HIV-1
Conditions
Keywords
HIV-1
Brief summary
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).
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).
Interventions
DRUGTruvada
Truvada once daily with continuation of the current NNRTI or PI at randomization.
Continuation of the zidovudine + lamivudine containing regimen plus the current NNRTI or PI at randomization.
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Limb Fat at Week 48 | Baseline to Week 48 | Limb fat was measured by DEXA. Change = Week 48 value minus baseline value. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Mitochondrial DNA/Nuclear DNA Ratio (Lymphocytes) | Baseline to Week 48 | Change = Week 48 value minus baseline value. |
| Change From Baseline in Lactate Concentration | Baseline to Week 48 | Change = Week 48 value minus baseline value. |
| Percentage of Days for Which Participants Were Compliant With Study Drug | Baseline to Week 72 | 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. |
| 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 | 48 weeks | Virologic failure was defined as two consecutive HIV RNA values \> 400 copies/mL. |
| Change From Baseline in Cluster Determinant 4 (CD4) Cell Count | Baseline to Week 48 | Change = Week 48 value minus baseline value. |
| Change From Baseline in Fasting Serum Triglycerides | Baseline to Week 48 | Change = Week 48 value minus baseline value. |
| Change From Baseline in the Mitochondrial DNA/Nuclear DNA Ratio (Oral Mucosa) | Baseline to Week 48 | Change = Week 48 value minus baseline value. |
| Change From Baseline in Fasting Low Density Lipoprotein Cholesterol (LDL) | Baseline to Week 48 | Change = Week 48 value minus baseline value. |
| Change From Baseline in Fasting High Density Lipoprotein Cholesterol (HDL) | Baseline to Week 48 | Change = Week 48 value minus baseline value. |
| Change From Baseline in Hemoglobin | Baseline to Week 48 | Change = Week 48 value minus baseline value. |
| Percent Change From Baseline in Hematocrit | Baseline to Week 48 | Change = Week 48 value minus baseline value expressed as median percent change. |
| Change From Baseline in Waist Circumference/Hip Circumference Ratio | Baseline to Week 48 | Change = Week 48 value minus baseline value. |
| Percentage of Participants With Any Adverse Event | 72 weeks | 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. |
| Percentage of Participants Who Discontinue the Study Prematurely (Before Week 48) Due to Adverse Events. | 48 weeks | — |
| Change From Baseline in Fasting Total Cholesterol | Baseline to Week 48 | Change = Week 48 value minus baseline value. |
Countries
Spain
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Truvada Truvada + NNRTI or PI. | 39 |
| Zidovudine/Lamivudine Zidovudine/lamivudine + NNRTI or PI. | 41 |
| Total | 80 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 4 |
| Overall Study | Noncompliance | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Zidovudine/Lamivudine | Truvada | Total |
|---|---|---|---|
| Age, Continuous | 44 years STANDARD_DEVIATION 7.4 | 44 years STANDARD_DEVIATION 10.6 | 44 years STANDARD_DEVIATION 9 |
| Cluster determinant 4 (CD4) cell count | 504.0 cells/mm^3 | 655.0 cells/mm^3 | 600.5 cells/mm^3 |
| HIV-1 RNA Level < 50 copies/mL | 39 Participants | 38 Participants | 77.0 Participants |
| HIV-1 RNA Level 50 to < 400 copies/mL | 2 Participants | 1 Participants | 3.0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 1.0 Participants |
| Race/Ethnicity, Customized Black, of African heritage | 2 Participants | 1 Participants | 3.0 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 1 Participants | 2.0 Participants |
| Race/Ethnicity, Customized White | 38 Participants | 36 Participants | 74.0 Participants |
| Region of Enrollment Spain | 41 participants | 39 participants | 80.0 participants |
| Sex: Female, Male Female | 4 Participants | 11 Participants | 15.0 Participants |
| Sex: Female, Male Male | 37 Participants | 28 Participants | 65.0 Participants |
| Total limb fat | 3589 grams (g) | 3565 grams (g) | 3589 grams (g) |
| Years on zidovudine (AZT)/lamivudine (3TC) | 6.2 Years | 5.8 Years | 5.9 Years |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 24 / — | 28 / — |
| serious Total, serious adverse events | 4 / — | 3 / — |
Outcome results
Primary
Change From Baseline in Limb Fat at Week 48
Limb fat was measured by DEXA. Change = Week 48 value minus baseline value.
