HIV Infections
Conditions
Keywords
HIV incidence, HIV prevention, Tenofovir, Emtricitabine, Botswana, HIV seronegativity, PrEP
Brief summary
This study is an open label and is an extension to the TDF2 study in which the investigators offered daily oral tenofovir/emtricitabine (TDF/FTC) for a maximum of 12 months to HIV uninfected former participants of the TDF2 study.
Detailed description
This open label phase builds on a unique opportunity provided by the end of the randomized phase of the TDF 2 study. The randomized study provided a well-characterized cohort of persons who received standard prevention interventions, including monthly testing, counseling, and condoms. The primary intervention that will change in the open label phase is the provision of information about the demonstrated efficacy and safety of PrEP including counseling about how PrEP is not 100% effective, provision of open label rather than blinded study medication, and a shortened visit schedule designed to more closely approximate what would be feasible in an implementation program. This open label phase will therefore serve as an opportunity to gather additional information relevant to the delivery and uptake of daily oral PrEP that may help inform eventual more wide scale PrEP implementation in Botswana.The OLE also leverages unique opportunities to address important questions about how information about PrEP safety and efficacy might affect risk behavior. The randomized trial showed that condom use (81.9% in the TDF/FTC group and 79.7% in the placebo group, p = 0.21) and the number of participants with more than one sexual partner in the previous month (14.2% in the TDF/FTC group and 14.1% in the placebo group, p = 0.86) between the two groups was similar. The underlying premise of this OLE is that information about PrEP efficacy and the knowledge of taking active drug rather than placebo might alter perception of HIV risk. This extension seeks to determine whether this trend will occur in the cohort after individuals receive information and counseling about the partial protective efficacy of PrEP and to identify risk factors for changes in risk behavior. The randomized trial revealed that reported drug adherence between the two arms was almost identical at 84.1% in the TDF/FTC group and 83.7% in the placebo arm (p = 0.79). The investigators have designed this open label phase in order to determine 1) if the knowledge of receiving active drug and the receipt of information about PrEP safety and partial efficacy at the onset of the open label phase could have substantial effects on pill use and 2) to identify individual factors associated with this impact. In addition, the open label extension will provide more information about the long term safety of Truvada.
Interventions
Sponsors
Botswana Ministry of Health
Centers for Disease Control and Prevention
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 64 Years
Healthy volunteers
Yes
Inclusion criteria
* Former TDF 2 participants * Willing and able to provide informed written consent for participation * If female, willing to use effective contraception during the trial (oral or injectable hormonal contraception, an intrauterine device \[IUD\], or who have had surgical interventions such as bilateral tubal ligation or hysterectomy) * Laboratory values as follows within 30 days prior to enrollment: * HIV uninfected by dual, parallel, rapid whole blood testing and HIV EIA * Serum phosphorus ≥ 2.2 mg/dL * Calculated creatinine clearance ≥ 60 mL/min
Exclusion criteria
* Positive urine pregnancy test (females) * Breastfeeding (females) * History of significant renal or bone disease * Any other clinical condition or prior therapy that, in the opinion of the physician would make the subject unsuitable for the OLE or unable to comply with the dosing requirements
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Sex Partners | Up to 12 months | Number of sex partners was assessed at baseline and each scheduled monthly visit, for up to 12 months. Responses to the following question refers to the number of partners reported in the past 30 days: In the past 30 days, with how many partners have you had sexual intercourse? |
| Extracellular Tenofovir (TFV) for Recent Drug Exposure | Up to 12 months | Dried blood spots were collected at each monthly study visit to characterize drug adherence by measuring extracellular tenofovir (TFV) for recent drug exposure (\ 24 hours). Of 229 participants, 196 participants had monthly DBSs available for analysis. A sampling algorithm was designed to make inference to TFV and TFV-DP levels at all 12 months. For the TFV extracellular analysis, participants were randomly assigned to one of three sampling schedules, with equal probability: (a) months 1, 2, 5, 8, and 11; (b) months 1, 3, 6, 9, and 12; and (c) months 1, 4, 7, 10, and 12. These 196 participants contributed a total of 777 monthly DBSs for the TFV extracellular analysis. Extracellular TFV detectability was defined as having a mean TFV level (of up to four measurements) equal to or greater than 5 ng/mL. |
| Intracellular Tenofovir-diphosphate (TFV-DP) | Up to 12 months | Dried blood spots were collected at each monthly study visit to characterize drug adherence by measuring intracellular tenofovir-diphosphate (TFV-DP) for long-term drug exposure (\ 7 days). The 196 participants who had monthly DBSs available were stratified by site, gender, and the 3 patterns previously assigned for the TFV extracellular analysis (2×2×3 = 12 strata). Then 60 participants were selected, 5 from each of the 12 strata, to balance by site, gender, and the above 3 patterns were maintained. In turn, the monthly DBSs indicated by the assigned pattern were analyzed. These 60 participants contributed a total of 237 monthly DBSs for the TFV-DP intracellular analysis. The observed TFV-DP levels in our study population were categorized as follows (units of drug in fmol/mL): 0 doses per week (\<912); 1 dose taken per week (≥912 and \<1824); 2 doses taken per week (≥1824 and \<2688); 3 doses taken per week (≥2688 and \<3600); 4 doses taken per week (≥3600 and \<4464); 5 to 7 doses taken |
