A Comprehensive Pharmacological and Clinical Review of Darunavir (DB01264)

Executive Summary

Darunavir is a second-generation, nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) that constitutes a critical component of modern antiretroviral therapy (ART). Identified by DrugBank ID DB01264 and CAS Number 206361-99-1, it was developed through a structure-based design approach to overcome the significant challenges of drug resistance that plagued first-generation PIs. Its mechanism of action involves potent inhibition of the HIV-1 protease enzyme, preventing the cleavage of viral Gag-Pol polyproteins and thereby halting the production of mature, infectious virions. A defining feature of Darunavir is its unique ability to form extensive hydrogen bonds with the highly conserved backbone of the protease active site, a property that confers an exceptionally high genetic barrier to resistance.

Clinically, Darunavir is never used alone. Due to extensive first-pass metabolism by the cytochrome P450 3A (CYP3A) enzyme system, it must be co-administered with a pharmacokinetic (PK) booster—either ritonavir or cobicistat. This boosting strategy dramatically increases its bioavailability and extends its half-life, allowing for once or twice-daily dosing. However, this reliance on potent CYP3A inhibition is also the source of its primary clinical limitation: a high potential for significant drug-drug interactions with a wide array of commonly prescribed medications.

Approved for use in both treatment-naïve and treatment-experienced adults and in pediatric patients three years of age and older, Darunavir's role in HIV treatment has evolved. While formerly a recommended first-line agent, the advent of integrase strand transfer inhibitors (INSTIs) with more favorable side effect and interaction profiles has shifted Darunavir to a specialized role. Current guidelines position it as a key agent for specific clinical scenarios, such as for patients initiating rapid ART before resistance results are available, for individuals with potential transmitted INSTI resistance, and as a cornerstone of salvage therapy for patients with extensive treatment histories and multidrug-resistant virus. Common adverse effects include gastrointestinal disturbances, headache, and rash. More serious, though less common, risks include hepatotoxicity, severe skin reactions, and metabolic complications such as hyperlipidemia and hyperglycemia. The development of fixed-dose combinations, including the single-tablet regimen Symtuza®, has simplified its administration, helping to maintain its relevance in an increasingly competitive therapeutic landscape.

Introduction and Drug Identification

Overview and Historical Context

Darunavir (DRV), developed under the investigational code TMC114, is a second-generation, nonpeptidic HIV-1 protease inhibitor (PI) that marked a significant advancement in the management of HIV infection.[1] The evolution of PIs began in the mid-1990s with first-generation agents like saquinavir, ritonavir, and indinavir.[4] While transformative at the time, these early drugs were frequently limited by severe side effects, complex dosing schedules with high pill burdens, substantial drug toxicities, and a low genetic barrier to resistance, with drug-resistant mutations often emerging within a year of use.[2]

In response to these challenges, Darunavir was engineered through a rational, structure-based drug design process. This effort, led by chemist Arun K. Ghosh at the University of Illinois at Chicago and developed by Tibotec (a subsidiary of Johnson & Johnson), specifically aimed to create a molecule that could form robust interactions with the HIV-1 protease active site, even in the presence of mutations that conferred resistance to older PIs.[1] The result was a potent inhibitor designed to overcome the limitations of its predecessors.

Darunavir received its initial accelerated approval from the U.S. Food and Drug Administration (FDA) on June 23, 2006.[6] This approval was for treatment-experienced adult patients, providing a critical new therapeutic option for individuals with multidrug-resistant HIV for whom other regimens had failed. This milestone was a direct result of its demonstrated efficacy against resistant viral strains. Its global importance in HIV treatment is further underscored by its inclusion on the World Health Organization's List of Essential Medicines.[1]

Drug Identification and Nomenclature

Precise identification of a pharmaceutical agent is fundamental for clinical practice, research, and regulatory affairs. Darunavir is known by a variety of names and identifiers across different contexts and databases. It is classified as a small molecule drug.[8]

Its primary brand name is Prezista®, under which it is marketed as a standalone agent.[1] To simplify complex HIV regimens, it is also available in several fixed-dose combination (FDC) products. These include Prezcobix® and Rezolsta®, which combine Darunavir with the pharmacokinetic booster cobicistat, and Symtuza®, a complete single-tablet regimen (STR) that includes Darunavir, cobicistat, emtricitabine, and tenofovir alafenamide.[1] During its development phase, it was widely referred to by its investigational code, TMC114 or TMC-114, and is also known by the synonym Derunavir.[2]

The Chemical Abstracts Service (CAS) has assigned the number 206361-99-1 to the free form of Darunavir.[2] Different salt or solvate forms have distinct CAS numbers, such as 635728-49-3 for darunavir ethanolate and 2281870-65-1 for darunavir dihydrate.[2] The comprehensive identifiers for Darunavir are consolidated in Table 1, providing a definitive reference for the compound.

Table 1: Key Identifiers and Properties of Darunavir

Property	Value	Source(s)
DrugBank ID	DB01264	6
Drug Type	Small Molecule	8
CAS Number (free)	206361-99-1	2
IUPAC Name	furan-4-yl] N--3-hydroxy-1-phenylbutan-2-yl]carbamate	5
Molecular Formula	C27​H37​N3​O7​S	8
Average Molecular Weight	547.66 g/mol	2
Monoisotopic Weight	547.235221243 g/mol	2
InChIKey	CJBJHOAVZSMMDJ-HEXNFIEUSA-N	2
SMILES	CC(C)CN(CC@HO)S(=O)(=O)C4=CC=C(C=C4)N
UNII	YO603Y8113
ChEMBL ID	CHEMBL1323
KEGG ID	D03656

Physicochemical Properties and Formulations

Chemical Structure and Properties

Darunavir's chemical structure is integral to its pharmacological activity and safety profile. It is a complex organic molecule classified as an N,N-disubstituted benzenesulfonamide, which also contains a furofuran moiety and a carbamate ester group. The full International Union of Pure and Applied Chemistry (IUPAC) name isfuran-4-yl] N--3-hydroxy-1-phenylbutan-2-yl]carbamate.

