HIV Infections
Conditions
Brief summary
The purpose of this study is to determine if pregnancy-limited, short-term combination HIV treatment regimens -- which were used solely for the prevention of mother to child transmission of HIV and discontinued postpartum -- decreases the effectiveness of a standard initial regimen of anti-HIV drugs when subsequent treatment is needed.
Detailed description
Stopping and restarting highly active antiretroviral therapy (HAART) is not generally recommended because it has the potential to allow drug-resistant HIV to emerge. However, to prevent mother-to-child transmission (MTCT), HIV infected women who are pregnant are temporarily put on HAART, even if HIV treatment is not indicated at the time. It is unknown if such short-term therapy affects the viral response to HAART later, when permanent therapy is clinically indicated. The purpose of this study is to determine if HAART taken to prevent MTCT during pregnancy has an effect on the ability of a standard initial regimen of HAART to suppress HIV viral load.\> \>\> \> \>\> Study follow-up will last for 48 weeks per participant. Participants will take a daily regimen of efavirenz and emtricitabine/tenofovir disoproxil fumarate. There will be 8 clinical visits in this study; visits will occur at baseline and at Weeks 2, 4, 8, 16, 24, 36, and 48. At each visit, a physical exam, blood and urine collection, and pregnancy tests will occur. At some visits, adherence, quality-of-life, and birth control interviews will be completed.\> \>\> \> \>\> Enrollment in this study will last until 47 participants have joined or until December 31, 2009, whichever comes later.
Interventions
DRUGEfavirenz
600-mg tablet taken orally daily
DRUGEmtricitabine/Tenofovir disoproxil fumarate
200-mg emtricitabine/300-mg tenofovir disoproxil fumarate tablet taken orally once daily
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* HIV-1 infected * Viral load of 500 copies/mL or more * Prior HAART for more than 7 days, but less than 40 weeks during at least one previous pregnancy for prevention of MTCT of HIV * Clinical or laboratory indication to start HAART, in the opinion of the participant's physician * Certain laboratory values * Willingness to use acceptable forms of contraception * Parent or guardian willing to provide informed consent, if applicable
Exclusion criteria
* Taking any antiretroviral medication within 24 weeks prior to study entry * Evidence of certain HIV-1 RT mutations within 90 days prior to study entry (version 1.0) * Evidence of certain HIV-1 RT mutations identified by standard bulk viral population genotypic resistance tests at any time prior to study entry, if available (version 2.0, 09/03/2009) * Treatment at any time, for any reason with nevirapine as a single agent OR addition of any part of the study regimen as a single agent to a failing regimen * Use of certain antihistamines, certain anti-infectives, cisapride, St John's wort, midazolam, triazolam, dihydroergotamine, ergonovine, ergotamine, or methylergonovine within 14 days prior to study entry * Use of HIV vaccine, chronic systemic corticosteroids, interleukins, interferons, other cytokines, or investigational therapy within 30 days prior to study entry * Acute or chronic therapy for certain serious medical illnesses within 14 days of study entry. Participants who have completed 7 days of therapy and are judged clinically stable are not excluded. * Cancer requiring systemic chemotherapy * Known allergy/sensitivity to the study drugs or their formulations * Current drug or alcohol use that, in the opinion of the investigator, would interfere with the study * Two consecutive HIV viral loads of more than 5,000 copies/mL 8 weeks or more following initiation of HAART during pregnancy and while still receiving HAART * Two consecutive viral loads of more than 400 copies/mL 24 weeks or more following initiation of HAART during pregnancy while still receiving HAART * Current imprisonment or involuntary incarceration in a medical facility for psychiatric or physical illness * Pregnancy or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Early Virologic Response | At Week 24 | Plasma HIV-1 Viral Load Fewer Than 400 Copies/ml |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Early Virologic Suppression | At Weeks 24 | Plasma HIV-1 Viral Load Fewer Than 50 Copies/ml |
| Percentage of Participants With Late Virologic Response | At Week 48 | Plasma HIV-1 Viral Load Fewer Than 400 Copies/ml |
| Time to Initial Virologic Response | Throughout study | Time from enrollment to scheduled week of first plasma HIV-1 RNA viral load fewer than 400 copies/mL. |
| Time to Initial Virological Failure | Throughout study | Virologic failure defined as two consecutive measurements of plasma HIV-1 RNA at least 400 copies/mL at or after the week 16 study visit. Time measured from enrollment. |
| Time to First Safety Event | Throughout study | Time from starting study treatment to first grade 3 or 4 sign/symptom or laboratory abnormality and at least one grade higher than baseline. Grading used the Division of AIDS (DAIDS) 2004 Severity of Adverse Events Tables. |
| Early Changes in CD4 Count From Baseline | At weeks 0(baseline), 4, 8, 16, 24 | Changes in CD4+ lymphocyte counts between study visit weeks 4, 8 16 and 24 and baseline. |
| Percentage of Participants With Late Virologic Suppression | At Week 48 | Plasma HIV-1 Viral Load Fewer Than 50 Copies/ml |
| Time to First Dose Modification | Throughout study | Time from starting study treatment to first dose/drug modification. |
| Late Change in CD4 Count From Baseline | At week 48 | Change in CD4+ lymphocyte counts between week 48 study visit and baseline. |
| Time to Loss of Virologic Response by Week 48 (Defined by FDA TLOVR Algorithm) | Throughout study | — |
Countries
Brazil, Peru, United States
Participant flow
Recruitment details
Study participants were recruited at 8 sites from 3 countries: 6 in the US, 1 in Brazil, 1 in Peru, between May 2007 to December 2009.
