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OBJECTIVE: To provide health care providers, patients, and the general public with a responsible assessment of currently available data on the management of hepatitis B. PARTICIPANTS: A non-DHHS, nonadvocate 12-member panel representing the fields of hepatology and liver transplantation, gastroenterology, public health and epidemiology, infectious diseases, pathology, oncology, family practice, internal medicine, and a public representative. In addition, 22 experts from pertinent fields presented data to the panel and conference audience. EVIDENCE: Presentations by experts and a systematic review of the literature prepared by the Minnesota Evidence-based Practice Center, through the Agency for Healthcare Research and Quality. Scientific evidence was given precedence over anecdotal experience. CONFERENCE PROCESS: The panel drafted its statement based on scientific evidence presented in open forum and on published scientific literature. The draft statement was presented on the final day of the conference and circulated to the audience for comment. The panel released a revised statement later that day at http://consensus.nih.gov. This statement is an independent report of the panel and is not a policy statement of the NIH or the Federal Government. CONCLUSIONS: The most important predictors of cirrhosis or hepatocellular carcinoma in persons who have chronic HBV are persistently elevated HBV DNA and ALT levels in blood. Other risk factors include HBV genotype C infection, male sex, older age, family history of hepatocellular carcinoma, and co-infection with HCV or HIV. The major goals of anti-HBV therapy are to prevent the development of progressive disease, specifically cirrhosis and liver failure, as well as hepatocellular carcinoma development and subsequent death. To date, no RCTs of anti-HBV therapies have demonstrated a beneficial impact on overall mortality, liver-specific mortality, or development of hepatocellular carcinoma. Most published reports of hepatitis therapy use changes in short-term virologic, biochemical, and histologic parameters to infer likelihood of long-term benefit. Approved therapies are associated with improvements in intermediate biomarkers, including HBV DNA, HBeAg loss or seroconversion, decreases in ALT levels, and improvement in liver histology (Table). Although various monitoring practices have been recommended, no clear evidence exists for an optimal approach. The most important research needs include representative prospective cohort studies to define the natural history of the disease and large RCTs of monotherapy and combined therapies, including placebo-controlled trials, that measure the effects on clinical health outcomes. Table. Criteria Useful in Determining for Whom Therapy is Indicated: Patients for whom therapy is indicated: Patients who have acute liver failure, cirrhosis and clinical complications, cirrhosis or advanced fibrosis and HBV DNA in serum, or reactivation of chronic HBV after chemotherapy or immunosuppression; Infants born to women who are HBsAg-positive (immunoglobulin and vaccination). Patients for whom therapy may be indicated: Patients in the immune-active phase who do not have advanced fibrosis or cirrhosis. Patients for whom immediate therapy is not routinely indicated: Patients with chronic hepatitis B in the immune-tolerant phase (with high levels of serum HBV DNA but normal serum ALT levels or little activity on liver biopsy); Patients in the inactive carrier or low replicative phase (with low levels of or no detectable HBV DNA in serum and normal serum ALT levels); Patients who have latent HBV infection (HBV DNA without HBsAg). We recommend routine screening for hepatitis B of newly arrived immigrants to the United States from countries where the HBV prevalence rate is greater than 2%. Screening will facilitate the provision of medical and public health services for infected patients and their families and provide public health data on the burden of disease in immigrant populations. The screening test should not be used to prohibit immigration.

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BACKGROUND: Triple sulfonamide vaginal cream has been used to treat bacterial vaginosis for many years. There are few studies in which triple sulfonamide cream has been compared with newer regimens. GOAL: To compare the efficacy and safety of clindamycin phosphate vaginal cream with that of triple sulfonamide vaginal cream in the treatment of bacterial vaginosis. STUDY DESIGN: In this double-blind, randomized multicenter study, nonpregnant women 16 years of age or older with symptomatic bacterial vaginosis were assigned to receive either 2% clindamycin phosphate vaginal cream or triple sulfonamide vaginal cream for 7 days. Follow-up visits were conducted 5 to 10 days and 25 to 39 days after completion of treatment. RESULTS: Clinical cure or improvement at 25 to 39 days was noted in 55 (69.6%) of 79 assessable participants who received clindamycin vaginal cream and in 33 (41.8%) of 79 women who received triple sulfonamide vaginal cream (P < 0.0001). Most of the difference between the treatment groups was noted in women with a history of bacterial vaginosis. Among women without a history of bacterial vaginosis, clindamycin and triple sulfonamide creams had similar efficacy. Evaluation of Gram-stained vaginal smears correlated with clinical outcome. Most patients in both treatment groups reported an improvement in symptoms. No significant difference was observed between the treatment groups in the incidence of adverse events. CONCLUSION: Clindamycin 2% vaginal cream is more effective than triple sulfonamide vaginal cream in the treatment of bacterial vaginosis.

