An update on drug-drug interactions in older adults living with human immunodeficiency virus (HIV)

Abstract

Introduction:

People with HIV are living longer due to advances in antiretroviral therapy. With improved life expectancy comes an increased lifetime risk of comorbid conditions – such as cardiovascular disease and cancer – and polypharmacy. Older adults, particularly those living with HIV, are more vulnerable to drug interactions and adverse effects, resulting in negative health outcomes.

Area covered:

Antiretrovirals are involved in many potential drug interactions with medications used to treat common comorbidities and geriatric conditions in an aging population of people with HIV. We review the mechanisms and management of significant drug-drug interactions involving antiretroviral medications and non-antiretroviral medications commonly used among older people living with HIV. The management of these interactions may require dose adjustments, medication switches to alternatives, enhanced monitoring, and considerations of patient- and disease-specific factors.

Expert opinion:

Clinicians managing comorbid conditions among older people with HIV must be particularly vigilant to side effect profiles, drug-drug interactions, pill burden, and cost when optimizing treatment. To support healthier aging among people living with HIV, there is a growing need for antiretroviral stewardship, multidisciplinary care models, and advances that promote insight into the correlations between an individual, their conditions, and their medications.

1. Aging adults with HIV: a growing demographic

People with HIV (PWH) on effective antiretrovirals (ARVs) are living longer, bringing priority to new and adapted strategies to care for an aging HIV-positive population [1,2]. A recent study estimated the average life expectancy for men and women with HIV starting antiretroviral therapy (ART) in the modern ART era to be 77 years and 79 years, respectively, compared to 80 years and 86 years for men and women in a comparator general population without HIV infection [3]. While there is no consensus for the age that defines ‘older’ people with HIV, we will use 50 years or older to align with the United States Centers of Disease Control and Prevention (CDC) and the cutoffs used in the majority of studies on HIV and aging published to date. However, with gains in life expectancies, the future definition of the term “older” among HIV-positive adults will likely evolve to align with the 60 or 65 years of age used conventionally. People ≥50 years old account for about 16% of new HIV diagnoses in the U.S. in recent years, and comprise 53% of the U.S. population of PWH in 2021 (571,623 PWH ≥50 years with 143,958 aged ≥65 years) [4]. In Sub-Saharan Africa, expanding treatment coverage is predicted to result in a tripling of the HIV-positive population aged ≥50 years, to 9.1 million, by the year 2040 [5].

Older adults are diagnosed at later stages of HIV infection, with higher rates of HIV-related complications [6]. PWH have a higher, and increasing, risk of developing certain comorbidities and experiencing multiple concurrent comorbidities compared to HIV-negative peers, which may be due to HIV-related inflammation and immune activation, higher rates of traditional behavioral risk factors or detrimental social determinants of health, and ART-related effects or drug interactions [7–10]. The result is elevated rates of atherosclerosis and cardiovascular disease, diabetes, end-stage liver disease, and certain malignancies, among other conditions [7,11–14]. These increased comorbidities may lead to further impacts on mental health, frailty, psychosocial stressors, and healthcare needs [15–17].

A higher burden of comorbidities in older PWH increases the risk of polypharmacy, typically defined as the daily use of ≥5 medications. In HIV-positive populations, this is often defined as the simultaneous use of ≥5 non-HIV drugs [18–20]. In a large study of 2018 U.S. medical claims data for PWH and age-matched HIV-negative controls, significantly more PWH had ≥2 documented comorbidities and were receiving ≥5 non-ARV prescriptions, versus controls [20]. Other studies have found similarly high burden of polypharmacy among PWH, particularly at older ages [17,19,21,22]. Polypharmacy has been associated with a myriad of negative health outcomes – from unfavorable patient concerns about HIV treatment and virologic outcomes, to falls, frailty, hospitalization, and death – which may overlap with age-related morbidity [23–30]. While some polypharmacy may be appropriate to manage multimorbidity, inappropriate polypharmacy may be an indicator of fragmented care and improper medication reconciliation, and can lead to excess drug-drug interactions, adherence issues, medication errors and adverse drug events.

Older adults experience greater risks of medication side effects due to altered medication absorption, distribution, and clearance due to physiologic changes such as decreased gastric blood flow, leaner body mass, and declines in renal and hepatic functions [31]. Cognitive, visual, or auditory issues may impact accurate dosing or administration of prescribed medications, especially related to pill size, timing, or food requirements [32]. Compounding this, many ARVs are metabolized by or impact cytochrome P450 (CYP) system enzymes (e.g., CYP3A4, CYP2D6), which are also commonly involved in non-ARV drug metabolism [33]. Potential drug-drug interactions involving ARVs, including those requiring dosing adjustment or switching therapy, are frequent [21,22,34]. A 2022 Danish study reported that 52% of 337 PWH were receiving medications for which dose monitoring or adjustment was indicated due to potential interactions; 4.5% were receiving contraindicated combinations [35].

The American Geriatrics Society has published guidelines (commonly referred to as the Beers Criteria^®) [36] to reduce the overuse of potentially inappropriate medications (PIMs) among older adults, with medications such as anticholinergics, sulfonylureas, and anticoagulants listed with recommendations to avoid or use with extreme caution if no other treatment alternatives are available. Although some HIV treatment guidelines provide in-depth discussion regarding care of older adults living with HIV [37,38], guidance specific to reducing polypharmacy and PIM use in older PWH are not currently available despite studies describing high prevalence of polypharmacy and PIM prescribing in this population [39]. As a result, clinicians must adapt available data and strategies to address potentially inappropriate polypharmacy among their older patients with HIV: Deprescribing of antiretrovirals and non-antiretrovirals, including the use of available tools to identify, reduce, and prevent the use of PIMs; “antiretroviral stewardship” comprised of evidence-based practices to optimize the use of ARVs and reduce medication errors in PWH, particularly among hospitalized patients; and multidisciplinary collaboration that facilitates evaluation of drugs and drug combinations in relationship to patients’ goals of care [40–44]. Barriers to these strategies include patient concerns about medication changes, healthcare providers’ lack of time or specific training, and – an issue that may be prevalent in HIV care settings – a real or perceived lack of healthcare system expertise, staffing, resources, or infrastructure to provide integrated or collaborative care [40,42,43].

Additional barriers to optimally treating older PWH involve knowledge gaps, as older adults are not included or are included at low rates in clinical trials. In a large study establishing the efficacy of daily emtricitabine/tenofovir disoproxil fumarate (F/TDF) – an ARV already being used in HIV treatment – to prevent HIV acquisition in men who have sex with men as pre-exposure prophylaxis (PrEP), only 11% of study participants were over age 40 years and study participants with serious comorbidities or baseline renal dysfunction were excluded [45]. While oral PrEP was groundbreaking, this drug was found to have potential bone and renal toxicity, particularly among older patients, and alternatives to F/TDF remain inaccessible for many due to availability, insurance and cost [46–51]. Similarly, long-acting injectable ARVs present new options for improving ART adherence and tolerability, but an understanding of their unique risks and considerations in older adults are limited by typically younger populations represented in studies [32]. In the phase 2b-3 trials among men who have sex with men and transgender women of long-acting injectable cabotegravir-rilpivirine for HIV maintenance and long-acting injectable cabotegravir for HIV prevention, only 11–26% and 2.7% of participants, respectively, were age ≥50 years [52–54].

This narrative review updates our 2017 review, describing drug interactions and pharmacological issues – including those involving newer ARVs and non-HIV drugs and incorporating recent insights into drug metabolism and transport – among older people with HIV, but may also be relevant for practitioners participating in HIV preventative care for older patients or treatment of PWH of any age [55]. An initial literature review of peer-reviewed publications was performed in PubMed, using keywords “Anti-HIV Agents,” “Pharmacokinetics,” “Aging” and related terms, “Comorbidities,” “Polypharmacy,” “Drug Interactions,” focusing on data published since our prior comprehensive review on this topic. Subsequent queries included multiple Medical Subject Headings (MeSH) search terms related to specific drug classes, agents, and comorbidities. Open-access and subscription online databases and manufacturer-provided product information were used to supplement the literature review for specific interactions. If major guidelines or databases provided discrepant drug-ARV interactions or recommendations, we reported those supported by peer-reviewed reports, for example primary pharmacokinetics/pharmacodynamics in vitro and clinical studies, if available, and/or from ≥2 aligned resources.

The findings in this current review highlight the emerging need for healthcare providers to be vigilant not only for complications involving ARVs, which are known to have a high potential for drug interactions, but also for other issues related to polypharmacy and adverse effects involving non-HIV medications, particularly among older patients. While traditionally, many such issues may have been relegated to primary care and geriatric clinics, there is a growing recognition that with an aging, medically-complex HIV-positive population, new approaches are needed. Integrated and/or collaborative multidisciplinary care models and intentional antiretroviral stewardship are increasingly important tools for improving patient outcomes and safety [42,56,57].

1.1. Mechanisms of HIV antiretroviral drug-drug interactions

Nine ARV drug classes are currently available for HIV treatment. Attachment, post-attachment, entry, and fusion inhibitors act at the initial steps in the HIV life cycle, nucleoside/nucleotide and non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs) target reverse transcription of the viral RNA genome, integrase strand transfer inhibitors (INSTIs) block integration of viral DNA into the host cell DNA, and protease inhibitors (PIs) inhibit cleavage and processing of viral polyproteins. Newer capsid inhibitors target the HIV capsid protein, interfering with both early and late stages of the viral life cycle.

Pharmacokinetic interactions of drug disposition – absorption, distribution, metabolism, and elimination – can lead to alterations in systemic levels of ARV and/or the interacting drug when transport, efflux, or metabolism of one is influenced by the other via common pathways. For an enzymatic pathway, a drug may be a substrate, meaning its levels may be impacted by co-administration with certain other drugs; an inhibitor and/or inducer, causing impacts on metabolism of other substrate drugs; or a combination of these, with the potential for complex bi-directional interactions [58]. Resultant decreased drug levels may impact treatment efficacy, whereas elevated drug levels increase toxicity and side effect potential. The metabolic pathway involved in many clinically significant pharmacokinetic drug-drug interactions is the CYP enzyme system, with common isoenzymes CYP3A4, CYP2B6, CYP2C9, CYP2C19, and CYP2D6. Uridine-diphospho-glucuronosyltransferase (UGT) enzymes in the phase II glucuronidation metabolic pathway are also implicated in ARV drug interactions [59]. Among drug transporters, P-glycoprotein (P-gp) is commonly involved in pharmacokinetic interactions; however, there is an increasing understanding of the role of other drug transporters in ARV drug-drug interactions, such as the breast cancer resistance protein (BCRP), organic anion transporter (OAT), organic cation transporter (OCT), and multidrug and toxin extrusion protein (MATE) [60].

Table 1 lists ARVs currently used, with their associated CYP, UGT, and drug transporter pathways and effects. Generally, NRTIs are not metabolized by CYP and therefore are not expected to be involved in drug interactions through this mechanism, with the exception of zidovudine which is minimally metabolized via CYP. Tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are both pro-drugs of the active form tenofovir (TFV), and both are substrates of BCRP and P-gp transporters. Therefore drugs which inhibit or induce these transporters can, respectively, increase or decrease TDF and TAF absorption and serum concentrations [64,65,92] Additionally, drugs which inhibit or induce, or compete for uptake by, renal transporters OAT and multidrug resistance protein (MRP) can affect TFV elimination [93].

Table 1: Metabolism and elimination of antiretrovirals.

Adapted with permission from Chary et al. [55], © 2017 Informa UK Limited.

