The pattern of paediatric blast injury in Afghanistan.

INTRODUCTION: Between 2009 and 2015, 3746 children died, and 7904 were injured as a result of armed conflict within Afghanistan. Improvised explosive devices (IEDs) and explosive remnants of war accounted for 29% of child casualties in 2015. The aim of this study was to review the burden of paediatric blast injuries admitted to Camp Bastion, Afghanistan, and to investigate the hypothesis that children suffer proportionally more head injuries than adults. METHOD: A retrospective analysis was undertaken of prospectively collected data derived from the UK Joint Theatre Trauma Registry of ambulant paediatric (aged 2-15 years) admissions with blast injuries at the Role 3 Field Hospital, Camp Bastion from June 2006 to March 2013. The data set included demographic information, injury profile and severity (New Injury Severity Score) and operative findings. The pattern of injuries were investigated by looking at trends in the number and severity of injuries sustained by each body region. RESULTS: During this period, 295 admissions were identified, 76% of whom were male, with an overall mortality rate of 18.5%. The most common blast mechanism was an IED (68%) causing 80% of fatalities. The lower extremities were the most commonly injured body region, accounting for 31% of total injuries and occurring in 62% of cases. 24.3% of children between 2 and 7 years suffered severe head or neck injuries compared with 19.8% of children aged between 8 and 15 years. 34% of head injuries were rated unsurvivable and accounted for 88% of fatalities. 77% of cases required an operation with a mean operating time of 125 min. The most common first operations were debridement of soft tissues (50%), laparotomy (16%) and lower limb amputation (11%). CONCLUSION: Although paediatric blast casualties represented a small percentage of the overall workload at Camp Bastion Role 3 Medical Facility, the pattern of injuries seen suggests that children are more likely to sustain severe head, face and neck injuries than adults.

Valaciclovir versus aciclovir for herpes simplex virus infection in HIV-infected individuals: two randomized trials.

Our objective was to evaluate valaciclovir for anogenital herpes in HIV-infected individuals using 2 controlled trials conducted before highly active antiretroviral therapy (HAART) was used. In Study 1, 1062 patients (CD4+ > or = 100 cells/mm(3)) received suppressive valaciclovir or aciclovir for one year and were assessed monthly. In Study 2, 467 patients were treated episodically for > or =5 days with valaciclovir or aciclovir and evaluated daily. Valaciclovir was as effective as aciclovir for suppression and episodic treatment of herpes. Hazard ratios [95% confidence interval (CI)] for time to recurrence for valaciclovir 500 mg twice daily and 1000 mg once daily vs aciclovir were 0.73[0.50, 1.06], P=0.10, and 1.31[0.94, 1.82], P=0.11. Valaciclovir 500 mg twice daily was superior to 1000 mg once daily, P=0.001. Valaciclovir 1000 mg twice daily was comparable to aciclovir on herpes episode duration (hazard ratio 0.92[0.75, 1.14]). Adverse events were similar among treatments. In conclusion, valaciclovir is a safe, effective, convenient alternative to aciclovir for HSV infection in HIV-infected individuals.

Antiviral therapy for herpes zoster: randomized, controlled clinical trial of valacyclovir and famciclovir therapy in immunocompetent patients 50 years and older.

OBJECTIVE: To compare the efficacy and safety of valacyclovir hydrochloride and famciclovir for the treatment of herpes zoster. DESIGN: A double-blind, randomized, controlled, multicenter clinical trial in which patients received 7 days of treatment and were followed up for 24 weeks. SETTINGS: Patients reported directly to specialist centers or were referred from primary care centers. PATIENTS: There were 597 otherwise healthy immunocompetent outpatients, aged 50 years and older, who presented within 72 hours of onset of zoster rash. INTERVENTIONS: Treatment with valacyclovir hydrochloride (1 g 3 times daily) or famciclovir (500 mg 3 times daily) for 7 days. MAIN OUTCOME MEASURES: Resolution of zoster-associated pain and postherpetic neuralgia, rash healing, and treatment safety. RESULTS: Intent-to-treat analysis did not detect statistically significant differences for valacyclovir vs famciclovir on resolution of zoster-associated pain (hazard ratio, 1. 02; 95% confidence interval, 0.84-1.23; P =.84). Furthermore, no differences were evident between treatments on rash healing rates and on a range of analyses of postherpetic neuralgia. Safety profiles for valacyclovir and famciclovir were similar, with headache and nausea being the more common adverse events. CONCLUSIONS: Valacyclovir treatment is comparable to famciclovir treatment in speeding the resolution of zoster-associated pain and postherpetic neuralgia. Current wholesale prices indicate that valacyclovir is the more cost-effective treatment for herpes zoster ($83.90 vs $140.70 per course).

