Keywords

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FormalPara Key Points

  • Older and frail patients with human immunodeficiency virus (HIV) constitute a treatment challenge in terms of the cumulative effects of aging and antiretroviral therapy (ART).

  • ART is recommended for patients >50 years of age, regardless of CD4 cell count, in consideration that the risk of non-AIDS-related complications may increase and the immunologic response to ART may be reduced in older patients with HIV.

  • Recommended antiretroviral (ARV) drug choices for the elderly are the same as for the general population. However, due to age related comorbidities, specific drug toxicities should be considered when choosing drug regimens.

  • Current guidelines do not recommend age or frailty as criteria for ARV switching. Three major issues frequently coexisting in this special population may indicate ARV switch: comorbidities, greater medication use and age-related changes in pharmacokinetics, and pharmacodynamics.

Older and frail patients with HIV constitute a treatment challenge in terms of the cumulative effects of aging and ART. There are currently no specific treatment guidelines available that focus on the older population, mainly due to the limited information on the efficacy and safety of selected ARV regimens for older patients. Most recently, regulatory agencies such as the Food and Drug Administration (FDA) and European Medicine Agency (EMA) request age stratification (above or under 50 years of age) in the analysis of the results for registrational clinical trials. However, due to the exclusion of patients with comorbidities, the included elderly population may not be representative. Furthermore, ‘frailty’ as the phenotype of biological aging is not considered in the development of treatment guidelines.

HIV experts and primary care providers should work together to optimize the medical care of older and frail patients with HIV and complex comorbidities, in addition to preventing secondary transmission of HIV among older adults.

General issues regarding ARV toxicity (cardiovascular, renal, bone, polypharmacy, and drug–drug interactions), although improved, are still a matter of concern when managing ARVs, particularly so in the elderly population.

10.1 When to Start Antiretroviral Therapy

Current Department of Health and Human Services guidelines [1] recommend starting ARV therapy in patients with HIV aged >50 years, regardless of CD4+ cell count. This is due to increased rates of progression of untreated HIV disease, immune senescence, comorbidities that are exacerbated by CD4+ cell loss, and inferior immune reconstitution after the initiation of therapy [2–12].

International Antiviral Society guidelines base their recommendations on the principle of ‘treatment as prevention’ and reinforce this level of recommendation in the elderly population [13]. European AIDS Clinical Society (EACS) guidelines, on the other hand, do mention age categories to suggest an intensified screening for comorbidities in the elderly population but do not suggest any age category for starting ARV in the adult population [14].

Several studies have documented that CD4 T cell recovery after starting ART is generally less robust in older patients than in younger patients [1, 11, 15–18]. This incomplete immune recovery occurs both in patients with CD4+ cell counts below and above 350 cells/mm3 [11, 16–22]. These inferior clinical outcomes in older patients with HIV are not explained by poor virological results; older patients have an improved adherence to therapy [23, 24], more often achieve virological control of HIV replication, and subsequently develop virological breakthrough less often than younger patients [23, 25–28].

A systematic review and meta-analysis of 12 studies that included adherence data showed that older age was associated with a 27 % reduced risk of non-adherence to ART (relative risk 0.72; 95 % CI 0.64–0.82), including both short-term and long-term adherence [29].

10.2 What to Start

Recommended ARV drug choices for the elderly are the same as for the general population. However, in consideration of age-related comorbidities, specific drug toxicities should be taken into account when choosing drug regimens. Table 10.1 summarizes ART-associated common and/or severe adverse effects to be considered in the treatment of the elderly population at higher risk of comorbidities [30].

Table 10.1 Antiretroviral therapy-associated common and/or severe adverse effects
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Particular attention should be paid to postmenopausal women or women entering menopause. Menopause is a physiological time frame where rapid hormonal, biochemical, anthropometric, and psychological changes occur, making women more vulnerable to ARV toxicities. The most relevant comorbidity in this category is osteoporosis.

Disentangling the effects of menopause in comorbidity onset requires well-designed studies with adequate numbers of HIV-infected and HIV-uninfected women. Future studies should follow women from premenopause through menopause, using both surveys and laboratory measurements for menopause diagnosis, and control for confounders related to normal aging processes, in order to inform optimal clinical management for menopausal women living with HIV.

Altogether, we may say that randomized clinical trials able to inform ARV choice in patients with comorbidities are still limited, but a changing landscape is appearing.

