REVIEW URRENT C OPINION
Emerging concepts on the use of antiretroviral therapy in older adults living with HIV infection Alan Winston a,b and Jonathan Underwood a,b
Purpose of review With the overwhelming success of combination antiretroviral therapy, HIV infection is now a chronic, but manageable, medical condition. Consequently, HIV-infected cohorts are ageing leading to new challenges in the life-long management of this condition. Here, we review recent data concerning the modern treatment of older HIV-infected adults. Recent findings HIV-infected cohorts are ageing with the majority of those infected predicted to be more than 50 years old within the next 2 decades. There is emerging evidence of increased antiretroviral drug exposure in older individuals, but the evidence this leads to increased toxicity is less clear-cut. In addition, the choice of antiretroviral agents is more challenging in older HIV-infected patients because of the presence of comorbidities, which occur more commonly and at a younger age than in HIV-uninfected individuals and because of a higher propensity for drug–drug interactions due to the use of concomitant medications. Specific recommendations regarding antiretroviral treatment of older HIV-infected individuals are lacking and prospective trials in older age groups are urgently needed. Summary The use of antiretroviral therapies in older individuals is complex. Development of novel antiretrovirals and antiretroviral combinations with a low propensity for toxicity, drug–drug interactions and reliable pharmacology regardless of age is urgently needed. Keywords ageing, antiretroviral therapy, comorbidity, HIV infection
INTRODUCTION Although inconceivable just 2 decades ago, life expectancy for people living with HIV infection (PLWH) now approaches that of HIV-uninfected populations [1 ]. This improvement in life expectancy is secondary to the advent of effective antiretroviral therapy that acts by controlling HIV-viral replication and thereby allowing immune recovery and the prevention of HIV-associated disease progression. These extraordinary advances are now leading to novel clinical challenges. Firstly, the demographics of PLWH are changing and for the first time the cohort is ageing, with the number of PLWH in the United Kingdom over the age of 50 years rising from one in eight a decade ago to one in four in 2012. Similar patterns are reported in other European countries, North America and Australasia [2 ]. Secondly, as antiretroviral therapy does not eradicate HIV infection, it is required lifelong with knowledge surrounding the use and the potential &&
&&
complexities of antiretroviral therapy in older individuals lacking. In this article, we review the impact ageing may have on HIV infection and drug metabolism and then consider the implications this may have on the selection of antiretroviral agents in older PLWH.
AGEING WITH HIV INFECTION The ageing process results in defects of both the innate and adaptive immune systems, as well as a
Section of Infectious Diseases, Imperial College London and Department of HIV and GU Medicine, St. Mary’s Hospital, Imperial Healthcare NHS Trust, London, UK b
Correspondence to Dr Alan Winston, Clinical Reader and Consultant Physician, Clinical Trials, Winston-Churchill Wing, St. Mary’s Hospital, Praed Street, London W2 1NY, UK. Tel: +44 20 3312 1603; fax: +44 20 3312 6123; e-mail: [email protected] Curr Opin Infect Dis 2015, 28:17–22 DOI:10.1097/QCO.0000000000000117
0951-7375 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-infectiousdiseases.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
HIV infections and AIDS
KEY POINTS Globally, HIV-infected populations are ageing and comorbidities are becoming more common which may increase the propensity for antiretroviral toxicity. Concomitant medication use is common in older HIVinfected individuals with the proclivity for clinically significant drug–drug interactions higher than in younger individuals. The clinical pharmacology of antiretroviral agents may differ in older patients compared with younger patients. Tailoring antiretroviral therapy to avoid exacerbation of comorbid states, drug–drug interaction and the pharmacological effects of ageing is possible but challenging with the currently available antiretroviral agents. The development of future antiretroviral agents with a low propensity for drug–drug interactions, end-organ toxicity and a lack of pharmacological differences in older patients is urgently needed.
