Vidarabine versus acyclovir therapy in herpes simplex encephalitis

We randomly assigned 208 patients who underwent brain biopsy for presumptive herpes simplex encephalitis to receive either vidarabine (15 mg per kilogram of body weight per day) or acyclovir (30 mg per kilogram per day) for 10 days. Sixty-nine patients (33 percent) had biopsy-proved disease; 37 received vidarabine, and 32 acyclovir. The mortality in the vidarabine recipients was 54 percent, as compared with 28 percent in the acyclovir recipients (P = 0.008). Six-month mortality varied according to the Glasgow coma score at the onset of therapy. For scores of greater than 10, 7 to 10, and less than or equal to 6, mortality was 42, 46, and 67 percent in the patients treated with vidarabine, as compared with 0, 25, and 25 percent in those treated with acyclovir. A six-month morbidity assessment using an adapted scoring system revealed that 5 of 37 patients receiving vidarabine (14 percent) as compared with 12 of 32 receiving acyclovir (38 percent) were functioning normally (P = 0.021). Eight vidarabine-treated patients (22 percent) and three acyclovir-treated patients (9 percent) had moderate debility. Patients under 30 years of age and with a Glasgow coma score above 10 had the best outcome with acyclovir treatment. We conclude that acyclovir is currently the treatment of choice for biopsy-proved herpes simplex encephalitis.     

Treatment of mucocutaneous herpes simplex virus infections unresponsive to acyclovir with topical foscarnet cream in AIDS patients: a phase I/II study.

The efficacy and toxicity of foscarnet cream for the treatment of mucocutaneous herpes simplex virus lesions or lesions that were clinically unresponsive to systemic acyclovir treatment (median, 30.5 days) in AIDS patients were studied in a phase I/II, open-label, nonrandomized multicenter trial. In the study, 20 patients with advanced stages of AIDS were treated with foscarnet 1% cream five times a day for a mean duration of 34.5 days. Response of index lesions (n = 20) was judged to be completely healed (8 lesions), excellent (4 lesions), or good (1 lesion) in 65% of lesions. The median time to first negative herpes simplex virus culture of index lesion was 8 days. Among 15 patients with pain at baseline, 11 had complete resolution of pain and 2 had at least a 50% reduction. Clinical adverse events included skin ulceration (4 patients), application site reactions (3 patients), fever (3 patients), and headache (3 patients). Five (25%) patients developed new lesions due to herpes simplex virus at sites other than those being treated topically while enrolled in the study. Topical foscarnet 1% cream appears to be a safe and effective treatment for acyclovir-unresponsive mucocutaneous herpes simplex virus infection in AIDS patients.     

A controlled trial comparing vidarabine with acyclovir in neonatal herpes simplex virus infection. Infectious Diseases Collaborative Antiviral Study Group

BACKGROUND. Despite the use of vidarabine, herpes simplex virus (HSV) infection in neonates continues to be a disease of high morbidity and mortality. We undertook a controlled trial comparing vidarabine with acyclovir for the treatment of neonatal HSV infection. METHODS. Babies less than one month of age with virologically confirmed HSV infection were randomly and blindly assigned to receive either intravenous vidarabine (30 mg per kilogram of body weight per day; n = 95) or acyclovir (30 mg per kilogram per day; n = 107) for 10 days. Actuarial rates of mortality and morbidity among the survivors after one year were compared overall and according to the extent of the disease at entry into the study (infection confined to the skin, eyes, or mouth; encephalitis; or disseminated disease). RESULTS. After adjustment for differences between groups in the extent of disease, there was no difference between vidarabine and acyclovir in either morbidity (P = 0.83) or mortality (P = 0.27). None of the 85 babies with disease confined to the skin, eyes, or mouth died. Of the 31 babies in this group who were treated with vidarabine and followed for a year, 88 percent (22 of 25) were judged to be developing normally after one year, as compared with 98 percent (45 of 46) of the 54 treated with acyclovir (95 percent confidence interval for the difference, -4 to 24). For the 71 babies with encephalitis, mortality was 14 percent with vidarabine (5 of 36) and with acyclovir (5 of 35); of the survivors, 43 percent (13 of 30) and 29 percent (8 of 28), respectively, were developing normally after one year (95 percent confidence interval for the difference, -11 to 39). For the 46 babies with disseminated disease, mortality was 50 percent (14 of 28) with vidarabine and 61 percent (11 of 18) with acyclovir (95 percent confidence interval for the difference, -20 to 40); of the survivors, 58 percent (7 of 12) and 60 percent (3 of 5), respectively, were judged to be developing normally after one year (95 percent confidence interval for the difference, -40 to 50). Both medications were without serious toxic effects. CONCLUSIONS. In this multicenter, randomized, blinded study there were no differences in outcome between vidarabine and acyclovir in the treatment of neonatal HSV infection. The study lacked statistical power to determine whether there were sizable differences within the subgroups of those with localized HSV, encephalitis, or disseminated disease.     

