Charles A. Schable

Transmission of Human Immunodeficiency Virus Type 1 from a Seronegative Organ and Tissue Donor

BACKGROUND Since 1985, donors of organs or tissues for transplantation in the United States have been screened for human immunodeficiency virus type 1 (HIV-1), and more than 60,000 organs and 1 million tissues have been transplanted. We describe a case of transmission of HIV-1 by transplantation of organs and tissues procured between the time the donor became infected and the appearance of antibodies. The donor was a 22-year-old man who died 32 hours after a gunshot wound; he had no known risk factors for HIV-1 infection and was seronegative. METHODS We reviewed the processing and distribution of all the transplanted organs and tissues, reviewed the medical histories of the donor and HIV-1-infected recipients, tested stored donor lymphocytes for HIV-1 by viral culture and the polymerase chain reaction, and tested stored serum samples from four organ recipients for HIV-1 antigen and antibody. RESULTS HIV-1 was detected in cultured lymphocytes from the donor. Of 58 tissues and organs obtained from the donor, 52 could be accounted for by the hospitals that received them. Of the 48 identified recipients, 41 were tested for HIV-1 antibody. All four recipients of organs and all three recipients of unprocessed fresh-frozen bone were infected with HIV-1. However, 34 recipients of other tissues--2 receiving corneas, 3 receiving lyophilized soft tissue, 25 receiving ethanol-treated bone, 3 receiving dura mater treated with gamma radiation, and 1 receiving marrow-evacuated, fresh-frozen bone--tested negative for HIV-1 antibody. Despite immunosuppressive chemotherapy, HIV-1 antibody appeared between 26 and 54 days after transplantation in the three organ recipients who survived more than four weeks. CONCLUSIONS Although rare, transmission of HIV-1 by seronegative organ and tissue donors can occur. Improvements in the methods used to screen donors for HIV-1, advances in techniques of virus inactivation, prompt reporting of HIV infection in recipients, and accurate accounting of distributed allografts would help to reduce further this already exceedingly low risk.

The Prevention of Hepatitis B with Vaccine: Report of the Centers for Disease Control Multi-Center Efficacy Trial Among Homosexual Men

A randomized, double-blind, vaccine/placebo trial of the Merck 20-micrograms hepatitis B virus (HBV) vaccine was done among 1402 homosexual men attending venereal disease clinics in five American cities. Vaccination was followed by only minimal side effects. Two doses of vaccine induced antibody in 80% of vaccine recipients. A booster dose 6 months after the first dose induced antibody in 85% of recipients and markedly increased the proportion of recipients who produced high antibody titers. The incidence of HBV events was markedly less in the vaccine recipients compared to that in the placebo recipients (p = 0.0004). Between month 3 and 15 after the first dose, 56 more significant HBV events (hepatitis, or hepatitis B surface antigen positive, or both) occurred in the placebo group while only 11 occurred in the vaccine group. Ten of the 11 HBV events in the vaccine recipients occurred in hypo- or nonresponders to the vaccine. This vaccine appears to be safe, immunogenic, and efficacious in preventing infection with hepatitis B virus.

Surveillance of HIV Infection and Zidovudine Use among Health Care Workers after Occupational Exposure to HIV-Infected Blood