Drug Class Generic name (Drug abbreviation)	Reference	Metabolism & Transporter Effects				Elimination/Excretion
		Substrate	Induces	Inhibits	Transporter activity
Nucleoside Reverse Transcriptase Inhibitor (NRTI) a
Abacavir (ABC)	[61]	---	---	---	MRP2 inhibitor	Eliminated through metabolism by alcohol dehydrogenase and glucuronyl transferase
Emtricitabine (FTC)	[62]	---	---	---	---	Principally renal (~86% unchanged, 13% as metabolites)
Lamivudine (3TC)	[63]	---	---	---	MRP2 inhibitor	Active renal secretion via the organic cationic transport (OCT) system
Tenofovir disoproxil fumarate (TDF) and Tenofovir alafenamide (TAF)	[64] [65]	---	---	TDF only: CYP1A2 (minor)	P-gp, BCRP substrate TAF also OATP1B1, OATP1B3 substrate	TDF and TAF are pro-drugs of tenofovir (active form) which is renally eliminated (70–80%) by a combination of glomerular filtration and active tubular secretion
Non-nucleoside Reverse Transcriptase Inhibitor (NNRTI) a
Doravirine (DOR)	[66]	CYP3A	---	---	---	Eliminated primarily through metabolism by CYP3A, 6% excreted as unchanged drug in the urine, and minor excretion of unchanged drug in feces
Efavirenz (EFV)	[67,68]	CYP3A4 CYP2B6	CYP2B6 CYP3A4 CYP2C19	CYP2C9 CYP2C19 CYP3A4	---	Excreted in feces 16–61% (majority unchanged drug) and urine 14–34% (primarily as metabolites)
Etravirine (ETR)	[69]	CYP2C19 CYP2C9 CYP3A4	CYP3A4	CYP2C9 CYP2C19	P-gp inhibitor	Unchanged etravirine mostly excreted in feces (~81–86%), and not detected in urine
Rilpivirine (RPV)	[70]	CYP3A	---	---	---	Mainly excreted via feces (85%). Only trace amounts (<1%) of unchanged rilpivirine found in urine
Protease Inhibitor (PI) a
Atazanavir (ATV)	[71]	CYP3A4	---	CYP3A4 CYP1A2 CYP2C8 CYP2C9 UGT1A1	---	7% is excreted unchanged in urine
Darunavir (DRV)	[72]	CYP3A4	---	CYP3A4 CYP2D6	P-gp substrate & inhibitor	Mostly excreted in feces (79.5%, 41.2% as unchanged drug), ~14% in urine (7.7% as unchanged drug)
Ritonavir (RTV or /r)		See: “Pharmacokinetic Enhancer” section below
Integrase Strand Transfer Inhibitor (INSTI)
Bictegravir (BIC)	[73]	CYP3A UGT1A1	---	---	OCT2, MATE1 inhibitor	35% excreted in urine and 60.3% in feces
Cabotegravir (CAB)	[74,75]	UGT1A1 UGT1A9	---	---	---	Eliminated primarily through metabolism by UGT1A1, and to a minor extent UGT1A9; 0% and 47% are excreted in urine and feces, respectively, as unchanged drug
Dolutegravir (DTG)	[76]	CYP3A UGT1A1 UGT1A3 UGT1A9	---	---	P-gp, BCRP substrate OCT2 inhibitor	53% excreted as unchanged drug in feces; in urine excreted 31% as metabolites and <1% as unchanged drug
Elvitegravir (EVG)	[77,78]	CYP3A4 UGT1A1 UGT1A3	CYP2C9	---	---	95% of dose is recovered in feces, with hepatobiliary excretion; 6.7% excreted in urine
Raltegravir (RAL)	[79]	UGT1A1	---	---	---	Eliminated mainly by metabolism via UGT1A1-mediated glucuronidation in liver. Renal clearance is only a minor pathway
Fusion, Attachment, Post-attachment, Capsid & Entry Inhibitors
Enfuvirtide (T-20)	[80]	---	---	---	---	Primarily eliminated via catabolism to its constituent amino acids
Fostemsavir (FTR)	[81]	CYP3A4		BCRP OATP1B1 OATP1B3	P-gp, BRCP substrate BCRP, OATP1B1, OATP1B3 inhibitor	Fostemsavir is the pro-drug of temsavir (active form); Temsavir is excreted in urine 51% (<2% as unchanged drug) and feces 33% (1.1% as unchanged drug)
Ibalizumab (IBA)	[82,83]	---	---	---	---	As a recombinant humanized monoclonal antibody, thought to be broken down into constituent amino acids without drug-specific renal/hepatic elimination. Per manufacturer, no drug interaction studies conducted, however interactions not expected based on ibalizumab target-mediated distribution.
Lenacapavir (LEN)	[84]	CYP3A UGT1A1	---	CYP3A	P-gp substrate P-gp, BCRP inhibitor	Primarily excreted in feces (76%, 33% as unchanged drug), <1% in urine
Maraviroc (MVC)	[85]	CYP3A	---	---	P-gp substrate	Primarily excreted in feces (76%, 25% as unchanged drug), ~20% in urine (8% as unchanged drug)
Pharmacokinetic Enhancer
Ritonavir (RTV or /r)	[86–89]	CYP1A2 CYP2B6 CYP2D6 CYP3A	CYP1A2 CYP2B6 CYP2C9 CYP2C19 CYP3A4 UGT1A1	CYP2C9 CYP2C19 CYP2D6 CYP3A	P-gp substrate P-gp, BCRP, OATP1B1, OATP1B3, MATE1 inhibitor	11% of dose is excreted into urine
Cobicistatb (COBI or /c)	[88–91]	CYP2D6 CYP3A	---	CYP2D6 CYP3A	P-gp, BCRP, OATP1B1, OATP1B3, MATE1 inhibitor	Mainly excreted in feces (~86%); ~8% excreted in urine

Abbreviations: MRP2: Multi-drug resistance-associated protein 2; UGT: UDP-glucuronosyltransferases; P-gp: P-glycoprotein; BCRP: Breast cancer resistance protein; OATP: organic anion-transporting polypeptide; OCT2: Organic cation transporter 2; MATE: multidrug and toxin extrusion protein

CYP (in bold lettering): major substrate or strong inhibitor/inducer

^aAntiretrovirals not shown due to uncommon use in current clinical practice: didanosine, stavudine, zidovudine; delavirdine, nevirapine; fosamprenavir, indinavir, lopinavir/ritonavir, nelfinavir, saquinavir, tipranavir

^bCobicistat does not have HIV-1 antiretroviral activity; it is used to pharmacokinetically enhance, or “boost,” other antiretroviral drug levels

In contrast, providers must be vigilant for drug interactions involving NNRTI and PI classes. NNRTIs are CYP substrates, affected by strong CYP inducers or inhibitors; aside from rilpivirine and doravirine which are purely CYP substrates, most NNRTIs are also inducers of CYP3A4 and can lower levels of drugs metabolized through this CYP isoenzyme. Efavirenz and etravirine also exhibit inhibitory effects on other CYP isoenzymes (e.g., CYP2C9, CYP2C19). PIs have significant ARV-related drug interactions, as both CYP substrates and potent inhibitors; the most potent PI involved in CYP interactions is ritonavir (RTV).

While RTV has HIV antiviral activity at higher dosages, in current clinical use its pharmacokinetic properties are leveraged using low doses (typically 100–200 mg/day) as a pharmacokinetic “booster” via CYP inhibition to increase systemic levels of a co-administered PI. The non-ARV cobicistat is similarly used in co-formulated ART to “boost” levels of PI or INSTI co-medications via CYP inhibition. While both of these pharmacologic boosters are strong CYP3A inhibitors, they also exhibit different and varying degrees of activity with CYP and UGT isoenzymes as well as transporters, which can result in changes in serum concentrations of other interacting drugs when switching between RTV and cobicistat, or vice versa [87–89,91,94–96]. Table 1 lists the similarities and key differences between RTV and cobicistat, including that cobicistat is a CYP3A and CYP2D6 inhibitor without CYP induction effects, while RTV can inhibit and induce multiple CYP isoenzymes (e.g., CYP3A, CYP2D6, CYP2C9, and CYP2C19) as well as induce UGT1A1 isoenzyme.

Drugs in the INSTI class are UGT substrates to various degrees which makes them susceptible to interactions with strong UGT inhibitors or inducers (e.g., as a UGT1A1 inducer, rifampin can significantly lower serum levels of INSTIs [97]). Additionally, certain INSTIs are CYP3A substrates: bictegravir is equally metabolized by UGT1A1 and CYP3A [73] whereas dolutegravir is primarily metabolized by UGT1A1 with some metabolism contributed by CYP3A [76]. Elvitegravir is a major substrate of CYP3A4 but also exhibits moderate CYP2C9 induction effects [77,78]. Co-formulation with cobicistat “boosts” levels of elvitegravir to therapeutic concentrations, however, additional interactions with other co-administered drugs should be evaluated due to cobicistat’s potent CYP inhibition.

Drugs with novel mechanisms of action have been recently approved primarily for salvage therapy; potential drug interactions are described, but more data may emerge as real-world use and applications broaden. Fostemsavir is an attachment inhibitor approved for use in combination ART for treatment-experienced PWH with multidrug-resistance, an indication of increasing importance when managing older patients who may have long-standing HIV. In fact, older adults comprised 43% of patients in the phase 3 clinical trial leading to its U.S. approval [98]. Fostemsavir is a substrate of CYP3A4, P-gp, and BCRP, and per product labeling should not be co-administered with strong CYP3A4 inducers, though it can be combined with NNRTIs and other weak CYP inducers [99]. Its active moiety inhibits several drug transporters (e.g., OAT, BCRP), so it is expected to impact the plasma concentrations of substrates of these transporters [81]. It has been associated with transaminases elevations, especially in those with hepatitis coinfection, and additional caution should be used if co-administered with other QTc-prolonging medications [97]. Ibalizumab-uiyk, also approved for multidrug-resistant HIV, is a long-acting monoclonal antibody that blocks HIV entry as a post-attachment inhibitor [100]. There are no anticipated drug interactions related to CYP metabolism or drug transporters [82,97,101]. Lenacapavir is a viral capsid inhibitor currently approved for multidrug-resistant HIV, and being studied in co-formulation with other long-acting agents [102]. Administration of lenacapavir with strong CYP3A4 inducers is contraindicated, as lenacapavir is a substrate of CYP3A4 as well as P-gp and UGT1A1. Lenacapavir itself is a moderate inhibitor of CYP3A4, P-gp, and BCRP. It cannot be given with boosted atazanavir or efavirenz, but it can be co-administered with most other ARVs [103]. Due to the long half-lives of lenacapavir and ibalizumab-uiyk, clinicians should be aware that drug levels may persist at clinically significant concentrations even if these drugs were not recently administered or on a patient’s active medication list; vigilance for drug interactions and rigorous medication reconciliation by all involved prescribers is warranted [84].

Extrapolation from other similar structure/class drug studies is often utilized absent direct studies of specific ARV interactions. Clinicians caring for PWH must be knowledgeable about ARV and key non-ARV pharmacokinetics and pharmacodynamics, to anticipate potential interactions and risks in a little-studied population or scenarios. Understanding ARV drug interactions can be supplemented by available electronic databases; since occasional discrepancies (e.g., degree of drug interaction severity) may exist between sources, it is recommended to cross-check at least 2 to 3 databases, in addition to national or society guidelines, and to recognize the limitations of available interaction data [104,105]. Healthcare providers should also be aware that, in some research or drug interaction databases, it may be useful or necessary to query individual components of co-formulated or single-tablet regimen ARV medications (Supplemental Table 1). Subscription drug databases with drug interaction checking platforms include Lexi-Comp^® (http://online.lexi.com) and MICROMEDEX^® (http://www.micromedexsolutions.com). Open-access resources for ARV/non-ARV drug interactions include University of Liverpool HIV Drug Interactions website (http://www.hiv-druginteractions.org), UHN Toronto General Hospital Immunodeficiency Clinic’s Drug Therapy Guide (https://hivclinic.ca/app), and HIV treatment guidelines such as those published by the U.S. Department of Health and Human Services (HHS) [106].