The presence of the sulfonamide group is of clinical note, as it raises a theoretical concern for cross-sensitivity reactions in patients with a known allergy to sulfa drugs. While clinical data suggest the risk is low, caution is advised in the official prescribing information. The molecular formula of Darunavir is

C27​H37​N3​O7​S, with an average molecular weight of 547.66 g/mol.

In its pure form, Darunavir is a white to off-white powder or amorphous solid. Its solubility characteristics are a key determinant of its formulation and pharmacokinetic behavior. It is poorly soluble in aqueous media; the ethanolate form has a solubility of approximately 0.15 mg/mL in water at 20°C. This low aqueous solubility contributes to its inherently poor oral bioavailability when administered alone. Conversely, it is soluble in organic solvents such as dimethyl sulfoxide (DMSO) and dimethylformamide (DMF). In terms of stability, the compound is stable enough for shipment at ambient temperatures but requires refrigerated or frozen conditions (-20°C) for long-term storage to ensure its chemical integrity.

Formulations and Strengths

The pharmaceutical development of Darunavir has yielded a variety of formulations designed to meet diverse clinical needs, from treating young children to simplifying regimens for adults. This progression from standalone tablets to comprehensive single-tablet regimens reflects a broader trend in HIV therapy focused on improving patient adherence by reducing pill burden.

Initially, Darunavir was available only as a single-agent product, Prezista®, which must be co-administered with a separate PK booster. To accommodate different dosing requirements, particularly for pediatric patients, Prezista® is supplied in multiple strengths:

• Tablets: 75 mg, 150 mg, 600 mg, and 800 mg.
• Oral Suspension: A liquid formulation with a concentration of 100 mg/mL is available for pediatric patients or adults who cannot swallow tablets.

The evolution of Darunavir's formulation strategy highlights the pharmaceutical industry's response to the clinical imperative of simplifying treatment to enhance adherence. The initial requirement to take Darunavir with a separate booster and other antiretrovirals resulted in a high pill burden, a known barrier to consistent medication intake. The first step toward simplification was the development of fixed-dose combinations (FDCs) that co-formulated Darunavir with a booster. The introduction of Prezcobix® (and Rezolsta®) combined 800 mg of Darunavir with 150 mg of the booster cobicistat, reducing the regimen by one pill.

The ultimate achievement in this trajectory is the single-tablet regimen (STR), which combines a complete ART regimen into one daily pill. Symtuza® represents this pinnacle for Darunavir, integrating the potent, high-resistance-barrier PI with a modern nucleoside reverse transcriptase inhibitor (NRTI) backbone (200 mg emtricitabine and 10 mg tenofovir alafenamide) and the booster cobicistat (150 mg). The availability of Symtuza® allows Darunavir to remain a competitive option, particularly for initial therapy in select scenarios, by offering the convenience of an STR that was previously exclusive to INSTI-based regimens. This formulation diversity ensures that the clinical benefits of Darunavir can be delivered in a patient-friendly manner, addressing one of the historical disadvantages of PI-based therapy.

Pharmacology

Mechanism of Action

Darunavir exerts its antiviral effect by acting as a competitive, nonpeptidic inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease enzyme. This aspartic protease is absolutely essential for the viral life cycle. Following the integration of viral DNA into the host cell's genome and subsequent transcription and translation, the virus produces large, non-functional polyprotein precursors, namely Gag and Gag-Pol. The HIV-1 protease functions like a molecular scissor, cleaving these polyproteins at specific sites to release the individual mature structural proteins (such as matrix, capsid, and nucleocapsid) and essential viral enzymes (such as reverse transcriptase, integrase, and the protease itself). This cleavage process, known as proteolytic processing, is a prerequisite for the assembly and maturation of new, fully infectious virions.

Darunavir potently and selectively binds to the active site of the HIV-1 protease, physically obstructing the access of the natural polyprotein substrates. By blocking this critical enzymatic step, it prevents the maturation of viral particles. Furthermore, evidence suggests that Darunavir also inhibits the dimerization of the protease enzyme, a conformational change necessary for its catalytic activity. The ultimate result is the production of immature, disorganized, and non-infectious viral particles from the surface of infected cells, which effectively terminates the viral replication cycle and prevents the spread of the infection to new cells.

The remarkable potency and high genetic barrier to resistance of Darunavir are rooted in its specific molecular interactions with the protease enzyme. Its structure was intentionally designed to maximize hydrogen bonding with the enzyme's active site. Critically, many of these bonds are formed with the peptide backbone of the protease, particularly at highly conserved residues within the catalytic triad (Asp25, Asp25') and the flexible "flap" regions that cover the active site (Asp29, Asp30, Asp30', and Gly27). Because the backbone conformation is essential for the enzyme's structural integrity, it is far less prone to mutation than the amino acid side chains. This "backbone binding" hypothesis is the cornerstone of Darunavir's durability. While first-generation PIs interacted primarily with mutable side chains, Darunavir's ability to anchor to the stable backbone allows it to maintain its binding affinity and inhibitory activity even when resistance mutations emerge elsewhere in the enzyme. This molecular strategy directly translates into a high barrier to resistance, making Darunavir a robust and reliable agent for managing HIV, especially in the face of pre-existing resistance. Additionally, its inherent molecular flexibility allows it to adapt its conformation to fit within the subtly altered shapes of mutated protease enzymes, further contributing to its broad activity against resistant strains.

