Clinical trial NCT00055120: When to Start Anti-HIV Drugs in Patients With Opportunistic Infections
Official title: A Phase IV Study of Antiretroviral Therapy for HIV Infected Adults Presenting With Acute Opportunistic Infections: Immediate Versus Deferred Initiation of Antiretroviral Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: HIV Infections
AIDS-Related Opportunistic Infections
Keywords: Anti-HIV Agents
Disease Progression
Drug Administration Schedule
Viral Load
HIV-1
Treatment Outcome
Survival Analysis
Treatment Naive
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2003-02-20
Enrollment: 283
Sex: ALL
Minimum age (years): 13
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: DIAGNOSTIC

Brief summary: The purpose of this study is to evaluate the effect of starting anti-HIV drugs in HIV infected patients who are being treated for opportunistic infections (OIs). This study will follow two patient groups: those who received anti-HIV drugs soon after being diagnosed with an OI and patients with OIs who deferred beginning anti-HIV drugs until after recovering from the OI.

Detailed description: Despite the advent of highly active antiretroviral therapy (HAART), many HIV infected patients without access to antiretroviral therapy (ART) present with acute OIs. Such presentations pose a management problem, as there are currently no data available as to whether initiating HAART during the acute presentation is of benefit. Reports of an immune reconstitution inflammatory syndrome (IRIS) marked by increasing hypoxia or new pulmonary infiltrates have been associated with the initiation of ART in patients with AIDS. There is also concern as to drug interactions between ART and antimicrobials used to treat the presenting OI. This study will evaluate the possible benefits and costs of initiating ART in HIV infected patients who present with an AIDS-defining OI.

There are 2 steps in this study. In Step 1, patients will be randomly assigned to one of two study arms. Arm A will receive ART within 2 weeks of starting therapy for the acute OI. Arm B will have ART deferred until Step 2, at least 4 weeks and no more than 32 weeks after beginning therapy for the acute OI. Only Arm B participants will enter Step 2, which will likely begin between Weeks 6 and 12. The study will make the following drugs available for construction of an antiretroviral (ARV) regimen: emtricitabine/tenofovir disoproxil fumarate (FTC/TDF), lopinavir/ritonavir (LPV/RTV), and stavudine (d4T). Use of other ARV drugs is at the discretion of the study official. Drug regimen additions and substitutions will be made on a case-by-case basis.

Patients will be followed for 48 weeks and will have 10 study visits. All study visits will include a physical exam, medication history, and blood collection. Patients will be asked to complete questionnaires assessing health status and adherence at selected visits.

Eligibility criteria: Note: Participants who enrolled in this study prior to Version 3.0 will be offered and allowed to switch to FTC/TDF if they wish. However, participants under the age of 18 cannot receive FTC/TDF through this study.

Inclusion Criteria for Step 1:

* HIV-1 infected
* Currently being treated for OI (including Pneumocystis carinii pneumonia \[PCP\]; cryptococcal meningitis; disseminated histoplasmosis; disseminated Mycobacterium avium complex \[MAC\]; cytomegalovirus \[CMV\] retinitis; CMV encephalitis; toxoplasmic encephalitis; other atypical non-tuberculous, non-MAC mycobacterial infections; or other serious, invasive BIs). Participants who have tuberculosis (TB) alone are ineligible for this study. Participants with bacterial pneumonia or serious BI must have a CD4 count less than 200 cells/mm3 within 30 days prior to study entry. Participants with other serious OIs, including other AIDS-defining and -related OIs for which appropriate therapy other than ART exists are eligible, pending investigator approval. Participants' current OI treatment must have been started within 14 days prior to study entry, but may have been discontinued prior to study entry.
* Able to take oral medications
* Parent or guardian willing to provide informed consent, if applicable
* Willing to use acceptable methods of contraception

Exclusion Criteria for Step 1:

* Any ART within 8 weeks prior to study entry
* 31 or more days of any ARV within 6 months prior to entry
* History of more than one virologic, immunologic, or clinical treatment failure while on a HAART regimen, or a history of more than one regimen change for unknown reasons
* Systemic cancer chemotherapy within 30 days prior to study entry
* Immunomodulators within 30 days prior to study entry, including growth factors, immune globulin, interleukins, and interferons (unless for hepatitis C virus or Kaposi's sarcoma)
* Investigational ARV agents at study entry
* Systemic investigational agents (except ARV drugs) within 30 days prior to study entry will be allowed at the study official's discretion
* Anticipated use of certain medications
* Kidney failure requiring dialysis
* Current drug or alcohol use that, in the opinion of the study official, would interfere with the study
* Treatment for current, first-treated, and diagnosed OI or BI for more than 14 days prior to study entry
* Known resistance to ART that prohibits administration of an effective ART regimen
* Current OI has recurred within 90 days prior to study entry. Recurrent BIs are not excluded.
* Pregnant or breastfeeding

