Discriminators between hantavirus-infected and -uninfected persons enrolled in a trial of intravenous ribavirin for presumptive hantavirus pulmonary syndrome.

To provide a potentially therapeutic intervention and to collect clinical and laboratory data during an outbreak of hantavirus pulmonary syndrome (HPS), 140 patients from the United States with suspected HPS were enrolled for investigational intravenous ribavirin treatment. HPS was subsequently laboratory confirmed in 30 persons and not confirmed in 105 persons with adequate specimens. Patients with HPS were significantly more likely than were hantavirus-negative patients to report myalgias from onset of symptoms through hospitalization, nausea at outpatient presentation, and diarrhea and nausea at the time of hospitalization; they were significantly less likely to report respiratory symptoms early in the illness. The groups did not differ with regard to time from the onset of illness to the point at which they sought care; time from onset, hospitalization, or enrollment to death was significantly shorter for patients with HPS. At the time of hospitalization, patients with HPS more commonly had myelocytes, metamyelocytes, or promyelocytes on a peripheral blood smear, and significantly more of them had thrombocytopenia, hemoconcentration, and hypocapnia. Patterns of clinical symptoms, the pace of clinical evolution, and specific clinical laboratory parameters discriminated between these 2 groups.

Intravenous ribavirin for hantavirus pulmonary syndrome: safety and tolerance during 1 year of open-label experience. Ribavirin Study Group.

Intravenous ribavirin was provided non-selectively for investigational open-label use among persons with suspected hantavirus pulmonary syndrome (HPS) in the United States between 4 June 1993 and 1 September 1994. Therapy was initiated prior to laboratory confirmation of hantavirus infection because most deaths from HPS occur within 48 h of hospitalization. Thirty patients with confirmed HPS, 105 patients without HPS and 5 patients without adequate diagnostic testing for HPS were enrolled. This observational study arguably provides the most complete information available on ribavirin-associated adverse effects. Although ribavirin was generally well tolerated, 71% of recipients became anaemic and 19% underwent transfusion. An apparent excess of hyperamylasaemia/pancreatitis was either therapy-associated or due to enrollment bias. The 30 enrolled HPS patients had a case-fatality rate of 47% (14/30). It is not possible to assess efficacy with this study design. However, comparison of survival curves for the 30 enrolled HPS patients and 34 patients who developed HPS during the same time period but were not enrolled did not suggest an appreciable drug effect. A randomized, placebo-controlled trial that enrolls patients during the prodrome phase would be necessary to assess the efficacy and further define the safety of intravenous ribavirin for HPS.

Sorivudine versus acyclovir for treatment of dermatomal herpes zoster in human immunodeficiency virus-infected patients: results from a randomized, controlled clinical trial. Collaborative Antiviral Study Group/AIDS Clinical Trials Group, Herpes Zoster Study Group.

The present randomized, double-blind, placebo-controlled, multicenter clinical trial was designed to compare the efficacy and tolerability of sorivudine [1-beta-D-arabinofuranosyl-E-(2-bromovinyl)uracil] and acyclovir for the treatment of dermatomal herpes zoster in human immunodeficiency virus (HIV)-seropositive patients. A total of 170 HIV-seropositive adults presenting with herpes zoster (confirmed by direct fluorescent-antigen testing and/or viral culture) were enrolled and randomized to receive a 10-day course of orally administered sorivudine (40 mg once daily plus acyclovir placebos) or acyclovir (800 mg five times daily plus sorivudine placebo). Patients were monitored daily to document the events of cutaneous healing, pain, zoster-related complications, and drug-related adverse events. Patients were reassessed on days 21 and 28 and then once monthly for 1 year. The primary efficacy endpoint was time to the cessation of new vesicle formation. Secondary efficacy endpoints included times to other events of cutaneous healing, resolution of pain, and frequency of dissemination and zoster recurrence. In a multivariate analysis, sorivudine was superior to acyclovir for reducing the times to the cessation of new vesicle formation (relative risk [RR] = 1.54, 95% confidence interval [CI] = 1.00 to 2.36; P = 0.049) and total lesion crusting (RR = 1.48, 95% CI = 1.07 to 2.04; P = 0.017). In a univariate analysis, there was a trend favoring sorivudine for the cessation of new vesicle formation (median of 3 versus 4 days; P = 0.07) and a significant advantage for time to total lesion crusting (median of 7 versus 8 days; P = 0.02). The time to the resolution of zoster-associated pain, the frequency of dissemination, and the frequency of zoster recurrence were not different between the two treatment groups. Both drugs were well tolerated. Sorivudine is an effective drug for the treatment of herpes zoster in HIV-infected patients and results in accelerated cutaneous healing when compared with acyclovir therapy.

