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A5279: Phase III Clinical Trial of Ultra-Short-Course Rifapentine/Isoniazid for the Prevention of Active Tuberculosis in HIV-Infected Individuals with Latent Tuberculosis Infection

Description

The World Health Organization (WHO) estimates that in 2009 there were 9.4 million new cases of TB, and 1.68 million people died as a result of TB. Among new TB cases, 1.1 million occurred in people who were HIV-coinfected, and 35% of TB deaths were among HIV-coinfected individuals. In Africa, TB is the leading AIDS-related opportunistic infection. Latent TB infection occurs when people are infected with the bacteria that cause TB, but they do not have any symptoms of TB infection. Latent TB can develop into active TB, and HIV-infected people have an increased risk of progressing from latent TB to active TB. INH is a medication that is prescribed for people with latent TB to help prevent active TB from developing. The standard INH treatment regimen is 6 to 9 months; a shorter treatment regimen may prove to be as effective and may improve adherence. The purpose of this study is to compare the safety and effectiveness of a 4-week daily regimen of RPT plus INH to a standard 9-month daily INH regimen for TB prevention in HIV-infected individuals. This study will enroll HIV-infected people who do not have evidence of active TB but who are at high risk of developing active TB. Participants will be randomly assigned to receive RPT and INH once a day for 4 weeks or INH once a day for 9 months. All participants will receive pyridoxine (vitamin B6) with each dose of INH to help prevent possible side effects. Study visits will occur at baseline and Weeks 2, 4, 8, 12, 16, 20, 24, and 36. At select study visits, participants will undergo a physical exam, clinical assessment, blood collection, and a chest radiograph or chest computed tomography (CT) scan (if needed). Some participants will have their blood stored for future testing. Follow-up study visits will occur every 12 weeks starting at Week 48 and will continue for 3 years after the last participant is enrolled.

Phase

Phase 3 - a treatment has shown activity against a particular disease, where it is either added to existing treatment or compared to the standard treatment.

Inclusion and Exclusion Criteria

  • - HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral load. Two or more HIV-1 RNA viral loads of greater than 1,000 copies/mL are also acceptable as documentation of HIV infection. More information on this criterion can be found in the protocol. - Tuberculin skin test (TST) reactivity greater than or equal to 5 mm or a positive interferon gamma release assay (IGRA) at any time prior to study entry, OR living in a high TB burden area. More information on this criterion can be found in the protocol. - Laboratory values obtained within 30 days prior to study entry:
  • Absolute neutrophil count (ANC) greater than 750 cells/mm^3
  • Hemoglobin greater than or equal to 7.4 g/dL
  • Platelet count greater than or equal to 50,000/mm^3
  • AST (SGOT) and ALT (SGPT) less than or equal to three times the upper limit of normal (ULN)
  • Total bilirubin less than or equal to 2.5 times the ULN - Chest radiograph or chest CT scan without evidence of active tuberculosis, unless one has been performed within 30 days prior to entry - Female participants of reproductive potential must have a negative serum or urine pregnancy test performed within 7 days prior to study entry. More information on this criterion can be found in the protocol. - All participants must agree not to participate in a conception process (e.g., active attempt to become pregnant or to impregnate, donate sperm, in vitro fertilization) while receiving RPT and for 6 weeks after stopping this drug - Female participants who are participating in sexual activity that could lead to pregnancy must agree to use one reliable non-hormonal form of contraceptive (i.e., condoms, intrauterine device [IUD]), diaphragm with spermicide, or cervical cap with spermicide) while receiving RPT and for 6 weeks after stopping this drug. More information on this criterion can be found in the protocol. - Weight of greater than or equal to 30 kg - Participant or legal guardian is able and willing to provide informed consent

  • Treatment for active or latent TB (pulmonary or extrapulmonary) within 2 years prior to study entry or, at screening, presence of any confirmed or probable TB based on criteria listed in the current ACTG Diagnosis Appendix
  • History of multi-drug resistant (MDR) or extensively-drug resistant (XDR) TB at any time prior to study entry
  • Known exposure to MDR or XDR TB (e.g., household member of a person with MDR or XDR TB) at any time prior to study entry
  • Treatment for more than 14 consecutive days with a rifamycin or more than 30 consecutive days with INH at any time during the 2 years prior to enrollment
  • For participants taking antiretroviral therapy (ART) at study entry, only approved nucleoside reverse transcriptase inhibitors (NRTIs) with efavirenz (EFV) or nevirapine (NVP) for at least 4 weeks are permitted. Any other regimens at entry are exclusionary. A list of approved antiretroviral drugs is located on the A5279 protocol-specific webpage (PSWP). Participants on NVP must be dosed at 200 mg twice daily (BID). NOTE A: NVP trough levels will be evaluated in the first 90 participants in Arm A who are receiving NVP at entry and who meet other criteria in Section 10.0 of the protocol, after which enrolment for participants on NVP may be temporarily halted. NVP PK data will be evaluated to determine whether standard NVP dosing results in adequate PK drug exposure in the presence of RPT treatment. If the A5279 team determines that concomitant dosing of NVP and RPT results in adequate drug exposure, the study may continue enrollment of participants receiving NVP. NOTE B: Participants randomized to Arm A may initiate any ART regimen after completing 4 weeks of RPT/INH. Participants randomized to Arm B may initiate any ART regimen after study entry.
  • History of liver cirrhosis at any time prior to study entry
  • Evidence of acute hepatitis, such as abdominal pain, jaundice, dark urine, and/or light stools within 90 days prior to study entry
  • Diagnosis of porphyria at any time prior to study entry
  • Peripheral neuropathy greater than or equal to Grade 2 according to the December 2004 (Clarification, August 2009) Division of AIDS (DAIDS) Toxicity Table, within 90 days prior to study entry
  • Known allergy/sensitivity or any hypersensitivity to components of study drugs or their formulation
  • Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements
  • Serious illness requiring systemic treatment and/or hospitalization within 30 days prior to study entry
  • Breastfeeding

Sites

  • California

    • Usc La Nichd Crs, Alhambra, California, 91803
    • UCLA CARE Center CRS, Los Angeles, California, 90035
    • Harbor-UCLA CRS, Torrance, California, 90502
    • UCSD Antiviral Research Center CRS, San Diego, California, 92103
    • Ucsf Hiv/Aids Crs, San Francisco, California, 94110
  • Colorado

    • Denver Public Health CRS, Denver, Colorado, 80204
    • University of Colorado Hospital CRS, Aurora, Colorado, 80045
    • Univ. of Colorado Denver NICHD CRS, Aurora, Colorado, 80045
  • Washington

    • Seattle Children's Research Institute CRS, Seattle, Washington, 98101
  • Texas

    • Trinity Health and Wellness Center CRS, Dallas, Texas, 75208
    • Houston AIDS Research Team CRS, Houston, Texas, 77030
  • Illinois

    • Rush University CRS, Chicago, Illinois, 60612
    • Northwestern University CRS, Chicago, Illinois, 60611
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