Dolutegravir: A Comprehensive Pharmacological and Clinical Review

1. Introduction

1.1. Overview of Dolutegravir as an Antiretroviral Agent

Dolutegravir (DrugBank ID: DB08930, CAS Number: 1051375-16-6) is a second-generation integrase strand transfer inhibitor (INSTI) that has become a cornerstone in the contemporary management of Human Immunodeficiency Virus type 1 (HIV-1) infection. As a small molecule antiviral agent, dolutegravir is administered in combination with other antiretroviral drugs to suppress viral replication. Its primary mechanism of action involves blocking the strand transfer step of viral genome integration into the host cell's DNA [User Query]. This targeted viral process has no direct counterpart in human cellular mechanisms, a characteristic that contributes significantly to dolutegravir's generally favorable tolerability and minimal toxicity profile observed in clinical practice.[1] This specificity for a viral enzyme is a highly desirable attribute for antiretroviral agents intended for long-term administration, as is typical in HIV-1 management, potentially reducing the burden of off-target effects often associated with older drug classes.

1.2. Development and Key Approval Milestones

Dolutegravir was developed by ViiV Healthcare.[3] It received its initial approval from the U.S. Food and Drug Administration (FDA) on August 12, 2013, under the brand name Tivicay [User Query]. This was followed by approvals from other regulatory agencies, including the European Medicines Agency (EMA). A significant milestone in its development was the approval of Juluca (dolutegravir/rilpivirine) on November 21, 2017, which marked the advent of the first complete two-drug regimen for the treatment of adults with HIV-1 [User Query]. This innovation signaled a shift towards simplifying treatment regimens. Further fixed-dose combinations (FDCs) incorporating dolutegravir have since become available, including Dovato (dolutegravir/lamivudine) and Triumeq (dolutegravir/abacavir/lamivudine), underscoring its versatility and central role in HIV therapy.[3] The strategic development from a single agent to its inclusion in multiple FDCs, particularly two-drug regimens, reflects a significant evolution in HIV treatment philosophy, aiming to reduce long-term drug exposure and pill burden while maintaining high efficacy.

1.3. Therapeutic Significance in HIV-1 Management

Dolutegravir-based regimens are prominently featured in major international HIV treatment guidelines, such as those from the World Health Organization (WHO), often as preferred options for both first-line and second-line antiretroviral therapy (ART).[7] This strong recommendation is founded on a robust body of evidence demonstrating its superior or non-inferior virological efficacy compared to previous standards of care, a favorable safety and tolerability profile, a high genetic barrier to the development of drug resistance, and the convenience of once-daily dosing for many patient populations.[8] The introduction of dolutegravir represented a considerable advancement over earlier-generation INSTIs and other antiretroviral classes, offering improved outcomes and simplified treatment approaches for individuals living with HIV-1.

2. Pharmacology

2.1. Mechanism of Action

Dolutegravir exerts its antiviral effect by specifically inhibiting the HIV-1 integrase enzyme. This enzyme is crucial for the viral replication cycle, as it catalyzes the insertion of the viral DNA (reverse transcribed from viral RNA) into the host cell's chromosomal DNA. Dolutegravir binds to the active site of the integrase enzyme, effectively blocking the strand transfer step of this integration process.[1] The mechanism involves the chelation of divalent metal ions, typically magnesium (Mg2+), which are essential cofactors located within the catalytic core of the integrase enzyme. By sequestering these metal ions, dolutegravir prevents the enzyme from properly processing the viral DNA ends and covalently joining them to the host DNA.[2]

A distinguishing feature of dolutegravir, when compared to first-generation INSTIs such as raltegravir and elvitegravir, is its molecular interaction with the target enzyme. Dolutegravir has been shown to have a slower rate of dissociation from the integrase-DNA complex. Furthermore, it appears capable of occupying more space within the catalytic site, particularly the region vacated by the displaced viral DNA end.[2] These distinct binding kinetics and deeper penetration into the active site are thought to be key contributors to dolutegravir's higher genetic barrier to resistance. A prolonged interaction with its target means that the virus would likely need to accumulate multiple or more significant mutations to effectively evade the drug's inhibitory action, compared to drugs with faster off-rates. This sustained enzyme inhibition is a critical factor in its robust antiviral activity, even against some viral strains that have developed resistance to earlier INSTIs. The chemical property of dolutegravir enabling chelation of divalent cations is not only fundamental to its enzymatic inhibition but also underlies its pharmacokinetic interaction with polyvalent cation-containing medications in the gastrointestinal tract, a distinct phenomenon discussed later.

2.2. Pharmacodynamics

Dolutegravir demonstrates potent in vitro antiviral activity against a range of laboratory strains and clinical isolates of wild-type HIV-1. The mean half-maximal effective concentration (EC50​) values are typically observed in the low nanomolar range, for instance, between 0.5 nM and 2.1 nM in peripheral blood mononuclear cells (PBMCs) and MT-4 T-cell lines.[1] The pharmacodynamic profile of dolutegravir is characterized by a clear relationship between drug exposure, particularly trough plasma concentrations (Cmin​ or Cτ​), and virologic response. Clinical studies have established that the achieved trough concentrations with standard dosing regimens are substantially higher than the protein-adjusted EC90​ (the concentration required to inhibit 90% of viral replication in vitro, adjusted for plasma protein binding) for wild-type HIV-1.[11] This ensures sustained virologic suppression and contributes to its high efficacy and the difficulty with which resistance emerges.

3. Pharmacokinetics

The pharmacokinetic (PK) properties of dolutegravir have been extensively studied in healthy volunteers and HIV-1-infected individuals, revealing a profile conducive to effective antiretroviral therapy.[13]

3.1. Absorption and Bioavailability

Following oral administration, dolutegravir is absorbed with peak plasma concentrations (Tmax​) typically reached 2 to 3 hours post-dose.[13] With once-daily dosing, pharmacokinetic steady-state is generally achieved within approximately 5 days, showing an average accumulation ratio for area under the concentration-time curve (AUC), maximum concentration (Cmax​), and concentration at 24 hours (C24h​) ranging from 1.2 to 1.5.[13] Dolutegravir exhibits less than dose-proportional increases in plasma concentrations at doses above 50 mg.[13] The absolute bioavailability of dolutegravir has not been definitively established.[13] In vitro studies have identified dolutegravir as a substrate for P-glycoprotein (P-gp), a drug efflux transporter.[13]

The presence of food influences dolutegravir absorption. Food intake generally increases the extent of absorption and slows the rate at which it is absorbed. Specifically, low-, moderate-, and high-fat meals have been shown to increase dolutegravir AUC(0−∞)​ by 33%, 41%, and 66%, respectively. Concurrently, Cmax​ increases by 46%, 52%, and 67%, respectively, and Tmax​ is prolonged from approximately 2 hours under fasted conditions to 3, 4, or 5 hours with low-, moderate-, or high-fat meals, respectively.[11] Despite these observed increases in exposure, dolutegravir can generally be administered with or without food, as these changes are not anticipated to adversely impact clinical safety or efficacy in most patients.[11] However, this pharmacokinetic food effect can be strategically utilized; in the presence of certain integrase class resistance mutations, particularly those involving the Q148 pathway, administering dolutegravir with food is preferred to enhance systemic exposure and potentially overcome reduced viral susceptibility.[15] This nuanced recommendation highlights how a generally non-critical PK interaction can become a therapeutic consideration in specific clinical scenarios, aiming to maximize drug concentrations against less sensitive viral strains.

