Drug-drug interactions between COVID-19 therapeutics and antiretroviral treatment: the evidence to date

Abstract

Introduction:

With new effective treatments for SARS-CoV-2, patient outcomes have greatly improved. However, new medications bring a risk of drug interactions with other medications. People living with HIV (PLWH) are at particular risk for these interactions due to heightened risk of immunosuppression, polypharmacy, and overlap in affected organs. It is critical to identify drug interactions are a significant barrier to care for PLWH. Establishing a better understanding of the pharmacologic relationships between COVID-19 therapies and antiretrovirals will improve patient-centered care in COVID-19.

Areas covered:

Potential drug-drug interactions between Human Immunodeficiency Virus (HIV) and COVID-19 treatments are detailed and reviewed here. The mechanisms seen in these interactions include alterations in metabolic enzymes, drug transporters, pharmacoenhancement, and organ toxicities. We also review the limitations and solutions that can be used to combat drug-drug interactions between these two disease states.

Expert opinion:

While current drug interactions are relatively mild between HIV and COVID-19 therapies, improvements in identifying these beforehand must take place as new therapies are approved. Antiretroviral therapy (ART) is essential in PLWH and must be maintained when treating COVID-19. As advancements in care occur, there is the possibility that newly approved drugs may have additional unknown interactions.

1.0. Introduction

With the emergence of the COVID-19 global pandemic, there was considerable concern for immunocompromised patients. Human immunodeficiency virus (HIV) infection compromises the immune system, making people with HIV more susceptible to severe disease ¹. Meta-analyses published in 2022 show that people living with HIV (PLWH) account for 2% of the world’s COVID-19 cases ². Furthermore, the Centers for Disease Control and Prevention (CDC) identifies PLWH as having elevated risk for severe illness due to COVID-19. Two of the factors that contribute to an increased risk in these patients are not being on antiretroviral therapy (ART) and having advanced HIV. Antiretroviral therapy is the cornerstone of treatment for PLWH, limiting disease progression, reducing the risk of transmission, and ultimately prolonging patients’ lives ³. Virally suppressed PLWH on ART exhibited similar risk to people living without HIV (PLWoH) in the absence of other major comorbidities ². This data shows that ART has the capability of neutralizing the risk of COVID-19 progression associated with having HIV.

Antiretroviral therapies include antivirals of multiple mechanisms that inhibit key enzymes for HIV virulence and replications. Drug classes among antiretroviral therapies include integrase strand inhibitors (INSTIs), nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTI/NNRTIs), and protease inhibitors (PIs), among others. Generally, antiretroviral regimens utilize drugs from multiple classes in order to better reduce viral load and limit viral resistance to therapy ^{4, 5}. The Department of Health and Human Services publishes and updates comprehensive guidelines on how to initiate and design ART to fit a patient based on their clinical characteristics. Typically, initial therapy will include two NRTIs with the addition of an INSTI, NNRTI, or a boosted PI ³. Due to the multidrug nature of HIV regimens and the pharmacokinetic profile of the drugs used, drug-drug interactions are common with ART ³.

Since the onset of the COVID-19 pandemic, many drugs have emerged as potential therapies to treat individuals suffering from SARS-CoV-2 infection. Early in the pandemic, some antiretroviral therapies such as lopinavir-ritonavir were used in attempt to treat COVID-19, ultimately showing no benefit in larger trials ^{6, 7}. Currently multiple therapeutic modalities exist, including antiviral therapies, corticosteroids, kinase inhibitors, monoclonal antibodies, and other miscellaneous agents ⁸. Importantly, therapies for treating COVID-19 have rapidly evolved, and continue to rapidly evolve, many therapies which have been used in the past for treating COVID-19 are no longer used to due decreased efficacy, or a worsened side effect profile compared to newer treatments. The combination of nirmatrelvir and ritonavir is fully approved by the us FDA for managing mild to moderate COVID-19, after previously being available under an emergency use authorization. Molnupiravir is available under an emergency use authorization for individuals with mild-moderate COVID-19 at high risk of disease progression for whom alternative COVID-19 treatments are not clinically appropriate. Among these therapies, drugs with relevant contemporary use and clinical benefit have been evaluated for any possible drug-drug interactions with ART ⁹.

Health organizations around the world including BHIVA, IDSA, EACS, NIH, IAS, and DHHS have all made similar recommendations for starting a standard course of treatment for COVID-19 in PLWH ². Improving clinician understanding of COVID-19 therapeutics and their interaction with chronic therapies like ART is a stepping stone for improving patient-centered care in COVID-19.

2.0. Therapeutically relevant Metabolic Enzymes

Metabolic enzymes such as cytochrome P450 (CYP) enzymes and Uridine 5’-diphospho-glucuronosyltransferase (UGT) play a key role in drug metabolism and are associated with drug-drug interactions ^{10, 11}. More than 70% of drugs are metabolized by Cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes that are predominantly located in the liver ^{10, 12}. Induction or inhibition of these enzymes causes alterations in drug metabolism that may lead to different treatment outcomes. These changes have downstream effects on dosing for therapeutic efficacy while minimizing toxicities based on therapeutic efficacy and possible toxicity. Understanding the interaction between drugs and their metabolic enzymes allow health care providers to evaluate effective and safe regimens for each patient. Common drugs for HIV-1 and SARS-CoV-2 which are substrates of relevant transporters are outlined in table 1.

Table 1.

