Keywords

7.1 Introduction

Treatment of HIV disease has greatly enhanced our understanding of the molecular basis leading to drug-drug interactions. HIV protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs ), critical components of early antiretroviral therapy (ART), are subject to a number of clinically significant drug-drug interactions. Early effective ART consisted of either a PI- or NNRTI-based regimen in combination with two nucleosides. Although effective, these two therapeutic platforms had major drawbacks, which included a large number of pills, multiple daily dosing, intolerance, and significant impact on metabolic clearance. For example, PIs can alter metabolic clearance by both inhibiting a wide variety of cytochrome P450 (CYP) enzymes and inducing the expression of phase II enzymes such as glucuronidation . In contrast, NNRTIs are well-known inducers of CYP450 isoenzymes that increase the clearance of concomitantly administered drugs.

In the past decade, ART regimens have undergone dramatic improvements in terms of tolerability and simplification (given once or twice daily). Two early changes significantly improved ART tolerability and adherence. One was the development of more tolerable agents such as the NNRTI, efavirenz, and PI, atazanavir, with pharmacokinetic (PK) profiles that also permitted once daily administration. The second was a fortuitous discovery that the PI ritonavir (RTV) could prolong systemic PK of a concomitantly administered PI, opening the potential to dose PIs once daily with low doses of RTV. The ability to reduce dosing frequency also improved adherence which ultimately improved clinical outcomes. In addition, the development of new ARVs with increased potency meant lower daily dosages could be used and permitted co-formulation of various individual components into a single pill, more commonly referred to as fixed-dose combination tablets or FDC (Table 7.1).

Table 7.1 Fixed-dose combinations (FDCs) of antiretroviral agents
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More recently, a potent new class of ART, integrase inhibitors (INIs), has set a new standard as the most potent and well-tolerated agents available with a high genetic barrier to resistance. Raltegravir (RAL) was the first INI approved which did not require use of RTV as a pharmacoenhancing agent. Subsequently, elvitegravir (EVG) was co-formulated with the first alternative pharmacokinetic booster, cobicistat (COBI ), to enable once daily dosing. Elvitegravir is available as a complete, single-tablet regimen (STR ) which includes COBI and dual NRTIs, emtricitabine and tenofovir disoproxil fumarate (TDF), in Stribild™ or with another tenofovir prodrug , tenofovir alafenamide (TAF) , in Genvoya™ . Dolutegravir (DTG) is the first second-generation INI with a PK profile that also supports once daily dosing but without the need for pharmacokinetic boosting agents such as RTV and COBI. Dolutegravir has also been co-formulated as a STR with dual NRTIs, lamivudine (3TC) and abacavir (ABC ), in Triumeq™ . Among the recently approved INIs, elvitegravir FDC regimens have similar potential for drug-drug interactions as PIs or NNRTIs , as elvitegravir is a CYP3A substrate co-formulated with a potent CYP3A inhibitor. In contrast, raltegravir and dolutegravir have a lower potential for drug-drug interactions because their metabolic pathway involves glucuronidation and thus have lower propensity for being a victim or perpetrator of drug-drug interactions.

This chapter will make extensive use of tables for reference, while the text will provide historical context and discussions about the molecular basis of drug-drug interactions and address key drug-drug interactions issues with PIs and INIs . Internet websites are continually updated with the latest antiretroviral drug-drug interaction information that may be useful to the reader [1,2,3,4].

7.2 Pharmacology of ART

7.2.1 Protease Inhibitors

PIs were the first class of antiretrovirals to dramatically improve HIV morbidity and mortality [5]. PIs are potent ARVs that exhibit durable antiretroviral suppression and have a high genetic barrier to resistance. To enhance efficacy, PIs are commonly co-administered with other ARV agents from different therapeutic classes to produce additive to synergistic antiviral activity. The introduction of PIs as part of the antiretroviral regimen led to the term, highly active antiretroviral therapy (HAART ), which has since been simplified to antiretroviral therapy (ART). HIV protease inhibitors competitively inhibit HIV protease. PIs are peptidomimetic agents that bind and inhibit viral proteases from liberating the active peptide moieties from a virally produced pro-peptide preventing further viral propagation from infected cells. Numerous PIs have been approved since their introduction in the early 1990s; however, no new agents have been approved in this class since 2006, apart from the new pharmacokinetic boosting agent, cobicistat. Atazanavir, darunavir, and lopinavir are still employed in the treatment of HIV-infected adults and children in combination with a pharmacokinetic enhancer (ritonavir or cobicistat) and other antiretroviral agents, but the use of other HIV PIs has declined.

