Older HIV-infected adults: complex patients—comorbidity (I)
Life expectancy in people living with HIV has increased in the past decades, since the introduction of highly active antiretroviral treatment. Increased survival comes along with new challenges for the HIV physician, as these patients will present comorbidities inherent to ageing that can appear more frequently and at younger age than the general population. The older HIV patient poses a unique challenge, as management should take into account different factors, some related to global ageing such as geriatric syndromes, traditional risk factors, social vulnerability, and age-related diseases, and others related to HIV infection like ART toxicity, drug–drug interactions, immune dysregulation and chronic inflammation. All the above can amount to great polypharmacy and multimorbidity that physician have to be aware of. Little is known about the best screening, management and treatment strategies to improve long-term health outcomes in this ageing population. The following article briefly reviews the main comorbidities that can affect the ageing HIV patient.
KeywordsHIV Ageing Comorbidities Chronicity
During the last decades, we have witnessed an important milestone in medicine: the introduction of potent antiretroviral treatment (ART) in people living with HIV (PLWH) and the increase of ART coverage worldwide has dramatically improved survival in PLWH. Recent data show that life expectancy is fast approaching that of the general population [1, 2]. The increase in life expectancy, an outstanding achievement, comes along with the ageing phenomenon in HIV medicine. A recent European modelling study based on data from the Athena cohort estimated that in 2030, 73% of PLWH in Europe will be aged 50 years or older, and that nearly 40% will be older than 65 . This is a consequence of longer survival but also of an increasing frequency of new HIV diagnosis in people above their fifties. Data from the European Centre of Diseases Control in 2016 showed that 39% of PLWH are considered to be older adults and in some specific countries, they contribute to 20% of the new diagnosis. These data are of utmost importance because older patients have higher risk of delayed diagnosis  and higher risk of progression—even after adjusting for CD4+ T cell count, HIV-RNA and stage of disease .
As a consequence of these demographic changes, age-related co-morbidities will increase. PLWH, although virologically controlled, are at higher risk for non-AIDS comorbidities such as cardiovascular diseases, malignancies, renal insufficiency, bone diseases and neurocognitive impairment . Data from a variety of cohorts show that PLWH have a higher burden of comorbidities, especially in the older age group, in comparison with HIV-negative matched controls [8, 9, 10, 11].
These diseases are typically age related, but in the context of HIV, the explanation for their higher frequency is likely to be multifactorial. ART toxicity, higher frequency of classical risk factors, chronic inflammation and immune dysregulation are key players. HIV infection associates accelerated immunosenescence that affects both the innate and adaptive immunity. In fact, ageing and HIV infection share immunologic features such as inversion of CD4:CD8 ratio, expansion of terminally differentiated CD8+ T cells, higher levels of inflammatory cytokines and other co-infections such as CMV or herpes virus; which are related to non-AIDS-related morbidity and mortality in both PLWH and non-infected nonagenarians [12, 13, 14]. Some interesting reports show that HIV-infected patients have a biological age (measured by the so-called epigenetic clock) 5–7 years older than chronologic age [15, 16]. It is not yet fully understood how HIV affects the natural ageing process. It is not yet clear if HIV accelerates ageing by itself or if classic ageing-related co-morbidities, ART chronic immune activation and inflammation are driving the complexity of ageing in PLWH.
If HIV infection has a differential impact on the ageing process and how this occurs is an important question. The following article reviews the main co-morbidities in older HIV-infected patients.
Metabolic and cardiovascular risk factors
There are data reporting PLWH have a higher proportion of hypertension, dyslipidemia and diabetes than the uninfected population . However, it is difficult to assess to which extent HIV infection is responsible per se for their incidence in older HIV patients, since other factors—i.e., lifestyle—clearly predispose to these diseases. This could explain why we can find a prevalence of 86% hypertension, 74% dyslipidemia and 28% of diabetes in a cohort of HIV patients aged over 70 from Washington DC , but of 43, 60 and 22%, respectively, in another observational cohort of patients over 75 years from France .
European guidelines have acknowledged the need to detect these comorbidities and suggest initial treatment strategies, although specific recommendations for screening and management in HIV elderly patients are currently lacking.
