A Comprehensive Monograph on the Dolutegravir/Rilpivirine Fixed-Dose Combination (Juluca®) for HIV-1 Maintenance Therapy

Executive Summary

The fixed-dose combination (FDC) of dolutegravir 50 mg and rilpivirine 25 mg, marketed as Juluca®, represents a significant evolution in the management of Human Immunodeficiency Virus Type 1 (HIV-1) infection. Its approval marked the introduction of the first complete, single-pill, two-drug regimen (2DR) for the maintenance treatment of adults with HIV-1.[1] The specific indication for this therapy is as a replacement (switch) regimen for adults who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral therapy (ART) for at least six months, with no history of treatment failure and no known or suspected resistance to either component.[3] This therapeutic strategy challenges the long-standing paradigm of three- or four-drug ART, aiming to reduce cumulative lifetime drug exposure.

The regimen's robust efficacy is rooted in its dual mechanism of action, which targets two distinct and critical stages of the HIV-1 lifecycle. Dolutegravir, a second-generation integrase strand transfer inhibitor (INSTI), prevents the integration of viral DNA into the host cell's genome, while rilpivirine, a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), blocks the conversion of viral RNA to DNA.[6] This synergistic blockade provides potent and durable viral suppression. The rationale for this 2DR is to minimize the number of antiretroviral agents a patient is exposed to over a lifetime, thereby potentially reducing the risk of long-term, cumulative drug-associated toxicities.[9]

Pivotal clinical evidence supporting the approval of dolutegravir/rilpivirine comes from the identical Phase III SWORD-1 and SWORD-2 trials. These studies demonstrated that switching to the two-drug regimen was non-inferior to continuing a standard three- or four-drug regimen in maintaining virologic suppression at 48 weeks.[9] Long-term follow-up data through 148 weeks confirmed the regimen's durable efficacy, with a very low rate of virologic failure and no development of resistance to the integrase inhibitor component.[13] Furthermore, the trials highlighted a key benefit of this nucleoside reverse transcriptase inhibitor (NRTI)-sparing regimen: significant improvements in bone and renal biomarkers in patients who switched from tenofovir disoproxil fumarate (TDF)-containing regimens.

The safety profile of dolutegravir/rilpivirine is generally well-tolerated, with the most common adverse effects being diarrhea and headache.[14] However, the regimen carries important warnings for potentially serious adverse reactions, including severe skin and hypersensitivity reactions, hepatotoxicity, and depressive disorders, which require vigilant clinical monitoring.[4] A primary clinical management challenge is the regimen's specific administration requirements and complex drug-drug interaction profile. It must be administered with a meal to ensure adequate absorption of rilpivirine, and its efficacy can be severely compromised by co-administration with common medications such as proton pump inhibitors, certain anticonvulsants, and supplements or antacids containing polyvalent cations.[5]

In conclusion, dolutegravir/rilpivirine is a valuable NRTI-sparing switch option for carefully selected, virologically suppressed adults with HIV-1. It offers the benefits of regimen simplification and a potential reduction in long-term renal and bone toxicity. However, its successful implementation in clinical practice is contingent upon meticulous patient selection, comprehensive counseling on administration requirements, and diligent management of its extensive drug-drug interaction profile.

Pharmacological Profile

Component Overview and Classification

The fixed-dose combination tablet Juluca® contains two distinct and potent active pharmaceutical ingredients that target the HIV-1 virus.[15]

Dolutegravir: This component is classified as a second-generation Integrase Strand Transfer Inhibitor (INSTI).[4] As a core component of modern antiretroviral therapy, dolutegravir is utilized in various combination regimens for the treatment of HIV-1 infection.[3] It is marketed individually under the brand name Tivicay®.[3]

Rilpivirine: This component is classified as a second-generation Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) and is structurally a diarylpyrimidine derivative.[4] Compared to first-generation NNRTIs such as efavirenz, rilpivirine is characterized by higher potency, a longer plasma half-life, and a more favorable side-effect profile.[18] It is marketed as a single agent under the brand name Edurant®.[15]

Combination Product: The FDC product, Juluca®, is formulated as a single pink, oval, biconvex tablet debossed with “SV J3T” on one side.[5] Each tablet contains 50 mg of dolutegravir (equivalent to 52.6 mg of dolutegravir sodium) and 25 mg of rilpivirine (equivalent to 27.5 mg of rilpivirine hydrochloride).[4]

Dual Mechanism of Action

The high efficacy of the dolutegravir/rilpivirine regimen is derived from its synergistic inhibition of two separate, essential enzymes in the HIV-1 replication cycle. This dual blockade provides a robust barrier to viral propagation.

