HIV
Conditions
Keywords
HIV, treatment-experienced, protease inhibitor, adherence, lipids
Brief summary
Darunavir is a nonpeptidic protease inhibitor with a high genetic barrier to resistance that evolved from a prototype compound synthesized using structure-based design strategies. Once-daily darunavir at 800mg boosted with 100mg of ritonavir is an effective antiretroviral agent indicated for HIV-infected treatment-naïve patients. In treatment-experienced patients, darunavir was initially approved for twice-daily administration boosted with twice-daily ritonavir at 600mg and 100mg, respectively. Recently, once-daily darunavir/ritonavir was approved for use in treatment-experienced adult patients with viremia with no darunavir resistance mutations. In treatment-experienced patients with viral suppression, switching from an antiretroviral taken twice-daily to a once-daily dose is an attractive option to promote greater patient acceptability and adherence, and potentially minimize side effects and toxicities. Because of darunavir/ritonavir's high genetic barrier to resistance and well-established safety profile at a once-daily dose, switching patients with virologic suppression from twice-daily darunavir/ritonavir to once-daily darunavir/ritonavir will likely confer attributes more favorable to patients through a simplified dosing schedule and lower potential for lipid elevation without the loss of virologic control. DRIVESHAFT is a 48-week Phase 4, randomized, open label, comparative study. The study will be conducted in 60 HIV-1 infected, antiretroviral experienced, virologically-suppressed patients on regimens containing darunavir 600mg/ ritonavir 100mg twice-daily and a minimum of two other antiretrovirals, with a history of 0-1 darunavir-associated resistance mutations. Subjects will be randomized 1:1 to switch to darunavir 800mg/ ritonavir 100mg once-daily or continue on their current regimen. Rates of virologic suppression of once-daily darunavir/ritonavir regimens relative to darunavir/ritonavir twice-daily regimens will be compared, and safety, change from baseline fasting lipid parameters, and adherence will be evaluated.
Detailed description
The Darunavir/Ritonavir In Virologically-suppressed Experienced Subjects Halving an Antiretroviral by Finetuning Therapy (DRIVESHAFT) study was a prospective, randomized, single-centre, two-arm, open-label 48-week pilot study. The aim of DRIVESHAFT was to evaluate the safety and efficacy of switching the DRV/r component from twice-daily to once-daily 800/100 mg compared with those remaining on current therapy among HIV-1-infected, treatment-experienced patients with 0-1 DRV RAMs on a stable regimen including twice-daily DRV/r 600/100 mg. The study was conducted at The Ruth M Rothstein CORE Center (Chicago, IL, USA). The sample size was determined upon feasibility as a single-site study and not powered for non-inferiority. Study enrolment was planned for 60 participants randomized 1:1 to one of two arms: the switch arm from DRV/r 600/100 mg twice daily to DRV/r 800/100 mg once/daily plus current ARV regimen including a minimum of two other agents or remain on current ARV regimen with minimum of three agents inclusive of twice-daily DRV/r. Two DRV 400 mg tablets were used in the once-daily DRV/r arm, with DRV 600 mg tablets administered in the twice-daily DRV/r arm. DRIVESHAFT inclusion criteria included HIV-1-infected adult (\>18 years of age), HIV-1 RNA measurements \<40 copies/ml (using a local assay) over at least 12 weeks on a stable regimen including DRV/r 600/100 mg twice daily plus a minimum of two other ARVs, screening HIV-1 RNA\<40 copies/ml, have undergone genotypic testing at any time prior to starting current antiretroviral therapy (ART) with evidence of \<2 cumulative DRV RAMs, CD4+ T-cell count \>50 cells/mm3, and a negative serum pregnancy test at screening visit Participants who were randomized and received at least one dose of study medication were included in efficacy analysis, and the primary end point was the proportion of participants with HIV-1 RNA\<40 copies/ml at week 48.
