HIV infection in older adults

INTRODUCTION — Most of the literature on human immunodeficiency virus (HIV) infection in older adults defines older as ≥50 years of age. Emerging evidence has suggested that this is an appropriate threshold for "older" people living with HIV, as they experience age-related comorbidities and geriatric conditions at relatively younger ages compared with the general population. With increasing survival resulting from antiretroviral therapy (ART), the proportion of patients with HIV who are in this older age bracket has increased substantially [1]. Additionally, new HIV infections in older adults also contribute to the increasing numbers of older adults living with HIV. Whether HIV accelerates or accentuates aging remains a source of ongoing debate [2].

The same recommendations on management of HIV infection in adults and adolescents apply to older adults as well, but certain issues are of particular importance in this population:

●Epidemiology, risk factors, and delays in diagnosis due to unsuspected HIV infection

●Antiretroviral use in the older population (pharmacokinetics and polypharmacy)

●Age-related differences in immune responses to HIV and ART

●Non-acquired immunodeficiency syndrome (AIDS)-related morbidities and geriatric conditions

●HIV-related mortality

This topic discusses these issues specific to the older adult with HIV. Most major guidelines (International Antiviral Society-USA Panel, Department of Health and Human Services, European AIDS Clinical Society, World Health Organization) for ART and general HIV management include specific recommendations for the care of older adults. The diagnosis, antiretroviral management, and general management of HIV infection are discussed in detail elsewhere. (See "Screening and diagnostic testing for HIV infection" and "When to initiate antiretroviral therapy in persons with HIV" and "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach" and "Initial evaluation of adults with HIV" and "Primary care of adults with HIV".)

EPIDEMIOLOGY

Prevalence and incidence — A growing proportion of people with HIV worldwide are aged 50 years and older [3]. By the end of 2016, an estimated 5.7 million individuals age 50 years and older were living with HIV infection. These numbers will continue to increase with the continued rollout of antiretroviral therapy throughout the world, and by 2020, an estimated 21 percent of people living with HIV globally will be in this older age group [3].

While 80 percent of older adults with HIV live in low- and middle-income countries, the proportion of older adults with HIV is greater in high-income/resource-rich settings, where 33 percent of the adult population with HIV is 50 years and older [3]. In resource-limited settings the proportion of HIV infection in older adults is increasing as well (figure 1). One study estimated that over the next 30 years in rural South Africa, the prevalence of HIV infection among persons older than 50 years will double [4].

While those aging with HIV comprise the majority of older adults living with HIV, new infections in older adults also occur. In 2019, approximately 11 percent of new HIV infections occurred in adults age 55 and older [5]. Global estimates report 110,000 new infections in persons of this age group in 2016, and the majority of them lived in sub-Saharan Africa [3].

Despite these numbers, prevention in older adults is often not discussed, and delayed diagnoses in older adults routinely occur. (See 'Delayed diagnosis of HIV' below.)

Risk factors for new infections in older adults — Sexual exposure is the most common mode of transmission for HIV infection in adults older than 50 years [6-8]. Injection drug use is an important but less common risk factor; in the United States, it accounted for 13 and 9 percent of new HIV infections in females and males, respectively, in 2017 [6]. Twenty-four percent of people who inject drugs without HIV age 50 or older used a syringe after someone else [9].

●For males, including those aged 50 years or older, male-to-male sexual contact is the most common HIV transmission risk in the United States, Europe, and Australia [10]. In the United States in 2019, among men who have sex with men (MSM) age 55 or older, the number of new HIV diagnoses increased 5 percent from 2015 (from 1635 to 1718), while in other age groups, infections in MSM decreased or stayed the same [5]. In a 2017 European study, however, older adults (age ≥50 years) were more likely to acquire HIV through heterosexual contact compared with younger adults [11]. In most of the rest of the world, HIV infection in males is most commonly acquired through heterosexual transmission.

●For females aged 50 years or older, the primary exposure is through heterosexual contact. Certain age-related issues may cause older females to be at higher risk for HIV acquisition, such as vulvovaginal atrophy [7,12]. Aging females are less likely to use barrier contraception methods to prevent pregnancy, which may put them at risk for HIV acquisition if they entered a new sexual partnership [7].

Delayed diagnosis of HIV — Underdiagnosis of HIV infection among older patients continues to be a significant problem. This problem persists, in part, because both clinicians and older adults underestimate risks of HIV acquisition. In the United States, the Centers for Disease Control and Prevention (CDC) and US Preventive Services Task Force recommend routine screening for HIV infection in individuals 15 to 65 years old and screening for older adults at increased risk [13,14]. Given that many clinicians underestimate risk in older adults, UpToDate and some other expert groups recommend screening through older ages or regardless of age [15,16]. Nevertheless, based on data from the CDC National Health Interview Survey data, only an estimated 25 percent of adults 50 years of age and older have been screened for HIV [17]. (See "Screening and diagnostic testing for HIV infection", section on 'Routine screening'.)