In general, PIs are large-molecular-weight compounds that often have low water solubility leading to poor oral bioavailability and necessitating large oral doses and concomitant administration of food in many cases to increase bioavailability. Atazanavir has pH-dependent absorption and should be used with caution with gastric-acid modifiers. The majority are highly protein bound and undergo extensive hepatic metabolism via CYP3A and may require multiple daily dosing in the absence of a pharmacoenhancing agent . Hepatic impairment increases PI exposures; however, renal excretion is typically minimal supporting recommendations for no dosage adjustment in renal impairment. PIs are metabolically eliminated by hepatic clearance and are also known to inhibit CYP3A activity or UGT activity [6]. RTV is a potent inhibitor of CYP3A which was a fortuitous discovery that ultimately shifted its use away from a primary ART agent to its use as a low-dose PK-enhancing drug. This boosting effect of RTV was discovered during evaluation of RTV with another PI, saquinavir (SQV ), to determine if the combination could enhance antiretroviral activity. Initially, the reduction of circulating HIV was attributed to synergistic antiviral activity but was later found to be the result of RTV’s ability to prolong the plasma half-life of SQV and increase its total drug exposure. The added antiviral activities were found to be a drug-drug interaction, whereby RTV potently blocked CYP3A4and reduced the metabolic elimination of the co-administered PI. This strategy was later employed to reduce the pill burden and dosing frequency of other PIs such as indinavir (IDV ), lopinavir (LPV ), atazanavir (ATV ), darunavir (DRV ), and tipranavir (TPV ) using much lower doses of RTV that still retained potent CYP inhibition but exerted little antiretroviral activity. The majority of DDI studies with PIs have focused on their ability to act as substrates, inhibitors, or inducers of CYP3A4 and P-gp transport; however, PIs are also known to inhibit active transport processes with the most prominent interactions involving OATPs and OCTs. Key drug-drug interactions with protease inhibitors are summarized in Table 7.2.

Table 7.2 Drug-drug interactions with HIV protease inhibitors
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7.2.2 Integrase Inhibitors

HIV integrase is one of three viral enzymes that are critical for viral replication. Since it is only expressed in virally infected cells, this has been an obvious target to block HIV proliferation and an area of active research for decades. After viral penetration into the host cell and viral DNA replication, the viral DNA integrates into the host genome through a series of DNA cutting and joining reactions. The function of this multipurpose viral enzyme is to remove the 3′-end from the viral DNA to enable the viral DNA strand to be transferred into the host genome. The resultant viral DNA is then joined and inserted into the host genome. After viral DNA insertion, cellular enzymes are activated to repair the single gaps found in the DNA and remove the unpaired nucleotides. HIV integrase inhibitors (INIs) bind to Mg+2 within the enzyme catalytic site to effectively disrupt binding to viral DNA, thus blocking the viral strand transfer step [7].

The HIV integrase strand transfer inhibitor or integrase inhibitor (INSTI or INI) class of drugs includes raltegravir, elvitegravir, and dolutegravir. Their introduction has revolutionized the management of HIV infection for several reasons. They are characterized as among the most potent and efficacious antiretroviral agents as exemplified by an initial rapid achievement of virologic suppression that is durable over time. They exhibit favorable safety and tolerability profiles, have a high genetic barrier to resistance without cross-resistance to other agents, and have manageable drug-drug interaction profiles (Table 7.3). Most are available in fixed-dose combinations (FDC) with other antiretrovirals to constitute a complete, single-tablet regimen that can be administered once daily (Table 7.1). These features explain why these compounds have transformed how HIV is currently being managed.

Table 7.3 Drug-drug interactions with INIs
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7.2.2.1 Raltegravir

Raltegravir (RAL) was the first integrase inhibitor to receive FDA approval for the treatment of HIV. Raltegravir is a small molecule with a beta-diketo acid moiety that selectively inhibits the strand transfer step of viral integration. Its introduction into clinical use was a paradigm changing moment as it was one of the most potent treatment options developed at the time and with a completely new mechanism of action which was especially important for heavily treatment-experienced patients in desperate need for alternative options that were also well tolerated with potential to significantly improve patient adherence.

Raltegravir is approved for twice daily administration (400 mg twice daily) and, more recently, for once daily administration (1200 mg once daily) (Isentress PI). Raltegravir does not require PK boosting with RTV or COBI . It has a low oral bioavailability of 32% with large interindividual variability in exposure. Potential reasons for its high pharmacokinetic variability include whether it is dosed with food, pH-dependent solubility impacting absorption, differences in UGT1A1 expression or polymorphisms, and drug interactions. For example, pharmacokinetic variability increases when RAL is dosed with food, as a high fat meal increased AUC and C max by approximately twofold and increased C12h by 4.1-fold, while T max was delayed for up to 12 h in some healthy volunteers [8]. It has an initial distribution half-life of 1 h, which is followed by a beta terminal half-life that is approximately 9 h. Similar to other INI, raltegravir is eliminated through UGT1A1-mediated metabolism. At clinically achievable concentrations, raltegravir is not a CYP substrate which explains why it has few drug-drug interactions. In addition, raltegravir is not an inhibitor or inducer of CYP expression.

