Randomized trial of a slow-release versus a standard formulation of cytarabine for the intrathecal treatment of lymphomatous meningitis.

PURPOSE: To evaluate the efficacy and safety of a slow-release formulation of cytarabine (DepoCyt; Chiron Corp, Emeryville, CA, and Skye Pharma, Inc, San Diego, CA) that maintains cytotoxic concentrations of cytarabine (ara-C) in the CSF of most patients for more than 14 days. PATIENTS AND METHODS: Twenty-eight patients with lymphoma and a positive CSF cytology were randomized to receive DepoCyt 50 mg once every 2 weeks or free ara-C 50 mg twice a week for 1 month. Patients whose CSF cytology converted to negative and who did not have neurologic progression received an additional 3 months of consolidation therapy and then 4 months of maintenance therapy. All patients received dexamethasone 4 mg orally bid on days 1 through 5 of each 2-week cycle. RESULTS: The response rate was 71% for DepoCyt and 15% for ara-C on an intent-to-treat basis (P =.006). All of the patients on the DepoCyt arm but only 53% of those on the ara-C arm were able to complete the planned 1-month induction therapy regimen. Time to neurologic progression and survival trend in favor of DepoCyt (median, 78.5 v 42 days and 99.5 v 63 days, respectively; P >.05). DepoCyt treatment was associated with an improved mean change in Karnofsky performance score at the end of induction (P =.041). The major adverse events on both arms were headache and arachnoiditis, which were often caused by the underlying disease. CONCLUSION: DepoCyt injected once every 2 weeks produced a high response rate and a better quality of life as measured by Karnofsky score relative to that produced by free ara-C injected twice a week.

Incidence of human immunodeficiency virus-related and nonrelated malignancies in a large cohort of homosexual men.

PURPOSE: To determine if the rates of malignancies other than Kaposi's sarcoma (KS) and non-Hodgkin's lymphoma (NHL) are increased in human immunodeficiency virus (HIV)-infected homosexual men. SUBJECTS AND METHODS: From 1984 through 1993, 1,199 homosexual men were studied in the Pittsburgh component of the Multicenter AIDS Cohort Study (MACS), an examination of the natural history of HIV infection. The cohort consisted of 769 HIV-seronegative (SN) participants and 430 seropositive (SP) members who were either seroprevalent at the time of enrollment or who seroconverted during the study. Cancer incidence data were collected through semiannual visits, phone interviews, medical records, and death certificates. Five thousand seven hundred eight person-years and 2,344 person-years were contributed to the study by the SN and SP men, respectively. RESULTS: In addition to 44 cases of KS, 13 NHLs, and 3 CNS lymphomas (CNSLs), 27 other malignancies occurred (three nonmelanoma skin cancers and eight other malignancies in the SP group, eight nonmelanoma skin cancers, and eight other malignancies in the SN group). Age-adjusted rates were calculated for both groups and compared with each other and with rates for the general male population in Pennsylvania. There were no differences between the SN group and the general population. Among the SP group, the combined frequency of all cancers other than KS, NHL, CNSL, and nonmelanoma skin cancers was statistically significantly increased in comparison to both the SN group and the general population. This increase was secondary to an unusually increased frequency of both seminoma and Hodgkin's disease. CONCLUSION: These findings support the hypothesis that the incidences of cancers other than KS and lymphoma are moderately increased in the setting of HIV infection and immunosuppression.

Prognostic factors in human immunodeficiency virus-positive patients with a CD4+ lymphocyte count < 50/microL.

This analysis investigated variability of survival time in a cohort of 553 human immunodeficiency virus type 1 (HIV-1)-infected homosexual or bisexual men with < 50 CD4+ cells/microL. Median survival after the first CD4+ cell count < 50/microL was 1.34 years; 25% survived > or = 2 years. Multivariate analysis showed longer survival with concurrent acyclovir and zidovudine use, hemoglobin > or = 12 g/dL, and full-time employment (P < .0001). Other significant covariates associated with longer survival included African-American race, no prior AIDS illness, weight loss < 4.5 kg, and zidovudine use (with or without concurrent acyclovir) after CD4+ cells fell to < 50/microL. An easily derived score identified Multicenter AIDS Cohort Study subjects likely to survive > 2 years after CD4+ cell count was < 50/microL. Survival once CD4+ cell count fell below 50/microL may be longer for persons with a good performance status and specific clinical markers. Health care providers should consider these variables in decision-making strategies and design of clinical trials.

Factors associated with participation in HIV antibody screening and results disclosure.