| Self-reported Drug Adherence Over the Past 3 Days | Up to 12 Months | A 30-day supply of TDF/FTC was dispensed at each monthly visit, for up to 12 months. Participants were asked monthly about their drug adherence and were asked to recall their time of dosing over the past 3 days. Question: Please think back to \[yesterday, 2 days ago, 3 days ago\]. What time did you take Truvada? Was it in the morning, afternoon, evening, or you weren't able to take the pill that day? |
| Number of Sex Acts by Condom Usage | Up to 12 months | Number of sex acts by condom usage was assessed at baseline and each scheduled monthly visit, for up to 12 months. Responses to the following question refers to the number of sex acts with up to 3 partners. In the past 30 days, how many times did you have sex with \['this partner'\]? When I ask about the number of times you had sex, please count each sexual act. For example, if you had 2 rounds of sexual intercourse with your partner on a single evening, count that as two times you had sex. Please remember that this only refers to vaginal and anal sex. It does not refer to oral sex. To assess condom use by sex act, the following question was asked to assess the number of sex acts with condoms and without condoms with up to 3 partners: Of the \_\_\_ sex acts, how many times did you not use condoms the entire time? |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Serious Adverse Events | Up to 12 Months | Study visits were scheduled every month until study completion. Participants were instructed to return to the clinic for evaluation in event of illness. Participants reported any adverse effects (AEs) at monthly or interim visits and were determined as serious adverse events (SAE) when at least possibly related to study drug. DAIDS Table for Grading Severity of Adult Adverse Experiences for Vaccine & Prevention Research Programs was used for grading. Definitions: Grade 3-'probably related'-strong temporal relationship to study product that cannot be explained by participant's clinical state or other factors and a causal relationship is biologically plausible. Grade 4-'definitely related'-distinct temporal relationship to administration of the study product that cannot be explained by the participant's clinical state or other factors or AE occurs on re-challenge or the AE is a known reaction to the product or chemical group or can be predicted by the product's pharmacology. |
| HIV Seroconversion | Up to 12 Months | Study visits were scheduled every month until completion of the study and during monthly study visits, HIV testing was performed, for up to 12 months. During monthly visits, routine HIV testing was performed with two HIV rapid tests. If HIV-infection was suspected, HIV antigen-antibody (Ag/Ab) combination enzyme immunoassay (EIA) (Bio-Rad, GS HIV Combo Ag/Ab EIA) testing was performed, and RNA viral load was measured. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| TDF-FTC as PrEP Eligible HIV-uninfected participants were offered 12 months of oral Tenofovir Disoproxil Fumarate 300 mg + Emtricitabine 200 mg (TDF-FTC) once daily in the form of a single tablet regardless of their original study assignment in randomized phase.
Tenofovir Disoproxil Fumarate 300 mg + Emtricitabine 200 mg | 229 |
| Total | 229 |
Baseline characteristics
| Characteristic | TDF-FTC as PrEP |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 229 Participants |
| Age, Continuous | 30 years |
| Education Level Post-secondary | 84 Participants |
| Education Level Primary or less | 4 Participants |
| Education Level Secondary | 141 Participants |
| Employment Status Employed | 178 Participants |
| Employment Status Unemployed | 51 Participants |
| Enrollment Site Francistown | 97 Participants |
| Enrollment Site Gaborone | 132 Participants |
| Felt at risk for HIV No | 46 Participants |
| Felt at risk for HIV Yes | 183 Participants |
| Had an HIV test since TDF2 Study No | 17 Participants |
| Had an HIV test since TDF2 Study Yes | 212 Participants |
| Marital Status Cohabitating | 37 Participants |
| Marital Status Married | 18 Participants |
| Marital Status Separated/Widowed | 11 Participants |
| Marital Status Single | 163 Participants |
| Race/Ethnicity, Customized Black | 229 Participants |
| Region of Enrollment Botswana | 229 participants |
| Risk from partner for HIV No | 73 Participants |
| Risk from partner for HIV Yes | 156 Participants |
| Sex: Female, Male Female | 102 Participants |
| Sex: Female, Male Male | 127 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 169 / 229 |
| serious Total, serious adverse events | 8 / 229 |
Outcome results
Primary
Extracellular Tenofovir (TFV) for Recent Drug Exposure
Dried blood spots were collected at each monthly study visit to characterize drug adherence by measuring extracellular tenofovir (TFV) for recent drug exposure (\ 24 hours). Of 229 participants, 196 participants had monthly DBSs available for analysis. A sampling algorithm was designed to make inference to TFV and TFV-DP levels at all 12 months. For the TFV extracellular analysis, participants were randomly assigned to one of three sampling schedules, with equal probability: (a) months 1, 2, 5, 8, and 11; (b) months 1, 3, 6, 9, and 12; and (c) months 1, 4, 7, 10, and 12. These 196 participants contributed a total of 777 monthly DBSs for the TFV extracellular analysis. Extracellular TFV detectability was defined as having a mean TFV level (of up to four measurements) equal to or greater than 5 ng/mL.
