The Geriatric Syndromes: Frailty, Multimorbidity and Polypharmacy

Major reductions in HIV-associated mortality have increased the median life expectancy of adults with HIV infection. However, immunodeficiency and illnesses involving inflammatory processes e.g. cardiovascular, bone, renal and liver disease, cancers and neurocognitive decline are clustering in older people with HIV infection leading to a “geriatric syndrome” not usually seen in individuals without HIV infection until later in life. [3, 5] This syndrome is characterised by multimorbidity, consequent polypharmacy, delirium, falls, incontinence and frailty, [114] which reduce function and quality of life. [3] This “geriatric syndrome” is highly prevalent, affecting up to 30-50% of people with HIV infection over 50 years of age in some cohorts. [3] As half the current population of people with HIV infection is over 50 years of age in Australia, there is a pressing need to manage multimorbidity in older people with HIV infection, with a major shift in the notion of care delivery to this group, and a call for a new clinical care framework incorporating the principles of geriatric medicine. [10, 115]


Frailty can be measured by different algorithms, with the definition of frailty being controversial. Using the Fried criteria, the Frailty Phenotype has been defined by the presence of three or more of five criteria: unintentional weight loss of 4.5 kg in the past year; exhaustion; diminished grip strength; slow walking speed; and low physical activity. [4] [10] These criteria may occur more frequently in people with HIV infection. The cumulative burden of co-morbidities and their respective therapies contributes to frailty in people with HIV infection, with an estimated prevalence, depending on definition and cohort, of 5-19%. [4, 116] Another validated measure is the Frailty Index, where frailty is the result of an accumulation of health deficits over time, and the severity of frailty can predict adverse health outcomes [4, 117, 118] Frailty is also conceptualised by a “biologic age”, describing an overall physiologic vulnerability to various stressors. [4, 10, 117] Frailty is a “significant variable”, its presence indicates greater risk for negative health outcomes including falls, reduced mobility, and independence, accompanied by increased hospitalizations, and increased need for medical care and death. [4, 10]

The prevalence of frailty and relationship with quality of life was assessed in older (>50 years) Australian men living with HIV utilising three different frailty measurements. [119] Over one quarter had four or more co-morbidities, one third had depression and over one half were receiving five or more non-ART medications. The prevalence of frailty varied from 10.8% to 22.6% depending upon which Frailty measurement tool was used. [119] The Frailty phenotype was significantly associated with pre-1996 ART initiation (OR 3.56, CI 1.23-10.36, p = 0.020) and depression (OR 3.74 CI 1.24- 11.27, p = 0.019). Frailty defined by any of the instruments was associated with significantly poorer quality of life, emphasizing the importance of identifying frailty and measuring quality of life. [119]

Frailty in the general population has been associated with activation of the innate immune system, and HIV infection has been recognised as a driver of age-related comorbidities, including frailty, through chronic activation of the innate immune system and immune senescence. [117]  An important element of clinical frailty is loss of skeletal muscle mass, or sarcopenia, which is associated with extrinsic factors including lifestyle, nutrition and comorbidities, all of which are common to HIV infection. As a result, impairment in objective measures of physical function occurs. [4] Predicted mortality is significantly greater with the combination of both HIV and impaired physical function. Other clinical consequences of these impairments in physical function and frailty include and falls, impaired quality of life and hospitalisations. [4, 120-123]

In the general population, interventions aimed at increasing physical activity and improving nutrition have been shown to be effective and are recommended for integration into an HIV model of care. [4, 124-126] In the clinic setting, simple measures can be instituted to assess physical function and capacity, such as gait speed on a 4.5 metre walk, time to rise from a chair and grip strength. [122, 127] Repeat measurements can be used for monitoring and therefore guide interventions to prevent, slow or reverse impairments and frailty. [4]

Key recommendations

  1. Multi-morbidity and associated medical therapies can lead to polypharmacy and frailty, both associated with poor outcomes in older people with HIV infection. The definition of frailty is controversial, but can be measured with several clinically applicable tools, including the Frailty Phenotype and the Frailty Index.
  2. The recognition of frailty in the ageing HIV population is important; in population studies it has been associated with poorer quality of life. It also can be used by the HIV provider to individualize treatment goals for chronic comorbidities and therefore help to improve health outcomes.
  3. Consider screening people with HIV infection at risk of frailty by monitoring for functional physical impairment; by measuring gait speed on a 4.5-metre walk, time to rise from a chair and grip strength.
  4. Consider implementation of lifestyle measures, such as increasing physical activity and improving nutrition to help decrease or modify the risk of frailty in older people with HIV infection.


Multimorbidity is defined as ‘the co-existence of two or more chronic conditions, each one of which is either a physical non-communicable disease, a mental health condition or an infectious disease’. [128] Older people with HIV infection exhibit a significantly higher prevalence of multimorbidity than their age-matched counterparts. [10, 115] This has been associated with increased mortality, complexity of care and healthcare costs while reducing quality of life. [129]

In the Australian context, the prevalence and factors associated with multimorbidity among people with HIV infection is high, with 54.5% of individuals having two or more chronic health conditions together with HIV, the most common being a mental health disorder, the next most common CVD. [129]

Key recommendations

  1. Appropriately screen older people with HIV infection for chronic disease(s), acknowledging a high prevalence of multimorbidity and associated decreased quality of life and poor outcome including unplanned admission to hospital.
  2. Actively assess older people with HIV infection for multimorbidity patterns – which may be interwoven by a common underlying risk factor, including lifestyle or risk-taking behaviour(s).