The Centers for Disease Control reported in October 1991 that many people at risk for human immunodeficiency virus (HIV) infection had not been tested for antibodies to HIV. This study identifies differences among 110 gay and bisexual men in three small cities in Pennsylvania who decided whether to be tested for antibodies to HIV and, if so, whether to return for results. These men were given self-administered questionnaires and were offered free and confidential HIV antibody tests. Fifty percent of the men refused testing. Of those tested, only 35 percent returned to obtain test results. Contrary to other health prevention data, education was significantly and inversely related to being tested and to returning for results. Men who most often participated in the institutionalized gay community were least likely to be tested. The findings suggest that gay men who are most aware of the potential psychosocial problems associated with HIV antibody testing are more likely to avoid testing.

Guidelines for disclosing HIV-antibody test results to clients.

Because of new preventive therapies, HIV-antibody testing of asymptomatic individuals now has clear clinical benefits. Consequently, greater numbers of individuals are expected to seek testing. This article, based on the authors' experiences with disclosing HIV-antibody test results to a high-risk group of men, makes recommendations for how best to present HIV-antibody results. Disclosing HIV-antibody results provides an educational opportunity as well as a psychological challenge for clinicians. Some unusual client reactions are detailed in the case studies.

Affective and behavioral responses of gay and bisexual men to HIV antibody testing.

Fifty-six gay and bisexual men were tested for antibody to the human immunodeficiency virus. Twenty-two subjects who tested positive, 22 subjects who tested negative, and 12 subjects who chose not to learn the test results were surveyed by questionnaire after one week and after about six months after testing. Subjects who tested positive and those who tested negative were also compared two weeks after learning results. Subjects who tested positive experienced an increase in anxiety, depression, and AIDS anxiety, and subjects who tested negative experienced a decrease in these feelings after learning results. Subjects who did not learn the results of their tests experienced no change in these feelings. All three groups altered their sexual behavior. Subjects were more likely to tell test results to lovers and to regular sexual partners than to casual sexual partners. Implications for social work practice are discussed.

Association of hepatitis B surface antigen and core antibody with acquisition and manifestations of human immunodeficiency virus type 1 (HIV-1) infection.

We examined the associations between seropositivity for hepatitis B virus (HBV) with the presence or development of antibodies to human immunodeficiency virus (HIV-1) and with HIV-1 induced T-helper lymphocyte deficiency or acquired immunodeficiency syndrome (AIDS). Serologic data on HBV and HIV-1, cytometric enumeration of CD4+ lymphocytes, clinical events (AIDS by Centers for Disease Control criteria) and hepatitis B vaccination histories were available on 4,498 homosexual participants in the Multicenter AIDS Cohort Study, Men were classified as to previous infection with HBV and prevalent or incident infection with HIV-1. Although there was an association between seropositivity for HBV infection and HIV-1 infection at enrollment (odds ratios anti-HBc 2.6; HBsAg 4.2), the relation between HBV seropositivity and subsequent seroconversion to HIV-1 was weaker (odds ratios 1.3 and 1.6). HIV-1 seroconversion was also associated with a history of certain other sexually transmitted diseases, but predisposing sexual practices did not account for the association between HBV and HIV-1 infection. Seropositivity for HBV infection at entry was not related to initially low or more rapid subsequent decline in T-helper lymphocyte counts and was not associated with an increased incidence of AIDS during 2.5 years of follow-up. History of vaccination against HBV did not appear to decrease susceptibility to HIV-1 infection or to subsequent progression of immunodeficiency. We conclude that prior HBV infection is unlikely to be specifically associated with acquisition of HIV-1 infection and is unrelated to more rapid progression of HIV-1-induced immunodeficiency.

Sexual transmission efficiency of hepatitis B virus and human immunodeficiency virus among homosexual men.

The relative sexual transmission efficiency of hepatitis B virus (HBV) and human immunodeficiency virus type 1 (HIV-1) was investigated by a prospective study of homosexual men in Pittsburgh, Pa, from the Multicenter AIDS Cohort Study. During the 30-month follow-up, 19.8% and 7.8% of the initially seronegative HBV and HIV-1 groups were estimated to seroconvert to HBV and HIV-1, respectively. The significantly higher cumulative HBV seroconversion rate occurred despite a much lower prevalence of hepatitis B carriers (7% were hepatitis B surface antigen positive) compared with HIV-1 carriers (22% were HIV-1 antibody positive). The sexual exposure profile of HBV and HIV-1 seroconverters was similar during the 6 months prior to seroconversion, supporting the link between anal intercourse and acquisition of either infection. However, insertive, not receptive, anal intercourse was the major risk factor identified for HBV seroconversion, suggesting that transurethral exposure is an important mode of transmission. These data suggest that HBV is transmitted 8.6-fold more efficiently than HIV-1 among homosexual men studied and underscore the benefits of both HBV immunization and use of condoms during intercourse to prevent HBV infection.