Time frame: Baseline to Week 48
Population: Treated participants. Number of participants analyzed is those with baseline and post-baseline DEXA data. Last post-baseline observation carried forward (LOCF) method was used if the Week 48 limb fat value was missing.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Truvada | Change From Baseline in Limb Fat at Week 48 | 392 grams (g) |
| Zidovudine/Lamivudine | Change From Baseline in Limb Fat at Week 48 | -257 grams (g) |
Comparison: Null Hypothesis: changes from baseline in the two treatment groups are equal. Alternative Hypothesis: changes from baseline in the two treatment groups are different (two sided).p-value: 0.0014Wilcoxon Rank Sum test
Secondary
Change From Baseline in Cluster Determinant 4 (CD4) Cell Count
Change = Week 48 value minus baseline value.
Time frame: Baseline to Week 48
Population: Treated participants. Missing values were excluded.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Truvada | Change From Baseline in Cluster Determinant 4 (CD4) Cell Count | 60.5 cells/mm^3 |
| Zidovudine/Lamivudine | Change From Baseline in Cluster Determinant 4 (CD4) Cell Count | 9.0 cells/mm^3 |
Comparison: Null Hypothesis: changes from baseline in the two treatment groups are equal. Alternative Hypothesis: changes from baseline in the two treatment groups are different (two sided).p-value: 0.0789Wilcoxon Rank Sum test
Secondary
Change From Baseline in Fasting High Density Lipoprotein Cholesterol (HDL)
Change = Week 48 value minus baseline value.
Time frame: Baseline to Week 48
Population: Treated participants. Missing values were excluded.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Truvada | Change From Baseline in Fasting High Density Lipoprotein Cholesterol (HDL) | -2.0 mg/dL |
| Zidovudine/Lamivudine | Change From Baseline in Fasting High Density Lipoprotein Cholesterol (HDL) | 2.0 mg/dL |
Comparison: Null Hypothesis: changes from baseline in the two treatment groups are equal. Alternative Hypothesis: changes from baseline in the two treatment groups are different (two sided).p-value: 0.2907Wilcoxon Rank Sum test
Secondary
Change From Baseline in Fasting Low Density Lipoprotein Cholesterol (LDL)
Change = Week 48 value minus baseline value.
Time frame: Baseline to Week 48
Population: Treated participants. Missing values were excluded.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Truvada | Change From Baseline in Fasting Low Density Lipoprotein Cholesterol (LDL) | 7.0 mg/dL |
| Zidovudine/Lamivudine | Change From Baseline in Fasting Low Density Lipoprotein Cholesterol (LDL) | 5.0 mg/dL |
Comparison: Null Hypothesis: changes from baseline in the two treatment groups are equal. Alternative Hypothesis: changes from baseline in the two treatment groups are different (two sided).p-value: 0.6638Wilcoxon Rank Sum test
Secondary
Change From Baseline in Fasting Serum Triglycerides
Change = Week 48 value minus baseline value.
Time frame: Baseline to Week 48
Population: Treated participants. Missing values were excluded.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Truvada | Change From Baseline in Fasting Serum Triglycerides | 1.5 mg/dL |
| Zidovudine/Lamivudine | Change From Baseline in Fasting Serum Triglycerides | 4.0 mg/dL |
Comparison: Null Hypothesis: changes from baseline in the two treatment groups are equal. Alternative Hypothesis: changes from baseline in the two treatment groups are different (two sided).p-value: 0.9633Wilcoxon Rank Sum test
Secondary
Change From Baseline in Fasting Total Cholesterol
Change = Week 48 value minus baseline value.
