CLINICAL ASSESSMENT OF HYPERSENSITIVITY TO ISONIAZID AND RIFAPENTINE IN STUDY 26

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. OBJECTIVE: The primary objective is to investigate a possible antibody-mediated hypersensitivity/flu-like illness that is sometimes accompanied by hypotension, occurring in patients treated with isoniazid 900 mg plus rifapentine 900 mg once-weekly or with isoniazid 300 mg daily. The secondary objective is to assess serum tryptase levels in persons with hypersensitivity syndrome associated with hypotension, uticaria-angioedema, or acute bronchospasm. RESEARCH PLAN: Patients in both treatment arms who do not have signs or symptoms of the hypersensitivity syndrome will have 10 cc of blood obtained at baseline before taking any study drug and again after 12 weeks of treatment. The blood will be collected in a serum separator tube and processed for storage and shipment to the facility designated by protocol (Johns Hopkins DACI Reference Laboratory). Controls who agree to participate in the sub-study will undergo the informed consent process at the first visit after study enrollment and before taking any medication. METHODS: The study design is a case-control study nested within a multi-center, prospective, randomized, open-label phase III clinical trial comparing the effectiveness of two treatment regimens for latent tuberculosis infection: "A study of the effectiveness and tolerability of weekly rifapentine/isoniazid for three months versus daily isoniazid for nine months for the treatment of latent tuberculosis infection" (TB Trials Consortium Study 26). Cases and controls will be recruited from among trial participants who are all high-risk tuberculin skin-test reactors who require treatment of latent infection to prevent tuberculosis. For this sub-study, a case is a clinical trial participant in either treatment arm who meets the definition of potential hypersensitivity syndrome. Controls will be participants from both study arms who do not meet the case definition. Sera from controls will be used to relate the frequency and intensity of drug-specific immune responses to the observed clinical hypersensitivity syndromes. A relatively small number of patients are expected to develop hypersensitivity syndrome in Study 26. To achieve sufficient power with a low number of cases, a case-control ratio of 1:4 will be implemented. CLINICAL RELEVANCE: The administration of anti-tuberculosis therapy has been made easier by the use of intermittent regimens (once or twice-weekly) instead of daily treatment regimens. Although these intermittent regimens are generally well-tolerated, intermittent rifampin has been associated with the development of a hypersensitivity syndrome which appears to be immune-mediated. This hypersensitivity syndrome can consist of any of the following influenza-like symptoms, either alone or in combination: fever, shivering, faintness, headache, myalgia, and arthralgia. Isoniazid can also cause a hypersensitivity reaction, but it is characterized by fever, skin eruptions, lymphadenopathy, and vasculitis. Rarely, INH can cause a flu-like syndrome. To date, both regimens in Study 26 have been generally well tolerated but some patients may have developed a hypersensitivity reaction. It is unclear whether this reaction is attributable to isoniazid, rifapentine, or both. Therefore, this study proposes to assess this possible hypersensitivity syndrome in greater detail.