Preventing HIV infection in gay and bisexual men: experimental evaluation of attitude change from two risk reduction interventions.

In the course of learning their HIV serostatus, gay and bisexual men participated in small discussion groups aimed at increasing their practice of safer sex. Small discussion groups were randomly assigned to receive one of two interventions: a lecture/discussion by a gay health educator, or an intervention that included the lecture/discussion followed by a small group process aimed at increasing social skills for safer sex and at increasing peer support for safer sex. Men completed questionnaires relating to their knowledge about HIV and AIDS, attitudes toward sexual behavior change, and self-reported sexual behavior. At second follow-up, one year post-intervention, men who had received skills training and peer support endorsed significantly stronger attitudes in favor of safer sex than did men receiving lecture/discussion only. In particular, skills training and peer support caused greater reduction of the value placed on ejaculation inside the partner, stronger endorsement of plans to use condoms, and greater reduction of negative attitudes about condoms, than did lecture/discussion only. These results are helpful to design interventions for men who continue to engage in riskful behavior.

Factors related to seroconversion among homo- and bisexual men after attending a risk-reduction educational session.

Thirteen homosexual men, volunteers in a study of the natural history of HIV, who seroconverted to HIV after participating in an educational program on HIV prevention, were interviewed about the circumstances leading to their seroconversion. Six men had participated in unprotected anal intercourse with at least one partner whom they believed was HIV-negative. Four men attributed their conversion to mental health problems or to drug and alcohol use. Two men's seroconversions could not be ascertained and one man attributed seroconversion to a condom break. Most men who had learned how to avoid infection, and had successfully done so for a time, had knowingly engaged in unsafe behaviors because of strong emotional responses to certain partners or because of mental health or drug and alcohol-related problems. Skills training for dealing with partners who pressure men to behave unsafely is needed, as is mental health and drug and alcohol counseling for men at risk for HIV infection.

Association of human immunodeficiency virus (HIV) p24 antigenemia with decrease in CD4+ lymphocytes and onset of acquired immunodeficiency syndrome during the early phase of HIV infection.

Human immunodeficiency virus (HIV) p24 antigenemia was assessed in a longitudinal study of 52 homosexual men who developed serum antibody to HIV. Antibody seroconversion to HIV as defined by a positive HIV enzyme immunoassay (EIA) confirmed by Western (immuno-) blot was associated with three major patterns of HIV antigenemia. In the first pattern, a transient antigenemia was noted 6 (six subjects) and 12 (one subject) months prior to detection of antibody by HIV EIA and Western blot in 7 (13.5%) of the 52 men. Use of an EIA employing a recombinant envelope protein (ENV9) was able to detect antibody in four of these seven men at the time of this early antigenemia. In the second pattern, HIV p24 antigenemia occurred in 8 (15.4%) of the 52 subjects within the first 12 months after HIV antibody seroconversion. No p24 antigen was detected in the 37 (71.1%) remaining subjects. CD4+ cell numbers were lower in antigen-positive men before and after antibody seroconversion. Development of acquired immunodeficiency syndrome (AIDS) or AIDS-related complex was strongly associated with evidence of persistent p24 antigenemia during the early, postseroconversion period. HIV p24 antigenemia may be of value in determining appropriate cohorts for drug therapy trials for subjects with early-phase HIV infection.

Enhanced antibody responses to Epstein-Barr virus in HIV-infected homosexual men.

We investigated the association between human immunodeficiency virus (HIV) and Epstein-Barr virus (EBV) infections in 593 homosexual men. The status of EBV infection in this group was evaluated based on serological evidence of EBV-specific antibody responses. The geometric mean titers (GMT) of antibody to EBV capsid antigen (EBV-VCA) (1:154) and EBV early antigen (EA) (1:16) in 141 HIV-seropositive men were significantly higher than respective titers in 452 HIV seronegative men (1:95 and 1:12). Antibody titers to EBV were higher in HIV-infected men with lymphadenopathy than in asymptomatic HIV-seropositive men. However, these correlation were less evident in patients with AIDS-related complex. Elevated antibody titers to EBV were found to be independent of levels of total serum IgG. Cytomegalovirus (CMV) antibody titers were also found to be significantly increased among HIV-seropositive men, independent of total IgG. Antibody titers to EBV were not correlated with those to CMV in either HIV-seronegative or HIV-seropositive men. Subjects without evidence of HIV infection, but who had high antibody titers to EBV-VCA and EBV-EA, had elevated mean numbers of CD3+, CD4+, and CD8+ cells, and lower levels of CD4+/CD8+ cell ratios compared to subjects with low EBV-antibody titers. This study suggests that the elevated levels of circulating antibodies against EBV in homosexual men are associated with loss of control of latent EBV due to HIV infection.

