Cyclosporine A in Combination With Abacavir Sulfate, Lamivudine, and Zidovudine and Lopinavir/Ritonavir in HIV

Study Overview
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Brief Summary
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Cyclosporine A (CsA) is a common long-term treatment used to inhibit the immune response in transplant patients who receive donor organs. CsA may also help people with HIV. The purpose of this study is to determine the safety of and immune response to CsA when given with abacavir sulfate (ABC), lamivudine (3TC), and zidovudine (AZT), (ABC/3TC/AZT) and lopinavir/ritonavir (LPV/r) to HIV infected adults in the early stages of infection. Study hypothesis: The combination of CsA and LPV/r given to acutely infected individuals will result in lower levels of proviral DNA and latent infectious virus at 48 weeks compared to acute infected individuals treated with LPV/r alone.

Detailed Description
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During the early stages of HIV infection, HIV replicates unchecked, massive numbers of cluster of differentiation 4 (CD4) T cells are infected and destroyed, and other CD4 cells become infected but enter a latent phase. This latent pool of infected CD4 cells poses a difficult challenge in eliminating HIV infection during the early stages of infection because the cells persist for long periods, even with highly active effective antiretroviral therapy, and may later become active. CsA is popularly used as a lifelong immunosuppressant for organ transplant patients. CsA inhibits cellular activation, including CD4 cell activation and proliferation. By reducing CD4 cell activation during acute HIV infection, fewer CD4 cells may be infected and die; more importantly, there may be fewer latent cells with the potential to become active later in the disease. However, CsA has many potential toxic effects, including renal damage, and may affect neurologic, endocrine, and hepatic organ systems. In a previous small study of adults with acute HIV infection, a short 8-week course of CsA was well tolerated, and it is thought that a 4-week course of CsA may result in substantial reduction in both viral load and T cell activation, outweighing any potential toxic effects sustained during the one month treatment. This study will evaluate the safety of and immune response to a 4-week course of CsA with ABC/3TC/AZT and LPV/r compared to ABC/3TC/AZT and LPV/r alone in patients with acute HIV infection. This 48-week study will randomly assign patients to one of two arms. During the first 4 weeks of the study, Arm A will receive one tablet of ABC/3TC/AZT twice daily, 3 capsules or 2 tablets of LPV/r twice daily, and liquid CsA (dose determined by weight) twice daily. At Week 5, Arm A patients will stop CsA but continue both ABC/3TC/AZT and LPV/r. Arm B will receive one tablet of ABC/3TC/AZT twice daily and 3 capsules or 2 tablets of LPV/r twice daily for all 48 weeks. On a case-by-case basis, an investigator may wish to prescribe ABC/3TC rather than ABC/3TC/AZT at initial therapy. Participants with ABC hypersensitivity will be given 3TC/AZT instead of ABC/3TC/AZT. A complete physical exam and medical history assessment will occur at study entry and at Week 48. Study visits will occur every week until Week 4, then every 4 weeks until the end of the study. Blood and urine collection and clinical assessments will occur at each study visit. Additionally, patients in Arm A only will undergo CsA level monitoring at Day 3 and Weeks 1, 2, and 3; CsA dosage may be adjusted as necessary.

Official Title
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A Randomized Phase II Study of the Safety, Immunologic, and Virologic Effects of Cyclosporine A in Conjunction With Trizivir(R) and Kaletra(R) Versus Trizivir(R) and Kaletra(R) Alone During Primary HIV-1 Infection

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Abacavir sulfate, Lamivudine, and Zidovudine
* Drug: Lopinavir/Ritonavir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Acute HIV infection with HIV viral load of more than 50,000 copies/ml AND either negative ELISA OR Western blot with 5 bands or less within 4 weeks prior to study entry Hepatitis B surface antigen negative within 12 weeks prior to study entry Hepatitis C antibody negative within 12 weeks prior to study entry Willing to use acceptable methods of contraception Exclusion Criteria: Prior antiretroviral therapy. A patient who has undergone Post Exposure Prophylaxis (PEP) taken at least 6 months prior to study entry is not excluded. Allergy or hypersensitivity to any study medications or their components Require certain medications, including those that may alter CsA levels or cause renal dysfunction. More information on this criterion can be found in the protocol. Any medical or psychiatric condition, including alcohol or drug abuse, that may interfere with adherence to study requirements Weight less than 88 lbs (40 kg) Uncontrolled hypertension History of pancreatitis History of cancer. Participants with cancer in remission who have not had treatment for at least 3 years may be eligible for this study. Pregnancy or breastfeeding

Ages Eligible for Study
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Minimum Age: 18 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cyclosporin<br>Cyclosporin arm (Arm A) will receive one tablet of Abacavir sulfate, Lamivudine, and Zidovudine (ABC/3TC/AZT) twice daily, 3 capsules or 2 tablets of lopinavir/ritonavir (LPV/r) twice daily, and liquid cyclosporin A (CsA) (dose determined by weight) twice daily. At Week 5, Arm A patients will stop CsA but continue both ABC/3TC/AZT and LPV/r. | Drug: Abacavir sulfate, Lamivudine, and Zidovudine<br>* antiretroviral therapy<br>* Other names: Trizivir;Drug: Lopinavir/Ritonavir<br>* antiretroviral therapy<br>* Other names: Kaletra;|
| Experimental: No Cyclosporin<br>The No Cyclosporin arm (Arm B) will receive one tablet of Abacavir sulfate, Lamivudine, and Zidovudine (ABC/3TC/AZT) twice daily and 3 capsules or 2 tablets of lopinavir/ritonavir (LPV/r) twice daily for all 48 weeks | Drug: Abacavir sulfate, Lamivudine, and Zidovudine<br>* antiretroviral therapy<br>* Other names: Trizivir;Drug: Lopinavir/Ritonavir<br>* antiretroviral therapy<br>* Other names: Kaletra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Levels of Proviral DNA in Peripheral Blood Mononuclear Cells (PBMC) (log10) |  | At 48 weeks after the start of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events Related to Study Medication | Grade 1-4 adverse events related to study medication | Up to 48 weeks | 
| Proviral DNA Levels (log10) |  | At Week 24 | 
| Proviral DNA (log10) |  | At Week 12 | 
| HIV-1 Viral Load Levels |  | At Week 48 | 
| Number of Patients With Viral Load Less Than 50 Copies/ml |  | Week 48 | 
| CD4 T Cell Levels |  | At Week 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Infection, Treatment Naive