Relationship of CD4 lymphocyte counts to survival in a cohort of hemophiliacs infected with HIV. Multicenter Hemophilia Cohort Study.

Although CD4 positive lymphocyte counts are important predictors of clinical events in persons infected with human immunodeficiency virus (HIV), little is known about their predictive value for survival. We analyzed CD4 counts obtained regularly since 1983 with regard to survival in a multicenter cohort study of 921 HIV-infected hemophiliacs of whom 177 have died. Dates of seroconversion were determined from stored serum samples. Cumulative mortality and actuarial survival rates were calculated from the first time the mean of two consecutive CD4 counts decreased from levels of > 500 to 200-499, 100-199, 50-99, and < 50 cells/microliter. The death rate per 100 patient years of observation was 0.87 (95% CI 0.27, 1.47) for those with CD4 counts of > 500 cells/microliter and increased progressively to 26.23 (95% CI 21.29, 31.17) for those with CD4 counts of < 50/microliter. HIV-related deaths occurred in 50 of 58 who died with CD4 counts of < 300/microliter compared to 0 of 6 who died with CD4 counts of > 500/microliter. The median CD4 count most proximal to death was 39.5 (range, 1-945). The 10-year actuarial estimate of survival from seroconversion was 77.3 +/- 2% for 546 persons who seroconverted at age > or = 18 years compared to 90.5 +/- 2% for 375 persons who seroconverted at age < 18. Survival decreased at each CD4 level to a median of 27 months at CD4 counts of < 50/microliter. At each CD4 level, younger patients survived longer than older patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Case report: oat cell cancer and renal failure.

A 55-year-old woman on chronic hemodialysis was treated for small-cell lung cancer and associated symptoms of a paraneoplastic syndrome. Partial remission with an antineoplastic agent, an antineoplastic antibiotic, and vincristine was achieved. When the tumor advanced, carboplatin and etoposide resulted in a complete remission. Marked symptomatic improvement occurred with minimal side effects. Such examples indicate that carefully selected patients with renal failure may respond to chemotherapy and an improved quality of life.

Human immunodeficiency virus-related conditions in children and adults with hemophilia: rates, relationship to CD4 counts, and predictive value.

To further elucidate the natural history of human immunodeficiency virus (HIV) infection, we studied intermediate HIV-related conditions occurring before acquired immunodeficiency syndrome (AIDS) in a prospectively observed multicenter cohort of 738 HIV-infected persons with hemophilia. We analyzed the frequency in adults and children of common HIV-related conditions and the relative risk of AIDS after occurrence of these conditions, controlling for age at seroconversion and the percentage of CD4+ lymphocytes. Thrombocytopenia was the most frequently observed condition with cumulative incidences of 43% +/- 7% in adults and 27% +/- 6% in children and adolescents by 10 years after seroconversion. Oral candidiasis, fever, weight loss, and non-AIDS pneumonia were two to four times more common in adults than children, whereas herpes zoster risk was similar in the two age groups. HIV-related conditions were infrequent during the first 4 years of infection, particularly in children. With the exception of thrombocytopenia, mean CD4 counts were less than 350 cells/microL at the onset of the conditions. The relative hazard of AIDS after oral candidiasis was 18 in children and 3.8 in adults. Relative hazard in adults was also increased after persistent fever (10), weight loss (3.2), and non-AIDS pneumonia (2.2). Herpes zoster and thrombocytopenia were not significantly associated with AIDS in either age group. We conclude that intermediate HIV-related conditions occur more frequently in adults than in children with hemophilia. Persistent fever is the strongest predictor of AIDS in adults, whereas oral candidiasis is the strongest predictor in children. These findings should facilitate the design and conduct of clinical trials as well as the management of HIV-infected children and adults.

Role of splenectomy in the management of hemophilic patients with human immunodeficiency virus-associated immunopathic thrombocytopenic purpura.

