HIV Infections
Conditions
Keywords
HIV, Antiretroviral Therapy (ART), Efavirenz (EFV), Dose reduction
Brief summary
Clinical data suggests that the standard dose of the anti-HIV medication, efavirenz (EFV), could be reduced without compromising its effectiveness. Lower drug doses could have fewer side effects and would make EFV more affordable. The purpose of this study is to compare the safety and effectiveness, over 96 weeks, of standard (600mg) versus reduced dose (400mg) EFV in controlling HIV as part of initial combination antiretroviral therapy.
Detailed description
In this international, multicenter trial, 630 HIV infected patients who have not received any previous treatment for their HIV-infection will be enrolled. Participants will be randomized equally (1:1) to receive Truvada (tenofovir and emtricitabine) with either the standard or reduced dose of EFV. Neither the study doctor nor the participant will know which treatment the participant is receiving. Physical examinations, laboratory analyses and questionnaires will be performed at the 11 study visits at screening, baseline (Week 0), Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96. The primary aim of this study is to compare between treatment groups the proportion of patients with undetectable HIV viral load (HIV RNA \< 200 copies/mL) after 48 weeks. Information on immune function, drug adherence, resistance to antiretrovirals, quality of life, mental state and HIV-related conditions will also be collected. Blood samples will be collected for future testing. Interim analyses will be performed when the first 125 participants in each treatment group reach week 24 and when all participants reach week 24. These interim analyses will provide an early check that the reduced dose of EFV suppresses HIV infection as effectively as the standard dose of EFV. A follow-up analysis will be performed when all participants reach week 96.
Interventions
DRUGEfavirenz 600mg
3 x EFV 200 milligram (mg) tablets once daily
DRUGEfavirenz 400mg
2 x EFV 200 milligram (mg) tablets plus 1x matched EFV placebo tablet once daily
Sponsors
Kirby Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* HIV-1 positive by licensed diagnostic test * aged \>16 years of age (or minimum age as determined by local regulations or as legal requirements dictate) * 50 \< cluster of differentiation (CD)4 \<500 cells/µL * No prior AIDS-defining illness, using the Center for Diseases Control 1993 Case Definition (except pulmonary tuberculosis) * HIV RNA ≥1000 copies/mL * no prior exposure to antiretroviral therapy (ART) (including short course ART for preventing MTCT) * calculated creatinine clearance (CLCr) more than or equal to 50 mL/min (Cockcroft-Gault formula) * provision of written informed consent.
Exclusion criteria
* the following laboratory values: * absolute neutrophil count (ANC) \<500 cells/μL * hemoglobin \<7.0 g/dL * platelet count \<50,000 cells/μL * alanine aminotransferase and/or aspartate aminotransferase \>5 x upper limit of normal * pregnant women or nursing mothers * active opportunistic or malignant disease not under adequate control * use of immunomodulators within 30 days prior to screening * use of any prohibited medications * current alcohol or illicit substance use that might adversely affect study participation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Plasma HIV-1 RNA <200 Copies/mL 48 Weeks After Randomisation | 48 weeks | Percentage of participants in each of the treatment arms with centrally quantified plasma HIV-1 RNA viral load \<200 copies/mL 48 weeks after randomisation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in CD4+ T-cell Count | Baseline and 2 years | Mean change from baseline to week 96 in CD4+ T-cell count/mm3 between the two treatment arms |
| Clinical Endpoints: Opportunistic Disease or Death, and Serious Non-AIDS-defining Events and Non-AIDS-related Mortality | up to 2 years | Number of participants in each randomised arm diagnosed with a serious non-AIDS defining event, who die from an AIDS-defining event, who die from a non-AIDS-defining event |
| Change From Baseline in Metabolic Endpoints | Baseline and 2 years | Change from baseline to week 96 in fasted total cholesterol, high density cholesterol and low density cholesterol, and glucose between randomised treatment arms |
| Adherence: Median Scores of Self-reported Adherence to Randomised Study Medications | 2 years | AIDS Clinical Trials Group (ACTG) 7-day adherence questionnaire scores. Maximum value is all pills taken every day; minimum value is no pills taken per day. Higher scores indicate a better outcome. |
| Percentage of Participants With Plasma HIV-1 RNA <400 Copies/mL and <50 Copies/mL at 48 and 96 Weeks After Randomisation | Baseline and 2 years | Percentage of participants in each of the two treatment arms with plasma HIV-1 RNA \<400 copies/mL and \<50 copies/mL at 48 and 96 weeks after randomisation |
| Change in Selected Serum Biochemical Parameters | Baseline and 2 years | Change from baseline to week 96 in alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase levels between randomised treatment arms |
| Change From Baseline in Estimate Creatinine Clearance | Baseline and 2 years | Change from baseline to week 96 in estimate creatinine clearance between randomised treatment arms |
| Steady-state Efavirenz Concentrations | Week 4 | Steady-state efavirenz mid-dosing interval plasma concentrations |
| Change From Baseline in Fasted Insulin Levels | Baseline and 2 years | Change from baseline to week 96 in fasted insulin levels |
Countries
Australia
Participant flow
Recruitment details
38 clinical centres (primary and tertiary care facilities) in 13 countries on 5 continents screened a total of 768 patents who had provided informed consent between Aug 4, 2011 and March 19, 2012.