Older individuals are frequently not perceived by their clinicians as being at risk for HIV infection and, consequently, are less likely to be tested for HIV compared with younger adults [1,18]. Despite many clinicians' perceptions, sexual activity remains common among older adults. In a survey of over 3000 older adults in the United States, sexual activity within the prior 12 months was reported by 73 percent of those aged 57 to 64 years, 53 percent of those aged 65 to 74 years, and 26 percent of those aged 75 to 85 years [19]. In all age brackets, a higher proportion of males reported being sexually active than females. However, in this same study, only 38 percent of males and 22 percent of females age 50 years or older had discussed sex with a health care provider.

Furthermore, older adults, even those who engage in sexual behaviors that increase the risk of exposure, may not perceive themselves to be at risk for HIV or other sexually transmitted infections (STIs) [20]. This may be due, in part, to lack of education about STIs.

When testing for HIV is undertaken in the older patient, the diagnosis is often made late in the natural history of the individual's disease, when the patient has already progressed to AIDS. Advanced HIV may present with the gradual onset of weight loss, low-grade fever, and fatigue, leading clinicians to evaluate for cancer in older adults but overlook HIV as part of the differential diagnosis [18]. Similarly, advanced HIV disease can present with cognitive symptoms, and an HIV diagnosis should be considered in a workup of new cognitive complaints.

Late diagnoses among adults aged 50 years and older were evaluated in a study of 8255 older adults who accessed HIV care in England, Wales, and Northern Ireland [21]. Almost half of older adults were diagnosed late (with CD4 cell count <200 cells/microL) compared with a third of younger adults. Older adults who were diagnosed late were 14 times more likely to die within a year of diagnosis compared with older adults who were not diagnosed late (14 versus 1 percent) and were 2.4 times more likely to die than younger adults who were diagnosed late. Of older adults diagnosed between 2000 and 2007, 48 percent acquired their infection when they were ≥50 years old. Findings from France and Italy and in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) have similar findings and indicated that a greater proportion of adults older than 50 years had an AIDS-defining diagnosis at or within three months of presentation compared with younger adults [22-24]. Unfortunately, a study from 2022 shows this trend has not changed over time. Using data from the International Epidemiology Databases to Evaluate AIDS global consortium, in nearly every region people age 50 or older presented for care with lower CD4 counts compared with younger patients. People age 50 to 64 often comprise the largest percentage of patients who present late to care (defined as having a CD4 count <350 cells/microL) [25].

Prevention of HIV — Despite the number of new infections that occur in older adults, few prevention campaigns have specifically targeted older adults [3,25].

Pre-exposure prophylaxis (PrEP) is a highly effective strategy for preventing HIV in people at high risk for acquisition. No studies have specifically examined PrEP in older adults, however. Although older adults can also benefit from PrEP, they may be at higher risk of side effects from tenofovir disoproxil fumarate (TDF), including decline in renal function and loss of bone mineral density [26]. This was observed in the Pre-Exposure Prophylaxis Initiative open-label extension study, in which participants who received PrEP and were 40 years or older had greater declines in creatinine clearance than younger participants [27]. TDF is only approved for adults with an estimated glomerular filtration rate (eGFR) >60 mL/min/1.73m². For MSM and transgender women with an eGFR between 30 to 60 mL/min/1.73m² or with known osteopenia or osteoporosis, tenofovir alafenamide (TAF) in combination with emtricitabine could be an option instead as the DISCOVER trial showed less bone and renal toxicity in those receiving TAF versus TDF. However, the median age in this study was 34 years [28]. Older adults may warrant more frequent monitoring of renal function while taking PrEP. While the long-acting injectable cabotegravir, approved for PrEP at the end of 2021, may have less toxicities for older adults, only 123 individuals (67 in the cabotegravir group) over age 50 or older were included in the original clinical trial among cisgender men and transgender women [29]. Recommendations for use of and monitoring during PrEP are discussed in detail elsewhere. (See "HIV pre-exposure prophylaxis", section on 'Determining eligibility for prep' and "HIV pre-exposure prophylaxis", section on 'Patient monitoring'.)

ANTIRETROVIRAL USE

Indications and selection — Antiretroviral therapy (ART) reduces HIV-related morbidity and mortality, even in individuals with very high CD4 cell counts [30,31]. The World Health Organization (WHO) as well as expert groups in the United States and Europe recommend ART for all patients with HIV infection, regardless of CD4 cell count [32-36]. A section in the United States Department of Health and Human Services (HHS) guidelines on the treatment of the older patient with HIV emphasized this recommendation for universal ART for patients older than 50 years of age because of a higher risk of non-AIDS-related complications in this age group and the reduced immunologic response to ART with advanced age. The strength of the evidence supporting these treatment guidelines and selection of antiretroviral regimens are reviewed in detail separately. (See "When to initiate antiretroviral therapy in persons with HIV" and "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".)

