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Frequent Reactivation of Herpes Simplex Virus among HIV+ Patients Treated with HAART
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The Journal of Infectious Diseases August 15, 2004;190:693-696
Christine M. Posavad,1,4 Anna Wald,1,2,3 Steven Kuntz,1 Meei Li Huang,1 Stacy Selke,1 Elizabeth Krantz,1 and Lawrence Corey1,2,4
Departments of 1Laboratory Medicine, 2Medicine, and 3Epidemiology, University of Washington, and 4Program in Infectious Diseases, Fred Hutchinson Cancer Research Center, Seattle, Washington
BACKGROUND
Highly active antiretroviral therapy (HAART) has resulted in the suppression of HIV-1 replication, with subsequent increases in memory and naive CD4 lymphocyte responses and in vitro and in vivo evidence of immune recovery. HIV-1--infected patients with cytomegalovirus (CMV) retinitis who have a sustained response to HAART can discontinue CMV maintenance treatment without relapse of retinitis. Resolution of CMV retinitis after HAART has been associated with an increase in CMV-specific CD4 T cell responses. Similarly, HAART has been associated with reductions in complications related to human herpes virus (HHV) type 8 infection in HIV-1--infected individuals.
Herpes simplex virus (HSV) type 2 was one of the first opportunistic infections to be described in persons with AIDS. HSV-1 infection is nearly universal, and seroprevalence of HSV-2 ranges from 50% to 95% of HIV-1--infected persons. HSV-2 is shed more frequently in HIV-1--infected persons than in HIV-1--negative persons. Genital HSV-2 infection is the predominant cause of genital ulcer disease worldwide, and HSV-2 seropositivity has been associated with increased risk of acquisition of HIV-1. HIV-1 RNA is frequently detected in genital HSV lesions, and a significant correlation has been observed between the detection of HIV-1 RNA and HSV-2 DNA levels in genital secretions of HIV-1--infected women. For HIV-1--infected persons with genital ulcers, an increase in the efficiency of the sexual transmission of HIV-1 has been reported.
The studies mentioned above were conducted prior to the introduction of HAART. We sought to evaluate whether HAART reconstituted host immune responses to HSV and whether these alterations in immune responses were associated with an effect on mucosal HSV reactivation and disease.
ABSTRACT
The effect of highly active antiretroviral therapy (HAART) on control of herpes simplex virus (HSV) in human immunodeficiency virus (HIV) type 1--infected subjects is not known. Among 28 HAART-treated and 49 untreated subjects with HIV-1 and HSV-2 infections, mucosal HSV shedding (median, 18% and 29% of days positive for HSV DNA, respectively; P = .08) and HSV DNA level (median, 56,250 and 50,000 copies/mL, respectively; P = .20) were similar. Treated subjects reported significantly fewer days with HSV lesions, compared with untreated subjects (2.8% vs. 11.3% of days, respectively; P = .001). Thus, mucosal HSV shedding and HSV-2 reactivation were still frequent among treated subjects, even though HAART was associated with fewer days with HSV lesions.
RESULTS
The median duration of documented HIV-1 infection in both the HAART-treated and untreated groups was 9 years. At study entry, 28 of the 77 HIV-1--infected subjects were treated with HAART for a median of 21 months (range, 2--46 months), and 49 were untreated. Of the 77 HIV-1--infected subjects in the study, all were seropositive for HSV-2: 51 (66%) had antibodies to HSV-1 and HSV-2, and 26 (34%) had antibodies to HSV-2 only. At study entry, the median CD4 cell count was similar for the untreated (322 cells) and HAART-treated (307 cells) groups (P = .525). The median plasma HIV-1 RNA level for the untreated group was 18,793 copies/mL, compared with 170 copies/mL for the HAART-treated group (P < .001); 11 of the 28 HAART-treated subjects had HIV-1 RNA levels <50 copies/mL.
The 77 study participants collected samples of oral and genital secretions for a median of 59 days (range, 30--96 days); in total, samples from 4462 days were evaluated. HSV DNA was detected in mucosal swab specimens from the oropharynx on 8.4% of total days and from the genital region on 27.3% of total days. Specimens from both sites were positive for HSV DNA on 4.5% of total days. The frequency of HSV shedding was reduced, but not significantly, among HAART-treated, HIV-1--infected subjects (median, 17.7% of total days; range, 0%--86% of total days), compared with untreated HIV-1--infected subjects (median, 29.3% of total days; range, 0%--92% of total days), and was associated with a relative risk of 0.72 (95% confidence interval [CI], 0.50--1.04; P = .08). The amount of HSV DNA shed from mucosal sites was also similar in HAART-treated subjects (median, 56,250 copies/mL; range, 500--5 x 106 copies/ml) untreated subjects (median, 50,000 copies/mL; range, 500--5 x 106 copies/ml). Similar estimates were obtained for genital HSV shedding among HAART-treated subjects, compared with untreated subjects, and were associated with a relative risk of 0.72 (95% CI, 0.47--1.10; P = .13).
In contrast to HSV shedding, days with HSV lesions were fewer among HAART-treated subjects, compared with untreated subjects (median, 2.8% vs. 11.3% of total days, respectively; relative risk, 0.38; 95% CI, 0.21--0.66; P = .001). This decrease in the frequency of lesions was also true for the risk of genital HSV lesions only (relative risk, 0.44; 95% CI, 0.24--0.80; P = .007).