Dolutegravir (INSTI Action): Dolutegravir exerts its antiviral effect by targeting HIV-1 integrase, an enzyme encoded by the virus that is indispensable for its replication.[7] Specifically, dolutegravir functions as an integrase strand transfer inhibitor. The HIV lifecycle requires the virus to integrate its genetic material into the host cell's DNA. This process involves the integrase enzyme catalyzing the insertion of viral DNA into the host genome. Dolutegravir binds with high affinity to the active site of the integrase enzyme, effectively blocking the crucial "strand transfer" step.[4] By preventing the covalent insertion of viral DNA into the host chromosome, dolutegravir halts the replication cycle at a late stage, thereby preventing the establishment of a productive infection in newly infected cells and reducing the viral load.[6]

Rilpivirine (NNRTI Action): Rilpivirine is a non-competitive inhibitor of the HIV-1 reverse transcriptase (RT) enzyme.[4] As a retrovirus, HIV carries its genetic information as RNA and must convert it into DNA before it can be integrated into the host genome. This conversion is performed by the RT enzyme. Rilpivirine binds directly to a hydrophobic, allosteric pocket on the RT enzyme, distinct from the active site where nucleosides bind.[8] This binding induces a conformational change in the enzyme's structure, which inhibits its catalytic activity and blocks the DNA polymerase function required for reverse transcription.[6] Rilpivirine is highly specific for viral RT and does not inhibit human cellular DNA polymerases α, β, or γ, which accounts for its targeted antiviral activity.[4]

The strategic pairing of these two drug classes is a cornerstone of the regimen's design. The combination leverages the exceptionally high genetic barrier to resistance of dolutegravir, which serves as a durable anchor for the regimen, with the established potency of a second-generation NNRTI. While NNRTIs as a class have a lower barrier to resistance, pairing rilpivirine with a robust INSTI like dolutegravir mitigates this risk in the context of maintenance therapy for virologically suppressed patients. This pharmacological rationale allows for the simplification to two drugs without compromising the long-term virologic control necessary for successful HIV management.

Clinical Pharmacokinetics and Metabolism

The absorption, distribution, metabolism, and elimination (ADME) properties of dolutegravir and rilpivirine are distinct and have critical implications for the clinical use of the combination tablet, particularly regarding administration requirements and drug-drug interactions.

Absorption:

• Following oral administration, dolutegravir is rapidly absorbed, with a time to maximum plasma concentration ($T_{max}$) of 2-3 hours.[16] Rilpivirine absorption is slightly slower, with a $T_{max}$ of 4-5 hours.[8]
• Food Effect: The administration of Juluca® with a meal is mandatory.[5] This requirement is primarily driven by the pharmacokinetic properties of rilpivirine. The bioavailability of rilpivirine is significantly reduced in a fasted state (by approximately 40%) or when taken with only a high-protein nutritional drink (by approximately 50%).[8] Food, particularly a meal that is not low-fat, enhances its absorption.
• Gastric pH Dependence: The absorption of rilpivirine is highly dependent on an acidic gastric environment for optimal solubility.[8] Medications that increase gastric pH, such as proton pump inhibitors (PPIs) and H2-receptor antagonists, can markedly decrease rilpivirine plasma concentrations, potentially leading to a loss of virologic response. This pH dependency is the basis for the contraindication with PPIs and the strict timing requirements for administration with other acid-reducing agents.[5]
• Chelation: The absorption of dolutegravir can be significantly reduced by chelation with polyvalent cations, such as calcium, iron, magnesium, and aluminum, which are commonly found in antacids, laxatives, and mineral supplements.[16] This interaction necessitates specific timing instructions to separate the administration of Juluca® from these products.[5]