Health care workers are at risk for human immunodeficiency virus (HIV) infection after an occupational exposure to blood, certain other body fluids, and tissue from an HIV-infected patient [1, 2]. Zidovudine has been used after exposure to reduce this risk, despite the lack of data on efficacy and limited data on toxicity when used for this purpose [3-5]. In 1983, the Centers for Disease Control and Prevention (CDC) began a national voluntary surveillance project to estimate the risk for HIV transmission after a single exposure to HIV-infected blood [6]. In October 1988, the project was expanded to collect information describing the use of postexposure zidovudine among enrolled workers. In this update of the ongoing surveillance project, we focus on the patterns of use and associated toxicity of postexposure zidovudine use among enrolled workers and report the failure of zidovudine to prevent HIV infection in one worker. Methods CDC Surveillance Project The surveillance project has been described previously [6, 7]. In brief, workers in a group of participating health care institutions throughout the United States are voluntarily enrolled by cooperating investigators after an exposure to blood from a patient with documented HIV infection as a result of percutaneous injury (for example, a needlestick or a cut from a sharp object), contamination of mucous membranes, or contamination of nonintact skin. (Extensive or prolonged blood contact with intact skin may constitute an occupational exposure [4], but workers with intact skin exposures are not enrolled in this project.) Epidemiologic information and a blood specimen for HIV serologic testing are collected by the cooperating investigator at a baseline visit within 1 month after exposure and at follow-up visits 6 weeks, 3 months, 6 months, and 1 year after exposure. At enrollment, workers complete and mail directly to the CDC an anonymous questionnaire that includes information on nonoccupational risk factors for HIV infection. Workers who seroconvert are interviewed in person by an investigator using a standard CDC protocol for the interview of persons with no identified risk. Human immunodeficiency virus serologic testing is done either at the CDC or at the cooperating institutions laboratory, with all positive results confirmed at the CDC. Use of Postexposure Zidovudine In October 1988, the surveillance project was expanded to collect additional information on the postexposure use and toxicity of antiviral agents, such as zidovudine. A standardized protocol for offering or using postexposure zidovudine was not provided by the CDC; in accordance with the Public Health Service statement [4], individual cooperating investigators and exposed workers determined whether postexposure zidovudine would be used, and, among those using zidovudine, the dosage and duration of prophylaxis. Adverse Events At the 6-week follow-up visit, the cooperating investigators were asked to record reported symptoms on a standardized checklist provided by the CDC, as well as the zidovudine regimen, if used. In this surveillance project, a standard protocol for laboratory testing for adverse effects (for example, anemia) of zidovudine was not provided by the CDC; such tests were done at the discretion of the cooperating investigator, who recorded the test date and any results outside the testing laboratorys normal range. Statistical Analysis Data were analyzed using PRODAS (Conceptual Software, Houston, Texas), Epi-Info (CDC, Atlanta, Georgia), and the Statistical Analysis System (SAS Institute, Inc., Cary, North Carolina). The upper bounds of the 95% CI were calculated using the binomial distribution. Because of missing data, totals for specific analyses may not equal the total number of enrolled workers. Results From August 1983 through June 1992, 1245 workers from 312 institutions were enrolled and tested for HIV antibody at baseline and at least 180 days after exposure. These workers comprised nurses (64%), physicians and dentists (12%), phlebotomists (8%), laboratory workers (6%), medical students (2%), housekeepers (1%), and other workers (such as technicians and physician and nursing assistants) (8%). Exposures to HIV-infected Blood and Risk for HIV Infection A total of 1245 workers were enrolled and tested for HIV antibody at baseline and at least 180 days after exposure. These workers had been exposed to blood from source patients who had AIDS as defined by the CDC surveillance case definition in use at the time of enrollment, (1012 [81%] exposures) [8], who were HIV-antibody positive and symptomatic but who did not have AIDS (68 [5%] exposures), or were HIV-antibody positive and asymptomatic (165 [13%] exposures). Exposure types were percutaneous injury (1103; 89%) and blood contact with mucous membranes (67; 5%) or nonintact skin (75; 6%). The 1103 percutaneous injuries were caused by syringe needles (375; 34%), intravenous needles (343; 31%), suture needles (41; 4%), and