The identification of risk factors associated with persistent pain following herpes zoster.

Demographic and clinical characteristics of patients with herpes zoster at the time of presentation predict the duration and severity of pain on long-term follow-up. Analyses by Cox's proportional hazard models of six databases from controlled trials of antiviral drugs (total subjects = 2367) identified covariates for zoster-associated pain; all tests for significance were two-sided. Age strongly influenced pain outcome: patients > or = 50 years old were significantly more likely to have prolonged zoster-associated pain compared with those < 30 years old. Patients with prodromal symptoms or moderate or severe pain at presentation were also more likely to experience prolonged zoster-associated pain. Neither time to initiating treatment after rash onset nor sex of patient influenced pain outcome. Advancing age, prodromal symptoms, and acute pain severity at presentation predicted those individuals most at risk of prolonged pain and postherpetic neuralgia. When two or more of these factors were present, the risk of persistent pain was increased.

Treatment of acute herpes zoster: effect of early (< 48 h) versus late (48-72 h) therapy with acyclovir and valaciclovir on prolonged pain.

The efficacy of early versus late treatment with acyclovir and valaciclovir on zoster-associated pain was assessed from two databases (1076 patients) that were compiled from randomized trials. Early treatment was started < 48 h and late treatment was started 48-72 h after the onset of cutaneous herpes zoster. Median times to complete resolution of zoster-associated pain were 28 and 62 days, respectively, for patients (> or = 18 years of age) treated with acyclovir and placebo within 48 h (hazard ratio [HR], 1.68; 95% confidence limit [95% CL], 1.19, 2.38) and 28 and 58 days, respectively, for those treated later (HR, 2.20; 95% CL, 1.03, 4.71). In the valaciclovir versus acyclovir study (in patients > or = 50 years of age), the corresponding figures were 44 and 51 days for patients treated early (HR, 1.28; 95% CL, 1.03, 1.60) and 36 and 48 days for those treated later (HR, 1.40; 95% CL, 1.04, 1.87). Acyclovir significantly shortened the time to complete resolution of zoster-associated pain compared with placebo (and valaciclovir was superior to acyclovir in this regard) even when therapy was delayed up to 72 h after rash onset.

Valaciclovir versus aciclovir in patient initiated treatment of recurrent genital herpes: a randomised, double blind clinical trial. International Valaciclovir HSV Study Group.

OBJECTIVE: To compare the efficacy and safety of twice daily valaciclovir with five times daily aciclovir in the treatment of an episode of recurrent genital herpes simplex virus (HSV) infection in immunocompetent individuals. METHODS: 739 patients with a history of recurrent genital HSV infection received either oral valaciclovir (500 mg twice daily) or aciclovir (200 mg five times daily) for 5-days for treatment of their next recurrent episode in a controlled, randomised, double blind trial. Patients self initiated therapy at the first signs and/or symptoms of the HSV recurrence, then were assessed in clinic on five occasions over 7 days, and twice weekly thereafter until lesions had healed. Safety was evaluated through adverse experience reports and haematology and biochemistry monitoring. RESULTS: No significant differences were detected between valaciclovir and aciclovir for the primary endpoint, the duration of all signs and symptoms which included lesion healing and pain/discomfort. The hazard ratio [95% confidence interval] for valaciclovir v aciclovir was 0.93 [0.79, 1.08]. Lesion healing time was similar in each treatment group (hazard ratio valaciclovir v aciclovir 0.96 [0.80, 1.14]). The odds ratio of valaciclovir v aciclovir in preventing the development of vesicular/ulcerative lesions was 1.08 [0.82, 1.42]. Percentages of patients in whom all HSV cultures were negative were similar in the valaciclovir and aciclovir groups at 59% and 54% respectively; for patients having equal to or more than one positive culture result after treatment initiation, cessation of virus shedding was similarly rapid for the two treatments (hazard ratio 0.98 [0.75, 1.27]). The safety profiles of valaciclovir and aciclovir were comparable with adverse experiences being infrequent and generally mild. CONCLUSION: This study has demonstrated that valaciclovir 500 mg twice daily is equivalent in efficacy to aciclovir 200 mg five times daily as episodic treatment of recurrent genital HSV infection. Valaciclovir maintains the established efficacy and safety of aciclovir but offers a much more convenient twice daily dosing regimen.

