The incidence of herpes zoster in the general population is 1.5 to 3 per 1000, and it occurs 8 to 10 times more frequently in patients aged 60 years and older than in those aged less than 60 years.1-4 HIV patients have been noted to have much higher zoster incidence rates (up to 10 times higher) than the general population.5-7 Before the introduction of highly active antiretroviral therapy (HAART), these reported rates ranged between 29.4 and 51.5 per 1000 person-years (PYs).6,7 The immune deterioration associated with progression of the disease may mimic the age-associated immunosenescence observed in the elderly population8 and may explain the increased zoster incidence noted in the HIV population.
Previous studies have suggested that HIV patients manifest uniquely dramatic and protracted herpes zoster infections compared with the immunocompetent host.9 HIV patients tend to have recurrent zoster episodes, multidermatomal involvement, and even systemic disease. Before HAART, the incidence of post-herpetic neuralgia (PHN) in HIV patients was the same compared with the general population but was remarkable, considering the much younger age of the patients.10 Other complications such as ocular involvement, bacterial superinfection, myelitis, meningitis, and chronic atypical skin lesions have also been reported to be higher in patients with advanced HIV disease.10
Since HAART became the standard of care in 1996, many changes have been observed in the HIV epidemic that may be expected to have an impact on the incidence of herpes zoster in this population. Patients with HIV are living longer and may be more susceptible to developing zoster through natural cell-mediated decline associated with aging. The impact of HAART on the incidence of herpes zoster in HIV patients is not fully understood. There are few reliable estimates of the current incidence of zoster in the HAART era, although a recent study in HIV-positive women demonstrated an increased risk of herpes zoster in women with decreasing CD4 counts.5 The following study aims to describe the incidence and clinical characteristics of herpes zoster in the HIV-infected host, to delineate risk factors for initial zoster further, and to evaluate the risk of developing complications from zoster in the current era of HAART.
Patient and Data Collection
The Johns Hopkins University AIDS Service provides comprehensive primary and subspecialty care for HIV-infected patients. At the time of registration in the clinic, patients undergo an evaluation by a physician or physician's assistant and a social worker. The clinic-based medical record maintains information on all confirmed medical and surgical diagnoses, hospitalizations, and laboratory information as well as a section for each visit to document prescribed therapy by treatment name, dose, and number of refills. The records are also updated when prescriptions are filled over the telephone or mailed to patients.
An observational database has been maintained on clinic patients to obtain extensive information about patients followed in our clinic. Trained monitors use structured data collection forms to extract extensive demographic, clinical, laboratory, pharmaceutic, and psychosocial data as well as death information from patient charts and from the hospital's automated databases at baseline and every 6 months thereafter. Maintenance of our database and use of its contents for analysis of patient outcomes are approved by the Institutional Review Board of the Johns Hopkins University School of Medicine. Patients receiving longitudinal primary HIV care who were enrolled in our clinic were eligible for inclusion in our analysis.
For this study, we identified all new cases of zoster diagnosed between January 1, 1997 and December 31, 2001. Charts were systematically reviewed by one of the authors (RK). The clinical characteristics and sequelae of all new occurrences of zoster and the CD4 cell count and HIV-1 RNA load at the time of the occurrence of zoster or within 3 months were recorded.
For our analysis, HIV transmission risk factors included injection drug use (IDU), men who have sex with men (MSM), and heterosexual transmission, which was defined as heterosexual activity with a partner at high risk for HIV or sex with an HIV-infected individual. Risk factor assignment was not mutually exclusive because patients could have multiple HIV risk factors. HAART was defined as (1) 3 or more nucleosides; (2) any use of 1 or more protease inhibitors (PIs) or a nonnucleoside reverse transcriptase inhibitor (RTI) in combination with 2 or more nucleoside RTIs; or (3) a PI, nonnucleoside RTI, or nucleoside RTI combination. Patients were considered to be on HAART if they received any of these combinations. Immune reconstruction was defined as an increase in CD4 count of at least 50 cells/mm3 over the CD4 nadir since on HAART therapy. Time on HAART was defined as the amount of time between HAART initiation and date of presentation of a zoster event. HAART initiated within 90 days of a zoster event was considered a recent start. AIDS diagnosis was defined by a prior AIDS-defining illness based on 1993 Centers for Disease Control and Prevention (CDC) criteria, including a CD4 count less than 200 cells/mm3. HIV-1 RNA levels were dichotomized to <10,000 and ≥10,000 copies/mL.
