Acyclovir Has Low but Detectable Influence on HLA-B*57:01 Specificity without Inducing Hypersensitivity.

Immune mediated adverse drug reactions (IM-ADRs) remain a significant source of patient morbidity that have more recently been shown to be associated with specific class I and/or II human leukocyte antigen (HLA) alleles. Abacavir-induced hypersensitivity syndrome is a CD8+ T cell dependent IM-ADR that is exclusively mediated by HLA-B*57:01. We and others have previously shown that abacavir can occupy the floor of the peptide binding groove of HLA-B*57:01 molecules, increasing the affinity of certain self peptides resulting in an altered peptide-binding repertoire. Here, we have identified another drug, acyclovir, which appears to act in a similar fashion. As with abacavir, acyclovir showed a dose dependent increase in affinity for peptides with valine and isoleucine at their C-terminus. In agreement with the binding studies, HLA-B*57:01 peptide-elution studies performed in the presence of acyclovir revealed an increased number of endogenously bound peptides with a C-terminal isoleucine. Accordingly, we have hypothesized that acyclovir acts by the same mechanism as abacavir, although our data also suggest the overall effect is much smaller: the largest changes of peptide affinity for acyclovir were 2-5 fold, whereas for abacavir this effect was as much as 1000-fold. Unlike abacavir, acyclovir is not known to cause IM-ADRs. We conclude that the modest effect of acyclovir on HLA binding affinity in contrast to the large effect of abacavir is insufficient to trigger a hypersensitivity syndrome. We further support this by functional in vitro studies where acyclovir, unlike abacavir, was unable to produce an increase in IFN-γ upon expansion of HLA-B*57:01+ PBMCs from healthy donors. Using abacavir and acyclovir as examples we therefore propose an in vitro pre-clinical screening strategy, whereby thresholds can be applied to MHC-peptide binding assays to determine the likelihood that a drug could cause a clinically relevant IM-ADR.

Prevention of herpes simplex virus induced stromal keratitis by a glycoprotein B-specific monoclonal antibody.

The increasing incidence of acyclovir (ACV) and multidrug-resistant strains in patients with corneal HSV-1 infections leading to Herpetic Stromal Keratitis (HSK) is a major health problem in industrialized countries and often results in blindness. To overcome this obstacle, we have previously developed an HSV-gB-specific monoclonal antibody (mAb 2c) that proved to be highly protective in immunodeficient NOD/SCID-mice towards genital infections. In the present study, we examined the effectivity of mAb 2c in preventing the immunopathological disease HSK in the HSK BALB/c mouse model. Therefore, mice were inoculated with HSV-1 strain KOS on the scarified cornea to induce HSK and subsequently either systemically or topically treated with mAb 2c. Systemic treatment was performed by intravenous administration of mAb 2c 24 h prior to infection (pre-exposure prophylaxis) or 24, 40, and 56 hours after infection (post-exposure immunotherapy). Topical treatment was performed by periodical inoculations (5 times per day) of antibody-containing eye drops as control, starting at 24 h post infection. Systemic antibody treatment markedly reduced viral loads at the site of infection and completely protected mice from developing HSK. The administration of the antiviral antibody prior or post infection was equally effective. Topical treatment had no improving effect on the severity of HSK. In conclusion, our data demonstrate that mAb 2c proved to be an excellent drug for the treatment of corneal HSV-infections and for prevention of HSK and blindness. Moreover, the humanized counterpart (mAb hu2c) was equally effective in protecting mice from HSV-induced HSK when compared to the parental mouse antibody. These results warrant the future development of this antibody as a novel approach for the treatment of corneal HSV-infections in humans.

Herpes simplex virus oesophagitis in a pregnant woman.

Herpes simplex virus (HSV) oesophagitis is well described in immunocompromised patients. In immunocompetent individuals HSV oesophagitis is rare. We present a case of HSV oesophagitis in a pregnant woman. A possible explanation for HSV oesophagitis during pregnancy is the decreased cellular immunity, leading to an increased frequency and severity of viral infections. Antiviral therapy is advocated in pregnancy.

Decrease in CD4+ T-cell counts in patients with multiple myeloma treated with bortezomib.