None of the first-list ART regimens are recommended over the others for older adults [32]. The choice of ART regimen should take into account existing medications and comorbidities, particularly liver and kidney disease [1,32]. This is especially true for older adults, as many have polypharmacy, often defined as taking five or more medications. Polypharmacy is a risk factor for adverse drug events, drug-drug interactions, inappropriate medication, delirium, falls, fractures, and poor adherence [37].

When selecting an antiretroviral regimen, cytochrome P450 interactions of protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTIs), uridine diphosphate glucuronosyltransferase (UGT) 1A1 enzyme interactions with integrase inhibitors, and P-glycoprotein effects of antiretroviral agents should be considered to minimize risk for drug-drug interactions [32]. Attention should also be paid to the pharmacokinetic enhancers ritonavir and cobicistat, as both are potent Cyp3A4 inhibitors and have other effects on cytochrome P450 and UGT systems. With integrase inhibitor-based regimens, interactions and timing of administration of polyvalent cations including calcium and iron supplements must be considered, as they can effect absorption of the integrase inhibitor [32]. (See 'Safety and tolerability' below and 'Polypharmacy' below.)

Immunologic recovery with ART — Most studies have demonstrated that, despite successful ART and viral suppression, immune recovery is less robust with increasing age, highlighting the importance of diagnosis and treatment of HIV earlier [38-43].

The following observational studies illustrate the range of findings:

●In a study of 92,130 adults with HIV who initiated ART in Zambia, increased age at ART initiation was associated with worse clinical outcomes [38]. The median age was 34 years and 6281 (6.8 percent) were aged ≥50 years. Compared with 16 to 29 year olds, adults with HIV in age brackets older than 40 years had reduced CD4 cell count recovery during ART.

●Among 12,196 treatment-naïve patients with HIV who initiated ART and were included in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD), the mean baseline CD4 cell count was similar by age [39]. The immunologic response after 24 months of treatment decreased with increasing age starting at age 40. Older age did not have an effect on viral suppression in this observational cohort.

●A French prospective study that evaluated treatment outcomes in 3015 treatment-naïve patients (401 of whom were over age 50) reported that rates of viral suppression were better in older patients [40]. Despite better virologic control, CD4 cell recovery was slower and the risk of clinical progression to an AIDS-defining illness was higher in the older age group (hazard ratio [HR] 1.52; 95% CI 1.2-2.0).

Adherence and viral suppression — Several studies have suggested that patients older than 50 years with HIV tend to be more adherent with antiretroviral medications than younger individuals, with some studies reporting more than 95 percent adherence [40,44-48]. Rates of viral suppression are accordingly higher. In a retrospective case-control study, 101 patients with HIV and a mean age of 57 years were matched to 202 younger patients with HIV and a mean age of 33 years [44]. Older patients with HIV were less likely to interrupt ART than younger patients (11 versus 26 percent). It is unclear whether this represented better medication adherence or tolerability. Increased medication exposure translated into better rates of viral suppression (47 versus 34 percent) with comparable immunologic outcomes.

Less is known about adherence to non-antiretroviral medications used to treat HIV-associated morbidities, although some studies have suggested that older adults may be more adherent to antiretroviral medications than to medications for other comorbidities [49].

Safety and tolerability — There are few studies that have examined the tolerability and safety of ART in older patients with HIV, who may have decreased renal and hepatic function and may have other comorbidities, placing them at greater risk of adverse effects [50]. Many studies were done with older HIV medications, which are less well tolerated than more contemporary antiretroviral agents such as integrase inhibitors. Although there are no recommendations for dose adjustments of antiretroviral agents based on age alone, renal and hepatic function should be carefully assessed in the older patient with HIV on an ongoing basis and regimen modifications made accordingly. (See "Overview of antiretroviral agents used to treat HIV".)

Limited safety and tolerability data are summarized below:

●In a retrospective study in Germany, age >60 years was associated with an increased rate of dolutegravir discontinuation due to neuropsychiatric effects [51]; however, a subsequent Spanish study did not find similar association between older age and dolutegravir discontinuation [52].

●In a study from 2001 of patients with HIV who initiated a protease inhibitor (PI)-containing regimen, the majority of patients older than 60 years had switched to an NNRTI-containing regimen by 24 months of follow-up because of adverse events (64 versus 35 percent of patients younger than 40 years) [53]. Similarly, another study of 508 treatment-naïve patients who started ART from 2000 to 2005 reported that the rate of treatment changes due to toxicity was associated with increasing age (for every 10-year increase in age the incidence rate ratio was 1.28, 98% CI 1.04-1.57) [54].

Drug toxicity in the older age group may be related to age-associated physiologic changes that alter pharmacokinetics, such as increased adiposity (which affects distribution of fat-soluble drugs), increased gastric pH, decreased albumin levels, and changes in the cytochrome p450 enzyme system [50]. Since both NNRTIs and PIs are metabolized by cytochrome p450, older patients with HIV may have significantly higher drug exposure when treated with antiretroviral agents. This principle was well illustrated in a study (ACTG 5015) in which patients with HIV received ritonavir-boosted lopinavir-based therapy [55]. Concentrations of lopinavir and ritonavir were measured at 24, 36, and 96 weeks. Increasing age was negatively associated with lopinavir clearance. Changes in drug elimination in aging may lead to increased vulnerability to short- and long-term drug toxicities in this patient population.