AIDS prevention in homosexual and bisexual men: results of a randomized trial evaluating two risk reduction interventions.

This study evaluates two AIDS risk-reduction interventions targeted at homosexual and bisexual men. Participants were randomized into two peer-led interventions: both involved a lecture on 'safer sex', and one provided a skills-training component during which men could discuss and rehearse the negotiation of safer sexual encounters. Follow-up data collection assessed self-reported changes in sexual behavior at 6 and 12 months. Skills training increased condom use for insertive anal intercourse. In sessions providing skills training, condom use increased, on average, by 44% between pre-test and second follow-up compared with only 11% on average in sessions which did not provide such training.

Variables influencing condom use in a cohort of gay and bisexual men.

Nine hundred fifty-five of 1,384 (69 per cent) gay and bisexual men enrolled in a prospective study of the natural history of human immunodeficiency virus (HIV) infection who reported engaging in anal intercourse in the past six months were surveyed about condom use practices for both insertive (IAI) and receptive anal intercourse (RAI). The following results were obtained: 23 per cent of the men reported that they always used condoms for IAI and 21 per cent for RAI; 32 per cent sometimes used condoms for IAI; 28 per cent sometimes used condoms for RAI; 45 per cent never used condoms for IAI; and 50 per cent never used condoms for RAI. Multiple logistic regression analysis revealed that the following variables were associated with both insertive and receptive condom use: condom acceptability; a history of multiple and/or anonymous partners in the past six months, and the number of partners with whom one is "high" (drugs/alcohol) during sex. Knowledge of positive HIV serostatus was more strongly associated with receptive than with insertive use. Condom use is a relatively complex health-related behavior, and condom promotion programs should not limit themselves to stressing the dangers of unprotected intercourse.

HIV-1-specific production of IFN-gamma and modulation by recombinant IL-2 during early HIV-1 infection.

Specific cellular immune responses to human immunodeficiency virus type 1 (HIV-1) were assessed in mononuclear leukocyte cultures from homosexual men with documented, early phase HIV-1 infection. Cell cultures from men with a mean duration of 1.3 yr (range, 0.3 to 2.2 yr) of HIV-1 infection were treated with UV-inactivated, whole, purified HIV-1 Ag together with various concentrations of rIL-2. Cell supernatants were harvested after 5-day incubation and assayed for IFN activity against encephalomyocarditis virus in human WISH cells. IFN subtypes were characterized by neutralization of antiviral activity with antiserum specific for human IFN-gamma and IFN-alpha. Results showed that cultures from 68% (17 of 25) of the HIV-1-seropositive subjects produced "immune" IFN-gamma in response to whole HIV-1 Ag plus rIL-2. IFN-gamma was induced in only 20% (5 of 25) of cultures treated with HIV-1 Ag alone. Enhancement of HIV-1-specific IFN-gamma production by rIL-2 was synergistic rather than additive in that titers induced by the mixture were consistently higher than the sum of IFN titers induced by HIV-1 or rIL-2 alone. This effect was not demonstrable in cultures from 18 HIV-1-seronegative men. Similarly, HIV-1-immune specific augmentation of IFN-gamma production by rIL-2 was noted for PENV9, a recombinant HIV-1 envelope glycoprotein gp41 and gp120 fragment. Production of IFN-gamma may be an important, HIV-1-immune specific parameter in the host response to this retrovirus.

Defective T-cell colony formation and IL-2 receptor expression at all stages of HIV infection.

The T-cell colony assay is a highly sensitive measure of immunological dysfunction. The present study evaluated this in vitro response in asymptomatic HIV-infected homosexuals, those with chronic adenopathy as their only clinical manifestation and patients with either ARC or AIDS. The mean colony count in antibody-positive asymptomatic individuals was significantly reduced when compared to either heterosexual controls or antibody-negative homosexuals. Furthermore, there were no differences in the responses of these antibody-positive individuals and those with chronic lymphadenopathy as their only clinical manifestation. By contrast, patients with AIDS or ARC showed a profound defect; this suggests that the colony assay can detect a functional gradient across the spectrum of HIV infections. Colony growth was correlated with the absolute number of T-helper cells and the ability of PHA-stimulated lymphocytes to express IL-2 receptors; no correlation was found with the number of suppressor/cytotoxic cells or in vitro production of IL-2. Recent HIV seroconverters had normal colony counts but impaired ability to express IL-2 receptors. These data suggest a sequential loss of T-cell function as a result of HIV infection; the earliest manifestations are impaired expression of IL-2 receptors and reduced proliferative responses, as measured in the colony assay.