Distribution: Both dolutegravir and rilpivirine are extensively bound to plasma proteins (greater than 99%), primarily albumin.[8]

Metabolism:

• Dolutegravir is primarily metabolized by uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), with a minor contribution from the cytochrome P450 (CYP) 3A4 enzyme.[5]
• Rilpivirine is predominantly metabolized by the CYP3A4 system, with a smaller role for CYP3A5.[8]

Elimination:

• Dolutegravir has a terminal half-life of approximately 14 hours, which supports convenient once-daily dosing.[16]
• Rilpivirine has a notably longer terminal half-life of approximately 45-50 hours.[8] Elimination occurs primarily via the feces (85%), with a very small amount excreted in the urine (6.1%).[8]

The distinct pharmacokinetic profiles of the two components are directly responsible for the regimen's complex clinical management requirements. While the single-pill formulation offers simplification in pill burden, it introduces significant complexity in patient counseling and medication management. The critical dependence of rilpivirine on food and acidic pH, the susceptibility of dolutegravir to cation chelation, and the reliance of both drugs on major metabolic pathways (UGT1A1 and CYP3A4) create a high potential for clinically significant drug-drug and drug-food interactions. This pharmacological reality means that the "simplification" to two drugs necessitates a heightened level of clinical vigilance from prescribers, pharmacists, and patients to ensure therapeutic success.

Pharmacokinetic Parameter	Dolutegravir	Rilpivirine
$T_{max}$ (Time to Peak Concentration)	2-3 hours 16	4-5 hours 8
Food Effect	Absorption increased with food 24	Mandatory administration with a meal. Bioavailability reduced by 40-50% without food 8
Gastric pH Dependence	Not significantly affected	Highly dependent on acidic pH. Absorption is severely reduced by acid-suppressing agents 8
Plasma Protein Binding	>99% 16	~99.7% 8
Primary Metabolism Pathway(s)	UGT1A1 (major), CYP3A4 (minor) 5	CYP3A4 (major), CYP3A5 (minor) 8
Terminal Half-life	~14 hours 16	~45-50 hours 8
Primary Elimination Route	Feces (unchanged drug and metabolites), Urine (metabolites)	Feces (85%), Urine (6.1%) 8

Resistance and Virologic Profile

The long-term durability of an antiretroviral regimen is closely linked to its genetic barrier to resistance. The dolutegravir/rilpivirine combination benefits from the high resistance barrier of its INSTI component.

Dolutegravir: As a second-generation INSTI, dolutegravir possesses a high genetic barrier to the development of resistance, particularly in treatment-naive individuals. In clinical trials of first-line therapy, the emergence of resistance-associated mutations at the time of virologic failure was a rare event.[16] While specific mutations, such as R263K, can be selected under drug pressure, they confer only a modest decrease in susceptibility to dolutegravir and often come at a cost to viral fitness, which may limit the potential for viral rebound.[16] However, it is important to note that the standard 50 mg dose of dolutegravir present in Juluca® may be insufficient for patients with pre-existing resistance to other INSTIs.[26]

Rilpivirine: In line with the NNRTI class, rilpivirine has a lower genetic barrier to resistance compared to dolutegravir. A single mutation can sometimes lead to high-level resistance. Furthermore, there is a potential for cross-resistance with other NNRTIs, such as efavirenz and nevirapine.[17]

Clinical Trial Resistance Findings: The SWORD-1 and SWORD-2 trials provided robust clinical data on the resistance profile of the combination regimen in its intended population. Over a follow-up period of 148 weeks, among the very few participants who experienced confirmed virologic failure, there were no cases of treatment-emergent resistance to dolutegravir.[13] NNRTI resistance-associated mutations were identified in only six participants, representing less than 1% of the total study population on the two-drug regimen.[13]

This strong resistance profile is a direct consequence of the trial's strict inclusion criteria and the regimen's indication. The SWORD studies exclusively enrolled patients who were already virologically suppressed for an extended period and had no history of treatment failure or known resistance mutations.[3] This pre-selection of a low-risk population is fundamental to the regimen's success. Rilpivirine, for instance, has demonstrated a higher risk of failure in treatment-naive patients with high baseline viral loads (>100,000 copies/mL).[8] Therefore, the regulatory approval and clinical guidelines for dolutegravir/rilpivirine appropriately restrict its use to a switch strategy in stable, suppressed patients. This ensures the regimen is used only in the population where its high barrier to resistance and long-term durability have been rigorously demonstrated.

