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Michael is a 64-year-old homosexual male. He tested positive for HIV in 2008: He had last tested negative in 1998. At diagnosis, his CD4 count was 124 cells per µl blood and his HIV viral load was high, at 123,545 copies per ml blood. With a CD4 count less than 350 cells per µl blood, he was deemed to be a late presenter. His HIV genotypic analysis suggested that there was no antiretroviral therapy (ART) drug class that he could not be given.
Michael had a 15-year history of hypertension, for which he was taking a calcium channel blocker, amlodipine 10mg once daily, and an angiotensin-converting enzyme (ACE) inhibitor, lisinopril 5mg.
He also had an inferior myocardial infarction (MI) three years previously and had two stents inserted into the right coronary artery. As a consequence, his cardiologist started secondary prevention with bisoprolol 2.5mg once daily, aspirin 75mg once daily and atorvastatin 10mg.
At initial presentation, apart from generalised adenopathy, nothing abnormal was noted to suggest an AIDS-defining illness. His chest x-ray was normal and ECG findings were consistent with a previous right-sided MI.
A decision was made by his HIV physician to start Michael on a combination ART single-tablet regimen containing tenofovir, emtricitabine and efavirenz. He was also put on an antibiotic combination, sulfamethoxazole and trimethoprim, as pneumocystis jiroveci pneumonia prophylaxis. Because of a possible interaction of efavirenz with atorvastatin, the HIV pharmacist recommended a switch to rosuvastatin.
Initially, Michael fared well and apart from a few tolerable abnormal dreams likely related to efavirenz, he was happy to stay on his medications. Over the next six months, Michael’s viral load became undetectable and his CD4 count climbed to 455. The antibiotic combination was stopped.
One year later, it was noted at review that Michael’s mood had deteriorated. It was felt at the time that this may be related to his efavirenz. He was referred for psychiatric review and the efavirenz was switched to another drug in the same class, a non-nucleoside reverse transcriptase inhibitor, rilpivirine.
The psychiatrist put Michael on a selective serotonin reuptake inhibitor (SSRI), sertraline 50mg, once daily. His mood improved.
Over the past few years, Michael’s renal function deteriorated. A rising creatinine and a declining eGFR evidenced this. His bone function similarly deteriorated and he had osteopaenia, identified on DEXA scanning. Both renal and bone disease can be explained by tenofovir, a nucleotide reverse transcriptase inhibitor. Michael was switched to tenofovir alafenamide (TAF), which does not have the same toxicity profile as tenofovir.
Michael is now in his mid-60s. His HIV progression has been halted on ART but he has multiple medical comorbidities — cardiovascular disease, bone disease, renal impairment and depression. He is attending HIV, cardiology, nephrology and psychiatric services. A geriatric review has been arranged.
We have come a long way in the care of people living with Human Immunodeficiency Virus (HIV) since its identification as the cause of the Acquired Immunodeficiency Syndrome (AIDS) in 1984.
Thanks to the advances in HIV medication, people are surviving longer with HIV disease. In 2013, it was estimated that 26 per cent of the HIV-positive cohort in the US was aged 55 years of age and over.
In Canada, the number of older adults living with HIV had doubled in the last 20 years and in Western Europe, the number aged 50 years and over is believed to have quadrupled in the last 10 years. Recent statistical modelling work from the AIDS Therapy in the Netherlands (ATHENA) cohort predicted that over 70 per cent of HIV-infected patients will be 50 years of age or older by 2030. They also predicted that over 80 per cent of HIV-infected patients will have at least one non-HIV related morbidity, and that 28 per cent of HIV-infected patients will have more than three. They also noted that 54 per cent of HIV-infected patients will, in addition to their antiretroviral therapy (ART), be prescribed co-medications in 2030, with 20 per cent taking three or more co-medications. This change will be largely driven by increasing prevalence of cardiovascular disease and associated drugs prescribed in this ageing cohort. Because of contraindications and drug-drug interactions, in 2030, 40 per cent of patients could have complications with the currently-recommended first-line HIV regimens.
New cases of HIV are also being diagnosed in the older population, some of which were recently acquired and some acquired many years ago. In Ireland in 2016, there were 508 new cases of HIV notified to the Health Protection Surveillance Centre. Of these, 50 (10 per cent) of new diagnoses were in the over-50 age cohort and 50 per cent of those were ‘late presenters’, identified by CD4 count of less than 350 cells per µl blood or an AIDS-defining illness.
Those older patients diagnosed with advanced disease can present serious challenges to HIV specialists. Many older people are sexually active, including those living with HIV but they may not have the knowledge of how to prevent transmission. Many widowed or divorced people are dating again and women, no longer worried about pregnancy, may not practise safe sex. In addition, the ready availability of erectile dysfunction medications prolongs the sex lives of many older men. As we age, our visits to our primary healthcare providers increase, but older people may be less likely than younger people to discuss issues pertaining to sex with their GPs. Furthermore, doctors may not be comfortable discussing these issues with patients whom they will have known for many years.
