PROGNOSTIC METHOD

Abstract: A method of forecasting whether an individual having lymphadenopathy syndrome (LAS) will develop Acquired Immune Deficiency Syndrome (AIDS) is described and involves conducting in vitro T4 diagnostic assays and determining whether the mean T4 lymphocyte count is prognostic of conversion to AIDS in the LAS population.

Description: PROGNOSTIC METHOD BACKGROUND OF THE INVENTION Primary immunodeficiency is a very rare, but devastating, condition in which there is a partial or total collapse or absence of one or more classes of immune responses. It is typified by recurrent or chronic life-threatening infections and by the necessity for its victims to live in rigorously controlled, sterile conditions. There is no existing treatment other than isolation of the patient from all potential sources of infection. In secondary immunodeficiency, the immune system function is reduced and may appear as a result of age, disease or the use of certain therapies, such as cytostatic radiotherapy or chemotherapy for cancer. Patients whose immune system function is reduced are vulnerable to both viral and other infections, and treatment of such infections may be complicated and/or protracted. Acquired Immune Deficiency Syndrome (AIDS) is a recently identified syndrome in which a person's immune system after functioning normally ceases to function adequately. The etiology of Acquired Immune Deficiency Syndrome has not yet been unequivocally established, although ETLV-III virus is believed to be implicated, and no effective treatment has yet been found. Because of the breakdown in the immune system, such individuals are highly vulnerable to infections and there has been a high mortality from opportunistic infections and Kaposi's sarcoma. See, e.g. "I munocompromised Homo¬ sexuals" (Editorial) Lancet 1981, ii: 1325-6; Center for Disease Control, "Epidemiological Aspects of the Current Outbreak of Kaposi's Sarcoma and Opportunistic Infections", New Enσland Journal of Medicine 1982, 306: 248-52; Gerstoft et al., "Severe Acquired Immuno¬ deficiency in European Homosexual Men", British Medical Journal 1982, 285: 17-19. The two year mortality rate has been reported to be as high as 80%. Lymphadenopathy Syndrome (LAS) is also believed to be caused by the HTLV-III virus. For reasons which are unknown, some Lymphadenopathy Syndrome patients develop AIDS while others do not. A diagnostic method of forecasting whether an individual suffering from Lymphadenopathy Syndrome will develop or will not develop AIDS is, therefore, quite valuable. One of the characteristics of both Lymphadenopathy Syndrome and Acquired Immune Deficiency Syndrome is a decrease in the number of T helper cells defined phenotypically by T4 or Leu 3 monoclonal antibodies. . In Nicholson et al., "Alterations of Functional Subsets of T Helper and T Suppressor Cell Populations in Acquired Immunodeficiency Syndrome (AIDS) and Chronic Unexplained Lymphadenopathy", Journal of Clinical Immunology, Vol. 5: 267-274 (1985), a study of the distribution of Leu 8 and Ia on T cells cf the helper (T4) and suppressor (T8) phenotype in homosexual men with chronic unexplained lymphadeno¬ pathy, homosexual men with Acquired Immune Deficiency Syndrome, and homosexual and heterosexual controls is described. The authors determined that there was a decrease in the T4:Leu 8 subset of helper T cells in both conditions. However, in the AIDS patients, the T4:Leu 8~ subset was decreased while in the lymphadeno¬ pathy patients, it was not. While potentially useful in the basic research which is being carried out, the measurement of particular functional subsets of T cells is, to the treating physician, most inconvenient. It has now been determined that the degree of T4 suppression in lymphadenopathy patients provides a reasonable predictive factor to forecast which of the individuals will develop Acquired Immune Deficiency Syndrome, without having to analyze T4 subsets which is both inconvenient and time consuming. While all of the ARC patients have reduced T4 populations, it has been noted that those who develop Acquired Immune Deficiency Syndrome have a significantly lower T4 count than those who do not. It now appears that a T4 lymphocyte count in the neighborhood of 300 cells/mm 3 divides the individuals into those who are likely to develop Acquired Immune Deficiency Syndrome and those who are not. A statistically significant (i.e. p < 0.05) drop in the T4 count upon serial, time spaced assays is also indicative of those LAS individuals who will probably develop AIDS. - A - Serial assays can be conducted at fixed time intervals, e.g., weekly, monthly or bimonthly, or in combinations of such intervals. Preferably, assays will be conducted at least once a month. Numerous in vitro assays for the measurement of T4 are known and any of these can be employed. Many of these assays are commercially available. OK-T monoclonal antibody-based assays, such as those manu¬ factured by Ortho Pharmaceutical Co., are preferred. As part of a double blind study, nineteen homosexual men who had lymphadenopathy syndrome and who also had oral thrush, persistent diarrhea, with loss in excess of ten percent of body weight and/or persistent unexplained fever were prospec ively evaluated. All of these individuals showed antibodies to HTLV-III in Elisa and Western Blot analytical procedures. Seven of the 19 individuals who had ARC developed Acquired Immune Deficiency Syndrome over a period of two to eight months with a median development time of three months. Four of these patients developed Pneumocvs is carnii pneumonia, one developed Kaposi's sarcoma, one developed disseminated Mvcobacterium avium intracellulare and one developed disseminated cyto- megalovirus infection. Three of the seven individuals died at two, three and eight months, respectively, during the course of this study. The T4 lymphocytes of these individuals were measured at the start of the study with a mean value of 131+145 cells/mm 3 ' . Six months or less into the study (depending on individual survival), this group had a mean T4 count of 153+158 cells/mm . It was also noted that while the initial T4 lymphocyte counts for the members of this group were not significantly different, those living individuals with AIDS at the end of the study period had a significantly higher (p < 0.05) mean T4 lymDhocyte count (235+.143 cells/mm ) relative to those who had died (29+22 cells/mm ) . The twelve remaining individuals had lymphadenopathy syndrome and life table analysis revealed a 57% AIDS free survival at ten months, range 4-10 months. The initial mean T4 lymphocyte count of the individuals in this group was 335+275 cells/mm and about six months into the study, the mean T4 lymphocyte 3 count was 257_+230 cells/mm . These results show that the initial T4 lymphocyte counts were significantly lower in the group which developed AIDS and the difference was statistically significant. Various changes and modifications can be made in the method described above by the skilled artisan without departing from the spirit and scope of the invention.