Polypharmacy is common in older people with HIV infection, and more common compared to the general population of a similar age. [3, 4, 8, 28, 130] This places them at higher risk for clinically significant drug-drug interactions between ART and other prescribed medications. [3, 8, 28] Polypharmacy (the use of 5 or more prescription medications) is associated with worse health outcomes in older people with HIV infection, [4, 8, 131] and may include excessive, unnecessary or non-indicated medications. [4]  Prescribers should also be aware of substance use (e.g. alcohol, marijuana), which is common and can impact risks associated with polypharmacy, including suboptimal adherence and increase susceptibility to adverse drug reactions. [3] Negative consequences arising from polypharmacy are compounded in the elderly and include an increased risk of falls, drug-drug interactions, toxicity, geriatric syndromes (falls, fractures and cognitive decline) and poor adherence. These consequences translate into increased clinic and hospital visits as well as emergency admissions. [3, 4]

Medication review should occur regularly, given the high potential for drug-drug interactions, particularly at the time of starting or switching ART and concomitant medications, but also when there is a new clinical concern or biochemical abnormality on recent laboratory investigations. [28] Drug-drug interactions are common and can be missed by prescribers [4, 28, 35] and may be greater than predicted in older people with HIV infection, who often have multiple healthcare providers.

Ritonavir inhibits cytochrome P450 3A4 (CYP3 A4) and other hepatic cytochrome P450 enzymes and therefore inhibits the hepatic metabolism of many medications with resulting increased blood levels of concomitant medication and potential toxicity. [132]  Cobicistat, an alternative boosting agent is a more specific inhibitor (i.e. no inhibitory effects on CYP2C8 and is a weaker inhibitor of CYP2D6). [132] Therefore, expected drug-drug interactions can be different and the two boosting agents should not be used interchangeably when considering drug-drug interactions. [132] Other effects of ritonavir and cobicistat include inhibition of intestinal transporters P-gp which will affect the absorption and metabolism of other drugs.

The absorption of some antiretroviral drugs may be altered by other medications through chelation of divalent cations (e.g. integrase inhibitors) and through changes in gastric pH (e.g. atazanavir, rilpivirine). [4]  A recent retrospective study found that people with HIV infection aged 50 years and older had a higher rate of potential drug-drug interactions compared with younger people. [8] Antiretroviral drugs may act as both “perpetrators” and “victims” of drug-drug interactions; for example, if they are combined with other CYP 3A4 enzyme inducers (e.g. rifampicin, older anti-epileptic drugs) or enzyme inhibitors. [4]

It is important to check for drug-drug interactions whenever there is a change in ART or co-medications, for example at the Liverpool HIV drug interaction database at, which contains information on the metabolic pathway and related risk of drug-drug interactions with antiretroviral drugs and co-medications.

An example of an important interaction common for older people with HIV infection is the use of ticagrelor, an antiplatelet therapy, one of the preferred agents in the management of ischaemic heart disease. It is primarily metabolised by CYP 450 3A4, and therefore subject to significant drug interactions with ART. Co-administration with PIs, ritonavir or cobicistat, all potent inhibitors of CYP3A4, is not recommended given significant increases in serum concentrations of ticagrelor and increased risk of bleeding. In addition, co-administration with NNRTIs – such as nevirapine, etravirine, or efavirenz, which are moderate CYP3A4 inducers, may result in reduced efficacy of ticagrelor. [8]

Some studies have shown better adherence to ART among older people with HIV infection compared with their younger counterparts. [28] [133-135] Reasons for potential suboptimal adherence and subsequent treatment failure in older people with HIV infection include complex dosing, high pill burden, polypharmacy, inability to pay for medications, limited health literacy, mood disturbance and neurocognitive impairment. [28] [136] Older women  with HIV infection and severe menopausal symptoms may also be at greater risk of suboptimal ART adherence and adverse HIV outcomes. [28, 137]

In summary, regular medication reviews by either an experienced HIV pharmacist or clinician should be performed on a regular basis. Unnecessary medications should be discontinued, regimens simplified and adherence aids (pillboxes, daily calendars, family support) recommended. [4, 28] Specific information on drug-drug interactions should be sought, and HIV care providers should be proactive in terms of anticipating and monitoring drug-drug interactions when either starting, changing or discontinuing a new medication. [4]

Key recommendations

  1. A full medication review by either an experienced HIV pharmacist or clinician should occur at each clinic or hospital encounter.
  2. Clinicians should be proactive in the cessation of unnecessary medications, and monitoring for drug-drug interactions when either starting, changing or discontinuing any medication.
  3. HIV care providers should practise heightened awareness of polypharmacy (5 or more medications) in older people with HIV infection, given the associated negative health outcomes.
  4. The medication history must also include over-the-counter medications, herbal supplements and lifestyle related substance use.
  5. Older people with HIV infection are strongly encouraged to engage with evidence-based memory aids for medications (i.e. pillboxes, medication calendars, family support) in order to optimise medication and ART adherence.
  6. Clinicians are advised to encourage adherence and screen for potential barriers, including reduced health literacy, cost, neurocognitive impairment, and severe menopausal symptoms.
  7. ART can be both responsible for and vulnerable to drug-drug interactions; there are readily available online drug-drug interaction resources which should be accessed for all people with HIV infection receiving other medications.

Whilst ritonavir and cobicistat are equivalent in their inhibition of the cytochrome P450 3A4, cobicistat is more limited in other enzymatic inhibition and is not responsible for enzyme induction. If there is a switch in ART between either agent, a comprehensive review of current medications should be undertaken.