Interferon Alpha 2b Intensification in HIV-Positive Individuals on Antiretroviral Therapy

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )
ClinicalTrials.gov Identifier:
NCT01295515
First received: February 11, 2011
Last updated: July 19, 2014
Last verified: July 2014
  Purpose

Background:

  • Antiretroviral therapy (ART) has been able to improve the lifespan of individuals infected with human immunodeficiency virus type 1 (HIV-1), but ART requires continuous treatment that has substantial consequences on quality of life. ART suppresses HIV-1 virus levels below the limits of detection in current tests, but does not completely eradicate the virus from the blood. Recent research is attempting to determine whether this persistent infection stems from a low-level infection where new cells are continually infected with HIV, or from cells that live for a long time after infection. ART is very active against the virus in new cells, but has no effect on long-lived cells that are already infected with HIV-1 at the start of ART. As a result, new strategies may be necessary to reduce or eradicate these 'reservoir' cells.
  • Interferon is a natural substance made by the body to combat virus infections, but can also be made as an injectable drug known as PEGINTRON. PEGINTRON injections have been approved to treat hepatitis C infection, including in patients with HIV infection. Earlier studies of HIV-infected individuals who were not on any ART showed that interferon reduced the level of HIV in the blood. Researchers are interested in determining whether PEGINTRON therapy will also reduce the residual low levels of HIV in patients who are already taking ART.

Objectives:

- To evaluate the effectiveness of PEGINTRON injections on HIV levels in participants currently undergoing antiretroviral therapy.

Eligibility:

- Individuals at least 18 years of age who have been diagnosed with HIV, are currently undergoing antiretroviral therapy, and have maintained HIV virus blood counts that are not detectable by current commercial tests for at least 12 months before the start of the study.

Design:

  • This study will involve separate screening and treatment processes.
  • Participants will be screened with a physical examination and medical history, including blood and urine samples. The screening analysis to determine study eligibility will take several weeks. Participants will have apheresis to provide sufficient numbers of blood cells for evaluation by the study researchers.
  • Eligible participants will begin a 4-week course of PEGINTRON injections using the standard dose of PEGINTRON that is approved for treatment of chronic hepatitis C. Participants will have weekly injections and have frequent blood tests to measure HIV virus levels.
  • Participants who experience problems in maintaining safe numbers of white blood cells during the study may receive injections of filgrastim to increase their white blood cell count.
  • After the 4 weeks of treatment, participants will return for additional blood tests on study days 28, 35, 42, 49, 56, and 84, and Weeks 16, 24, 36, and 48 (i.e., through the end of 1 year after the start of the study).

Condition Intervention Phase
HIV Infection
Drug: Pegylated Interferon Alpha 2b (PEGINTRON)
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Effect of Interferon Alpha 2b Intensification on HIV-1 Residual Viremia in Individuals Suppressed on Antiretroviral Therapy

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • This is a non-randomized, single arm pilot study of 10 participants to investigate the effect of interferon alpha on HIV-1 production in HIV-infected individuals with HIV-1 RNA levels of & lt; 50 copies/mL. [ Time Frame: week 4 compared to week 0 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Investigate HIV-1 genetic variation in individuals undergoing interferon therapy. [ Time Frame: week 4 of therapy ] [ Designated as safety issue: No ]
  • Investigate the safety and tolerability of PEG INF 2b in HIV-1 infected individuals taking FDA-approved antiretrovirals in combinations recommended by Department of Health and Human Services (DHHS) guidelines. [ Time Frame: week four of therapy ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 65
Study Start Date: January 2011
Estimated Study Completion Date: January 2016
Estimated Primary Completion Date: January 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
Interferon treatment
Drug: Pegylated Interferon Alpha 2b (PEGINTRON)
pegylated preparation of interferon alpha 2b

Detailed Description:

As a result of combination antiretroviral therapy (ART), morbidity and mortality from acquired immunodeficiency syndrome has declined significantly in the past 12 years, at least in developed countries. Human immunodeficiency virus type 1 (HIV-1) infected individuals now live longer, but must undergo continuous therapy that has substantial consequences on quality of life.