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BACKGROUND AND OBJECTIVES: Trichomonas vaginalis is a common vaginal pathogen. Oral metronidazole is the drug of choice for the treatment of trichomoniasis. Oral metronidazole, however, may cause unpleasant side effects and is contraindicated during the first trimester of pregnancy. In vitro studies and preliminary clinical data have suggested that intravaginal clotrimazole may be effective against this pathogen. GOALS: To compare the efficacy of clotrimazole vaginal tablets, oral metronidazole, and vaginal suppositories containing sulfanilamide, aminacrine, and allantoin (AVC suppositories) in the treatment of women with symptomatic trichomoniasis. STUDY DESIGN: In a multicenter, open-label trial conducted in 1982 and 1983, 168 symptomatic women with microscopically evident vaginal trichomoniasis were randomized to receive any of 2 g of metronidazole as a single oral dose, two 100-mg clotrimazole vaginal tablets once a day for 7 days, or vaginal suppositories containing 1.05 g of sulfanilamide, 14 mg of aminacrine hydrochloride, and 140 mg of allantoin (AVC suppositories) twice a day for 7 days. Wet mounts and cultures were repated at 1 to 2 and 4 to 6 weeks after completion of treatment. RESULTS: The number of patients who had positive cultures after treatment were 40/45 (88.9%) in the clotrimazole group, 35/43 (81.4%) in the AVC suppository group, and 9/45 (20%) in the metronidazole group (P < 0.001). All treatments were associated with a reduction in reported symptoms. Oral metrohidazole was more effective in reducing symptoms than either of the topical preparations. Adverse events, mostly mild or moderate in severity, were reported by 7 (14.6%) of 48 patients who had received oral metronidazole and 4 (7.8%) of 51 women who used AVC suppositories. There were no adverse events reported by the 50 women who used clotrimazole vaginal tablets. CONCLUSIONS: Oral metronidazole was more effective in eradicating T. vaginalis than clotrimazole vaginal tablets or AVC vaginal suppositories. All three regimens reduced symptoms; oral metronidazole was more effective in reducing symptoms than either topical preparation.

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PURPOSE: To develop a model for calculating the cost of a four-year undergraduate medical education at the University of Virginia School of Medicine (UVA) in 1994-95. METHOD: All data were based on faculty contact hours (FCHs), the primary driver of cost. (An FCH was an hour during which a faculty member was actively teaching.) First- and second-year data were derived from a published curriculum schedule. Third-year data were derived from hours spent in each clerkship and a series of calculations to assess direct teaching time in each clerkship accurately. Fourth-year data were modeled on an artificial but typical program consisting of the required clerkship in neurology, a two-day course in advanced cardiac life support, and seven elective blocks; electives were chosen based on relative overall popularity. The number of full-time-equivalent (FTE) faculty required was calculated. The salary costs of UVA full-time faculty were calculated. Other total direct costs, including the costs of support and administrative services as well as the costs of the educational contributions of housestaff and contract faculty, were calculated. The overall cost, including direct and indirect costs, was calculated. An average of 139 students per year was assumed. RESULTS: The total number of FCHs was just under 100,000. The number of FTE faculty required was 223. UVA faculty salary and fringe benefits totaled $29,400,000. The costs of support and administrative services totaled $4,100,000; the costs of housestaff and contract faculty totaled $2,300,000. The overall educational costs totaled $49,600,000. CONCLUSION: The overall cost of a four-year medical education at UVA was $357,000 per student. Although the process of calculating this cost was complex and, at times, based on assumptions open to debate, the model developed can be applied to any medical education setting.

