Dolutegravir Plus Lamivudine Dual Therapy in Treatment Naïve HIV-1 Patients

Study Overview
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Brief Summary
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This study was done to see if the combination of two anti-HIV medicines, dolutegravir (DTG, Tivicay) and lamivudine (3TC, Epivir) taken once a day, provide a safe, effective, and well-tolerated treatment for HIV. DTG is a type of HIV medicine called an integrase inhibitor; 3TC is a type of HIV medicine called a reverse transcriptase inhibitor. DTG works by blocking integrase and 3TC works by blocking reverse transcriptase, two HIV proteins (enzymes). This prevents HIV from multiplying and lowers the viral load (amount of HIV in the blood). Both DTG and 3TC are currently part of Food and Drug Administration (FDA) recommended regimens along with a third active drug. Since some HIV medicines have side effects and are costly, there is interest in whether HIV can be successfully controlled with fewer than three HIV drugs.

Detailed Description
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This study was a phase II, single-arm, open-label pilot study designed to estimate the efficacy of dolutegravir (DTG) plus lamivudine (3TC) as initial combination ART (antiretroviral therapy) in HIV-1 infected treatment naive participants. The target enrollment was 120 participants with a cap of N=90 participants with screening HIV-1 RNA <= 100,000 copies/mL. The study aimed to enroll >= 20% women. The expected follow-up for each participant was 52 weeks. Visits occurred at screening, entry, and weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 from study entry. All signs/symptoms within 30 days prior to entry were recorded. Subsequently, grade 2 or higher rash and all other grade 3 or higher signs and symptoms were recorded. All participants underwent routine monitoring including plasma HIV-1 RNA levels, CD4+ cell count, hematology, chemistry, urinalysis, and pregnancy testing (for women of reproductive potential). Population-based protease (PR), reverse transcriptase (RT) and integrase genotyping were done at the time of confirmed virologic failure. Plasma samples were stored for potential future studies to assess the impact of adherence, drug-resistant minority viral variants, and DTG exposure on virologic and CD4+ cell count responses to DTG plus 3TC. All participants also underwent UGT1A1 genotyping.

Official Title
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A Study to Evaluate Dolutegravir Plus Lamivudine Dual Therapy for the Treatment of Naïve HIV-1-infected Participants

Conditions
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HIV-1 Infection

Intervention / Treatment
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* Drug: Dolutegravir
* Drug: Lamivudine


