HIV-1 Infections, HIV Infections
Conditions
Keywords
HIV infection, HIV uninfected partners, Double Blind, Placebo, Seroconversion, TDF, FTC TDF, Safety, HIV Seronegativity
Brief summary
Randomized, blinded, placebo-controlled trial to demonstrate if pre-exposure prophylaxis decreases HIV-1 acquisition among HIV-1 uninfected individuals within HIV-1 discordant couples.
Detailed description
HIV-1 uninfected individuals within HIV-1 discordant partnerships are at high-risk for HIV-acquisition. The majority of HIV-1 transmissions to adults in Africa occur within stable, HIV-1 discordant couples. Pre-exposure chemoprophylaxis, in which an HIV-1 uninfected individual at high risk for contracting HIV-1 takes antiretroviral medications to maintain blood and genital drug levels sufficient to prevent HIV-1 acquisition, has been proposed as a potential HIV-1 prevention strategy. This study was a randomized, blinded, placebo-controlled trial to demonstrate if pre-exposure prophylaxis decreases HIV-1 acquisition among HIV-1 uninfected individuals within HIV-1 discordant couples. The HIV-1 uninfected partner was randomized in a 1:1:1 ratio to one of three arms: once daily Tenofovir Disoproxil Fumarate (TDF), Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) or Placebo. Couples were followed up to 36 months; the HIV uninfected partner attended monthly visits and the HIV infected partner quarterly visits. All participants received a comprehensive package of HIV prevention services including individual and couples counseling, free condoms, and male circumcision referrals. Participants who seroconverted during follow-up stopped the study drug but continued with follow-up.
Interventions
TDF 300 mg tablet, once daily + Placebo FTC/TDF orally, once daily.
FTC/TDF - 200 mg tablet, once daily + Placebo TDF orally, once daily
DRUGPlacebo
Placebo TDF & Placebo FTC/TDF, 1 tablet each daily.
Sponsors
Bill and Melinda Gates Foundation
University of Washington
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
for HIV-1 uninfected partner: * Partner within an HIV-1 discordant heterosexual relationship * One partner meets study eligibility for HIV-1 uninfected study participant and the other partner meets study eligibility criteria for HIV-1 infected participant * Plan to remain in the relationship for the duration of the study period * Adequate renal, hepatic & hematologic function * Negative Hepatitis B surface antigen test * Willing and able to provide written informed consent & locator information
Exclusion criteria
for HIV-1 uninfected partner: * Current pregnancy, or planning to become pregnant during the study period * Currently breastfeeding * Concurrent enrollment in another HIV-1 vaccine or prevention trial * Receiving ongoing antiretroviral therapy * Repeated positive urine dipstick tests for glycosuria or proteinuria * Active and serious infections * History of pathological bone fractures not related to trauma Inclusion Criteria for HIV-1 infected partner: * Partner within an HIV-1 discordant heterosexual relationship * One partner meets study eligibility for HIV-1 uninfected study participant and the other partner meets study eligibility criteria for HIV-1 infected participant * HIV-1 infected based on positive EIA * No history of any clinical AIDS-defining diagnoses * Plan to remain in the relationship for the duration of the study period * Willing and able to provide written informed consent & locator information
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of HIV-1 Seroconversion Among HIV-1 Uninfected Participants | Up to 36 months | The efficacy of once daily PrEP in preventing HIV-1 acquisition among uninfected heterosexuals in HIV-1 discordant partnerships, measured by calculating the HIV incidence per 100 person-years in each of three arms. |
| Number of Participants With Serious Adverse Events (SAEs) | Up to 36 months | Safety of daily TDF or FTC/TDF among HIV-1 uninfected individuals randomized to TDF or FTC/TDF compared to those randomized to placebo measured as the number of participants with Serious Adverse Events (SAEs) during follow-up. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Seroconverters With an HIV-1 Mutation Conferring Resistance to TDF or FTC | Up to 36 months | HIV-1 resistance as measured by the number of seroconverters who had an HIV-1 reverse transcriptase mutation (K65R, K70E, M184I, or M184V) conferring resistance to TDF or FTC. These mutation types were pre-defined. Plasma samples for resistance testing were collected at the visit seroconversion was first detected and again at a visit within 1 month of seroconversion. Mutations detected at either of those visits are reported. Both seroconverters found to have a resistance mutation had been HIV infected at enrollment (TDF arm: n=1; FTC-TDF arm: n=1). |