BACKGROUND: Bortezomib is highly effective in multiple myeloma and is widely used in this disease. Recently, an increased incidence of varicella zoster virus (VZV) reactivation was reported in patients with myeloma undergoing bortezomib treatment. PATIENTS AND METHODS: We investigated the influence of bortezomib on T-cell subpopulations in 53 patients with myeloma before initiation of bortezomib and during therapy. RESULTS: A decrease of CD4+ T cells was seen in 41 of 53 patients (77%). The median CD3+/CD4+ lymphocyte counts declined from 494/microL (range, 130-2187/microL) to 274/microL (range, 41-1404/microL) during bortezomib treatment (P < .001). In the majority of patients (40 of 53 patients, 75%), CD4+ lymphocytes dropped to < 400/microL during bortezomib treatment, and in 18 of 53 patients (33.9%) the CD4+ T cells fell below 200/microL. The minimum CD4S+ cell count was observed at a median of 6 weeks (range, 2-22 weeks) after initiation of treatment. The incidence of herpes zoster reactivation was 5.7% in the whole population of patients with myeloma receiving bortezomib. Nineteen of 53 patients received acyclovir at a dose of 400 mg daily as prophylaxis against VZV reactivation. In this group, none of the patients developed herpes zoster. The incidence of VZV reactivation in patients not receiving acyclovir was 3 of 34 (8.8%). Importantly, occurrence of herpes zoster was associated with reduced CD4+ T-cell subpopulation: all patients who developed herpes zoster had CD4+ lymphocytes < 400/microL. CONCLUSION: Our results show that bortezomib leads to a transient decrease in CD4+ lymphocytes, accompanied by an increased incidence of VZV infections. The antiviral prophylaxis with acyclovir is effective in patients with myeloma treated with bortezomib.

Aciclovir oral para profilaxis posexposición familiar a varicela / Oral acyclovir as family prophylaxis after exposure to varicella

Objetivo. Determinar si la varicela puede prevenir-se por la administración de aciclovir oral durante elperíodo de incubación de la enfermedad. Población, material y métodos. Se administró acicloviroral (20 o 40 mg/kg/día) durante cinco días a 26 niños expuestos a la enfermedad por contacto familiar, comenzando nueve días después del inicio clínico de la enfermedad en el hermano considerado como caso índice. La aparición de varicela clínica se comparó con doce pacientes que estuvieron expuestos a la enfermedad por contacto familiar, pero que no recibieron ningún tratamiento y constituyeron el grupo de control. Se evaluó a través de inmunofluorescencia indirecta el porcentaje de pacientes que presentó seroconversión luego de recibir tratamiento con aciclovir. Resultados. Ninguno de los 26 niños que recibieron aciclovir desarrolló enfermedad clínica, mientras que todos los que no recibieron tratamiento (12 casos) presentaron el exantema característico de la varicela. Del total de pacientes (26) que recibieron aciclovir, independientemente de la dosis adminis-trada, no concurrieron a control 7 (26,9%). De los 19 pacientes restantes, 17 hicieron seroconversión (89,5% intervalo de confianza 95%; 66,9 a 98,7%), mientras que 2 pacientes (10,5%) no la presentaron. Conclusiones. Los resultados obtenidos en este estudio demuestran la efectividad del aciclovir oral paraprevenir la aparición de varicela en los niños susceptibles expuestos a esta enfermedad por contacto familiar. Ninguno de los pacientes que en nuestra serie recibió tratamiento profiláctico con aciclovir (independientemente de la dosis administrada) desarrolló varicela clínica, mientras que el 89,5% de ellos (excluyendo los casos perdidos) tuvo evidencia serológica de infección por virus varicela-zóster.(AU)

Objective. To determine whether administration ofacyclovir during the incubation period of varicellacan prevent the development of disease. Population, material & methods. Oral acyclovir (20-40mg/kg/d) was administered during five days to 26 children, nine days after the initial exposure to a household contact with varicella. Development of clinical disease and seroconversion in this group of children were compared to a control group of 12 children exposed to varicella zoster virus who did not receive prophylactic acyclovir. The percentage of patients who presented seroconversion after receiving acyclovir was evaluated by immunofluores-cence.(AU)

Aciclovir oral para profilaxis posexposición familiar a varicela / Oral acyclovir as family prophylaxis after exposure to varicella