7.2.2.2 Elvitegravir

Elvitegravir (EVG, E) is the second INI that received FDA approval. Similar to raltegravir, EVG is a potent INI with antiviral activity in the subnanomolar range. It is available as a single entity and as part of two complete single-tablet antiretroviral regimens with cobicistat (COBI , C), emtricitabine (FTC, F), and either tenofovir disoproxil fumarate (E/C/F/TDF, Stribild™) or tenofovir alafenamide (E/C/F/TAF, Genvoya™ ). Since its plasma half-life alone is short, it must be co-administered with a pharmacoenhancer like COBI or RTV to prolong the half-life to approximately 9.5 h to permit once daily dosing [9].

Elvitegravir is metabolized primarily via CYP3A4 with a minor component via UDP-glucuronosyltransferase (UGT) 1A1 and 1A3. As stated earlier, EVG requires pharmacoenhancement by COBI and the presence of food to improve its systemic exposure [10]. Thus, EVG-containing regimens are prone to complex drug interactions via CYP3A similar to those observed with PI and NNRTI classes. EVG is a weak inhibitor of P-gp transport; however, COBI and RTV are both clinically relevant P-gp inhibitors. Additionally, EVG and COBI are substrates and inhibitors of the transporters breast cancer resistant protein (BCRP), organic anionic transporter-B1 (OATP1B1), and OATP1B3 [11, 12]. The use of TAF as an alternative to TDF-based fixed-dose combination tablets of EVG does not generally change the overall drug interaction liability of EVG FDC tablets, rather improved reduction in the incidence of TDF-related renal and bone adverse effects has been reported in some studies.

Elvitegravir has a number of clinically relevant drug-drug interactions. Elvitegravir is contraindicated when used with drugs that are dependent on CYP3A-mediated clearance with a narrow therapeutic index (Table 7.3). In particular, EVG is contraindicated when used together with rifamycins like rifampin and rifapentine. Combining EVG with the potent CYP3A inducers, rifapentine or rifampin, will reduce EVG levels below the threshold required for HIV suppression. When elvitegravir has to be used in combination with a rifamycin, rifabutin may be a good alternative in this scenario since this is a weak CYP3A inducer. In healthy volunteers, rifabutin administered at an adjusted dose of 150 mg every other day significantly reduced elvitegravir C min by 67% with concurrent COBI administration [13]. However, doubling the EVG dose to 300 mg once daily and switching the pharmacokinetic booster to low dose RTV mitigate this interaction and permit co-administration with dose-adjusted rifabutin [14]. However, increased monitoring for rifabutin-associated adverse effects is required as a result of increased rifabutin and desacetyl-rifabutin metabolite concentrations with EVG/r co-administration. Other potent CYP3A enzyme inducers should not be co-administered with EVG, regardless if COBI, within fixed dose tablet regimens, or RTV, with boosted PI regimens, is used for pharmacoenchancement.

In treatment-experienced subjects receiving RTV-boosted PIs with atazanavir or lopinavir, the dose of EVG must be reduced as a result of potent UGT1A1 inhibition by these PIs. In healthy volunteers, EVG exposures increased up to 2.8-fold when co-administered with ATV 300 mg/RTV 100 mg daily and increased by 2.3-fold when co-administered with LPV 400 mg/RTV 100 mg twice daily [15]. Thus, concomitant use with these RTV-boosted protease inhibitors requires a dose reduction in EVG from 150 to 85 mg once daily.

Overall, EVG-containing regimens are prone to complex CYP3A-mediated drug interactions similar to those observed with PI and NNRTI classes but unlike other members of the integrase class. EVG is contraindicated for use with drugs dependent on CYP3A-mediated clearance possessing a narrow therapeutic index and drugs with potent CYP3A induction potential. Healthcare providers are advised to evaluate the potential for drug-drug interactions when prescribing EVG-containing regimens due to potent enzyme and transporter inhibition by RTV and COBI .

7.2.2.3 Dolutegravir

Dolutegravir (DTG) is a potent, second-generation INI with antiviral activity against raltegravir- and elvitegravir-resistant virus. It exhibits low to moderate variability in plasma concentrations and does not require COBI or RTV boosting or food for optimal drug exposures. DTG is available as a single entity and as a component of a STR (Triumeq™ ) which is combined with two nucleosides abacavir (ABC ) and lamivudine (3TC) (Table 7.1).

