When to Start Anti-HIV Drugs in Patients With Opportunistic Infections

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase IV Study of Antiretroviral Therapy for HIV Infected Adults Presenting With Acute Opportunistic Infections: Immediate Versus Deferred Initiation of Antiretroviral Therapy

Conditions
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HIV Infections, AIDS-Related Opportunistic Infections

Intervention / Treatment
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* Drug: Emtricitabine/tenofovir disoproxil fumarate
* Drug: Lopinavir/ritonavir
* Drug: Stavudine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 13 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Emtricitabine/tenofovir disoproxil fumarate|nan|
|Drug: Lopinavir/ritonavir|nan|
|Drug: Stavudine|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HIV-1 plasma viral load at all timepoints up to and including Week 48 |  |  | 
| CD4 counts at all timepoints up to and including Week 48 |  |  | 
| changes in ARV regimen for lack of efficacy |  |  | 
| 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 |  |  | 
| 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 |  |  | 
| HIV-1 drug resistance over time (genotype) |  |  | 
| health care resource use, including total inpatient days and emergency room visits compared in the two groups |  |  | 
| quality of life (QOL) and functional status outcomes, including overall self-reported QOL and functional status compared in the two groups at Week 48 |  |  | 
| 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 |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anti-HIV Agents, Disease Progression, Drug Administration Schedule, Viral Load, HIV-1, Treatment Outcome, Survival Analysis, Treatment Naive