Objetivo. Determinar si la varicela puede prevenir-se por la administración de aciclovir oral durante elperíodo de incubación de la enfermedad. Población, material y métodos. Se administró acicloviroral (20 o 40 mg/kg/día) durante cinco días a 26 niños expuestos a la enfermedad por contacto familiar, comenzando nueve días después del inicio clínico de la enfermedad en el hermano considerado como caso índice. La aparición de varicela clínica se comparó con doce pacientes que estuvieron expuestos a la enfermedad por contacto familiar, pero que no recibieron ningún tratamiento y constituyeron el grupo de control. Se evaluó a través de inmunofluorescencia indirecta el porcentaje de pacientes que presentó seroconversión luego de recibir tratamiento con aciclovir. Resultados. Ninguno de los 26 niños que recibieron aciclovir desarrolló enfermedad clínica, mientras que todos los que no recibieron tratamiento (12 casos) presentaron el exantema característico de la varicela. Del total de pacientes (26) que recibieron aciclovir, independientemente de la dosis adminis-trada, no concurrieron a control 7 (26,9%). De los 19 pacientes restantes, 17 hicieron seroconversión (89,5% intervalo de confianza 95%; 66,9 a 98,7%), mientras que 2 pacientes (10,5%) no la presentaron. Conclusiones. Los resultados obtenidos en este estudio demuestran la efectividad del aciclovir oral paraprevenir la aparición de varicela en los niños susceptibles expuestos a esta enfermedad por contacto familiar. Ninguno de los pacientes que en nuestra serie recibió tratamiento profiláctico con aciclovir (independientemente de la dosis administrada) desarrolló varicela clínica, mientras que el 89,5% de ellos (excluyendo los casos perdidos) tuvo evidencia serológica de infección por virus varicela-zóster.

Objective. To determine whether administration ofacyclovir during the incubation period of varicellacan prevent the development of disease. Population, material & methods. Oral acyclovir (20-40mg/kg/d) was administered during five days to 26 children, nine days after the initial exposure to a household contact with varicella. Development of clinical disease and seroconversion in this group of children were compared to a control group of 12 children exposed to varicella zoster virus who did not receive prophylactic acyclovir. The percentage of patients who presented seroconversion after receiving acyclovir was evaluated by immunofluores-cence.

[Localized bullous eruption after intravenous injection of aciclovir: toxic or immunoallergic mechanism?]. / Eruption bulleuse localisée après injection intraveineuse d'aciclovir: mécanisme toxique ou immunoallergique?

OBJECTIVE: To report a case of bullous eruption at and far from the site of aciclovir injection. CASE REPORT: A 50-year-old man was treated with intravenous aciclovir for Herpes simplex meningoencephalitis. Ten days after treatment onset, blisters appeared on his right forearm, at and far from the site of aciclovir injection. DISCUSSION: This adverse effect has not been frequently reported. To date, bullous eruptions were considered to result from extravasation of the aciclovir solution. In this case, an immunoallergic pattern was discussed with the presence of a histological leukocytoclastic vasculitis.

Intravenous penciclovir for treatment of herpes simplex infections in immunocompromised patients: results of a multicenter, acyclovir-controlled trial. The Penciclovir Immunocompromised Study Group.

The efficacy and safety of penciclovir (PCV) for the treatment of herpes simplex virus (HSV) infections in immunocompromised (IC) patients were studied in a double-blind, acyclovir (ACV)-controlled, multicenter study. A total of 342 patients with mucocutaneous HSV infections received 5 mg of PCV per kg every 12 or 8 h (q12h or q8h) or 5 mg of ACV per kg q8h, beginning within 72 h of lesion onset and continuing for up to 7 days. The mean age of the patients was 49 years; 94% were white and 52% were female. The main reasons for their IC states were hematologic disorder (63%) and transplant plus hematologic disorder (16%). Clinical and virological assessments were performed daily during the 7-day treatment and then every other day until lesion healing. The primary efficacy parameter addressed new lesion formation. Secondary end points focused on viral shedding, healing, and pain. Approximately 20% of patients in each treatment group developed new lesions during therapy; thus, equivalence with ACV (defined prospectively) was demonstrated for both q12h and q8h PCV regimens. For all three treatment groups, the median time to the cessation of viral shedding was 4 days and the median time to complete healing was 8 days; there were no statistically significant differences in the rates of complete healing or the cessation of viral shedding when the results for PCV q12h and q8h were compared with those for ACV q8h. In addition, there was no statistically significant difference between PCV q12h or q8h, compared with ACV q8h, for the resolution of pain. PCV was well tolerated, with an adverse event profile comparable to that of ACV. In conclusion, PCV q12h is a well-tolerated and effective therapy for mucocutaneous HSV infection in IC patients and offers a reduced frequency of dosing compared with ACV q8h.

