Peripheral Body Fat Distribution After Switching Zidovudine and Lamivudine to Truvada (RECOMB)

Pilot Phase IV, Multicenter, Randomized, Open-label and Controlled Study to Assess the Evolution of Peripheral Body Fat Distribution After Switching From Zidovudine Containing Backbone to Truvada in HIV-1-infected Patients on HAART (RECOMB Study).

This study evaluated changes in body fat distribution in human immunodeficiency virus type 1 (HIV-1) infected participants who either switched from a zidovudine- plus lamivudine- containing highly active antiretroviral therapy (HAART) regimen to a regimen containing Truvada® (a fixed-dose combination tablet of emtricitabine [FTC, 200 mg] and tenofovir disoproxil fumarate [TDF, 300 mg]) or who remained on a zidovudine- plus lamivudine-containing regimen. Subjects continued their protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor (NNRTI).

Study Overview

• Status: Completed
• Conditions: HIV-1
• Intervention / Treatment: Drug: Truvada; Drug: Zidovudine/lamivudine

Detailed Description

Standard care for the treatment of HIV infection involves the use of a combination of three antiretroviral drugs. The initial recommended regimen in antiretroviral-naive patients according to therapeutic guidelines of the US Department of Health and Human Resources (DHHS) includes two nucleoside reverse transcriptase inhibitors (NRTIs) and a third drug from another class (PI or NRTI).

The use of nucleoside analogues, especially stavudine and zidovudine, is associated with untoward side effects, including lipodystrophy hepatic steatosis/lactic acidosis syndrome, peripheral neuropathy, and anemia. However, Truvada has a low potential for both mitochondrial toxicity and fat distribution disturbances.

As described in the Consensus Document of the Spanish Group for the Study of AIDS (GESIDA), and the AIDS National Plan from the Spanish Ministry of Health "Recommendations on metabolic alterations and body fat distribution", studies should focus on the evaluation of body fat disturbances after antiretroviral drug substitutions, based on the basic assumption of virologic control of the patient and equivalence in potency of the new drug regarding virological control. In addition, studies based on selective substitution of antiretroviral drugs in HIV-1 infected patients under virological control, are recommended in the European Medicines Agency (EMA) in the "Guideline on the clinical development of medicinal products for the treatment of HIV infection".

In this study, stable, virologically controlled, HIV-1 infected participants receiving antiretroviral regimens containing zidovudine and lamivudine were randomized to switch to Truvada or to stay on their zidovudine- plus lamivudine-containing regimen. Participants in both groups continued the third drug of their antiretroviral regimen (either an NNRTI or PI). Changes in limb fat in the two groups were assessed using dual-energy x-ray absorptiometry (DEXA).

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Phase 4

Contacts and Locations

Study Locations

• Spain
  • Madrid, Spain, E-28036
    • Gilead Sciences, S.L.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• HIV-1 infection documented by confirmed positive HIV-1 antibody test and/or positive polymerase chain reaction for HIV-1 ribonucleic acid (RNA).
• Adult patients (over 18 years of age).
• Current HAART regimen containing zidovudine + lamivudine at usual doses for at least 6 months.
• Viral load < 50 copies/mL on the last two consecutive determinations, under zidovudine + lamivudine containing HAART regimen.
• For women of childbearing potential, negative urine pregnancy test at screening visit.
• Agreement to take part in the study and sign the informed consent.
• Patients on lipid lowering treatment were allowed to participate in the study only if the lipid-lowering treatment (either statins or fibrates) was stable for at least 8 weeks prior to screening and it was not expected to change during the first 3 months of the study.

Exclusion Criteria:

