Antiretroviral therapy (ART) has profoundly improved the health and lifespan of HIV-infected people. Although current ART regimens swiftly limit HIV viral replication after initiation, some individuals with comorbid infections experience an increase in symptoms related to the primary infection, a phenomenon known as Immune Reconstitution Inflammatory Syndrome (IRIS). In people infected with both HIV and HSV-2, an increased frequency of ulcerative genital lesions shortly after beginning ART may occur. While the appearance of IRIS due to herpesviruses has been described, reports of a correlation between ART and HSV shedding or lesions have been mixed, prompting the Corey lab in the Vaccine and Infectious Disease Division and the University of Washington Virology Research Clinic (VRC) to initiate a study of HSV data from participants with HSV-2 and HIV coinfection. Dr. Emily Ford, the physician-scientist leading the study, recently published these findings in AIDS.
This study reviewed historical data from patients who had been prospectively enrolled in observational studies of genital HSV reactivation among HIV positive men and women at the VRC between 1998 and 2003. Included were 45 HIV and HSV-2 coinfected people who had participated in at least one 30 day HSV shedding study, with some initiating the study while already receiving ART and with other patients beginning or ceasing ART within the study timeframe. Using the patients’ genital swabs stored by the VRC, the authors first defined rates of genital HSV shedding by severity of HIV disease, measured by decreased blood CD4+ T cell counts. In patients with CD4 cells >200/ul, HSV was detected on fewer days, indicating fewer HSV shedding events and decreased HSV activity in people with less severe HIV-mediated T cell loss.
To investigate the relationship between ART and the rate of HSV shedding, a surrogate marker of HSV severity, the researchers compared HSV shedding rates between untreated patients, patients treated with ART within 90 days of study initiation (recent ART), and those receiving ART for more than 90 days (established ART). On average, shedding was found to occur most frequently in people with recent ART and least frequently in untreated people. Likewise, HSV viral load (from genital swabs) was found to be highest in patients on recent ART, with established ART and untreated patients sharing similarly lower viral loads. The authors also compared duration of shedding episodes, measured in days. Recent ART patient episodes persisted longer than established ART or untreated. Although HSV shedding indicates viral activity, it does not always lead to recurrence of genital lesion symptoms. Among each of the three groups, persons on established ART reported the fewest days with ulcerative symptoms, and those recently starting ART had a similar lesion frequency compared to those off ART.
Although genital HSV shedding and viral load were elevated in persons within 90 days of ART initiation, statistical analyses revealed that HSV shedding and symptoms decreased by 2% for every subsequent month of ART treatment. Additionally, analyses found that higher HIV RNA titers in untreated people were directly associated with higher HSV shedding frequencies. Together, these findings suggest that even though ART initiation is associated with a spike in HSV viral shedding, prolonged treatment ultimately decreases HSV activity and supports the use of ART not only for HIV control but to also decrease frequencies of HSV lesions in HIV-infected patients. Furthermore, more severe HIV disease and higher HIV viral loads were associated with increased HSV shedding, supporting previous observations that coinfected patients not taking ART experience worse HSV-mediated disease compared to patients on prolonged ART.
Ford’s study corroborated previous reports that HSV shedding and lesions were increased in patients upon initiation of ART. Importantly, she points out that this paper is the first to demonstrate that HSV shedding rates decrease over time in patients on ART, despite this early rise. Although this study is the first to document a time-dependent decrease in HSV shedding after ART initiation, Ford reports these conclusions are generally consistent with clinical observations, stating that “an improvement in shedding over time is more consistent with our clinical experience with persons with HIV and HSV and our understanding of these diseases.” She credits the longitudinal sampling and range of ART experiences of their research for capturing the decrease in HSV shedding that may have been missed in other studies with shorter durations of follow up. Although these findings support the current hypothesis that HSV-related IRIS is the result of a loss of control of HSV by the immune system, the mechanisms behind this immune dysregulation are unclear. Ford and colleagues speculate that an imbalance in T cell subsets-possibly an increase in regulatory T cells-that is triggered in response to ART may be to blame; however, she states that much research regarding T cell functionality and cell-cell interaction needs to be conducted in order to define the mechanism of herpesvirus-related IRIS.
Ford ES, Magaret AS, Spak CW, Selke S, Kuntz S, Corey L, Wald A. 2018. Increase in HSV shedding at initiation of antiretroviral therapy and decrease in shedding over time on antiretroviral therapy in HIV and HSV-2 infected persons. AIDS 13;32(17):2525-253.
This work was funded by the National Institutes of Health.
Fred Hutch/UW Cancer Consortium faculty members Anna Wald (UW/FH), Larry Corey (UW/FH), and Amalia Magaret (UW/FH) contributed to this work.