HIV-1-infection
Conditions
Keywords
antiretroviral naive triple therapy. Dolutegravir-Lamivudine, dual-therapy
Brief summary
Protocol Title: DOLCE: Dolutegravir-Lamivudine for naïve HIV-Infected Patients with ≤200 CD4/mm3 Protocol Number: FH-57 Study Objectives: To assess the antiviral activity at week 48 of DTG+3TC among naïve HIV patients with a CD4 count ≤200 cells /mm3.
Detailed description
Primary endpoint: Proportion of patients with viral load \< 50 copies/mL at week 48 using the ITT-exposed analysis (FDA snapshot) for the intent-to-treat exposed (ITT-E) population. Secondary Objectives: * To assess the antiviral activity of DTG+3TC and DTG+TDF/XTC at week 24 * To evaluate the safety and tolerability of DTG+3TC and DTG+TDF/XTC over time * To assess the antiviral activity of DTG+3TC and DTG+TDF/XTC at week 48 in patients with baseline viral load \>100,000 c/mL * To evaluate immunological activity (CD4+ lymphocyte \[CD4 counts\]) at Week 24 and Week 48 * To assess the development of HIV-1 resistance in patients with virologic failure or viral rebound treated with DTG+3TC or DTG+TDF/XTC * To evaluate the incidence of disease progression (HIV-associated conditions, AIDS and death) of DTG + 3TC and DTG + TDF/XTC over time. Secondary endpoints: * Proportion of patients treated with DTG+3TC and DTG+TDF/XTC with HIV-1 levels of less than 50 copies/mL at week 24 * Frequency, type and severity of adverse events and laboratory abnormalities and proportion of patients who discontinue DTG+3TC or DTG+TDF/XTC due to adverse events or death * Proportion of patients with baseline HIV-1 RNA \>100,000 c/mL that achieve virological suppression at week 48 weeks, * Changes in CD4 count, CD8 count and CD4/CD8 ratio between baseline and 48 weeks * Number and type of resistance mutations in case of virologic failure (defined as a confirmed viral above 200 copies/mL after week 24 copies/mL or viral rebound at any timepoint) * Incidence of IRIS and disease progression (HIV associated conditions, AIDS and death). Tertiary objectives: ● TDF/XTCTo explore change in health-related quality-of-life for subjects treated with DTG plus 3TC and DTG + TDF/XTC Tertiary endpoints: ● Change from Baseline in health-related quality of life using EQ-5D-5L and PHQ9 at Weeks 24, and 48 Patient Population: HIV-1-infected subjects aged \>18 years who are naïve to antiretroviral therapy with ≤200 CD4 cell/mm3 Study Design: Prospective, Phase IV, randomized, multicenter, parallel group study design Regimens: Dolutegravir 50 mg /lamivudine 300 mg QD FDC. Dolutegravir 50 mg QD plus tenofovir 300 mg/emtricitabine 200mg or plus tenofovir 300 mg/ lamivudine 300 mg. Duration: 48 weeks Sample size:230 subjects
Interventions
DRUGIntervention Arm: dolutegravir/lamivudine
1 pill QD
DRUGComparator ARM: TDF/XTC plus Dolutegravir (XTC stand for lamivudine OR emtricitabine)
1 pill of each QD
Sponsors
ViiV Healthcare
Federal University of Bahia
Fundación Huésped
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. Subject has voluntarily signed and dated an informed consent form, approved by an Institutional Review Board (IRB) / Independent Ethics Committee (IEC), after the nature of the study has been explained and the subject has had the opportunity to ask questions. 2. Documented HIV-1 infection defined as a positive rapid test or ELISA plus a plasma HIV-1 RNA (\>1,000 copies/mL) or a positive western blot. A previous result performed on the last 30 days can be used. 3. ≥18 years of age 4. Naïve to ARV therapies (defined as ≤ 10 days of prior therapy with any antiretroviral therapy following an HIV diagnosis). Previous use of PrEP or PEP is allowed if there is documented HIV seronegativity between the last prophylactic dose and the date of HIV diagnosis. 5. HIV RNA at screening visit \> or = 1,000 copies/mL. A previous result performed on the last 30 days can be used. 6. CD4 at screening \< or = 200 cells/mL A previous result performed on the last 30 days can be used. 7. Subjects can comply with protocol requirements. 8. Subject agrees not to take any medication during the study, including over-the-counter medicines or herbal preparations, without the approval of the trial physician. 9. Subject's general medical condition, in the investigator's opinion, does not interfere with assessments and completion of the study. 10. A female may be eligible to enter and participate in the study if she is not pregnant (as confirmed by serum pregnancy test negative at screening, and a urine negative test at baseline), not lactating and at least one of the following condition applies: 1. Women with non-reproductive potential, defined as pre-menospausal females with documented tubal ligation or hysterectomy, or bilateral oophorectomy; or as post-menospausal women defined as 12 months of spontaneous amenorrhea, and ≥45 years of age in women without hormonal replacement therapy. 2. Women with reproductive potential and agrees to follow one of the contraceptive options listed in the Appendix 3 from at least 15 days prior to the first dose of medication and until at least 30 days after the last dose of study medication and completion of the follow-up visit. Any contraception method must be used consistently, in accordance with the approved product label. All subjects participating in the study should be counselled on safer sexual practices including the use of effective barrier methods and the choice of effective contraceptive method should be documented in the eCRF.
