HIV
Conditions
Keywords
microbicides, women, HIV prevention, PrEP, Tenofovir gel
Brief summary
The purpose of this study is to assess the effectiveness of an implementation model which integrates tenofovir gel provision into existing family planning services.
Detailed description
The CAPRISA 008 trial is a two-arm, open-label, randomized controlled trial that is being conducted at the CAPRISA eThekwini and CAPRISA Vulindlela Clinics and their neighboring public sector family planning services in KwaZulu-Natal, South Africa. Up to 700 consenting sexually active, HIV-uninfected women aged 18 years and older who previously participated in an antiretroviral (ARV) prevention study will be enrolled and followed for a maximum 30 months. All women will be provided with 1% tenofovir gel but will be randomised to either receive their gel through a public sector family planning services with 2-3 monthly provision (intervention arm) or through the CAPRISA research clinics with monthly provision (control arm). All women in the trial will be provided with the standard package of HIV prevention and reproductive health services. Participants in both study arms will be provided with a supply of single-use, pre-filled applicators of 1% tenofovir gel. While in the study, participants will be advised and supported to follow the CAPRISA 004 pre- and post-dosing strategy, namely BAT24, where the first dose of tenofovir gel is applied within 12 hours before anticipated coitus and a second dose as soon as possible but within 12 hours after coitus, with a maximum of two doses of gel in a 24-hour period. The primary objective of this trial is to assess the effectiveness of an implementation model for tenofovir gel provision through family planning services.
Interventions
DRUG1% tenofovir gel
Participants will be randomized to receive 1% tenofovir gel through either: * Public sector family planning services with 2-3 monthly provision and monitoring of 1% tenofovir gel and the use of QI methodology to promote reliable service delivery (intervention arm), or * The CAPRISA research clinics with monthly provision and monitoring of 1% tenofovir gel (control arm).
Sponsors
CONRAD
Gilead Sciences
FHI 360
Institute for Healthcare Improvement
Centre for the AIDS Programme of Research in South Africa
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Age 18 years and older * Women who previously participated in an ARV prevention study * Currently utilizing or agreeing to attend designated public sector family planning services * Able and willing to provide first person informed consent to be screened for, and to enroll in, the study * Able and willing to provide adequate locator information for study retention purposes * Sexually active (at least one coital act in the last 3 months prior to screening) * HIV negative (by HIV testing performed by study staff within 30 days of enrollment) * Negative pregnancy test performed by study staff within 21 days of enrollment * Agree to use a non-barrier form of contraceptive * Agree to adhere to study visits and procedures
Exclusion criteria
* Has a creatinine clearance \< 50ml/min * Has any other condition that, based on the opinion of the Investigator or designee, would preclude provision of informed consent, make participation in the study unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Number of Returned Used Applicators Per Month (i.e in 30 Days) | Between 2012 to 2015, up to 28 months | The primary endpoint is the mean number of returned used applicators per month. Since participants in the intervention arm followed two and three monthly schedule (as opposed to monthly in the intervention arm), the number of returned used applicators per month for each participant will be estimated as the total number of returned applicators at that visit divided by the number of days since the previous visit, multiplied by 30. Thus a uniform distribution of gel use will be assumed in participants whom we did not see monthly. Intent to treat and per protocol analyses were carried out of this outcome. Intent to treat population includes all participants who were randomized, met pre-randomization eligibility criteria and who have post-enrollment follow-up data. The per protocol population is a subset of the intent to treat population.The per-protocol analysis excluded visits where no gel had been dispensed for \>120 days. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pregnancy Incidence Rates | Between 2012 and 2015, up to 28 months | Time to pregnancy, was as the difference between the estimated date of conception and the enrolment date, plus one. The date of conception was defined as 14 days after the last normal menstrual period or the estimated date of delivery minus 40 weeks if the first date of last normal menstrual period is not available or the midpoint between the date of the first positive pregnancy test and the date of the previous negative pregnancy test. The censoring time for a woman who did not become pregnant during the study equals the difference between the calculated censoring date and the enrolment date, plus one. |