A study presented at the 2015 Conference on Retroviruses and Opportunistic Infections assessed the safety, tolerability, and efficacy of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) single-tablet regimen (STR) in treatment-naïve and treatment-experienced HIV-positive adult participants with estimated glomerular filtration rate (eGFR) between 30 and 69 mL/min, in which the median baseline age was 58 years [31]. Switching to E/C/F/TAF was associated with no change in actual GFR, reductions in proteinuria and markers of proximal renal tubular function, and improvements in hip and spine bone mineral density (BMD). Adverse events, grades, and frequencies were similar in patients with a baseline eGFR <50 and ≥50 mL/min. These 48-week data support the virological efficacy and renal and bone safety of once daily, single-tablet E/C/F/TAF therapy for patients with HIV and mild to moderate renal impairment (eGFR 30–69 mL/min). This particular drug combination has a 15-times lower concentration in serum than tenofovir, is 7-times more concentrated in the intracellular lymphocyte cytoplasm, appears to have a limited bone and kidney toxicity, and qualifies to be studied as the nucleoside reverse transcriptase inhibitor (NRTI) backbone of the aging patient [32–34].

10.3 What to Change

Switching a successful ARV regimen should be done carefully and only when the potential benefits of the change outweigh the potential complications of altering treatment. The fundamental principle of regimen switching is to maintain viral suppression. Before any treatment switch is implemented, it is critical to review the following:

  • the patient’s medical and full ARV history (including prior virologic responses);

  • resistance test results;

  • viral tropism (when maraviroc [MVC] is being considered);

  • human leukocyte antigen (HLA) B*5701 status (when abacavir [ABC] is being considered);

  • comorbidities;

  • adherence history;

  • concomitant medications and supplements (and their potential for drug interactions); and

  • prior intolerances to any ARV drug.

Current guidelines do not recommend age or frailty as criteria for ARV switching. Nevertheless, three major issues frequently coexisting in this special population may suggest the need for an ARV switch, and are discussed in the following sections.

10.3.1 Comorbid Conditions

Bone, kidney, metabolic, and cardiovascular health impairment, for example, are more frequent in older adults with HIV and should be closely monitored in such patients. In the past 15 years, the availability of new and less toxic drugs have allowed a progressive switch from a reactive strategy, based on ARV switch in patients with clinical comorbidities, into a more aggressive pre-emptive strategy in which the switch is made to prevent the risk of functional decline of organ reserve. Table 10.2 summarizes switch strategies to cope with specific adverse event risk, providing a rationale for ARV choice [30].

Table 10.2 Antiretroviral therapy-associated adverse events that can be managed with substitution of alternative antiretroviral agent
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10.3.2 Greater Medication Use

Polypharmacy in both the general older population and in patients with HIV infection is very common. Recent data from the Swiss HIV Cohort demonstrate that among patients 65 years of age and older, 14 % received medications from four or more classes of non-HIV medications, and lipid-lowering agents were the most commonly prescribed non-ART medication [35]. These data are consistent with findings from the Veteran’s Administration Cohort Study (VACS), wherein among those 50 years of age and older, 55 % were on five or more daily medications [36]. These studies report prescription medication only and therefore likely underestimate the prevalence of polypharmacy.

Use of prescription and over the counter medication, herbal supplements, and even recreational drugs increase the possibility of complex and unpredictable drug–drug interactions (DDIs) [37–39]. Polypharmacy has also been associated with increased risk of adverse drug reactions, increased hospitalizations, poor adherence, falls, and fractures [40–45].

In this context, elevated pill burden and risk of severe DDIs appear to give an advantage to INSTI-highly active antiretroviral therapy (HAART) (regimen with particular regards to fixed-dose combination and/or drugs with no ritonavir or cobicistat boosting). The new NNRTI, rilpivirine, appears to have limited DDIs. DDI occurs more commonly with boosted PI regimens.

10.3.3 Age-Related Changes in Pharmacokinetics and Pharmacodynamics

Pharmacokinetic (PK) changes associated with aging include a reduction in renal and hepatic clearance and an increase in volume of distribution of lipid soluble drugs (leading to a prolongation of elimination half-life). Pharmacodynamic (PD) changes involve altered (usually increased) sensitivity to several classes of drugs, such as anticoagulants, cardiovascular, and psychotropic drugs [46] (Table 10.3).

