HIV, HIV Infections
Conditions
Keywords
HIV, Second line treatment, WHO recommendations, Africa, Treatment strategies, treatment experienced
Brief summary
Since the first line antiretroviral (ARV) treatment is now largely accessible in the Sub-Saharian Africa countries, documentation of virological failure, drug resistance patterns and second line treatment evaluation are still to be consolidated in settings where viral load monitoring is not available and non-B HIV subtype is predominant. This trial aims at evaluating the efficacy and tolerance of 3 different second line treatment strategies: two recommended by WHO combine two non-nucleoside reverse transcriptase inhibitor associated with a ritonavir boosted protease inhibitor (emtricitabine-tenofovir-lopinavir/ritonavir and abacavir-didanosine-lopinavir/ritonavir); the third strategy combines emtricitabine-tenofovir-darunavir/ritonavir and is not yet evaluated in Sub-Saharian Africa. Darunavir has a potentially superior antiviral efficacy, a better tolerance and its single daily administration may facilitate treatment adherence.
Interventions
DRUGemtricitabine/tenofovir + lopinavir/ritonavir (WHO recommended second line)
Emtricitabine 200 mg/tenofovir 300 mg 1 tablet/day with food + Lopinavir 200 mg/Ritonavir 50 mg 2 tablets in the morning and 2 tablets in the evening
DRUGabacavir + didanosine + lopinavir/ritonavir (WHO recommended second line)
Didanosine 1 entero-coated capsule/day in fasting conditions (dosage 250 mg if weight \< 60 kg, 400 mg if weight \> 60 kg) + abacavir 300 mg 1 tablet in the morning and in the evening + Lopinavir 200 mg/Ritonavir 50 mg 2 tablets morning and evening
DRUGemtricitabine/tenofovir + darunavir + ritonavir (Second line strategy under evaluation)
Emtricitabine 200 mg/tenofovir 300 mg 1 tablet/day with food + darunavir 400 mg 2 tablets + ritonavir 100 mg 1 capsule, in a single dose with food
Sponsors
Gilead Sciences
Janssen Pharmaceutica
ANRS, Emerging Infectious Diseases
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
* Patient over the age of 18 years at pre-inclusion and monitored under outpatient conditions * Documented HIV-1 infection regardless of clinical stage and CD4 lymphocyte count * Patient with treatment failure after first-line antiretroviral treatment with a combination including a non-nucleoside reverse transcriptase inhibitor and two nucleoside reverse transcriptase inhibitors, failure being defined as 2 measurements (at 1 month interval) of plasma HIV RNA levels \> 1000 copies/ml after at least 6 months of uninterrupted treatment * Adherence (\> 80%) to first- line antiretroviral treatment (questionnaire) at pre inclusion * Patient agrees not to take any concomitant medication during the trial without informing the investigator * Informed consent signed no later than D-15 * For women in childbearing age: negative pregnancy test at inclusion, with no plan of pregnancy in the coming 12 months and agreeing to use mechanical contraception (with or without hormonal contraception) during the study
Exclusion criteria
* Infection with HIV-2 or HIV-1 groups O or N or HIV1+2 * Deficiency of the patient, making it difficult, if not impossible, for him/her to take part in the trial or understand the information provided to him/her * Participation in any other clinical trial * Presence of an uncontrolled, ongoing opportunistic infection or of any severe or progressive disease * First-line treatment with a protease inhibitor, abacavir, tenofovir or ddI * Ongoing treatment with rifampicin * Severe hepatic insufficiency (TP \< 50%) * ALAT \> 3 x ULN * Creatinine clearance calculated by Cockcroft formula \< 50 ml/min * Hb ≤ 8 g/dl * Platelets \< 50,000 cells/mm3 * Neutrophiles \< 500 cells/ mm3 * Use of drugs prohibited in the context of this trial (drugs contraindicated by the SCP of the trial drugs) - in the event of tuberculosis or malaria during the trial, a list of authorized medicines and, if necessary, a dose adjustment of the antiretroviral medication will be provided * Pregnancy or lactation