| Percentage of Participants Achieving Adherence >80%. | Between 2012 and 2015, up to 28 months | Self-reported adherence to the tenofovir gel dosing strategy.Gel adherence was defined as the estimated proportion of reported sex acts covered by two gel doses and calculated for each woman by dividing half the number of returned used applicators each month by the number of reported sex acts that month.For participants attending 2-3 monthly clinic visits, their number of gels used in the last 30 days will be estimated as the total number of returned used gels, divided by the number of days between the current and the previous visit, times 30. |
| HIV Viral Load Among HIV Seroconverters | Between 2012 and 2015, up to 28 months | This is mean log transformed HIV viral load measured at the first visit post HIV infection. |
| HIV Incidence Rates | Between 2012 and 2015, up to 28 months | Time to HIV infection was calculated as the difference between estimated date of infection (midpoint between the last negative HIV test date and the first confirmed positive HIV test date) and enrolment date, plus one. Where a participant has a positive PCR and a negative rapid test on the same date, the date of infection is calculated as 14 days prior to this date. Women who do not become HIV positive before their last study visit will be censored on the day of their last negative HIV test. Their follow-up time will be calculated as the difference between date of censoring and enrolment date, plus one. |
| Human Papillomavirus Incidence Rates | Between 2012 and 2015, up to 28 months | For the calculation of the incidence rate, seroconversion was assumed to have occurred at the midpoint between the first positive HPV test and the previous HPV negative test. |
| Percentage of Participants With Detectable Tenofovir Levels From Vaginal Samples at 12 Months of Follow-up | All participants with drug levels at 12 months of follow-up | Percentage of participants with detectable tenofovir levels from vaginal samples at 12 months of follow-up. All drug levels below limit of quantification were considered to be undetectable. |
| Product Acceptability | At study completion, up to 28 months | This is the number of participants who reported that they liked the study product. The questionnaire was administered at study exit, therefore participants who were loss to follow-up and those who died could not complete the questionnaire. |
| Tenofovir Resistance Among HIV Seroconverters | Between 2012 and 2015, up to 28 months | — |
Countries
South Africa
Participant flow
Pre-assignment details
448 were assessed for eligibility and 382 were randomized. However, only 372 were eligible for study participation. Of the 10 who were ineligibly enrolled: 6 were HIV positive at enrollment, 2 were co-enrolled in another trial, 1 had no post-randomization follow-up data and 1 was pregnant at enrollment.
Participants by arm
| Arm | Count |
|---|---|
| Intervention 1% tenofovir gel provision through a public sector family planning services with 2-3 monthly provision and monitoring and the use of QI methodology to promote reliable service delivery
1% tenofovir gel: Participants will be randomized to receive 1% tenofovir gel through either:
* Public sector family planning services with 2-3 monthly provision and monitoring of 1% tenofovir gel and the use of QI methodology to promote reliable service delivery (intervention arm), or
* The CAPRISA research clinics with monthly provision and monitoring of 1% tenofovir gel (control arm). | 189 |
| Control monthly 1% tenofovir gel provision and monitoring through CAPRISA research clinics
1% tenofovir gel: Participants will be randomized to receive 1% tenofovir gel through either:
* Public sector family planning services with 2-3 monthly provision and monitoring of 1% tenofovir gel and the use of QI methodology to promote reliable service delivery (intervention arm), or
* The CAPRISA research clinics with monthly provision and monitoring of 1% tenofovir gel (control arm). | 183 |
| Total | 372 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 2 |
| Overall Study | Investigator decision | 1 | 1 |
| Overall Study | Lost to Follow-up | 4 | 3 |
| Overall Study | Relocated | 0 | 1 |
| Overall Study | Withdrawal by Subject | 10 | 9 |
Baseline characteristics
| Characteristic | Intervention | Total | Control |
|---|---|---|---|
| Age, Continuous | 29.5 years STANDARD_DEVIATION 5.8 | 29.4 years STANDARD_DEVIATION 5.5 | 29.3 years STANDARD_DEVIATION 5.3 |
| Contraception Injectable | 139 Participants | 279 Participants | 140 Participants |
| Contraception Oral | 43 Participants | 75 Participants | 32 Participants |
| Contraception Sterilized | 7 Participants | 18 Participants | 11 Participants |