Time frame: Up to 12 months
Population: Of 229 participants, 196 participants had monthly DBSs available for analysis over a period of 12 months. These 196 participants contributed a total of 777 monthly DBSs for the TFV extracellular analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TDF-FTC as PrEP | Extracellular Tenofovir (TFV) for Recent Drug Exposure | No detectable TFV | 64 number of DBS samples |
| TDF-FTC as PrEP | Extracellular Tenofovir (TFV) for Recent Drug Exposure | Detectable TFV | 713 number of DBS samples |
Primary
Intracellular Tenofovir-diphosphate (TFV-DP)
Dried blood spots were collected at each monthly study visit to characterize drug adherence by measuring intracellular tenofovir-diphosphate (TFV-DP) for long-term drug exposure (\ 7 days). The 196 participants who had monthly DBSs available were stratified by site, gender, and the 3 patterns previously assigned for the TFV extracellular analysis (2×2×3 = 12 strata). Then 60 participants were selected, 5 from each of the 12 strata, to balance by site, gender, and the above 3 patterns were maintained. In turn, the monthly DBSs indicated by the assigned pattern were analyzed. These 60 participants contributed a total of 237 monthly DBSs for the TFV-DP intracellular analysis. The observed TFV-DP levels in our study population were categorized as follows (units of drug in fmol/mL): 0 doses per week (\<912); 1 dose taken per week (≥912 and \<1824); 2 doses taken per week (≥1824 and \<2688); 3 doses taken per week (≥2688 and \<3600); 4 doses taken per week (≥3600 and \<4464); 5 to 7 doses taken
Time frame: Up to 12 months
Population: Of the 196 participants with monthly DBSs available over a period of 12 months, 60 participants were selected for TFV-DP intracellular analysis and contributed a total of 237 monthly DBSs for the TFV-DP intracellular analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TDF-FTC as PrEP | Intracellular Tenofovir-diphosphate (TFV-DP) | 5 doses per week | 20 number of DBS samples |
| TDF-FTC as PrEP | Intracellular Tenofovir-diphosphate (TFV-DP) | 2 doses per week | 4 number of DBS samples |
| TDF-FTC as PrEP | Intracellular Tenofovir-diphosphate (TFV-DP) | 4 doses per week | 6 number of DBS samples |
| TDF-FTC as PrEP | Intracellular Tenofovir-diphosphate (TFV-DP) | 7 doses per week | 141 number of DBS samples |
| TDF-FTC as PrEP | Intracellular Tenofovir-diphosphate (TFV-DP) | 6 doses per week | 29 number of DBS samples |
| TDF-FTC as PrEP | Intracellular Tenofovir-diphosphate (TFV-DP) | 3 doses per week | 12 number of DBS samples |
| TDF-FTC as PrEP | Intracellular Tenofovir-diphosphate (TFV-DP) | 1 dose per week | 5 number of DBS samples |
| TDF-FTC as PrEP | Intracellular Tenofovir-diphosphate (TFV-DP) | 0 doses per week | 19 number of DBS samples |
Primary
Number of Sex Acts by Condom Usage
Number of sex acts by condom usage was assessed at baseline and each scheduled monthly visit, for up to 12 months. Responses to the following question refers to the number of sex acts with up to 3 partners. In the past 30 days, how many times did you have sex with \['this partner'\]? When I ask about the number of times you had sex, please count each sexual act. For example, if you had 2 rounds of sexual intercourse with your partner on a single evening, count that as two times you had sex. Please remember that this only refers to vaginal and anal sex. It does not refer to oral sex. To assess condom use by sex act, the following question was asked to assess the number of sex acts with condoms and without condoms with up to 3 partners: Of the \_\_\_ sex acts, how many times did you not use condoms the entire time?