2. Common comorbidities in older PWH and related ARV interactions

For older PWH, drugs related to cardiovascular disease are the most prescribed non-HIV medications, and common comorbidities for which multiple medications may be prescribed also include diabetes, chronic kidney disease, osteoporosis, cancer, and chronic pain. One analysis of enrollees aged ≥65 years in a U.S. medical claims database found that over 50% of PWH were prescribed a drug for dyslipidemia, with antihypertensive agents, antidepressants, gastrointestinal medications, and analgesics also commonly prescribed [17].

2.1. Cardiovascular comorbidities

2.1.1. Cardiovascular medications: drugs used to treat arrhythmias and hypertension

Frequency of arrhythmias among hospitalized PWH increased between 2005 and 2014, with low CD4+ T-cell counts (i.e., <200 cells/mm³) and older age independently associated with some types of arrhythmias like atrial fibrillation [107–109]. Additionally, higher rates of prolonged corrected QT interval (QTc), a risk factor for serious arrhythmia and death, is observed in PWH [110]. Alarmingly, sudden cardiac death (SCD) was found to be the third leading cause of mortality in an urban HIV-positive cohort: those who died from SCD had higher rates of pre-existing cardiac conditions – including hypertension, myocardial infarction (MI) and arrhythmias – than those who died of other causes, highlighting the importance of addressing cardiac conditions [110,111].

Co-administering certain ARVs and antiarrhythmics could result in drug interactions that increase the risk of unintended electrophysiologic changes. Systemic levels of amiodarone may be increased by strong CYP3A4 inhibitors like PIs and cobicistat, enhancing amiodarone’s proarrhythmic effects [112]. Notably, concurrent use of the antiarrhythmic dofetilide with INSTIs dolutegravir or bictegravir is contraindicated due to risk of QTc prolongation and severe/fatal arrhythmias, based on expected increases in dofetilide exposure via INSTI-mediated renal OCT2 transporter inhibition [73,76,113]. Bictegravir also inhibits renal transporter MATE1, which can further affect dofetilide excretion [114].

Notably, certain ARVs such as rilpivirine, efavirenz, lopinavir/ritonavir, and atazanavir can lead to QTc prolongation on their own, often with increased risk at higher doses or when used in combination with other QTc-prolonging agents [97]. The newer antiretroviral fostemsavir has been linked to dose-dependent QTc prolongation, but only at supratherapeutic doses; one modeling study suggested that with approved therapeutic doses, meaningful QTc effects may not occur even when fostemsavir is given with medications that inhibit its metabolism (e.g., CYP3A4, BCRP, and P‐gp inhibitors) and increase exposure to its active moiety [115,116]. In general, heightened consideration of potential QTc effects should be given when these ARVs are co-administered with medications – including other components of the ART regimen – that have the potential to increase plasma concentrations of that ARV or that independently increase risk of prolonged QTc interval/Torsades de Pointes, and when these combinations are given to patients with a history of QTc prolongation or other relevant pre-existing cardiac disease [97,116].

Hypertension is commonly diagnosed among PWH globally [117–119]. Hypertension treatment goals and recommendations are not different based on HIV status, but providers should screen for drug-drug interactions between ARVs and antihypertensives. Given the range of dosing and drug options, antihypertensives can often be dose-adjusted or titrated to effect, or switched to another class, if there is a significant medication interaction with ARVs. In general, diuretics, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs) have minimal-to-no CYP metabolism, so interactions with ARVs that inhibit or induce CYP are not expected. When calcium channel blockers (such as amlodipine and diltiazem) and certain beta blockers (such as metoprolol and propranolol) are used, caution with concurrent CYP inhibitors like PIs and cobicistat should be used as systemic levels of the antihypertensives may increase. A recent review details drug interactions between ARVs and antihypertensives [120]. Newer ARVs approved since its publication include ibalizumab-uiyk and cabotegravir, which are not expected to interact with antihypertensives. Bictegravir, doravirine, and temsavir (of which fostemsavir is a pro-drug) levels may be increased by diltiazem and verapamil, although no ARV dosage adjustments are recommended; and lenacapavir has theoretical bi-directional CYP interactions with verapamil and diltiazem that may result in increased levels of both drugs with unknown clinical significance [106,121].

2.1.2. Cardiovascular medications: drugs used to treat dyslipidemias

In addition to sudden cardiac death, PWH are at higher risk of other cardiovascular events like MI and stroke, with some studies estimating MI risk among PWH to be nearly double that of people without HIV [12]. Mechanisms include age-related factors, specific ARV-related cardiovascular risk, coinfection, dyslipidemia and metabolic disorders, disproportionate rates of cardiovascular behavioral risks like smoking, and HIV-associated inflammation and immune activation [122,123].

Results from the long-awaited REPRIEVE trial in 2023 suggest that many older adults living with HIV – even those not meeting criteria for high atherosclerotic disease risk – should be taking hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors, or statins, to decrease MI and stroke risk [124]. This large clinical trial found that pitavastatin reduced the risk of major adverse cardiovascular events by approximately 35%, compared to placebo, in PWH on ART aged ≥40 years with low-to-moderate Atherosclerotic Cardiovascular Disease risk (ASCVD) risk. Included patients were aged 40–75 years (median 50 years) with 8.7% of patients over 60 years, likely reflecting the study design exclusion of persons with higher ASCVD risk scores, known heart disease, or existing statin use. For included patients ≥60 years, pitavastatin was especially effective, lowering risk major cardiovascular adverse events by 70% (HR 0.30, 95% CI 0.12–0.75). The potential implications of large-scale increases in statin use across multiple HIV-positive populations on rates of statin-related incident diabetes mellitus, side effects, and drug interactions are unknown, as is whether the same results would be seen with different statins [125].

Statins have many potential drug interactions with ARVs. Pitavastatin was chosen for REPRIEVE because of its metabolism via UGT and lack of major ARV interactions, but most other statins are metabolized by CYP enzymes. While PI-based regimens have become less common in favor of INSTIs, CYP3A4-inhibiting PIs and cobicistat may increase statin levels, severe statin toxicity reported [126–130]. In the presence of PIs/cobicistat, lovastatin and simvastatin are contraindicated, and pravastatin should be used with caution particularly when co-administered with boosted darunavir; otherwise clinicians should start statins at the lowest possible dose, titrating up with careful monitoring, and some – like atorvastatin and rosuvastatin – have recommended daily maximum dosages [97,106]. Conversely, certain NNRTIs (i.e., efavirenz and etravirine) exhibit CYP3A4 induction and CYP2C9 inhibition, therefore statins like atorvastatin, lovastatin, and simvastatin may have decreased efficacy, whereas increased fluvastatin exposure could occur via the CYP2C9 pathway [97,106,121]. The NNRTIs doravirine and rilpivirine and INSTIs have no clinically significant statin interactions.

2.1.3. Cardiovascular medications: anticoagulants and antiplatelet agents

Interactions involving anticoagulants are important as they can lead to bleeding or thrombosis risk (see Table 2). Anticoagulants heparin and low-molecular weight heparins (LMWH) do not have expected interactions with ARVs as heparin does not undergo enzymatic degradation and LMWHs like enoxaparin undergo hepatic metabolism via pathways unrelated to CYP [131,132]. Conversely, oral anticoagulants warfarin and direct oral anticoagulants (DOACs), with the exception of dabigatran, undergo extensive CYP metabolism. Of the factor Xa inhibitors (apixaban, edoxaban, rivaroxaban), apixaban and rivaroxaban are major CYP3A4 substrates, leading to significant interactions with PI-, NNRTI-, and cobicistat-containing ARV regimens that inhibit or induce this pathway [133–135]. Additionally, all DOACs including factor Xa inhibitors and dabigatran are P-gp substrates [136].

Table 2.

Anticoagulants and Antiplatelet Interactions with ARVs [97,106,121]

Medication	NRTIs	NNRTIs	PIs	Cobicistat	INSTIs	Lenacapavir
Anticoagulants
Apixaban		↓ Apixaban1	↑ Apixaban2,3,6	↑ Apixaban4,5,6		↑ Apixaban7,8
Dabigatran			↑/↓ Dabigatran3,9	↑ Dabigatran5,9		↑ Dabigatran7,8
Edoxaban			↑ Edoxaban3	↑ Edoxaban5,10		↑ Edoxaban8
Rivaroxaban		↓ Rivaroxaban1	↑ Rivaroxaban2,3	↑ Rivaroxaban4,5		↑ Rivaroxaban7,8,11
Warfarin		↑/↓ Warfarin1,12,13	↑/↓ Warfarin2,13,14	↑ Warfarin4,14		↑ Warfarin7,14
Antiplatelets
Clopidogrel		↓ Clopidogrel15,16	↓ Clopidogrel2,16	↓ Clopidogrel5,16		↓ Clopidogrel7,16
Prasugrel			↓ Prasugrel2,17	↓ Prasugrel5,17
Ticagrelor		↓Ticagrelor1	↑ Ticagrelor2	↑ Ticagrelor4		↑ Ticagrelor7

Legend:*

= Avoid = Consider dose modification or close monitoring = No known interactions and/or no dose modification recommended

Abbreviations: ARVs: antiretrovirals; NRTI: nucleoside/nucleotide reverse transcriptase inhibitor; NNRTI: non-nucleoside reverse transcriptase inhibitor; PI: protease inhibitor; INSTI: integrase strand transfer inhibitor; /c: cobicistat-boosted; /r: ritonavir-boosted

^*If major databases or guidelines provided discrepant drug-ARV interactions or recommendations: table entry reflects information from ≥2 aligned resources

¹Due to efavirenz, etravirine, and nevirapine CYP3A4 induction

²Due to atazanavir, darunavir, and ritonavir CYP3A4 inhibition

³Due to ritonavir P-gp inhibition

⁴Due to cobicistat CYP3A4 inhibition

⁵Due to cobicistat P-gp inhibition

⁶Do not coadminister PI or cobicistat when lowest dose apixaban 2.5 mg BID is required based on indication/age/renal function; consider 50% apixaban dose reduction for indications/patients normally requiring 5–10mg BID.

⁷Due to lenacapavir CYP3A4 inhibition.

⁸Due to lenacapavir P-gp inhibition.

⁹If dabigatran is coadministered with a pharmacokinetic booster, ritonavir may be preferred due to less clinically significant effects on dabigatran levels compared to cobicistat

¹⁰Edoxaban 30 mg daily recommended when indication is deep vein thrombosis/pulmonary embolism. No dose adjustment recommended for stroke prevention indication.

¹¹Recommend close monitoring for rivaroxaban-related bleeding and adjust rivaroxaban dosage as necessary

¹²Due to efavirenz and etravirine CYP2C9 inhibition

¹³Due to ritonavir CYP2C9 induction

¹⁴Recommend close monitoring of international normalized ratio (INR) +/− warfarin dosage adjustment with: efavirenz, etravirine, nevirapine; atazanavir, darunavir, ritonavir; cobicistat.

