HIV-1 Infection
Conditions
Keywords
HIV-1
Brief summary
The study will assess whether Atazanavir/ritonavir monotherapy provides a non-inferior proportion of virological efficacy with respect to ATV/RTV + 2 NRTIs in patients with stable suppressed viremia and no prior virologic failures.
Detailed description
This is a randomised (1:1), multicentre, comparative, parallel-group, prospective, open label, non-inferiority controlled clinical trial. Enrolled patients, taking an ATV/r based HAART and with stable HIV-RNA \< 50c/ml (24 weeks), will be randomized to: * continue the same regimen ATV/RTV 300mg/100mg OD plus 2 NRTIs (according to the specific dosing schedule) as backbone (HAART arm) with ATV/r * or simplify therapy to ATV/RTV 300mg/100mg OD as monotherapy (Monotherapy arm) with ATV/r The study follow up will be 96 weeks after randomization and primary objective will be evaluated at week 48. Patients will be followed every 4 weeks for the first 16 weeks, and then every 8 weeks until week 48, then every 12 weeks until week 96 or discontinuation ; at each visit the following evaluations will be performed: * clinical assessment. * routine laboratory tests (hematological tests and hematochemistry) including creatinine, phosphorus, calcium, alkaline phosphatase, gammaGT; urine analysis, lipid profile, level of HIV-RNA and CD4 cell counts. During follow-up, at randomization, week 48, week 96 or discontinuation, patients will additionally undergo: * Fat redistribution evaluation by DEXA (dual-energy X-ray absorptiometry * Vertebral and femoral bone mineral density evaluation by DEXA. * ECG; * Glicate haemoglobin. * Adherence assessment (questionnaire and/or pills counts). * Neurocognitive evaluation \[HIV-associated neurocognitive disorders (HANDs) evaluated by validated neuropsychological tests\]. In case of viral rebound (defined as 2 consecutive measurement of HIV-RNA \> 50 c/ml) patients will be immediately contacted in order to perform genotypic tests. Furthermore a plasma PK analysis will also be performed. Any patients with virological rebound will be selected for a reintensification therapy with NRTIs and if not suppressed after 12 weeks they will be discontinued.
Interventions
DRUGAtazanavir/ritonavir monotherapy
Monotherapy Simplification Strategy with Atazanavir/ritonavir 300/100 mg once daily for 96 weeks.
Sponsors
Bristol-Myers Squibb
IRCCS San Raffaele
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
* HIV infected patients * age \> 18 years * On treatment with ATV/r plus 2 NRTIs for at least 48 weeks * Virological suppression (HIV-RNA\<50 c/ml) by at least 24 weeks with ATV/r plus 2 NRTIs * No virologic failure after the initiation of the first antiretroviral therapy. Previous treatment changes due to toxicity or treatment simplifications will be permitted only if occurred with documented virological suppression. * CD4 cells nadir \>100 cells/µL * PPI and H2-receptor antagonists as follows: the proton-pump inhibitors should not be used; if H2-receptor antagonists are co-administered, a dose equivalent to famotidine 20 mg BID should not be exceeded.
Exclusion criteria
* Pregnancy and breast feeding women * AIDS defining events * Evidence of active HBV infection (HBsAg positive) * Previous virological failure * History of resistance to ATV * Use of contraindicated medications
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients With Treatment Failure (TF) | Up to week 48 | Proportion of patients with treatment failure defined as having one of the following events: confirmed viral rebound (CVR) or treatment discontinuation for any cause. CVR was established when 2 consecutive viral load values (HIV-1 RNA)\>50 copies/mL occurred within 2 weeks during follow-up. In case of CVR, patients treated with atazanavir/ritonavir monotherapy had to re-introduce their previous 2NRTIs (re-intensification) and, if not suppressed (HIV-1 RNA \<50 copies /ml) after 12 weeks, discontinued from the study. Re-intensification was considered as treatment failure in the primary analysis conducted according to the intention-to-treat principle (intention-to-treat analysis with re-intensification equal failure, ITT=Failure) while it was not in the secondary analysis (intention-to-treat analysis with re-intensification equal success, ITT=Success). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy and Safety | week 96 | Proportion of pts with confirmed virological and treatment failure at w96. Change in CD4 cell counts. Occurrence of viral resistance to atazanavir in pts with confirmed virologic failure. Proportion of pts with adverse events, with ≥grade 2 adverse events or abnormal laboratory tests, proportion of pts with side effects leading to discontinuation. Body fat redistribution and vertebral and femoral bone mineral density. Adherence changes; changes in HIV-associated neurocognitive disorders. Difference in levels of activated Tcells and pro-inflammatory cytokines between treatment groups. |