elusive and are likely multifactorial, with many mechanisms proposed including low-level HIV replication despite effective antiretroviral therapy leading to end-organ damage, chronic inflammation, the direct toxicity of antiretroviral drugs, immunesenescence secondary to immune-system damage prior to the initiation of antiretroviral therapy and the presence of traditional risk factors such as smoking and recreational drug use which are highly prevalent in HIV-infected populations. More recently, there has been greater interest in markers of biological ageing such as telomere length. A recent report from South Africa [12 ] found significantly shorter telomeres, a previously validated biomarker of biological ageing, in HIV-infected individuals compared with HIV-uninfected matched controls. Telomere shortening may be due to the inhibition of telomerase, which is itself a reverse transcriptase and is the enzyme responsible for elongating telomeres and maintaining cell viability [13], by HIV nucleoside reverse-transcriptase inhibitors (NRTIs) such as tenofovir [14 ]. Whatever the underlying cause of these comorbidities, their presence poses clinical challenges, as the selection of antiretroviral therapy in an ageing population is complex for several reasons. Firstly, the general clinical pharmacology of many of the currently licensed antiretroviral drugs may differ in older patients compared with younger patients, which may be associated with differences in clinical outcomes. Secondly, end-organ toxicities are a major limitation of the use of several antiretroviral agents. In an older population with more frequent comorbidities, the choice of usable antiretroviral agents quickly becomes limited if clinicians wish to avoid those with a known toxicity that may become exacerbated in comorbid states. Although there are over 25 licensed antiretroviral agents, many of the toxicities are cross-class and therefore the presence of one specific comorbidity may limit the use of numerous drugs. Thirdly, many modern antiretroviral drugs are prone to drug–drug interactions due to their metabolic pathways. In populations receiving numerous concomitant medications for the management of other conditions, again the choice of suitable antiretroviral agents rapidly becomes difficult. &
&&
the interface between them, with several abnormalities in T-cell function described [3]. Comorbid chronic illnesses exacerbate these changes, which are probably responsible for some of the dramatic increases in infection rates reported in older individuals [4]. Perhaps unsurprisingly, without antiretroviral therapy, accelerated HIV disease progression is reported in older individuals which is associated with higher HIV viral loads, a more rapid CD4 cell decline and a greater risk of AIDS-defining illnesses [5,6]. Age also impacts on the correlation between CD4 cell loss and markers of disease progression such as lower haemoglobin and plasma albumin [7 ]. In the setting of effective antiretroviral therapy, AIDS-defining conditions have become increasingly rare in PLWH; however, the presence of noninfectious or non-AIDS-related comorbidities has become increasingly prevalent [8 ]. Many of these comorbid conditions are those associated with ageing, such as cardiovascular disease, cognitive impairment, renal insufficiency, reduced bone mineral density and diabetes which appear to occur more frequently and at an earlier age in PLWH compared with comparative populations [9]. For some comorbidities, an increased prevalence is only evident in older patients. When compared to a matched control population, a recent study has reported reductions in bone mineral density to only be present in PLWH over the age of 40 years [10 ]. A recent study has also reported that the ‘frailty’ phenotype is more common in those with HIV infection [11 ]. The pathogenic mechanisms underlying this accelerated ageing phenotype remain &
&&
&&
&
18
www.co-infectiousdiseases.com
Ageing and clinical pharmacology Drug exposure, treatment outcomes and drugassociated toxicities may differ in older versus younger individuals. Regarding drug handling by the human body, older patients may experience changes in drug exposure as several elements of drug pharmacokinetics are affected, including Volume 28 Number 1 February 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Ageing and antiretroviral therapy Winston and Underwood
changes in absorption, distribution, metabolism and elimination. Data from several other disease areas suggest that such changes may be of clinical relevance. In general, in older patients, slower metabolism of some drugs has been reported and therefore lower doses may be required to achieve therapeutic efficacy. Furthermore, adverse events have been reported at lower concentrations and more frequently when compared with younger patients. Specific examples include the use of antiarrhythmic agents [15] and antiepileptic agents [16] whereby plasma exposure of specific agents (here referenced digoxin and lamotrigine, respectively) has been reported to be greater in older patients compared with younger patients and drug-related toxicities more frequently observed.
SPECIFIC CONSIDERATIONS FOR ANTIRETROVIRAL AGENTS IN OLDER PATIENTS All the key elements of drug pharmacokinetics (absorption, distribution, metabolism and elimination) are relevant to the antiretroviral agents in current clinical use and may have implications for their use in older individuals [17 ]. See Table 1 for a summary of potential changes and their potential impact on antiretroviral drug exposure.