Transporter and metabolic enzyme substrates, inducers, and inhibitors

Drug	CYP Enzymes	UGT	SLCs	P-gp
COVID-19	Substrate Inhibitor Inducer	Substrate Inhibitor Inducer	Substrate Inhibitor Inducer	Substrate Inhibitor Inducer
Baricitinib	3A4(minor)		OAT 1/3	minor
Corticosteroids	3A4(major) 3A4(variable)			minor
Nirmatrelvir/r	3A4(major) 3A4(strong) 2B6(mod)	1A1(mod)		minor
Remdesivir	3A4(minor)		OTAP1B1/1B3	minor
Ritonavir	3A4(major) 3A4(strong) 2B6(mod)	1A1(mod)		minor
Tofacitinib	3A4 (major)
HIV Drugs
Atazanavir	3A4(major) 3A4(strong)	1A1(mod)	OATP1B1/1B3(mod)
Bictegravir	3A4	1A1(mod)	OCT2(mod)
Cabotegravir		1A1 , 1A9(mod)	OAT 1/3(mod)	minor
Cobicistat	3A4(major) 3A4(strong)		OATP1B1/1B3(mod)	moderate
Darunavir	3A4(major) 3A4(strong), 2D6(mod)			minor
Dolutegravir	3A4(minor)	1A1, 1A3, 1A9(mod)	OCT2	minor
Doravirine Rilpivirine	3A4(major)
Efavirenz	2B6 ,3A4(major) 2B69, 3A4(mod)	1A1, 1A4(mod)
Elvitegravir	3A4(major)	1A1, 1A3(mod)
Etravirine	2C19, 2C9, 3A4(major) 3A4(mod)
Lenacapavir	3A4(major) 3A4(mod)	1A1(mod)		minor
Lopinavir/r	3A4(major) 3A4(strong) 2B6(mod)	1A1(mod)	OATP1B1/1B3(mod)	minor
Maraviroc	3A4(major)		OATP1B1/1B3(mod)	minor
Nevirapine	3A4(major) 3A4(weak), 2B6(mod)
Raltegravir		1A1
Tenofovir (TAF/TDF)			OAT1/3,OATP1B1/1(mod)	major

2.1. Cytochrome P450

CYP enzymes are heme proteins that play an essential role in phase I metabolism of various compounds and their clearance. Phase I metabolism occurs when these enzymes convert drugs into more polar molecules by adding polar functional groups. The process activates or deactivates the drugs and yields metabolites ¹⁰.

Although there are more than 50 CYP enzymes, two enzymes: CYP3A4 and CYP2D6, are responsible for the metabolism of most drugs ¹³. For HIV and SARS-CoV-2 treatments specifically, the majority of drugs are substrates of or act on these two enzymes. While most drugs have a primary CYP enzyme associated with their metabolism, others are substrates for multiple CYP pathways. CYP enzyme inhibition and induction are major mechanisms that cause pharmacokinetic drug-drug interactions. While inhibiting these enzymes can lead to increased exposure and toxicities, induction can lead to decreased exposure and therapeutic failures ¹⁴.

A prototypical example of metabolic changes is phenytoin, which induces CYP1A2, CYP2C9, CYP2C19, and CYP3A4, leading to decreased bioavailability of their substrates, such as digoxin ¹⁵. However, it is also possible to use enzyme modulation as a strategy. For example, the anti-HIV drug ritonavir has minimal antiretroviral activity but is extremely potent at inhibiting the activity of CYP3A4. Ritonavir’s potent inhibition of CYP3A4 is used to enhance the efficacy of CYP3A4 substrates by improving their bioavailability ¹⁶. When adding new drugs to a patient’s regimen, reviewing and monitoring CYP-mediated interactions is crucial.

2.2. UDP-glucuronosyltransferase

UGTs are a family of enzymes responsible for a phase II metabolic process, glucuronidation. Glucuronidation is the process of making a substrate more hydrophilic by conjugating glucuronic acid to the substrate, making it easier to eliminate through urinary excretion ¹⁷. There are over 20 UGT enzymes, each metabolizing different drugs ¹⁸. Clinically, the most important UGT enzymes are in the UGT1A family ¹⁹. Similar to the CYP enzymes, induction can lead to treatment failure, while inhibition of the UGT enzyme can lead to drug toxicities. Rifampin is an example, as it induces UGT1A1, which can lead to decreased bioavailability of its substrates, such as raltegravir ²⁰. Reductions in drug bioavailability are detrimental to treatment as they can cause drug levels to fall below the therapeutic range. A dose increase is often sufficient to overcome this deficiency; however, this increases the risk of toxicity ²¹.

3.0. Therapeutically relevant Drug Transporters

While metabolic enzymes such as cytochrome P450 command much of the attention surrounding drug-drug interactions, it is also important to consider the role of drug-transporting enzymes such as P-glycoprotein (P-gp) and solute carriers (SLC). Membrane uptake and efflux affect drug distribution and impact the pharmacokinetic profile of many drugs. Understanding how drug transporters interact with their substrates allows providers to evaluate the therapeutic implications of transporter-mediated interactions. HIV-1 and SARS-CoV-2 which are substrates of relevant transporters are outlined in table 1.

3.1. P-glycoprotein

P-gp, also called ATP binding cassette subfamily B1 (ABCB1), is the most well-known and widely studied drug transporter, having the ability to bind a diverse array of structures ^{22, 23}. Some COVID-19 therapeutics and ARTs may induce, inhibit, or be substrates of P-gp, leading to interactions between the two classes when coadministered. Distributed in the liver, kidney, intestines, and various other sites throughout the body, P-gp acts as an efflux pump to move foreign compounds out of the cytoplasm into extracellular spaces such as the urine, the blood, and the intestinal lumen ²⁴. As a result, the inhibition or induction of P-gp can result in clinically significant alterations to a drug’s pharmacokinetic parameters. For instance, inhibition of P-gp in the gut may reduce efflux and improve absorption, whereas inhibition in the kidneys may limit excretion and result in accumulation in the blood. One study with known P-gp inducers rifampin and phenytoin showed significant reductions in drug exposure across multiple P-gp substrates ²⁵. In general, providers should recognize that drugs altering the function of P-gp can compromise the standard pharmacokinetics of its substrates, leading to unanticipated toxicity or therapeutic failure.