¹⁵Due to efavirenz, etravirine CYP2C19 inhibition

¹⁶Decrease in clopidogrel active metabolite results in decreased antiplatelet activity

¹⁷Decrease in prasugrel active metabolite with adequate platelet inhibition observed

CYP3A4-inhibiting PIs and cobicistat significantly increase systemic exposure to factor Xa inhibitors and co-administration with rivaroxaban is not recommended. Apixaban dosage should be reduced by 50% when co-administered, but because even at a reduced dose apixaban anticoagulant effects may still result in bleeding events, concurrent therapy should be avoided in patients who may already require the lowest apixaban dosage [106]. Because edoxaban is a P-gp substrate with some minor metabolism by CYP3A4, interactions with strong P-gp inhibitors such as RTV and cobicistat are likely to bear more clinical significance. Edoxaban has been successfully used with ART regimens consisting of CYP3A4 substrates such as rilpivirine and non-CYP-affecting agents such as raltegravir [135,137]. Although per the product labeling, dose reduction of edoxaban is not necessary with concomitant use, closer monitoring of edoxaban use with P-gp inhibitors, including vigilance for increased bleeding risk, is warranted [135].

Due to mixed data on the safety of dabigatran with CYP inhibitor cobicistat, co-administration can be considered in persons with normal renal function only with vigilant monitoring; however, once-daily RTV appears safe with dabigatran in patients with normal renal function. Based on limited case series, the interaction between RTV and dabigatran appears to be less clinically significant compared to cobicistat with concurrent dabigatran; therefore RTV may be preferred over cobicistat if dabigatran must be co-administered with a boosted ART regimen [138–141].

Warfarin is a racemic mixture of its R-enantiomer, primarily metabolized by CYP1A2 and CYP3A4, and S-enantiomer, primarily metabolized by CYP2C9 and roughly 5 times more potent, meaning inhibition or induction of CYP2C9 can have greater potential impact on warfarin’s anticoagulant effect than those impacting R-enantiomer metabolism [142,143]. Although both ritonavir and cobicistat inhibit CYP3A4, which – in isolation – could potentially increase warfarin concentrations, RTV exhibits additional CYP2C9 induction effects that may actually result in a net decrease in warfarin levels. Conversely, in patients on stable warfarin therapy, a switch from RTV-boosted to cobicistat-boosted ART may result in higher international normalized ratio (INR) and bleeding time, so warfarin dose adjustments may be necessary even when making seemingly minor ART “booster” changes [88,144].

Potential interactions involving concomitant ARVs and antiplatelet agents have been identified in in vitro studies despite limited clinical outcomes data. Clopidogrel is a prodrug that requires activation primarily via CYP3A and CYP2C19 while prasugrel is less dependent on CYP for activation, undergoing initial hydrolysis then oxidation by CYP3A and CYP2B6 [145,146]. Co-administration of RTV or cobicistat with clopidogrel led to diminished antiplatelet effect in limited clinical studies, whereas no similar decrease in antiplatelet activity was seen with prasugrel co-administration, leading to the recommendation of prasugrel as the preferred antiplatelet agent in the presence of RTV- or cobicistat-boosted ART unless other clinical patient-specific considerations are present [121,147]. Finally, ticagrelor is not a prodrug but is metabolized by CYP3A, and concurrent administration with RTV is contraindicated due to potential increases in ticagrelor levels; however, more research is needed on the option of dose-reduction of ticagrelor in patients taking RTV [148,149].

2.2. Diabetes mellitus, type 2

The prevalence of diabetes mellitus type 2 (DM2) is 10–14% among PWH, nearly double that seen in the general population (5–8%) [13,150]. The American Diabetes Association (ADA) recommends screening all PWH for diabetes, with repeat testing in 3–6 months if the result is near the margin threshold; there is no separate HIV-specific guidance for diabetes management from the ADA [151]. Notably, clinicians should be aware hemoglobin A1c may underestimate average blood glucose levels in PWH [152–154]. Factors associated with higher rates of diabetes in PWH include age-related metabolic changes, lifestyle factors, comedications and comorbidities associated with insulin resistance, HIV-associated chronic inflammation, and the obesity epidemic currently reported [13,150]. PIs and, to a lesser extent, INSTIs are associated with a risk of insulin resistance, hyperglycemia, and incident diabetes; additionally, use of PIs, INSTI dolutegravir, and NRTI tenofovir alafenamide are associated with weight gain [155–157]. Statins may further increase risk for diabetes in older PWH [125].

2.2.1. Diabetes medications: metformin

Metformin is a common first-line medication for pre-diabetes or diabetes, and metformin and rosiglitazone may be used for HIV-associated lipodystrophy [158–160]. Metformin-associated lactic acidosis is a rare but life-threatening adverse drug effect; while co-administration with ARVs or other drugs that increase metformin levels could increase risk of this complication, it is usually observed only with very high doses or overdoses, and in the setting of predisposing factors including renal insufficiency, hepatic or cardiac failure, or sepsis [161–163]. Metformin must be renally dosed, with both HIV and DM2 conferring increased CKD risk. Metformin has interactions with the INSTIs dolutegravir and bictegravir, via their inhibition of OCT2 and MATE1 transport lowering renal clearance of metformin [97]. U.S. guidelines recommend starting metformin at the lowest dose when co-administering with dolutegravir and monitoring for adverse events of metformin with either INSTI [164]. Additionally, metformin may decrease the serum concentration of the NNRTI doravirine but no dose adjustment is required [68].

2.2.2. Diabetes medications: GLP-1 and SGLT2 inhibitors

Semaglutide, liraglutide, and tirzepatide are glucagon-like peptide 1 (GLP-1) receptor agonists used for management of diabetes and weight loss [165]. None of the GLP-1 receptor agonists are expected to have direct drug interactions with antiretrovirals. Notably, in the SUSTAIN 1–5 trials for approval of semaglutide, similar efficacy was seen when comparing patients ≥65 years old to younger patients, although elderly patients experienced more adverse events, primarily gastrointestinal, with higher discontinuation rates [166].

The SGLT2 inhibitor empagliflozin has no known drug interactions with ARVs, whereas RTV and rifampin may decrease concentrations of the SGLT-2 inhibitor canagliflozin due to induction of UGT enzymes (e.g., UGT1A9, 2B4) and canagliflozin dosage adjustment may be warranted [97]. SGLT2 inhibitors carry increased risk of kidney injury and urinary tract infections, thus close monitoring of renal function is recommended, particularly in older patients with pre-existing renal insufficiency or concurrent nephrotoxic medications. Our prior review discusses interactions with sulfonylureas and DPP4-inhibitors [55].

2.3. Neurologic disorders

Older PWH encounter an array of neurologic conditions, including dementia and cognitive decline, headaches, stroke, and seizures, which may be related to structural lesions or opportunistic infection [167–169]. Although detailed discussion of these is outside the scope of this review, guidance on appropriate use of antiepileptic drugs (AEDs) in older populations is available; clinicians should note that some AEDs are metabolized via CYP2C19 [170,171]. Moreover, some AEDs like carbamazepine and phenytoin are CYP3A4 inducers and are contraindicated with several ARVs – including TAF, and multiple PIs and INSTIs – due to potential for decreased ARV concentrations [97]. Similarly, while headache prevalence among PWH is high and promising newer classes of drugs are available for migraine treatment, many of these rely on CYP3A4 isoenzymes and OATP1B3 transporters, so drug interactions should be checked when co-administering with ARVs [170].

2.3.1. Neurologic disorders: treatments for dementia

While incidence of severe HIV-associated neurocognitive disorder (HAND) has markedly declined among PWH due to effective ART, the global burden of HAND remains high [172]. HAND can progress to dementia and may be difficult to distinguish from Alzheimer’s Dementia (AD), which is typically more progressive [173–175]. Data is lacking regarding the ability of AD medications, like cholinesterase inhibitor donepezil and newer monoclonal antibodies aducanumab and lecanemab, to treat HAND. While all antipsychotics carry a boxed warning about increased mortality among elderly patients with dementia, atypical antipsychotics like quetiapine and newly-approved brexipiprazole may be useful for dementia-related agitation [176]. However, the Beers Criteria^® published by the American Geriatrics Society continue to recommend avoiding quetiapine and other atypical antipsychotics, except under FDA-approved indications such as schizophrenia and bipolar disorder [36]. Metabolized by both CYP3A4 and CYP2D6, brexipiprazole should be significantly dose-modified when co-administered with PIs or cobicistat, or in patients known to be CYP2D6 poor metabolizers [97,177]. Quetiapine co-administration with a strong CYP3A4 inhibitor should similarly be avoided or quetiapine given at one-sixth of the original dose. When either quetiapine or brexipiprazole are given with moderate CYP3A4 inducers efavirenz and etravirine, monitoring for diminished efficacy is needed. Quetiapine can prolong the QTc interval so electrocardiogram monitoring is warranted when co-administered with the NNRTI rilpivirine which can also increase QTc interval [97].

2.3.2. Neurologic disorders: Parkinson’s disease

There is a limited understanding of any linkage between HIV and Parkinson’s Disease (PD), and whether HIV alters risk of PD; parkinsonism can, however, be a manifestation of HIV encephalopathy or HIV-associated dementia [178]. HIV-associated cognitive deficits and PD may even share common underlying mechanisms that could be accelerated by or related to aging [179]. Management of PD often involves dopamimetic drugs such as carbidopa-levodopa, pramipexole, ropinirole and apomorphine; catechol-o-methyl-transferase (COMT) inhibitors tolcapone, opicapone and entacapone; monoamine oxidase type B (MAO-B) inhibitors like rasagiline; and the dopamine promotor amantadine. These medications are generally safe to use with ART and have been reported to be generally well-tolerated [97,180].

2.4. Chronic pain

Pain – and specifically chronic pain, defined as pain lasting longer than 3 consecutive months – is a common comorbidity among PWH, and is estimated to affect up to 90% of PWH [181–187]. Pain, particularly untreated or symptomatic pain syndromes, among PWH has been associated with functional impairment, poor retention in care, decreased ARV adherence and virologic failure [188,189]. Among older PWH, chronic pain is associated with social determinants of health linked with vulnerability, making appropriate pain management critical for older PWH [185,187]. Older age, higher prevalence of substance use and mental health comorbidities, and multifactorial symptoms increase the complexity of pain management in this population [190]. Historically, chronic pain and analgesic use among PWH was tied to sensory neuropathy from early ARVs or AIDS-related complications; however, with advances in ART and the increased life expectancy among ART-treated PWH, chronic pain is increasingly related to other chronic diseases or age-related conditions.

Analgesic use is common among older PWH, and opioids/analgesics are often implicated in drug-drug interactions [191,192]. The Infectious Diseases Society of America (IDSA) has published a clinical practice guideline for the management of chronic pain in PWH, including recommended pharmacologic and non-pharmacologic treatments as well as a recommendation for clinicians to be knowledgeable about – and be prepared to identify, monitor, and manage – common pharmacologic interactions between opioid analgesics and ART [193].

2.4.1. Chronic pain: non-opioid analgesic medications

Recommended non-opioid pharmacologic treatments for non-neuropathic pain include acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDS). While there are few drug-drug interactions involving these medications and ART, chronic NSAID use is associated with gastrointestinal ulcers or bleeding. Concurrent gastric acid-lowering medications – like proton-pump inhibitors (PPI) or histamine H2-receptor antagonists (H2RA) – impact systemic levels of certain ARVs such as PI atazanavir and NNRTI rilpivirine. Chronic NSAID use is also associated with increased blood pressure and renal insufficiency, effects which may overlap with or be exacerbated by renal side effects from other potentially nephrotoxic medications (e.g., tenofovir) and prompt dose adjustments or discontinuation of some ARVs. Chronic or high-dose acetaminophen use requires close monitoring, particularly among PWH at higher risk of hepatotoxicity – such as those with chronic viral hepatitis, alcohol use disorder, or concomitant hepatotoxic medications – and doses should not exceed 2 g/day among people with liver disease; ARVs requiring dose-adjustment in the setting of moderate-to-severe hepatic dysfunction include abacavir and atazanavir [106].