Clinical Evidence from Pivotal Trials (SWORD-1 & SWORD-2)

Study Design and Rationale

The regulatory approval of the dolutegravir/rilpivirine fixed-dose combination was primarily supported by data from two large, identical Phase III clinical trials: SWORD-1 (NCT02429791) and SWORD-2 (NCT02422797).[11] These were randomized, multicenter, open-label, non-inferiority studies designed to challenge the long-standing paradigm of three- or four-drug antiretroviral therapy.

Objective: The primary objective of the SWORD program was to evaluate the efficacy, safety, and tolerability of switching virologically suppressed adults from their current, stable three- or four-drug antiretroviral regimen (CAR) to a two-drug regimen consisting of dolutegravir (50 mg) plus rilpivirine (25 mg) administered once daily.[27]

Population: The trials collectively enrolled 1,024 adults with HIV-1 infection from 13 countries.[9] The key inclusion criteria were designed to select a stable, low-risk population:

• Virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable ART regimen for at least six months prior to screening.[9]
• No history of virologic failure on any prior regimen.[10]
• No known or documented resistance-associated mutations to INSTIs or NNRTIs.13 The participants' CAR at baseline consisted of two nucleoside reverse transcriptase inhibitors (NRTIs) plus a third agent, which could be an INSTI, an NNRTI, or a boosted protease inhibitor (PI).27

Study Arms and Phases: The study design included two main phases to assess both short-term non-inferiority and long-term durability:

• Early Switch Phase (Day 1 to Week 52): Participants were randomized on a 1:1 basis to either switch immediately to the open-label two-drug regimen of dolutegravir plus rilpivirine (administered as separate tablets) or to continue their existing CAR.[27]
• Late Switch Phase (Week 52 to Week 148): At Week 52, participants in the CAR arm who remained virologically suppressed were given the option to switch to the dolutegravir plus rilpivirine regimen. All participants then continued on the two-drug regimen in an open-label extension phase, allowing for the collection of long-term efficacy and safety data up to 148 weeks.[27]

Efficacy Outcomes: Virologic Suppression and Durability

The SWORD trials successfully met their primary and secondary endpoints, providing robust evidence for the efficacy and durability of the two-drug regimen in the specified patient population.

Primary Endpoint (48 Weeks): The primary endpoint was the proportion of participants with plasma HIV-1 RNA <50 copies/mL at Week 48. The pooled analysis of both studies demonstrated that the two-drug regimen of dolutegravir plus rilpivirine was non-inferior to continuing a three- or four-drug CAR. Virologic suppression was maintained in 95% of participants in the two-drug regimen arm (486 out of 513) and 95% of participants in the CAR arm (485 out of 511).[9] The rate of virologic failure was exceptionally low in both groups: <1% in the dolutegravir plus rilpivirine arm and 1% in the CAR arm.[9]

Long-Term Durability (148 Weeks): The open-label extension phase provided critical data on the long-term durability of the two-drug regimen. The pooled analysis at Week 148, using the FDA snapshot algorithm, showed high and sustained rates of virologic suppression [13]:

• In the Early-Switch Group, who had 148 weeks of exposure to the two-drug regimen, 84% (432 out of 513) maintained HIV-1 RNA <50 copies/mL.
• In the Late-Switch Group, who had 96 weeks of exposure, 90% (428 out of 477) maintained suppression.
• Through the entire 148-week period, only 11 participants (1%) across both groups met the protocol-defined criteria for confirmed virologic withdrawal, underscoring the regimen's high efficacy and durability in this select population.[13]