other needles (228; 21%); scalpels (41; 4%); lancets (27; 2%); and other sharp objects (48; 4%). Among 1103 workers with percutaneous injuries who were HIV seronegative at baseline, 4 (0.36%; upper limit CI, 0.83%) seroconverted to HIV. Among workers with percutaneous injury, the seroconversion rate after exposure to blood from source patients with AIDS was 0.44% (4 of 899; upper limit CI, 1.01%); the seroconversion rate was not statistically different after exposure to blood from source patients who were HIV-antibody positive and symptomatic but who were without AIDS (0 of 57, P > 0.2) or source patients who were HIV-antibody positive and asymptomatic (0 of 147, P > 0.2). No seroconversions occurred among workers with blood exposure of mucous membranes (67 workers; upper limit CI, 4.31%) or skin (75 workers; upper limit CI, 3.87%). An additional 497 workers enrolled in the early 1980s, before HIV-antibody testing was available, were tested for HIV antibody at least 180 days after exposure but not at baseline. One of these workers was HIV-antibody positive when first tested 10 months after exposure [7]. At that time, a sex partner of this worker was also tested and found to be HIV seropositive; the dates of HIV infection for this worker and partner are unknown. Including these 497 workers, the HIV seroprevalence rate was 0.32% (5 of 1532; upper limit CI, 0.68%) after percutaneous exposure, 0% (0 of 100; upper limit CI, 2.9%) after mucous membrane exposure, and 0% (0 of 110; upper limit CI, 2.7%) after skin exposure to HIV-infected blood. Of the four workers enrolled in this project who have seroconverted after exposure to HIV, three have been previously described [6, 7]. The fourth worker, a female laboratory worker, was injured in 1992 by a 21-gauge syringe needle after doing a phlebotomy on a patient who was known to have AIDS. The worker reported no behavioral risk factors for HIV infection, except for having had sexual contact with a person at risk for HIV infection more than 1 year before her injury. The worker began taking zidovudine 2 hours after the injury, in a dose of 100 mg, five times a day, for the first day and then 200 mg, five times per day, for 16 additional days (Table 1, report 5). The worker discontinued use of zidovudine after 17 days because of nausea, fatigue, and myalgia. Thirty-eight days after exposure, the worker developed fever, malaise, fatigue, nausea, arthralgia, myalgia, and rash. Serologic test results for HIV were negative for specimens of the workers blood collected on the day of the injury and 6 weeks afterward, were indeterminate by enzyme immunoassay and positive by Western blot 3 months after injury, and were positive by both enzyme immunoassay and Western blot 4 months after injury. The source patient was not known to have received zidovudine before the needlestick incident. Table 1. Reported Instances of Failure of Postexposure Zidovudine To Prevent HIV Infection in Health Care Workers after Percutaneous Exposure to HIV-infected Blood To determine whether the worker was infected with zidovudine-resistant virus, peripheral blood mononuclear cells were collected from the worker and the source patient 3 months and 8 months after exposure, respectively. At the Walter Reed Army Institute of Research (Washington, D.C.), cells from the worker were positive for HIV-1 using the polymerase chain reaction (PCR), but efforts to isolate the virus for phenotypic zidovudine-susceptibility testing were not successful. Nested PCR to detect mutations in the HIV reverse transcriptase at amino acid position 215 associated with zidovudine resistance did not show alterations at that site in peripheral blood mononuclear cells from either worker or source patient [9] (D. Mayers. Personal communication). At the CDC, direct sequencing of the HIV-1 reverse-transcriptase gene (amplified by PCR from the workers peripheral blood mononuclear cells [10]) showed no mutations at position 215 or at the four other amino acid positions (positions 41, 67, 70, and 219) known to be associated with zidovudine resistance [11, 12] (data not shown). Use of Postexposure Zidovudine From October 1988 to June 1992, the period when use of zidovudine was studied, 848 workers were enrolled. Postexposure zidovudine was used by 265 (31%) of these workers. Of 200 cooperating investigators who enrolled workers during this period, 110 (55%) reported that at least one worker used zidovudine. Zidovudine was prescribed in doses ranging from 200 to 1800 mg/d (median, 1000 mg/d) and for periods of 1 to 180 days (median, 42 days). The interval from exposure to first dose of zidovudine ranged from less than 5 minutes to 17 days (median, 4 hours). No clinically significant changes in prescribed regimens of zidovudine were seen during the study period (data not shown). The proportion of enrolled workers using zidovudine increased from 5% in the fourth quarter of 1988 to 50% in the third quarter of 1990 and has been stable subseq