Interventions
DRUGTwice-daily combination Darunavir and ritonavir
Subjects randomized 1:1 to remain on regimens containing combination Darunavir 600mg plus Ritonavir 100mg twice-daily
DRUGOnce-daily combination Darunavir and ritonavir
Subjects randomized 1:1 to switch to from combination Darunavir 600mg plus Ritonavir 100mg twice-daily at baseline to the experimental combination Darunavir 800mg plus Ritonavir 100mg once-daily for 48 weeks
Sponsors
Tibotec Therapeutics, a Division of Ortho Biotech Products, L.P., USA
Ruth M. Rothstein CORE Center
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
1. ART-experienced, HIV-1 infected subjects ≥18 years of age. 2. A female subject is eligible to enter and participate in the study if she: 1. is of non-childbearing potential defined as either post-menopausal (12 months of spontaneous amenorrhea and ≥45 years of age) or physically incapable of becoming pregnant with documented tubal ligation, hysterectomy, or bilateral oophorectomy or, 2. is of child-bearing potential, with a negative pregnancy test at both Screen and Day 1 and agrees to one of the following methods of contraception to avoid pregnancy: * Complete abstinence from intercourse from 2 weeks prior to administration of study medications, throughout the study, and for at least 2 weeks after discontinuation of all study medications. * Double barrier method (male condom/spermicide, male condom/diaphragm, diaphragm/spermicide). * Approved hormonal contraception may be administered with darunavir/ritonavir * Any intrauterine device (IUD) with published data showing that the expected failure rate is \<1% per year * Any other method with published data showing that the expected failure rate is \<1% per year. Any contraception method must be used consistently and in accordance with the approved product label. All subjects participating in the study should be counseled on safer sexual practices including the use of effective barrier methods (e.g. male condom/spermicide). 3. CD4 \>50 cells/mm3 4. HIV-1 RNA concentrations at undetectable levels (according to local assay being used) for at least 12 weeks on stable current regimen 5. Current regimen includes darunavir/ritonavir 600/100 mg twice-daily plus a minimum of two other antiretrovirals 6. Negative serum pregnancy test at screening visit
Exclusion criteria
Subjects meeting any of the following criteria must not be enrolled in the study: 1. Known hypersensitivity reaction to agents being utilized in the study 2. \>1 cumulative darunavir associated mutations (V11I, V32I, L33F, I47V, I50V, I54L or M, T74P, L76V, I84V, or L89V) detected from any previous genotype or a VircoTYPE HIV-1 darunavir fold-change \>10.0 on any previous virtual phenotype 3. Pregnant or breast feeding woman 4. Liver dysfunction with Child-Pugh class C disease or decompensated cirrhosis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary Efficacy Endpoint for Virologic Suppression in HIV-infected Subjects | 48 weeks after randomization to study medication | Proportion of subjects with plasma HIV-1 RNA \<40 c/mL at Week 48 using a Missing, Switch, or Discontinuation = Failure (MSDF) algorithm as codified by the FDA's snapshot algorithm |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Secondary Efficacy Endpoints | Within 24 weeks after randomization to study medication | •Proportion of subjects with plasma HIV-1 RNA \>200 c/mL at Week 24 |
| Change in Total Cholesterol From Baseline to 48 Weeks | Within 48 weeks of randomization baseline to study medications | Absolute change in lipid parameter (total cholesterol mg/dl) of once-daily versus twice-daily darunavir/ritonavir containing regimens over 48 weeks |
| Absolute Value Change in CD4+ From Baseline to Week 48 | 48 weeks after randomization baseline to study medications | Absolute value increase in CD4+ cells/mm3 from baseline to week 48 |
| Assessment of Virologic Failure | Within 48 weeks of randomization to study medications | •Assess the development of viral resistance in subjects experiencing virological failure |
| Number of Participants With Greater Than 95% Adherence at 48 Weeks | Within 48 weeks of randomization to study medications | Characterize adherence to once-daily versus twice-daily darunavir/ritonavir containing regimens using the Modified Medication Adherence Self-Report Inventory (M-MASRI) scale |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Once-daily Darunavir/Ritonavir Subjects switched from Darunavir 600mg plus Ritonavir 100mg twice-daily to Darunavir 800mg plus Ritonavir 100mg once-daily
Once-daily Darunavir/ritonavir: Subjects switched from Darunavir 600mg plus Ritonavir 100mg twice-daily at baseline to Darunavir 800mg plus Ritonavir 100mg once-daily for 48 weeks | 30 |