Pre-assignment details
768 screened:132 did not satisfy eligibility: 2 prior AIDS-defining illness; 3 previous antiretroviral therapy; 15 HIV RNA out of range; 44 cluster of differentiation (CD)4 count out of range; 13 lab values out of range; 2 pregnant; 9 intercurrent illness; 2 illicit substance use; 30 exceeded screen time; 4 clinician exclusion; 9 withdrew consent.
Participants by arm
| Arm | Count |
|---|---|
| 600mg Efavirenz Eligible patients will be centrally randomised to receive tenofovir (TDF) (300mg qd)/emtricitabine (FTC) (200mg qd) + EFV (600mg qd; 3 x 200mg qd)
Efavirenz: 3 x EFV 200mg tablets once daily | 309 |
| 400mg Efavirenz Eligible patients will be centrally randomised to receive TDF (300mg qd)/FTC (200mg qd) + EFV (400mg qd; 2 x 200mg + 1 x 200mg placebo qd).
Efavirenz: 2 x EFV 200mg tablets plus 1x matched EFV placebo tablet once daily | 321 |
| Total | 630 |
Baseline characteristics
| Characteristic | 600mg Efavirenz | Total | 400mg Efavirenz |
|---|---|---|---|
| Age, Continuous | 35.8 years STANDARD_DEVIATION 10 | 36.0 years STANDARD_DEVIATION 10 | 36.1 years STANDARD_DEVIATION 10 |
| CDC HIV infection clinical category category A | 265 participants | 529 participants | 264 participants |
| CDC HIV infection clinical category category B | 33 participants | 79 participants | 46 participants |
| CDC HIV infection clinical category category C | 11 participants | 22 participants | 11 participants |
| Current smoker | 87 participants | 169 participants | 82 participants |
| Glucose (mmol/L) | 4.84 mmol per Litre STANDARD_DEVIATION 1.78 | 4.75 mmol per Litre STANDARD_DEVIATION 1.43 | 4.66 mmol per Litre STANDARD_DEVIATION 0.98 |
| Hep B Sag +ve | 12 participants | 27 participants | 15 participants |
| Hep C ab +ve | 3 participants | 8 participants | 5 participants |
| HIV transmission risk heterosexual | 156 participants | 312 participants | 156 participants |
| HIV transmission risk homo/bisexual | 134 participants | 272 participants | 138 participants |
| HIV transmission risk injecting drug user/not known | 19 participants | 46 participants | 27 participants |
| Insulin (mU/L) | 8.28 mU per Litre STANDARD_DEVIATION 9.7 | 8.27 mU per Litre STANDARD_DEVIATION 11.4 | 8.26 mU per Litre STANDARD_DEVIATION 12.9 |
| Mean BMI (kg/m^2) | 24.3 kg per m2 STANDARD_DEVIATION 5.2 | 24.2 kg per m2 STANDARD_DEVIATION 4.9 | 24.0 kg per m2 STANDARD_DEVIATION 4.7 |
| Mean creatinine clearance (mL/min) | 120 mL per min STANDARD_DEVIATION 32.4 | 118.7 mL per min STANDARD_DEVIATION 31 | 117.4 mL per min STANDARD_DEVIATION 29.7 |
| Mean HDL chol (mmol/L) | 1.03 mmol per Litre STANDARD_DEVIATION 0.31 | 1.03 mmol per Litre STANDARD_DEVIATION 0.32 | 1.04 mmol per Litre STANDARD_DEVIATION 0.32 |
| Mean LDL chol (mmol/L) | 2.47 mmol per Litre STANDARD_DEVIATION 0.84 | 2.51 mmol per Litre STANDARD_DEVIATION 0.88 | 2.54 mmol per Litre STANDARD_DEVIATION 0.93 |
| Mean nadir cluster of differentiation (CD)4+ cell count | 252 cells per mm3 STANDARD_DEVIATION 90 | 250 cells per mm3 STANDARD_DEVIATION 89 | 248 cells per mm3 STANDARD_DEVIATION 88 |