ART suppresses HIV-1 viremia below the limits of detection in current commercial assays (50 copies/mL plasma). Although therapy is not immediately curative, previous studies were optimistic, suggesting prolonged duration of suppressive therapy could result in eventual viral eradication. More recent data suggest, however, that HIV-1 RNA persists even after prolonged suppressive therapy. The origin of this residual viremia is yet not defined but data from several sources, including our own, indicate that persistent viremia may be the product of viral genome production from chronically infected long-lived reservoirs, and not from new ongoing cycles of HIV-1 infection.

Antiretrovirals are extremely active against replicating cells, and can thus successfully stop viral replication, but have no effect on long-lived viral reservoirs of cells already infected with HIV-1 at the time antiretroviral therapy is initiated. As a result, new strategies may be necessary to reduce or eradicate long-lived reservoirs.

Interferon alpha is a natural cytokine with antiviral activity. Prior to the introduction of antiretroviral therapy, several studies demonstrated modest effect of interferon alpha in HIV-1 viremia in active cycles of infection in infected individuals. Interferon alpha was also effective in vitro in decreasing virus production from cells chronically infected with HIV-1. With the introduction of potent antiretroviral therapy, interferon was not developed as a direct anti-HIV drug. Interferon alpha is relatively effective in therapy of hepatitis C virus (HCV) infection, and has been used in HIV-1/HCV coinfected individuals. Recently, Kottilil and coworkers in the Laboratory of Immunoregulation NIAID have shown a decrease in HIV-1 RNA levels in HCV coinfected participants treated with pegylated interferon alpha and ribavirin. In stored samples from that study, we conducted a retrospective trial on samples from participants with HIV-1 RNA levels of < 50 copies/mL, showing a further reduction in residual viremia using an ultrasensitive Single Copy Assay (SCA) developed in our laboratory.

In this protocol we will conduct a prospective, non-randomized, single arm, pilot study to investigate the effect of pegylated interferon alpha 2b on HIV-1 RNA levels as an additional drug in participants undergoing suppressive antiretroviral therapy with viral RNA levels suppressed to less than 50 copies/mL plasma. We will determine whether interferon alpha therapy will reduce residual viremia in participants on suppressive ART, which will expand our understanding of persistent low-level viremia in HIV-1 infected individuals.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

To be eligible for study participation, a volunteer must satisfy all of the following inclusion criteria:

  1. Age greater than or equal to 18 years.
  2. Documentation of HIV-1 infection by any licensed ELISA test and confirmed by a Western Blot.
  3. Receiving a DHHS-approved ARV regimen.
  4. HIV-1 RNA levels less than detectable by current commercial means (e.g., Roche Amplicor, b-DNA test) for a minimum of 12 months prior to screening at all time points, and with at least 2 measurements in this 12 month window.
  5. HIV-1 RNA levels greater than or equal to 0.1 copies/mL by SCA at screening visit.
  6. CD4 greater than or equal to 300 cells/mm(3) at pre-entry visit within 14 days prior to enrollment.
  7. Ability to sign informed consent and willingness to comply with the study requirements and clinic policies.
  8. No evidence of viral hepatitis co-infection as assessed by Hepatitis C antibody, HCV RNA, and hepatitis B surface antigen; determinations at pre-entry visit within 28 days prior to enrollment.
  9. No history of or evidence of autoimmune hepatitis or other autoimmune disorders at screening, or Antinuclear antibody (ANA > 3 times upper limit of normal.
  10. Laboratory values at pre-entry visit within 14 days prior to enrollment:

    • Alkaline phosphatase < 2.0 times upper limit of normal
    • Alanine transaminase (ALT) < 2.0 times upper limit of normal
    • Total bilirubin < 2.5 mg/dL (< 40 mg/dL if on Atazanavir)
    • Creatinine clearance greater than or equal to 60 mL/min as estimated by the Cockcroft-Gault equation
    • Neutrophil count greater than or equal 1500 cells/mm(3)
    • Platelets greater than or equal to 150,000/ mm(3)
    • Hemoglobin greater than or equal to 12.0 mg/dL for men and > 11.0 g/dL for women
    • Fasting glucose < 126 mg/dL
  11. No history or evidence of significant clinical depression at screening that in the opinion of the investigator would affect the ability of the patient to participate in the study, or which would constitute a threat for his/her health in case of relapse upon INF treatment. The Beck Depression Inventory score must be less than or equal to 13 at pre-entry visit.
  12. No history of INF/PEG-INF therapy.
  13. If capable of pregnancy: use of effective contraception during study: effective contraception methods include abstinence, surgical sterilization of either partner, barrier methods such as diaphragm, condom, cap or sponge, or use of hormonal contraception with an anti-HIV regimen that will not alter metabolism of hormonal contraception.
  14. Participants must have primary medical care outside this protocol: participants will have to provide Primary Care Doctor s contact information.

EXCLUSION CRITERIA:

A volunteer will be ineligible to participate in this study if any of the following criteria are met:

  1. History of neoplastic disease requiring cytotoxic therapy including hydroxyurea.
  2. Use of long-term systemic corticosteroids, immunosuppressive agents, or cytotoxic agents within 60 days prior to enrollment.
  3. Any vaccination within 30 days prior to enrollment. Individuals interested in participating who require vaccination will delay screening until 30 day period is completed.
  4. Concurrent therapy with investigational cytokines including IL-2 or IL-12 during the course of the study. Prior administration of cytokines is not an exclusion criterion; at least 4 months from most recent cycle of IL-2 or IL-12 is required.
  5. Any febrile illness (> 38 degrees C) in the 3 weeks prior to enrollment or any acute therapy for a serious infection completed within 30 days prior to enrollment.
  6. Current pregnancy or lactation, history of pregnancy in the last 4 months.
  7. Preexisting autoimmune disorders including inflammatory bowel diseases, psoriasis, idiopathic thrombocytopenic purpura, lupus erythematous, autoimmune hemolytic anemia, scleroderma, severe psoriasis, rheumatoid arthritis, and optic neuritis.
  8. History of severe retinopathy or evidence of severe retinopathy judged by pre-entry ophthalmologic examination.
  9. Known allergy/sensitivity to study drug or its formulation.
  10. History of seizure disorders or current anticonvulsant use.
  11. Any history of medical conditions associated with chronic liver disease (genetic hemochromatosis, alcoholic liver disease, toxin exposures, and autoimmune hepatitis) or documented cirrhosis due to any cause.
  12. History of pulmonary disease associated with functional limitation.
  13. Documented history of thyroid disease.
  14. Active drug or alcohol use or dependence, which in the opinion of the investigator, would interfere with complying with the study requirements.
  15. Known hypersensitivity to Escherichia coli-derived products such as filgrastim.
  16. Any systemic illness that will make it unlikely that the subject will be able to return for the required study visits.
  17. History of, or any condition that in the opinion of the investigator would interfere with the conduct of the study, or it would not be in the best interest of the subject to enroll in this study.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01295515

Contacts
Contact: Gabbie M Diaz, R.N. (301) 435-8019 diazgm@mail.nih.gov
Contact: Frank Maldarelli, M.D. (301) 435-8019 fmalli@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL)    800-411-1222 ext TTY8664111010    prpl@mail.cc.nih.gov   
United States, Pennsylvania
University of Pittsburgh Recruiting
Pittsburgh, Pennsylvania, United States, 15261
Sponsors and Collaborators
Investigators
Principal Investigator: Frank Maldarelli, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )
ClinicalTrials.gov Identifier: NCT01295515     History of Changes
Other Study ID Numbers: 110057, 11-I-0057
Study First Received: February 11, 2011
Last Updated: July 19, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
HIV
Replication
Antiretroviral
Interferon
Reservoirs

Additional relevant MeSH terms:
HIV Infections
Acquired Immunodeficiency Syndrome
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Interferon-alpha
Interferons
Peginterferon alfa-2b
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents

ClinicalTrials.gov processed this record on August 01, 2014