Time frame: Up to 12 months
Population: Among 229 participants, 102 participants were women and 127 participants were men. Analyses were stratified by sex.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| TDF-FTC as PrEP | Number of Sex Acts by Condom Usage | Number of condomless sex acts among men | 1.70 sex acts | Standard Deviation 4.34 |
| TDF-FTC as PrEP | Number of Sex Acts by Condom Usage | Number of sex acts among women | 4.01 sex acts | Standard Deviation 5.26 |
| TDF-FTC as PrEP | Number of Sex Acts by Condom Usage | Number of sex acts among men | 5.95 sex acts | Standard Deviation 6.67 |
| TDF-FTC as PrEP | Number of Sex Acts by Condom Usage | Number of condomless sex acts among women | 1.28 sex acts | Standard Deviation 3.72 |
| TDF-FTC as PrEP | Number of Sex Acts by Condom Usage | Number of sex acts involving a condom among women | 2.72 sex acts | Standard Deviation 3.7 |
| TDF-FTC as PrEP | Number of Sex Acts by Condom Usage | Number of sex acts involving a condom among men | 4.24 sex acts | Standard Deviation 5.19 |
Primary
Number of Sex Partners
Number of sex partners was assessed at baseline and each scheduled monthly visit, for up to 12 months. Responses to the following question refers to the number of partners reported in the past 30 days: In the past 30 days, with how many partners have you had sexual intercourse?
Time frame: Up to 12 months
Population: Among 229 participants, 102 participants were women and 127 participants were men. Analyses were stratified by sex.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| TDF-FTC as PrEP | Number of Sex Partners | Number of sex partners among women, overall | 0.87 sexual partners | Standard Deviation 0.53 |
| TDF-FTC as PrEP | Number of Sex Partners | Number of sex partners among men, overall | 1.03 sexual partners | Standard Deviation 0.74 |
Primary
Self-reported Drug Adherence Over the Past 3 Days
A 30-day supply of TDF/FTC was dispensed at each monthly visit, for up to 12 months. Participants were asked monthly about their drug adherence and were asked to recall their time of dosing over the past 3 days. Question: Please think back to \[yesterday, 2 days ago, 3 days ago\]. What time did you take Truvada? Was it in the morning, afternoon, evening, or you weren't able to take the pill that day?
Time frame: Up to 12 Months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| TDF-FTC as PrEP | Self-reported Drug Adherence Over the Past 3 Days | No doses taken in past 3 days | 19 Participants |
| TDF-FTC as PrEP | Self-reported Drug Adherence Over the Past 3 Days | Took daily dosage in past 3 days | 199 Participants |
| TDF-FTC as PrEP | Self-reported Drug Adherence Over the Past 3 Days | Took 2 doses in past 3 days | 9 Participants |
| TDF-FTC as PrEP | Self-reported Drug Adherence Over the Past 3 Days | Took 1 doses in past 3 days | 2 Participants |
Secondary
HIV Seroconversion
Study visits were scheduled every month until completion of the study and during monthly study visits, HIV testing was performed, for up to 12 months. During monthly visits, routine HIV testing was performed with two HIV rapid tests. If HIV-infection was suspected, HIV antigen-antibody (Ag/Ab) combination enzyme immunoassay (EIA) (Bio-Rad, GS HIV Combo Ag/Ab EIA) testing was performed, and RNA viral load was measured.
Time frame: Up to 12 Months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TDF-FTC as PrEP | HIV Seroconversion | 0 Participants |
Secondary
Serious Adverse Events
Study visits were scheduled every month until study completion. Participants were instructed to return to the clinic for evaluation in event of illness. Participants reported any adverse effects (AEs) at monthly or interim visits and were determined as serious adverse events (SAE) when at least possibly related to study drug. DAIDS Table for Grading Severity of Adult Adverse Experiences for Vaccine & Prevention Research Programs was used for grading. Definitions: Grade 3-'probably related'-strong temporal relationship to study product that cannot be explained by participant's clinical state or other factors and a causal relationship is biologically plausible. Grade 4-'definitely related'-distinct temporal relationship to administration of the study product that cannot be explained by the participant's clinical state or other factors or AE occurs on re-challenge or the AE is a known reaction to the product or chemical group or can be predicted by the product's pharmacology.
Time frame: Up to 12 Months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TDF-FTC as PrEP | Serious Adverse Events | Hyperamylasemia, Grade 3 | 2 participants |
| TDF-FTC as PrEP | Serious Adverse Events | Hypophosphatemia, Grade 3 | 5 participants |
| TDF-FTC as PrEP | Serious Adverse Events | Hypercreatininemia, Grade 1 | 1 participants |