Gregory J. Mertz

Acyclovir-Resistant Herpes Simplex Virus Infections in Patients with the Acquired Immunodeficiency Syndrome

RECURRENT herpes simplex virus (HSV) infections are frequent in patients with the acquired immunodeficiency syndrome (AIDS). Although they are usually self-limiting in the normal host, such infecti...

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.

Acyclovir with and without Prednisone for the Treatment of Herpes Zoster: A Randomized, Placebo-Controlled Trial

Herpes zoster results from the reactivation of latent varicella-zoster virus located in the dorsal root ganglia. The condition is common in elderly and immunocompromised patients. Although herpes zoster is not a reportable disease, an estimated 300 000 to 500 000 cases occur annually in the United States [1]. In immunocompetent persons, the most notable manifestations are acute neuritis and persistent pain, traditionally called postherpetic neuralgia. Recent clinical trials of acyclovir [2-5], valaciclovir [6], and famciclovir [7, 8] showed that antiviral therapy helps heal cutaneous lesions and relieve pain in patients with herpes zoster. When our clinical trial was initiated, several studies had already reported that corticosteroid therapy could potentially decrease the incidence or duration of postherpetic neuralgia [9-14]. Despite their small sample sizes and use of inadequate controls, these clinical trials resulted in the widespread adoption of prednisone as the standard therapy for herpes zoster. It was hoped that this agent would prevent persistent or chronic pain. More recent studies [15-18] did not confirm the validity of this approach. A large study that used acyclovir with or without prednisolone for as long as 21 days showed no beneficial effect of steroids on persistent pain [19]. Nevertheless, many physicians continue to use therapy with both antiviral drugs and corticosteroids to manage herpes zoster. We and other members of the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group did a clinical trial to determine the effect of adding corticosteroids to acyclovir for the treatment of herpes zoster. Our key study end points were measurements of pain and quality of life. Methods Patients Eligible participants were immunocompetent adults older than 50 years of age who presented with a localized dermatomal vesicular rash that was clinically consistent with herpes zoster and had been present for less than 72 hours. Patients were referred to participating investigators by community physicians or from university-affiliated clinics. The diagnosis was confirmed by the isolation of varicellazoster virus in tissue culture and by serologic testing. We excluded patients who required immunosuppressive therapy; patients with cancer; women capable of conceiving and bearing a child; patients who had a history of hypertension (diastolic pressure > 100 mm Hg) or were receiving antihypertensive treatment; patients with osteoporosis or insulin-dependent diabetes mellitus; patients who had received other antiviral drugs or immune globulin products within the 4 weeks before the study began; and patients with a history of glycosuria or hyperglycemia. Other concurrent medications or illnesses did not warrant exclusion. All patients gave informed consent before randomization. The informed consent document was approved by all local institutional review boards in compliance with regulations of the U.S. Food and Drug Administration. Interventions We used a 2 2 factorial study design to randomly allocate the 208 eligible and consenting patients. Patients received one of the following regimens: 1) acyclovir plus prednisone, 2) acyclovir plus prednisone placebo, 3) prednisone plus acyclovir placebo, or 4) placebos for both prednisone and acyclovir. Acyclovir was administered orally, 800 mg five times daily, for 21 days. Prednisone was administered orally at 60 mg/d for days 1 to 7, 30 mg/d for days 8 to 14, and 15 mg/d for days 15 to 21. All research personnel remained blinded to drug assignments until the study was completed and the database was locked. All matched medications (acyclovir plus prednisone placebo and prednisone plus acyclovir placebo) were identical in taste and appearance. With a 2 2 factorial design, two treatments are evaluated simultaneously in one study. This design allows the assessment of an individual intervention and of the combined effects of multiple interventions (in our study, acyclovir and prednisone). The main or individual effect of acyclovir represents the difference between the effect of acyclovir therapy and the effect of no acyclovir therapy. We compared the patients who received acyclovir (the acyclovir plus prednisone group and the acyclovir plus prednisone placebo group) with the patients who did not receive acyclovir (the prednisone plus acyclovir placebo group and the placebo group). Similarly, the main effect of prednisone represents the difference between the effect of prednisone therapy and the effect of no prednisone therapy. We compared the two groups that received prednisone with the two groups that did not. This study design also allowed us to compare the combined effect of acyclovir and prednisone