Immunopathic thrombocytopenic purpura (ITP) can be a life-threatening complication of human immunodeficiency virus (HIV) infection in patients with hemophilia and can seriously compromise quality of life if not managed effectively. We report here complete response to splenectomy in four severe hemophiliacs with HIV-associated ITP. All patients were symptomatic, had platelet counts less than 25,000/mm3, and had failed at least one non-surgical therapy prior to splenectomy. All patients tolerated surgery well and obtained an immediate and durable complete response. In addition to our experience, a review of the literature shows that splenectomy is well tolerated and provides the most effective long-term solution for hemophiliacs with HIV-ITP.

Comparison of methods for HIV isolation from monocytes and lymphocytes of seropositive asymptomatic hemophiliacs and homosexuals.

1. Since monocyte-macrophages have been recognized as HIV targets in addition to CD4+ T-lymphocytes, we have evaluated HIV infection of purified peripheral blood mononuclear cell fractions obtained from 10 seropositive asymptomatic hemophiliacs and compared it with that of 10 asymptomatic homosexual patients. 2. HIV was isolated more frequently from the lymphocytes than the monocytes of both groups of patients. 3. HIV preferentially replicated in phytohemagglutinin-stimulated lymphocytes compared with growth factor-treated monocytes. Monocytes did not preferentially harbour HIV in either group.

Comparison of methods for HIV isolation from monocytes and lymphocytes of seropositive asymptomatic hemophiliacs and homosexuals

1. Since monocyte-macrophages have been recognized as HIV targets in addition to CD4+ T-lymphocytes, we have evaluated HIV infection of purified peripheral blood mononuclear cell fractions obtained from 10 seropositive asymptomatic hemophiliacs and compared with that of 10 assymptomatic homosexual patients. 2. HIV was isolated more frequently from the lymphocytes than the monocytes of both groups of patients. 3. HIV preferential replicated in phytohemagglutinin-stimulated lymphocytes compared with growth factor-treated monocytes. Monocytes did not preferentially harbour HIV in either group

A prospective study of human immunodeficiency virus type 1 infection and the development of AIDS in subjects with hemophilia.

We evaluated a multicenter cohort of 1219 subjects with hemophilia or related disorders prospectively, focusing on 319 subjects with documented dates of seroconversion to human immunodeficiency virus type 1 (HIV-1). The incidence rate of the acquired immunodeficiency syndrome (AIDS) after seroconversion was 2.67 per 100 person-years and was directly related to age (from 0.83 in persons 1 to 11 years old up to 5.66 in persons 35 to 70 years old; Ptrend = 0.00003). The annual incidence of AIDS ranged from zero during the first year after seroconversion to 7 percent during the eighth year, with eight-year cumulative rates (+/- SE) of 13.3 +/- 5.3 percent for ages 1 to 17, 26.8 +/- 6.4 percent for ages 18 to 34, and 43.7 +/- 16.4 percent for ages 35 to 70. Serial immunologic and virologic markers (total numbers of CD4 lymphocytes, presence of serum interferon or HIV-1 p24 antigen, and low or absent serum levels of anti-p24 or anti-gp120) predicted a high risk for the subsequent development of AIDS. Adults 35 to 70 years old had a higher incidence of low CD4 counts than younger subjects (P less than or equal to 0.005), whereas adolescents had a low rate of anti-p24 loss (P = 0.0007) and subjects 1 to 17 years old had a lower incidence of AIDS after loss of anti-p24 (P = 0.03). These findings not only demonstrate that the risk of AIDS is related directly to age but also suggest that older adults are disproportionately affected during the earlier phases of HIV disease, that adolescents may have a low replication rate of HIV, and that children and adolescents may tolerate severe immunodeficiency better because they have fewer other infections or because of some unmeasured, age-dependent cofactor or immune alteration in the later phase of HIV disease.

Exposure of heterosexuals to human immunodeficiency virus and viremia: evidence for continuing risks in spouses of hemophiliacs.