Profilaxis de la varicela con aciclovir en un hogar infantil

De mayo a julio de 1996 se le administró aciclovir, 20 mg/kg/día cada 6 horas por diez días a 29 niños, 4 a 9 días despues de exponerse al caso índice de varicela. Ninguno desarrolló la enfermedad. La mitad de 16 niños a los cuales se les hizo anticuerpos fueron negativos y por lo tanto susceptibles a la enfermedad. Por el contrario 16 (14.75 por ciento) de un grupo de niños expuestos a varicela en 1993, sin profilaxis desarrollaron la enfermedad (p<0.024). En conclusión el Aciclovir profiláctico es efectivo y puede ser una alternativa a la inmunogammaglobulina y a la vacuna en los lugares en que éstas no se consiguen fácilmente

Successful oral acyclovir desensitization.

A 65-year-old woman with the acquired immunodeficiency syndrome (AIDS) complicated by recurrent mucocutaneous herpes simplex virus (HSV) infection developed angioedema on the initiation of her second course of oral acyclovir therapy. Oral rechallenge in hospital three days later confirmed acyclovir hypersensitivity. Vidarabine and foscarnet therapies were abandoned after treatment failure and unacceptable toxicity. Acyclovir desensitization was accomplished using a protocol derived from oral penicillin desensitization regimens. Mucocutaneous HSV infection responded to intravenous acyclovir followed by chronic oral suppression without recurrences of HSV or hypersensitivity. This report is an example of acyclovir hypersensitivity and successful oral desensitization.

[Neonatal herpes: recurrence after treatment with acyclovir]. / Herpès néonatal: rechute après traitement par acyclovir.

A case of cutaneous herpes relapse with meningitis is reported in a 1.5 month-old infant treated during the first three weeks of life with acyclovir (ACV) for a neonatal herpes infection. Such a relapse has previously been described in older children as well as in adults. In this case report, there was immunological response to herpes virus infection, 2.5 months after the onset of the infection. The relapse is discussed taking into account the mechanism of action of ACV, the age of the patient and the immunological response profile. Because of the high risk of neurological involvement, we suggest that the relapse should be treated with ACV for a period of time longer than actually recommended.

Uptake of antitetanus F(ab')2 fragments into eukaryotic cells.

1. In order to introduce antitetanus immunoglobulin fragments into eukaryotic cells, either antitetanus F(ab')2 or Fab' fragments have been linked to carrier molecules. Aciclovir, horseradish peroxidase, wheat germ agglutinin, and transferrin were tried as carriers. 2. F(ab')2-aciclovir and Fab'-horseradish peroxidase were not internalized by NG108-15 neurohybridoma cells. 3. [Fab']2-wheat germ agglutinin and F(ab')2-transferrin conjugates were internalized into various cells. 4. F(ab')2-transferrin conjugates were made with three different linkers: N-succinimidyl 3-(2-pyridyldithio) propionate, bis-maleimido hexane, and bis-maleimidoethoxy propane. All three conjugates were internalized but had a different fate inside the cells.

Radioimmunoassay for desciclovir, 2-[(2-amino-9H-purin-9-yl)methoxy]ethanol, a prodrug for the antiviral acyclovir.

A direct radioimmunoassay for the detection of desciclovir (DCV)(2) in biological fluids has been developed. The radioimmunoassay was validated by comparing results obtained from human plasma samples analyzed by both this RIA and a gas chromatographic method. None of the crossreactivities noted interfere with the assay system. Although the succinylated antigen has a slightly higher affinity constant, the non-succinylated tritiated antigen was chosen for routine use. The assay is sensitive with an I50 value of 20 nM and with a lower limit of detection of about 3 nM. Intra-assay precision gave sample coefficients of variation which ranged from 2.2 to 9.6% for the standard curve with human plasma and from 2.0 to 8.2% for the standard curve with human urine. Inter-assay precision and accuracy were within acceptable limits.