9.1. Background
9.1.1. Epidemiology
Approximately 20% to 30% of the general population develop herpes zoster during their lifetime, and this figure rises to as high as 50% for those over 85 years of age (Brisson et al., 2001). HIV-infected patients are at higher risk of developing this condition than age-matched, HIV-uninfected individuals. The overall incidence of herpes zoster in HIV-infected persons is around 30 per 1000 person-years (Buchbinder et al., 1992). In contrast, the overall incidence of herpes zoster in the general population is about 1.5 to 3.0 cases per 1000 persons (Donahue et al., 1995; Ragozzino et al., 1982). This difference is seen even in the paediatric age group, with <1 case per 1000 person-years in the general population (Civen et al., 2009) as compared to 10 cases per 1000 person-years in the HIV-infected population (Gona et al., 2006). Herpes zoster may occur at any time in the course of HIV-induced immunosuppression, and may be the first clinical clue to suggest undiagnosed HIV infection. Recurrent episodes of herpes zoster may occur in HIV-infected patients, and appear to be more common than in the HIV-uninfected population (Buchbinder et al., 1992).
9.1.2. Pathogenesis and clinical features
Primary infection with varicella zoster virus (also known as chickenpox) results in viral latency in dorsal root, cranial and autonomic system ganglia. Reactivation of the varicella virus, due to decreased cellular immunity,often associated with ageing, chemotherapy or immunosuppression, results in herpes zoster infection, also known as shingles. Herpes zoster manifests as painful cutaneous eruptions of clusters of vesicles over an erythematous base distributed over a single dermatome or two or more contiguous dermatomes; they are invariably unilateral and do not cross the midline. Rarely the rash of herpes zoster can be more widespread and affect three or more dermatomes. This condition is called disseminated zoster, which can be difficult to distinguish from varicella. It generally occurs only in people with compromised immune systems.
9.2. Recommendations
For all HIV-infected children, adolescents and adults (including pregnant women) with herpes zoster, acyclovir is recommended to prevent dissemination and for resolution of disease (at any time in the course of the disease).
(Strong recommendation, low quality evidence)
All children, adolescents and adults presenting with herpes zoster with unknown HIV status should be offered an HIV test and, if positive, assessed for ART eligibility.
(Strong recommendation, low quality evidence)
Remarks
Acyclovir, famciclovir and valaciclovir are all effective in the treatment of herpes zoster. Acyclovir is specifically listed due to its inclusion on the WHO Model list of essential medicines.a
Famciclovir and valaciclovir are acceptable alternatives when available. Relevant drug interactions are described in
ANNEX 2.
These recommendations apply to HIV-negative children and adults as well.
9.3. Review question and summary of evidence
The review question was: among children and adults living with HIV infection (with and without ART) (P), what is the effectiveness of antivirals (acyclovir, valaciclovir, famciclovir or brivudin) for management of herpes zoster (I) comparing one with the other (C) in resolution of lesions and the time to resolution of lesions (O)?
Acyclovir
In the systematic review by Stephen and colleagues done for these guidelines (in preparation), 13 relevant studies were identified. In five studies (Balfour et al., 1983; Bean et al., 1982; McGill et al., 1983; McKendrick et al., 1984; McKendrick et al., 1986) the time to cessation of new lesions was observed in 200 subjects on acyclovir and 206 subjects on placebo. There was significant beneficial effect (earlier stoppage of new lesions) in subjects on acyclovir (hazard ratio [HR] 0.65; 95% CI 0.51 to 0.83). There was very low heterogeneity between studies (I2=18%). All studies tended to show a beneficial effect of acyclovir, although only two were statistically significant.
Two studies (van den Broek et al., 1984; Wassilew et al., 1987) reported mean time to cessation of new lesions, with a mean difference of 0.59 days (95% CI -1.11 to -0.89), i.e. half a day earlier in the acyclovir group. The numbers examined were 55 in the acyclovir and 53 in the placebo group. Wassilew and colleagues (1987) also reported mean time to healing of lesions, with a mean difference of 7.4 days (95% CI -15.78 to 0.98) which was not significant. There were 29 individuals in each group.