| HPV prevalence | 20 Participants | 31 Participants | 11 Participants |
| HSV-2 prevalence | 174 Participants | 333 Participants | 159 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 189 Participants | 372 Participants | 183 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment South Africa | 189 participants | 372 participants | 183 participants |
| Sex acts in past 30 days | 4 Acts | 4 Acts | 4 Acts |
| Sex: Female, Male Female | 189 Participants | 372 Participants | 183 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 189 | 2 / 183 |
| other Total, other adverse events | 166 / 189 | 181 / 183 |
| serious Total, serious adverse events | 13 / 189 | 17 / 183 |
Outcome results
Primary
Mean Number of Returned Used Applicators Per Month (i.e in 30 Days)
The primary endpoint is the mean number of returned used applicators per month. Since participants in the intervention arm followed two and three monthly schedule (as opposed to monthly in the intervention arm), the number of returned used applicators per month for each participant will be estimated as the total number of returned applicators at that visit divided by the number of days since the previous visit, multiplied by 30. Thus a uniform distribution of gel use will be assumed in participants whom we did not see monthly. Intent to treat and per protocol analyses were carried out of this outcome. Intent to treat population includes all participants who were randomized, met pre-randomization eligibility criteria and who have post-enrollment follow-up data. The per protocol population is a subset of the intent to treat population.The per-protocol analysis excluded visits where no gel had been dispensed for \>120 days.
Time frame: Between 2012 to 2015, up to 28 months
Population: Intent to treat population and the per protocol population (excluding all subsequent data collected from participants who were not dispensed product for more than 120 days).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Intervention | Mean Number of Returned Used Applicators Per Month (i.e in 30 Days) | Intent to treat analyses | 5.2 Used gel applicators per month |
| Intervention | Mean Number of Returned Used Applicators Per Month (i.e in 30 Days) | Per protocol analyses | 5.5 Used gel applicators per month |
| Control | Mean Number of Returned Used Applicators Per Month (i.e in 30 Days) | Intent to treat analyses | 5.7 Used gel applicators per month |
| Control | Mean Number of Returned Used Applicators Per Month (i.e in 30 Days) | Per protocol analyses | 5.8 Used gel applicators per month |
Comparison: Intent to treat population (all participants who were randomized, met pre-randomization eligibility criteria and who have post-enrollment follow-up data) was used for this analyses.95% CI: [-1.16, 0.21]
Comparison: This is the analyses from the per protocol population (excluding all subsequent data collected from participants who were not dispensed product for more than 120 days).95% CI: [-0.98, 0.48]
Secondary
HIV Incidence Rates
Time to HIV infection was calculated as the difference between estimated date of infection (midpoint between the last negative HIV test date and the first confirmed positive HIV test date) and enrolment date, plus one. Where a participant has a positive PCR and a negative rapid test on the same date, the date of infection is calculated as 14 days prior to this date. Women who do not become HIV positive before their last study visit will be censored on the day of their last negative HIV test. Their follow-up time will be calculated as the difference between date of censoring and enrolment date, plus one.
Time frame: Between 2012 and 2015, up to 28 months
Population: Intent to treat population(all participants who were randomized, met pre-randomization eligibility criteria and who have post-enrollment follow-up data).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intervention | HIV Incidence Rates | 3.5 Incidence rate/100 women years |
| Control | HIV Incidence Rates | 3.6 Incidence rate/100 women years |
Comparison: The power was not calculated for all the secondary outcomes.p-value: 0.92895% CI: [0.4, 2.35]z-test
Secondary
HIV Viral Load Among HIV Seroconverters
This is mean log transformed HIV viral load measured at the first visit post HIV infection.
Time frame: Between 2012 and 2015, up to 28 months
Population: All participants who became HIV infected
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intervention | HIV Viral Load Among HIV Seroconverters | 4.4 log10 copies/ml | Standard Deviation 1.3 |
| Control | HIV Viral Load Among HIV Seroconverters | 4.8 log10 copies/ml | Standard Deviation 0.9 |
p-value: 0.455t-test, 2 sided
Secondary
Human Papillomavirus Incidence Rates
For the calculation of the incidence rate, seroconversion was assumed to have occurred at the midpoint between the first positive HPV test and the previous HPV negative test.