2.4.2. Chronic pain: opioid medications

Opioid analgesics may be utilized as short-term, or second- or third-line treatment, for non-neuropathic pain among PWH, if potential benefits are felt to outweigh risks associated with side effects, misuse, diversion and addiction [193]. PWH are more likely to be prescribed opioids, at higher doses, and experience risk factors for opioid misuse than their HIV-negative counterparts [194–196]. Opioid misuse and even prescription opioid use are associated with adverse outcomes for PWH [197–199]. Both CDC and IDSA clinical practice guidelines for prescribing opioids for pain recommend starting with the lowest effective dose, at the longest effective interval, and using caution when prescribing at any dosage for non-acute pain [193,200]. Older PWH are at an increased risk of medication-related psychotropic effects, due to both polypharmacy and age-related changes in metabolism; this is particularly true with opioids, with adverse effects ranging from increased fall risk, confusion and delirium to apnea and central respiratory depression. Even tramadol, a weak and mixed centrally-acting opioid, has been linked with serotonin syndrome, hypoglycemia, hyponatremia, and treatment-related seizures, as well as increased risk of ER utilization and falls/fractures among older adults [201–205]. Concurrent administration of opioid analgesics with sedative hypnotic or substances (e.g., benzodiazepines, alcohol) may further increase risks of serious adverse effects among older adults.

Metabolism of opioid analgesics and potential complex ARV-opioid drug interactions, primarily involving HIV protease inhibitors and cobicistat, have been extensively reviewed elsewhere [55,206]. Significant interactions between opioids and INSTIs are not expected, whereas dose adjustments or monitoring for opioid-related adverse effects or withdrawal are needed when opioids are co-administered with drugs from PI or NNRTI classes, as well as with pharmacologic boosters.

2.5. Co-infection and antimicrobials

A detailed review of drug-drug interactions involved with opportunistic or other infection treatment in older PWH is outside of the scope of this review, and discussion will be limited to newer drugs and drug interaction data [106]. Interactions between ARVs and antimicrobials are generally low in frequency, but when they occur they have the potential to be high in severity [207]. Prescribers should consult drug interaction databases or HIV guidelines when prescribing antimicrobials to PWH on ART, particularly in the setting of polypharmacy, with attention to not only drug distribution and elimination pathways but also QTc prolongation risk.

2.5.1. Co-infection and antimicrobials: rifamycins

The pharmacokinetics of rifamycins like rifampin – which are used to treat some bacterial infections including mycobacterial disease like tuberculosis – and interactions with newer ARVs are of increasing significance. Rifamycins induce numerous metabolic enzymes and affect several drug transporters, with both rifampin and rifapentine having potent induction effects. In general, rifabutin is a less-potent CYP3A4 inducer, but it is still a CYP3A4 substrate and may be difficult or expensive to obtain as an alternative to rifampin. Overall, co-administration of any rifamycin with ART requires caution and monitoring due to multiple potential interactions and related toxicities.

Tenofovir alafenamide (TAF) is a substrate of transporters which rifampin induces – such as P-gp, BCRP, OATP1B1 – resulting in a lower exposure of TAF. Some studies suggest that co-administration of TAF and rifampin could result in adequate intracellular levels of the active tenofovir metabolite effective in suppressing HIV viral replication, particularly if the dosing frequency of TAF is increased to twice-daily. However, currently co-administration of any rifamycin with TAF is not recommended per product labelling [65,208–210].

Newer INSTIs like dolutegravir, bictegravir, and cabotegravir are also affected by rifamycin co-administration. Currently, dolutegravir 50mg twice-daily is recommended when given concurrently with rifampin, supported by the INSPIRING study [211]. While co-administration of rifampin with dolutegravir dosages of 50mg or 100mg once daily is known to reduce dolutegravir trough concentrations, some studies have preliminarily found that standard dolutegravir dose of 50mg once-daily co-administered with rifampin in PWH may still be effective in achieving virologic suppression [212,213]. A similar study is underway evaluating the safety, efficacy and pharmacokinetics of bictegravir-based ART for treating HIV while on rifampin-based treatment for tuberculosis, but current product labelling states that co-administration of bictegravir (currently available only in the single-tablet co-formulation of bictegravir/emtricitabine/TAF) with rifampin is contraindicated, and co-administration with rifabutin or rifapentine is not recommended [73,214]. Cabotegravir and rifampin or rifapentine co-administration is also contraindicated; rifabutin can be given with cabotegravir oral formulation, but not with co-packaged cabotegravir/rilpivirine injection due to anticipated rifabutin-related decreases in rilpivirine concentration [164]. Given INSTIs are increasingly recommended as a first-line ART for the treatment of HIV infection, and tuberculosis continues to be a leading cause of morbidity and mortality globally among PWH, it is critical that additional studies characterize optimal dosing, long-term safety, and efficacy of newer ARV-rifamycin co-administration.

Overall, in PWH who require treatment for active or latent tuberculosis, clinicians should carefully review treatment guidelines and, particularly with rifamycins, assess for potential contraindicated combinations, drug interactions, and required ARV or rifamycin dose adjustments. Multiple classes of ARVs, including PIs, NNRTIs, INSTIs, fostemsavir and lenacapavir may be affected, particularly by rifampin; while most NRTIs – except TAF – and some entry inhibitors (enfuvirtide, ibalizumab-uiyk) are not expected to have significant drug interactions with these tuberculosis comedications, many commonly-used ARV components that are not contraindicated with rifamycins will require dose modification (e.g., dolutegravir, raltegravir, maraviroc). Clinicians should consider rifabutin as an alternative to rifampin, given its less-potent CYP3A4 induction, particularly with some INSTI (dolutegravir, raltegravir) and RTV-boosted PI regimens; however, dosing of rifabutin, a CYP substrate, may also require dose adjustment with NNRTIs or PIs [164,215].

2.5.2. Co-infection and antimicrobials: antibiotics for sexually transmitted infections

Rising rates of sexually transmitted infections (STIs) among the general population and in PWH have been observed over the past two decades, with incidence of syphilis, chlamydia and gonorrhea increasing in key populations globally [216–218]. STIs also increase the risk of new HIV transmission and acquisition [219,220]. Moreover, STIs can significantly impact health and quality of life, and higher STI rates are observed among PWH compared to their HIV-negative peers [218,221]. While greater STI incidence is typically associated with younger populations, a study of U.S. Veterans found that between 2009 and 2019, rates of syphilis rose disproportionately among those with HIV (mean age at syphilis diagnosis 50 years). While syphilis incidence decreased with older age, the incidence in the lowest-risk (i.e., oldest) group of PWH was still higher than that seen in the highest-risk (i.e., youngest) HIV-negative group [218].

Pharmacokinetic interactions between the antimicrobials used to treat STIs and ARVs are generally infrequent. However, co-administration of ARVs with some antibiotics – including doxycycline, an antibiotic used to treat chlamydia and syphilis but also found to have a potential role in pre-exposure prophylaxis of certain STIs – has been studied [222,223]. NNRTI CYP inducers like etravirine and efavirenz, but not doravirine or rilpivirine, can reduce doxycycline concentrations, as has been demonstrated with other metabolic enzyme inducers. In addition, tetracyclines like doxycycline – and, less commonly, select other antibiotics like clindamycin – have been associated with drug- or pill-induced esophagitis. In addition to discontinuing the offending drug, treatment often includes short-term PPIs and antacids, which can interact with the absorption of certain ARVs as discussed in section 2.11. Caution is recommended when co-administering azithromycin with ARVs that may prolong QTc, such as rilpivirine, which has been shown to prolong the QTc interval in healthy subjects at supratherapeutic doses, and efavirenz, which may be associated with QTc prolongation among those with a genetic CYP2B6 variant [224,225].

2.5.3. Co-infection and antimicrobials: Mpox treatment

Emerging infections have also been associated with sexual contact, including a global outbreak of mpox occurring in 2022; high rates of HIV coinfection among mpox cases were observed in the 2022–2023 outbreak [226–228]. An antiviral developed to treat smallpox (variola) disease in humans, called tecovirimat, has been used globally to treat mpox, within the constraints of varying regulatory protocols and typically in specific patient populations, or with persistent or more symptomatic disease.

Clinicians should use caution when co-administering some ARVs with tecovirimat, though co-administration has not been studied. Tecovirimat is a substrate of UGT isoenzymes (UGT1A1, 1A3 and 1A4); however, co-administration with strong UGT inhibitors or inducers – including RTV – is not expected to significantly impact levels of tecovirimat enough to require dose adjustment, due to additional metabolic pathways. On the other hand, tecovirimat and its metabolite are weak inducers of CYP3A4 and CYP2B6, causing the potential for decreased plasma exposure and efficacy of drugs which are substrates of these isoenzymes, particularly if the substrate is sensitive to CYP induction and/or has a narrow therapeutic window. Rilpivirine exposure, for example, may be reduced by up to 30%; recommendations range from using the combination with caution without dose-adjustment to increasing the dose of oral rilpivirine to 50mg once-daily during co-administration [68,121,229]. For intramuscular (IM) rilpivirine-containing regimens (i.e., cabotegravir/rilpivirine) some experts recommend avoiding new initiation of this ART regimen during and for 2 weeks after the period of tecovirimat administration, or for those who have already received their initial cabotegravir/rilpivirine dose, supplementing with an additional 25mg dose of oral rilpivirine once-daily [230,231]. Similar cautions related to tecovirimat’s weak CYP3A4 induction exist for co-administration with doravirine, darunavir, and maraviroc with no dose adjustments recommended [106,229].

2.5.4. Co-infection and antimicrobials: antifungal agents

While the incidence of opportunistic infection (OI) has declined among PWH in recent decades, OIs including fungal disease remain an important cause of morbidity worldwide in people with advanced HIV and among PWH who are immunosuppressed due to other conditions. Invasive fungal infections (IFI) resistant to available therapies has led to the development of new antifungal medications, including newer triazoles such as posaconazole and isavuconazonium, which are often used as second-line or salvage therapy for IFI. Evolving data may have implications for ARV interactions: among older antifungals, historically amphotericin B deoxycholate or liposomal formulations have been preferred for the initial treatment of diseases like cryptococcosis [230]. A recent phase 3 study demonstrated non-inferiority of single-dose liposomal amphotericin B, combined with flucytosine and fluconazole, for the treatment of HIV-associated cryptococcal meningitis when compared to more prolonged initial treatment courses with amphotericin and flucytosine [232]. Fluconazole is also a mainstay for the prevention (prophylaxis) of cryptococcal disease and the treatment of other common OIs including mucocutaneous candidiasis. Other azoles, and amphotericin, are administered in the treatment of histoplasmosis [230].

Azole antifungals carry a high risk of serious drug-drug interactions. All azoles inhibit CYP isoenzymes (all inhibit CYP3A4, and older triazoles also inhibit CYP2C9 and CYP2C19) and transporters (i.e., fluconazole and isavuconazonium inhibit UGT, and itraconazole and isavuconazonium inhibit P-gp). Itraconazole, voriconazole, and isavuconazonium are also as substrates of CYP isoenzymes [59,124,125]. Further, pharmacogenomic factors impact metabolism of some azoles like voriconazole (related to CYP2C19 polymorphisms), leading to significant variability between individuals in drug serum concentrations and interactions [233]. If an azole is used in a PWH on ART, careful assessment for possible drug-drug interactions must be completed beforehand, and close monitoring for efficacy and toxicity, with therapeutic drug monitoring if appropriate and available, may be needed. Age and some comorbidities – particularly hepatic disorders – can impact the degree and timeline for azole drug interactions, including slower offset of enzyme inhibitory effects, and result in potentially greater risks for toxicity issues with this drug class among older PWH [234].

