HIV Infections
Conditions
Keywords
HIV incidence, HIV prevention, Tenofovir, Emtricitabine, Botswana, HIV seronegativity
Brief summary
This study tested whether taking a pill of tenofovir and emtricitabine (two antiretroviral medicines) was safe for sexually-active young adults in Botswana without HIV infection and whether it reduced their risk of getting an HIV infection.
Detailed description
Twelve hundred and nineteen healthy, sexually active women and men, 18-39 years old, without HIV infection were enrolled in Francistown and Gaborone, Botswana. They were provided with free male and female condoms, repeated individualized risk-reduction counseling, diagnosis and treatment of sexually transmitted diseases, and women will be provided with a choice of effective family planning methods. In addition, volunteers were randomized to receive either Tenofovir and emtricitabine (in a single pill) or a placebo pill to take once a day. Volunteers were seen monthly for at least 12 months to monitor for side effects and toxicities and to test their HIV status. Persons who become HIV infected during the trial received ongoing supportive counseling, CD4 and viral load monitoring, education about HIV infection/disease, and access to HIV care including free antiretrovirals when clinically indicated. Volunteer safety was monitored by a local ethics committee, Centers for Disease Control Institutional Review Board (CDC IRB) and an independent data safety and monitoring board
Interventions
DRUGPlacebo Oral Tablet
Sponsors
Botswana Ministry of Health
Gilead Sciences
Centers for Disease Control and Prevention
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 39 Years
Healthy volunteers
Yes
Inclusion criteria
* citizen of Botswana 18-39 years old * sexually active * HIV uninfected * Hepatitis B and C uninfected * Calculated creatinine clearance \>= 60 mL/min * hemoglobin \>= 8 gm/dL * ALT and AST \<= 2x ULN * total bilirubin \<= 1.5 mg/dL * total serum amylase \<= 1.5x ULN * Serum phosphorus \>= 2.2 mg/dL * willing to use hormonal contraception (females) * living within 1 hours travel of study clinic * pass comprehension test * willing and able to give informed consent
Exclusion criteria
* 18-20 without parent/guardian consent * history of significant renal or bone disease * any chronic illness requiring ongoing prescription medication * pregnant or breastfeeding * planning to move away from site in the next year * participating in another HIV prevention or vaccine safety trial * any other clinical condition or prior therapy that, in the opinion of the study physician, would make the volunteer unsuitable for the study or unable to comply with the dosing requirements
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Adverse Drug Reactions in the Tenofovir/Emtricitabine and Placebo Arms | Monthly, for up to 3 years | Study visits were scheduled every 30 days until completion of the study, and participants were instructed to return to the clinic for evaluation in the event of an illness. Participants reported any adverse effects at monthly visits and interim visits. |
| HIV Incidence in the Tenofovir/Emtricitabine and Placebo Arms | Monthly, for up to 3 years | Study visits were scheduled every 30 days until completion of the study and during monthly study visits, we performed testing for HIV infection. At completion of the study, we tested all participants for HIV infection, using an enzyme-linked immunosorbent assay (ELISA).The primary efficacy end point was the difference in the rates of HIV infection between participants assigned to receive TDF-FTC and those assigned to receive placebo. The initial efficacy analysis included all study participants who were randomly assigned to receive a study medication (intention-to-treat cohort). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Condom Use During Study: Number of Participants With >=1 Condomless Sex Acts | 12 months | We assessed condom use of the enrolled participants by face-to-face interviews (at baseline and monthly thereafter) and provided a comprehensive package of HIV prevention services, including individualized counseling on risk reduction, free male and female condoms, and screening for sexually transmitted infections followed, if applicable, by partner notification and treatment. |
| Rates of Adherence to Study Medication | 36 months | The rates of adherence to study medication by treatment arm was assessed over the entire course of the study. This comparison was done by assessing the percentage of pills taken by participants within each study arm. The difference between the 2 arms was compared with a Fisher' exact test. |
| Antiretroviral (ARV) Resistance Patterns in Seroconverters | At time HIV infection diagnosed,1 month post-time of HIV infection diagnosis, and 6 months post-time of HIV infection diagnosis | Participants who seroconverted had blood samples taken at the time of infection and at one month and six months post seroconversion to detect any HIV resistance mutations. |
| CD4 Evaluation After HIV Seroconversion | 1-year post seroconversion | Study medication was stopped when HIV infected was diagnosed. Seroconvertors were referred for clinical care and followed an additional year with scheduled quarterly CD4+ cell count assessments. A model-estimated geometric mean of the CD4+ cell counts by each treatment group was evaluated. |
Countries
Botswana, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| TDF-FTC, Condoms, Risk Counseling Participants randomized to the active arm received daily oral TDF-FTC along with male and female condoms, personalized risk reduction counseling, adherence counseling, and routine monitoring for HIV infection, laboratory abnormalities, and adverse events.