Primary outcomes:
measure: Survival, recurrence of presenting OI/bacterial infection (BI) or incidence of new AIDS-defining events, and HIV-1 plasma viral load at Week 48
Secondary outcomes:
measure: HIV-1 plasma viral load at all timepoints up to and including Week 48
measure: CD4 counts at all timepoints up to and including Week 48
measure: changes in ARV regimen for lack of efficacy
measure: efficacy of treatment and clinical outcomes for specific OI/BI, including duration of and complications of treatment, incidence and duration of hospitalization, rate of relapse/recurrence, and incidence of IRIS and impact on outcomes in the two arms
measure: safety and tolerability, measured by Grade 3 and 4 signs and symptoms and laboratory toxicities, ART and OI/BI treatment changes and dose modifications due to toxicities, and IRIS
measure: HIV-1 drug resistance over time (genotype)
measure: health care resource use, including total inpatient days and emergency room visits compared in the two groups
measure: quality of life (QOL) and functional status outcomes, including overall self-reported QOL and functional status compared in the two groups at Week 48
measure: adherence, including self-reported adherence to all ARVs over the study period, examined for relationship with primary study outcomes, including death, progression, and viral suppression
Other outcomes:
Locations:
city: Sacramento
country: United States
facility: University of California, Davis Medical Center
state: California
city: San Diego
country: United States
facility: University of California, San Diego Antiviral Rese
state: California
city: San Francisco
country: United States
facility: San Francisco General Hospital
state: California
city: Stanford
country: United States
facility: San Mateo County AIDS Program
state: California
city: Stanford
country: United States
facility: Santa Clara Valley Medical Center
state: California
city: Stanford
country: United States
facility: Stanford Univ
state: California
city: Stanford
country: United States
facility: Willow Clinic
state: California
city: Torrance
country: United States
facility: Harbor General/UCLA
state: California
city: Denver
country: United States
facility: University of Colorado Health Sciences Center, Denver
state: Colorado
city: Miami
country: United States
facility: Univ of Miami
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: Cook County Hospital Core Center
state: Illinois
city: Indianapolis
country: United States
facility: Methodist Hospital of Indiana
state: Indiana
city: Indianapolis
country: United States
facility: Indiana University Hosp
state: Indiana
city: Indianapolis
country: United States
facility: Wishard Hospital
state: Indiana
city: Baltimore
country: United States
facility: University of Maryland, Institute of Human Virology
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Harvard (Massachusetts General Hospital)
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess - West Campus
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Womens Hospital
state: Massachusetts
city: Minneapolis
country: United States
facility: Hennepin County Medical Clinic
state: Minnesota
city: St. Louis
country: United States
facility: St. Louis Connect Care
state: Missouri
city: St. Louis
country: United States
facility: Washington University (St. Louis)
state: Missouri
city: New York
country: United States
facility: Beth Israel Medical Center
state: New York
city: New York
country: United States
facility: NYU/Bellevue
state: New York
city: New York
country: United States
facility: Columbia University
state: New York
city: Rochester
country: United States
facility: Community Health Network, Inc.
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: Case Western Reserve University
state: Ohio
city: Cleveland
country: United States
facility: MetroHealth Medical Center
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Philadelphia
country: United States
facility: Presbyterian Medical Center - University of PA
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania, Philadelphia
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Providence
country: United States
facility: The Miriam Hospital
state: Rhode Island
city: Nashville
country: United States
facility: Comprehensive Care Clinic
state: Tennessee
city: Dallas
country: United States
facility: University of Texas, Southwestern Medical Center
state: Texas
city: Galveston
country: United States
facility: Univ of Texas, Galveston
state: Texas
city: Seattle
country: United States
facility: University of Washington (Seattle)
state: Washington
city: San Juan
country: Puerto Rico
facility: University of Puerto Rico
city: Parktown
country: South Africa
facility: University of Witwatersrand
state: Johannesburg
Study officials:
affiliation: Division of Infectious Diseases, Stanford University
name: Andrew R. Zolopa, MD
role: STUDY_CHAIR
References:
citation: Wislez M, Bergot E, Antoine M, Parrot A, Carette MF, Mayaud C, Cadranel J. Acute respiratory failure following HAART introduction in patients treated for Pneumocystis carinii pneumonia. Am J Respir Crit Care Med. 2001 Sep 1;164(5):847-51. doi: 10.1164/ajrccm.164.5.2007034.
citation: Bartlett JA, DeMasi R, Quinn J, Moxham C, Rousseau F. Overview of the effectiveness of triple combination therapy in antiretroviral-naive HIV-1 infected adults. AIDS. 2001 Jul 27;15(11):1369-77. doi: 10.1097/00002030-200107270-00006.
citation: Hamill RJ. Immune restoration syndrome in AIDS and mycoses. Program and abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy; December 16-19, 2001; Chicago, IL. Abtract 1272.
citation: Nunez M, Asencio R, Valencia ME, Leal M, Gonzalez-Lahoz J, Soriano V. Rate, causes, and clinical implications of presenting with low CD4+ cell counts in the era of highly active antiretroviral therapy. AIDS Res Hum Retroviruses. 2003 May;19(5):363-8. doi: 10.1089/088922203765551719.
citation: Sax PE, Sloan CE, Schackman BR, Grant PM, Rong J, Zolopa AR, Powderly W, Losina E, Freedberg KA; Cepac US And Actg A5164 Investigators. Early antiretroviral therapy for patients with acute aids-related opportunistic infections: a cost-effectiveness analysis of ACTG A5164. HIV Clin Trials. 2010 Sep-Oct;11(5):248-59. doi: 10.1310/hct1105-248.
citation: Grant PM, Komarow L, Andersen J, Sereti I, Pahwa S, Lederman MM, Eron J, Sanne I, Powderly W, Hogg E, Suckow C, Zolopa A. Risk factor analyses for immune reconstitution inflammatory syndrome in a randomized study of early vs. deferred ART during an opportunistic infection. PLoS One. 2010 Jul 1;5(7):e11416. doi: 10.1371/journal.pone.0011416.
citation: Zolopa A, Andersen J, Powderly W, Sanchez A, Sanne I, Suckow C, Hogg E, Komarow L. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PLoS One. 2009;4(5):e5575. doi: 10.1371/journal.pone.0005575. Epub 2009 May 18.