Rand L. Stoneburner

Survival with the acquired immunodeficiency syndrome. Experience with 5833 cases in New York City.

In a cohort of 5833 subjects in whom the acquired immunodeficiency syndrome (AIDS) was diagnosed in New York City before 1986, the cumulative probability of survival (mean +/- SE) was 48.8 +/- 0.7 percent at one year and 15.2 +/- 1.8 percent at five years. The group with the most favorable survival rate--white homosexual men 30 to 34 years old who presented with Kaposis sarcoma only--had a one-year cumulative probability of survival of 80.5 percent; that group was used as the reference group in assessing the effect of five variables: sex, race or ethnic background, age, probable route of acquiring AIDS (risk group), and manifestations of AIDS at diagnosis. The range in the mortality rate was greater than threefold, depending on these variables. Black women who acquired the disease through intravenous drug abuse, for example, had a particularly poor prognosis. The manifestations of disease at diagnosis had the most influence on survival, accounting on average for 56.3 percent of the excess risk. This variable was followed in importance by age (12.2 percent), race or ethnicity (10.6 percent), risk group (8.4 percent), and sex (8.0 percent), with 4.5 percent of the risk attributable to interactions between variables. When we compared subcohorts based on the year of diagnosis (1981 through 1985), we found a significant improvement in the one-year cumulative probability of survival among subjects with Pneumocystis carinii pneumonia, but not among subjects without P. carinii pneumonia.

Heterosexual transmission of HIV-1 associated with the use of smokable freebase cocaine (crack)

A study of risk factors for HIV-1 infection was conducted at a sexually transmitted disease clinic in an area of New York City where the cumulative incidence of AIDS in adults through mid-1990 was 9.1 per 1000 of the population and where the use of illicit drugs, including smokable freebase cocaine (crack), is common. The overall seroprevalence among volunteers was 12% (369 out of 3084), with 80% of those who were seropositive reporting risk behavior associated with HIV-1 infection, including male-to-male sexual contact, intravenous drug use and heterosexual contact with an intravenous drug user. The seroprevalence in individuals denying these risks was 3.6% (50 out of 1389) and 4.2% (22 out of 522) in men and women, respectively. Among these individuals, the behaviors significantly associated with infection were use of crack and prostitution in women, and history of syphilis and crack use in men. These results suggest that in areas where the level of HIV-1 infection in heterosexual intravenous drug users is high and the use of crack is common, increased sexual activity (including the exchange of drugs or money for sex) may result in increased heterosexual transmission of HIV-1.

A larger spectrum of severe HIV-1--related disease in intravenous drug users in New York City

Increasing mortality in intravenous (IV) drug users not reported to surveillance as acquired immunodeficiency syndrome (AIDS) has occurred in New York City coincident with the AIDS epidemic. From 1981 to 1986, narcotics-related deaths increased on average 32% per year from 492 in 1981 to 1996 in 1986. This increase included deaths from AIDS increasing from 0 to 905 and deaths from other causes, many of which were infectious diseases, increasing from 492 to 1091. Investigations of these deaths suggest a causal association with human immunodeficiency virus (HIV) infection. These deaths may represent a spectrum of HIV-related disease that has not been identified through AIDS surveillance and has resulted in a large underestimation of the impact of AIDS on IV drug users and blacks and Hispanics.

HIV-1 Seroconversion in Patients with and without Genital Ulcer Disease: A Prospective Study