3.2. Distribution

Dolutegravir is extensively bound to human plasma proteins, with a binding percentage of $\geq$98.9% based on in vivo data. This binding is reported to be independent of the plasma concentration of dolutegravir.[13] The apparent volume of distribution (Vd/F) following a 50 mg once-daily administration is estimated to be 17.4 L, based on population pharmacokinetic analyses.[13]

Dolutegravir demonstrates penetration into the cerebrospinal fluid (CSF). In a study involving 11 treatment-naive subjects receiving dolutegravir 50 mg daily in combination with abacavir/lamivudine, the median dolutegravir concentration in CSF was 18 ng/mL (range: 4 ng/mL to 232 ng/mL) when measured 2 to 6 hours post-dose after 2 weeks of treatment.[13] While CSF penetration is confirmed, the direct clinical relevance of these concentrations for controlling viral reservoirs in the central nervous system is not fully established.

3.3. Metabolism

The primary metabolic pathway for dolutegravir is glucuronidation, mediated predominantly by the enzyme uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1).[1] The cytochrome P450 (CYP) enzyme system, specifically CYP3A, plays a minor role in its metabolism.[1] In vitro studies also indicate that dolutegravir can be a substrate for UGT1A3 and UGT1A9.[1] This reliance on UGT1A1 rather than extensive CYP450 metabolism contributes to a relatively lower potential for many common drug-drug interactions compared to antiretrovirals that are heavily metabolized by CYP enzymes. Nevertheless, potent inducers or inhibitors of UGT1A1 can still significantly affect dolutegravir concentrations, necessitating dose adjustments in certain situations.[13]

3.4. Excretion

Following a single oral dose of radiolabeled dolutegravir, approximately 53% of the total administered dose is excreted unchanged in the feces.[1] Urinary excretion accounts for about 31% of the total oral dose. This fraction comprises an ether glucuronide of dolutegravir (representing 18.9% of the total dose), a metabolite formed by oxidation at the benzylic carbon (3.0% of the total dose), and its hydrolytic N-dealkylation product (3.6% of the total dose).[1] The renal elimination of unchanged dolutegravir is minimal, accounting for less than 1% of the administered dose.[1] Dolutegravir has a terminal half-life of approximately 14 hours, and its apparent clearance (CL/F) is estimated to be around 1.0 L/h, based on population pharmacokinetic analyses.[13]

3.5. Specific Formulations

Dolutegravir is available in different oral formulations, including film-coated tablets and dispersible tablets for oral suspension. It is critical to note that these formulations are not bioequivalent on a milligram-per-milligram basis due to differences in bioavailability. For instance, for adults, a 50 mg film-coated tablet provides exposure comparable to 30 mg of the dispersible tablet formulation.[15] Therefore, patients switching between these formulations must adhere to the specific dosing recommendations for the particular formulation being used to ensure appropriate drug exposure and avoid under- or over-dosing. This distinction is particularly crucial for pediatric patients or individuals with swallowing difficulties who may rely on the dispersible formulation.

The following table summarizes key pharmacokinetic parameters for dolutegravir:

Table 1: Summary of Dolutegravir Pharmacokinetic Parameters

Parameter	Value	Reference(s)
Tmax​ (fasted)	2-3 hours	13
Food Effect on AUC(0−∞)​ (High-Fat Meal)	Increased by 66%	11
Food Effect on Cmax​ (High-Fat Meal)	Increased by 67%	11
Protein Binding	$\geq$98.9%	13
Apparent Volume of Distribution (Vd/F)	17.4 L	13
CSF Penetration (Median Conc.)	18 ng/mL (range 4-232 ng/mL)	13
Primary Metabolic Pathway	Glucuronidation via UGT1A1	1
Minor Metabolic Pathway	Oxidation via CYP3A	1
Primary Excretion Route (Unchanged Drug)	Feces (~53%)	1
Secondary Excretion Route (Metabolites)	Urine (~31% as metabolites)	1
Terminal Half-life (t1/2​)	~14 hours	13
Apparent Clearance (CL/F)	~1.0 L/h	13

4. Clinical Efficacy

Dolutegravir has demonstrated robust clinical efficacy across a spectrum of HIV-1 infected patient populations, including treatment-naive individuals, treatment-experienced but INSTI-naive patients, and as a component of maintenance therapy.

4.1. In Treatment-Naive Adults

Several pivotal Phase 3 trials have established the efficacy of dolutegravir in antiretroviral-naive adults:

• SINGLE Trial: This randomized, double-blind study compared once-daily dolutegravir (50 mg) plus abacavir/lamivudine (ABC/3TC) fixed-dose combination with the once-daily fixed-dose combination of efavirenz/tenofovir disoproxil fumarate/emtricitabine (EFV/TDF/FTC). At week 48, the dolutegravir-based regimen demonstrated superiority, with 88% of patients achieving HIV-1 RNA <50 copies/mL compared to 81% in the EFV/TDF/FTC arm.[10] This superiority was sustained through week 144, with response rates of 71% for DTG + ABC/3TC versus 63% for EFV/TDF/FTC.[17] A key factor contributing to this superior outcome was a significantly lower rate of discontinuations due to adverse events in the dolutegravir arm (4% vs. 14% through week 144).[17] Importantly, no treatment-emergent resistance to either integrase inhibitors or nucleoside reverse transcriptase inhibitors (NRTIs) was observed in patients receiving the dolutegravir-based regimen through week 144.[17] The SINGLE trial was instrumental in positioning DTG + ABC/3TC as a highly effective and better-tolerated first-line option over a widely used efavirenz-containing regimen, with the absence of resistance development being a particularly notable finding.[18]
• SPRING-2 Trial: This randomized, double-blind, non-inferiority study compared once-daily dolutegravir (50 mg) with twice-daily raltegravir (400 mg), a first-generation INSTI, both administered with an investigator-selected dual NRTI backbone (TDF/FTC or ABC/3TC). At the primary endpoint of week 48, dolutegravir was non-inferior to raltegravir, with 88% and 85% of patients, respectively, achieving HIV-1 RNA <50 copies/mL.[8] Non-inferiority was maintained at week 96 (81% in the dolutegravir group vs. 76% in the raltegravir group).[8] Notably, virological non-response was less frequent in the dolutegravir group (5%) compared to the raltegravir group (10%) at week 96.[8] Crucially, no evidence of treatment-emergent resistance to dolutegravir was detected in patients who experienced virological failure on the dolutegravir arm.[20] This trial established once-daily dolutegravir as an effective and convenient alternative to twice-daily raltegravir for treatment-naive individuals.[21]
• FLAMINGO Trial: This open-label, non-inferiority (with pre-specified superiority testing) study compared once-daily dolutegravir (50 mg) with once-daily darunavir boosted with ritonavir (DRV/r 800/100 mg), a standard-of-care protease inhibitor, both in combination with a dual NRTI backbone. At week 48, dolutegravir demonstrated superiority to DRV/r, with 90% of patients in the dolutegravir arm achieving HIV-1 RNA <50 copies/mL compared to 83% in the DRV/r arm (adjusted difference 7.1%, 95% CI 0.9-13.2; p=0.025).[10] This superiority was largely attributed to fewer discontinuations due to adverse events in the dolutegravir group (2% vs. 4%) and notably better virologic response rates among patients with high baseline viral loads (>100,000 copies/mL), where 93% of dolutegravir recipients achieved viral suppression compared to 70% of those on DRV/r.[18] No treatment-emergent resistance was observed in either group.[10] The FLAMINGO trial highlighted dolutegravir's advantages over a potent boosted protease inhibitor regimen, particularly in patients with high initial viral burdens, and underscored its better tolerability profile.[10]
• D2ARLING Trial: This Phase 4, randomized, open-label, non-inferiority trial evaluated the efficacy of a two-drug regimen (2DR) of dolutegravir (50 mg) plus lamivudine (300 mg) compared to a dolutegravir-based three-drug regimen (DTG + TDF/FTC or TDF/3TC) in treatment-naive individuals for whom baseline resistance testing was not available. At week 48, the DTG + 3TC regimen was non-inferior to the three-drug regimen, with 92% and 89% of participants, respectively, achieving HIV-1 RNA <50 copies/mL (difference 2.62%; 95% CI -5.3 to 10.6).[22] No participants in the DTG + 3TC arm experienced protocol-defined virological failure, and none developed treatment-emergent resistance mutations to any study drugs.[22] These findings support the initiation of DTG + 3TC as a 2DR for initial HIV-1 therapy, even in the absence of baseline resistance testing, particularly in settings where the prevalence of transmitted drug resistance to these agents is presumed to be low.

The consistent theme of better tolerability leading to fewer discontinuations, as seen in the SINGLE and FLAMINGO trials, is a significant factor in dolutegravir's comparative trial successes. While virologic potency is essential, a drug's ability to be well-tolerated allows for better adherence and persistence on therapy, which translates to superior long-term outcomes in head-to-head comparisons. Furthermore, the robust efficacy observed in patients with high baseline viral loads in trials like FLAMINGO and SAILING suggests an intrinsic potency or a more forgiving profile when the initial virologic challenge is substantial.

4.2. In Treatment-Experienced, Integrase-Naive Adults

• SAILING Trial: This randomized, double-blind, non-inferiority (with pre-specified superiority testing) study compared once-daily dolutegravir (50 mg) with twice-daily raltegravir (400 mg) in antiretroviral-experienced, INSTI-naive adults with resistance to at least two other antiretroviral classes, both given with an optimized background regimen. At week 48, dolutegravir was found to be statistically superior to raltegravir, with 71% of patients in the dolutegravir arm achieving HIV-1 RNA <50 copies/mL compared to 64% in the raltegravir arm (adjusted difference 7.4%, 95% CI 0.7-14.2; p=0.03).[9] Critically, significantly fewer patients experienced virological failure with treatment-emergent integrase inhibitor resistance in the dolutegravir group (1%, 4 patients) compared to the raltegravir group (5%, 17 patients) (adjusted difference -3.7%, 95% CI -6.1 to -1.2; p=0.003).[9] The superiority of dolutegravir was driven by fewer withdrawals due to lack of efficacy, a lower number of protocol-defined virologic failures, and the substantially lower rate of emergent resistance.[23] Dolutegravir also demonstrated better performance in patients with high baseline viral loads (>50,000 copies/mL: 62% vs. 47%) and in those whose background regimen did not include a fully active darunavir.[23] The SAILING trial established dolutegravir as a more robust and durable option than raltegravir in this treatment-experienced, INSTI-naive population, particularly emphasizing its higher genetic barrier to resistance.

4.3. As Maintenance Therapy

• LAMIDOL Trial: This open-label, single-arm, multicenter trial assessed the efficacy of switching to a 2DR of once-daily dolutegravir (50 mg) plus lamivudine (300 mg) in HIV-1 infected patients who were virologically suppressed (plasma viral load $\leq$50 copies/mL for $\geq$2 years, CD4 nadir >200 cells/mm$^3$, and wild-type HIV prior to treatment initiation) on first-line triple-drug regimens.[21] The overall success rate (defined by maintaining viral suppression) at week 48 was 97% (95% CI: 94%-100%), meeting the study's design expectation.[21] Only three therapeutic failures were reported: one virological failure at week 4, one patient lost to follow-up, and one interruption of therapy after a viral blip (which subsequently resolved). Importantly, neither the M184V mutation (conferring lamivudine resistance) nor any integrase resistance mutations were detected after virological failure or blips.[21] The LAMIDOL trial provides supportive evidence for DTG + 3TC as a promising and effective maintenance strategy, allowing for simplification from a three-drug regimen in appropriately selected, virologically suppressed patients.

The emergence and validation of 2DRs centered around dolutegravir, such as DTG+3TC in the D2ARLING and LAMIDOL trials, represent a significant evolution in HIV treatment paradigms. This shift away from the traditional three-drug backbone is largely enabled by dolutegravir's high potency and robust resistance barrier, which allow for regimen simplification without compromising virologic control in suitable patients, aiming to reduce long-term drug exposure and potential toxicities.

The following table summarizes the key efficacy outcomes from these pivotal clinical trials:

Table 2: Summary of Key Phase 3/4 Clinical Trial Efficacy Outcomes for Dolutegravir

Trial Name	Patient Population	Comparator(s)	Primary Endpoint (% HIV RNA <50 copies/mL at Week X)	Dolutegravir Arm Result	Comparator Arm Result	Key Conclusion (Non-inferiority/Superiority)	Emergent INSTI Resistance (DTG vs. Comparator)	Reference(s)
SINGLE	Naive	EFV/TDF/FTC	Week 48	88%	81%	Superiority	None vs. N/A (EFV is NNRTI)	10
SPRING-2	Naive	Raltegravir (+ dual NRTI)	Week 48	88%	85%	Non-inferiority	None vs. 1 patient (6% of failures)	8
FLAMINGO	Naive	Darunavir/ritonavir (+ dual NRTI)	Week 48	90%	83%	Superiority	None vs. None	10
D2ARLING	Naive (no baseline resistance testing)	DTG + TDF/FTC or TDF/3TC	Week 48	92%	89%	Non-inferiority	None vs. None	22
SAILING	Experienced, INSTI-Naive	Raltegravir (+ OBR)	Week 48	71%	64%	Superiority	1% (4 patients) vs. 5% (17 patients)	9
LAMIDOL	Suppressed (switch to DTG+3TC)	N/A (single arm, switch from triple therapy)	Week 48 (success rate)	97%	N/A	Promising maintenance strategy	None detected	21

OBR: Optimized Background Regimen

5. Safety and Tolerability

Dolutegravir is generally recognized for its favorable safety and tolerability profile, a factor that significantly contributes to its widespread use and patient adherence.

