Antiretroviral Therapy for Advanced HIV Disease in South Africa

Study Overview
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Brief Summary
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This study will determine how well four different antiretroviral drug therapies work in patients with advanced HIV disease. The trial is part of the South Africa-U.S. Project Phidisa Programme - a collaboration between the South African Military Health Service (SAMHS) of the South African National Defense Force (SANDF), the U.S. Department of Defense, and the U.S. National Institutes of Health - to help prevent HIV transmission among South African military and civilian employees and their families. Members of the SANDF with HIV infection may be eligible for this study. HIV-infected family members who are 14 years of age and older may also participate. All participants must have a CD4 count of less than 200 or an AIDS-defining illness. Participants are randomly assigned to one of the following four antiretroviral drug regimens, which require taking 5 pills or more every day: AZT (zidovudine) + ddl (didanosine) + EFV (efavirenz) AZT (zidovudine) + ddl (didanosine) + r/LPV (lopinavir/ritonavir) D4T (stavudine) + 3TC (lamivudine) + EFV (efavirenz) D4T (stavudine) + 3TC (lamivudine) + r/LPV (lopinavir/ritonavir) Patients are followed for up to 6 years. Clinic visits are scheduled once a month for the first 3 months and then once every 3 months for the next five years. Patients undergo a medical history, physical examination, and blood tests at each visit, and complete questionnaires of behavior, quality of life, and force readiness every year.

Detailed Description
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This is a randomized, open label 2x2 factorial study of four regimens of initial therapy. I. AZT + ddl + EFV II. AZT + ddl + r/LPV III. D4T + 3TC + EFV IV. D4T + 3TC + r/LPV Eligible patients will commence their randomly allocated study drugs as soon as possible after randomization. Episodes of treatment limiting toxicity will be managed in keeping with protocol specified guidelines. Patients who experience treatment failures (as specified in the protocol) will be managed by changing their regimen to that corresponding to one of the other treatment groups.

Official Title
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Randomized, Open-Label 2x2 Factorial Study to Compare the Safety and Efficacy of Different Combination Antiretroviral Therapy Regimens in Treatment Naive Patients With Advanced HIV Disease and/or CD4+ Cell Counts Less Than 200 Cells/MicroL

Conditions
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HIV

Intervention / Treatment
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* Drug: Zidovudine
* Drug: Stavudine
* Drug: Didanosine
* Drug: Lamivudine
* Drug: Efavirenz
* Drug: Lopinavir/Ritonavir


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Uniformed SANDF personnel or family members of SANDF personnel who are registered as eligible for health services from the SAMHS. HIV positive as diagnosed and/or confirmed in PHIDISA I OR documented HIV infection from an accredited source. CD4+ cell count less than 200 cells/microL (or less than or equal to 14% for patients post-splenectomy) AND/OR any AIDS defining illness currently or historically. Patients with pulmonary tuberculosis must have a CD4+ cell count less than 200 cells/microL. Patients with KS must have a CD4+ cell count less than 200 cells/microL unless their sarcoma is progressive and/or requires chemotherapy. Antiretroviral treatment naive (less than 7 days cumulative exposure to any antiretroviral drug) or treated for post-exposure prophylaxis without becoming HIV infected at that time. Laboratory variables as follows: Haemoglobin greater than or equal to 9.0g/dL for men and greater than or equal to 8.0g/dL for women. Absolute neutrophil count greater than or equal to 500 cells/microL. Platelet count greater than or equal to 25,000/mm(3). Serum transaminase (ALT or AST) less than or equal to 5 times upper limit of normal (ULN). 14 years or older. Likely to be compliant with study procedures and clinical visits in the opinion of the clinical investigator (guidance is provided in the protocol to assist clinicians in making this decision). Have completed the PHIDISA treatment adherence counseling session. Provision of written informed consent. EXCLUSION CRITERIA: Any history of pancreatitis or serious pathology indicative of increased risk for pancreatitis. Current requirement for use of a medication that is contra-indicated with the PHIDISA II study drugs. Where possible, alternate therapies should be selected in order to facilitate randomization. Patients entering the study with tuberculosis should defer screening and randomization until successful completion of an induction course of anti-mycobacterium therapy including rifampicin. As appropriate this patient could recommence screening when starting the maintenance regimen of anti-tubercular drugs excluding rifampicin. Pregnancy (following delivery, such women may be enrolled).

Ages Eligible for Study
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Minimum Age: 14 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: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: AZT+DDI+EFV<br>Zidovudine,Didanosine,Efavirenz ( Zidovudine 600 mg once daily,Didanosine <60 kg/125 mg twice daily or >60kg/200 mg twice daily,Efavirenz 600 mg once daily) | Drug: Zidovudine<br>* 600 mg once daily<br>* Other names: AZT;Drug: Didanosine<br>* <60 kg/125 mg twice daily or >60kg/200 mg twice daily<br>* Other names: DDI;Drug: Efavirenz<br>* 600 mg once daily<br>* Other names: EFV;|
| Active Comparator: AZT+DDI+r/LPV<br>Zidovudine,Didanosine,Lopinavir/Ritonavir(AZT 600 mg once daily,DDI 100 mg twice daily,r/LPV 400mg/100mg twice daily) | Drug: Zidovudine<br>* 600 mg once daily<br>* Other names: AZT;Drug: Didanosine<br>* <60 kg/125 mg twice daily or >60kg/200 mg twice daily<br>* Other names: DDI;Drug: Lopinavir/Ritonavir<br>* r/LPV 400mg/100mg twice daily<br>* Other names: Kaletra;|
| Active Comparator: d4T+3TC+EFV<br>Stavudine,Lamivudine,Efavirenz(d4T 40 mg twice daily,3TC 300 mg once daily,EFV 600 mg once daily) | Drug: Stavudine<br>* 40 mg once daily<br>* Other names: D4T;Drug: Lamivudine<br>* 300 mg once daily<br>* Other names: 3TC;Drug: Efavirenz<br>* 600 mg once daily<br>* Other names: EFV;|
| Active Comparator: d4T+3TC+r/LPV<br>Stavudine,Lamivudine,Lopinavir/Ritonavir(d4T 40m mg twice daily,3TC 300 mg once daily,r/LPV 400mg/100mg twice daily) | Drug: Stavudine<br>* 40 mg once daily<br>* Other names: D4T;Drug: Lamivudine<br>* 300 mg once daily<br>* Other names: 3TC;Drug: Lopinavir/Ritonavir<br>* r/LPV 400mg/100mg twice daily<br>* Other names: Kaletra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression to AIDS or Death in tx naïve Pts With Adv HIV dx in the Four Randomly Assigned Regimens. | Progression of disease, AIDS, or death in treatment naive patients with advanced HIV diagnosis will be evaluated in the four randomly assigned regimens. | January 2004 until March 31 2008 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serious Adverse Events | Safety outcomes in four different randomly assigned regimens | January 2004 until March 31, 2008 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AIDS, Protease Inhibitors, Reverse Transcriptase Inhibitors, Opportunistic Infections, Resource-Poor