| Twice-daily Darunavir/Ritonavir Subjects remain on regimens containing Darunavir 600mg plus Ritonavir 100mg twice-daily
Twice-daily Darunavir/ritonavir: Subjects remain on regimens containing Darunavir 600mg plus Ritonavir 100mg twice-daily | 30 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Twice-daily Darunavir/Ritonavir | Once-daily Darunavir/Ritonavir | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 29 Participants | 30 Participants | 59 Participants |
| Age, Continuous | 49 years | 48 years | 48 years |
| Region of Enrollment United States | 30 participants | 30 participants | 60 participants |
| Sex: Female, Male Female | 5 Participants | 6 Participants | 11 Participants |
| Sex: Female, Male Male | 25 Participants | 24 Participants | 49 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 30 | 0 / 30 |
| serious Total, serious adverse events | 0 / 30 | 0 / 30 |
Outcome results
Primary
Primary Efficacy Endpoint for Virologic Suppression in HIV-infected Subjects
Proportion of subjects with plasma HIV-1 RNA \<40 c/mL at Week 48 using a Missing, Switch, or Discontinuation = Failure (MSDF) algorithm as codified by the FDA's snapshot algorithm
Time frame: 48 weeks after randomization to study medication
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Once-daily Darunavir/Ritonavir | Primary Efficacy Endpoint for Virologic Suppression in HIV-infected Subjects | 27 participants |
| Twice-daily Darunavir/Ritonavir | Primary Efficacy Endpoint for Virologic Suppression in HIV-infected Subjects | 25 participants |
Secondary
Absolute Value Change in CD4+ From Baseline to Week 48
Absolute value increase in CD4+ cells/mm3 from baseline to week 48
Time frame: 48 weeks after randomization baseline to study medications
Population: Population for outcome of subjects measuring absolute change in CD4+ at week 48
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Once-daily Darunavir/Ritonavir | Absolute Value Change in CD4+ From Baseline to Week 48 | 19 cells/mm3 | Standard Error 0.592 |
| Twice-daily Darunavir/Ritonavir | Absolute Value Change in CD4+ From Baseline to Week 48 | 39 cells/mm3 | Standard Error 0.592 |
p-value: <0.05t-test, 2 sided
Secondary
Assessment of Virologic Failure
•Assess the development of viral resistance in subjects experiencing virological failure
Time frame: Within 48 weeks of randomization to study medications
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Once-daily Darunavir/Ritonavir | Assessment of Virologic Failure | 0 participants with resistance for failure |
| Twice-daily Darunavir/Ritonavir | Assessment of Virologic Failure | 0 participants with resistance for failure |
Secondary
Change in Total Cholesterol From Baseline to 48 Weeks
Absolute change in lipid parameter (total cholesterol mg/dl) of once-daily versus twice-daily darunavir/ritonavir containing regimens over 48 weeks
Time frame: Within 48 weeks of randomization baseline to study medications
Population: Mean within person change in total cholesterol mg/dl from baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Once-daily Darunavir/Ritonavir | Change in Total Cholesterol From Baseline to 48 Weeks | -14.2 mg/dl | Standard Error 0.148 |
| Twice-daily Darunavir/Ritonavir | Change in Total Cholesterol From Baseline to 48 Weeks | -3.8 mg/dl | Standard Error 0.148 |
Comparison: p valuep-value: <0.05t-test, 2 sided
Secondary
Number of Participants With Greater Than 95% Adherence at 48 Weeks
Characterize adherence to once-daily versus twice-daily darunavir/ritonavir containing regimens using the Modified Medication Adherence Self-Report Inventory (M-MASRI) scale
Time frame: Within 48 weeks of randomization to study medications
Population: Percentage of \>95% adherence at week 48
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Once-daily Darunavir/Ritonavir | Number of Participants With Greater Than 95% Adherence at 48 Weeks | 22 Participants |
| Twice-daily Darunavir/Ritonavir | Number of Participants With Greater Than 95% Adherence at 48 Weeks | 20 Participants |
Secondary
Secondary Efficacy Endpoints
•Proportion of subjects with plasma HIV-1 RNA \>200 c/mL at Week 24
Time frame: Within 24 weeks after randomization to study medication
Population: Population for outcome of subjects with plasma HIV-1 RNA \>200 copies/ML at week 24
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Once-daily Darunavir/Ritonavir | Secondary Efficacy Endpoints | 0 Participants |
| Twice-daily Darunavir/Ritonavir | Secondary Efficacy Endpoints | 0 Participants |
Secondary
Secondary Efficacy Endpoints
•Proportion of subjects with plasma HIV-1 RNA \<40 c/mL at Week 24
Time frame: week 24
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Once-daily Darunavir/Ritonavir | Secondary Efficacy Endpoints | 29 Participants |
| Twice-daily Darunavir/Ritonavir | Secondary Efficacy Endpoints | 25 Participants |