3.2. Solute Carriers

Another family of transporters involved in the distribution of both COVID-19 therapies and HIV ARTs is the solute carriers (SLC). Within the SLC superfamily, the organic anion transporters (OAT) and organic anion transporting polypeptides (OATP) have a role in the disposition of antiretrovirals and SARS-CoV-2 therapies.

For the OAT family, OAT1 and OAT3 are the most significant for the distribution and excretion of organic anions; these transporters work to move solutes from the blood into the proximal tubular cells of the kidney for excretion ²⁶. Inhibition of these transporters by drugs or other exogenous compounds has generated concern over its impact on the renal excretion of drugs ²⁷.

Another member of the SLC superfamily are the organic anion transporting polypeptides (OATPs). Among those most associated with drug interactions, OATP1B1 and 1B3 are of the greatest significance for HIV-1 and SARS-CoV-2 therapeutics. These transporters, found in the liver, facilitate the movement of compounds into the cytoplasm of hepatocytes, where drug metabolism is carried out ²⁸. Similarly to the other transporters discussed, the function of these transporters can be altered in a way that affects drug distribution and exposure.

4.0. Inhibition of metabolic enzymes and drug transporters

For the treatment of HIV, the use of protease inhibitors (PIs) and certain combination therapies requires boosting with pharmacoenhancers, which include ritonavir and cobicistat. These drugs are potent inhibitors of CYP3A4, with little to no antiretroviral activity ²⁹. Coadministered with other antiretrovirals, ritonavir and cobicistat are beneficial in supporting ART efficacy, but causing potent CYP3A4 inhibition and miscellaneous enzyme interactions can also create the possibility for multiple drug-drug interactions.

4.1. Nirmatrelvir-ritonavir

With the approval of nirmatrelvir-ritonavir (NMV/r) as an outpatient therapy for SARS-CoV-2 infections, there is a high potential for drug-drug interactions with a patient’s HIV therapeutics. With nirmatrelvir-ritonavir regimens, PLWH take 200 mg of ritonavir daily in addition to the ritonavir or cobicistat that may already be in their ART regimen. CYP3A inhibition by ritonavir has been studied and shown to occur in a dose-dependent manner such that higher doses of ritonavir causes more CYP3A inhibition ³⁰. Furthermore, antiretrovirals for the treatment of HIV include multiple CYP3A4 substrates, causing concern for interactions between NMV/r and ARTs that do not include ritonavir or cobicistat. For instance, coadministration of ritonavir 100 mg twice daily with maraviroc showed an increase in the area under the curve (AUC) of maraviroc up to 161% in comparison to maraviroc alone ³¹. This demonstrates that the presence of ritonavir 100 mg in nirmatrelvir-ritonavir combinations can have an unintended boosting effect on antiretroviral regimens that contain CYP3A4 substrates. Interaction reports compiled by the French Society of Pharmacology and Therapeutics (SFPT) propose that maraviroc, efavirenz, etravirine, and nevirapine are not recommended to use with concomitant nirmatrelvir-ritonavir. Additionally, as the duration of nirmatrelvir-ritonavir treatment is short, the SFPT suggests continuing to take boosted PI regimens (ritonavir/cobicistat) and monitor for adverse effects ³². Interestingly, 2022 guidelines updates for PLWH that are prescribed nirmatrelvir-ritonavir suggest that patients take this medication for all five days without any adjustment to their antiretroviral regimen, including for patients receiving regimens including pharmacoenhancement ³¹. Since nirmatrelvir-ritonavir is used outpatient, there is limited potential for clinical monitoring. This may prevent its utilization due to known drug-drug interactions.

4.2. Inhibition of CYP3A4

The use of pharmacoenhancers in daily HIV regimens can have a pharmacokinetic impact on the drugs used for the treatment of SARS-CoV-2. Of the therapies currently used to treat SARS-CoV-2 infections, some are metabolized by CYP3A4. These include dexamethasone, methylprednisolone, baricitinib, remdesivir, and nirmatrelvir-ritonavir ^{33, 34, #79, 35}. CYP3A4 plays a minor role in the metabolism of baricitinib and remdesivir, with remdesivir also being metabolized by CYP2C8 and CYP2D6 ^{33, 34}. The metabolism of the glucocorticoids dexamethasone and methylprednisolone primarily occurs via CYP3A4. In the presence of “boosted” ART regimens, inhibition of CYP3A4 by ritonavir and cobicistat can lead to elevated exposure to dexamethasone and methylprednisolone ³⁶. Reports on dexamethasone’s drug interactions express concern over potential for Cushing syndrome, a series of complications resulting from long-term exposure to corticosteroids when coadministered in high doses with cobicistat ³⁵. This interaction is echoed by increased reports of iatrogenic Cushing’s syndrome resulting from the coadministration of glucocorticoids and ritonavir or cobicistat-containing regimens ^37–39. It should be noted that this interaction has been observed with inhaled corticosteroids, and that budesonide inhalation is sometimes used in the treatment of COVID-19 ³⁸.

As noted previously, remdesivir is metabolized by three CYPs: CYP3A4, CYP2C8, and CYP2D6. The degree of remdesivir’s CYP metabolism is limited, as it is mostly converted to its active form through carboxylesterase 1 (CES1) and cathepsin A ⁴⁰. The NIH COVID-19 Treatment Guidelines state that remdesivir levels are unlikely to be altered by CYP activity and that remdesivir can be administered with strong CYP450 inhibitors ⁸. One animal study suggests possible synergistic effects with the use of cobicistat and remdesivir ⁴¹.

The Janus kinase (JAK) inhibitors baricitinib and tofacitinib are both CYP3A4 substrates ^{33, 42}. The package insert for baricitinib states that there were no clinically meaningful interactions when tested in conjunction with ketoconazole, a known CYP3A4 inhibitor ³³. However, for tofacitinib, reductions in dosing frequency to once daily are recommended when using a strong CYP3A4 inhibitor – for instance, ritonavir or cobicistat ⁴². CYP3A4 interactions with tofacitinib should be monitored closely, as this medication has US boxed warnings for serious infections, malignancies, cardiovascular events, and thromboses ⁴².