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of Patients With Plasma HIV RNA < 50 Copies/mL | 48 weeks |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Gain in CD4 Cells Between Baseline and W48 | between baseline and 48 weeks | median gain in circulating CD4 cells between baseline and W48 |
| Number of Patients With WHO Stage 3 and 4 HIV Related Events | between baseline and 48 weeks | patients having a diagnosis of HIV related event classified as stage 3 or 4 |
| Patients With Plasma HIV RNA < 200 Copies/ml | 48 weeks | number of patients with plasma HIV RNA below 200 copies/ml |
| Number of Patients Discontinuing Study Treatment | between baseline and W48 | number of patients discounting treatment because of adverse events |
| Tolerance: Gastrointestinal Complains | between baseline and 48 weeks | Gastrointestinal complaints (grade 1 to 4) between baseline and W48. |
| Tolerance: Neuropathies (Grade 1 to 4) | between baseline and W48 | any symptom of peripheral neuropathy |
| Tolerance: Equal or Superior to a 25% Reduction in eGFR (Glomerular Filtration Rate) | between baseline and W48 | evaluation of estimated glomerular filtration rate and number of participant with a decrease equal or superior to 25% of the baseline value |
| Adherence | between baseline and W48 | number of patients in different categories of adherence as measured by questionnaire |
| Number of Patients With Resistance Mutations | between W12 and W48 | number of patients with resistance mutations after second line treatment failure (HIV RNA\> 1000 copies/ml) |
| Development of Metabolic Syndrome | from baseline to week 48 | number of patients developing metabolic syndrome over a period of 48 weeks |
| Number of Patients With HIV Plasma Viral Load < 50 Copies/ml | Week 24 | Snapshot of patients with HIV viral load less then 50 copies/ml at week 24 |
| Number of Patients With HIV Plasma Viral Load < 200 Copies/ml | Week 24 | number of patients having a plasma viral load below 200 copies/ml at week 24 |
Countries
Burkina Faso, Cameroon, Senegal
Participant flow
Recruitment details
Recruitment in three study sites (Yaoundé, Dakar and Bobo Dioulasso) in HIV day care clinics from January 2010 to September 2012.
Pre-assignment details
584 patients assessed for eligibility, 130 excluded primary (13.9%) because control viral load decreased below 1000 copies/mL after adherence support.
Participants by arm
| Arm | Count |
|---|---|
| Arm A emtricitabine/tenofovir + lopinavir/ritonavir (WHO recommended second line)
emtricitabine/tenofovir + lopinavir/ritonavir (WHO recommended second line): Emtricitabine 200 mg/tenofovir 300 mg 1 tablet/day with food + Lopinavir 200 mg/Ritonavir 50 mg 2 tablets in the morning and 2 tablets in the evening | 152 |
| Arm B abacavir + didanosine + lopinavir/ritonavir (WHO recommended second line)
abacavir + didanosine + lopinavir/ritonavir (WHO recommended second line): Didanosine 1 entero-coated capsule/day in fasting conditions (dosage 250 mg if weight \< 60 kg, 400 mg if weight \> 60 kg) + abacavir 300 mg 1 tablet in the morning and in the evening + Lopinavir 200 mg/Ritonavir 50 mg 2 tablets morning and evening | 145 |
| Arm C emtricitabine/tenofovir + darunavir + ritonavir (Second line strategy under evaluation)
emtricitabine/tenofovir + darunavir + ritonavir (Second line strategy under evaluation): Emtricitabine 200 mg/tenofovir 300 mg 1 tablet/day with food + darunavir 400 mg 2 tablets + ritonavir 100 mg 1 capsule, in a single dose with food | 154 |
| Total | 451 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 1 | 2 | 3 |
| Overall Study | Lost to Follow-up | 1 | 2 | 1 |