Pharmacodynamics and Antiviral Activity

The pharmacodynamic profile of Darunavir is characterized by its potent and broad-spectrum antiviral activity. In vitro studies have consistently demonstrated its efficacy against a wide array of HIV-1 laboratory strains and primary clinical isolates. In acutely infected T-cell lines and peripheral blood mononuclear cells, it exhibits median half-maximal effective concentration (EC50​) values in the low nanomolar range, typically from 1.2 to 8.5 nM. Against specific cell lines like MT-2, the half-maximal inhibitory concentration (

IC50​) is as low as 3 nM.

This high potency is a direct consequence of its exceptionally strong binding affinity for the HIV-1 protease. The dissociation constant (Kd​), a measure of the drug-target binding strength, is reported to be an exceptionally low 4.5 x 10−12 M. This indicates a binding interaction that is 100 to 1,000 times stronger than that of many other PIs, providing a significant therapeutic advantage.

Darunavir's activity extends across various HIV-1 subtypes, including group M (subtypes A, B, C, D, E, F, G) and group O isolates, as well as laboratory strains of HIV-2. This broad coverage makes it a versatile agent for use in diverse patient populations globally. In a clinical setting, the administration of boosted Darunavir as part of a combination ART regimen translates these in vitro properties into tangible therapeutic benefits. It leads to a rapid and sustained decrease in plasma HIV-1 RNA levels (viral load) and a corresponding increase in the count of CD4+ T-lymphocytes. These two surrogate markers are the primary measures of ART efficacy and are directly correlated with a reduction in HIV-related morbidity and mortality, including a decreased risk of opportunistic infections and AIDS-defining illnesses.

Resistance Profile and Genetic Barrier

A defining and clinically crucial characteristic of Darunavir is its high genetic barrier to resistance. It was specifically developed to be active against HIV strains that had already acquired resistance mutations to earlier PIs, and this remains its most significant therapeutic advantage. The concept of a "high barrier" means that multiple specific viral mutations are required to significantly compromise the drug's activity, making the development of clinically relevant resistance a slow and difficult process for the virus. For boosted PI regimens, particularly those containing Darunavir, virologic failure is infrequently associated with the selection of new, major PI resistance-associated mutations (RAMs).

This robustness is evident in its in vitro resistance profile. Studies have shown that Darunavir retains potent activity against 90% of more than 3,000 clinical isolates that were resistant to other commonly used PIs, such as amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir. Even when faced with multidrug-resistant protease variants that reduce its binding affinity 13-fold, the interaction remains 1.5 orders of magnitude tighter than that of first-generation PIs, often preserving sufficient activity for viral suppression.

While highly resilient, Darunavir is not impervious to resistance. A specific set of DRV-RAMs has been identified that, when accumulated, can reduce its susceptibility. The presence of these mutations has direct clinical implications, as dosing recommendations for Darunavir differ for patients with and without DRV-RAMs. Patients with at least one DRV-RAM require a twice-daily dosing regimen (600 mg of Darunavir with 100 mg of ritonavir) to achieve adequate drug concentrations to overcome the reduced susceptibility, whereas treatment-naïve patients or those without DRV-RAMs can typically be treated with a once-daily regimen. Furthermore, Darunavir-resistant viruses have been observed to have limited cross-resistance to the PI tipranavir, suggesting a potential, albeit limited, sequential use of these agents in highly treatment-experienced patients.

Pharmacokinetics (ADME)

The Critical Role of Pharmacokinetic Boosting

The entire pharmacokinetic (PK) profile and clinical utility of Darunavir are fundamentally dependent on its co-administration with a PK enhancer, or "booster." Darunavir is a substrate for both the hepatic cytochrome P450 3A (CYP3A) enzyme system, the body's primary drug-metabolizing engine, and the P-glycoprotein (P-gp) efflux pump, which actively transports drugs out of cells and back into the gut lumen. When Darunavir is administered alone, it undergoes extensive first-pass metabolism in the gut wall and liver, leading to very low and sub-therapeutic plasma concentrations. The absolute oral bioavailability of an unboosted 600 mg dose of Darunavir is a mere 37%.

To overcome this metabolic vulnerability, Darunavir must always be administered with a potent inhibitor of CYP3A. The two boosters used for this purpose are ritonavir (Norvir®) and cobicistat (Tybost®). These agents pharmacologically enhance Darunavir by potently inhibiting its CYP3A-mediated metabolism. This inhibition has a profound effect: it increases the absolute bioavailability of Darunavir to 82% and results in a dramatic 14-fold increase in overall drug exposure (AUC). This boosting strategy is what makes Darunavir a viable therapeutic agent, allowing for effective antiviral concentrations to be maintained with convenient once or twice-daily dosing schedules. Failure to administer Darunavir with a booster and with food will result in a loss of efficacy.

