From NATAP http://natap.org/
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The Incidence of, Risk Factors for, and Sequelae of Herpes Zoster
Among HIV Patients in the HAART Era

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.

“…..This study has several important findings. Firstt, 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…. suggesting that moderate
degrees of immunodeficiency puts patients at an increased risk of
zoster, whereas profound immunodeficiency does not….. 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….

…… 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 (post-hepatic neuralgia) is consistent with the pre-HAART
era… ¦

…. Our results are consistent with prior studies showing the
probabiility that an HIV-infected patient will have a recurrent zoster
episode within 1 year of the initial event is estimated at 12%....

…… Patients with MSM as an HIV risk factor were less likely ly 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…..

….. More aggressive HIV patient-specific treatment guidelines, whichh
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.�

JAIDS Journal of Acquired Immune Deficiency Syndromes:  Volume 40(2)
1 October 2005  pp 169-174

Gebo, Kelly A MD, MPH*; Kalyani, Rita MD*; Moore, Richard D MD, MHS*;
Polydefkis, Michael J MD†

BACKGROUND

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.

Abstract
Background: Whereas the incidence, risk factors, and clinical sequelae
of herpes zoster have been studied in the general population and in
HIV patients in the era before highly active antiretroviral therapy
(HAART), they have yet to be fully understood in the current era of
HAART.

Methods: We conducted a retrospective cohort study of patients
enrolled in an urban HIV clinic between January 1, 1997 and December
31, 2001. Patients with an episode of herpes zoster during this period
were identified, and their charts were reviewed. A nested case-control
analysis was used to assess factors associated with an initial episode
of herpes zoster. Multivariate conditional logistic regression
analyses were used to assess risk factors for zoster. Logistic
regression was performed to assess factors associated with complicated
zoster.

DISCUSSION
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.

Zoster Complications

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.

Results

Two hundred eighty-two episodes of herpes zoster were identified in
239 patients. Of these episodes, 158 were new occurrences of zoster
and 124 were recurrent zoster events. The incidence of zoster during
the study period was 3.2 per 100 person-years of follow-up.

The incident cases reflected the clinic population, with most patients
being male (63%) and African American (77%) and having injection drug
use as their HIV risk factor (49%). The mean age of the patients was
41 years. Sixty-seven percent of patients had single dermatomal
involvement, and the thorax was involved in 41%.

In multivariate regression, being on HAART (odds ratio [OR] = 2.39,
95% confidence interval [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) compared with a CD4
count less than 50 cells/mm3 were associated with an increased risk of
zoster.

Twenty-eight patients (18%) developed post-herpetic neuralgia (PHN),
and 29 patients (18%) had other complications. Male-to-male sex as an
HIV risk factor (P = 0.02) and being on HAART at a zoster episode (P =
0.03) were protective against complicated zoster.

Conclusions: Our results suggest that zoster infection rates have not
changed in the current HAART era but that a significant percentage of
patients develop complications, particularly PHN, which is quite
remarkable considering the young age of our population.

METHODS
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.

Definitions
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

RESULTS
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).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.

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