A Comprehensive Pharmacological and Clinical Monograph on Dolutegravir and Lamivudine

I. Overview and Therapeutic Classification

Introduction to Dolutegravir/Lamivudine

The combination of dolutegravir and lamivudine represents a significant evolution in the management of Human Immunodeficiency Virus Type 1 (HIV-1) infection. As a complete, once-daily, single-tablet regimen, it embodies a strategic shift in antiretroviral therapy (ART), challenging the long-standing paradigm of using three or four drugs for initial and maintenance treatment.[1] The development of this two-drug regimen (2DR) was predicated on the principle of minimizing a patient's lifelong exposure to antiretroviral agents (ARVs) without compromising virologic efficacy or the high barrier to resistance that is characteristic of modern dolutegravir-based therapies.[1] By providing a powerful and simplified treatment option, this combination addresses key goals of contemporary HIV care: long-term safety, tolerability, and adherence.

The clinical validation of a potent 2DR marks a pivotal moment in HIV therapeutics. It reflects a mature understanding of viral dynamics and drug pharmacology, where the potency and genetic barrier of a core agent like dolutegravir are sufficient to allow for a simplified nucleoside reverse transcriptase inhibitor (NRTI) backbone. This "less is more" philosophy moves away from the historical necessity of multi-agent combinations designed to overcome less potent drugs and lower resistance barriers, toward a more refined approach focused on optimizing the long-term health and quality of life for individuals living with a chronic condition.

Available Fixed-Dose Combination Products

The active pharmaceutical ingredients dolutegravir and lamivudine are available in distinct fixed-dose combination products, each with a unique composition and clinical profile that dictates its appropriate use. A clear understanding of these formulations is essential for safe and effective prescribing.

Dovato

Dovato is the primary subject of this monograph and is the formulation that constitutes the two-drug regimen. It is a fixed-dose combination tablet containing 50 mg of dolutegravir and 300 mg of lamivudine.[3] Manufactured by ViiV Healthcare, Dovato is presented as an oval, biconvex, white, film-coated tablet, which is debossed with “SV 137” on one face to aid in identification.[3] It is indicated as a complete regimen for the treatment of HIV-1 infection and is not intended for co-administration with other antiretroviral agents.[1]

Triumeq and Triumeq PD

Triumeq is a related but fundamentally different product that incorporates dolutegravir and lamivudine as part of a three-drug, single-tablet regimen. In addition to 50 mg of dolutegravir and 300 mg of lamivudine, each Triumeq tablet contains 600 mg of a third antiretroviral agent, abacavir.[6] A pediatric formulation, Triumeq PD, is available as tablets for oral suspension, containing proportionately lower doses of the three components: 60 mg of abacavir, 5 mg of dolutegravir, and 30 mg of lamivudine.[6]

The inclusion of abacavir in Triumeq introduces a critical and non-negotiable clinical consideration that is absent for Dovato. Abacavir is associated with a risk of a serious and potentially fatal hypersensitivity reaction. This risk is strongly linked to the presence of the human leukocyte antigen allele HLA−B∗5701.[6] Consequently, genetic screening for the

HLA−B∗5701 allele is mandatory for all patients prior to initiating therapy with any abacavir-containing product, including Triumeq.[6] A positive test result is an absolute contraindication to its use. This starkly contrasts with Dovato, for which no such genetic pre-screening is required. This distinction underscores that while the products share two common components, their safety profiles and the clinical workflows required for their initiation are fundamentally different. A clinician cannot view them as interchangeable; patient selection is dictated at the outset by the unique safety profile of the third agent in the Triumeq formulation.

Pharmacological Classification and Therapeutic Context

The dolutegravir and lamivudine combination is classified as an antiviral combination product for the treatment of HIV-1 infection.[4] Each component belongs to a distinct class of antiretroviral drugs, and their complementary mechanisms of action provide potent and comprehensive inhibition of the viral lifecycle.

• Dolutegravir: This agent is a second-generation Integrase Strand Transfer Inhibitor (INSTI).[3] INSTIs represent one of the most potent and well-tolerated classes of modern antiretroviral drugs and are recommended as a core component of first-line therapy by major international treatment guidelines.
• Lamivudine: This agent is a Nucleoside Analogue Reverse Transcriptase Inhibitor (NRTI).[3] NRTIs form the "backbone" of most antiretroviral regimens and were among the first classes of drugs developed to treat HIV.

As a complete regimen, Dovato is designed to be used alone for the treatment of HIV-1 and should not be co-administered with other antiretroviral drugs.[1] This single-tablet approach simplifies the treatment regimen, which can enhance patient adherence and reduce the risk of medication errors, while also minimizing the potential for cumulative drug toxicities and drug-drug interactions associated with more complex multi-pill regimens.

II. Molecular Mechanism of Action

The high efficacy of the dolutegravir and lamivudine combination stems from its dual-pronged attack on two separate, essential stages of the HIV-1 replication cycle. By inhibiting both reverse transcription and integration, the regimen creates a formidable barrier to viral propagation.

