Herpesviruses Reactivation In Hiv-Infected Women Initiating ART (HERA)

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.

- 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