4.3. Inhibition of P-glycoprotein

As well as being strong inhibitors of CYP3A4, ritonavir and cobicistat both potently inhibit P-glycoprotein (P-gp) ^{43, 44}. Despite the ubiquity of P-gp distribution and functional ambiguity, typically inhibition of P-gp is associated with improved drug bioavailability and thus increased drug exposure. Dabigatran etexilate, an anticoagulant, is a drug not metabolized by CYPs that is only known to be transported by P-gp, making it a model substrate for studying P-gp-mediated drug interactions. One study aimed at detailing P-gp inhibition by ritonavir and cobicistat found that cobicistat caused significant increases in dabigatran AUC and in thrombin time, while ritonavir did not ⁴⁵. The results of this study detail the variable pharmacokinetic and clinical outcomes that P-gp inhibition can cause. COVID-19 drugs that are substrates for P-gp include remdesivir, nirmatrelvir-ritonavir, baricitinib, dexamethasone, and hydrocortisone. Nirmatrelvir and ritonavir are also inhibitors of P-gp, while remdesivir, baricitinib, dexamethasone, and hydrocortisone are considered minor substrates of P-gp ^{33, 34, #79, 43, 46, 47}. PLWH taking boosted-PIs may experience pharmacokinetic alterations in these COVID-19 therapies owing to P-gp inhibition. The magnitude of these changes will depend on the pharmacoenhancer being used and the pharmacokinetic profile of the substrates involved ⁴⁵. Just as boosted PI-based regimens may affect COVID-19 therapies through P-gp inhibition, the use of nirmatrelvir-ritonavir can have an impact on antiretrovirals that are P-gp substrates. Since nirmatrelvir-ritonavir inhibits P-gp, taking nirmatrelvir-ritonavir for COVID-19 has the potential to affect the bioavailability and elimination of ARTs that are P-gp substrates. Antiretrovirals that are P-gp substrates include cabotegravir, cobicistat, darunavir, dolutegravir, lenacapavir, maraviroc, ritonavir, and tenofovir-based drugs ^{31, 33, 34, 42–44, 48, 49}.

4.4. Inhibition of OATP

Cobicistat and atazanavir are inhibitors of both OATP1B1 and OATP1B3 ⁴⁴. As previously stated, these enzymes are responsible for facilitating the hepatocellular uptake of certain drugs, notably statins ⁵⁰. Administration of elvitegravir-cobicistat with the OATP1B1/1B3 substrate rosuvastatin increased the Cmax of rosuvastatin 10 mg by 89% and the AUC by 38% in comparison to rosuvastatin alone ⁵⁰. A study evaluating the effect of anti-COVID-19 drugs on multiple transporters found that remdesivir, lopinavir, and ritonavir inhibited the OATP1B1 and OATP1B3 mediated transport of the test compound pyranine ⁵¹.The clinical implications of this in vitro study are unclear, but it demonstrates pharmacokinetic alterations in OATP substrates with the use of both ART and remdesivir. Remdesivir’s prescribing information states that, in vitro, it is both an inhibitor and a substrate of OATP1B1, but only an inhibitor of OATP1B3 ³⁴. With remdesivir’s relatively short half-life, there is little concern surrounding its ability to cause drug-drug interactions with ART through OATP1B1/1B3 ⁵¹. While concern for transporter-mediated reactions can often be dismissed, awareness of the potential for pharmacokinetic changes can be an important utility when treating acute disease states like COVID-19.

5.0. Induction of Metabolic Enzymes

Metabolic enzymes can be induced, resulting in increased expression of the enzyme, and decreased bioavailability of substrates. This is especially crucial in HIV, as sustained antiretroviral concentrations are necessary to suppress the viral load to an undetectable level. Currently used HIV and SARS-CoV-2 therapeutics can induce CYP3A4.Glucocorticoids such as dexamethasone for treating COVID-19, and efavirenz, etravirine, and nevirapine for treating HIV are all known to induce CYP3A4 ^{35, 52–54}. Unlike inhibition, induction is not immediate as protein expression takes several days, resulting in higher levels of enzymatic activity ¹⁴.

5.1. Dexamethasone

Which therapies are used for the treatment of SARS-CoV-2 depends on the patient’s clinical and hospitalization status ⁵⁵. Treatment regimens for non-hospitalized patients can be divided into regimens for those with a high risk of progression and for those without. Treatments for hospitalized patients vary based on the degree of supplemental oxygen required⁵⁶. Dexamethasone is utilized as a treatment for SARS-CoV-2 infection and was shown in the RECOVERY trial to be safe and effective in most patients requiring supplemental oxygen ⁵⁵. In this trial, dexamethasone was found to decrease the 28-day mortality and increase pulmonary function of hospitalized patients requiring any degree of supplemental oxygen ⁵⁵. However, since dexamethasone is both a CYP3A4 substrate and dose-dependent CYP3A4 inducer, there is a high potential for drug-drug interactions. Importantly, this interaction is most relevant at the moderate to high doses which may be used for patients with severe SARS-CoV-2 ³⁵.

5.2. Antiretroviral Cytochrome P450 3A4 Inducers

Since enzyme induction can take days to weeks, chronic, rather than acute, therapies that induce CYP3A4 are of greater concern when discussing the drug-drug interactions between these classes. The NNRTIs nevirapine, etravirine, and efavirenz are CYP3A4 inducers that are used in the treatment of HIV ^52–54. CYP3A4 induction by these drugs can compromise the bioavailability of other drugs taken by the patient; this can complicate the administration and prescribing of medications for the acute treatment of COVID-19.

