HIV infection in older patients: new therapies

teaser

Kelly A Gebo
MD MPH
Assistant Professor of Medicine
Department of Medicine
Johns Hopkins University School of Medicine
Baltimore, MD
USA
E:[email protected]
Supported by the National Institute of Drug Abuse
(K23-DA00523)

There is a growing prevalence of HIV infection in people over the age of 50 years.(1–3) The reasons for this include:

• People living with HIV are growing older and living longer due to highly active antiretroviral therapy (HAART).
• A growing number of older patients becoming infected with HIV through high-risk exposures.

As a result, the number of HIV-infected ­individuals over 65 years has grown by 10 times in the past 10 years.(3)

Some preliminary data suggest that older patients may not respond as well to HAART as younger patients. Specifically, immune recovery may be less good, and both morbidity and mortality rates may be higher.(4–17) Older age is also associated with a higher incidence of other comorbidities, and older age may increase the risk of the toxicities from antiretro‑viral therapies used to treat HIV.(18,19) This article will explore the epidemiology, morbidity and mortality, response to HAART and toxicities of HAART in HIV-positive patients over the age of 50 years.

Epidemiology
In the USA, the number of AIDS cases reported in adults 50 years and over quintupled between 1990 and 2001, from 16,288 to 90,513.(2) Overall, 19% of people living with AIDS at the end of 2000 were 50 years or over.(2) This increase in AIDS prevalence in adults over the age of 50 years is due to prolonged longevity in HIV-infected patients treated with HAART and to an increase in primary HIV infection in adults age 50 years and over.

Morbidity and mortality
In the pre-HAART era, numerous studies demonstrated that patients diagnosed with AIDS at an older age had higher mortality and decreased AIDS-free survival compared with younger patients.(4–17) In addition, AIDS-related illnesses have been shown to occur at higher CD4 counts in patients over the age of 30 years than in younger patients,(17) and older AIDS patients do worse with AIDS-related conditions than younger patients.(20–22)

Recently, Perez and Moore demonstrated a significant mortality benefit in older HIV patients on HAART in an urban cohort.(23) No significant difference in the survival rate was found between the older (83%) and younger (89%) patients who received HAART (p=0.29), and it was concluded that the effect of HAART improves the survival rate for older individuals, which supports the use of HAART in this group. Another research team, however, demonstrated that older patients had a significantly higher risk of AIDS progression than younger patients, even after adjustment for HAART.(24)

In the pre-HAART era, morbidity and mortality were significantly greater in older patients; however, larger studies will be needed to evaluate current morbidity and mortality trends in older patients treated with HAART.

Response to HAART
HAART is effective at treating HIV infection; however, data regarding clinical, immunological and virological benefit in older patients treated with HAART have been mixed. Data from the early HAART era suggested that age is inversely proportional to how quickly the immune system recovers after the initiation of HAART,(25) while other data have suggested that virological outcome may not be different in patients over the age of 55 years compared with those under 35 years treated with HAART. However, the immunological response appears to be blunted in older individuals.(26)

A recent study by Manfredi and colleagues evaluated 44 patients 55–65 years of age and 13 patients older than 65 years of age. After 12 months of therapy, the mean drop in viraemia was 1.0 log(10) in younger patients, compared with 0.5 log(10) in older patients. The immune recovery was significantly slower and more blunted in patients aged 65 years and over compared with younger patients. These authors concluded that age affected the immuno­logical response to HAART more than the virological response.(27)

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In contrast, a study by Knobel and colleagues found no significant difference in the virological and immunological outcomes between patients aged 60 years and over compared with patients 40 years and under treated with HAART after a 24-month follow-up. While there was a more favourable clinical course in the older patients, the adverse events rates were significantly higher in the older group (64% vs 35%).(28)

Larger controlled trials involving older patients will be needed to evaluate which antiretroviral therapies might be most effective in this population, as current data are based on smaller, nonrandomised studies. For now, current guidelines for HAART regimens should be applied to HIV-positive older patients; however, immunological, virological and clinical response should be monitored carefully, as recovery may be blunted in older patients.