Pre-assignment details
HIV-infected women, at least 16 years of age, whose only prior exposure to anti-retrovirals (ARVs) was for the purpose of prevention of mother-to-child transmission, who now qualify to start ARVs for their own health.
Participants by arm
| Arm | Count |
|---|---|
| EFV + FTC/TDF Participants will take a daily regimen of efavirenz and emtricitabine/tenofovir disoproxil fumarate for 48 weeks | 54 |
| Total | 54 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 7 |
| Overall Study | Pregnancy | 1 |
Baseline characteristics
| Characteristic | EFV + FTC/TDF |
|---|---|
| Age, Continuous | 29 years STANDARD_DEVIATION 7 |
| Age, Customized Between 19 and 25 years | 19 participants |
| Age, Customized Between 26 and 30 years | 16 participants |
| Age, Customized Between 31 and 35 years | 9 participants |
| Age, Customized Between 36 and 40 years | 6 participants |
| Age, Customized Between 40 and 45 years | 4 participants |
| CD4 count, Categorical 400 or more cells/mm^3 | 5 participants |
| CD4 count, Categorical < 50 cells/mm^3 | 1 participants |
| CD4 count, Categorical Between 100 and 199 cells/mm^3 | 15 participants |
| CD4 count, Categorical Between 200 and 299 cells/mm^3 | 18 participants |
| CD4 count, Categorical Between 300 and 399 cells/mm^3 | 15 participants |
| CD4 count, Categorical Between 50 and 99 cells/mm^3 | 0 participants |
| CD4 count, Continuous | 264 cells/mm^3 STANDARD_DEVIATION 104 |
| Plasma HIV-1 RNA, Categorical <= 400 copies/mL | 0 participants |
| Plasma HIV-1 RNA, Categorical Between 10,001 and 50,000 copies/mL | 20 participants |
| Plasma HIV-1 RNA, Categorical Between 1001 and 10,000 copies/mL | 8 participants |
| Plasma HIV-1 RNA, Categorical Between 401 and 1000 copies/mL | 1 participants |
| Plasma HIV-1 RNA, Categorical Between 50,001 and 75,000 copies/mL | 11 participants |
| Plasma HIV-1 RNA, Categorical Between 75,001 and 250,000 copies/mL | 12 participants |
| Plasma HIV-1 RNA, Categorical More than 250,000 copies/mL | 2 participants |
| Plasma HIV-1 RNA, Continuous | 4.5 log10 copies/mL STANDARD_DEVIATION 0.6 |
| Region of Enrollment Brazil | 22 participants |
| Region of Enrollment Peru | 20 participants |
| Region of Enrollment United States | 12 participants |
| Sex: Female, Male Female | 54 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 41 / 54 |
| serious Total, serious adverse events | 1 / 54 |
Outcome results
Primary
Percentage of Participants With Early Virologic Response
Plasma HIV-1 Viral Load Fewer Than 400 Copies/ml
Time frame: At Week 24
Population: Intention to treat (ignoring current study treatment status or history); closest measurement to week 24 used; missing measurements ignored. Exact binomial confidence interval calculated using method of Blyth-Still-Casella.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EFV + FTC/TDF | Percentage of Participants With Early Virologic Response | 80.8 percentage of participants |
Secondary
Early Changes in CD4 Count From Baseline
Changes in CD4+ lymphocyte counts between study visit weeks 4, 8 16 and 24 and baseline.
Time frame: At weeks 0(baseline), 4, 8, 16, 24
Population: Intent to treat (study treatment status and history ignored); missing measurements ignored.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| EFV + FTC/TDF | Early Changes in CD4 Count From Baseline | Change from baseline to week 4 | 105 cells/mm^3 | Standard Deviation 108 |
| EFV + FTC/TDF | Early Changes in CD4 Count From Baseline | Change from baseline to week 8 | 118 cells/mm^3 | Standard Deviation 87 |
| EFV + FTC/TDF | Early Changes in CD4 Count From Baseline | Change from baseline to week 16 | 138 cells/mm^3 | Standard Deviation 112 |
| EFV + FTC/TDF | Early Changes in CD4 Count From Baseline | Change from baseline to week 24 | 147 cells/mm^3 | Standard Deviation 147 |
Secondary
Late Change in CD4 Count From Baseline
Change in CD4+ lymphocyte counts between week 48 study visit and baseline.