DTG is primarily metabolized by UGT 1A1 with a minor contribution from CYP3A4 and has a favorable drug interaction profile similar to raltegravir, which also undergoes glucuronidation. Although DTG is a substrate for UGT1A3, UGT1A9, and the efflux transporters P-gp and BCRP, it has a low potential to cause drug-drug interactions. DTG does not induce or inhibit CYP or UGT enzymes. Additionally, it has relatively little impact on major efflux transporters such as P-gp or MRPs [16]. DTG has been shown to potently inhibit renal organic cation transporter, OCT2 and MATE-1, which results in a reduction in creatinine secretion in the renal proximal tubule. This causes a benign increase in serum creatinine concentrations which consequently causes an artificial decline in calculated glomerular filtration rate.

Dolutegravir exposures can be impacted when co-administered with potent CYP3A inducers such as tipranavir, fosamprenavir, efavirenz, and rifampin. When co-administered with moderate to strong UGT1A1 and CYP3A inducers, DTG exposures can be reduced requiring either dose adjustment or employment of mitigating strategies. Rifampin, a potent inducer of CYP and efflux transporters, can significantly decrease dolutegravir plasma concentrations. This interaction can be mitigated by simply increasing the dolutegravir dosage to 50 mg BID. Similar to raltegravir, but unlike elvitegravir, dolutegravir may be administered with rifabutin without dose adjustment [17].

NNRTIs like efavirenz and etravirine are known CYP3A inducers, and both agents are able to reduce DTG plasma concentrations. Efavirenz can significantly reduce DTG plasma C min by 75%; therefore, the dose of DTG must be increased to 50 mg twice daily to overcome this interaction [18]. Surprisingly, etravirine dramatically reduced plasma DTG C min by 88% likely due to combined UGT and CYP3A induction; however, this interaction can be attenuated with the addition of specific RTV-boosted PIs, either DRV /RTV or LPV /RTV [19]. Therefore, no dose adjustment in DTG is necessary when co-administered with etravirine and RTV-boosted PIs, DRV/RTV and LPV/RTV. Similarly, when DTG is combined with enzyme-inducing PIs like tipranavir or fosamprenavir, even the addition of RTV cannot mitigate the enzyme-inducing effect; therefore, DTG requires dose adjustment when co-administered with these agents.

When DTG is combined with atazanavir (ATV ), a potent competitive inhibitor of UGT-mediated metabolism, plasma DTG C min increased by 2.8-fold and AUC by 1.9-fold compared with ATV alone. However, when RTV was added to ATV, the increase in DTG exposure was attenuated possibly via RTV-mediated induction of UGT metabolism [19, 20]. Additionally, there were no safety issues as a result of higher DTG concentrations with atazanavir co-administration in clinical trials; therefore, no dose adjustment of DTG is required.

7.2.3 Drug Interactions to Improve Bioavailability and Dosing

7.2.3.1 Pharmacoenhancement of PIs

As previously mentioned, RTV is a potent CYP3A4 inhibitor found in high levels in the gut wall and liver [21]. These inhibitory properties can be exploited to increase plasma concentrations of co-administered PIs with RTV. The resultant effect is increased PI exposure leading to improved antiviral activity while permitting a lower dosage and dosing frequency of the co-administered PI and potentially reducing the incidence of adverse effects.

RTV is ideally suited to boosting, as it acts both on first-pass metabolism and on hepatic clearance. Thus, CYP3A4 and P-gp found in the intestinal walls can be inhibited using RTV and thus overcome poor intrinsic bioavailability. When RTV 200 mg was co-administered with SQV , a three- to eightfold increase SQV exposure was realized when compared with unboosted SQV [22]. For PIs with good bioavailability but a short half-life, RTV-mediated inhibition of CYP3A4 can decrease hepatic clearance and therefore extend the half-life of a co-administered PI.

Ideally, boosting should maintain drug concentrations that are within the therapeutic window. This means that the C min should fall within a zone above the minimum effective concentration for viral inhibition, while C max should fall below the threshold for toxicity. If an agent has a narrow therapeutic window, boosting is likely to increase the frequency or magnitude of adverse effects, even if boosting has a relatively minor effect on C max. For example, IDV has good bioavailability, but its relatively short half-life requires frequent dosing to prevent suboptimal plasma levels, a shortcoming that can be overcome by boosting with RTV [23]. Although the increase in IDV C max from boosting is small, it is apparently sufficient to substantially increase risk of nephrolithiasis [24]. In contrast, addition of RTV to a PI with low bioavailability, like SQV or LPV , results in greatly increased C max without increased toxicity, probably because these drugs have intrinsically lower toxicity [25].