Table 1. Age-related changes in drug pharmacokinetics and potential effects on antiretroviral drugs Potential age related changes to pharmacokinetic characteristics and potential effects on plasma drug exposure Liberation & Absorption (Absorption rate, bioavailability)
Distribution (volume of distribution)
gastric pH
albumin
gastric emptying
body fat %
GI p-gp and CYP activity
lean muscle %
/
PIs
PIs
rilpivirine
NNRTIs
maraviroc
Maraviroc INSTIs
Metabolism (clearance)
Excretion (clearance)
albumin liver mass
renal function
hepatic CYP activity PIs NNRTIs Maraviroc
NRTIs (particularly tenofovir)
&&
Antiretroviral clinical pharmacology Regarding absorption, many antiretroviral drugs require an acidic gastric environment for optimal absorption. This includes some of the protease inhibitors (saquinavir, indinavir and atazanavir) and the nonnucleoside reverse-transcriptase inhibitors (NNRTIs: rilprivirine). Although gastric acidity may itself not substantially change physiologically with age, the use of drugs to lower gastric acidity is reported to be more frequent in older PLWH [18] and therefore this potential interaction is likely to have greater clinical relevance. Age-associated delayed gastric-emptying, decreased gastrointestinal motility and reduced intestinal enzymatic (e.g., cytochrome P450 3A4) and transport protein (e.g., p-glycoprotein) activity all have potentially complex interactions with antiretroviral drugs. The term ‘drug distribution’ encompasses the delivery of a drug within the plasma compartment and also within other body compartments, known as sanctuary sites. With regards to the plasma compartment, body fat composition is a major determinant of a drug’s distribution. Reduction and abnormalities in the distribution of body fat composition are well described in chronic HIV disease which are thought to be secondary to the underlying diseases process itself (due to changes
INSTIs In this column the probable clinical relevance is indicated by: likely to be significant; possibly significant; no asterisks indicate a theoretical but probably clinically insignificant effect. CYP, cytochrome P450 enzymes; GI, gastrointestinal; INSTIs, integrase strand transfer inhibitors; NNRTIs, non-nucleoside reverse-transcriptase inhibitors; NRTIs, nucleoside reverse-transcriptase inhibitors; p-gp, p-glycoprotein; PIs, protease inhibitors.
in lipid metabolism or secondary to weight loss in untreated HIV disease) and are also associated with specific antiretroviral agents (e.g., zidovudine therapy, although the use of such agents is now limited due to these toxicities). However, the legacy effects of alterations in body fat composition from historical antiretroviral use in previous decades, along with the physiological effects on loss of body fat with ageing, could theoretically lead to alterations in drug handling in older PLWH. In recent years, a great deal of attention has been focused on the exposure of antiretroviral agents in sanctuary sites. Specific areas of interest include the genital tract and the central nervous system (CNS). The implication of low drug exposure in the genital tract is the risk of incomplete suppression of HIV replication, which potentially increases the risk of onward transmission of HIV infection through sexual exposure. Given that physiological changes occur within the genital tract with ageing, there is a theoretical concern antiretroviral drug exposure could differ with age; however, to our knowledge, there are no reports assessing genital tract exposure
0951-7375 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-infectiousdiseases.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
19
HIV infections and AIDS
of antiretroviral agents in younger versus older PLWH. This may be potentially important and warrants further study given reports of high-risk sexual behaviour in older men both with, and at risk of developing, HIV infection [19]. Exposure of antiretroviral agents within the CNS is complex. Low drug concentrations could be associated with HIV-viral replication within this site and ensuing HIV-associated CNS disease, whereas high drug concentrations could be associated with neuronal toxicities potentially leading to clinical CNS toxicity. Drug concentrations within the CNS compartment may be dependent on transmembrane transporters such as p-glycoprotein, the activity of which may wane physiologically with ageing. One study reported that age was the most influential factor of the cerebrospinal fluid exposure of antiretroviral drugs [20]. In general, greater exposure was observed in the cerebrospinal fluid of older individuals, in keeping with the hypothesis that p-glycoprotein function may be diminished; however, the effects seen varied dramatically between specific drugs. The effects of age on the metabolism of a drug could vary depending on the mechanism of the