Exclusion criteria
1. Women who are pregnant or breastfeeding, or women who plan to become pregnant in the next year. 2. Subjects testing positive for Hepatitis B surface antigen (+HBsAg) at screening, or anticipated need for Hepatitis C virus (HCV) therapy with drugs with potential drug-drug interaction during the study. 3. Subjects with severe hepatic impairment (Child-Pugh class C), or unstable liver disease (ascites, encephalopathy, coagulopathy, or oesophageal or gastric varices) or cirrhosis. 4. Opportunistic infections that impede to start ART immediately (specifically tuberculosis, meningeal tuberculosis or cryptococcosis within the first month of specific treatment). Subjects with other suspected or confirmed active opportunistic infections and subjects with cryptococcal disease after the initial period can be included if she/he can follow the protocol and if her/his participation could benefit the subject. A clear documentation of these aspects must to be done in the clinical chart of the participant. 5. Subjects who in the investigator's judgment, pose a significant suicidality risk. 6. History or presence of allergy to the study drugs or their components or drugs of their class 7. Treatment with any of the following agents within 28 days of screening: radiation therapy; cytotoxic chemotherapeutic agents; any immunomodulators that alter immune responses; or treatment with an HIV-1 immunotherapeutic vaccine within 90 days of screening; or exposure to an experimental drug or experimental vaccine within either 28 days, 5 half-lives of the test agent, or twice the duration of the biological effect of the test agent, whichever is longer, prior to the first dose of investigational product. 8. Any previous evidence of resistance to dolutegravir (defined as the presence of G118R, Q148 H/K/R or R263K), to lamivudine (presence of the mutation M184V) or resistance to tenofovir (mutation K65R or more than 3 TAMs) with a Sanger sequence method or using next-generation sequencing (NGS) at a frequency \>15%. If the subject does not have a previous resistance test, samples will be taken at the screening visit and the subject can be randomized and start the study. while awaiting the results (see section 4.8). 9. Any verified Grade 4 abnormality. 10. Alanine aminotransferase (ALT) ≥ 5 times the upper limit of normal (ULN), or ALT ≥ 3xULN and bilirubin ≥ 1.5xULN (with \>35% direct bilirubin). 11. Creatinine clearance of \<50mL/min via Cockroft-Gault method.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Antiviral Activity at Week 48 of DTG+3TC Among ART-naïve HIV Patients With a CD4 Count ≤200 Cells/mm3. | Week 48 | Percentage of patients with viral load \< 50 copies/mL at week 48 using the ITT-exposed analysis (FDA snapshot) for the intent-to-treat exposed (ITT-E) population. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability of DTG+3TC and DTG+TDF/XTC Over Time | week 48 | Percentage of patients who discontinue treatment due to adverse events or death |
| Antiviral Activity of DTG+3TC and DTG+TDF/XTC at Week 48 in Patients With Baseline Viral Load >100,000 c/mL | Week 48 | Percentage of patients with baseline viral load \>100,000 c/mL that reach HIV-1 levels of less than 50 copies/mL at week 48 |
| Antiviral Activity of DTG+3TC and DTG+TDF/XTC (TDF/FTC or TDF/3TC) at Week 24 | Week 24 | Percentage of patients treated with DTG+3TC and DTG+TDF/XTC with HIV-1 levels of less than 50 copies/mL at week 24 |
| Development of HIV-1 Resistance in Patients With Virologic Failure or Viral Rebound Whilst Being Treated With DTG+3TC or DTG+TDF/XTC | week 48 | Number and type of resistance mutations in case of virologic failure (defined as a confirmed viral above 200 copies/mL on or after week 24 or confirmed viral rebound at any timepoint) |
| Incidence of IRIS or Disease Progression (HIV Associated Conditions, AIDS and Death). | week 48 | Evaluation of disease progression incidence (HIV-associated conditions, AIDS and death) with DTG+3TC and DTG + TDF/XTC treatment over time |
| Changes in Lymphocytes Subsets Between Baseline and 48 Weeks | Week 48 | Changes in lymphocytes CD4 cells count per mL |
Countries
Argentina, Brazil
Participant flow
Recruitment details
Recruitment period: May 17th, 2021 - May 04th, 2023. Sites from Argentina and Brazil.