Other antifungals, such as echinocandins and the synthetic allylamine terbinafine, used for onychomycosis, are expected to have minimal interactions with ARVs. However, it is important to assess for toxicities (e.g., hepatotoxicity) which may overlap with HIV-related conditions or medications with closer monitoring [235].

2.5.5. Co-infection and antimicrobials: COVID-19 treatment

The prevention and management of SARS-CoV-2 infection, or COVID-19, generally does not differ based on HIV status, and every effort should be made to encourage vaccination in PWH to minimize the risk of serious infection. Given several approved and investigational therapies, co-treatment of COVID-19 in PWH requires attention to potential drug interactions, HIV- or age-related comorbidities like renal insufficiency, and overlapping toxicities. One therapeutic option for non-hospitalized people with COVID-19 includes RTV-boosted nirmatrelvir. There are special considerations if the patient is already on RTV- or cobicistat-boosted ART or is on ART that interacts with RTV. PWH on a boosted ART regimen can receive the 5-day course of RTV-boosted nirmatrelvir without any changes to their ART regimen, meaning they can be on two RTV-boosted therapies, or one RTV- and one cobicistat-boosted regimen, for that brief period [236]. When treating COVID-19, it is crucial to avoid altering a patient’s ART without consulting with an HIV specialist, and baseline ART and OI therapies should be continued uninterrupted whenever possible. In PWH on unboosted ART regimens, clinicians should still review potential drug interactions and overlapping toxicities among COVID-19 treatments, ARVs, and other medications.

2.5.6. Co-infection and antimicrobials: hepatitis C virus treatment

Due to the potential detrimental impacts of HIV on the course of chronic hepatitis C virus (HCV) infection, and the morbidity and mortality associated with chronic HCV among PWH, it is a high priority to not only treat all HIV/HCV-coinfected persons with ARVs but also assure that they can successfully complete an HCV antiviral regimen when indicated. The availability of many effective HCV regimens should allow for all coinfected patients to be successfully treated while accounting for drug-drug interactions and overlapping toxicities. Several reviews and guidance documents, in addition to HIV- and HCV-specific interactions checkers can be found to guide the management of HCV in coinfected patients [121,237–240].

Some key HIV antiretroviral-HCV antiviral drug interactions include the potential for ledipasvir and velpatasvir to increase tenofovir levels, thereby increasing risk for nephrotoxicity, when co-administered with TDF due to their P-gp and BCRP transporter inhibition activity; however, concurrent use with TAF is considered a safer option due to generally lower systemic tenofovir levels associated with TAF [240]. RTV- and cobicistat-boosted PIs, as well as cobicistat-boosted elvitegravir, should not be co-administered with elbasvir/grazoprevir due to significant increases in both grazoprevir and elbasvir levels due to PI and booster CYP3A inhibition [121,241]. Co-administration of glecaprevir/pibrentasvir with boosted PIs should be avoided due to significant increases in glecaprevir concentrations, whereas co-administration with boosted-elvitegravir may be considered with close monitoring for hepatotoxicity [121,241]. With NNRTIs efavirenz and etravirine, co-administration with velpatasvir, glecaprevir/pibrentasvir, and elbasvir/grazoprevir is not recommended due to reduction of the HCV antiviral drugs’ levels from NNRTI CYP induction [121,241].

2.6. Chemotherapy and immunotherapy

While rates of AIDS-defining cancers (non-Hodgkin lymphoma, Kaposi sarcoma, cervical cancer) continue to decline, older PWH are facing higher rates for non-AIDS-defining cancer (NADC) such as liver and anal cancers and Hodgkin lymphoma [14,242]. This is likely due to an altered immune system, higher prevalence of oncogenic viruses such as HPV, higher rates of tobacco and alcohol use, and disparities in cancer screening [243]. A 2018 analysis of PWH in the U.S. estimated continued increases in NADC between 2010 and 2030 [244].

The 2018 National Comprehensive Cancer Network (NCCN) guidelines for Cancer in People Living with HIV highlight that NNRTIs, PIs, and boosters such as cobicistat and RTV have the highest drug interaction potential with cancer chemotherapy due to CYP3A inhibition or induction [245]. Switching to INSTIs during chemotherapy has been shown to maintain HIV suppression and decrease side effects [246]. Table 3 discusses interactions between co-administered ART and common cancer therapeutics, including immunotherapy. For adjunctive nausea treatment, the antiemetic aprepitant, a substance P/neurokinin 1 receptor antagonist, is a moderate CYP3A4 inhibitor and a weak CYP2C9 inducer, so may interact with some ARVs [97]. Olanzapine is not an inhibitor or inducer of CYP isoenzymes but can prolong QTc and should be used with caution with ARVs such as RTV [97].

Table 3.

Oncology Medication Interactions with ARVs [97,106,121,247]

Chemotherapy	NRTIs	NNRTIs	PIs	Cobicistat	INSTIs	Fostemsavir/Lenacapavir
Abiraterone		↓ Abiraterone1	↑ Abiraterone2	↑ Abiraterone3
Androgen receptor inhibitors (Apalutamide, Enzalutamide)	↑/↓ Tenofovir5	↓ NNRTIs6 ↓ Apalutamide ↓ Enzalutamide	↓ PIs6 ↑ Apalutamide ↑ Enzalutamide	↓ Cobicistat6	↓ INSTIs7	↓ Fostemsavir ↓ Lenacapavir6
Anthracycline (Daunorubicin, Idarubicin, Doxorubicin)		↓ Doxorubicin1	↑ Doxorubicin8	↑ Doxorubicin9		↑Doxorubicin8
Aromatase Inhibitors (Exemestane, Letrozole)		↓ Exemestane1
Bortezomib		↓ Bortezomib1	↑ Bortezomib2	↑ Bortezomib3		↑ Bortezomib4
Checkpoint immunotherapy (Cobimetinib, Pembrolizumab, Nivolumab, Atezolizumab, Ipilimumab, Relatlimab)		↓ Cobimetinib1	↑ Cobimetinib2	↑ Cobimetinib3		↑ Cobimetinib4
Corticosteroids (Dexamethasone, Prednisone)		↓ Rilpivirine10	↓ PIs10	↓ Cobicistat10	↓ Bictegravir10 ↓ Elvitegravir10	↑ Dexamethasone4 ↑ Prednisone4
		↓ NNRTIs10	↑ Dexamethasone2 ↑ Prednisone2	↑ Dexamethasone3 ↑ Prednisone3
		↓ Dexamethasone1 ↓ Prednisone1
Cytarabine
Cyclophosphamide		↑ Cyclophosphamide11	↑ Cyclophosphamide12
Dacarbazine
Epipodophyllo-toxins (Etoposide, Teniposide)		↓ Etoposide1 ↓ Teniposide1	↑ Etoposide13 ↑ Teniposide13	↑ Etoposide14 ↑ Teniposide14
Erlotinib		↓ Erlotinib1	↑ Erlotinib2	↑ Erlotinib3		↑ Erlotinib4
Fluoropyrimidines (Capecitabine, Fluorouracil (5-FU))		↑ QTc prolongation risk with Rilpivirine and Efavirenz				↑ QTc prolongation risk with Fostemsavir
Gemcitabine
Imatinib		↑ NNRTIs15	↑ PIs15	↑ Imatinib3	↑ Elvitegravir15	↑ Imatinib4
		↓ Imatinib1	↑ Imatinib2
Irinotecan		↓ Irinotecan1	↑ Irinotecan16	↑ Irinotecan3		↑ Irinotecan4
Ifosfamide	Monitor for nephrotoxicity (TAF/TDF)	↓ Ifosfamide17	↓ Ifosfamide active metabolites2	↓ Ifosfamide active metabolites3		↓ Ifosfamide active metabolites4
Methotrexate	Monitor for nephrotoxicity (TDF)18
Platin derivatives (Cisplatin, Carboplatin, Oxaliplatin)	Monitor for nephrotoxicity (TDF)	Oxaliplatin: ↑ QTc prolongation risk with Rilpivirine and Efavirenz
Sunitinib		↓ Sunitinib1 ↑ QTc prolongation risk with Rilpivirine and Efavirenz	↑ Sunitinib2	↑ Sunitinib3		↑ Sunitinib4 ↑ QTc prolongation risk with Fostemsavir
Tamoxifen		↓ NNRTIs19 ↓ Tamoxifen1 ↑ QTc prolongation risk with Rilpivirine and Efavirenz	↓ Tamoxifen active metabolites20	↓ Tamoxifen active metabolites20
Taxanes (Paclitaxel, Docetaxel)		↓ Paclitaxel1	↑ Paclitaxel2	↑ Paclitaxel3 ↑ Docetaxel3		↑ Paclitaxel4 ↑ Docetaxel4
			↑ Docetaxel2
Vinca alkaloids (Vincristine, Vinblastine, Vinorelbine)		↓ Vincristine1 ↓ Vinblastine1 ↓ Vinorelbine1	↑ Vincristine2 ↑ Vinblastine2 ↑ Vinorelbine2	↑ Vincristine3 ↑ Vinblastine3 ↑ Vinorelbine3		↑ Vincristine4 ↑ Vinblastine4 ↑ Vinorelbine4

Legend:*

= Avoid = Consider dose modification or close monitoring = No known interactions and/or no dose modification recommended

Abbreviations: ARVs: antiretrovirals; NRTI: nucleoside/nucleotide reverse transcriptase inhibitor; NNRTI: non-nucleoside reverse transcriptase inhibitor; PI: protease inhibitor; INSTI: integrase strand transfer inhibitor; /c: cobicistat-boosted; /r: ritonavir-boosted; TAF: tenofovir alafenamide; TDF: tenofovir disoproxil fumarate

^*If major databases or guidelines provided discrepant drug-ARV interactions or recommendations: table entry reflects information from ≥2 aligned resources

¹Due to CYP3A4 induction by efavirenz andetravirine

²Due to CYP3A4 inhibition by atazanavir, darunavir, and ritonavir

³Due to CYP3A4 inhibition by cobicistat

⁴Due to CYPE3A4 inhibition by lenacapavir

⁵P-gp inducer apalutamide may decrease TAF concentrations; P-gp inhibitor enzalutamide may increase TDF concentrations

⁶Apalutamide/enzalutamide CYP3A4 induction lowers NNRTI/PI/cobicistat/fostemsavir/lenacapavir levels: Generally avoid coadministration

⁷Due to UGT1A1 induction by apalutamide/enzalutamide, and further CYP3A4 induction effects on bictegravir, dolutegravir, and elvitegravir: Generally avoid coadministration. If no alternatives, use higher dolutegravir dose 50mg BID

⁸Due to CYP3A4 inhibition by PIs and lenacapavir and P-gp inhibition by ritonavir. Less interaction with liposomal doxorubicin versus conventional formulation.

⁹Due to CYP3A4 and P-gp inhibition by cobicistat. Less interaction with liposomal doxorubicin versus conventional formulation.

¹⁰Due to dose-dependent dexamethasone CYP3A4 induction: Do not coadminister rilpivirine if >1 dose dexamethasone planned.

¹¹Due to CYP2B6 induction by efavirenz

¹²Unclear mechanism; ritonavir may increase cyclophosphamide active metabolites via CYP2B6 induction

¹³Due to P-gp inhibition by ritonavir; atazanavir and darunavir may further etoposide and teniposide levels via CYP3A4 inhibition.