Table 10.3 Potential impact of age-related changes on pharmacokinetics
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Aging is associated with a decrease in renal tubular secretion, glomerular filtration, and decreased functioning of the hepatic CYP450 [38, 48, 49]. A better understanding of the effects of aging on the clinical pharmacology of therapeutic agents would enhance the quality of prescribing.

In this context, the age-related changes in drug handling (PK) and response (PD) appear to provide advantages and disadvantages to the different ARV classes:

  • Integrase inhibitor therapy offers the advantages of a favorable safety profile, good tolerability, and absence of significant DDIs.

  • Fusion inhibitors have a null impact on PK and PD.

  • NNRTIs and PIs may act as inducers or inhibitors of CYP metabolism and permeability glycoprotein transporters. NRTIs may enhance some metabolic toxicities, in particular interfering with mitochondrial function.

The general principles (mentioned above) that guide the choice for ART use in day-to-day management of ARV in older patients with HIV are summarized in Table 10.4.

Table 10.4 Guiding principles for the choice of antiretroviral use in older patients with HIV
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Frailty has not been considered as a factor in choosing specific ARV regimens either in treatment-naïve or in treatment-experienced patients with HIV.

10.3.4 Clinical Trials

A recent analysis from the Modena HIV Metabolic Clinic (MHMC) aimed to describe patterns of ARV use in relation to age, gender, and frailty (Figs. 10.1 and 10.2) [50]. In the retrospective review of data from 1240 participants with undetectable viral load and CD4 cell count ≥500 cells/μL (providing 5024 annual study visits) frailty was retrospectively quantified via 37-item frailty index, based on the cumulative deficits model. Frailty index variables excluded markers of HIV severity or immune depletion [50].

Figure 10.1
figure 1

Age and frailty spectrum in different antiretroviral drug classes in patients currently exposed to treatment [50]

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Figure 10.2
figure 2

Age and frailty spectrum in different antiretroviral regimens in patients currently exposed to treatment [50]

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Regardless of the retrospective observational study design, which does not allow for any causative correlation, differences in ARV use were observed in relation to frailty and age. Patients on INSTI, NRTI-sparing regimens, or dual therapy were more likely to have a higher frailty index, independent of age. This may be the result of a clinical attitude towards ARV selection in frail patients, which could be the proof of principle for future randomized clinical trials, using the frailty index as a primary end point. Alternatively, the frailty index may be used as an inclusion criterion to stratify overall health of patients.

It is premature to state that INSTI regimens, NRTI-sparing regimens (usually dual therapy), and mono-PI therapy should be preferred in frail patients, nevertheless, in consideration of a progressive day-to-day use of these regimens in elderly and frail patients, the following sections summarize clinical studies using these treatment options.

Table 10.5 Dual therapy with INSTI based regimens in treatment-naïve patients
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Table 10.6 Dual therapy with INSTI-based regimens in treatment-experienced patients
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Table 10.7 Studies with NRTI-sparing regimens in treatment-naïve patients
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Table 10.8 Studies with NRTI-sparing regimens in treatment-experienced patients
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Table 10.9 Studies with NRTI-sparing regimens in treatment-experienced patients (virologically supressed on standard antiretroviral therapy)
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Table 10.10 Studies with mono-PI therapy in treatment-naïve patients
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Table 10.11 Studies with mono-PI in treatment-experienced patients
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Regardless of the small sample size in many of these studies the overall number of patients who have been enrolled in total is considerably high and it may be argued that a significant amount of clinical experience already exists with these regimens.

10.3.4.1 INSTI-Based Regimens

Integrase inhibitor (INI) therapy offers the advantages of a favorable safety profile, good tolerability, and absence of significant DDIs, in addition to high efficacy.

Messiaen et al. [51] conducted a review and meta-analysis of studies that used INIs in ARV-naïve and treatment-experienced patients with either virological failure or were switching while virologically suppressed. Combination treatment with INIs and dual NRTIs showed to be more beneficial for treatment-naïve patients compared to other currently used treatment strategies. In treatment-experienced patients with virological failure, use of INSTIs also proved to be beneficial. However, in patients with a history of therapy failure, switching a high genetic barrier drug towards an INI was not supported.

A summary of studies investigating INSTI therapy in treatment-naïve and treatment-experienced patients can be found in Tables 10.5 and 10.6, respectively.

10.3.4.2 NRTI-Sparing Regimens

One of the most important arguments in favor of the assessment of NRTI-sparing regimens has been a growing understanding of the long-term toxicity profile of the newer, relatively safe NRTIs in common use currently, such as tenofovir and abacavir. Newer drugs with high potency and often with a more favorable safety profile are becoming available, leading to an interest in NRTI-sparing regimens.