A recent meta-analysis estimated that a quarter of HIV individuals have hypertension. The prevalence was two times higher in patients aged over 50 than those younger than 40 years of age. Interestingly, there was a significant association between ART exposure and a higher prevalence of hypertension that was consistent across all age groups . Another meta-analysis of 39 studies including more than 44,000 patients concluded that ART was associated with higher systolic and diastolic BP, and a higher risk for hypertension in treated versus naïve HIV individuals . However, ART was not linked to a significant risk of hypertension in a recent analysis from the D:A:D cohort . Asides from traditional demographic, lifestyle and genetic risk factors for hypertension, and the aforementioned effect of ART, other HIV-related factors such as nadir CD4+ T-cells count, lipodystrophy, viral or ART-mediated endothelial dysfunction have been proposed as additional elements for developing hypertension .
With reports of increasing incidence of hypertension in HIV patients , the improvement in life expectancy and the established association between age and hypertension, it is not far-fetched to believe that the burden of this disease is set to dramatically increase in the elderly population. European AIDS clinical Society (EACS) HIV guidelines recommend initiating anti-hypertensive treatment in patients over 55 years with a calcium-channel blocker (CCB), for a blood pressure (BP) target under 140/90 mmHg . However, CCB can potentially have significant drug–drug interactions (DDIs) with boosted protease inhibitors (PIs), efavirenz, nevirapine, etravirine and elvitegravir/cobicistat. DDIs are particularly important in the elderly population who are also prone to suffer drug-related side effects such as electrolyte disturbances or higher risk of falls owing to pharmacodynamic and pharmacokinetic effects, which complicate the management of hypertension in this population . Also increasing the complexity of hypertension management is a diverse recommendation regarding BP target: current guidelines distance themselves from previous conservative recommendations and now suggest an systolic BP target under 130 mmHg (AHA/ACA guidelines) or 130–139 mmHg (ESC/ESH guidelines) for patients aged over 65 [28, 29]. Notwithstanding, the guidelines do stress out the need to individually assess the elderly patient’s functionality to tailor BP target and treatment. This is considerably important for the ageing HIV patient in whom frailty, comorbidity and polypharmacy ought to be deeply considered. Data from the EuroSIDA cohort showed that 58% of patients with indication for hypertension treatment modified their BP, but that among those less likely to attain BP control were the older patients, and those with dyslipidemia or diabetes . Importantly, modelling data suggest that adequate control of hypertension and other traditional risk factors in HIV patients (i.e., smoking, dyslipidemia) would avert more cases of cardiovascular diseases than strictly HIV-related interventions .
Ideally, a clinical trial should be designed to address the particularities of older HIV-infected patient and find the right balance between a maximum benefit of BP control and a lower risk of side effects and DDIs.
A metabolic model for HIV dyslipidemia suggests that patients have hyperlipolytic activity in peripheral tissues producing VLDL cholesterol and triglycerides (TG), with subsequent high levels of LDL and dysfunctional HDL . In addition, ART is linked to dyslipidemia, mostly through PIs and to a lesser extent abacavir, with tenofovir disoproxyl fumarate (TDF) exerting a “protective” role that has not yet been observed with tenofovir alafenamide . LDL-c—which is most related to cardiovascular disease—and total cholesterol (TC) increase with age, whereas HDL-c declines . Statins are the most efficacious lipid-lowering therapy in primary and secondary prevention. Numerous studies demonstrate that statins reduce cardiovascular morbidity and mortality, many showing greater event reduction in elderly than younger patients . A meta-analysis did not observe any significant differences in the effect among statins on HDL, LDL or TG in HIV-infected patients, although atorvastatin did show greater benefit reducing total cholesterol .
Current general dyslipidemia guidelines use different risk scores to establish the thresholds for treatment and recommended LDL targets. ESC/EAS guidelines recommendations for statins in older patients with established cardiovascular disease are similar to those for younger ones but advise to start at a lower dose and titrate with caution, and also recommend considering their use in primary prevention . EACS HIV guidelines recommend lipid-lowering therapy for patients with cardiovascular disease, type 2 diabetes or at cardiovascular risk (10% risk at 10 years) to an ideal target of LDL < 80 mg/dL, with statins preferably in addition to lifestyle modifications and in some cases, change of ART .
A recent study reflected that physicians were less likely to prescribe statins to high risk HIV-infected patients compared to the uninfected population . Asides from polypharmacy and DDIs, important concerns in the elderly population are new onset statin-associated diabetes—to which elderly patients are particularly at risk—and statin muscle toxicity, which is increased in ageing patients due to lower muscle mass and reduced drug metabolism [39, 40]. The risk of adverse side effects could be counterbalanced by the anti-inflammatory and immunomodulatory effect statins may exert upon HIV-infected patients .