therapy with the effect of either therapy alone or with the effect of placebo. Outcome Measures and Surveillance Our primary end points were the persistence of pain and assessments of quality of life (return to 100% usual activity, return to uninterrupted sleep, and cessation of use of analgesic agents) during a 6-month period. Secondary end points were cutaneous healing and clinical or laboratory evidence of toxicity. After enrollment, patients were evaluated daily until the skin was completely healed. The number of new vesicles formed, extent of healing (measured by the presence of vesiculation, pustulation, scabbing, and total healing), severity of pain, and analgesic requirements were recorded at each visit. Acute neuritis was assessed during the first month after enrollment. Each patient was asked to rate his or her pain as none, mild, moderate, or severe or incapacitating. The effect of herpes zoster on usual activity (measured as a percentage reduction in activity), continued analgesic requirements, and the ability to sleep without interruption was also recorded at each visit. After lesions had completely healed, patients were followed monthly for the 6 months after therapy began and were assessed for persistence of pain, analgesic requirements, and quality-of-life measures. We used two analyses to measure chronic pain. First, postherpetic neuralgia was defined as pain that was present 30 days after disease onset and that continued until complete resolution or 6 months. Because we sought to maintain the principles of the intention-to-treat analysis and include patients with no pain at 30 days after disease onset, we assigned such patients a value of zero for the time to resolution of postherpetic neuralgia. Second, pain associated with zoster was defined as the continuum of pain extending from study enrollment until final resolution. This second analysis included all patients from the time of enrollment. For all pain analyses, resolution of pain was defined as the last occurrence of any pain attributed to herpes zoster. Time to return to uninterrupted sleep was assessed by the patient as the time when he or she was no longer awakened by pain or altered sensations attributable to herpes zoster. Similarly, times to cessation of the use of analgesic agents and return to 100% usual activity were defined as the first recorded time to that event with no subsequent documented relapse. Blood and urine samples were tested for evidence of treatment toxicity every week for the first 4 weeks. Assessments included a complete blood count with differential and platelet determinations; urinalysis; and quantitation of serum and urine levels of urea, creatinine, bilirubin, glucose, and aspartate glutamyltransferase. Adverse clinical events, regardless of their probability of being associated with drug administration, were reported immediately by telephone or facsimile to the central unit at the University of Alabama at Birmingham. Randomization The Biostatistical Unit of the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group at the University of Alabama at Birmingham used a computer-generated randomization code to randomly assign patients to one of the four treatment groups. Randomization was done in blocks of four. Estimation of Sample Size The sample size was calculated according to assumptions of the main effect of acyclovir that were based on data available when the trial was designed. The null hypothesis was that patients receiving acyclovir and those not receiving acyclovir would have equal rates of persistent pain at 6 months. On the basis of a one-sided test procedure that had a significance level of 0.025 and of a projected 20% detected difference between treatment groups, we calculated that a sample size of 256 patients was needed to achieve a power of 90%. Because of slow accrual during the latter stages of the trial (which was probably caused by the widespread acceptance and availability of oral acyclovir), the study was terminated with a total enrollment of 208 patients. Two hundred one of the 208 patients were included in the final analysis, yielding a power of 82%. Interim Analysis A Data Safety and Monitoring Board was established by the National Institute of Allergy and Infectious Diseases through the Division of Microbiology and Infectious Diseases to monitor the progress of the trial and any adverse events. However, no interim analyses of efficacy end points were done. Statistical Analysis The clinical response measurements for time-to-event variables were estimated using the Kaplan-Meier method and were compared using the log-rank test. We used a Cox regression model to analyze the main effects of acyclovir and prednisone and their interaction, with adjustments for other covariates. The main effects of acyclovir and prednisone were each represented in the Cox model as a dummy variable coded as 0 or 1. The interaction of these drugs was represented as the product of the two dummy variables. We also used a Cox model to compare each treatment group with the placebo group, with adjustment for all specified covariates (sex, race, age, duration of lesions before enrollment, number of lesions at entry, seve