Since the beginning of the acquired immunodeficiency syndrome (AIDS) epidemic, two predominant and distinct epidemiologic patterns of human immunodeficiency virus (HIV-1) transmission have been reported. In North America and Western Europe, although heterosexual transmission has been increasing [1], men exposed to HIV-1 through sexual contact with other men and injection drug users (users of illicit drugs) are the predominant groups at risk for development of AIDS [2]. The second pattern, prevalent in Africa and parts of Asia and the Caribbean, is predominantly characterized by heterosexual transmission, with a nearly equal male-to-female ratio of patients [3, 4]. The reasons for these different patterns of transmission have not been fully identified, but studies have addressed the possibility that the presence of genital ulcers, especially chancroid, has enhanced heterosexual transmission [5, 6]. Sexually transmitted diseases that result in a disrupted genital epithelium, such as syphilis, chancroid, and herpes, have been associated with heterosexual transmission of HIV-1 using retrospective studies in the United States [7-10] and both retrospective [11] and prospective studies in sub-Saharan Africa [12, 13]. In New York City, an ongoing epidemic of genital ulcer disease has occurred in communities where HIV-1 infection related to injection drug use is well documented [10, 14]. The number of cases of primary and secondary syphilis reported to the New York City Department of Health increased from 2157 in 1985 to 4231 in 1990. The number of reported cases of chancroid increased from 1323 in 1985 to 2277 in 1989. Consequently, a prospective study of HIV-1 seroconversion was initiated to further characterize the relation between genital ulcer disease and HIV-1 transmission in primarily heterosexual persons in the United States. Methods Study Population This study was done in 1 of the 12 inner-city, sexually transmitted disease clinics operated by the New York City Department of Health. The study site is located in an area of New York City where the cumulative incidence of AIDS in adults through 1990 was 1 per 100 persons (New York City AIDS Case Surveillance data) and illicit drug use, including crack (smokable freebase cocaine) use, is common. In 1990, this clinic provided care to 14 243 persons: 9589 (67%) were men and 4654 were women. Primary or secondary syphilis was diagnosed in 226 patients, and 113 were found to have chancroid. From 1988 to 1989, the HIV-1 prevalence in this clinic was 7.8%, estimated by a serosurvey that was done without using patient identifiers (Weisfuse I. Personal communication). Study Population Recruitment into the study consisted of two phases. In the first phase, all of the approximately 28 000 persons attending the clinic for diagnosis or treatment of a sexually transmitted disease during the study period were asked to participate in a study of the prevalence of HIV-1 infection and associated risk factors. Those who agreed (n = 2893) received HIV-1 pretest counseling and were given a return appointment to receive test results and post-test counseling. Those with a diagnosis of genital ulcer were recruited more intensively. Thus, approximately 700 (24%) of the 2893 participants recruited into phase 1 had genital ulcers. These 700 participants with genital ulcer disease represented more than 80% of all patients seen in the clinic with ulcers during the study period. Study interviewers administered standardized questionnaires in either English or Spanish. Information on demographic characteristics, socioeconomic status, and risk behavior associated with HIV-1 transmission was collected, as previously described [14]. Of the 2543 participants who were HIV negative, 1679 returned for post-test counseling 3 weeks after initial study enrollment and were asked to participate in the prospective component (or phase 2) of the study. For those who agreed, an additional questionnaire was administered to identify potential HIV-1-related high-risk behavior during three periods of interest: the 6 months before the initial clinic visit, the 10 days before the symptom developed that resulted in the clinic visit, and the period while the symptoms were present. The questioning focused on intravenous drug use and the number of sexual contacts and the type of sexual activities with intravenous drug users, homosexual or bisexual men, prostitutes, and others. The regularity of condom use was determined using the following scale: always, usually (>50%), sometimes (approximately 50%), rarely (<50%), and never. Anonymous HIV-1 testing was available for patients who did not want to participate in the study or who did not have a sexually transmitted disease. At the time of enrollment in phase 2, participants were asked to return to the clinic for a third time, approximately 3 months after the initial clinic visit. For the participants who returned for the final follow-up visit, a repeated serum sample for HIV-1 testing was obtained, and a questionnaire similar to that described above was administered to identify high-risk behavior for the period between the two HIV-1 antibody tests. Informed consent was obtained for both phases of the study, and the study was approved by the institutional review boards of the New York City Department of Health and the Centers for Disease Control and Prevention. Laboratory Methods Patients with a genital ulcer had the following diagnostic tests: syphilis serology, dark-field examination of ulcer exudate for Treponema pallidum, Gram stain of ulcer exudate, microbiologic culture for Haemophilus ducreyi using blood and chocolate media, and Tzanck smear for herpes virus. Testing for syphilis was done using the rapid plasma reagin card test (Hynson, Wescott, and Dunning; Baltimore, Maryland) and the microhemagglutination assay for T. pallidum (Fujirebio Inc., Tokyo, Japan, and Ames Division, Miles Laboratory, Elkhart, Indiana). Haemophilus ducreyi was isolated using previously described methods [15]. Antibody testing for HIV-1 was done by an enzyme-linked immunosorbent assay (DuPont, Wilmington, Delaware), followed by a confirmatory Western blot analysis of all reactive samples using reagents prepared by the Laboratory of Retrovirology and Immunobiology of the New York City Department of Health [16]. Diagnosis of Genital Ulcer Disease Primary syphilis was diagnosed when a genital ulcer was present and the ulcer exudate was dark-field positive, the rapid plasma reagin card test was positive, or the patient had recent contact with a person known to have syphilis. A diagnosis of chancroid was made when a positive culture occurred for H. ducreyi, if Gram stain of the ulcer exudate showed pleomorphic gram-negative rods, or if clinical findings suggested chancroid (tender or multiple ulcers, painful inguinal adenitis) with a negative dark-field examination as well as a negative syphilis serologic test result and a negative Tzanck smear. Genital herpes was diagnosed when the lesions were vesicular or recurrent or an ulcer had a positive Tzanck smear. In the absence of, or with negative, microbiologic and serologic data, the clinical diagnosis was made by the supervising physician in the clinic and not by study personnel. Statistical Analysis Analysis was done using the SAS statistical software system, version 6.06 (SAS Institute, Inc., Cary, North Carolina). The strength of the association between individual categorical variables or continuous variables grouped categorically and HIV-1 seroconversion was evaluated by the relative risk, and 95% direct precision-based CIs were obtained. Statistical relations were tested by the chi-square test or the Fisher exact test (two-tailed). Differences between continuous variables were analyzed by the Student t-test (two-tailed), the Wilcoxon rank-sum test, or the median test. The SAS LOGIST procedure was used to fit the multiple logistic regression model to the single binary outcome variable (HIV seroconversion or no seroconversion). The adjusted odds ratios obtained in this model approximated the adjusted relative risk. Measurement of Risk Index For heterosexual men, a summary measure was constructed of the risk for HIV-1 transmission attributable to a combination of the probability of encountering and the frequency of exposure to an HIV-1-infected partner. The sexual risk index was generated for the period from 6 months before the clinic visit through the second HIV test. Indices were computed by taking the sum of the products of the number of sexual contacts with partners in each of four risk groups (prostitutes, female intravenous drug users, women with chancroid, and women with no risk) and the estimated HIV-1 seroprevalence among the members of that group. Prevalence estimates for risk groups were determined from among our own study participants during phase 1, unblinded risk-factor serosurvey because sexual contacts were likely to occur in the local geographic area. The overall seroprevalence for the 644 women with no risk in phase 1 was 6%, for the 88 injection drug users it was 44%, for the 167 female prostitutes it was 29%, and for the 26 women with chancroid it was 19%. Using these values, risk indices were generated for four groups of male study participants: those with chancroid who did and did not seroconvert and those without chancroid who did and did not seroconvert. The risk indices were scaled proportionately from 0 to 100 for graphic presentation. Statistical comparisons were done between the Sexual Risk Index medians of the patients with chancroid and those without chancroid who seroconverted; between those without chancroid who seroconverted and those without chancroid who did not seroconvert; and between patients with chancroid who seroconverted and all patients who did not seroconvert using the median test. Results Of the 2543 seronegative persons identified in the cross-sectional component (phase 1) of the study, 1679 (62%) r

