Clinical trial NCT00000899: A Study on the Effect of Chemotherapy Combined With Anti-HIV Drugs in HIV-Positive Patients
Official title: Effect of Cytoreductive Chemotherapy Combined With Highly Active Antiretroviral Therapy on Lymph Node HIV DNA in HIV-Infected Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: HIV Infections
Keywords: Cyclophosphamide
Dose-Response Relationship, Drug
Drug Therapy, Combination
Granulocyte Colony-Stimulating Factor
Combined Modality Therapy
Antineoplastic Agents
Lymph Nodes
Stavudine
HIV Protease Inhibitors
Lamivudine
DNA, Viral
RNA, Viral
Reverse Transcriptase Inhibitors
Anti-HIV Agents
Nelfinavir
Antineoplastic Agents, Alkylating
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2001-08-31
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine the safety of anti-HIV drugs combined with low-dose chemotherapy (consisting of cyclophosphamide \[CTX\]) in HIV-positive patients. This study examines whether this combination therapy can reduce the number of HIV-infected cells hidden in the lymph nodes and blood.

Current anti-HIV drug treatments can greatly reduce the levels of HIV in the human body. However, HIV can hide in certain immune cells and escape the drugs' effects. Chemotherapy using CTX destroys these immune cells. When used with standard anti-HIV drug treatments, CTX may be able to speed up the elimination of HIV-infected cells.

Detailed description: HAART is a potent suppressor of plasma and lymph node HIV RNA. However, studies suggest that HAART cannot significantly diminish reservoirs of chronically HIV-infected cells. Strategies designed to eradicate all HIV infection should seek to actively target these reservoirs. CTX administration has been shown to eliminate a large number of lymphoid tissue T cells and macrophages, appearing to actively target chronically HIV-infected cells. As lymphoid organs are repopulated following initial depletion with CTX, HAART may protect repopulating cells from becoming HIV-infected, resulting in a net additional removal of the HIV-infected lymphoid reservoir.

In Step 1 of this 2-step protocol, all patients receive a HAART regimen of nelfinavir (NFV) plus stavudine (d4T) plus lamivudine (3TC). Patients who achieve an acceptable virologic response, defined as 2 consecutive HIV RNA determinations below 500 copies/ml at least 2 weeks apart between Weeks 4 and 16 of Step 1 \[AS PER AMENDMENT 10/30/98: defined as 2 consecutive plasma HIV RNA determinations below 50 copies/ml by the Roche Ultrasensitive assay within a 4-week period between Weeks 4 and 24\], are randomized to Arm A or B of Step 2. In Arm A, patients receive NFV plus d4T plus 3TC. In Arm B, patients receive NFV plus d4T plus 3TC plus 3 escalating doses of CTX at 6-week intervals. Patients in both arms are followed for at least 52 weeks following randomization to Step 2. During this time, patients undergo blood tests and lymph node biopsies to measure HIV DNA and RNA levels and to characterize the T cell population. Additionally, patients undergo a chest CT of the thymus before randomization to Step 2 and at Week 52 of Step 2. Cerebrospinal fluid may be obtained at Week 52 to determine the amount of HIV RNA and DNA present. \[AS PER AMENDMENT 10/30/98: G-CSF is given after the first dose of CTX, at the discretion of the investigator, and after the second and third doses, for up to 14 days, until the absolute neutrophil count is 10,000 cells/mm3. Also, CTX doses may be modified based on pharmacokinetic study results.\]

Eligibility criteria: Inclusion Criteria

You may be eligible for this study if you:

* Are HIV-positive.
* Have a CD4 count above 300 cells/mm3 within 30 days of study entry.
* Have an HIV viral load between 10,000 and 200,000 copies/ml.
* Are between the ages of 18 and 50.
* Agree to practice abstinence or to use a barrier method of birth control during the study (such as condoms).

Exclusion Criteria

You may not be eligible for this study if you:

* Have had cancer requiring chemotherapy or radiotherapy or certain nervous system diseases.
* Are sensitive to E. coli-derived proteins.
* Have an active AIDS-defining illness.
* Require certain medications.
* Are pregnant or breast-feeding.

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Chapel Hill
country: United States
facility: Univ of North Carolina
state: North Carolina
city: Durham
country: United States
facility: Duke Univ Med Ctr
state: North Carolina
Study officials:
affiliation: Duke Univ Med Ctr
name: John A. Bartlett, MD
role: STUDY_CHAIR
References:
citation: Bartlett JA, Silberman M, Miralles GD, Sevin A, Pruitt S, Ottinger J, Gryszowka V, Fiscus S, Bucy BP. Antiretroviral therapy (ART) plus cyclophosphamide (CTX) to diminish HIV DNA in lymphoid tissue. 8th Conf Retro and Opportun Infect. 2001 Feb 4-8 (abstract no 16)
citation: Bartlett JA, Miralles GD, Sevin AD, Silberman M, Pruitt SK, Ottinger J, Gryszowska V, Fiscus SA, Bucy RP; ACTG 380 Study Team. Addition of cyclophosphamide to antiretroviral therapy does not diminish the cellular reservoir in HIV-infected persons. AIDS Res Hum Retroviruses. 2002 May 20;18(8):535-43. doi: 10.1089/088922202753747888.