| Number of Participants With a Sexually Transmitted Infection (STI) During Follow-up | Up to 36 months | Prevalence of STIs measured as the number of participants with a positive test result for N. gonorrhoeae, C. trachomatis, or T. vaginalis during follow-up. Participants were tested for STIs at annual follow-up visits and at intervening visits at which the participant presented with symptoms of an STI. Assessment for symptomatic sexually transmitted infections was conducted quarterly. N. gonorrhoeae and C. trachomatis testing were by APTIMA Combo 2 (Gen-Probe) or COBAS Amplicor (Roche Diagnostics). T. vaginalis testing was by APTIMA TV TMA (Gen-Probe) or In Pouch TV (Biomed Diagnostics). |
| Prevalence of Unprotected Sex During Follow-up | Up to 36 months | Sexual risk behavior of participants, measured as the percentage of visits when participants reported having unprotected sex during follow-up. |
| Study Drug Adherence: Total Number of Study Drug Doses Taken of the Total Dispensed Doses. | Up to 36 months | Adherence to study medication as assessed by pill count at follow-up visits. We assessed the total number of doses taken of the total dispensed doses. |
| Length Among Infants Born to Female Participants Taking Study Drug | up to 12 months | The slope of the linear model of the growth of infants (length) during the entirety of follow-up. The length of the infant was measured as a z-score, in terms of standard deviations from the age and gender specific median using the World Health Organization growth curve, accounting for skewness. The slope, representing the change over time of the z-score, was calculated using all available z-scores over 12 months and regressing against study month. |
| Weight Among Infants Born to Female Participants Taking Study Drug | up to 12 months | The slope of the linear model of the growth of infants (weight) during the entirety of follow-up. The weight of the infant was measured as a z-score, in terms of standard deviations from the age and gender specific median using the World Health Organization growth curve, accounting for skewness. The slope, representing the change over time of the z-score, was calculated using all available z-scores over 12 months and regressing against study month. |
| Head Circumference Among Infants Born to Female Participants Taking Study Drug | up to 12 months | The slope of the linear model of the growth of infants (head circumference) during the entirety of follow-up. The head circumference of the infant was measured as a z-score, in terms of standard deviations from the age and gender specific median using the World Health Organization growth curve, accounting for skewness. The slope, representing the change over time of the z-score, was calculated using all available z-scores over 12 months and regressing against study month. |
| Congenital Abnormalities Among Infants Born to Female Participants Taking Study Drug. | Up to 36 months | Infant outcomes measured as the number of live-born infants born to female participants taking study drug that had any congenital anomalies. |
| Study Drug Adherence: Self-reported Missed Doses of Study Drug | Up to 36 months | Adherence to study drug measured as the percentage of visits when participants reported missing 1) any dose of study drug in the prior month and 2) 2 or more consecutive doses of study drug. |
Countries
Kenya, Uganda
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tenofovir Disoproxil Fumarate (TDF) TDF 300 mg tablet, once daily + Placebo FTC/TDF orally, once daily. | 1,584 |
| Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) FTC/TDF - 200 mg tablet, once daily + Placebo TDF orally, once daily | 1,579 |
| Placebo Placebo TDF & Placebo FTC/TDF, 1 tablet each daily. | 1,584 |
| Total | 4,747 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Ineligible | 5 | 4 | 2 |
| Overall Study | Lost to Follow-up | 7 | 8 | 10 |
Baseline characteristics
| Characteristic | Tenofovir Disoproxil Fumarate (TDF) | Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) | Placebo | Total |
|---|---|---|---|---|
| Age, Customized 18-24 years | 184 participants | 177 participants | 172 participants | 533 participants |
| Age, Customized 25-34 years | 721 participants | 690 participants | 688 participants | 2099 participants |
| Age, Customized 35-44 years | 480 participants | 498 participants | 513 participants | 1491 participants |