¹⁴Due to p-glycoprotein inhibition by cobicistat

¹⁵Interaction due to CYP3A4 inhibition by imatinib

¹⁶Due to atazanavir UGT/CYP3A4 inhibition, irinotecan levels may increase: Do not coadminister. Generally avoid coadministration with boosted darunavir; if no alternatives, monitor for irinotecan toxicity

¹⁷Due to CYP3A4 induction by efavirenz and etravirine and increased ifosfamide metabolism causing alterations in therapeutic effects

¹⁸Potential for additive nephrotoxicity; methotrexate and TDF levels may also be affected by competition for OAT-mediated elimination

¹⁹Due to tamoxifen CYP3A4 induction, NNRTI levels may be decreased

²⁰Due to CYP3A4 and CYP2D6 inhibition by PIs/cobicistat causing increased tamoxifen parent compound and decreased tamoxifen active metabolites

For newer checkpoint immunotherapies, interactions with ARVs mainly involve CYP3A4 induction or inhibition. Cobimetinib, which inhibits BRAF pathway – found in melanoma and other cancers – and is metabolized by CYP3A4, is contraindicated with concurrent CYP3A4 inhibitors such as darunavir, RTV, and cobicistat [97]. However, there are no known ARV-immune checkpoint inhibitor interactions for PD-1 inhibitors pembrolizumab and nivolumab, the PD-L1 inhibitor atezolizumab, the CTLA-4 inhibitor ipilimumab, and LAG-3 inhibitor relatlimab [97]. These newer therapies have been used safely and effectively in PWH [248].

2.7. Solid organ transplant

PWH are increasingly experiencing chronic end-organ disease and failure as they age, with 2–4 times higher risk of developing end-stage renal disease (ESRD) compared to those without HIV and significant ESRD- and end-stage liver disease (ESLD)-associated mortality. However, due to growing research demonstrating favorable solid organ transplantation (SOT) outcomes for PWH and global advocacy including the HIV Organ Policy Equity (HOPE) Act in the U.S., PWH are gaining access to SOT [11,249,250].

As seen in Table 4, SOT in PWH involves complex drug interactions. While there are no significant interactions between induction agents and ARVs, calcineurin inhibitors cyclosporine, sirolimus, and tacrolimus are involved in multiple interactions due to CYP3A4 metabolism. Additionally, TDF and TAF – which may be indicated for treatment or prevention of hepatitis B after transplant – and tacrolimus may have overlapping and interacting nephrotoxic effects, while cyclosporine can increase TDF/TAF concentrations via P-gp inhibition [97].

Table 4:

Solid Organ Transplant Medication Interactions with ARVs [97,106,121]

Medication	NRTIs	NNRTIs	PIs	Cobicistat	INSTIs	Fostemsavir/Lenacapavir
Induction
Induction
Alemtuzumab
Basiliximab
Thymoglobulin
Immunosuppressive **
Azathioprine
Everolimus		↓ Everolimus1	↑ Everolimus2	↑ Everolimus2		↑ Everolimus3
Cyclosporine	↑ TAF/TDF4	↓ Cyclosporine5	↑ Cyclosporine6	↑ Cyclosporine6		↑ Cyclosporine3
Mycophenolate
Sirolimus	Monitor for nephrotoxicity (TDF)	↓ Sirolimus5	↑ Sirolimus7	↑ Sirolimus7		↑ Sirolimus3
Tacrolimus	Monitor for nephrotoxicity (TAF/TDF)	↓ Tacrolimus5	↑ Tacrolimus8	↑ Tacrolimus8		↑ Tacrolimus3

Legend:*

= Avoid = Consider dose modification or close monitoring = No known interactions and/or no dose modification recommended

Abbreviations: ARVs: antiretrovirals; NRTI: nucleoside/nucleotide reverse transcriptase inhibitor; NNRTI: non-nucleoside reverse transcriptase inhibitor; PI: protease inhibitor; INSTI: integrase strand transfer inhibitor; /c: cobicistat-boosted; /r: ritonavir-boosted

^*If major databases or guidelines provided discrepant drug-ARV interactions or recommendations: table entry reflects information from ≥2 aligned resources

^**Interactions between ARVs and corticosteroids are listed in Table 3 “Oncology Medication Interactions with ARVs”

¹Due to efavirenz and etravirine CYP3A4 induction

²Due to CYP3A4/P-gp inhibition by PIs/cobicistat: Do not coadminister due to risk of increased everolimus exposure.

³Due to CYP3A4 inhibition by lenacapavir. Magnitude of interaction with everolimus is increased if co-administered with a P-gp inhibitor. Consider dose reduction of immunosuppressive and close monitoring if coadministered.

⁴Due to P-gp inhibition by cyclosporine

⁵Due to CYP3A4 induction by efavirenz and etravirine

⁶Due to CYP3A4 inhibition by PIs/cobicistat: Increased cyclosporine exposure expected, therapeutic drug monitoring recommended.

⁷Due to CYP3A4/P-gp inhibition by PIs/cobicistat: General avoid coadministration. Consider sirolimus dose reduction and close monitoring if coadministered.

⁸Due to CYP3A4/P-gp inhibition by PIs/cobicistat: Consider alternatives; dose reduction of immunosuppressive with close monitoring and therapeutic drug monitoring recommended if coadministered.

Several cohort studies reported higher rates of early rejection in transplant recipients with HIV, with possible causes including increased immune activation and potential drug interactions reducing immunosuppressive levels or under-dosing [11,251]. These results highlight important considerations clinicians must have about peri-transplant medications, particularly in the setting of drugs involving CYP. With broader ART options including INSTIs, drug interactions should play a diminishing role in impacting SOT outcomes.

2.8. Gender health

This section discusses unique considerations regarding women’s health and gender affirming care. A discussion of medications used in men’s health issues, including alpha-1 adrenergic antagonists for benign prostatic hyperplasia and phosphodiesterase-5 inhibitors for erectile dysfunction, and hypothyroidism treatment can be found in our prior review [55].

2.8.1. Gender health: women’s health medications

For older women living with HIV, hormone replacement therapy can interact with ARVs in the PI class. U.S. HIV treatment guidelines note PIs increase concentrations of drosperidone, medroxyprogesterone, and micronized progesterone, with conflicting data regarding whether estrogen levels are increased or decreased [215]. Thus, older women with HIV on PIs should be closely monitored if they choose hormone replacement therapy to manage perimenopausal and menopausal symptoms. Women are also more susceptible to weight gain from ART over time than men [252].

All PWH, but especially women, are at increased risk of osteopenia and osteoporosis. No dosage adjustments or contraindications exist with bisphosphonates, selective estrogen receptor modulators, denosumab, teriparatide, or calcitonin [247]. In addition, switch studies found improvements in bone density when patients were switched from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) [253]. It is also important to remember pill burden when instituting therapy for osteopenia or osteoporosis, for instance recommending a combined vitamin D/calcium formulation instead of separate supplements; please see section 2.11 for discussion of ARV interactions with calcium supplementation.

2.8.2. Gender health: gender-affirming care

Transgender women are at high risk of acquiring HIV infection; with up to 62% prevalence in Black/African American transgender women [254]. Transgender women have lower retention in care, and less HIV viral suppression than men [255]. As transgender individuals have traditionally faced many stigmas from the healthcare system, it is important to use gender-inclusive language in any interaction with the patient, including paper forms, and to provide gender-affirming and non-discriminatory care [38,256]. There is some data to suggest that ART adherence is increased when patients are satisfied with their gender-affirming care [257].

For feminizing therapy, transdermal preparations of estradiol have decreased risk of thromboembolism and are therefore preferred in individuals over 40 years old [258]. Cobicistat likely boosts levels of estradiol due to CYP3A4 inhibition and possibly OATP1B1 inhibition [91,97,259]. There is mixed data regarding whether RTV increases or decreases estradiol levels whereas NNRTIs efavirenz and etravirine decrease estradiol levels due to CYP3A4 induction [97]. Cobicistat likely boosts cyproterone while RTV can decrease levels of cyproterone [97]. Less data is available regarding ARV interactions with progesterone. For masculinizing therapy, there is also less data regarding the interaction between testosterone with ARVs.

2.9. Complementary and alternative medicine

Prevalence of complementary and alternative medicine (CAM) use – which includes herbal and dietary supplements – among PWH ranges from 33% to 90%, depending on the demographic studied [260–265]. Thus, including non-prescription products in medication reconciliation is crucial to recognizing polypharmacy, medication risks and interactions [266–271]. For example, significant interaction concerns exist with concurrent use of St. John’s wort and ARVs metabolized through CYP3A4 enzymes (e.g., NNRTIs, PIs, and INSTIs elvitegravir, bictegravir, and potentially dolutegravir, fostemsavir, lenacapavir) due to St. John’s wort’s CYP induction effects, which can result in significant ARV drug level reductions and increased risk for HIV treatment failure [97,272,273]. This interaction highlights the need for healthcare providers to query and investigate CAM product use among their patients and to assess for potential interactions with ART; additional detailed reviews of interactions involving ARVs and select herbal and dietary supplements have been published elsewhere [272–274]. Although data on drug-herb interactions are generally limited or unstudied, references like the Natural Medicines Comprehensive Database (“NatMed Pro”, TRC Healthcare; https://naturalmedicines.therapeuticresearch.com/) may provide additional insights into potential pharmacokinetic and pharmacodynamic interactions with CAM.

2.10. Substance use disorders

Opioid-, alcohol- and other substance-use disorders (SUDs) are a growing concern among older adults, and diagnosis of substance use disorders may be delayed, missed, or undertreated in older patients, leading to significant medical morbidity [275–278]. Drug interactions between ARVs and SUD treatment medications are described in Table 5. Vigilance for CYP3A4-mediated drug interactions is particularly required when prescribing buprenorphine or methadone for opioid use disorders.

Table 5:

Substance Use Disorder Treatment Interactions with ARVs [97,106,121,279]

Substance	Pharmacologic therapy (line of therapy)	NRTIs	NNRTIs	PIs	Cobicistat	INSTIs	Fostemsavir/ Lenacapavir
Alcohol	Naltrexone (1)
	Acamprosate (2)
Cocaine	Topiramate (1)
	Long-acting dextroamphetamine-amphetamine (2)			↑ Amphetamines1	↑ Amphetamines1
Metham-phetamine	Bupropion with naltrexone		↓ Bupropion2	↓ Bupropion3	↑ Bupropion4
Opioid	Buprenorphine (1)		↓ Buprenorphine5	↓Atazanavir6	↑ Buprenorphine7		↑ Buprenorphine8
				↑Buprenorphine6
	Methadone (2)	↓ Methadone9	↓ Methadone10	↑/↓ Methadone11	↑ Methadone7		↑ Methadone8 ↑ QTc prolongation risk with Fostemsavir

Legend:*

= Avoid = Consider dose modification or close monitoring = No known interactions and/or no dose modification recommended

Abbreviations: (1): First line treatment; (2): Second line treatment; ARVs: antiretrovirals; NRTI: nucleoside/nucleotide reverse transcriptase inhibitor; NNRTI: non-nucleoside reverse transcriptase inhibitor; PI: protease inhibitor; INSTI: integrase strand transfer inhibitor; /c: cobicistat-boosted; /r: ritonavir-boosted

^*If major databases or guidelines provided discrepant drug-ARV interactions or recommendations: table entry reflects information from ≥2 aligned resources

¹Due to CYP2D6 inhibition by darunavir, and to a lesser extent inhibition by ritonavir and cobicistat

²Due to CYP2B6 induction by efavirenz

³Ritonavir CYP2B6 induction may decrease bupropion levels: titrate bupropion based on clinical response

⁴Elvitegravir/cobicistat CYP3A4 inhibition may increase bupropion levels: monitor

⁵Due efavirenz and etravirine CYP3A4 induction

⁶Avoid coadministration of buprenorphine and unboosted atazanavir due to decreases in atazanavir and increases in buprenorphine. When coadministered with boosted PI, monitor for increased or prolonged buprenorphine effects due to PI CYP3A4 inhibition.

