HIV Infection
Conditions
Brief summary
The purpose of this study is to examine safety and tolerability of daily tenofovir use in HIV-uninfected men.
Detailed description
This study will assess the clinical and behavioral safety and tolerability of oral daily TDF use as pre-exposure prophylaxis (PrEP) to prevent HIV infection in uninfected men.
Interventions
DRUGtenofovir disoproxil fumarate
study product taken daily
DRUGplacebo
study product taken daily
Sponsors
San Francisco Department of Public Health
AIDS Research Consortium of Atlanta
Centers for Disease Control and Prevention
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
MALE
Age
18 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy biologic male (male at birth) * 18-60 years of age * HIV-1 negative by licensed, commercially available, FDA-approved whole blood rapid enzyme immunoassay (EIA) at screening and enrollment * Reports any anal sex with a man in the last 12 months * Able to understand and pass comprehension assessment questionnaire * Able to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures * Able to understand English * Adequate renal function: calculated creatinine clearance of at least 70 mL/min * Hepatic transaminases (AST and ALT) less than or equal to 2x upper limit of normal (ULN) * Total bilirubin less than or equal to 1.5 mg/dL * Absolute neutrophil count at least 1,500/mm3; * Platelets at least 100,000/mm3; * Hemoglobin at least 9.5 g/dL * Serum amylase less than or equal to 1.5 x ULN * Biochemical profile: within normal limits for serum phosphorus, potassium, sodium, and calcium. * Hepatitis B surface antigen negative * Normal urine dipstick or urinalysis (UA)
Exclusion criteria
* Active untreated syphilis * Current uncontrolled hypertension (blood pressure \> 160/100 mmHg) * Mutually monogamous for \> one year with a known HIV antibody negative partner * History of chronic renal disease, known osteoporosis, osteomalacia, or osteopenia * Current or expected participation in other longitudinal HIV behavioral or biomedical research study * Current HIV antiretroviral use * Receiving or planning to receive on-going therapy with any nephrotoxic agents or experimental/investigational agents * Previous or expected requirements for the administration of immunosuppressive/ immunomodulatory therapy (e.g. chronic systemic steroids, interferon, interleukins, chemotherapy, radiation). * Evidence of a gastrointestinal malabsorption syndrome or chronic nausea or vomiting which may confer an inability to receive an orally administered medication. * Current alcohol or substance abuse judged by the investigator to potentially interfere with participant compliance. * Imminently life-threatening medical conditions (malignancy, immunosuppressive disease \[e.g. lymphoma\]), or other serious disease or conditions (e.g. cardiovascular, renal, diabetes) within the last 5 years or that are unstable and/or require chronic medication that would impede compliance with study requirements and complicate the interpretation of adverse events * Expected to be non-compliant with study visits or planning to move within 24 months to an area where the study will not be conducted * Any other clinical or social condition, prior therapy, occupation, or other responsibility, that, in the opinion of the investigator, would interfere with, or serve as a contraindication to study participation or compliance with the dosing requirements.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Safety--Creatinine Elevations | 24 months (immediate arm) and 15 months (delayed arm) | Grade 3 or 4 Creatinine elevations (per National Institutes of Health Division of AIDS toxicity scale) |
| Clinical Safety--Hypophosphatemia | 24 months (immediate arm), 15 months (delayed arm) | Grade 3 or 4 hypophosphatemia (per National Institutes of Health Division of AIDS toxicity scale) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Breakthrough HIV Infections | 24 months (immediate arm) and 15 months (delayed arm) | Number of participants with HIV seroconversions occuring while on study drug |
| Adherence to Study Drug | 24 months (immediate arm) and 15 months (delayed arm) | Estimated exposure to study drug (active and placebo) as assessed by Medication Event Monitoring System (MEMS) caps. |
| Behavioral Safety--Unprotected Anal Sex (UAS) | Nine months | Change in percent of participants reporting unprotected anal intercourse--baseline vs. months 3 through 9 on study. |
Other
| Measure | Time frame | Description |
|---|---|---|
| >5% Bone Mineral Density Decline at Femoral Neck | 24 months (immediate arm), 15 months (delayed arm) | Percent of San Francisco participants in the TDF vs. placebo groups who were found to have \>5% decline in Bone Mineral Density at the femoral neck. |
Countries
United States
Participant flow
Recruitment details
Recruitment began in 1/2005 and was completed in 7/2007. Participant follow-up was completed in July 2009. Participants were recruited from: San Francisco Dept. of Public Health AIDS Research Consortium of Atlanta Fenway Health
Pre-assignment details
After an initial screening visit, participants were required to meet all enrollment criteria again at the enrollment visit.
