The gradual expansion of HIV services globally and the rapid therapeutic and management advances seen over the last four decades has meant that PLWH are living beyond the age of 50 years, provided that they receive quality-assured monitoring and surveillance of their HIV infection ^[1][2][1,2]. Different types of cART are widely used, with the desired aim of achieving the undetectable HIV-1 viral load seen in most cohorts of PLWH [3]. However, living longer can be associated with observed increases in different medical conditions, as well as cART being associated with different side effects ^[4][5][4,5], and this is reflected in PLWH in both resource-limited and rich countries. This may also be associated with risk of developing neurodegenerative disease, dementia, diabetes, obesity, chronic kidney disease, osteoporosis, frailty, and some cancers ^{[1][6][7][8][9][10]}[1,6,7,8,9,10]. The risk of fracture also increases in association with osteoporosis and the increased risk of falls [11]. OPLWH are likely to be isolated, and this makes them more prone to mental-health-related illnesses such as anxiety, depression and addiction. This can further cause significant increases in social issues related to stigma, isolation, housing availability and ongoing social support in any one community ^[12][13][12,13].

These age-related issues are expected to increase in OPLWH in the near future. The success of the UNAIDS statement of achieving global 90-90-90 targets (90% aware of their status, 90% on HIV medication, and 90% have viral suppression) has further highlighted the needs of this particular cohort and indeed, a more ambitious 95-95-95 target is hoping to be achieved by 2030. The programme started in 2014 and just eight countries met the targets in 2020. In 2021, the 95-95-95 target was achieved in two countries ^[2][14][15][2,14,15]. It is estimated that one-fifth of PLWH globally are above the age of 50 years old (around 7.5 million) [2]. Currently, half of total PLWH in the USA are above the age of 50 years old, 15% of PLWH are over 50 years old in sub-Saharan countries and in the Netherlands the number of PLWH aged 50 years is expected to reach 70% by the year 2030 [5].

Despite the improvement in the medical care and treatment of HIV, significant numbers of PLWH die from HIV and HIV-related complications. In systematic reviews and meta-analyses, it was shown that the pooled proportion of patients readmitted to hospital after discharge was 18.8% (95% CI 15.3–22.3) and the percentage who died post-discharge was 14.1% (10.8–17.3). This analysis was conducted in 29 cohorts, including 92,781 PLWH. The study showed that inpatient treatment with cART during hospitalisation was protective against post-discharge mortality. Higher mortalities were seen in Africa (23.1% [16.5–29.7]) than in the USA (7.5% [4.4–10.6]). Importantly, mortality risk factors were associated with a long hospital stay, discharge against medical advice, low CD4 cell counts at admission and lack of follow-up care after discharge [16]. Palliative care is needed to provide symptomatic control such as pain management, anxiety, and nausea, which will further improve wellbeing. Palliative care training also needs to be offered to health professionals caring for OPLWH ^[17][18][17,18].

2. Medical Challenges

HIV can be associated with different and serious medical conditions that can lead to fatal outcomes. The medical conditions will represent extra challenges for geriatricians providing care within the service, which is already overwhelmed with similar conditions in patients without HIV and these are due to the following ^{[19][20][21][22][23][24][25][26][27]}[19,20,21,22,23,24,25,26,27]:

• Lack of global plans to establish quality-assured geriatric HIV services.
• Scarcity of clinical trials available in elderly populations living with HIV.
• No clinical guidelines are available about the best strategies in the management of medical conditions in elderly populations living with HIV.
• Issues in relation to geriatricians.
  • Global shortage of trainee and accredited geriatricians.
  • Extreme shortages of geriatricians trained in HIV care and a lack of specific provisions in infectious diseases and related training schemes to provide in-depth knowledge in this area.
  • No clear consensus about a defined age or range a patient will need to see geriatricians, as it can range broadly from the age of 50 or 65 years old.
  • The screening tools used in geriatric medicine are not yet validated in/for HIV populations.
• Lack of needed guidance for intensive care physicians about who will and will not benefit from admission to intensive care units.
• Lack of guidance for primary care physicians in the management of medical conditions in elderly populations with HIV.
• Guidance and consensus are needed for community geriatric service.
• The need for hospital and community pharmacists to be educated in dealing with drug interactions.
• Lack of training in HIV care for occupational therapists, physiotherapists and other allied healthcare specialties, e.g., dietitians and podiatrists.
• Provision of extra funding and capacity building for all the reasons noted above.

