HIV Infections
Conditions
Keywords
second line antiretroviral therapy, dolutegravir
Brief summary
The strategy to support virological suppression on second-line antiretroviral treatment (ART) includes the provision of ART that has a low pill burden, good tolerability, low toxicity, is easily monitored, has a high barrier to resistance, and that is low cost. The fixed-dose combination of tenofovir-lamivudine-dolutegravir offers significant advantage as a potential second-line regimen compared to the World Health Organization standard of care second-line regimen of zidovudine-lamivudine-dolutegravir, in terms of cost, tolerability and monitoring requirements. The ARTIST study is a phase 2, randomised, double-blind, placebo-controlled trial aiming to determine the proportion of patients achieving virological suppression when recycling the tenofovir-emtricitabine/lamivudine backbone with dolutegravir (tenofovir-lamivudine-dolutegravir fixed-dose combination) as a second-line with and without a lead-in supplementary dose of dolutegravir, in patients failing a tenofovir-emtricitabine/lamivudine-efavirenz first-line regimen. There is evidence to suggest that even in the presence of resistance mutations to tenofovir and lamivudine (K65R or M184V/I), using this backbone with dolutegravir will provide an effective second-line regimen in patients who have failed a first-line regimen of tenofovir-emtricitabine/lamivudine-efavirenz. The strategy of giving a lead-in supplementary dose of dolutegravir is in view of the inducing effect of efavirenz on dolutegravir metabolism and transport that persists for 2 weeks after efavirenz is stopped; the inducing effect decreases with time after efavirenz is stopped. Given that these patients will have elevated viral loads, a high baseline risk of nucleoside reverse transcriptase inhibitor (NRTI) resistance and efavirenz resistance, and the inducing effect of efavirenz on dolutegravir metabolism and transport that persists for 2 weeks, this study will comprise two stages. The first stage will evaluate virological suppression in 62 participants initiated on the fixed-dose combination of tenofovir-lamivudine-dolutegravir with a lead-in supplementary dose of dolutegravir for the first 14 days. The study will progress to the second stage if this strategy proves effective, and 130 participants will then be randomised to receive the fixed-dose combination of tenofovir-lamivudine-dolutegravir with and without this lead-in dose. The primary endpoint is virological suppression (viral load \<50 copies/mL) at 24 weeks. A pharmacokinetic sub-study will be conducted on 12 participants in stage 1 and 24 participants in stage 2, to assess the trough concentrations of dolutegravir and off-treatment concentrations of efavirenz at day 3, 7, 14, and 28. This is to evaluate the need for the lead-in supplementary dose of dolutegravir.
Interventions
Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet with a lead-in supplementary dose of 50 mg dolutegravir taken 12 hours later for the first 14 days, with continuation of tenofovir-lamivudine-dolutegravir for the duration of the study (48 weeks).
DRUGPlacebo
Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet with a matching placebo taken 12 hours later for the first 14 days, with continuation of tenofovir-lamivudine-dolutegravir for the duration of the study (48 weeks).
Sponsors
Wellcome Trust
Médecins Sans Frontières, Belgium
University of Cape Town
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
This study will be a phase 2, randomised, double-blind, placebo-controlled trial of tenofovir-lamivudine-dolutegravir fixed-dose combination daily with a lead-in supplementary 50 mg dose of dolutegravir versus matching placebo taken 12 hours later for the first 14 days in patients failing a first-line tenofovir-emtricitabine/lamivudine-efavirenz regimen.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
HIV positive patients over 18 years old, who have failed first-line ART regimen of tenofovir-emtricitabine/lamivudine-efavirenz, are able to attend the study clinic for one year of scheduled visits and who have given written, informed consent will be enrolled in this study. In female patients of child-bearing potential, those willing to use effective and reliable contraception for the duration of the study will be eligible. Failure of a first-line regimen is defined as a viral load (VL) of \>1000 copies/mL (within the previous two months) and an immediately prior VL \>1000 copies/mL, taken 2-24 months prior (based on data captured by National Health Laboratory Service).