5.1. Common Adverse Events

In clinical trials involving adult populations, dolutegravir has been shown to be well-tolerated.[1] The most frequently reported adverse events (typically defined as occurring in $\geq$2% of participants in any one adult trial) are generally mild to moderate in intensity. These commonly include insomnia, fatigue, and headache.[1] Gastrointestinal disturbances such as nausea and diarrhea are also among the more common side effects.[1] Other reported events include nasopharyngitis, dizziness, rash, and abnormal dreams.[1] Laboratory abnormalities that have been noted include elevations in cholesterol, triglycerides, lipase, glucose (hyperglycemia), creatine kinase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin.[25] The overall low rates of discontinuation due to adverse events in pivotal clinical trials, often lower than comparator arms, underscore its good tolerability and contribute to its favorable standing in comparative efficacy assessments.[17]

5.2. Serious Adverse Events and Warnings

Despite its generally good safety profile, certain serious adverse events and warnings are associated with dolutegravir use, as outlined in regulatory agency labeling and observed in clinical studies:

• Hypersensitivity Reactions: Although infrequent (reported in $\leq$1% of subjects in Phase 3 trials), hypersensitivity reactions to dolutegravir have occurred. These reactions are characterized by a constellation of symptoms including rash, constitutional findings (such as fever, general malaise, fatigue, muscle or joint aches), and sometimes organ dysfunction, which can include liver injury and eosinophilia.[4] It is imperative that dolutegravir and any other suspect agents be discontinued immediately if signs or symptoms suggestive of a hypersensitivity reaction develop. A delay in stopping treatment can result in a life-threatening reaction. Patients who have experienced a previous hypersensitivity reaction to dolutegravir should not be re-challenged.[13] The potential severity of this rare event necessitates thorough patient education on recognizing early manifestations.
• Hepatotoxicity: Elevations in liver chemistries, including transaminase elevations, have been reported in patients receiving dolutegravir-containing regimens. Individuals with pre-existing liver disease, such as chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) co-infection, may be at an increased risk for the development or worsening of these liver enzyme elevations.[4] Routine monitoring for hepatotoxicity is recommended, particularly in this patient subgroup. In some instances, these transaminase elevations have been consistent with an immune reconstitution syndrome or, in patients with HBV, a flare of hepatitis B, especially if anti-hepatitis B therapy was withdrawn.[13]
• Embryo-fetal Toxicity (Neural Tube Defects): A potential, though small, risk of neural tube defects (NTDs) has been associated with dolutegravir use at the time of conception and in early pregnancy. Consequently, alternative antiretroviral treatments should be considered during this period. Adolescents and adults of childbearing potential should be counseled on this risk and the importance of using effective contraception while on dolutegravir.[24] (This is discussed in further detail in Section 8.1).
• Immune Reconstitution Syndrome: As with other combination antiretroviral therapies, immune reconstitution syndrome has been reported in patients treated with dolutegravir. During the initial phase of ART, irovecii* pneumonia, or tuberculosis) may occur, potentially requiring further evaluation and treatment.[13]
• Fat Redistribution/Accumulation: Redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (often termed "buffalo hump"), peripheral and facial wasting, breast enlargement, and a "cushingoid appearance," has been observed in patients receiving antiretroviral therapy. The underlying mechanism and long-term consequences of these lipodystrophic changes are not fully understood, and a causal relationship specifically with dolutegravir has not been definitively established.[13]
• Changes in Serum Creatinine: Dolutegravir is known to inhibit the organic cation transporter 2 (OCT2) in the renal tubules, which is involved in the active tubular secretion of creatinine. This inhibition leads to small, generally non-progressive increases in serum creatinine (typically around 0.1-0.2 mg/dL) and decreases in estimated creatinine clearance, without affecting the actual glomerular filtration rate (GFR).[1] This is an expected pharmacological effect of dolutegravir and is not usually indicative of worsening renal function or nephrotoxicity. Clinicians need to be aware of this phenomenon to avoid misinterpreting routine renal function tests.
• Lactic Acidosis and Severe Hepatomegaly with Steatosis: While these are class warnings more historically associated with older nucleoside reverse transcriptase inhibitors (NRTIs), fixed-dose combinations containing dolutegravir and NRTIs (like lamivudine in Dovato) carry relevant warnings. For example, Dovato (DTG/3TC) has a boxed warning concerning the emergence of lamivudine-resistant HBV and exacerbations of HBV in co-infected patients upon discontinuation. The label also mentions severe liver problems and lactic acid build-up as potential serious side effects.[4]

6. Drug Interactions

Dolutegravir is subject to several clinically significant drug-drug interactions, primarily involving polyvalent cations, certain UGT1A1/CYP3A enzyme inducers, and drugs that are substrates of the renal transporter OCT2.

6.1. Interactions with Polyvalent Cations (Antacids, Mineral Supplements)

Coadministration of dolutegravir with products containing polyvalent cations, such as antacids (containing magnesium or aluminum), sucralfate, or mineral supplements (containing iron or calcium), can significantly decrease the absorption of dolutegravir. This interaction occurs due to the formation of poorly soluble chelation complexes between dolutegravir and the polyvalent cations in the gastrointestinal tract, leading to reduced dolutegravir plasma concentrations and potentially compromising its antiviral efficacy.[2]

To manage this interaction, specific administration timing is recommended: dolutegravir should be administered at least 2 hours before or 6 hours after taking medications containing these polyvalent cations.[2] An important exception exists for calcium and iron supplements: if dolutegravir (as Tivicay or in the FDC Dovato) is taken with food, these supplements can be co-administered at the same time.[25] This flexibility when taken with food may be due to food mitigating the chelation effect, possibly by altering gastric conditions or by the cations binding to food components. However, this adds a layer of complexity to patient counseling, requiring clear instructions to ensure adherence and maintain therapeutic dolutegravir levels.

6.2. Contraindication with Dofetilide

The coadministration of dolutegravir with dofetilide, an antiarrhythmic agent, is contraindicated.[4] Dolutegravir is an inhibitor of the renal organic cation transporter 2 (OCT2), which plays a crucial role in the renal clearance of dofetilide. By inhibiting OCT2, dolutegravir can significantly increase dofetilide plasma concentrations.[13] Elevated dofetilide levels pose a substantial risk of serious and potentially life-threatening cardiac arrhythmias, including Torsades de Pointes.[25] This contraindication underscores the critical importance of recognizing transporter-mediated drug interactions, as a pharmacokinetic effect (OCT2 inhibition) can lead to severe pharmacodynamic consequences, especially with drugs like dofetilide that have a narrow therapeutic index.