Transfusion-associated acquired immunodeficiency syndrome. Evidence for persistent infection in blood donors.

To investigate whether infection with human T-cell lymphotropic virus/lymphadenopathy-associated virus (HTLV-III/LAV) may be persistent in asymptomatic persons and to correlate infection with seropositivity the authors performed virologic and serologic studies in 25 of 30 persons who were identified as being at high risk for the acquired immunodeficiency syndrome (AIDS) and who had donated blood to patients who later contracted transfusion-associated AIDS. High-risk donors were those who belonged to a high-risk population had AIDS or a closely related condition or had a low ratio of helper to suppressor T lymphocytes. The authors performed similar studies in 6 of the 24 patients with AIDS who had received donations from this group. HTLV-III/LAV was isolated from 22 of the 25 donors between 12 and 52 months (mean 28) after they had donated blood and from all 6 recipients between 14 and 37 months (mean 26) after they had received blood. Of the 22 virus-positive donors 2 have contracted AIDS 5 have generalized lymphadenopathy and 15 (68%) remain asymptomatic. Antibodies to HTLV-III/LAV were detectable by the enzyme-linked immunosorbent assay in serum samples obtained from each person at the time the virus was isolated. It is concluded that infection with HTLV-III/LAV may be persistent and asymptomatic for years. This demonstrates that viremic patients may be asymptomatic supports the use of serologic screening of donated blood to supplement current procedures for the prevention of transfusion-associated AIDS. (authors)

Predictors of survival in HIV-infected tuberculosis patients

ObjectiveTo ascertain predictors of survival in HIV-infected tuberculosis (TB) patients. DesignRetrospective cohort study. SettingNew York City public hospital. PatientsFifty-four consecutive HIV-seropositive patients with newly diagnosed TB and no other AIDS-defining illnesses. Main outcome measuresCD4+ T-lymphocyte counts, completion of anti-TB therapy, repeat hospitalizations with TB, and survival. ResultsForty-five (84%) of the 54 patients died a median of 15 months after TB diagnosis (range, 1–80 months), five (9%) were alive after a median of 81 months (range, 75–84 months), and four (7%) were lost to follow-up after a median of 42 months (range, 30–66 months). In univariate analyses, disseminated TB, intrathoracic adenopathy, oral candidiasis and CD4 count depletion were each associated with decreased survival. In a multivariate analysis, CD4 count depletion was the only independent predictor of decreased survival. Repeat hospitalization with TB occurred in 10 out of 15 patients who did not complete anti-TB therapy compared with one out of 21 patients who completed anti-TB therapy (P < 0.001). ConclusionThe clinical presentation of TB and CD4 count at TB diagnosis are each predictive of survival in HIV-seropositive TB patients. The CD4 count is the only independent predictor of survival.