metabolism of specific agents. The activity of the hepatic cytochrome P450 isoenzymes may diminish with age; therefore, drugs metabolized via this route (e.g., protease inhibitors and NNRTIs) may be prone to increased exposure with age. Conversely, drugs metabolized via other metabolic pathways, such as glucuronidation (e.g., raltegravir), which may vary less with age, may be less prone to such interactions. Some reports have suggested that these effects may be of clinical relevance. In one study assessing antiretroviral drug exposure from routine clinical therapeutic drug monitoring in the United Kingdom [21 ], increased exposure of the HIV protease inhibitors was associated with older age, whereas changes in the exposure of other classes of antiretroviral agents were not observed to be associated with age. Given that the metabolism of the HIV protease inhibitors is highly dependent on the hepatic cytochrome P450 isoenzymes, this finding would be in keeping with the above hypothesis. However, although the increased exposure of the HIV protease inhibitors with age was highly statistically significant, whether this has any clinical relevance remains unknown. Similar findings have been reported within a pharmacokinetic study assessing the HIV protease inhibitor lopinavir/ritonavir in older and younger PLWH in whom greater lopinavir exposure and reduced lopinavir clearance was associated with increasing age [22]. Raltegravir, an HIV integrase inhibitor, is predominantly metabolized via glucuronidation and &
20
www.co-infectiousdiseases.com
therefore differences in exposure in older PLWH, based on its metabolic pathway, would not theoretically be expected. In a small pharmacokinetic study assessing the exposure of raltegravir in PLWH over the age of 60 years, no differences in raltegravir exposure were observed compared with younger PLWH [23]. Elimination routes of antiretroviral agents differ for different drugs and classes with elimination routes including faecal elimination for the HIV protease inhibitors and renal elimination for the nucleotide reverse-transcriptase inhibitors, particularly tenofovir. As renal function declines with age, one could expect reduced elimination and greater exposure of tenofovir in older patients. A pharmacokinetic study in HIV-infected women has suggested this to be the case, in which increasing age and decreasing BMI was reported to be associated with increased plasma tenofovir exposure [24 ]. This may have deleterious consequences on renal function and bone mineral density in a group already at risk of renal and bone toxicity. &&
Pharmacodynamic effects of antiretroviral therapy in older patients Treatment outcomes, with respect to virological control, are reported, in general, to be good in older PLWH with rates of achievement of suppression of HIV viraemia even greater than in younger PLWH [25]. This may be due to greater compliance with therapy in older individuals. However, not all treatment outcomes are better when compared with younger individuals with poorer immunological responses to therapy well described [26] and increased rates of antiretroviral discontinuation due to toxicities reported for older patients [27]. The underlying reasons for increased toxicity and higher rates of antiretroviral treatment discontinuation in older patients have not been well described. Although one may postulate these could be due to differences in plasma drug exposure or due to end-organ toxicity in patients with comorbid conditions, such data do not exist.
Drug–drug interactions The Swiss HIV cohort is the largest study assessing the use of concomitant medication and the potential for drug–drug interactions with antiretroviral agents in older patients [18]. In this study, the authors reviewed drug prescriptions administered to almost 1500 PLWH (1020 age >50). Not surprisingly, older patients were more likely to receive one or more concomitant medication compared with younger patients but also had a higher risk of being Volume 28 Number 1 February 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Ageing and antiretroviral therapy Winston and Underwood
administered a concomitant medication in which a drug–drug interaction of clinical significance was considered likely to occur (51% versus 35% for older and younger patients, respectively). However, no differences in tolerability or antiretroviral treatment success were noted within this study. A more recent study of PLWH aged over 60 showed substantially higher medication issues than the HIV-uninfected, matched controls [28 ]. In summary, the potential for clinically significant drug–drug interactions increases with age; however, no reports have described whether clinically significant sequelae arising from such interactions are more likely to be encountered in older patients compared with younger patients. &
