HIV Australia | Vol. 8 No. 3 | October 2010

PROF JENNIFER HOY and DR OLGA VUJOVIC shed light on the complex interplay between antiretroviral therapy and symptoms of chronic disease due to ageing or HIV.

The benefits of antiretroviral therapy in prevention of progression of HIV to AIDS – and thereby in improving survival of people living with HIV – have been known for 15 years.

The SMART study, which compared continuous antiretroviral treatment (ART) keeping the viral load as low as possible with intermittent treatment used only when the CD4 cell count dropped below 250 cells, was pivotal in enhancing understanding of the effects of adherence to ART. It showed that ART not only prevents HIV-related opportunistic infections, but also many non-AIDS complications such as heart disease, cancer, kidney and liver disease. It also showed that these complications are more common at lower CD4 cell counts. ¹ We learnt from this study that is NOT smart to stop ART.

The unexpected findings from the SMART study also influenced many treatment guidelines, with some extrapolating the findings to mean that ART should be commenced as soon as HIV infection is diagnosed. Such guidelines are contentious; the clinical trial evidence for starting treatment below 350 CD4 cells is clear but there is a lack of good quality data to support the commencement of treatment at CD4 cell counts above 500 cells. The benefits of preventing the AIDS-related diseases and HIV-related non-AIDS complications have not been compared with the risks of ART, which include immediate adverse effects, risk of development of resistance and limitation of future treatment options, as well as long term toxicity for people with high CD4 cell counts – a risk especially important for older HIV-positive people.

An ageing cohort

In the last two years, approximately 30% of all new HIV diagnoses in Australia have occurred in individuals aged 50 years and over, and it is anticipated that 50% of those living with HIV in 2015 will be over the age of 50 years. ² In Victoria, those over the age of 50 are seven times more likely to be diagnosed with HIV when their CD4 cell count is less than 200 cells or when they have an AIDS illness. ³ Studies have reported a 50% increased risk of clinical disease progression and poorer survival in those aged over 50, despite initiation of combination ART. ⁴ This greater prevalence of co-morbid conditions normally associated with ageing is largely responsible for the greater mortality observed in the older HIV-positive person.

Although the recommendations for when to initiate ART do not differ for older adults with HIV infection, the choice of ART needs to be individualised with respect to pre-existing disease. The potential impacts of the recent trend towards earlier antiretroviral treatment given an older HIV-positive population require careful consideration.

Management of HIV is complicated by the presence of co-morbidites such as hypertension, metabolic disorders such as diabetes, insulin resistance and hyperlipidemia, liver disease, renal impairment, bone disease, neurocognitive impairment and cancer. Co-morbidities already experienced by older HIV-positive people need to be taken into account as potential short- and long-term toxicity may have great impact on the older HIV-positive individual.

The example of cardiovascular disease underscores the complexity of the relationship between HIV infection, ageing and ART. Observational studies and randomised trials have clearly reported an increased risk of cardiovascular disease among people with HIV – a risk that is greater for older patients and those with lower CD4 cell counts. But observational studies have also reported increased rates of myocardial infarction (heart attack) with specific antiretroviral drugs. Protease inhibitor containing regimens were the first to be shown to be associated with increased myocardial infarction, with the relative risk per additional year of protease inhibitor greater than the risk per additional year of age. ⁵ The risk varies according to different protease inhibitors, and the mechanism by which these drugs cause increased cardiovascular disease is thought to be the changes in blood cholesterol and triglycerides caused by these drugs. ⁶ The current use of abacavir has also been associated with an increased risk of myocardial infarction, although the causative mechanism is not yet understood. ⁷

Older individuals initiating ART are less likely to restore their immune system. Despite successful treatment with ART and achieving sustained virological suppression, people over the age of 50 years have slower rates of CD4 cell recovery and smaller CD4 cell increases. The average monthly CD4 cell increase for the first six months after initiation of ART is significantly lower for older adults (37 cells/month versus 42 cells/month in those less than 50 years), and the less robust and delayed CD4 cell recovery was maintained from 6 to 12 months. ⁸ These differences may persist for at least five years. Other studies have shown no differences in the CD4 cell increases between older and younger patients. ⁹

On a more positive note, it has been observed that older HIV-positive people are more likely to achieve complete virological suppression and achieve virological suppression faster in response to ART. This was observed with protease inhibitor based ART. Older individuals are also less likely to develop virological breakthrough or treatment failure, which is most likely related to better adherence to treatment. ^{10, 11}
The clinical consequences of incomplete immune recovery include the serious non-AIDS illnesses (greater rates of cardiovascular disease, liver disease, kidney disease, bone disease and fractures, neurocognitive impairment, cancer) in addition to HIV-related opportunistic infections.