7.2.3.2 Cobicistat

Cobicistat (COBI , Tybost™ ) is a structural analog of RTV developed as an alternative pharmacokinetic boosting agent. Although RTV co-administration can improve the pharmacokinetic profile of a co-administered PI, low-dose RTV is also associated with many metabolic side effects including hyperlipidemia and hypercholesterolemia. Advantages of COBI include its lack of antiretroviral activity at the dosage employed, its lower potential to alter lipid metabolism compared with RTV, and its availability as FDC with PIs such as darunavir (DRV ) and atazanavir (ATV ) and the integrase inhibitor, elvitegravir (EVG), to block CYP3A-mediated metabolism of the parent compound to enable once a day dosing. COBI and RTV share some similarities in pharmacokinetics. For example, COBI has a plasma t 1/2 of approximately 3 h, which is similar to that found for RTV (t 1/2 3–5 h), and COBI inactivates CYP3A enzymes in a time- and concentration-dependent manner similar to RTV. COBI and RTV have both been shown to inhibit the activity of multiple transporters. In vitro, COBI is an inhibitor of Pgp, BCRP, organic anion-transporting polypeptide 1B1 and 1B3 (OATP 1B1 and 1B3), and renal tubular cell drug transporters like multidrug and toxin extrusion protein 1 (MATE-1) and organic cation transporter 1 (OCT1) [26].

In general, COBI and RTV are considered to be equipotent in CYP3A inhibition potential and therefore can be used interchangeably to boost systemic exposures of CYP3A substrates. However, there are notable differences in their ability to inhibit or induce other CYP isoenzymes and glucuronyltransferase activity which can make it difficult to predict the magnitude and direction of drug-drug interactions when using RTV or COBI with concomitant drugs that are metabolized by multiple CYPs or that undergo glucuronidation. Moreover, given that RTV is co-formulated with various other PIs and COBI is co-formulated with EVG, the parent PI, EVG, and the choice of PK boosting agent will all contribute to the net interaction observed with a concomitantly administered agent. COBI is distinct from RTV in that it does not inhibit CYP2C8, is considered a weak 2D6 inhibitor, and does not induce CYP isoenzymes 1A2, 2B6, 2C9, and 2C19 or glucuronyltransferase activity [27]. In addition, other drugs may impact COBI exposures. For example, combining COBI 150 mg BID with tipranavir 500 mg BID resulted in a significantly lower COBI C max and a reduction in COBI t 1/2 to 2.2 h [13, 28]. These results further support the observation that tipranavir can significantly induce metabolic enzymes leading to enhanced COBI clearance. Therefore, when COBI is combined with tipranavir, a dosage increase of COBI to 200 mg BID may be necessary; however, there is no recommended TPV/COBI dosing regimen approved in current product labeling [26].

Regimens containing 150 mg of cobicistat and darunavir, atazanavir, and elvitegravir are considered to provide bioequivalent exposures compared to these same regimens containing 100 mg of RTV. Drug interaction studies comparing COBI vs RTV-containing regimens and third agents are limited and based on extrapolation of interaction data with RTV. Relative bioavailability studies have been conducted to compare pharmacokinetic exposures of concomitantly administered PIs and COBI versus RTV. In healthy volunteers receiving DRV 800 mg/COBI 150 mg, DRV C max and AUC24 were comparable to those receiving 800 mg DRV/100 mg RTV, as the geometric mean ratio was 1.03, 0.694, and 1.02 for C max, C tau, and AUCtau, respectively. However, both C0 and C24 were approximately 30% lower when DRV was combined with 150 mg COBI as compared to 100 mg RTV [29]. However, DRV AUC0–12, C max, and C tau were comparable between the two pharmacoenhancers when DRV/COBI 600/150 mg BID was compared to DRV/RTV 600/100 BID, yet the use of DRV/COBI BID is not considered interchangeable and is not recommended per product labeling [26]. When either EVG or etravirine was added to DRV/COBI 600/150 BID, no changes in DRV PK were noted. Similarly, bioequivalent exposures were demonstrated between ATV 300 mg/COBI 150 mg and ATV 300 mg/RTV 100 mg, as geometric mean ratios (GMR) for C max, C tau, and AUC were 0.923, 0.976, and 1.01, respectively, following a meal in healthy volunteers.

7.3 Issues with ARV Drug-Drug Interactions

Specific interactions with PIs and INIs and concomitant medications are summarized in Tables 7.2 and 7.3. For additional information on interactions with PIs and INIs with antifungals, antimalarials, antimycobacterials, and hepatitis C agents, the reader is referred to Chaps. 12, 15, 17, and 18, respectively.

7.3.1 Interactions with pH-Altering Agents and Polyvalent Cations

Drug-drug interactions exist between ARVs that require low gastric pH for absorption and drugs that raise gastric pH such as proton pump inhibitors (PPI), histamine-2 (H2) receptor blockers, and antacids. In one study involving 200 HIV patients, 88% reported taking a PPI, H2-blocker, or antacid, individually or in combination [30]. More importantly, 95% used over-the-counter agents alone or in combination with a prescription drug, underscoring the importance of asking patients about nonprescription medications.