When to start treatment Guidance for the initiation of antiretroviral therapy differs by country and organization. The WHO strongly recommends initiation of antiretroviral in all those with CD4 T-lymphocyte counts of less than 500 cells/ml [29]. In contrast, the International Antiviral Society USA [30] and the British HIV Association [31] recommend initiation at more liberal (at any CD4 count) or conservative (
Emerging concepts on the use of antiretroviral therapy in older adults living with HIV infection Alan Winston a,b and Jonathan Underwood a,b
Purpose of review With the overwhelming success of combination antiretroviral therapy, HIV infection is now a chronic, but manageable, medical condition. Consequently, HIV-infected cohorts are ageing leading to new challenges in the life-long management of this condition. Here, we review recent data concerning the modern treatment of older HIV-infected adults. Recent findings HIV-infected cohorts are ageing with the majority of those infected predicted to be more than 50 years old within the next 2 decades. There is emerging evidence of increased antiretroviral drug exposure in older individuals, but the evidence this leads to increased toxicity is less clear-cut. In addition, the choice of antiretroviral agents is more challenging in older HIV-infected patients because of the presence of comorbidities, which occur more commonly and at a younger age than in HIV-uninfected individuals and because of a higher propensity for drug–drug interactions due to the use of concomitant medications. Specific recommendations regarding antiretroviral treatment of older HIV-infected individuals are lacking and prospective trials in older age groups are urgently needed. Summary The use of antiretroviral therapies in older individuals is complex. Development of novel antiretrovirals and antiretroviral combinations with a low propensity for toxicity, drug–drug interactions and reliable pharmacology regardless of age is urgently needed. Keywords ageing, antiretroviral therapy, comorbidity, HIV infection
INTRODUCTION Although inconceivable just 2 decades ago, life expectancy for people living with HIV infection (PLWH) now approaches that of HIV-uninfected populations [1 ]. This improvement in life expectancy is secondary to the advent of effective antiretroviral therapy that acts by controlling HIV-viral replication and thereby allowing immune recovery and the prevention of HIV-associated disease progression. These extraordinary advances are now leading to novel clinical challenges. Firstly, the demographics of PLWH are changing and for the first time the cohort is ageing, with the number of PLWH in the United Kingdom over the age of 50 years rising from one in eight a decade ago to one in four in 2012. Similar patterns are reported in other European countries, North America and Australasia [2 ]. Secondly, as antiretroviral therapy does not eradicate HIV infection, it is required lifelong with knowledge surrounding the use and the potential &&
&&
complexities of antiretroviral therapy in older individuals lacking. In this article, we review the impact ageing may have on HIV infection and drug metabolism and then consider the implications this may have on the selection of antiretroviral agents in older PLWH.
AGEING WITH HIV INFECTION The ageing process results in defects of both the innate and adaptive immune systems, as well as a
Section of Infectious Diseases, Imperial College London and Department of HIV and GU Medicine, St. Mary’s Hospital, Imperial Healthcare NHS Trust, London, UK b
Correspondence to Dr Alan Winston, Clinical Reader and Consultant Physician, Clinical Trials, Winston-Churchill Wing, St. Mary’s Hospital, Praed Street, London W2 1NY, UK. Tel: +44 20 3312 1603; fax: +44 20 3312 6123; e-mail: [email protected] Curr Opin Infect Dis 2015, 28:17–22 DOI:10.1097/QCO.0000000000000117
0951-7375 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-infectiousdiseases.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
HIV infections and AIDS
KEY POINTS Globally, HIV-infected populations are ageing and comorbidities are becoming more common which may increase the propensity for antiretroviral toxicity. Concomitant medication use is common in older HIVinfected individuals with the proclivity for clinically significant drug–drug interactions higher than in younger individuals. The clinical pharmacology of antiretroviral agents may differ in older patients compared with younger patients. Tailoring antiretroviral therapy to avoid exacerbation of comorbid states, drug–drug interaction and the pharmacological effects of ageing is possible but challenging with the currently available antiretroviral agents. The development of future antiretroviral agents with a low propensity for drug–drug interactions, end-organ toxicity and a lack of pharmacological differences in older patients is urgently needed.