Participation Criteria
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Eligibility Criteria
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NOTE: Further information on the eligibility criteria can be found in the study protocol. Inclusion Criteria: HIV-1 infection. Plasma HIV-1 RNA ≥1000 copies/mL and <500,000 copies/mL obtained within 90 days prior to study entry. No evidence of any RT, any integrase, or major protease resistance mutation (according to the 2014 IAS-USA drug resistance mutations list, available at https://www.iasusa.org/sites/default/files/tam/22-3-642.pdf) based on pre-ARV (antiretroviral) treatment genotype performed any time prior to study entry. ARV treatment drug-naive (defined as no previous ARV treatment at any time prior to study entry, with the exception of successful post-exposure prophylaxis (PEP) or pre-exposure prophylaxis (PrEP). The following laboratory values obtained within 45 days prior to study entry: ANC (absolute neutrophil count) ≥750/mm^3 Hemoglobin ≥10.0 g/dL Platelets ≥ 50,000/mm^3 Calculated creatinine clearance (CrCl) ≥50 mL/min, as estimated by the Cockcroft-Gault equation AST (aspartate aminotransferase) <5 x ULN (upper limit of normal) ALT (alanine aminotransferase) <5x ULN Total bilirubin <1.5 x ULN Hepatitis B surface antigen negative within 45 days prior to study entry. For women with reproductive potential, negative serum or urine pregnancy test at screening and within 48 hours prior to study entry. If participating in sexual activity that could lead to pregnancy, female participants with reproductive potential must have agreed to use one form of contraceptive as listed in the protocol while receiving protocol-specified medications and for 30 days after stopping the medications. Ability and willingness of participant or legal representative to provide informed consent. Exclusion Criteria: Serious illness requiring systemic treatment and/or hospitalization. Treatment within 30 days prior to study entry with immune modulators such as systemic steroids, interleukins, interferons, granulocyte colony-stimulating factor (G-CSF), erythropoietin, or any investigational therapy. Pregnancy or breastfeeding. Receipt of systemic cytotoxic chemotherapy or dofetilide. Known allergy/sensitivity to any of the study drugs or their formulations. Active drug or alcohol use or dependence that may interfere with adherence to study requirements, in the opinion of the site investigator. Active hepatitis C virus (HCV) treatment or anticipated need for treatment within study period. Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice), known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). Severe hepatic impairment (Class C) as determined by Child-Pugh classification.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: DTG 50 mg + 3TC 300 mg<br>Dolutegravir 50mg and Lamivudine 300mg, orally daily | Drug: Dolutegravir<br>* Participants were prescribed 50 mg of DTG orally daily<br>* Other names: DTG;Drug: Lamivudine<br>* Participants were prescribed 300 mg of 3TC orally daily.<br>* Other names: 3TC;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Virologic Status at Week 24 | Numbers of Participants With Virologic Success, Virologic Non-Success, and no Virologic Data at Week 24 Window are provided below. Virologic success is defined as HIV-1 RNA <50 copies/mL and on study treatment (FDA Snapshot definition). | At 24 weeks after study entry | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Virologic Status at Week 12 | Numbers of Participants With Virologic Success, Virologic Non-Success, and no Virologic Data at Week 12 Window are provided below. Virologic success is defined as HIV-1 RNA <50 copies/mL and on study treatment (FDA Snapshot definition). | At 12 weeks after study entry | 
| Virologic Status at Week 48 | Numbers of Participants With Virologic Success, Virologic Non-Success, and no Virologic Data at Week 48 Window are provided below. Virologic success is defined as HIV-1 RNA <50 copies/mL and on study treatment (FDA Snapshot definition). | At 48 weeks after study entry | 
| Virologic Failure | Virologic failure is defined as follows: Weeks 16 or 20: confirmed plasma HIV-1 RNA > 400 copies/mL Week 24 or later: confirmed plasma HIV-1 RNA > 200 copies/mL Participants were evaluated for virologic failure regardless of whether on study treatment. Confirmation was determined based on any two consecutive evaluations meeting the virologic failure definition regardless of the time between them. Participants discontinuing the study (for any reason, including death and lost to follow-up) were considered virologic failures if their last measurement met the definition of virologic failure but no confirmatory measurement was obtained. All other participants' follow-up was censored immediately after the last available plasma HIV-1 RNA measurement. | Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48 | 
| Proportion of Participants With Plasma HIV-1 RNA < 50 Copies/mL - Missing = Failure | Proportion of participants with HIV-1 RNA < 50 copies/mL by week, ITT (Intention To Treat; missing/off study/off treatment = failure) population. | Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48 | 
| Proportion of Participants With Plasma HIV-1 RNA < 200 Copies/mL - Missing = Failure | Proportion of participants with HIV-1 RNA < 200 copies/mL by week, ITT (missing/off study/off treatment = failure) population. | Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48 | 
| Proportion of Participants With Plasma HIV-1 RNA <50 Copies/mL - Missing = Ignored | Proportion of participants with HIV-1 RNA < 50 copies/mL by week, ITT (missing = ignored) population. | Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48 | 
| Proportion of Participants With Plasma HIV-1 RNA <200 Copies/mL- ITT Missing = Ignored | Proportion of participants with HIV-1 RNA < 200 copies/mL by week, ITT (missing = ignored) population. | Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48 | 
| Proportion of Participants With Plasma HIV-1 RNA <50 Copies/mL- As Treated | Proportion of participants with HIV-1 RNA < 50 copies/mL by week, as treated population. | Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48 | 
| Proportion of Participants With Plasma HIV-1 RNA <200 Copies/mL- As Treated | Proportion of participants with HIV-1 RNA < 200 copies/mL by week, as treated population. | Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48 | 
| CD4+ Cell Count | CD4+ cell counts by study week. | Baseline, weeks 4, 12, 24, and 48 | 
| Change in CD4+ Cell Count | Change in CD4+ cell counts by study week. Change was calculated as value at the later visit minus the value at baseline. | Baseline, weeks 4, 12, 24, and 48 | 
| Number of HIV-1 Drug Resistance Mutation Occurrences in Participants | Number of HIV-1 drug resistance mutation occurrences participants with virologic failure and FDA snapshot non-successes. Participants that had one drug class resistance mutation may have one or more mutations. | at the time of virologic failure | 
| Fasting Lipids and Glucose | Fasting lipids include: total cholesterol, triglycerides, LDL cholesterol, HDL cholesterol, and glucose. Fasting was set to be 8 hours prior to the sample collection. | Baseline and week 48 | 
| Creatinine Clearance | Creatinine clearance was estimated by the Cockcroft-Gault equation. | Baseline, weeks 4, 12, 24, 32, 40 and 48 | 
| Number of Participants With Grade 3 of Higher Adverse Events | Number of participants who experienced an AE (sign/symptom or laboratory abnormality) of Grade 3 or higher. The AEs were graded by the clinicians according to the Division of AIDS (DAIDS) AE Grading Table (see reference in the Protocol Section) as follows: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Potentially Life-Threatening. | from study treatment dispensation through up to week 52 or until study discontinuation |