This reliance on a booster is a double-edged sword that defines Darunavir's entire clinical profile. The very mechanism that makes it effective—potent CYP3A inhibition—is also the source of its most significant clinical challenge: drug-drug interactions. Because CYP3A metabolizes a vast number of other medications (e.g., statins, anticoagulants, corticosteroids, and many others), co-administering boosted Darunavir can dangerously increase the levels of these other drugs, leading to toxicity. This is not an unintended side effect but a direct and predictable consequence of its mechanism of administration. Consequently, a clinician prescribing Darunavir is not just managing one drug; they are managing a potent metabolic inhibitor and must meticulously review a patient's entire medication list for potential interactions. This pharmacokinetic reality shapes its safety profile, its contraindications, and its place in therapy relative to newer agents with cleaner interaction profiles.

Absorption

The absorption of Darunavir is significantly influenced by the presence of food. When boosted Darunavir is taken with a meal, its maximum plasma concentration (Cmax​) and area under the curve (AUC) are increased by approximately 30% compared to when it is taken in a fasted state. This food effect is clinically significant, and patients must be counseled to always take their Darunavir dose with food to ensure optimal absorption and efficacy. Studies have shown that drug exposure is similar across a wide range of meal types, from low-fat (240 kcal, 12 g fat) to high-fat (928 kcal, 56 g fat), indicating that the presence of food, rather than its specific content, is the key factor.

Following oral administration, the time to reach maximum plasma concentration (Tmax​) is approximately 2.5 to 4 hours. Absorption can also be affected by certain drug interactions. For example, co-administration with antacids containing polyvalent cations can reduce absorption, and it is recommended that these medications be taken at least 1 hour before or 2 hours after the Darunavir dose.

Distribution

Once absorbed into the systemic circulation, Darunavir exhibits extensive distribution into body tissues. Its volume of distribution (Vd​) is relatively large, with reported values ranging from 130 L to approximately 220 L. This indicates that the drug does not remain confined to the plasma compartment but distributes into extravascular spaces.

Darunavir is highly bound to plasma proteins, with approximately 95% of the drug in circulation bound. It binds primarily to alpha 1-acid glycoprotein (AAG), an acute-phase reactant protein, and to a lesser extent, to albumin. This high degree of protein binding can influence its distribution and potential for drug interactions.

Metabolism

Darunavir is extensively metabolized in the liver. The primary metabolic pathway involves oxidation, mediated almost exclusively by the CYP3A family of cytochrome P450 enzymes. The co-administered PK booster, either ritonavir or cobicistat, serves to potently inhibit this CYP3A-mediated metabolism, thereby increasing Darunavir's plasma concentrations and prolonging its duration of action. Although several oxidative metabolites of Darunavir have been identified, they are at least 10-fold less active than the parent compound and do not make a significant contribution to its overall antiviral effect.

Excretion and Half-Life

The elimination of Darunavir occurs primarily through metabolism, with subsequent excretion of metabolites and unchanged drug in the feces and urine. A mass balance study conducted in healthy volunteers receiving a single radiolabeled dose of boosted Darunavir showed that approximately 79.5% of the administered dose was recovered in the feces, while 13.9% was recovered in the urine.

The impact of the PK booster is clearly demonstrated in the excretion profile. In boosted administration, a substantial portion of the excreted drug is unchanged Darunavir (48.8% of the dose in feces and 7.7% in urine). This contrasts sharply with unboosted administration, where very little unchanged drug is excreted (8.0% in feces and 1.2% in urine), reflecting the extensive metabolism that occurs in the absence of a booster.

The systemic clearance of Darunavir is significantly reduced by boosting, from 32.8 L/h when administered alone to 5.9 L/h when co-administered with ritonavir. This reduced clearance contributes to a terminal elimination half-life of approximately 15 hours for boosted Darunavir, a duration that conveniently supports once or twice-daily dosing regimens. Renal clearance is a minor pathway of elimination for Darunavir.

Clinical Efficacy and Therapeutic Use

Approved Indications and Patient Populations

Darunavir, when co-administered with a pharmacokinetic booster (ritonavir or cobicistat) and in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Its approval covers a broad range of patients, reflecting its robust efficacy and high barrier to resistance.

• Adults and Adolescents: Darunavir is approved for use in both treatment-naïve adults (those who have never received HIV treatment) and treatment-experienced adults (those who have previously been on other ART regimens). This dual indication was granted after clinical trials demonstrated its efficacy in both populations.
• Pediatric Patients: The use of Darunavir is approved for children aged 3 years and older who weigh at least 10 kg. The availability of an oral suspension and low-strength tablets facilitates its use in this population. However, Darunavir is explicitly not recommended for use in children younger than 3 years of age. This restriction is based on preclinical studies in juvenile rats that showed toxicity and mortality, raising safety concerns for very young children.
• Other Uses: Beyond its primary indication for treatment, Darunavir is sometimes included in regimens for post-exposure prophylaxis (PEP) for individuals, such as healthcare workers, who have had a potential occupational or non-occupational exposure to HIV.

Dosing and Administration

Correct dosing of Darunavir is critical for achieving therapeutic efficacy while minimizing the risk of adverse events and the development of drug resistance. The dosing strategy is complex and must be tailored to the individual patient based on their age, body weight, prior treatment history, and the presence or absence of Darunavir resistance-associated mutations (DRV-RAMs). A crucial administration requirement is that Darunavir must always be taken with food to ensure adequate absorption and bioavailability.

The recommended dosing regimens are summarized in Table 2.