Time frame: At week 48
Population: Participants with a CD4+ lymphocyte cell count result from the week 48 study visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EFV + FTC/TDF | Late Change in CD4 Count From Baseline | 194 cells/mm^3 | Standard Deviation 185 |
Secondary
Percentage of Participants With Early Virologic Suppression
Plasma HIV-1 Viral Load Fewer Than 50 Copies/ml
Time frame: At Weeks 24
Population: ITT (ignoring current study treatment status and history); missing values ignored and closest value to week 24 used if multiple results available. 2 fewer results available compared to primary outcome b/c testing by ultrasensitive assay may have been retrospective.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EFV + FTC/TDF | Percentage of Participants With Early Virologic Suppression | 72.0 percentage of participants |
Secondary
Percentage of Participants With Late Virologic Response
Plasma HIV-1 Viral Load Fewer Than 400 Copies/ml
Time frame: At Week 48
Population: Participants with plasma HIV-1 RNA viral load result available from week 48 study visit.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EFV + FTC/TDF | Percentage of Participants With Late Virologic Response | 80.43 percentage |
Secondary
Percentage of Participants With Late Virologic Suppression
Plasma HIV-1 Viral Load Fewer Than 50 Copies/ml
Time frame: At Week 48
Population: Participants with ultra-sensitive (detectable to 50 copies/mL) plasma HIV-1 RNA result available from week 48 visit.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EFV + FTC/TDF | Percentage of Participants With Late Virologic Suppression | 70.5 percentage |
Secondary
Time to First Dose Modification
Time from starting study treatment to first dose/drug modification.
Time frame: Throughout study
Population: All enrolled participants who started study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| EFV + FTC/TDF | Time to First Dose Modification | 10th percentile | 1.9 weeks |
| EFV + FTC/TDF | Time to First Dose Modification | 15th percentile | 24.9 weeks |
| EFV + FTC/TDF | Time to First Dose Modification | 20th percentile | 25.7 weeks |
Secondary
Time to First Safety Event
Time from starting study treatment to first grade 3 or 4 sign/symptom or laboratory abnormality and at least one grade higher than baseline. Grading used the Division of AIDS (DAIDS) 2004 Severity of Adverse Events Tables.
Time frame: Throughout study
Population: All enrolled participants who started study treatment (which in this case, matches the number of participants enrolled.)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| EFV + FTC/TDF | Time to First Safety Event | 5th percentile | 4.1 weeks |
| EFV + FTC/TDF | Time to First Safety Event | 10th percentile | 24.4 weeks |
| EFV + FTC/TDF | Time to First Safety Event | 15th percentile | 33.1 weeks |
Secondary
Time to Initial Virological Failure
Virologic failure defined as two consecutive measurements of plasma HIV-1 RNA at least 400 copies/mL at or after the week 16 study visit. Time measured from enrollment.
Time frame: Throughout study
Population: All participants enrolled are included.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| EFV + FTC/TDF | Time to Initial Virological Failure | 5th percentile | 16 weeks |
| EFV + FTC/TDF | Time to Initial Virological Failure | 10th percentile | 16 weeks |
| EFV + FTC/TDF | Time to Initial Virological Failure | 15th percentile | 24 weeks |
Secondary
Time to Initial Virologic Response
Time from enrollment to scheduled week of first plasma HIV-1 RNA viral load fewer than 400 copies/mL.
Time frame: Throughout study
Population: All enrolled participants included.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| EFV + FTC/TDF | Time to Initial Virologic Response | 50th percentile | 2 weeks |
| EFV + FTC/TDF | Time to Initial Virologic Response | 75th percentile | 8 weeks |
| EFV + FTC/TDF | Time to Initial Virologic Response | 95th percentile | 24 weeks |
Secondary
Time to Loss of Virologic Response by Week 48 (Defined by FDA TLOVR Algorithm)
Time frame: Throughout study
Population: All enrolled participants included.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| EFV + FTC/TDF | Time to Loss of Virologic Response by Week 48 (Defined by FDA TLOVR Algorithm) | 10th percentile | 16 weeks |
| EFV + FTC/TDF | Time to Loss of Virologic Response by Week 48 (Defined by FDA TLOVR Algorithm) | 15th percentile | 24 weeks |
| EFV + FTC/TDF | Time to Loss of Virologic Response by Week 48 (Defined by FDA TLOVR Algorithm) | 20th percentile | 24 weeks |