Treatment of varicella-zoster virus infection in severely immunocompromised patients. A randomized comparison of acyclovir and vidarabine

In a prospective, randomized trial, we compared intravenous acyclovir and vidarabine in the treatment of varicella-zoster virus infection in severely immunocompromised patients who presented within 72 hours of onset of the infection. Eleven patients were treated in each group. Cutaneous dissemination of infection occurred in none of the 10 acyclovir recipients and in 5 of the 10 vidarabine recipients who had presented with localized dermatomal disease (P = 0.016). As compared with vidarabine, acyclovir treatment shortened the median periods during which cultures were positive for the virus (four vs. seven days, P = 0.004) and new lesions formed (three vs. six days, P = 0.03). Acyclovir also shortened the median interval until the first decrease in pain (4 vs. 7 days, P = 0.005), the pustulation of all lesions (4 vs. 7 days, P = 0.0004), the crusting of all lesions (7 vs. 17 days, P = 0.0003), and the complete healing of lesions (17 vs. 28 days, P = 0.003). In addition, acyclovir reduced the incidence of fever (two vs. eight patients, P = 0.015). We conclude that acyclovir is better than vidarabine for the treatment of varicella-zoster infection in immunocompromised patients.     

Prevention of reactivated herpes simplex infection by human leukocyte interferon after operation on the trigeminal root.

Microneurosurgical procedures on the trigeminal-nerve root are often followed by reactivation of herpes simplex virus infection, manifested by herpes labialis or oropharyngeal herpesvirus shedding or both. In a double-blind study of the ability of human leukocyte interferon to prevent this reactivation, patients with a history of herpes labialis were given 7 x 10(4) U of interferon per kilogram of body weight per day or placebo for five days beginning on the day before operation. In 18 patients treated with placebo, herpes labialis developed in 10, and virus shedding in the oropharynx in 15. In 19 patients treated with interferon, lesions developed in five, and shedding in eight. The frequency of reactivation as measured by lesions or positive throat cultures or both was significantly reduced by interferon (P less than 0.05). Of 127 daily throat-wash cultures in the placebo group, 42 per cent were positive for herpesvirus, but of 134 in the interferon group, only 9 per cent were positive (P less than 0.001). We conclude that interferon at a well-tolerated dosage reduces reactivation of latent herpes simplex virus infection after a potent operative stimulus.     

Novel mutations in the thymidine kinase and DNA polymerase genes of acyclovir and foscarnet resistant herpes simplex viruses infecting an immunocompromised patient.

BACKGROUND: Mutations in the thymidine kinase (TK) and DNA polymerase (pol) genes of herpes simplex virus (HSV) may confer resistance to antiviral drugs, particularly in the context of immunosuppression induced by infection with the human immunodeficiency virus (HIV). OBJECTIVES: To characterise the HSV type 2 (HSV-2) TK and DNA pol genes in an immunocompromised patient with clinical resistance to both acyclovir and foscarnet. STUDY DESIGN: The TK and DNA pol genes of isolates obtained over a 2-year period from an AIDS patient with severe genital herpes infection were characterised both phenotypically and genotypically. RESULTS: HSV strains that were acyclovir resistant/foscarnet sensitive, acyclovir sensitive/foscarnet sensitive and acyclovir resistant/foscarnet resistant were isolated during this time. The TK gene of all the acyclovir resistant isolates contained a large 969 bp deletion which extended into a downstream untranslated region. The foscarnet resistance was associated with an S725G mutation in a conserved region (region II) of the herpesvirus DNA pol gene. CONCLUSIONS: Clinical and virological suppression of the infection was not always associated with subsequent reactivation with wild-type virus. Mutations of the nature we describe have not previously been reported occurring simultaneously in HSV strains isolated from patients treated with acyclovir and foscarnet.     