| Mean total chol (mmol/L) | 4.15 mmol per Litre STANDARD_DEVIATION 0.93 | 4.20 mmol per Litre STANDARD_DEVIATION 0.94 | 4.24 mmol per Litre STANDARD_DEVIATION 0.95 |
| Mean triglycerides (mmol/L) | 1.24 mmol per Litre STANDARD_DEVIATION 0.69 | 1.25 mmol per Litre STANDARD_DEVIATION 0.7 | 1.25 mmol per Litre STANDARD_DEVIATION 0.72 |
| Median plasma HIV RNA | 4.73 log10 copies per mL | 4.75 log10 copies per mL | 4.76 log10 copies per mL |
| Race/Ethnicity, Customized African | 116 participants | 234 participants | 118 participants |
| Race/Ethnicity, Customized Asian | 103 participants | 209 participants | 106 participants |
| Race/Ethnicity, Customized White | 90 participants | 187 participants | 97 participants |
| Sex: Female, Male Female | 103 Participants | 203 Participants | 100 Participants |
| Sex: Female, Male Male | 206 Participants | 427 Participants | 221 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 7 / 309 | 3 / 321 |
| other Total, other adverse events | 273 / 309 | 286 / 321 |
| serious Total, serious adverse events | 25 / 309 | 23 / 321 |
Outcome results
Primary
Percentage of Participants With Plasma HIV-1 RNA <200 Copies/mL 48 Weeks After Randomisation
Percentage of participants in each of the treatment arms with centrally quantified plasma HIV-1 RNA viral load \<200 copies/mL 48 weeks after randomisation.
Time frame: 48 weeks
Population: modified intention to treat including all randomised patients who took at least one dose of study medication AND attended at least one follow-up visit.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 600mg Efavirenz | Percentage of Participants With Plasma HIV-1 RNA <200 Copies/mL 48 Weeks After Randomisation | 92.2 percentage of participants |
| 400mg Efavirenz | Percentage of Participants With Plasma HIV-1 RNA <200 Copies/mL 48 Weeks After Randomisation | 94.1 percentage of participants |
Comparison: Sample size calculation assumes 85% of participants randomised to 600mg EFV arm will have plasma HIV RNA \<200 copies/ml at 48 weeks. Assuming no difference between randomised treatments in proportion with plasma HIV RNA \<200 copies/mL, to have 90% power to demonstrate non-inferiority in the intention to treat (ITT) analysis using a 10% non-inferiority margin will require 286 participants per arm, making a total of 572 participants. Power for modified ITT analysis was 93%.p-value: 0.05Pearson's chi-squared
Comparison: To ensure the per protocol (PP) analysis has 90% power to demonstrate non-inferiority, the sample size was inflated for patients who switch treatment for toxicity. This is estimated to be no more than 10% randomised patients. To ensure 90% power to demonstrate non-inferiority in the ITT and PP analyses, a total of 630 (315 per arm) patients will be randomised giving 93% power for the ITT analysis. Null hypothesis: no statistically significant difference between the 600mg and 400mg EFV regimens.p-value: 0.05Chi-squared
Secondary
Adherence: Median Scores of Self-reported Adherence to Randomised Study Medications
AIDS Clinical Trials Group (ACTG) 7-day adherence questionnaire scores. Maximum value is all pills taken every day; minimum value is no pills taken per day. Higher scores indicate a better outcome.