2.1. Neurocognitive Disease and Dementia

Alzheimer’s disease (AD) can also be seen in PLWH at middle or older age [28]. The risk of dementia will increase significantly at the age of ≥65 years [29]. The estimated prevalence was suggested to be 2–5% ^[29][30][31][29,30,31]. HIV-associated dementia (HAD) can be seen in ageing populations living with HIV, whereas HIV-associated neurocognitive disorders were more prevalent in the pre-cART era [32]. However, HIV-associated neurocognitive disorder (HAND) is seen in mild and subtle forms and can be difficult to diagnose. As both conditions can present similarly, both conditions can be classified and managed on best clinical practice, as no definitive treatment is available [33]. In a systematic review and meta-analysis, the prevalence of HAND was estimated to be 50.41%. Factors that can lead to HAND were low level of education, older age, advanced stage of the illness, low CD4 counts of <500 cells/μL and depression ^[34][35][34,35]. Age duration of HIV infection and low CD4 counts appear to represent the main factors leading to HAND [29]. Other factors such as HIV co-infection and other sexually transmitted diseases such as syphilis, hepatitis C and cytomegalovirus can also increase HAND prevalence ^[36][37][36,37]. Other non-communicable diseases that increase risks of HAND development are diabetes, hypertension, obesity and insulin resistance ^[38][39][38,39]. Previous and prolonged depression and apathy can also be contributing factors. The cART, efavirenz was also reported to be associated with cognitive impairment, along with other cARTs such as atzanavir, nevirapine, abacavir and etravirine, whereas less neurotoxicity was noted with tenofovir, darunavir and emtricitabine [40]. Dementia in HIV populations tends to affect fronto-striato-thalamo-cortical circuits. Therefore, in the early stages of HIV infection, individuals may be asymptomatic or develop hyperreflexia. With the progression of HIV and dementia, individuals may develop hypertonia, tremors and clonuses. Features related to Parkinsonism may infrequently develop with slowness in processing information as an important and early diagnostic feature of HAND ^[41][42][41,42]. This can be associated with mental slowness and attention and memory deficits. It is noted that episodic memory impairment with psychomotor slowing can be seen as sensitive indicators in HAND [43]. Regular screening for HAND using validated questionnaires can help in establishing the diagnosis. For instance, The European AIDS society (EACS) recommends regular screening using three questions: (1) Do you have memory loss? (2) Do you feel slowness in planning and solving a problem? and (3) Do you have a problem in paying attention? One positive answer to one of the three questions warrants further investigations. EACS also recommends excluding cofounding factors such as depression, substance abuse or excessive drinking of alcohol [44]. The screening tools used in HAD are the HIV dementia scale (HDS) and international HIV dementia scale (IHDS). The IHDS is easy to utilise and is widely used in different countries, especially where resources are limited. No previous training is required, and it accurately assesses memory, motor speed and psychomotor functions [45]. In a systematic review and meta-analysis, the IHDS showed a sensitivity of 79.4% and a specificity of 65.4% in detecting HAD [46]. The mini-mental state examination (MMSE) and the Montreal cognitive assessment (MoCA) can be used in HAD, but MoCA has more sensitivity and specificity than MMSE ^[47][48][47,48]. The Italian Society for Infectious and Tropical Diseases recommended screening all individuals with HIV for dementia and also recommended using the MoCA [49]. The British HIV Association and the American Association of Infectious Diseases also recommend screening for dementia in the new patients and then once per year ^[50][51][50,51]. No treatment for dementia is yet available, but in HAD the option will be treatment of underlying causes, optimisation of CD4 count through using cART and acetylcholinesterase inhibitors such as memantine ^[52][53][52,53].

2.2. Bone Disease and Osteoporosis

HIV is a condition of chronic inflammation that is associated with a risk of osteoporosis. OPLWH are also at risk of dementia, and this may increase the risk of neglect, falls and bone fractures. The osteoporosis seen in PLWH can potentially begin at the age of 40 or 50 years old [11]. Importantly, HIV per se is an independent risk factor for bone fractures [54]. Hepatitis C virus (HCV) coinfection is associated with a greater risk of osteoporosis and fractures than HIV per se [55]. Some cARTs may also be involved in osteoporosis, such as tenofovir disoproxil fumarate (TDF) ^[56][57][56,57]. Therefore, is not surprising that the risk of fracture increases with HIV. For instance, the fracture risk was found to be 35 to 68% in comparison with the non-HIV-infected population ^[58][59][58,59]. Importantly, the prevalence of vertebral fracture prevalence was found to be 11.1% in PLWH [60]. In clinical practice, the use of the fracture risk assessment tool (FRAX) and measurement of bone mineral density (BMD) via a DEXA scan are widely used in HIV clinics around the world. Bisphosphonates in association with vitamin D and calcium replacement remains the main treatment [61]. Fractures can also be due to increased falls in OPLWH. The cost of living and managing fractures and osteoporosis in older people with HIV can add more burden to the healthcare systems due to the disability and need for special care.