Syphilis treatment response in HIV-infected individuals

The adequacy of treatment for syphilis has routinely been evaluated by the serological response, i.e. the rapid plasma reagin test (RPR). Since the description of AIDS and HIV aspects of both the natural history of syphilis and the response of Treponema pallidum to treatment have come under increased scrutiny. With concurrent epidemics of HIV and syphilis in New York City, a serological case-control study was done to determine whether HIV-infected individuals given treatment for primary or secondary syphilis have a modified serological response. All study participants had primary or secondary syphilis and paired specimens available for testing. Cases were defined as people who were HIV-positive and were compared with controls who were HIV-negative. HIV-infected patients with primary syphilis when compared with HIV-negative controls were less likely to have a fourfold or greater RPR decrease or seroreversion within 6 months of treatment [15 out of 28 versus 153 out of 210; odds ratio = 0.4, P less than 0.05]. Cases and controls with secondary syphilis had similar serological responses after treatment for syphilis. Although this study adds to the growing body of literature which suggests that HIV may alter the RPR response, prospective studies are needed to determine definitively whether HIV alters the serological response to therapy in patients with early syphilis.

Preparation for phase III HIV vaccine efficacy trials: methods for the determination of HIV incidence.

Objective:Accurate estimates of HIV incidence that reflect the effect of non-vaccine interventions (education, counselling, condom promotion, and possibly sexually transmitted disease treatment) and that may be provided in a Phase III vaccine efficacy trial, are needed so that vaccine trial population sample sizes can be accurately determined. In order to avoid delays in the implementation of efficacy trials, well characterized cohorts must also be developed and available to participate in such trials. We reviewed the potential study populations, the epidemiologic methods for the determination of HIV incidence (using open cohort, closed cohort, and seroprevalence data methods), and the need for the development of population cohorts in preparation for Phase III HIV vaccine efficacy trials. Setting:Phase III trials in developed and developing countries. Methods:Comparison of open and closed cohorts and those using seroprevalence data to estimate HIV incidence. Results:Open and closed cohorts each have disadvantages and advantages. However, the open cohort may be more suitable for determining estimates of HIV incidence that reflect non-vaccine interventions and for the development of a well characterized cohort available to participate in efficacy trials. Conclusion:Careful preparation of research infrastructures and population cohorts will help ensure the successful conduct of scientifically and ethically sound HIV vaccine efficacy trials in the future.

DECLINES IN PROPORTION OF KAPOSI'S SARCOMA AMONG CASES OF AIDS IN MULTIPLE RISK GROUPS IN NEW YORK CITY

The variation in Kaposis sarcoma (KS) as a clinical manifestation of HIV infection has been 1 of the more puzzling aspects of the AIDS epidemic in the US. The proportion of AIDS cases with KS has been highest in the homosexual/bisexual male risk group, for reasons unknown. Over the past few years there has been a sharp decline in KS as a proportion of AIDS cases: KS (without other AIDS diagnoses) was the initial diagnosis in 1/3 of the 1st 1000 cases of AIDS reported to the Centers for Disease Control (CDC); in 1/4 of the 16,500 cases reported up to the end of January, 1986; and in only 1/10 of the 11,000 cases reported to CDC between January and August, 1987. Compared to other AIDS diagnoses, KS is associated with both longer survival times after diagnosis and lower medical costs. Thus, understanding of the trend in proportion of KS cases is needed both for possible insight into the pathogenesis of HIV infection and for planning health services for AIDS. The almost total absence of KS in the heterosexual partners suggests that some co-factor is necessary for the development of KS in the presence of HIV infection. If KS were simply an early response to HIV infection, then the proportion of KS cases in the heterosexual partner group should be very high. 1 explanation is that HIV had spread to more and more people in different groups who have not been sufficiently exposed to the co-factor. Rather than reflecting equivalent risk reduction in different groups, the delines in the proportions of KS among recent AIDS cases probably represent wider spread of HIV before any conscious risk reduction.

Intravenous drug use and the heterosexual transmission of the human immunodeficiency virus

Women, and men who deny homosexual activity, account for slightly more than one third (3,929/7,696) of the cases of acquired immunodeficiency syndrome (AIDS) in New York City through September 1986.1 This percentage has been rising during the course of the epidemic. Intravenous (IV) drug users account for more than half (2,261/3,929) of these heterosexual cases, and an additional 134 cases have occurred in persons known to be heterosexual partners of IV drug users. The connections between AIDS, IV drug use, and the heterosexual transmission of the human immunodeficiency virus (HIV) pose one of the more difficult public health challenges facing the city and the country. In this paper we review data relevant to two questions: potential heterosexual transmission among IV drug users, and potential transmission from IV drug users to heterosexual partners who do not inject drugs.