Coccidiomycosis presenting as a popliteal cyst.

Coccidiomycosis is a fungal infection that primarily causes pulmonary disease. Extrapulmonary dissemination can occur to the musculoskeletal system with the knee joint most frequently involved. This case report describes a patient with coccidiomycosis whose initial presentation was of a popliteal cyst. The need for aggressive surgical and antibiotic treatment to eradicate this infection is discussed. Coccidiomycosis should be considered in a differential diagnosis of patients with popliteal cysts without other obvious etiologies.

Oral famciclovir for suppression of recurrent genital herpes simplex virus infection in women. A multicenter, double-blind, placebo-controlled trial. Collaborative Famciclovir Genital Herpes Research Group.

OBJECTIVE: To evaluate the efficacy and safety of oral famciclovir in the suppression of genital herpes. METHODS: In this randomized, double-blind, placebo-controlled trial that was performed at 11 university and 9 private ambulatory care referral centers, 375 women who were 18 years of age or older and had a history of 6 or more episodes of genital herpes during 12 of the last 24 months in the absence of suppressive therapy were treated for 4 months with oral famciclovir, 125 mg once daily or twice daily, 250 mg once daily or twice daily, 500 mg once daily, or placebo. The primary outcome measures included the time to first clinically and virologically confirmed recurrences, and safety as measured by clinical laboratory tests and adverse experiences. RESULTS: The median time to first recurrence was 82 days in the placebo group, 114 days in those receiving famciclovir, 125 mg once daily, and more than 120 days in the other treatment groups. When compared with placebo recipients, the time to the first clinical recurrence was significantly prolonged in subjects who received famciclovir, 125 mg twice daily (hazard ratio, 1.8; 95% confidence interval, 1.0-3.0; P = .03), and in those who received famciclovir, 250 mg twice daily (hazard ratio, 3.6; 95% confidence interval, 1.9-6.9; P < .001). Treatment was well tolerated, and there was no evidence of emergence of resistance during or after suppressive famciclovir therapy. CONCLUSIONS: Oral famciclovir, 250 mg, given twice daily for 4 months is an effective, well-tolerated treatment for the suppression of genital herpes in women with frequent recurrences, but single daily doses produced less complete suppression of genital herpes.

Acyclovir with and without prednisone for the treatment of herpes zoster. A randomized, placebo-controlled trial. The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group.

OBJECTIVE: To determine the effect of acyclovir and prednisone treatment of herpes zoster on chronic pain and quality-of-life outcomes. DESIGN: Randomized, double-blind, placebo-controlled study with a 2 x 2 factorial design. SETTING: 15 university hospitals or affilliated clinics. PATIENTS: 208 immunocompetent patients older than 50 years of age who had localized herpes zoster that developed less than 72 hours before study enrollment. INTERVENTION: Acyclovir or a matched placebo was administered orally, 800 mg five times daily, for 21 days. Prednisone or a matched placebo was administered orally at 60 mg/d for the first 7 days, 30 mg/d for days 8 to 14, and 15 mg/d for days 15 to 21. The four treatments regimens given were acyclovir plus prednisone; acyclovir plus prednisone placebo; prednisone plus acyclovir placebo; and placebos for both acyclovir and prednisone. MEASUREMENTS: Patients were monitored daily for the first 28 days for lesion healing, resolution of pain, return to usual activity, and return to uninterrupted sleep. Monitoring was then done monthly for 6 months. Patients documented analgesic requirements each day, and adverse events and laboratory abnormalities were recorded at each clinical visit. An intention-to-treat analysis was used. RESULTS: Patients were randomly allocated to receive one of the four regimens. Demographic characteristics were similar for each group. Time to total crusting and healing was accelerated for patients receiving acyclovir plus prednisone compared with patients receiving two placebos; the risk ratios were 2.27 (95% Cl, 1.46 to 3.55) for total crusting and 2.07 (Cl, 1.26 to 3.38) for healing. Similarly, compared with the placebo group, patients receiving acyclovir plus prednisone had accelerated time to cessation of acute neuritis (risk ratio, 3.02 [Cl, 1.42 to 6.41]), time to return to uninterrupted sleep (risk ratio, 2.12 [Cl, 1.25 to 3.58]); time to return to usual daily activity (risk ratio, 3.22 [Cl, 1.92 to 5.40]); and time to cessation of analgesic therapy (risk ratio, 3.15 [Cl, 1.69 to 5.89]). In the acyclovir plus prednisone group, resolution of pain during the 6 months after disease onset did not statistically differ from that in the other groups. No important clinical or laboratory adverse events occurred in any group. CONCLUSIONS: In relatively healthy persons older than 50 years of age who have localized herpes zoster, combined acyclovir and prednisone therapy can improve quality of life.