A Double-Blind Study of Oral Acyclovir for Suppression of Recurrences of Genital Herpes Simplex Virus Infection

Patients with frequently recurring genital herpes were enrolled in a double-blind placebo-controlled trial comparing 200-mg acyclovir capsules, given five or two times daily, with placebo. Of 47 placebo recipients, 44 (94 per cent) had recurrences during the 120-day treatment period, compared with 13 (29 per cent) of 45 patients treated with acyclovir five times daily and 18 of 51 (35 per cent) treated with acyclovir twice daily (P less than 0.001 for each regimen compared with placebo). The median time to the first clinical recurrence was 18 days in placebo recipients, compared with over 120 days in both acyclovir-treated groups (P less than 0.001 for both groups compared with placebo). The mean monthly recurrence rate during the medication period was 0.86 in placebo recipients, compared with 0.13 in patients treated with acyclovir five times daily and 0.14 in patients treated with acyclovir twice daily (P less than 0.001 for both groups compared with placebo). While receiving therapy, 86 of 96 acyclovir-treated patients had over a 50 per cent reduction in their pretreatment recurrence rate. Breakthrough recurrences in acyclovir recipients were of shorter duration and associated with a lower frequency of viral shedding than recurrences in placebo recipients. After medication was discontinued, the subsequent recurrence rate returned to pretreatment frequencies. Daily oral acyclovir was well tolerated. We conclude that oral acyclovir given for four months markedly reduces but does not completely prevent recurrences of genital herpes and does not influence the long-term natural history of the disease.

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.

Placebo-Controlled, Double-Blind Trial of Intravenous Ribavirin for the Treatment of Hantavirus Cardiopulmonary Syndrome in North America

UNLABELLED BACKGROUND. Ribavirin is active in vitro against hantaviruses, but the findings of an open trial of the use of intravenous ribavirin for the treatment of hantavirus cardiopulmonary syndrome (HCPS) were inconclusive. METHODS Subjects with suspected HCPS in the prodrome or cardiopulmonary phase but without shock were eligible for randomization to receive either intravenous ribavirin (33 mg/kg [<or=2 g], followed by 16 mg/kg [<or=1 g] given every 6 h for 4 days and by 8 mg/kg [<or=.5 g] given every 8 h for 3 days) or placebo (administered for 7 days or until the initial Sin Nombre virus antibody test result was confirmed to be negative). The primary outcome was survival at day 28 of the study without the need for extracorporeal membrane oxygenation (ECMO). RESULTS Thirty-six subjects were enrolled in the trial from March 1996 through July 2001, at which point the study was terminated prematurely because of both the slow rate of accrual of subjects and the findings of a futility analysis. Of the 36 subjects enrolled, 23 (all of whom were enrolled during the cardiopulmonary stage of HCPS) had HCPS confirmed by serologic testing. The severity of illness at entry into the study was similar among the 10 subjects with HCPS who received ribavirin and the 13 subjects with HCPS who received placebo. The proportion of subjects who survived and who did not require ECMO was similar among ribavirin recipients and placebo recipients (70% vs. 62%, respectively); 2 ribavirin recipients and 2 placebo recipients died, including 3 of 7 subjects treated with ECMO. The frequency of adverse events, including anemia, was similar between treatment groups. CONCLUSIONS The rate of accrual of subjects in the present study was inadequate to clearly assess the safety or efficacy of ribavirin in the treatment of HCPS. However, ribavirin was well tolerated, and the lack of trends supporting the use of intravenous ribavirin suggests that it is probably ineffective in the treatment of HCPS in the cardiopulmonary stage.

Diagnosis and treatment of new world hantavirus infections.