2.3. Falls

HIV is also associated with an increase in the risk of falls. For instance, the prevalence of falls is estimated to be around 12% to 41% [62]. Different studies have shown different related risk factors. Several studies showed an association with decreased physical functions and cognitive impairment ^[63][64][63,64]. OPLWH taking multiple medications can contribute to polypharmacy, which is also regarded as a risk factor for falls. This, in turn, can lead to an increase in co-morbidities that are also potentially linked to peripheral neuropathy ^{[63][64][65][66][67]}[63,64,65,66,67]. Importantly, older age, female and white race were also associated with an increase in falls. The behaviour of the individuals may increase the risk of falls ^[65][66][67][65,66,67], for instance, substance abuse, having pets and depression are linked with a high risk of falls ^[63][64][67][63,64,67]. It is plausible that OPLWH have low BMD, which also makes them more at risk of having falls associated with fracture. The high risk of falls and fracture may increase the risk of lowered mobility and disabilities in the future. Therefore, falls and osteoporosis may represent a challenge in the management of PLWH.

2.4. Frailty

Frailty is defined as “an ageing-related syndrome of physiological decline, characterised by marked vulnerability leading to adverse health outcomes” [68]. The symptoms associated with frailty include weakness and fatigue, medical complexities and reduced tolerance to medical and surgical interventions [69]. Frailty is an important issue in geriatric medicine. It is an independent risk factor for the development of cognitive decline [70]. Therefore, the clinicians in all disciplines need to have an awareness of frailty and the associated risks for adverse health outcomes; early identification can improve care for this most vulnerable subset of patients. Frailty is attributed to the fact that ageing causes dysregulation in the normal physiological responses to stressors, resulting in a lack of adaptation and dysfunction of the normal homeostatic responses [71]. Among the risk factors are age, duration of HIV infection >20 years, duration of cART use and smoking [71]. Sarcopenia, which is defined as decreased muscle mass, strength and performance, also shares features of frailty [72]. Sarcopenia prevalence in OPLWH is 24.1% in comparison with 11.1% in individuals without HIV [73]. In a multicentre AIDS cohort study (MACS) bone strength sub-study, the odds of frailty were 4.5 higher in the presence of sarcopenia. It was suggested that there is an interaction between frailty, sarcopenia and functional decline and that sarcopenia can potentiate frailty [74]. Part of the recommendations of the EACS is to screen for frailty once per year for those above 50 years old [75]. There are different tools that can be used to screen for frailty. For instance, The Chelsea and Westminster HIV Clinic in London, UK, published their 10 years of experience in an ageing population with HIV. They used clinical frailty score (CFS) (made up of nine grades, 1 very fit and 9 terminally ill, which is easy to use and widely applied and, most importantly, is a reliable score) and the cut off for referral to a dedicated HIV geriatric service was 5 [76]. HIV is regarded as independent risk factor for frailty; thus, the association of frailty and HIV is associated with high mortality and morbidity ^[77][78][77,78]. The main aim of treatment is the management of disabilities and co-morbidities and all associated geriatric syndromes. For instance, nutrition, exercise and treatment of all reversible causes, including sarcopenia. Frailty is always managed by a multidisciplinary team including geriatricians, HIV physicians, physiotherapists, dietitians, pharmacists, psychologists, social care providers and an occupational therapist if possible [71].