Dolutegravir (Integrase Strand Transfer Inhibitor)

Target and Action

Dolutegravir exerts its antiviral effect by specifically targeting and inhibiting the HIV-1 integrase enzyme.[12] This viral enzyme is critical for the replication process, as it catalyzes the insertion of the viral genome into the host cell's DNA. Dolutegravir's mechanism is precise: it binds to the active site of the integrase enzyme, a region that contains divalent magnesium ions (

Mg2+) essential for its catalytic activity.[15] By chelating these metal ions, dolutegravir effectively blocks the key "strand transfer" step of the integration process.[3]

Consequence of Inhibition

The strand transfer reaction is the final and irreversible step of integration, where the viral DNA is covalently linked to the host cell's chromosomal DNA. By preventing this step, dolutegravir ensures that the viral DNA cannot become a permanent part of the host T-lymphocyte's genome.[14] The unintegrated viral DNA is unable to effectively commandeer the host's cellular machinery for transcription and the production of new viral proteins and RNA. Consequently, the HIV replication cycle is arrested, leading to a rapid decline in plasma viral load.[14] This mechanism of action has no homologous process in human cells, which contributes to the favorable tolerability and low toxicity profile of the INSTI class.[12]

Pharmacological Profile and Resistance Barrier

Dolutegravir's molecular pharmacology is a key determinant of its clinical performance, particularly its high barrier to the development of drug resistance. Compared to first-generation INSTIs such as raltegravir, dolutegravir exhibits a significantly longer dissociative half-life from the integrase-DNA complex.[12] This "tight binding" characteristic means that the drug remains attached to its target for an extended period, providing sustained inhibition even if plasma concentrations fluctuate. In vitro resistance selection experiments have demonstrated this high barrier; while resistance to raltegravir could be selected within 28 days, no highly resistant viral mutants were isolated in the presence of dolutegravir even after 112 days of culture.[15] This robust resistance profile is a direct result of its molecular interaction with the integrase enzyme and translates into the durable virologic control and low rates of treatment-emergent resistance observed in large-scale clinical trials. Dolutegravir is primarily metabolized via glucuronidation by the enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1), with a minor contribution from the cytochrome P450 enzyme CYP3A4, a factor that influences its drug-drug interaction profile.[15]

Lamivudine (Nucleoside Reverse Transcriptase Inhibitor)

Target and Action

Lamivudine, also known as 3TC, is a synthetic nucleoside analogue of cytosine.[13] As a prodrug, it is inactive upon administration and requires intracellular activation. Within the host cell, lamivudine is phosphorylated by cellular kinases to its active moiety, lamivudine 5'-triphosphate (3TC-TP).[17] This active triphosphate form is a structural mimic of the natural nucleoside deoxycytidine triphosphate (dCTP), one of the essential building blocks for DNA synthesis.[18]

Consequence of Inhibition

The primary target of 3TC-TP is the HIV-1 reverse transcriptase (RT) enzyme. This enzyme is responsible for the uniquely retroviral process of converting the single-stranded viral RNA genome into double-stranded proviral DNA. 3TC-TP competitively inhibits the RT enzyme by competing with the natural dCTP substrate for incorporation into the nascent viral DNA chain.[3] Once 3TC-TP is incorporated, it acts as a chain terminator. The lamivudine molecule lacks the crucial 3'-hydroxyl (

−OH) group that is required to form the next phosphodiester bond in the elongating DNA backbone. This structural difference makes further extension of the DNA chain impossible, leading to the premature termination of reverse transcription.[13] This effectively prevents the formation of a complete proviral DNA, thereby blocking a step that must occur before integration can be attempted.

Pharmacological Profile and Enduring Utility

Lamivudine has remained a cornerstone of ART for decades, a longevity attributable to its favorable pharmacological profile. It is a potent inhibitor of HIV-1 RT at concentrations that exhibit markedly low cytotoxicity against human cellular DNA polymerases, providing a wide therapeutic window.[13] It is absorbed rapidly after oral administration, with a serum half-life of approximately 5 to 7 hours.[13] However, the intracellular half-life of its active 3TC-TP metabolite is substantially longer, ranging from 15.5 to 19 hours in infected cells, which provides the pharmacokinetic rationale for convenient once-daily dosing.[19]

The role of lamivudine in a modern 2DR is more nuanced than simply being an additive agent. While the development of the M184V mutation in the RT enzyme confers high-level resistance to lamivudine, this mutation comes at a significant cost to the virus. The M184V substitution is located in the highly conserved tyrosine-methionine-aspartate-aspartate (YMDD) motif of the enzyme's catalytic site. The mutation impairs the enzyme's processivity and catalytic function, resulting in a significant reduction in viral fitness or replicative capacity.[13] Paradoxically, this mutation has also been shown to re-sensitize the virus to certain other NRTIs, such as zidovudine and tenofovir.[13] Therefore, even in the setting of resistance, the pressure exerted by lamivudine can force the virus into a less fit state, providing a residual virologic benefit. This multifaceted profile—good safety, a distinct mechanism from INSTIs, and the fitness cost of its primary resistance mutation—explains its enduring value as a partner agent for a potent core drug like dolutegravir.

Dual-Action Synergy

The combination of dolutegravir and lamivudine provides a powerful and synergistic blockade of HIV-1 replication by targeting two distinct and essential enzymatic steps in series:

1. Reverse Transcription Inhibition (Lamivudine): Prevents the synthesis of viral DNA from the viral RNA template.
2. Integration Inhibition (Dolutegravir): Prevents the incorporation of any successfully synthesized viral DNA into the host cell genome.

This dual mechanism ensures a comprehensive suppression of the viral lifecycle.[20] In vitro combination studies have confirmed that the two agents are not antagonistic to one another, allowing for their combined use to achieve potent antiviral activity.[3]

III. Clinical Efficacy in Treatment-Naïve Populations: The GEMINI Trials

The foundational evidence for the use of the dolutegravir/lamivudine 2DR as an initial therapy for HIV-1 infection was established in the landmark GEMINI-1 and GEMINI-2 clinical trials. These studies were designed to rigorously test whether this novel two-drug approach could match the efficacy of a standard-of-care, three-drug regimen.

Study Design and Population

GEMINI-1 (NCT02831673) and GEMINI-2 (NCT02831764) were identical, Phase III, randomized, double-blind, multicenter, non-inferiority studies conducted across 187 centers in 21 countries.[23] The robust, duplicate design was intended to provide a high level of evidence and ensure the reproducibility of the findings.

