Drug – bio-affecting and body treating compositions – Lymphokine – Interleukin
Reexamination Certificate
2001-10-09
2003-06-17
Stucker, Jeffrey (Department: 1648)
Drug, bio-affecting and body treating compositions
Lymphokine
Interleukin
C514S049000, C514S050000, C514S252100, C514S255010, C514S256000, C514S934000
Reexamination Certificate
active
06579521
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to methods of therapy for human immunodeficiency virus (HIV) infection, more particularly to the use of intermittent antiretroviral therapy in combination with interleukin-2 (IL-2) to promote long-lasting immunologic control of HIV.
BACKGROUND OF THE INVENTION
Infection with the human immunodeficiency virus (HIV) results in progressive deterioration of the immune system in most infected subjects. During disease progression, key cells associated with the immune system become infected with HIV, including, e.g., CD4+ T cells, macrophages/monocytes, and glial cells. Prolonged HIV infection frequently culminates in the development of AIDS. In the late stages of this disease, the immune system is severely compromised due to loss or dysfunction of CD4+ T cells (Shearer et al. (1991)
AIDS
5:245-253).
HIV-1-specific CD8+ cytotoxic T lymphocytes appear to be critical in the immunologic control of HIV-1 soon after the acquisition of infection. CTL precursors specific for cells expressing several HIV-1 gene products, including Gag, Pol, and Env antigens, are detectable within three weeks of the primary infection syndrome (Koup et al. (1994)
J. Virol.
68:4650-4655). Since CTL activity is antigen driven, the waning in responding T-cell subsets that generally occurs with the passage of time is not unexpected. The clinical significance of this cellular immune response to HIV has been demonstrated in a number of studies, and impairment of this response appears to be associated with more rapid disease progression. Lymphokines elaborated by HIV-specific CD4+ T-cells are critical in supporting the genesis of these mature cytotoxic T lymphocytes directed against HIV-1 (Rosenberg et al. (1997)
Science
278:1447-1450), lending credence to the notion that virus-specific T-helper cells are necessary for maintenance of effective immunity to HIV.
Anti-retroviral drugs, such as reverse transcriptase inhibitors, viral protease inhibitors, and viral entry inhibitors, have been used to treat HIV infection (Caliendo et al. (1994)
Clin. Infect. Dis.
18:516-524). More recently, treatment with combinations of these agents, known as highly active antiretroviral therapy (HAART), has been used to effectively suppress replication of HIV (Gulick et al. (1997)
N. Engl. J. Med.
337:734-9 (see comments); Hammer et al. (1997)
N. Engl. J. Med.
337:725-733). However, HAART is primarily efficacious with regard to the prevention of the spread of infection into uninfected cells. This therapy cannot efficiently reduce the residual, latent proviral DNA integrated into the host cellular genome (Wong et al. (1997)
Science
278:1291-1295 (see comments); Finzi et al. (1997)
Science
278:1295-1300 (see comments); Finzi et al. (1999)
Nat. Med.
5:512-517; Zhang et al. (1999)
N. Engl. J. Med.
340:1605-1613).
Anecdotal reports of individuals who have discontinued HAART have revealed a rapid relapse of viremia, most often within a few weeks of ceasing anti-viral therapy (Ruiz et al. (2000)
AIDS
14:397-403). Consequently, HAART must be administered indefinitely to prevent reactivation of latent virus. Continuous treatment with HAART is problematic, as HAART regimens are expensive, are difficult to comply with, and have many side effects. In addition, prolonged treatment with antiretroviral agents often leads to the emergence of drug resistant viral strains (Larder et al. (1989)
Science
246:1155-1158; Kellam et al. (1992)
Proc. Natl. Acad. Sci. USA
89:1934-1938; St. Clair et al. (1991)
Science
253:1557-1559). The emergence of drug-resistant viral strains is delayed with combination treatment aimed at different points in the HIV replication cycle (D'Aquila (1994)
Clin. Lab. Med.