| Overall Study | Protocol Violation | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Arm A | Arm B | Arm C | Total |
|---|---|---|---|---|
| Age, Continuous | 38 years | 38 years | 36 years | 38 years |
| CD4 cells count | 199 cells/mm3 | 195 cells/mm3 | 153 cells/mm3 | 183 cells/mm3 |
| Gender Female | 113 Participants | 105 Participants | 106 Participants | 324 Participants |
| Gender Male | 39 Participants | 40 Participants | 48 Participants | 127 Participants |
| HIV RNA Viral Load | 4.4 log10 (copies/ml) | 4.6 log10 (copies/ml) | 4.5 log10 (copies/ml) | 4.5 log10 (copies/ml) |
| Region of Enrollment Burkina Faso | 30 participants | 28 participants | 32 participants | 90 participants |
| Region of Enrollment Cameroon | 101 participants | 99 participants | 102 participants | 302 participants |
| Region of Enrollment Senegal | 21 participants | 18 participants | 20 participants | 59 participants |
| Resistance to the three first-line drugs | 84 participants | 77 participants | 88 participants | 249 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 131 / 152 | 122 / 145 | 118 / 154 |
| serious Total, serious adverse events | 13 / 152 | 22 / 145 | 19 / 154 |
Outcome results
Primary
Number of Patients With Plasma HIV RNA < 50 Copies/mL
Time frame: 48 weeks
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A | Number of Patients With Plasma HIV RNA < 50 Copies/mL | 105 participants |
| Arm B | Number of Patients With Plasma HIV RNA < 50 Copies/mL | 92 participants |
| Arm C | Number of Patients With Plasma HIV RNA < 50 Copies/mL | 97 participants |
95% CI: [-5.1, 16.4]
95% CI: [-4.5, 16.7]
Secondary
Adherence
number of patients in different categories of adherence as measured by questionnaire
Time frame: between baseline and W48
Population: patients with data available
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A | Adherence | At least once 80-95% | 89 participants |
| Arm A | Adherence | Always above 95% | 50 participants |
| Arm A | Adherence | At least once < 80% | 11 participants |
| Arm B | Adherence | At least once 80-95% | 72 participants |
| Arm B | Adherence | Always above 95% | 54 participants |
| Arm B | Adherence | At least once < 80% | 14 participants |
| Arm C | Adherence | Always above 95% | 67 participants |
| Arm C | Adherence | At least once < 80% | 4 participants |
| Arm C | Adherence | At least once 80-95% | 78 participants |
Secondary
Development of Metabolic Syndrome
number of patients developing metabolic syndrome over a period of 48 weeks
Time frame: from baseline to week 48
Population: population with data available
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A | Development of Metabolic Syndrome | 12 Participants |
| Arm B | Development of Metabolic Syndrome | 21 Participants |
| Arm C | Development of Metabolic Syndrome | 9 Participants |
Secondary
Gain in CD4 Cells Between Baseline and W48
median gain in circulating CD4 cells between baseline and W48
Time frame: between baseline and 48 weeks
Population: ITT with data available
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A | Gain in CD4 Cells Between Baseline and W48 | 133 cell/mm3 |
| Arm B | Gain in CD4 Cells Between Baseline and W48 | 136 cell/mm3 |
| Arm C | Gain in CD4 Cells Between Baseline and W48 | 115 cell/mm3 |
Secondary
Number of Patients Discontinuing Study Treatment
number of patients discounting treatment because of adverse events
Time frame: between baseline and W48
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A | Number of Patients Discontinuing Study Treatment | 0 participants |
| Arm B | Number of Patients Discontinuing Study Treatment | 4 participants |
| Arm C | Number of Patients Discontinuing Study Treatment | 1 participants |
Secondary
Number of Patients With HIV Plasma Viral Load < 200 Copies/ml
number of patients having a plasma viral load below 200 copies/ml at week 24