elusive and are likely multifactorial, with many mechanisms proposed including low-level HIV replication despite effective antiretroviral therapy leading to end-organ damage, chronic inflammation, the direct toxicity of antiretroviral drugs, immunesenescence secondary to immune-system damage prior to the initiation of antiretroviral therapy and the presence of traditional risk factors such as smoking and recreational drug use which are highly prevalent in HIV-infected populations. More recently, there has been greater interest in markers of biological ageing such as telomere length. A recent report from South Africa [12 ] found significantly shorter telomeres, a previously validated biomarker of biological ageing, in HIV-infected individuals compared with HIV-uninfected matched controls. Telomere shortening may be due to the inhibition of telomerase, which is itself a reverse transcriptase and is the enzyme responsible for elongating telomeres and maintaining cell viability [13], by HIV nucleoside reverse-transcriptase inhibitors (NRTIs) such as tenofovir [14 ]. Whatever the underlying cause of these comorbidities, their presence poses clinical challenges, as the selection of antiretroviral therapy in an ageing population is complex for several reasons. Firstly, the general clinical pharmacology of many of the currently licensed antiretroviral drugs may differ in older patients compared with younger patients, which may be associated with differences in clinical outcomes. Secondly, end-organ toxicities are a major limitation of the use of several antiretroviral agents. In an older population with more frequent comorbidities, the choice of usable antiretroviral agents quickly becomes limited if clinicians wish to avoid those with a known toxicity that may become exacerbated in comorbid states. Although there are over 25 licensed antiretroviral agents, many of the toxicities are cross-class and therefore the presence of one specific comorbidity may limit the use of numerous drugs. Thirdly, many modern antiretroviral drugs are prone to drug–drug interactions due to their metabolic pathways. In populations receiving numerous concomitant medications for the management of other conditions, again the choice of suitable antiretroviral agents rapidly becomes difficult. &
&&
the interface between them, with several abnormalities in T-cell function described [3]. Comorbid chronic illnesses exacerbate these changes, which are probably responsible for some of the dramatic increases in infection rates reported in older individuals [4]. Perhaps unsurprisingly, without antiretroviral therapy, accelerated HIV disease progression is reported in older individuals which is associated with higher HIV viral loads, a more rapid CD4 cell decline and a greater risk of AIDS-defining illnesses [5,6]. Age also impacts on the correlation between CD4 cell loss and markers of disease progression such as lower haemoglobin and plasma albumin [7 ]. In the setting of effective antiretroviral therapy, AIDS-defining conditions have become increasingly rare in PLWH; however, the presence of noninfectious or non-AIDS-related comorbidities has become increasingly prevalent [8 ]. Many of these comorbid conditions are those associated with ageing, such as cardiovascular disease, cognitive impairment, renal insufficiency, reduced bone mineral density and diabetes which appear to occur more frequently and at an earlier age in PLWH compared with comparative populations [9]. For some comorbidities, an increased prevalence is only evident in older patients. When compared to a matched control population, a recent study has reported reductions in bone mineral density to only be present in PLWH over the age of 40 years [10 ]. A recent study has also reported that the ‘frailty’ phenotype is more common in those with HIV infection [11 ]. The pathogenic mechanisms underlying this accelerated ageing phenotype remain &
&&
&&
&
18
www.co-infectiousdiseases.com
Ageing and clinical pharmacology Drug exposure, treatment outcomes and drugassociated toxicities may differ in older versus younger individuals. Regarding drug handling by the human body, older patients may experience changes in drug exposure as several elements of drug pharmacokinetics are affected, including Volume 28 Number 1 February 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Ageing and antiretroviral therapy Winston and Underwood
changes in absorption, distribution, metabolism and elimination. Data from several other disease areas suggest that such changes may be of clinical relevance. In general, in older patients, slower metabolism of some drugs has been reported and therefore lower doses may be required to achieve therapeutic efficacy. Furthermore, adverse events have been reported at lower concentrations and more frequently when compared with younger patients. Specific examples include the use of antiarrhythmic agents [15] and antiepileptic agents [16] whereby plasma exposure of specific agents (here referenced digoxin and lamotrigine, respectively) has been reported to be greater in older patients compared with younger patients and drug-related toxicities more frequently observed.
SPECIFIC CONSIDERATIONS FOR ANTIRETROVIRAL AGENTS IN OLDER PATIENTS All the key elements of drug pharmacokinetics (absorption, distribution, metabolism and elimination) are relevant to the antiretroviral agents in current clinical use and may have implications for their use in older individuals [17 ]. See Table 1 for a summary of potential changes and their potential impact on antiretroviral drug exposure.