Key Outcome	Dolutegravir + Rilpivirine Arm	Current Antiretroviral Regimen (CAR) Arm
Efficacy
Virologic Suppression (HIV-1 RNA <50 c/mL) at Week 48 9	95% (486/513)	95% (485/511)
Virologic Suppression at Week 148 (Early Switch Group) 13	84% (432/513)	N/A (Switched to 2DR at Week 52)
Confirmed Virologic Withdrawal (through Week 148) 13	1% (11 participants total)	N/A
Treatment-Emergent INSTI Resistance (through Week 148) 13	0%	N/A
Treatment-Emergent NNRTI Resistance (through Week 148) 13	<1% (6 participants total)	N/A
Safety
Discontinuations due to AEs (at Week 48) 9	4% (21 participants)	<1% (3 participants)
Grade 2-4 Drug-Related AEs (through Week 148, Early Switch Group) 13	6% (31 participants)	N/A

Safety and Tolerability Findings

The overall safety profile of the dolutegravir plus rilpivirine regimen in the SWORD trials was favorable and consistent with the known safety profiles of the individual components.[9]

Adverse Events (AEs):

• The most commonly reported adverse events (occurring in >5% of participants) in the dolutegravir plus rilpivirine arm were nasopharyngitis, headache, diarrhea, and upper respiratory tract infection.[9]
• Long-term data from the 148-week analysis showed a low incidence of moderate-to-severe (Grade 2-4) drug-related adverse events. These were observed in 6% (31 out of 513) of participants in the early-switch group and 3% (16 out of 477) in the late-switch group, indicating good long-term tolerability.[13]

Discontinuations due to AEs: During the initial 48-week randomized phase, a higher proportion of participants discontinued treatment due to adverse events in the switch arm (4%, or 21 participants) compared to the CAR arm (<1%, or 3 participants).[9] This observation is not uncommon in open-label switch studies, as patients moving from a long-term, well-tolerated regimen to a new one may be more sensitive to new side effects.

Impact on Bone and Renal Biomarkers

A particularly significant finding from the SWORD program was the positive impact of the two-drug regimen on key safety biomarkers, providing evidence for a tangible clinical benefit beyond simple virologic control. This was most pronounced in participants who switched from regimens containing tenofovir disoproxil fumarate (TDF), an NRTI known for its association with potential long-term renal and bone toxicity.

Bone Mineral Density (BMD): A substudy of the SWORD trials specifically assessed changes in bone health. At Week 48, participants who switched from a TDF-containing regimen to the NRTI-sparing dolutegravir plus rilpivirine regimen demonstrated statistically significant increases in mean BMD at both the total hip (1.34%) and lumbar spine.[12]

Renal Biomarkers: Similarly, participants who were taking TDF prior to entering the study showed significant improvements in key renal biomarkers after switching to the two-drug regimen.[13]

These findings are clinically important as they provide direct evidence supporting a key rationale for two-drug, NRTI-sparing regimens. The primary goal of the SWORD trials was to establish non-inferiority in viral suppression, which they achieved. However, the secondary findings on bone and renal health addressed a more nuanced but critical question: whether this simplified regimen could be safer over the long term. The data strongly suggest that for patients on TDF-based therapies, switching to dolutegravir/rilpivirine can not only maintain efficacy but also actively reverse negative trends in bone and renal health markers. This positions the regimen not merely as an alternative, but as a potentially superior long-term strategy for mitigating the cumulative toxicities associated with lifelong ART, a central objective in the modern management of an aging HIV population.

Clinical Use and Patient Management

Approved Indications and Patient Selection

The clinical application of dolutegravir/rilpivirine (Juluca®) is highly specific and is governed by strict criteria derived directly from the population studied in the pivotal SWORD trials.

Indication: Juluca® is indicated as a complete regimen for the treatment of HIV-1 infection in adults to replace the current antiretroviral regimen in those who meet all of the following criteria [1]:

1. Virologically Suppressed: Patients must have a plasma HIV-1 RNA level of less than 50 copies per mL.
2. Stable on ART: The virologic suppression must have been maintained on a stable antiretroviral regimen for at least the preceding six months.
3. No History of Treatment Failure: The patient must not have experienced virologic failure on any prior or current antiretroviral regimen.
4. No Known or Suspected Resistance: There should be no history of resistance, or clinically suspected resistance, to any drug in the integrase inhibitor or NNRTI class.

