Short-course intravenous aciclovir treatment for cutaneous herpes zoster in patients with HIV infection

INTRODUCTION

Herpes zoster (HZ) often accompanies declining cell-mediated immunity and immune suppression. HIV infection is strongly associated with cutaneous HZ. Incidence rates of cutaneous HZ in patients with HIV infection are 29–52 cases/1000 person-years, which are 15–25 times greater than the incidence rates in the general population. ¹

Since the early 1990s, our unit has treated cutaneous HZ in patients with HIV infection with three days of intravenous aciclovir at a dose of 250 or 500 mg eight hourly. ² The course is extended by one to two days if new vesicles continue to develop on day 3 of treatment. The use of intravenous rather than oral aciclovir reflected our concerns about the efficacy of oral aciclovir in this clinical context and the decision of New Zealand's medicine regulatory authorities not to fund oral valaciclovir or famciclovir for cutaneous HZ, when they became available.

The aim of this study was to review our treatment of cutaneous HZ treated with intravenous aciclovir alone for three days in adults with HIV infection.

MATERIALS AND METHODS

We reviewed the medical records of all adult patients with HIV infection admitted to Auckland City Hospital with cutaneous HZ in the 15-year period from January 1995 to December 2009.

The following definitions were used: localized cutaneous HZ was vesicles limited to contiguous dermatomes with fewer than 20 vesicles outside those dermatomes; ³ disseminated cutaneous HZ was 20 or more vesicles occurring outside those dermatomes; ³ early relapse was a further episode of HZ that began within eight weeks of stopping intravenous aciclovir treatment and late relapse a further episode of HZ that began more than eight weeks after stopping intravenous aciclovir treatment; postherpetic neuralgia was pain persisting for greater than one month after healing of cutaneous HZ. ⁴

We excluded patients with extracutaneous HZ and patients who received oral aciclovir before or after the course of intravenous aciclovir.

In the absence of a clinically established optimal dose of intravenous aciclovir for this indication, we elected to use standard vial doses, of either 250 mg for lighter patients or 500 mg for heavier patients.

This study received approval from the Northern X Regional Ethics Committee.

RESULTS

Seventy patients received intravenous aciclovir during the 15-year review period. We excluded 19 patients who received oral aciclovir in addition to intravenous aciclovir; 14 received oral aciclovir before admission to hospital and five received oral aciclovir following intravenous aciclovir. The remaining 51 patients are the subjects of this case series. The clinical diagnosis was made by one of seven infectious disease physicians.

Forty-six patients were men and five were women. The median age was 40 (range 23–69) years. Self-reported ethnicity was New Zealand European (n = 21), Maori (n = 7), south-east Asian (n = 7), Pacific Island person (n = 6), African (n = 5) and other (n = 5).

The median CD4 count taken during the episode or within the last six months was 297 (range 10–703) cells/mm.³ Thirty-one patients were receiving a three-agent antiretroviral regimen. Two patients started a similar regimen at the time of this episode.

Forty-four patients had localized cutaneous HZ and seven patients had disseminated cutaneous HZ. The median duration of vesicular rash prior to admission, recorded for 41 patients, was two (range 1–8) days.

Patients received a median of nine (range 3–17) doses of intravenous aciclovir given eight-hourly. Those with localized cutaneous HZ received a median of nine (range 3–17) doses and those with disseminated cutaneous HZ received a median of 10 (range 9–15) doses of intravenous aciclovir.

In nine patients, new vesicles developed after starting intravenous aciclovir; in five, the final day that new vesicles developed was day 1, and in four, day 2 of intravenous aciclovir treatment. No patient progressed to disseminated or extracutaneous disease during treatment.

The median weight, recorded for 43 patients on admission or within the last six months, was 77.6 (range 49.8–119.5) kg. The median dose of intravenous aciclovir for these patients was 6.5 (range 2.9–10.8) mg/kg.

Patients were followed for a median of 24 (range 1–165) months. Five patients had more than one episode of cutaneous HZ during the review period. One patient relapsed early with disseminated cutaneous HZ, three days after intravenous aciclovir treatment finished. His CD4 count was 10 cells/mm³, he weighed 50 kg and received nine doses of intravenous aciclovir 250 mg (5 mg/kg) eight-hourly for localized cutaneous HZ. No new vesicles developed during treatment of the initial episode of cutaneous HZ. After retreatment, he did not relapse during the following 83 months. Four patients relapsed late a median of 9.5 (range 4–15) months after treatment of the initial episode of cutaneous HZ. Seven patients (13.7%) developed postherpetic neuralgia. Seven patients (13.7%) died; no deaths were related to HZ.

The five patients excluded because they received oral aciclovir following intravenous aciclovir received a median of 11 (range 7–16) doses of intravenous aciclovir at a median dose of 5.1 (range 2.9–15.6) mg/kg, then a median of five (range 1–7) days of oral aciclovir. All five patients had localized cutaneous HZ and no new vesicles developed on treatment.