A review by Acchra and Boyd [60] examined studies of NRTI-sparing regimens in adult patients with HIV (Tables 10.7, 10.8, and 10.9). They found that an NRTI-sparing strategy (with an INI and boosted PI) was supported in the treatment of experienced patients on a failing regimen. In naïve patients, or in those switching from virologically suppressive regimens, evidence was sparse and largely came from small exploratory trials or observational studies. In such cases caution should be exercised in choosing the right patient and new ARV regimen, in order to avoid virological failure. Another concern was the residual toxicity of the ritonavir boost in PI-containing NRTI-sparing regimens. Additional research is needed to understand the true potential of NRTI-sparing regimens and how to minimize adverse effects associated with ritonavir-boosting.

10.3.4.3 Mono-PI Therapy

The potential benefits from switching from a triple drug regimen to ritonavir-boosted PI (PI/r) monotherapy is currently a topic of some interest (Tables 10.10 and 10.11), as it allows reduction of NRTI-related toxicity (lipoatrophy, renal disease, BMD loss) and reduced cost versus dual or triple therapy, while retaining other classes as future treatment options. There is an increased risk of low level viremia with monotherapy, but this has been shown to be reversible with NRTI re-introduction. The emergence of PI resistance has been rare on PI/r monotherapy and re-introduction of NRTI remains possible in such cases.

Such a strategy can only be considered in stable, long-term virologically suppressed patients who have demonstrated good adherence to ART, have no history of PI failure, do not have chronic hepatitis B, do not have HIV-associated neurocognitive disorders, and who are able to tolerate low dose ritonavir [101].

The recent PIVOT study [99] (Table 10.11) randomized 587 UK patients, who already had an undetectable viral load on stable treatment, to either PI/r monotherapy or triple therapy. It included 4 years of follow-up. Approximately 80 % in the boosted PI monotherapy arm used darunavir/r (DRV/r), 14 % lopinavir/r (LPV/r), and 7 % another PI. Viral load rebounded much more frequently in the monotherapy group (35 %) compared to the triple therapy group (3.2 %). All rebounds on monotherapy re-suppressed either spontaneously or with NRTI re-introduction. The PI arm was non-inferior on the primary outcome of loss of future drug options. There were no significant differences in serious disease complications, adverse events, or neurocognitive function between the arms [99].

The PROTEA trial [93] (Table 10.11) randomized 273 patients with HIV-1 RNA <50 copies/mL for over 24 weeks on current ARVs. Patients were switched to DRV/r 800/100 mg once-daily, either as monotherapy or with two NRTIs. Monotherapy showed lower efficacy (86 %) versus triple ART at week 48 (95 %). However, this lower efficacy was seen mainly in patients with CD4 nadir levels below 200 cells/μL. There was no development of PI resistance [93].

The European AIDS Clinical Society guidelines state that PI/r monotherapy with either DRV/r or LPV/r, twice-daily, might represent an option in persons with intolerance to NRTIs or for treatment simplification in substance abusers with documented frequent interruption of combination ART. Such a strategy should only be applied to persons without a history of failure on prior PI-based therapy, who have had a HIV-viral load <50 copies/mL in at least the past 6 months, and who do not have chronic hepatitis B infection [14].

10.4 Future Perspectives

The success of HAART has significantly changed the pattern of HIV infection in developed countries, with the ‘graying’ of the HIV-infected population as an important testament to its success. This has provided new challenges relating to the care of older patients, particularly with regard to the management of comorbidities and ART toxicity, which scientists and physicians are addressing through the refinement of existing ART, the development of new agents, and a growing focus on a more holistic approach to care (involving the integration of concepts from general medicine and geriatrics into HIV care).

It is evident that the management of ART in patients aging with HIV implies a detailed knowledge of patient health in both physical and psychological domains in order to tailor the most appropriate ARV regimen. Therefore, the choice of regimen goes beyond the goal of achieving HIV viral load below the limit of detection and contributes to the overall management of the health profile.

Future research should investigate the association between frailty and ARV choice in people living with HIV. In this context frailty may be useful either as inclusion criteria or as a clinical end point for randomized clinical trials comparing ARV treatment regimens in elderly patients with HIV. This knowledge and experience will likely be extremely useful in the care of older patients.