Time frame: Baseline to Week 48
Population: Treated participants. Missing values were excluded.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Truvada | Change From Baseline in Fasting Total Cholesterol | 4.5 mg/dL |
| Zidovudine/Lamivudine | Change From Baseline in Fasting Total Cholesterol | 1.0 mg/dL |
Comparison: Null Hypothesis: changes from baseline in the two treatment groups are equal. Alternative Hypothesis: changes from baseline in the two treatment groups are different (two sided).p-value: 0.9686Wilcoxon Rank Sum test
Secondary
Change From Baseline in Hemoglobin
Change = Week 48 value minus baseline value.
Time frame: Baseline to Week 48
Population: Treated participants. Missing values were excluded.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Truvada | Change From Baseline in Hemoglobin | 0.9 g/dL |
| Zidovudine/Lamivudine | Change From Baseline in Hemoglobin | 0.3 g/dL |
Comparison: Null Hypothesis: changes from baseline in the two treatment groups are equal. Alternative Hypothesis: changes from baseline in the two treatment groups are different (two sided).p-value: 0.0072Wilcoxon Rank Sum test
Secondary
Change From Baseline in Lactate Concentration
Change = Week 48 value minus baseline value.
Time frame: Baseline to Week 48
Population: Treated participants. Missing values were excluded.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Truvada | Change From Baseline in Lactate Concentration | -0.23 mmol/L |
| Zidovudine/Lamivudine | Change From Baseline in Lactate Concentration | 0.09 mmol/L |
Comparison: Null Hypothesis: changes from baseline in the two treatment groups are equal. Alternative Hypothesis: changes from baseline in the two treatment groups are different (two sided).p-value: 0.0078Wilcoxon Rank Sum test
Secondary
Change From Baseline in the Mitochondrial DNA/Nuclear DNA Ratio (Lymphocytes)
Change = Week 48 value minus baseline value.
Time frame: Baseline to Week 48
Population: Treated participants. Missing values were excluded.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Truvada | Change From Baseline in the Mitochondrial DNA/Nuclear DNA Ratio (Lymphocytes) | 36.0 Ratio |
| Zidovudine/Lamivudine | Change From Baseline in the Mitochondrial DNA/Nuclear DNA Ratio (Lymphocytes) | 43.0 Ratio |
Comparison: Null Hypothesis: changes from baseline in the two treatment groups are equal. Alternative Hypothesis: changes from baseline in the two treatment groups are different (two sided).p-value: 0.9725Wilcoxon Rank Sum test
Secondary
Change From Baseline in the Mitochondrial DNA/Nuclear DNA Ratio (Oral Mucosa)
Change = Week 48 value minus baseline value.
Time frame: Baseline to Week 48
Population: Treated participants. Missing values were excluded.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Truvada | Change From Baseline in the Mitochondrial DNA/Nuclear DNA Ratio (Oral Mucosa) | 62.0 Ratio |
| Zidovudine/Lamivudine | Change From Baseline in the Mitochondrial DNA/Nuclear DNA Ratio (Oral Mucosa) | 97.0 Ratio |
Comparison: Null Hypothesis: changes from baseline in the two treatment groups are equal. Alternative Hypothesis: changes from baseline in the two treatment groups are different (two sided).p-value: 0.9713Wilcoxon Rank Sum test
Secondary
Change From Baseline in Waist Circumference/Hip Circumference Ratio
Change = Week 48 value minus baseline value.
Time frame: Baseline to Week 48
Population: Treated participants. Missing values were excluded. Assessment of waist and hip circumference was added to the study schedule via protocol amendment part way through the study. This resulted in small numbers of subjects having data available for this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Truvada | Change From Baseline in Waist Circumference/Hip Circumference Ratio | -0.01 Ratio |
| Zidovudine/Lamivudine | Change From Baseline in Waist Circumference/Hip Circumference Ratio | 0.01 Ratio |
Comparison: Null Hypothesis: changes from baseline in the two treatment groups are equal. Alternative Hypothesis: changes from baseline in the two treatment groups are different (two sided).p-value: 0.1785Wilcoxon Rank Sum test
Secondary
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.