Pre-assignment details
Eligible participants were non-pregnant, not breastfeeding adults (18 years or older) living with HIV-1, ART naïve, having plasma HIV-1 (pVL) RNA ≥1,000 copies/mL and, CD4 cll counts≤ 200 cells/mm³ at screening. Key exclusión criteria included a positive Hepatitis B coinfection, pre-existing major viral resistance mutations to DTG, 3TC, or TDF, active opportunistic infections, liver or kidney disease.
Participants by arm
| Arm | Count |
|---|---|
| Experimental : Dolutegravir Plus Lamivudine DOVATO: Dolutegravir 50mg/lamivudine 300 mg, FDC, 1 coformulated tablet QD | 153 |
| Active Comparator : TDF/XTC Plus Dolutegravir (XTC Stands for Lamivudine OR Emtricitabine) Unit Dose:
* TDF/FTC 300/200 mg, 1 coformulated tablet QD (FDC) plus Dolutegravir 50 mg, 1 tablet QD OR
* TDF/3TC 300/300 mg, 1 coformulated tablet QD (FDC) plus Dolutegravir 50 mg, 1 tablet QD | 77 |
| Total | 230 |
Baseline characteristics
| Characteristic | Experimental : Dolutegravir Plus Lamivudine | Active Comparator : TDF/XTC Plus Dolutegravir (XTC Stands for Lamivudine OR Emtricitabine) | Total |
|---|---|---|---|
| Age, Continuous | 36 years | 34 years | 35 years |
| CD4 cell count | 109 cell/mL | 128 cell/mL | 116 cell/mL |
| Race/Ethnicity, Customized Race Black | 26 Participants | 9 Participants | 35 Participants |
| Race/Ethnicity, Customized Race Native | 8 Participants | 0 Participants | 8 Participants |
| Race/Ethnicity, Customized Race Other (Hispanic- Latino/Mixed) | 67 Participants | 31 Participants | 98 Participants |
| Race/Ethnicity, Customized Race White | 52 Participants | 37 Participants | 89 Participants |
| Sex: Female, Male Female | 35 Participants | 21 Participants | 56 Participants |
| Sex: Female, Male Male | 118 Participants | 56 Participants | 174 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 152 | 2 / 77 |
| other Total, other adverse events | 37 / 152 | 21 / 77 |
| serious Total, serious adverse events | 15 / 152 | 9 / 77 |
Outcome results
Primary
Antiviral Activity at Week 48 of DTG+3TC Among ART-naïve HIV Patients With a CD4 Count ≤200 Cells/mm3.
Percentage of patients with viral load \< 50 copies/mL at week 48 using the ITT-exposed analysis (FDA snapshot) for the intent-to-treat exposed (ITT-E) population.
