Herpesviruses Reactivation In Hiv-Infected Women Initiating ART (HERA)
Keywords
Abstract
Description
Initiation of antiretroviral therapy (ART) can lead to a short-term increase of herpes virus-related illnesses including genital herpes flares, higher likelihood of varicella zoster virus (VZV), cytomegalovirus (CMV) uveitis or other end-organ disease, and herpes simplex virus (HSV) associated encephalitis. Herpesvirus reactivation upon ART initiation may be related to immune restoration disease of immune reconstitution inflammatory syndrome (IRIS), but the etiology is unclear. We hypothesize that ART initiation can induce herpesvirus reactivation causing increased cellular, systemic, and localized immune activation and that alterations of interferon (IFN) pathways during initial HIV viral suppression are involved in this reactivation.
To investigate these mechanisms, we propose to document the incidence of clinical herpetic disease and viral shedding in vaginal and oral secretions from HIV-positive women initiating ART and to assess the associations between viral shedding or clinical disease and cellular, mucosal, and systemic immune activation. We will determine the role of IFN pathway in herpesvirus reactivation following initiation of ART. We will also evaluate the potential impact of herpesvirus reactivation on HIV cellular reservoirs by comparing residual HIV plasma viral replication and cell-associated virus prior to and 52 weeks after ART initiation.
We propose to recruit up to 200 HIV-infected women initiating ART at the NIH Clinical Center (n=30 to 40) and between the Villa Maria Hospital, Rakai Health Sciences Program (RHSP) site in Kalisizo, Uganda and Kalisizo Hospital ARV clinic (n=160 to 170). Women will be recruited regardless of CD4+ T-cell count, presence of opportunistic infections and co-infection status. Pregnant women will be excluded. During 8 study visits to occur over a 12-month period, participants will receive standard-of-care treatment for HIV and opportunistic infections. Blood, vaginal fluid and oral swabs collected at study visits will be tested for viral levels of HIV and various herpesviruses. Vaginal samples will also be used to study differences in vaginal microbiota between women with and without herpetic disease prior and after ART. Plasma samples will be tested for antibody levels (IgG) specific for different herpesviruses to examine changes in anti-herpetic humoral responses. ART adherence will be monitored in plasma using high-resolution mass spectrometry.
Dates
| Last Verified: | 02/13/2020 |
| First Submitted: | 03/21/2017 |
| Estimated Enrollment Submitted: | 03/21/2017 |
| First Posted: | 03/27/2017 |
| Last Update Submitted: | 02/25/2020 |
| Last Update Posted: | 02/26/2020 |
| Actual Study Start Date: | 06/14/2018 |
| Estimated Primary Completion Date: | 01/31/2021 |
| Estimated Study Completion Date: | 01/31/2021 |
Condition or disease
Phase
Arm Groups
| Arm | Intervention/treatment |
|---|---|
| Females Females participants who are about to start first line antiretroviral therapy. |
Eligibility Criteria
| Ages Eligible for Study | 18 Years To 18 Years |
| Sexes Eligible for Study | Female |
| Sampling method | Non-Probability Sample |
| Accepts Healthy Volunteers | Yes |
| Criteria | - INCLUSION CRITERIA: 1. At least 18 years of age 2. Female 3. Weight >40 kilograms 4. A diagnosis of HIV infection as documented by any positive serological test (ELISA, HIV rapid test, or Western Blot) 5. Participants in Uganda must be eligible for ART by current clinical guidelines in Uganda 6. Willingness to begin ART 7. Will allow storage of biological sample EXCLUSION CRITERIA: 1. Previous exposure to ART (participants with a brief exposure (<3 months) that occurred greater thatn or equal to 6 months prior to screening will be eligible to enroll if, the opinion of the investigator, the ART usage will not impact the scientific validity of the protocol) 2. On acyclovir, valacyclovir, valganciclovir, or ganciclovir treatment 3. Pregnancy or intent to become pregnant during the study period 4. Intrauterine device (IUD) use 5. Inability to follow study instructions, according to the investigator's judgment 6. Active, serious infections other than HIV infection that may interfere with study participation (eg, severe cerebral toxoplasmosis or cryptococcal meningitis) during the 2 weeks prior to enrollment 7. Malignancies requiring chemotherapy 8. Therapy with systemic corticosteroids, immunosuppressants or immunomodulating agents 9. Any condition that, in the investigator s opinion, may put the participant at undue risk or compromise the study's scientific objectives |
Outcome
Primary Outcome Measures
1. Compare the prevalence of herpetic disease, demonstrated by viral shedding of HSV-1 and 2 in the vaginal secretions of HIV-positive women prior to and 4 and 8 weeks after ART initiation. [prior to and at 4 and 8 weeks after inititian of antiretroviral treatment]
Secondary Outcome Measures
1. To estimate the associations of viral shedding or clinical herpetic disease post-ART at weeks 4 or 8 with concurrent and baselinemeasurement of systemic inflammation (IL-6, CRP, TNF or sCD14). [at week 4 and at week 8]
2. To estimate the associations of viral shedding or clinical herpetic disease post-ART at weeks 4 or 8 with concurrent and baseline measurements of cellular activation (CD4 and CD8 T cells expressing HLADR/CD38). [at week 4 and at week 8]
3. To estimate the associations of viral shedding or clinical herpetic disease in genital area post-ART at weeks 4 or 8 with concurrent and baseline measurements of cytokine levels in vaginal secretions. [at week 4 and at week 8]