Toxicities
HIV-infected patients are now suffering from the many toxicities of antiretroviral therapy. The adverse effects of HAART include disorders of lipid and glucose metabolism, cardiovascular disease, hepatitis, pancreatitis, peripheral neuropathy, lipodystrophy, osteopenia, osteoporosis, avascular bone necrosis and lactic acidosis.(18,19,29–38) The pathophysiological mechanisms of these toxicities include mitochondrial abnormalities as well as metabolic and endocrinological disorders. In many patients, the mechanism appears to be multifactorial.

Due to the increased risk of pancreatitis and vascular disease, lipid abnormalities in older patients may be more dangerous than in younger patients. Treatment with protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been associated with several metabolic disorders, including dyslipidaemia.(35,39) PIs can cause increased triglycerides, total cholesterol and low-density lipoprotein (LDL) levels, and several studies suggest that the metabolic disturbances may vary according to the PI used.(31,37,40,41) Ritonavir-containing regimens have been associated with the most pronounced elevations of total cholesterol and triglyceride levels, and nelfinavir-containing regimens have been associated with a lower risk of having a reduced high-density lipoprotein (HDL) level, while saquinavir-containing regimens have been associated with a lower risk of having an elevated total cholesterol:HDL ratio.(42) In addition, NNRTIs may increase total cholesterol and LDL levels and induce a concomitant increase in HDL, in contrast to PI regimens.(43)

Nephrotoxicity and hepatotoxicity are particularly relevant in older HIV patients. Tenofovir and ­indinavir are nephrotoxic and should be used with caution in elderly patients. Calculating creatinine clearance in older patients is essential, as older patients may have lower creatinine clearance than younger patients at the same creatinine level. In addition, most PIs and non-nucleoside drugs can exacerbate hepatic insufficiency in those with pre­-existing liver disease. Currently, little data exist on the dosing of many HAART drugs in older patients with impaired renal or hepatic clearance.

There are many pharmacological interactions between antiretroviral agents and drugs used to treat comorbidities. Lovastatin and simvastatin are contraindicated with PIs due to potentially toxic levels of the lipid-lowering agents. Alternative agents such as pravastatin and fluvastatin may be better choices. Proton pump inhibitors, which are commonly used to treat gastro-oesophageal reflux disease in older patients, are contraindicated with atazanavir and delavirdine. In addition, cisparide is contraindicated with all PIs due to the potential for cardiac ­arrhythmias. PIs can increase the level of erectile dysfunctional drugs such as sildenafil and should be used with caution. Concomitant use of benzo­diazepines and PIs or NNRTIs can result in excessive sedation. In general, shorter-acting agents such as temazepam, oxazepam and lorazepam are better choices than midazolam and triazolam in patients on HAART. Terfinadine is contraindicated with HAART, as it interacts with both PIs and NNRTIs. Amprenavir and astemizole are both metabolised by cytochrome P450, which could result in an increased plasma concentration of astemizole. Therefore, these medications should not be used together. Finally, concomitant use of herbal medications and antiretroviral therapy is currently under study, but echinacea and St John’s wort are known to interact with antiretrovirals and may lower PI levels. Patients should be warned of these interactions when starting HAART.

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 treatments for these illnesses in older patients. Most trials evaluating new antiretroviral drugs excluded patients with advanced age and/or concurrent disorders, and very few studies have offered subanalysis comparing outcomes of older patients with younger ones. Older age is associated with a higher rate of adverse events in in- and outpatients; therefore, careful monitoring is required with use of any antiretroviral and opportunistic illness prophylaxis medications in older HIV-positive patients.(44,45)

Conclusions
HIV infection in people over 50 years is becoming a more significant problem for patients and care providers. Older patients have worse HIV status at diagnosis, a more severe HIV course, more opportunistic illnesses and malignancies, shortened survival and shorter AIDS-free intervals than younger patients.

While HAART therapy is effective at reducing AIDS-related complications and should be used in older patients, this should be done with caution.  Providers should ask about use of concomitant drugs for comorbidities, avoid nephrotoxic and hepatotoxic drugs when possible, and consider side-effects of other drugs, particularly insulin resistance, dyslipidaemia and cardiovascular disease, when selecting a HAART regimen in an older patient.

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