Time to lesion healing was examined in three studies (McKendrick et al., 1984; McKendrick et al., 1986; McGill et al., 1983). Analysis of 135 subjects in the acyclovir and 148 in the placebo group demonstrated a significant beneficial effect of acyclovir (HR 1.48; 95% CI 1.06 to 2.05). There was very low heterogeneity between studies (I2=20%). All studies tended to show a beneficial effect of acyclovir, although only one study was statistically significant.
Famciclovir
Time to lesion healing was examined in three studies (Shen et al., 2004; Degreef & Famciclovir Herpes Zoster Clinical Study Group, 1994; Tyring et al., 2001). Analysis of 275 subjects in the famciclovir and 294 in the acyclovir group did not demonstrate a significant beneficial effect of famciclovir over acyclovir (HR 1.18; 95% CI 0.98 to 1.41). There was negligible heterogeneity between studies. All studies tended to show a beneficial effect of famciclovir, although none was statistically significant.
Valacyclovir
Analysis of time to cessation of new lesions was only possible in one study (Beutner et al., 1995) with 384 and 375 subjects examined in the valacyclovir and acyclovir groups respectively. However, the difference was not significant (HR 1.03; 95% CI 0.89 to 1.20).
Time to lesion healing was examined in two studies (Beutner et al., 1995; Raju et al., 2011). Analysis of 414 subjects in the valacyclovir and 406 in the acyclovir group did not demonstrate a significant beneficial effect of valacyclovir over acyclovir (HR 1.01; 95% CI 0.88 to 1.16). There was negligible heterogeneity between studies. All studies tended to show a beneficial effect of valacyclovir, although none was statistically significant.
9.4. Rationale for recommendations
Acyclovir, famciclovir and valaciclovir are all effective in the treatment of herpes zoster, in decreasing the time to cessation of new lesions and also in decreasing the time to total healing of rash. Resolution of herpes zoster is accelerated with any of the following: oral acyclovir 800 mg five times daily for seven days; valacyclovir 1000 mg three times daily for seven days; or famciclovir 750 mg once daily, 500 mg twice daily, or 250 mg three times daily for seven days. Although most studies tended to show a beneficial effect for famciclovir and valacyclovir over acyclovir, none was statistically significant.
Although there are no RCTs in children, the generally accepted optimal initial therapy for immunocompromised children with herpes zoster is 80 mg/kg per day by mouth (20 mg/kg four times per day, maximum of 800 mg per dose) or in severe infections intravenous acyclovir 500 mg/m2 per dose or 10 mg/kg per dose, given intravenously every eight hours. The duration of therapy is seven days, or two days after the cessation of the formation of new lesions (Arvin, 2002).
Adverse effects, costs, availability and other implementation considerations
The safety profiles of acyclovir, valacyclovir and famcyclovir are similar, with headaches and nausea/vomiting the most frequent adverse effects. Caution is required when acyclovir is given to a patient on tenofovir as acyclovir has been incriminated in increasing renal impairment, in particular when intravenous acyclovir and tenofovir are administered in the same patient.
All three drugs are equally effective. However, acyclovir is more likely to be available in low- or medium-resource countries, and it costs much less than the other newer drugs (see ANNEX 3). Valacyclovir and famcyclovir offer a simpler dosing schedule than acyclovir. Choosing between these two drugs depends on the patient’s compliance and on the physician’s habits.
Based on the quality of evidence, the magnitude of effect, balance of benefits versus disadvantages, availability, cost and feasibility, the strength of the recommendation of acyclovir for the treatment of herpes zoster in HIV-infected children and adults is categorized as strong with low quality evidence.
9.5. Research gaps
Areas of needed research identified include:
Evaluation of different doses of acyclovir treatment, in the HIV-infected and general populations;
Use of other antivirals against varicella with improved bioavailability (i.e. valaciclovir and famciclovir) in paediatric populations.