⁷Due to cobicistat CYP3A4 inhibition

⁸Due to lenacapavir CYP3A4 inhibition.

⁹Related specifically to abacavir: Limited data suggests abacavir and methadone may mutually decrease levels of the other drug when coadministered

¹⁰Methadone dosage adjustment should be considered with efavirenz. Close monitoring for methadone withdrawal is recommended when initiating etravirine and rilpivirine.

¹¹Ritonavir may decrease methadone via CYP2B6 induction; other PIs likely increase methadone via CYP3A4 inhibition. Monitor as appropriate.

2.11. Gastric acid-lowering agents and polyvalent cations

Gastric acid-lowering agents such as PPIs, H2RAs, and antacids have the potential to impact drug absorption by altering conditions in the gastrointestinal tract. The NNRTI rilpivirine has pH-dependent oral bioavailability. Pharmacokinetic studies have shown that co-administration of omeprazole with oral rilpivirine can cause a 65% decrease in rilpivirine area-under-the-curve (AUC) drug concentration leading to the recommendation to avoid the combination of oral rilpivirine and PPIs. However, this interaction is not present with the injectable form of rilpivirine, which is in the long-acting co-packaged cabotegravir/rilpivirine combination [280,281]. Because H2RAs have a shorter duration of effect on gastric pH, dose separation can avoid the interaction: for example, administration of famotidine 12 hours before or four hours after rilpivirine has been found effective in avoiding the interaction, while administration of famotidine two hours before rilpivirine resulted in a 76% decrease in rilpivirine AUC [282].

The PI atazanavir also requires sufficient gastric acid for absorption and caution is advised with concurrent acid suppressant use. A pharmacokinetic study found rabeprazole given prior to RTV-boosted atazanavir administration resulted in a 70% reduction in atazanavir C_max and AUC [283]. In a separate study of people with HIV, co-administration of low- and high-dose famotidine with RTV-boosted atazanavir resulted in 13% and 23% reduction, respectively, of atazanavir exposure [284].

Multiple over-the-counter drugs for gastrointestinal issues, such as antacids and laxatives, may also contain polyvalent cations (e.g., aluminum, calcium, magnesium). Co-administration with certain medications like INSTIs can lead to chelation and decrease gut absorption, so timed separation of drugs is often recommended [285]. For example, simultaneous administration of bictegravir and antacids containing polyvalent cations decreases bictegravir exposure by almost 80%; when administered 2 hours prior to the antacid, only 13% decrease was observed [73,285,286]. Per guidelines and product labeling, recommendations are to administer bictegravir ≥2 hours before or ≥2 hours (and per some guidelines, ≥6 hours) after antacids or polyvalent cation products containing aluminum, magnesium, or calcium, especially under fasted conditions [73,164]. However, bictegravir may be taken simultaneously with antacids or supplements containing calcium (or supplements containing iron), if taken together with food [73,286]. Our prior review provides additional in-depth discussion of ARV-polyvalent cation interactions and drug-specific recommendations [55].

4. Conclusion

PWH on effective ART are living longer – and are developing attendant comorbidities as they age. HIV care must evolve to address patients’ HIV- and age-related concerns and comorbid conditions – as well as associated risks of polypharmacy, side effects, and drug interactions – through evidence-based medicine and care collaboration. With expertise in ARV metabolic pathways and a foundational knowledge of non-HIV therapeutics, HIV specialists are well-poised to assure awareness, prevention, and management of clinically significant drug interactions to support healthy aging in their older patients.

5. Expert opinion

As described here and by others, people with HIV on combination ART are living longer and aging. Over 50% of PWH in the U.S. are aged ≥50 years, a proportion that is expected to rise to 70% by as early as 2030 [287,288]. Many remain undiagnosed or if diagnosed, not in care or on continuous ART [289]. Globally, goals and strategies have been established to reduce new HIV-associated morbidity and mortality and address barriers in the HIV care continuum [290,291]. These goals are ambitious and target key necessary efforts, but they remain difficult to achieve globally [292].

Additional strategies to prevent or cure HIV infection continue to be explored, but large-scale success remains elusive. Despite over 30 years of research and clinical trials, no approved HIV vaccine exists although efforts have led to expanding knowledge in this field [293]. HIV cure strategies focus on removing integrated HIV from cells and compartments using medications, broadly neutralizing antibodies (bNAbs), CCR5-Δ32 stem cell transplantation, or clustered regularly interspaced short palindromic repeats (CRISPR/Cas9) gene editing technologies [294]. Until further progress is made, ARVs remain the cornerstone for both HIV prevention, by reducing onward HIV transmission and as effective pre-exposure prophylaxis, and treatment.

Over 40 HIV medications and co-formulated products have been approved for HIV treatment. Newer ARVs with novel mechanisms of action have available data on pharmacokinetics and drug disposition from clinical trials, though older PWH are variably represented. Many investigational ARVs fall into existing classes of ART; however, new classes of ARVs such as oral reverse transcriptase translocation inhibitor (NRTTI) islatravir and injectable, long-acting bNAbs which bind to HIV envelope epitopes are currently being studied, in combination with approved agents such as doravirine, lenacapavir or bictegravir [295]. New formulations such as long-acting injectable (LAI) ARVs also continue to be developed.

The impacts of these new ART agents on drug interactions, polypharmacy and adverse events among older HIV-positive adults are unknown. Reformulating conventional ARVs like tenofovir, lamivudine, and dolutegravir as LAI using drug-combination-nanoparticle (DcNP) technology to extend duration of activity could expand available treatment modalities and options to PWH who have difficulty taking daily medications or managing multiple comedications [296]. While LAIs may reduce pill burden and address some barriers to ART adherence experienced by older PWH, they also present unique challenges given long dosing intervals, leading to longer windows for potential drug-drug interactions when new medications are prescribed. They are also unlikely to significantly alter the impacts of polypharmacy and multimorbidity on older PWH. This underscores the need for a robust understanding of LAI and other new agents’ pharmacokinetics and clinical applications in this age group. As new medications enter the market, clinicians and patients will have to consider potential drug-drug interactions, even when there is a paucity of data available for older PWH, people with multiple comorbidities, and other populations typically under-represented in clinical trials. Long-acting agents that are intermittently administered – for example, as LAIs or implantable agents – also pose a potential risk if not accounted for upon medication reconciliation, particularly for patients with fragmented care.

Prospect of novel treatment approaches, while promising, thus also highlight the increasing importance of multidisciplinary HIV care models, together with polypharmacy management and antiretroviral stewardship, as the HIV-positive population ages [32]. Multidisciplinary care models for PWH – which may include collaboration and coordination between clinicians, pharmacists, nurses, psychologists, social workers, and others – not only support medication adherence and safety, but address patients’ holistic needs and goals of health care, which change as people age [38]. Multidisciplinary care models may further provide integration of multiple services and specialties; the opportunities for improved collaboration and communication between prescribers presented by such models have the potential to improve patient engagement, polypharmacy, HIV outcomes, and the management of multimorbidity [43,297,298].

The next frontier in HIV is the advancement of personalized medicine and HIV pharmacogenomics, which studies how a person’s genetic profile or population-level genetic variations can impact the metabolism, transport, tolerability, or efficacy of ARVs. While HLA-B*5701 screening for the risk of abacavir hypersensitivity has been integrated into HIV clinical care for many years, the use of pharmacogenomics in HIV treatment and prevention is a more nascent field. Other areas of medicine have been working to understand how to incorporate pharmacogenetics, typically defined more narrowly as the interactions between variations in a specific gene and an individual’s response to a medication, and pharmacogenomics to tailor treatment with certain medications or medication classes, such as antiplatelet therapy and oncologic agents.

There is a growing body of data providing insight on the role of a person’s genetics in their drug exposure and outcomes with various ARVs, like maraviroc and etravirine, and assessing the impacts of genetic variations in certain genes or proteins on the neuropsychiatric effects of ARVs like efavirenz and dolutegravir [299]. Commercial pharmacogenomics panels testing for multiple alleles, including in CYP2D6 (efavirenz), UGT1A (atazanavir) and HLA-B*5701 (abacavir) genes, are increasingly available in limited healthcare settings. Still, more research on the application and larger-scale clinical implementation of this data is needed. It is also largely unknown how genetics could play a role in the risk of drug-drug interactions among PWH [299]. For an older person with HIV on multiple medications, in an individual with virologic failure for whom a salvage regimen is being considered, or in a person being prescribed a drug with a narrow efficacy or toxicity window, pharmacogenomics to tailor ART regimens may have even greater benefits. As PWH age with more comorbidities, and novel ARVs and drugs for comorbid conditions become available, further data and screening capabilities – together with advancements in therapeutic drug monitoring (TDM) – are needed to identify additional pharmacogenetic/pharmacogenomics targets and their role in clinical HIV care [300]. This understanding could support the development of individualized, optimal selection and dosing of HIV treatment or prevention medications [301].

Supplementary Material

Supplemental Table 1

Supplemental Table 1: Fixed-dose combination antiretrovirals. Adapted with permission from Chary et al. [55] © 2017 Informa UK Limited.

Article highlights.

• Due to advances in highly-effective antiretroviral medications and improved HIV screening, life expectancy for people with HIV (PWH) on treatment has been increasing and now approaches that of the HIV-negative general population.

• With greater life expectancy comes an increasingly older HIV-positive population, with evolving challenges and healthcare needs; the proportion of people with HIV in older age ranges is expected to continue to rise globally over coming decades.

• Older PWH have a higher prevalence and risk of non-HIV-related comorbidities than their age-matched peers, which may include age-related or ‘geriatric’ syndromes and conditions associated with traditional risk factors, such as cardiovascular disease, diabetes mellitus, end-stage renal disease, malignancy, chronic and liver disease, certain sexually transmitted infections, and substance use disorders.

• Healthcare practitioners and their patients must be prepared to face the increasing role that comorbid conditions, including multiple concurrent comorbidities called “multimorbidity,” will play in the practical management of HIV, particular among older PWH.

• Polypharmacy is highly prevalent among older PWH, often related to long-term management of HIV and concurrent comorbid conditions, and contributes to morbidity and mortality in older persons due to drug-drug interactions, potentially inappropriate medications or dosages, and other unintended side effects.

• This review highlights many drug-drug interactions in older PWH that clinicians should be aware of when caring for this vulnerable patient demographic, with reference to additional resources that can be used at the point of care.

Common acronyms and initialisms used

ADE

Adverse drug event

ARV

Antiretroviral

ART

Antiretroviral therapy

BCRP

Breast cancer resistance protein (drug transporter)

CDC

Centers for Disease Control and Prevention (United States)

CYP

Cytochrome P450 (enzyme; e.g., CYP3A4, CYP2D6)

HHS

U.S. Department of Health and Human Services

EMA

European Medicines Agency (European Union)

FDA

Food and Drug Administration (United States)

HIV

Human Immunodeficiency Virus

INSTI

Integrase strand transfer inhibitor

LAI

Long-acting injectables

NNRTI

Non-nucleoside reverse transcriptase inhibitor

NRTI

Nucleos(t)ide reverse transcriptase inhibitor

OAT

Organic anion transporter

OCT

Organic cation transporter

P-gp

P-glycoprotein (drug transporter)

PI

Protease inhibitor

PWH

People (living) with HIV

RTV

Ritonavir (protease inhibitor antiretroviral)

STI

Sexually transmitted infection

UGT

Uridine-diphospho-glucuronosyltransferase (enzyme