Patient Selection: This regimen is explicitly intended as a switch therapy for maintenance and is not approved for use in treatment-naive individuals or for treating patients who are not virologically suppressed. Before initiating a switch to Juluca®, clinicians must conduct a thorough review of the patient's complete antiretroviral treatment history, including all prior regimens, reasons for any switches, and any available historical resistance test results. The regimen is not recommended for use in pediatric patients under 18 years of age due to insufficient safety and efficacy data.[15]

Dosing, Administration, and Patient Counseling

Adherence to specific administration guidelines is critical for the efficacy of dolutegravir/rilpivirine. Comprehensive patient counseling on these points is a cornerstone of successful therapy.

Dosage: The recommended dosage is one tablet (containing dolutegravir 50 mg and rilpivirine 25 mg) taken orally once daily.[4]

Administration:

• Must Be Taken with a Meal: This is a non-negotiable requirement for adequate absorption of the rilpivirine component. Patients should be counseled that a meal is necessary and that a protein-rich nutritional drink or a light snack is not a sufficient substitute.[5]
• The tablet should be swallowed whole and not crushed or chewed.[33]

Missed Dose Instructions:

• If a dose is missed, the patient should take it with a meal as soon as they remember, provided that the next scheduled dose is not due within 12 hours.[32]
• If the next dose is due within 12 hours, the patient should skip the missed dose and simply resume their usual dosing schedule.
• Patients must be explicitly instructed not to take a double dose to compensate for a missed dose.[23]

Vomiting:

• If a patient vomits within 4 hours of taking their dose, they should take another tablet with a meal to ensure adequate drug levels are maintained.[23]
• If vomiting occurs more than 4 hours after administration, an additional dose is not necessary as sufficient absorption is presumed to have occurred.[23]

Contraindications and Management of Drug-Drug Interactions

The dolutegravir/rilpivirine combination has a complex and clinically significant drug-drug interaction profile that requires careful management. Some interactions are absolute contraindications, while others require specific timing or dose adjustments.

Absolute Contraindications: Co-administration of Juluca® with the following drugs is contraindicated due to the potential for life-threatening adverse events or a profound loss of virologic efficacy [5]:

• Antiarrhythmic: Dofetilide. Dolutegravir inhibits the renal transporter OCT2, which can lead to dangerously increased dofetilide concentrations and a risk of torsades de pointes.
• Potent CYP3A4 Inducers: These drugs significantly lower plasma concentrations of rilpivirine, leading to a high risk of virologic failure and resistance development. This class includes:
• Anticonvulsants: Carbamazepine, oxcarbazepine, phenobarbital, phenytoin.
• Antimycobacterials: Rifampin, rifapentine.
• Systemic Glucocorticoid: Dexamethasone (when used for more than a single-dose treatment).
• Herbal Product: St. John's wort (Hypericum perforatum).
• Proton Pump Inhibitors (PPIs): This class includes esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole. By increasing gastric pH, they severely impair the absorption of rilpivirine, risking therapeutic failure.

The management of drug interactions is one of the most critical aspects of prescribing this regimen. The following table serves as a clinical guide to the most significant interactions.