Reduced drug clearance is also associated with heart failure, cirrhosis, or conditions that diminish cardiac output and hepatic blood flow. Higher drug exposure may result in greater drug intolerance and/or organ toxicity.

Polypharmacy — A high burden of medication use and resultant prescribing problems, such as drug-drug interaction and potentially inappropriate medications, are issues for older patients among the general population who have multiple comorbidities and are a particular challenge for older patients with HIV. The American Geriatrics Society Beers Criteria and the screening tool of older people's prescriptions/screening tool to alert to right treatment (STOPP/START) criteria include examples of potentially inappropriate medications [56,57]. A thorough review of all medications and supplements is an important component of care for older patients with HIV. Potentially inappropriate medications are often a good place to begin considerations for deprescribing. The European AIDS Clinical Society guidelines include an algorithm for approaching prescribing in older people with HIV and include selected examples of drug classes to avoid in older adults with HIV [34]. Clinical HIV guidelines all reference concerns for polypharmacy, and studies of older adults with HIV have found polypharmacy and associated prescribing issues are associated with falls, frailty, and hospitalizations [58-60].

One of the first studies to highlight this issue was a study of 1500 participants in the Swiss HIV Cohort Study published in 2010 [61]. Adults 50 years of age and older were more likely to have potential drug-drug interactions compared with younger adults with HIV (51 versus 35 percent). Among the older adults, potential interactions with antiretroviral agents occurred mainly with cardiovascular drugs, central nervous system agents (including anxiolytics, antidepressants, and anticonvulsants), and methadone. The Swiss HIV Cohort repeated their study when integrase inhibitors, which tend to have fewer drug-drug interactions, became first-line therapies. In their updated study, among 9298 participants with a median age of 51, 2 percent had a contraindicated drug-drug interaction (the same rate as in the prior study) but interactions with potential harm or minimal risk were 43 percent compared with 59 percent in the prior study. The risk of having potential drug-drug interactions was associated with increasing age [62]. Similarly, in a San Francisco-based study of 89 patients with HIV older than 60 years, the median number of medications per patient was 13, and 70 percent of patients had at least one potential category D drug-drug interaction (consider modification) compared with 39 percent of age- and sex-matched patients without HIV [63]. One-third of the drug interactions among patients with HIV were between non-antiretroviral medications. This study also examined potentially inappropriate medications using the American Geriatrics Society Beers Criteria and found that over half of adults with HIV were prescribed at least one potentially inappropriate medication compared with 29 percent of the adults without HIV. In an Italian cohort, 16 percent of 535 people had at least one potentially inappropriate medication [64]. Among 175 participants age 75 and older in the Swiss HIV Cohort, 67 percent had a potential prescribing issue including potentially inappropriate medications from the Beers and STOPP/START lists and significant drug-drug interactions [65].

Specific drug interactions can be reviewed in the drug interactions program included with UpToDate. A general discussion of drug prescribing for older adults, and deprescribing in general are found elsewhere. (See "Drug prescribing for older adults" and "Deprescribing".)

NON-AIDS MORBIDITY

Overall burden — Successful antiretroviral therapy (ART) has lengthened survival in individuals with HIV and has led to changing patterns of morbidities and mortality. As deaths from AIDS and opportunistic infections have declined, age-related medical conditions have become more prevalent (see 'HIV-related mortality' below). In a retrospective analysis of United States health care insurance databases (commercial, Medicaid, and Medicare) between 2003 and 2013 that included over 60,000 patients with HIV, the most common comorbidities were essential hypertension (recorded in 31, 39, and 76 percent, respectively), hyperlipidemia (29, 22, and 50 percent), and endocrine disease (22, 27, and 54 percent) [66]. The proportion of patients with each of these diagnoses increased over the ten-year study period and was highest in Medicare beneficiaries. Other reported comorbidities included deep vein thrombosis, hepatitis C virus infection, renal impairment, thyroid disease, and liver disease.

Overall, patients with HIV appear to have a higher risk of certain comorbid conditions compared with the general population. This is due, in part, to chronic inflammation and immune activation from HIV, side effects of ART, and traditional risk factors such as alcohol and tobacco use, which are more common in older adults with HIV [1,67]. (See 'Immune activation' below.)