HIV PIs are susceptible to drug-drug interactions with agents that alter gastric pH. When PIs are co-administered with antacids, reductions in atazanavir (ATV ), tipranavir (TPV ), and amprenavir/fosamprenavir exposure have been noted; therefore, it is recommended to stagger PI doses 2 h before or 1–2 h after antacid dosing. Concomitant H2 antagonists reduced unboosted atazanavir AUC by 41% with famotidine and reduced amprenavir AUC by 30% with ranitidine. Therefore, it is recommended that H2 antagonists should not exceed 20 mg of famotidine or its equivalent with unboosted ATV or 40 mg of famotidine or its equivalent with boosted ATV and that a 2–10-h dose separation strategy is employed [31]. When proton pump inhibitors are used together with PIs, there is generally no significant interaction, except when using atazanavir; therefore, it is not recommended to use PPIs in combination with atazanavir.

HIV INIs demonstrate varying propensities of interaction with concomitant cation-containing products, such as aluminum, magnesium, and calcium-containing antacids, which may be a result of chelation and/or pH-related changes in drug absorption. Cation interactions arise from the ability of INIs to form a complex with divalent cations in the active site of the integrase enzyme, which can effectively reduce the amount of drug available for absorption. Concurrent or staggered administration of aluminum- and/or magnesium-containing antacids is not recommended with RAL because these agents can reduce RAL exposure by greater than 50%. Raltegravir exhibits pH-dependent solubility which may explain why C max and AUC were not significantly altered with concurrent magnesium antacid administration, as increasing pH improves RAL solubility initially; however, the net impact is an overall reduction in RAL exposures, likely a consequence of large quantities of metal cations available for chelation [32,33,34]. However, the impact on RAL exposures is product dependent as concurrent calcium carbonate antacid administration only modestly reduced RAL C min by 32%. A 2-h dose separation is required between EVG and concomitant aluminum- or magnesium-containing antacid administration to avoid a 40–50% reduction in EVG AUC with simultaneous administration. Dolutegravir requires a 2- to 6-h dose separation with concurrent polyvalent cation administration as simultaneous administration of magnesium- or aluminum-containing antacids reduced DTG AUC by 74%. Alternatively, products containing iron and calcium-containing products may be co-administered at the same time as DTG if also administered with food [35].

7.3.2 Interactions with Anticoagulants

PI interactions with anticoagulants or antiplatelets have been well-established. The co-administration of thrombin inhibitors such as apixaban, dabigatran, edoxaban, and rivaroxaban with any PI will increase thrombin inhibitor concentrations; thus, it is recommended these agents be avoided with PIs. The only exception is dabigatran with PI, when the creatinine clearance is greater than 50 mL/min where no dosage adjustment is required. Similarly, the thrombin receptor antagonist, vorapaxar, should be avoided with PIs. When PI/RTV is co-administered with warfarin, warfarin levels are expected to decrease, and thus titration of warfarin dosage may be necessary to attain targeted anticoagulation levels.

7.3.3 Interactions with Anticonvulsants

As expected, the co-administration of anticonvulsants and HIV PIs will lead to significant drug-drug interactions. In general, PIs cause an increase in levels of anticonvulsants such as carbamazepine and ethosuximide. In contrast, phenytoin and phenobarbital are potent inducers of CYP, and thus co-administration of these anticonvulsants with PIs will lead to reduced PI levels, and the combination may severely impact efficacy of both classes of drugs. It is recommended that other classes of ART such as integrase inhibitors be substituted or a change to a noninteracting anticonvulsant, such as levetiracetam, be considered. All currently marketed integrase inhibitors are substrates for CYP isoenzymes and/or undergo glucuronidation, and therefore anticonvulsants with potent enzyme induction potential, such as phenytoin, phenobarbital, carbamazepine, and oxcarbazepine, are not recommended with concomitant INIs.

7.3.4 Interactions with Steroids

Steroids are widely used immunosuppressive agents for the treatment of inflammation and allergic reactions. HIV patients receiving ART and steroid therapy should be aware of potential drug-drug interactions, particularly when immunosuppressive steroids such as dexamethasone, fluticasone, and methylprednisolone are utilized. Increased fluticasone systemic concentrations have been shown when inhaled fluticasone is co-administered with ART combinations containing COBI or RTV. Thus, chronic use of steroids in combination with RTV- or COBI -containing regimens may enhance the risk for adrenal insufficiency and Cushing’s syndrome and is therefore not recommended.

7.3.5 Interactions with Oral Contraceptives

Hormonal contraceptives are frequently co-administered in HIV-infected populations, and drug interactions with various antiretroviral classes have been demonstrated. Hormonal contraceptives consist of steroids that are eliminated by phase I and II metabolic enzymes. Unboosted PI therapy typically results in slightly increased ethinyl estradiol or norethindrone concentrations partly from phase I enzyme inhibition. For example, ATV is a potent inhibitor of UGT that can increase ethinyl estradiol AUC by 48% and norethindrone AUC by 110%. However, many boosted PIs cause a reduction in ethinyl estradiol exposures, and alternative forms of contraception are recommended. RTV alters the expression of the phase II metabolic enzyme, uridine 5′-diphospho-glucuronosyltransferase (UGT) .