Locations of herpes simplex virus type 2 glycoprotein B epitopes recognized by human serum immunoglobulin G antibodies.

Herpes simplex virus type 2 (HSV-2) glycoprotein B (gB-2) gene segments were expressed as recombinant proteins in Escherichia coli. gB-2 recombinant proteins were reacted with human serum immunoglobulin G (IgG) antibodies in Western immunoblot assays. Initially, samples were tested for the presence of HSV-1-specific antibodies and HSV-2-specific antibodies by using HSV-infected cell lysates as antigen targets in Western blot assays. Serum samples that contained HSV-2-specific IgG (n = 58), HSV-1-specific IgG (n = 33), or no detectable HSV antibodies (n = 31) were tested for reactivities with the gB-2 recombinant proteins. In 58 of 58 samples that contained HSV-2-specific IgG, antibodies were present that reacted strongly with a gB-2 amino-proximal segment between amino acids (aa) 18 and 75. Three of 33 serum samples that contained HSV-1- and not HSV-2-specific IgG (as defined by the HSV lysate Western blot assay) reacted with this segment. Both HSV-2 antibodies and HSV-1 antibodies reacted strongly with a carboxy-terminal gB-2 segment between aa 819 and 904; a second minor cross-reactive region was mapped to a gB-2 segment between aa 564 and 626. The gB-2 segment from aa 18 to 75 may constitute a useful reagent for the virus type-specific serodiagnosis of HSV-2 infections. Further studies will be required to determine the relative sensitivities and specificities of the assay for gB-2 aa 18 to 75, HSV gG assays, and HSV lysate Western blot assays for detecting virus type-specific antibody responses in acute and chronic HSV-2 infections.

Cardiopulmonary manifestations of hantavirus pulmonary syndrome.

OBJECTIVE: To describe the clinical characteristics of a group of patients infected with the newly recognized hantavirus in the Southwestern United States. DESIGN: Case series. SETTING: Tertiary referral center. PATIENTS: All patients with confirmed hantavirus infection admitted to the University of New Mexico Hospital between May 1, 1993 and January 1, 1994. INTERVENTIONS: Records of patients with hantavirus infection were reviewed to collect all pertinent clinical data. MEASUREMENTS AND MAIN RESULTS: Pulmonary disease in these patients was characterized by hypoxemia covering a wide range of severity. The cause of hypoxemia was an increased permeability (noncardiac) pulmonary edema which could be differentiated from hydrostatic (cardiac) pulmonary edema by its association with low pulmonary artery occlusion pressures and increased protein content of edema fluid. Hemodynamic measurements in severe cases showed a shock state characterized by a low cardiac index (range 1.6 to 3.0 L/min/min2), a low stroke volume index (range 10.5 to 29 mL/m2), and high systemic vascular resistance index (range 1,653 to 2,997 dyne.sec/cm5.m2). Progression to death was associated with worsening cardiac dysfunction unresponsive to treatment and causing oxygen debt and lactic acidosis. CONCLUSIONS: The two major life-threatening pathophysiologic changes in Hantavirus Pulmonary Syndrome are increased permeability pulmonary edema, and an atypical form of septic shock caused by myocardial depression and hypovolemia.

Management of genital herpes.