Exclusion criteria
* If the patient has two VLs 2-3 months apart: \>2 log drop in VLs between the most recent VL (within the previous two months) and the immediately prior VL (taken 2-3 months prior) * CD4 count \<100 cells/microlitre * Estimated glomerular filtration rate (eGFR) \<50 mL/min/1.73 m2 using the Modification of Diet in Renal Disease (MDRD) formula * Alanine aminotransferase \>100 U/L or total bilirubin \>twice the upper limit of normal * Pregnant or desire to become pregnant during the study period (48 weeks) * Breastfeeding * Being treated for active tuberculosis (TB) or concern that patient has undiagnosed active TB (based on symptom screening) as rifampicin reduces the concentrations of dolutegravir and thus requires dose adjustments * Any current diagnosis of malignancy * Allergy or intolerance to one of the drugs in regimen * Active, severe psychiatric disease judged likely to impact adherence * Current substance abuse judged likely to impact adherence * On treatment for AIDS-defining condition (not including secondary prophylaxis maintenance therapy) * Any other clinical condition that in the opinion of an investigator puts the patient at increased risk if participating in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Virological Suppression at 24 Weeks | 24 weeks | Proportion of participants with HIV viral load \<50 copies/mL at 24 weeks analysed by modified intention to treat (ITT) and according to the FDA snapshot algorithm |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Virological Suppression at 12 Weeks (Modified ITT) | 12 weeks | Proportion of participants with HIV viral load \<50 copies/mL at 12 weeks analysed by modified ITT. |
| Antiretroviral Resistance Mutations by Genotypic Resistance Testing | 24 weeks | To describe dolutegravir resistance or emergent resistance mutations to tenofovir or lamivudine in participants eligible for genotypic resistance testing by 24 weeks |
| CD4 Change at 24 Weeks | 24 weeks | Change in CD4 count from screening to week 24 |
| Virological Suppression at 24 Weeks (Sensitivity Analysis) | 24 weeks | Proportion of participants with HIV viral load \<50 copies/mL at 24 weeks using pre-specified sensitivity analyses |
| All-cause Mortality | 24 weeks | To describe all-cause mortality. |
| Adherence to Treatment | 24 weeks | To describe tenofovir-diphosphate (TFV-DP) concentrations (ng/mL) at 24 weeks |
| Geometric Mean Ratio (GMR) of Dolutegravir Trough Concentrations on Day 7 Versus Day 28 | First 28 days | To evaluate the geometric mean ratio (GMR) of dolutegravir trough concentrations on day 7 versus day 28 |
| Adverse Events | 24 weeks | To describe grade 3 or 4 adverse events and serious adverse events |
Countries
South Africa
Participant flow
Pre-assignment details
Stage 1 of the ARTIST study was a single-arm prospective cohort study of second-line TLD regimen with supplementary dolutegravir dose (50 mg twice daily) for two weeks in patients failing a NNRTI-based regimen. After completion of stage 1, the study progressed to enrol 130 participants in stage 2.
Participants by arm
| Arm | Count |
|---|---|
| Stage 2: Supplementary Dose Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet daily with an additional dolutegravir 50 mg dose taken 12 hours later for the first 14 days.
Dolutegravir 50 mg: Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet with a lead-in supplementary dose of 50 mg dolutegravir taken 12 hours later for the first 14 days, with continuation of tenofovir-lamivudine-dolutegravir for the duration of the study (48 weeks). | 65 |
| Stage 2: Placebo Dose Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet daily with a matching placebo taken 12 hours later for the first 14 days.
Placebo: Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet with a matching placebo taken 12 hours later for the first 14 days, with continuation of tenofovir-lamivudine-dolutegravir for the duration of the study (48 weeks). | 65 |
| Stage 1: TLD Regimen With Supplementary Dolutegravir Dose Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet daily with an additional dolutegravir 50 mg dose taken 12 hours later for the first 14 days.