Time frame: 2 years
Population: Number of participants attending week 96 visit
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 600mg Efavirenz | Adherence: Median Scores of Self-reported Adherence to Randomised Study Medications | All pills taken | 256 Participants |
| 600mg Efavirenz | Adherence: Median Scores of Self-reported Adherence to Randomised Study Medications | Most pills taken | 7 Participants |
| 600mg Efavirenz | Adherence: Median Scores of Self-reported Adherence to Randomised Study Medications | About half pills taken | 1 Participants |
| 600mg Efavirenz | Adherence: Median Scores of Self-reported Adherence to Randomised Study Medications | No pills taken | 16 Participants |
| 400mg Efavirenz | Adherence: Median Scores of Self-reported Adherence to Randomised Study Medications | No pills taken | 8 Participants |
| 400mg Efavirenz | Adherence: Median Scores of Self-reported Adherence to Randomised Study Medications | All pills taken | 271 Participants |
| 400mg Efavirenz | Adherence: Median Scores of Self-reported Adherence to Randomised Study Medications | About half pills taken | 1 Participants |
| 400mg Efavirenz | Adherence: Median Scores of Self-reported Adherence to Randomised Study Medications | Most pills taken | 12 Participants |
Secondary
Change From Baseline in Estimate Creatinine Clearance
Change from baseline to week 96 in estimate creatinine clearance between randomised treatment arms
Time frame: Baseline and 2 years
Population: Available data analysis
| Arm | Measure | Value (MEAN) |
|---|---|---|
| 600mg Efavirenz | Change From Baseline in Estimate Creatinine Clearance | -0.17 millilitres per minute |
| 400mg Efavirenz | Change From Baseline in Estimate Creatinine Clearance | 1.59 millilitres per minute |
Secondary
Change From Baseline in Fasted Insulin Levels
Change from baseline to week 96 in fasted insulin levels
Time frame: Baseline and 2 years
Population: Available data analysis
| Arm | Measure | Value (MEAN) |
|---|---|---|
| 600mg Efavirenz | Change From Baseline in Fasted Insulin Levels | -0.11 mU per litre |
| 400mg Efavirenz | Change From Baseline in Fasted Insulin Levels | 0.3 mU per litre |
Secondary
Change From Baseline in Metabolic Endpoints
Change from baseline to week 96 in fasted total cholesterol, high density cholesterol and low density cholesterol, and glucose between randomised treatment arms
Time frame: Baseline and 2 years
Population: Available data analysis
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| 600mg Efavirenz | Change From Baseline in Metabolic Endpoints | Total cholesterol mmol/L | 0.62 mmol per Litre |
| 600mg Efavirenz | Change From Baseline in Metabolic Endpoints | HDL mmol/L | 0.35 mmol per Litre |
| 600mg Efavirenz | Change From Baseline in Metabolic Endpoints | LDL mmol/L | 0.21 mmol per Litre |
| 600mg Efavirenz | Change From Baseline in Metabolic Endpoints | Blood glucose mmol/L | 0.24 mmol per Litre |
| 400mg Efavirenz | Change From Baseline in Metabolic Endpoints | Blood glucose mmol/L | 0.40 mmol per Litre |
| 400mg Efavirenz | Change From Baseline in Metabolic Endpoints | Total cholesterol mmol/L | 0.54 mmol per Litre |
| 400mg Efavirenz | Change From Baseline in Metabolic Endpoints | LDL mmol/L | 0.16 mmol per Litre |
| 400mg Efavirenz | Change From Baseline in Metabolic Endpoints | HDL mmol/L | 0.30 mmol per Litre |
Secondary
Change in Selected Serum Biochemical Parameters
Change from baseline to week 96 in alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase levels between randomised treatment arms
Time frame: Baseline and 2 years
Population: Available data analysis
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| 600mg Efavirenz | Change in Selected Serum Biochemical Parameters | Alanine aminotransferase | 6.53 Units per Litre |
| 600mg Efavirenz | Change in Selected Serum Biochemical Parameters | Aspartate aminotransferase | 1.71 Units per Litre |
| 600mg Efavirenz | Change in Selected Serum Biochemical Parameters | Alkaline phosphatase | 26.75 Units per Litre |
| 400mg Efavirenz | Change in Selected Serum Biochemical Parameters | Alanine aminotransferase | 0.64 Units per Litre |
| 400mg Efavirenz | Change in Selected Serum Biochemical Parameters | Aspartate aminotransferase | -1.23 Units per Litre |
| 400mg Efavirenz | Change in Selected Serum Biochemical Parameters | Alkaline phosphatase | 21.23 Units per Litre |
Secondary
