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.

Clinical efficacy of high-dose acyclovir in patients with human immunodeficiency virus infection: a meta-analysis of randomized individual patient data.

A meta-analysis of 8 randomized trials (1792 patients, 2947 patient-years of follow-up) showed that acyclovir (> or = 3200 mg/day) offered a significant survival benefit (P = .006 by log-rank test) in human immunodeficiency virus (HIV) infection. The treatment effect did not vary significantly in patient subgroups of different CD4 cell counts, hemoglobin levels, age, race, and sex, and with or without AIDS diagnosis. Acyclovir treatment (hazard ratio, 0.78; 95% confidence interval [CI], 0.65-0.93), higher CD4 cell count (P < .001), higher hemoglobin level (P < .001), and younger age (P < .001) reduced the hazard of mortality. Acyclovir decreased herpes simplex virus infections (odds ratio [OR], 0.28; 95% CI, 0.21-0.37) and varicella-zoster virus infections (OR, 0.29; 95% CI, 0.13-0.63) but not cytomegalovirus disease or mortality from lymphoma or Kaposi's sarcoma. A survival advantage was seen specifically in studies with high incidence of clinical herpesvirus infections (> or = 25% per year). Given the wide confidence intervals, the small effect in low-risk patients, and recent changes in HIV therapeutics, the results should be interpreted cautiously, but the meta-analysis supports the importance of pathogenetic interactions between herpesviruses and HIV.

A randomized controlled trial of acyclovir versus netivudine for treatment of herpes zoster. International Zoster Study Group.

Oral acyclovir has become the standard of care for treatment of acute herpes zoster. Netivudine is a novel antiviral with greater in-vitro activity against varicella zoster virus. It was compared with acyclovir in a randomized, double-blind, controlled trial in immunocompetent adults with herpes zoster. Patients with rash for less than 72 h were assigned to receive either acyclovir or netivudine, then assessed regularly for 6 months. No evidence for a dose response with netivudine was found, so intent-to-treat analyses of all 511 enrolled patients compared acyclovir with netivudine. The time to complete cessation of pain (P = 0.007) and to cessation of moderate to excruciating pain (P = 0.005) was accelerated in acyclovir recipients. Rash outcomes and adverse event profiles were similar for both treatments. This study has confirmed the efficacy of acyclovir in decreasing the duration and severity of pain following herpes zoster. Greater in-vitro activity of newer agents may not necessarily provide greater benefit in humans.

Antiviral drugs in development for herpes zoster.

Until recently aciclovir has been the only licensed drug for the treatment of herpes zoster. A number of new drugs have emerged over the past few years which offered the potential for improved efficacy or ease of administration. With the completion of the first efficacy trials for each of these agents it has become apparent that, whilst less frequent dosing can he accomplished, it is not easy to significantly improve on the efficacy of aciclovir. Increasing age, the presence of prodromal pain and more severe pain at presentation have, however, been found to predispose to a longer duration of pain. Taking cessation of pain as the single most important parameter, at least for the older immunocompetent population as a whole, only valaciclovir has, to date, been shown to be superior to standard therapy with aciclovir. This review utilises primarily intent-to-treat data to illustrate the relative efficacy of the different therapies.

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.

Long-term zidovudine treatment of asymptomatic HIV-1-infected subjects.

Eighteen asymptomatic men with persistent human immunodeficiency virus type 1 (HIV-1) p24 antigenemia were treated with zidovudine 250-500 mg (+/- acyclovir 800 mg) 6-hourly for 4-12 weeks, and thereafter with zidovudine 500 mg (+/- acyclovir 1600 mg) 12-hourly for 92 weeks. Six additional HIV-1 p24 antigenemic subjects were treated with zidovudine 500 mg 12-hourly for 76 weeks. Disease progression occurred in 4 subjects, despite sustained reduction of serum HIV-1 p24 antigen levels: Pneumocystis carinii pneumonia was diagnosed after 60, 80, 90 and 93 weeks, respectively. The median CD4+ cell count of these 4 men at study entry was 0.2 x 10(9)/l, and it declined to 0.07 x 10(9)/l at the moment AIDS was diagnosed. In 20 subjects no disease progression occurred. The median CD4+ cell count of these 20 men at study entry was 0.4 x 10(9)/l and it was 0.45 x 10(9)/l at the end of the study period. Median serum HIV-1 p24 antigen levels at the end of the study period were 42% lower than at study entry in these 20 subjects. In 5/20 men, an initial decline was followed by a rise in antigen levels to above pretreatment value. Treatment with zidovudine was well tolerated. Anemia caused symptoms in 3/24 men, but prolonged leucopenia or neutropenia did not occur. None developed clinical or convincing biochemical evidence of zidovudine-associated myopathy.

The prophylactic role of intravenous and long-term oral acyclovir after allogeneic bone marrow transplantation.

Eighty-two patients were randomly allocated to receive intravenous acyclovir 5 mg kg-1 t.d.s. for 23 days followed by oral acyclovir 800 mg 6-hourly for 6 months or matching placebos after allogeneic bone marrow transplantation. Herpes simplex and varicella zoster virus infections were significantly reduced during the period of administration of acyclovir. No reduction in cytomegalovirus infection was demonstrated. The drug was not toxic.

Effect of zidovudine on serum human immunodeficiency virus antigen levels in symptom-free subjects.