DURATION OF HUMAN IMMUNODEFICIENCY VIRUS INFECTION BEFORE DETECTION OF ANTIBODY

To estimate the duration and frequency of the period of HIV infection without detectable antibody, modelling techniques were applied to results of detection of HIV DNA by means of the polymerase chain reaction (PCR) and to data from cases in published reports. PCR was carried out with gag and env region primers on samples from 27 homosexual and 12 haemophilic men for whom stored samples were available from before and after seroconversion; serum was also tested for p24 antigen by antigen-capture enzyme immunoassay. HIV DNA was detectable before seroconversion in 4 men; in all 4 PCR was positive only in the seronegative sample taken closest to the time of seroconversion. In 3 men antigen was detected before seroconversion; in each case HIV DNA was also detected. By a Markov model, the time from infection with HIV (as assessed by detection of HIV DNA) to first detection of HIV antibody was estimated to be 2.4 (SE 2.1) months for the median individual. Modelling of cases of HIV infection with known exposure in published reports gave a median estimate of 2.1 (0.1) months from exposure to antibody detection, and 95% of cases would be expected to seroconvert within 5.8 (0.6) months. HIV infection for longer than 6 months without detectable antibody seems uncommon.

Posttransfusion Non-A, Non-B Hepatitis: Physicochemical Properties of Two Distinct Agents

Abstract Two separate and distinct episodes of non-At non-B hepatitis were induced in each of two chimpanzees by two inocula: one containing a chloroform-resistant agent and the other containing a chloroform-sensitive agent. Both agents were recovered from liver tissue and plasma obtained from a single chimpanzee during the acute and chronic phases of infection with a factor VIII concentrate, respectively. The chloroform-resistant agent did not cause unique changes in hepatocytes; in contrast, the chloroform-sensitive agent did induce the formation of cytoplasmic tubules, convoluted endoplasmic reticulum, and dense reticular inclusion bodies. The latter changes are similar in character to those induced in infected cells by some enveloped mammalian RNA viruses.

Sensitivity of United States HIV antibody tests for detection of HIV-1 group O infections.

Infections by highly divergent strains of HIV-1, first detected in central Africa and grouped provisionally as group O, have not been reliably detected by certain European HIV screening tests. Serum specimens from eight probable group O infections from Cameroon were tested by ten HIV assays licensed by the US Food and Drug Administration. All assays based on synthetic peptides or recombinant antigens failed to detect at least one of the infections; assays based on whole-virus lysates performed better. Divergent HIV strains may be undetected by current HIV tests. Thus active surveillance for and characterisation of HIV variants to evaluate and, when necessary, modify current tests is urgently needed.

Seroprevalence Rates of Human Immunodeficiency Virus Infection at Sentinel Hospitals in the United States

Abstract Background and Methods. To evaluate the epidemiology of infection with human immunodeficiency virus type 1 (HIV–1) in selected urban communities in the United States, we instituted active surveillance at sentinel hospitals by anonymous testing of samples of blood specimens for HIV–1 antibody. To reflect better the rates of HIV–1 seroprevalence in the communities served by the sentinel hospitals, we excluded specimens from all patients with diagnoses that are often associated with HIV infection. Results. From January 1988 to June 1989, 89,547 specimens were tested at 26 hospitals in 21 cities. The overall rate of HIV–1 seroprevalence was 1.3 percent, but it ranged from 0.1 to 7.8 percent according to hospital (median, 0.7 percent). The age distribution of persons seropositive for HIV–1 was similar across hospitals and closely paralleled that of persons with the acquired immunodeficiency syndrome (AIDS). In areas of low seroprevalence, HIV–1 infections were highly concentrated among men. However, t...

An outbreak of hepatitis B in a dental practice.

