Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1997-09-10
2003-06-10
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S051000
Reexamination Certificate
active
06576622
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a method for treating a human with human immunodeficiency virus infection. The method comprises administering to the human a therapeutically effective amount of a thymidine analog, which analog acts as an inhibitor of viral reverse transcriptase necessary for viral replication of human immunodeficiency virus, and a thymidylate synthase inhibitor. In other embodiments, the method further comprises administering to the human a therapeutically effective amount of a folate antagonist or hydroxyurea, or both.
DESCRIPTION OF THE BACKGROUND
The disclosures referred to herein to illustrate the background of the invention and to provide additional detail with respect to its practice are incorporated herein by reference. For convenience, the disclosures are referenced in the following text and respectively grouped in the appended bibliography.
Sanctuary Growth of HIV in the Presence of AZT
Acquired immunodeficiency syndrome (AIDS) is believed to be caused by the human immunodeficiency virus (HIV). Human immunodeficiency virus is a retrovirus which replicates in a human host cell. The human immunodeficiency virus appears to preferentially attack helper T-cells (T-lymphocytes or OKT4-bearing T-cells). When the helper T-cells are invaded by the virus, the T-cells become a human immunodeficiency virus producer. The helper T-cells are quickly destroyed causing the B-cells and other T-cells, normally stimulated by helper T-cells, to no longer function normally or produce sufficient lymphokines and antibodies to destroy the invading virus or other invading microbes.
Although the human immunodeficiency virus does not necessarily cause death, the virus generally causes the immune system to be so depressed that the human develops secondary infections such as herpes, cytomegalovirus, pneumocystis carinni, toxoplasmosis, tuberculosis, other mycobacteria, and other opportunistic infections. Kaposi's sarcoma, lymphomas, and cervical cancer may also occur. Some humans infected with the human immunodeficiency virus appear to live with little or no symptoms, but appear to have persistent infections, while others suffer mild immune system depression with symptoms such as weight loss, malaise, fever, and swollen lymph nodes. These syndromes have been called persistent generalized lymphadenopathy syndrome (PGL) and AIDS related complex (ARC) and generally develop into AIDS. Humans infected with the AIDS virus are believed to be persistently infective to others.
Human immunodeficiency virus is an extremely heterogeneous virus. The clinical significance of this heterogeneity is evidenced by the ability of the virus to evade immunological pressure, survive drug selective pressure, and adapt to a variety of cell types and growth conditions. A comparison of isolates among infected patients has revealed significant diversity, and within a given patient, changes in the predominant isolate over time have been noted and characterized. In fact, each patient infected with human immunodeficiency virus harbors a “quasispecies” of virus with a multitude of undetected viral variants present and capable of responding to a broad range of selective pressures, such as those imposed by the immune system or antiviral drug therapy. Therefore, diversity is a major obstacle to pharmacologic or immunologic control of human immunodeficiency virus infection. Human immunodeficiency virus infection has multiple mechanisms to maximize its potential for genetic heterogeneity. These mechanisms result in an extremely diverse population of virus capable of responding to a broad range of selective pressures, including the immune system and antiretroviral therapy, with the outgrowth of genetically altered virus.
When a patient with human immunodeficiency virus infection is initiated on antiretroviral therapy, there is generally a virologic response characterized by declining viremia and antigenemia (5,7,19,20,25). Unfortunately, the currently available antiretroviral agents which have undergone clinical evaluation have only limited benefit because most patients will ultimately have evidence of worsening disease and increasing viral burden. This progression often occurs in association with the emergence of drug-resistant human immunodeficiency virus. For example, most patients who are treated with 3′-azido-3′-deoxythymidine (AZT) will have initial evidence, of improvement of clinical and laboratory parameters of human immunodeficiency virus infection (7,20). The duration of this benefit varies from patient to patient and is likely to be disease stage related (21). Ultimately, however, most patients will have progressive disease and genotypic or phenotypic evidence of the appearance of AZT-resistant human immunodeficiency virus (9,12). Since clinical failure and the appearance of virus with high level resistance to AZT both occur with evidence of increasing levels of viremia and changes in viral tropism, it has been difficult to ascribe the clinical failure solely to the development of AZT resistance (2,11). Nevertheless, it seems likely that AZT resistance ultimately contributes to the clinical failure seen in most patients receiving prolonged AZT therapy.
While the development of viral-encoded drug resistance may contribute to the limited efficacy of currently used antiretroviral agents, it cannot explain all of the in vitro and in vivo phenomena associated with viral replication in the presence of an antiretroviral agent. For example, many patients will have continued evidence of viral replication after initiation of AZT therapy, but the isolated virus will remain sensitive to AZT when analyzed in tissue culture (7,20). In contrast, high level human immunodeficiency virus resistance to many of the non-nucleoside reverse transcriptase inhibitors develops very rapidly in culture and in patients (13,16,22,23). Some of these differences may relate to the complexity and prevalence of viral variants harboring pre-existing drug resistance mutations prior to the application of the selective pressure. However, some of the differences may be due to cellular heterogeneity in the uptake or metabolism of the antiretroviral agents, that is, each cell population may have some cells that are refractory to the antiviral effects of the drug. This would allow a subset of the cellular population to be successfully infected by genetically drug-sensitive human immunodeficiency virus in the presence of the antiviral drug. Depending upon the prevalence of drug-resistant human immunodeficiency virus in the initial population, the relative rates of replication of drug-resistant and drug-sensitive virus, and the percentage of cells refractory to the antiviral effects of the drug, different patterns of viral breakthrough would emerge. Notably, the non-nucleoside reverse transcriptase inhibitors do not undergo cellular metabolism and cellular effects of uptake or metabolism may be less likely in this setting. This is consistent with the observation that viral-encoded drug resistance to the non-nucleoside reverse transcriptase inhibitors develops very rapidly under selection in tissue culture and in patients. In fact, the rapid, development of resistance in patients suggests that the blood and plasma compartment of virus is subjected to drug selective pressure. The presence of human immunodeficiency virus, but lack of AZT-resistant human immunodeficiency virus, early after the initiation of AZT suggests that a component of this viral pool may be capable of averting selective drug pressure in vivo. Continued viral replication in cells in which, AZT is an ineffective antiretroviral agent could conceivably result in the continued growth of virus that is sensitive to AZT. An increase in the number of these cells over time could also alter viral growth kinetics in the presence of AZT without the emergence of virus with high level AZT resistance. Therefore, many mechanisms may contribute to the inability of an antiviral agent to completely suppress human immunodeficiency virus infection. Viral growth in
Medina Daniel
Strair Roger
Tung Peter
Perkins Coie LLP
Travers Russell
University of Medicine & Dentistry of New Jersey
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