Comparative trial of acyclovir and vidarabine in disseminated varicella-zoster virus infections in immunocompromised patients

A comparative assessment of vidarabine and acyclovir in the treatment of varicella and disseminated zoster in immunosuppressed patients was undertaken. Thirty-eight immunosuppressed patients with varicella (N = 18) or disseminated zoster (N = 20) were treated intravenously with 10 mg/kg/day of vidarabine or 30 mg/kg/day of acyclovir for 5 days according to a preestablished code within each diagnosis group--varicella and disseminated zoster. Two deaths, although not directly related to VZV infection, were observed in the vidarabine-treated varicella group. The times to cessation of formation of new lesions and to the disappearance of fever were similar for vidarabine and acyclovir in each group. In the varicella group, VZV was isolated on day 5 in four out of five vidarabine patients versus one out of five acyclovir patients. No severe adverse effects were observed with either drug. Neutropenia present in patients of both drug groups was transitory and most often related to previous cytolytic chemotherapy. These data suggest that either vidarabine or acyclovir could be used in the treatment of severe VZV infections in immunosuppressed patients, although a larger number of patients would be required for definitive conclusion. Because of the large amount of solute required for vidarabine administration, acyclovir may be preferred when the risk of cardiorespiratory failure is high.     

A trial of topical acyclovir in genital herpes simplex virus infections

Seventy-seven patients with first episodes of genital herpes and 111 with recurrent episodes were enrolled in a double-blind trial comparing topical acyclovir with a placebo (polyethylene glycol ointment). Among acyclovir-treated patients with first-episode primary genital herpes, the mean duration of viral shedding (4.1 days) and the time to complete crusting of lesions present at the initiation of therapy (7.1 days) were shorter than among placebo recipients (7.0 and 10.5 days, respectively) (P less than 0.05). Acyclovir-treated patients with recurrent herpes had a shorter duration of viral shedding than placebo recipients (0.95 vs. 1.90 days) (P = 0.03). Among the patients with recurrent herpes, acyclovir reduced the time to crusting of lesions in men but had no effect on the symptoms or healing times in women. Topical acyclovir shortens the duration of viral shedding and accelerates healing of some genital herpes simplex virus infections.     

Acyclovir for prevention of cytomegalovirus infection and disease after allogeneic marrow transplantation

Patients undergoing allogeneic bone marrow transplantation who are seropositive for cytomegalovirus are vulnerable to serious cytomegalovirus infection, presumably because of reactivation of latent endogenous virus and severe immunosuppression. We administered intravenous acyclovir from 5 days before to 30 days after allogeneic marrow transplantation for hematologic neoplasms in an effort to prevent cytomegalovirus infection and disease in patients seropositive for cytomegalovirus before transplantation. Eighty-six patients seropositive for both cytomegalovirus and herpes simplex virus before transplantation received acyclovir, whereas 65 patients seropositive only for cytomegalovirus served as controls (acyclovir is the standard prophylactic agent against herpes simplex virus in this setting). The probability that cytomegalovirus infection would develop within the first 100 days after transplantation was 0.70 among acyclovir recipients and 0.87 among control patients at medians of 62 and 40 days after transplantation, respectively (P = 0.0001 by log-rank test). Invasive cytomegalovirus disease developed in 19 acyclovir recipients (22 percent) and 25 control patients (38 percent) (P = 0.008). Survival within the first 100 days after transplantation was better among acyclovir recipients (P = 0.002). Acyclovir prophylaxis was associated with a relative risk of 0.5 or less for the development of cytomegalovirus infection or disease or for death within the first 100 days after transplantation (P less than or equal to 0.04), in proportional-hazards regression analysis. We conclude that prophylaxis with intravenous acyclovir significantly reduced the risk of both cytomegalovirus infection and cytomegalovirus disease in seropositive patients after allogeneic bone marrow transplantation and that it was also associated with significantly improved survival.     