The prevalence of diabetes mellitus (DM) in PLWH varies according to different cohorts. USA data revealed that one out of ten HIV patients under care had DM, a prevalence higher than the general population and closely related to age (those aged over 60 had a DM prevalence of nearly 20%), obesity, time since HIV diagnosis and mean CD4+ T-cells count . In a Canadian study, HIV-infected patients aged over 50 had an incidence of DM of 1.61/100 person-years, 1.39 higher than uninfected men, and there was an association with prior exposure to first-generation ART . ART initiation can induce weight gain within the first year that is associated with increased incidence of DM compared to similar weight gain in the uninfected population . Older ART have been linked to DM: indinavir, ritonavir, atazanavir, zidovudine, didanosine, lamivudine, efavirenz, stavudine and nevirapine were linked to higher DM rates, although this finding was inconsistent across studies . Considering the current recommendation to treat all patients, authors alert of the expected increase of the burden of DM.
Current diabetes guidelines recommend assessment of functional, social and psychological function to better establish glycaemic targets, as it is acknowledged that elderly individuals can suffer from specific conditions (cognitive decline, polypharmacy, urinary incontinence, falls) that may undermine their self-care capacity. An individualised approach to determine glycemic targets depending on functional status and co-morbidities allows for less stringent A1C targets (< 7.5 for the elderly vs. < 8–8.5% for the frail). EACS guidelines recommend treatment initially with metformin and adding other oral antidiabetics or insulin to achieve a target A1C < 6.5–7% . Interestingly, switching to an integrase inhibitor—and more evident with dolutegravir/abacavir/lamivudine—has been recently associated with higher weight gain and a non-significant increase in A1C compared to continuing treatment with efavirenz/tenofovir/emtricitabine; the importance of this finding is likely to be better defined in the coming years .
The effect of ageing combined with both HIV and diabetes should be better outlined, as, for example, all three can affect cognitive function through different pathways but can also synergistically hasten their effects.
Cardiovascular disease (CVD) is a leading cause of mortality in PLWH, although recent data from USA show a decrease in cardiovascular mortality that probably reflects earlier ART initiation and better management of CV risk factors . A recent modelling study estimates that the incidence of CVD will increase 55% between 2015 and 2030 . PLWH have a higher prevalence of different cardiovascular diseases such as myocardial infarction , stroke , peripheral artery disease , sudden cardiac death  and heart failure . A recent systematic review found that global risk for cardiovascular diseases in PLWH is increased by twofold and is responsible for a high amount of disability-adjusted life-years .
There are some special issues regarding the association between myocardial infarction and some antiretroviral drugs such as abacavir  and darunavir . The selection of ART is critical especially in older HIV-infected patients. Recent data show that the use of PIs in PLWH with heart failure is associated with higher mortality and greater hospitalizations rates . Older HIV-infected patients should be treated with lipid-friendly drugs whenever possible. Integrase inhibitor-based regimens are preferred due to their potency, low drug interactions and long-term safety profile.
Although the choice of ART is important to reduce inflammation and metabolic impact, it is most important to adequately control cardiovascular risk factors . One of the most effective interventions is smoking cessation, as smoking contributes to a higher myocardial infarction risk among PLWH in comparison with general population . EACS guidelines recommend an aggressive management of cardiovascular risk factors and pro-active ART switching to drugs with the most favourable metabolic profile.
Prevention strategies of cardiovascular diseases in PLWH should be the same as the general population, with some specific precautions on DDIs and adverse events in older patients. However, data from several studies show that statins and acetylsalicilic acid are less prescribed in PLWH in comparison with general population [38, 58]. This could be explained by DDIs, polypharmacy, poor drug adherence and specific concerns regarding the use of statins in the elderly (greater adverse events, fall on functional status, and influence on cognitive performance) .
Until interventional studies are available to better address the primary and secondary prevention strategies in older HIV-infected patients, we should apply the evidence available for the general population.