Human immunodeficiency virus and hepatitis delta virus in homosexual men. A study of four cohorts.

The prevalence of hepatitis delta virus antibodies was determined in four cohorts of homosexual or bisexual men positive for hepatitis B surface antigen who were evaluated between April 1984 and April 1985. Antibodies to hepatitis delta virus were found in 16 of 106 men in Los Angeles (15.1%; 95% confidence interval [Cl], 8.3% to 21.9%); 6 of 64 men in San Francisco (9.4%; 95% Cl, 3.5% to 19.3%); 1 of 76 men in Pittsburgh (1.3%; 95% Cl, 0.03% to 7.1%); and 0 of 52 men in Chicago (0%; 95% Cl, 0% to 5.6%). From 44.0% to 65.4% of men negative for hepatitis delta virus and all men positive for hepatitis delta virus but one (P less than 0.0001) were positive for antibodies to human immunodeficiency virus (HIV). In multivariate analysis, infection with hepatitis delta virus was associated with intravenous drug use (adjusted odds ratio [OR] = 6.7, P less than 0.01), with sexual activity as measured by number of partners (adjusted OR = 8.4, p less than 0.01), and probably with rectal trauma (adjusted OR = 3.9, P = 0.17). As with HIV infection, prevalence of hepatitis delta virus infection in homosexual men differs by location and is most likely transmitted both sexually and parenterally.

Infection with the human immunodeficiency virus: clinical manifestations and their relationship to immune deficiency. A report from the Multicenter AIDS Cohort Study.

In 1984 a large prospective study of gay and bisexual men was begun to elucidate the natural history of the human immunodeficiency virus (HIV) infection. At two successive semiannual examinations, clinical or hematologic abnormalities were found up to 13 times more often among HIV-seropositive men (n = 1611) than HIV-seronegative men (n = 2646). More than 30% of the seropositive participants had persistent generalized lymphadenopathy, independent of T-helper lymphocyte (CD4) counts and most other signs and symptoms. Other clinical manifestations such as thrush, anemia, thrombocytopenia, neutropenia, fever, and fatigue occurred with only slightly reduced CD4 counts (400 to 700/mm3) and appeared to increase exponentially with progressively lower counts. A simple systematically derived clinical index using these manifestations identified more than 70% of the seropositive men with significant T-helper cell depletion. This kind of clinical index may be useful for assessing groups of HIV-infected persons, especially those whose T-lymphocyte numbers and function cannot be readily measured.

The HIV antibody test: why gay and bisexual men want or do not want to know their results.

Beginning in the latter part of 1985, 2,047 gay and bisexual men who were enrolled in the Pitt Men's Study, the Pittsburgh cohort of the Multicenter AIDS Cohort Study (MACS), were invited by mail to learn the results of their antibody test for HIV infection--human immunodeficiency virus infection. Participants were asked to complete and return a questionnaire designed to assess the factors influencing their (a) decision about learning the results, (b) recent sexual behavior, (c) knowledge about acquired immunodeficiency syndrome (AIDS), and (d) attitudes toward AIDS risk reduction. Of those men, 1,251 (61 percent) accepted the invitation, 188 (9 percent) declined, and 608 (30 percent) failed to respond. Fifty-four percent of the cohort subsequently learned their results. There were no significant differences in demographic, behavioral, and attitudinal characteristics or HIV seroprevalence between the men who accepted and those who declined. However, significant demographic differences were noted between the men who responded to the invitation versus those who did not; the latter group was composed of a greater proportion of men who were younger, nonwhite, and less educated. The most frequently cited reason (90 percent) why men wanted their test results was to determine if they had been infected with HIV. Of those who declined, 30 percent cited concerns about the psychological impact of learning about a positive result as being the most important factor for their decision. The two most frequently selected reasons for declining were the belief that the test is not predictive of the development of AIDS (48 percent) and concern about the worry that a positive result would produce (48 percent). These findings are discussed in the context of a nationwide, voluntary HIV screening program for gay and bisexual men.