Treatment of first episodes of genital herpes simplex virus infection with oral acyclovir. A randomized double-blind controlled trial in normal subjects

We performed a double-blind placebo-controlled trial of oral acyclovir in the treatment of first episodes of genital herpes simplex virus infections in 48 young adults (31 women and 17 men). Subjects were randomized to receive either placebo or acyclovir (200 mg per dose) five times daily for 10 days; they were examined on at least eight visits until healed and at monthly visits thereafter. Acyclovir treatment, as compared with placebo, significantly reduced virus shedding, new lesion formation after 48 hours, and the duration of genital lesions in both men and women. The total duration and severity of clinical symptoms (such as pain, adenopathy, dysuria, and malaise) were significantly reduced by acyclovir in both men and women by the third and fourth day, respectively (P less than or equal to 0.025), as compared with placebo. No toxicity was observed. Recurrence rates have so far been similar in placebo and acyclovir recipients. Oral acyclovir treatment of first-episode genital herpes simplex virus infections is clinically effective, but it does not seem to prevent virus latency or associated recurrent disease.     

Acyclovir-resistant herpes simplex encephalitis in a patient treated with anti-tumor necrosis factor-α monoclonal antibodies

Herpes simplex virus is the most common cause of severe sporadic encephalitis. We report a case of herpes simplex type 1-encephalitis in a 50-year-old woman receiving anti-tumor necrosis factor-α monoclonal antibodies adalimumab. Although she was an acyclovir naïve patient, a mixed viral population (wild-type and acyclovir-resistant bearing a thymidine-kinase mutation) was identified in the cerebrospinal fluid. The virus in cerebrospinal fluid evolved and a second thymidine-kinase mutant virus emerged. Combined foscavir and acyclovir treatment resolved the herpes simplex encephalitis. To our knowledge, this is the first report of acyclovir-resistant herpes simplex encephalitis in a patient treated with adalimumab.     

Pathogenicity and response to topical antiviral therapy in a murine model of acyclovir-sensitive and acyclovir-resistant herpes simplex viruses isolated from the same patient.

BACKGROUND: Acyclovir-resistant herpes simplex viruses (HSV) are commonly recovered from immunocompromised individuals who exhibit chronic and/or disseminated herpetic lesions. OBJECTIVES AND STUDY DESIGN: The virulence and response to topical acyclovir therapy were evaluated in a mouse model of zosteriform cutaneous HSV infection using two HSV-1 isolates from the same immunocompromised patient (one susceptible and one resistant to acyclovir). RESULTS: The acyclovir-resistant virus, with a Thr63Ile change in the ATP-binding site of the thymidine kinase gene, produced almost as many skin lesions as the wild-type susceptible virus. As expected from in vitro susceptibility data, the herpetic lesions of the mice infected with the drug-resistant virus did not respond to topical acyclovir therapy. CONCLUSIONS: Some thymidine kinase HSV mutants associated with drug resistance may retain their pathogenicity at least in the mouse model described in this study.     

Acyclovir prophylaxis of herpes-simplex-virus infections

We conducted a double-blind, placebo-controlled study of acyclovir prophylaxis against infection with herpes simplex virus (HSV) in 20 seropositive recipients of bone-marrow transplants. Acyclovir or placebo was administered for 18 days, starting three days before transplantation. Culture-positive HSV lesions developed during the study in seven of the 10 patients who received placebo. In contrast, no such lesions appeared in the 10 patients who received acyclovir (P congruent to 0.003). None of the patients had evidence of drug toxicity. Five of the patients treated with acyclovir had mild culture-positive HSV infections after cessation of the drug, and two additional patients shed virus without having lesions. Acyclovir appears to be a potent inhibitor of HSV replication. Although acyclovir does no appear to eradicate latent infection, it can provide effective prophylaxis against reactivated infections.     

Adenine arabinoside therapy of biopsy-proved herpes simplex encephalitis. National Institute of Allergy and Infectious Diseases collaborative antiviral study.