Table 2: Recommended Dosing of Boosted Darunavir in Adult and Pediatric Patients

Patient Population	Darunavir Dose	Booster Dose	Frequency	Notes	Source(s)
Adults & Adolescents (≥40 kg)
Treatment-Naïve or Treatment-Experienced with NO DRV-RAMs	800 mg	Ritonavir 100 mg OR Cobicistat 150 mg	Once Daily	This is the standard once-daily regimen for most adult patients.
Treatment-Experienced with at least ONE DRV-RAM	600 mg	Ritonavir 100 mg	Twice Daily	Higher frequency is needed to overcome reduced susceptibility. Cobicistat is not indicated for this regimen.
Pregnant Patients	600 mg	Ritonavir 100 mg	Twice Daily	Twice-daily dosing is recommended to compensate for lower drug exposure during pregnancy.
Pediatric Patients (3 to <18 years)
Treatment-Naïve or Treatment-Experienced with NO DRV-RAMs (Once Daily)
Weight 15 kg to <30 kg	600 mg	Ritonavir 100 mg	Once Daily	Dose based on weight bands.
Weight 30 kg to <40 kg	675 mg	Ritonavir 100 mg	Once Daily	Oral suspension may be required to achieve this dose.
Weight ≥40 kg	800 mg	Ritonavir 100 mg	Once Daily	Same as adult dose.
Treatment-Experienced with at least ONE DRV-RAM (Twice Daily)
Weight 15 kg to <30 kg	375 mg	Ritonavir 48 mg (or 50 mg)	Twice Daily	Precise ritonavir dose may require oral solution.
Weight 30 kg to <40 kg	450 mg	Ritonavir 60 mg	Twice Daily
Weight ≥40 kg	600 mg	Ritonavir 100 mg	Twice Daily	Same as adult dose for this population.

Note: Dosing for children weighing 10 kg to <15 kg is also available and highly specific, requiring careful calculation by a healthcare provider.

Efficacy in Pivotal Clinical Trials

The clinical development of Darunavir has been supported by a series of pivotal trials that established its efficacy across different patient populations and in comparison to other antiretroviral agents.

• Treatment-Experienced Patients (POWER 1 & 2): These Phase IIb studies were instrumental in securing Darunavir's initial FDA approval. They enrolled heavily treatment-experienced patients with extensive PI resistance. The results demonstrated that boosted Darunavir provided a statistically superior virologic response (reduction in HIV-1 RNA) and immunologic response (increase in CD4+ cells) compared to an investigator-selected comparator PI regimen. These trials firmly established Darunavir as a powerful new tool for salvage therapy.
• Treatment-Naïve Patients (ARTEMIS): To expand its indication, the ARTEMIS study compared once-daily boosted Darunavir (800/100 mg) to the then-standard-of-care boosted PI, lopinavir/ritonavir (Kaletra), in treatment-naïve patients. The study found that Darunavir was non-inferior to lopinavir/ritonavir at 48 weeks. A subsequent analysis at 96 weeks showed that Darunavir was actually superior in achieving virologic suppression. This landmark trial led to the FDA's approval of once-daily Darunavir for first-line therapy in 2008.
• Dosing Regimen Optimization (ODIN): The ODIN trial addressed whether a simplified once-daily regimen could be used in treatment-experienced patients. It compared once-daily Darunavir/ritonavir (800/100 mg) to the standard twice-daily dose (600/100 mg) in treatment-experienced patients who did not have any DRV-RAMs at baseline. The study concluded that the once-daily dose was non-inferior to the twice-daily dose, providing a more convenient option for this specific patient subgroup.
• Comparative Efficacy Trials:
• FLAMINGO Study: This head-to-head trial compared boosted Darunavir with the integrase strand transfer inhibitor (INSTI) dolutegravir (DTG), both in combination with two NRTIs, in treatment-naïve patients. At 96 weeks, DTG demonstrated significantly higher rates of virologic suppression. The Darunavir group had more virologic failures, particularly in patients with high baseline viral loads (>100,000 copies/mL). This study was a key piece of evidence contributing to the shift in treatment guidelines favoring INSTIs as the preferred first-line agents for most patients.
• DRIVE-FORWARD Study: This trial compared boosted Darunavir to the non-nucleoside reverse transcriptase inhibitor (NNRTI) doravirine (DOR). Doravirine was found to be non-inferior to Darunavir at 48 weeks and superior at 96 weeks. Additionally, doravirine was associated with a more favorable lipid profile, with smaller increases in LDL cholesterol and triglycerides.
• AMBER Study: This trial evaluated the efficacy and safety of the single-tablet regimen Symtuza® (DRV/c/TAF/FTC). It was found to be non-inferior to a multi-pill regimen consisting of boosted Darunavir plus TDF/FTC in treatment-naïve patients. Importantly, the TAF-containing STR demonstrated an improved renal and bone safety profile compared to the TDF-containing regimen, highlighting the benefits of modern NRTI backbones.

Position in Major HIV Treatment Guidelines (DHHS)

The role of Darunavir in HIV treatment has evolved significantly, as reflected in the U.S. Department of Health and Human Services (DHHS) guidelines for adults and adolescents. This evolution is a direct result of the accumulation of clinical trial data, particularly from studies comparing PIs to newer agent classes like INSTIs.

While once a "Recommended" first-line agent, boosted Darunavir-based regimens have been moved to the category of "Other Initial Antiretroviral Regimens for Certain Clinical Scenarios". The primary "Recommended" regimens for most people with HIV are now based on INSTIs, such as those containing bictegravir or dolutegravir, due to their high efficacy, good tolerability, and generally cleaner drug-drug interaction profiles.