6.3. Interaction with Metformin

Dolutegravir has been shown to significantly increase plasma concentrations (both AUC and Cmax​) of metformin, an oral antihyperglycemic agent, in a dose-dependent manner.[27] When dolutegravir 50 mg is administered once daily, metformin AUC increases by approximately 79% and Cmax​ by 66%. With dolutegravir 50 mg twice daily, metformin AUC increases by about 145% and Cmax​ by 111%.[27]

The primary mechanism for this interaction is the inhibition of OCT2 by dolutegravir, which reduces the renal tubular secretion of metformin.[27] Dolutegravir is a more potent inhibitor of OCT2 (IC$_{50}$ = 1.9 µM) compared to its inhibition of MATE1/2-K (IC$_{50}$ = 6.3-25 µM).[28] While OCT2 inhibition is the main driver, the observed magnitude of the increase in metformin exposure was somewhat higher than might be anticipated based solely on OCT2 inhibition and the known fraction of metformin clearance mediated by active tubular secretion, suggesting that other unidentified processes might also contribute to this interaction.[27]

Given the significant increase in metformin exposure, clinical recommendations include considering dose adjustments of metformin to maintain optimal glycemic control when dolutegravir is initiated or discontinued in a patient taking metformin. Patients should be monitored for metformin-related adverse effects, although the risk of hypoglycemia is not typically increased with metformin monotherapy, and the plasma concentrations observed in interaction studies were generally below those associated with lactic acidosis.[26]

6.4. Interactions with UGT1A/CYP3A Inducers and Inhibitors

As dolutegravir is primarily metabolized by UGT1A1 with a minor contribution from CYP3A, drugs that induce these enzymes can decrease dolutegravir plasma concentrations, potentially reducing its efficacy. Potent inducers include efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, rifampin, carbamazepine, oxcarbazepine, phenytoin, phenobarbital, and the herbal product St. John's wort (Hypericum perforatum).[13]

For treatment-naive or treatment-experienced INSTI-naive patients, when dolutegravir (Tivicay) is coadministered with potent UGT1A/CYP3A inducers such as efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, or rifampin, the dolutegravir dose should be increased to 50 mg twice daily.[13] If Dovato (DTG/3TC) is coadministered with carbamazepine or rifampin, an additional 50 mg dose of dolutegravir (as Tivicay) should be taken, separated by 12 hours from the Dovato dose.[26] Coadministration of Dovato with oxcarbazepine, phenobarbital, phenytoin, or St. John's wort should be avoided due to insufficient data to make dosing recommendations.[26] Etravirine, when administered without boosted protease inhibitors, also decreases dolutegravir concentrations, and the recommended adult dose of dolutegravir in this scenario is 50 mg twice daily.[15] Conversely, potent inhibitors of UGT1A1 or CYP3A could theoretically increase dolutegravir concentrations, but this is generally less of a clinical concern requiring dose adjustment for dolutegravir itself, though interactions with other co-administered drugs may still occur.

6.5. Other Clinically Relevant Interactions

Several other drug interactions with dolutegravir warrant attention:

• Daclatasvir: No clinically relevant pharmacokinetic interaction has been observed between dolutegravir and daclatasvir. Therefore, no dose adjustment is necessary for either agent when coadministered.[15]
• Oral Contraceptives (norgestimate/ethinyl estradiol): Dolutegravir does not have a clinically significant effect on the pharmacokinetics of these oral contraceptives. No dose adjustment of the contraceptive is needed when coadministered with dolutegravir.[15]
• Methadone: No clinically relevant pharmacokinetic interaction occurs between dolutegravir and methadone. No dose adjustment is necessary for either drug.[15]
• Dalfampridine: Dolutegravir may increase plasma levels of dalfampridine through inhibition of OCT2 and multidrug and toxin extrusion transporter 1 (MATE1). Since elevated dalfampridine concentrations increase the risk of seizures, the potential benefits of coadministration should be carefully weighed against this risk.[25]
• Sorbitol: When possible, the repeated use of sorbitol-containing medicines with Dovato (dolutegravir/lamivudine) should be avoided. Sorbitol can decrease the concentrations of lamivudine, one of the components of Dovato.[26]

The following table summarizes key drug interactions with dolutegravir and provides management recommendations:

Table 3: Clinically Significant Drug Interactions with Dolutegravir and Management Recommendations

Interacting Agent/Class	Mechanism of Interaction	Effect on Dolutegravir or Co-administered Drug	Clinical Recommendation	Reference(s)
Dofetilide	OCT2 inhibition by dolutegravir	Increased dofetilide levels	Contraindicated due to risk of serious/life-threatening arrhythmias	4
Polyvalent Cations (Mg, Al, Ca, Fe antacids/supplements)	Chelation in GI tract	Decreased dolutegravir absorption and plasma concentrations	Administer dolutegravir 2 hours before or 6 hours after polyvalent cations. If taken with food, dolutegravir and Ca/Fe supplements can be taken together (Tivicay, Dovato).	2
Metformin	OCT2 inhibition by dolutegravir	Increased metformin plasma exposure (AUC and Cmax​)	Consider metformin dose adjustment to maintain glycemic control when starting/stopping dolutegravir. Refer to metformin PI.	26
Rifampin	Potent UGT1A1/CYP3A induction	Decreased dolutegravir plasma concentrations	Increase dolutegravir (Tivicay) dose to 50 mg BID. For Dovato, add DTG 50 mg 12h apart from Dovato.	13
Efavirenz	Potent UGT1A1/CYP3A induction	Decreased dolutegravir plasma concentrations	Increase dolutegravir (Tivicay) dose to 50 mg BID.	13
Carbamazepine	Potent UGT1A1/CYP3A induction	Decreased dolutegravir plasma concentrations	For Dovato, add DTG 50 mg 12h apart from Dovato. For Tivicay, consider 50 mg BID if INSTI-naive.	15
St. John's wort (Hypericum perforatum)	Potent UGT1A1/CYP3A induction	Decreased dolutegravir plasma concentrations	Avoid coadministration with Dovato. For Tivicay, if INSTI-naive, increase dose to 50 mg BID.	15
Oxcarbazepine, Phenobarbital, Phenytoin	Potent UGT1A1/CYP3A induction	Decreased dolutegravir plasma concentrations	Avoid coadministration with Dovato. For Tivicay, if INSTI-naive, increase dose to 50 mg BID.	15
Dalfampridine	OCT2 and MATE1 inhibition by dolutegravir	Increased dalfampridine levels	Potential for increased risk of seizures. Weigh benefits vs. risks.	25
Sorbitol (repeated use)	Potential to decrease lamivudine concentrations (in Dovato)	Decreased lamivudine exposure	When possible, avoid concomitant use with Dovato.	26

7. Resistance Profile

Dolutegravir is characterized by a relatively high genetic barrier to resistance, especially when compared to first-generation INSTIs. This property is a significant clinical advantage, contributing to its durable efficacy.