Tenofovir Disoproxil Fumarate 300 mg + Emtricitabine 200 mg: Daily oral single dose pill containing 300 mg TDF and 200 mg FTC. | 611 |
| Placebo, Condoms, Risk Counseling Participants randomized to the placebo arm received a daily oral placebo tablet along with male and female condoms, personalized risk reduction counseling, adherence counseling, and routine monitoring for HIV infection, laboratory abnormalities, and adverse events.
TDF-FTC placebo: Placebo comparator for TDF-FTC | 608 |
| Total | 1,219 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 4 |
| Overall Study | Had other reasons | 5 | 6 |
| Overall Study | HIV-infected at enrollment | 1 | 2 |
| Overall Study | Lost to Follow-up | 52 | 63 |
| Overall Study | Never started drug | 9 | 7 |
| Overall Study | Relocated | 49 | 36 |
| Overall Study | Were withdrawn by investigator | 10 | 6 |
| Overall Study | Withdrawal by Subject | 90 | 74 |
Baseline characteristics
| Characteristic | TDF-FTC, Condoms, Risk Counseling | Placebo, Condoms, Risk Counseling | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 611 Participants | 608 Participants | 1219 Participants |
| Region of Enrollment Botswana | 611 participants | 608 participants | 1219 participants |
| Sex: Female, Male Female | 280 Participants | 277 Participants | 557 Participants |
| Sex: Female, Male Male | 331 Participants | 331 Participants | 662 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 557 / 611 | 536 / 608 |
| serious Total, serious adverse events | 42 / 611 | 44 / 608 |
Outcome results
Primary
HIV Incidence in the Tenofovir/Emtricitabine and Placebo Arms
Study visits were scheduled every 30 days until completion of the study and during monthly study visits, we performed testing for HIV infection. At completion of the study, we tested all participants for HIV infection, using an enzyme-linked immunosorbent assay (ELISA).The primary efficacy end point was the difference in the rates of HIV infection between participants assigned to receive TDF-FTC and those assigned to receive placebo. The initial efficacy analysis included all study participants who were randomly assigned to receive a study medication (intention-to-treat cohort).
Time frame: Monthly, for up to 3 years
Population: Of the 1219, 3 were excluded from analysis because HIV-infected at the time of enrollment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TDF-FTC, Condoms, Risk Counseling | HIV Incidence in the Tenofovir/Emtricitabine and Placebo Arms | 1.2 infections/100 person-years |
| Placebo, Condoms, Risk Counseling | HIV Incidence in the Tenofovir/Emtricitabine and Placebo Arms | 3.1 infections/100 person-years |
Comparison: The primary efficacy end point was the difference in the rates of HIV infection between participants assigned to receive TDF-FTC and those assigned to receive placebo. The primary hypothesis was that TDF-FTC, as compared with placebo, would reduce the rate of HIV infection by at least 65%, with a predefined lower boundary for the 95% confidence interval of 10%.p-value: 0.0395% CI: [21.5, 83.4]Regression, Cox
Primary
Percentage of Participants With Adverse Drug Reactions in the Tenofovir/Emtricitabine and Placebo Arms
Study visits were scheduled every 30 days until completion of the study, and participants were instructed to return to the clinic for evaluation in the event of an illness. Participants reported any adverse effects at monthly visits and interim visits.