Time frame: Week 24
Population: ITT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A | Number of Patients With HIV Plasma Viral Load < 200 Copies/ml | 127 Participants |
| Arm B | Number of Patients With HIV Plasma Viral Load < 200 Copies/ml | 117 Participants |
| Arm C | Number of Patients With HIV Plasma Viral Load < 200 Copies/ml | 129 Participants |
Secondary
Number of Patients With HIV Plasma Viral Load < 50 Copies/ml
Snapshot of patients with HIV viral load less then 50 copies/ml at week 24
Time frame: Week 24
Population: ITT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A | Number of Patients With HIV Plasma Viral Load < 50 Copies/ml | 90 Participants |
| Arm B | Number of Patients With HIV Plasma Viral Load < 50 Copies/ml | 81 Participants |
| Arm C | Number of Patients With HIV Plasma Viral Load < 50 Copies/ml | 97 Participants |
Secondary
Number of Patients With Resistance Mutations
number of patients with resistance mutations after second line treatment failure (HIV RNA\> 1000 copies/ml)
Time frame: between W12 and W48
Population: patients who failed second line (2 HIV RNA measure above 1000 copies/ml)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A | Number of Patients With Resistance Mutations | 0 participants |
| Arm B | Number of Patients With Resistance Mutations | 0 participants |
| Arm C | Number of Patients With Resistance Mutations | 0 participants |
Secondary
Number of Patients With WHO Stage 3 and 4 HIV Related Events
patients having a diagnosis of HIV related event classified as stage 3 or 4
Time frame: between baseline and 48 weeks
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A | Number of Patients With WHO Stage 3 and 4 HIV Related Events | 17 participants |
| Arm B | Number of Patients With WHO Stage 3 and 4 HIV Related Events | 23 participants |
| Arm C | Number of Patients With WHO Stage 3 and 4 HIV Related Events | 30 participants |
Secondary
Patients With Plasma HIV RNA < 200 Copies/ml
number of patients with plasma HIV RNA below 200 copies/ml
Time frame: 48 weeks
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A | Patients With Plasma HIV RNA < 200 Copies/ml | 130 participants |
| Arm B | Patients With Plasma HIV RNA < 200 Copies/ml | 118 participants |
| Arm C | Patients With Plasma HIV RNA < 200 Copies/ml | 127 participants |
Secondary
Tolerance: Equal or Superior to a 25% Reduction in eGFR (Glomerular Filtration Rate)
evaluation of estimated glomerular filtration rate and number of participant with a decrease equal or superior to 25% of the baseline value
Time frame: between baseline and W48
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A | Tolerance: Equal or Superior to a 25% Reduction in eGFR (Glomerular Filtration Rate) | 28 participants |
| Arm B | Tolerance: Equal or Superior to a 25% Reduction in eGFR (Glomerular Filtration Rate) | 14 participants |
| Arm C | Tolerance: Equal or Superior to a 25% Reduction in eGFR (Glomerular Filtration Rate) | 19 participants |
p-value: 0.13Chi-squared
Secondary
Tolerance: Gastrointestinal Complains
Gastrointestinal complaints (grade 1 to 4) between baseline and W48.
Time frame: between baseline and 48 weeks
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A | Tolerance: Gastrointestinal Complains | 50 participants |
| Arm B | Tolerance: Gastrointestinal Complains | 48 participants |
| Arm C | Tolerance: Gastrointestinal Complains | 26 participants |
p-value: 0.001Chi-squared
Secondary
Tolerance: Neuropathies (Grade 1 to 4)
any symptom of peripheral neuropathy
Time frame: between baseline and W48
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A | Tolerance: Neuropathies (Grade 1 to 4) | 5 participants |
| Arm B | Tolerance: Neuropathies (Grade 1 to 4) | 11 participants |
| Arm C | Tolerance: Neuropathies (Grade 1 to 4) | 8 participants |
p-value: 0.26Chi-squared