7.1. Genetic Barrier to Resistance

The term "high genetic barrier" implies that multiple viral mutations, or specific combinations thereof, are typically necessary to confer clinically significant resistance to dolutegravir.[2] This contrasts with some antiretroviral agents where a single mutation can lead to high-level resistance. However, this barrier is not absolute. Resistance to dolutegravir can and does emerge, particularly under conditions that favor viral replication in the presence of suboptimal drug concentrations, such as poor adherence, pre-existing low-level resistance that might not be detected by standard assays, or in situations of functional monotherapy (where other drugs in the regimen are inactive).[7] The observation of resistance emerging even in INSTI-naive individuals, though at low rates in controlled clinical trials, underscores the importance of ongoing surveillance and adherence support in broader clinical application.

7.2. Key Resistance Mutations and Pathways

Several distinct mutational pathways have been identified that can reduce susceptibility to dolutegravir. The patterns of emergent mutations can differ based on the patient's prior INSTI exposure and the specific clinical context:

• In INSTI-naive patients experiencing virological failure on dolutegravir-based regimens: The most frequently observed primary resistance mutations are R263K and G118R.[7] Other non-polymorphic mutations that have been reported in this population, often in combination with primary mutations or as part of more complex patterns, include E138K/T, N155H, Q148K, S230R, T66I, and H51Y.[29]
• In virologically suppressed patients experiencing failure on dolutegravir monotherapy (an investigational approach not recommended for standard care): Common mutations have included N155H, Q148H/R, R263K, G118R, and S147G.[29] The selection pressure under monotherapy can differ from combination therapy.
• In INSTI-experienced patients (with prior failure on raltegravir or elvitegravir) who subsequently fail a dolutegravir-containing regimen: The mutational landscape is often more complex. R263K or G118R are not typically selected as new primary mutations in this setting. Instead, common emergent or accumulating mutations include T97A, E138K/A/T, N155H, L74M/I, and mutations within the Q148 pathway (e.g., Q148H often accompanied by G140S) or S147G.[29]

Specific mutational pathways have distinct characteristics:

* The R263K mutation often appears as a single primary mutation or in combination with minor accessory mutations. It typically confers a relatively low-level reduction in dolutegravir susceptibility, often around 2-fold.7

* The G118R mutation can also emerge and may be associated with a more significant reduction in dolutegravir susceptibility, generally >5-fold. When G118R is combined with other mutations, such as T66I and E138K, it can lead to high-level resistance and potentially pan-INSTI resistance, meaning resistance to all drugs in the class.7

* The Q148H/R/K mutations are particularly significant. While a Q148 mutation alone may not drastically reduce dolutegravir susceptibility, its combination with one or more secondary mutations (e.g., G140S/A, E138K, L74I) can lead to substantial and high-level resistance to dolutegravir and other INSTIs.29

* The N155H mutation, when present alone or with only one additional INSTI resistance mutation, usually results in less than a 2-fold reduction in dolutegravir susceptibility. However, its impact can be greater when it co-occurs with Q148 pathway mutations or multiple other resistance mutations.29

Understanding these distinct mutational pathways is critical for interpreting genotypic resistance tests. The implications of, for example, an R263K mutation are different from a G118R or a complex Q148 pathway mutation in terms of residual drug activity and options for future therapy.

7.3. Impact of Mutations on Dolutegravir Susceptibility

The degree to which these mutations affect dolutegravir's antiviral activity is quantified by in vitro susceptibility testing, often reported as a "fold-change" (FC) in the EC50​ value compared to wild-type virus. For mutations in the Q148 pathway, a 3- to 4-fold reduction in dolutegravir susceptibility has been associated with a measurably reduced virologic response to therapy, while a 10-fold reduction is linked to a markedly diminished response.[29] The precise clinical significance thresholds for fold-changes associated with the R263K or G118R pathways are less clearly defined.[29] Furthermore, some INSTI resistance mutations, notably G118R and R263K, have been shown to reduce the replication capacity of HIV-1 in vitro. This impaired viral fitness might influence their clinical impact and the rate at which they emerge or persist.[29]

7.4. Cross-Resistance with Other Integrase Inhibitors

Dolutegravir generally retains antiviral activity against many HIV-1 isolates that are resistant to first-generation INSTIs like raltegravir and elvitegravir, especially if the resistance is due to single mutations such as Y143R, T66I, or E92Q.[2] However, high-level cross-resistance can occur. This is particularly true for viruses harboring Q148 pathway mutations when combined with other secondary INSTI resistance mutations.[15] As mentioned, the G118R pathway, if it evolves to include additional mutations like T66I and E138K, can confer broad or pan-INSTI resistance, limiting future treatment options within this class.[7]

7.5. Resistance in Real-World Settings

While clinical trials provide controlled data, real-world observations are crucial. In clinical trials, the emergence of dolutegravir-selected DRMs in INSTI-naive patients failing dual NRTI + DTG-based ART has been reported in up to 3.8% of ART-experienced individuals and around 0.7% in ART-naive individuals.[7] There are concerns that the rates of resistance emergence might be higher in real-world resource-limited settings. Factors contributing to this could include highly standardized regimens with limited flexibility, challenges in maintaining optimal adherence, interruptions in drug supply, and restricted access to routine viral load monitoring and genotypic resistance testing.[7]

Furthermore, emerging evidence suggests that resistance patterns and their frequencies might vary depending on the HIV-1 subtype. For instance, some data indicate that non-B subtypes might exhibit higher frequencies of G118R and Q148 pathway mutations, whereas R263K might be more predominant in subtype B infections.[7] Given that non-B subtypes are prevalent in many regions where dolutegravir is being extensively deployed, these potential subtype-specific differences in resistance development could have significant global health implications and warrant dedicated surveillance.

The following table summarizes key dolutegravir resistance mutations and their characteristics:

Table 4: Key Dolutegravir Resistance Mutations and Their Impact

Mutation(s)	Typical Clinical Setting of Emergence	Fold-Change in Dolutegravir Susceptibility (Approximate Range)	Impact on Replication Capacity (if known)	Cross-Resistance to other INSTIs	Reference(s)
R263K (often alone or +M50I/H51Y/E138K)	INSTI-Naive (primary or monotherapy)	~2-fold (alone); up to 10-15 fold with G118R/N155H/Q148R	Reduced	Minimal alone; increased with additional mutations	7
G118R (alone or +T66A/L74I/T97A/E138K)	INSTI-Naive (primary or monotherapy)	5-15 fold (alone/some combos); >15-fold (e.g., +T66I+E138K)	Reduced	Partial to high; G118R+T66I+E138K can lead to pan-INSTI resistance	7
N155H (alone or + other mutations)	INSTI-Naive (esp. monotherapy), INSTI-Experienced	<2-fold (alone); 2 to >15-fold with Q148H/R or multiple others	Variable	Variable; contributes to cross-resistance with other mutations	29
Q148H/R/K + G140S/A and/or E138K/A/T (± L74I)	INSTI-Experienced (common); INSTI-Naive (less common, esp. monotherapy)	3-fold (Q148H+G140S) to >20-fold (complex patterns)	Variable	High-level cross-resistance to raltegravir, elvitegravir; significant impact on dolutegravir	15
T97A	INSTI-Experienced (often with other mutations)	Minor alone; contributes with other mutations	Not well defined	Accessory mutation, contributes to resistance to other INSTIs	29

8. Use in Specific Populations

The use of dolutegravir in specific populations requires careful consideration of unique physiological states, potential risks, and available data.