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BACKGROUND AND OBJECTIVES: Lactoferrin has served as a marker for leukocytes (polymorphonuclear neutrophils [PMN]) in clinical specimens. GOAL: To investigate the potential of a lactoferrin latex agglutination test in the differential diagnosis of female genital infection. STUDY DESIGN: Lactoferrin was quantified in the vaginal discharge of women with genital infections. Polymorphonuclear neutrophils were added to vaginal discharge and observed over 8 hours. RESULTS: Vaginal lactoferrin titers were significantly elevated in women with trichomoniasis, candidiasis, and bacterial vaginosis (BV). Using a lactoferrin titer of > or = 1:40, the assay has a sensitivity of 79.3% and a specificity of 83.3% for the presence of trichomoniasis or bacterial vaginosis. Vaginal discharge from women with BV significantly destroyed added PMN. CONCLUSIONS: Vaginal lactoferrin determinations may provide a useful screen for inflammatory genital infections and identify individuals who require additional diagnostic evaluation. The observed absence of PMN in bacterial vaginosis may result from the destruction of PMN in vaginal discharge rather than the absence of a primary inflammatory response.

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The records were reviewed of five human immunodeficiency virus (HIV) type 1-infected patients who underwent splenectomy, four for HIV-associated thrombocytopenia and one for gastric compression secondary to splenomegaly. After splenectomy, the four adult patients all had marked, sustained increases in their absolute CD4 lymphocyte counts; greater increases were observed in CD8 lymphocyte counts, accounting for decreases in the CD4:CD8 ratios. In patients 5 (one of triplets, all of whom were infected with HIV after a blood transfusion), absolute CD4 lymphocyte counts were stabilized after splenectomy; the other siblings manifested a decline in CD4 counts, which was associated with a delay in physical development and recurrent episodes of varicella. Immunohistochemical staining of spleen sections demonstrated significantly higher numbers of CD4 cells in splenic tissue from HIV-infected patients than from patients splenectomized secondary to trauma (2,070 +/- 284 vs. 962 +/- 296; p = 0.025). In addition, the HIV-infected patients had significantly higher percentages of CD4 lymphocytes in splenic tissue than in peripheral blood (49.3 +/- 11.0 vs. 20.3 +/- 7.9; p = 0.005), suggesting that CD4 cells were sequestered in the spleens of these patients. These findings have implications for the management of splenectomized HIV-infected patients with regard to optimal timing of initiation of zidovudine therapy and for prophylaxis of Pneumocystis carinii pneumonia.

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An enzymeimmunoassay test performed well in comparison with cell culture in detecting chlamydial infections among 209 women at a public health clinic, detecting 73% of the infected patients. Clinical and epidemiological criteria alone identified only 52%. The authors consider the test an essential supplement to other criteria when looking for chlamydial infection in a high risk population.

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Trichomonas vaginalis is estimated to infect 4 million women per year in the United States. The diagnosis of trichomoniasis is predominantly achieved by direct microscopic examination of vaginal exudates. This subjective diagnostic procedure is reported to be 75% sensitive under ideal circumstances. We have developed an enzyme-linked immunosorbent assay (ELISA) for the detection of T. vaginalis directly from vaginal exudates. The ELISA employs a monoclonal antibody specific for a 65-kilodalton surface polypeptide of T. vaginalis as the capture antibody in a sandwich format. A polyclonal rabbit anti-T. vaginalis antibody labeled with horseradish peroxidase serves as the probe. An evaluation of vaginal specimens from women attending clinics revealed a sensitivity and specificity of the ELISA of 89 and 97%, respectively, versus the culture technique. These results indicate the usefulness of this ELISA as an alternative to microscopic and culture methods for the detection of T. vaginalis in vaginal exudates.

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The spectrum of sexually transmitted diseases observed among homosexual men is diverse, but in general includes the same infections observed among heterosexuals. A systematic approach to the diagnosis of these diseases, incorporating sexual history, predominant symptoms, findings from physical examination, and office laboratory evaluation will frequently yield a specific diagnosis. Prompt diagnosis and treatment of patients, and when appropriate, of contacts are of critical importance to the prevention of unnecessary morbidity and further transmission of disease.