The trials collectively enrolled a large and diverse population of over 1,400 ART-naïve adults with HIV-1 infection.[1] Key inclusion criteria required participants to have a screening plasma HIV-1 RNA level between 1,000 and 500,000 copies/mL.[1] Participants were randomized on a 1:1 basis to receive one of two once-daily regimens:

• Two-Drug Regimen (2DR): Dolutegravir 50 mg plus lamivudine 300 mg.
• Three-Drug Regimen (3DR): Dolutegravir 50 mg plus a fixed-dose combination of tenofovir disoproxil fumarate 300 mg and emtricitabine 200 mg (TDF/FTC).[23]

Randomization was stratified by screening HIV-1 RNA (≤100,000 vs. >100,000 copies/mL) and screening CD4+ cell count (≤200 vs. >200 cells/mm³) to ensure balance in these key prognostic factors between the treatment arms.[23]

Primary and Long-Term Efficacy Endpoints

The primary objective of the GEMINI trials was to demonstrate that the 2DR was non-inferior to the 3DR in achieving virologic suppression. The results were consistent and durable across multiple time points.

• Primary Endpoint (Week 48): The primary analysis at 48 weeks demonstrated that the 2DR met the non-inferiority criteria. In a pooled analysis of both studies, 91% of participants in the dolutegravir/lamivudine arm achieved virologic suppression (defined as HIV-1 RNA <50 copies/mL) compared to 93% in the dolutegravir + TDF/FTC arm, according to the FDA Snapshot algorithm.[24]
• Long-Term Durability (Week 96): The non-inferior efficacy of the 2DR was sustained through 96 weeks of follow-up. At this time point, 86.0% of participants in the 2DR arm maintained virologic suppression, compared to 89.5% in the 3DR arm.[26]
• Extended Long-Term Durability (Week 144 / 3 Years): The durability of the 2DR was further confirmed at the 144-week analysis. Virologic suppression was maintained in 82% of participants in the 2DR arm and 84% of participants in the 3DR arm, reinforcing the long-term viability of the two-drug approach.[24]

Efficacy in Key Subgroups

A critical aspect of the GEMINI trials was the evaluation of the 2DR's performance in patient subgroups that have historically been considered more challenging to treat. The results in these subgroups were pivotal in building clinical confidence in the regimen.

• High Baseline Viral Load: The trials directly challenged the long-held clinical tenet that patients with high viral loads require more complex, three-drug regimens for initial suppression. The data demonstrated that the potency of the 2DR was sufficient even in this population. A post-hoc analysis of participants with a very high baseline viral load (≥500,000 copies/mL) found that 85% of those receiving the 2DR achieved virologic suppression at Week 48, and 77% maintained suppression at Week 144. These rates were comparable to those seen in the 3DR arm (80% at both time points).[28] This finding was instrumental in redefining clinical perceptions of potency, shifting the focus from the number of drugs in a regimen to the intrinsic power and resistance barrier of the core agent, dolutegravir. It provided the evidence base for clinicians to confidently initiate a 2DR in a patient population previously thought to require a more aggressive initial therapy.
• Low Baseline CD4+ Count: The trials included and stratified for patients with significant immunosuppression (baseline CD4+ count ≤200 cells/mm³). Efficacy was maintained in this subgroup, and the immunological recovery was robust and comparable between the two treatment arms. Mean increases in CD4+ cell counts from baseline were similar across all baseline viral load categories and in both the 2DR and 3DR groups through 144 weeks.[23]

Resistance Profile

Perhaps the most compelling finding from the GEMINI trials, beyond non-inferior efficacy, was the regimen's exceptionally high barrier to resistance. In the chronic management of HIV, preserving future treatment options is a paramount goal. The data from GEMINI showed that even in the rare instances of virologic failure, the regimen did not compromise future options. Through 144 weeks of follow-up, no participant who met the protocol-defined criteria for confirmed virologic failure in either the 2DR or 3DR arm developed treatment-emergent resistance mutations to either integrase inhibitors or nucleoside reverse transcriptase inhibitors.[2]

This outcome is of profound clinical importance. It indicates that if the dolutegravir/lamivudine regimen fails virologically, it tends to do so "cleanly," without generating mutations that would confer cross-resistance to the powerful INSTI class or other NRTIs. This significantly de-risks the clinical decision to start with a 2DR, as clinicians can be confident that in the unlikely event of failure, the patient's future treatment options, particularly with other INSTI-based regimens, will remain fully viable.

IV. Efficacy in Virologically Suppressed Switch Populations: The TANGO Trial

While the GEMINI trials established the efficacy of dolutegravir/lamivudine for initiating ART, the TANGO study was designed to answer a different but equally important clinical question: can patients who are already virologically suppressed on a stable, standard three-drug regimen safely switch to this 2DR and maintain that suppression?

Study Design and Population

The TANGO study (NCT03446573) was a Phase III, randomized, open-label, active-controlled, non-inferiority trial.[31] The trial enrolled 741 adults with HIV-1 who were virologically suppressed (defined as HIV-1 RNA <50 copies/mL for at least six months) on a stable regimen containing tenofovir alafenamide (TAF) and at least two other drugs.[31] The inclusion of patients on TAF-based regimens was significant, as TAF represents a modern, widely used component of first-line therapy with an improved renal and bone safety profile compared to its predecessor, TDF.

Participants were randomized on a 1:1 basis to either:

• Switch Arm: Discontinue their current regimen and switch to the fixed-dose 2DR of dolutegravir/lamivudine (Dovato).
• Continuation Arm: Continue their baseline TAF-based regimen.[31]

Primary and Long-Term Efficacy Endpoints

The primary objective was to demonstrate that switching to the 2DR was non-inferior to continuing the existing TAF-based regimen in maintaining virologic control.

