A Trial Evaluating Maintenance Therapy With Lamivudine (Epivir®) and Dolutegravir (Tivicay®) in Human Immunodeficiency Virus 1 (HIV-1) Infected Patients Virologically Suppressed With Triple Highly Active Antiretroviral Therapy (HAART) (ANRS 167 Lamidol)

Study Overview
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Brief Summary
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The principal objective is to evaluate the antiviral efficacy of 48 weeks treatment with the two-drugs combination dolutegravir(Tivicay®) and lamivudine(TEpivir®) in HIV-1 infected patients virologically suppressed with triple HAART.

Detailed Description
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Secondary objectives: The following parameters will be evaluated : Evolution of CD4 cells and CD8 cells Tolerance to treatment Emergence of resistance mutations at time of virological failure HIV viral load measured with ultrasensitive assay (threshold 1 copy/mL) at Day 0, Week 8, Week 32 and Week 56 Influence of total DNA at Day 0 on the occurrence of virological failure or blip Plasma levels of dolutegravir(Tivicay®) and lamivudine in participants with virological failure Adherence to treatment Quality of life Medico-economic aspects Dolutegravir(Tivicay®) and Nucleosidic Reverse Transcriptase Inhibitors (NRTIs) levels, and HIV viral load in semen in a subgroup of 20 participants. Methodology: Pilot trial, multicentric, national, prospective, no randomized and no comparative.

Official Title
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A Pilot Trial Evaluating Maintenance Therapy With Lamivudine(Epivir®) and Dolutegravir(Tivicay®) in Human Immunodeficiency Virus 1 (HIV-1) Infected Patients Virologically Suppressed With Triple HAART - ANRS 167 Lamidol

Conditions
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HIV-1 Infection

Intervention / Treatment
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* Drug: dolutegravir (Tivicay®) - Phase 1
* Drug: lamivudine (Epivir®) - Phase 2
* Drug: dolutegravir (Tivicay®) - Phase 2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-1 infected patient Age ≥ 18 years CD4 cell count nadir > 200/mm3 Genotype on pre-HAART interpreted with the last version of the ANRS AC11 resistance group's algorithm which presents: no major mutation on protease among: D30N, V32I, M46I/L, I47A/V, G48V, I50L/V, 154M/L, L76V, V82A/F/T/S, I84V, N88D/S, L90M,- no mutation on RT (except the mutation A98S if the patient is not infected by the virus subtype C), no mutation on integrase (if the genotype is available), First-line treatment with suppressive triple HAART (2 NRTI + either 1 PI/r, 1 NNRTI or 1 INI). The initial treatment may have changed a maximum of two times but only once for toxicity (changes such Epivir / Ziagen to Kivexa, are not considered as a change of treatment). However, treatment has to be unchanged in the last 6 months Plasma HIV RNA ≤ 50 copies/mL for ≥ 2 years with at least 2 viral load determinations per year. Blips (HIV viral load between 50 and 200 copies/mL but ≤ 50 copies/mL on control sample) are allowed except in the last 6 months. The total number of blips must not exceed 3 in the last 2 years Negative Hepatitis Bs Antigen Effective contraception for women of childbearing potential Informed consent form signed by patient and investigator Patient enrolled in or a beneficiary of a Social Security programme (State Medical Aid (Aide Médicale d'Etat AME in France) is not a Social Security programme) Exclusion Criteria: HIV-2 infection Positive HBc Ac isolated Hepatitis B Virus (HBV) co-infected patients (positive Hepatitis Bs Ag at inclusion) Chronic hepatitis C currently treated or needing therapy in the next 12 months History of HIV-associated neurocognitive disorders Current pregnancy or breastfeeding No effective contraception for the women of childbearing Previous treatment with chemotherapy (except bleomycin on Kaposi disease's treatment) or immunotherapy Grade > 2 abnormality for usual biological parameters (liver function tests, blood cell count) ALT(Alanine Aminotransferase) ≥ 5 x upper limit of normal value (ULN) or AST (Aspartate Aminotransferase) ≥ 3 x ULN and bilirubinemia ≥ 1.5 x ULN (with 35% direct bilirubinemia) Unstable liver disease (ascitis, encephalopathy, coagulopathy, hypoalbuminemia, oesophageal or gastric varices or persistent jaundice) Known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) Creatininemia clearance below 50 mL/min (Cockroft-Gault method) History or presence of allergy to the trial drugs or their components Severe hepatic insufficiency (Child Pugh Class C) Patients participating in another clinical trial including an exclusion period that is still in force during the screening phase Patients under sauvegarde de justice (judicial protection due to temporarily and slightly diminished mental or physical faculties) or under legal guardianship.

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: dolutegravir(Tivicay®) and lamivudine(Epivir®)<br> | Drug: dolutegravir (Tivicay®) - Phase 1<br>* • Phase 1 (8 weeks) : switch of the third agent with dolutegravir(Tivicay®) 50 mg once a day.<br>Drug: lamivudine (Epivir®) - Phase 2<br>* • Phase 2 (48 weeks): combination with lamivudine (Epivir®) 300 mg once a day + dolutegravir (Tivicay®) 50 mg once a day. Only participants with plasma HIV RNA ≤ 50 cp/mL at Week 8 will continue on phase 2.<br>Drug: dolutegravir (Tivicay®) - Phase 2<br>* • Phase 2 (48 weeks): combination with lamivudine (Epivir®) 300 mg once a day + dolutegravir (Tivicay®) 50 mg once a day. Only participants with plasma HIV RNA ≤ 50 cp/mL at Week 8 will continue on phase 2.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Virological success without any intercurrent event leading to interrupt the strategy of the trial (analysis) | Virological failure is defined by plasma HIV RNA > 50 cp/mL on 2 following samples at 2 to 4 weeks apart. | from week 8 to week 56 (± 4 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evolution of CD4 and CD8 lymphocytes count (analysis) | Evaluation was calculated as the CD4 count at the corresponding week minus the baseline CD4 count | from week 8 to week 32 and week 56 | 
| Percentage of participants who discontinued the strategy of the trial for toxicity or with adverse event of grade 3 or 4 (analysis) |  | week 56 | 
| Profile of resistance mutations in plasma in case of virological failure |  | week 56 | 
| Percentage of participants with plasma HIV RNA < 1 cp/mL |  | Day 0, week 8, week 32 and week 56 | 
| Influence of total DNA on the occurrence of virological failure or blip | Influence of total DNA at Day 0 on the occurrence of virological failure or blip | from Day 0 to week 56 | 
| Measure of concentrations of dolutegravir(Tivicay®) and lamivudine(Epivir®) in case of virological failure or with a blip |  | week 56 | 
| Measure of adherence to treatment (self-reported) |  | Day 0, week 4, week 8, week 32 and week 56 | 
| Measure of quality of life (self-reported) |  | Day 0, week 8 and week 56 | 
| Comparison of Medico-economic substudy (analysis) | Evaluation of medico-economic aspects. Evaluate the direct medical cost related to dolutegravir and lamivudine versus the cost of the previous treatment. | week 56 | 
| Sperm substudy measure of concentration | Measure of concentrations of dolutegravir and NRTI, and HIV RNA in semen at Week 8 and Week 32 in a subgroup of 20 participants | Week 8 and week 32 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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dolutegravir(Tivicay®), lamivudine(Epivir®), HIV-1, efficacy, safety