Dolutegravir 50 mg: Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet with a lead-in supplementary dose of 50 mg dolutegravir taken 12 hours later for the first 14 days, with continuation of tenofovir-lamivudine-dolutegravir for the duration of the study (48 weeks). | 62 |
| Total | 192 |
Baseline characteristics
| Characteristic | Total | Stage 1: TLD Regimen With Supplementary Dolutegravir Dose | Stage 2: Placebo Dose | Stage 2: Supplementary Dose |
|---|---|---|---|---|
| Age, Continuous | 38 years | 37 years | 39 years | 38 years |
| BMI | 29.0 kg/m2 | 27.8 kg/m2 | 30.1 kg/m2 | 28.4 kg/m2 |
| CD4 cell count | 246 cells/μL | 259 cells/μL | 250 cells/μL | 246 cells/μL |
| HIV-1 RNA | 4.02 log10 copies/mL | 3.98 log10 copies/mL | 4.01 log10 copies/mL | 4.12 log10 copies/mL |
| Race/Ethnicity, Customized Black | 192 Participants | 62 Participants | 65 Participants | 65 Participants |
| Resistance to 1 NRTI | 39 Participants | 14 Participants | 10 Participants | 15 Participants |
| Resistance to both NRTIs | 127 Participants | 36 Participants | 45 Participants | 46 Participants |
| Sex: Female, Male Female | 132 Participants | 43 Participants | 47 Participants | 42 Participants |
| Sex: Female, Male Male | 60 Participants | 19 Participants | 18 Participants | 23 Participants |
| TFV-DP concentration | 960 fmol/punch | 1186 fmol/punch | 1052 fmol/punch | 948 fmol/punch |
| Time receiving first-line ART | 88 months | 62 months | 93 months | 77 months |
| Two fully active NRTIs | 10 Participants | 6 Participants | 2 Participants | 2 Participants |
| Weight | 77 kg | 71 kg | 80 kg | 74 kg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 65 | 0 / 65 | 0 / 62 |
| other Total, other adverse events | 2 / 65 | 5 / 65 | 3 / 62 |
| serious Total, serious adverse events | 2 / 65 | 0 / 65 | 9 / 62 |
Outcome results
Primary
Virological Suppression at 24 Weeks
Proportion of participants with HIV viral load \<50 copies/mL at 24 weeks analysed by modified intention to treat (ITT) and according to the FDA snapshot algorithm
Time frame: 24 weeks
Population: mITT analysis excludes those switching study drug for reasons of stopping contraception or desire to become pregnant, becoming pregnant, transfer out for nonclinical reasons, and death from non-HIV and nondrug causes.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stage 2: Supplementary Dose | Virological Suppression at 24 Weeks | 55 Participants |
| Stage 2: Placebo Dose | Virological Suppression at 24 Weeks | 53 Participants |
| Stage 1: TLD Regimen With Supplementary Dolutegravir Dose | Virological Suppression at 24 Weeks | 53 Participants |
Secondary
Adherence to Treatment
To describe tenofovir-diphosphate (TFV-DP) concentrations (ng/mL) at 24 weeks
Time frame: 24 weeks
Population: We monitored adherence with tenofovir diphosphate (TFV-DP) concentrations using stored dried blood spot specimens.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 2: Supplementary Dose | Adherence to Treatment | 1354 fmol/punch |
| Stage 2: Placebo Dose | Adherence to Treatment | 1393 fmol/punch |
| Stage 1: TLD Regimen With Supplementary Dolutegravir Dose | Adherence to Treatment | 1186 fmol/punch |
Secondary
Adverse Events
To describe grade 3 or 4 adverse events and serious adverse events
Time frame: 24 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stage 2: Supplementary Dose | Adverse Events | 4 Participants |
| Stage 2: Placebo Dose | Adverse Events | 5 Participants |
| Stage 1: TLD Regimen With Supplementary Dolutegravir Dose | Adverse Events | 12 Participants |
Secondary
All-cause Mortality
To describe all-cause mortality.
