Clinical trial NCT00084149: Cyclosporine A in Combination With Abacavir Sulfate, Lamivudine, and Zidovudine and Lopinavir/Ritonavir in HIV
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infections
Keywords: Acute Infection
Treatment Naive
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2004-06-08
Enrollment: 54
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Levels of Proviral DNA in Peripheral Blood Mononuclear Cells (PBMC) (log10)
timeFrame: At 48 weeks after the start of treatment
Secondary outcomes:
measure: Adverse Events Related to Study Medication
timeFrame: Up to 48 weeks
measure: Proviral DNA Levels (log10)
timeFrame: At Week 24
measure: Proviral DNA (log10)
timeFrame: At Week 12
measure: HIV-1 Viral Load Levels
timeFrame: At Week 48
measure: Number of Patients With Viral Load Less Than 50 Copies/ml
timeFrame: Week 48
measure: CD4 T Cell Levels
timeFrame: At Week 48
Other outcomes:
Locations:
city: Minneapolis
country: United States
facility: University of Minnesota, ACTU
state: Minnesota
city: New York
country: United States
facility: Beth Israel Med. Ctr., ACTU
state: New York
city: New York
country: United States
facility: NY Univ. HIV/AIDS CRS
state: New York
city: Cleveland
country: United States
facility: MetroHealth CRS
state: Ohio
Study officials:
affiliation: Aaron Diamond AIDS Research Center
name: Martin Markowitz, MD
role: STUDY_CHAIR
affiliation: Department of Medicine, University of California at San Diego
name: Susan Little, MD
role: STUDY_CHAIR
References:
citation: Ravot E, Lisziewicz J, Lori F. New uses for old drugs in HIV infection: the role of hydroxyurea, cyclosporin and thalidomide. Drugs. 1999 Dec;58(6):953-63. doi: 10.2165/00003495-199958060-00001.
citation: Rizzardi GP, Harari A, Capiluppi B, Tambussi G, Ellefsen K, Ciuffreda D, Champagne P, Bart PA, Chave JP, Lazzarin A, Pantaleo G. Treatment of primary HIV-1 infection with cyclosporin A coupled with highly active antiretroviral therapy. J Clin Invest. 2002 Mar;109(5):681-8. doi: 10.1172/JCI14522.
citation: Rizzardi GP, Lazzarin A, Pantaleo G. Potential role of immune modulation in the effective long-term control of HIV-1 infection. J Biol Regul Homeost Agents. 2002 Jan-Mar;16(1):83-90.