Participants by arm
| Arm | Count |
|---|---|
| Tenofovir Disoproxil Fumarate Active arm: assigned to take TDF, 300mg po daily. | 201 |
| Placebo Placebo arm--received matching placebo | 199 |
| Total | 400 |
Baseline characteristics
| Characteristic | Placebo | Tenofovir Disoproxil Fumarate | 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 | 199 Participants | 201 Participants | 400 Participants |
| Age, Continuous | 36.7 years STANDARD_DEVIATION 11 | 38.7 years STANDARD_DEVIATION 9.3 | 37.7 years STANDARD_DEVIATION 10.2 |
| Region of Enrollment United States | 199 participants | 201 participants | 400 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 199 Participants | 201 Participants | 400 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 149 / 186 | 146 / 187 |
| serious Total, serious adverse events | 10 / 186 | 8 / 187 |
Outcome results
Primary
Clinical Safety--Creatinine Elevations
Grade 3 or 4 Creatinine elevations (per National Institutes of Health Division of AIDS toxicity scale)
Time frame: 24 months (immediate arm) and 15 months (delayed arm)
Population: For biomedical outcomes, a treatment emergent cohort was defined. Participants entered the TE cohort with first dispense and exited with the first occurrence of: (1) completion of follow-up, (2) 30 days after permanent drug interruption, or (3) 30 days after last visit. For delayed arm participants,time before initiation of drug was excluded.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenofovir Disoproxil Fumarate | Clinical Safety--Creatinine Elevations | 0 Participants |
| Placebo | Clinical Safety--Creatinine Elevations | 0 Participants |
Primary
Clinical Safety--Hypophosphatemia
Grade 3 or 4 hypophosphatemia (per National Institutes of Health Division of AIDS toxicity scale)
Time frame: 24 months (immediate arm), 15 months (delayed arm)
Population: For biomedical outcomes, a treatment emergent cohort was defined which included only those participants who received study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenofovir Disoproxil Fumarate | Clinical Safety--Hypophosphatemia | 1 participants |
| Placebo | Clinical Safety--Hypophosphatemia | 5 participants |
Secondary
Adherence to Study Drug
Estimated exposure to study drug (active and placebo) as assessed by Medication Event Monitoring System (MEMS) caps.
Time frame: 24 months (immediate arm) and 15 months (delayed arm)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenofovir Disoproxil Fumarate | Adherence to Study Drug | 77 percentage of doses |
Secondary
Behavioral Safety--Unprotected Anal Sex (UAS)
Change in percent of participants reporting unprotected anal intercourse--baseline vs. months 3 through 9 on study.
Time frame: Nine months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenofovir Disoproxil Fumarate | Behavioral Safety--Unprotected Anal Sex (UAS) | -9 percentage of ppts reporting UAS |
Secondary
Number of Breakthrough HIV Infections
Number of participants with HIV seroconversions occuring while on study drug
Time frame: 24 months (immediate arm) and 15 months (delayed arm)
Population: For biomedical outcomes, a treatment emergent cohort was defined which included only those participants who received study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenofovir Disoproxil Fumarate | Number of Breakthrough HIV Infections | 0 participants |
| Placebo | Number of Breakthrough HIV Infections | 4 participants |
Other Pre-specified
>5% Bone Mineral Density Decline at Femoral Neck
Percent of San Francisco participants in the TDF vs. placebo groups who were found to have \>5% decline in Bone Mineral Density at the femoral neck.
Time frame: 24 months (immediate arm), 15 months (delayed arm)
Population: For biomedical outcomes, a treatment emergent cohort was defined which included only those participants who received study drug. In addition, this analysis population includes only those participants for whom bone density analyses were performed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenofovir Disoproxil Fumarate | >5% Bone Mineral Density Decline at Femoral Neck | 13 percentage of participants |
| Placebo | >5% Bone Mineral Density Decline at Femoral Neck | 6 percentage of participants |