Impact of a Short-Term Analytical Treatment Interruption and Re-Initiation of Antiretroviral Therapy on Immunologic and Virologic Parameters in HIV-Infected Individuals

While antiretroviral therapy (ART) has improved the clinical outcome for HIV-infected
individuals, persistence of viral reservoirs in the peripheral blood and lymphoid tissues
remains a hurdle to the eradication of virus. The vast majority of HIV-infected individuals
treated with ART experience plasma viral rebound within weeks of cessation of therapy.
Considering that current research regarding treatment has been heavily focused on developing
strategies aimed at achieving sustained virologic remission in the absence of ART, it is of
crucial importance to investigate the impact of short-term treatment interruption and
re-initiation of ART on transcriptional, immunologic, and virologic parameters in
HIV-infected individuals. Currently, much of our knowledge regarding the mechanism of viral
rebound is based on investigations using structured treatment interruptions in supervised
clinical settings dating back to 1999. Subsequent studies, performed primarily in chronically
infected patients to minimize treatment exposure and toxicity, revealed poor outcomes in
terms of viral rebound, clinical events and mortality 3-11 leading to the abandonment of this
genre of investigation. However, various aspects have been identified as potential
contributors to the observed negative outcomes including outmoded ART regimens, infrequent
post-interruption monitoring, and repeated cycles of prolonged analytical treatment
interruption (ATI). While long-term ATI was found to be associated with a decrease in CD4+ T
cells, persistent plasma viremia, and an increased risk of opportunistic infections, it is
unclear whether short term ATI elicits similar immunologic and virologic consequences in
those receiving modern and efficacious ART. Furthermore, the mechanism, kinetics, degree, as
well as immunologic and virologic predictors, of plasma viral rebound in patients receiving
contemporary antiretroviral drug regimens after cessation of ART have not been explicitly
investigated. Nor has the impact of persistent HIV reservoir size been fully correlated to
the dynamics of plasma viral rebound in patients receiving modern drug regimens. As we
develop clinical trials aimed at therapeutic and curative interventions, an integral
component in design will require an ATI phase. Characterizing the corollaries of brief
treatment cessation and re-initiation of ART on the dynamics of immunologic parameters and
HIV reservoirs will provide valuable information for the design of future trials essential to
our interpretation of the results as well as to ensuring the safest environment for the
patients. We propose to examine the effect of ATI on plasma viral rebound, changes in
immunologic parameters and the dynamics of viral reservoirs in HIV-infected individuals
receiving state-of-the-art antiretroviral drug regimens following discontinuation and
reinitiation of therapy.

- INCLUSION CRITERIA:

- Age, 18-65 years

- Documented HIV-1 infection and clinically stable

- In general good health, with an identified primary health care provider for medical
management of HIV infection and willing to maintain a relationship with a primary
health care provider for medical management of HIV infection while participating in
the study

- CD4+ T cell count greater than 450 cells/mm^3 at screening

- Documentation of continuous ART treatment with suppression of plasma viral level below
the limit of detection for greater than or equal to 2 years. Subjects with blips
(i.e., detectable viral levels on ART) prior to creening may be included provided they
satisfy the following criteria:

- The blips are less than 400 copies/mL, and

- Succeeding viral levels return to levels below the limit of detection on
subsequent testing

- Willingness to undergo ATI

- Willingness to restart ART once restart criteria are met

Laboratory values within pre-defined limits at screening:

- Absolute neutrophil count greater than 1,000/mm^3

- Hemoglobin (Hgb) levels greater than 10.0 g/dL for men and greater than 9.0 g/dL for
women

- Platelet count greater than 150,000/mm^3

- Estimated glomerular filtration rate (eGFR) greater than or equal to 60 mL/min as
determined by the NIH Clinical Center (CC) laboratory

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels of less
than 2.5 x upper limit normal (ULN)

- Willingness to have samples stored for future research

EXCLUSION CRITERIA:

- Chronic hepatitis B, as evidenced by a positive test for hepatitis B surface antigen
(HBsAg), an isolated positive Hepatitis B core antibody (negative HBsAg and anti-HBV
Ab) and/or positive Hepatitis B virus (HBV) DNA.