• Primary Endpoint (Week 48): The study successfully met its primary endpoint. At 48 weeks, the proportion of participants maintaining virologic suppression (HIV-1 RNA <50 c/mL) was high and statistically non-inferior in both arms: 93.2% in the group that switched to dolutegravir/lamivudine versus 93.0% in the group that continued their TAF-based regimen.[31]
• Long-Term Durability (Week 144 / 3 Years): The non-inferiority in maintaining virologic suppression was sustained through three years of follow-up. At Week 144, 85.9% of participants in the 2DR switch arm had HIV-1 RNA <50 c/mL, compared to 81.7% in the TAF-based regimen arm.[34]

These results provided high-quality evidence to support a "de-escalation" or "simplification" strategy in HIV management. They demonstrated that for patients who have already achieved stable virologic control, the third antiretroviral agent in their regimen may be redundant and can be safely removed by switching to the dolutegravir/lamivudine 2DR. This allows for a reduction in long-term cumulative drug exposure without sacrificing virologic efficacy.

Resistance Profile

Consistent with the findings from the GEMINI trials, the TANGO study reinforced the high resistance barrier of the dolutegravir/lamivudine regimen. Through 144 weeks of the study, a remarkable zero participants (0 out of 369) in the arm that switched to the 2DR met the protocol-defined criteria for confirmed virologic failure.[34] This finding provided strong reassurance that switching to a 2DR does not increase the risk of resistance development in a treatment-experienced, virologically suppressed population.

Safety and Biomarker Changes

While overall adverse event rates were similar between the two study arms, an important secondary finding related to changes in key safety biomarkers.[34] The analysis of renal and bone biomarkers showed a statistically significant trend favoring the dolutegravir/lamivudine arm.[26] This outcome is pharmacologically predictable, as the switch involved discontinuing the tenofovir alafenamide component of the baseline regimen. Although TAF has a better safety profile than its predecessor TDF, it is still associated with potential long-term effects on renal function and bone mineral density.

This observation has significant clinical implications. For many stable patients, the primary driver for switching from a TAF-based regimen to Dovato may not be a change in efficacy (which was equivalent) but rather the opportunity to improve the long-term safety profile of their ART. By removing the tenofovir component entirely, clinicians can proactively mitigate the potential for future renal and bone-related toxicities, a particularly important consideration for an aging population of people living with HIV who may have other comorbidities. This makes the favorable biomarker data a key differentiator and a compelling clinical rationale for considering a switch.

V. Use in Special Populations: The DANCE Trial and Other Considerations

The applicability of an antiretroviral regimen across diverse patient populations is a critical determinant of its clinical utility. Evidence from dedicated studies and pharmacokinetic analyses has defined the use of dolutegravir/lamivudine in adolescents, older adults, and individuals with organ impairment.

Adolescent Population: The DANCE Trial

The DANCE trial (NCT03682848) was a pivotal study that provided the evidence base for expanding the indication of dolutegravir/lamivudine to younger populations.

• Study Design: DANCE was a Phase 3b, single-arm, multicenter, open-label study specifically designed to evaluate the efficacy, safety, and pharmacokinetics of the fixed-dose combination of dolutegravir/lamivudine (Dovato) in ART-naïve adolescents.[20] The study enrolled participants aged ≥12 to <18 years who weighed at least 25 kg.[20]
• Efficacy and Safety: The trial demonstrated high rates of virologic efficacy that were comparable to those observed in adult studies. At the 48-week primary endpoint, 26 out of 30 participants (87%) had achieved and were maintaining viral suppression.[35] The safety profile in adolescents was also found to be consistent with the established profile in adults.[35] Subsequent analysis at 96 weeks confirmed the sustained efficacy and safety of the regimen in this population.[36]
• Regulatory Impact: The positive results from the DANCE study were instrumental in securing regulatory approvals for adolescent use. On April 8, 2024, the U.S. Food and Drug Administration (FDA) approved an expanded indication for Dovato for the treatment of HIV-1 in adolescents aged 12 years and older and weighing at least 25 kg.[5] This made Dovato the first and only oral, two-drug, single-tablet regimen available for this patient population.[20] Similarly, the European Medicines Agency (EMA) approved its use for adolescents older than 12 years of age who weigh at least 40 kg.[21]

The approval for adolescent use is strategically significant for the long-term management of HIV. By establishing safety and efficacy early in a patient's life, it allows for the initiation of a simplified 2DR from the outset of their treatment journey. This approach prioritizes the reduction of cumulative, lifelong drug exposure, which is a central goal of modern ART for a chronic condition that requires decades of therapy.

Geriatric Population (≥65 years)

The available data on the use of dolutegravir/lamivudine in geriatric patients are limited.[39] However, based on the known pharmacology of the individual components, no specific dose adjustment is recommended based on age alone.[39] Clinical management in older adults should be individualized and guided primarily by an assessment of their renal function and a careful review of potential drug-drug interactions related to polypharmacy and comorbidities.[9]

Renal Impairment

The use of Dovato in patients with renal impairment is constrained by its nature as a fixed-dose combination product.

• Severe Renal Impairment (Creatinine Clearance [CrCl] < 30 mL/min): Dovato is not recommended in this population.[39] This is not due to an inherent toxicity of the combination but rather a logistical limitation. The lamivudine component requires significant dose reduction in patients with severe renal impairment to avoid drug accumulation and potential toxicity.[17] Because this dose adjustment cannot be made with the fixed-dose tablet, its use is precluded.[41] In such cases, the individual components would need to be prescribed separately at their appropriately adjusted doses.
• Moderate Renal Impairment (CrCl 30-49 mL/min): Dovato may be used in this population, but it requires caution and careful monitoring.[40] Patients in this range of renal function can experience significantly higher exposure to lamivudine (1.6- to 3.3-fold) compared to those with normal renal function.[40] Therefore, clinicians should monitor these patients for lamivudine-related adverse events, particularly hematologic toxicities such as neutropenia or anemia.[39] If such toxicities develop and a dose adjustment of lamivudine is indicated, Dovato must be discontinued and the treatment regimen reconstructed using the individual components.[39]

Hepatic Impairment

The recommendations for use in patients with hepatic impairment are based on the Child-Pugh classification system.