Clinical Endpoints: Opportunistic Disease or Death, and Serious Non-AIDS-defining Events and Non-AIDS-related Mortality
Number of participants in each randomised arm diagnosed with a serious non-AIDS defining event, who die from an AIDS-defining event, who die from a non-AIDS-defining event
Time frame: up to 2 years
Population: modified ITT population
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 600mg Efavirenz | Clinical Endpoints: Opportunistic Disease or Death, and Serious Non-AIDS-defining Events and Non-AIDS-related Mortality | AIDS event deaths | 2 Participants |
| 600mg Efavirenz | Clinical Endpoints: Opportunistic Disease or Death, and Serious Non-AIDS-defining Events and Non-AIDS-related Mortality | serious non-AIDS events | 3 Participants |
| 600mg Efavirenz | Clinical Endpoints: Opportunistic Disease or Death, and Serious Non-AIDS-defining Events and Non-AIDS-related Mortality | non-AIDS deaths | 5 Participants |
| 600mg Efavirenz | Clinical Endpoints: Opportunistic Disease or Death, and Serious Non-AIDS-defining Events and Non-AIDS-related Mortality | No disease/death | 292 Participants |
| 600mg Efavirenz | Clinical Endpoints: Opportunistic Disease or Death, and Serious Non-AIDS-defining Events and Non-AIDS-related Mortality | AIDS events | 7 Participants |
| 400mg Efavirenz | Clinical Endpoints: Opportunistic Disease or Death, and Serious Non-AIDS-defining Events and Non-AIDS-related Mortality | No disease/death | 301 Participants |
| 400mg Efavirenz | Clinical Endpoints: Opportunistic Disease or Death, and Serious Non-AIDS-defining Events and Non-AIDS-related Mortality | AIDS events | 14 Participants |
| 400mg Efavirenz | Clinical Endpoints: Opportunistic Disease or Death, and Serious Non-AIDS-defining Events and Non-AIDS-related Mortality | AIDS event deaths | 0 Participants |
| 400mg Efavirenz | Clinical Endpoints: Opportunistic Disease or Death, and Serious Non-AIDS-defining Events and Non-AIDS-related Mortality | non-AIDS deaths | 3 Participants |
| 400mg Efavirenz | Clinical Endpoints: Opportunistic Disease or Death, and Serious Non-AIDS-defining Events and Non-AIDS-related Mortality | serious non-AIDS events | 3 Participants |
Secondary
Mean Change From Baseline in CD4+ T-cell Count
Mean change from baseline to week 96 in CD4+ T-cell count/mm3 between the two treatment arms
Time frame: Baseline and 2 years
Population: modified ITT (all participants who received at least one dose of study treatment and attended at least one follow up visit, irrespective of treatment received)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| 600mg Efavirenz | Mean Change From Baseline in CD4+ T-cell Count | 209 cells per mm3 |
| 400mg Efavirenz | Mean Change From Baseline in CD4+ T-cell Count | 235 cells per mm3 |
Secondary
Percentage of Participants With Plasma HIV-1 RNA <400 Copies/mL and <50 Copies/mL at 48 and 96 Weeks After Randomisation
Percentage of participants in each of the two treatment arms with plasma HIV-1 RNA \<400 copies/mL and \<50 copies/mL at 48 and 96 weeks after randomisation
Time frame: Baseline and 2 years
Population: Modified ITT including all randomised participants who took at least one dose of study medication and attended at least one follow-up visit
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 600mg Efavirenz | Percentage of Participants With Plasma HIV-1 RNA <400 Copies/mL and <50 Copies/mL at 48 and 96 Weeks After Randomisation | HIV-1 RNA <50cp/mL | 268 participants |
| 600mg Efavirenz | Percentage of Participants With Plasma HIV-1 RNA <400 Copies/mL and <50 Copies/mL at 48 and 96 Weeks After Randomisation | HIV-1 RNA <400cp/mL | 280 participants |
| 400mg Efavirenz | Percentage of Participants With Plasma HIV-1 RNA <400 Copies/mL and <50 Copies/mL at 48 and 96 Weeks After Randomisation | HIV-1 RNA <400cp/mL | 291 participants |
| 400mg Efavirenz | Percentage of Participants With Plasma HIV-1 RNA <400 Copies/mL and <50 Copies/mL at 48 and 96 Weeks After Randomisation | HIV-1 RNA <50cp/mL | 277 participants |
p-value: 0.05Chi-squared
Secondary
Steady-state Efavirenz Concentrations
Steady-state efavirenz mid-dosing interval plasma concentrations
Time frame: Week 4
Population: Available data analysis
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| 600mg Efavirenz | Steady-state Efavirenz Concentrations | 2.85 milligram per Litre |
| 400mg Efavirenz | Steady-state Efavirenz Concentrations | 2.10 milligram per Litre |