As an example, in a study of 540 individuals with HIV and 524 controls without HIV ≥45 years old, HIV infection was independently associated with a higher burden of age-associated comorbidities, including cardiovascular, metabolic, pulmonary, renal, bone, and malignant disease [68]. The prevalence of each comorbidity documented was numerically higher among individuals with HIV, and the differences were statistically significant for hypertension, myocardial infarction, peripheral arterial disease, and impaired renal function. Multimorbidity, or having two or more comorbidities, was more common among the adults with HIV, and in both groups, prevalence increased with age. Similarly, a case-control study demonstrated that among patients with HIV aged 41 to 50 years, the prevalence multimorbidity was comparable to that among controls without HIV aged 51 to 60 years, suggesting an earlier age of onset [69]. Factors associated with multimorbidity were nadir CD4 cell count <200 cells/microL, older age, male sex, and prolonged ART exposure. Emerging evidence, primarily from Italy, suggests that patterns of comorbidities and risk of multimorbidity may vary between those aging with HIV ("long-term survivors") and those older adults newly diagnosed with HIV [70,71].

It is important to distinguish multimorbidity from comorbidity alone, as the approaches can be different, given that many individual disease guidelines were not developed for those with multimorbidities. Additionally, clinicians must not only consider comorbidities, but geriatric conditions such as falls and functional impairments along with neurocognitive disorders for older adults living with HIV [72]. (See "Multiple chronic conditions".)

HIV clinical guidelines reflect this as well and include recommendations to screen for comorbid conditions such as cardiovascular disease and geriatric conditions such as frailty, social isolation, and neurocognitive disorders [33-35,73]. An overview of some of the main conditions facing older adults with HIV is presented here with links to more detailed chapters.

Immune activation — HIV infection causes immune activation with inflammation that is most intense in the early stages of infection and persists despite antiretroviral therapy. Causes of this persistent inflammatory state are poorly understood, but viral persistence and microbial translocation from the gastrointestinal tract (ie, "leaky gut") are thought to play important roles [74]. Laboratory markers of inflammation that are elevated during this chronic inflammatory state include interleukin (IL)-6, D-dimer, high-sensitivity C-reactive protein (CRP), and soluble CD14 [75,76]. As demonstrated in several trials, ART that successfully controls HIV infection reduces these inflammatory markers but does not return them to normal levels [76,77].

Studies have also emphasized the role of untreated HIV infection on aging and have concluded that immune activation results in "immunosenescence" (eg, accelerated aging of T cells) [78,79]. The implication of this observation is that a person with HIV infection is physiologically older than indicated by birth date; however, it is not clear that these changes are reversed by ART [80].

Cardiovascular disease — Increased survival among individuals with HIV has given way to increased prevalence of metabolic disorders such as glucose intolerance and diabetes mellitus, lipodystrophy, and dyslipidemia. There is a high prevalence of these and other cardiovascular risk factors among individuals with versus without HIV within the same age group [81-83]. Furthermore, in a study of over 80,000 veterans in the United States, HIV infection was associated with a higher risk of myocardial infarction even after adjusting for traditional risk factors [84]. Age greater than 50 itself greatly increases the risk of admission for cardiovascular disease (incidence rate ratio compared with those <35 years old 5.01, 95% CI 3.41-7.38) [85]. These findings highlight the importance of addressing modifiable factors at clinic visits. With the aging of the patient population with HIV, it is likely that rates of cardiovascular disease may increase unless interventions, such as smoking cessation and weight reduction, are undertaken. The American Heart Association issued a scientific statement summarizing knowledge and suggestion prevention and management strategies for people with HIV [86].

The epidemiology, pathogenesis, and management of cardiovascular risk in patients with HIV are discussed elsewhere. (See "Epidemiology of cardiovascular disease and risk factors in patients with HIV" and "Pathogenesis and biomarkers of cardiovascular disease in patients with HIV" and "Management of cardiovascular risk (including dyslipidemia) in patients with HIV".)

Neurologic complications

Neurocognitive disorders — Older adults with HIV are at risk for neurocognitive disorders, whether associated with HIV infection itself or other factors.

The most severe form of HIV-associated neurocognitive disorders is HIV-associated dementia, classically manifested as a subacute onset of impairments in subcortical function, such as decreased attention/concentration and psychomotor slowing. Although the overall prevalence of HIV-associated neurocognitive disorders has not changed since the early days of the HIV/AIDS epidemic, milder forms, including asymptomatic neurocognitive impairment and mild neurocognitive disease, have become more frequent manifestations.

Several studies have suggested that increasing age is a risk factor for HIV-associated neurocognitive disorders [87-89]. In one study of patients with HIV, the odds of having HIV-associated dementia were threefold higher among 106 patients older than 50 years than among 96 patients aged 20 to 39 years after adjusting for education, race, substance use, antiretroviral use, HIV RNA level, CD4 cell count, and Beck Depression Inventory score [87]. In a subsequent AIDS Clinical Trials Group (ACTG) cohort study of 3300 antiretroviral-naïve adults initiating treatment, older individuals were more likely to have neurocognitive impairment after adjusting for other variables [88].

Longitudinal studies involving larger numbers of older individuals are needed to determine whether there are age-related differences in the prevalence, nature, and severity of HIV-associated cognitive dysfunction. Additionally, as the population of older adults with HIV ages further, distinguishing between HIV-associated neurocognitive disorders and other neurodegenerative disorders, especially Alzheimer's disease, will be critically important.