• Mild to Moderate Hepatic Impairment (Child-Pugh Grade A or B): No dosage adjustment of Dovato is required for these patients.[39]
• Severe Hepatic Impairment (Child-Pugh Grade C): Dovato is not recommended for use in patients with severe hepatic impairment. There are no available clinical data to establish its safety and efficacy in this population.[35]

VI. Dosing, Administration, and Patient Counseling

The effective and safe use of dolutegravir/lamivudine requires adherence to specific guidelines for dosing, administration, pre-initiation testing, and management of missed doses. Clear patient counseling on these aspects is essential for optimal therapeutic outcomes.

Standard Dosage

The recommended dosage regimen for Dovato is consistent for all approved populations:

• Adults and Adolescents (≥12 years of age and weighing at least 25 kg or at least 40 kg [E.U. indication]): One tablet, containing 50 mg of dolutegravir and 300 mg of lamivudine, taken orally once daily.[3]

Administration Instructions

• With or Without Food: Dovato can be administered with or without food, which provides flexibility for the patient.[3]
• Tablet Integrity: The tablet should be swallowed whole. It must not be chewed, cut, or crushed, as this could alter the pharmacokinetic properties of the medication.[8]
• Consistency: Patients should be counseled to take their dose at approximately the same time each day to maintain stable plasma drug concentrations.[11]

Management of Missed Doses

Clear instructions for managing a missed dose are crucial to maintain adherence and prevent virologic rebound.

• If a patient misses a dose of Dovato, they should take it as soon as they remember, provided that the next scheduled dose is not due within 4 hours.
• If the next dose is due within 4 hours, the patient should skip the missed dose and resume the normal dosing schedule.
• Patients must be explicitly instructed not to take two doses at once to make up for a missed dose.[6]

Required Testing Before Initiation of Therapy

Before a patient starts treatment with Dovato, two key laboratory tests are mandatory to ensure patient safety.

• Hepatitis B Virus (HBV) Screening: All patients must be tested for the presence of HBV infection prior to or at the time of initiating Dovato.[1] This is because the lamivudine component is active against HBV, and discontinuing the medication in a co-infected patient can lead to a severe acute exacerbation, or "flare," of their hepatitis B.[1]
• Pregnancy Testing: Pregnancy testing must be performed for all individuals of childbearing potential before starting Dovato.[3] This is due to a potential risk of neural tube defects associated with dolutegravir exposure at the time of conception and during the first trimester of pregnancy. Effective contraception is also recommended during treatment.[3]

Packaging and Storage

Dovato is available in different packaging options to suit patient preferences, including standard 30-count bottles and convenient "on-the-go" blister packs. The blister packs are perforated and designed to be portable and to help patients track their doses.[45]

Table: Dosing Adjustments for Specific Patient Populations and Co-administered Drugs

Because Dovato is a fixed-dose combination, its use is limited in certain clinical scenarios where dose adjustment of an individual component is necessary. The following table consolidates the recommendations for specific patient populations and for co-administration with interacting medications, providing a critical reference tool for prescribers to ensure safe and effective use.

Condition / Co-administered Drug	Recommended Dosing Adjustment / Action	Source Snippets
Patient Populations
Renal Impairment (CrCl < 30 mL/min)	Not Recommended (due to fixed-dose inflexibility)	39
Renal Impairment (CrCl 30-49 mL/min)	Use with caution; monitor for lamivudine-related toxicities.	40
Severe Hepatic Impairment (Child-Pugh C)	Not Recommended (no data available)	35
Concomitant Medications
Carbamazepine or Rifampin	Take one Dovato tablet once daily, followed by an additional dolutegravir 50-mg tablet approximately 12 hours later.	3
Efavirenz, Nevirapine, Tipranavir/ritonavir	Requires an additional 50mg tablet of dolutegravir approx. 12 hours after the Dovato dose.	39
Oxcarbazepine, Phenobarbital, Phenytoin, St. John's wort	Avoid co-administration.	45
Dofetilide	Contraindicated. Do not co-administer.	41
Dalfampridine	Co-administration elevates dalfampridine levels, increasing seizure risk. Weigh benefits against risks.	45
Metformin	Monitor renal function and consider metformin dose adjustment.	42
Polyvalent Cation-containing Antacids/Laxatives (Mg, Al) or Sucralfate	Administer Dovato 2 hours before or 6 hours after.	39
Calcium or Iron Supplements	With food: Can be taken at the same time as Dovato. Without food: Administer Dovato 2 hours before or 6 hours after the supplement.	39
Sorbitol-containing medicines	Avoid chronic co-administration when possible.	45

VII. Safety and Tolerability Profile

The safety and tolerability profile of dolutegravir/lamivudine has been well-characterized through an extensive clinical development program. While generally well-tolerated, the regimen is associated with several important warnings, precautions, and potential adverse reactions that require diligent clinical monitoring.

Boxed Warning: Patients Co-infected with HIV-1 and Hepatitis B Virus (HBV)

The most prominent warning associated with Dovato concerns its use in patients co-infected with HIV-1 and HBV, and it is highlighted as a boxed warning in the U.S. Prescribing Information.[3] This warning encompasses two distinct but related risks stemming from the activity of lamivudine against HBV.