Interacting Drug/Class	Effect on Dolutegravir/Rilpivirine	Clinical Recommendation
Contraindicated
Dofetilide	↑ Dofetilide concentration (risk of arrhythmia)	Coadministration is contraindicated. 5
Proton Pump Inhibitors (PPIs)	↓ Rilpivirine concentration (risk of virologic failure)	Coadministration is contraindicated. 5
Potent CYP3A4 Inducers (Rifampin, Rifapentine, Carbamazepine, Phenytoin, St. John's wort, etc.)	↓↓ Dolutegravir & Rilpivirine concentrations (risk of virologic failure)	Coadministration is contraindicated. 5
Requires Dose/Time Separation
Antacids (containing Al, Mg, Ca)	↓ Dolutegravir & Rilpivirine concentrations	Administer Juluca® at least 4 hours before or 6 hours after taking antacids. 5
H2-Receptor Antagonists (e.g., Famotidine)	↓ Rilpivirine concentration	Administer Juluca® at least 12 hours before or 4 hours after taking H2-receptor antagonists. 5
Calcium & Iron Supplements	↓ Dolutegravir concentration	Can be taken together with Juluca® with a meal. Otherwise, administer Juluca® at least 4 hours before or 6 hours after supplements. 5
Requires Dose Adjustment
Rifabutin	↓ Rilpivirine concentration	An additional 25 mg tablet of rilpivirine must be taken concurrently with Juluca® once daily with a meal for the duration of rifabutin therapy. 5
Requires Monitoring
Metformin	↑ Metformin concentration	Monitor clinical response and consider metformin dose adjustment, especially at initiation. Refer to metformin prescribing information. 5
Macrolides (Clarithromycin, Erythromycin)	↑ Rilpivirine concentration	Consider alternatives where possible, such as azithromycin. 5

Considerations for Special Populations

The use of dolutegravir/rilpivirine requires specific considerations in certain patient populations.

Renal Impairment:

• Mild-to-Moderate (Creatinine Clearance [CrCl] ≥30 mL/min): No dosage adjustment is required.[4]
• Severe (CrCl <30 mL/min): While no dose adjustment is specified, increased monitoring for adverse effects is recommended. Use is not recommended in INSTI-experienced patients with certain resistance mutations, as decreased dolutegravir concentrations may occur, risking loss of efficacy.[4]

Hepatic Impairment:

• Mild-to-Moderate (Child-Pugh Class A or B): No dosage adjustment is necessary.[16]
• Severe (Child-Pugh Class C): The regimen has not been studied in this population and is therefore not recommended.[32]
• Hepatitis B or C Co-infection: Patients with chronic hepatitis B (HBV) or C (HCV) co-infection may be at an increased risk for the development or worsening of liver transaminase elevations. Regular monitoring of liver function is recommended in these patients.[15]

Elderly (≥65 years):

• Clinical trials included a limited number of participants aged 65 and over. While no specific dose adjustment is recommended, caution should be exercised due to the greater frequency of decreased renal, hepatic, or cardiac function, as well as a higher likelihood of concomitant diseases and polypharmacy in this population.[32]

Pregnancy and Individuals of Childbearing Potential:

• Major Warning on Neural Tube Defects: A potential risk of neural tube defects has been associated with dolutegravir use at the time of conception and during the first trimester of pregnancy.[5]
• Clinical Recommendations:
• Pregnancy testing is required before initiating Juluca® in individuals of childbearing potential.[5]
• An alternative antiretroviral regimen should be considered for those who are planning to become pregnant or who are in the first trimester.[5]
• Individuals of childbearing potential should be counseled on the use of effective contraception.[5]
• Pharmacokinetic Changes in Pregnancy: Studies have shown that pregnancy can lead to lower plasma exposures of both dolutegravir and rilpivirine. Such lower exposures have been associated with an increased risk of virologic failure. Therefore, the use of Juluca® during pregnancy is not recommended.[32]
• Breastfeeding: Breastfeeding is not recommended for individuals with HIV to prevent the risk of postnatal transmission of the virus to the infant. Additionally, the components of Juluca® may be present in breast milk.[24]

Regulatory and Therapeutic Context

Global Regulatory Approval History

Dolutegravir/rilpivirine (Juluca®) was a pioneering therapy, being the first complete, single-pill, two-drug regimen approved for the maintenance treatment of HIV-1. Its approval by major global regulatory agencies marked a new era in HIV management.

