Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized Clinical Trial of Immediate Versus Standard Antiretroviral Therapy for HIV-infected Adults Presenting With Cryptococcal Meningitis
Brief Summary: The goal of this randomized clinical trial is to compare early versus standard timing of initiation of antiretroviral therapy (ART) with respect to clearance of Cryptococcus neoformans from cerebrospinal fluid (CSF) among HIV-infected adults with Cryptococcal Meningitis.

The investigators hypothesize that early ART mediates more rapid clearance of C. neoformans from CSF, as manifested by a greater rate of decrease in C. neoformans colony forming units (CFUs) during the first 28 days after initiating antifungal treatment.

Secondary hypotheses are that recovery of pathogen specific cellular immunity directed at C. neoformans, as manifested by increases in the number and function of C. neoformans-specific peripheral blood mononuclear cells is associated with 1) ART and 2) pathogen clearance. In addition, patients randomized to the intervention arm will have more rapid clearance of antigen levels in CSF and serum and will have a lower incidence of grade 3 and 4 Adverse events.


Options:
A: Inclusion Criteria:

* First episode of cryptococcal meningitis as evidenced by a positive cerebrospinal fluid (CSF) stain or cryptococcal antigen, CSF culture pending
* Documentation of proven diagnosis of HIV-1 infection by acceptable labs at any time in the past: this testing includes Enzyme-linked immunosorbent assay (ELISA) or approved rapid testing method with confirmation by Western blot, a second positive ELISA, a positive HIV antigen, or HIV RNA detection.

OR

-Presumptive diagnosis of HIV-1 by approved rapid testing method at screening. This testing must be confirmed by a second ELISA (or Western blot), a positive HIV antigen, or HIV RNA detection within 10 days of study entry.

OR

* Presumptive HIV+. If serologic testing is not available, a history of an AIDS-defining illness (Category C, CDC, 1993) or any of the following conditions: extrapulmonary Pneumocystis carinii disease; multi-dermatomal herpes zoster (\>10 lesions in a non-contiguous site); American trypanosomiasis (Chagas disease) of the CNS; Penicillium marneffei disease; visceral leishmaniasis; non-Hodgkin's lymphoma of any cell-type; Hodgkin's lymphoma; bartonellosis; microsporidiosis (\>1 month's duration); nocardiosis; invasive aspergillosis; or Rhodococcus equi disease. Confirmation of HIV infection by lab testing, i.e., ELISA or approved rapid testing method with confirmation by Western blot, a second positive ELISA, a positive HIV antigen, or HIV RNA detection must be performed within 10 days of study entry.
* Subjects who are 13 years of age or greater.
* Baseline electrocardiogram (ECG) with QTc interval less than or equal to 500 milliseconds as determined by use of Fredericia's Correction formula.
* Ability of subject or legally authorized representative to give informed consent. For subjects who are unable to provide informed consent, sites will follow their own individual Institutional Review Board (IRB) policy regarding the informed consent process.

Exclusion Criteria:

* Pregnancy. Urine or serum testing must be performed at study entry or within the 7 days prior to study entry.
* Women of childbearing potential unwilling to use a medically approved and highly effective form of birth control while on study drug and for 2 weeks after last dose. Acceptable forms of birth control include an intrauterine device (IUD), oral contraceptives, condoms, abstinence, injectable contraceptive, or any other highly effective means of birth control. (A highly effective method of birth control is defined as those which result in a low failure rate \[i.e. less than 1 percent per year\] when used consistently and correctly.) Emergency contraceptive treatment and coitus interruptus are not considered effective forms of contraception.
* Breastfeeding.
* A concurrent central nervous system (CNS) process that in the opinion of the investigator would interfere with assessment of response, such as lymphoma, toxoplasmosis, or tuberculosis.
* Other conditions that in the opinion of the investigator would jeopardize the safety of a subject participating in the study or would render the subject unable to comply with the study plan, such as homelessness or IV drug use.
* Estimated creatinine clearance of less than 50 mL/min. NOTE: Testing must be performed at study entry or within the 7 days prior to study entry.
* Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 5x the upper limit of normal or bilirubin greater than 2.5 x the upper limit of normal. Results from tests performed within the 7 days prior to study entry may be used.
* Known intolerance of or allergy to fluconazole or amphotericin B.
* Subjects unlikely to survive for 2 weeks.
* Coma.
* More than 3 days of any systemic antifungal therapy for this fungal infection, or the need for concurrent systemic antifungal therapy, including flucytosine or interferon-g. Subjects taking fluconazole at less than or equal to 200 mg/day for prophylaxis are not excluded.
* Inability to take oral medications.
* Subjects who have received the following drugs within 7 days of study enrollment: rifampin, rifamycin, rifabutin, phenytoin, carbamazepine, cyclosporin A, tacrolimus, sirolimus, or long-acting barbiturates.
* Subjects who are receiving nevirapine at baseline.
* Strong clinical suspicion of untreated active tuberculosis. (Patients on anti-TB therapy not including rifampin or rifamycin may be eligible.)
* Previous participation in this study or ongoing participation in another trial with an investigational drug.
* Prior case of cryptococcosis with diagnosed central nervous system involvement.
B: Inclusion Criteria:

* HIV infection documented by a positive HIV antibody test at enrollment;
* Adult men and women (age\>18);
* Cryptococcal meningitis infection documented by a positive CSF CRAG or CSF identification of C. neoformans.
* Place of residence is located within a 50km radius of Harare.

Exclusion Criteria:

* Previous diagnosis (\>1 week) of and treatment for cryptococcal meningitis
* Currently on ARVs, or have been intermittently on and off ART in the past.
* Concurrent use of medications that affect the metabolism of fluconazole e.g., antiseizure medications, oral hypoglycaemic agents.
* History of cardiac failure and or predisposition to arrhythmias will be excluded.
* They are pregnant or active lactation women
* History of active hepatitis or hepatic or renal dysfunction will be excluded.
C: Inclusion Criteria:

* HIV 1 infection confirmed by licensed ELISA kit and/or detectable Viral load.
* Confirmed Cryptococcal meningitis on the current admission by India ink or CSF cryptococcal antigen
* ART naive at the time of enrollment
* 21 years old and above
* Ability and willingness to give written informed consent to participate in the study
* Able (as assessed by the patient's medical team)to initiate amphotericin B for cryptococcal meningitis
* Initiated amphotericin B 72 hours or less prior to assessment for enrollment or not on amphotericin B at the time of assessment for enrollment
* Agrees to obtain outpatient care after discharge within 50 kilometers from Princess Marina Hospital,Scottish Livingstone Hospital and Bamalete Lutheran Hospital

Exclusion Criteria:

* Recent (within the past 4 weeks) antifungal use
* Pregnant or breastfeeding
* Initiated anti-tubercular therapy 2 weeks or less prior to assessment for enrollment.
* Bacterial meningitis at the time of assessment for enrollment.
* Recent (within the past 1 month) use of the following:systemic cancer chemotherapy,oral or intravenous corticosteroids or other immunomodulators.
* Judged by study coordinator to be likely to initiate chemotherapy or any other immunomodulatory therapy prior to the 4 week LP.
* Imprisoned.
D: Inclusion Criteria:

* HIV-infection, documented by ELISA
* Antiretroviral medication naïve (excluding mother-to-child transmission therapy)
* Age \>14 years
* Cryptococcal meningitis diagnosed by either culture or CSF cryptococcal antigen (CRAG)
* Ability and willingness of the participant or legal guardian/representative to give informed consent.
* Receiving amphotericin-based anti-fungal therapy

Exclusion Criteria:

* Study entry prior to receipt of \<7 days or \>11 days of amphotericin therapy
* History of prior, known cryptococcal meningitis
* Inability to take enteral medication
* Receiving chemotherapy or other immunosuppressant medications
* Cannot or unlikely to attend regular clinic visits
* Contraindication to immediate or delayed HIV therapy based on serious co-morbidities or co-infections, or laboratory values
* Pregnancy or Breastfeeding
* Female participants of childbearing potential who are participating in sexual activity that could lead to pregnancy must agree to use two reliable methods of contraception

Answer: C