Complicated zoster was defined as the occurrence of 1 or more of the following conditions: an ocular, visceral, or neurologic complication consistent with zoster and not attributable to another pathologic process or a recurrent zoster episode within 180 days of an initial zoster diagnosis. PHN was defined as pain for longer than 4 weeks after the resolution of skin lesions.11,12
Statistical analyses were performed using Stata 8.0 (Stata Corporation, College Station, TX). The mean and standard deviation were used for describing normally distributed data, whereas the median and interquartile ranges were used for describing nonparametric data. If there was a normal distribution, continuous variables were analyzed with the Student t test; the Wilcoxon rank-sum test was used for analysis of nonparametric data. Categoric variables were analyzed with the Fisher exact test.
Poisson regression was used to compare rates of herpes zoster and complicated zoster across time. A nested case-control analysis was used to assess factors associated with an initial episode of herpes zoster. Four controls without a history of herpes zoster were randomly selected from the overall cohort for each case. Controls were matched on cohort enrollment date and duration of follow-up. Multivariate conditional logistic regression analyses were used to assess risk factors for an initial episode of zoster.
Logistic regression was used for determining predictors of complicated zoster. Separate univariate regression analyses were performed to identify individual variables associated with the development of complicated zoster (P < 0.05). Possible interactions between pairs of significant variables were tested by combining variables in the logistic regression. There were no significant interactions between the demographic characteristics of race, age, or gender and HIV risk factor.
Variables reaching statistical significance at the 0.20 level in univariate analyses were included in the final multivariate regressions using stepwise procedures. All reported P values are 2-tailed.
Between January 1997 and December 2001, 2543 patients were followed for a total of 8777 PYs of follow-up. Two hundred ninety-one events occurred in 248 patients during the study period. Nine patients who had a documented episode of zoster noted in their medical records but no documentation of the actual zoster at the time it occurred were excluded from the analysis because related clinical characteristics could not be assessed. The remaining 282 episodes of herpes zoster occurred in 239 patients during the study interval and were used for the following analysis. Of these, 124 were recurrent zoster events and 158 were incident cases. The incidence of zoster over the entire study period was 3.2 per 100 PYs of follow-up.
Among incident cases, most patients were male (63%) and African American (77%) and had IDU as their HIV risk factor (49%) (Table 1). The mean patient age was 41 years (range: 23-58 years). These demographics are similar to those of the entire clinic population. More than 60% of patients used tobacco, approximately half had used alcohol, and more than 40% had used illicit drugs in the month before zoster occurrence.
The study population had advanced HIV disease, with 66% of patients being AIDS defined. Of the 158 patients, 11 had no documented CD4 cell count and 12 had no documented HIV-1 RNA level within 3 months of a zoster event. Among the remaining patients, the median CD4 count at a zoster event was 218 cells/mm3 and the median HIV-1 RNA level was 2251 copies/mL. Thirty-five patients (24%) had HIV-1 RNA loads less than 400 copies/mL, and 12 patients (8%) had HIV-1 RNA loads less than 50 copies/mL.
One hundred patients (63%) were on HAART at a zoster event for a median of 517 days (range: 22-1727 days). Thirteen patients started HAART within 90 days of a zoster event. Five patients who were seen at an outside hospital for their zoster had unknown dermatomal involvement. Among the remaining patients, two thirds had single dermatomal involvement and the thoracic dermatome was the most commonly involved site, affecting 41% of patients. Fifty patients (33%) had multidermatomal involvement, and 14 patients (9%) had involvement of 3 or more dermatomes.
One hundred thirteen patients (72%) had a comorbid condition. The most prevalent comorbidities in the study population included depression (43%), hepatitis C virus (37%), and hepatitis B virus (9%). We were unable to obtain the records of 7 patients who were treated at an outside hospital for their zoster event. Among the remaining 151 cases, 93% of patients were prescribed an antiviral drug for zoster infection. The remaining 18 patients presented to the clinic after rash healing, and therefore were given symptomatic or no treatment. Valacyclovir was the most commonly prescribed medication, with 52% of patients receiving this medication. Thirty-six patients (23%) were hospitalized for zoster; of these, 33 patients (22%) were treated with intravenous acyclovir.
In the case-control analysis, risk factors for an initial herpes zoster outbreak included use of HAART at the herpes zoster outbreak (OR = 2.39, 95% CI: 1.65 to 3.49) and a CD4 count of 50 to 200 cells/mm3 (OR = 2.69, 95% CI: 1.44 to 5.01) at the zoster outbreak compared with a CD4 count less than 50 cells/mm3 (Table 2). The incidence of zoster in patients with a CD4 count greater than 200 cells/mm3 was not significantly different than in those with a CD4 count less than 50 cells/mm3. In multivariate regression, CD4 cell count and HAART use remained significant predictors of zoster outbreak. Age, race, HIV risk factor, HIV-1 RNA level, income, and insurance were not associated with a zoster outbreak.