Early diagnosis is essential and including HIV on the differential diagnosis of unexplained viral illnesses, rashes and enlarged lymph glands, to name but a few, is essential in primary care. Following the presentation of the Strategic Timing of Antiretroviral Treatment (START) study at the 8th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, held in Vancouver, Canada, in July 2015, the case for early initiation of ART, immediately following diagnosis, was endorsed for reduction in AIDS events, non-AIDS events and death.
We need to lower our threshold for testing for HIV and diagnose everyone who is HIV-positive early in their disease and treat as soon as possible. This will surely result in increased life expectancy for those on treatment and will decrease onward transmission. This decreased onward HIV transmission with ART is termed ‘treatment as prevention’ (TAP).
Increase in life expectancy
With this increase in life expectancy comes the issue of dealing with an expected increase in age-related comorbidities, high blood pressure, high cholesterol and diabetes, polypharmacy and the potential drug-drug interactions with ART. In one study from the US, 70 per cent of HIV-positive persons over 60 years of age were on at least one medication which could potentially cause a drug-drug interaction.
As mentioned, as we get older, many of us succumb to age-related comorbidities. So too do those older patients living with HIV. We need to be mindful that some HIV medications might exacerbate heart disease and should be avoided in these patients. Similarly, some drugs might cause bone mineral density loss and should be avoided in postmenopausal women for whom osteoporosis might be an issue. An older person may have a degree of neurocognitive impairment. Again, some drugs might exacerbate this impairment in the setting of HIV infection. In a recent presentation in Dublin, Dr Giovanni Guaraldi, Assistant Professor of Infectious Diseases at the University of Modena and Reggio Emilia, Italy, noted that in a cohort of less than 200 ageing HIV patients, there were 40 different ART regimens prescribed to them.
Pharmacoenhancers in ART regimens include ritonavir and cobicistat and co-administration of these drugs with other HIV medications boost the levels of the HIV drugs: This makes them more effective in treating HIV disease. It is essential when prescribing other medications, such as statins for lowering cholesterol, some blood pressure drugs and antidepressants, to name a few, that prescribers be aware the levels of these drugs change. Expert pharmaceutical advice should be sought if prescribing such medicines to someone on ART.
Causation and correlation
It has been postulated that HIV infection is associated with premature ageing. It has also been suggested that despite viral suppression with ART, there remains a low-grade immune activation and inflammation, which contributes to an accelerated ageing process. This may manifest in premature cardiovascular disease, decreased bone mineral density, neurocognitive impairment, renal disease and malignancies. The levels of some but not all biomarkers of inflammation and immune activation in HIV-infected patients return to those of uninfected individuals within the first year following treatment.
The effect of such immune activation is unclear in the context of the ageing patient. Chronic cytomegalovirus (CMV) infection, a common persistent viral co-infection in both older HIV-negative people and people living with HIV, appears to be a likely important aetiology and underlying mechanism for activation of immune and inflammatory pathways that contribute to premature ageing.
This view of HIV is being challenged. It has been argued that this accelerated ageing may be solely attributable to lifestyle. Either way, with an ageing HIV-positive cohort, HIV care providers need to recognise and manage the multiple comorbidities and age-related symptoms.
According to Dr Harjot Singh, Infectious Diseases Consultant and Assistant Professor of Medicine in the Division of Infectious Diseases at Cornell University, New York, US, geriatric principles can help meet this challenge, as preservation of function and optimisation of social and psychological health are relevant to the care of ageing HIV-infected adults, even those who are not yet ‘old’.
Age-related morbidities are often subtle clinically and may go unnoticed by HIV healthcare providers. To date, little is known about the role of geriatricians in HIV care and few clinics have incorporated geriatricians into HIV services. As with those not living with HIV, geriatricians use the notion of frailty rather than chronological age to better describe general health and the ‘geriatric syndrome’. According to Dr Singh, frailty rather than multimorbidities allows us to “grasp the complexity of age-related pathophysiologic changes and does so in ways that can alert us to effective clinical interventions”. Bearing this in mind, two people living with HIV might have identical non-HIV related comorbidities but may have very different ageing trajectories.
Several geriatric models of care have been proposed in the setting of the older patient living with HIV; referral to geriatric services, incorporating geriatric assessment in the HIV clinic and assessment in the home. Either way, there will be resource implications as geriatric services in Ireland are already stretched to capacity and the older population is facing a significant increase in the coming years.
We as HIV physicians will need to screen for frailty and to assess common geriatric symptoms such as delirium, impaired mobility and falls.
We also need to be especially mindful of polypharmacy because, to my knowledge, there have been few randomised controlled drug trials on ART for those aged 65 and over.
We must also consider obstacles to care in this ageing cohort, such as social isolation and HIV-related stigma. This patient group will have lived through a time when HIV infection meant certain death and they may have lost family and friends to this once ‘killer disease’. Ignorance about HIV abounds, even in 2017.
In summary, with an ageing HIV population, clinical management may be optimised by close collaboration of HIV specialists with primary care providers and gerontology services well versed in the care of complex multimorbidities. Continued expert pharmacy support is essential. A ‘shared-care’ approach must be the ‘way to go’.