There is risk of transmission of human immunodeficiency virus (HIV) in sexually active couples, one of whom is seropositive. However, the frequency of such HIV transmission is not known. We have surveyed a population of monogamous hemophiliacs treated with potentially-infected coagulation factor concentrates during 1980-1984. We found high titers of antibodies to HIV in 24 of 30 hemophiliacs and in four of 30 spouses. The duration of HIV exposure from unprotected sexual intercourse ranged from greater than 12 to 78 months. The acquired immunodeficiency syndrome (AIDS) developed in six hemophiliac husbands, and one seropositive wife has lymphadenopathy. We were concerned that viremia with HIV might be the primary determinant of transmission to the men's wives. Circulating HIV was found in all of four hemophiliacs with AIDS, both of two with AIDS-related complex (ARC), four of 14 asymptomatic hemophiliacs, and two of four seropositive spouses. Isolation of HIV was less likely from asymptomatic hemophiliacs (29%) than from asymptomatic seropositive men (71%) in other high-risk groups. Our studies suggest that HIV was transmitted to 17% of the spouses of hemophiliacs. Efforts to educate all such couples about the risk of HIV infection remain imperative.

T cells expressing high levels of non-major histocompatibility complex (MHC)-restricted cytotoxicity are present in early and late clinical phases of human immunodeficiency virus 1 (HIV-1) infection.

Cytotoxic cells appear to play an important role in host defense against viral infection. In HIV-1 infection there is an expansion of the Leu7-positive lymphocyte population which is associated with cytotoxic activity. Since a form of non-MHC-restricted T-cell cytotoxicity [lectin-dependent cell cytotoxicity (LDCC)] has been reported to be mediated by CD3+Leu7+ cells, we evaluated LDCC and Leu7-positive lymphocyte populations in HIV-1-infected subjects and healthy controls. Both LDCC and percentages of Leu7+CD3+ and Leu7+CD2+ cells were increased in HIV-1-infected individuals as compared to controls. However, the CD3+Leu7+ lymphocyte population was increased to a greater degree than the CD8+Leu7+ population and a minor Leu7+ cell population (Leu7+CD4+) was expanded in the early stages of infection. Lectin-dependent cell cytotoxicity was positively correlated with the percentages of Leu7+CD3+ cells. Thus T-cells with the capacity to mediate high levels of non-MHC-restricted cytotoxicity are present in increased proportions in HIV-1-infected individuals and persist in advanced disease. Further studies are required to see if these cells participate in HIV-specific cytotoxicity or reflect an aberrant, ineffective, or immunologically detrimental response to the virus.

Effects of contrast media on fibrinogen and factor VIII.

Factor VIII and fibrinogen play an important role in hemostasis and thrombosis because they help bridge functions between platelets, endothelial cells, and the soluble coagulation system. In the present study, we found that the various contrast media examined in concentrations adequate to cause marked anticoagulation did not markedly affect either factor VIII or fibrinogen. These media act predominantly as inhibitors of other fibrinogen functions, not as protein denaturation agents.

Treatment of epidemic Kaposi's sarcoma with a combination of interferon-alpha 2b and etoposide.

A prospective clinical trial of concomitant interferon-alpha 2b and etoposide was conducted in 24 previously untreated patients with epidemic Kaposi's sarcoma. Eight of 21 evaluable patients (38%) achieved either a complete response (1 patient) or a partial response (7 patients). None of the responders had a prior history of opportunistic infection. Hematologic toxicity was severe, and 8 patients developed an opportunistic infection. The combination of interferon-alpha 2b and etoposide has modest activity, but no additive or synergistic activity was evident in the dose and schedule utilized in this study. The exact role for interferon-alpha in epidemic Kaposi's sarcoma, both as a single agent and in combinations, remains to be determined.

Human immunodeficiency virus infection in hemophiliac patients. A three-year prospective evaluation.

Thirty-seven heterosexual hemophiliac patients underwent prospective evaluation with clinical examinations, serologic studies for antibody to human immunodeficiency virus (HIV), and tests of immune function for an average of 37 months. At the time of entry into the study in 1982 to 1983, 18 subjects (49 percent) were already seropositive for HIV and 11 (30 percent) had persistent generalized lymphadenopathy. Seventy percent of the total population were clinically asymptomatic. In nine subjects, seroconversion occurred during the study such that 81 percent of the population was seropositive at the conclusion. During the same period, lymphadenopathy developed in six subjects, there was progression to AIDS-related complex (ARC) in four, and acquired immunodeficiency syndrome (AIDS) developed in one patient. Thus, at the end of the study, 54 percent were clinically asymptomatic, 32 percent had persistent lymphadenopathy, and 11 percent had ARC. Subjects who remained seronegative had received less factor concentrate than seropositive subjects, remained asymptomatic, and had normal results on tests of immune function. In those who had experienced seroconversion, there were decreased absolute numbers of CD4+ lymphocytes prior to seroconversion, and abnormalities of lymphocyte function developed after seroconversion. The development of persistent generalized lymphadenopathy was associated temporally with seroconversion. The presence of persistent generalized lymphadenopathy did not appear to be associated with an increased risk for AIDS in seropositive persons, since the condition of most hemophiliac patients with persistent generalized lymphadenopathy at the time of initial evaluation remained clinically and immunologically stable. In contrast to patients with persistent generalized lymphadenopathy, asymptomatic seropositive subjects had progressive abnormalities of lymphocyte function over time that were independent of the numbers of CD4+ cells in the peripheral blood.