Darunavir's clinical role is now more specialized, leveraging its primary strength: a high genetic barrier to resistance. The guidelines position it as a strategic tool for situations where resistance is a key concern:

• Rapid ART Initiation: When initiating ART immediately after diagnosis ("rapid start") and before genotypic resistance test results are available, a boosted PI regimen is a recommended option. This is because transmitted resistance to PIs is uncommon, making it a reliable choice to ensure initial viral suppression.
• History of CAB-LA PrEP: For individuals who acquire HIV despite using long-acting cabotegravir (CAB-LA) for pre-exposure prophylaxis (PrEP), there is a risk of transmitted INSTI resistance. In this scenario, a boosted Darunavir regimen is recommended as the initial therapy pending the results of INSTI resistance testing.
• Salvage Therapy: For patients experiencing virologic failure on other regimens, particularly those with complex treatment histories, Darunavir is a cornerstone of salvage therapy. For instance, in patients failing a first-line NNRTI-based regimen, a combination of dolutegravir plus boosted Darunavir is a recommended salvage option.

In the context of pregnancy, ritonavir-boosted Darunavir (DRV/r) administered twice daily is a recommended PI option. In contrast, cobicistat-boosted Darunavir (DRV/c) and once-daily DRV/r are generally not recommended during pregnancy due to evidence of substantially lower drug concentrations during the second and third trimesters, which poses a risk of virologic failure and perinatal transmission.

This shift in guidelines does not diminish Darunavir's importance but rather refines its application. It has transitioned from a general-purpose frontline agent to a high-value, specialized asset for managing the most challenging clinical scenarios in HIV care: uncertainty and resistance. Its value is no longer defined by being the optimal choice for every patient, but by being one of the most robust and reliable options for some of the most difficult-to-treat individuals.

Safety and Tolerability Profile

Common and Serious Adverse Events

Darunavir, particularly when boosted with ritonavir or cobicistat, is generally well-tolerated by most patients. However, like all antiretroviral agents, it is associated with a range of potential adverse events, from common and mild to rare but severe.

• Common Adverse Reactions: The most frequently reported adverse drug reactions, occurring in 2-5% or more of patients in clinical trials, are primarily gastrointestinal in nature. These include diarrhea, nausea, abdominal pain, and vomiting. Headache and rash are also common. Rash occurs in approximately 7-10% of patients and is typically mild-to-moderate in severity. It often appears within the first four weeks of treatment and frequently resolves with continued dosing without requiring discontinuation of the drug.
• Metabolic Complications: As a member of the protease inhibitor class, Darunavir is associated with several metabolic complications, which are considered class effects:
• Hyperglycemia and Diabetes Mellitus: New-onset diabetes, worsening of pre-existing diabetes, and hyperglycemia have been reported.
• Lipodystrophy: Changes in body fat, including redistribution (e.g., central fat accumulation) and/or loss of peripheral fat, can occur with long-term ART, including PI-based regimens.
• Hyperlipidemia: Increases in total cholesterol, LDL cholesterol, and triglycerides are known side effects of PIs. While Darunavir may have a more favorable lipid profile than some older PIs, monitoring is still required.
• Serious Adverse Reactions: Although rare, several potentially life-threatening adverse reactions have been associated with Darunavir:
• Hepatotoxicity: Drug-induced hepatitis, including acute and cytolytic hepatitis, has been reported in approximately 0.5% of patients in clinical trials. Post-marketing surveillance has identified rare cases of severe liver injury, including some fatalities. The risk of hepatotoxicity is significantly increased in patients with pre-existing liver dysfunction, such as chronic hepatitis B or C co-infection, or cirrhosis.
• Severe Skin Reactions: In rare instances (<0.4%), Darunavir can cause severe or life-threatening skin reactions. These include Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), Drug Rash with Eosinophilia and Systemic Symptoms (DRESS), and Acute Generalized Exanthematous Pustulosis (AGEP). These reactions can be accompanied by fever, malaise, and organ involvement, and require immediate discontinuation of the drug.
• Other Reported Events: Other clinically significant events reported with PI use, including Darunavir, are an increased risk of bleeding events in patients with hemophilia, the development of Immune Reconstitution Inflammatory Syndrome (IRIS) upon initiation of ART, myalgia (muscle pain), and osteonecrosis (bone death).

Warnings, Precautions, and Contraindications

The prescribing information for Darunavir includes several important warnings, precautions, and contraindications to ensure its safe use. Notably, based on the provided FDA labels, there is no black box warning for Darunavir.

• Hepatotoxicity Warning: Due to the risk of liver injury, it is recommended that liver function tests (AST/ALT) be conducted prior to initiating therapy and monitored regularly during treatment. Monitoring should be more frequent during the first several months of therapy and in patients with underlying chronic hepatitis B or C, or cirrhosis. Therapy should be promptly interrupted or discontinued if there is evidence of new or worsening liver dysfunction, such as clinically significant enzyme elevations or symptoms like jaundice, fatigue, or anorexia.
• Severe Skin Reactions Warning: Patients must be educated about the signs and symptoms of severe skin reactions. They should be instructed to contact their healthcare provider immediately if they develop a severe rash or a rash accompanied by systemic symptoms like fever, blisters, oral lesions, conjunctivitis, or muscle/joint aches. Darunavir must be discontinued immediately if such a reaction is suspected.
• Sulfa Allergy Precaution: Darunavir contains a sulfonamide chemical group. Although clinical trials have shown that the incidence and severity of rash are similar in patients with or without a history of sulfonamide allergy, the official recommendation is to use Darunavir with caution in this population.
• Contraindications: Darunavir is contraindicated in several situations:
• Co-administration with specific drugs: It must not be co-administered with medications that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations could lead to serious or life-threatening events. Examples include the alpha-blocker alfuzosin, ergot derivatives (e.g., ergotamine), the antipsychotic pimozide, and the statins lovastatin and simvastatin.
• Severe Hepatic Impairment: Due to its extensive hepatic metabolism, Darunavir is contraindicated for use in patients with severe liver disease (Child-Pugh Class C).