DISCUSSION

Our results suggest that intravenous aciclovir treatment at a median dose of 6.5 mg/kg for three days is as effective as longer treatment durations and/or higher doses widely recommended for prevention of local progression, dissemination and early relapse of cutaneous HZ in patients with HIV infection. ^5,6

The most important weakness of this study evaluating treatment duration is that five patients who received oral aciclovir after intravenous aciclovir were excluded. However, these patients represent only 10% of the studied cohort and within the constraints of this retrospective evaluation, they did not differ in any definable way from the remainder of the cohort studied.

Published guidelines recommend that HIV-infected patients with localized cutaneous HZ should be treated with oral valaciclovir, famciclovir or aciclovir for 7–10 days and those with extensive or severe cutaneous HZ should be treated with intravenous aciclovir at a dose of 10–15 mg/kg eight-hourly followed by oral valaciclovir, famciclovir or aciclovir for 10–14 days or until all lesions are cleared. ^5,6 There are no comparative clinical studies of treatment duration of cutaneous HZ in patients with HIV infection or in any other group of immunocompromised patients. One study assessing treatment duration of cutaneous HZ in immunocompetent patients over 50 years of age showed that 14 days treatment conferred no benefits over seven days treatment using either valaciclovir at a dose of 1000 mg three times daily or aciclovir at a dose of 800 mg five times daily. ⁷

Varicella zoster virus (VZV) can be cultured from vesicles only up to 24 hours after new vesicle formation has stopped in intravenous aciclovir-treated immunocompetent and immunocompromised patients. ^8,9 The risk of dissemination would end at this time point; therefore, there seems no reason to continue antivirals for more than 24 hours after new vesicle formation has stopped. It was our intention to extend the treatment duration in patients who continued to develop new vesicles on day 3 of treatment but no patient in this study developed new vesicles after day 2 of intravenous aciclovir.

If early relapse occurred at increased frequency with shorter courses of treatment, it too would argue for longer treatment duration; however, only one patient (2%) in this study relapsed early with cutaneous HZ three days after the treatment of the initial episode finished, and he had the lowest CD4 count in our patient group. Our data therefore support the safety of shorter treatment durations.

Late relapse is a feature of the epidemiology of cutaneous HZ in patients with HIV infection. The treatment duration of an episode of cutaneous HZ, whether this is three or seven to 14 days, seems unlikely to alter the natural history of late relapses of cutaneous HZ, years or even months later for this latent virus infection. Thus, the frequency of late relapses does not seem to be a logical measure of potential failure in the evaluation of treatment duration for cutaneous HZ.

Seven patients (13.7%) developed postherpetic neuralgia in our study compared with a similar 18% in a retrospective study of HIV-infected patients published in the combination antiretroviral therapy era. ¹⁰

Inhibitory concentrations of aciclovir for VZV isolates lie between 0.12 and 5.2 mg/L. ^11–13 Oral aciclovir given at 800 mg five times daily results in mean peak plasma concentrations of only 1.6 mg/L, whereas intravenous aciclovir administered at 5 and 10 mg/kg gives mean peak plasma concentrations of 9.8 and 20.7 mg/L, respectively. ¹¹ These data argue against oral aciclovir for cutaneous HZ in the immunocompromised but do support the use of intravenous aciclovir at 5 mg/kg, rather than at 10 mg/kg, as an effective dose for the treatment of cutaneous HZ in any patient. Oral valaciclovir, the prodrug of aciclovir, at a dose of 1000 mg three times daily produces similar peak and trough levels and total daily exposure to aciclovir as intravenous aciclovir 5 mg/kg eight-hourly. ¹⁴

It is not our intention to suggest that intravenous aciclovir at a dose of 5 mg/kg (or 6.5 mg/kg as we actually used) eight hourly for three days needs to be used routinely to treat cutaneous HZ in patients with HIV infection. We would argue that oral valaciclovir 1000 mg three times daily for three days would, on the basis of pharmacokinetic data, ¹⁴ be as effective as our intravenous aciclovir regimen for three days. Clearly, a blanket advisory suggestion to ‘complete a 10- to 14-day course’, or to continue ‘until all lesions are cleared’ ‘for severe cutaneous disease’, while driven by concerns about local progression, dissemination and possible visceral involvement, will be excessive for nearly all patients.

In summary, we need prospective studies evaluating shorter treatment durations of antiviral drugs for cutaneous HZ in patients with HIV infection, other immunocompromised patients and, of course, in the immunocompetent. Our results suggest that intravenous aciclovir for three days is as effective as the widely recommended longer treatment durations for cutaneous HZ in patients with HIV infection. The importance of shorter treatment durations of antimicrobials to slow down the spread of antimicrobial resistance has recently been highlighted. ^15,16 We also suggest that the widely recommended dose of intravenous aciclovir of 10–15 mg/kg eight-hourly for the treatment of severe cutaneous HZ in patients with HIV infection is unnecessarily high: it has certainly never been properly clinically evaluated. If shorter treatment durations of antivirals (and lower doses of intravenous aciclovir) were shown to be of equal efficacy in proper trials, then the benefits in terms of compliance, adverse effects and costs for both immunocompetent and immunocompromised patients are obvious.

DECLARATION

There were no sources of funding for this research. There is no potential conflict of interest related to this submission.