In the French Dat’AIDS cohort, including more than 17,000 patients aged over 50, the prevalence of chronic kidney disease (CKD) increased significantly in HIV-infected geriatric population (> 75 years) compared to those aged between 50 and 74 (29.4% and 4.5%, respectively), despite similar rates of virologic suppression . A comparison of two EuroSIDA cross-sectional cohorts (2006 and 2014) yielded an older population in the most recent cohort (44% of patients aged over 50) that, despite higher proportion of virologic control and better immunologic status, had the largest increase in CKD prevalence, particularly in individuals aged over 60 (18.5% in 2006 vs. 23.2% in 2014) . Guaraldi et al.  observed that CKD was significantly more prevalent in HIV patients compared to uninfected controls across all ages, and reported a prevalence of 24% of CKD in HIV patients aged over 60.
Asides from traditional risk factors for CKD, HIV-infected patients have specific factors (low CD4+ T-cells count, high viral load, HIV-nephropathy, nephrotoxic ART, HCV co-infection) that may predispose to the disease. Notably, the prevalence of HIV-associated nephropathy has decreased in high-income countries, where other renal manifestations such as focal and segmental glomerulosclerosis and HIV-associated immune complex kidney disease have become more prevalent. Indinavir, atazanavir, PIs and TDF are associated with increased risk of CKD with age and lower baseline glomerular filtration rate being risk factors. Dolutegravir and cobicistat inhibit tubular creatinine transport, although this does not translate intrinsic nephrotoxicity . Elderly PLWH are expected to have an additional reduction on renal function apart from the physiological ageing decline (10 ml/min decline in glomerular filtration rate per decade).
Management of CKD in the elderly includes treatment of co-morbidities, acidosis, uraemia, anaemia, avoiding fluid overload and nephrotoxic drugs. Older HIV-infected patients are particularly at risk for DDIs and adverse reactions owing to aged- related altered bioavailability and underlying renal disease. To avoid them, treatment simplification using as fewer drugs and doses as possible, following the axiom “start low, go slow” for new drugs and coordination among health providers are advisable, along with renal function control and regular review of treatment. CKD also is linked to frailty; so, a multidisciplinary approach that takes into consideration adequate nutrition, exercise training, medication review and appropriate shared decision-making and anticipatory planning in end-stage renal disease is also desirable .
One of the cornerstones of treating kidney disease in HIV patients is ART. Other strategies include adequate control of co-morbidities, ACEIs or angiotensin II inhibitors if hypertension or proteinuria are present, identifying and withdrawing offending drugs and switching ART when treatment-associated toxicity is suspected. Specifically, the nephrotoxic effect of specific drugs can be reversed with drug discontinuation . ART simplification in this setting may reduce drug-cumulated toxicity and timely referral to nephrologist is warranted.
PLWH face an increased risk of osteoporosis and fragility fractures associated with ageing, chronic HIV, and the toxicity arising from long-term ART. Osteoporosis prevalence in PLWH is estimated between 5 and 20% and according to some authors close to 15%, more than three times higher compared to the uninfected population [63, 64]. In terms of bone mineral density (BMD) globally, a decrease up to 6 times higher has been observed.
The pathogenesis of low BMD and osteoporosis in HIV is unclear. It seems to be the result of the combination of a direct mechanism—the pro-inflammatory state, immune activation, bone cells modulation by HIV proteins—and indirect mechanisms secondary to ART and the excess of common risk factors (low weight, smoking, increased basal metabolism, opioids intake) more prevalent in PLWH [65, 66, 67, 68]. Recently, several studies have published the association between an increased risk of low BMD with time of HIV infection, viral load, more severe HIV disease (reflected as lower CD4+ T cells nadir) and ART, especially TDF [66, 69].
It is well established that exposure to ART affects BMD, but differing between ART classes and individual antiretroviral agents within a particular drug class. ART initiation is linked to bone loss, up to 4% decline depending on the drugs used, which later stabilises . Data from the SMART study, published in 2009, that compared intermittent ART guided by CD4+ T-cells count vs. continuous ART, support this hypothesis. Patients treated with ART continuously presented a decrease in annual BMD of 0.8% in the hip, 0.4% in the spine, compared to patients with intermittent ART who presented a significantly lower decrease . The bone substudy of START clinical trial, which compared patients who started treatment with CD4+ T-cells count greater than 500 cells/μL with patients who deferred treatment (until they reached 350 cells/μL), demonstrated also the association between ART and BMD loss. In the spine, an average difference in 2.2% lower BMD was found in the immediate ART group and 2.1% lower in hip in the immediate ART group [71, 72]. Greater losses in BMD are observed with ART containing certain nucleoside reverse transcriptase inhibitors and PIs . Nowadays, TDF is the ART more implicated in BMD loss both in naïve and ART experienced [73, 74, 75]. Newer strategies such as nuke-sparing regimens have demonstrated improvements in BMD . In the last years, tenofovir alafenamide (TAF) has been used instead of TDF and has demonstrated smaller reductions in hip and lumbar spine BMD compared with TDF .