• Patients on current FTC or TDF therapy.
• Patients with previous history of virological failure on an FTC or TDF-containing regimen.
• Patients receiving a non-registered antiretroviral drug.
• Patients receiving a triple-nucleoside antiretroviral combination.
• Hypersensitivity to one of the components of the dosage forms of TDF or FTC, or previous history of intolerance to one of those drugs.
• Known history of drug abuse or chronic alcohol consumption
• Women who were pregnant or breast feeding, or female of childbearing potential who did not use an adequate method of contraception according to the investigator's judgment.
• Active opportunistic infection or documented infection within the previous 4 weeks.
• Documented active malignant disease (excluding Kaposi sarcoma limited to the skin).
• Renal disease with creatinine clearance < 50 mL/min.
• Concomitant use of nephrotoxic or immuno-suppressive drugs which could not be stopped without affecting the safety of the patient.
• Receiving on-going therapy with systemic corticosteroids, Interleukin-2 or chemotherapy.
• Patients who were not to be included in the study according to the investigator's criterion.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Truvada; Truvada + NNRTI or PI.	Drug: Truvada; Truvada once daily with continuation of the current NNRTI or PI at randomization.
Active Comparator: Zidovudine/lamivudine; Zidovudine/lamivudine + NNRTI or PI.	Drug: Zidovudine/lamivudine; Continuation of the zidovudine + lamivudine containing regimen plus the current NNRTI or PI at randomization.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Limb Fat at Week 48	Limb fat was measured by DEXA. Change = Week 48 value minus baseline value.	Baseline to Week 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in the Mitochondrial DNA/Nuclear DNA Ratio (Oral Mucosa)	Change = Week 48 value minus baseline value.	Baseline to Week 48
Change From Baseline in the Mitochondrial DNA/Nuclear DNA Ratio (Lymphocytes)	Change = Week 48 value minus baseline value.	Baseline to Week 48
Change From Baseline in Lactate Concentration	Change = Week 48 value minus baseline value.	Baseline to Week 48
Percentage of Days for Which Participants Were Compliant With Study Drug	Compliance = [1 - [(sum of days with a missed dose [per Question 6 study medication assessment questionnaire (SMAQ)])/(sum of days between SMAQ visits)]] *100 for visits with SMAQ data. An assessable visit is one where the number of missed days was reported [Question 6] and the number of days between SMAQ visits could be calculated.	Baseline to Week 72
Percentage of Participants Who Maintain Confirmed HIV-1 RNA < 50 Copies/mL		48 weeks
Percentage of Participants With HIV-1 RNA > 50 and < 400 Copies/mL		48 weeks
Percentage of Participants With Virologic Failure	Virologic failure was defined as two consecutive HIV RNA values > 400 copies/mL.	48 weeks
Change From Baseline in Cluster Determinant 4 (CD4) Cell Count	Change = Week 48 value minus baseline value.	Baseline to Week 48
Change From Baseline in Fasting Serum Triglycerides	Change = Week 48 value minus baseline value.	Baseline to Week 48
Change From Baseline in Fasting Total Cholesterol	Change = Week 48 value minus baseline value.	Baseline to Week 48
Change From Baseline in Fasting Low Density Lipoprotein Cholesterol (LDL)	Change = Week 48 value minus baseline value.	Baseline to Week 48
Change From Baseline in Fasting High Density Lipoprotein Cholesterol (HDL)	Change = Week 48 value minus baseline value.	Baseline to Week 48
Change From Baseline in Hemoglobin	Change = Week 48 value minus baseline value.	Baseline to Week 48
Percent Change From Baseline in Hematocrit	Change = Week 48 value minus baseline value expressed as median percent change.	Baseline to Week 48
Change From Baseline in Waist Circumference/Hip Circumference Ratio	Change = Week 48 value minus baseline value.	Baseline to Week 48
Percentage of Participants With Any Adverse Event	Participants with treatment-emergent adverse events were analyzed. Adverse events were defined as any untoward medical occurrence in a clinical investigation subject administered a medicinal product and which did not necessarily have a causal relationship with study treatment, and were categorized using the Medical Dictionary for Regulatory Activities (MedDRA) Version 11. Treatment-emergent adverse events were events that met one of the following criteria: Began or worsened in severity or relationship to study drug, on or after the date of the first dose of study drug and on or before the date of the last dose of study drug plus 30 days.; Had no recorded start date.	72 weeks
Percentage of Participants Who Discontinue the Study Prematurely (Before Week 48) Due to Adverse Events.		48 weeks

Collaborators and Investigators

• Sponsor: Gilead Sciences
• Investigators: Study Director: Pedro Ferrer, Gilead Sciences, S.L.

Study record dates

Study Major Dates

• Study Start: May 1, 2006
• Primary Completion (Actual): March 1, 2008
• Study Completion (Actual): September 1, 2008

Study Registration Dates

• First Submitted: May 9, 2006
• First Submitted That Met QC Criteria: May 9, 2006
• First Posted (Estimate): May 11, 2006

Study Record Updates

• Last Update Posted (Estimate): August 17, 2015
• Last Update Submitted That Met QC Criteria: August 13, 2015
• Last Verified: August 1, 2015

More Information

Terms related to this study

• Keywords: HIV-1
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antimetabolites; Lamivudine; Zidovudine; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
• Other Study ID Numbers: GS-ES-164-0154