Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized Trial to Compare Effectiveness of 4 Months Rifampin (4 RIF) With 9 Months Isoniazid (9 INH) in the Prevention of Active TB in Children: The P4v9 Trial
Brief Summary: Tuberculosis (TB) is spread by airborne transmission from adults with active contiguous TB to children, especially those living in the same household. Once children are exposed and infected they are at very high risk to develop active TB - which can be lethal if not detected and treated promptly. This makes it very important to detect TB infection as soon as possible, and treat this while it is still latent or dormant. Current therapy for latent TB infection is 9 months of Isoniazid; this is very effective if taken properly but because treatment is so long many children do not finish this. Four months of Rifampin is a recommended alternative. In adults this has been shown to be safer with much higher completion rates. However the effectiveness of this treatment is unclear, and is being studied in an ongoing study. The investigators plan to compare the safety as well as the acceptability and effectiveness of 4 months Rifampin with 9 months Isoniazid (standard treatment) in children in several sites in Canada and other countries.

It is hypothesized that among children at high risk for development of active TB, intolerance/adverse events will not be worse (non-inferiority), among those randomized to 4RIF compared to those randomized to 9INH. In addition completion of latent tuberculosis infection (LTBI) therapy will be significantly greater (superiority), and subsequent rates of active TB will not be significantly higher (non-inferiority) in children taking 4RIF.


Options:
A: Inclusion Criteria:

* Mother is HIV-infected. Hard copy documentation of the mother's HIV infection is unnecessary if a positive DNA PCR from her infant is available.
* Received Bacille Calmette-Guerin (BCG) vaccine up to and including the 30th day of life and at least 90 days prior to study entry
* Able to complete all study requirements
* Physician assessment of age-appropriate neurodevelopment in which the chronological age is corrected for gestational age for prematurely born infants
* Parent or legal guardian able and willing to provide signed informed consent
* Plan to live in the study area for at least 4 years
* For inclusion in HIV-infected stratum, infant must have a positive HIV-1 DNA PCR; for inclusion in HIV-uninfected stratum, infant must have a negative HIV-1 DNA PCR performed at \>= 4 weeks of age

Exclusion Criteria:

* Previous diagnosis of TB infection, TB disease or current treatment for TB infection or TB disease
* Previous receipt of INH
* Contact with a known acid fast bacilli (AFB) sputum smear or culture-positive case of TB before study entry
* Current acute or recurrent (3 or more prior episodes) lower respiratory tract disease
* Chronic persistent diarrhea
* Failure to thrive
* Contraindications for use of INH or TMP/SMX
* Require certain medications
* Known or suspected immune system diseases other than HIV
* Current or previous diagnosis of or treatment for cancer
* Current immunosuppressive therapy greater than 1 mg/kg/day of prednisone or equivalent
* Anticipated long-term oral or intravenous corticosteroid therapy (greater than 3 weeks). Those receiving nonsteroidal anti-inflammatory agents and inhaled corticosteroids are not excluded.
* Grade 3 or greater AST/SGOT, ALT/SGPT, ANC, hemoglobin, platelet count, rash, neuropathy, or myopathy at screening
* Any Grade 4 clinical or laboratory toxicity within 14 days prior to study entry
* Other acute or chronic conditions that, in the opinion of the investigator, may interfere with the study
B: Inclusion Criteria:

* HIV-infected children
* Resident in Cape Town
* Informed consent obtainable
* weight \> 2.5kg
* Access to transport
* HAART use for not less than 2 months but not more than 12 months with no significant demonstrated toxicity and good adherence

Exclusion Criteria:

* Chronic diarrhoea
* Current use of INH prophylaxis
* Prior hypersensitivity to INH prior history of allergy to sulphur drugs
* Prior history of allergy to sulphur drugs
* Severe anaemia (haemoglobin less than 7 gm/dl)
* Neutropenia (absoloute neutrophil count less than 400 cells)
* Thrombocytopenia (platelet count \< 50 000/uL)
* Non-reversible renal failure
* Clinical hepatitis
* Exposure to household TB contact, requiring INH prophylaxis
C: Inclusion Criteria:

* Children (age \<18) with documented positive TST (or in the absence of TST, a positive QFT or T-Spot) and prescribed 9INH for LTBI for the following indications:

  1. HIV positive (TST \>5 mm or QFT+)
  2. Age 5 or less (TST \>5 mm or QFT+)
  3. Other reason for immuno-compromised state - such as therapy for malignancy or post-transplant (TST \>5 mm or QFT+)
  4. Contact: with adult or adolescent with active contagious pulmonary TB. (TST \>5 mm or QFT +)
  5. Have both of the following factors if TST = 10-14mm or QFT + or one factor if TST \>15mm :

     1. Arrival in Canada, Australia, or Saudi Arabia in the past 2 years from countries with estimated annual incidence of active TB greater than 100 per 100,000
     2. Body mass index (BMI) less than 10th percentile for their age

Exclusion Criteria:

* Patients who were contacts of TB cases known to be resistant to Isoniazid, Rifampin, or both.
* Known HIV-infected individuals on anti-retroviral agents whose efficacy would be substantially reduced by Rifampin, unless therapy can safely be changed to agents not affected by Rifampin.
* Pregnant women - Rifampin and Isoniazid are considered safe in pregnancy but therapy is usually deferred until 2-3 months post-partum to avoid fetal risk and the potential for increased hepato-toxicity immediately post partum.
* Patients on any medication with clinically important drug interactions with Isoniazid or Rifampin, which their physician believes would make either arm contra-indicated.
* Patients with a history of allergy/hypersensitivity to Isoniazid or to Rifampin, Rifabutin, or Rifapentine.
* Patients with active TB. Patients initially suspected to have active TB can be randomized once this has been excluded.
* Prior complete LTBI therapy or if children have taken \>1 week and are still taking the treatment. Children will be eligible if they took an incomplete LTBI therapy (less than 80% of recommended total dose) but \> 6 months ago.
D: Inclusion Criteria:

The inclusion criteria for this study will be San Francisco Jail inmates, age 18 or older (the jail does not house juveniles) having evidence of M. tuberculosis infection by positive tuberculin skin test (a documented reactive tuberculin skin test to 0.1 mL containing 5 Tuberculin Units) who meet current national criteria for therapy for tuberculosis infection and can provide informed consent.

Exclusion Criteria:

* Ineligible for either therapy regimen for any of the following reasons:

  1. history of treatment-limiting reaction to isoniazid or rifamycins;
  2. pregnancy or breast feeding;
  3. active tuberculosis;
  4. an aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>3 times the upper limit of normal;
  5. bilirubin \>2 times the upper limit of normal;
  6. platelets \<150 K/mm3;
  7. taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors (NNRTIs);
* Unable to communicate in English or Spanish;
* Unable or unwilling to provide informed consent;
* Not in the routine level of jail security for any reason (housed in "special security" areas);
* Any condition that, in the best judgment of the investigator, would pose a risk to the subject during the study.

Answer: C