| Age, Customized 45 years and older | 199 participants | 214 participants | 211 participants | 624 participants |
| Percentage of participants who had unprotected sex in the past month | 27.9 percentage of participants | 26.3 percentage of participants | 25.8 percentage of participants | 26.7 percentage of participants |
| Region of Enrollment Kenya | 700 participants | 698 participants | 697 participants | 2095 participants |
| Region of Enrollment Uganda | 884 participants | 881 participants | 887 participants | 2652 participants |
| Sex: Female, Male Female | 598 Participants | 566 Participants | 621 Participants | 1785 Participants |
| Sex: Female, Male Male | 986 Participants | 1013 Participants | 963 Participants | 2962 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 1,306 / 1,584 | 1,316 / 1,579 | 1,297 / 1,584 |
| serious Total, serious adverse events | 118 / 1,584 | 115 / 1,579 | 118 / 1,584 |
Outcome results
Primary
Incidence of HIV-1 Seroconversion Among HIV-1 Uninfected Participants
The efficacy of once daily PrEP in preventing HIV-1 acquisition among uninfected heterosexuals in HIV-1 discordant partnerships, measured by calculating the HIV incidence per 100 person-years in each of three arms.
Time frame: Up to 36 months
Population: All randomized participants, less those who were found to ineligible (n=11), less those found to be infected at enrollment (n=14), and less those who did not return for any follow-up (n=25).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenofovir Disoproxil Fumarate (TDF) | Incidence of HIV-1 Seroconversion Among HIV-1 Uninfected Participants | 0.65 events per 100 person years |
| Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) | Incidence of HIV-1 Seroconversion Among HIV-1 Uninfected Participants | 0.50 events per 100 person years |
| Placebo | Incidence of HIV-1 Seroconversion Among HIV-1 Uninfected Participants | 1.99 events per 100 person years |
Comparison: We used Cox regression stratified according to site, to estimate the relative rates of time to first positive HIV-1 serologic test.p-value: <0.00195% CI: [0.19, 0.56]Regression, Cox
Comparison: We used Cox regression stratified according to site, to estimate the relative rates of time to first positive HIV-1 serologic test.p-value: <0.00195% CI: [0.13, 0.45]Regression, Cox
Primary
Number of Participants With Serious Adverse Events (SAEs)
Safety of daily TDF or FTC/TDF among HIV-1 uninfected individuals randomized to TDF or FTC/TDF compared to those randomized to placebo measured as the number of participants with Serious Adverse Events (SAEs) during follow-up.
Time frame: Up to 36 months
Population: Randomized participants, less those found to be ineligible (n=11)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenofovir Disoproxil Fumarate (TDF) | Number of Participants With Serious Adverse Events (SAEs) | 118 Participants |
| Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) | Number of Participants With Serious Adverse Events (SAEs) | 115 Participants |
| Placebo | Number of Participants With Serious Adverse Events (SAEs) | 118 Participants |
p-value: 1Fisher Exact
p-value: 0.89Fisher Exact
Secondary
Congenital Abnormalities Among Infants Born to Female Participants Taking Study Drug.
Infant outcomes measured as the number of live-born infants born to female participants taking study drug that had any congenital anomalies.
Time frame: Up to 36 months
Population: Randomized female participants, less those found to be ineligible (n=7)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenofovir Disoproxil Fumarate (TDF) | Congenital Abnormalities Among Infants Born to Female Participants Taking Study Drug. | 4 Number of live-born infants |
| Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) | Congenital Abnormalities Among Infants Born to Female Participants Taking Study Drug. | 4 Number of live-born infants |
| Placebo | Congenital Abnormalities Among Infants Born to Female Participants Taking Study Drug. | 5 Number of live-born infants |
p-value: 0.51Regression, Logistic
p-value: 0.86Regression, Logistic
Secondary
Head Circumference Among Infants Born to Female Participants Taking Study Drug
The slope of the linear model of the growth of infants (head circumference) during the entirety of follow-up. The head circumference of the infant was measured as a z-score, in terms of standard deviations from the age and gender specific median using the World Health Organization growth curve, accounting for skewness. The slope, representing the change over time of the z-score, was calculated using all available z-scores over 12 months and regressing against study month.