Oral acyclovir is the therapy of choice for treatment of first-episode genital herpes, for suppression of frequently recurrent genital herpes, and, in selected patients, for episodic treatment of recurrent genital herpes. Topical acyclovir therapy is relatively or totally ineffective and is therefore discouraged. Indications for intravenous acyclovir therapy of mucocutaneous HSV infections include patients hospitalized with severe first-episode genital herpes and immunocompromised patients who have severe infections or who cannot swallow the oral preparation. The most promising investigational drugs are the oral prodrugs valaciclovir and famciclovir. Famciclovir is licensed in the U.S. for treatment of zoster but not for treatment of mucocutaneous genital herpes. When used for episodic therapy of recurrent genital herpes, both famciclovir and valaciclovir effectively reduce the duration of viral shedding, lesion healing times, and the duration of symptoms. Suppressive therapy with famciclovir has also been shown to be effective in reducing the frequency of episodes in women with frequently recurring genital herpes. Although these drugs can be given less frequently than oral acyclovir, there is yet no clear indication that they are more effective or better tolerated than oral acyclovir.

Clarithromycin-induced mania in two patients with AIDS.

Acute psychosis was observed in two patients with AIDS who were treated with clarithromycin for disseminated Mycobacterium avium complex infection. The psychosis resolved when treatment with clarithromycin was discontinued and recurred when it was resumed. An adverse response to clarithromycin therapy is a rare but curable cause of acute psychosis in patients with AIDS.

Recurrence and resistance patterns of herpes simplex virus following cessation of > or = 6 years of chronic suppression with acyclovir. Acyclovir Study Group.

Questions have arisen regarding the clinical outcome and the possible selection of resistant virus when patients with genital herpes discontinue prolonged chronic acyclovir; 239 immunocompetent patients with a history of frequently recurring genital herpes who stopped successful suppressive therapy after 6 years were studied. Of the patients, 85.8% had at least one recurrence and 75% had at least two recurrences in the subsequent year (median time to first and second recurrence, 68 and 180 days, respectively). Herpes simplex virus isolates recovered from these patients had a median acyclovir sensitivity of 0.79 micrograms/mL and 4 (3.5%) were resistant (> or = 3 micrograms/mL). These values are comparable to those of pretherapy isolates and to reported values of isolates from acyclovir-naive patients. Also, paired pre- and posttherapy isolates from 13 patients showed no trend toward development of resistance. Thus, even after 6 years of acyclovir suppression, most patients continue to have recurrences, but the selection of resistant virus has not been observed.

Epidemiology of genital herpes infections.

Much has been learned in the last decade about the epidemiology of genital herpes infections, including new information about seroprevalence and the risk of transmission of genital herpes to sex partners and at delivery. Unfortunately, the type-specific serologic assays now routinely used in these studies are not widely available, and commercially available assays that claim to be type-specific are not. Thus, most clinicians still do not have access to reliable type-specific assays. In cross-sectional seroprevalence studies, detection of HSV-2 antibody is positively associated with increasing age, lower levels of income or education, increased numbers of sexual partners, black or Hispanic race, female gender, male homosexual activity, and HIV infection. In addition, studies cited in this review have clarified the clinical spectrum of genital herpes infection in persons who have transmitted genital herpes to a sex partner, have shed virus asymptomatically, or are found to have HSV-2 antibody. Ten percent to 40% of these individuals are aware that they have genital herpes, whereas the remaining 60% to 90% are not. Among the latter, at least half have a history of recurrent genital lesions typical of genital herpes or can be taught to recognize typical, symptomatic episodes within 6 months if examined promptly after the onset of any unexplained genital symptoms. The remainder, about a third of the total, have no history of genital herpes and remain asymptomatic despite a careful history and follow-up examinations; in women in this group, asymptomatic shedding of HSV can be identified. Atypical lesions appear to play an important but as yet incompletely defined role. Most persons who transmit genital herpes to a sex partner or at delivery do not have a history of lesions at the time of transmission of HSV infection, suggesting that asymptomatic shedding or atypical, unrecognized lesions are responsible for most cases of transmission. In heterosexual couples, the risk of acquisition of HSV-2 infection from a sex partner with genital herpes is lowest in men (less than 5%), higher in HSV-1 seropositive women (less than 10%), and highest (about 30%) in women without antibody to HSV-1 or HSV-2. The risk of transmission to infants exposed to asymptomatic shedding at delivery is low (about 3%) in women with or without a history of genital herpes if HSV antibody of the same type is present in cord blood.(ABSTRACT TRUNCATED AT 400 WORDS)

Disseminated herpes zoster in the immunocompromised host: a comparative trial of acyclovir and vidarabine. The NIAID Collaborative Antiviral Study Group.