Although the loss of bone mass is accepted as a surrogate marker for fragility fractures in the general population, the correlation among BMD, the incidence of fractures and ART is not well established. Host factors, HIV-specific variables and comorbidities contribute to the risk of femoral and vertebral fractures [78, 79, 80]. There is a strong association between HIV infection and the incidence of hip fractures, with a fivefold increase in HIV-infected patients, regardless of sex, age, smoking, alcohol consumption and comorbidities . It has also shown a 75% increase in the risk of all clinical fractures and a 60% increase in the risk of clinical fractures other than hip in HIV-infected patients, corroborating previous studies showing similar associations [81, 82]. Previous studies have published that cumulative exposure to TDF and, among PIs, lopinavir/ritonavir was independently predictive of increased risk of osteoporotic fracture . However recently, data from EuroSIDA study showed that past and current exposure to TDF, but not cumulative exposure, is independently associated with increased fracture risk among PLWH, and there was no association for any other ART .
Cancer risk rises with age, although the age-related risk of individual types of cancers varies. PLWH are at increased risk of malignancies compared with the general population: this is the case for AIDS-defining cancers, but also for most of non-AIDS-defining cancers, with some exceptions [84, 85]. A recent case–control study of individuals over 65 years showed that 10% of PLWH developed cancer over a period of 5 years .
The incidence of AIDS-defining cancers is expected to decline with early ART initiation. Data from a recent study showed that there is a decline with age in AIDS-defining cancers, from 77% of excess of cancer to 22% for people aged 70 and older .
Not all non-AIDS-defining cancers show an increased prevalence in PLWH. Some are clearly increased such as anal, lung, Hodgkin disease, and hepatocellular carcinoma, while others seem to be less frequent (prostate and mama) . Immunodeficiency, increased rates of smoking and oncogenic virus co-infections are key players [89, 90]. A low CD4+ T cell count is associated with an increased incidence of certain non-AIDS-defining malignancies. Starting ART earlier may decrease the rate of developing many common cancers, especially lung cancer. The incidence of lung cancer was significantly decreased with a higher current CD4+ T cell count; however, older age significantly increases the rate of lung cancer and was a strong predictor for non-AIDS-defining cancers .
Treating cancer in older HIV-infected individuals is challenging, as there are specific factors such as DDIs, increased risk of opportunistic infections, concomitant co-morbidities, polypharmacy, etc. Preventive measures are critical and recent reports suggest decreases in the incidence of non-Hodgkin lymphoma and some non-AIDS-defining cancers (anus, liver, and lung) [92, 93]. Efforts should focus on tobacco cessation as PLWH lose more life-years through smoking than through HIV infection .
Despite earlier ART initiation and better-tolerated drugs with good long-term safety, age-associated diseases are more frequent in PLWH. We do not yet know if the ageing effect on co-morbidities and mortality in PLWH is stronger in comparison with the general population. Whether decreasing the residual inflammation, intrinsic to HIV infection and physiologic ageing, will be beneficial in terms of mortality and morbidity remains to be known. In the meantime, HIV physicians should provide the highest quality of care with regards to screening, prevention and treatment of age-related diseases, ideally with a multidisciplinary approach. Early HIV diagnosis and treatment in older patients, improvement of the cascade of care, reduction of social isolation, stigma and health inequities should be part of an integrative programme aimed at reducing the gap between older PLWH and the general population.
Rosa de Miguel is supported by a Río Hortega fellowship from the Fondo de Investigación Sanitaria.
Compliance with ethical standards
Conflict of interest
Dr. Bernardino reports grants and personal fees from Gilead Sciences, personal fees from ViiV Healthcare, Janssen Pharmaceuticals, and Merck Sharp & Dohme, outside the submitted work. Dr de Miguel reports personal fees from Gilead Sciences and Janssen Pharma outside the submitted work. Dr Montejano received personal fees from Janssen Pharmaceuticals, personal fees from Merck Sharp & Dohme, and Gilead Sciences outside the submitted work.
This article does not contain any studies with human participants or animals performed by any of the authors.
For this type of study informed consent is not required.
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