RECOMB: Peripheral Body Fat Distribution After Switching From AZT Containing Backbone to Truvada

Condition(s) targeted: HIV-1

Intervention: Truvada (Drug)

Phase: Phase 4

Status: Active, not recruiting

Sponsored by: Gilead Sciences

Official(s) and/or principal investigator(s):
Pedro Ferrer, Study Director, Affiliation: Gilead Sciences, S.L.

In this study patients pretreated with regimens containing AZT, will change the NRTI backbone to Truvada, a fix dose combination of Tenofovir and Emtricitabine, which are drugs with a low potential of both mitochondrial toxicity and fat distribution disturbances. The third drug of the combination will be the same as that previously taken by the patient together with NRTI-backbone including AZT (NNRTI or PIs).

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

Study design: Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Safety/Efficacy Study

Primary outcome: Objective assessment: of change from baseline in limb fat at Week 48 as measured by DEXA.

Secondary outcome:

Change in the mitochondrial DNA/nuclear DNA ratio in the different visits compared with baseline.

Change in lactate concentration in the different visits compared with baseline.

Proportion of patients who maintain confirmed VIH-1 RNA levels of < 50 copies/mL.

Proportion of patients with HIV-1 RNA levels between >50 and <400 copies/mL.

Proportion of patients with virologic failure defines as confirmed with two consecutive HIV RNA >400 copies/mL.

Time to loss of virological response, defined as the time elapsed from the patient's first dose of study drug to confirmed HIV-1 RNA levels of > 50 and < 400 copies/mL, death caused by the disease, medication discontinuation, or addition of a new antire

Time to definite virological failure, defined as the time elapsed from the patient's first dose of study drug to confirmed HIV-1 RNA levels of > 400 copies/mL.

Change in CD4+ cell counts in the different study visits compared with baseline.

Change in serum triglycerides, total cholesterol, LDL, and HDL fractions in the different study visits compared with baseline.

Change in hemoglobin and hematocrit concentrations in the different visits compared with baseline.

Proportion of patients with different specific mutations after virological failure.

Proportion of patients who show treatment adherence (assessed according to SMQA questionnaire)

Proportion of patients with any adverse event.

Proportion of patients for each adverse event.

Distribution of the intensity if each adverse event (the greatest intensity for each adverse event within a patient will be considered).

Distribution of the relationship between the adverse effect and the study drug (the strongest relation with the study drug for each adverse event within each patient will be considered).

Proportion of patients who discontinue the study prematurely (before week 48) due to adverse events.

Detailed description: Standard care for the treatment of HIV infection involves the use of a combination of three antiretroviral drugs. Currently, the initial recommended regimen in antiretroviral-naïve patients according to therapeutic guidelines of the US Department of Health and Human Resources (DHHS) includes two NRTIs and a third drug from another family (PI, NNRTI). Recent data also suggest that the use of nucleoside analogues especially stavudine and zidovudine (AZT) is associated with untoward side effects, including lipodystrophy hepatic steatosis/lactic acidosis syndrome, peripheral neuropathy, and anemia. The concern of long-term toxicity of antiretroviral agents is becoming a criterion for the selection of the most adequate treatment for each individual patient.

As there are described in the Consensus Document of the Spanish Group for the Study of AIDS (GESIDA) and AIDS National Plan from the Spanish Ministry of Health "Recommendations on metabolic alterations and body fat distribution", studies focus on the evaluation of body fat disturbances after antiretroviral drug substitutions, are based on the basic assumption of virologic control of the patient and equivalence in potency of the new drug regarding virological control. The design of this study fulfills both assumptions: Patients to be included will have viral load below 50 copies/mL what ensures virological control and, on the other hand, the study treatment (Truvada) is at least equipotent to the switched one, even superior as 934 Study data shows. Recently the CHMP and European Commission have approved a Truvada SmPC variation that includes the statement that the combination of tenofovir DF and emtricitabine has showed superior antiviral efficacy compared with a fixed combination of zidovudine and lamivudine (Combivir), when administered with efavirenz.