Countries
Italy
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Atazanavir/Ritonavir Monotherapy Patients will simplify therapy to ATV/RTV 300mg/100mg OD as monotherapy
Atazanavir/ritonavir monotherapy: Monotherapy Simplification Strategy with Atazanavir/ritonavir 300/100 mg once daily for 96 weeks. | 51 |
| Atazanavir/Ritonavir Triple Therapy Patients will continue the same regimen ATV/RTV 300mg/100mg OD plus 2 NRTIs as backbone | 52 |
| Total | 103 |
Baseline characteristics
| Characteristic | Atazanavir/Ritonavir Triple Therapy | Total | Atazanavir/Ritonavir Monotherapy |
|---|---|---|---|
| Age, Continuous | 41.7 years | 41.5 years | 41.4 years |
| CD4+ | 570 cells/mm3 | 575 cells/mm3 | 599 cells/mm3 |
| HCV coinfection Absent | 42 participants | 82 participants | 40 participants |
| HCV coinfection Present | 10 participants | 21 participants | 11 participants |
| HIV-1 RNA <50 copies/ml | 18 months | 19 months | 20 months |
| HIV-RNA at ARV start | 42630 copies/mL | 59062 copies/mL | 79399 copies/mL |
| nadir CD4+ | 278 cells/mm3 | 276 cells/mm3 | 274 cells/mm3 |
| Region of Enrollment Italy | 52 participants | 103 participants | 51 participants |
| Sex: Female, Male Female | 7 Participants | 16 Participants | 9 Participants |
| Sex: Female, Male Male | 45 Participants | 87 Participants | 42 Participants |
| Years of antiretroviral treatment | 25 years | 25 years | 25 years |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 51 | 7 / 52 |
| serious Total, serious adverse events | 2 / 51 | 0 / 52 |
Outcome results
Primary
Proportion of Patients With Treatment Failure (TF)
Proportion of patients with treatment failure defined as having one of the following events: confirmed viral rebound (CVR) or treatment discontinuation for any cause. CVR was established when 2 consecutive viral load values (HIV-1 RNA)\>50 copies/mL occurred within 2 weeks during follow-up. In case of CVR, patients treated with atazanavir/ritonavir monotherapy had to re-introduce their previous 2NRTIs (re-intensification) and, if not suppressed (HIV-1 RNA \<50 copies /ml) after 12 weeks, discontinued from the study. Re-intensification was considered as treatment failure in the primary analysis conducted according to the intention-to-treat principle (intention-to-treat analysis with re-intensification equal failure, ITT=Failure) while it was not in the secondary analysis (intention-to-treat analysis with re-intensification equal success, ITT=Success).
Time frame: Up to week 48
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Atazanavir/Ritonavir Monotherapy | Proportion of Patients With Treatment Failure (TF) | ITT=Failure analysis | 27.5 percentage of patients |
| Atazanavir/Ritonavir Monotherapy | Proportion of Patients With Treatment Failure (TF) | ITT=Success analysis | 7.9 percentage of patients |
| Atazanavir/Ritonavir Triple Therapy | Proportion of Patients With Treatment Failure (TF) | ITT=Failure analysis | 15.4 percentage of patients |
| Atazanavir/Ritonavir Triple Therapy | Proportion of Patients With Treatment Failure (TF) | ITT=Success analysis | 15.4 percentage of patients |
Comparison: Here are reported the results of the 48-week interim analyses according to the intention-to-treat (ITT) principle. ITT=F (with re-intensification=failure) and the ITT=S (with re-intensification=success) treatment failure results are shown.~Based on the efficacy data review, in June 2013, an independent Data and Safety Monitoring Board (DSMB) recommended to stop further patients' enrolment and to follow-up the enrolled patients until 96 weeks, after having signed an updated informed consent.
Secondary
Efficacy and Safety
Proportion of pts with confirmed virological and treatment failure at w96. Change in CD4 cell counts. Occurrence of viral resistance to atazanavir in pts with confirmed virologic failure. Proportion of pts with adverse events, with ≥grade 2 adverse events or abnormal laboratory tests, proportion of pts with side effects leading to discontinuation. Body fat redistribution and vertebral and femoral bone mineral density. Adherence changes; changes in HIV-associated neurocognitive disorders. Difference in levels of activated Tcells and pro-inflammatory cytokines between treatment groups.
Time frame: week 96