Purpose of reviewThe purpose of this review is to summarize the current knowledge regarding the diagnosis and treatment of indigenous new world hantavirus infections. Recent findingsRecent studies have defined the incubation period of new world hantavirus infections, provided additional evidence for person-to-person transmission of Andes virus, described a rapid method for the presumptive diagnosis of infection in the cardiopulmonary phase through a review of the peripheral smear, and suggested that intravenous ribavirin is probably not effective for the treatment of new world hantavirus infections when started in the cardiopulmonary phase. SummaryPresumptive diagnosis may be made by a review of the peripheral blood smear after the onset of the cardiopulmonary phase. Critical care management includes the avoidance of fluid overload, pressors to maintain cardiac output, and the use of extracorporeal membrane oxygenation in the most severe cases, but treatment with intravenous ribavirin is probably not effective.

Prospective Evaluation of Household Contacts of Persons with Hantavirus Cardiopulmonary Syndrome in Chile

BACKGROUND Andes virus (ANDV) infection, which has a case fatality rate of 37% in Chile, often occurs in household clusters and may be transmitted from person to person. METHODS To determine the incidence and risk factors for additional household cases, we conducted a prospective study among recent household contacts of persons with hantavirus cardiopulmonary syndrome (HCPS) in Chile, including testing of serum for anti-hantavirus antibodies and blood cells for ANDV RNA by reverse-transcription polymerase chain reaction (RT-PCR). RESULTS We enrolled 76 index case patients and 476 household contacts, of whom 16 (3.4%) developed HCPS; 32.6% of 92 cases occurred in household clusters. The risk of HCPS was 17.6% among sex partners of index case patients, versus 1.2% among other household contacts (P<.001). Person-to-person transmission was definite in 3, probable in 9, and possible in 2 of the 16 additional household case patients. We detected ANDV RNA by RT-PCR in peripheral blood cells 5-15 days before the onset of symptoms or the appearance of anti-hantavirus antibodies. CONCLUSIONS In recent household contacts of persons with HCPS in Chile, the risk of HCPS was greatest among sex partners. Among the household contacts who developed HCPS, viremia preceded the onset of symptoms and the appearance of anti-hantavirus antibodies by up to 2 weeks.

New developments in the epidemiology, natural history and management of genital herpes

The prevalence of genital herpes is increasing in several populations worldwide. Factors that may be contributing to this increase include greater numbers of sexual partners, the high frequency of asymptomatic infections, poor use of safe sexual practices, and possibly the decreased incidence of childhood oral herpes simplex virus infection. Transmission occurs via skin-to-skin or mucous membrane contact during periods of viral shedding when lesions are present but may also occur when the patient is unaware of the lesions or when lesions are not clinically apparent. This has important implications for strategies to prevent transmission of the disease. The introduction of the antiherpes agent, acyclovir, and more recently famciclovir and valacyclovir, facilitates the management of genital herpes. Treatment of first-episode genital herpes reduces the severity and duration of symptoms, time to lesion healing, and cessation of viral shedding. Episodic treatment of recurrences as they occur may be of benefit to some patients. Daily suppressive therapy significantly reduces the frequency of recurrences and asymptomatic viral shedding. Accordingly, patients who experience frequent or severe recurrences, those particularly troubled by their disease, and those who wish to reduce the frequency of asymptomatic infection generally prefer suppressive therapy. The possibility that suppressive therapy may have an impact on transmission of the disease is currently under investigation. Antiviral treatments have important implications for public health and may help reduce the psychological and psychosocial impact of genital herpes on individual patients.

First Human Isolate of Hantavirus (Andes virus) in the Americas

We isolated Andes virus (formal name: Andes virus [ANDV], a species in the genus Hantavirus), from serum of an asymptomatic 10-year-old Chilean boy who died 6 days later of hantavirus pulmonary syndrome (HPS). The serum was obtained 12 days after his grandmother died from HPS and 2 days before he became febrile. No hantavirus immunoglobulin (Ig) G or IgM antibodies were detected in the serum sample. After three blind passages, ANDV antigens were detected in Vero E6 cells by immunofluorescence assay and enzyme-linked immunosorbent assay, and ANDV RNA was detected by reverse transcription-polymerase chain reaction. A fragment of the virus genome showed 96.2% nucleotide identity with that of prototype ANDV. To our knowledge, this is the first isolation of any agent of hemorrhagic fever with renal syndrome from a human and the first such isolation of hantavirus before symptoms of that syndrome or HPS began.