Time frame: Baseline to Week 72
Population: Treated participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Truvada | Percentage of Days for Which Participants Were Compliant With Study Drug | 100.0 Percentage of days with compliance |
| Zidovudine/Lamivudine | Percentage of Days for Which Participants Were Compliant With Study Drug | 100.0 Percentage of days with compliance |
Comparison: Null Hypothesis: percentages of days with compliance in the two treatment groups are equal. Alternative Hypothesis: percentages of days with compliance in the two treatment groups are different (two sided).p-value: 0.6984Wilcoxon Rank Sum test
Secondary
Percentage of Participants Who Discontinue the Study Prematurely (Before Week 48) Due to Adverse Events.
Time frame: 48 weeks
Population: Treated participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Truvada | Percentage of Participants Who Discontinue the Study Prematurely (Before Week 48) Due to Adverse Events. | 3 Percentage of participants |
| Zidovudine/Lamivudine | Percentage of Participants Who Discontinue the Study Prematurely (Before Week 48) Due to Adverse Events. | 10 Percentage of participants |
Secondary
Percentage of Participants Who Maintain Confirmed HIV-1 RNA < 50 Copies/mL
Time frame: 48 weeks
Population: Treated participants. Missing values were treated as failure (i.e., as HIV-1 RNA greater than or equal to 50 copies/mL).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Truvada | Percentage of Participants Who Maintain Confirmed HIV-1 RNA < 50 Copies/mL | 92.3 Percentage of participants |
| Zidovudine/Lamivudine | Percentage of Participants Who Maintain Confirmed HIV-1 RNA < 50 Copies/mL | 78.0 Percentage of participants |
Comparison: Null Hypothesis: treatment is not associated with the observed virologic response.~Alternative Hypothesis: treatment is associated with the observed virologic response.p-value: 0.116595% CI: [-0.9, 29.4]Fisher Exact
Secondary
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.
Time frame: 72 weeks
Population: Treated participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Truvada | Percentage of Participants With Any Adverse Event | 77 Percentage of participants |
| Zidovudine/Lamivudine | Percentage of Participants With Any Adverse Event | 85 Percentage of participants |
Secondary
Percentage of Participants With HIV-1 RNA > 50 and < 400 Copies/mL
Time frame: 48 weeks
Population: Treated participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Truvada | Percentage of Participants With HIV-1 RNA > 50 and < 400 Copies/mL | 0 Percentage of participants |
| Zidovudine/Lamivudine | Percentage of Participants With HIV-1 RNA > 50 and < 400 Copies/mL | 5 Percentage of participants |
Secondary
Percentage of Participants With Virologic Failure
Virologic failure was defined as two consecutive HIV RNA values \> 400 copies/mL.
Time frame: 48 weeks
Population: Treated participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Truvada | Percentage of Participants With Virologic Failure | 0 Percentage of participants |
| Zidovudine/Lamivudine | Percentage of Participants With Virologic Failure | 0 Percentage of participants |
Secondary
Percent Change From Baseline in Hematocrit
Change = Week 48 value minus baseline value expressed as median percent change.
Time frame: Baseline to Week 48
Population: Treated participants. Missing values were excluded.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Truvada | Percent Change From Baseline in Hematocrit | 2.7 Percent change in hematocrit |
| Zidovudine/Lamivudine | Percent Change From Baseline in Hematocrit | 1.0 Percent change in hematocrit |
Comparison: Null Hypothesis: changes from baseline in the two treatment groups are equal. Alternative Hypothesis: changes from baseline in the two treatment groups are different (two sided).p-value: 0.0006Wilcoxon Rank Sum test