8.1. Pregnancy and Conception

The recommendations for dolutegravir use during pregnancy and around the time of conception have evolved significantly based on accumulating pharmacovigilance data.

• Evolution of Neural Tube Defect (NTD) Risk Assessment: In May 2018, preliminary data from an ongoing observational study (Tsepamo study) in Botswana raised a safety concern regarding a potential increased risk of neural tube defects (NTDs) in infants born to women who were receiving dolutegravir at the time of conception or during early pregnancy.30 This initial signal prompted cautionary statements from regulatory bodies like the FDA and EMA, and led to interim adjustments in treatment guidelines from organizations such as the WHO and the U.S. Department of Health and Human Services (DHHS).30 However, subsequent and more comprehensive analyses from the Tsepamo study, along with data from other surveillance systems, have provided a more refined understanding of this risk. While a very small potential increased risk of NTDs with periconceptional dolutegravir exposure cannot be entirely excluded, the magnitude of this risk appears to be lower than initially reported.[32] For instance, updated data from Botswana indicated a prevalence of NTDs of 0.19% (19 infants per 10,000 deliveries) among women taking dolutegravir around conception, compared to 0.07% (7 infants per 10,000 deliveries) in women taking efavirenz-based regimens or in women without HIV infection in the same setting.[32] Importantly, this risk of NTDs in infants exposed to dolutegravir around conception was no longer statistically significantly elevated when compared with infants exposed to any non-dolutegravir antiretroviral regimen around conception in that study.[32] Furthermore, studies have consistently shown no increase in NTDs in infants born to women who initiated dolutegravir later in pregnancy, after the first trimester.[30] This dynamic evolution of safety information, from an initial concerning signal to a more nuanced understanding of a very small potential risk, is a testament to the importance of robust, ongoing pharmacovigilance and has had profound implications for global HIV treatment strategies for women.
• Current Guidelines and Recommendations: Reflecting the updated data, major treatment guidelines have revised their recommendations. As of February 2021, the DHHS Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission recommends dolutegravir as a Preferred antiretroviral drug throughout pregnancy, and also as a Preferred option for women who are trying to conceive.32 This change was based on the reassessment of the NTD risk as very small, balanced against the significant benefits of dolutegravir, which include once-daily dosing, good tolerability, and rapid and durable viral load suppression—all crucial for maternal health and the prevention of perinatal HIV transmission. Despite the revised recommendations, counseling and informed decision-making remain paramount. Healthcare providers should discuss the available data on risks and benefits with women of childbearing potential.[32] Folic acid supplementation, at a minimum dose of 400 mcg daily, is universally recommended for all women who are pregnant or might conceive, as it is known to reduce the risk of NTDs in the general population.[32]
• Pharmacokinetics in Pregnancy: Pharmacokinetic studies have shown that dolutegravir plasma concentrations can be moderately lower during pregnancy compared to postpartum. For example, dolutegravir AUC has been reported to be reduced by approximately 21% to 26% during pregnancy, with trough concentrations (Ctrough​) also reduced.12 However, even with these reductions, Ctrough​ values during pregnancy generally remain well above the 90% effective concentration (EC90​) for wild-type HIV-1. Consequently, no dose adjustment for dolutegravir is currently recommended during pregnancy.12
• Placental Transfer and Breast Milk: Dolutegravir exhibits high placental transfer, with median cord blood-to-maternal plasma concentration ratios reported to be around 1.21 to 1.25.12 Dolutegravir is also excreted into human breast milk, albeit in small amounts; the median breast milk to maternal plasma concentration ratio is approximately 0.033.12 In settings where safe and feasible alternatives to breastfeeding are available, women living with HIV are generally advised not to breastfeed their infants to prevent postnatal HIV transmission, irrespective of the antiretroviral regimen.15

8.2. Pediatric Patients

• Approved Indications and Dosing: Dolutegravir is indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in children and adolescents, with specific age and weight criteria varying by formulation and regulatory agency.13 Dosing is weight-based and formulation-specific:
• Film-coated tablets (e.g., 50 mg) are generally approved for children aged 6 years and older and weighing at least 14 kg.[15]
• Tablets for oral suspension (dispersible tablets) (e.g., 5 mg, 10 mg) are available for younger children, typically from 4 weeks of age and weighing at least 3 kg.[15] These dispersible tablets are not bioequivalent to the film-coated tablets on a milligram-for-milligram basis and require specific dosing charts.[15] The availability of these pediatric-friendly formulations, while crucial for administration, necessitates careful prescriber education to ensure correct dosing and avoid errors due to differing bioavailability. Dose adjustments, often involving a switch from once-daily to twice-daily administration of the weight-based dose, may be necessary if dolutegravir is coadministered with potent UGT1A/CYP3A inducers like efavirenz or rifampin.[15]
• Efficacy and Safety: Clinical data support the efficacy and safety of dolutegravir in pediatric populations, with outcomes generally comparable to those observed in adults.8 However, there are insufficient data to recommend a specific dose for dolutegravir in children and adolescents who have documented resistance to integrase inhibitors.15

The following table provides a summary of EMA-recommended dosing for dolutegravir dispersible tablets in pediatric populations without INSTI resistance:

Table 5: Dolutegravir Dosing in Pediatric Populations (Tivicay Dispersible Tablets - EMA Recommendations)

Body Weight (kg)	Age	Once-Daily Dose (mg)	Twice-Daily Dose (mg)	Reference(s)
3 to < 6 kg	≥ 4 weeks	5	Not Applicable	15
6 to < 10 kg	< 6 months	10	5	15
	≥ 6 months	15	10	15
10 to < 14 kg	≥ 6 months	20	10	15
14 to < 20 kg	≥ 6 months	25	15	15
≥ 20 kg	≥ 6 months	30	15	15

Note: If certain UGT1A or CYP3A inducers are coadministered, the weight-based once-daily dose should be administered twice daily.[15] These are EMA recommendations; FDA dosing for 10 mg dispersible tablets may vary slightly.