We evaluated adenine arabinoside (vidarabine) for treatment of herpes simplex encephalitis in a placebo-controlled study. In 28 cases proved by isolation of Type 1 virus from brain biopsy, treatment reduced mortality from 70 to 28 per cent (P = 0.03), and over 50 per cent of treated survivors had no or only moderately debilitating neurologic sequelae. This improvement was achieved without evidence of acute drug toxicity. Thus, adenine arabinoside has a good therapeutic index (efficacy/toxicity) for the treatment of Type 1 herpes simplex encephalitis. However, the drug must be given early in the course of infection before the advent of coma to have a beneficial effect. Moreover, it should be coupled with brain biopsy for specific diagnosis to avoid unnecessary treatment of nonresponsive encephalitides that can mimic herpes simplex.     

Infection due to acyclovir resistant herpes simplex virus in patients undergoing allogeneic hematopoietic stem cell transplantation

Over an eight-month period from October 1997 to May 1998, four patients who had received bone marrow transplant (BMT) from unrelated donor presented with severe mucosal cutaneous infections involving acyclovir resistant herpes simplex virus 1 (HSV-1). The four isolates were acyclovir (ACV) resistant, three of which were also foscarnet resistant as determined by the dye uptake method. The sequencing of the thymidine kinase (TK) gene did not permit to establish a relation between mutations and resistance to ACV. Three patients were considered as clinically cured of their HSV infection by replacement of ACV or foscarnet with either valacyclovir (one case) or cidofovir (two cases) but eventually two of them died of graft vs host disease. One patient died of extensive HSV infection despite administration of cidofovir. This study emphasizes the importance of monitoring the herpes virus resistance to antiviral drugs in bone marrow transplant recipients and the usefulness of the evaluation of novel antiviral drug for treatment of infections due to strains of HSV resistant to ACV and foscarnet that occur in about 5% of immunocompromised patients.     

Fulminant, acyclovir-resistant, herpes simplex virus type 2 hepatitis in an immunocompetent woman

We report an immunocompetent woman with multisystem organ failure following herpes simplex virus type 2 (HSV-2) hepatitis. After she initially responded to intravenous acyclovir, she was switched to oral valacyclovir. She developed respiratory failure and opportunistic infections and died. Autopsy confirmed disseminated HSV infection, and lung tissue grew acyclovir-resistant HSV-2.     

Failure of neutral-red photodynamic inactivation in recurrent herpes simplex virus infections.

Because photodynamic inactivation of herpes simplex virus infections may not be free of hazard, the efficacy of photodynamic inactivation with neutral red and light was evaluated in a placebo-controlled study of 170 episodes of recurrent herpes simplex virus infection in 96 patients. The preparation of neutral red that was used was shown to photoinactivate herpes simplex virus in vitro, but had no significant effect on the rate of resolution of herpetic lesions (P greater than 0.10) or on the frequency of subsequent recurrences (P greater than 0.10), except for orolabial lesions, in which an adverse effect on the rate of subsequent recurrences was observed (P less than 0.05). In the absence of demonstrated efficacy, the routine use of neutral red and light in patients with recurrent herpes simplex virus infections should be discontinued. Furthermore, other photoactive dyes should not be used until their efficacy has been demonstrated by suitably controlled clinical trials.     

Suppression of frequently recurring genital herpes. A placebo-controlled double-blind trial of oral acyclovir

We studied 35 otherwise healthy adults with frequently recurring genital herpes (greater than or equal to 1 episode per month), in a double-blind trial comparing oral acyclovir with placebo capsules for suppression of recurrent infection. The patients were treated for 125 days unless herpes recurred. Among 32 evaluable patients, there were significantly fewer recurrences during acyclovir treatment (4 of 16) than during placebo treatment (16 of 16, P less than 0.001). The mean duration of therapy was significantly longer for patients receiving acyclovir than for those receiving placebo (114.9 vs. 24.8 days, P less than 0.001). Of 19 patients who had recurrences in the blind trial, only 2 had recurrences when given acyclovir in a second, open-study phase. All patients had recurrences after completing acyclovir treatment. The therapy was well tolerated, with minimal gastrointestinal upset and one hypersensitivity reaction. Studies of the viral isolates demonstrated that lesions developing in patients receiving acyclovir contained drug-resistant virus. Later recurrences in these patients were associated with drug-sensitive virus. We conclude that oral acyclovir suppresses genital herpes in patients with frequent recurrences, but the potential for problems with drug resistance and the long-term safety need to be more fully explored.     