- Chronic hepatitis C virus (HCV) infection as evidenced by a positive test for HCV RNA.
Subjects with a positive test for HCV antibody and a negative test for HCV RNA are
eligible.

- Has a history of institution of ART within 12 weeks of being diagnosed with acute or
early HIV-1, where acute/early infection is defined by any one of the following:

- Positive HIV-1 enzyme immunoassay (EIA) with negative/indeterminate HIV-1 western
blot that subsequently becomes positive

- Negative HIV-1 EIA within the past 4 months and HIV-1 RNA levels of greater than
400,000 copies/mL, in the setting of a potential exposure to HIV-1.

- Negative rapid HIV-1 within one month prior to a positive HIV-1 EIA and HIV-1
western blot

- Low level HIV antibodies (positive EIA or western blot) with a non-reactive
detuned EIA

- Documented nadir CD4+ T cell count less than 200 cells /mm^3

--Patients with a nadir CD4+ T cell count between 100-200 are not excluded, provided
their current CD4+ T cell count has been >450 the past 3 years

---Subjects with dips (i.e., transient decreases in their CD4 count) prior to
screening may be included provided they satisfy the following criteria:

- a. The dips are > 350 cells/mL, and

- b. Succeeding CD4 counts return to levels above 450 cells/mL on subsequent
testing

- Any history of AIDS defining opportunistic infections

- Subjects with history of receiving ART consisting of mono or dual drug therapy

- Documented multiclass antiretroviral drug resistance that, in the judgement of the
investigator, would pose a risk of virologic failure should additional mutations
develop during the study

- Any experimental non-HIV vaccination received within 2 weeks prior to study enrollment
and at any time during the study.

- Any licensed or experimental non-HIV vaccination (e.g., hepatitis B, influenza,
pneumococcal polysaccharide) received within 2 weeks prior to study enrollment/Day 0

- Receipt of other investigational study agent within 28 days of enrollment/day 0 and at
any time during the study

- Any active malignancy that may require systemic chemotherapy or radiation therapy

- Systemic immunosuppressive medications received within 3 months prior to enrollment.
The following are not excluded: (1)corticosteroid nasal spray or inhaler; (2) topical
corticosteroids for mild, uncomplicated dermatitis; and (3) oral/parenteral
corticosteroids administered for non-chronic conditions not expected to recur (length
of therapy less than or equal to 10 days, with completion in greater than or equal to
30 days prior to enrollment/day 0)

- History of or other clinical evidence of:

- Significant or unstable cardiac disease (e.g., angina, congestive heart failure,
recent myocardial infarction)

- Severe illness, malignancy, immunodeficiency other than HIV, active systemic
infection other than HIV, or any other condition that, in the opinion of the
investigator, would make the subject unsuitable for the study

- Active drug or alcohol abuse or any other pattern of behavior that, in the opinion of
the investigator, would interfere with adherence to study requirements

- Both male and female subjects to remain completely abstinent of potentially
reproductive sexual intercourse (e.g. due to a committed lifestyle) or to consistently
use BOTH a barrier method with a spermicide (male or female condom) AND ALSO one of
the below listed methods of birth control:

- Continuous/daily hormonal methods including oral contraceptive pills, patch,
implant/injection, etc.

- Surgical sterilization of either partner, of sufficient duration to be effective,
and NOT known to have failed.

- Intrauterine device.

- Females of childbearing potential must not be breast-feeding, possibly or actually
pregnant, must not have had unprotected intercourse for one month prior to enrollment
, and must agree not to become pregnant beginning from enrollment in the study to at
least 8 weeks after the end of analytical treatment interruption.