Use in Special Populations

The use of Darunavir requires specific considerations in certain patient populations.

• Pregnancy: The choice of Darunavir formulation and dosing is critical during pregnancy. Pharmacokinetic studies have shown that drug exposures of both Darunavir and its booster cobicistat are substantially lower during the second and third trimesters. To avoid the risk of sub-therapeutic levels, virologic failure, and perinatal HIV transmission, ritonavir-boosted Darunavir (DRV/r) dosed at 600 mg/100 mg twice daily is the recommended regimen. Once-daily DRV/r and all cobicistat-boosted Darunavir (DRV/c) regimens are not recommended for use during pregnancy. Data from the Antiretroviral Pregnancy Registry (APR) have monitored a sufficient number of first-trimester exposures to Darunavir and have not detected an increased risk of overall birth defects.
• Lactation: To prevent the risk of postnatal transmission of HIV to the infant, women with HIV are instructed not to breastfeed, regardless of their antiretroviral therapy. It is not known if Darunavir passes into human breast milk.
• Pediatrics: Darunavir is approved for children aged 3 years and older weighing at least 10 kg. However, it is not recommended for use in children younger than 3 years due to toxicity observed in juvenile animal studies. Dosing in the pediatric population is complex, based on body weight, and stratified by treatment experience and resistance profile, requiring careful calculation by the healthcare provider.
• Hepatic Impairment: No dose adjustment is necessary for patients with mild or moderate hepatic impairment (Child-Pugh Class A or B). However, it is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C).
• Renal Impairment: Since renal clearance of Darunavir is minimal, no dose adjustment is required for patients with any degree of renal impairment. It is considered unlikely to be removed by hemodialysis.

Drug-Drug Interactions (DDIs)

Pharmacokinetic Mechanisms of Interaction

The drug-drug interaction profile of Darunavir is extensive and clinically significant, primarily driven by the potent enzymatic inhibition of its mandatory pharmacokinetic boosters, ritonavir and cobicistat. Boosted Darunavir regimens act as strong inhibitors of the cytochrome P450 3A (CYP3A) isoenzyme, which is responsible for the metabolism of a vast number of drugs across many therapeutic classes. Additionally, boosted Darunavir can moderately inhibit CYP2D6 and may induce other metabolic pathways, creating a complex interaction profile. This potent inhibition of drug metabolism can lead to dangerously elevated plasma concentrations of co-administered medications, increasing the risk of toxicity. Conversely, drugs that are strong inducers of CYP3A (e.g., rifampin, certain anticonvulsants) can significantly lower Darunavir concentrations, leading to a loss of virologic efficacy and the potential for drug resistance. Due to this complexity, there are over 500 documented drug interactions with Darunavir, with more than 100 classified as major, requiring avoidance or careful management.

Clinically Significant Interactions and Management

Managing DDIs is a cornerstone of safe prescribing for any boosted Darunavir regimen. A thorough medication review, including prescription, over-the-counter, and herbal products, is essential before initiation and during therapy. Table 3 summarizes the management of key, clinically significant interactions.

Table 3: Management of Key Drug-Drug Interactions with Boosted Darunavir

Concomitant Drug Class	Specific Drug(s)	Interaction and Clinical Effect	Management Recommendation	Source(s)
HMG-CoA Reductase Inhibitors (Statins)	Simvastatin, Lovastatin	Significantly increased statin levels, high risk of myopathy and rhabdomyolysis.	Contraindicated.
	Atorvastatin, Rosuvastatin	Increased statin levels.	Initiate at the lowest possible dose and titrate cautiously. Do not exceed 20 mg/day of atorvastatin or rosuvastatin. Monitor for muscle pain/weakness.
	Pravastatin, Pitavastatin	Minimal interaction; preferred agents.	Initiate at a low dose and monitor. Pravastatin levels may be slightly increased.
Anticoagulants / Antiplatelets	Rivaroxaban, Ticagrelor, Clopidogrel, Vorapaxar	Increased anticoagulant/antiplatelet levels (risk of bleeding) or decreased efficacy (clopidogrel).	Contraindicated or Do not coadminister.
	Warfarin	Unpredictable effect on INR (may increase or decrease depending on booster).	Monitor INR frequently, especially upon initiation or discontinuation of the PI. Adjust warfarin dose accordingly.
	Apixaban	Increased apixaban levels.	Reduce apixaban dose by 50% for standard doses; avoid in patients on low-dose apixaban.
Corticosteroids (Inhaled, Nasal, Systemic, Injectable)	Fluticasone, Budesonide, Mometasone, Betamethasone, Triamcinolone	Significantly increased systemic steroid exposure, leading to Cushing's syndrome and adrenal suppression.	Avoid co-administration. If essential, use with extreme caution and monitor for systemic steroid effects. Beclomethasone is a safer alternative.
Anticonvulsants (CYP3A Inducers)	Carbamazepine, Phenytoin, Phenobarbital	May significantly decrease Darunavir levels, risking virologic failure.	Contraindicated (especially with cobicistat). With ritonavir, use is highly discouraged; requires intensive monitoring of both drug levels if unavoidable.
Antimycobacterials	Rifampin	Potent CYP3A inducer; drastically reduces Darunavir levels.	Contraindicated.
	Rifabutin	Darunavir increases rifabutin levels.	Reduce rifabutin dose (e.g., to 150 mg every other day or daily) and monitor for rifabutin toxicity (e.g., uveitis, neutropenia).
PDE5 Inhibitors	Sildenafil, Tadalafil, Vardenafil, Avanafil	Significantly increased PDE5 inhibitor levels.	For erectile dysfunction: Reduce dose significantly (e.g., sildenafil 25 mg every 48 hours). For pulmonary arterial hypertension (PAH): Contraindicated.
Psychotropic Agents	Pimozide, Lurasidone	Increased levels with risk of life-threatening cardiac arrhythmias.	Contraindicated.
	Trazodone, certain Benzodiazepines (Midazolam, Triazolam, Alprazolam)	Increased levels with risk of profound sedation and respiratory depression.	Oral midazolam and triazolam are contraindicated. Use others with extreme caution and consider dose reduction. Lorazepam, oxazepam, and temazepam are safer alternatives.
Ergot Derivatives	Dihydroergotamine, Ergotamine	Increased levels with risk of acute ergot toxicity (vasospasm, ischemia).	Contraindicated.
Hormonal Contraceptives	Ethinyl estradiol-containing products	Darunavir may decrease estrogen levels, potentially reducing contraceptive efficacy.	Use of alternative or additional (barrier) contraceptive methods is recommended.
Herbal Products	St. John's Wort	Potent CYP3A inducer; significantly reduces Darunavir levels.	Contraindicated.