Time frame: 24 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stage 2: Supplementary Dose | All-cause Mortality | 1 Participants |
| Stage 2: Placebo Dose | All-cause Mortality | 0 Participants |
| Stage 1: TLD Regimen With Supplementary Dolutegravir Dose | All-cause Mortality | 0 Participants |
Secondary
Antiretroviral Resistance Mutations by Genotypic Resistance Testing
To describe dolutegravir resistance or emergent resistance mutations to tenofovir or lamivudine in participants eligible for genotypic resistance testing by 24 weeks
Time frame: 24 weeks
Population: If any HIV-1 RNA after week 12 was ≥50 copies/mL, or if there was \<1 log10 decline in HIV-1 RNA from baseline, or if HIV-1 RNA was suppressed and sub- sequently rebound to ≥50 copies/mL, enhanced adherence counseling was performed, and HIV-1 RNA measurement was repeated after 2 weeks. If the repeat HIV-1 RNA was ≥500 copies/mL, a genotypic antiretroviral resistance test was performed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stage 2: Supplementary Dose | Antiretroviral Resistance Mutations by Genotypic Resistance Testing | 0 Participants |
| Stage 2: Placebo Dose | Antiretroviral Resistance Mutations by Genotypic Resistance Testing | 0 Participants |
| Stage 1: TLD Regimen With Supplementary Dolutegravir Dose | Antiretroviral Resistance Mutations by Genotypic Resistance Testing | 0 Participants |
Secondary
CD4 Change at 24 Weeks
Change in CD4 count from screening to week 24
Time frame: 24 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 2: Supplementary Dose | CD4 Change at 24 Weeks | 88 cells/μL |
| Stage 2: Placebo Dose | CD4 Change at 24 Weeks | 75 cells/μL |
| Stage 1: TLD Regimen With Supplementary Dolutegravir Dose | CD4 Change at 24 Weeks | 99 cells/μL |
Secondary
Geometric Mean Ratio (GMR) of Dolutegravir Trough Concentrations on Day 7 Versus Day 28
To evaluate the geometric mean ratio (GMR) of dolutegravir trough concentrations on day 7 versus day 28
Time frame: First 28 days
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Stage 2: Supplementary Dose | Geometric Mean Ratio (GMR) of Dolutegravir Trough Concentrations on Day 7 Versus Day 28 | 1.654 ratio |
| Stage 2: Placebo Dose | Geometric Mean Ratio (GMR) of Dolutegravir Trough Concentrations on Day 7 Versus Day 28 | 0.637 ratio |
| Stage 1: TLD Regimen With Supplementary Dolutegravir Dose | Geometric Mean Ratio (GMR) of Dolutegravir Trough Concentrations on Day 7 Versus Day 28 | 1.654 ratio |
Secondary
Virological Suppression at 12 Weeks (Modified ITT)
Proportion of participants with HIV viral load \<50 copies/mL at 12 weeks analysed by modified ITT.
Time frame: 12 weeks
Population: mITT analysis excludes those switching study drug for reasons of stopping contraception or desire to become pregnant, becoming pregnant, transfer out for nonclinical reasons, and death from non-HIV and nondrug causes.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stage 2: Supplementary Dose | Virological Suppression at 12 Weeks (Modified ITT) | 53 Participants |
| Stage 2: Placebo Dose | Virological Suppression at 12 Weeks (Modified ITT) | 55 Participants |
| Stage 1: TLD Regimen With Supplementary Dolutegravir Dose | Virological Suppression at 12 Weeks (Modified ITT) | 45 Participants |
Secondary
Virological Suppression at 24 Weeks (Sensitivity Analysis)
Proportion of participants with HIV viral load \<50 copies/mL at 24 weeks using pre-specified sensitivity analyses
Time frame: 24 weeks
Population: Sensitivity analysis excludes those excluded from mITT analysis, as well as loss to follow-up, missing viral load within the window, switching study drug for reasons other than treatment failure, and evidence of poor adherence (tenofovir diphosphate \<350 fmol/punch).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stage 2: Supplementary Dose | Virological Suppression at 24 Weeks (Sensitivity Analysis) | 55 Participants |
| Stage 2: Placebo Dose | Virological Suppression at 24 Weeks (Sensitivity Analysis) | 53 Participants |
| Stage 1: TLD Regimen With Supplementary Dolutegravir Dose | Virological Suppression at 24 Weeks (Sensitivity Analysis) | 53 Participants |