Some therapies used in the treatment of COVID-19 are CYP3A4 substrates. The interaction between CYP3A4 inducers and dexamethasone is of the most concern. The COVID-19 treatment guidelines recommend that most patients receiving supplemental oxygen should also be given dexamethasone, often in combination with remdesivir, baricitinib, or tocilizumab ⁵⁷. Induction of CYP3A4 by the antiretrovirals listed above can reduce dexamethasone concentrations and compromise dexamethasone efficacy, especially when a low dose of dexamethasone (<1.5 mg) is used ³⁵. A study evaluating the effects of ART on glucocorticoid exposure found that patients in the efavirenz group exhibited a 40% reduction in the half-life of prednisolone compared to patients not on ART ⁵⁸. In the context of patients requiring supplemental oxygen for severe COVID-19, awareness of these interactions can be crucial in assuring the effectiveness of life-saving therapies.

There is concern with the interaction between the CYP3A4 inducers and NMV/r. The COVID-19 treatment guidelines dictate that most patients who meet the criteria for a high risk of disease progression that are outpatient should be given NMV/r. Induction of CYP3A4 by the antiretrovirals listed above can reduce NMV/r concentrations and compromise NMV/r efficacy ^{32, 59}. A study evaluating the effects of efavirenz on maraviroc when combined with lopinavir/ritonavir found that the boosting effect of ritonavir on maraviroc was diminished by about 65%% of AUC and Cmax⁵⁹. In the context of outpatient care, these interactions can be detrimental to those seeking care.

5.3. Corticosteroids Used in COVID-19 Treatments

Dexamethasone is a CYP3A4 inducer³⁵. When coadministered with CYP3A4 substrates, moderate doses (1.5 - 6 mg) of dexamethasone increases the metabolism of substrates and lead to lower plasma concentrations of these substrates³⁵. A number of the drugs used for the treatment of HIV are substrates of CYP3A4, including nevirapine, etravirine, efavirenz, doravirine, rilpivirine, bictegravir, and maraviroc. Coadministration with the CYP3A4 inducer rifampicin, decreased oral rilpivirine Cmax and AUC by 69% and 80%, respectively, compared to rilpivirine alone ⁶⁰. This demonstrates that moderately dose dexamethasone can have an unintended dampening effect on antiretroviral regimens that contain CYP3A4 substrates. Some antiretrovirals such as maraviroc and doravirine have recommended dose increases that may be necessary to overcome the effects of CYP3A4 inducers to ensure optimal therapeutic levels ^61–63.

The package inserts for rilpivirine and cabotegravir/rilpivirine state that these drugs should not be coadministered with dexamethasone if it is being used for more than a single dose ^{64, 65}. This creates a conflict with the use of dexamethasone for the treatment of COVID-19, as current guidelines recommend maintaining patients on their current ART therapies without drug substitution, where possible ⁸. There are other corticosteroids which do not induce CYP3A4 to this degree; however, they are less widely studied for COVID-19. These include prednisone, methylprednisolone, and hydrocortisone, which have been deemed acceptable when dexamethasone is not available or possible to use ⁸. Dexamethasone induced induction of CYP3A4 may result in subtherapeutic concentrations of injected cabotegravir and rilpivirine, prior when the next dose should be administered. One modeling study suggests that this interaction may be overcome by the additional administration of oral rilpivirine along with the injection ⁶⁶ .

While some drugs can be dose adjusted safely, others such as rilpivirine require additional caution ⁶⁷. A three-fold increase in the normal rilpivirine dose is associated with QTc prolongation, creating concern to make dose increases in the presence of CYP3A4 inducers.⁶⁷. Rilpivirine is also combined with cabotegravir in a depot shot given every 1-2 months. If CYP3A4 is induced, rilpivirine is cleared faster from the body, including both oral and injectable administration. As a result, the drug’s effect may not last the full dosing interval and viral rebound could possibly occur ⁶³.

5.4. UDP-glucuronosyltransferase (UGT) inducers

Although best known for its pharmacoenhancing ability, ritonavir is also a UGT1A1 inducer. It is part of NMV/r that is commonly used to treat COVID-19 in the outpatient setting ^{8, 68}. Similar to CYP3A4 inducers, UGT1A1 enzyme inducers lower the bioavailability of its substrates; however, UGT1A1 has different substrates and inducers than CYP3A4 ^{21, 69, 70}. A number of the drugs used for the treatment of HIV are substrates of UGT1A1, including cabotegravir, bictegravir, dolutegravir, elvitegravir, and raltegravir ^70–74. Coadministration of steady-state rifampin 600 mg, a UGT1A1 inducer, and cabotegravir 30 mg, a UGT1A1 substrate, has been shown to decrease oral cabotegravir AUC and half-life by approximately 60% ⁷⁰. This demonstrates that the use of UGT1A1 inducers like ritonavir may cause UGT1A1 substrates to fall below therapeutic levels. The package inserts for oral and injectable cabotegravir and cabotegravir/rilpivirine state that strong UGT1A1 inducers should not be coadministered with cabotegravir ^{32, 75, 76}. It is assumed that since the drug is metabolized in the liver, UGT1A1 induction accelerates the clearance of intramuscular cabotegravir.

The degree of UGT1A1 induction caused by NMV/r over the five day treatment period is unclear. The SFPT classify the interaction between NMV/r and INSTIs as weak, and state that NMV/r can be used without dose adjustments to either therapy ³². However, the in vivo study mentioned above cautions against the coadministration of a UGT1A1 inducer and cabotegravir, which is listed as a contraindication in the labeling for cabotegravir therapies^{32, 54, 70} . With this clinical conflict, it is important to recognize that there are alternative outpatient therapies available which do not induce UGT1A1, such as molnupiravir or remdesivir^{8, 35, 77}. If providers are prescribing NMV/r to patients receiving cabotegravir/rilpivirine, they should use caution as therapeutic drug monitoring is limited in outpatient settings ⁷⁰. Similar to CYP3A4 induction, UGT1A1 induction can be overcome by decreasing the cabotegravir/rilpivirine dosing interval from every 8 weeks to every 4 weeks. A study showed splitting the cabotegravir 400 mg dose into 2 equal doses of 200 mg together was shown to increase AUC by 2 fold ^{66, 78}. However, more studies are needed to determine the specific pharmacokinetic profile of depot injections in the presence of inducers and inhibitors.

