Bangkok Tenofovir Study, an HIV Pre-exposure Prophylaxis Trial, Bangkok, Thailand

Study of the Safety and Efficacy of Daily Tenofovir to Prevent HIV Infection Among Injection Drug Users in Bangkok, Thailand

The primary goals of this study are to assess the safety and efficacy of daily tenofovir to prevent parenteral HIV infection among injection drug users (IDUs). Assessment of changes in HIV associated risk behaviors, adherence to study drug, and, among IDU who become HIV-infected during the trial, evaluation of HIV viral load set point, CD4 counts, genetic characterization of infecting HIV viruses, and antiretroviral resistance will also be done.

This is a phase II/III, randomized, double-blind, placebo-controlled study of the safety and efficacy of chemoprophylactic tenofovir, administered orally once daily to IDUs. The study will be conducted in Bangkok at 17 BMA Drug Treatment Clinics. Study participants will be randomized (1:1) to receive tenofovir 300 mg or placebo. Participants will be evaluated for adverse events and HIV seroconversion.

Primary endpoints: The primary efficacy endpoint will be measured by rates of HIV seroconversion measured at monthly intervals. The primary safety endpoints will be measured by the frequency of Grade 3 or 4 renal or hepatic function laboratory toxicities or clinical toxicities in blinded tenofovir and placebo arms, as defined by the Gilead-modified NIAID Adult Common Toxicity Tables, and which cannot be directly attributed to a cause other than study medications; and the frequency of adverse clinical events in tenofovir and placebo arms.

Secondary endpoints: Changes in HIV associated risk behaviors will be measured by rates of reported injection drug use and injection drug use frequency during the trial; rates of reported needle sharing; the number of unprotected sexual acts over the course of the trial; number of reported sexual partners over the course of the trial; and proportional use of condoms during sexual intercourse.

Medication adherence will be measured as: rates, by interview and documentation on tenofovir adherence card, of participants taking at least six (86%) of seven daily doses of study drug each of the four weeks preceding the monthly study visit. Differences in virologic and immunologic responses to HIV infection among tenofovir and placebo recipients will be measured by: plasma viral load, measured by quantitative RNA PCR, a predictor of clinical progression of HIV disease; 14 CD4 cell counts will be measured by flow cytometry. Rates and nature of HIV antiretroviral genotypic and phenotypic resistance will be measured. Genetic characteristics of infecting HIV viruses including DNA sequence analysis and antibody binding studies will be conducted.

In phase II, participants will be followed months 0, 1, 2, 3, then 3 monthly with hematology and chemistry tests and laboratory evaluations of renal and hepatic function until 200 person-years of observation are accrued. At that point, a DSMB safety assessment will be conducted. Follow-up of enrolled participants will continue during the DSMB safety assessment. If safety is confirmed, all phase II participants will continue, and additional participants will be enrolled into the phase III portion of the trial. Accrual of the target enrollment of 2,400 IDUs is anticipated to take 48 months.

Participants will choose between two follow-up schedules: monthly (every 4 weeks) or monthly plus daily with directly observed therapy (DOT). During DOT visits clinic staff will witness the participant swallow his/her study medication and clinic staff will initial the participant's tenofovir adherence card. Monthly visits will be the same for both groups and will include an assessment of tenofovir adherence and adverse events, a pill count and collection of unused pills, provision of a new 1 month supply of study medication, pre- and post-test HIV counseling, rapid oral HIV testing, urine pregnancy test (for female participants), HIV risk reduction counseling, and medication adherence counseling. At 3, 6, and every 3 months thereafter monthly procedures will be supplemented with a risk behavior questionnaire.

Inclusion Criteria:

• Report injection drug use in the 6 months before screening
• Possess a Thai National Identification Card
• Laboratory values as follows within 2 weeks before enrollment:
• HIV oral fluid test non-reactive at screening and pre-enrollment visits
• Hemoglobin 9 gm/dL
• ALT and AST 2.5 x upper limit of normal (ULN)
• Total bilirubin 1.5 mg/dL
• Serum amylase 1.5 x ULN
• Serum phosphorus 2.2 mg/dL
• No evidence of current or chronic Hepatitis B infection by serology
• Calculated creatinine clearance 60 mL/min by the Cockcroft-Gault formula where creatinine clearance in mL/min = Male: (140 - age in years) x (wt in kg)/72 x (serum creatinine in mg/dL) Female:(140 - age in years) x (wt in kg) x 0.85/72 x (serum creatinine in mg/dL)
• Willing to abstain from sexual intercourse or use effective contraception during the trial (oral, injection, or barrier), for women
• Willing and able to provide informed consent for study participation
• Available and committed to DOT or monthly follow-up for at least 12 months

Exclusion Criteria:

• Clinic physicians will determine if a subject with chronic illness requiring prescription medication can not enroll (medication used for drug treatment is allowed)
• Positive urine pregnancy test
• Breastfeeding
• History of significant renal, liver, or bone disease
• Any other clinical condition or prior therapy that, in the opinion of the clinic physician, would make the subject unsuitable for the study or unable to comply with the dosing requirements
• Concurrent participation in any other HIV prevention trial or drug/vaccine safety trial. AIDSVAX B/E HIV vaccine trial (CDC protocol #2076) participants and Extension Study (CDC protocol #3750) participants may be screened for enrollment in the Bangkok Tenofovir Study.