• Risk of Lamivudine-Resistant HBV: In co-infected patients, treatment with a lamivudine-containing regimen can lead to the selection and emergence of HBV variants with resistance mutations to lamivudine.[1] This can complicate the future management of the patient's chronic hepatitis B. Therefore, if Dovato is to be used in a co-infected patient, the addition of another agent active against HBV should be strongly considered to create a fully suppressive hepatitis B regimen.[1]
• Risk of Post-Treatment Exacerbations of HBV: A more acute risk is the potential for a severe flare-up of hepatitis B upon discontinuation of Dovato.[44] Because lamivudine suppresses HBV replication, its withdrawal can lead to a rapid rebound in HBV viral load and associated severe, acute hepatitis, which can be life-threatening.[1] For this reason, all patients co-infected with HIV-1 and HBV who discontinue Dovato must be closely monitored with both clinical assessments and laboratory follow-up (e.g., liver function tests) for at least several months after stopping treatment.[3]

Serious Adverse Reactions

Beyond the boxed warning, several other serious adverse reactions have been associated with the components of Dovato.

• Hypersensitivity Reactions: Serious hypersensitivity reactions have been reported with dolutegravir. These reactions are typically characterized by a constellation of symptoms, including rash, constitutional findings (such as fever, malaise, and fatigue), and occasionally evidence of organ dysfunction, including liver injury.[1] If a patient develops signs or symptoms consistent with a hypersensitivity reaction, Dovato must be discontinued immediately. A delay in stopping the medication can result in a life-threatening reaction.[1]
• Hepatotoxicity: Cases of hepatotoxicity, including elevated liver enzymes and, rarely, acute liver failure, have been reported in patients receiving dolutegravir-containing regimens.[44] This can occur even in patients without pre-existing liver disease or other identifiable risk factors. Patients with underlying chronic hepatitis B or C are at an increased risk for the worsening or development of transaminase elevations.[41] Regular monitoring of liver function is recommended for all patients, especially those with underlying hepatic disease.[44]
• Lactic Acidosis and Severe Hepatomegaly with Steatosis: This is a well-recognized, albeit rare, class effect of NRTI medications like lamivudine.[41] This serious metabolic complication can be fatal and is characterized by a buildup of lactic acid in the blood. The risk may be higher in female patients, individuals with obesity, and those on long-term NRTI therapy.[44] Clinical suspicion should be high in any patient presenting with unexplained tachypnea, dyspnea, or gastrointestinal symptoms such as nausea, vomiting, and abdominal pain.[44]
• Immune Reconstitution Inflammatory Syndrome (IRIS): This phenomenon can occur in any patient initiating effective ART. As the immune system begins to recover and strengthen, it may mount an exaggerated inflammatory response to previously undiagnosed, subclinical opportunistic infections (e.g., Mycobacterium avium complex, cytomegalovirus, tuberculosis).[6] IRIS can also manifest as the unmasking of autoimmune disorders such as Graves' disease or polymyositis.[31] The onset can be variable, sometimes occurring many months after treatment initiation.

Common and Less Common Adverse Events

Data from large clinical trials have provided a clear picture of the most frequently observed side effects.

• Most Common Adverse Events: The most common adverse reactions reported in clinical trials (occurring in ≥2% of participants) include headache, nausea, diarrhea, insomnia, fatigue, and anxiety.[5] These are typically mild to moderate in severity and often resolve as the patient continues therapy.
• Psychiatric Effects: Adverse events such as abnormal dreams, depression, and anxiety have been reported.[50] Suicidal ideation and attempts have been observed, though these events occurred primarily in patients with a pre-existing history of psychiatric illness.[26]
• Metabolic Changes: Weight gain has been observed in patients taking dolutegravir-based regimens.[33] Redistribution or accumulation of body fat (lipodystrophy) is a known adverse effect associated with some antiretroviral therapies.[50]
• Renal Effects: Dolutegravir is known to cause a small, benign increase in serum creatinine. This occurs within the first few weeks of treatment and remains stable thereafter. It is not indicative of a change in true renal function (glomerular filtration rate) but is rather a result of dolutegravir's inhibition of the organic cation transporter 2 (OCT2) in the renal tubules, which reduces the active secretion of creatinine.[15] This effect is predictable and should not be misinterpreted as renal toxicity.

Table: Summary of Adverse Reactions by Frequency and System Organ Class

The following table provides a structured overview of the adverse reactions associated with dolutegravir/lamivudine, categorized by system organ class and frequency of occurrence as reported in clinical trials and postmarketing experience.

System Organ Class	Frequency	Adverse Reaction	Source Snippets
Nervous System	Very Common (≥10%)	Headache	33
	Common (1% to <10%)	Dizziness, Insomnia, Abnormal dreams	33
Gastrointestinal	Very Common (≥10%)	Nausea, Diarrhea	33
	Common (1% to <10%)	Vomiting, Flatulence, Abdominal pain	50
Psychiatric	Common (1% to <10%)	Anxiety, Depression	5
	Uncommon (0.1% to <1%)	Suicidal ideation/attempt (primarily in patients with pre-existing psychiatric illness)	50
General	Common (1% to <10%)	Fatigue	5
Hepatobiliary	Postmarketing	Hepatotoxicity, Acute liver failure, Worsening of HBV	44
Metabolism	Incidence not known	Lactic Acidosis, Weight Gain	33
Skin/Hypersensitivity	Common (1% to <10%)	Rash, Pruritus	50
	Uncommon (0.1% to <1%)	Hypersensitivity reaction	1
Immune System	Frequency not reported	Immune Reconstitution Inflammatory Syndrome (IRIS)	6

VIII. Drug Interaction Profile: A Guide for Clinical Management

The dolutegravir component of Dovato is subject to several clinically significant drug-drug interactions that necessitate careful management, including dose adjustments, timing separation, or avoidance of co-administration. A thorough medication history is essential before initiating therapy.