While the other integrase inhibitors such as bictegravir, dolutegravir, elvitegravir, raltegravir are also UGT1A1 substrates, they are not contraindicated with UGT1A1 inducers ^{52, 71–73}. These drugs taken every day pose less concern as their concentrations will quickly rebound upon discontinuation of the UGT1A1 inducer. Since nirmatrelvir-ritonavir is used in an outpatient setting, there is limited potential for clinical monitoring. It may be beneficial to determine the AUC of the integrase inhibitors drugs 1 week after the last dose of nirmatrelvir-ritonavir to ensure adequate viral suppression.⁷⁹

6.0. Additive Organ Toxicity

6.1. Additive QT-prolongation

The QT interval is an electrocardiographic measure used to predict the risk of a life-threatening arrhythmia known as torsades de pointes (TdP). TdP is defined as twisting of the QRS complex. Some medications have the adverse effect of prolonging the QT-interval, and as such QT interval should be monitored. It is a common clinical precaution to avoid the prescribing of multiple QT-prolonging agents to reduce the risk of TdP. Tisdale et al. details that the risk of administering one QT-prolonging drug is similar to the risk of administering 2 or more QT-prolonging drugs at the same time ⁸⁰. One study directed at evaluating the potential for additive QT-prolongation evaluated drugs based on their Arizona Center for Education and Research on Therapeutics (AZCERT) classification. In regimens with multiple QT-prolonging drugs, the involvement of drugs with a known TdP risk were shown to result in additive effects on the QT interval ⁸¹. The AZCERT TdP defines the term risk classification as severity of the risk of TdP. The AZCERT classifications for COVID-19 and ARV drugs are listed in table 2 where applicable. Drugs that are not classified under AZCERT are not listed, meaning they either have not demonstrated QT-prolongation by Adverse Drug Event Causality Analysis (ADECA) standards or have not been evaluated for QT-prolongation.

Table 2:

AZCERT classifications for TdP risk

Drug	AZCERT TdP-risk classification
Atazanavir	Conditional
Efavirenz	possible
Lopinavir/ritonavir	possible
Remdesivir	possible
Rilpivirine	possible

Based on these studies, the AZCERT classification of the listed drugs, and the limited duration of COVID-19 therapies, the interaction between ARV and COVID-19 therapies is unlikely to yield meaningful QT prolongations in the absence of known TdP risks. However, CYP3A4 inhibition by NMR/r may lead to overexposure of atazanavir, and atazanavir’s conditional risk classification means that the risk of TdP is elevated in the presence of pharmacokinetic DDIs. In one study, ATV showed a patient’s QTc interval increasing two hours after taking the first dose. Although this result was not considered statistically different from baseline, it did show that ATV had a higher risk of QTc prolongation than other PIs⁸². EKG monitoring may be warranted while using the therapies listed above, especially drugs with possible TdP risk that have been shown to prolong the QT-interval ⁸³.

Drug interactions between ART and COVID-19 therapies could introduce a problem of QTc prolongation which can prove fatal to some patients especially those with an already established cardiac history. More studies need to be done with ART and COVID-19 therapies to more accurately establish a relationship between these drug interactions and QTc prolongation.

6.2. Additive Nephrotoxicity

When starting new medications, it is important to assess a patient’s renal function to inform therapeutic choices. Several studies have shown that patients developing an acute kidney injury (AKI) in any setting is a major risk factor for many other complications and significantly contributes to overall mortality⁸⁴. There are limited therapeutic options for the treatment of kidney injury, the best prevention method that can be used is avoiding nephrotoxic agents¹⁹. Avoiding kidney injuries is not only beneficial to overall mortality and morbidity patient outcomes but also cost-effective for these patients.

Concerns that can arise with the coadministration of COVID-19 treatments and ART is the potential for AKI. ⁸⁵. A case-control study found coadministration of acyclovir with ceftriaxone in children increased their risk of acute kidney injury ^{86, 87}. It is well documented that combinations of nephrotoxic agents have either an additive or synergistic effect on kidney injury ⁸⁸.

Both COVID-19 therapies and ARTs can be nephrotoxic or potentially nephrotoxic, and when combined may cause additive or synergistic acute kidney injuries ^88–91. Imatinib, which has previously been used to treat COVID-19 patients, and the antiretrovirals atazanavir, lopinavir/ritonavir, raltegravir, tenofovir alafenamide, and tenofovir disoproxil fumarate are all known to cause acute kidney injury to varying degrees. It is important to note that both PLWH and patients with COVID-19 are both at a higher risk of acute kidney injury as the diseases independently cause kidney damage ^{92, 93}. A study found that PLWH have a higher incidence of chronic kidney disease (CKD) (4.3% vs 2.1%) and hypertension (45.4% vs 30.5%) when compared to uninfected individuals ⁶⁷. There needs to be caution taken during these therapies, especially in these vulnerable populations when adding nephrotoxic agents to their established drug therapy.

Serum creatinine changes can also dictate drug selection as many drugs in both regimens are dose adjusted based on impaired creatinine clearance. The package insert for baricitinib recommends an adjusted dose below 30 mL/min and recommended against below 15 mL/min.

HIV induced acute kidney injury is relatively commonly due to dehydration, sepsis and drug therapies, while COVID induced AKI has mechanisms that predominantly include direct kidney injury resulting from tubular injury along with nephrotoxic drugs ^{94, 95}. PLWH tend to also have a higher incidence of CKD and AKI. One study showed the odds ratio of HIV patients acquiring AKI in pre-HAART was 2.9% which substantially increased to 6.0% in post-HAART therapy ⁹⁶.