Claims: WHAT IS CLAIMED IS: 1. A method of forecasting whether an individual having lymphadenopathy syndrome (LAS) will develop Acquired Immune Deficiency Syndrome (AIDS) which comprises conducting in vitro T4 diagnostic assays and determining whether the degree of decrease in the individual's T4 lymphocyte count is prognostic of conversion to AIDS. 2. The method of claim 1 wherein a plurality of time spaced assays are conducted. 3. " The method of claim 2 wherein the assays are conducted at least monthly. 4. The method of claim 1 wherein said determination step comprises determining whether the decrease in the T4 lymphocyte count is significantly significant (p < 0.05). 5. The method of claim 1 wherein said determination step comprises whether the T4 lymphocyte 3 count is less than 300 cells/mm . 6. A method of forecasting whether an individual having lymphadenopathy syndrome (LAS) will develop Acquired Immune Deficiency Syndrome (AIDS) which comprises conducting an in vitro T4 diagnostic assay and determining whether the mean T4 lymphocyte 3 count is less than 300 cells/mm .

Inventors: BITRAN JACOB D, HARRINGTON-FOWLER LINDA, BITRAN, JACOB, D., HARRINGTON-FOWLER, LINDA
Applicants: SERONO PHARMA PARTNERS, SERONO PHARMACEUTICAL PARTNERS
Application year: 1987
Main classification: C12Q1
IPC codes: G01N33