We investigated whether more-advanced HIV-1 disease was associated with higher rates of mucosal HSV reactivation. No significant correlations were observed between the rate of HSV shedding and CD4 cell count (r = -0.05; P = .80) or plasma HIV-1 RNA level (r = 0.10; P = .59) among HAART-treated, HIV-1--infected subjects. As in previous studies of untreated HIV-1--infected subjects, the rate of HSV shedding was inversely correlated with CD4 cell count (r = -0.22; P = .13) and was positively correlated with plasma HIV-1 RNA level (r = 0.29; P = .08).
AUTHOR DISCUSSION
Our data indicate that treatment of HIV-1--infected persons with HAART does not significantly reduce the frequency of mucosal HSV shedding in HIV-1--infected persons. However, the percentage of days that subjects reported HSV lesions was reduced among HAART-treated subjects, suggesting that the improvement in clinical HSV disease is more pronounced than the reduction in HSV shedding.
Our study has important implications for the clinical management of HSV-2 infection in HIV-1--infected persons. Whereas HAART appears to reduce CMV- and HHV-8--related complications, some manifestations of certain opportunistic infections have been exacerbated with the introduction of HAART. For example, increased occurrences of oral warts and herpes zoster episodes subsequent to HAART have been reported. Interestingly, chronic erosive HSV infection of the penis has been reported as a possible immune reconstitution disease. High levels of plasma HIV-1 RNA have been detected in genital lesions due to HSV-2. Although it is possible that lower plasma HIV-1 RNA levels will reduce the ability of HIV-1 to spread from genital lesions, the high frequency of HSV reactivation and the marked up-regulation of HIV-1 in HSV-infected cells all suggest that HSV reactivation may continue to facilitate the transmission of HIV-1. HSV appears to differ from CMV in that specific antiviral chemotherapy to reduce its reactivation needs to be continued and that even persons with high CD4 cell counts while undergoing HAART may want to continue suppressive therapy for genital herpes.
Methods
We enrolled 77 HIV-1--infected, HSV-2--seropositive subjects who volunteered for the study at the University of Washington Virology Research Clinic in Seattle. Serological documentation of HSV-2 infection, but not a clinical history of genital herpes, was required for study entry. Subjects were permitted to treat recurrences of HSV disease with anti-HSV therapy but not to take daily suppressive therapy for the duration of the study. Informed consent was obtained from all subjects, and all research activities involving human subjects were reviewed and approved by Institutional Review Boards (IRBs) of the University of Washington. The university's IRBs are duly constituted to comply with federal laws 45 CFR 46 and 21 CFR 56 and are assured by the Office for Human Research Protections (Federalwide Assurance 00006878).
HIV-1--infected subjects were classified as treated with HAART if, at the time of study entry, they had been receiving HAART (3 drugs in 2 of the following categories: protease inhibitor, nucleoside analogue, and nonnucleoside analogue) for at least 60 days; all other subjects were considered to be untreated. HIV-1 RNA levels were measured by use of both the Roche Amplicor assay (detection level, 500 HIV-1 RNA copies/mL) and the ultradirect assay (detection level, 50 HIV-1 RNA copies/mL) (Roche Diagnostic Systems). Absolute CD4 cell counts were assessed by flow cytometry. The laboratories performing these assays were certified by the College of American Pathologists and the National Institute of Allergy and Infectious Diseases AIDS Clinical Trial Group.
To evaluate the frequency of HSV reactivation, subjects used Dacron swabs to obtain daily samples of genital secretions for at least 30 consecutive days. The women were taught to obtain a swab specimen from the cervicovaginal, vulvar, and perianal areas and from the oropharynx. The men were taught to obtain a swab specimen from the penile skin, perianal area, and the oropharynx. The swabs were placed in polymerase chain reaction (PCR) buffer and delivered to the laboratory. Subjects maintained diaries of symptoms and signs of oral and genital herpes.
Detection of HSV-1 and HSV-2 in specimens from mucosal sites was performed by quantitative, real-time, fluorescence-based PCR, as described elsewhere. Samples were considered to be positive if they contained >copies HSV DNA/PCR reaction (20 uL) or 500 copies HSV DNA/mL of swab specimen. To calculate shedding rates, we included all positive episodes of HSV-1 and HSV-2 shedding from any site. Samples obtained on days when antiviral therapy was used for recurrences of HSV disease were included in this calculation, because HSV usually was detected in these samples. We calculated the median HSV DNA copy number per person, using the results for samples in which HSV DNA was detected.
Relationships between CD4 cell count, plasma HIV-1 RNA level, and HSV shedding were evaluated by use of Spearman's rank correlation. For HAART-treated versus untreated subjects, the risks of HSV shedding and of occurrence of lesions were evaluated by use of Poisson models with robust SEs. Separate models were constructed for HSV shedding and for occurrence of lesions. P values presented for these comparisons were obtained from the models. The amounts of HSV DNA found in samples from HAART-treated and untreated subjects were compared by use of the Mann-Whitney test. Statistical significance was defined as P < .05, with a 2-tailed a.
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