8.3. Patients with Hepatic or Renal Impairment

• Hepatic Impairment: No dosage adjustment for dolutegravir is necessary for patients with mild to moderate hepatic impairment (Child-Pugh Score A or B). Dolutegravir has not been studied in patients with severe hepatic impairment (Child-Pugh Score C) and is therefore not recommended for use in this population.[14]
• Renal Impairment: Dolutegravir itself (as Tivicay) generally does not require dose adjustment in patients with renal impairment because its renal clearance as unchanged drug is very low (<1%).[1] However, fixed-dose combinations containing dolutegravir (e.g., Triumeq, Dovato) may have limitations or contraindications in patients with significant renal impairment due to the pharmacokinetic properties and dosing restrictions of their other components (e.g., abacavir, lamivudine, tenofovir).[6] As previously noted, dolutegravir can cause a small, benign increase in serum creatinine by inhibiting its tubular secretion via OCT2, which should not be misinterpreted as worsening renal function.

8.4. Patients with HBV/HCV Co-infection

Patients with HIV-1 and co-infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) may be at an increased risk for the development or worsening of transaminase elevations when treated with dolutegravir-containing regimens. Close monitoring of liver function is recommended in these patients.[13]

A critical consideration for HIV/HBV co-infected patients is the HBV activity of NRTIs included in the regimen. Lamivudine (a component of Dovato and Triumeq) and tenofovir (often used as part of a dolutegravir-based regimen) possess activity against HBV. Discontinuation of these HBV-active agents in co-infected patients can lead to HBV reactivation or flares, characterized by sudden increases in HBV DNA and ALT levels.[4] Therefore, fixed-dose combinations like Dovato and Triumeq carry boxed warnings regarding the risk of lamivudine-resistant HBV emergence and exacerbations of HBV upon discontinuation in co-infected individuals. Careful management, including consideration of ongoing anti-HBV therapy, is essential if a dolutegravir-containing FDC with HBV activity is changed or stopped in these patients.

9. Regulatory Status and Formulations

Dolutegravir has received widespread regulatory approval and is available in various formulations to suit different patient needs.

9.1. FDA and EMA Approved Indications

• FDA: Dolutegravir is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients who meet specific age and weight criteria.[13] It is approved as a single-ingredient product (Tivicay) and as part of several fixed-dose combination tablets: Juluca (dolutegravir/rilpivirine), Dovato (dolutegravir/lamivudine), and Triumeq (dolutegravir/abacavir/lamivudine).[3]
• EMA (Tivicay): Tivicay is indicated in combination with other antiretroviral medicinal products for the treatment of HIV-1 infected adults, adolescents, and children, again with specific age and weight criteria depending on the formulation.[15] The EMA labeling provides guidance for its use in both treatment-naive and treatment-experienced patients, including those with certain patterns of INSTI resistance, where a twice-daily dosing regimen of 50 mg may be recommended, informed by the specific integrase resistance pattern.[15] This nuanced guidance for resistant strains, particularly when treatment options are limited due to advanced multi-class resistance, reflects an approach to potentially overcome reduced susceptibility with increased drug exposure.

The approval of multiple FDCs containing dolutegravir highlights its central role as a cornerstone agent in modern HIV therapy. This strategy facilitates regimen simplification, which can lead to improved adherence and quality of life for patients. The evolution from a single agent to a 3-drug FDC (Triumeq) and subsequently to 2-drug FDCs (Juluca, Dovato) reflects a significant trend in HIV treatment towards minimizing drug burden while maintaining high efficacy.

9.2. Available Formulations

Dolutegravir is available in the following formulations:

• Tivicay (dolutegravir single agent):
• Film-coated tablets: Commonly available in a 50 mg strength.[13] Other strengths (e.g., 10 mg, 25 mg) may also be available depending on the region.
• Tablets for oral suspension (dispersible tablets): These are designed for pediatric use or for patients who have difficulty swallowing film-coated tablets. The FDA-approved dispersible tablets are 10 mg, strawberry cream flavored [24], while the EMA has approved 5 mg dispersible tablets.[15] As previously noted, these are not bioequivalent to film-coated tablets on a mg-per-mg basis.
• Fixed-Dose Combinations (FDCs):
• Juluca: Contains dolutegravir 50 mg and rilpivirine 25 mg. This was the first FDA-approved complete two-drug regimen in a single tablet for HIV-1 maintenance therapy.[3]
• Dovato: Contains dolutegravir 50 mg and lamivudine 300 mg. Approved for use as a complete regimen for treatment-naive adults and for certain virologically suppressed patients switching regimens.[3]
• Triumeq: Contains dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg. A complete once-daily single-tablet regimen for HIV-1 infection, requiring HLA-B*5701 screening prior to initiation due to the abacavir component.[3]

10. Conclusion and Future Perspectives

10.1. Summary of Dolutegravir's Role in HIV-1 Therapy

Dolutegravir has fundamentally transformed the landscape of HIV-1 treatment since its introduction. Its combination of high virological efficacy, a generally favorable tolerability profile, a high genetic barrier to resistance, and the convenience of once-daily dosing for most patients has established it as a preferred agent in global HIV treatment guidelines. Its impact is evident in its widespread use in first-line therapy for treatment-naive individuals, its role in simplifying treatment through effective two-drug regimens, and its utility in managing certain treatment-experienced populations, including those with some prior INSTI exposure, albeit with careful consideration of resistance patterns. The success of dolutegravir has been a key driver in the broader acceptance and investigation of 2DRs as both initial and maintenance therapy, challenging the long-standing paradigm of triple-drug regimens.

10.2. Ongoing Research and Unmet Needs

Despite the significant advancements offered by dolutegravir, ongoing research and unmet needs persist in HIV-1 management. Continued long-term surveillance of dolutegravir-based regimens, especially 2DRs, is essential to monitor for any unforeseen late-emerging toxicities and to confirm sustained efficacy over decades of use.

A critical area of focus is the continued understanding and management of dolutegravir resistance. While the genetic barrier is high, resistance does emerge. Monitoring these resistance patterns in diverse real-world settings, particularly in regions with high HIV prevalence, varied viral subtypes, and potential challenges in adherence and healthcare access, is crucial.[7] The potential for different resistance pathways to emerge in non-B HIV subtypes, as suggested by some research, requires further investigation to ensure optimal treatment strategies globally.[7] This vigilance is paramount to preserving dolutegravir's long-term utility, especially in resource-limited settings where it forms the backbone of public health ART programs.

Further optimization of dolutegravir use in specific populations, such as the very young, the elderly with increasing comorbidities, and pregnant individuals (despite current favorable data), will continue to be an area of research. While not specifically covered in the provided information, the broader field of HIV research is also exploring the role of potent agents like dolutegravir in long-acting injectable formulations, HIV prevention strategies (Pre-Exposure Prophylaxis, PrEP), and as components of potential HIV cure strategies, areas where its favorable characteristics could be highly advantageous. The journey of dolutegravir from its development to its current prominent role exemplifies the remarkable progress in antiretroviral therapy, yet the ongoing pursuit of even better, safer, and more convenient treatments for all individuals living with HIV remains a global health priority.

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