2.5. Polypharmacy and Therapeutic Challenges

OPLWH on cART are aware that this is lifelong therapy. cART is usually given as a combination of different medications and, therefore, it is important for healthcare providers to be familiar with the side effects due to prolonged use. In addition, attention should be given to drug interactions and the risk of polypharmacy [79]. In the UK, the Liverpool HIV drug interactions checker (https://www.hiv-druginteractions.org/checker, accessed on 11 June 2023) is widely used in HIV clinics to assess the safety of other medications beside cART [80]. For instance, simvastatin is not recommended with cART, whereas statins that are not metabolised through the liver (e.g., rosuvastatin) may represent an alternative choice. Examples of the side effects of cART include older protease inhibitors that may cause hypertriglyceridemia, whereas the use of TDF is associated with risk of developing osteopenia and osteoporosis. Overall, there is an inadequate representation of the older population living without HIV in related clinical trials. This represents a challenge for dedicated healthcare providers, as the pharmacodynamics and pharmacokinetics of medication may change in frail older populations and may cause unnecessary side effects. On some occasions, useful medications may not be given due to unpredictable side effects [81]. The same situations can also be applied to OPLWH; thus, it is imperative that careful revision of all medication should be carried out annually, especially for those >50 years old.

2.6. Infections

HIV in an ageing population can have a serious impact on susceptibility to viral, bacterial and fungal infections. Ageing without HIV is a known risk factor for low immunity, and HIV per se is well known as a disease of the suppression of immunity. Therefore, in the ageing population living with HIV, infection is one of the serious causes of increases in mortality and morbidity. OPLWH may catch different infections such as tuberculosis, hepatitis, sexually transmitted diseases or other viral infections. In the UK, both The British HIV Association (BHIVA) and National Institute for Health and Care Excellence (NICE) advocate screening for latent TB infection (LTBI) and treating it, especially in high-risk individuals ^{[82][83][84][85]}[82,83,84,85]. Hepatitis, in general, is one of the major causes of mortality and morbidity in HIV (risk of liver cirrhosis and liver cancer). Hepatitis A, B or C can cause severe and long-lasting liver disease in PLWH, and vaccination is recommended (no sufficient evidence of benefit) ^{[86][87][88][89][90][91][92]}[86,87,88,89,90,91,92]. Cytomegalovirus (CMV) has been suggested as a co-factor for the rapid progression of HIV-1 disease, as well as inflammatory and immune response activation. End-organ CMV disease develops in high-risk HIV patients who present with common symptoms such as retinitis but can also involve multiple organs ^{[93][94][95][96]}[93,94,95,96]. During the COVID-19 pandemic, older age accompanied by chronic comorbidities was associated with severe outcomes in patients with HIV. Other factors included an absence of ART, low CD4 count and unsuppressed HIV load. There was no increased risk of COVID-19 critical care (ICU and intubation) in patients older than 50 years compared with younger age groups. The risk of death in OPLWH due to COVID-19 potentially increases with co-infection with tuberculosis ^{[97][98][99][100][101]}[97,98,99,100,101]. Other infections reported, such as sexually transmitted diseases, varicella zoster virus, pneumonia, urinary tract infections, fungal infections and parasitic infections ^{[102][103][104][105][106][107][108][109][110][111][112][113][114][115][116][117][118][119][120][121][122][123][124]}[102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124]. Further studies are needed to assess the prevalence of these infections in OPLWH.

2.7. Hypertension, Diabetes, Dyslipidaemia and Cardiovascular Disease

The risk of developing diabetes, hypertension, dyslipidaemia and cardiovascular disease increases with the duration of HIV and cART administration ^[1][6][8][9][1,6,8,9]. Unfortunately, the treatment of these conditions can lead to polypharmacy and significantly increase the risk of falls and fracture. Prolonged or regular hypoglycaemia may also enhance the risk of cognitive decline and increase the risk of cardiovascular disease. Diabetes per se can be associated with significant complications such as neuropathy, retinopathy, nephropathy and an elevated risk of developing cardiovascular disease ^[1][6][8][9][1,6,8,9]. Therefore, an HIV metabolic clinic is an integral part of HIV services. HIV metabolic clinic in Milton Keynes University Hospital showed promising outcomes in optimising parameters for the management of diabetes, dyslipidaemia and obesity [7]. Choosing the best cART in OPLWH is another medical challenge. The main aim will be to reduce side effects and have an adequate suppression of the viral load. Therefore, most global HIV-1 treatment guidelines suggest giving integrase strand transfer inhibitors (INSTIs) (such as bictegravir or dolutegravir) as a first-line treatment due to the reduced renal, bone and cardiac toxicities; this reduced toxicity is particularly important in an ageing patient. The nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) also have a greater number of metabolic side effects, e.g., more effect on lipids and glucose compared with INSTIs aids this decision-making process (usually in the form of an MDT), with the latter also having a lower pill burden and fewer drug–drug interactions with other medicines, thus being particularly invaluable for polypharmacy issues [9].