14:393-422). However, a significant portion of patients treated with combination therapy may eventually harbor strains of HIV having multi-drug resistance (Schinazi et al. (1994)
Int. Antiviral News
2:72-5).
Recombinant human interleukin-2 (IL-2) has been studied in the setting of HIV disease for over a decade. This immunobiologic agent, when administered intermittently by either the SC or CIV route in conjunction with antiretroviral therapy, produces prominent and sustained increases in the CD4+ T-cell count in the vast majority of HIV-infected patients who have been recently studied (Kovacs et al. (1996)
N. Engl. J. Med.
335:1350-1356; Davey et al. Abstract 689,
ICAAC
(San Francisco, Calif.), September, 1999; Arno et al. (1999)
JID
180:56-60; Carr et al. (1998)
J. Infect. Dis.
178(4):992-999; Hengge et al. (1998)
AIDS
12:F225-F234; Levy et al. (1999)
Lancet
353:1923-1929). The increase in the CD4+ T-cell compartment is polyclonal and is characterized by the genesis of CD4+ T-cells that are functional in vitro (Levy et al. (1999)
Lancet
353:1923-1929).
Intermittent cycles of IL-2 produce transient rises in plasma viral load in some HIV-infected subjects (Davey et al. (1997)
J. Infect. Dis.
175:781-789), however no controlled trials have demonstrated a deleterious long-term effect on viral burden. Indeed, several recent studies indicate IL-2 might have an antiviral effect (Davey et al. (1999)
J. Infect. Dis.
179:849-858). The reason an antiviral effect of IL-2 has been observed only in several recent studies might relate to the higher sensitivity of the assays employed and/or the use of HAART.
In vitro data have shown that the IL-2 responsiveness of CD4+ cells of subjects well controlled virologically on HAART is greater than that of cells culled from patients with suboptimal virologic control. However, cessation of HAART in patients receiving cycles of IL-2 therapy in the past frequently leads to virologic rebound (Davey et al. (1999) Abstract 689,
ICAAC
(San Francisco, Calif.), September, 1999).
Given the problems associated with prolonged treatment with HAART and the tendency for rapid viral rebound following cessation of this combination therapy, even in patients receiving IL-2 therapy in the past, better methods are needed to achieve longterm immunologic control of HIV.
SUMMARY OF THE INVENTION
Methods for promoting immunologic control of the human immunodeficiency virus (HIV) in an HIV-infected subject are provided. The methods comprise administering to the HIV-infected subject an antiviral therapy selected from highly active antiretroviral therapy (HAART) or dual protease inhibitor therapy for at least one cycle of an intermittent dosing regimen in combination with administration of a pharmaceutical composition comprising a therapeutically effective amount of interleukin-2 (IL-2) or variant thereof. HAART comprises daily administration of therapeutically effective amounts of at least three antiretroviral agents. An intermittent HAART dosing regimen comprises administering HAART until plasma viral RNA is undetectable in the patient and then discontinuing administration of HAART until plasma viral RNA reaches an acceptable threshold level in the patient. Therapeutically effective doses of IL-2 or variant thereof are administered daily or intermittently during each cycle of an intermittent HAART or other antiviral dosing regimen. The combination of daily or intermittent administration of IL-2 (or variant thereof) and intermittent HAART promotes immunologic control of viral replication, thereby prolonging the length of time a patient may discontinue HAART before viral rebound necessitates further administration of HAART. Administration of IL-2 therapy in combination with an intermittent HAART dosing regimen provides an effective method for treating a subject infected with HIV.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to methods of promoting immunologic control of human immunodeficiency virus (HIV), more particularly HIV-1, in an HIV-infected patient. By “immunologic control” is intended the ability of an HIV-infected patient to effectively mount a cellular immune defense against actively replicating HIV in the absence of antiretroviral agents. For purposes of the present invention, such
Blackburn Robert P.
Chiron Corporation
Launer Charlene A.
Spruill W. Murray
Stucker Jeffrey
LandOfFree
Methods of therapy for HIV infection does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Methods of therapy for HIV infection, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Methods of therapy for HIV infection will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3092169