Suppression of generation and replication of acyclovir-resistant herpes simplex virus by a sensitive virus

The role of acyclovir-sensitive herpes simplex virus (HSV) was analyzed in the process of its replacement by a resistant virus in vitro and in vivo in the aspect of acyclovir therapy. The mode of replacement of acyclovir-sensitive HSV with acyclovir-resistant HSV was examined by the passages of acyclovir-sensitive wild type HSV in Vero cells under acyclovir-treatment. The development of resistance was monitored more adequately by counting the number of acyclovir-resistant viruses in 10,000 plaque forming units than by the conventional susceptibility assay. The resistance increased with the proportion of thymidine kinase-deficient (TK(-)) viruses, when the susceptibilities of acyclovir-treated HSV population to 5'-iodo-2'deoxyuridine and phosphonoacetic acid were examined. The increased resistance was due to the increased proportion of acyclovir-resistant virus but not intermediately resistant virus. Infection with mixtures of TK(-) and acyclovir-sensitive strains rendered TK(-) sensitive to acyclovir, and virus yields were reduced to the levels of acyclovir-sensitive virus in Vero cells. Their yield reduction depended on the proportion of acyclovir-sensitive viruses and induction of TK activity. This reduction in virus yields of the mixture of TK(-) and acyclovir-sensitive strains was confirmed by acyclovir treatment in the skin of mice with cutaneous infection. Acyclovir treatment combined with superinfection of acyclovir-sensitive virus delayed the development of herpetic skin lesions due to acyclovir-resistant virus and reduced virus yields in the infected skin. Acyclovir-sensitive virus plays an important role in suppressing the generation and replication of acyclovir-resistant virus during acyclovir therapy.     

A controlled trial of fluconazole or amphotericin B to prevent relapse of cryptococcal meningitis in patients with the acquired immunodeficiency syndrome. The NIAID AIDS Clinical Trials Group and Mycoses Study Group.

BACKGROUND. After primary treatment for cryptococcal meningitis, patients with the acquired immunodeficiency syndrome (AIDS) require some form of continued suppressive therapy to prevent relapse. METHODS. We conducted a multicenter, randomized trial that compared fluconazole (200 mg per day given orally) with amphotericin B (1 mg per kilogram of body weight per week given intravenously) in patients with AIDS who had completed primary therapy for cryptococcal meningitis with amphotericin B (greater than or equal to 15 mg per kilogram). To be eligible, patients had to have at least two negative cultures of cerebrospinal fluid immediately before randomization. The primary end point was relapse of cryptococcal disease as confirmed by biopsy or culture. RESULTS. Of 218 patients initially enrolled, 119 were assigned to fluconazole and 99 to amphotericin B. Twenty-three patients were found not to have met the entry criteria; six other patients assigned to amphotericin B did not receive it and were lost to follow-up. Of the remaining 189 patients, after a median follow-up of 286 days 14 of 78 receiving amphotericin B (18 percent) and 2 of 111 assigned to fluconazole (2 percent) had relapses of symptomatic cryptococcal disease (P less than 0.001 by Fisher's exact test). There was a difference of 19 percent in the estimated probability of remaining relapse-free at one year between the fluconazole group (97 percent) and the amphotericin B group (78 percent) (95 percent confidence interval, 7 percent to 31 percent; P less than 0.001). Serious drug-related toxicity was more frequent in the amphotericin B group (P = 0.02), as were bacterial infections (P = 0.004) and bacteremia (P = 0.002). CONCLUSIONS. Fluconazole taken by mouth is superior to weekly intravenous therapy with amphotericin B to prevent relapse in patients with AIDS-associated cryptococcal meningitis after primary treatment with amphotericin B.