Contraindicated Medications

• Dofetilide: The co-administration of Dovato and dofetilide is strictly contraindicated.[41] Dolutegravir is an inhibitor of the renal organic cation transporter 2 (OCT2), which is responsible for the elimination of dofetilide.[46] Inhibition of this transporter can lead to a significant increase in dofetilide plasma concentrations, which elevates the risk of serious and potentially life-threatening cardiac arrhythmias, such as Torsades de Pointes.[41]

Significant Interactions Requiring Management

Polyvalent Cation-Containing Products

• Mechanism: Dolutegravir is susceptible to chelation by polyvalent cations, such as magnesium (Mg2+), aluminum (Al3+), calcium (Ca2+), and iron (Fe2+/Fe3+). When co-administered, these cations can bind to the dolutegravir molecule in the gastrointestinal tract, forming an insoluble complex that cannot be absorbed. This leads to a significant reduction in dolutegravir bioavailability and plasma concentrations, which can compromise its antiviral efficacy.[15]
• Management: Strict dose separation is the primary management strategy.
• Antacids, Laxatives, or Sucralfate: For products containing magnesium or aluminum, Dovato must be administered at least 2 hours before or 6 hours after the cation-containing product.[39]
• Calcium or Iron Supplements (including multivitamins): The management of this interaction depends on food intake.
• If taken with food, the food buffers the interaction, and Dovato and the calcium or iron supplement can be taken at the same time.[45]
• If taken in a fasted state, the interaction is significant, and the doses must be separated. Dovato should be taken 2 hours before or 6 hours after the supplement.[45]

UGT1A1 and CYP3A4 Inducers

• Mechanism: Dolutegravir is metabolized primarily by the UGT1A1 enzyme, with a minor contribution from CYP3A4.[15] Potent inducers of these metabolic pathways can significantly accelerate the clearance of dolutegravir, leading to sub-therapeutic plasma concentrations and an increased risk of virologic failure.[46]
• Management:
• Rifampin and Carbamazepine: These are potent inducers. When co-administered with Dovato, the standard 50 mg dose of dolutegravir is insufficient. An additional 50 mg dose of dolutegravir (as a separate tablet) must be administered approximately 12 hours after the daily Dovato dose.[3]
• Oxcarbazepine, Phenytoin, Phenobarbital, and St. John's Wort: These are also potent inducers. Co-administration with Dovato should be avoided, as there are insufficient data to provide a reliable dosing recommendation.[45]

Metformin

• Mechanism: As with dofetilide, dolutegravir inhibits the OCT2 transporter involved in the renal clearance of metformin.[15] This interaction can lead to increased plasma concentrations of metformin, thereby increasing the risk of metformin-related adverse effects, most notably lactic acidosis.[47]
• Management: The potential benefits and risks of co-administration must be carefully weighed. If used together, close clinical monitoring is warranted. Dose adjustment of metformin may be necessary, and clinicians should refer to the prescribing information for metformin for guidance.[42]

Sorbitol

• Mechanism: Chronic or regular co-administration of sorbitol, which is often used as an excipient or laxative, can decrease the absorption and concentration of lamivudine.[45]
• Management: The chronic use of sorbitol-containing medicines with Dovato should be avoided whenever possible to prevent a potential loss of virologic efficacy.[45]

Other Antiretrovirals

• Dovato is a complete HIV-1 treatment regimen. Therefore, co-administration with other antiretroviral drugs is not recommended as it provides no additional benefit and may increase the risk of toxicity.[1] It is particularly important not to co-administer Dovato with other products that contain lamivudine or its close chemical analogue, emtricitabine, as this would constitute a therapeutic duplication.[49]

Table: Clinically Significant Drug Interactions and Management Strategies

The following table synthesizes the key drug interactions into an actionable clinical reference guide. This tool is designed to assist clinicians and pharmacists in rapidly identifying potential interactions, understanding their mechanistic basis, and implementing the appropriate management strategy to ensure patient safety and therapeutic efficacy.

Interacting Agent(s)	Mechanism of Interaction	Potential Effect on Dovato or Co-administered Drug	Clinical Management Recommendation	Source Snippets
Dofetilide	Dolutegravir inhibits OCT2, decreasing dofetilide clearance.	Increased dofetilide levels, risk of life-threatening cardiac arrhythmias.	CONTRAINDICATED.	41
Rifampin, Carbamazepine	Potent inducers of UGT1A1 and CYP3A4.	Decreased dolutegravir concentration, risk of virologic failure.	Increase dolutegravir dose: Take one Dovato tablet + one 50 mg dolutegravir tablet 12 hours later.	3
Oxcarbazepine, Phenytoin, Phenobarbital, St. John's Wort	Potent inducers of UGT1A1 and CYP3A4.	Decreased dolutegravir concentration, risk of virologic failure.	Avoid co-administration.	45
Antacids, Laxatives, or Supplements with Mg, Al, Ca, Fe; Sucralfate	Chelation of dolutegravir in the GI tract.	Decreased dolutegravir absorption and efficacy.	Separate Doses: Take Dovato 2 hours before or 6 hours after. Exception: If taken with food, Ca/Fe supplements can be co-administered.	39
Metformin	Dolutegravir inhibits OCT2-mediated renal clearance of metformin.	Increased metformin concentration, risk of side effects (e.g., lactic acidosis).	Monitor closely. Consider metformin dose adjustment per metformin prescribing information.	42
Sorbitol (chronic use)	Decreases lamivudine absorption.	Decreased lamivudine concentration, potential loss of efficacy.	Avoid chronic co-administration when possible.	45
Other Antiretrovirals (including emtricitabine)	Dovato is a complete regimen; redundant therapy.	Increased risk of toxicity without added benefit.	Not recommended.	1

IX. Regulatory and Market Landscape

The regulatory and market status of the dolutegravir/lamivudine combination reflects its position as an innovative therapy in high-income countries, while its components are central to global public health initiatives in other parts of the world.

Regulatory Approvals

The fixed-dose combination of dolutegravir/lamivudine (Dovato) has received approval from major regulatory agencies worldwide, following a phased strategy of indication expansion based on accumulating clinical trial evidence.