In September 1978, cases of hepatitis B in two patients treated by the same dentist led to investigation of a dental practice in Baltimore, Maryland. The dentist had had acute hepatitis B in June 1978 and had remained positive for hepatitis B surface antigen and hepatitis B e antigen over the ensuing 6 months. He had continued to work while infected, wearing surgical gloves to minimize the risk of transmitting infection. Serologic follow-up of 764 patients showed that a total of six patients, three of whom were symptomatic, had developed hepatitis B infection after dental treatment. All six were among a group of 395 patients treated before the dentist began wearing gloves. In this group, patients having highly traumatic dental work (attack rate 6.9%) were at significantly higher risk than patients having either less traumatic work (attack rate 0.5%) or nontraumatic work (attack rate = 0, p less than 0.02). None of 369 patients treated only when the dentist wore gloves became infected, suggesting that gloves could reduce the risk of virus transmission by the dentist.

Risk of human immunodeficiency virus infection among emergency department workers

PURPOSE To estimate (1) the prevalence of human immunodeficiency virus (HIV) infection in emergency department (ED) patients, (2) the frequency of blood contact (BC) in ED workers (EDWs), (3) the efficacy of gloves in preventing BC, and (4) the risk of HIV infection in EDWs due to BC. PATIENTS AND METHODS We conducted an 8-month study in three pairs of inner-city and suburban hospital EDs in high AIDS incidence areas in the United States. At each hospital, blood specimens from approximately 3,400 ED patients were tested for HIV antibody. Observers monitored BC and glove use by EDWs. RESULTS HIV seroprevalence was 4.1 to 8.9 per 100 patient visits in the 3 inner-city EDs, 6.1 in 1 suburban ED, and 0.2 and 0.7 in the other 2 suburban EDs. The HIV infection status of 69% of the infected patients was unknown to ED staff. Seroprevalence rates were highest among patients aged 15 to 44 years, males, blacks and Hispanics, and patients with pneumonia. BC was observed in 379 (3.9%) of 9,793 procedures; 362 (95%) of the BCs were on skin, 11 (3%) were on mucous membranes, and 6 (2%) were percutaneous. Overall procedure-adjusted skin BC rates were 11.2 BCs per 100 procedures for ungloved workers and 1.3 for gloved EDWs (relative risk = 8.8; 95% confidence interval = 7.3 to 10.3). In the high HIV seroprevalence EDs studied, 1 in every 40 full-time ED physicians or nurses can expect an HIV-positive percutaneous BC annually; in the low HIV seroprevalence EDs studied, 1 in every 575. The annual occupational risk of HIV infection for an individual ED physician or nurse from performing procedures observed in this study is estimated as 0.008% to 0.026% (1 in 13,100 to 1 in 3,800) in a high HIV seroprevalence area and 0.0005% to 0.002% (1 in 187,000 to 1 in 55,000) in a low HIV seroprevalence area. CONCLUSIONS In both inner-city and suburban EDs, patient HIV seroprevalence varies with patient demographics and clinical presentation; the infection status of most HIV-positive patients is unknown to ED staff. The risk to an EDW of occupationally acquiring HIV infection varies by ED location and the nature and frequency of BC; this risk can be reduced by adherence to universal precautions.

Posttransfusion non-A, non-B hepatitis in chimpanzees

Posttransfusion non-A, non-B hepatitis associated with the formation of hepatocyte cytoplasmic tubules was experimentally transmitted to chimpanzees by intravenous inoculation of a proven-infectious plasma that had been pelleted and microfiltrated, or purified by a combination of pelleting and rate-zonal banding. The results of these studies indicate that a factor VIII-derived non-A, non-B tubule-forming agent will pass through an 80-nm membrane filter and that it can be recovered from infected plasma by use of a purification procedure that assumes the non-A, non-B tubule-forming agent is a small, enveloped virus. Our findings, in combination with the known sensitivity of the non-A, non-B tubule-forming agent to chloroform and its apparent lack of nucleic acid homology with hepatitis B virus, further suggest that at least one etiologic agent of human posttransfusion non-A, non-B hepatitis may be a small, enveloped RNA virus.