In addition, studies based on selective substitution of antiretroviral drugs in HIV-infected patients under virological control, are recommended in the EMEA in the "Guideline on the clinical development of medicinal products for the treatment of HIV infection". In this way, recently at the 10th European AIDS Conference Nov 17-20, 2005 Dublin, Ireland were comunicated the 24 weeks data from the COMET Study, in which 411 subjects switched from Combivir to Truvuda due to simplification or toxicitiy. At the moment of switching all subjects had HIV RNA < 400 copies/mL. Subjects improved virological suppression (significantly more patients with VL < 50 copies/mL at Week 24), excellent tolerability (95% of patients remained on treatment; 1. 5% discontinued for an adverse event), no patients discontinued for suboptimal virological response, significantly improved lipid profile through 12 weeks, significant increases in Hb, with a higher percentage of patients reporting an absence of fatigue at 24 weeks compared to baseline, significantly fewer patiens reported being bothered by regimen side effects compared to baseline, including fewer with adverse gastrointestinal effects and significantly more patients reported being "very satisfied" with the new treatment regimen.

Since there are available drugs, which are not associated with the development of body fat disturbances, it is possible to make changes in the antiretroviral drug combinations in order to avoid or improve these morphologic anomalies. Thymidine analogues, including zidovudine, are well known drugs to be associated to the development of alterations in the body fat distribution.

In this study patients pretreated with regimens containing AZT, will change the NRTI backbone to Truvada, a fix dose combination of Tenofovir and Emtricitabine, which are drugs with a low potential of both mitochondrial toxicity and fat distribution disturbances. The third drug of the combination will be the same as that previously taken by the patient together with NRTI-backbone including AZT (NNRTI or PIs).

Consequently, this study will assess changes in total and residual fat after the switching from AZT-containing backbone to Truvada.

Eligible patients must have been in zidovudine treatment at least during 6 months. The rational of this criterion is that it has been widely described that after this period of time, sub-clinical body fat changes can be developed, related to alterations on mitochondrial function and replication capacity of the subcutaneous adipose tissue. These changes could lead to an objective lipoatrophy (loss of 20% of peripheral fat) several months later. To asses the potential benefit of the switching to Truvada is the main reason that justifies this study. The objective of this study is to evaluate the changes in the body fat distribution measured by DEXA after switching from AZT containing backbone to Truvada.

The study uses a simplified combination for the treatment of HIV, so that prescribing a Truvada tablet once daily will make treatment of participating patients easier as compared with therapeutic regimens before enrollment. Accordingly, one of the objectives of the study is to assess adherence to antiretroviral treatment. For this purpose, the SMQA questionnaire, an instrument validated in Spain and in the treatment of HIV infection will be used.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- HIV-1 infection documented by confirmed positive HIV-1 antibody test and/or positive

PCR for HIV-1 RNA.

- Adult patients (over 18 years of age).

- Current HAART regimen containing AZT + 3TC at usual doses for at least during the

previous 6 months.

- Viral load < 50 copies/mL on the last two consecutive determinations, under AZT

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 will be allowed to participate in the study only

if the lipid-lowering treatment (either statins or fibrates) is stable for at least 8 weeks prior to screening and it is not expected to change this treatment during the first 3 months of the trial.

Exclusion Criteria:

- Patients on current TDF or FTC therapy.

- Patients with previous history of virological failure on FTC or TDF containing

regimen.

- Patients receiving a non-registered antiretroviral (ARV) drug.

- Patients receiving a triple nucleoside-ARV combination.

- Hypersensitivity to one of the components of the dosage forms of TDF or FTC, or

previous history of intolerance to one of these drugs.

- Known history of drug abuse or chronic alcohol consumption

- Women who are pregnant of breast feeding or female of childbearing potential who do

not use an adequate method of contraception according to the investigator's judgment.

- Current 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 (IL-2) or

chemotherapy.

- Patients who are not to be included in the study according to the investigator's

criterion.

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

Starting date: May 2006
Last updated: April 24, 2008