Among incident zoster cases, 51 patients (32%) experienced 59 complications. PHN was the most common complication, affecting 18% of patients, which is greater than previously reported in HIV-negative patients in the Rochester Minnesota Cohort (1945-1959)1 or the Harvard Pilgrim Health Care Cohort (1990-1992) (Table 3).13 Twenty-three patients had other complications, including ocular involvement, and 6 additional patients had PHN as well as another complication as follows: ocular involvement (2 patients), bacterial superinfection (2 patients), zoster recurrence within 6 months of a zoster event (1 patient), meningitis (1 patient), and Ramsay-Hunt syndrome (1 patient). Sixteen patients (10%) had herpes zoster ophthalmicus, and 10 patients (6%) had other ocular complications. Again, the incidence of these complications was greater than for either of the previously reported HIV-negative cohorts. The incidence of complicated zoster in this study did not change between 1997 and 2001. Eight patients experienced recurrent zoster within 6 months. Forty-four patients experienced complications within 60 days of a zoster event, resulting in a 60-day zoster complication risk of 27.8%. Seven patients experienced zoster recurrence between 60 and 180 days of an initial zoster event.
In univariate analysis, the HIV risk factors of MSM (OR = 0.69, 95% CI: 0.50 to 0.95) and being on HAART at the time of a zoster event (OR = 0.46, 95% CI: 0.23 to 0.92) were protective for complicated zoster. There was a trend for African-American race (OR = 2.34, 95% CI: 0.95 to 5.77) and an HIV-1 RNA level greater than 10,000 copies/mL to be associated with complicated zoster (OR = 2.16, 95% CI: 0.93 to 5.05). All other variables evaluated, including age, gender, CD4 cell count, time on HAART, recent start of HAART, immune reconstruction, location and number of dermatomes involved, and type and route of antiviral treatment, were not associated with complicated zoster.
In multivariate analysis, patients being on HAART (adjusted odds ratio [AOR] = 0.52, 95% CI: 0.26 to 1.04) and with MSM status (AOR = 0.72, 95% CI: 0.52 to 0.99) were less likely to develop complicated zoster than those not on HAART or those with other HIV risk factors (Table 4).
This study has several important findings. First, the incidence rate of herpes zoster among our urban cohort of HIV patients, 3.2 per 100 PYs of follow-up, is unchanged from the pre-HAART era10 and is nearly 10 times the incidence of 3.4 per 1000 PYs reported by Hope-Simpson4 in the general population. Also, patients on HAART and those with CD4 counts between 50 and 200 cells/mm3 seemed to be at the highest risk of a herpes zoster event. Finally, the complication rate among incident cases, particularly of PHN, was markedly higher than would be expected in an HIV-negative population of similar age.
Incidence and Risk Factors for Zoster
The incidence of zoster in the HAART era has not been well described, although our incidence is the same as that of a previously reported study in the pre-HAART era.10 The 10-fold increased of risk of zoster among HIV-negative and HIV-infected patients is consistent with several other studies.5-7 These data are consistent with those of others who have shown a constant incidence of some neurologic complications of HIV14 but a decreasing incidence of other HIV neurologic opportunistic infections, particularly cytomegalovirus (CMV), in the HAART era as compared with the pre-HAART era.
Studies evaluating the association between CD4 cell count and risk of zoster have yielded mixed results. Two previous studies5,7 demonstrated an increased risk with a decreasing CD4 cell count. In contrast, a study in MSM in San Francisco and a study in Uganda demonstrated no association between zoster and duration of HIV, which presumably reflects a decreasing CD4 cell count.6,15 In our report, the highest risk of zoster was in patients with a CD4 count between 50 and 200 cells/mm3, suggesting that moderate degrees of immunodeficiency puts patients at an increased risk of zoster, whereas profound immunodeficiency does not. This may signify that unlike other opportunistic illnesses such as Pneumocystis jiroveci (PCP) pneumonia or CMV that occur with profound immunosuppression, herpes zoster occurs in patients with immunodysregulation. Potentially consistent with this is the result of HAART being a risk factor for an initial zoster episode. A similar finding was reported in 2 smaller studies16,17 and might indicate that the improved immune function associated with HAART places patients at increased risk. The increased risk of zoster with recent initiation of HAART was thought to be attributable to an increase in CD8 cell count.16,17 In our study, there was no association with an increased risk of zoster or complicated zoster with a recent start of HAART, defined as within 90 days of the zoster period; however, we did not have information on CD8 count at time of the zoster outbreak. Of note, HIV-1 RNA load was not found to be associated with an increased risk of a zoster episode.
A broad spectrum of zoster-associated complications was seen in this population. The 60-day risk of complicated zoster in this HIV population was 32.3%, which is more than double the 60-day risk of complicated zoster found in general population studies, where estimates range between 11% and 13%,1,13 and contrasts with that of HIV patients in the pre-HAART era (risk of 40%).10 This is consistent with the hypothesis that HIV patients are more vulnerable to developing complications from herpes zoster than the general population.