Time frame: Between 2012 and 2015, up to 28 months
Population: This is the subset of intent to treat population. It includes all participants who had HPV negative results at randomisation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intervention | Human Papillomavirus Incidence Rates | 1.0 Incidence rate/100 women years |
| Control | Human Papillomavirus Incidence Rates | 3.0 Incidence rate/100 women years |
p-value: 0.09795% CI: [0.06, 1.32]z-test
Secondary
Percentage of Participants Achieving Adherence >80%.
Self-reported adherence to the tenofovir gel dosing strategy.Gel adherence was defined as the estimated proportion of reported sex acts covered by two gel doses and calculated for each woman by dividing half the number of returned used applicators each month by the number of reported sex acts that month.For participants attending 2-3 monthly clinic visits, their number of gels used in the last 30 days will be estimated as the total number of returned used gels, divided by the number of days between the current and the previous visit, times 30.
Time frame: Between 2012 and 2015, up to 28 months
Population: This is a subset of intent to treat population. It includes all participants who returned used gel applicators and also reported sex during follow-up.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intervention | Percentage of Participants Achieving Adherence >80%. | 70.2 percentage of participants |
| Control | Percentage of Participants Achieving Adherence >80%. | 65.2 percentage of participants |
Comparison: Power was not calculated for all secondary outcomes.p-value: 0.30495% CI: [0.94, 1.24]Regression, Log-binomial
Secondary
Percentage of Participants With Detectable Tenofovir Levels From Vaginal Samples at 12 Months of Follow-up
Percentage of participants with detectable tenofovir levels from vaginal samples at 12 months of follow-up. All drug levels below limit of quantification were considered to be undetectable.
Time frame: All participants with drug levels at 12 months of follow-up
Population: All participants with drug levels measured at 12 months of follow-up
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intervention | Percentage of Participants With Detectable Tenofovir Levels From Vaginal Samples at 12 Months of Follow-up | 39.5 percentage of participants |
| Control | Percentage of Participants With Detectable Tenofovir Levels From Vaginal Samples at 12 Months of Follow-up | 43.6 percentage of participants |
p-value: 0.46295% CI: [0.7, 1.18]Regression, Log-binomial
Secondary
Pregnancy Incidence Rates
Time to pregnancy, was as the difference between the estimated date of conception and the enrolment date, plus one. The date of conception was defined as 14 days after the last normal menstrual period or the estimated date of delivery minus 40 weeks if the first date of last normal menstrual period is not available or the midpoint between the date of the first positive pregnancy test and the date of the previous negative pregnancy test. The censoring time for a woman who did not become pregnant during the study equals the difference between the calculated censoring date and the enrolment date, plus one.
Time frame: Between 2012 and 2015, up to 28 months
Population: Intent to treat population(all participants who were randomized, met pre-randomization eligibility criteria and who have post-enrollment follow-up data).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intervention | Pregnancy Incidence Rates | 4.9 Incidence rate/100 women years |
| Control | Pregnancy Incidence Rates | 5.1 Incidence rate/100 women years |
Comparison: Power was not calculated for all the secondary outcomes.p-value: 0.89595% CI: [0.45, 2.04]z-test
Secondary
Product Acceptability
This is the number of participants who reported that they liked the study product. The questionnaire was administered at study exit, therefore participants who were loss to follow-up and those who died could not complete the questionnaire.
Time frame: At study completion, up to 28 months
Population: Participants who completed product acceptability questionnaire at study exit
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Product Acceptability | 180 Participants |
| Control | Product Acceptability | 170 Participants |
Secondary
Tenofovir Resistance Among HIV Seroconverters
Time frame: Between 2012 and 2015, up to 28 months
Population: Due to lack of funding, tenofovir resistance testing was not done in this study. However, we do have stored samples to fall back onto, should we secure funding.