A study done by the British HIV Association found that thirteen out of 64 patients on TDF therapy and given diclofenac developed an AKI shortly after starting diclofenac. In this study it was only the patients on TDF before starting diclofenac that developed an AKI while those patients on TDF-sparing cART therapy did not ⁹⁷.

NMV/r, currently approvedfor mild-moderate cases of COVID-19, the package insert includes a section for renal dose adjustments with an eGFR of >/= 30 to <60ml/min and is recommended against use in severe renal impairment (<30mL/min) ⁹⁸.

While molnupiravir can be safely used in patients with renal impairment, remdesivir is not safe due to the excipient betadex sulfobutyl ether sodium, used as a drug delivery system, and is renally cleared and accumulates in patients with decreased renal function. Administration of remdesivir is not recommended in patients with eGFR less than 30 mL/min ⁹⁹. Drugs account for approximately 20 percent of incidences of acute renal failure. Among older adults, the incidence of drug-induced nephrotoxicity may be as high as 66 percent compared to earlier studies due to the life expectancy increase with advancements in health care ¹⁰⁰.

For PLWH who need to receive therapy for COVID-19, the therapeutic goal is to maximize therapeutic efficacy while decreasing the likelihood of drug-drug interactions that could synergistically worsen kidney function. Many HIV and COVID-19 therapies currently in use each have a risk of causing kidney dysfunction as seen in table 3. Often with greater efficacy comes more serious adverse effects. Kidney damage is irreversible in most instances, so prevention is paramount to avoiding lifelong kidney damage.

Table 3.

Risk of organ damage for drugs of interest

Drug	Heart (QTc)	Liver	Kidney
COVID-19
Dexamethasone		X Δ
Hydrocortisone		X Δ
Imatinib	Possible	X Δ O	X O
Methylprednisolone		X Δ
Nirmatrelvir/r		X Δ
Remdesivir	Possible	X	X
Ritonavir	Possible	X Δ	Δ ▢
Ruxolitinib		X
Tofacitinib		X Δ O	Δ
Drug
HIV
Abacavir		X Δ	Δ
Atazanavir	Conditional	X Δ	X O
Bictegravir
Cabotegravir		X O	X
Cobicistat		X	X Δ ▢
Darunavir		X O
Dolutegravir		X Δ O	X ▢
Efavirenz	Possible	X Δ O
Elvitegravir		X
Emtricitabine		X
Lamivudine		X Δ
Lopinavir / r	Possible	X Δ ▢	X Δ O
Raltegravir		X Δ	X Δ O
Rilpivirine	Possible	X Δ	X Δ
Tenofovir AF		X	X Δ O
Tenofovir DF		X Δ	X

6.3. Additive Hepatotoxicity

One concern with the coadministration of ART and treatments for COVID-19 is the potential for injury to the liver. A study evaluating the risk of drug-induced liver injury (DILI) found that the combination of two or more hepatotoxic drugs increased the risk of DILI 6-fold¹⁰¹. One recent publication focused on patients hospitalized with SARS-CoV-2 infection found that administration of at least three potentially hepatotoxic drugs was correlated with hepatocellular injury ¹⁰². The introduction of multiple potent combinations has changed fatal outcomes of PLWH to that of a chronic one ¹⁰³.

Some antiretrovirals are considered hepatotoxic or potentially hepatotoxic. Nevirapine, for example, has a black boxed warning for hepatotoxicity ⁹. Evaluating the risk of DILI for patients on ART and the drugs used to treat COVID-19 is necessary, as SARS-CoV-2 is known to inflame and potentially injure the liver independent of drug therapy ¹⁰⁴. Drug-related transaminase elevations may affect drug selection for COVID-19 treatment. The package insert for remdesivir recommends considering discontinuation of remdesivir when alanine transaminase (ALT) is greater than 10 times the upper limits of the normal range (ULN) and to discontinue indefinitely when symptoms of liver inflammation are present ⁹. Receiving tocilizumab for COVID-19 was correlated with hepatocellular injury, and its emergency use authorization states that it is not recommended in patients with baseline ALT that is 10 times the ULN ^{12, 102}.Providers should be aware that the risk of DILI may be elevated when using these therapies in patients with potentially hepatotoxic ART, and that ART may elevate baseline transaminases to a degree that affects therapy selection. In addition, a randomized trial that included nevirapine and efavirenz (EFV), identified taking nevirapine once daily as being more hepatotoxic than taking it twice daily or once daily with EFV ¹⁰³. The typical onset of DILI was seen approximately in twelve weeks after initiating an ART therapy ¹⁰⁵.

Ritonavir (RTV) is a pharmacoenhancer that works by inhibiting CYP3A4, could also have a role in increasing the risk of having a liver injury due to concomitant hepatotoxic medications ¹⁰³. As previously noted, it is co-administered with nirmatrelvir for the treatment of SARS-CoV-2. The use of higher doses of RTV has been clinically reported to increase the chance of liver injury to a higher extent than the lower doses used for patients with COVID-19 ¹. Also, the combination therapy of RTV/LPV is contraindicated in patients with COVID-19 patients that are experiencing severe liver injury⁶². It is important for PLWH who also are being treated for COVID-19 to continue their ART, and it is thus important to monitor their therapy to avoid the risk of DILI.

Table 3 describes the organ toxicity profile of antiretroviral and COVID-19 drugs and provides a reference for the hepatic adverse effects of certain ARTs. PLWH are also at an increased risk for viral hepatitis, which harms the liver directly and is treated with known hepatotoxic drugs including rifampin and isoniazid ^{12, 102}.