Time frame: up to 12 months
Population: Infants born to women taking study drug during follow-up
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenofovir Disoproxil Fumarate (TDF) | Head Circumference Among Infants Born to Female Participants Taking Study Drug | -0.057 z-score difference per study month |
| Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) | Head Circumference Among Infants Born to Female Participants Taking Study Drug | -0.005 z-score difference per study month |
| Placebo | Head Circumference Among Infants Born to Female Participants Taking Study Drug | -0.079 z-score difference per study month |
p-value: 0.35Mixed Models Analysis
p-value: 0.008Mixed Models Analysis
Secondary
Length Among Infants Born to Female Participants Taking Study Drug
The slope of the linear model of the growth of infants (length) during the entirety of follow-up. The length of the infant was measured as a z-score, in terms of standard deviations from the age and gender specific median using the World Health Organization growth curve, accounting for skewness. The slope, representing the change over time of the z-score, was calculated using all available z-scores over 12 months and regressing against study month.
Time frame: up to 12 months
Population: Infants born to women taking study drug during follow-up
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenofovir Disoproxil Fumarate (TDF) | Length Among Infants Born to Female Participants Taking Study Drug | -0.006 z-score difference per study month |
| Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) | Length Among Infants Born to Female Participants Taking Study Drug | 0.036 z-score difference per study month |
| Placebo | Length Among Infants Born to Female Participants Taking Study Drug | -0.033 z-score difference per study month |
p-value: 0.42Mixed Models Analysis
p-value: 0.08Mixed Models Analysis
Secondary
Number of Participants With a Sexually Transmitted Infection (STI) During Follow-up
Prevalence of STIs measured as the number of participants with a positive test result for N. gonorrhoeae, C. trachomatis, or T. vaginalis during follow-up. Participants were tested for STIs at annual follow-up visits and at intervening visits at which the participant presented with symptoms of an STI. Assessment for symptomatic sexually transmitted infections was conducted quarterly. N. gonorrhoeae and C. trachomatis testing were by APTIMA Combo 2 (Gen-Probe) or COBAS Amplicor (Roche Diagnostics). T. vaginalis testing was by APTIMA TV TMA (Gen-Probe) or In Pouch TV (Biomed Diagnostics).
Time frame: Up to 36 months
Population: Randomized participants, less those found to be ineligible (n=11)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenofovir Disoproxil Fumarate (TDF) | Number of Participants With a Sexually Transmitted Infection (STI) During Follow-up | 102 participants |
| Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) | Number of Participants With a Sexually Transmitted Infection (STI) During Follow-up | 76 participants |
| Placebo | Number of Participants With a Sexually Transmitted Infection (STI) During Follow-up | 85 participants |
p-value: 0.24Regression, Logistic
p-value: 0.49Regression, Logistic
Secondary
Number of Seroconverters With an HIV-1 Mutation Conferring Resistance to TDF or FTC
HIV-1 resistance as measured by the number of seroconverters who had an HIV-1 reverse transcriptase mutation (K65R, K70E, M184I, or M184V) conferring resistance to TDF or FTC. These mutation types were pre-defined. Plasma samples for resistance testing were collected at the visit seroconversion was first detected and again at a visit within 1 month of seroconversion. Mutations detected at either of those visits are reported. Both seroconverters found to have a resistance mutation had been HIV infected at enrollment (TDF arm: n=1; FTC-TDF arm: n=1).