HIV-associated neurocognitive disorders are discussed in detail elsewhere. (See "HIV-associated neurocognitive disorders: Epidemiology, clinical manifestations, and diagnosis" and "HIV-associated neurocognitive disorders: Management".)

Peripheral neuropathy — Increased age is a risk factor for peripheral neuropathy. In an observational study of 2141 antiretroviral-naïve patients with HIV who were seen annually between 2000 and 2007, aging was associated with peripheral neuropathy despite virologic and immunologic control of HIV [90]. Aging was also associated with lower odds of recovery after neurotoxic antiretroviral drugs were discontinued. (See "Epidemiology, clinical manifestations, diagnosis, and treatment of HIV-associated distal symmetric polyneuropathy (HIV-DSPN)" and "Epidemiology, clinical manifestations, diagnosis, and treatment of HIV-associated distal symmetric polyneuropathy (HIV-DSPN)", section on 'Risk factors'.)

Malignancy — HIV infection is associated with an increased risk of certain malignancies, especially those related to infectious etiologies and smoking [91]. Increasing age among individuals with HIV is also a risk factor for malignancy.

Observational studies have suggested that some cancers (ie, lung, liver, anal) are occurring at relatively younger ages of diagnosis among patients with HIV compared with the general population. In a study of 15 HIV and cancer registry databases in the United States, including 212,055 persons with AIDS (restricted to non-White Hispanic persons and Black persons), the age at cancer diagnosis did not differ between AIDS patients and individuals without HIV after adjustments for different age compositions of the populations at risk, with the exception of lung and anal cancer (occurring at age 50 and 42 years versus 54 and 45 years in the controls without HIV) and Hodgkin lymphoma (occurring at age 42 versus 40 years) [92]. Another United States cohort study suggested that anal and lung cancer occurred on average four years earlier among people with HIV [93]. In a separate large North American study, the increased incidences of colorectal, anal, and liver cancer among individuals with HIV compared with those without HIV were specifically related to the increasing age of the HIV population [94].

The epidemiology and management considerations of malignant diseases in patients with HIV are discussed elsewhere. (See "HIV infection and malignancy: Epidemiology and pathogenesis", section on 'Epidemiology' and "HIV infection and malignancy: Management considerations".)

Bone health — Certain lifestyle and hormonal factors, which increase the risk of disordered bone metabolism, are prevalent in adults with HIV. These include physical inactivity, decreased intake of calcium and vitamin D, cigarette smoking, alcohol use, depression, opiate use, and low testosterone levels [95,96]. These factors add to the age-related risk of decreased bone density and fragility fractures. Antiretroviral toxicities, especially from tenofovir disoproxil fumarate (TDF) also contribute [97].

Bone disorders in patients with HIV are discussed in detail elsewhere. (See "Bone and calcium disorders in patients with HIV".)

Liver disease — Coinfection with hepatitis B and C viruses (HBV and HCV) is common in patients with HIV because of shared routes of transmission. Furthermore, HIV adversely impacts the natural history of each of these hepatitis viruses, with a higher likelihood of chronic infection and a faster rate of liver fibrosis progression. Thus, chronic liver disease is a frequent finding in older adults with HIV. (See "Epidemiology, clinical manifestations, and diagnosis of hepatitis B in patients living with HIV".)

Pulmonary disease — Pulmonary diseases represent a substantial burden of non-AIDS morbidity among older adults with HIV. In the Veterans Aging Cohort Study (VACS), consisting of 33,420 veterans with HIV and 66,840 veterans without HIV matched by age, sex, race, and ethnicity, the incidence of chronic obstructive pulmonary disease, lung cancer, pulmonary hypertension, pulmonary fibrosis, and pulmonary infections was significantly more common among veterans with HIV [98]. Bacterial pneumonia and chronic obstructive pulmonary disease were the most common. (See "Evaluation of pulmonary symptoms in persons with HIV".)

Sex-specific issues

Menopause — Menopause may occur earlier in females with HIV, and they may be more likely to experience menopausal symptoms, which can contribute to depression and anxiety [99]. Limited data are available about menopause and the use of hormonal replacement therapy in older females with HIV. This topic is discussed elsewhere. (See "HIV and women", section on 'Menstrual abnormalities and menopause'.)

Hypogonadism — Hypogonadism is common in males with HIV and has been associated with advanced disease and, in the ART era, persistent viremia [100]. In one study of the Multicenter AIDS Cohort Study (MACS) cohort, the rate of decline in testosterone level decline over 10 years appeared similar between males with and without HIV, although HIV may be associated with greater loss of diurnal variation [101]. This topic is discussed elsewhere. (See "Pituitary and adrenal gland dysfunction in patients with HIV".)

