Pap smears and colonoscopy, is an essential component of primary HIV care, especially in older patients.
The potential increased risk of cardiovascular and cerebrovascular disease with age is particularly relevant for HIV-infected patients. Age is an independent risk-factor for cardiovascular disease (CVD). While age in itself does not cause CVD, it may reflect the accumulation of atherosclerosis, the severity of which predicts the likelihood of suffering a major CVD event [Smith SC, Jr., et al. Circulation. 2004 Jun 29;109(25):3112-21]. Numerous studies have demonstrated an increased risk of cardiovascular and cerebrovascular events in HIV-infected patients, and several have found an association with HAART; it is unknown how much of the increased risk is attributable to age compared to HIV and/or use of HAART. Future work is needed to compare the rates of cardiovascular disease in older HIV-infected patients to age matched HIV-negative historical controls. Appropriately managing cardiovascular risk factors, including hypertension, lipid and glucose abnormalities, and tobacco abuse are essential for reducing the risk of cardiovascular disease from HAART in older HIV-infected patients.
Comorbidities will complicate management of the HIV-infected older patient. It is unclear whether HIV-infected older patients will have higher rates of these comorbidities than younger HIV-infected patients or HIV-negative age-matched controls. In addition, it is currently uncertain whether these comorbidities will have a synergistic effect with HIV in older adults. Therefore, it will be important to evaluate how HAART may interact with these comorbidities in future studies.
Metabolic toxicities related to HAART are a prominent consideration in HIV clinical practice and may be more common among older patients. Many of these complications are associated with both age and antiretroviral therapy, including disorders of lipid and glucose metabolism, cardiovascular disease, osteopenia, and osteoporosis.
Treatment with protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTIs) has been associated with several metabolic disorders, including dyslipdemia. Protease inhibitorbased regimens have been associated with increased triglycerides, total cholesterol, and LDL levels, and several studies suggest that the metabolic disturbances vary depending on the drug used. In addition, NNRTI-based HAART regimens and d4T may also increase total cholesterol and LDL levels, though often with a concomitant increase in HDL. These lipid abnormalities in older patients may be more dangerous than in younger patients because of increased risk of vascular disease and pancreatitis. Studies have not yet fully evaluated the independent effects of age and drug toxicity on this increased risk of vascular disease. Studies are needed identify the effects of particular drug combinations and age on the risk of vascular disease.
HIV-infected patients with renal or hepatic insufficiency deserve special attention when choosing antiretroviral regimens. Tenofovir DF and indinavir can be associated with nephrotoxicity and may be more dangerous in elderly patients, who typically have a lower creatinine clearance than younger patients. In addition, most protease inhibitors and NNRTIs can exacerbate hepatic insufficiency in those with pre-existing liver disease. Unfortunately, little data exist on dosing of these drugs in older patients with impaired renal or hepatic clearance. Close monitoring in some circumstances may be warranted. Interactions among antiretroviral agents are common and have been used to improve activity of some HAART regimens, as when ritonavir is used to improve the pharmacokinetics of other protease inhibitors. However, little data exist on the pharmacokinetics of these drugs in older patients, who may be more likely to experience drug-drug interactions. Therapeutic drug monitoring (TDM) may be useful in patients who are at high risk of adverse events and may be used to confirm therapeutic drug levels.
Pharmacologic interactions between antiretroviral agents and other drugs used in the elderly are common as well (Table 2). Toxic levels of the lipid lowering agents, lovastatin and simvastatin, may occur when they are coadministered with protease inhibitors, and these drugs are therefore contraindicated. Alternative agents including, pravastatin and lower doses of atorvastatin may be better choices. Cispride is contraindicated with all protease inhibitors due to the potential for cardiac arrhythmias. Drugs for erectile dysfunctional, such as sildenafil, should be used with caution in patients taking protease inhibitors or NNRTIs because of the potential for increased levels of sildenafil. Benzodiazepines and
antiretrovirals also interact. Agents such as temazepam, oxazepam, and lorazepam are better choices than midazolam and triazolam, which are generally contraindicated. Proton pump inhibitors are contraindicated
in patients taking atazanavir and delavirdine. Finally, concomitant use of herbal medications and antiretroviral therapy is currently under study, but echinacea and St. Johns’ wort are known to interact with antiretrovirals, and patients should be warned of these interactions.
In summary, there is a need for information about treatment tolerability, drug-drug interactions, short- and long-term toxicity, and interactions with underlying comorbidities and their therapies in older patients. Most randomized, controlled trials evaluating new antiretroviral drugs or chemoprophylaxis of HIV-related complications have excluded older patients and/or patients with concurrent disorders. Few studies have presented subanalyses comparing outcomes of older patients with younger ones. Toxicities and long term consequences of treatment are critically important in older HIV-infected patients. The role of age in the development of HIV-associated complications and drug toxicities needs to be studied.
HIV infection in adults over the age of 50 has been relatively ignored until recently. Controlled trials on the epidemiology, pathogenesis, and therapeutic and clinical outcomes of older HIV-infected patients are needed. As the HIV-infected population ages, there is a growing need to better determine the effectiveness of HAART in older patients, and to investigate factors associated with a more rapid course of HIV infection in patients over the age of 50. Older adults clearly have more comorbidities than younger patients, and the effect of these comorbidities on HIV progression is unknown. Drug toxicity due to HAART is significant, and these toxicities may be exacerbated in older patients. Research will be needed to document the safety, tolerability, and efficacy of HIV medications in older patients.
With the increased life expectancy of HIV-infected patients in the past ten years, the number of older patients with HIV infection is likely to continue to increase in the next decade. The significant decreases in HIV-associated morbidity and mortality may be partially tempered by the emergence of drug-resistant HIV and long-term toxicities from antiretroviral therapy. In addition, the growing number of patients with other comorbidities requiring pharmacologic treatment will make drug-drug interactions far more complicated. Future research evaluating drug toxicity in older patients will be essential for developing accurate treatment recommendations in older patients.
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