Time frame: Monthly, for up to 3 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TDF-FTC, Condoms, Risk Counseling | Percentage of Participants With Adverse Drug Reactions in the Tenofovir/Emtricitabine and Placebo Arms | 91.2 percentage of participants with AE |
| Placebo, Condoms, Risk Counseling | Percentage of Participants With Adverse Drug Reactions in the Tenofovir/Emtricitabine and Placebo Arms | 88.2 percentage of participants with AE |
Comparison: Safety analyses were performed in the intention-to-treat cohort. Primary safety end points included the frequency of adverse clinical or laboratory events.p-value: 0.003Regression, Cox
Secondary
Antiretroviral (ARV) Resistance Patterns in Seroconverters
Participants who seroconverted had blood samples taken at the time of infection and at one month and six months post seroconversion to detect any HIV resistance mutations.
Time frame: At time HIV infection diagnosed,1 month post-time of HIV infection diagnosis, and 6 months post-time of HIV infection diagnosis
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TDF-FTC, Condoms, Risk Counseling | Antiretroviral (ARV) Resistance Patterns in Seroconverters | 1 Participants |
| Placebo, Condoms, Risk Counseling | Antiretroviral (ARV) Resistance Patterns in Seroconverters | 1 Participants |
Secondary
CD4 Evaluation After HIV Seroconversion
Study medication was stopped when HIV infected was diagnosed. Seroconvertors were referred for clinical care and followed an additional year with scheduled quarterly CD4+ cell count assessments. A model-estimated geometric mean of the CD4+ cell counts by each treatment group was evaluated.
Time frame: 1-year post seroconversion
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| TDF-FTC, Condoms, Risk Counseling | CD4 Evaluation After HIV Seroconversion | 500 cells/microliter |
| Placebo, Condoms, Risk Counseling | CD4 Evaluation After HIV Seroconversion | 466 cells/microliter |
Secondary
Changes in Condom Use During Study: Number of Participants With >=1 Condomless Sex Acts
We assessed condom use of the enrolled participants by face-to-face interviews (at baseline and monthly thereafter) and provided a comprehensive package of HIV prevention services, including individualized counseling on risk reduction, free male and female condoms, and screening for sexually transmitted infections followed, if applicable, by partner notification and treatment.
Time frame: 12 months
Population: Of 1219, 19 excluded (3 HIV-infected at enrollment, 16 never started drug). Of the 1200, 24 reported no sex during study. Remaining total 1176 with \>=1 sex act included in analysis.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| TDF-FTC, Condoms, Risk Counseling | Changes in Condom Use During Study: Number of Participants With >=1 Condomless Sex Acts | Month 8 | 57 Participants |
| TDF-FTC, Condoms, Risk Counseling | Changes in Condom Use During Study: Number of Participants With >=1 Condomless Sex Acts | Month 4 | 73 Participants |
| TDF-FTC, Condoms, Risk Counseling | Changes in Condom Use During Study: Number of Participants With >=1 Condomless Sex Acts | Month 5 | 67 Participants |
| TDF-FTC, Condoms, Risk Counseling | Changes in Condom Use During Study: Number of Participants With >=1 Condomless Sex Acts | Month 6 | 70 Participants |
| TDF-FTC, Condoms, Risk Counseling | Changes in Condom Use During Study: Number of Participants With >=1 Condomless Sex Acts | Month 7 | 55 Participants |
| TDF-FTC, Condoms, Risk Counseling | Changes in Condom Use During Study: Number of Participants With >=1 Condomless Sex Acts | Baseline | 124 Participants |
| TDF-FTC, Condoms, Risk Counseling | Changes in Condom Use During Study: Number of Participants With >=1 Condomless Sex Acts | Month 1 | 94 Participants |
| TDF-FTC, Condoms, Risk Counseling | Changes in Condom Use During Study: Number of Participants With >=1 Condomless Sex Acts | Month 2 | 97 Participants |
