Suppressive Therapy for Genital Herpes Needs to Be Continued in HIV Patients on HAART Even Among Those with High CD4 Cell Counts

The use of 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. 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.

In the current study, researchers 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.

Results

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.

Discussion

The data from the present study 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 [emphasis added].

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.

This 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.

The authors conclude, “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.”

08/23/04

Reference
C M Posavad and others. Frequent Reactivation of Herpes Simplex Virus among HIV-1–Infected Patients Treated with Highly Active Antiretroviral Therapy. The Journal of Infectious Diseases 190(4): 693-696. August 15, 2004.