Clinical trial NCT01025427: HIV Persistence and Viral Reservoirs
Official title: Treating HIV-infected Elite Controllers as a Model of HIV Remission
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: HIV
HIV Infections
Keywords: HIV
HIV persistence
HIV reservoirs
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: California HIV/AIDS Research Program
name: Gilead Sciences
name: Merck Sharp & Dohme LLC
First posted: 2009-12-03
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Although highly active antiretroviral therapy (HAART) decreases HIV-associated mortality, it does not to completely restore health. Patients doing well on otherwise effective HAART remain at risk for cancer, cardiovascular/liver disease, osteopenia, and other "non-AIDS-defining" events. While complete eradication may never be feasible, a "functional cure" in which patients are able to maintain undetectable viral loads indefinitely without therapy may be possible. The best evidence for this are the so-called "elite" controllers, whom we define as individuals who are HIV-seropositive, with plasma HIV RNA levels below the level of conventional detection without treatment. Controllers may be conceptualized as a naturally occurring model of a functional cure (or "HIV remission"), and are ideal patients in which to study HIV persistence and the possibility of eradication.

We propose to conduct a pilot study to better characterize the reservoirs that lead to viral persistence in a group of well-characterized controllers. We propose two specific aims: 1) to characterize the dynamics of viral production in blood and gut-associated lymphoid tissue (GALT) in controllers; and 2) to prospectively treat 10 controllers with raltegravir, tenofovir/emtricitabine for 24 weeks and study the effects of HAART on viral dynamics and host inflammatory responses.

Our primary hypotheses are: 1) viral replication is ongoing in untreated controllers, 2) HAART will reduce viral replication in blood and GALT and decrease immune activation, and 3) higher levels of immune activation are associated with greater measures of microbial translocation and distribution of virus to more differentiated T cell subsets.


Eligibility criteria: Inclusion Criteria:

1. Age ≥18 years, and
2. HIV infection, and
3. Antiretroviral-naïve, and
4. CD4+ T cell count \>350 cells/mm3, and
5. "Controllers": antiretroviral untreated with 50-1000 copies/mL viral load for at least 12 months

Exclusion criteria:

1. Persons with known rheumatologic conditions (e.g., systemic lupus erythematosus), because of their predilection for biologic false-positive testing on HIV antibody tests.
2. Screening absolute neutrophil count \<1,000 cells/mm3, platelet count \<70,000 cells/mm3, hemoglobin \< 8 mg/dL, estimated creatinine clearance \<40 mL/minute, aspartate aminotransferase \>100 units/L, alanine aminotransferase \>100 units/L.
3. Screening genotype resistance testing showing resistance to tenofovir or emtricitabine.
4. Known kidney disease.
5. Known bone disease, including pathologic fractures.
6. Patients with chronic Hepatitis B infection, because of the risk of liver abnormalities after starting and stopping tenofovir/emtricitabine.
7. Concurrent treatment with lamivudine, adefovir, entecavir, or telbivudine.
8. Serious illness requiring hospitalization or parental antibiotics within the preceding 3 months.
9. Any vaccination 2 weeks prior to baseline (Day 0) visit and throughout the study period. NOTE: Because the study will most likely be actively recruiting during the influenza season, all subjects will be encouraged to receive their annual influenza vaccine at the screening visit (4 weeks prior to baseline \[Day 0\] visit) if they have not already been vaccinated for the 2009-10 season and if it is medically indicated.
10. Concurrent treatment with immunomodulatory drugs, or exposure to any immunomodulatory drug in the preceding 16 weeks (e.g. corticosteroid therapy equal to or exceeding a dose of 15 mg/day of prednisone for more than 10 days, IL-2, interferon-alpha, methotrexate, cancer chemotherapy). NOTE: Use of inhaled or nasal steroid use is not exclusionary.
11. Concurrent treatment with phenobarbital, phenytoin, or rifampin.
12. Pregnant or breastfeeding women. Females of childbearing potential must have a negative serum pregnancy test at screening and agree to use a double-barrier method of contraception throughout the study period.

Primary outcomes:
measure: Mean Change in Estimated Ultrasensitive Plasma HIV RNA Levels Between Baseline and Week 24
timeFrame: 24 weeks
Secondary outcomes:
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: San Francisco General Hospital
state: California
Study officials:
affiliation: University of California, San Francisco
name: Hiroyu Hatano, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hatano H, Yukl SA, Ferre AL, Graf EH, Somsouk M, Sinclair E, Abdel-Mohsen M, Liegler T, Harvill K, Hoh R, Palmer S, Bacchetti P, Hunt PW, Martin JN, McCune JM, Tracy RP, Busch MP, O'Doherty U, Shacklett BL, Wong JK, Deeks SG. Prospective antiretroviral treatment of asymptomatic, HIV-1 infected controllers. PLoS Pathog. 2013;9(10):e1003691. doi: 10.1371/journal.ppat.1003691. Epub 2013 Oct 10.