Table 1. Age-related changes in drug pharmacokinetics and potential effects on antiretroviral drugs Potential age related changes to pharmacokinetic characteristics and potential effects on plasma drug exposure Liberation & Absorption (Absorption rate, bioavailability)
Distribution (volume of distribution)
gastric pH
albumin
gastric emptying
body fat %
GI p-gp and CYP activity
lean muscle %
/
PIs
PIs
rilpivirine
NNRTIs
maraviroc
Maraviroc INSTIs
Metabolism (clearance)
Excretion (clearance)
albumin liver mass
renal function
hepatic CYP activity PIs NNRTIs Maraviroc
NRTIs (particularly tenofovir)
&&
Antiretroviral clinical pharmacology Regarding absorption, many antiretroviral drugs require an acidic gastric environment for optimal absorption. This includes some of the protease inhibitors (saquinavir, indinavir and atazanavir) and the nonnucleoside reverse-transcriptase inhibitors (NNRTIs: rilprivirine). Although gastric acidity may itself not substantially change physiologically with age, the use of drugs to lower gastric acidity is reported to be more frequent in older PLWH [18] and therefore this potential interaction is likely to have greater clinical relevance. Age-associated delayed gastric-emptying, decreased gastrointestinal motility and reduced intestinal enzymatic (e.g., cytochrome P450 3A4) and transport protein (e.g., p-glycoprotein) activity all have potentially complex interactions with antiretroviral drugs. The term ‘drug distribution’ encompasses the delivery of a drug within the plasma compartment and also within other body compartments, known as sanctuary sites. With regards to the plasma compartment, body fat composition is a major determinant of a drug’s distribution. Reduction and abnormalities in the distribution of body fat composition are well described in chronic HIV disease which are thought to be secondary to the underlying diseases process itself (due to changes
INSTIs In this column the probable clinical relevance is indicated by: likely to be significant; possibly significant; no asterisks indicate a theoretical but probably clinically insignificant effect. CYP, cytochrome P450 enzymes; GI, gastrointestinal; INSTIs, integrase strand transfer inhibitors; NNRTIs, non-nucleoside reverse-transcriptase inhibitors; NRTIs, nucleoside reverse-transcriptase inhibitors; p-gp, p-glycoprotein; PIs, protease inhibitors.
in lipid metabolism or secondary to weight loss in untreated HIV disease) and are also associated with specific antiretroviral agents (e.g., zidovudine therapy, although the use of such agents is now limited due to these toxicities). However, the legacy effects of alterations in body fat composition from historical antiretroviral use in previous decades, along with the physiological effects on loss of body fat with ageing, could theoretically lead to alterations in drug handling in older PLWH. In recent years, a great deal of attention has been focused on the exposure of antiretroviral agents in sanctuary sites. Specific areas of interest include the genital tract and the central nervous system (CNS). The implication of low drug exposure in the genital tract is the risk of incomplete suppression of HIV replication, which potentially increases the risk of onward transmission of HIV infection through sexual exposure. Given that physiological changes occur within the genital tract with ageing, there is a theoretical concern antiretroviral drug exposure could differ with age; however, to our knowledge, there are no reports assessing genital tract exposure
0951-7375 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-infectiousdiseases.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
19
HIV infections and AIDS
of antiretroviral agents in younger versus older PLWH. This may be potentially important and warrants further study given reports of high-risk sexual behaviour in older men both with, and at risk of developing, HIV infection [19]. Exposure of antiretroviral agents within the CNS is complex. Low drug concentrations could be associated with HIV-viral replication within this site and ensuing HIV-associated CNS disease, whereas high drug concentrations could be associated with neuronal toxicities potentially leading to clinical CNS toxicity. Drug concentrations within the CNS compartment may be dependent on transmembrane transporters such as p-glycoprotein, the activity of which may wane physiologically with ageing. One study reported that age was the most influential factor of the cerebrospinal fluid exposure of antiretroviral drugs [20]. In general, greater exposure was observed in the cerebrospinal fluid of older individuals, in keeping with the hypothesis that p-glycoprotein function may be diminished; however, the effects seen varied dramatically between specific drugs. The effects of age on the metabolism of a drug could vary depending on the mechanism of the metabolism of specific agents. The activity of the hepatic cytochrome P450 isoenzymes may diminish with age; therefore, drugs metabolized via this route (e.g., protease inhibitors and NNRTIs) may be