Time frame: Week 48
Population: One participant randomized to experimental arm was withdrawn before receiving any dose and therefore excluded from all analyses
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental : Dolutegravir Plus Lamivudine | Antiviral Activity at Week 48 of DTG+3TC Among ART-naïve HIV Patients With a CD4 Count ≤200 Cells/mm3. | 125 Participants |
| Active Comparator : TDF/XTC Plus Dolutegravir (XTC Stands for Lamivudine OR Emtricitabine) | Antiviral Activity at Week 48 of DTG+3TC Among ART-naïve HIV Patients With a CD4 Count ≤200 Cells/mm3. | 62 Participants |
Secondary
Antiviral Activity of DTG+3TC and DTG+TDF/XTC at Week 48 in Patients With Baseline Viral Load >100,000 c/mL
Percentage of patients with baseline viral load \>100,000 c/mL that reach HIV-1 levels of less than 50 copies/mL at week 48
Time frame: Week 48
Population: One participant randomized to experimental arm was withdrawn before receiving any dose and therefore excluded from all analyses
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental : Dolutegravir Plus Lamivudine | Antiviral Activity of DTG+3TC and DTG+TDF/XTC at Week 48 in Patients With Baseline Viral Load >100,000 c/mL | 76 Participants |
| Active Comparator : TDF/XTC Plus Dolutegravir (XTC Stands for Lamivudine OR Emtricitabine) | Antiviral Activity of DTG+3TC and DTG+TDF/XTC at Week 48 in Patients With Baseline Viral Load >100,000 c/mL | 36 Participants |
Secondary
Antiviral Activity of DTG+3TC and DTG+TDF/XTC (TDF/FTC or TDF/3TC) at Week 24
Percentage of patients treated with DTG+3TC and DTG+TDF/XTC with HIV-1 levels of less than 50 copies/mL at week 24
Time frame: Week 24
Population: One participant randomized to experimental arm was withdrawn before receiving any dose and therefore excluded from all analyses
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental : Dolutegravir Plus Lamivudine | Antiviral Activity of DTG+3TC and DTG+TDF/XTC (TDF/FTC or TDF/3TC) at Week 24 | 110 Participants |
| Active Comparator : TDF/XTC Plus Dolutegravir (XTC Stands for Lamivudine OR Emtricitabine) | Antiviral Activity of DTG+3TC and DTG+TDF/XTC (TDF/FTC or TDF/3TC) at Week 24 | 58 Participants |
Secondary
Changes in Lymphocytes Subsets Between Baseline and 48 Weeks
Changes in lymphocytes CD4 cells count per mL
Time frame: Week 48
Population: One participant randomized to experimental arm was withdrawn before receiving any dose and therefore excluded from all analyses
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental : Dolutegravir Plus Lamivudine | Changes in Lymphocytes Subsets Between Baseline and 48 Weeks | 200 cell/mL |
| Active Comparator : TDF/XTC Plus Dolutegravir (XTC Stands for Lamivudine OR Emtricitabine) | Changes in Lymphocytes Subsets Between Baseline and 48 Weeks | 177 cell/mL |
Secondary
Development of HIV-1 Resistance in Patients With Virologic Failure or Viral Rebound Whilst Being Treated With DTG+3TC or DTG+TDF/XTC
Number and type of resistance mutations in case of virologic failure (defined as a confirmed viral above 200 copies/mL on or after week 24 or confirmed viral rebound at any timepoint)
Time frame: week 48
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental : Dolutegravir Plus Lamivudine | Development of HIV-1 Resistance in Patients With Virologic Failure or Viral Rebound Whilst Being Treated With DTG+3TC or DTG+TDF/XTC | 0 Participants |
| Active Comparator : TDF/XTC Plus Dolutegravir (XTC Stands for Lamivudine OR Emtricitabine) | Development of HIV-1 Resistance in Patients With Virologic Failure or Viral Rebound Whilst Being Treated With DTG+3TC or DTG+TDF/XTC | 0 Participants |
Secondary
Incidence of IRIS or Disease Progression (HIV Associated Conditions, AIDS and Death).
Evaluation of disease progression incidence (HIV-associated conditions, AIDS and death) with DTG+3TC and DTG + TDF/XTC treatment over time
Time frame: week 48
Population: One participant randomized to experimental arm was withdrawn before receiving any dose and therefore excluded from all analyses.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental : Dolutegravir Plus Lamivudine | Incidence of IRIS or Disease Progression (HIV Associated Conditions, AIDS and Death). | 9 Participants |
| Active Comparator : TDF/XTC Plus Dolutegravir (XTC Stands for Lamivudine OR Emtricitabine) | Incidence of IRIS or Disease Progression (HIV Associated Conditions, AIDS and Death). | 6 Participants |
Secondary
Safety and Tolerability of DTG+3TC and DTG+TDF/XTC Over Time
Percentage of patients who discontinue treatment due to adverse events or death
Time frame: week 48
Population: One participant randomized to experimental arm was withdrawn before receiving any dose and therefore excluded from all analyses
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental : Dolutegravir Plus Lamivudine | Safety and Tolerability of DTG+3TC and DTG+TDF/XTC Over Time | 7 Participants |
| Active Comparator : TDF/XTC Plus Dolutegravir (XTC Stands for Lamivudine OR Emtricitabine) | Safety and Tolerability of DTG+3TC and DTG+TDF/XTC Over Time | 2 Participants |