Regulatory History and Conclusion

Regulatory Timeline

The regulatory journey of Darunavir reflects its evolution from a targeted salvage agent to a broader therapeutic option within the HIV treatment landscape. Key milestones in its history with the U.S. Food and Drug Administration (FDA) illustrate this progression:

• December 27, 2005: Tibotec Pharmaceuticals submitted the New Drug Application (NDA) for its investigational PI, then known as TMC114, to the FDA.
• June 23, 2006: The FDA granted accelerated approval to Prezista® (darunavir), co-administered with ritonavir, for the treatment of HIV-1 infection in treatment-experienced adult patients who had evidence of viral replication and HIV-1 strains resistant to other PIs. This marked its entry into the market as a critical new option for patients with limited treatment choices.
• October 22, 2008: Following the positive results of the ARTEMIS trial, the FDA expanded Darunavir's approval to include a once-daily dosing regimen for treatment-naïve adults, establishing it as a viable first-line therapy option.
• December 14, 2010: The FDA further refined its indication, approving the once-daily 800/100 mg regimen for treatment-experienced adults who had no Darunavir resistance-associated mutations (DRV-RAMs), based on the ODIN study. This provided a more convenient option for a subset of experienced patients.
• July 18, 2016: The FDA approved an update to the Prezista® label to include its use in pregnant women, providing crucial guidance for this special population.

This timeline demonstrates a strategic expansion of Darunavir's approved uses, driven by accumulating clinical evidence of its efficacy and safety in progressively broader patient populations.

Expert Conclusion and Future Perspective

Darunavir stands as a landmark achievement in the field of rational drug design and a pivotal agent in the history of HIV therapeutics. As a second-generation protease inhibitor, it was successfully engineered to address the critical clinical challenge of drug resistance that had limited the long-term efficacy of its predecessors. Its unique molecular structure, which facilitates robust binding to the conserved backbone of the HIV-1 protease, endowed it with a high genetic barrier to resistance and durable antiviral activity. This property cemented its role as a cornerstone of HIV therapy for more than a decade, particularly for patients with multidrug-resistant virus.

The primary strength of Darunavir—its high resistance barrier—remains its most valuable clinical asset today. This characteristic makes it an indispensable tool for managing heavily treatment-experienced patients with complex resistance histories and a reliable option for specific initial therapy scenarios where the risk of pre-existing or transmitted resistance is a primary concern.

However, the clinical profile of Darunavir is inseparably linked to the trade-offs of its required pharmacokinetic boosting. While essential for achieving therapeutic drug levels, the potent CYP3A4 inhibition by its boosters, ritonavir and cobicistat, creates a complex and challenging drug-drug interaction profile. This necessitates meticulous management of concomitant medications and contributes to a higher risk of metabolic side effects, such as hyperlipidemia and insulin resistance, compared to newer agent classes.

The treatment landscape for HIV has been fundamentally reshaped by the advent of highly potent and well-tolerated integrase strand transfer inhibitor (INSTI)-based single-tablet regimens. Clinical trial data consistently show that while Darunavir is highly effective, it is often non-inferior but seldom superior to modern INSTIs in terms of tolerability, regimen simplicity, and, in some head-to-head comparisons, virologic suppression in treatment-naïve populations. This evidence has logically led to the shift in clinical guidelines, which now favor INSTIs as the preferred first-line therapy for the majority of patients.

In conclusion, the clinical journey of Darunavir exemplifies the dynamic evolution of antiretroviral therapy. It has transitioned from a revolutionary salvage agent and a mainstream frontline competitor to a vital, specialized tool. Its future utility lies not in widespread competition with INSTIs for the broadest patient population, but in its strategic and targeted deployment where its unique, high-resistance-barrier profile is most critically needed: in complex salvage therapy, in cases of potential transmitted resistance (e.g., after CAB-LA PrEP failure), and for patients in whom INSTIs may be contraindicated or have failed. Darunavir remains a critical component of the global HIV treatment armamentarium, a testament to the power of structure-based drug design and a powerful reminder of the ongoing need for diverse mechanisms of action to effectively combat a highly adaptable and persistent pathogen.

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