• U.S. Food and Drug Administration (FDA):
• Initial Approval: Dovato was first approved by the FDA on April 8, 2019. This initial indication was for the treatment of HIV-1 infection in adults with no prior history of antiretroviral treatment.[1] This established its role as a first-line therapy option.
• First Expanded Indication: On August 6, 2020, the FDA expanded the indication to include its use as a replacement for the current antiretroviral regimen in adults who are virologically suppressed.[5] This approval was based on the TANGO trial data and established its utility as a simplification or "switch" option.
• Second Expanded Indication: On April 8, 2024, the indication was further expanded to include the treatment of adolescents aged 12 years and older and weighing at least 25 kg.[5] This approval, supported by the DANCE study, positioned Dovato as a treatment option for younger individuals beginning lifelong therapy.

This deliberate, sequential expansion of the label—from treatment-naïve adults, to virologically suppressed switch patients, and finally to adolescents—represents a logical and strategic approach. It allowed the clinical community to gain confidence with the novel 2DR concept in a standard population before its application was broadened to include maintenance therapy and long-term use from a younger age.

• European Medicines Agency (EMA):
• The EMA's Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion for Dovato in April 2019.[2]
• The European Commission granted full Marketing Authorisation in July 2019, approving Dovato for the treatment of HIV-1 in adults and adolescents older than 12 years of age and weighing at least 40 kg.[21]

Generic Availability

The availability of generic versions of dolutegravir/lamivudine is characterized by a significant global disparity, highlighting the impact of patent law and public health licensing agreements.

• United States and other High-Income Countries: In the United States, there is currently no therapeutically equivalent generic version of Dovato or the related three-drug product, Triumeq.[55] The products are protected by multiple patents, and patients are explicitly warned against purchasing potentially counterfeit and unsafe medications from fraudulent online pharmacies.[55] This situation is similar in most other high-income countries where the patents on the component drugs remain in force.
• Low- and Middle-Income Countries (LMICs): In stark contrast, generic fixed-dose combinations containing dolutegravir, lamivudine, and tenofovir disoproxil fumarate (a combination known as TLD) are widely available and have become the preferred and most widely used first-line ART regimen recommended by the World Health Organization (WHO).[57] This widespread access is made possible through voluntary licensing agreements between the originator pharmaceutical company and generic manufacturers, a mechanism designed to make essential medicines affordable in resource-limited settings. This creates a tale of two access realities: while a patient in the U.S. is prescribed a branded, patented 2DR, a patient in an LMIC has access to a WHO-recommended, generic 3DR containing the same core components, illustrating the complex interplay of intellectual property, economics, and global public health policy.

Patent and Exclusivity Status

The market exclusivity of branded Dovato and Triumeq in countries like the United States is protected by a portfolio of patents and regulatory exclusivities. Key patents covering the drug substances and products extend for several years, with expiration dates listed for 2027, 2029, and as far out as 2031.[55] Furthermore, periods of pediatric exclusivity, granted as an incentive for conducting studies in children and adolescents, can extend this market protection even further.[55] This patent landscape indicates that branded Dovato will likely remain the only available formulation of this specific 2DR in the U.S. market for the foreseeable future.

X. Conclusion

The fixed-dose combination of dolutegravir and lamivudine represents a validated and transformative approach to the treatment of HIV-1 infection. By leveraging the high potency and robust resistance barrier of the integrase inhibitor dolutegravir, this two-drug regimen has successfully challenged the traditional three-drug standard of care, offering a simplified yet powerful therapeutic option.

Key conclusions from this comprehensive analysis are as follows:

1. Non-Inferior Efficacy: Large-scale, randomized clinical trials (GEMINI-1 and GEMINI-2) have unequivocally demonstrated that the dolutegravir/lamivudine 2DR is non-inferior to a standard dolutegravir-based three-drug regimen in achieving and maintaining long-term virologic suppression in treatment-naïve adults. This efficacy holds true across diverse patient populations, including those with high baseline viral loads and low CD4+ cell counts—groups previously thought to require more complex initial therapy.
2. Validated Simplification Strategy: The TANGO trial provided robust evidence that virologically suppressed patients on a stable tenofovir alafenamide-based regimen can safely switch to the dolutegravir/lamivudine 2DR without loss of virologic control. This validates the regimen as a key tool for treatment simplification, allowing for the reduction of long-term drug burden and potential mitigation of toxicities associated with the discontinued agent.
3. High Barrier to Resistance: A hallmark of this regimen is its exceptionally high barrier to the development of treatment-emergent drug resistance. Across both treatment-naïve and switch populations, the incidence of resistance at the time of virologic failure has been extremely low to non-existent. This "clean" failure profile is a critical advantage, as it preserves future treatment options for patients.
4. Defined Safety Profile and Management: The regimen is generally well-tolerated, with a predictable safety profile. However, its use requires adherence to critical safety protocols. A boxed warning highlights the risk of severe hepatitis B exacerbations upon discontinuation in co-infected patients, mandating pre-treatment HBV screening and careful post-treatment monitoring. Clinicians must also remain vigilant for rare but serious adverse events such as hypersensitivity reactions, hepatotoxicity, and lactic acidosis.
5. Critical Importance of Interaction Management: Safe prescribing is contingent upon the diligent management of significant drug-drug interactions. The contraindication with dofetilide is absolute. The interaction with polyvalent cations (in antacids and supplements) requires strict dose separation, and co-administration with potent enzyme inducers necessitates either dose adjustment of dolutegravir or avoidance of the combination.

In summary, dolutegravir and lamivudine, as a single-tablet, once-daily regimen, offers a potent, durable, and well-tolerated treatment for HIV-1 that reduces a patient's exposure to antiretroviral agents. Its approval for treatment-naïve, switch, and adolescent populations has solidified its role as a cornerstone of modern HIV therapy. Its successful implementation in clinical practice depends on careful patient selection, particularly regarding HBV status and renal function, and a thorough understanding of its interaction profile to ensure both safety and sustained efficacy.

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