Seventy-three immunocompromised patients with disseminated herpes zoster were evaluated in a double-blind controlled trial of acyclovir (n = 37) versus vidarabine (n = 36) therapy. Acyclovir was administered at 30 mg/kg/day at 8-h intervals and vidarabine was given as a continuous 12-h infusion at 10 mg/kg/day for 7 days (longer if resolution of cutaneous or visceral disease was incomplete). No demographic differences existed between treatment groups. No deaths attributable to varicella-zoster virus infection occurred within 1 month of treatment. Neither rates of cutaneous healing, resolution of acute neuritis, and frequency of postherpetic neuralgia nor adverse clinical and laboratory events differed between treatment groups. Acyclovir recipients were discharged from the hospital more promptly than vidarabine recipients (P = .04, log rank test). These data indicate that disseminated herpes zoster is amenable to therapy with either acyclovir or vidarabine; resultant mortality is low.

Risk factors for the sexual transmission of genital herpes.

OBJECTIVE: To determine the risk of sexual transmission of genital herpes simplex virus (HSV) in heterosexual couples. DESIGN: Prospective study of couples who were participants in a clinical trial. Each source partner had symptomatic, recurrent genital HSV, and each susceptible partner was without serologic or clinical evidence of genital herpes. Couples were followed for a median of 334 days. SETTING: Two university-based research clinics. PATIENTS: One hundred forty-four heterosexual couples were studied out of an initial enrollment of 214 couples. MAIN OUTCOME MEASURES: Development of culture-proven HSV infection or type-specific antibodies in the susceptible partner. MAIN RESULTS: Transmission occurred in 14 (9.7%) couples, including 11 (16.9%) of 65 couples with male and 3 (3.8%) of 79 with female source partners (P = 0.05). The annual rate of acquisition was higher (31.8%) in susceptible female partners who lacked antibodies to either HSV type 1 or 2 at entry compared with females with HSV type 1 antibodies at entry (9.1%). Couples avoiding transmission of HSV reported fewer days with genital lesions in source partners. Detailed histories were available at the time of transmission in 13 couples. In nine couples, transmission occurred when the source partner was reported to be asymptomatic and in four, it resulted from sexual contact at the time of prodrome (1 case) or within hours before lesions were first noticed by the source partner (3 cases). CONCLUSIONS: Despite clear recognition of genital herpes in source partners, there was substantial risk for transmission; in 70% of patients, transmission appeared to result from sexual contact during periods of asymptomatic viral shedding. The risk for acquisition of HSV was higher in women than men, and previous HSV type 1 infection appeared to reduce the risk for acquisition of HSV type 2 infection among women.

Inhibition of human immunodeficiency virus type I replication by derivatives of gossypol.

Gossypol (I) and its derivatives gossylic nitrile-1,1'-diacetate (II), gossylic iminolactone (III) and gossylic lactone (IV) inhibit the replication of human immunodeficiency virus type 1 in vitro in the order III greater than I greater than II,IV, indicating that derivatives of gossypol can retain antiviral activities. All of the derivatives are less cytotoxic than gossypol.

Genital herpes simplex virus infections.

There has been a dramatic increase in patient visits to physicians for evaluation and treatment of genital herpes infections. This has resulted in part from an increase in genital herpes infections, particularly severe, first-episode genital herpes infections in adults without prior HSV-1 infection. Virus culture remains the most sensitive and specific method for diagnosis, and use of viral cultures is encouraged. Type-specific antibody tests have been employed in studies documenting the role of asymptomatic shedding of HSV in transmission of genital infections, the role of genital HSV in transmission of HIV, the predominance of asymptomatic and unrecognized infections in those infected with HSV-2, and the presence of past asymptomatic or unrecognized acquisition of HSV-2 in 25% of persons presenting with first-episode genital herpes. Unfortunately, commercially available serologic tests do not reliably differentiate between antibody to HSV-1 and HSV-2. Recent studies suggest that the annual risk of transmission from a sexual partner with genital herpes is about 10% in heterosexual couples. Currently, promotion of "safe sex" is the only available approach for prevention of transmission. However, ongoing research is focused on the development of an effective vaccine. Acyclovir should be used routinely in persons with first-episode genital herpes, but careful evaluation is needed in persons with recurrent genital herpes to determine whether episodic or suppressive treatment is indicated. Acyclovir should also be used routinely for episodic or suppressive treatment of HSV infections in persons with AIDS. Additional antiviral agents are needed for more effective suppressive therapy and for treatment of ACV-resistant HSV infections in the immunocompromised host.