Time frame: Up to 36 months
Population: Participants who seroconverted during the Partners PrEP trial, including those who were retrospectively found to be HIV infected at enrollment (TDF arm: n=5; FTC-TDF arm: n=3; placebo arm: n=6). For 4 of 96 HIV-1 seroconverters (TDF arm: n=2; FTC-TDF arm: n=1; placebo arm: n=1) HIV-1 RNA was unable to be amplified for HIV-1 resistance testing.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenofovir Disoproxil Fumarate (TDF) | Number of Seroconverters With an HIV-1 Mutation Conferring Resistance to TDF or FTC | 1 Participants |
| Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) | Number of Seroconverters With an HIV-1 Mutation Conferring Resistance to TDF or FTC | 1 Participants |
| Placebo | Number of Seroconverters With an HIV-1 Mutation Conferring Resistance to TDF or FTC | 0 Participants |
Secondary
Prevalence of Unprotected Sex During Follow-up
Sexual risk behavior of participants, measured as the percentage of visits when participants reported having unprotected sex during follow-up.
Time frame: Up to 36 months
Population: All randomized participants, less those found to be ineligible (n=11).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenofovir Disoproxil Fumarate (TDF) | Prevalence of Unprotected Sex During Follow-up | 14 percentage of visits |
| Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) | Prevalence of Unprotected Sex During Follow-up | 13 percentage of visits |
| Placebo | Prevalence of Unprotected Sex During Follow-up | 13 percentage of visits |
p-value: 0.32Regression, Logistic
p-value: 0.66Regression, Logistic
Secondary
Study Drug Adherence: Self-reported Missed Doses of Study Drug
Adherence to study drug measured as the percentage of visits when participants reported missing 1) any dose of study drug in the prior month and 2) 2 or more consecutive doses of study drug.
Time frame: Up to 36 months
Population: Participants with self-reported adherence.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tenofovir Disoproxil Fumarate (TDF) | Study Drug Adherence: Self-reported Missed Doses of Study Drug | Missed any doses | 15 percentage of visits |
| Tenofovir Disoproxil Fumarate (TDF) | Study Drug Adherence: Self-reported Missed Doses of Study Drug | Missed 2+ consecutive doses | 4 percentage of visits |
| Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) | Study Drug Adherence: Self-reported Missed Doses of Study Drug | Missed any doses | 15 percentage of visits |
| Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) | Study Drug Adherence: Self-reported Missed Doses of Study Drug | Missed 2+ consecutive doses | 4 percentage of visits |
| Placebo | Study Drug Adherence: Self-reported Missed Doses of Study Drug | Missed 2+ consecutive doses | 4 percentage of visits |
| Placebo | Study Drug Adherence: Self-reported Missed Doses of Study Drug | Missed any doses | 15 percentage of visits |
Secondary
Study Drug Adherence: Total Number of Study Drug Doses Taken of the Total Dispensed Doses.
Adherence to study medication as assessed by pill count at follow-up visits. We assessed the total number of doses taken of the total dispensed doses.
Time frame: Up to 36 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenofovir Disoproxil Fumarate (TDF) | Study Drug Adherence: Total Number of Study Drug Doses Taken of the Total Dispensed Doses. | 97 percentage of doses taken of dispensed |
| Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) | Study Drug Adherence: Total Number of Study Drug Doses Taken of the Total Dispensed Doses. | 97 percentage of doses taken of dispensed |
| Placebo | Study Drug Adherence: Total Number of Study Drug Doses Taken of the Total Dispensed Doses. | 97 percentage of doses taken of dispensed |
Secondary
Weight Among Infants Born to Female Participants Taking Study Drug
The slope of the linear model of the growth of infants (weight) during the entirety of follow-up. The weight of the infant was measured as a z-score, in terms of standard deviations from the age and gender specific median using the World Health Organization growth curve, accounting for skewness. The slope, representing the change over time of the z-score, was calculated using all available z-scores over 12 months and regressing against study month.
Time frame: up to 12 months
Population: Infants born to women taking study drug during follow-up
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenofovir Disoproxil Fumarate (TDF) | Weight Among Infants Born to Female Participants Taking Study Drug | -0.021 z-score difference per study month |
| Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) | Weight Among Infants Born to Female Participants Taking Study Drug | 0.009 z-score difference per study month |
| Placebo | Weight Among Infants Born to Female Participants Taking Study Drug | -0.056 z-score difference per study month |
p-value: 0.02Mixed Models Analysis
p-value: <0.001Mixed Models Analysis