Seroconversion to human immunodeficiency virus (HIV) in hemophiliacs. Relation to lymphadenopathy.

The authors studied the natural history of human immunodeficiency virus (HIV) exposure in 187 hemophiliacs followed for an average of 45 months. Overall, 55 percent developed antibody specific for HIV and 21 percent developed persistent generalized lymphadenopathy. Most patients seroconverted sometime between early 1982 and the end of 1984. Four patients developed acquired immune deficiency syndrome (AIDS) and four seropositive patients developed idiopathic thrombocytopenia (ITP). One of the four patients who developed AIDS and three of the four with ITP had preexisting lymphadenopathy. None of the 10 patients with lymphadenopathy or the 20 asymptomatic patients was seropositive for human T-lymphotropic virus, type I. Although seropositivity and lymphadenopathy have been found in many of the authors' patients, few have developed clinical disease that can be related to HIV infection.

Spontaneous suppressor cell activity in patients with the acquired immune deficiency syndrome and associated conditions.

Patients with the acquired immune deficiency syndrome (AIDS) have depressed cell-mediated immunity partially explained by a depletion of helper-inducer T-lymphocytes. We questioned if the remaining elements of the mononuclear cell (MNC) population also played a part in the immunologic abnormalities noted. We therefore evaluated the ability of MNC populations from homosexuals with AIDS and AIDS-associated conditions to suppress the mitogenic responses of control MNCs in an assay of "spontaneous suppressor" cell activity (SSCA). Asymptomatic homosexuals and homosexuals with chronic lymphadenopathy, Kaposi's sarcoma, or opportunistic infections (OIs) had levels of SSCA equal to or greater than that of control subjects. Levels were significantly higher in patients with lymphadenopathy (p less than or equal to 0.1) and in patients with OI (p less than or equal to 0.05). Although percentages of Ia+ cells were increased in all homosexual groups and highest in patients with OIs (p less than or equal to 0.05), percentages of either monocytes or suppressor/cytotoxic T-lymphocytes, potential mediators of SSCA function, did not correlate with levels of SSCA observed. Therefore, patients with AIDS and AIDS-associated conditions have MNC populations that appear to interact in producing normal or augmented down regulation of residual T-lymphocyte function, even in the face of helper/inducer T-lymphocyte depletion.

Coagulation factor concentrate usage and the risk of lymphadenopathy: a prospective study.

A prospective evaluation of 115 patients with hemophilia was performed between July 1982 and July 1983. During that period, 24 patients were seen with unexplained, generalized lymph node enlargement. The date lymphadenopathy occurred was recorded. No lymphadenopathy was found in 22 patients who did not receive coagulation factor concentrate. Factor usage was most closely related to the risks of lymphadenopathy (p = 0.004) even after controlling for age. A patient's age affected the risk of lymphadenopathy when the data were analyzed categorically (p = 0.008). A tendency was seen for heavily treated patients to develop lymph node enlargement earlier in the study period. Twenty-one of twenty-four (88%) patients with lymphadenopathy eventually developed HTLV-III/LAV antibodies and had abnormal T4/T8 ratios. These studies emphasize a close relationship between patients with hemophilia using coagulation factor concentrates and those with other risks for immune deficiency and lymphadenopathy. Close follow-up, optimal use of blood products, and further efforts to understand the importance of such changes are indicated in patients with hemophilia.