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The cytopathogenic mechanisms of Trichomonas vaginalis have been debated since the 1940s. We examined the following three proposed pathogenic mechanisms: contact-dependent extracellular killing, cytophagocytosis, and extracellular cytotoxins. Serial observations of Chinese hamster ovary (CHO) cell monolayers exposed to trichomonads revealed that (i) trichomonads form clumps, (ii) the clumps adhere to cells in culture, and (iii) monolayer destruction occurs only in areas of contact with T. vaginalis. Kinetic analysis of target cell killing by trichomonads revealed that the probability of CHO cell death was related to the probability of contact with T. vaginalis, supporting the observation by microscopy that trichomonads kill cells only by direct contact. Simultaneous studies of 111indium oxine label release from CHO cells and trypan blue dye exclusion demonstrated that T. vaginalis kills target cells without phagocytosis. Filtrates of trichomonad cultures or from media in which trichomonads were killing CHO cells had no effect on CHO cell monolayers, indicating that trichomonads do not kill cells by a cell-free or secreted cytotoxin. The microfilament inhibitor cytochalasin D (10 micrograms/ml) inhibited trichomonad killing of CHO cell monolayers by 80% (P less than 0.0001). In contrast, the microtubule inhibitor vinblastine (10(-6) M) caused only 17% inhibition of trichomonad destruction of CHO cell monolayers (P less than 0.020), whereas colchicine (10(-6) M) had no effect. T. vaginalis kills target cells by direct contact without phagocytosis. This event requires intact trichomonad microfilament function; microtubule function appears not to be essential.

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Although Trichomonas vaginalis causes one of the most common sexually transmitted diseases, little is known about the antigenic variation of the parasite or about differences between strains in epidemiology or virulence. Variation among isolates of T. vaginalis was investigated by using a panel of monoclonal antibodies, each reactive with different antigens, to test 88 isolates from diverse geographic areas of North America. All isolates of T. vaginalis reacted with at least one of the nine monoclonal antibodies; the individual antibodies reacted with 22%-76% of the isolates. A pool of two broadly reactive antibodies identified all isolates in the study. Four of the most narrowly reactive, or "specific," antibodies demonstrated differences in the antigenic composition of trichomonads isolated from patients in Seattle, Baltimore, and Brooklyn, New York (P less than .005 by chi 2 test). Application of these and other monoclonal antibody probes may facilitate epidemiological studies and provide rapid, reliable methods for direct diagnosis of trichomonads in clinical specimens.

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The emergence of metronidazole-resistant Trichomonas vaginalis and questions about the safety of metronidazole are significant concerns in treatment of trichomoniasis. At 24 h, a microtiter assay was used to test antimicrobial susceptibility of 16 recent isolates; the MICs of metronidazole ranged from less than 0.06 to 25 micrograms/ml. Observable motility as an endpoint correlated imperfectly with survival as measured in pour plates. Quantitative pour plate cultures of six T. vaginalis isolates after timed exposures to antimicrobial drugs demonstrated exquisite sensitivity to metronidazole with minimal trichomonacidal concentrations of 0.025 to 0.100 micrograms/ml. Killing of some T. vaginalis isolates by clotrimazole and rosoxacin occurred only at concentrations of 100 micrograms/ml. Resistance to both rosoxacin and clotrimazole correlated with increasing resistance to metronidazole (P less than 0.01).

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We have reported a case of Campylobacter osteomyelitis, which we believe has not been previously reported. Symptoms and signs were nonspecific, but darkfield microscopy of a suspension of isolated bacteria was useful in making a presumptive diagnosis. Initial parenteral therapy based on sensitivity testing and prolonged oral doxycycline therapy was successful.

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We used a combination of decision analytic and modeling techniques in constructing a model for study of the management of an asymptomatic woman presenting to a sexually transmitted disease clinic as a contact of a man with gonorrhea. Total cost (physical, emotional, and economic) is expressed in units of dysutility. Initially the probabilities and "costs" of anogenital gonorrhea, incubating syphilis, carriage of the agents of nongonococcal urethritis, and coincident pharyngeal gonorrhea are considered; complications and sequelae are then accounted for. The best strategy is to culture for Neisseria gonorrhoeae, treat immediately with tetracycline, and follow up sexual partners if the culture is positive. Dysutility values calculated for the strategies of just treating with standard regimens of tetracycline, procaine penicillin, or amoxicillin are 288, 310, and 560, respectively. Sensitivity analyses show that the most important factors in determining optimal strategy are the probabilities and costs associated with the patient's carriage of the agents of nongonococcal urethritis. In order for this decision to change, the dysutility value for nongonococcal urethritis would have to decrease to 17% of our best estimate, or the overall prevalence of nongonococcal urethritis would have to be reduced to 16% of our best estimate.

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