Geriatric syndromes and functional impairment — In addition to facing multimorbidity and polypharmacy, older adults with HIV may also be dealing with geriatric syndromes, such as falls, frailty, functional impairments, and disability. As with certain comorbidities, these geriatric syndromes may also occur at relatively younger ages in adults with HIV compared with the general population [72,102].

In one study of a San Francisco cohort of adults with HIV >50 years old, there was a high burden of these geriatric syndromes, with prefrailty being the most common [72]. Non-White race, lower CD4 nadir, and increasing number of comorbidities were associated with having more geriatric syndromes. Exposure to older antiretroviral medications, including azidothymidine (AZT) and didanosine (DDI), was associated with decreased risk; this may be related to some protective factors among individuals who have survived long enough to have used those older medications, rather than any benefit of the medications themselves. As in the general population, different geriatric syndromes such as frailty and falls are likely to co-occur in adults with HIV [103]. HIV clinical guidelines in the United States include recommendations to screen for geriatric conditions such as frailty, social isolation, and neurocognitive disorders [33,73].

Falls — Falls are a particularly important consideration in older adults with HIV given their increased risk of osteoporosis and fracture. Risk factors for falls, such as polypharmacy and peripheral neuropathy, are also common in adults with HIV. Observational cohorts have not clearly demonstrated increased risk of falls in older adults living with HIV; although in one study of males, balance problems were more prevalent [104,105]. Nevertheless, many studies report a high rate of falls in this population, at 25 percent or higher [72,106]. Prevention and management of falls are discussed elsewhere. (See "Falls in older persons: Risk factors and patient evaluation" and "Falls: Prevention in community-dwelling older persons".)

Frailty — Frailty is often defined as a state of decline and vulnerability in older adults, characterized by weakness and decreased physiologic reserve, which results in increased risk for multiple adverse outcomes. There is no standard definition or criteria for diagnosis, although the two primary models are the phenotypic model and the cumulative deficits model. The majority of studies evaluating frailty among patients with HIV have generally used the phenotypic model to identify frailty (weight loss, exhaustion, low activity, slowness, weak grip strength) but have defined these deficits differently [107,108]. Although in some studies, frailty appears to affect patients with HIV at a younger age than individuals without HIV [109,110], the risk of frailty among individuals with well-controlled HIV is similar to that in controls without HIV [111,112]. Factors associated with frailty in adults with HIV include increased age, low nadir and lower current CD4 cell count, detectable viremia, non-normal body mass index, depression, cognitive impairment, and less than high school education [72,107,113].

A more detailed discussion of frailty in the general population is found elsewhere. (See "Frailty" and "Comprehensive geriatric assessment".)

Functional impairment and disability — Functional impairment is common among older adults with HIV.

In an AIDS Clinical Trial Group (ACTG) cohort of over 1000 adults with HIV on ART with a median age of 51 years, self-reported impairment in at least one instrumental activity of daily living occurred in 18 percent [114]. Study participants most often reported impairment in activities involving housekeeping, transportation, or shopping. Neurocognitive impairment was most strongly associated with disability. There was also an association between disability and socioeconomic status, and an association with lifestyle factors, such as smoking and physical activity, suggested potential intervention targets to improve physical function.

Similarly, difficulty with one or more instrumental activities of daily living was seen in almost 50 percent of a San Francisco-based HIV cohort, with housework and shopping the most common deficits.

Objective measures of physical performance have also been studied, with the short physical performance battery (SPPB) frequently utilized. Among injection drug users with HIV, the SPPB predicted five-year mortality, with abnormal physical performance having the highest risk [115].(see "Office-based assessment of the older adult", section on 'Instrumental activities of daily living')

Social isolation and loneliness — In the general population, social isolation (an objective measure of social networks) and loneliness (a subjective measure) are associated with mortality [116,117]. Although there are few direct comparisons, older adults with HIV may have higher rates of social isolation and loneliness than the general population [118]. While older adults with HIV are more likely to live alone than younger adults with HIV, reports vary, and they may have similarly sized networks [119]. As in the general population, social isolation has been associated with hospitalization and mortality in older adults with HIV [120]. Loneliness and lack of social supports are also associated with mood disorders and sexual behaviors associated with sexually transmitted infection exposure [121,122].

HIV-RELATED MORTALITY — Overall, life expectancy for adults with HIV is improving and approaching that of the general population, especially with early treatment [77,123]. HIV-related mortality continues to decrease, and the proportion of deaths attributable to non-AIDS causes increases.

In the United States, in part because of the improved survival of patients older than 50 years with HIV, the median age at death from HIV infection has accordingly risen [10] (figure 2). Although earlier studies suggested that older patients with HIV had delayed immune recovery in response to ART, more recent data have shown that ART still has had a substantial impact on decreasing HIV-related mortality among older adults with HIV. (See 'Immunologic recovery with ART' above.)