| TDF-FTC, Condoms, Risk Counseling | Changes in Condom Use During Study: Number of Participants With >=1 Condomless Sex Acts | Month 3 | 92 Participants |
| TDF-FTC, Condoms, Risk Counseling | Changes in Condom Use During Study: Number of Participants With >=1 Condomless Sex Acts | Month 9 | 55 Participants |
| TDF-FTC, Condoms, Risk Counseling | Changes in Condom Use During Study: Number of Participants With >=1 Condomless Sex Acts | Month 10 | 51 Participants |
| TDF-FTC, Condoms, Risk Counseling | Changes in Condom Use During Study: Number of Participants With >=1 Condomless Sex Acts | Month 11 | 36 Participants |
| TDF-FTC, Condoms, Risk Counseling | Changes in Condom Use During Study: Number of Participants With >=1 Condomless Sex Acts | Month 12 | 54 Participants |
| Placebo, Condoms, Risk Counseling | Changes in Condom Use During Study: Number of Participants With >=1 Condomless Sex Acts | Month 11 | 33 Participants |
| Placebo, Condoms, Risk Counseling | Changes in Condom Use During Study: Number of Participants With >=1 Condomless Sex Acts | Month 2 | 90 Participants |
| Placebo, Condoms, Risk Counseling | Changes in Condom Use During Study: Number of Participants With >=1 Condomless Sex Acts | Month 4 | 66 Participants |
| Placebo, Condoms, Risk Counseling | Changes in Condom Use During Study: Number of Participants With >=1 Condomless Sex Acts | Month 10 | 36 Participants |
| Placebo, Condoms, Risk Counseling | Changes in Condom Use During Study: Number of Participants With >=1 Condomless Sex Acts | Month 5 | 61 Participants |
| Placebo, Condoms, Risk Counseling | Changes in Condom Use During Study: Number of Participants With >=1 Condomless Sex Acts | Month 3 | 83 Participants |
| Placebo, Condoms, Risk Counseling | Changes in Condom Use During Study: Number of Participants With >=1 Condomless Sex Acts | Month 6 | 67 Participants |
| Placebo, Condoms, Risk Counseling | Changes in Condom Use During Study: Number of Participants With >=1 Condomless Sex Acts | Month 8 | 49 Participants |
| Placebo, Condoms, Risk Counseling | Changes in Condom Use During Study: Number of Participants With >=1 Condomless Sex Acts | Month 7 | 45 Participants |
| Placebo, Condoms, Risk Counseling | Changes in Condom Use During Study: Number of Participants With >=1 Condomless Sex Acts | Month 12 | 30 Participants |
| Placebo, Condoms, Risk Counseling | Changes in Condom Use During Study: Number of Participants With >=1 Condomless Sex Acts | Baseline | 113 Participants |
| Placebo, Condoms, Risk Counseling | Changes in Condom Use During Study: Number of Participants With >=1 Condomless Sex Acts | Month 9 | 45 Participants |
| Placebo, Condoms, Risk Counseling | Changes in Condom Use During Study: Number of Participants With >=1 Condomless Sex Acts | Month 1 | 86 Participants |
Comparison: A logistic regression was used to estimate the odds of reporting zero condomless sex acts. The longitudinal dependent variable (number of condomless sex acts) was defined as:~Number of condomless vaginal sexual acts with both casual and main partners among those who reported having had at least one sexual partner in the previous 30 days.p-value: 0.00495% CI: [1.05, 1.28]Regression, Logistic
Secondary
Rates of Adherence to Study Medication
The rates of adherence to study medication by treatment arm was assessed over the entire course of the study. This comparison was done by assessing the percentage of pills taken by participants within each study arm. The difference between the 2 arms was compared with a Fisher' exact test.
Time frame: 36 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TDF-FTC, Condoms, Risk Counseling | Rates of Adherence to Study Medication | 93.5 Percentage of pills taken | Standard Deviation 0.136 |
| Placebo, Condoms, Risk Counseling | Rates of Adherence to Study Medication | 93.6 Percentage of pills taken | Standard Deviation 0.137 |
Comparison: Fisher's Exact Test was performed to test for differences between the treatment groups in terms of adherence based on pill count.p-value: 0.79Fisher Exact