PI-induced expression of phase II metabolism may partially explain why it is able to interact with nucleosides, steroidal compounds, methadone, and antipsychotic agents. Nucleosides such as abacavir and zidovudine are metabolized via glucuronidation, and thus co-administration of PIs with nucleosides can alter their plasma concentrations. Fortunately, nucleosides have wide therapeutic indices, so no dosage adjustments are necessary.

When PIs are combined with steroid compounds such as components of birth control pills like ethinyl estradiol (EE) and norethindrone (NE) , their systemic concentrations can be modified requiring a dose alteration. When an alternative to estradiols is needed, depo-medroxyprogesterone acetate (DMPA) can be utilized. One study evaluating 65 HIV-infected women receiving ART demonstrated no significant interaction between DMPA and EFV, NVP, or NFV [36]. There was no evidence of ovulation, although the study was limited to assessment of interactions with EFV, NVP, and NFV.

Although PIs are most notable in their interaction with oral contraceptives, integrase inhibitors also utilize this pathway for elimination, and thus potential drug-drug interaction between integrase inhibitors and hormonal contraceptives should always be considered. Although both estrogen- and progestin-containing products are available in addition to progestin-only formulations, the progestin component is generally considered to be most important for contraceptive activity.

No significant interaction was seen with either RAL or DTG when co-administered with hormonal contraceptives. However, co-administration of EVG/COBI /FTC/TDF with a norgestimate (NGNM) - and ethinyl estradiol (EE)-containing oral contraceptive resulted in a significant increase in progestin concentrations and reduced EE concentrations. Mean plasma AUC of NGMN increased by 2.26-fold, while the mean plasma AUC of EE was lowered by 0.75-fold. However, increasing the amount of EE to compensate for lower EE concentrations observed with EVG/COBI/FTC/TDF would likely require a higher strength NGNM/EE tablet, further increasing the potential for NGNM-related adverse events. Therefore, caution should be exercised with concomitant administration of NGMN/EE and EVG/COBI/FTC/TDF, and non-hormonal forms of contraception may be considered. However, when EVG was combined with PI/RTV, no change in EVG concentration was noted.

7.3.6 Interactions with Opioid and Psychotropic Agents

Methadone concentrations can be decreased when co-administered with various antiretroviral agents. While EFV and NVP are prominent for their negative interactions with methadone, several PIs, including NFV and LPV /r, also significantly lower methadone levels. This interaction can lead to opioid withdrawal whereby an inability to adjust methadone doses could prompt patients to interrupt or discontinue ART.

When INI are co-administered with methadone, no alteration in methadone levels was observed. However, when INI is combined with PI/RTV, the presence of RTV can induce glucuronidation resulting in lower methadone levels. In this scenario, it is advised that signs and symptoms of opioid withdrawal be closely monitored. Alternative opioids such as buprenorphine can be considered. EVG in combination with COBI increased buprenorphine AUC by 35% and increased buprenorphine metabolite concentrations by 42%. However, despite these PK changes, no adjustment is recommended.

Trazodone is a CYP3A4 substrate, and interactions with IDV and RTV can raise trazodone concentrations. A study in 10 healthy volunteers demonstrated that boosting doses of RTV (200 mg BID for 2 days) led to a 2.4-fold increase in exposure to trazodone. Study participants experienced nausea, hypotension, and syncope [37]. These observations suggest that caution is warranted whenever PIs are used concurrently with trazodone.

7.3.7 Interactions with HMG-Coenzyme a Reductase Inhibitors (Statins)

Limited data are available characterizing ARV drug interactions with HMG-coenzyme A reductase inhibitors (statins). Statins are frequently prescribed in the treatment of dyslipidemias in the HIV population which can be associated to the use of certain ARVs such as protease inhibitors (PIs). In general, statins are predominately metabolized by CYP isoenzymes and can involve drug transport via OATP, P-gP, BCRP, and OAT3 [38]. The majority of PIs inhibit the metabolism of statins through potent CYP3A enzyme inhibition which can increase statin concentrations leading to a clinically significant risk of myopathy and rhabdomyolysis . All PIs, with the exception of fosamprenavir, inhibit the OATP transporter. The degree of interaction varies by PI and statin; however, the potential for statin inhibition is considered greatest with simvastatin and lovastatin followed by atorvastatin and rosuvastatin. Simvastatin and lovastatin are contraindicated with PIs to avoid risk of myopathy. RTV-boosted PIs (ATV /r, DRV /r, and LPV /r) have been documented to increase rosuvastatin AUC from 50% to 200% and C max from 90% to 600%, resulting in cautious use and titrating with the lowest dose possible [39,40,41] which may be explained by PI-mediated inhibition of OATP transport as rosuvastatin is not metabolized by CYP3A to any significant extent or to inhibition of breast cancer resistance protein (BCRP). Overall, atorvastatin, rosuvastatin, or pravastatin may be considered in patients receiving PI-based regimens; however, dosing adjustments may still be required depending on the components of the ARV regimen. Pitavastatin and fluvastatin do not exhibit significant interactions with PIs and can generally be used without dose adjustments. No dose adjustment of statins is required when co-administered HIV integrase inhibitors, with the exception of elvitegravir co-administered with potent CYP3A inhibitors containing boosted PIs, RTV, or COBI which is similarly contraindicated with simvastatin and lovastatin, but cautious use with rosuvastatin is permitted [1].