As an example, in one observational study of over 3500 individuals with HIV in the United States, the mortality risk reduction associated with initiation of ART at a CD4 cell count threshold of 500 cells/microL rather than 250 to 300 cells/microL was greatest among patients aged 45 to 65 years [124]. Similarly, in a retrospective study from the United Kingdom, ART initiation at CD4 cell counts <200 cells/microL was associated with a greater reduction in mortality among adults ≥50 years old compared with younger adults (42 versus 12 percent fewer deaths) [125].

Nevertheless, other studies continue to suggest that older patients have a greater HIV-associated mortality than younger patients [38,42,126,127]. In a multinational study of 16,534 patients with HIV, with known duration of HIV infection, the excess mortality associated with HIV infection compared with the general population progressively declined among all age groups since the introduction of ART [126]. However, there remained an association between increasing age at seroconversion and excess mortality. In the United States, according to surveillance data, the proportion of persons surviving 12 to 36 months following a diagnosis of HIV or AIDS decreases as the age of diagnosis increases [10].

Prognosis — As in the general population, estimating prognosis is important to guide screening and treatment decisions in older adults with HIV, multimorbidity, and polypharmacy. Some tests and treatments pose immediate risks but delayed benefits, and so their value depends on life expectancy; for example, a life expectancy of eight years is needed to see benefits of tight glycemic control on prevention of microvascular complications from diabetes [128].

The Veterans Aging Cohort Study (VACS) Index is a prognostic index used to identify multisystem deterioration and susceptibility to adverse outcomes among patients with HIV [129,130]. It is based on several objective findings: age, CD4 cell count, HIV RNA level, hemoglobin level, aspartate and alanine aminotransferase levels, platelets, creatinine, and hepatitis C status. The VACS index has correlated with mortality in populations with HIV more closely than measures of age, CD4 cell count, and HIV RNA level alone. An online VACS calculator can generate five-year mortality risk. It has also correlated with risk of other poor outcomes, including fragility fractures and neurocognitive and functional impairment [131-133]. A newer version, VACS 2.0, incorporating albumin and other markers, is anticipated [134].

PREVENTIVE MEDICINE — As adults with HIV live longer, it is important for clinicians to keep in mind the routine age-appropriate screening examinations and immunizations that should be offered to the older patient (table 1 and figure 3). As in the general population, screening decisions should be based on life expectancy and not on age cut-offs alone. These issues are discussed in detail elsewhere. (See "Primary care of adults with HIV" and "Immunizations in persons with HIV" and "Geriatric health maintenance" and "Overview of preventive care in adults".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: HIV treatment in nonpregnant adults and adolescents" and "Society guideline links: Primary care of adults with HIV".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Starting treatment for HIV (The Basics)")

●Beyond the Basics topic (see "Patient education: Initial treatment of HIV (Beyond the Basics)")

SUMMARY

●Most of the literature on HIV infection in older adults defines older as ≥50 years of age. (See 'Introduction' above.)

●With the increasing survival of adults with HIV on antiretroviral therapy (ART) and new diagnoses occurring in older adults, the proportion of patients with HIV who are in this older age bracket has increased substantially worldwide. Sexual exposure is the most common mode of transmission for incident HIV infection in adults older than 50 years old. (See 'Prevalence and incidence' above and 'Risk factors for new infections in older adults' above.)

●Delayed diagnosis of HIV infection among older patients is a major problem. Older adults are frequently not perceived as being at risk for HIV and are less likely to be tested. Even when testing for HIV is undertaken in the older patient, the diagnosis is often made later in the natural history of their disease, which increases the risk of opportunistic infections and transmission to others. (See 'Risk factors for new infections in older adults' above and 'Delayed diagnosis of HIV' above.)

●As for all adults with HIV, ART should be initiated regardless of CD4 cell count in patients older than 50 years of age. The choice of the ART regimen takes into account existing medications, comorbidities, and potential organ system deficits. Older patients may especially be at risk for impaired liver or kidney dysfunction, which should be assessed on an ongoing basis. Additionally, polypharmacy is common in older adults and potential drug-drug interactions and other prescribing issues are critical considerations when selecting and managing ART regimens in older adults. (See 'Antiretroviral use' above and "When to initiate antiretroviral therapy in persons with HIV", section on 'Introduction' and "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".)

●The beneficial impact of ART on HIV-related mortality has been especially substantial among older patients, despite evidence of delayed immune recovery in this population. As deaths from AIDS and opportunistic infections have declined, however, age-associated medical comorbidities, such as cardiovascular, metabolic, liver, bone, and malignant disease, as well as geriatric conditions, have become more prevalent. These are particularly prevalent in individuals with HIV, in part because of chronic inflammation, immune activation, and immunosenescence associated with HIV. Clinical care of older patients with HIV focuses on identifying and modifying risk for such conditions. (See 'Non-AIDS morbidity' above and 'HIV-related mortality' above and "Primary care of adults with HIV".)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Nathalie Casau-Schulhof, MD, and Charulata Jain Sabharwal, MD, MPH, who contributed to earlier versions of this topic review.

UpToDate gratefully acknowledges John G Bartlett, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Infectious Diseases.