• United States (Food and Drug Administration - FDA): Juluca® received its first global approval from the FDA on November 21, 2017. This landmark decision established the viability of a two-drug maintenance strategy for virologically suppressed adults.[1]
• European Union (European Medicines Agency - EMA): Following a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) in March 2018, the European Commission granted marketing authorization for Juluca® in May 2018.[10]
• Canada (Health Canada): Approval was granted in May 2018, shortly after the EMA decision.[10]
• Australia (Therapeutic Goods Administration - TGA): The regimen was registered for use in Australia on June 20, 2018.[41]

The Role of Two-Drug Regimens in Modern HIV Therapy

The introduction of dolutegravir/rilpivirine represented a fundamental shift in the philosophy of long-term HIV treatment, challenging the established three-drug standard of care and paving the way for further innovation in regimen simplification.

Challenging the Three-Drug Paradigm: For more than two decades, the cornerstone of highly active antiretroviral therapy (HAART) was the combination of at least three active drugs, typically two NRTIs plus a third agent from another class (e.g., INSTI, NNRTI, or PI).[9] This approach was proven to be highly effective at suppressing viral replication and preventing the development of drug resistance. The successful outcomes of the SWORD-1 and SWORD-2 trials provided the first compelling, large-scale evidence that, for a carefully selected population of virologically suppressed patients, viral control could be durably maintained with just two drugs.[9]

Rationale for Two-Drug Regimens: The primary motivation for developing 2DRs is the reduction of lifelong cumulative drug exposure for people living with HIV. As HIV has transformed into a chronic, manageable condition, patients are expected to be on therapy for many decades. Minimizing the number of medications taken daily has the potential to reduce the long-term risk of cumulative toxicities, lessen the pill burden, and potentially improve quality of life.[1]

Benefits of NRTI-Sparing Strategies: A key advantage of the dolutegravir/rilpivirine combination is that it is an NRTI-sparing regimen. Certain NRTIs, particularly older agents like tenofovir disoproxil fumarate (TDF), have been associated with long-term renal and bone toxicities. As demonstrated in the SWORD trials, switching to an NRTI-sparing regimen can lead to measurable improvements in bone mineral density and renal biomarkers.[12] This strategy is particularly relevant for an aging HIV population that is at an increased risk for comorbidities such as osteoporosis and chronic kidney disease.

The Future of HIV Treatment: The approval and successful clinical integration of Juluca® validated the 2DR concept and spurred further research and development in this area. It served as a proof-of-concept that has led to the development of other innovative 2DRs, including the combination of dolutegravir/lamivudine for both treatment-naive and experienced patients, and the first long-acting injectable 2DR of cabotegravir/rilpivirine.[1] This evolution reflects a broader trend in HIV care toward optimizing long-term health outcomes by balancing potent virologic efficacy with improved safety and convenience.

Concluding Remarks and Future Perspectives

The fixed-dose combination of dolutegravir and rilpivirine is a highly effective and durable maintenance regimen for a meticulously selected population of virologically suppressed adults with HIV-1. Its introduction fundamentally altered the landscape of HIV therapy by validating the two-drug regimen as a viable long-term strategy.

The primary benefits of this regimen are clear: simplification to a single, once-daily pill; a high genetic barrier to the development of integrase inhibitor resistance; and the potential for improved long-term bone and renal safety through the avoidance of NRTIs. These advantages make it an attractive option for patients who are stable on their current therapy and are seeking to reduce their long-term medication burden and mitigate the risk of cumulative toxicities.

However, these benefits must be weighed against the regimen's significant clinical management challenges. The absolute requirement for administration with a meal, the potential for neuropsychiatric side effects associated with both components, the important warning regarding use in pregnancy, and a complex and extensive drug-drug interaction profile demand a high level of clinical vigilance and patient engagement. The contraindication with widely used proton pump inhibitors and the need for strict timing around antacids and supplements represent practical hurdles that may limit its suitability for some patients.

In conclusion, dolutegravir/rilpivirine holds a definitive place in the modern HIV treatment armamentarium as a pioneering two-drug, NRTI-sparing switch option. Its success is contingent not only on its pharmacological strengths but also on the careful selection of appropriate candidates and a collaborative partnership between clinicians and patients to navigate its specific administration and interaction requirements. As the first of its kind, Juluca® has served as a foundational therapy, solidifying the role of regimen simplification and toxicity reduction as key goals in the ongoing effort to improve the health and quality of life for all people living with HIV.

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