prone to increased exposure with age. Conversely, drugs metabolized via other metabolic pathways, such as glucuronidation (e.g., raltegravir), which may vary less with age, may be less prone to such interactions. Some reports have suggested that these effects may be of clinical relevance. In one study assessing antiretroviral drug exposure from routine clinical therapeutic drug monitoring in the United Kingdom [21 ], increased exposure of the HIV protease inhibitors was associated with older age, whereas changes in the exposure of other classes of antiretroviral agents were not observed to be associated with age. Given that the metabolism of the HIV protease inhibitors is highly dependent on the hepatic cytochrome P450 isoenzymes, this finding would be in keeping with the above hypothesis. However, although the increased exposure of the HIV protease inhibitors with age was highly statistically significant, whether this has any clinical relevance remains unknown. Similar findings have been reported within a pharmacokinetic study assessing the HIV protease inhibitor lopinavir/ritonavir in older and younger PLWH in whom greater lopinavir exposure and reduced lopinavir clearance was associated with increasing age [22]. Raltegravir, an HIV integrase inhibitor, is predominantly metabolized via glucuronidation and &
20
www.co-infectiousdiseases.com
therefore differences in exposure in older PLWH, based on its metabolic pathway, would not theoretically be expected. In a small pharmacokinetic study assessing the exposure of raltegravir in PLWH over the age of 60 years, no differences in raltegravir exposure were observed compared with younger PLWH [23]. Elimination routes of antiretroviral agents differ for different drugs and classes with elimination routes including faecal elimination for the HIV protease inhibitors and renal elimination for the nucleotide reverse-transcriptase inhibitors, particularly tenofovir. As renal function declines with age, one could expect reduced elimination and greater exposure of tenofovir in older patients. A pharmacokinetic study in HIV-infected women has suggested this to be the case, in which increasing age and decreasing BMI was reported to be associated with increased plasma tenofovir exposure [24 ]. This may have deleterious consequences on renal function and bone mineral density in a group already at risk of renal and bone toxicity. &&
Pharmacodynamic effects of antiretroviral therapy in older patients Treatment outcomes, with respect to virological control, are reported, in general, to be good in older PLWH with rates of achievement of suppression of HIV viraemia even greater than in younger PLWH [25]. This may be due to greater compliance with therapy in older individuals. However, not all treatment outcomes are better when compared with younger individuals with poorer immunological responses to therapy well described [26] and increased rates of antiretroviral discontinuation due to toxicities reported for older patients [27]. The underlying reasons for increased toxicity and higher rates of antiretroviral treatment discontinuation in older patients have not been well described. Although one may postulate these could be due to differences in plasma drug exposure or due to end-organ toxicity in patients with comorbid conditions, such data do not exist.
Drug–drug interactions The Swiss HIV cohort is the largest study assessing the use of concomitant medication and the potential for drug–drug interactions with antiretroviral agents in older patients [18]. In this study, the authors reviewed drug prescriptions administered to almost 1500 PLWH (1020 age >50). Not surprisingly, older patients were more likely to receive one or more concomitant medication compared with younger patients but also had a higher risk of being Volume 28 Number 1 February 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Ageing and antiretroviral therapy Winston and Underwood
administered a concomitant medication in which a drug–drug interaction of clinical significance was considered likely to occur (51% versus 35% for older and younger patients, respectively). However, no differences in tolerability or antiretroviral treatment success were noted within this study. A more recent study of PLWH aged over 60 showed substantially higher medication issues than the HIV-uninfected, matched controls [28 ]. In summary, the potential for clinically significant drug–drug interactions increases with age; however, no reports have described whether clinically significant sequelae arising from such interactions are more likely to be encountered in older patients compared with younger patients. &
When to start treatment Guidance for the initiation of antiretroviral therapy differs by country and organization. The WHO strongly recommends initiation of antiretroviral in all those with CD4 T-lymphocyte counts of less than 500 cells/ml [29]. In contrast, the International Antiviral Society USA [30] and the British HIV Association [31] recommend initiation at more liberal (at any CD4 count) or conservative (