7.0. Conclusion

Generally, ART and drugs for COVID-19 interact through various mechanisms and metabolic pathways. The clinical implications of these interactions are often minor, owing to low magnitude of interactions and short treatment durations. The consensus appears to be that PLWH receiving treatment for COVID-19 should be monitored for adverse effects or treatment failure in the context of major interactions, namely those mediated by the potent inhibition and induction of a metabolic enzyme or transporter. With newly introduced COVID-19 therapies and ever-evolving ART regimens, studies evaluating simultaneous or sequential administration of these drugs are few. For interactions where coadministration has not been studied, studies based on prototypical enzyme inhibitors and inducers can be used to make predictions about pharmacokinetic outcomes, but care must be taken, as this can miss actual drug interactions. For interactions resulting in serious adverse effects such as QTc prolongation or organ damage mediated by toxic drugs, a higher standard of pharmacovigilance is required.

8.0. Expert Opinion

We have described many of the interactions between currently used ARV and the current therapies used in the treatment of COVID-19. For example, starting a patient on NMV/r for COVID-19 can be detrimental to their efavirenz ART therapy, due to the inhibition of CYP3A4 affecting efavirenz concentrations ³². Further, the comorbidities which are relatively common in PLWH can account for additional drug interactions, requiring additional steps to handle. Many PLWH have higher rates of cancer, hypertension, asthma, and other diseases that require maintenance medications that cannot be interfered with due to worsening outcomes, limiting potential COVID-19 therapeutics ⁶⁷.

Antiretroviral medications have significantly improved over the years, and a key focus for new medications has been, and will continue to be to improve side effect profiles and the potential for drug-drug interactions. Before beginning therapy for COVID-19, it is critically important to obtain a complete medication profile. This is especially important for prescribing COVID-19 therapeutics for PLWH. The majority of outpatient treatment regimens for COVID-19 are prescribed for a short duration, most commonly 5 days for both molnupiravir and nirmatrelvir/r ¹⁰⁶. Based on this limited duration, the severity of potential drug-drug interactions must be considered. If a drug has a wide therapeutic index, with limited risk of toxicity, both drugs can likely be safely administered with only a limited risk of a severe adverse reactions. For drugs with a more narrow therapeutic index, or a higher risk of toxicity, it may be necessary to tailor therapy to avoid this interaction ¹⁰⁷. Nirmatrelvir/r is the medication which is most likely to be not used in these circumstances, with a need to use molnupiravir instead.

Understanding the mechanisms of action for antiretrovirals is essential for choosing a safe and efficacious treatment for COVID. For serious cases of COVID-19 requiring hospital admission and the use of alternate therapies such as tofacitinib, that is a CYP3A4 substrates, then a patients medication history would be an important factor when deciding to use these therapies ¹⁰⁸. A medications half-life is also an important factor to consider when looking at therapies. Drug-drug interactions where a drug has a long half-life may be particularly dangerous for patients due to an extended duration of the interaction ¹⁰⁹.The problem then becomes if a patient has an active drug in their system with a half-life over the normal course of treatment, such as five days for Paxlovid (NMR/r tablets), medication reconciliations can provide guidance for determining appropriate therapies. When a patient is on an established regimen of antiretrovirals, it is imperative to keep them on these antiretrovirals to maintain virologic suppression. Adding on new medications, especially those with long half-lives, can negatively impact their progress made with their antiretrovirals.

A previously discussed, PLWH are one of the many patient populations that incorporates multiple drug therapies in their regimens, predisposing them to more serious drug toxicities including DILI and AKI ¹¹⁰. Understanding the process of how a drug is being metabolized, such as if the drug is a substrate, inhibitor or an inducer of a metabolic enzyme or drug transporter plays a major role in determining an effective medication regimen for these patients who are at a higher risk of having adverse effects. Having a holistic understanding of other medications and disease states is essential before beginning new drugs or modifying existing therapy. Additional monitoring, as previously noted for rilpivirine as well as other medications may also be required. Despite new medications with improved effectiveness and safety profiles are being approved, having this information is still critically important.

SARS-CoV-2 has been and will continue to be a significant challenge in the future. Over the course of the SARS-CoV-2 pandemic, new mutations have evolved, and will continue to evolve going forward. To date, no approved small molecule therapeutics have had reduced efficacy against any new variants that have developed. This is dissimilar to approved monoclonal antibodies for SARS-CoV-2 treatment, which have been removed from the market due to decreased efficacy against circulating variants ¹¹¹. While it has not yet occurred, there is still the risk for SARS-CoV-2 to develop resistance to small molecule therapeutics. Based on this risk, it is critically important that small molecule drug development for the treatment of SARS-CoV-2 continues. Newer drugs with improved efficacy, side effect, and pharmacokinetic profiles has the strong potential to further improve patient outcomes to SARS-CoV-2.

This ongoing drug development must mimic the development cycle that occurred for antiretrovirals. Since the initial approval of antiretrovirals for the treatment of HIV-1, we have seen significant improvements in drug efficacy, side effect profile, and pharmacokinetic profile. This has resulted in the majority of patients being able to durably suppress viral replication with single tablet regimens with excellent side effect profiles ¹⁰⁹. Contrasted to outpatient treatment for SARS-CoV-2, which can require large pill volumes administered twice daily, there is significant room for improvement with current therapies.

While potent therapeutics to treat COVID-19 in PLWH have been introduced, the risk of drug-drug interactions remains a potential significant barrier for these patients. Due to the transient nature of many of the medications used for the treatment of SARS-CoV-2, many of the interactions may be of limited clinical importance. Further, many of the interactions outlined here are theoretical, rather than clinically confirmed. Due to the theoretical nature of many of these interactions, care is necessary if they are administered together, but the combinations are not necessarily contraindicated. Vaccination for SARS-CoV-2 remains the most cost-effective therapeutic intervention for all patients, and specifically for PLWH. Approved SARS-CoV-2 vaccines are able to significantly decrease the risk of acquiring disease and decreasing disease severity in those who still contract SARS-CoV-2 ¹¹². This decreases the need for COVID-19 therapeutics in these patients, which also decreases the risk of drug-drug interactions.