7.3.8 INI Interactions with Renal Transporters

As previously stated, dolutegravir potently inhibits renal organic cation transporter, OCT2, and multidrug and toxin extrusion transporter MATE1. DTG may increase the concentrations of drugs such as metformin and dofetilide or endogenous molecules such as creatinine that are dependent on OCT2-mediated transport for renal excretion. A modest 10–15% increase in serum creatinine observed in DTG clinical trials is attributed to potent OCT2 inhibition by DTG and does not indicate renal toxicity or actual reduction of glomerular filtration [42]. In healthy volunteers, metformin mean AUC increased by 1.8- to 2.5-fold and mean C max by 1.7- to 2.1-fold following metformin 500 mg twice daily administration with either once or twice daily DTG administration; therefore, limiting the total daily dose of metformin and monitoring of blood glucose are recommended [43]. Drugs that have a narrow therapeutic index, such as dofetilide and pilsicainide, which are dependent on OCT2-mediated transport, are contraindicated for use with DTG.

EVG is not known to modulate renal drug transporters; however, it requires pharmacokinetic boosting using either RTV or COBI . RTV demonstrates inhibitory activity for a wide range of transporters, including MATE-1, OAT1, OAT3, MRP2, MRP4, and P-gp, and thus may affect transport of drugs requiring these transporters. COBI is known to inhibit MATE-1 and P-gp drug transporters [44]. Given EVG/COBI is co-formulated with a nucleotide associated with renal toxicity (TDF) or the alternative TFV prodrug, TAF, renal function changes have been reported during use of EVG-containing regimens. COBI has been associated with reports of mild nonprogressive elevations in serum creatinine from inhibition of creatinine active tubular secretion without effecting glomerular filtration or overall renal function in clinical trials [45, 46]. Tenofovir is a substrate for OAT1, OAT3, and MRP4, and therefore inhibition of TFV influx or efflux from renal tubular cells may increase TFV exposure contributing to the observed 10–15% reduction in eGFR among patients receiving TDF and RTV or COBI-boosted PI- or INI-containing regimens [44]. TAF has less nephrotoxic potential when compared to TDF; however, limited long-term data exist on the renal impact of TAF-containing regimens given its recent approval [47,48,49]. The effect of COBI on creatinine clearance (CrCl) and iohexol-measured GFR demonstrated decreased CrCl but no effect on measured GFR (German) in healthy volunteers, suggesting the observed increase in renal-related adverse events with EVG-containing regimens may be attributed to COBI-mediated inhibition of TDF efflux by P-gp rather than COBI-mediated effects on MATE-1 transport [50, 51]. Overall, the inability to independently evaluate the renal effects of elvitegravir and COBI independently of TAF, TDF, or RTV limits our understanding of the predominant mechanisms that mediated renal function changes in EVG−/COBI-containing regimens.

In summary, although a wide spectrum of co-administered drugs may interact with antiretrovirals, much is presently known about these interactions and how to avoid their effects. A thorough history of prescription and nonprescription drugs, supplements, and herbs should identify key pharmacologic areas where potential interactions may be lurking.

7.4 Summary

Antiretroviral agents with novel mechanisms of action are constantly in development with hopes that these agents may constitute a curative treatment as seen with hepatitis C viral infection . While new classes of ART are expected to provide significant therapeutic benefits, they are also likely to further expand the number of potential drug-drug interactions. Integrase inhibitors have transformed the antiretroviral landscape with their intrinsic high-level potency, rapid attainment of virologic suppression, availability of complete single tablet regimens for once daily dosing, significant improvements in safety and tolerability, and high genetic barriers to resistance affording high efficacy rates. New advances in formulation technology are paving the way for longer-acting medications, including all injectable antiretroviral regimens, as an alternative to daily oral dosing and freedom from the daily reminder of HIV infection. Healthcare providers must remain vigilant in monitoring for drug interactions between antiretrovirals and medications used for the treatment of comorbidities. The vast array of websites and mobile applications are increasingly aiding in rapid identification of potential drug interactions at the bedside; however, the careful management of HIV disease requires a multidisciplinary focus optimized by contributions from experienced practitioners.