Antiretroviral treatment tolerability may decrease with age. A study from a large American healthcare provider has shown that older HIV-positive people have greater toxicity to ART compared to their younger counterparts. Older patients (over 50 years of age) were more likely to develop significant laboratory abnormalities after starting ART, including metabolic (increased glucose, cholesterol, and triglycerides), hematologic (white cell count and haemoglobin) and renal (creatinine) dysfunction. ¹² Another study made the observation that older patients have higher levels of blood glucose, cholesterol, triglycerides and creatinine prior to commencing ART, so that similar magnitudes of increase in these metabolic markers in the old and the young places the older HIV-positive person at greater risk of diabetes, metabolic syndrome, hypertension, hyperlipidemia and cardiovascular disease. ¹³

The ART drugs and medication used to treat other co-morbidites may have drug-drug interactions, which complicate their use. The risks of unrecognised drug interactions include HIV treatment failure and development of resistance if ART drug concentrations are lowered by other medication, OR increased adverse effects or overlapping toxicity of the ART drugs and the other medication. Older individuals are likely to be on multiple medications for co-morbidities such as hypertension, high cholesterol and diabetes, and polypharmacy may be difficult to manage. Dose adjustments may be required as new medications are started, with adjustments to the number of pills taken and frequency of dosing each day – some after meals, some before meals, some before sleep. This makes adherence complicated. However, although the likelihood of poor adherence to treatment generally increases with increasing pill burden and number of doses required each day, studies have shown that adherence is superior in those aged over 50 years. ¹⁴

The latest hypotheses generated to explain the worse outcome for people with HIV infection on ART compared with the general population of the same age suggest that despite HIV viral load levels below 50 copies/ml on ART, there is sufficient low level viral replication to induce persistent immune activation. This persistent immune activation leads to ‘immune exhaustion’ and the immune decline similar to that seen in healthy ageing. This immune senescence means there is a reduction in immune surveillance and increased disease, e.g. cancer, infections.

Monitoring of side-effects essential

The routine monitoring of older HIV-positive people on ART involves more than monitoring HIV viral load and CD4 cell counts – it requires consideration of the long term side effects of ART that affect cardiovascular risk, metabolic disease and diabetes, renal disease and bone health, and modifying ART in response to these co-morbidities. HIV management in older patients is complicated by the presence of co-morbidities; both HIV and ART itself may contribute to the co-morbidities, which themselves have an important bearing on the selection of ART regimen.

In order to achieve the best possible health outcomes for older people living with HIV, continual assessment and active interventions are required for HIV therapy and co-morbid conditions. In the current era, co-morbid conditions are responsible for an increasing burden of illness.

A robust approach includes patient education, prevention strategies (e.g. smoking cessation), in addition to aggressive management of established disease such as hypertension and hyperlipidaemia. A strong partnership approach between HIV-treating doctors and primary health care providers, underpinned by skilled nursing interventions, has been demonstrated to be an effective model of chronic disease management in other arenas and thus should be similarly effective for management of chronic disease in the context of HIV infection.

References

1. El-Sadr, W., Lundgren J., Neaton J., Gordin F., Abrams D., et al. (2006). Strategies for Management of Antiretroviral Therapy Study G, CD4+ count-guided interruption of antiretroviral treatment. New England Journal of Medicine, 355(22): 2283–96.

2. Murray, J., McDonald, A., Law, M. (2009). Rapidly ageing HIV epidemic among men who have sex with men in Australia. Sexual Health, 6(1):83–6.

3. Lemoh, C., Guy, R., Yohannes, K., Lewis, J., Street, A., Biggs, B., et al. (2009).Delayed diagnosis of HIV infection in Victoria 1994 to 2006. Sexual Health, 6(2):117–22.

4. Grabar S., Weiss L., Costagli

la D. (2006). HIV infection in older patients in the HAART era. Journal of Antimicrobial Chemotherapy, 57(1):4–7.

5. Group DADS, Friis-Moller, N., Reiss, P., Sabin, C., Weber, R., Monforte AdA, et al. (2007). Class of antiretroviral drugs and the risk of myocardial infarction. New England Journal of Medicine, 26;356(17):1723–35.

6. Worm, S., Sabin, C., Weber, R., Reiss, P., El-Sadr, W., Dabis, F., et al. (2010). Risk of myocardial infarction in patients with HIV infection exposed to specific individual antiretroviral drugs from the 3 major drug classes: the data collection on adverse events of anti-HIV drugs
(D:A:D) study. Journal of Infectious Diseases, 201(3):318–30.

7. Group DADS, Sabin, C., Worm, S., Weber, R., Reiss, P., El-Sadr, W., et al. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration.[Erratum appears in Lancet. 2008, 372(9635):292]. Lancet, 371(9622):1417–26.

8. Grabar, S., Kousignian, I., Sobel, A., Le Bras, P., Gasnault, J., Enel, P., et al. (2004). Immunologic and clinical responses to highly active antiretroviral therapy over 50 years of age. Results from the French Hospital Database on HIV. AIDS, 18(15):2029–38.

9. Greenbaum, A., Wilson, L., Keruly, J., Moore, R., Gebo, K. (2008). Effect of age and HAART regimen on clinical response in an urban cohort of HIV-infected individuals. AIDS, 22(17):2331–9.

10. Ibid.

11. Silverberg, M., Leyden, W., Horberg, M., DeLorenze, G., Klein, D., Quesenberry, C., Jr. (2007). Older age and the response to and tolerability of antiretroviral therapy. Archives of Internal Medicine, 167(7): 684–91.

12. Ibid.

13. Orlando, G., Meraviglia, P., Cordier, L., Meroni, L., Landonio, S., Giorgi, R., et al. (2006). Antiretroviral treatment and age-related comorbidities in a cohort of older HIV-infected patients. HIV Medicine, 7(8):549–57.

14. Silverberg, et al., op. cit.

Prof Jennifer Hoy is Professor Director of HIV Medicine and Head of the Victorian HIV Service, Infectious Diseases Unit, The Alfred Hospital and Monash University, Melbourne.

Dr Olga Vujovic is an Infectious Diseases Physician and Head of the Victorian HIV Consultancy, Infectious Diseases Unit, The Alfred Hospital.

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