Neurologic complications were common in this study, affecting 27% of all patients. PHN was the most common, occurring in 28 (18%) of patients, whereas 7 patients (4%) had aseptic meningitis, transverse myelitis, trigeminal neuralgia, or Ramsay-Hunt syndrome, which is remarkably high compared with that in the general population.18 The rate of PHN is consistent with the pre-HAART era.10
An earlier pre-HAART study at our institution found bacterial superinfection to be a common cutaneous complication of herpes zoster, occurring in 11.5% of HIV patients.10 We found less bacterial superinfection (4%) in our population, similar to the reported incidence of 2.3% in the general population.13 There was no association of complicated zoster with PCP prophylaxis or mycobacterium avium complex (MAC) prophylaxis, which could potentially decrease the risk of bacterial superinfection. It is possible that bacterial superinfection was not as common in our study because patients were not as susceptible to this complication while on HAART. Although HAART is best known to restore cellular immunity, in vitro data suggest that there is some improvement in B-cell function after initiation of HAART as well,19 which may help to explain the lower overall risk of bacterial infection.
The risk for patients with HIV of developing herpes zoster ophthalmicus has been reported to be 6.6 times higher than that of the general population.20 In this study, 16 patients (10%) had herpes zoster ophthalmicus and 10 patients (6%) had other ocular complications. This is consistent with what has been previously reported in non-HIV patients, in whom there have been reports of herpes zoster ophthalmicus in between 8% and 25% of zoster cases.1,4,21-23
Our results are consistent with prior studies showing the probability that an HIV-infected patient will have a recurrent zoster episode within 1 year of the initial event is estimated at 12%.24 Of the incident cases, we found that 8 patients (5%) had recurrent zoster episodes within the first 6 months of the initial zoster event and that 10% had recurrent episodes by 1 year. Rates of zoster recurrence in HIV patients are high when compared with the general population, where estimates range between 1% and 4%.25 In fact, of the 282 total episodes of herpes zoster we found during the follow-up period, a substantial proportion (44%) represented recurrent zoster events.
In contrast to previous work, there was no association between advanced age13 or lower CD4 cell counts10 and complicated zoster. Recent start of HAART was not associated with complicated zoster; however, a lower viral load and being on HAART at zoster onset were protective of complicated zoster. We believe that taken together, these results suggest that patients who are achieving virologic suppression on HAART may be less likely to develop other complications because their immune system is more able to control the zoster outbreak.
Patients with MSM as an HIV risk factor were less likely to develop complicated zoster than those with other HIV risk factors. One possible explanation for these results is that MSM accessed the health care system for their herpes zoster infection and began treatment more quickly. In addition, African-American patients were more likely to develop complications than white patients in univariate analysis; however, this result was no longer significant in multivariate analysis. This suggests that the benefit of HAART is a stronger factor than race in developing complicated zoster. Interestingly, unlike previous work, age and gender were not associated with the development of complicated zoster.1
In prior studies, multidermatomal involvement has been described as a complication of zoster.25 Multidermatomal involvement was not included as a complication of zoster in this study, however, because we wanted to evaluate the association of multidermatomal involvement with the development of subsequent complications. If multidermatomal involvement had been included in our definition of complicated zoster, 84 patients would have been identified as having complicated zoster, for an incidence rate of 53%.
There are several potential limitations to our study. First, our results are based on patients from a single institution with a high proportion of indigent patients and injection drug users. Our institution is a tertiary referral center and may not be reflective of all HIV clinics, although our findings may be generalizable to other urban HIV care sites. In addition, because of the extensive use of antivirals, we were unable to assess differences in complication rates by antiviral use, although no specific agent or duration from time of zoster prevention to initiation of antiviral was found to be associated with complicated zoster. Of note, valacyclovir, the most commonly used therapy in this study, is not approved for this use in HIV-infected patients. Also, we were unable to assess the impact of the varicella vaccine because immunization was uncommon in our clinic. Clearly, future studies are needed to evaluate the impact of varicella vaccination on the development of zoster. Finally, our study depended on accurate documentation by health care providers and patients, and therefore does not account for complications that may have occurred without available documentation. This would underestimate our already high complication rates, however.
This study has several important implications. The incidence of herpes zoster is unchanged from the pre-HAART era. Although the zoster complication rate remains high, antiviral agents were frequently used to treat zoster reactivation, suggesting that herpes zoster has considerable morbidity despite appropriate treatment in HIV patients. Treatment guidelines for PHN were developed for the immunocompetent patient older than 50 years of age, and current management of herpes zoster in HIV patients is based on extrapolation of these results. More aggressive HIV patient-specific treatment guidelines, which recognize that complications occur at a much higher rate and among a much younger HIV population, may be necessary to prevent the important complications of herpes zoster.
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