Multiple dose netivudine, a potent anti-varicella zoster virus agent, in healthy elderly volunteers and patients with shingles.

Netivudine is a nucleoside analogue with potent anti-varicella zoster virus activity. We now report two open studies of the pharmacokinetics and tolerability of netivudine in doses of 50, 100 and 200 mg twice daily. In one study, healthy volunteers received an initial, single dose followed, a week later, by repeat dosing for 9 1/2 days; in the other, patients with shingles were treated for 8 days and data were also recorded for rash resolution and pain duration and intensity. Netivudine was well tolerated in both studies. Plasma concentrations were similar in patients and healthy volunteers and increased in proportion to dose. Steady state concentrations were 15-25% lower than expected from single dose data, probably because of slightly decreased netivudine absorption after food. Elimination half-life was l4-20 h. Plasma concentrations of 5-propynyluracil (5-PU), the main metabolite of netivudine, did not increase in proportion to the netivudine dose and tended to be higher in patients than volunteers. 5-PU concentrations remained elevated for up to 72 h after the last netivudine dose, suggesting continued but slow release from unabsorbed netivudine in the gut lumen. New lesion formation ceased and vesicles crusted most quickly in the 200 mg group; zoster-associated pain intensity, was reduced in a dose-related manner.

Preliminary pharmacokinetics and safety of 882C87 in patients with herpes zoster.

882C87 [1-(beta-D-arabinofuranosyl)-5-propynyluracil] is a nucleoside analogue with potent and specific antiviral activity against varicella-zoster virus (VZV). The IC50 of 882C87 against VZV ranges from 0.6 to 3.8 microM. Potentially therapeutic plasma concentrations are readily achieved in humans; the pharmacokinetics have been previously evaluated in healthy young and elderly (> 65 years) volunteers following single oral doses of 50-400 mg. Thirty immunocompetent patients with localised herpes zoster were treated with 882C87. Groups of patients received 50 mg, 100 mg, or 200 mg tablets of 882C87 every 12 hours for 7 or 7.5 days (14 or 15 doses). Six patients in each group were over 60 years of age. Blood samples for determination of 882C87 concentrations were taken at entry, steady state, and during the elimination phase following the last dose. After the final doses of the 50 mg 100 mg, and 200 mg dosage regimens, the Cmax of 882C87 in patients over 60 years old was 7.7 +/- 3.1 microM, 12.6 +/- 3.5 microM, and 24.8 +/- 14.0 microM, respectively, and the AUCs 0-12 were 78.4 +/- 31.8 microM.hr, 137.5 +/- 22.8 microM.hr, and 272.5 +/- 170.5 microM.hr, respectively. Preliminary estimates of the elimination half-life ranged from 15.1 to 20.0 hr. These preliminary pharmacokinetic data confirmed good dose proportionality for AUC and Cmax with values between those predicted from single dose data in the young and those in elderly volunteers. The plasma concentration profiles at these doses were in excess of IC50 values and support the use of once- or twice-daily regimens in future studies of 882C87 in herpes zoster.

Zoster-associated chronic pain: an overview of clinical trials with acyclovir.

An overview of all the available placebo-controlled trial data for oral acyclovir in acute herpes zoster infection has confirmed that a dose of 800 mg five times daily for seven to ten days is effective in reducing the incidence of post-herpetic neuralgia and the duration of pain. Although one study failed to demonstrate such an effect, three other studies and a combined analysis, using the log rank test, did so. The duration of pain was shortened from an average of 86 to 49 days (p less than 0.001). Future studies will need to take account of these findings since oral acyclovir is most likely to be used as the standard reference therapy.