18 men with longstanding human immunodeficiency virus (HIV) antigenaemia but no symptoms received zidovudine in low-dose regimens (250 mg 6-hourly, 500 mg 6-hourly, or 500 mg 12-hourly) with or without acyclovir. Serum HIV antigen rose in only 1 patient and declined significantly in 13 (to below cut-off values in 9). In the 1 subject from whom HIV antigen positive cerebrospinal fluid was obtained, the fluid was antigen negative after 12 weeks of treatment. Acyclovir treatment alone or in addition did not seem to influence serum antigen levels. In 7 untreated men serum antigen levels rose or remained stable during follow-up. CD4+ cell counts increased in 14/18 treated subjects and 1/7 untreated subjects. No disease progression was observed in either group. Regression of enlarged lymph nodes was seen in the zidovudine-treated subjects. Adverse reactions to the study drugs were infrequent and mild. Anaemia caused symptoms in 2, but serious leucopenia or neutropenia was not observed.

Prevention of herpes simplex virus infections in susceptible patients.

Immunocompromised patients are at high risk of developing herpes simplex virus infections caused by reactivation of the virus. Intravenous and oral formulations of acyclovir have been shown to prevent most of these infections during the major at-risk periods when given prophylactically. Immunocompetent patients may also experience reactivation of herpes simplex virus leading most often to recurrent genital or labial infections. For those patients who experience frequent attacks, oral acyclovir can prevent most recurrences and is well tolerated when given as continuous suppressive therapy.

Acyclovir in first attacks of genital herpes and prevention of recurrences.

Sixty women patients experiencing a first attack of genital herpes were randomly treated with either oral acyclovir for 42 days or oral acyclovir for five days followed by placebo for 37 days. The median time to the first recurrence in patients receiving acyclovir for 42 days was 66.5 days compared with 24 days in those who received acyclovir for only five days (p less than 0.0001). This significant difference, however, was only observed for the treatment period. The frequency of recurrences was also reduced during the period of treatment in those who received prolonged treatment. During the subsequent follow up period, however, patients in both groups had a similar frequency of recurrences. Patients with infections due to herpes simplex virus type I (HSV I) had a significantly longer time to the first recurrence (p less than 0.001) and fewer recurrences (p less than 0.001) than those infected with HSV II, irrespective of treatment.

A pilot study of BW A515U (6-deoxyacyclovir) in chronic hepatitis B virus infection.

BW A515U (6-Deoxyacyclovir) is a pro-drug of acyclovir and almost 100% is absorbed orally. 250 mg orally 6-hourly for 10 days was given to 4 hepatitis B surface antigen/e antigen-positive carriers. No consistent effect on productive viral replication, as determined by serum DNA polymerase and DNA levels was observed. The changes that occurred in these markers and transaminases in 1 patient were attributed to a spontaneous depression of productive viral replication.

Recurrent genital herpes suppressed by oral acyclovir: a multicentre double blind trial.

Eighty-eight of 111 patients with frequently recurring genital herpes attending five centres completed a randomized, double-blind, cross over trial with 200 mg oral acyclovir four times daily for 84 days before or after a similar course of placebo tablets. During the course of placebo 77 (88%) patients reported the development of lesions, four (5%) the development of symptoms and/or erythema but no further signs of a recurrence and seven (8%) remained entirely free of symptoms and signs. In contrast during acyclovir therapy only 11 (13%) patients reported lesions, a further 37 (42%) the development of symptoms and/or erythema only, while 40 (45%) patients remained entirely free of symptoms and signs. For each parameter the difference between active and placebo treatments was highly significant (P less than 0.001). Median times to recurrence after the end of both courses were similar. The drug was well tolerated and the findings indicate that continuous oral acyclovir therapy has a place in the management of frequent recurrences of genital herpes though the indications are not entirely clear. One possibility is the suppression of recurrence at times when it would be especially unwelcome such as during examinations or holidays.

Prophylactic oral acyclovir after renal transplantation.

In a double-blind, controlled study 35 herpes simplex virus (HSV) antibody-positive patients were randomized to receive oral acyclovir 200 mg X 4 daily or placebo for 28 days following renal transplantation. The incidence of herpes virus infection was compared in both groups by weekly virus demonstration/isolation testing from throat swabs and urine, and by serum antibody demonstration. None of the 18 patients allocated to acyclovir showed any signs of HSV or varicella zoster virus (VZV) infection during the trial period, whereas 9 of 17 receiving placebo had signs of HSV (P less than 0.001) and 2 of VZV (P less than 0.05) infection. Because of systemic as well as local symptoms of infection in five of the placebo patients, the trial was interrupted and treatment with oral acyclovir instituted. All of them responded well with rapid disappearance of all symptoms. Cytomegalovirus (CMV) was isolated from the urine of two patients in both groups during the trial period; a significant antibody rise was seen later in three of them. There was no evidence of drug-related toxicity during the study.

Present and future of acyclovir.

Acyclovir is now established as an effective and well tolerated therapeutic agent for the management of at least the more common infections of the herpes virus group. Evaluation of the drug nevertheless continues, primarily to verify its value in those infections caused by cytomegalovirus (CMV) and Epstein-Barr virus (EBV). Furthermore with the development of analogues of acyclovir with better absorption profiles or enhanced anti-viral activity the future for this area of anti-viral therapy looks optimistic.